WO2025076017A1 - Carbamates for use as sarm1 inhibitors - Google Patents

Abstract

This invention relates to carbamate compounds of Formula (I), as further detailed herein, which are used for inhibition of SARM1 proteins, as well as compositions comprising these compounds and methods of treatment by their administration.

Description

CARBAMATES FOR USE AS SARM1 INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 63/588,208 filed on October 5, 2023 and U.S. Provisional Patent Application No. 63/683,372 filed on August 15, 2024, the contents of both which are incorporated herein by reference in their entirety.

FIELD OF THE DISCLOSURE

This invention relates to carbamate compounds of Formula (I), as further detailed herein, which are used for inhibition of SARM1 (selective androgen receptor modulator 1) proteins, as well as compositions comprising these compounds and methods of treatment by their administration.

BACKGROUND OF THE DISCLOSURE

Axonal degeneration is a hallmark of several neurological disorders including peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases (See, for example, Gerdts et al., SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 3482016, pp.453-457 and Krauss et al., (2020) Trends Pharmacol. Sci.41, 281, each of which is hereby incorporated by reference in its entirety). Neurodegenerative diseases and injuries are devastating to both patients and caregivers. Costs associated with these diseases currently exceed several hundred billion dollars annually in the Unites States alone. Since the incidence of many of these diseases and disorders increases with age, their incidence is rapidly increasing as demographics change.

BRIEF DESCRIPTION OF THE DISCLOSURE

In one aspect, the present disclosure is directed to a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is CR⁷ or N; X² is CR⁴, CHR⁴, or N; X³ is absent, CH, CH₂, NH, or S; X⁴ is N, CH₂, CH, NH, O, or S; X⁵ is CR⁸; Y is absent, CR⁵R⁶, or CH₂CH₂, wherein R⁵ and R⁶ are independently H, OH, CN, halo, C_1-6 alkyl, or C_1-6 cycloalkyl, or R⁵ and R⁶, taken together with the carbon to which they are bonded, form a C_3-6 cycloalkyl; Z is CH or N; one of Q¹ and Q² is N and the other is CR⁴; one of Q³ and Q⁴ is N and the other is CR⁴; or Q³ and Q⁴ are CR⁴; R^1a is H or C_1-6 alkyl; R^1b is selected from C_6-10 aryl, 5- to 10-membered heteroaryl, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, bicyclo[1.1.1]pentan-1-yl, and C_1-6 alkyl substituted with C_6-10 aryl or C_1-6 haloalkoxy; wherein each aryl, heteroaryl, cycloalkyl, and bicyclo[1.1.1]pentan-1-yl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, C_1-6 haloalkyl, and C_3-6 cycloalkyl; or R^1a and R^1b taken together with the carbon to which they are bonded, form a C_3-6 cycloalkyl; R² is H, OH, CN, or C_1-6 alkyl; R³ is selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-6 cycloalkyl, C_6-10 aryl, and 5- to 10- membered heteroaryl; R⁴ is H, halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, or C_1-6 hydroxyalkyl; R⁷ and R⁸ are either absent, or form a -CH₂- bridge between the carbon atoms to which they are attached; represents the point of attachment to the rest of the compound; and represents a single or double bond. Also provided are methods of making the compounds and methods of using the compounds for treatment of SARM1-mediated diseases and conditions. DETAILED DESCRIPTION OF THE DISCLOSURE DEFINITIONS The term “halogen” or “halo” refers to F, Cl, Br or I. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. The term "alkyl" refers to a saturated linear or branched-chain monovalent hydrocarbon radical. In one example, the alkyl radical is one to eighteen carbon atoms (C_1-18). In other examples, the alkyl radical is C_1-12, C_1-10, C_1-8, C_1-6, C_1-5, C_1-4, or C_1-3. Examples of alkyl groups include methyl (Me, –CH₃), ethyl (Et, –CH₂CH₃), 1-propyl (n-Pr, n-propyl, –CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, – CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, –CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, – CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, –CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, – C(CH₃)₃), 1-pentyl (n-pentyl, –CH₂CH₂CH₂CH₂CH₃), 2-pentyl (–CH(CH₃)CH₂CH₂CH₃), 3-pentyl (– CH(CH₂CH₃)₂), 2-methyl-2-butyl (-C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (–CH(CH₃)CH(CH₃)₂), 3- methyl-1-butyl (–CH2CH2CH(CH3)2), 2-methyl-1-butyl (–CH2CH(CH3)CH2CH3), 1-hexyl (– CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (–CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (– CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (–C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (– CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (–CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (– C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (–CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (– C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (–CH(CH₃)C(CH₃)₃, 1-heptyl and 1-octyl. The terms “cyano” or “nitrile” refers to –C≡N or –CN. The term "haloalkoxy" refers to -O-haloalkyl.

The term "hydroxy" refers to -OH.

The term "hydroxy alkyl" refers to alkyl substituted with one hydroxy substituent.

The term “aryl” refers to a carbocyclic aromatic group, whether or not fused to one or more groups, having the number of carbon atoms designated, or if no number is designated, up to 14 carbon atoms. One example includes aryl groups having 6-14 carbon atoms. Another example includes aryl groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, IH-indenyl, 2,3-dihydro-lH-indenyl, and the like (see, e.g., Lang’s Handbook of Chemistry (Dean, J. A., ed.) 13^th ed. Table 7-2 [1985]). A particular aryl is phenyl.

The term “cycloalkyl” refers to a saturated hydrocarbon ring group. Cycloalkyl encompasses mono-, bi-, tricyclic, spiro and bridged, saturated ring systems. In one example, the cycloalkyl group is 3 to 12 carbon atoms (C3-12). In other examples, cycloalkyl is C3-7, C3-8, C3-10, or C5-10. In other examples, the cycloalkyl group, as a monocycle, is C3-8, C3-6, or C5-6. In another example, the cycloalkyl group, as a bicycle, is C7-C12. In another example, the cycloalkyl group, as a spiro system, is C5-12. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of spirocycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro [2.5] octane and spiro [4.5] decane.

The term “heteroaryl” refers to any mono-, bi-, or tricyclic aromatic ring system containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang’s Handbook of Chemistry (Dean, J. A., ed.) 13^th ed. Table 7-2 [1985], Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is joined to the remainder of the molecule. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5-b]pyridazinyl, imidazol[l,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazolyl and indolyl.

In particular embodiments, a heteroaryl group is attached at a carbon atom of the heteroaryl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.

In certain embodiments, the heteroaryl group is N-attached. By way of example, nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3 -pyrroline, imidazole, imidazolidine, 2-imidazoline, 3- imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or P-carboline.

"Fused" refers to any ring structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with an existing ring structure in the compounds of the invention.

The term “haloalkyl” refers to an alkyl chain in which one or more hydrogen has been replaced by a halogen. Examples of haloalkyls are trifluoromethyl, difluoromethyl, and fluoromethyl.

The terms “compound(s) of the invention,” and “compound(s) of the present invention” and the like, unless otherwise indicated, include compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formulas (Ila)-(IIg), Formulas (Illa) and (Illb), Formulas (IV a) and (IVb), Formulas (IIa-1), (IIa-2) (IIa-3), (IIa-4), (IIa-5), (IIa-6), (IIb-1), (IIb-2), (IIb-3), (IIb-4), (IIb-5), (IIb-6), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IId-1), (IId-2), (IId-3), (IId-4), (IIe-1), (IIe-2), (IIe-3), (IIe-4), (IIf-1), (IIf-2), (IIf-3), (IIf-4), (IIf-5), (IIf-6), (IIg-1), (IIg-2), (IIg-3), (IIg-4), (IIg-5), and (IIg-6), and the compounds listed in the Tables herein, including stereoisomers (including atropisomers), geometric isomers, tautomers, isotopes, and salts (e.g., pharmaceutically acceptable salts) thereof.

The term “optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In another embodiment an optionally substituted group has 4 substituents. In another embodiment an optionally substituted group has 5 substituents. A_{s used herein a wavy line “ ” that intersects a bond in a chemical structure indicate the} point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule. A_{s used herein, “ ” represents a single or double bond in a chemical structure.} In certain embodiments, divalent groups are described generically without specific bonding configurations. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise. For example, in the group R¹–R²–R³, if the group R² is described as –CH₂C(O)–, then it is understood that this group can be bonded both as R¹–CH₂C(O)–R³, and as R¹–C(O)CH₂–R³, unless specified otherwise. The term “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate. Compounds of the invention may be in the form of a salt, such as a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” include both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term “pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particular base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine. In some embodiments, a salt is selected from a hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2- hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5- dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulfonate), napsylate (2-naphthalenesulfonate), camsylate (camphor-10-sulfonate, for example (1S)-(+)-10-camphorsulfonic acid salt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoic (2,2'- dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate). A “sterile” formulation is aseptic or free from all living microorganisms and their spores. The term “stereoisomers” refer to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like. The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. The term “diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC. The term “enantiomers” refer to two stereoisomers of a compound which are non- superimposable mirror images of one another. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. “Atropisomers” are stereoisomers arising because of hindered rotation around a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. The invention described herein also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (³H) and carbon-14 (¹⁴C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C and ¹⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Mixtures of particular diastereomeric compounds may be separated, or enriched in one or more particular diastereomers, by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated, or enantiomerically enriched, using the same techniques or others known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration and both of these configurations are within the scope of the invention. In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended. A “subject,” “individual,” or “patient” is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats. In certain embodiments, a mammal is a human. In embodiments comprising administration of a compound of to a patient, the patient is typically in need thereof. The terms “inhibiting” and “reducing,” or any variation of these terms, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of activity compared to normal. A “therapeutically effective amount" means an amount of a compound of the present invention, such as a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any other Formula specified herein, or a pharmaceutically acceptable salt thereof, that (i) treats or prevents the particular disease, condition or disorder, or (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, and optionally (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. “Treatment” (and variations such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In some embodiments, compounds of the invention, are used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented. A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time. Co- administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present. The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as SARM1. Accordingly, the terms "antagonist" and "inhibitors" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Isotopically-labeled compounds (e.g., those labeled with ³H and ¹⁴C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of the invention, one or more carbon atoms are replaced by ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any compound or composition of the invention. The use of the term “or” is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” Throughout this application, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. As used herein, “a” or “an” means one or more, unless clearly indicated otherwise. As used herein, “another” means at least a second or more. Headings used herein are intended only for organizational purposes. SARM1 INHIBITORS In an aspect, the invention provides compounds which are capable of selectively binding to and/or modulating a SARM1 protein. As noted, one aspect of the invention includes a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

X¹ is CR⁷ or N; X² is CR⁴, CHR⁴, or N; X³ is absent, CH, CH₂, NH, or S; X⁴ is N, CH₂, CH, NH, O, or S; X⁵ is CR⁸; Y is absent, CR⁵R⁶, or CH₂CH₂, wherein R⁵ and R⁶ are independently H, OH, CN, halo, C_1-6 alkyl, or C_1-6 cycloalkyl, or R⁵ and R⁶, taken together with the carbon to which they are bonded, form a C_3-6 cycloalkyl; Z is CH or N; one of Q¹ and Q² is N and the other is CR⁴; one of Q³ and Q⁴ is N and the other is CR⁴, or Q³ and Q⁴ are CR⁴; R^1a is H or C_1-6 alkyl; R^1b is selected from C_6-10 aryl, 5- to 10-membered heteroaryl, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, bicyclo[1.1.1]pentan-1-yl, and C_1-6 alkyl substituted with C_6-10 aryl or C_1-6 haloalkoxy; wherein each aryl, heteroaryl, cycloalkyl, and bicyclo[1.1.1]pentan-1-yl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, C_1-6 haloalkyl, and C_3-6 cycloalkyl; or R^1a and R^1b taken together with the carbon to which they are bonded, form a C_3-6 cycloalkyl; R² is H, OH, CN, or C1-6 alkyl; R³ is selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-6 cycloalkyl, C_6-10 aryl, and 5- to 10- membered heteroaryl; R⁴ is H, halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, or C_1-6 hydroxyalkyl; R⁷ and R⁸ are either absent, or form a -CH₂- bridge between the carbon atoms to which they are attached; represents the point of attachment to the rest of the compound; and represents a single or double bond. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, X¹ is CR⁷; X² is CHR⁴; X³ is absent or CH₂; X⁴ is CH₂ or O; X⁵ is CR⁸; and R⁷ and R⁸ form a -CH₂- bridge between the carbon atoms to which they are attached. In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, X¹ is CR⁷; X² is CHR⁴; X³ is absent; X⁴ is CH₂; X⁵ is CR⁸; and R⁷ and R⁸ form a -CH₂- bridge between the carbon atoms to which they are attached. In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, X¹ is CR⁷; X² is CHR⁴; X³ is CH₂; X⁴ is O; X⁵ is CR⁸; and R⁷ and R⁸ form a - CH₂- bridge between the carbon atoms to which they are attached. In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is selected from

wherein X¹, X², X³, X⁴, Q¹, Q² , Q³ and Q⁴ are as defined above. In some such embodiments, X¹ is C or N; X² is CR⁴ or N; X³ is CH, NH, or S; and X⁴ is N, CH, NH, or S. In some embodiments Q1 is N and Q² , Q³ and Q⁴ are CR⁴. In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring

the compound has Formula (II):

wherein Z, Y, X¹, X², X³, X⁴, R^1a, R^1b, R², and R³ are as defined for Formula (I). According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X¹ is C; X² is N; X³ is NH; and X⁴ is N. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X¹ is C; X² is CR⁴; X³ is NH; and X⁴ is N, wherein R⁴ is as defined for Formula (I). In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X¹ is N; X² is CR⁴; X³ is CH; and X⁴ is N, wherein R⁴ is as defined for Formula (I). In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X¹ is C; X² is CR⁴; X³ is S; and X⁴ is N, wherein R⁴ is as defined for Formula (I). In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X¹ is N; X² is N; X³ is CH; and X⁴ is N. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X¹ is C; X² is N; X³ is S; and X⁴ is N. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X¹ is C; X² is N; X³ is NH; and X⁴ is CH. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, Ring A is selected from

for Formula (I). In one such embodiment, R⁴ is H, halo, or C_1-6 hydroxyalkyl. In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, Ring A is selected from ,

According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, Ring A is selected from

According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, Ring A is selected from

,

According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIa):

wherein Z, Y, R^1a, R^1b, R², R³, and R⁴ are as defined for Formula (I). In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIb):

wherein Z, Y, R^1a, R^1b, R², and R³ are as defined for Formula (I). According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIc):

wherein Z, Y, R^1a, R^1b, R², and R³ are as defined for Formula (I). According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, the compound has Formula (IId):

wherein Z, Y, R^1a, R^1b, R², and R³ are as defined for Formula (I). According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIe):

wherein Z, Y, R^1a, R^1b, R², and R³ are as defined for Formula (I). According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIf):

wherein Z, Y, R^1a, R^1b, R², and R³ are as defined for Formula (I). According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIg):

wherein Z, Y, R^1a, R^1b, R², and R³ are as defined for Formula (I). According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound has Formula (III):

wherein Z, Y, R^1a, R^1b, R², and R³ are as defined for Formula I. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound has Formula (IV):

wherein Z, Y, R^1a, R^1b, R², and R³ are as defined for Formula I. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound has Formula (V)

wherein Z, Y, Q¹, Q², Q³, Q⁴, R^1a, R^1b, R², and R³ are as defined herein. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound has Formula (Va)

wherein Z, Y, Q³, Q⁴, R^1a, R^1b, R², and R³ are as defined herein. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, Z is N. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, Z is CH. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R³ is H. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R³ is methyl, phenyl or pyridinyl. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, Y is absent. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, Y is CH₂CH₂. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, Y is CR⁵R⁶, wherein R⁵ and R⁶ are as defined for Formula (I). In one such embodiment, R⁵ and R⁶ are independently H, OH, CN, or halo. In one such embodiment, R⁵ and R⁶ are H. In one such embodiment, R⁵ is H and R⁶ is OH or CN. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R² is H, OH, CN, or methyl. In some such embodiments, R² is H. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), ^{Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R1a} _{is H or methyl. In} some such embodiments, R^1a is H. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R^1a and R^1b taken together with the carbon to which they are bonded, form a C_3-6 cycloalkyl. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R^1b is selected from C_6-10 aryl, 5- to 10-membered heteroaryl, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, and C_{1- 6} alkyl substituted with C_6-10 aryl or C_1-6 haloalkoxy; wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, C_1-6 haloalkyl, and C_3-6 cycloalkyl. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R^1b is selected from C_6-10 aryl, 5- to 10-membered heteroaryl, and C_1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, and C_1-6 haloalkyl. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R^1b is selected from

_{, wherein each R} ⁹ _{is independently selected from C1-6 alkyl, halo, C1-6} haloalkyl, and C_3-6 cycloalkyl; and p is 0, 1, 2, 3, or 4. In some such embodiments, each R⁹ is independently selected from C_1-6 alkyl, halo, and C_1-6 haloalkyl. In some such embodiments, each R⁹ is independently selected from methyl, halo, and C₁ haloalkyl. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R^1b is selected from

is 1 or 2. In some such embodiments, each R⁹ is independently selected from C_1-6 alkyl, halo, and C_1-6 haloalkyl. In some such embodiments, each R⁹ is independently selected from methyl, halo, and C₁ haloalkyl. According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R^1b is selected from

_,

According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R^1b is selected from

According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or a pharmaceutically acceptable salt thereof, R^1b is

_. According to some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIIa) or Formula (IIIb):

wherein R⁶ is H, OH, or CN, and R^1a and R^1b are as defined for Formula (I). In one such embodiment, R^1a is H and R^1b is selected from C_6-10 aryl, 5- to 10-membered heteroaryl, and C_1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, and C_1-6 haloalkyl. In one such embodiment, each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently halo. According to some embodiments of the compound of Formula (I) or Formula (IV), or a pharmaceutically acceptable salt thereof, the compound has Formula (IVa) or Formula (IVb):

wherein R⁶ is H, OH, or CN, and R^1a and R^1b are as defined for Formula (I). In one such embodiment, wherein R^1a is H and R^1b is selected from C_6-10 aryl, 5- to 10-membered heteroaryl, and C_1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, and C_1-6 haloalkyl. In one such embodiment, each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently halo. According to some embodiments of the compound of Formula (I) or Formula (V), the compound has Formula (Va), (Vb), (Vc), (Vd), (Ve) or (Vf)

According to some embodiments of the compound of Formula (I), Formula (II), Formula (IIa), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIa-1), Formula (IIa- 2), Formula (IIa-3), Formula (IIa-4), Formula (IIa-5), or Formula (IIa-6):

wherein R^1a, R^1b, and R⁴ are as defined for Formula (I). In one such embodiment, R⁴ is H. According to some embodiments of the compound of Formula (I), Formula (II), Formula (IIb), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIb-1), Formula (IIb- 2), Formula (IIb-3), Formula (IIb-4), Formula (IIb-5), or Formula (IIb-6):

O

wherein R^1a and R^1b are as defined for Formula (I). According to some embodiments of the compound of Formula (I) , Formula (II), Formula (IIc), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIc-1), Formula (IIc- 2), Formula (IIc-3), Formula (IIc-4), Formula (IIc-5), or Formula (IIc-6):

wherein R^1a and R^1b are as defined for Formula (I). According to some embodiments of the compound of Formula (I), Formula (II), Formula (IId), or a pharmaceutically acceptable salt thereof, the compound has Formula (IId-1), Formula (IId- 2), Formula (IId-3), Formula (IId-4), Formula (IId-5), or Formula (IId-6):

wherein R^1a and R^1b are as defined for Formula (I). According to some embodiments of the compound of Formula (I), Formula (II), Formula (IIe), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIe-1), Formula (IIe- 2), Formula (IIe-3), Formula (IIe-4), Formula (IIe-5), or Formula (IIe-6):

wherein R^1a and R^1b are as defined for Formula (I). According to some embodiments of the compound of Formula (I), Formula (II), Formula (IIf), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIf-1), Formula (IIf- 2), Formula (IIf-3), Formula (IIf-4), Formula (IIf-5), or Formula (IIf-6):

wherein R^1a and R^1b are as defined for Formula (I). According to some embodiments of the compound of Formula (I), Formula (II), Formula (IIg), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIg-1), Formula (IIg- 2), Formula (IIg-3), Formula (IIg-4), Formula (IIg-5), or Formula (IIg-6):

wherein R^1a and R^1b are as defined for Formula (I). According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), or a pharmaceutically acceptable salt thereof, the compound is selected from the compounds in Table 1, shown below, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds of the present disclosure. Salts of such compounds are also contemplated. See the Examples section for preparation of such compounds. Compounds that do not have preparation details explicitly described in the Examples may be prepared by modifying the preparation details for other compounds provided herein, using methods generally known in the art.

The compounds of the invention (e.g., compounds of Formula (I), (II), (III), or (IV)), or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Embodiments of the present invention include all manner of rotamers and conformationally restricted states of a compound of the invention. Atropisomers, which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included. As an example, certain compounds of the invention may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer. In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) is a mixture of atropisomers. In other embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) is a substantially purified atropisomer. In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) is a substantially purified R- atropisomer. In some other embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) is a substantially purified R-atropisomer. SYNTHESIS OF SARM1 INHIBITORS Compounds of the present disclosure can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol. 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained herein. For illustrative purposes, reaction Schemes below provide routes for synthesizing the compounds of the invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used. Although some specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about −78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, or, about 20 °C. Some compounds in following schemes are depicted with generalized substituents; however, one skilled in the art will immediately appreciate that the nature of the substituents can varied to afford the various compounds contemplated in this invention. Moreover, the reaction conditions are exemplary and alternative conditions are well known. The reaction sequences in the following examples are not meant to limit the scope of the invention as set forth in the claims. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare other compounds of the present invention. For example, the synthesis of non- exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention. METHODS OF TREATMENT WITH AND USES OF SARM1 INHIBITORS The present disclosure provides a variety of uses and applications for compounds and/or compositions as described herein, for example in light of their activities and/or characteristics as described herein. In some embodiments, such uses may include therapeutic and/or diagnostic uses. Alternatively, in some embodiments such uses may include research, production, and/or other technological uses. In one aspect, the present disclosure provides methods comprising administering one or more compounds of Formula (I) to an individual, e.g., to treat, prevent, or reduce the risk of developing one or more conditions characterized by axonal degeneration. In some such embodiments, the compound of Formula (I) is a SARM1 inhibitor. For instance, in one aspect, the present disclosure provides a method of treating or preventing axonal degeneration comprising administering to an individual in need thereof a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In one aspect, the individual is a human. In one aspect, the individual has a condition characterized by axonal degeneration or is at risk of developing a condition characterized by axonal degeneration. Another embodiment of the present disclosure relates to a method of inhibiting SARM1 activity in an individual in need thereof, comprising steps of administering to said individual a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Inhibition of enzymes in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to biological assays, gene expression studies, and biological target identification. In certain embodiments, the present disclosure relates to a method of treating axonal degeneration in a biological sample or inhibiting SARM1 in a biological sample comprising the step of contacting said biological sample with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein are useful, for example as a method of for inhibiting the degradation of neurons derived from a subject. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein, are useful for inhibiting the degeneration of a neuron, or portion thereof, cultured in vitro. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein, are useful as stabilizing agents to promote in vitro neuronal survival. In some embodiments, the compounds and/or pharmaceutical compositions of the present disclosure inhibit NADase activity of SARM1. Alternatively, or additionally, in some embodiments, the compounds or pharmaceutical compositions of the present disclosure alleviate one or more attributes of neurodegeneration. In some embodiments, the present disclosure provides methods of treating a neurodegenerative disease or disorder comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In one aspect, the neurodegenerative disease is associated with axonal degeneration. In one aspect, the neurodegenerative disease is selected from amyotrophic lateral sclerosis (ALS), chemotherapy- induced peripheral neuropathy (CIPN), peripheral neuropathy, and multiple sclerosis (MS). In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein are useful, for example, in the practice of medicine. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein are useful, for example, to treat, prevent, or ameliorate axonal degeneration (e.g., one or more features or characteristics thereof). In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein are useful, for example to inhibit axonal degeneration, including axonal degeneration that results from reduction or depletion of NAD+. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example to prevent the axon distal to an axonal injury from degenerating. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein are useful, for example as a method for inhibiting the degradation of a peripheral nervous system neuron or a portion thereof. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein are useful, for example as a method for inhibiting or preventing degeneration of a central nervous system (neuron) or a portion thereof. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein is characterized that, when administered to a population of individuals, reduces one or more symptoms or features of neurodegeneration. For example, in some embodiments, a relevant symptom or feature may be selected from extent, rate, and/or timing of neuronal disruption. In certain embodiments, the present disclosure provides compounds that are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. Compounds provided by this disclosure are also useful for the study of SARM1 activity in biological and pathological phenomena and the comparative evaluation of new SARM1 activity inhibitors in vitro or in vivo. In certain embodiments, the present disclosure provides assays for identifying and/or characterizing compounds and/or compositions provided herein. In some embodiments, provided assays utilize particular reagents and/or systems (e.g., certain vector constructs and/or polypeptides) useful in assaying SARM1 activity. For example, in some embodiments, provided assays may utilize, for example, a SAM-TIR in which the SARM1 N-terminal auto-inhibitory domain is deleted, and/or one or more tagged versions of a TIR domain. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein are useful, for example as a method of for inhibiting the degradation of neurons derived from a subject. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein, are useful for inhibiting the degeneration of a neuron, or portion thereof, cultured in vitro. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein, are useful as stabilizing agents to promote in vitro neuronal survival. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein are useful, for example in affecting biomarkers associated with neurodegeneration. In some embodiments, changes in biomarkers can be detected systemically or with a sample of CSF, plasma, serum, and/or tissue from a subject. In some embodiments, one or more compounds and/or compositions can be used to affect a change in the concentration of NF-L and/or NF-H contained the CSF of a subject. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein can affect constitutive NAD and/or cADPR levels in neurons and/or axons. In some embodiments, one or more biomarkers of neurodegeneration comprises: concentration of NF-L in one or more of: a CSF sample, a blood sample, and a plasma sample from the subject; concentration of NF-H in one or more of: a CSF sample, a blood sample, and a plasma sample from the subject; concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a CSF sample, a blood sample, and a plasma sample from the subject; concentration of alpha-synuclein in one or more of: a CSF sample, a blood sample, and a plasma sample from the subject; constitutive NAD+ levels in neurons and/or axons of the subject; constitutive cADPR levels in neurons and/or axons of the subject; levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, GFAP, hFABP, MCP)-1, neurogranin, NSE, sAPPα, sAPPβ, sTREM 2, phospho-tau, or total-tau in one or more of: a CSF sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and levels of C-C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject. In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein can affect a detectable change in the levels of one or more neurodegeneration- associated proteins in a subject. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, GFAP, hFABP, MCP-1, neurogranin, NSE, sAPPα, sAPPβ, sTREM 2, phospho-tau, and/or total-tau. In some embodiments, one or more compounds and/or compositions as described herein can affect a change in cytokines and/or chemokines, including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and/or Il6. In some embodiments, compounds and/or compositions as described herein may be administered to individuals suffering from one or more diseases, disorders, or conditions. In some embodiments, the one or more diseases, disorders, or conditions are mediated by SARM1. In some embodiments, a neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration. In some embodiments, a neurodegenerative disease or disorder comprises an acute disease or disorder of the PNS. In some embodiments, an acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy. In some embodiments, a mechanical injury comprises a compression or entrapment injury or a pressure injury. In some embodiments, a compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone. In some embodiments, a pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure. In some embodiments, a chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin. In some embodiments, an epothilone is ixabepilone. In some embodiments, a taxane is paclitaxel or docetaxel. In some embodiments, a vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine. In some embodiments, a proteasome inhibitor is bortezomib. In some embodiments, a platinum-based drug is cisplatin, oxaliplatin, or carboplatin. In some embodiments, an auristatin is conjugated monomethyl auristatin E. In some embodiments, a neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS. In some embodiments, a chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder. In some embodiments, a chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies. In some embodiments, a systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa. In some embodiments, a pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes. In some embodiments, a metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder. In some embodiments, a neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS. In some embodiments, an acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis. In some embodiments, an ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy. In some embodiments, a traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer. In some embodiments, a viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV- associated dementia). In some embodiments, a neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS. In some embodiments, a chronic disease or disorder of the CNS comprises Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington’s disease (HD), senile dementia, Pick’s disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich’s ataxia, or spinal cord injury. In some embodiments, a chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder. In some embodiments, an optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide. In some embodiments, a traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE). In some embodiments, a metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders. In some embodiments, a neurodegenerative disease or disorder comprises a disease associated with neurodegeneration. In some embodiments, a neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes. In some embodiments, the condition is an acute peripheral neuropathy. Chemotherapy- induced peripheral neuropathy (CIPN) is an example of an acute peripheral neuropathy. CIPN can be associated with various drugs, such as, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin). In some embodiments, one or more compounds and/or pharmaceutical compositions as described herein are useful, for example, to treat one or more neurodegenerative diseases, disorders or conditions selected from neuropathies or axonopathies. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example to treat a neuropathy or axonopathy associated with axonal degeneration. In some embodiments, a neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In some embodiments, a neuropathy associated with axonal degeneration results from a de novo or somatic mutation. In some embodiments, a neuropathy associated with axonal degeneration is selected from a list contained herein. In some embodiments, a neuropathy or axonopathy is associated with axonal degeneration, including, but not limited to Parkinson’s disease, non-Parkinson’s disease, Alzheimer's disease, Herpes infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS. In some embodiments, one or more compounds or pharmaceutical compositions as described herein is characterized that, when administered to a population of subjects, reduces one or more symptoms or features of neurodegeneration. For example, in some embodiments, a relevant symptom or feature may be selected from extent, rate, and/or timing of neuronal disruption. In some embodiments, neuronal disruption may be or comprise axonal degradation, loss of synapses, loss of dendrites, loss of synaptic density, loss of dendritic arborization, loss of axonal branching, loss of neuronal density, loss of myelination, loss of neuronal cell bodies, loss of synaptic potentiation, loss of action-potential potentiation, loss of cytoskeletal stability, loss of axonal transport, loss of ion channel synthesis and turnover, loss of neurotransmitter synthesis, loss of neurotransmitter release and reuptake capabilities, loss of axon-potential propagation, neuronal hyperexcitability, and/or neuronal hypoexcitability. In some embodiments, neuronal disruption is characterized by an inability to maintain an appropriate resting neuronal membrane potential. In some embodiments, neuronal disruption is characterized by the appearance of inclusion bodies, plaques, and/or neurofibrillary tangles. In some embodiments, neuronal disruption is characterized by the appearance of stress granules. In some embodiments, neuronal disruption is characterized by the intracellular activation of one or more members of the cysteine-aspartic protease (Caspase) family. In some embodiments, neuronal disruption is characterized by a neuron undergoing programed cell death (e.g., apoptosis, pyroptosis, ferroapoptosis, and/or necrosis) and/or inflammation. In some embodiments, the neurodegenerative or neurological disease or disorder is associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage resulting from a leukoencephalopathy or a leukodystrophy. In some embodiments, the neurodegenerative or neurological disease or disorder is selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay- Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy (chemotherapy induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Glaucoma, Leber's hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, SMA, HSAN, adrenomyeloneuropathy, PSP, Friedrich’s ataxia, hereditary ataxias, noise induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathies and axonopathies, Guillain-Barre syndrome, AMAN, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxias, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, and NASH. In some embodiments, the present disclosure provides inhibitors of SARM1 activity for treatment of neurodegenerative or neurological diseases or disorders that involve axon degeneration or axonopathy. The present disclosure also provides methods of using inhibitors of SARM1 activity to treat, prevent or ameliorate axonal degeneration, axonopathies and neurodegenerative or neurological diseases or disorders that involve axonal degeneration. In some embodiments, the present disclosure provides methods of treating neurodegenerative or neurological diseases or disorders related to axonal degeneration, axonal damage, axonopathies, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage resulting from a leukoencephalopathy or a leukodystrophy. In some embodiments, neuropathies and axonopathies include any disease or condition involving neurons and/or supporting cells, such as for example, glia, muscle cells or fibroblasts, and, in particular, those diseases or conditions involving axonal damage. Axonal damage can be caused by traumatic injury or by non-mechanical injury due to diseases, conditions, or exposure to toxic molecules or drugs. The result of such damage can be degeneration or dysfunction of the axon and loss of functional neuronal activity. Disease and conditions producing or associated with such axonal damage are among a large number of neuropathic diseases and conditions. Such neuropathies can include peripheral neuropathies, central neuropathies, and combinations thereof. Furthermore, peripheral neuropathic manifestations can be produced by diseases focused primarily in the central nervous systems and central nervous system manifestations can be produced by essentially peripheral or systemic diseases. In some embodiments, a peripheral neuropathy can involve damage to the peripheral nerves, and/or can be caused by diseases of the nerves or as the result of systemic illnesses. Some such diseases can include diabetes, uremia, infectious diseases such as AIDs or leprosy, nutritional deficiencies, vascular or collagen disorders such as atherosclerosis, and autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. In some embodiments, peripheral nerve degeneration results from traumatic (mechanical) damage to nerves as well as chemical or thermal damage to nerves. Such conditions that injure peripheral nerves include compression or entrapment injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fracture or dislocated bones; pressure involving superficial nerves (ulna, radial, or peroneal) which can result from prolonged use of crutches or staying in one position for too long, or from a tumor; intraneural hemorrhage; ischemia; exposure to cold or radiation or certain medicines or toxic substances such as herbicides or pesticides. In particular, the nerve damage can result from chemical injury due to a cytotoxic anticancer agent such as, for example, taxol, cisplatinin, a proteasome inhibitor, or a vinca alkaloid such as vincristine. Typical symptoms of such peripheral neuropathies include weakness, numbness, paresthesia (abnormal sensations such as burning, tickling, pricking or tingling) and pain in the arms, hands, legs and/or feet. In some embodiments, a neuropathy is associated with mitochondrial dysfunction. Such neuropathies can exhibit decreased energy levels, i.e., decreased levels of NAD and ATP. In some embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy which includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders, among others. The common hallmark of these diseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation. In some embodiments, neuropathies include optic neuropathies such as glaucoma; retinal ganglion degeneration such as those associated with retinitis pigmentosa and outer retinal neuropathies; optic nerve neuritis and/or degeneration including that associated with multiple sclerosis; traumatic injury to the optic nerve which can include, for example, injury during tumor removal; hereditary optic neuropathies such as Kjer’s disease and Leber’s hereditary optic neuropathy; ischemic optic neuropathies, such as those secondary to giant cell arteritis; metabolic optic neuropathies such as neurodegenerative diseases including Leber’s neuropathy mentioned earlier, nutritional deficiencies such as deficiencies in vitamins B12 or folic acid, and toxicities such as due to ethambutol or cyanide; neuropathies caused by adverse drug reactions and neuropathies caused by vitamin deficiency. Ischemic optic neuropathies also include non-arteritic anterior ischemic optic neuropathy. In some embodiments neurodegenerative diseases that are associated with neuropathy or axonopathy in the central nervous system include a variety of diseases. Such diseases include those involving progressive dementia such as, for example, Alzheimer’s disease, senile dementia, Pick’s disease, and Huntington’s disease; central nervous system diseases affecting muscle function such as, for example, Parkinson’s disease, motor neuron diseases and progressive ataxias such as amyotrophic lateral sclerosis; demyelinating diseases such as, for example multiple sclerosis; viral encephalitides such as, for example, those caused by enteroviruses, arboviruses, and herpes simplex virus; and prion diseases. Mechanical injuries such as glaucoma or traumatic injuries to the head and spine can also cause nerve injury and degeneration in the brain and spinal cord. In addition, ischemia and stroke as well as conditions such as nutritional deficiency and chemical toxicity such as with chemotherapeutic agents can cause central nervous system neuropathies. In some embodiments, the present disclosure provides a method of treating a neuropathy or axonopathy associated with axonal degeneration. In some such embodiments, a neuropathy or axonopathy associated with axonal degeneration can be any of a number of neuropathies or axonopathies such as, for example, those that are hereditary or congenital or associated with Parkinson’s disease, Alzheimer's disease, Herpes infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS. In addition, neurodegenerative diseases not mentioned above as well as a subset of the above-mentioned diseases can also be treated with the methods of the present disclosure. Such subsets of diseases can include Parkinson’s disease or non-Parkinson’s diseases, or Alzheimer’s disease. In some embodiments, compounds and/or pharmaceutical compositions as described herein are administered to individuals suffering from or susceptible to a disease, disorder or condition as described herein; in some embodiments, such a disease, disorder or condition is characterized by axonal degeneration, such as one of the conditions mentioned herein. In some embodiments, an individual to whom a compound or pharmaceutical composition is administered as described herein exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration. In some embodiments, provided methods comprise administering a compound of Formula (I) to an individual in need thereof. In some such embodiments, the individual is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the individual has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration. In some embodiments, provided methods comprise administering a composition as described herein to a population of individuals in need thereof. In some embodiments, the population is drawn from individuals who engage in activities where the potential for traumatic neuronal injury is high. In some embodiments, the population is drawn from athletes who engage in contact sports or other high- risk activities. In some embodiments, the individual is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the individual is identified as being at risk of axonal degeneration, e.g., based on the individual’s genotype, a diagnosis of a condition associated with axonal degeneration, and/or exposure to an agent and/or a condition that induces axonal degeneration. In some embodiments, the individual is at risk of developing a neurodegenerative disorder. In some embodiments the individual is elderly. In some embodiments, the individual is known to have a genetic risk factor for neurodegeneration. In some embodiments, the individual has a family history of neurodegenerative disease. In some embodiments, the individual expresses one or more copies of a known genetic risk factor for neurodegeneration. In some embodiments, the individual is drawn from a population with a high incidence of neurodegeneration. In some embodiments, the individual has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In some embodiments, the individual has one or more copies of the ApoE4 allele. In some embodiments, individuals to which a compound or pharmaceutical composition as described herein is administered may be or comprise individuals suffering from or susceptible to a neurodegenerative disease, disorder or condition. In some embodiments, a neurodegenerative disease, disorder or condition may be or comprise a traumatic neuronal injury. In some embodiments, a traumatic neuronal injury is blunt force trauma, a closed-head injury, an open head injury, exposure to a concussive and/or explosive force, a penetrating injury into the brain cavity or innervated region of the body. In some embodiments, a traumatic neuronal injury is a force which causes the axons to deform, stretch, crush or sheer. In some embodiments, the individual engages in an activity identified as a risk factor for neuronal degradation, e.g., a subject that engages in contact sports or occupations with a high chance for traumatic neuronal injury. For example, the individual may be a patient who is receiving, or is prescribed, a chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin). In some embodiments, provided methods comprise administering a pharmaceutical composition as described herein to an individual or population of individuals based on the presence or absence of one or more biomarkers. In some embodiments, provided methods further comprise monitoring the level of a biomarker in an individual or population of individuals and adjusting the dosing regimen accordingly. DOSAGE AND ADMINISTRATION The present invention provides pharmaceutical compositions or medicaments containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. An embodiment, therefore, includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient. In one example, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, with the desired degree of purity may be formulated by mixing with physiologically acceptable excipients, i.e., excipients that are non-toxic to recipients at the dosages and concentrations employed into a dosage form at ambient temperature and at the appropriate pH. The pH of the formulation depends mainly on the particular use and the concentration of compound, but typically ranges anywhere from about 3 to about 8. In another embodiment, compound of the present invention, or a pharmaceutically acceptable salt thereof is sterile. The compound of the present invention, or a pharmaceutically acceptable salt thereof may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the severity of the disorder, the particular patient being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “therapeutically effective amount” of the compound of the present invention, or a pharmaceutically acceptable salt thereof to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit SARM1 activity. Typically such amount may be below the amount that is toxic to normal cells, or the patient as a whole. The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation 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-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container may have deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid- glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. A dose to treat human patients may range from about 0.01 mg to about 1000 mg of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. A dose may be administered once a day (QD), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy. A therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. A therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof and an excipient. Suitable excipients include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, for example ascorbic acid), colorants (e.g. inorganic pigments, for example iron oxides) and taste and/or odour correctants, and are well known to those skilled in the art and are described in detail in, e.g., Ansel, H. 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, R. C., Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, surfactants, lubricating agents, suspending agents, preservatives, opaquing agents, glidants, processing aids, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses. In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added. In other embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of the compound of the present invention, or a pharmaceutically acceptable salt thereof are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques and excipients are optionally used as suitable. Pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. Pharmaceutical compositions include at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, described herein as an active ingredient. The active ingredient is in free-acid or freebase form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, excipients, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances. Methods for the preparation of compositions comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof described herein include formulating the compound of the present invention, or a pharmaceutically acceptable salt thereof with one or more inert, pharmaceutically acceptable excipients to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth. In some embodiments, pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl- containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran. Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers. Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range. Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride. Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. Still other useful compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite. In certain embodiments, aqueous suspension compositions are packaged in single-dose non- reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or excipients useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary excipient therefore. Veterinary excipients are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route. ARTICLES OF MANUFACTURE In another embodiment of the invention, an article of manufacture, or "kit", containing materials useful for the treatment of the diseases and disorders described above is provided. In one embodiment, the kit comprises a container comprising compound of the present invention, or a pharmaceutically acceptable salt thereof. The kit may further comprise a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound of the present invention, or a pharmaceutically acceptable salt thereof or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of the present invention, or a pharmaceutically acceptable salt thereof. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution or dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound of the present invention, or a pharmaceutically acceptable salt thereof, such as tablets or capsules. Such a kit can include a number of unit dosages. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. EXAMPLES The following examples illustrate the preparation and biological evaluation of compounds within the scope of the invention. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. Abbreviations Abbreviations used in the following examples may include: CDI: 1,1-carbonyldiimidazole DCE: dichloroethane DCM: dichloromethane DEA: diethylamine DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMEDA: 1,2-dimethylethylenediamine DMF: dimethylformamide DMSO: dimethylsulfoxide EtOAc: ethyl acetate EtOH: ethanol HFIP: 1,1,3,3,-hexafluoro-2-propanol HOAc: acetic acid HPLC: high performance liquid chromatography i-PrOH: isopropanol LCMS: liquid chromatography-mass spectrometry MeOH: methanol MeCN: Acetonitrile MsCl: methanesulfonyl chloride MTBE: methyl tert-butyl ether n-BuOH: n-butanol NMR: nuclear magnetic resonance TBAF: tetra-n-butylammonium fluoride TBSCl: tert-butyldimethylsilyl chloride TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran TLC: thin layer chromatography prep-TLC: preparative thin layer chromatography SFC: supercritical fluid chromatography Analytical Procedures Chiral Analytical Separation Methods: Chiral analytical separation methods (e.g., supercritical fluid chromatography (SFC), and high performance liquid chromatography (HPLC)) used in the following synthetic examples are summarized in the table below.

LCMS Analytical Methods Agilent 10-min: Experiments were performed on an Agilent 1290 UHPLC coupled with Agilent MSD (6140) mass spectrometer using ESI as ionization source. The LC separation was using a Phenomenex XB-C18, 1.7mm, 50 × 2.1 mm column at a flow rate of 0.4 ml / minute. MPA (mobile phase A) was water with 0.1% FA and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2% MPB and ended at 98% MPB over 7 min and held at 98%B for 1.5 min following equilibration for 1.5 min. LC column temperature was 40 ^oC . UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments. Agilent 30-min: Experiments were performed on an Agilent 1290 HPLC coupled with Agilent MSD (6140) mass spectrometer using ESI as ionization source. The LC separation was done on an Agilent Zorbax Eclipse XDB-C18, 3.5 um, 100 × 3.0 mm column at a flow rate of 0.7 ml/minute. MPA (mobile phase A) was water with 0.1% FA and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2% MPB and ended at 98% MPB over 25.5 min and held at 98%B for 2.5 min following equilibration for 1.5 min. LC column temperature was 40 ^oC. UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments. Thermo qE 10-min: The samples were analyzed on a Dionex Ultimate 3000 coupled with Thermo Scientific Q Exactive HRMS using ESI as ionization source. The LC separation was done on a Phenomenex XB-C18, 1.7μm, 50 × 2.1 mm column at a flow rate of 0.4 ml / minute. MPA (mobile phase A) was water with 0.1% FA and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2 % MPB and ended at 98% MPB over 7 min and held at 98% MPB for 1.5 min following an equilibration for 1.5 min. LC column temperature was 40 ^oC. UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments. Thermo qE 30-min: The samples were analyzed on a Dionex Ultimate 3000 coupled with Thermo Scientific Q Exactive HRMS using ESI as ionization source. The LC separation was done on an Agilent Zorbax Eclipse XDB-C18, 3.5 um, 100 × 3.0 mm column at a flow rate of 0.7 ml/minute. MPA (mobile phase A) was water with 0.1% FA and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2% MPB and ended at 98% MPB over 25.5 min and held at 98%B for 2.5 min following equilibration for 1.5 min. LC column temperature was 40 ^oC. UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments. Experimental Procedures Intermediate 1: 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

Step 1: Synthesis of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

A mixture of 3,5-dibromo-1H-pyrazole (50.0 g, 221 mmol) and K₂CO₃ (91.8 g, 664 mmol) in MeCN (350 mL) was stirred at 25 °C for 0.5 h under nitrogen atmosphere. Then SEM-Cl (40.6 g, 244 mmol, 43.1 mL) was added dropwise at 25 ^oC and then stirred for 16 hr. The mixture was refluxed at 80 ^oC for 3.5 hrs. LCMS showed the starting material was consumed completely. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a crude product. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 10/1). 3,5- dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (50.5 g, 142 mmol, 64.1% yield) was obtained as a colorless oil. LCMS: (ESI, m/z) [M+H] ⁺ = 357, RT = 0.640 min. ¹H NMR: (400 MHz, CDCl₃) δ ppm -0.04 - 0.12 (m, 9 H) 0.87 - 0.98 (m, 2 H) 3.56 - 3.73 (m, 2 H) 5.44 (s, 2 H) 6.38 (s, 1 H). Step 2: Synthesis of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (INT-1)

To a mixture of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (200 g, 562 mmol), pyridin-4-ylboronic acid (75.9 g, 617 mmol) and K₂CO₃ (233 g, 1.68 mol) in dioxane (1000 mL) and H₂O (400 mL) was added Pd(dppf)Cl₂ (20.6 g, 28.1 mmol). The reaction mixture was stirred at 100 °C for 45 min under nitrogen atmosphere. LCMS showed the starting material was consumed completely. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (500 mL) and brine (800 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (800 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=3/1). INT-1 (260 g, 734 mmol, 43.6% yield) was obtained as a yellow oil. LCMS: (ESI, m/z) [M+H] ⁺ = 355, RT = 0.468 min. ¹H NMR: (400 MHz, CDCl₃) δ ppm -0.05 - 0.09 (m, 9 H) 0.86 - 1.06 (m, 2 H) 3.62 - 3.91 (m, 2 H) 5.36 - 5.63 (m, 2 H) 6.52 - 6.80 (m, 1 H) 7.53 - 7.72 (m, 2 H) 8.62 - 8.79 (m, 2 H). Intermediate 2: 6-(4-chloro-3-fluoro-phenyl)-1,3-oxazinan-2-one

I^{ntermediate 2} Step 1: Synthesis of 3- amino-1-(4-chloro-3-fluoro-phenyl)propan-1-ol

To a solution of 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propanenitrile (10.7 g, 54.15 mmol) in THF was added LiAlH₄ (4.11 g, 108.31 mmol) portion wise at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 0.5 h, the resulting mixture was stirred at 60 °C for 3 hrs. After cooling to 0 °C, the reaction was quenched with addition of water (4.1 mL), 15% NaOH solution (4.1 mL) and water (8.2 mL). The mixture was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 13-43% / FA in water) to give 3- amino-1-(4-chloro-3-fluoro-phenyl)propan-1-ol (4.5 g, 41% yield) as a yellow oil. LCMS: (ESI, m/z) [M+H]⁺ = 204.1 Step 2: Synthesis of 6-(4-chloro-3-fluoro-phenyl)-1,3-oxazinan-2-one (INT-2)

To a solution of 3-amino-1-(4-chloro-3-fluoro-phenyl)propan-1-ol (4.3 g, 21.2 mmol) and DIPEA (11.08 mL, 63.64 mmol) in DCM (120 mL) was added CDI (5.16 g, 31.82 mmol) portion wise at 0 ℃. The resulting mixture stirred at room temperature for 16 hrs. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (SiO₂, 5% methanol in dichloromethane) to give 6-(4-chloro-3-fluoro-phenyl)-1,3-oxazinan-2-one (Intermediate 2, 2.35 g, 48% yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.41 (t, J = 8.0Hz, 1H), 7.23 - 7.17 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H), 5.32 - 5.26 (m, 1H), 3.49 - 3.30 (m, 2H), 2.25 - 2.16 (m, 1H), 2.06 - 1.93 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 230.1

Examples 1a and 1b

Step 1: Synthesis of 3-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)-1- (4-chloro-3-fluorophenyl)propan-1-ol

To a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (3 g, 8.4 mmol) in n-BuOH (20 mL) was added DIPEA (4.4 mL, 25.2 mmol) and 3-amino-1-(4-chloro-3- fluoro-phenyl)propan-1-ol (3.4 g, 8.4 mmol). The reaction mixture at 120 °C for 12 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (SiO₂, 90% ethyl acetate in petroleum ether) to afford to 3-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- triazol-5-yl)amino)-1-(4-chloro-3-fluorophenyl)propan-1-ol (3.5 g, 87% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 479.0 Step 2: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propan-1-ol

A mixture of 3-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)- 1-(4-chloro-3-fluorophenyl)propan-1-ol (6.0 g, 12.5 mmol), pyridine-4-boronicacid (1.8 g, 15 mmol), K₂CO₃ (5.2 g, 37.51 mmol) and Pd(dppf)Cl₂ (915 mg, 1.25 mmol) in 1,4-dioxane (80 mL) and H₂O (16 mL) was stirred at 110 °C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 80% ethyl acetate in petroleum ether) to afford 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-triazol-5-yl)amino)propan-1-ol (3.1g, 52% yield) as a brown solid. Step 3: Synthesis of 6-(4-chloro-3-fluoro-phenyl)-3-[5-(4-pyridyl)-2-(2-trimethylsilylethoxymethyl)- 1,2,4-triazol-3-yl]-1,3-oxazinan-2-one

To a solution of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propan-1-ol (3.1 g, 6.48 mmol), DIPEA (4.3 mL, 25.94 mmol) and DMAP (158 mg, 1.3 mmol) in DMF (80 mL) was added CDI (2.1 g, 12.97 mmol). The reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with water (50 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 3% methanol in dichloromethane) to afford 6-(4- chloro-3-fluoro-phenyl)-3-[5-(4-pyridyl)-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-1,3- oxazinan-2-one (2 g, 61% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 478.1 Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3- oxazinan-2-one

A solution of 6-(4-chloro-3-fluoro-phenyl)-3-[5-(4-pyridyl)-2-(2-trimethylsilylethoxymethyl)- 1,2,4-triazol-3-yl]-1,3-oxazinan-2-one (2 g, 3.97 mmol) in 5% TFA/HFIP (30 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in MeOH (50 mL). The reaction mixture was adjusted to pH = 8 with saturated NaHCO₃ solution. The mixture was filtered and the filtrate was concentrated. The residue was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 25-55% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford 6-(4- chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (800 mg, 54% yield) as a white solid. LCMS: (ESI, m/z) [M+H] ⁺ = 374.0 Step 5: Chiral Separation of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-

6-(4-Chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (850 mg, 1.47 mmol) was separated by chiral SFC (Chiralcel OJ (250 mm x 30 mm, 10 um), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 45/55; 80 mL/min) to afford 6-(4-chloro-3-fluorophenyl)- 3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Example 1a, peak 1, Rt = 2.186 min, 209 mg, 25% yield) and 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3- oxazinan-2-one (Example 1b, peak 2, Rt = 2.807 min, 258 mg, 30% yield) both as white solid. Example 1a: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.67 (d, J = 4.8 Hz, 2H), 7.90 (d, J = 4.8 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 10.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.69 (d, J = 10.4 Hz, 1H), 4.22 - 4.19 (m, 1H), 4.03 - 3.97 (m, 1H), 2.45 - 2.40 (m, 1H), 2.37 - 2.26 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 374.0 Example 1b: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.67 (d, J = 4.8 Hz, 2H), 7.90 (d, J = 4.8 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 10.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.70 (d, J = 10.4 Hz, 1H), 4.22 – 4.19 (m, 1H), 4.03 - 3.97 (m, 1H), 2.45 - 2.40 (s, 1H), 2.37 - 2.25 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 3740 Examples 2a and 2b

To a solution of 3-amino-1-phenylpropan-1-ol (1.0 g, 6.61 mmol) in DCM（125 mL）was added CDI (1.07 g, 6.61 mmol). The reaction was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction was quenched with H₂O (30 mL), and the resulting solution was extracted with DCM (30 x 3 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 90% ethyl acetate in petroleum ether) to afford 6-phenyl-1,3-oxazinan-2-one (676 mg, 52% yield) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.38 - 7.26 (m, 5H), 5.73 (s, 1H), 5.37-5.34 (m, 1H), 3.50 - 3.46 (m, 1H), 3.41 - 3.36 (m, 1H), 2.15 - 2.11 (m, 1H), 2.10 - 2.08 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 178.1 Step 2: Synthesis of 6-phenyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)-1,3-oxazinan-2-one

To a mixture of 6-phenyl-1,3-oxazinan-2-one (500 mg, 2.82 mmol) and 4-(3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridine (1100 mg, 1.70 mmol) in 1,4-Dioxane (25 mL) was added DMEDA (0.06 mL, 0.56 mmol), CuI (108 mg, 0.56 mmol), K₂CO₃ (1.17 g, 8.47 mmol). The mixture was stirred at 110 ^oC for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 35% ethyl acetate in petroleum ether) to afford 6-phenyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)-1,3-oxazinan-2-one (380 mg, 28% yield) as a white solid. ¹H NMR (CDCl_3, 400 MHz): δ 8.71 (s, 2H), 7.63 (d, J = 5.2 Hz, 2H), 7.45 - 7.33 (m, 5H), 7.16 (s, 1H), 5.47 – 5.44 (m, 1H), 5.37 (s, 2H), 4.16 - 4.12 (m, 1H), 3.98-3.97 (m, 1H), 3.77 - 3.73 (m, 2H), 2.45 - 2.42 (m, 1H), 2.35 - 2.32 (m, 1H), 0.97 (t, J = 8.0 Hz, 2H), 0.06 (s, 9H). LCMS: (ESI, m/z) [M+H] ⁺ = 451.6

A solution of 6-phenyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 5-yl)-1,3-oxazinan-2-one (150 mg, 0.33 mmol) in 5% TFA/HFIP (10 mL, 6.49 mmol) was stirred at room temperature for 3 hours. The mixture was concentrated and saturated NaHCO₃ (6 mL) was added. The mixture was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with water (5 mL) and brine (3 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 3% methanol in dichloromethane) to give 6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2- one (90 mg, 84 % yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 320.9 Step 4: Chiral Separation of 6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex.

6-Phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (90 mg, 0.28 mmol) was separated by chiral SFC (Chiralcel OD (250 mm x 30 mm, 5 um), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 60/40; 80 mL/min) to give (R)-6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one (Example 2a,peak 1, Rt = 2.872 min, 18.5 mg, 20% yield) as a white solid and (S)-6- phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Example 2b, peak 2, Rt = 3.860 min, 13.8 mg, 15% yield) as a white solid. Example 2a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.33 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.46 - 7.40 (m, 5H), 7.16 (s, 1H), 5.59 - 5.55 (m, 1H), 3.98 - 3.87 (m, 2H), 2.42 - 2.38 (m, 1H), 2.32 - 2.25 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 321.0 Example 2b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.35 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.46 - 7.38 (m, 5H), 7.16 (s, 1H), 5.58 - 5.56 (m, 1H), 3.99 - 3.87 (m, 2H), 2.41 - 2.27 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 321.0 Examples 3a and 3b

Step 1 – 2: Synthesis of 6-(4-Chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one

6-(4-Chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one was prepared using the general procedure described for the preparation of 6-phenyl-3-(3-(pyridin-4-yl)- 1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Example 2a & Example 2b) by replacing 6-phenyl-1,3- oxazinan-2-one with 6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one in Step 2. LCMS: (ESI, m/z) [M+H]⁺ =372.9 Step 3: Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-

6-(4-Chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (290 mg, 0.78 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um), Supercritical CO₂ / i-PrOH + 0.1% NH₄OH = 40/60; 80 mL/min) to afford 6-(4-chloro-3-fluorophenyl)-3-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Example 3a, peak 1, Rt = 2.359 min, 58 mg, 20% yield) and 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Example 3b, peak 2, Rt = 3.850 min, 35 mg, 12% yield) both as white solid. Example 3a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.35 (br s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.74 - 7.66 (m, 3H), 7.55 - 7.36 (m, 2H), 7.14 (s, 1H), 5.62 - 5.59 (m, 1H), 3.99 - 3.85 (m, 2H), 2.44 - 2.40 (m, 1H), 2.27 - 2.23 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ =372.9 Example 3b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.37 (br s, 1H), 8.66 - 8.64 (m, 2H), 7.75 - 7.67 (m, 3H), 7.56 - 7.34 (m, 2H), 7.14 (s, 1H), 5.63 - 5.59 (m, 1H), 4.05 - 4.01 (m, 1H), 3.91 - 3.87 (m, 1H), 2.45 - 2.40 (m, 1H), 2.27 - 2.24 (m, 1H). LCMS: (ESI, m/z) [M+H] ⁺ =373.0 Examples 4a and 4b

To a solution of 6-fluoronicotinaldehyde (6 g, 47.9 mmol) in THF (60 mL) was added allylmagnesium bromide (1 M, 55.16 mL, 55.16 mmol) at 0 ^oC slowly under nitrogen atmosphere. The reaction was stirred at 0 ^oC for 2 hours. The reaction was quenched with saturated NH₄Cl (50 mL) solution and extracted with ethyl acetate (60 mL). The organic layer was washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 25% ethyl acetate in petroleum ether) to afford 1-(6- fluoropyridin-3-yl)but-3-en-1-ol (4 g, 50% yield) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 8.20 (s, 1H), 7.86 - 7.81 (m, 1H), 6.94 (dd, J = 8.4, 3.2 Hz, 1H), 5.84 - 5.75 (m, 1H), 5.23 - 5.18 (m, 2H), 4.82 (t, J = 6.4 Hz, 1H), 2.57 - 2.47 (m, 2H), 2.16 (s, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 168.1 Step 2: Synthesis of 5-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-2-fluoropyridine

To a solution of 1-(6-fluoropyridin-3-yl)but-3-en-1-ol (4.0 g, 23.9 mmol) in DCM (60 mL) was added imidazole (4.9 g, 71.7 mmol) and tert-butylchlorodimethylsilane (5.4 g, 35.8 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 5% ethyl acetate in petroleum ether) to afford 5-(1- ((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-2-fluoropyridine (6 g, 89% yield) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 8.11 (d, J = 2.0 Hz, 1H), 7.78 - 7.74 (m, 1H), 6.90 (dd, J = 2.8, 8.4 Hz, 1H), 5.77 - 5.68 (m, 1H), 5.06 - 4.97 (m, 2H), 4.75 (t, J = 6.0 Hz, 1H), 2.49 - 2.37 (m, 2H), 0.88 (s, 9H), 0.07 (s, 3H), -0.10 (s, 3H). LCMS: (ESI, m/z) [M+H]⁺ = 282.1 Step 3: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propanal

To a solution of 5-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-2-fluoropyridine (5.0 g, 17.7 mmol) in THF (100 mL) and water (100 mL) was added K2OsO4 (654 mg, 1.78 mmol) and NaIO₄ (13.3 g, 62.1 mmol) portionwise at 0 ^oC. The reaction was stirred at room temperature for 16 hrs. The mixture was filtered and the filtrate was extracted with ethyl acetate (200 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 15% ethyl acetate in petroleum ether) to afford 3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propanal (2.9 g, 58% yield) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 9.79 (t, J = 1.6 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.83 - 7.78 (m, 1H), 6.93 (dd, J = 8.4, 2.8 Hz, 1H), 5.31 - 5.28 (m, 1H), 2.94 - 2.88 (m, 1H), 2.70 - 2.66 (m, 1H), 0.86 (s, 9H), 0.08 (s, 3H), -0.11 (s, 3H). LCMS: (ESI, m/z) [M+H]⁺ = 284.1 Step 4: Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3-(pyridin-4- yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine

To a solution of 3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propanal (1.2 g, 4.23 mmol) in DCE (20 mL) was added 3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- triazol-5-amine (1.18 g, 4.06 mmol) and AcOH (0.24 mL, 4.23 mmol). After stirring at room temperature for 30 min, NaBH(OAc)₃ (1.35 g, 6.35 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs. The reaction was quenched with saturated NaHCO₃ (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 50% ethyl acetate in petroleum ether) to afford N-(3-((tert- butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine (540 mg, 23% yield) as a yellow oil. LCMS: (ESI, m/z) [M+H]⁺ = 559.2 Step 5: Synthesis of 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-

To a solution of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine (440 mg, 0.79 mmol) in THF (5 mL) was added TBAF (1 M in THF, 1.18 mL, 1.18 mmol). The reaction was stirred at room temperature for 2 hrs. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 90% ethyl acetate in petroleum ether) to afford 1-(6-fluoropyridin-3-yl)-3-((3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propan-1-ol (310 mg, 89% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 445.2 Step 6: Synthesis of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one

To a solution of 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propan-1-ol (285 mg, 0.64 mmol) in DMF (3 mL) was added DIEA (0.42 mL, 2.56 mmol), CDI (311 mg, 1.92 mmol) and DMAP (15 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 3 hrs and then 100 ^oC for 16 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 100% ethyl acetate in petroleum ether) to afford 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (260 mg, 86% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H] ⁺ = 471.1 Step 7: Synthesis of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan- 2-one

A solution of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (250 mg, 0.53 mmol) in 5% TFA/HFIP (8 mL) was stirred at room temperature for 5 hrs. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (20 mL) and saturated NaHCO3 solution (20 mL) were added. The water layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 0-30% / FA in water) to afford the 6-(6- fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (130 mg, 72% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 340.9 Step 8: Chiral Separation of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-

6-(6-Fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (130 mg was separated by chiral SFC (Chiralpak IG (250 × 30 mm, 10 um), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 40/60; 80 mL/min) to give 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4- triazol-5-yl)-1,3-oxazinan-2-one (Example 4a, peak 1, Rt = 3.211 min, 32 mg, 25% yield) and 6-(6- fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Example 4b, peak 2, Rt = 4.506 min, 32 mg, 25% yield) both as white solids. Example 4a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.88 (br s, 1H), 8.68 (d, J = 6.0 Hz, 2H), 8.38 (d, J = 1.6 Hz, 1H), 8.20 - 8.11 (m, 1H), 7.90 (d, J = 6.0 Hz, 2H), 7.30 (dd, J = 8.4, 2.4 Hz, 1H), 5.78 - 5.75 (m, 1H), 4.28 - 4.21 (m, 1H), 4.06 - 3.96 (m, 1H), 2.46 - 2.38 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 340.9 Example 4b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.88 (br s, 1H), 8.68 (d, J = 6.0 Hz, 2H), 8.38 (d, J = 1.6 Hz, 1H), 8.20 - 8.11 (m, 1H), 7.90 (d, J = 6.0 Hz, 2H), 7.30 (dd, J = 8.4, 2.4 Hz, 1H), 5.78 - 5.74 (m, 1H), 4.28 - 4.20 (m, 1H), 4.06 - 3.97 (m, 1H), 2.46 - 2.38 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 340.9 Example 5a and 5b

To a solution of 3-(3,4-difluorophenyl)-3-oxo-propanenitrile (5.0 g, 27.6 mmol) in Tetrahydrofuran (100 mL) was added LiAlH₄ (2.5 M, 33.12 mL, 82.81 mmol) dropwise at 0 ^oC under nitrogen atmosphere. After addition, the mixture was stirred at 60 ^oC for 3 hours under nitrogen atmosphere. After cooling to 0 ^oC, the reaction was quenched with H₂O (3.2 mL), 15% NaOH aqueous solution (3.2 mL) and H₂O (9.6 mL). The mixture was dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to afford 3-amino-1-(3,4- difluorophenyl)propan-1-ol (5 g crude), which was used directly in the next step without further purification. LCMS: (ESI, m/z) [M+H] ⁺ = 188.1 Step 2 – 5: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3- oxazinan-2-one

6-(3,4-Difluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one was prepared using the general procedure described for the preparation of 6-(4-chloro-3-fluorophenyl)-3- (3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Example 1a/1b and Example 2a/2b) by replacing 3-amino-1-(4-chloro-3-fluoro-phenyl)propan-1-ol with 3-amino-1-(3,4- difluorophenyl)propan-1-ol in Step 1. LCMS: (ESI, m/z) [M+H]⁺ = 357.9 Step 6: Chiral Separation of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3- oxazinan-2-one (Ex.5a & 5b)

6-(3,4-Difluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (322 mg, 0.90 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 µm), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 40/60; 80 mL/min) to afford 6-(3,4-difluorophenyl)-3-(3-(pyridin-4- yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Example 5a, peak 1, Rt = 1.942 min, 108 mg, 34% yield) and 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Example 5b, peak 2, Rt = 2.931 min, 121 mg, 37% yield) both as white solids. Example 5a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.83 (s, 1H), 8.67 (d, J = 4.8 Hz, 2H), 7.90 (d, J = 6.0 Hz, 2H), 7.64 - 7.57 (m, 1H), 7.56 - 7.49 (m, 1H), 7.38 - 7.32 (m, 1H), 5.69 - 5.64 (m, 1H), 4.27 - 4.20 (m, 1H), 4.06 - 3.96 (m, 1H), 2.46 - 2.28 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 357.9 Example 5b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.86 (br s, 1H), 8.68 (d, J = 5.6 Hz, 2H), 7.90 (d, J = 6.0 Hz, 2H), 7.64 - 7.57 (m, 1H), 7.56 - 7.49 (m, 1H), 7.38 - 7.32 (m, 1H), 5.69 - 5.64 (m, 1H), 4.28 - 4.20 (m, 1H), 4.06 - 3.96 (m, 1H), 2.46 - 2.28 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 358.0 Examples 6a and 6b

To a mixture of 3-(4-fluorophenyl)-3-oxopropanenitrile (5.0 g, 30.65 mmol) in THF (120 mL) was added LiAlH₄ (2.5 M in THF, 36.78 mL, 91.94 mmol) dropwise at 0 ^oC under nitrogen atmosphere. After addition, the reaction was stirred at 60 ^oC for 48 hrs. After cooling to 0 ^oC, the reaction was quenched with H₂O (3.5 mL), 15% NaOH aqueous solution (3.5 mL) and H₂O (10 mL). The mixture was dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to afford 3-amino-1-(4-fluorophenyl)propan-1-ol (3 g crude) as a yellow oil, which was used directly for next step without purification. LCMS: (ESI, m/z) [M+H]⁺ = 170.3 Step 2 – 5: Synthesis of 6-(4-Fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2- one

6-(4-Fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one was prepared using the general procedure described for the preparation of 6-(4-chloro-3-fluorophenyl)-3- (3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Examples 1a/1b and Example 2a/2b) by replacing 3-amino-1-(4-chloro-3-fluoro-phenyl)propan-1-ol with 3-amino-1-(4- fluorophenyl)propan-1-ol in Step 1. LCMS: (ESI, m/z) [M+H]⁺ = 339.9 Step 6: Chiral Separation of 6-(4-Fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3- oxazinan-2-one (Ex.6a & 6b)

6-(4-Fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (200 mg, 0.59 mmol) was separated by chiral SFC (Phenomenex Cellulose-2 (250 mm x 30 mm, 10 µm), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 44/56; 150 mL/min) to afford 6-(4-Fluorophenyl)-3-(3- (pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Ex 6a, peak 1, Rt = 2.273 min, 58 mg, 29% yield) and 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Ex 6b, peak 2, Rt = 2.807 min, 57 mg, 28% yield) both as white solids. Example 6a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.81 (s, 1H), 8.68 (d, J = 3.6 Hz, 2H), 7.90 (d, J = 6.0 Hz, 2H), 7.59 - 7.48 (m, 2H), 7.33 - 7.24 (m, 2H), 5.67 (dd, J = 10.8, 2.8 Hz, 1H), 4.28 - 4.17 (m, 1H), 4.07 - 3.96 (m, 1H), 2.46 - 2.27 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 339.9 Example 6b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.85 (s, 1H), 8.68 (d, J = 6.0 Hz, 2H), 7.90 (d, J = 4.8 Hz, 2H), 7.60 - 7.49 (m, 2H), 7.33 - 7.24 (m, 2H), 5.67 (dd, J = 10.8, 2.8 Hz, 1H), 4.28 - 4.17 (m, 1H), 4.07 - 3.95 (m, 1H), 2.47 - 2.24 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 339.9

Examples 7a and 7b

Step 1 – 7: Synthesis of 6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)- 1,3-oxazinan-2-one

6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2- one was prepared using the general procedure described for the preparation of 6-(6-fluoropyridin-3- yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Example 4a and Example 4b) by replacing 6-fluoronicotinaldehyde with 6-chloro-5-fluoropyridine-3-carbaldehyde in Step 1. LCMS: (ESI, m/z) [M+H]⁺ = 374.9 Step 8: Chiral Separation of 6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-

6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2- one (400 mg) was separated by chiral SFC (Chiralcel OJ (250 mm x 30 mm, 10 µm), Supercritical CO₂ / i-PrOH + 0.1% NH₄OH = 40/60; 80 mL/min) to afford 6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3- (pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Example 7a, peak 1, Rt = 1.581 min, 95.3 mg, 24% yield) and 6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3- oxazinan-2-one (Example 7b, peak 2, Rt = 2.434 min, 99.9 mg, 25% yield) both as white solids. Example 7a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.90 (br s, 1H), 8.67 (d, J = 6.0 Hz, 2H), 8.44 (d, J = 1.6 Hz,), 8.15 (dd, J = 8.0, 1.6 Hz, 1H), 7.90 (d, J = 6.4 Hz, 2H), 5.81 - 5.78 (m, 1H), 4.27 - 4.22 (m, 1H), 4.04 - 3.95 (m, 1H), 2.54 - 2.50 (m, 1H), 2.42 - 2.34 (m, 1H). LCMS: (ESI, m/z) [M+H] = 374.9 Example 7b: ¹H NMR: (DMSO-d₆, 400 MHz) δ 13.91 (br s, 1H), 8.67 (d, J = 6.0 Hz, 2H), 8.44 (d, J = 1.6 Hz, 1H), 8.15 (dd, J = 8.0, 1.6 Hz,, 1H), 7.90 (d, J = 6.4 Hz, 2H), 5.81 - 5.78 (m, 1H), 4.27 - 4.22 (m, 1H), 4.05 - 3.95 (m, 1H), 2.54 - 2.50 (m, 1H), 2.45 - 2.34 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 374.9 Examples 8a and 8b

Step 1: Synthesis of 3-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)propanenitrile

To a solution of acetonitrile (7.6 mL, 146.25 mmol) in THF (150 mL) was added n-BuLi (58.5 mL, 146.25 mmol) dropwise at -78 ^oC under nitrogen atmosphere. After stirring at -78 ^oC for 20 minutes, a solution of methyl 6-(trifluoromethyl) pyridine-3-carboxylate (15.0 g, 73.12 mmol) in THF (15 mL) was added dropwise. The mixture was stirred at -78 ^oC for 1 hour under nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous NH₄Cl (50 mL) solution and then extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 15% EE (25% ethyl alcohol in ethyl acetate) in petroleum ether) to afford 3-oxo-3-[6-(trifluoromethyl)-3-pyridyl]propanenitrile (7.1 g, 45% yield) as a yellow oil. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.93 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 4.20 (s, 2H).

To a solution of 3-oxo-3-[6-(trifluoromethyl)-3-pyridyl] propanenitrile (3.7 g, 17.28 mmol) in MeOH (60 mL) was added sodium borohydride (3.3 g, 86.39 mmol) at 0 ^oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours under nitrogen atmosphere. The reaction was quenched with water (20 mL) and concentrated. The aqueous was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford 3-hydroxy-3-(6- (trifluoromethyl)pyridin-3-yl)propanenitrile (3.5 g, 94% yield) as a yellow oil, which was used directly in next step without further purification. ¹H NMR (CDCl₃, 400 MHz): δ 8.74 (d, J = 1.2 Hz, 1H), 8.02 (dd, J = 8.0, 1.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 5.22 (t, J = 6.0 Hz, 1H), 2.90 - 2.78 (m, 2H).

To a mixture of 3-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)propanenitrile (3.5 g, 15.22 mmol) in THF (70 mL) was added LiAlH₄ (2.5 M, 12.2 mL, 30.44 mmol) dropwise at 0 ^oC. The reaction was stirred at 60 ^oC for 3 hours under nitrogen atmosphere. After cooling to 0 ^oC, the reaction was quenched with water (1.5 mL), 15% aqueous NaOH solution (1.5 mL) and water (5 mL). The mixture was dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to afford 3-amino-1-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (3.3 g crude) as a yellow oil, which was used directly in next step without further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.02 (dd, J = 8.0 Hz, 1H), 7.88 - 7.85 (m, 1H), 4.88 (t, J = 6.4 Hz, 1H), 2.71 - 2.60 (m, 2H), 1.74 - 1.65 (m, 2H). Step 4 — 7: Synthesis of 3-(3-(Pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3- yl)-1,3-oxazinan-2-one

3-(3-(Pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2- one was prepared using the general procedure described for the preparation of 1a/1b by replacing 3- amino-1-(4-chloro-3-fluoro-phenyl)propan-1-ol with 3-amino-1-(6-(trifluoromethyl)pyridin-3- yl)propan-1-ol in Step 1. LCMS: (ESI, m/z) [M+H]⁺ = 391.0 Step 8: Chiral separation of 3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-

3-(3-(Pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2- one (127 mg, 0.33 mmol) was separated by chiral SFC (Chiralpak OJ (250 mm x 30 mm, 10 µm), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 55/45; 80 mL/min) to afford to 3-(3-(pyridin-4-yl)-1H- 1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one (Ex 8a, peak 1, Rt = 0.976 min, 40 mg, 31% yield) and 3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin- 3-yl)-1,3-oxazinan-2-one (Ex 8b, peak 2, Rt = 1.415 min, 38 mg, 30% yield) both as white solids. Example 8a^{: 1}H NMR (DMSO-d₆, 400 MHz): δ 13.96 (s, 1H), 8.91 (s, 1H), 8.68 (d, J = 6.0 Hz, 2H), 8.22 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 5.2 Hz, 2H), 5.88 - 5.86 (m, 1H), 4.25 - 4.20 (m, 1H), 4.08 - 4.00 (m, 1H), 2.56 - 2.34 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 391.0 Example 8b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.89 (s, 1H), 8.91 (s, 1H), 8.68 (d, J = 6.0 Hz, 2H), 8.22 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 6.0 Hz, 2H), 5.88 - 5.86 (m, 1H), 4.27 - 4.22 (m, 1H), 4.08 - 4.00 (m, 1H), 2.56 - 2.34 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 391.0 Examples 9a and 9b

Step 1: Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3-(pyridin-4-

To a solution of 3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propanal (3 g, 10.5 mmol) in DCE (30 mL) and MeOH (30 mL) was added 3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (3.1 g, 10.5 mmol) and AcOH (60 uL, 1.06 mmol). The reaction mixture was stirred at 70 ^oC for 2 hours, and then NaBH(OAc)₃ (2 g, 31.7 mmol) was added. The reaction was stirred at 70 ^oC for 2 hours. After cooling to room temperature, the reaction was quenched with saturated NaHCO₃ solution (100 mL) and extrated with ethyl acetate (200 mL). The organic layer was washed withbrine (100 mL), dried over anhydrous Na₂SO₄ filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 40% ethyl acetate in petroleum ether) to afford N-(3-((tert-butyldimethylsilyl)oxy)-3-(6- fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (3.6 g, 61% yield) as yellow oil. LCMS: (ESI, m/z) [M+H]⁺ = 558.3 Step 2: Synthesis of 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)amino)propan-1-ol

To a solution of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (3 g, 5.3 mmol) in THF (30 mL) was added TBAF (1 m in THF, 8 mL, 8 mmol). The reaction was stirred at room temperature for 1 hour. The reactionwas quenched with water (150 mL) and extrated with ethyl acetate (150 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (SiO₂, 80% ethyl acetate in petroleum ether) to afford 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propan-1-ol (2.1 g, 88% yield) as a brown oil. LCMS: (ESI, m/z) [M+H]⁺ = 444.2 Step 3: Synthesis of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)-1,3-oxazinan-2-one

solution of 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propan-1-ol (1.6 g, 3.76 mmol) in DMF (17 mL) were added DIPEA (2.5 mL, 15.06 mmol), CDI (1.8 g, 11.29 mmol) and DMAP (91 mg, 0.75 mmol). The reaction was stirred at room temperature for 1 hour and then heated at 100 ^oC for 16 hours. Ethyl acetate (150 mL) was added, and the organic layer was washed with brine (150 mL x 2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (SiO₂, 80% ethyl acetate in petroleum ether) to afford 6-(6- fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one (1.3 g, 74% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 470.2 Step 4: Synthesis of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)-1,3-oxazinan-2-one

A solution of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2- one (800 mg, 1.7mmol) in 15% TFA/HFIP (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was re-dissolved in ethyl acetate (20 mL) and washed with NaHCO₃ solution (20 mL). The organic layer was dried over anhydrous Na₂SO₄, filterated and concentrated under reduced pressure. The crude was purified by reverse phase chromatography (acetonitrile: 20-50% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford 6-(6- fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one (500 mg, 86% yield) as a white solid. Step 5: Chiral Separation of 6-(6-Fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-

6-(6-Fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (500 mg, 1.47 mmol) was separated by chiral SFC (Chiralcel SS (250 mm x 25 mm, 10 um), Supercritical CO₂ / MeOH + 0.1% NH₄OH = 55/45; 80 mL/min) to afford 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)- 1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 9a, peak 1, Rt = 3.268 min, 195.1 mg, 38% yield) and 6-(6- fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 9b, peak 2, Rt = 4.010 min, 201.6 mg, 39% yield) both as white solid. Example 9a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.34 (br s, 1H), 8.66 - 8.61 (m, 2H), 8.36 (d, J = 2.0 Hz, 1H), 8.16 - 8.10 (m, 1H), 7.76 - 7.71 (m, 2H), 7.29 (dd, J = 2.8, 8.8 Hz, 1H), 7.14 (s, 1H), 5.71 - 5.64 (m, 1H), 4.10 - 4.00 (m, 1H), 3.96 - 3.84 (m, 1H), 2.47 - 2.28 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 339.9 Example 9b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.56 (br s, 1H), 8.66 - 8.61 (m, 2H), 8.36 (d, J = 2.0 Hz, 1H), 8.17 - 8.09 (m, 1H), 7.76 - 7.70 (m, 2H), 7.29 (dd, J = 2.8, 8.4 Hz, 1H), 7.14 (s, 1H), 5.72 - 5.62 (m, 1H), 4.12 - 3.99 (m, 1H), 3.96 - 3.84 (m, 1H), 2.47 - 2.30 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 340.0 Examples 10a and 10b

Step 1: Synthesis of tert-butyl (3-(3,4-difluorophenyl)-3-hydroxypropyl)

To a solution of 3-amino-1-(3,4-difluorophenyl)propan-1-ol (4.5g, 24.0 mmol) in DCM (90 mL) was added di-tert-butyl dicarbonate (6.6 mL, 28.9 mmol) and triethylamine (10.0 mL, 72.1 mmol). The mixture was stirred at room temperature for 16 h, and then was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 0-50% ethyl acetate in petroleum ether) to afford tert-butyl (3-(3,4-difluorophenyl)-3-hydroxypropyl)carbamate (1.5 g, 23% yield) as a brown oil. ¹H NMR (DMSO-d_6, 400 MHz): δ 7.37 - 7.31 (m, 2H), 7.17 - 7.12 (m, 1H), 6.77 (s, 1H), 5.39 (d, J = 4.8 Hz, 1H), 4.59 - 4.52 (m, 1H), 3.01 - 2.91 (m, 2H), 1.70 - 1.62 (m, 2H), 1.36 (s, 9H). Step 2: Synthesis of 6-(3,4-difluorophenyl)-1,3-oxazinan-2-one

To a solution of NaH (60% in mineral oil, 359 mg, 8.98 mmol) in anhydrous DMF (25 mL) was added tert-butyl (3-(3,4-difluorophenyl)-3-hydroxypropyl)carbamate (1.72 g, 5.99 mmol) at 0 ^oC under nitrogen atmosphere. After stirring at 0 ^oC for 0.5 h, the mixture was warmed to room temperature for 2 hours. The reaction mixture was quenched with saturated NH₄Cl solution (10 mL) and concentrated. The residue was purified by flash column chromatography (SiO₂, 0-15% ethyl acetate in petroleum ether) to give 6-(3,4-difluorophenyl)-1,3-oxazinan-2-one (720 mg, 49% yield) as a yellow oil. ¹H NMR (CDCl_3, 400 MHz): δ 7.24 - 7.13 (m, 3H), 6.98 (s, 1H), 5.32 - 5.20 (m, 1H), 3.48 - 3.35 (m, 2H), 2.20 - 2.10 (m, 1H), 2.08 - 1.94 (m, 1 H). Step 3: Synthesis of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-

To a mixture of 6-(3,4-difluorophenyl)-1,3-oxazinan-2-one (670 mg, 3.1 mmol), 4-(5-bromo- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (1.3 g, 3.8 mol) in 1,4-dioxane (15 mL) was added DMEDA (0.1 mL, 0.6 mmol), K₂CO₃ (1.4 g, 10.1 mmol) and CuI (120 mg, 0.6 mmol). The mixture was stirred at 110 ^oC for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 0-30% ethyl acetate in petroleum ether to afford 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (870 mg, 53% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 487.2

A solution of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)-1,3-oxazinan-2-one (620 mg, 1.3 mmol) in 5% TFA/HFIP (28 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and saturated NaHCO₃ (6 mL) was added. The mixture was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with water (5 mL) and brine (3 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one (450 mg, 71% yield) as a white solid, which was used directly in the next step without further purification. LCMS: (ESI, m/z) [M+H]⁺ = 357.1 Step 5: Chiral Separation of 6-(3,4-Difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-

6-(3,4-Difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (450 mg, 1.26 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um), Supercritical CO₂ / i-PrOH + 0.1% NH₄OH = 40/60; 80 mL / min) to afford 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)- 1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 10a,peak 1, Rt = 1,485 min, 122 mg, 27% yield) as a white solid and 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 10b, peak 2, Rt = 2,426 min, 132 mg, 29% yield) as a white solid. Example 10a: ¹H NMR (DMSO-d₆, 400 MHz): δ = 13.35 (s, 1H), 8.63 (d, J = 5.6 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.60 - 7.48 (m, 2H), 7.35 - 7.29 (m, 1H), 7.16 (s, 1H), 5.61 - 5.52 (m, 1H), 4.08 - 3.98 (m, 1H), 3.94 - 3.830 (m, 1H), 2.44 - 2.35 (m, 1H), 2.33 - 2.20 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 357.1 Example 10b: ¹H NMR (DMSO-d₆, 400 MHz): δ = 13.34 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.60 - 7.48 (m, 2H), 7.35 - 7.29 (m, 1H), 7.15 (s, 1H), 5.61 - 5.52 (m, 1H), 4.08 - 3.98 (m, 1H), 3.94 - 3.83 (m, 1H), 2.44 - 2.35 (m, 1H), 2.33 - 2.20 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 357.1 Examples 11a and 11b

Step 1: Synthesis of 6-(4-fluorophenyl)-1,3-oxazinan-2-one

To a solution of 3-amino-1-(4-fluorophenyl)propan-1-ol (1.0 g, 5.91 mmol) and DIPEA (3.09 mL, 17.73 mmol) in THF (40 mL) was added CDI (1.44 g, 8.87 mmol). The mixture was stirred at room temperature for 2 hours and then stirred at 60 ℃ for 16 hours. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile: 18-48% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford 6-(4-fluorophenyl)-1,3-oxazinan-2-one (260 mg, 19% yield) as a white solid. ¹H NMR (CDCl3, 400 MHz): δ 7.41 - 7.33 (m, 2H), 7.09 (t, J = 8.8 Hz, 2H), 5.65 (s, 1H), 5.33 (dd, J = 2.8, 10.4 Hz, 1H), 3.56 - 3.46 (m, 1H), 3.45 - 3.37 (m, 1H), 2.26 - 2.17 (m, 1H), 2.14 - 2.05 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 196.1 Step 2: Synthesis of 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)-1,3-oxazinan-2-one

To a mixture of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (400 mg, 1.13 mmol), 6-(4-fluorophenyl)-1,3-oxazinan-2-one (220 mg, 1.13 mmol) in 1,4-dioxane (6 mL) was added DMDACH (0.02 mL, 0.23 mmol), CuI (43 mg, 0.23 mmol) and K₂CO₃ (468 mg, 3.39 mmol). The mixture was stirred at 110 ^oC for 16 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 50% EE (ethyl acetate/ethanol = 3/1) in petroleum ether) to afford 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 38% yield) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 8.74 - 8.68 (m, 2H), 7.63 - 7.57 (m, 2H), 7.47 - 7.37 (m, 2H), 7.15 - 7.07 (m, 3H), 5.33 (dd, J = 2.8, 10.0 Hz, 1H), 5.37 (s, 2 H), 4.22 - 4.14 (m, 1H), 4.03-3.91 (m, 1H), 3.75 (t, J = 8.4 Hz, 2H), 2.49 - 2.39 (m, 1H), 2.36 - 2.24 (m, 1H), 1.00 - 0.94 (m, 2H), 0.03 - 0.00 (m, 9H).

A mixture of 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 0.43 mmol) in 5% TFA / HFIP solution (6 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL), and then was adjusted to pH = 8 with saturated NaHCO₃ solution. The organic phase was separated, and the aqueous phase was extracted with DCM (5 mL x 2). The combines organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 29-59% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford 6-(4-fluorophenyl)-3-[3-(4-pyridyl)-1H-pyrazol-5- yl]-1,3-oxazinan-2-one (80 mg, 55% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 339.1 Step 4: Chiral Separation of 6-(4-Fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-

6-(4-Fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (80 mg, 0.24 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um); Supercritical CO₂ / EtOH + 0.1% NH₄OH = 60/40; 80 mL/min) to afford the desired product 6-(4-fluorophenyl)-3-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 11a, 24.0 mg, peak 1, Rt = 1.860 min, 29% yield) and the desired product 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan- 2-one (Ex 11b, 20.1 mg, peak 2, Rt = 2.556 min, 24% yield) both as white solid. Example 11a: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.63 (d, J = 5.6 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.52 (dd, J = 5.6, 8.4 Hz, 2H), 7.27 (t, J = 8.8 Hz, 2H), 7.13 (s, 1H), 5.60 - 5.52 (m, 1H), 4.02 - 3.96 (m, 1H), 3.94 - 3.84 (m, 1H), 2.40 - 2.22 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 338.9 Example 11b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.34 (s, 1H), 8.63 (d, J = 5.2 Hz, 2H), 7.73 (d, J = 5.2 Hz, 2H), 7.55 - 7.48 (m, 2H), 7.27 (t, J = 8.8 Hz, 2H), 7.16 (s, 1H), 5.60 - 5.52 (m, 1H), 4.03 - 3.94 (m, 1H), 3.92 - 3.82 (m, 1H), 2.40 - 2.22 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 339.1 Examples 12a and 12b

Step 1: Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propyl)-3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine

To a solution of 3-((tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propanal (1.64 g, 5.16 mmol) in DCE (15 mL) and MeOH (15 mL) was added 3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (1.5 g, 5.16 mmol l) and AcOH (34 mg, 0.52 mmol). After stirring at room temperature for 30 minutes, NaBH₃CN (974 mg, 15.49 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then heated at 50 ^oC for 16 hours. After cooling to room temperature, the reaction was quenched with saturated NaHCO₃ solution (50 mL) and extrated with ethyl acetate (100 mL). The organic layer was washed withbrine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (SiO₂, 0-20% ethyl acetate in petroleum ether) to give N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (900 mg, 29% yield) as yellow oil. LCMS: (ESI, m/z) [M+H]⁺ = 592.2 Step 2: Synthesis of 1-(6-chloro-5-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-

To a solution of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propyl)- 3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (900 mg, 1.52 mmol) in THF (10 mL) was added TBAF (1 M in THF, 2.3 mL, 2.3 mmol). The reaction was stirred at room temperature for 2 hours, ethyl acetate (50 mL) and the water (50 mL) were added. The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (SiO₂, 0-80% ethyl acetate in petroleum ether) to give 1-(6-chloro-5-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propan-1-ol (570 mg, 78% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 478.1 Step 3: Synthesis of 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one

To a solution of 1-(6-chloro-5-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propan-1-ol (560 mg, 1.17 mmol) in DMF (6 mL) were added DIPEA (0.77 mL, 4.69 mmol), CDI (570 mg, 3.51 mmol) and DMAP (29 mg, 0.23 mmol). The reaction was stirred at room temperature for 1 hours, then heated stirred at 100 ^oC for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 60-70% ethyl acetate in petroleum ether) to give 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (460 mg, 78% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 504.1 Step 4: Synthesis of 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one

A solution of 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (460 mg, 0.91 mmol) in 10% TFA/HFIP (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and then NaHCO₃ solution (30 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (acetonitrile: 31-61% / 0.05% NH₄OH in water) to afford 6-(6- chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 58% yield) as a white solid. Step 5: Chiral separation of 6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)- 1,3-oxazinan-2-one (Ex 12a & 12b)

6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 5 um), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 50/50; 50 mL/min) to afford 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin- 4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 12a, peak 1, Rt = 2.390 min, 59.5 mg, 29% yield) and 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 12b, peak 2, Rt =3.177 min, 66.2 mg, 33% yield) both as white solid. Example 12a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.36 (br s, 1H), 8.64 (d, J = 6.0 Hz, 2H), 8.42 (d, J = 1.6 Hz, 1H), 8.14 - 8.10 (m, 1H), 7.73 (d, J = 6.0 Hz, 2H), 7.15 (br s, 1H), 5.73 - 5.69 (m, 1H), 4.10 – 3.98 (m, 1H), 3.94 - 3.85 (m, 1H), 2.47 - 2.41 (m, 1H), 2.39 - 2.28 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 374.0. Example 12b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.35 (br s, 1H), 8.64 (d, J = 6.0 Hz, 2H), 8.42 (d, J = 1.6 Hz, 1H), 8.14 - 8.10 (m, 1H), 7.73 (d, J = 6.0 Hz, 2H), 7.14 (br s, 1H), 5.74 - 5.70 (m, 1H), 4.10 - 3.99 (m, 1H), 3.95 - 3.85 (m, 1H), 2.45 - 2.40 (m, 1H), 2.39 - 2.28 (m, 1H). LCMS: (ESI, m/z) [M+H] ⁺ = 374.0. Examples 13a and 13b

To a solution of 3-amino-1-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (4.4 g crude, 20.0 mmol) and TEA (6.07 g, 60.0 mmol) in DCM (90 mL) was added Boc₂O (5.5 mL, 24.0 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 0-35% ethyl acetate in petroleum ether) to afford tert-butyl (3-hydroxy-3-(6-(trifluoromethyl)pyridin-3- yl)propyl)carbamate (1.05 g, 16% yield) as a yellow oil. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.00 (dd, J = 1.2, 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 5.2 Hz, 1H), 5.62 (d, J = 4.4 Hz, 1H), 4.75 (q, J = 5.6 Hz, 1H), 3.12 - 2.85 (m, 2H), 1.76 (q, J = 7.20 Hz, 2 H), 1.36 (s, 9H). Step 2: Synthesis of 6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one

To a solution of tert-butyl (3-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)carbamate (800 mg, 2.5 mmol) in DMF (12 mL) under nitrogen atmosphere was added NaH (60% in mineral oil, 150 mg, 3.8 mmol) at 0 ^oC. After stirring at 0 ^oC for 15 min, the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NH₄Cl solution (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0-5% methanol in dichloromethane) to give 6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one (200 mg, 33% yield) as a yellow oil. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.81 (d, J = 1.60 Hz, 1H), 8.10 (dd, J = 8.0, 2.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 5.56 (dd, J = 10.4, 2.4 Hz, 1H), 3.32 - 3.26 (m, 1H), 3.24 - 3.14 (m, 1H), 2.30 - 2.17 (m, 1H), 2.05 - 1.90 (m, 1H). Step 3: Synthesis of 3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one

To a solution of 6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one (290 mg, 1.2 mmol) and 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (459 mg, 1.3 mmol) in 1,4-dioxane (6 mL) was added DMEDA (0.04 mL, 0.4 mmol), K₂CO₃ (488 mg, 3.5 mmol) and CuI (67 mg, 0.4 mmol). The mixture was stirred at 110 ^oC for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was filtered and under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 0-14% EE (25% ethanol in ethyl acetate) in petroleum ether) to give 3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6- (6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one (220 mg, 36% yield) as yellow solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.88 (s, 1H), 8.73 - 8.66 (m, 2H), 8.18 (dd, J = 8.4, 2.4 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.72 - 7.60 (m, 2H), 7.02 (s, 1 H), 5.81 (dd, J = 10.4, 2.4 Hz, 1H), 5.45 (s, 2H), 4.12 - 4.00 (m, 1H), 3.95 - 3.88 (m, 1H), 3.63 (t, J = 8.0 Hz, 2H), 2.55 - 2.50 (m, 1H), 2.40 - 2.27 (m, 1H), 0.84 (t, J = 8.0 Hz, 2H), -0.06 (s, 9H). Step 4: Synthesis of 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3- oxazinan-2-one

A solution of 3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one (220 mg, 0.4 mmol) in 5% TFA / HFIP (5 mL) was stirred at room temperature for 16 hours. The mixture was adjusted to pH=7 with saturated NaHCO₃ solution and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 28-58% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to give 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one (90 mg, 55% yield) as a yellow solid. Step 5: Chiral Separation of 3-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-

3-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one (110 mg, 0.3 mmol) was separated by chiral SFC (Regis (S,S) Whelk-01 (250 mm x 25 mm, 10 um), Supercritical CO₂ / MeOH + 0.1% NH₄OH = 55/45; 80 mL/min) to give 3-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one (13a, peak 1, Rt = 2.403 min, 44.4 mg, 40% yield) and 3-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)- 1,3-oxazinan-2-one (13b, peak 2, Rt = 3.029 min, 201.6 mg, 39% yield) both as white solid. Example 13a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.39 (s, 1H), 8.89 (s, 1H), 8.64 (d, J = 4.8 Hz, 2 H), 8.20 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 5.6 Hz, 2H), 7.17 (s, 1H), 5.82 - 5.78 (m, 1H), 4.10 - 4.00 (m, 1 H) 3.99 - 3.85 (m, 1H), 2.62 - 2.54 (m, 1H), 2.40 - 2.27 (m, 1 H). LCMS: (ESI, m/z) [M+H]⁺ = 390.1 Example 13b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.38 (s, 1H), 8.89 (s, 1H), 8.64 (d, J = 4.8 Hz, 2 H), 8.19 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 5.6 Hz, 2H), 7.17 (s, 1H), 5.82 - 5.78 (m, 1H), 4.10 - 4.00 (m, 1H), 3.99 - 3.85 (m, 1H), 2.62 - 2.54 (m, 1H), 2.40 - 2.27 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 390.1 Examples 14a and 14b

Step 1: Synthesis of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridazine

To a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.0 g, 5.62 mmol) in DMF (30 mL) and 4-(tributylstannyl)pyridazine (3.1 g, 8.42 mmol)was added Pd(PPh₃)₂Cl₂ (394 mg, 0.56 mmol), and LiCl (476 mg, 11.23 mmol). The resulting mixture was stirred at 100 ^oC for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was passed through a pad of Celite and washed with ethyl acetate (50 mL). The organic layer was washed with water (10 mL), dried over anhydrous Na₂SO₄, filtrate and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 20% ethyl acetate in petroleum ether) to afford 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridazine (600 mg, 30% yield) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 9.56 - 9.48 (m, 1H), 9.40 - 9.39 (m, 1H), 7.97 - 7.95 (m, 1H), 7.17 (s, 1H), 5.56 (s, 2H), 3.62 (t, J = 8.4 Hz, 2H), 0.83 (t, J = 8.4 Hz, 2H), - 0.07(s, 9H). Step 2: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1-((2-

To a mixture of 6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (355 mg, 1.55 mmol) and 4- (5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridazine (500 mg, 1.41 mmol) in 1,4-dioxane (10 mL) was added DMEDA (0.03 mL, 0.28 mmol), CuI (54 mg, 0.28 mmol) and K₂CO₃ (583 mg, 4.22 mmol). The resulting mixture was stirred at 110 ^oC for 16 hrs under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 15% ethyl acetate in petroleum ether) to afford 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4- yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (220 mg, 31% yield) as a white solid. Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan- 2-one

A solution of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (300 mg, 0.60 mmol) in 5% TFA/HFIP (21 mL) at room temperature for 8 h. The mixture was concentrated and adjusted to pH = 8 with NaHCO₃ (20 mL), and then ethyl acetate (15 mL) was added. The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 3% methanol in dichloromethane) to afford 6-(4-chloro-3- fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 90% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 374.0 Step 4: Chiral Separation of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-

6-(4-Chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 0.54 mmol) was separated by chiral SFC (Chiralcel IG (250 mm x 30 mm, 10 um), Supercritical CO₂ / i-PrOH + 0.1% NH₄OH = 60/40; 80 mL/min) to give crude product 160 mg peak 1 and 50 mg peak 2. The peak 1 was repurified by reverse phase chromatography (acetonitrile: 28-58% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-1,3-oxazinan-2-one (Example 14a, Rt = 2.711 min, 16.9 mg, 8% yield) as a white solid. The peak 2 was repurified by reverse phase chromatography (acetonitrile: 27-57% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-1,3-oxazinan-2-one (Example 14b, Rt = 3.600 min, 17.2 mg, 8% yield) as a white solid. Example 14a: ¹H NMR (DMSO-d6, 400 MHz): δ 9.64 (s, 1H), 9.27 (d, J = 5.6 Hz, 1H), 8.03 - 7.94 (m, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 10.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 5.62 (d, J = 9.6 Hz, 1H), 4.00 - 3.92 (m, 1H), 3.95 - 3.86 (m, 1H), 2.45 - 2.38 (m, 1H), 2.33 - 2.23 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 374.0 Example 14b: ¹H NMR (DMSO-d₆, 400 MHz): δ 9.64 (s, 1H), 9.27 (d, J = 4.8 Hz, 1H), 7.99 - 7.98 (m, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.55 - 7.52 (m, 1H), 7.34 (d, J = 9.6 Hz, 1H), 7.26 (s, 1H), 5.61 (d, J = 8.4 Hz, 1H), 4.02 - 3.95 (m, 1H), 3.94 - 3.86 (m, 1H), 2.45 - 2.40 (m, 1H), 2.33 - 2.23 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 373.9 Examples 15a and 15b

Step 1: Synthesis of ethyl 3,5-dibromo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate

To a solution of ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate (5.0 g, 16.78 mmol) in DMF (50 mL) was added NaH (60% in mineral oil, 0.8 g, 20.14 mmol) at 0 ^oC under nitrogen atmosphere. After stirring at 0 ^oC for 30 min, SEM-Cl (3.56 mL, 20.14 mmol) was added dropwise. The reaction was stirred at room temperature for 4 hrs. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 20% ethyl acetate in petroleum ether) to afford ethyl 3,5- dibromo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (6.2 g, 86% yield) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 5.51 (s, 2H), 4.37 (q, J = 6.8 Hz, 2H), 3.65 (t, J = 8.0 Hz, 2H), (t, J = 7.2 Hz, 3H), 0.96 - 0.87 (m, 2H), 0.02 (s, 9H).

To a solution of ethyl 3,5-dibromo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (10.5 g, 24.52 mmol) in THF (100 mL) was added DIBAL-H (49.04 mL, 49.04 mmol) dropwise at - 78 ^oC under nitrogen condition. The mixture was stirred at -78 ^oC for 30 min under nitrogen atmosphere, and then the mixture was warmed up to room temperature and stirred for 16 hrs. The mixture was quenched with saturated Rochelle salt solution (50 mL), diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 20% ethyl acetate in petroleum ether) to afford (3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol (6.0 g, 63% yield) as a yellow oil. ¹H NMR: (CDCl₃, 400 MHz): δ 5.45 (s, 2H), 4.52 (s, 2H), 3.63 (t, J = 8.4 Hz, 2H), 0.92 (t, J = 8.0 Hz, 2H), -0.01 (s, 9H). Step 3: Synthesis of 3,5-dibromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2-

To a solution of (3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol (5.7 g, 14.76 mmol) and imidazole (1.5 g, 22.14 mmol) in DCM (60 mL) was added TBSCl (3.3 g, 22.14 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3) and. The combined organic phases were washed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 20% ethyl acetate in petroleum ether) to afford 3,5-dibromo-4-(((tert- butyldimethylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (7.2 g, 95% yield) as a yellow oil. LCMS: (ESI, m/z) [M+H]⁺ = 240.1 Step 4: Synthesis of 4-(5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2-

To a solution of 3,5-dibromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole (6.7 g, 13.39 mmol), potassium carbonate (5.6 g, 40.17 mmol) and pyridin-4-ylboronic acid (1.81 g, 14.73 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was added Pd(dppf)Cl₂ (0.98 g, 1.34 mmol) at room temperature. The mixture stirred at 80 ^oC for 16 hrs under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 50% ethyl acetate in petroleum ether) to afford 4-(5-bromo-4-(((tert- butyldimethylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (2.7 g, 40% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 498.2 Step 5: Synthesis of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one

To a solution of 4-(5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (1.19 g, 2.4 mmol) and 6-(4-chloro-3-fluoro- phenyl)-1,3-oxazinan-2-one (500 mg, 2.18 mmol) in 1,4-dioxane (10 mL) was added K₃PO₄ (1.39 g, 6.53 mmol), DMEDA (0.07 mL, 0.65 mmol) and CuI (124 mg, 0.65 mmol) at room temperature. The reaction was stirred at 110 ^oC for 16 hrs under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 30% ethyl acetate (25% ethanol) in petroleum ether) to give 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(pyridin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (360 mg, 26% yield) as a yellow oil. ¹H NMR (DMSO-d_6, 400 MHz): δ 8.74 (d, J = 6.0 Hz, 2H), 7.69 (t, J = 8.4 Hz, 1H), 7.59 (d, J = 6.0 Hz, 2H), 7.52 (d, J = 12.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 5.64 - 5.61 (m, 1H), 5.35 (s, 2H), 4.42 (s, 2H), 3.85 - 3.77 (m, 1H), 3.73 - 3.65 (m, 1H), 3.55 (t, J = 8.0 Hz, 2H), 2.45 - 2.40 (m, 1H), 2.31 - 2.18 (m, 1H), 0.80 (t, J = 8.4 Hz, 2H), 0.76 (s, 9H), -0.08 (s, 15H). Step 6: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-(hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazol-5- yl)-1,3-oxazinan-2-one

A solution 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (160 mg, 0.25 mmol) in 2 M HCl in 1,4-dioxane (3 mL) at room temperature for 1 h. The reaction was concentrated and saturated NaHCO₃ solution (3 mL) was added. After stirring at room temperature for 30 min, the solution was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 35% ethyl acetate (25% ethanol) in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-3-(4- (hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (64 mg, 64% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 403.0 Step 7: Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-3-(4-(hydroxymethyl)-3-(pyridin-4-yl)-1H-

6-(4-Chloro-3-fluorophenyl)-3-(4-(hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one (86 mg, 0.21 mmol) was purified by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um); Supercritical CO₂ / i-PrOH + 0.1% NH₄OH = 50/50; 80 mL/min) to afford 6-(4-chloro-3- fluorophenyl)-3-(4-(hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Example 15a, peak 1, Rt = 3.010 min, 32 mg, 37% yield) and 6-(4-chloro-3-fluoro-phenyl)-3-[4- (hydroxymethyl)-3-(4-pyridyl)-1H-pyrazol-5-yl]-1,3-oxazinan-2-one (Example 15b, peak 2, Rt = 4.514 min, 36 mg, 42% yield) both as white solid. Example 15a: ¹H NMR (DMSO-d_6, 400 MHz): δ 13.46 (s, 1H), 8.69 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 5.67 - 5.64 (m, 1H), 4.93 (s, 1H), 4.39 (s, 2H), 3.87 - 3.80 (m, 1H), 3.70 - 3.60 (m, 1H), 2.42 - 2.27 (m, 2H). LCMS: (ESI, m/z) [M+H] ⁺ = 403.0 Example 15b: ¹H NMR: (DMSO-d_6, 400 MHz): δ 13.45 (s, 1H), 8.70 (d, J = 6.0 Hz, 2H), 7.80 - 7.70 (m, 3H), 7.38 (d, J = 8.4 Hz, 1H), 5.67 - 5.64 (m, 1H), 4.92 (s, 1H), 4.39 (s, 2H), 3.87 - 3.83 (m, 1H), 3.69 - 3.67 (m, 1H), 2.42 - 2.27 (m, 2H). LCMS: (ESI, m/z) [M+H] ⁺ = 403.1 Examples 16a and 16b

Step 1: Synthesis of 3,5-dibromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a solution of 3,5-dibromo-4-methyl-1H-pyrazole (2.8 g, 11.6 mmol) and K₂CO₃ (4.8 g, 35.0 mmol) in MeCN (40 mL) were added SEM-Cl (2.2 mL, 12.8 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (SiO₂, 5% ethyl acetate in petroleum ether) to give crude product, which was further purified by reverse phase chromatography (acetonitrile: 68-98% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford 3,5-dibromo-4-methyl- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.5 g, 35% yield) as brown oil. ¹H NMR (CDCl₃, 400 MHz): δ 5.42 (s, 2H), 3.61 (t, J = 8.0 Hz, 2H), 2.02 (s, 3H), 0.91 (t, J = 8.4 Hz, 2H), -0.01 (s, 9H). Step 2: Synthesis of 4-(5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3- yl)pyridine

To a solution of 3,5-dibromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.3 g, 3.5 mmol) and pyridin-4-ylboronic acid (431 mg, 3.5 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added K₂CO₃ (1.5 g, 10.5 mmol) and Pd(dppf)Cl₂ (256 mg, 0.35 mmol). The reaction mixture was stirred at 100 ^oC for 2 hrs under nitrogen atmosphere. After cooling to room temperature, ethyl acetate (30 mL) was added. The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 20% ethyl acetate in petroleum ether) to afford 4-(5- bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (460 mg, 35% yield) as colorless oil. LCMS: (ESI, m/z) [M+H]⁺ = 368.0 Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1-((2-

To a solution of 4-(5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3- yl)pyridine (460 mg, 1.25 mmol), 6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (430 mg, 1.87 mmol) and K₂O₃ (517 mg, 3.75 mmol) in 1,4-dioxane (5 mL) were added, DMEDA (22 mg, 0.25 mmol) and CuI (47 mg, 0.25 mmol). The reaction was stirred at 100 ^oC for 16 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 60% ethyl acetate in petroleum ether) to afford 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (260 mg, 40% yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.75 (d, J = 5.6 Hz, 2H), 7.51 - 7.43 (m, 3H), 7.31 - 7.27 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 5.53 - 5.46 (m, 1H), 5.28 (s, 2H), 3.99 - 3.88 (m, 1H), 3.85 - 3.79 (m, 1H), 3.76 - 3.68 (m, 2H), 2.48 - 2.25 (m, 2H), 2.03 (s, 3H), 1.01 - 0.91 (m, 2H), 0.01 (s, 9H). LCMS: (ESI, m/z) [M+H]⁺ = 517.1 Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one

A solution of 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (220 mg, 0.42 mmol) in 2 M HCl in dioxane (6 mL, 12 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and ethyl acetate (20 mL) was added. The mixture was adjusted to pH = 8 with saturated NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 33-63%/0.05% NH4OH + 10 mM NH4HCO3 in water) to afford 6-(4-chloro-3- fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (140 mg, 85% yield) as a white solid. Step 5: Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5- yl)-1,3-oxazinan-2-one (Ex 16a & 16b)

6-(4-Chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2- one (140 mg, 0.37 mmol) was separated by chiral SFC (Chiralcel ID (250 mm x 25 mm, 10 um), Supercritical CO₂ / IPA + 0.1% NH₄OH = 55/45; 80 mL/min) to afford 6-(4-chloro-3-fluorophenyl)- 3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 16a, peak 1, Rt = 4.173 min, 50.8 mg, 34% yield) and 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)- 1,3-oxazinan-2-one (Ex 16b, peak 2, Rt = 4.943 min, 45.9 mg, 31% yield) both as white solid. Example 16a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.29 (s, 1H), 8.69 (d, J = 5.2 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 2H), 7.56 (dd, J = 1.6, 10.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 5.71 - 5.63 (m, 1H), 3.85 - 3.73 (m, 1H), 3.67 - 3.57 (m, 1H), 2.42 - 2.23 (m, 2H), 2.09 (s, 3H). LCMS: (ESI, m/z) [M+H]⁺ = 387.0 Example

400 MHz): δ 13.27 (s, 1H), 8.69 (d, J = 5.6 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 6.0 Hz, 2H),7.57 - 7.52 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.72 - 5.63 (m, 1H), 3.85 - 3.75 (m, 1H), 3.67 - 3.57 (m, 1H), 2.43 - 2.23 (m, 2H), 2.09 (s, 3H). LCMS: (ESI, m/z) [M+H]⁺ = 387.0 Examples 17a and 17b

Step 1: Synthesis of 4-(4-bromo-2H-1,2,3-triazol-2-yl)pyridine

To a mixture of 4-bromo-2H-1,2,3-triazole (2.0 g, 13.52 mmol) in DMF (20 mL) was added K₂CO₃ (5.6 g, 40.55mmol) and 4-fluoropyridine (1.6 g, 16.22 mmol). The mixture was stirred at 100 ℃ for 16 hours. After cooling to room temperature, the reaction was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 50% ethyl acetate in petroleum ether) to afford 4-(4-bromo-2H-1,2,3-triazol-2-yl)pyridine (1.2 g, 39% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 224.9 Step 2: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3- oxazinan-2-one

To a mixture of 4-(4-bromo-2H-1,2,3-triazol-2-yl)pyridine (200 mg, 0.87 mmol) and 6-(4- chloro-3-fluorophenyl)-1,3-oxazinan-2-one (216 mg, 0.96 mmol) in 1,4-dioxane (5 mL) was added CuI (33 mg, 0.17 mmol), DMEDA (0.02 mL, 0.17 mmol) and K₃PO₄ (555 mg, 2.61 mmol). The resulting mixture was stirred at 110 ^oC for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 10% methyl alcohol in dichloromethane) to afford 6-(4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)- 1,3-oxazinan-2-one (200 mg, 61% yield) as a yellow oil. LCMS: (ESI, m/z) [M+H]⁺ = 374.0. Step 3: Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)- 1,3-oxazinan-2-one (Ex 17a & 17b)

6-(4-Chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-oxazinan-2-one (200 mg, 0.54 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 µm), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 45/55; 80 mL/min) to afford 6-(4-chloro-3-fluorophenyl)- 3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-oxazinan-2-one (Example 17a, peak 1, Rt = 2.115 min, 48 mg, 24% yield) and 6-(4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3- oxazinan-2-one (Example 17b, peak 2, Rt = 2.367 min, 47 mg, 23% yield) both as white solids. Example 17a: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.74 - 8.72 (m, 2H), 8.41 (s, 1H), 7.93 - 7.91 (m, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.56 (dd, J = 10.4, 2.0, Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 5.70 - 5.67 (m, 1H), 4.18 - 4.08 (m, 1H), 4.04 - 3.95 (m, 1H), 2.48 - 2.44 (m, 1H), 2.37 - 2.29 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 374.0 Example 17b: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.74 - 8.72 (m, 2H), 8.41 (s, 1H), 7.93 - 7.91 (m, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.56 (dd, J = 10.4, 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 5.70 - 5.66 (m, 1H), 4.15 - 4.08 (m, 1H), 4.05 - 3.96 (m, 1H), 2.48 - 2.44 (m, 1H), 2.38 - 2.29 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 373.9 Examples 18a and 18b

Step 1: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one

To a solution of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one (200 mg, 0.54 mmol) in MeCN (3 mL) was added Selectfluor (285 mg, 0.80 mmol) at 0 ^oC. Then the mixture was stirred at room temperature for 1.5 hrs. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 x 3 mL). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 20% ethyl acetate (25% ethanol) in petroleum ether) to afford 6-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H- pyrazol-5-yl)-1,3-oxazinan-2-one (110 mg, 53% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 391.0 Step 2: Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5- yl)-1,3-oxazinan-2-one (Ex. 18a & 18b)

6-(4-Chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2- one (110 mg, 0.28 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 µm), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 40/60; 80 mL/min) to afford 6-(4-chloro-3-fluorophenyl)- 3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Example 18a, peak 1, Rt = 1.303 min, 27 mg, 25% yield) and 6-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5- yl)-1,3-oxazinan-2-one (Example 18b, peak 2, Rt = 2.024 min, 28 mg, 25% yield) both as white solids. Example 18a: ¹H NMR (DMSO-d_6, 400 MHz): δ 8.71 (d, J = 5.2 Hz, 2H), 7.71 - 7.67 (m, 3H), 7.57 - 7.54 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 5.69 - 5.66 (m, 1H), 3.89 - 3.84 (m, 1H), 3.77 - 3.75 (m, 1H), 2.42 - 2.22 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 391.0 Example 18b: ¹H NMR (DMSO-d_6, 400 MHz): δ 8.71 (d, J = 5.2 Hz, 2H), 7.71 - 7.67 (m, 3H), 7.56 - 7.54 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 5.69 - 5.66 (m, 1H), 3.90 - 3.83 (m, 1H), 3.77 - 3.72 (m, 1H), 2.42 - 2.22 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 391.0. Examples 19a and 19b

To a mixture of 4-bromo-1H-pyrazole (1.0 g, 6.80 mmol) and K₂CO₃ (2.82 g, 20.41 mmol) in DMF (25 mL) was added 4-fluoropyridine (0.99 g, 10.21 mmol). The mixture was stirred at 100 ^oC for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (25 mL) and filtered to afford 4-(4-bromo-1H-pyrazol-1-yl) pyridine (600 mg, 39% yield) as a white solid, which was used directly in next step without further purification. Step 2: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1,3-oxazinan-2- one

To a mixture of methyl 4-(4-bromo-1H-pyrazol-1-yl)pyridine (195 mg, 0.87 mmol) and 6-(4- chloro-3-fluorophenyl)-1,3-oxazinan-2-one (200 mg, 0.87 mmol) in 1,4-dioxane (4 mL) was added DMEDA (0.02 mL, 0.17 mmol), CuI (33 mg, 0.17 mmol) and K₃PO₄ (555 mg, 2.61 mmol). The resulting mixture was stirred at 110 ^oC for 16 hrs under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 70% ethyl acetate in petroleum ether) to afford 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1,3- oxazinan-2-one (200 mg, 62% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 373.0. Step 3: Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1, 3-

6-(4-Chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1, 3-oxazinan-2-one (200 mg, 0.54 mmol) was separated by chiral SFC (Chiralpak IH (250 mm x 30 mm, 10 µm), Supercritical CO₂ / MeOH + 0.1% NH₄OH = 55/45; 150 mL/min) to afford 6-(4-chloro-3-fluorophenyl)-3-(1- (pyridin-4-yl)-1H-pyrazol-4-yl)-1, 3-oxazinan-2-one (Example 19a, peak 1, Rt = 3.790 min, 43.1 mg, 22% yield) and 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1, 3-oxazinan-2-one (Example 19b, peak 2, Rt = 3.962 min, 40.9 mg, 20% yield) as a white solid. Example 19a: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.79 (s, 1H), 8.64 (d, J = 6.4 Hz, 2H), 8.17 (s, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.68 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 10.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.63 - 5.59 (m, 1H), 3.92 - 3.84 (m, 1H), 3.78 - 3.72 (m, 1H), 2.45 - 2.40 (m, 1H), 2.35 - 2.25 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 372.9 Example 19b: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.79 (s, 1H), 8.64 (d, J = 6.4 Hz, 2H), 8.17 (s, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.68 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 10.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.63 - 5.59 (m, 1H), 3.93 - 3.83 (m, 1H), 3.79 - 3.72 (m, 1H), 2.44 - 2.40 (m, 1H), 2.35 - 2.24 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 372.9 Examples 20a and 20b

Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propan-1-amine

To a mixture of 3-amino-1-(4-chloro-3-fluoro-phenyl)propan-1-ol (4.4 g, 21.6 mmol) and imidazole (4.4 g, 64.8 mmol) in DCM (50mL) was added an TBSCl (4.9 g, 32.4 mmol). The mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 57-87% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to give 3-((tert- butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propan-1-amine (1.0 g, 15% yield) as a yellow oil. ¹H NMR (DMSO-d₆, 400 MHz): δ = 7.54 (t, J = 8.0 Hz 1H), 7.35 - 7.25 (m, 1H), 7.22 - 7.14 (m, 1H), 5.90 - 5.85 (m, 1H), 2.63 - 2.51 (m, 2H), 1.77 - 1.55 (m, 2H), 0.85 (s, 9H), 0.08 - 0.01 (s, 3H), -0.15 (s,3H). Step 2: Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propyl)-3- (pyridin-4-yl)isothiazol-5-amine

To a mixture of 5-bromo-3-(4-pyridyl)isothiazole (260 mg, 1.08 mmol) and 3-((tert- butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propan-1-amine (514 mg, 1.62 mmol) in 2- methyl-2-butanol (16 mL) was added Cs₂CO₃ (1.05 g, 3.24 mmol) and Brettphos Pd G3 (98 mg, 0.11 mmol). The mixture was stirred at 110 ^oC for 16 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 50% EtOAc in petroleum ether) to give N-(3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propyl)-3-(pyridin-4- yl)isothiazol-5-amine (350 mg, 89% yield) as yellow oil. LCMS: (ESI, m/z) [M+H]⁺ = 478.2 Step 3: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)isothiazol-5-yl)amino)propan-1- ol

To a mixture of N-(3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propyl)-3- (pyridin-4-yl)isothiazol-5-amine (350 mg, 0.73 mmol) in THF (10 mL) was added TBAF (1.0 M in THF, 1.46 mL, 1.46 mmol). The mixture was stirred at room temperature for 5 hours under nitrogen atmosphere. The mixture was diluted with EtOAc (20 mL) and washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 80% EE (25% ethanol in ethyl acetate) in petroleum ether) to give 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4- yl)isothiazol-5-yl)amino)propan-1-ol (200 mg, 75% yield) as a colorless oil. LCMS: (ESI, m/z) [M+H]⁺ = 364.1 Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazol-5-yl)-1,3-oxazinan-2- one

To a solution of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)isothiazol-5- yl)amino)propan-1-ol (200 mg, 0.35 mmol) and DIPEA in DMF (5 mL) was added CDI (112. mg, 0.69 mmol). The mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. The residue was purified by reverse phase chromatography (acetonitrile: 50-80% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazol-5-yl)- 1,3-oxazinan-2-one (100 mg, 47% yield) as a white solid. Step 5: Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazol-5-yl)-1,3-

6-(4-Chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazol-5-yl)-1,3-oxazinan-2-one (130 mg, 0.33 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 60/40; 80 mL/min) to afford 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4- yl)isothiazol-5-yl)-1,3-oxazinan-2-one (20a, peak 1, Rt = 1.659 min, 45.1 mg, 35% yield) and 6-(4- chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazol-5-yl)-1,3-oxazinan-2-one (20b, peak 2, Rt = 2.771 min, 44.3 mg, 34% yield) both as white solid. Example 20a: ¹H NMR (DMSO-d₆, 400 MHz): δ = 8.71 (d, J = 5.6 Hz, 2H), 7.99 (d, J = 6.0 Hz, 2H), 7.84 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.38 (d, J = 8.8 Hz, 1H), 5.82 - 5.72 (m, 1H), 4.16 - 4.03 (m, 2H), 2.59 - 2.53 (m, 1H), 2.48 - 2.38 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 389.9 Example 20b: ¹H NMR (DMSO-d₆, 400 MHz): δ = 8.71 (d, J = 5.2 Hz, 2H), 7.99 (d, J = 5.6 Hz, 2H), 7.84 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.42 - 7.33 (m, 1H), 5.84 - 5.71 (m, 1H), 4.16 - 4.03 (m, 2H), 2.59 - 2.53 (m, 1H), 2.48 - 2.38 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 389.9 Example 21

A mixture of Zinc (10.31 g, 157.67 mmol), 1,2-dibromoethane (1.1 mL, 12.61 mmol) and chlorotrimethylsilane (1.6 mL, 12.61 mmol) in THF (200 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. Then to the mixture was added a solution of ethyl 2-bromo-2,2- difluoroacetate (19.20 g, 94.6 mmol) and 4-chloro-3-fluorobenzaldehyde (10.0 g, 63.07 mmol) in THF (100 mL) dropwise at room temperature. The resulting mixture was heated at 75 °C for 2 h. After cooling to room temperature, the reaction was quenched with ice / water (200 mL) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with water (200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 3% EtOAc in petroleum ether) to give ethyl 3-(4-chloro-3- fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (9.00 g, 50% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.42 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 9.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 5.20 - 5.14 (m, 1H), 4.34 (q, J = 7.2 Hz, 2H), 2.64 (s, 1H), 1.33 (t, J = 7.2 Hz, 3H).

A mixture of ethyl 3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (9.00 g, 31.84 mmol) and NH₃ (7 M in methanol, 45.49 mL, 318.43 mmol) was stirred at room temperature for 4 hours. The mixture was concentrated to give crude 3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3- hydroxypropanamide (8.00 g, 99% yield) as a white solid, which was used directly for the next step without further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.06 (s, 1H), 7.92 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 10.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 5.6 Hz, 1H), 5.19-5.11 (m, 1H).

To a mixture of 3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3-hydroxypropanamide (8.0 g, 31.54 mmol) in THF (160 mL) under nitrogen atmosphere was added BH₃-Me₂S (10 M, 22.08 mL, 220.80 mmol) dropwise at 0 °C. The resulting solution was stirred at 80 °C for 16 hours. After cooling to room temperature, the reaction was quenched with MeOH (60 mL) and then resulting mixture concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 3% methanol + 1% NH₄OH in dichloromethane) to give 3-amino-1-(4-chloro- 3-fluorophenyl)-2,2-difluoropropan-1-ol (3.70 g, 49% yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.57 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 10.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.03 - 4.97 (m, 1H), 3.09 - 2.98 (m, 1H), 2.91 - 2.80 (m, 1H).

To a solution of 3-amino-1-(4-chloro-3-fluorophenyl)-2,2-difluoropropan-1-ol (1.60 g, 6.68 mmol) and DIPEA (5.82 mL, 33.39 mmol) in DMA (30 mL) then added CDI (2.17 g, 13.35 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (SiO₂, 10% - 50% EE (EtOAc/EtOH = 3:1) in petroleum ether) to give 6-(4-chloro-3- fluorophenyl)-5,5-difluoro-1,3-oxazinan-2-one (1.6 g, 90% yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.01 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 10.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 5.94 (d, J = 21.6 Hz, 1H), 3.89 - 3.73 (m, 1H), 3.70 - 3.59 (m, 1H). Step 5: Synthesis of 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1-((2-

To a solution of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (230 mg, 0.65 mmol), 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-1,3-oxazinan-2-one (241 mg, 0.91 mmol) in 1,4-dioxane (10 mL) was added K₃PO₄ (276 mg, 1.3 mmol) and tBuBrettPhos Pd G3 (56 mg, 0.06 mmol). The mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL) and then the organic layer was washed with water (10 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep - TLC (50% ethyl acetate in petroleum ether) to afford 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (100 mg, 29% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 539.2 Step 6: Synthesis of 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-

A solution of 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (100 mg, 0.19 mmol) in 5% TFA / HFIP (2.90 mL, 1.90 mmol) at room temperature for 16 h. The mixture was concentrated and the residue was diluted with EtOAc (6 mL). The organic layer was adjusted to pH = 8 with saturated NaHCO₃ solution (2 mL). The organic layer was washed with brine (3 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 34-64% / 0.05%NH₄OH + 10 mM NH₄HCO₃ in water) to give 6-(4- chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (15.5 mg, 20 % yield) as a white solid. Example 21: ¹H NMR (DMSO-d₆, 400 MHz):δ = 13.54 (s, 1H), 8.66 (d, J = 4.8 Hz, 2H), 7.80 - 7.72 (m, 3H), 7.52 (d, J = 10.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 6.20 (d, J = 21.6 Hz, 1H), 4.52 - 4.40 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 409.0 Examples 22a and 22b

A mixture of Zinc (4.2 g, 64.24mmol), 1,2-dibromoethane (0.14mL, 1.6mmol) and TMS-Cl (0.21 mL, 1.66 mmol) in THF (50 mL) was stirred at 50 °C for 0.5 h under nitrogen atmosphere. After cooling to room temperature, a solution of 4-chloro-3-fluorobenzaldehyde (5.0 g, 31.53 mmol) and ethyl 2-bromo-2-fluoroacetate (4.47 mL, 37.84 mmol) in THF (10mL) was added dropwise. After addition, the reaction was heated at 90 °C for 0.5 h. After cooling to room temperature, the reaction was quenched with 1M HCl solution and adjusted pH to 4-6. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0-15% EtOAc in petroleum ether) to afford ethyl 3-(4-chloro-3- fluorophenyl)-2-fluoro-3-hydroxypropanoate (5 g, 56% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.44 - 7.37 (m, 1H), 7.27 - 7.21 (m, 1H), 7.15 - 7.10 (m, 1H), 5.18 - 5.08 (m, 1H), 5.06 - 4.91 (m, 1H), 4.30 - 4.19 (m, 2H), 3.23 - 2.95 (m, 1H), 1.30 - 1.21 (m, 3H).

To a solution of ethyl 3-(4-chloro-3-fluorophenyl)-2-fluoro-3-hydroxypropanoate (5.0 g, 18.89 mmol) in MeOH (5 mL) was added NH₃ solution (7 M in MeOH, 20 mL, 140 mmol). The resulting solution was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give 3-(4-chloro-3-fluorophenyl)-2-fluoro-3-hydroxypropanamide (4.2 g, 94 % yield) as a white solid. The crude product was directly used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆): δ 7.60 - 7.50 (m, 2H), 7.47 - 7.12 (m, 3H), 6.14 - 6.03 (m, 1H), 5.13 - 4.89 (m, 2H).

To a solution of 3-(4-chloro-3-fluorophenyl)-2-fluoro-3-hydroxypropanamide (4.2 g, 17.83 mmol) in THF (45 mL) was added BH₃-Me₂S solution (10 M, 10 mL, 100 mmol) dropwise at room temperature under nitrogen atmosphere. Then the reaction mixture was heated at 80 °C for 2 h. After cooling to room temperature, the reaction was quenched with methanol (70 mL) and then stirred room temperature for 4 h. The mixture was concentrated under reduced pressure to give the crude residue, which was purified by flash column chromatography (SiO₂, 0-6% MeOH (0.1% NH₃·H₂O) in DCM) to afford 3-amino-1-(4-chloro-3-fluorophenyl)-2-fluoropropan-1-ol (2 g, 49% yield) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆): δ 7.55 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 10.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.85 - 4.72 (m, 1H), 4.52 - 4.31 (m, 1H), 2.80 - 2.67 (m, 2H). LCMS: (ESI, m/z) [M+H]⁺ = 222.0 Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one C^{DI (4 equiv} ₎

To a solution of 3-amino-1-(4-chloro-3-fluorophenyl)-2-fluoropropan-1-ol (2.0 g, 9.02 mmol) and DIPEA (2.5 mL, 14.04 mmol) in DMA (25 mL) was added CDI (5.8 g, 35.77mmol) at 0 ^oC. The resulting mixture was stirred at room temperature for 12 h. Then DMAP (70 mg, 0.57 mmol) was added and the mixture was stirred at 100 °C for 2 h. After cooling to room temperature, H₂O (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 0-45% (EtOAc/EtOH = 3/1) in petroleum ether) to afford trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3- oxazinan-2-one (1 g crude) and cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one (0.4 g crude). The crude trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one (1.4 g) was purified by reverse phase chromatography (acetonitrile: 25-55% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one (590 mg, 26 % yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.71 (t, J = 8.0 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.43 (d, J = 2.0, 10.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.77 - 5.69 (m, 1H), 5.38 - 5.21 (m, 1H), 3.40 - 3.33 (m, 1H), 3.21 - 3.05 (m, 1H). The crude cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one (0.4 g) was further purified ^{by reverse phase chromatography (acetonitrile: 25-55% / 0.05% NH} _{4OH + 10 mM NH4HCO3 in} water) to afford cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one (200 mg, 9% yield) as a white solid. 1.6,

A mixture of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (750 mg, 2.12 mmol), trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one (800 mg, 3.23 mmol), tBuBrettPhos Pd G3 (120 mg, 0.14 mmol) and K₃PO₄ (1.0 g, 4.71 mmol) in 1,4-dioxane (15mL) was heated at 110°C for 12 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂,0-20% (EtOAc / EtOH = 3:1) in petroleum ether) to give trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (450 mg, 16% yield) as a light yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 521.2 Step 6a: Synthesis of trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-

A solution of trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (400 mg, 0.77 mmol) in 5% TFA/HFIP (10 mL) at room temperature for 12 hrs. Then the reaction residue was poured into saturated NaHCO₃ solution (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 44-74% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)-1,3-oxazinan-2-one (21 mg, 8% yield) as a white solid. Example 22a^{: 1}H NMR (400 MHz, DMSO-d₆): δ 13.43 (s, 1H), 8.64 (d, J = 6.0 Hz, 2H), 7.75 - 7.70 (m, 3H), 7.56 - 7.51 (m, 1H), 7.29 - 7.24 (m, 1H), 7. 18 (s, 1H), 5.99 - 5.91 (m, 1H), 5.68 - 5.52 (m, 1H), 4.29 - 4.14 (m, 1H), 3.84 - 3.67 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 391.0 Step 6b: Synthesis of Cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-

Cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan- 2-one (23b) was prepared using the general procedure described for the preparation of trans-6-(4- chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (23a) by replacing trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one with cis-6-(4-chloro-3- fluorophenyl)-5-fluoro-1,3-oxazinan-2-one in Step 5. The title compound was purified by reverse phase chromatography (acetonitrile: 44-74% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (6.7 mg, 8% yield) as a white solid. Example 22b: ¹H NMR (400 MHz, DMSO-d₆): δ 13.35 (br s, 1H), 8.67 - 8.62 (m, 2H), 7.77 - 7.74 (m, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 5.94 (d, J = 29.2 Hz, 1H), 5.52 (d, J = 46.8 Hz, 1H), 4.38 - 4.29 (m, 1H), 4.28 - 4.13 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 390.9

A solution of 2-bromo-1-(4-chloro-3-fluorophenyl)ethan-1-one (4 g, 15.91 mmol) and PPh₃ (4.17 g, 15.91 mmol) in toluene (30 mL) was stirred at 80 ^oC for 16 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filter cake was wash with toluene (10 mL x 3) to afford (2-(4-chloro-3-fluorophenyl)-2-oxoethyl)triphenylphosphonium bromide (7.6 g, 90% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 433.0 Step 2: Synthesis of 1-(4-chloro-3-fluorophenyl)-2-(oxetan-3-ylidene)ethan-1-one

A solution of (2-(4-chloro-3-fluorophenyl)-2-oxoethyl)triphenylphosphonium bromide (7.6 g, 14.79 mmol) in DCM (10 mL) was added NaOH (1 M, 30 mL, 29.59 mmol) at room temperature. After stirring for at room temperature 2 h, the mixture was diluted with H₂O (5 mL) and extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford 6.4 g crude. Then the 6.4 g crude was dissolve in THF (60 mL), and oxetan-3-one (1.28 g, 17.74 mmol) was added to at 25 ^oC. The mixture was stirred at 70 ^oC for 16 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 0-10% ethyl acetate in petroleum ether) to afford 1-(4-chloro-3-fluorophenyl)-2-(oxetan-3-ylidene)ethan-1-one (2.2 g, 66% yield) as white solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.76 - 7.63 (m, 2H), 7.56 - 7.50 (m, 1H), 6.78 - 6.74 (m, 1H), 5.70 - 5.65 (m, 2H), 5.49 - 5.41 (m, 2H). Step 3: Synthesis of 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)amino)oxetan-3-yl)ethan-1-one

To a stirred solution of 3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-amine (848 mg, 5.29 mmol) and TEA (223 mg, 2.21 mmol) in acetonitrile (3 mL) was added a solution of 1-(4-chloro-3- fluorophenyl)-2-(oxetan-3-ylidene)ethan-1-one (1 g, 4.41 mmol) in MeCN (10 mL) slowly at 0 ^oC. The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO₂, 0-50% ethyl acetate in petroleum ether) to afford 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)amino)oxetan-3-yl)ethan-1-one (800 mg, 46% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.44 (d, J = 5.6 Hz, 2H), 7.99 (d, J = 9.6 Hz, 1H), 7.84 - 7.89 (m, 1H), 7.75 - 7.83 (m, 1H), 7.16 (d, J = 5.6 Hz, 2H), 4.56 (d, J = 6.0 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H), 3.75 (s, 2H), 3.14 (s, 1H), 2.03 (s, 6H). LCMS: (ESI, m/z) [M+H]⁺ = 387.0 Step 4: Synthesis of 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-

To a stirred solution of 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)amino)oxetan-3-yl)ethan-1-one (800 mg, 2.07 mmol) in THF (10 mL) was added LiAlH4 (2.5 M in THF, 0.9 mL, 2.25 mmol) slowly at 0 ^oC under nitrogen atmosphere. After stirring at at 0 ^oC for 1 h, the reaction was quenched with H₂O (0.1 mL), 15% NaOH solution (0.1 mL) and H₂O (0.3 mL) at 0 ^oC. After 5 min, anhydrous Na₂SO₄ was added. After 30 min, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 0-50% (ethyl acetate / ethanol = 3/1) in petroleum ether) to afford 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)amino)oxetan-3-yl)ethan-1-ol (468 mg , 54% yield) as a yellow solid. LCMS: (ESI, m/z) [M+H]⁺ = 389.1 Step 5: Synthesis of 8-(4-chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-

To a solution of 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)amino)oxetan-3-yl)ethan-1-ol (438 mg, 1.13 mmol) and N-ethyl-N-isopropyl-propan-2-amine (582 mg, 4.51 mmol) in DMF (10 mL) was added CDI (365 mg, 2.25 mmol) at room temperature. The reaction was stirred at 100 ^oC for 16 h. After cooling to room temperature, the mixture was quenched with NH₄Cl (10 mL), diluted with H₂O (5 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 0-50% Ethyl acetate in petroleum ether) to afford 8-(4-chloro-3-fluorophenyl)-5-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5-azaspiro[3.5]nonan-6-one (321mg, 67% yield) as yellow oil. LCMS: (ESI, m/z) [M+H+2]⁺ = 417.1 Step 6: Chiral Separation of 8-(4-Chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)-2,7-dioxa-5-azaspiro[3.5]nonan-6-one (Ex 23a & 23b)

8-(4-Chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5- azaspiro[3.5]nonan-6-one (321 mg, 0.77 mmol) was separated by chiral SFC (Chiralcel OD (250 mm x 30 mm, 10 µm), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 60/40; 150 mL/min) to afford 8-(4- chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5-azaspiro[3.5]nonan- 6-one (Ex 23a, peak 1, Rt = 1.831 min, 101.4 mg, 31% yield) and 8-(4-chloro-3-fluorophenyl)-5-(3- (pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5-azaspiro[3.5]nonan-6-one (Ex 23b, peak 2, Rt = 2.013 min, 77.5 mg, 24% yield) both as white solids. Example 23a: ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 - 8.48 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.36 - 7.29 (m, 3H), 5.28 (d, J = 10.8 Hz, 1H), 5.15 (d, J = 7.6 Hz, 1H), 4.94 (d, J = 7.2 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H), 4.44 (d, J = 7.6 Hz, 1H), 2.84 - 2.76 (m, 4H), 2.74 - 2.68 (m, 3H), 2.43 - 2.35 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 415.1 Example 23b: ¹H NMR (400 MHz, DMSO-d₆): δ 8.55 - 8.49 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.36 - 7.29 (m, 3H), 5.28 (d, J = 10.8 Hz, 1H), 5.15 (d, J = 7.6 Hz, 1H), 4.94 (d, J = 7.2 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H), 4.44 (d, J = 7.6 Hz, 1H), 2.83 - 2.75 (m, 4H), 2.73 - 2.68 (m, 3H), 2.43 - 2.35 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 415.1

Examples 24a and 24b

Step 1: Synthesis of 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propanenitrile

To a solution of MeCN (5.13 mL, 98.71 mmol) in THF (200 mL) at -78 ^oC was added n-BuLi (39.48 mL, 98.71 mmol) dropwise under nitrogen atmosphere. After stirring at -78 ^oC for 30 min, a solution of ethyl 4-chloro-3-fluoro-benzoate (10.0 g, 49.36mmol) in THF (10 mL) was added dropwise at -78 ^oC. After stirring at -78 ^oC for 1 h, the reaction mixture was quenched with saturated NH₄Cl solution (50 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give crude 3- (4-chloro-3-fluoro-phenyl)-3-oxo-propanenitrile (9.7 g) as a brown oil, which was used directly in next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 2.0, 10.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 2.80 (d, J =2.4 Hz, 2H), 1.77 - 1.75 (m, 3H). Step 2: Synthesis of crude 4-amino-2-(4-chloro-3-fluoro-phenyl) butan-2-ol

To a solution of 3-(4-chloro-3-fluoro-phenyl)-3-hydroxy-butanenitrile (1 g, 4.68 mmol) in THF (20 mL) under nitrogen atmosphere was added BH₃-Me₂S (4.68 mL, 46.81mmol) dropwise at 0 ^oC. The reaction mixture was stirred at room temperature for 0.5 h and then stirred at 60 ^oC for 16 h. After cooling to 0 ^oC, the reaction was quenched with MeOH (5 mL) and the heated at 60 ^oC for 1 h. The mixture was concentrated to give crude 4-amino-2-(4-chloro-3-fluoro-phenyl) butan-2-ol (1 g) as a brown oil, which was used directly in next step without further purification. LCMS: (ESI, m/z) [M+H]⁺ = 218.1

To a solution of 4-amino-2-(4-chloro-3-fluorophenyl)butan-2-ol (1.0 g, 4.59 mmol) and TEA (1.28 mL, 9.19 mmol) in DCM (20 mL) was add Cbz-Cl (0.79 mL, 5.51 mmol) dropwise at 0 ^oC under nitrogen atmosphere. After stirring at room temperature for 16 h, the reaction was quenched with water (20 mL). The aqueous phase was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 25% ethyl acetate in petroleum ether) to afford benzyl (3-(4-chloro-3-fluorophenyl)-3- hydroxybutyl)carbamate (800 mg, 62% yield) as white oil. LCMS: (ESI, m/z) [M-OH]⁺ = 334.2

To a solution of benzyl (3-(4-chloro-3-fluorophenyl)-3-hydroxybutyl)carbamate (800 mg, 2.27 mmol) in anhydrous DMF (10 mL) under nitrogen atmosphere was added NaH (60% in mineral oil, 91 mg, 2.27 mmol) at 0 ^oC. After stirring at 0 ^oC for 30 min, the reaction mixture was warmed to room temperature and then stirred at room temperature for 16 h. The reaction was quenched with saturated. NH₄Cl solution (20 mL) and extrated with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0-15% ethyl acetate in petroleum ether) to 4-(4-chloro-3-fluorophenyl)-4-methylpiperidin-2- one (450 mg, 82% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.45 - 7.36 (m, 1H), 7.19 (dd, J = 2.4, 10.4 Hz, 1H), 7.11 (dd, J = 2.4, 8.8 Hz, 1H), 5.74 - 5.59 (m, 1H), 3.37 - 3.27 (m, 1H), 3.09 - 3.00 (m, 1H), 2.32 - 2.22 (m, 1H), 2.21 - 2.10 (m, 1H), 1.68 (s, 3H). Step 5: Synthesis of 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl) ethoxy) ethyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one

To a mixture of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (500 mg, 1.41 mmol), 4-(4-chloro-3-fluorophenyl)-4-methylpiperidin-2-one (378 mg, 1.55 mmol) in 1,4-dioxane (20 mL) was added DMEDA (25 mg, 0.28 mmol), CuI (54 mg, 0.28 mmol) and K₂CO₃ (900 mg, 4.23 mmol). The mixture was stirred at 110 ^oC for 16 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 50% ethyl acetate in petroleum ether) to afford 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl) ethoxy) ethyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (45 mg, 69% yield) as yellow oil. LCMS: (ESI, m/z) [M+H]⁺ = 517.1 Step 6: Synthesis of 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one

A mixture of 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (500 mg, 0.97 mmol) in 5% TFA / HFIP solution (6 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL), and then was adjusted to pH = 8 with saturated NaHCO₃ solution. The organic phase was separated, and the aqueous phase was extracted with DCM (5 mL x 2). The combines organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 39-69% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2- one (200 mg, 53% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 387.0 Step 7: Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-

6-(4-Chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2- one (200 mg, 0.52 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um); Supercritical CO₂ / EtOH + 0.1% NH₄OH = 40/60; 45 mL/min) to afford 6-6-(4-chloro-3- fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 24a, 63.2 mg, peak 1, Rt = 1.308 min, 32% yield) and 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 24b, 46 mg, peak 2, Rt = 1.769 min, 23% yield) both as white solid. Example 24a: ¹H NMR (400 MHz, DMSO-d₆): δ 13.30 (s, 1H), 8.62 (d, J = 6.4 Hz, 2H), 7.71 - 7.68 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.51 (dd, J = 1.6, 10.8 Hz, 1H), 7.30 (dd, J = 2.4, 8.8 Hz, 1H), 7.12 (s, 1H), 3.97 - 3.86 (m, 1H), 3.43 - 3.37 (m, 1H), 2.72 - 2.61 (m, 1H), 2.44 - 2.34 (m, 1H), 1.65 (s, 3H). LCMS: (ESI, m/z) [M+H]⁺ = 387.0 Example 24b: ¹H NMR (400 MHz, DMSO-d₆): δ 13.30 (s, 1H), 8.62 ( d, J = 6.8 Hz, 2H), 7.70 (d, J = 6.4 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.30 (dd, J = 2.4, 8.8 Hz, 1H), 7.12 ( s, 1H), 3.98 - 3.87 (m, 1H), 3.41 - 3.37 (m, 1H), 2.72 - 2.61 (m, 1H), 2.45 - 2.31 (m, 1H), 1.65 (s, 3H). LCMS: (ESI, m/z) [M+H]⁺ = 387.0 Examples 25a and 25b

Step 1: Synthesis of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3- methylpyridine

To a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.0 g, 2.81 mmol), 3-methylpyridine-4-boronicacid (384 mg, 2.81 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added K₂CO₃ (1.16 g, 8.42 mmol) and Pd(dppf)Cl₂ (205 mg, 0.28 mmol). The reaction mixture was stirred at 100 ^oC for 2 hrs under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (1% methanol in dichloromethane) to give 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3- methylpyridine (460 mg, 44 % yield) as a brown solid. LCMS: (ESI, m/z) [M+H]⁺ = 368.0 Step 2: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1-((2-

To a solution of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3- methylpyridine (500 mg, 1.36 mmol), 6-(4-chloro-3-fluoro-phenyl)-1,3-oxazinan-2-one (467 mg, 2.04 mmol) in 1,4-dioxane (10 mL) was added K₂CO₃ (563 mg, 4.07 mmol), DMEDA (0.03 mL, 0.27 mmol) and CuI (52 mg, 0.27 mmol) at room temperature. The reaction mixture was stirred at 110 ^oC for 16 hrs under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 50% ethyl acetate in petroleum ether) to afford 6-(4-chloro-3- fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one (400 mg, 57 % yield) as a yellow oil. Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3- oxazinan-2-one

A solution of 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (560 mg, 1.12 mmol) in 15% TFA/HFIP (10 mL) at room temperature for 3 hrs. The mixture was concentrated and adjusted to pH = 8 with NaHCO₃ (10 mL), and then ethyl acetate (10 mL) was added. The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 40-70% / 0.1% NH4HCO3 in water) to afford 6-(4- chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (210 mg, 51% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 386.9 Step 4: Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-

6-(4-Chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2- one (210 mg, 0.56 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 60/40; 80 mL/min) to give crude product 160 mg peak 1 and 50 mg peak 2. The peak 1 was repurified by reverse phase chromatography (acetonitrile: 28-58% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(3- methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 25a, Rt = 1.965 min, 66.3 mg, 31% yield) and 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2- one (Ex 25b, Rt = 2.809 min, 59 mg, 28 % yield) both as a white solid. Example 25a: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.06 (br s, 1H), 8.61 - 8.40 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.57 - 7.42 (m, 2H), 7.35 - 7.33 (m, 1H), 6.92 (s, 1H), 5.62-5.58 (m, 1H), 4.08 - 3.98 (m, 1H), 3.94 - 3.82 (m, 1H), 2.45 - 2.30 (m, 4H), 2.28 - 2.17 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 386.9 Example 25b: ¹H NMR (DMSO-d₆, 400 MHz): δ 13.05 (s, 1H), 8.55 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.35 - 7.33 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.65 - 5.55 (m, 1H), 4.08 - 3.98 (m, 1H), 3.95 - 3.80 (m, 1H), 2.45 - 2.32 (m, 4H), 2.31 - 2.19 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 386.9 Example 26

To a solution of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (11.2 g, 40.4 mmol) and pyridin-4-ylboronic acid (4.97 g, 40.4 mol) in 1,4-dioxane (150 mL) and water (30 mL) was added 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (2.96 g, 4.04 mmol) and K₂CO₃ (16.75 g, 121.2 mmol). The resulting mixture was heated at 110 ^oC for 16 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, 30% ethyl acetate in petroleum ether) to 4-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine (8.74 g, 61% yield) as a brown solid. LCMS: (ESI, m/z) [M+H]⁺ = 276.2

To a solution of 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine (8.24 g, 29.92 mmol) in THF (140 ml) at -78 ^oC was added n-BuLi (2.5 M, 15.56 mL, 38.89 mmol) dropwise under nitrogen atmosphere. After stirring at -78 ^oC for 30 min, a solution of NBS (6.92 g, 38.89 mmol) in THF (20 mL) was added dropwise at -78 ^oC. After stirring at -78 ^oC for 4 hours, the reaction was quenched by adding water (30 mL) at 0 ^oC, and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, 30% ethyl acetate in petroleum ether) to give 4-(2-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine (3.4 g, 30 % yield) as brown solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.67 (d, J = 6.0 Hz, 2H), 7.53 (d, J = 5.6 Hz, 2H), 7.29 (s, 1H), 5.33 (s, 2H), 3.72 (t, J = 8.0 Hz, 2H), 0.98 (t, J = 8.0 Hz, 2H), 0.02 (s, 9H). LCMS: (ESI, m/z) [M+H]⁺ = 354.0 Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(5-(pyridin-4-yl)-1-((2-

To a solution of 4-(2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine (400 mg, 1.13 mmol) and 6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (389 mg, 1.69 mmol) in 1,4-dioxane (7 mL) was added K₂CO₃ (390 mg, 2.8 mmol), Pd₂(dba)₃ (207 mg, 0.23 mmol), Brettphos (121 mg, 0.23 mmol) and Brettphos Pd G3 (102 mg, 0.11 mmol). The resulting mixture was heated at 110 ^oC for 16 h under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 50% ethyl acetate in petroleum ether) to give 6-(4-chloro-3- fluorophenyl)-3-(5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1,3- oxazinan-2-one (55 mg, 10% yield) as a brown solid. LCMS: (ESI, m/z) [M+H]⁺ = 503.1 Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-(pyridin-4-yl)-1H-imidazol-2-yl)-1,3-oxazinan-

A solution of 6-(4-chloro-3-fluorophenyl)-3-(5-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1,3-oxazinan-2-one (55 mg, 0.11 mmol) in 5% TFA in HFIP (2 mL) was stirred at room temperature for 2 hours. The mixture was diluted with DCM (5 mL), and then was adjusted pH = 8 with saturated aqueous NaHCO₃ solution. The organic phase was separated, and the aqueous phase was extracted with DCM (5 mL x 2). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (10% Methyl alcohol in DCM) to give the crude product, which was further purified by reverse phase chromatography (acetonitrile: 38-68% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to give 6-(4-chloro-3-fluorophenyl)-3-(4-(pyridin-4-yl)-1H-imidazol-2- yl)-1,3-oxazinan-2-one (Ex.26, 13.1 mg, 32% yield). Example 26: ¹H NMR (DMSO-d₆, 400 MHz): δ 12.06 (br s, 1H), 8.48 (d, J = 6.0 Hz, 2H), 7.73 - 7.65 (m, 4H), 7.57 - 7.54 (m, 1H), 7.38 - 7.33 (m, 1H), 5.68 - 5.62 (m, 1H), 4.24 - 4.17 (m, 1H), 3.99 - 3.91 (m, 1H), 2.43 - 2.38 (m, 1H), 2.34 - 2.24 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 373.0 Examples 27a and 27b

Step 1: Synthesis of 1-phenyl-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)propan-1-one

To a stirred solution of 3-chloro-1-phenyl-propan-1-one (600 mg, 3.56 mmol), K₂CO₃ (1.97 g, 14.23 mmol), 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.4 g, 7.12 mmol) and KI (1.7 g, 10.67 mmol) in MeCN (25 mL) at room temperature. The mixture was stirred at 70 °C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 3% methanol in dichloromethane) to afford 1-phenyl-3-((3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)amino)propan-1-one (1.0 g, 30% yield) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.49 - 8.46 (m, 2H), 7.98 - 7.96 (m, 2H), 7.67 - 7.63 (m, 1H), 7.56 - 7.52 (m, 2H), 7.25 - 7.20 (m, 2H), 3.17 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 2.02 (s, 6H).

To a solution of 1-phenyl-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)propan-1-one (1.0 g, 3.42 mmol) in MeOH (100 mL) was added NaBH₄ (420 mg, 11.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated NH₄Cl (3 mL), filtered and concentrated. The residue was purified by flash column chromatography (SiO₂, 3% methanol in dichloromethane) to afford 1-phenyl-3-[[3-(4-pyridyl)-1- bicyclo[1.1.1]pentanyl]amino]propan-1-ol (600 mg, 60% yield) as a yellow oil. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.50 - 8.45 (m, 2H), 7.34 - 7.30 (m, 4H), 7.23 - 7.21 (m, 3H), 4.67 - 4.64 (m, 1H), 3.34 (s, 1H), 2.60 (t, J = 6.8 Hz, 2H), 1.98 (s, 6H), 1.75 - 1.67 (m, 2H). Step 3: Synthesis of 6-phenyl-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2-one

To a solution of 1-phenyl-3-[[3-(4-pyridyl)-1-bicyclo[1.1.1]pentanyl]amino]propan-1-ol (200 mg, 0.68 mmol) in DMF (6 mL) were added DIPEA (0.34 mL, 2.04 mmol) and CDI (165 mg, 1.02 mmol). The reaction was stirred at room temperature for 16 hrs. The mixture was purified by reverse phase chromatography (acetonitrile: 28-58% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford 6-phenyl-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2-one (105 mg，48% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 321.0 Step 4: Chiral Separation of 6-Phenyl-3-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentanyl]-1,3-oxazinan-2-one

6-Phenyl-3-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentanyl]-1,3-oxazinan-2-one (100 mg, 0.31 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm,10 um), CO2 / EtOH + 0.1% NH4OH = 60/40; 80 mL/min) to afford 6-phenyl-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2- one (Example 27a, peak 1, Rt = 1.966 min, 42 mg, 42% yield) and 6-phenyl-3-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2-one (Example 27b, peak 2, Rt = 2.458 min, 37 mg, 37% yield) both as white solid. Example 27a: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.51 (d, J =5.6 Hz, 2H), 7.44 - 7.36 (m, 5H), 7.28 (d, J = 5.6 Hz, 2H), 5.37 - 5.34 (m, 1H), 3.48 - 3.42 (m, 1H), 3.38 - 3.32 (m, 1H), 2.42 -2.32 (m, 6H), 2.28 - 2.20 (m, 1H), 2.15 - 2.00 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 321.0 Example 27b: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.51 (d, J =5.6 Hz, 2H), 7.44 - 7.36 (m, 5H), 7.28 (d, J = 5.6 Hz, 2H), 5.37 - 5.34 (m, 1H), 3.47 - 3.40 (m, 1H), 3.38 - 3.32 (m, 1H), 2.42 - 2.32 (m, 6H), 2.29 - 2.20 (m, 1H), 2.10 - 1.98 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 321.0 Example 28

To a RBF equipped with a stir bar, 4-(tert-butoxycarbonylamino)-2-oxabicyclo[2.1.1]hexane- 1-carboxylic acid (1000 mg, 4.1 mmol, 1 equiv.) and MeOH (50 mL) were added followed by a couple drops of sulfuric acid. The mixture was stirred until complete consumption of the starting materials was confirmed by LCMS analysis. Upon completion, amberlyst A21 resin (free base) was added to remove residual acid, and the mixture was filtered and concentrated. This gave methyl 4- (tert-butoxycarbonylamino)-2-oxabicyclo[2.1.1]hexane-1-carboxylate (812 mg, 3.2 mmol, 77% Yield) as a white solid. LCMS (ESI) [M-tBu+H]⁺ = 202.150. ¹H NMR (400 MHz, CDCl3) δ 5.10 (s, 1H), 3.89 (s, 2H), 3.79 (s, 3H), 2.45 (s, 2H), 2.22 – 2.12 (m, 2H), 1.45 (s, 9H). Step 2: Synthesis of tert-butyl (1-(4-hydroxyhepta-1,6-dien-4-yl)-2-oxabicyclo[2.1.1]hexan-4- yl)carbamate

To a RBF equipped with a stir bar, methyl 4-(tert-butoxycarbonylamino)-2- oxabicyclo[2.1.1]hexane-1-carboxylate (1000 mg, 3.9 mmol, 1 equiv.) and THF (20 mL) were added. To a separate flask cooled to 0 °C, allylmagnesium bromide (1 mol/L) in diethyl ether (20 mL, 20 mmol, 5 equiv) was added. To this solution, the solution of ester in THF was slowly added dropwise. The reaction was stirred for 10 min at 0 °C then allowed to warm to room temperature and stirred for an additional 20 min. The reaction was quenched with sat. aq. NH₄Cl then extracted with DCM. The organic fractions were dried over MgSO₄, filtered, and concentrated. Purification via column (0 to 100% iPrOAc in heptane) gave tert-butyl N-[1-(1-allyl-1-hydroxy-but-3-enyl)-2- oxabicyclo[2.1.1]hexan-4-yl]carbamate (625 mg, 2.0 mmol, 52% Yield). ¹H NMR (400 MHz, CDCl3) δ 6.00 – 5.81 (m, 2H), 5.15 (s, 2H), 5.12 (d, J = 3.8 Hz, 2H), 5.03 (s, 1H), 3.79 (s, 2H), 2.47 – 2.29 (m, 4H), 2.08 (s, 2H), 2.02 – 1.85 (m, 2H), 1.47 (s, 9H).

To a vial equipped with a stir bar, tert-butyl N-[1-(1-allyl-1-hydroxy-but-3-enyl)-2- oxabicyclo[2.1.1]hexan-4-yl]carbamate (1700 mg, 5.5 mmol, 1 equiv.) and 9:1 DCM:MeOH (55 mL) were added. The mixture was cooled to -78 °C and ozone was bubbled through the solution until the mixture turned blue (~10 min). At this time, the ozone flow was stopped N2 was bubbled through the mixture until it was colorless, then triphenylphosphine (polymer supported) (21000 mg, 331 mmol, 6 equiv.) was added and the mixture was stirred for 30 min at -78 °C. The reaction was warmed to room temperature and stirred for 1 hour. The mixture was filtered through celite and concentrated. The crude material was used in the next step without purification and taken up in MeOH (25 mL). A solution of ammonium acetate (6353 mg, 82 mmol, 15 equiv.) in MeOH (25 mL) was added and the reaction stirred at 50 °C until complete consumption of the starting materials was confirmed by LCMS analysis. Upon completion, the mixture was concentrated directly, then triturated with ether and filtered twice to remove residual ammonium acetate. The filtrate was concentrated. This gave a residue that was triturated with water to give a white suspension which was filtered. The white solid was collected and found to be pure tert-butyl N-[1-(4-pyridyl)-2-oxabicyclo[2.1.1]hexan-4- yl]carbamate (750 mg, 2.7 mmol, 50% Yield). The aqueous filtrate was extracted 4 times with DCM and the organic layers were combined and concentrated. This afforded an additional 360 mg of the desired compound in slightly lower purity (yellow solid). This material was purified via column (5- 10% MeOH in DCM) to afford and additional 250 mg of the desired compound as a white solid (67% total yield over 2 steps). LCMS (ESI) [M+H]⁺ = 277.192. ¹H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 6.3 Hz, 2H), 7.33 (d, J = 4.5 Hz, 2H), 5.18 (s, 1H), 3.93 (s, 2H), 2.47 (s, 2H), 2.23 – 2.14 (m, 2H), 1.47 (s, 9H).

To a vial equipped with a stir bar, tert-butyl N-[1-(4-pyridyl)-2-oxabicyclo[2.1.1]hexan-4- yl]carbamate (250 mg, 0.9 mmol, 1 equiv.) and MeOH (5 mL) were added. In a separate vial, a solution of HCl/MeOH was prepared by adding acetyl chloride (355 mg, 0.322 mL, 4.5 mmol, 5 equiv.) to MeOH (5 mL) slowly dropwise while stirring. This solution was added to that of the boc- protected amine. The mixture was stirred until complete consumption of the starting materials was confirmed by LCMS analysis. Upon completion, the mixture was concentrated to afford 1-(4- pyridyl)-2-oxabicyclo[2.1.1]hexan-4-amine dihydrochloride (212 mg, 0.85 mmol, 94% Yield) as an ^{off-white solid. LCMS (ESI) [M+H]+} _{= 177.200} Steps 6 – 8: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((1-(pyridin-4-yl)-2- oxabicyclo[2.1.1]hexan-4-yl)amino)propan-1-ol (Ex 28)

To a vial equipped with a stir bar, 1-(4-pyridyl)-2-oxabicyclo[2.1.1]hexan-4- amine;dihydrochloride (25 mg, 0.1 mmol, 1 equiv.), paraformaldehyde (6.4 mg, 0.2 mmol, 2 equiv.), 1-(4-chloro-3-fluoro-phenyl)ethanone (26 mg, 0.15 mmol, 1.5 equiv.), and EtOH (0.1 mL) were added. The reaction was heated to 75 °C and stirred overnight. After stirring overnight, 100 uL each of water and MeOH were added to the reaction mixture, which was then cooled to 0 °C and excess sodium borohydride was added. Once all of the ketone was reduced, as confirmed by LCM analysis, the reaction was quenched with 2M HCl (aq) and extracted with DCM (1 mL). The organic layer was back extracted with dilute HCl (aq) and the combined aqueous layers were purified via preparative HPLC (5-50% MeCN in water, 0.01% TFA modifier). This afforded 1-(4-chloro-3-fluoro-phenyl)-3- [[1-(4-pyridyl)-2-oxabicyclo[2.1.1]hexan-4-yl]amino]propan-1-ol as the bis TFA salt. This material was then taken up in DMF (1 mL) and TEA (excess) was added followed by excess CDI. The reaction was heated to 50 °C and stirred until complete consumption of the starting materials was confirmed by LCMS analysis. At this time the reaction was quenched with sat. aq. NaHCO₃ and extracted with DCM. The combined organic fractions were dried over MgSO₄, filtered, and concentrated. Purification via preparative HPLC (5 – 50% MeCN in water) gave 6-(4-chloro-3-fluorophenyl)-3-(1- (pyridin-4-yl)-2-oxabicyclo[2.1.1]hexan-4-yl)-1,3-oxazinan-2-one (Example 28, 5 mg, 0.013 mmol, 12% yield over 3 steps) as a white solid. Example 28: LCMS (ESI) [M+H]⁺ = 389.045/391.020 (3:1). ¹H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.4 Hz, 2H), 7.43 (td, J = 7.2, 1.9 Hz, 1H), 7.33 (d, J = 4.5 Hz, 2H), 7.21 (d, J = 10.2 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 5.30 (d, J = 10.4 Hz, 1H), 4.11 – 3.96 (m, 2H), 3.62 – 3.50 (m, 1H), 3.48 – 3.37 (m, 1H), 2.50 (t, J = 8.0 Hz, 1H), 2.41 (t, J = 9.4 Hz, 1H), 2.37 – 2.25 (m, 3H), 2.20 – 2.07 (m, 1H). Examples 29a and 29b

Step 1: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)amino)propan-1-one

A mixture of 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine (1.0 g HCl salt, 6.24 mmol) and paraformaldehyde (262 mg, 8.74 mmol) and in EtOH (6 mL) was stirred at room temperature for 15 min under nitrogen atmosphere. Then 1-(4-chloro-3-fluorophenyl)ethan-1-one (1.1 g, 6.24 mmol) was added and the mixture was stirred at 75 ℃ for 10 hrs. The reaction mixture was used directly in next step without further purification. Step 2: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-

To a solution of crude 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan- 1-yl)amino)propan-1-one in MeOH (10 mL) was added NaBH4 (1.0 g, 27.07 mmol) portionwise at 0 °C. Then reaction mixture was stirred at room temperature for 2 hrs. The reaction was quenched with 2 M HCl (10 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 35-65% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)amino)propan-1-ol (400 mg, 18% yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.47 (d, J = 5.6 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.35 - 7.32 (m, 1H), 7.23 - 7.21 (m, 3H), 5.57 (s, 1H), 4.70 (t, J = 6.0 Hz, 1H), 2.63 - 2.55 (m, 3H), 1.99 (s, 6H), 1.74 - 1.69 (m, 2H). Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3- oxazinan-2-one

To a solution of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)amino)propan-1-ol (400 mg, 1.15mmol) in DMF (5 mL) was added DIPEA (0.76 mL, 4.61 mmol) and CDI (374 mg, 2.31 mmol). The reaction was stirred at room temperature for 16 hrs. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 35-65% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2-one (400 mg, 93% yield) as a white solid. LCMS: (ESI, m/z) [M+H]⁺ = 373.1 Step 4: Chiral Separation of 6-(4-chloro-3-fluoro-phenyl)-3-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentanyl]-

6-(4-Chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2- one (400 mg, 1.07 mmol) was separated by chiral SFC (Regis (S, S) whelk-O1 (250 mm x 25 mm, 10 m), Supercritical CO₂ / EtOH + 0.1% NH₄OH = 45/55; 8 mL/min) to afford 6-(4-chloro-3-fluoro- phenyl)-3-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentanyl]-1,3-oxazinan-2-one (Example 29a, peak 1, Rt = 2.864 min, 164 mg, 41% yield) and 6-(4-chloro-3-fluoro-phenyl)-3-[3-(4-pyridyl)-1- bicyclo[1.1.1]pentanyl]-1,3-oxazinan-2-one (Example 29b, peak 2, Rt = 3.455 min, 192 mg, 48% yield) both as white solid. Example 29a: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.51 (d, J = 5.2 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 10.4 Hz, 1H), 7.30 - 7.27 (m, 3H), 5.41 - 5.38 (m, 1H), 3.48 - 3.37 (m, 2H), 2.47 - 2.34 (m, 6H), 2.30 - 2.19 (m, 1H), 2.12 - 1.95 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 373.0 Example 29b: ¹H NMR (DMSO-d₆, 400 MHz): δ 8.51 (d, J = 5.2 Hz, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 10.4 Hz, 1H), 7.30 - 7.27 (m, 3H), 5.41 - 5.38 (m, 1H), 3.48 - 3.35 (m, 2H), 2.44 - 2.33 (m, 6H), 2.30 - 2.20 (m, 1H), 2.12 - 1.95 (m, 1H). LCMS: (ESI, m/z) [M+H]⁺ = 373.0 Characterization Table

Preparation of recombinant human SARM1 protein. pRK5 plasmid containing human SARM1 (E26-T274, EC 3.2.2.6) with N-terminal His and C-terminal Avi and Flag tags was transfected into Expi293F^TM cells (ThermoFisher Scientific #A14527) were cultured in Expi293 expression medium at 37 °C, 8% CO2. Cells were seeded at 2.5– 3 × 10⁶ viable cells per ml and transfected with 0.8 mg/ml DNA construct using 1:3 PEI Max transfection reagent (PolySciences #24765). Post transfection, cells were fed and 4mM valproic acid was added. The cells were harvested after 48 h, by centrifuging at 500 × g, 15 min, 4 °C. For purification, cell paste was resuspended in (100 mL per liter of cell paste) ice-cold lysis buffer (50 mM Tris-HCl pH 8.0, 200mM NaCl, 5 % Glycerol, 1.0 mM TCEP (Tris-HCl(2- carboxyethyl)phosphine), 10 Roche Complete EDTA-Free Protease Inhibitor Cocktail Tablets (Millipore Sigma #4693132001) and cells were homogenized then disrupted by double passage using Microfluidizer â Processor (Microfluidics Model M-110Y). Insoluble matter was separated by ultracentrifugation at 40,000 RPM for 1 hour. The soluble supernatant was decanted and passed through a monoclonal ANTI-FLAG^® M2 antibody (Millipore Sigma #F1804). The resin column was equilibrated with Lysis Buffer and the bound protein was eluted by 100 ug/mL of 3X FLAG^® Peptide (Sigma-Aldrich #F4799). The eluent protein was injected on a Superdex 200 16/60 (Amersham Biosciences # GE28-9893-35) column equilibrated in 25 mM Tris pH 8.0, 1 mM TCEP, 150 mM NaCl, 5% Glycerol. LCMS Assay Protocol The enzymatic assay was performed in 384-well polypropylene plate in assay buffer (50 mM Tris pH 7.5, 0.5 mM dithiothreitol, 0.05 %w/v bovine gamma globulin) in a final assay volume of 15 µL. Recombinant full-length SARM1(E26-T274) with a final concentration of 7.5 nM was pre- incubated with the respective compound at 1% DMSO final assay concentration for 15 min at room temperature. The reaction was initiated by addition of 20 µM NAD and 20 µM NMN, final concentrations. After a 45 min room temperature incubation, the reaction was terminated by addition of 60 µL methanol. Samples were diluted in water (4 µL samples + 80 µL water) and nicotinamide concentrations were analyzed by liquid chromatography mass spectrometry using a Waters Acquity UPLC coupled to a AB Sciex 4500 triple quadropole mass spectrometer. Percent inhibition was calculated as (sample – low control)/(high control – low control) x 100. IC50 values were calculated from an 11-point dose response curve using a four-parameter logistic model. Cellular Viability Assay The ability of compounds to rescue cells from SARM1-induced death were tested in HEK cells stably transfected with a doxycycline inducible construct encoding constitutively active form of SARM1 that is missing ARM domain (SAM-TIR). Cell viability was determined 24 hours after addition of doxycycline by measuring ATP levels using a commercially available kit (CellTiter-Glo, Promega). The results of dose-response experiments were normalized to a neutral control (doxycycline plus DMSO) and a blank control (no doxycycline plus DMSO) and fitted to a four- parameter logistic model to calculate EC50 values. References: CellTiter-Glo assay. CellTiter-Glo® 2.0 Assay Technical Manual TM403 (promega.com). Potency Data Table

Automated Hepatocyte Stability Assay Parent compound depletion is measured by comparing the amount of drug at timepoints 60, 120, 180 and 240 min to a reference amount at the initial starting time 0 min. Metabolic stability studies in hepatocytes are performed using cryopreserved primary human, rat, and mouse hepatocytes. Incubations are performed at 1 µM drug concentration and 0.5 million cells mL^-1 at 37°C with 5% CO₂. Hepatocytes are prepared manually by thawing in INVITROGRO HT media and diluted to 1 million cells mL^-1 with DMEM buffer. Compound dilution, incubation, and various liquid handling procedures are carried out using a Tecan Fluent liquid handling system. The automated assay is composed of two separately coded protocols. The first protocol is the compound dilution protocol where test compounds are diluted from stock vials and aliquoted to the incubation plates. The second protocol is the incubation protocol, which adds the hepatocytes, incubates the plates, and quenches the plates at their respective timepoints. In the dilution protocol, compounds at 1 mM in DMSO are diluted 500-fold to 2 µM in a two- step serial dilution using DMEM. Compounds are first diluted to 10 µM by adding 5 µL of test compound to 495 µL DMEM and mixing via aspiration. Subsequently, 200 µL of the 10 µM compound is added to 800 µL DMEM and mixed to reach the target concentration of 2 µM. 50 µL of 2 µM drug is added in triplicate columns to 5 separate round bottom 96-well plates using the Fluent FCA multi-dispense. One plate is allocated for each timepoint (i.e., 0 min, 60 min, 120 min, 180 min, 240 min) being taken during the time course. In the incubation protocol, 50 µL of 1 million cells mL^-1 is added to each well of each plate using wide-bore tips (Tecan Pure, Männedorf, Switzerland). The hepatocytes are placed on an INHECO Thermoshake RM on-deck shaking incubator set at 37°C and 650 rpm to keep the cells in suspension until they are added to each plate. After addition of the cells, the plates are immediately lidded and placed in the attached Thermo Cytomat 2 incubator set at 37°C with 5% CO₂ to be quenched with 200 µL of ACN containing internal standard (IS) at their respective times. The T0 min plate is immediately quenched after hepatocytes are added. The ACN quench solution is kept on an identical on-deck incubator set at 4°C to mitigate evaporation over the course of the experiment. Upon quenching, samples are centrifuged at 3700 rpm for 10 minutes utilizing a below-deck Agilent vSpin centrifuge, and the supernatant is added to a separate plate for LC-MS analysis. Standard 200 µL Tecan MCA tips are assigned per set to aliquot the ACN quench and supernatant and are rinsed in methanol (MeOH) in between each use to prevent cross-timepoint contamination. Permeability Assay Protocols Madin-Darby Kidney cells (MDCKI) were obtained from the ATCC, (Manassas, VA). CRISPR Cas9 was used to knock-out the endogenous canine Mdr1 gene to generate the gMDCK cell line. The human MDR1 and ABCG2 (BCRP) genes were stably overexpressed in the gMDCKI cells. Cells were maintained in Dulbecco’s Modified Eagle Medium supplemented with 10% fetal bovine serum, pen-strep, puromycin and plasmocin before seeding on Millipore Millicell-24 well plates at 2.5 x 10⁵ cells/mL and allowed to grow for 5 days. Prior to the permeability experiment cell monolayers were equilibrated in transport buffer (Hank’s Balanced Salt Solution with 10 mM HEPES, pH 7.4) for 60 minutes at 37°C with 5% CO2 and 95% relative humidity. Test compound dose solutions were prepared at 1 µM in transport buffer containing the monolayer integrity marker lucifer yellow (100 µM). The dose solutions were added to the donor chambers and transport buffer was added to all receiver chambers. The permeability was examined in the apical to basolateral (A:B) and basolateral to apical (B:A) directions. The receiver chambers were sampled at 60, 120, and 180 min and were replenished with fresh transport buffer. Lucifer yellow was measured using a fluorescence plate reader (ex: 425 nm; em: 530 nm) and compound concentrations in the donor and receiving compartments were determined by LC-MS/MS analysis. The apparent permeability (P_app) in the A:B and B:A directions was calculated as follows: P_app = (dQ/dt)•(1/AC₀), Where: dQ/dt = rate of compound appearance in the receiver compartment; A = surface area of the insert; and C₀ = initial substrate concentration at time 0 min. This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is CR⁷ or N; X² is CR⁴, CHR⁴, or N; X³ is absent, CH, CH₂, NH, or S; X⁴ is N, CH₂, CH, NH, O, or S; X⁵ is CR⁸; Y is absent, CR⁵R⁶, or CH₂CH₂, wherein R⁵ and R⁶ are independently H, OH, CN, halo, C_1-6 alkyl, or C_1-6 cycloalkyl, or R⁵ and R⁶, taken together with the carbon to which they are bonded, form a C_3-6 cycloalkyl; Z is CH or N; one of Q¹ and Q² is N and the other is CR⁴; one of Q³ and Q⁴ is N and the other is CR⁴; or Q³ and Q⁴ are CR⁴; R^1a is H or C_{1 6} alkyl; R^1b is selected from C_6-10 aryl, 5- to 10-membered heteroaryl, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, bicyclo[1.1.1]pentan-1-yl, and C_1-6 alkyl substituted with C_6-10 aryl or C_1-6 haloalkoxy; wherein each aryl, heteroaryl, cycloalkyl, and bicyclo[1.1.1]pentan-1-yl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, C_1-6 haloalkyl, and C_3-6 cycloalkyl; or R^1a and R^1b taken together with the carbon to which they are bonded, form a C_3-6 cycloalkyl; R² is H, OH, CN, or C_1-6 alkyl; R³ is selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-6 cycloalkyl, C_6-10 aryl, and 5- to 10- membered heteroaryl; R⁴ is H, halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, or C_1-6 hydroxyalkyl; R⁷ and R⁸ are either absent, or form a -CH₂- bridge between the carbon atoms to which they are attached; represents the point of attachment to the rest of the compound; and represents a single or double bond.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X¹ is CR⁷; X² is CHR⁴; X³ is absent or CH₂; X⁴ is CH₂ or O; X⁵ is CR⁸; and R⁷ and R⁸ form a -CH₂- bridge between the carbon atoms to which they are attached.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X¹ is CR⁷; X² is CHR⁴; X³ is absent; X⁴ is CH₂; X⁵ is CR⁸; and R⁷ and R⁸ form a -CH₂- bridge between the carbon atoms to which they are attached.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X¹ is CR⁷; X² is CHR⁴; X³ is CH₂; X⁴ is O; X⁵ is CR⁸; and R⁷ and R⁸ form a -CH₂- bridge between the carbon atoms to which they are attached.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

7. The compound of claim 6, having Formula (III):

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 6, having Formula (IV):

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 6, having Formula (V):

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 6, having Formula (Va):

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein Ring

compound has Formula (II):

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X¹ is C; X² is N; X³ is NH; and X⁴ is N.

13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X¹ is C; X² is CR⁴; X³ is NH; and X⁴ is N.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X¹ is N; X² is CR⁴; X³ is CH; and X⁴ is N.

15. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X¹ is C; X² is CR⁴; X³ is S; and X⁴ is N.

16. The compound of any one of claims 13-15, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H.

17. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X¹ is N; X² is N; X³ is CH; and X⁴ is N.

18. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X¹ is C; X² is N; X³ is S; and X⁴ is N.

19. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X¹ is C; X² is N; X³ is NH; and X⁴ is CH.16. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H, halo, methyl, or C_1-6 hydroxyalkyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H.

22. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from ,

23. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from ,

24. The compound of claim 11, having Formula (IIa):

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R⁴ .

26. The compound of claim 11, having Formula (IIb):

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 11, having Formula (IIc):

or a pharmaceutically acceptable salt thereof.

28. The compound of claim 11, having Formula (IId):

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 11, having Formula (IIe):

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 11, having Formula (IIf):

or a pharmaceutically acceptable salt thereof.

31. The compound of claim 11, having Formula (IIg):

or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Z is N.

33. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

34. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R³ is H.

35. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R³ is methyl, phenyl, or pyridinyl.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Y is absent.

37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Y is CH₂CH₂.

38. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Y is CR⁵R⁶.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ are independently H, OH, CN, or halo.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ are H.

41. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ is OH or CN.37.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein R² is H, OH, CN, or methyl.

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein R² is H.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R^1a is H or methyl.

45. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R^1a is H.

46. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R^1a and R^1b taken together with the carbon to which they are bonded, form a C_3-6 cycloalkyl.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein R^1b is selected from C_6-10 aryl, 5- to 10-membered heteroaryl, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, and C_1-6 alkyl substituted with C_6-10 aryl or C_1-6 haloalkoxy; wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, C_1-6 haloalkyl, and C_3-6 cycloalkyl.

48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R^1b is selected from C_6-10 aryl, 5- to 10-membered heteroaryl, and C_1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, and C_1-6 haloalkyl.

49. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein R^1b is selected from ,

haloalkyl, and C_3-6 cycloalkyl; and p is 0, 1, 2, 3, or 4.

50. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R^1b is selected from

_{, wherein p is} 1 or 2.

51. The compound of claim 49 or 50, or a pharmaceutically acceptable salt thereof, wherein each R⁹ is independently selected from C_1-6 alkyl, halo, and C_1-6 haloalkyl.

52. The compound of claim 49 or 50, or a pharmaceutically acceptable salt thereof, wherein each R⁹ is independently selected from methyl, halo, and C₁ haloalkyl.

53. The compound of claim 1, having Formula (IIIa) or (IIIb):

or a pharmaceutically acceptable salt thereof, wherein R⁶ is H, OH, or CN.

54. The compound of claim 1, having Formula (IVa) or (IVb):

or a pharmaceutically acceptable salt thereof, wherein R⁶ is H, OH, or CN.

55. The compound of claim 1, having Formula (Va), (Vb), (Vc), (Vd), (Ve) or (Vf)

or a pharmaceutically acceptable salt thereof.

56. The compound of claim 53-54, or a pharmaceutically acceptable salt thereof, wherein R^1a is H and R^1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl, and C1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C_1-6 alkyl, halo, and C_1-6 haloalkyl.

57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently halo.

58. The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof.

59. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H.

60. The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof.

61. The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof.

62. The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof.

63. The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof.

64. The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof.

65. The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof.

66. A compound or a pharmaceutically acceptable salt thereof as provided in Table 1.

67. A pharmaceutical composition comprising the compound of any one of claims 1-66, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

68. The pharmaceutical composition of claim 66, wherein the pharmaceutical composition is formulated for oral administration.

69. The pharmaceutical composition of claim 67, wherein the pharmaceutical composition is formulated for injection.

70. A method of treating or preventing axonal degeneration comprising administering to an individual in need thereof a therapeutically effective amount of the compound of any one of claims 1-66, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 66-68.

71. The method of claim 70, wherein the individual is a human.

72. The method of claim 70 or 71, wherein the individual (i) has a condition characterized by axonal degeneration or (ii) is at risk of developing a condition characterized by axonal degeneration.

73. A method of treating a neurodegenerative disease, the method comprising administering to an individual in need thereof a therapeutically effective amount of the compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 66-68.

74. The method of claim 73, wherein the neurodegenerative disease is selected from ALS, CIPN, peripheral neuropathy, and MS.

75. The method of any one of claims 70-74, wherein the administering is via the oral route.

76. The method of any one of claims 70-74, wherein the administering is via injection.

77. A method of inhibiting SARM1 comprising contacting a biological sample with a therapeutically effective amount of the compound of any one of claims 1-66, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 66-68.