Lactams for use as SARM1 inhibitors

Abstract

This invention relates to lactam 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

LACTAMS FOR USE AS SARM1 INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 588,206 filed on October 5, 2023 and U.S. Provisional Patent Application No.63 / 679,941 filed on August 6, 2024, the contents of both which are incorporated herein by reference in their entirety. FIELD OF THE DISCLOSURE This invention relates to lactam 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 pharmaceutically acceptable salts thereof; P38594-WOwherein:X1is CR7or N; X2is CR4, CHR4, or N; X3is absent, CH, CH2, NH, or S; X4is N, CH2, CH, NH, O, or S; X5is CR8; Y is absent, CR5R6, or CH2CH2, wherein R5and R6are independently H, OH, CN, halo, C1-6alkyl, or C1-6cycloalkyl, or R5and R6, taken together with the carbon to which they are bonded, form a C3-6cycloalkyl; Z is CH or N; one of Q1and Q2is N and the other is CR4; one of Q3and Q4is N and the other is CR4; or Q3and Q4are CR4; R1ais H or C1-6alkyl; R1bis selected from C6-10aryl, 5- to 10-membered heteroaryl, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, bicyclo[1.1.1]pentan-1-yl, and C1-6alkyl substituted with C6-10aryl or C1-6haloalkoxy; 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 C1-6alkyl, halo, C1-6 haloalkyl, C1-6 alkoxy, and C3-6 cycloalkyl; or R1aand R1btaken together with the carbon to which they are bonded, form a C3-6cycloalkyl; R1cis H, F, or C1-6alkyl; R2is H, OH, CN, oxo or C1-6alkyl; R3is selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R4is H, halo, cyano, C1-6haloalkyl, or C1-6hydroxyalkyl; R7and R8are 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 P38594-WOrepresents a single or double bond. Also provided are methods of using the compounds for treatment of SARM1-mediated diseases and indications and methods of making the compounds. 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 (C1-18). In other examples, the alkyl radical is C1-12, C1-10, C1-8, C1-6, C1-5, C1-4, or C1-3. 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 "hydroxyalkyl" refers to alkyl substituted with one hydroxy substituent. The term “alkoxy” refers to –O–alkyl. 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, 1H-indenyl, 2,3-dihydro-1H-indenyl, P38594-WOand the like (see, e.g., Lang’s Handbook of Chemistry (Dean, J. A., ed.) 13thed. 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[2.2.1]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.) 13thed. 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[1,5-b]pyridazinyl, imidazol[1,2-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. P38594-WOIn 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, 1H-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-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 (IIa)-(IIg), Formulas (IIIa)-(IIIc), Formulas (IVa)-(IVc), 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), (IId-5), (IId-6), (IIe-1), (IIe-2), (IIe-3), (IIe-4), (IIe-5), (IIe-6), (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. As 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. As 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 R2is P38594-WOdescribed 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), P38594-WOnapadisylate (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 P38594-WOwhere 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 as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I, and125I. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with3H and14C) 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 as15O,13N,11C and18F 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. P38594-WOSimilarly, 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 P38594-WOdisorder, (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. The term "agonist" as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition. 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 as2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O,17O,18O,32P,33P,35S,18F,36Cl,123I, and125I, respectively. Isotopically-labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated P38594-WO(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 by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and18F 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; P38594-WOwherein:X1is CR7or N; X2is CR4, CHR4, or N; X3is absent, CH, CH2, NH, or S; X4is N, CH2, CH, NH, O, or S; X5is CR8; Y is absent, CR5R6, or CH2CH2, wherein R5and R6are independently H, OH, CN, halo, C1-6alkyl, or C1-6cycloalkyl, or R5and R6, taken together with the carbon to which they are bonded, form a C3-6cycloalkyl; Z is CH or N; one of Q1and Q2is N and the other is CR4; one of Q3and Q4is N and the other is CR4; or Q3and Q4are CR4; R1ais H or C1-6alkyl; R1bis selected from C6-10aryl, 5- to 10-membered heteroaryl, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, bicyclo[1.1.1]pentan-1-yl, and C1-6alkyl substituted with C6-10aryl or C1-6haloalkoxy; 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 C1-6alkyl, halo, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl; or R1aand R1btaken together with the carbon to which they are bonded, form a C3-6cycloalkyl; R1cis H, F, or C1-6alkyl; R2is H, OH, CN, oxo or C1-6alkyl; R3is selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R4is H, halo, cyano, C1-6 haloalkyl, or C1-6 hydroxyalkyl; R7and R8are either absent, or form a -CH2- bridge between the carbon atoms to which they are attached; P38594-WOrepresents 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, X1is CR7; X2is CHR4; X3is absent or CH2; X4is CH2or O; X5is CR8; and R7and R8form a -CH2- bridge between the carbon atoms to which they are attached. In one such embodiment, R4is H. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, X1is CR7; X2is CHR4; X3is absent; X4is CH2; X5is CR8; and R7and R8form a -CH2- bridge between the carbon atoms to which they are attached. In one such embodiment, R4is H. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, X1is CR7; X2is CHR4; X3is CH2; X4is O; X5is CR8; and R7and R8form a - CH2- bridge between the carbon atoms to which they are attached. In one such embodiment, R4is H. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is selected fromX2, X3, X4, Q1, Q2, Q3and Q4are as defined above. In some such embodiments, X1is C or N; X2is CR4or N; X3is CH, NH, or S; and X4is N, CH, NH, or S. In some embodiments Q1 is N and Q2, Q3and Q4are CR4. In one such embodiment, R4is H. According to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ringthe compound has Formula (II):P38594-WOwherein Z, Y, X1, X2, X3, X4, R1a, R1b, R1c, R2, and R3are as defined for Formula (I). According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X1is C; X2is N; X3is NH; and X4is N. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X1is C; X2is CR4; X3is NH; and X4is N, wherein R4is as defined for Formula (I). In one such embodiment, R4is H. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X1is N; X2is CR4; X3is CH; and X4is N, wherein R4is as defined for Formula (I). In one such embodiment, R4is H. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X1is C; X2is CR4; X3is S; and X4is N, wherein R4is as defined for Formula (I). In one such embodiment, R4is H. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X1is N; X2is N; X3is CH; and X4is N. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X1is N; X2is N; X3is CH; and X4is CH. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, X1is C; X2is N; X3is NH; and X4is CH. According to some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, Ring A is selected fromwherein R4is as defined for Formula (I). In one such embodiment, R4is H, halo, or C1-6hydroxyalkyl. In one such embodiment, R4is 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 P38594-WOAccording 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, R1a, R1b, R1c, R2, R3, and R4are as defined for Formula (I). In one such embodiment, R4is 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):(IIb), P38594-WOwherein Z, Y, R1a, R1b, R1c, R2, and R3are 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):(IIc), wherein Z, Y, R1a, R1b, R1c, R2, and R3are 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):(IId), wherein Z, Y, R1a, R1b, R1c, R2, and R3are 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):(IIe), wherein Z, Y, R1a, R1b, R1c, R2, and R3are 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): P38594-WOwherein Z, Y, R1a, R1b, R1c, R2, and R3are 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, R1a, R1b, R1c, R2, and R3are 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, R1a, R1b, R1c, R2, and R3are as defined for Formula I. A ccording to some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound has Formula (IV):P38594-WOwherein Z, Y, R1a, R1b, R1c, R2, and R3are 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, R1a, R1b, R2, and R3are as defined herein. A 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, R1a, R1b, R2, and R3are 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, R3is H, cyclopropyl, phenyl, or pyridinyl. In one such embodiment, R3is 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, Y is absent. P38594-WOAccording 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 R5and R6are as defined for Formula (I). In one such embodiment, R5and R6are independently H, OH, CN, or halo. In one such embodiment, R5and R6are H. In one such embodiment, R5is H and R6is 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, R2is H, OH, CN, oxo or methyl. In some such embodiments, R2is 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, R1ais H or methyl. In some such embodiments, R1ais 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, R1aand R1btaken together with the carbon to which they are bonded, form a C3-6cycloalkyl. 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, R1bis selected from C6-10aryl, 5- to 10-membered heteroaryl, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and C1-6alkyl substituted with C6-10aryl or C1-6haloalkoxy; wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, halo, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl. 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, R1bis selected from C6-10aryl and 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, halo, C1-6alkoxy, and C1-6haloalkyl. P38594-WOAccording 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, R1bis selected from,wherein each R9is independently selected from C1-6alkyl, halo, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl; and p is 0, 1, 2, 3, or 4. In some such embodiments, each R9is independently selected from C1-6alkyl, halo, C1-6haloalkyl, and C1-6alkoxy. In some such embodiments, each R9is independently selected from methyl, halo, C1haloalkyl and methoxy. 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, R1bis selected fromP38594-WOwherein p is 1 or 2. In some such embodiments, each R9is independently selected from C1-6alkyl, halo, C1-6haloalkyl and C1-6alkoxy. In some such embodiments, each R9is independently selected from methyl, halo, C1haloalkyl, and methoxy. 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, R1bis selected fromP38594-WOP38594-WOAccording 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, R1bis selected from P38594-WOAccording 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, R1bis.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, R1cis 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, R1cis F. P38594-WOAccording to some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt thereof, the compound has Formula (IIIa), Formula (IIIb), or Formula (IIIc):wherein R6is H, OH, or CN, and R1a, R1b, and R1care as defined for Formula (I). In one such embodiment, wherein R1ais H and R1bis selected from C6-10aryl and 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, halo, and C1-6haloalkyl. 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 a pharmaceutically acceptable salt thereof, the compound has Formula (IIId):wherein Z, Y, R1a, R1b, R1cand R3are as defined for Formula I. P38594-WOAccording to some embodiments of the compound of Formula (I) or Formula (IV), or a pharmaceutically acceptable salt thereof, the compound has Formula (IVa), Formula (IVb), or Formula (IVc):wherein R6is H, OH, or CN, and R1a, R1b, and R1care as defined for Formula (I). In one such embodiment, wherein R1ais H and R1bis selected from C6-10aryl and 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, halo, and C1-6haloalkyl. 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 a pharmaceutically acceptable salt thereof, the compound has Formula (IVd): P38594-WOwherein Z, Y, R1a, R1b, R1cand R3are as defined for Formula I. According to some embodiments of the compound of Formula (I) or Formula (V), the compound has Formula (Va), (Vb), (Vc), (Vd), (Ve) or (Vf)P38594-WOAccording 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 R1a, R1b, R1c, and R4are as defined for Formula (I). In one such embodiment, R4is H. In one such embodiment, R1cis H or F. 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): P38594-WOwherein R1a, R1b, and R1care 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):P38594-WOwherein R1a, R1b, and R1care 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 R1a, R1b, and R1care 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): P38594-WOwherein R1a, R1b, and R1care 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): P38594-WOwherein R1a, R1b, and R1care 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): P38594-WOwherein R1a, R1b, and R1care 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.P38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOP38594-WOIn another embodiment of the compound of Formula (I), (II), (III), or (IV), the compound is a compound corresponding to Compound of Formula IIa-1 or Compound of Formula IIIa, or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of Formula (I) or Formula (III), the compound is a compound corresponding to Compound 73, Compound 74, Compound 41a or Compound 41b, or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of Formula (I) or Formula (II), the compound is a compound corresponding to Compound 5a, Compound 5b, Compound 14a, Compound 14b, or Compound 50, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is Compound 50. In one embodiment, the compound is Compound 73. In one embodiment, the compound is Compound 74. In one embodiment, the compound is Compound 5a. In one embodiment, the compound is Compound 5b. In one embodiment, the compound is Compound 14a. In one embodiment, the compound is Compound 14b. In one embodiment, the compound is Compound 41a. In one embodiment, the compound is Compound 41b. 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 P38594-WOto 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 enantiomers. In other embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) is a substantially purified enantiomerr. In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) is a substantially purified R- enantiomer. In some other embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) is a substantially purified S- enantiomer. 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 & P38594-WOSons: 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. P38594-WOMETHODS 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 P38594-WOembodiments, 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 P38594-WOSARM1 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 P38594-WOcerebrospinal 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), P38594-WOchronic 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. P38594-WOIn 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 myelinolysis, 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. P38594-WOIn 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 hyperexitability, 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 P38594-WOtangles. 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 P38594-WOor 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 P38594-WO(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 P38594-WOaxonopathy 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 P38594-WOa 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 P38594-WOtherapeutically 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 P38594-WOgamma-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: P38594-WOLippincott, 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 P38594-WOsuitable 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. P38594-WOPharmaceutical 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. P38594-WOIn 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. P38594-WOStill 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 P38594-WOarticle 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 The following abbreviations are used in the Examples: CDI: 1,1-carbonyldiimidazole DCE: dichloroethane DCM: dichloromethane DEA: diethylamine DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMDACH: (1S,2S)-(+)-N,N'-Dimethylcyclohexane-1,2-diamine DMEDA: 1,2-dimethylethylenediamine DMF: dimethylformamide DMSO: dimethylsulfoxide EE: EtOAc / EtOH EtOAc: ethyl acetate P38594-WOEtOH: 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 SEM-Cl: 2-(trimethylsilyl)ethoxymethyl chloride 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. For compounds purified by column chromatography (C.C.), refer to synthetic experimental procedures.P38594-WOP38594-WOP38594-WOP38594-WOP38594-WOLCMS 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 40oC. 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 40oC. 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 40oC. 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 P38594-WOon 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 40oC. 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-pyrazoleStep 1: Synthesis of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleA 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 25oC for 16 hr. The mixture was refluxed at 80oC 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). P38594-WOStep 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). 3,5-dibromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole INT-1 (260 g, 734 mmol, 43.6% yield) was obtained as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ ppm -0.05 - 0.09 (m, 8 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). LCMS: (ESI, m / z) [M+H]+= 355, RT = 0.468 min. Intermediate 2Step 1: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)piperidin-2-one P38594-WOTo a mixture of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (2.0 g, 5.64 mmol), piperidin-2-one (840 mg, 8.47 mmol), and K3PO4(3.6 g, 17 mmol) in 1,4-dioxane (30 mL) was added Brettphos Pd G3 ( 511 mg, 0.56 mmol), Brettphos (606 mg, 1.13 mmol) and Pd2(dba)3(513 mg, 0.56 mmol). The mixture was stirred at 110 ℃ for 16 hours 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 flash column chromatography (SiO2, 50% EtOAc in petroleum ether) to afford 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-one (1 g, 48% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz): δ 8.69 (d, J = 6.0 Hz, 2H), 7.60 (d, J = 6.0 Hz, 2H), 7.18 (s, 1H), 5.38 (s, 2H), 3.94 (t, J = 6.0 Hz, 2H), 3.75 (t, J = 8.0 Hz, 2H), 2.60 (t, J = 6.4 Hz, 2H), 1.98 - 1.89 (m, 4H), 0.965 (t, J = 8.4 Hz, 2H), 0.01 (s, 9H). LCMS: (ESI, m / z) [M+H]+= 529.1 Step 2: Synthesis of 3-(phenylselanyl)-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-oneTo a solution of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)piperidin-2-one (5.0 g, 13.42 mmol) in THF (50 mL) added LDA (10.07 mL, 20.13 mmol) dropwise at -78oC under nitrogen atmosphere. After stirring at -78oC for 1 hour, a solution of benzeneselenenyl bromide (4.75 g, 20.13 mmol) in THF (50 mL) was added. The mixture was stirred at -78oC for 1 hour and then was stirred at room temperature for 16 hours. The reaction mixture was quenched with NH4Cl (10 mL), and the residue was dissolved in DCM (200 mL). The organic phase was washed with water (50 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (SiO2, 0-50% ethyl acetate in petroleum ether) to afford 3-(phenylselanyl)-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)piperidin-2-one (2.8 g, 40% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= P38594-WO373.1 Step 3: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5,6- dihydropyridin-2(1H)-one (INT-2)To a mixture of 3-(phenylselanyl)-1-(3-(pyridin- 4 -yl)-1-((2-(trimethylsilyl) ethoxy) methyl)- 1H-pyrazol-5-yl) piperidin-2-one (5.0 g, 9.48 mmol) and NaHCO3(0.96 g, 11.37 mmol) in methyl alcohol (160 mL) and water (32 mL) was added NaIO4(4.05 g, 18.95 mmol). Then the mixture was stirred at 60oC for 16 h. After cooling to room temperature, the resulting mixture was quenched by NaHCO3(20 mL) and extracted with DCM (300 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0-25% petroleum ether in (Ethyl acetate / ethanol = 3:1)) to afford 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5,6-dihydropyridin- 2(1H)-one (Intermediate 2, 2.4 g, 68% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz): δ 8.70 (d, J = 6.0 Hz, 2H), 7.61 (d, J = 6.0 Hz, 2H), 7.21 (s, 1H), 6.81 - 6.73 (m, 1H), 6.11 - 6.04 (m, 1H), 5.38 (s, 2H), 4.18 (t, J = 6.8 Hz, 2H), 3.79 - 3.71 (m, 2H), 2.58 - 2.44 (m, 2H), 1.01 - 0.93 (m, 2H), 0.02 (s, 9H). LCMS: (ESI, m / z) [M+H]+= 371.1 Intermediate 3Step 1: Synthesis of 4-hydroxy-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)piperidin-2-oneTo a mixture of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (10.0 g, 28 mmol), 4-hydroxypiperidin-2-one (4.87 g, 42 mmol) and K2CO3(11.7 g, 84 mmol) in 1,4- P38594-WOdioxane (120 mL) was added CuI (0.19 mL, 5.64 mmol) and DMEDA (0.61 mL, 5.64 mmol). The mixture was stirred at 110 ℃ for 16 hours 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 flash column chromatography (SiO2, 30% EE (EtOAc / EtOH = 3 / 1) in petroleum ether) to afford 4-hydroxy-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)piperidin-2-one (4.8 g, 44% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz): δ 8.69 (d, J = 6.0 Hz, 2H), 7.60 (d, J = 6.0 Hz, 2H), 7.17 (s, 1H), 5.38 (s, 2H), 4.39 - 4.27 (m, 1H), 4.20 - 4.11 (m, 1H), 3.99 - 3.88 (m, 1H), 3.75 (t, J = 8.0 Hz, 2H), 2.98 - 2.81 (m, 1H), 2.68 - 2.60 (m, 1H), 2.27 - 2.12 (m, 2H), 2.09 - 2.02 (m, 1H), 0.97 (t, J = 8.4 Hz, 2H), 0.01 (s, 9H). LCMS: (ESI, m / z) [M+H]+= 289.3 Step 2: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5,6- dihydropyridin-2(1H)-one (INT-3)To a solution of 4-hydroxy-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-one (4.8 g, 12 mmol) and TEA (5 mL, 37 mmol) in DCM (100 mL) was added Ms2O (3.44 g, 19 mmol). The reaction mixture was stirred at room temperature for 5 hours. Then DBU (3.7 mL, 24 mmol) was added and the mixture was still stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous NH4Cl solution (50 mL). The organic phase was separated, and the aqueous phase was extracted with DCM (50 mL x 2). The combined the organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 20% EE (EtOAc / EtOH =3 / 1) in petroleum ether) to afford 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)- 5,6-dihydropyridin-2(1H)-one (INT-3, 4 g, 79% yield) as a yellow oil.1H NMR (DMSO-d6, 400 MHz): δ 8.69 (d, J = 5.6 Hz, 2H), 7.72 - 7.58 (m, 2H), 7.09 (s, 1H), 6.93 - 6.84 (m, 1H), 6.01 - 5.89 (m, 1H), 5.43 (s, 2H), 4.05 (t, J = 6.8 Hz, 2H), 3.62 (t, J = 6.8 Hz, 2H), 0.95 - 0.71 (m, 2H), -0.07 (s, 9H). LCMS: (ESI, m / z) [M+H]+= 371.3 Intermediate 4P38594-WOStep 1: Synthesis of 4-((tert-butyldimethylsilyl)oxy)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2- oneTo a solution of 4-(4-bromo-1H-pyrazol-1-yl)pyridine (500 mg, 2.23 mmol), 4-((tert- butyldimethylsilyl)oxy)piperidin-2-one (767 mg, 3.35 mmol) in 1,4-dioxane (10 mL) was added DMEDA (0.05 mL, 0.45 mmol), K2CO3(925 mg, 6.69 mmol) and CuI (85 mg, 0.45 mmol). The mixture was stirred at 110 °C 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 afford 4-((tert-butyldimethylsilyl)oxy)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-one (360 mg, 43% yield) as a white solid.1H NMR (CDCl3, 400 MHz): δ 8.80 - 8.59 (m, 3H), 7.90 (s, 1H), 7.81 - 7.73 (m, 2H), 4.33 - 4.25 (m, 1H), 4.03 - 3.92 (m, 1H), 3.75 - 3.65 (m, 1H), 2.81 - 2.71 (m, 1H), 2.66 - 2.56 (m, 1H), 2.18 - 2.02 (m, 2H), 0.89 (s, 9H), 0.11 (d, J = 2.0 Hz, 6H). LCMS: (ESI, m / z) [M+H]+= 373.1A solution of 4-((tert-butyldimethylsilyl)oxy)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin- 2-one (1.0 g, 2.68 mmol) in HCl / MeOH (6 mL, 13 mmol) slowly at room temperature. The mixture was clear, and then became cloudy over the course of 2 minutes. The mixture was concentrated and added NaHCO3saturated solution to adjust pH = 8, then the mixture was concentrate and purified by flash column chromatography (SiO2, 6% MeOH in DCM) to afford 4-hydroxy-1-(1-(pyridin-4-yl)- 1H-pyrazol-4-yl)piperidin-2-one (560 mg, 81% yield) as a white solid.1H NMR (DMSO-d6, 400 MHz): δ 8.83 (s, 1H), 8.70 - 8.60 (m, 2H), 8.22 (s, 1H), 7.92 - 7.81 (m, 2H), 5.11 (d, J = 3.6 Hz, 1H), 4.14 - 4.05 (m, 1H), 3.87 - 3.77 (m, 1H), 3.69 - 3.61 (m, 1H), 2.72 - 2.64 (m, 1H), 2.40 - 2.31 (m, 1H), 2.14 - 2.00 (m, 1H), 1.94 - 1.85 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 259.1 P38594-WOExamples 1a and 1bStep 1: Synthesis of (4-phenyl-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)piperidin-2-one)To a vial equipped with a stir bar was added INT-1 (50 mg, 1 equiv, 0.14 mmol), 4- phenylpiperidin-2-one (74.2 mg, 3.0 equiv, 0.42 mmol), BrettPhos Pd G3 (13.45 mg, 0.1 equiv, 0.014 mmol), and K3PO4(94.5 mg, 3.0 equiv, 0.42 mmol). The reaction was placed under nitrogen and diluted with anhydrous 1,4-dioxane (1.4 mL, 0.1 M). The reaction was stirred at 110oC for 16 h under nitrogen. After cooling to room temperature, the mixture was diluted with water and extracted with DCM / MeOH (3 x 5 mL). The combined organics were dried with MgSO4, filtered, and rotovaped. The crude material (4-phenyl-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)piperidin-2-one) was taken to the next step without further purification. LCMS: (ESI, m / z) [M+H]+= 449.1 Step 2: Synthesis of 4-phenyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-oneTo a vial equipped with a stir bar and 4-phenyl-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one was added TFA (1 mL). The reaction was stirred at room temperature for 1 hour upon which no residual starting material was observed by LCMS. The TFA was evaporated and the material was purified by prep HPLC (XSelect CSH Prep C18, 50 mm x 30 mm, 5 µm), 0.1% Ammonium hydroxide in water / acetonitrile using a gradient of P38594-WO20% to 60% acetonitrile; 60 mL / min, 25oC) to yield 4-phenyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one as a white solid (30.1 mg, 67% yield). LCMS: (ESI, m / z) [M+H]+= 319.10 Step 3: Chiral separation of 4-phenyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex.1a & 1b)4-phenyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (30 mg, 0.094 mmol) was separated by chiral SFC (PIC 200 Chiral (150 mm x 21.2 mm, 5 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 65 / 35; 70 mL / min, 40oC) to afford 4-phenyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Example 1a, peak 1, 12.1 mg) and 4-phenyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Example 1b, peak 2, 8.87 mg) both as white solid. Example 1a:1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.72 (d, J = 5.4 Hz, 2H), 7.35 (m, 4H), 7.25 (tt, J = 6.3, 3.1 Hz, 2H), 4.03 (s, 1H), 3.82 (td, J = 4.81, 11.8, 1H), 3.23 (m, 1H), 2.78 – 2.61 (m, 2H), 2.2–2.03 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 319.10 Example 1b:1H NMR (400 MHz, DMSO) δ 13.32 (s, 1H), 8.63 (d, J = 4.8 Hz, 2H), 7.73 (d, J = 5.6 Hz, 2H), 7.35 (d, J = 5.4 Hz, 4H), 7.30 – 7.20 (m, 2H), 4.02 (bs, 1H), 3.82 (td, J = 11.8, 4.8 Hz, 1H), 2.78 – 2.61 (m, 2H), 2.22 – 2.04 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 319.10Step 1: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-4- (trifluoromethyl)piperidin-2-oneP38594-WOTo a mixture of 4-(trifluoromethyl)piperidin-2-one (400 mg, 2.39 mmol), 4-(5-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)pyridine (1.27 g, 3.59 mmol) in 1,4-dioxane (20 mL) was added DMDACH (0.08 mL, 0.48 mmol), CuI (92 mg, 0.48 mmol) and K2CO3(248 mg, 1.8 mmol). The mixture was stirred at 110oC 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 reverse phase chromatography (acetonitrile: 40-70% / 0.05% NH4OH + 10 mM NH4HCO3 in water) to give 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- triazol-5-yl)-4-(trifluoromethyl)piperidin-2-one (30 mg, 6% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 442.1 Step 2: Synthesis of 1-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-4-(trifluoromethyl)piperidin-2-one (Ex 2)A mixture of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)- 4-(trifluoromethyl)piperidin-2-one (60 mg, 0.14 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 pH = 8 with saturated NaHCO3solution. 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: 13-43% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 1-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-4- (trifluoromethyl)piperidin-2-one (12.7 mg, 30% yield) as a white solid.1H NMR (DMSO-d6, 400 MHz): δ 13.96 (s, 1H), 8.68 (d, J = 6.0 Hz, 2H), 7.90 (d, J = 5.6 Hz, 2H), 4.34 - 4.25 (m, 1H), 3.95 - 3.86 (m, 1H), 3.20 - 3.10 (m, 1H), 2.85 - 2.75 (m, 1H), 2.72 - 2.60 (m, 1H), 2.29 - 2.20 (m, 1H), 2.04 - 1.85 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 311.9. Example 3P38594-WOStep 1: Synthesis of 4-phenyl-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- triazol-5-yl)piperidin-2-oneTo a mixture of 4-phenylpiperidin-2-one (329 mg, 1.88 mmol) and 4-(5-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)pyridine (1.0 g, 2.82 mmol) in 1,4-dioxane (5 mL) was added DMDACH (53 mg, 0.38 mmol), CuI (71 mg, 0.38 mmol) and K2CO3(778 mg, 5.63 mmol). The resulting mixture was stirred at 110oC 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, 0-5% methanol in ethyl acetate) to afford 200 mg crude, which was further purified by preparative-TLC (10% methanol in dichloromethane) to afford 4-phenyl-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (45 mg, 5% yield) as a yellow solid.A solution of 4-phenyl-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- triazol-5-yl)piperidin-2-one (95 mg, 0.21 mmol) in 5% TFA / HFIP solution (5 mL) was stirred at room temperature for 2 hours. The reaction was concentrated, the residue was dissolved in DCM (3 mL), and the pH was adjusted to 8 with saturated NaHCO3 solution. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile: 36-66% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4-phenyl-1-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin- 2-one (27 mg, 39% yield) as a white solid.1H NMR (DMSO-d6, 400 MHz): δ 8.67 - 8.62 (m, 2H), 7.92 - 7.86 (m, 2H), 7.39 - 7.33 (m, 4H), 7.29 - 7.22 (m, 1H), 4.24 - 4.12 (m, 1H), 3.98 - 3.86 (m, 1H), 3.25 - 3.20 (m, 1H), 2.81 - 2.74 (m, 2H), 2.24 - 2.07 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 320.0. P38594-WOExamples 4a and 4bStep 1: Synthesis of tert-butyl 4-(4-chloro-3-fluoro-phenyl)-2-oxo-piperidine-1-carboxylateTo a mixture of tert-butyl 2-oxo-5,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 10.14 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added 4-chloro-3-fluorophenylboronicacid (5.3 g, 30.42 mmol), K2CO3(4.2 g, 30.42 mmol), BINAP (1.26 g, 2.03 mmol), chloro(1,5- cyclooctadiene)rhodium(I)dimer (0.5 g, 1.01 mmol). The reaction mixture was stirred at 80oC for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and diluted with water (50 mL). The organic phase was separated and the aqueous phase was extracted 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 crude was purified by flash column chromatography (SiO2, 20% ethyl acetate in petroleum ether) to afford tert- butyl 4-(4-chloro-3-fluoro-phenyl)-2-oxo-piperidine-1-carboxylate (2.4 g, 72% yield) as a white solid.1H NMR (CDCl3, 400 MHz): δ 7.37 (t, J = 8.0 Hz, 1H), 7.01 (m, J = 6.0 Hz, 1H), 6.96 - 6.92 (m, 1H), 3.93 - 3.85 (m, 1H), 3.66 - 3.57 (m, 1H), 3.18 - 3.06 (m, 1H), 2.88 - 2.79 (m, 1H), 2.62 - 2.52 (m, P38594-WO1H), 2.25 - 2.15 (m, 1H), 1.98 - 1.87 (m, 1H), 1.55 (s, 9H). LCMS: (ESI, m / z) [M+H]+= 254.1 Step 2: Synthesis of 4-(4-chloro-3-fluorophenyl)piperidin-2-oneA mixture of tert-butyl 4-(4-chloro-3-fluoro-phenyl)-2-oxo-piperidine-1-carboxylate (3.0 g, 9.15 mmol) in 5% TFA / HFIP solution (30 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL), and then treated with aqueous saturated NaHCO3until pH = 8. The organic phase was separated, and the aqueous phase was extracted with DCM (10 mL x 2). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 4-(4-chloro-3- fluorophenyl)piperidin-2-one (1.3 g, 62% yield) as a white solid.1H NMR (DMSO-d6, 400 MHz): δ 7.58 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.40 - 7.35 (m, , 1H), 7.20 - 7.15 (m, 1H), 3.26 - 3.16 (m, 2H), 3.13 - 3.04 (m, 1H), 2.43 - 2.25 (m, 2H), 1.93 - 1.76 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 228.1 Step 3: Synthesis of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-oneTo a mixture of 4-(4-chloro-3-fluoro-phenyl)piperidin-2-one (390 mg, 1.71 mmol), 4-(5- bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)pyridine (1.22 g, 3.43 mmol) in 1,4- dioxane (10 mL) was added DMDACH (48 mg, 0.34 mmol), CuI (130 mg, 0.69 mmol) and K2CO3(710 mg, 5.14 mmol). The mixture was stirred at 110 °C 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 (silica gel, 100% ethyl acetate in petroleum ether) to afford 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (100 mg, 12% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+= 502.1 P38594-WOStep 4: Synthesis of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2- oneA mixture of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (140 mg, 0.28 mmol) in 5% TFA / HFIP solution (8 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 treated with aqueous saturated NaHCO3until pH = 8. 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 to afford 4-(4-chloro-3-fluorophenyl)-1-(3- (pyridin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (100 mg, 96%) as a white solid. Step 5: Chiral Separation of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-one (Ex.4a & 4b)4-(4-Chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (130 mg, 0.35 mmol) was separated by chiral SFC (Chiralcel OJ (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 55 / 45; 80 mL / min) to afford 4-(4-chloro-3-fluorophenyl)-1-(3- (pyridin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (Example 4a, peak 1, Rt = 1.890 min, 31.2 mg, 24% yield) and 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (Example 4b, peak 2, Rt = 2.417 min, 25 mg, 19% yield) both as white solid. Example 4a:1H NMR (DMSO-d6, 400 MHz): δ = 13.98 (s, 1H), 8.67 (d, J = 6.0 Hz, 2H), 7.90 (d, J = 6.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.26 - 7.20 (m, 1H), 4.30 - 4.21 (m, 1H), 3.99 - 3.84 (m, 1H), 3.38 - 3.35 (m, 1H), 2.84 - 2.77 (m, 2H), 2.25 - 2.06 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 372.0. Example 4b:1H NMR (DMSO-d6, 400 MHz): δ = 13.98 (s, 1H), 8.67 (d, J = 6.0 Hz, 2H), 7.89 (d, J = 6.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.26 - 7.20 (m, 1H), 4.32 - 4.20 (m, 1H), 3.983.86 (m, 1H), 3.38 - 3.35 (m, 1H), 2.87 - 2.74 (m, 2H), 2.26 - 2.06 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 372.0. P38594-WOExamples 5a and 5bStep 1: Synthesis of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-oneTo a solution of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)- 5,6-dihydropyridin-2(1H)-one (1 g, 2.7 mmol) in dioxane (20 mL) and water (2 mL) was added (4- chloro-3-fluorophenyl)boronic acid (705 mg, 4.05 mmol), BINAP (336 mg, 0.54 mmol), KOH (151 mg, 2.7 mmol) and [Rh(COD)Cl]2(133 mg, 0.27 mmol). The reaction mixture was stirred at 80oC for 16 hrs under nitrogen atmosphere. After cooling to room temperature, ethyl acetate (30 mL) and water (30 mL) were added. The organic layer was separated and washed with brine (20 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (SiO2, 70% ethyl acetate in petroleum ether) to afford 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-one (420 mg, 31% yield) as a brown solid.1H NMR (CDCl3, 400 MHz): δ 8.71 (d, J = 6.0 Hz, 2H), 7.61 (d, J = 6.0 Hz, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.06 (d, J = 10.0 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 5.39 (s, 2H), 4.25 - 4.17 (m, 1H), 3.95 - 3.84 (m, 1H), 3.76 (t, J = 8.4 Hz, 2H), 3.29 - 3.16 (m, 1H), 2.99 - 2.88 (m, 1H), 2.74 - 2.64 (m, 1H), 2.35 - 2.25 (m, 1H), 2.14 - 2.06 (m, 1H), 0.97 (t, J = 8.4 Hz, 2H), 0.01 (s, 9H). LCMS: (ESI, m / z) [M+H]+= 501.1. Step 2: Synthesis of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one P38594-WOA solution of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (370 mg, 0.74 mmol) in 5% TFA / HFIP (8 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and NaHCO3solution (10 mL) were added. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 38-68% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4-(4-chloro-3- fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (140 mg, 51% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 371.0. Step 3: Chiral Separation of 4-(4-Chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Ex.5a & 5b)4-(4-Chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (140 mg) 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 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (Example 5a, peak 1, Rt = 2.293 min, 35.3 mg, 25% yield) and 4-(4- chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Example 5b, peak 2, Rt = 3.226 min, 43.5 mg, 31% yield) both as white solid. Example 5a:1H NMR (DMSO-d6, 400 MHz): δ = 13.34 (s, 1H), 8.64 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.46 (dd, J = 11.2, 2.0 Hz, 1H), 7.28 - 7.15 (m, 2H), 4.12 - 3.99 (m, 1H), 3.87 - 3.75 (m, 1H), 3.30 - 3.22 (m, 1H), 2.79 - 2.64 (m, 2H), 2.23 - 2.04 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 371.0. Example 5b:1H NMR (DMSO-d6, 400 MHz): δ = 13.32 (s, 1H), 8.66 - 8.58 (m, 2H), 7.76 - 7.69 (m, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.45 (dd, J = 10.8, 2.0 Hz, 1H), 7.27 - 7.14 (m, 2H), 4.09 - 3.98 (m, 1H), 3.86 - 3.75 (m, 1H), 3.28 - 3.24 (m, 1H), 2.77 - 2.68 (m, 2H), 2.22 - 2.02 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 371.0. P38594-WOExamples 6a and 6bStep 1: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(6- (trifluoromethyl)pyridin-3-yl)piperidin-2-oneTo a mixture of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)- 5,6-dihydropyridin-2(1H)-one (700 mg, 1.89 mmol) and (6-(trifluoromethyl)pyridin-3-yl)boronic acid (546 mg, 2.86 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added [Rh(COD)Cl]2(98 mg, 0.20 mmol), K2CO3(525 mg, 3.8 mmol) and BINAP (238 mg, 0.38 mmol). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. After cooling to room temperature, ethyl acetate (30 mL) and water (30 mL) were added. The organic layer was separated, washed with brine (20 mL), dried over anhydrous Na2SO4and filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (SiO2, 0-30% (EtOAc / EtOH = 3 / 1) in petroleum ether) to afford 1-(3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(6-(trifluoromethyl)pyridin-3- yl)piperidin-2-one (700 mg crude) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 518.3 Step 2: Synthesis of 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)piperidin- 2-oneA solution of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(6 P38594-WO(trifluoromethyl)pyridin-3-yl)piperidin-2-one (700 mg crude) in 5% TFA / HFIP (8 mL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and NaHCO3solution (10 mL) were added. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 41-71% / 0.1% NH4OH in water) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(6-(trifluoromethyl)pyridin-3- yl)piperidin-2-one (42 mg, 6% yield over 2 steps) as a white solid. LCMS: (ESI, m / z) [M+H]+= 388.0. Step 3: Chiral Separation of 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(6-(trifluoromethyl)pyridin-3- yl)piperidin-2-one (Ex 6a & 6b)1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)piperidin-2-one (50 mg, 0.13 mmol) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 55 / 45; 100 mL / min) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4- (6-(trifluoromethyl)pyridin-3-yl)piperidin-2-one (Example 6a, peak 1, Rt = 1.606 min, 11 mg, 22% yield) and 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)piperidin-2-one (Example 6b, peak 2, Rt = 2.070 min, 12 mg, 24%) both as white solid. Example 6a:1H NMR (400 MHz, DMSO-d6): δ = 13.37 (s, 1H), 8.79 (s, 1H), 8.68 - 8.59 (m, 2H), 8.08 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.29 (s, 1H), 4.16 - 4.05 (m, 1H), 3.89 - 3.79 (m, 1H), 3.46 - 3.42 (m, 1H), 2.85 - 2.74 (m, 2H), 2.29 - 2.13 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 388.0. Example 6b:1H NMR (400 MHz, DMSO-d6): δ = 13.37 (s, 1H), 8.79 (s, 1H), 8.68 - 8.59 (m, 2H), 8.08 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.29 (s, 1H), 4.16 - 4.05 (m, 1H), 3.89 - 3.78 (m, 1H), 3.46 - 3.42 (m, 1H), 2.85 - 2.73 (m, 2H), 2.29 - 2.13 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 388.0. P38594-WOExamples 7a and 7bStep 1: Synthesis of 4-(6-fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)piperidin-2-oneA solution of 4-bromo-1-methyl-1H-pyrazole with 5-bromo-2-fluoropyridine (1.0 g, 2.57 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC, 1.63 g, 4.12 mmol) in t-BuOMe (15 mL) was stirred at room temperature for 5 minutes under nitrogen atmosphere. Then pyridine (0.33 mL, 4.12 mmol) in t-BuOMe (5 mL) was added dropwise at room temperature over 5 minutes. The resulting solution was stirred at room temperature for 20 minutes under nitrogen atmosphere. A pink solid precipitated out during this time. Then the solution was filtered and the filtrate was added into another mixture of 4-bromo-1-methyl-1H-pyrazole (400 mg, 2.48 mmol), NiBr2·dtbbpy (60 mg, 0.12 mmol), phthalimide (146 mg, 0.99 mmol), quinuclidine (483 mg, 4.34 mmol) and Ir(ppy)2(dtbbpy)PF6(34 mg, 0.04 mmol) in DMA (8 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours under 450 nm LED modules at 100% light intensity with maximum fan speed of 1500 rpm stirring rate in a Pennoc Integrated Photoreactor. The reaction was diluted in water (10 mL) and extracted with ethyl acetate (10 mL x 2). 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 P38594-WO(40% EE (ethyl acetate / ethanol=3 / 1) in petroleum ether) to yield 4-(6-fluoropyridin-3-yl)-1-(3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one. Step 2: Synthesis of 4-(6-Fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (700 mg, 1.55 mmol) in 5% TFA / HFIP solution (20 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 treated with aqueous saturated NaHCO3until pH = 8. The organic phase was separated, and the aqueous phase was extracted with DCM (10 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: 17-47% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4-(6- Fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one as a white solid. Step 3: Chiral Separation of 4-(6-Fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-4-(6-Fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (150 mg, 0.44 mmol) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to afford 4-(6-fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (Ex 7a, peak 1, Rt = 2.315 min, 58.2 mg, 38%) and 4-(6-fluoropyridin- 3-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 7b, peak 2, Rt = 3.073 min, 54.7 mg, 36% yield) both as white solid. Example 7a:1H NMR (DMSO-d6, 400 MHz): δ 13.34 (br s, 1H), 8.63 (d, J = 4.0 Hz, 2H), 8.22 (d, J = 2.0 Hz, 1H), 8.06 - 7.96 (m, 1H), 7.73 (d, J = 4.8 Hz, 2H), 7.29 (s, 1H), 7.18 (dd, J = 2.8, 8.4 Hz, 1H), 4.15 - 4.00 (m, 1H), 3.87 - 3.73 (m, 1H), 3.40 - 3.34 (m, 1H), 2.80 - 2.68 (m, 2H), 2.24 - 2.02 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 338.0 P38594-WOExample 7b:1H NMR (DMSO-d6, 400 MHz): δ 13.35 (br s, 1H), 8.63 (d, J = 5.6 Hz, 2H), 8.22 (d, J = 2.4 Hz, 1H), 8.06 - 7.95 (m, 1H), 7.73 (d, J = 6.0 Hz, 2H), 7.29 (s, 1H), 7.18 (dd, J = 2.8, 8.4 Hz, 1H), 4.15 - 4.01 (m, 1H), 3.87 - 3.78 (m, 1H), 3.44 - 3.36 (m, 1H), 2.77 - 2.70 (m, 2H), 2.23 - 2.02 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 338.1 Examples 8a and 8bStep 1: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(4- (trifluoromethyl)phenyl)piperidin-2-oneTo a mixture of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)- 5,6-dihydropyridin-2(1H)-one (1.00 g, 2.70 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (768 mg, 4.05 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added [Rh(COD)Cl]2(133 mg, 0.30 mmol), K2CO3(373 mg, 2.70 mmol) and BINAP (336 mg, 0.54 mmol). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. 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 in petroleum ether) to afford 1-(3-(pyridin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(4-(trifluoromethyl)phenyl)piperidin-2-one (240 mg crude) as a yellow solid, which was used directly in next step without further purification. LCMS: (ESI, m / z) [M+H]+= 517.2 Step 2: Synthesis of 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(4-(trifluoromethyl)phenyl)piperidin-2-one P38594-WOA solution of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(4- (trifluoromethyl)phenyl)piperidin-2-one (240 mg crude) in 5% TFA / HFIP (4 mL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and NaHCO3solution (10 mL) were added. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 45-75% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(4- (trifluoromethyl)phenyl)piperidin-2-one (80 mg, 7% yield over 2 steps) as a white solid. LCMS: (ESI, m / z) [M+H]+= 387.1 Step 3: Chiral Separation of 1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(4- (trifluoromethyl)phenyl)piperidin-2-one (Ex.8a & 8b)1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(4-(trifluoromethyl)phenyl)piperidin-2-one (80 mg, 0.21 mmol) was separated by chiral SFC (Chiralpak AS (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 75 / 25; 150 mL / min) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(4- (trifluoromethyl)phenyl)piperidin-2-one (Example 8a, peak 1, Rt = 3.717 min, 35.4 mg, 44% yield) and 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(4-(trifluoromethyl)phenyl)piperidin-2-one (Example 8b, peak 2, Rt = 4.260 min, 33.1 mg, 41% yield) both as white solid. Example 8a:1H NMR (DMSO-d6, 400 MHz): δ = 13.34 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.79 - 7.66 (m, 4H), 7.58 (d, J = 8.4 Hz, 2H), 7.24 (s, 1H), 4.06 - 3.95 (m, 1H), 3.91 - 3.77 (m, 1H), 3.42 - 3.36 (m, 1H), 2.80 - 2.65 (m, 2H), 2.25 - 2.06 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 387.0 Example 8b:1H NMR (DMSO-d6, 400 MHz): δ = 13.33 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.79 - 7.66 (m, 4H), 7.59 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 4.06 - 3.95 (m, 1H), 3.91 - 3.77 (m, 1H), 3.42 - 3.36 (m, 1H), 2.80 - 2.65 (m, 2H), 2.25 - 2.06 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 387.0. P38594-WOExamples 9a and 9bStep 1: Synthesis of 4-(2-fluorophenyl)-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-oneTo a mixture of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)- 5,6-dihydropyridin-2(1H)-one (300 mg, 0.81 mmol) and (2-fluorophenyl)boronic acid (170 mg, 1.21 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added K2CO3(112 mg, 0.81 mmol), BINAP (101 mg, 0.16 mmol), [Rh(COD)Cl]2(40 mg, 0.08 mmol). The reaction mixture was stirred at 80oC for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (SiO2, 30-60% ethyl acetate in petroleum ether) to afford 4-(2-fluorophenyl)-1-(3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (280 mg, 59% yield) as yellow oil. LCMS: (ESI, m / z) [M+H]+= 467.1P38594-WOA mixture of 4-(2-fluorophenyl)-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-one (280 mg, 0.6 mmol) in 10% TFA / HFIP solution (30 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 mL), and then treated with aqueous saturated NaHCO3until pH = 8. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 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: 37-67% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4-(2-fluorophenyl)-1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (130 mg, 64% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 337.0. Step 3: Chiral separation of 4-(2-Fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one4-(2-Fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (100 mg, 0.30 mmol) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 75 / 25; 50 mL / min) to afford (2-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Ex 9a, peak 1, Rt = 1.448 min, 45.5 mg, 45% yield) and (2-fluorophenyl)-1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 9b, peak 2, Rt =1.691 min, 39.5 mg, 39% yield) both as white solids. Example 9a:1H NMR (DMSO-d6, 400 MHz): δ 13.34 (s, 1H), 8.63 (d, J = 6.4 Hz, 2H), 7.74 - 7.70 (m, 2H), 7.44 - 7.37 (m, 1H), 7.35 - 7.29 (m, 1H), 7.28 - 7.13 (m, 3H), 4.06 - 3.95 (m, 1H), 3.90 - 3.79 (m, 1H), 3.57 - 3.47 (m, 1H), 2.76 - 2.66 (m, 2H), 2.22 - 2.09 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 337.0 Example 9b:1H NMR (DMSO-d6, 400 MHz): δ 13.34 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 6.0 Hz, 2H), 7.44 - 7.37 (m, 1H), 7.35 - 7.29 (m, 1H), 7.28 - 7.13 (m, 3H), 4.08 - 3.98 (m, 1H), 3.90 - 3.80 (m, 1H), 3.58 - 3.46 (m, 1H), 2.74 - 2.68 (m, 2H), 2.20 - 2.11 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 337.0 P38594-WOExample 10To a solution of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5,6- dihydropyridin-2(1H)-one (300 mg, 0.81 mmol) and 1-bromo-2-fluorobenzene (284 mg, 1.62 mmol) in DMF (5 mL) was added Pd2(dba)3(37 mg, 0.04 mmol), Amphos (22 mg, 0.08 mmol), N-Methyldicyclohexylamine (0.35 mL, 1.62 mmol) under nitrogen atmosphere. The reaction mixture was heated at 100oC for 16 hours. After cooling to room temperature, the mixture was diluted with water (5 mL), and extracted with ethyl acetate (20 mL x 3). 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- 30% EE (25% ethanol in ethyl acetate) in petroleum ether) to afford 4-(2-fluorophenyl)-1-(3-(pyridin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5,6-dihydropyridin-2(1H)-one (210 mg, 56% yield) as colorless oil. LCMS: (ESI, m / z) [M+H]+= 465.3 Step 2: Synthesis of 4-(2-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-5,6-dihydropyridin-2(1H)-oneA solution of 4-(2-fluorophenyl)-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 5-yl)-5,6-dihydropyridin-2(1H)-one (210 mg, 0.45 mmol) in 5% TFA in HFIP (8 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to remove TFA. Then the residue was poured into aq. NaHCO3(5 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: 35-65% / 0.05% NH4OH + 10 mM NH4HCO3in water) P38594-WOto give 4-(2-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-5,6-dihydropyridin-2(1H)-one (Ex 10, 22.5 mg, 15% yield) as a white solid. Example 10:1H NMR (DMSO-d6, 400 MHz): δ 13.37 (br s, 1H), 8.63 (d, J = 5.6 Hz, 2H), 7.76 - 7.71 (m, 2H), 7.65 - 7.60 (m, 1H), 7.52 - 7.46 (m, 1H), 7.36 - 7.28 (m, 3H), 6.29 (s, 1H), 4.28 - 4.09 (m, 2H), 3.03 - 2.87 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 334.9. Examples 11a and 11b4-(3,5-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of 9a and 9b by replacing (2- fluorophenyl)boronic acid with (3,5-difluorophenyl)boronic acid in Step 1. Step 3: Chiral separation of 4-(3,5-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-4-(3,5-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (135 mg, 0.38 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um), Supercritical CO2 / i- PrOH + 0.1% NH4OH = 40 / 60; 60 mL / min) to afford 30 mg crude of peak 1 and 4-(4-fluorophenyl)- 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex. 11b, peak 2, Rt = 2.267 min, 27.9 mg, 20% yield) both as white solids. 30 mg peak 1 was repurified by reverse phase chromatography (acetonitrile: 42-72% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4-(3,5-difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Ex 11a), peak 1, Rt = 1.552 min, 15.2 mg, 11% yield) as a white solid. P38594-WOExample 11a:1H NMR (DMSO-d6, 400 MHz): δ 13.42 - 13.29 (m, 1H), 8.63 (d, J = 4.0 Hz, 2H), 7.72 (d, J = 4.4 Hz, 2H), 7.28 (s, 1H), 7.15 - 7.06 (m, 3H), 4.13 - 4.00 (m, 1H), 3.83 - 3.76 (m, 1H), 3.31 - 3.25 (m, 1H), 2.80 - 2.63 (m, 2H), 2.22 - 2.03 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 355.0 Example 11b:1H NMR (DMSO-d6, 400 MHz): δ 13.40 - 13.18 (m, 1H), 8.69 - 8.54 (m, 2H), 7.72 (d, J = 4.8 Hz, 2H), 7.28 (s, 1H), 7.17 - 7.02 (m, 3H), 4.13 - 4.00 (m, 1H), 3.85 - 3.73 (m, 1H), 3.30 - 3.22 (m, 1H), 2.78 - 2.64 (m, 2H), 2.22 - 2.02 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 355.0Step 1 — 2: Synthesis of 4-(3-Fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one4-(3-Fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and 9b by replacing (2- fluorophenyl)boronic acid with (3-fluorophenyl)boronic acid in Step 1. Step 3: Chiral Separation of 4-(3-Fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 12a & 12b)P38594-WO4-(3-Fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (200 mg, 0.59 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / i-PrOH + 0.1% NH4OH = 45 / 55; 80 mL / min) to afford 4-(3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Ex. 12a, peak 1, Rt = 0.927 min, 70 mg, 35% yield) and 4-(3-fluorophenyl)-1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 12b, peak 2, Rt = 1.250 min, 55 mg, 28% yield) both as white solids. Example 12a:1H NMR (DMSO-d6, 400 MHz): δ 13.33 (br s, 1H), 8.67 - 8.59 (m, 2H), 7.76 - 7.69 (m, 2H), 7.45 - 7.32 (m, 1H), 7.26 - 7.15 (m, 3H), 7.09 - 7.04 (m, 1H), 4.08 - 3.95 (m, 1H), 3.84 - 3.77 (m, 1H), 3.28 - 3.20 (m, 1H), 2.78 - 2.61 (m, 2H), 2.23 - 2.01 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 337.0 Example 12b:1H NMR (DMSO-d6, 400 MHz): δ 13.35 (br s, 1H), 8.65 (d, J = 6.0 Hz, 2H), 7.89 (d, J = 6.0 Hz, 2H), 7.45 - 7.32 (m, 1H), 7.26 - 7.20 (m, 1H), 4.13 - 3.98 (m, 1H), 3.89 - 3.72 (m, 1H), 3.28 - 3.20 (m, 1H), 2.81 - 2.62 (m, 2H), 2.24 - 2.01 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 337.0 Examples 13a and 13b4-(4-Fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and 9b by replacing 4-bromo-1-methyl- 1H-pyrazole with 1-bromo-4-fluorobenzene in Step 1. P38594-WOStep 3: Chiral Separation of 4-(4-Fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one4-(4-Fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (60 mg, 0.18 mmol) was separated by chiral SFC (Cellulose-2 (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 65 / 35; 150 mL / min) to afford 4-(4-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Ex 13a, peak 1, Rt = 4.050 min, 16.2 mg, 27% yield) and 4-(4-fluorophenyl)-1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 13b, peak 2, Rt = 4.538 min, 8.7 mg, 14% yield) both as white solids. Example 13a:1H NMR (DMSO-d6, 400 MHz): δ 13.35 (s, 1H), 8.63 (d, J = 4.0 Hz, 2H), 7.72 (d, J = 4.4 Hz, 2H), 7.38 (dd, J = 5.6, 8.4 Hz, 2H), 7.28 (s, 1H), 7.17 (t, J = 8.8 Hz, 2H), 4.11 - 3.97 (m, 1H), 3.87 - 3.74 (m, 1H), 3.29 - 3.19 (m, 1H), 2.79 - 2.58 (m, 2H), 2.21 - 1.99 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 336.9 Example 13b:1H NMR (DMSO-d6, 400 MHz): δ 13.36 (s, 1H), 8.64 (d, J = 3.6 Hz, 2H), 7.73 (d, J = 4.4 Hz, 2H), 7.39 (dd, J = 5.6, 8.4 Hz, 2H), 7.29 (s, 1H), 7.18 (t, J = 8.8 Hz, 2H), 4.11 - 3.98 (m, 1H), 3.89 - 3.74 (m, 1H), 3.29 - 3.20 (m, 1H), 2.78 - 2.61 (m, 2H), 2.22 - 2.02 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 337.0 Examples 14a and 14bStep 1 — 2: Synthesis of 4-(3,4-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one P38594-WO4-(3,4-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and 9b by replacing (2- fluorophenyl)boronic acid with (3,4-difluorophenyl)boronic acid in Step 1. Step 3: Chiral Separation of 4-(3,4-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-4-(3,4-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (170 mg, 0.47 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / i- PrOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to afford 4-(3,4-difluorophenyl)-1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (Ex 14a, peak 1, Rt = 0.915 min, 51 mg, 30% yield) and 4-(3,4- difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 14b, peak 2, Rt = 1.290 min, 50 mg, 30% yield) both as white solids. Example 14a:1H NMR (DMSO-d6, 400 MHz): δ 13.35 (br s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 6.0 Hz, 2H), 7.54 - 7.34 (m, 2H), 7.28 (br s, 1H), 7.22 - 7.17 (m, 1H), 4.11 - 4.01 (m, 1H), 3.84 - 3.72 (m, 1H), 3.30 - 3.20 (m, 1H), 2.79 - 2.64 (m, 2H), 2.22 - 2.01 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 355.0 Example 14b:1H NMR (DMSO-d6, 400 MHz): δ 13.36 (s, 1H), 8.64 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 6.0 Hz, 2H), 7.53 - 7.35 (m, 2H), 7.28 (br s, 1H), 7.23 - 7.16 (m, 1H), 4.12 - 4.02 (m, 1H), 3.86 - 3.73 (m, 1H), 3.29 - 3.21 (m, 1H), 2.78 - 2.64 (m, 2H), 2.24 - 2.00 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 355.0 P38594-WOExamples 15a and 15bStep 1 — 2: Synthesis of 4-(3-Methoxyphenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one4-(3-Methoxyphenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and 9b by replacing (2- fluorophenyl)boronic acid with (3-methoxyphenyl)boronic acid in Step 1. Step 3: Chiral Separation of 4-(3-Methoxyphenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-4-(3-Methoxyphenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (140 mg, 0.40) was separated by chiral SFC (Chiralcel OD (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to afford 4-(3-methoxyphenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Ex 15a, peak 1, Rt = 2.502 min, 56.6 mg, 40% yield) and 4-(3-methoxyphenyl)-1- (3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 15b, peak 2, Rt = 2.924 min, 62.5 mg, 44% yield) both as white solids. Example 15a:1H NMR (DMSO-d6, 400 MHz): δ 13.32 (br s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 6.0 Hz, 2H), 7.31 - 7.12 (m, 2H), 6.94 - 6.87 (m, 2H), 6.84 - 6.78 (m, 1H), 4.08 - 3.95 (m, P38594-WO1H), 3.85 - 3.77 (m, 1H), 3.75 (s, 3H), 3.26 - 3.15 (m, 1H), 2.73 - 2.63 (m, 2H), 2.21 - 2.06 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 349.1 Example 15b:1H NMR (DMSO-d6, 400 MHz): δ 13.33 (br s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 6.0 Hz, 2H), 7.32 - 7.14 (m, 2H), 6.94 - 6.87 (m, 2H), 6.85 - 6.78 (m, 1H), 4.07 - 3.96 (m, 1H), 3.86 - 3.78 (m, 1H), 3.76 (s, 3H), 3.23 - 3.17 (m, 1H), 2.73 - 2.66 (m, 2H), 2.21 - 2.05 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 349.1 Examples 16a and 16bTo a mixture of 2-chloro-5-(trifluoromethyl)pyrazine (2.0 g, 11 mmol), tert-butyl 6-oxo-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.3 g, 16 mmol) in 1,4-dioxane (15 mL) and H2O (5 mL) was added Pd(dppf)Cl2(800 mg, 1.1 mmol) and Na2CO3(3.5 g, 33 mmol). The mixture was stirred at 110oC 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, 20% EE (Ethyl acetate / ethanol=3 / 1) in petroleum ether) to afford 4-(5-(trifluoromethyl)pyrazin-2-yl)-5,6- dihydropyridin-2(1H)-one (1.4 g, 37% yield) as a yellow oil. P38594-WO1H NMR (CDCl3, 400 MHz): δ 9.02 (s, 1H), 8.98 (s, 1H), 6.78 (d, J = 1.6 Hz, 1H), 6.02 (s, 1H), 3.70 - 3.59 (m, 2H), 3.10 - 2.93 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 243.9To a solution of 4-(5-(trifluoromethyl)pyrazin-2-yl)-5,6-dihydropyridin-2(1H)-one (1.0 g, 4.11 mmol) in MeOH (20 mL) was added Pd / C (10%, 875 mg, 0.82 mmol). The mixture was stirred at room temperature for 16 hours under H2(45 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 20-50% / 0.225% FA in water) to afford 4-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-2- one (200 mg, 20% yield) as a white solid.1H NMR (CDCl3, 400 MHz): δ 8.93 (s, 1H), 8.64 (s, 1H), 5.98 (s, 1H), 3.53 - 3.37 (m, 3H), 2.91 - 2.65 (m, 2H), 2.28 - 2.03 (m, 2H). Step 3: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(5- (trifluoromethyl)pyrazin-2-yl)piperidin-2-oneTo a mixture of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (200 mg, 0.56 mmol), 4-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-2-one (138 mg, 0.56 mmol) in 1,4- dioxane (5 mL) was added DMEDA (0.01 mL, 0.11 mmol), CuI (21 mg, 0.11 mmol) and K2CO3 (234 mg, 1.69 mmol). The mixture was stirred at 110oC 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 1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-2-one (200 mg, 68% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 519.1 P38594-WOStep 4: Synthesis of 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperidin- 2-oneA solution of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(5- (trifluoromethyl)pyrazin-2-yl)piperidin-2-one (200 mg, 0.38 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 treated with aqueous saturated NaHCO3 until pH = 8. 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 NH4HCO3in water) to afford 1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-2-one (100 mg, 67% yield) as a white solids. LCMS: (ESI, m / z) [M+H]+= 389.1 Step 5: Chiral Separation of 1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(5-(trifluoromethyl)pyrazin-2-1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-2-one (110 mg, 0.30 mmol) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 40 / 60; 80 mL / min) to give 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(5- (trifluoromethyl)pyrazin-2-yl)piperidin-2-one (Ex 16a, peak 1, Rt = 1.901 min, 32.6 mg, 29% yield) and 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-2-one (Ex 16b, peak 2, Rt = 3.743 min, 31.4 mg, 28% yield) both as a white solid. Example 16a:1H NMR (DMSO-d6, 400 MHz): δ 13.32 (br s, 1H), 9.16 (s, 1H), 8.95 (s, 1H), 8.63 (d, J = 5.6 Hz, 2H), 7.72 (d, J = 6.0 Hz, 2H), 7.24 (s, 1H), 4.02 - 3.83 (m, 2H), 3.79 - 3.65 (m, 1H), 2.94 - 2.80 (m, 2H), 2.42 - 2.29 (m, 1H), 2.23 - 2.11 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 389.0 P38594-WOExample 16b:1H NMR (DMSO-d6, 400 MHz): δ 13.31 (br s, 1H), 9.16 (s, 1H), 8.95 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.75 - 7.68 (m, 2H), 7.22 (s, 1H), 4.00 - 3.84 (m, 2H), 3.79 - 3.66 (m, 1H), 2.90 - 2.82 (m, 2H), 2.42 - 2.33 (m, 1H), 2.25 - 2.10 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 389.0 Examples 17a and 17bStep 1 — 2: Synthesis of 1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)phenyl)piperidin- 2-one1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)phenyl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and 9b by replacing (2- fluorophenyl)boronic acid with (3-(trifluoromethyl)phenyl)boronic acid in Step 1. Step 3: Chiral Separation of 1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3-1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)phenyl)piperidin-2-one (160 mg, 0.41 mmol) was separated 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 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3- (trifluoromethyl)phenyl)piperidin-2-one (Ex 17a, peak 1, Rt = 3.125 min, 59.5 mg, 37% yield) and 4- P38594-WO(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 17b, peak 2, Rt = 4.076 min, 54.1mg, 34% yield) both as white solids. Example 17a:1H NMR (DMSO-d6, 400 MHz): δ 13.36 (br s, 1H), 8.69 - 8.58 (m, 2H), 7.76 - 7.66 (m, 4H), 7.63 - 7.58 (m, 2H), 7.29 (s, 1H), 4.15 - 4.03 (m, 1H), 3.88 - 3.79 (m, 1H), 3.40 - 3.39 (m, 1H), 2.78 - 2.72 (m, 2H), 2.23 - 2.14 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 387.0 Example 17b:1H NMR (DMSO-d6, 400 MHz): δ 13.36 (br s, 1H), 8.69 - 8.58 (m, 2H), 7.76 - 7.66 (m, 4H), 7.63 - 7.58 (m, 2H), 7.29 (s, 1H), 4.15 - 4.00 (m, 1H), 3.89 - 3.77 (m, 1H), 3.40 - 3.39 (m, 1H), 2.80 - 2.71 (m, 2H), 2.23 - 2.10 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 387.0 Examples 18a and 18bStep 1 — 2: Synthesis of 4-(4-Chloro-3-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one4-(4-Chloro-3-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and 9b by replacing (2-fluorophenyl)boronic acid with (4-chloro-3-(trifluoromethyl)phenyl)boronic acid in Step 1. Step 3: Chiral Separation of 4-(4-Chloro-3-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol- 5-yl)piperidin-2-one (Ex.18a & 18b)P38594-WO4-(4-Chloro-3-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (155 mg, 0.37 mmol) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 60 / 40; 60 mL / min) to afford 4-(4-chloro-3- (trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 18a, peak 1, Rt = 3.435 min, 30.1 mg, 19% yield) and 4-(4-chloro-3-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (Ex 18b, peak 2, Rt = 4.715 min, 45.8 mg, 29% yield) both as white solids. Example 18a:1H NMR (DMSO-d6, 400 MHz): δ = 13.37 (s, 1H), 8.65 - 8.63 (m, 2H), 7.83 (s, 1H), 7.78 - 7.66 (m, 4H), 7.29 (s, 1H), 4.11 - 4.01 (m, 1H), 3.85 - 3.75 (m, 1H), 3.40 - 3.35 (m, 1H), 2.80 - 2.70 (m, 2H), 2.20 - 2.04 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 421.0 Example 18b:1H NMR (DMSO-d6, 400 MHz): δ = 13.35 (s, 1H), 8.63 (d, J = 4.4 Hz, 2H), 7.83 (s, 1H), 7.78 - 7.66 (m, 4H), 7.28 (s, 1H), 4.11 - 4.01 (m, 1H), 3.85 - 3.75 (m, 1H), 3.45 - 3.38 (m, 1H), 2.80 - 2.70 (m, 2H), 2.20 - 2.05 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 421.0 Example 19Step 1 – 2: Synthesis of 4-Cyclopropyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one4-Cyclopropyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 19) was prepared using the general procedure described for the preparation of 4-cyclobutyl-1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (Ex 20a and Ex 20b) by replacing cyclobutylmagnesium bromide with cyclopropylmagnesium bromide in Step 1. The title compound was purified by reverse phase chromatography (acetonitrile: 28-58% / 0.05% NH4OH + 10 mM NH4HCO3 in water) to afford 4- cyclopropyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (10 mg, 15% yield) as a white solid. Example 19:1H NMR (DMSO-d6, 400 MHz): δ 13.63 (s, 1H), 8.70 (d, J = 6.0 Hz, 2H), 8.36 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 6.0 Hz, 2H), 7.74 (d, J = 7.2 Hz, 1H), 7.51 - 7.39 (m, 4H), 7.34 (t, J = 7.6 Hz, 1H), 4.77 - 4.46 (m, 3H), 4.13 - 4.02 (m, 1H), 4.01 - 3.98 (m, 1H). LCMS (ESI, m / z) [M+H]+= 282.9 P38594-WOExamples 20a and 20bStep 1: Synthesis of 4-cyclobutyl-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 5-yl)piperidin-2-oneTo a solution of copper(I)bromide-dimethylsulfide (2.2 g, 10.8 mmol) in THF (20 mL) cyclobutylmagnesium bromide (0.5 M, 43.2 mL, 21.59 mmol) was added at 0oC under nitrogen atmosphere. After stirring at 0oC for 30 minutes, 1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5,6-dihydropyridin-2(1H)-one (800 mg, 2.16 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL) and then extracted by ethyl acetate (20 mL). The organic phase 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, 0-50% Ethyl acetate in petroleum ether) to afford 4-cyclobutyl-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (200 mg, 22% yield) as yellow oil. LCMS: (ESI, m / z) [M+H]+= 427.3 Step 2: Synthesis of 4-cyclobutyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-oneA solution of 4-cyclobutyl-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-one (200 mg, 0.47 mmol) in 5% TFA / HFIP (4 mL) was stirred at room P38594-WOtemperature for 2 hours. The residue was dissolved in DCM (5 mL), and then treated with aqueous saturated NaHCO3until pH = 8. 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 reverse phase chromatography (acetonitrile: 37-67% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4- cyclobutyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (90 mg, 65% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 297.2 Step 3: Chiral Separation of 4-Cyclobutyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex. 23a & 23b)4-Cyclobutyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (90 mg, 0.30 mmol) was separated by chiral SFC (Chiralpak IH (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 65 / 35; 100 mL / min) to afford 4-cyclobutyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin- 2-one (Example 20a, peak 1, Rt = 3.835 min, 31 mg, 35% yield) and 4-cyclobutyl-1-(3-(pyridin-4-yl)- 1H-pyrazol-5-yl)piperidin-2-one (Example 20b, peak 2, Rt = 4.109 min, 30 mg, 34% yield) both as white solids. Example 20a:1H NMR (DMSO-d6, 400 MHz): δ 13.29 (s, 1H), 8.61 (d, J = 5.2 Hz, 2H), 7.70 (d, J = 5.2 Hz, 2H), 7.24 (s, 1H), 4.00 - 3.91 (m, 1H), 3.70 - 3.62 (m, 1H), 2.48 - 2.41 (m, 1H), 2.18 - 1.62 (m, 10H), 1.50 - 1.41 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 297.2 Example 20b:1H NMR (DMSO-d6, 400 MHz): δ 13.28 (s, 1H), 8.61 (d, J = 5.2 Hz, 2H), 7.70 (d, J = 5.2 Hz, 2H), 7.22 (s, 1H), 4.00 - 3.91 (m, 1H), 3.70 - 3.61 (m, 1H), 2.48 - 2.41 (m, 1H), 2.17 - 1.62 (m, 10H), 1.50 - 1.40 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 297.2 Examples 21a and 21bP38594-WOStep 1: Synthesis of 4-cyclopentyl-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-oneTo a solution of copper(I)bromide-dimethylsulfide (0.55 g, 2.7 mmol) in THF (8 mL) was added cyclopentylmagnesium bromide (1M in THF, 5.4 mL, 5.4 mmol) at 0oC under nitrogen atmosphere. After stirring at 0oC for 30 minutes, a solution of 1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5,6-dihydropyridin-2(1H)-one (200 mg, 0.54 mmol) in THF (2 mL) was added at -78oC. The mixture was warmed up to room temperature and stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous NH4Cl solution (5 mL) and then extracted by ethyl acetate (20 mL). The organic phase 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, 0-30% Ethyl acetate in petroleum ether) to afford 4- cyclopentyl-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (130 mg, 55% yield) as a colorless oil. LCMS: (ESI, m / z) [M+H]+= 441.3A solution of 4-cyclopentyl-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-one (130 mg, 0.3 mmol) in 5% TFA / HFIP (5 mL) was stirred at room temperature for 3 hours. The reaction was concentrated, the residue was dissolved in DCM (5 mL) and the pH was adjusted to 8 with saturated NaHCO3solution. 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 to afford 4-cyclopentyl-1- (3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (90 mg, 98%) as a light yellow solid. LCMS: (ESI, m / z) [M+H]+= 311.2 Step 3: Chiral Separation of 4-Cyclopentyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl) piperidin-2-one (Ex 21a & 21b) P38594-WO4-Cyclopentyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl) piperidin-2-one (90 mg, 0.29 mmol). was separated by chiral SFC (Chiralpak IH (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 55 / 45; 150 mL / min) to afford 4-cyclopentyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl) piperidin-2-one (Ex 21a, peak 1, Rt = 2.952 min, 25.8 mg, 29% yield) and 4-cyclobutyl-1-(3-(pyridin- 4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 21b, peak 2, Rt = 3.338 min, 30 mg, 33% yield) both as white solids. Example 21a:1H NMR (DMSO-d6, 400 MHz): δ 13.29 (s, 1H), 8.62 (d, J = 5.2 Hz, 2H), 7.71 (d, J = 5.6 Hz, 2H), 7.24 (s, 1H), 4.05 - 3.95 (m, 1H), 3.71 - 3.61 (m, 1H), 2.25 - 2.16 (m, 1H), 2.08 - 1.99 (m, 1H), 1.79 - 1.51 (m, 10H), 1.21 - 1.12 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 311.0 Example 21b:1H NMR (DMSO-d6, 400 MHz): δ 13.28 (s, 1H), 8.61 (d, J = 4.4 Hz, 2H), 7.71 (d, J = 5.2 Hz, 2H), 7.23 (s, 1H), 4.05 - 3.95 (m, 1H), 3.70 - 3.61 (m, 1H), 2.25 - 2.16 (m, 1H), 2.08 - 1.99 (m, 1H), 1.79 - 1.51 (m, 10H), 1.21 - 1.11 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 311.0 Examples 22a and 22bStep 1 — 2: Synthesis of 4-cyclohexyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-oneP38594-WO4-cyclohexyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 21a and 21b by replacing cyclopentylmagnesium bromide with cyclohexylmagnesium bromide in Step 1. LCMS: (ESI, m / z) [M+H]+= 325.2 Step 3: Chiral Separation of 4-Cyclohexyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 22a & 22b)4-Cyclohexyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (110 mg, 0.34 mmol). was separated by chiral SFC (Chiralpak AS (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 75 / 25; 150 mL / min) to afford 4-cyclohexyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin- 2-one (Ex 22a, peak 1, Rt = 3.384 min, 32.1 mg, 29% yield) and 4-cyclohexyl-1-(3-(pyridin-4-yl)- 1H-pyrazol-5-yl)piperidin-2-one (Ex 22b, peak 2, Rt = 3.678 min, 24.7 mg, 22% yield) both as white solids. Example 22a:1H NMR (DMSO-d6, 400 MHz): δ 13.27 (br s, 1H), 8.61 (d, J = 5.6 Hz, 2H), 7.70 (d, J = 6.0 Hz, 2H), 7.20 (br s, 1H), 4.08 - 3.90 (m, 1H), 3.70 - 3.57 (m, 1H), 2.50 - 2.46 (m, 1H), 2.28 - 2.16 (m, 1H), 2.07 - 1.96 (m, 1H), 1.80 - 1.60 (m, 6H), 1.59 - 1.47 (m, 1H), 1.26 - 1.11 (m, 4H), 1.04 - 0.88 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 325.2 Example 22b:1H NMR (DMSO-d6, 400 MHz): δ 13.28 (br s, 1H), 8.61 (d, J = 6.0 Hz, 2H), 7.70 (d, J = 6.0 Hz, 2H), 7.21 (br s, 1H), 4.08 - 3.90 (m, 1H), 3.68 - 3.57 (m, 1H), 2.50 - 2.46 (m, 1H), 2.28 - 2.18 (m, 1H), 2.07 - 1.96 (m, 1H), 1.80 - 1.60 (m, 6H), 1.59 - 1.46 (m, 1H), 1.26 - 1.12 (m, 4H), 1.03 - 0.88 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 325.2 Example 23P38594-WOStep 1: Synthesis of 4-(1-methylcyclopropyl)-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)piperidin-2-oneIn a 40 mL vial were added 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)-5,6-dihydropyridin-2(1H)-one (400 mg, 1.08 mmol), Ir[dF(CF3)ppy]2(dtbbpy) (80 mg, 0.07 mmol), 1-methylcyclopropane-1-carboxylic acid (216 mg, 2.16 mmol), KH2PO4(360 mg, 2.07 mmol) in DMF (8mL). The vial was purged with nitrogen and then sealed. The vial was placed in the integrated photoreactor (450 nm LED light) for 48 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 66-96% / 0.05% NH4OH + 10 mM NH4HCO3in water) to give 4-(1-methylcyclopropyl)-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (45 mg, 9% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz): δ 8.69 (d, J = 5.6 Hz, 2H), 7.60 (d, J = 6.4 Hz, 2H), 7.17 (s, 1H), 5.37 (s, 2H), 4.22 - 4.16 (m, 1H), 3.77 - 3.72 (m, 2H), 3.71 - 3.63 (m, 1H), 2.67 - 2.58 (m, 1H), 2.52 - 2.41 (m, 1H), 2.06 - 1.97 (m, 1H), 1.81 - 1.71 (m, 1H), 1.40 - 1.25 (m, 1H), 1.02 (s, 3H), 0.96 (t, J = 8.0 Hz, 2H), 0.40 - 0.34 (m, 2H), 0.33 - 0.28 (m, 2H), 0.01 (s, 9H). LCMS (ESI, m / z) [M+H]+= 427.1 Step 2: Synthesis of 4-(1-methylcyclopropyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 23)A mixture of 4-(1-methylcyclopropyl)-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (40 mg, 0.09 mmol) in 5% TFA / HFIP solution (1.1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL), and then treated with aqueous saturated NaHCO3until pH = 8. The organic phase was separated, and the aqueous phase was extracted with DCM (10 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 P38594-WOchromatography (acetonitrile: 40-70% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4-(1- methylcyclopropyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (9.5 mg, 34% yield) both as a white solid. Example 23:1H NMR (DMSO-d6, 400 MHz): δ 13.35 (s, 1H), 8.71 - 8.53 (m, 2H), 7.78 - 7.64 (m, 2H), 7.22 (br s, 1H), 4.14 - 3.98 (m, 1H), 3.65 - 3.55 (m, 1H), 2.46 - 2.31 (m, 2H), 1.98 - 1.87 (m, 1H), 1.69 - 1.54 (m, 1H), 1.42 - 1.30 (m, 1H), 0.97 (s, 3H), 0.41 - 0.33 (m, 2H), 0.27 - 0.19 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 297.0 Examples 24a and 24bStep 1: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4- (2,2,2-trifluoroethoxy)piperidin-2-oneTo a solution of 4-hydroxy-1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-one (500 mg, 1.35 mmol) in 2,2,2-trifluoroethanol (2.5 mL) was added sodium 2,2,2-trifluoroethanolate (329 mg, 2.7 mmol) and CuCl2(18 mg, 0.13 mmol). The reaction mixture was stirred at 70oC for 16 h. After cooling to room temperature, the reaction was quenched with water (4 mL) and then extracted with ethyl acetate ethyl acetate (4 mL). The organic layer was washed with brine (3 mL) dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and concentrated. The crude was purified by prep-TLC (50% ethyl acetate in petroleum ether) to give 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(2,2,2- trifluoroethoxy)piperidin-2-one (120 mg, 19% yield) as a colorless oil. LCMS: (ESI, m / z) [M+H]+= 471.2 Step 2: Synthesis of 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(2,2,2-trifluoroethoxy)piperidin-2-one P38594-WOA mixture of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4- (2,2,2-trifluoroethoxy)piperidin-2-one (120 mg, 0.26 mmol) in 15% TFA / HFIP solution (8 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), and then treated with aqueous saturated NaHCO3until pH = 8. The organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 28- 58% / 0.1% NH4OH in water) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(2,2,2- trifluoroethoxy)piperidin-2-one (60 mg, 69 % yield) as a white solid. Step 3: Chiral Separation of 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(2,2,2-trifluoroethoxy)piperidin-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(2,2,2-trifluoroethoxy)piperidin-2-one (70 mg, 0.21 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / i- PrOH + 0.1% NH4OH = 40 / 60; 80 mL / min) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(2,2,2- trifluoroethoxy)piperidin-2-one (Ex 24a, peak 1, Rt = 1.706 min, 22.5 mg, 32% yield) and 1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)-4-(2,2,2-trifluoroethoxy)piperidin-2-one (Ex 24b, peak 2, Rt = 2.254 min, 22.7 mg, 32% yield) both as white solid. Example 24a:1H NMR (DMSO-d6, 400 MHz): δ 13.32 (br s, 1H), 8.62 (d, J = 5.6 Hz, 2H), 7.71 (d, J = 6.0 Hz, 2H), 7.23 (br s, 1H), 4.22 - 4.05 (m, 3H), 3.93 - 3.75 (m, 2H), 2.88 - 2.82 (m, 1H), 2.58 - 2.55 (m, 1H), 2.21 - 2.01 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 341.1 Example 24b:1H NMR (DMSO-d6, 400 MHz): δ 13.35 (br s, 1H), 8.62 (d, J = 5.6 Hz, 2H), 7.71 (d, J = 5.6 Hz, 2H), 7.22 (br s, 1H), 4.29 - 4.03 (m, 3H), 3.95 - 3.73 (m, 2H), 2.89 - 2.82 (m, 1H), 2.58 - 2.54 (m, 1H), 2.22 - 1.98 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 340.9 P38594-WOExamples 25a and 25bStep 1: Synthesis of 4-(trifluoromethoxymethyl)piperidin-2-one selectfluor (1.5 equiv)AgSO(43CF3 equivequi)KF (4v)2-fluoropyridiSCF(n3e (4equiv3eq )TMuiv)EtOAc, 50 °C, 16 hTo a mixture of 4-(hydroxymethyl)piperidin-2-one (4.0 g, 30.97 mmol), 1-fluoro-4-methyl- 1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (14.86 g, 46.45 mmol), AgSO3CF3 (31.83 g, 123.88 mmol) and KF (7.2 g, 123.88 mmol) in ethyl acetate (80 mL) was 2-fluoropyridine (10.66 mL, 123.88 mmol) and trimethyl(trifluoromethyl)silane (13.73 mL, 92.91 mmol). The mixture was stirred at 50oC for 16 hours under nitrogen condition. 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, 40%-100% ethyl acetate in petroleum ether) to afford the crude product. The crude product was purified by reverse phase chromatography (acetonitrile: 15-45% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4- (trifluoromethoxymethyl)piperidin-2-one (1.5 g, 25% yield) as a black solid.1H NMR (DMSO-d6, 400 MHz) δ = 7.52 (s, 1H), 4.05 - 3.93 (m, 2H), 3.22 - 3.06 (m, 2H), 2.27 - 2.11 (m, 2H), 1.99 - 1.88 (m, 1H), 1.87 - 1.77 (m, 1H), 1.47 - 1.31 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 198.1. Step 2: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4- ((trifluoromethoxy)methyl)piperidin-2-one P38594-WOTo a solution of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (500 mg, 1.41 mmol) and 4-(trifluoromethoxymethyl)piperidin-2-one (306 mg, 1.55 mmol) in tetrahydrofuran (20 mL) was added sodium trimethyl(oxido)silane (395 mg, 3.53 mmol) and GPhos Pd G6 (133 mg, 0.14 mmol). The mixture was stirred at 70 °C for 3 hours 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, 60% ethyl acetate in petroleum ether) to afford 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)-4-((trifluoromethoxy)methyl)piperidin-2-one (220 mg, 33% yield) as colorless oil. LCMS: (ESI, m / z) [M+H]+= 471.2. Step 3: Synthesis of 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-((trifluoromethoxy)methyl)piperidin-2-oneA solution of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4- ((trifluoromethoxy)methyl)piperidin-2-one (350 mg, 0.74 mmol) in 5% TFA / HFIP (14 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 treated with aqueous saturatedThe aqueous phase was extracted with dichloromethane (10 mL x 2). The were 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 NH4HCO3in water) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-((trifluoromethoxy)methyl)piperidin-2-one (220 mg, 87% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 341.1 Step 4: Chiral Separation of 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4- ((trifluoromethoxy)methyl)piperidin-2-one (Ex.25a & 25b) P38594-WO1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-((trifluoromethoxy)methyl)piperidin-2-one (220 mg, 0.59 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4- ((trifluoromethoxy)methyl)piperidin-2-one (Ex 25a, peak 1, Rt = 1.657 min, 78 mg, 35% yield) and 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-((trifluoromethoxy)methyl)piperidin-2-one (Ex 25b, peak 2, Rt = 2.256 min, 76 mg, 34% yield) both as white solid. Example 25a:1H NMR: (DMSO-d6, 400 MHz) δ 13.10 (s, 1H), 8.61 (d, J = 4.8 Hz, 2H), 7.69 (d, J = 4.8 Hz, 2H), 7.19 (s, 1H), 4.12 - 3.98 (m, 3H), 3.83 - 3.72 (m, 1H), 2.65 - 2.56 (m, 1H), 2.47 - 2.38 (m, 1H), 2.36 - 2.28 (m, 1H), 2.15 - 2.04 (m, 1H), 1.77 - 1.63 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 341.1 Example 25b:1H NMR: (DMSO-d6, 400 MHz) δ 13.10 (s, 1H), 8.61 (d, J = 5.6 Hz, 2H), 7.69 (d, J = 5.2 Hz, 2H), 7.16 (s, 1H), 4.14 - 3.97 (m, 3H), 3.83 - 3.71 (m, 1H), 2.64 - 2.57 (m, 1H), 2.45 - 2.38 (m, 1H), 2.36 - 2.28 (m, 1H), 2.14 - 2.04 (m, 1H), 1.78 - 1.63 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 341.1 Examples 26a and 26bStep 1: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5,6- dihydropyridin-2(1H)-one P38594-WOIn a 40 mL vial were added 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)-5,6-dihydropyridin-2(1H)-one (500 mg, 1.35mmol), 1,1,1-trifluoro-3-iodopropane (0.32 mL, 2.7 mmol), TEA (0.39 mL, 2.77 mmol) , 4CzIPN (50 mg, 0.06mmol) in MeCN (12mL) and H2O(1.2mL). The vial was purged with nitrogen and then sealed. The vial was placed in the integrated photoreactor (450 nm LED light) for 24 h. The mixture was concentrated under concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 15-20%EE (EtOAc / EtOH = 3:1) in petroleum ether) to afford 1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(3,3,3-trifluoropropyl)piperidin-2-one (150 mg crude, 60% purity) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 469.0A mixture of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4- (3,3,3-trifluoropropyl)piperidin-2-one (120 mg crude, 60% purity) in 5% TFA / HFIP solution (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. Then the reaction residue was poured into saturated NaHCO3(5 mL), then 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: 42- 72% / 0.1% NH4OH in water) to afford to give 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,3,3- trifluoropropyl)piperidin-2-one (35 mg, 10% yield over two steps) as a white solid. LCMS: (ESI, m / z) [M+H]+=339.0 Step 3: Chiral Separation of 1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,3,3-trifluoropropyl)piperidin- 2-one (Ex 26a & 26b) P38594-WO1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,3,3-trifluoropropyl)piperidin-2-one (50 mg, 0.15 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 45 / 55; 80 mL / min) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,3,3- trifluoropropyl)piperidin-2-one (Ex 26a, peak 1, Rt = 1.573 min, 20.2 mg, 40% yield) and 1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,3,3-trifluoropropyl)piperidin-2-one (Ex 26b, peak 2, Rt = 3.031 min, 20.5mg, 41% yield) both as white solids. Example 26a:1H NMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 8.62 (d, J = 4.4 Hz, 2H), 7.71 (d, J = 4.8 Hz, 2H), 7.24 (s, 1H), 4.13 - 3.89 (m, 1H), 3.73 - 3.61 (m, 1H), 2.64 - 2.54 (m, 1H), 2.43 - 2.28 (m, 2H), 2.26 - 2.15 (m, 1H), 2.09 - 1.88 (m, 2H), 1.62 - 1.48 (m, 3H). LCMS: (ESI, m / z) [M+H]+= 339.0 Example 26b:1H NMR (400 MHz, DMSO-d6): δ 13.32 (s, 1H), 8.64 - 8.59 (m, 2H), 7.74 - 7.66 (m, 2H), 7.25 - (s, 1H), 4.07 - 3.95 (m, 1H), 3.72 - 3.58 (m, 1H), 2.64 - 2.54 (m, 1H), 2.39 - 2.29 (m, 2H), 2.26 - 2.15 (m, 1H), 2.07 - 1.92 (m, 2H), 1.59 - 1.48 (m, 3H). LCMS: (ESI, m / z) [M+H]+=339.0 Examples 27a and 27bStep 1— 2: Synthesis of 1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(1-(trifluoromethyl)-1H-pyrazol-4- yl)piperidin-2-oneP38594-WO1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 7a & 7b by replacing 5- bromo-2-fluoropyridine with 4-bromo-1-(trifluoromethyl)-1H-pyrazole in Step 1. Step 3: Chiral Separation of 1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(1-(trifluoromethyl)-1H-pyrazol-1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)piperidin-2-one (100 mg, 0.27 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um), Supercritical CO2 / i-PrOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4- (1-(trifluoromethyl)-1H-pyrazol-4-yl)piperidin-2-one (Ex 27a, peak 1, Rt = 0.881 min, 47.3 mg, 46% yield) and 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)piperidin-2- one (Ex 27b, peak 2, Rt = 2.964 min, 47.2 mg, 46% yield) both as white solids. Example 27a:1H NMR (DMSO-d6, 400 MHz): δ 13.33 (s, 1H), 8.66 - 2.58 (m, 2H), 8.41 (s, 1H), 8.01 (s, 1H), 7.72 (d, J = 4.8 Hz, 2H), 7.27 (s, 1H), 4.07 - 3.95 (m, 1H), 3.85 - 3.74 (m, 1H), 3.29 - 3.20 (m, 1H), 2.90 -2.80 (m, 1H), 2.70 - 2.57 (m, 1H), 2.34 - 2.25 (m, 1H), 2.02-1.92 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 377.0 Example 27b:1H NMR (DMSO-d6, 400 MHz): δ 13.32 (s, 1H), 8.62 (d, J = 5.2 Hz, 2H), 8.41 (s, 1H), 8.01 (s, 1H), 7.72 (d, J = 5.6 Hz, 2H), 7.23 (s, 1H), 4.07 - 3.95 (s, 1H), 3.88 - 3.73 (m, 1H), 3.22 - 3.12 (m, 1H), 2.90 -2.80 (m, 1H), 2.70 - 2.57 (m, 1H), 2.34 - 2.25 (m, 1H), 2.01 - 1.90 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 377.0 Examples 28a and 28bP38594-WO4-(Isothiazol-4-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 7a and 7b by replacing 5-bromo-2- fluoropyridine with 4-bromoisothiazole in Step 1. Step 3: Chiral Separation of 4-(Isothiazol-4-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 28a & 28b)4-(Isothiazol-4-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (100 mg, 0.31 mmol) was separated by chiral SFC (Chiralpak IH (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 55 / 45; 100 mL / min) to afford 4-(isothiazol-4-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Ex 28a, peak 1, Rt = 4.528 min, 37.4 mg, 37%) and 4-(isothiazol-4-yl)-1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 28b, peak 2, Rt = 4.932 min, 33.6 mg, 34% yield) both as white solids. Example 28a:1H NMR (DMSO-d6, 400 MHz): δ 13.33 (s, 1H), 8.86 (s, 1H), 8.72 - 8.51 (m, 3H), 7.72 (d, J = 6.0 Hz, 2H), 7.24 (s, 1H), 4.05 - 3.92 (m, 1H), 3.89 - 3.77 (m, 1H), 3.52 - 3.42 (m, 1H), 2.92 - 2.82 (m, 1H), 2.76 - 2.64 (m, 1H), 2.39 - 2.28 (m, 1H), 2.13 - 1.98 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 326.0 Example 28b:1H NMR (DMSO-d6, 400 MHz): δ 13.33 (s, 1H), 8.86 (s, 1H), 8.72 - 8.51 (m, 3H), 7.72 (d, J = 5.6 Hz, 2H), 7.25 (s, 1H), 4.05 - 3.92 (m, 1H), 3.89 - 3.77 (m, 1H), 3.52 - 3.42 (m, 1H), 2.92 - 2.82 (m, 1H), 2.76 - 2.64 (m, 1H), 2.38 - 2.26 (m, 1H), 2.15 - 2.00 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 326.0 P38594-WOExamples 29a and 29bStep 1 — 2: Synthesis of 4-(2-Chlorothiazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2- one4-(2-Chlorothiazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 7a and 7b by replacing 5-bromo-2- fluoropyridine with 5-bromo-2-chlorothiazole in Step 1. Step 3: Chiral Separation of 4-(2-Chlorothiazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-4-(2-Chlorothiazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (70 mg, 0.19 mmol mmol) was separated by chiral SFC (Chiralpak AS (250 mm x 30 mm, 10 um), Supercritical CO2 / i-PrOH + 0.1% NH4OH = 50 / 50; 150 mL / min) to afford 4-(2-chlorothiazol-5-yl)-1-(3-(pyridin- 4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 29a, peak 1, Rt = 1.463 min, 20.1 mg, 26% yield) and 4- (2-chlorothiazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 29b, peak 2, Rt = 2.378 min, 25.3 mg, 34% yield) both as white solids. Example 29a:1H NMR (DMSO-d6, 400 MHz): δ 13.36 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 5.6 Hz, 2H), 7.57 (s, 1H), 7.27 (s, 1H), 4.13 - 3.99 (m, 1H), 3.89 - 3.78 (m, 1H), 3.69-3.59 P38594-WO(m, 1H), 2.92 - 2.82 (m, 1H), 2.73 - 2.60 (m, 1H), 2.39 - 2.26 (m, 1H), 2.14 - 2.00 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 360.0 Example 29b:1H NMR (DMSO-d6, 400 MHz): δ = 13.33 (s, 1H), 8.62 (d, J = 5.2 Hz, 2H), 7.72 (d, J = 6.0 Hz, 2H), 7.57 (s, 1H), 7.23 (s, 1H), 4.10 - 3.93 (m, 1H), 3.87 - 3.78 (m, 1H), 3.66 - 3.55 (m, 1H), 2.94 - 2.82 (m, 1H), 2.75 - 2.65 (m, 1H), 2.37 - 2.26 (m, 1H), 2.13 - 2.01 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 360.2 Examples 30a and 30bTo a solution of 3-chloro-1-methyl-1H-pyrazole (4.0 g, 34.3 mmol) in THF (40 mL) was added n- BuLi (2.5 M, 15.1 mL, 37.7 mmol) dropwise at -60oC under nitrogen atmosphere. After stirring at - 60oC for 1 hour, then a solution of CBr4(11.3 g, 34.3 mmol) in THF (20 mL) was added dropwise. After stirring at -60oC for 1 hour under nitrogen atmosphere. The reaction was quenched with water (50 mL) and then extracted with ethyl acetate (80 mL). The organic layer was washed with brine (80 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- bromo-3-chloro-1-methyl-1H-pyrazole (3 g, 44% yield) as yellow oil.1H NMR (CDCl3, 400 MHz): δ = 6.22 (s, 1H), 3.83 (s, 3H). LCMS: (ESI, m / z) [M+H]+= 194.9 Step 2 — 3: Synthesis of 4-(3-Chloro-1-methyl-1H-pyrazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one P38594-WO4-(3-Chloro-1-methyl-1H-pyrazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 7a and 7b by replacing 5-bromo-2-fluoropyridine with 5-bromo-3-chloro-1-methyl-1H-pyrazole in Step 1. Step 4: Chiral Separation of 4-(3-Chloro-1-methyl-1H-pyrazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol- 5-yl)piperidin-2-one (Ex 30a & 30b)4-(3-Chloro-1-methyl-1H-pyrazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (250 mg, 0.70 mmol) was separated by chiral SFC (Chiralcel OJ (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to afford 4-(3-chloro-1-methyl-1H- pyrazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 30a, peak 1, Rt = 0.885 min, 91.5 mg, 36% yield) and 4-(3-chloro-1-methyl-1H-pyrazol-5-yl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Ex 30b, peak 2, Rt = 2.182 min, 77.2 mg, 30% yield) both as white solids. Example 30a:1H NMR (DMSO-d6, 400 MHz): δ = 13.36 (br s, 1H), 8.63 (d, J = 5.2 Hz, 2H), 7.72 (d, J = 5.2 Hz, 2H), 7.27 (s, 1H), 6.24 (s, 1H), 4.12 - 3.97 (m, 1H), 3.91 - 3.81 (m, 1H), 3.78 (s, 3H), 3.52 - 3.41 (m, 1H), 2.85 - 2.72 (m, 1H), 2.66 - 2.55 (m, 1H), 2.27 - 2.16 (m, 1H), 2.04 - 1.88 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 357.0 Example 30b:1H NMR (DMSO-d6, 400 MHz): δ = 13.35 (br s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 6.0 Hz, 2H), 7.26 (s, 1H), 6.24 (s, 1H), 4.11 - 3.94 (m, 1H), 3.91 - 3.81 (m, 1H), 3.78 (s, 3H), 3.52 - 3.41 (m, 1H), 2.83 - 2.73 (m, 1H), 2.66 - 2.55 (m, 1H), 2.27 - 2.15 (m, 1H), 2.02 - 1.89 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 357.1. Example 31Step 1 – 2: Synthesis of 4-benzyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)pyrrolidin-2-one (Ex 31) 4-benzyl-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)pyrrolidin-2-one was prepared using the general P38594-WOprocedure for Examples 1a and 1b using 4-benzylpyrrolidin-2-one (74.2 mg, 3 equiv, 0.42 mmol) in place of 4-phenylpiperidin-2-one in step 1. The material was purified by prep HPLC (XSelect CSH Prep C18, 50 mm x 30 mm, 5 µm), 0.1% Ammonium hydroxide in water / acetonitrile using a gradient of 20% to 60% acetonitrile; 60 mL / min, 25oC) to yield 4-benzyl-1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)pyrrolidin-2-one as a racemic white solid (15 mg, 33% yield). Example 31:1H NMR (400 MHz, DMSO) δ 13.21 (s, 1H), 8.65 – 8.57 (d, J = 6.2, 2H), 7.75 – 7.69 (d, J = 6.23, 2H), 7.37 – 7.30 (m, 2H), 7.30 – 7.18 (m, 4H), 3.89 (dd, J = 10.0, 7.0 Hz, 1H), 3.57 (dd, J = 10.1, 5.1 Hz, 1H), 2.80 (m, 3H), 2.58 (dd, J = 16.6, 7.7 Hz, 1H), 2.36 – 2.26 (dd, J = 16.6 1H). LCMS: (ESI, m / z) [M+H]+= 319.1. Example 32 Step 1: Synthesis of methyl 3-(3,6-dichloropyridazin-4-yl)bicyclo[1.1.1]pentane-1-carboxylateTo a vial equipped with a stir bar, 1-(1,3-dioxoisoindolin-2-yl) 3-methyl bicyclo[1.1.1]pentane-1,3-dicarboxylate [prepared via known literature procedure ref: Org. Lett.2020, 22, 4, 1648–1654] (2000 mg, 6.3 mmol, 1 equiv.), 3,6-dichloropyridazine (2835 mg, 19 mmol, 3 equiv.), and Ir(ppy)3(42 mg, 0.06 mmol, 0.01 equiv.) were added followed by DMSO (45 mL). The reaction was degassed by sparging with N2for 5-10 minutes. The mixture was placed in front of two blue LEDs (without fan, setup reaches about 40 °C). The mixture was stirred until complete consumption of the starting materials was confirmed by LCMS analysis. On completion, the reaction mixture was purified directly by preparative HPLC (30-70% MeCN, 0.1% FA modifier). This afforded methyl 3-(3,6-dichloropyridazin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (520 mg, 30% Yield) as an off-white semi-solid. LCMS (ESI) [M+H]+= 330.100, 332.100 (5:3).1H NMR (400 MHz, MeOD) δ 7.67 (s, 1H), 2.48 (s, 6H), 1.45 (s, 9H). Steps 2 – 3: Synthesis of mesityl-λ3-iodanediyl bis(3-(3,6-dichloropyridazin-4- yl)bicyclo[1.1.1]pentane-1-carboxylate)P38594-WOTo a vial equipped with a stir bar, methyl 3-(3,6-dichloropyridazin-4- yl)bicyclo[1.1.1]pentane-1-carboxylate (100 mg, 0.37 mmol, 1 equiv.) and THF (1 mL) were added followed by NaOH (1 M, aq) (0.4 mL, 0.4 mmol, 1.1 equiv.). The mixture was stirred until complete consumption of the starting materials was confirmed by LCMS analysis. At this time, citric acid (141 mg, 0.7 mmol, 2.0 equiv.) was added, and the mixture was extracted 5 times with DCM. This afforded 3-(3,6-dichloropyridazin-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (90 mg, 0.35 mmol, 95% Yield) as a solid which was used without purification. LCMS (ESI) [M+H]+= 258.852, 260.832 (5:3) To a vial equipped with a stir bar, 3-(3,6-dichloropyridazin-4-yl)bicyclo[1.1.1]pentane-1- carboxylic acid (90 mg, 0.35 mmol, 2.1 equiv.) and mesityl-λ3-iodanediyl diacetate (60 mg, 0.16 mmol, 1 equiv.) were added followed by toluene (5 mL). After full dissolution, the mixture was concentrated directly on a rotavap at 50 ºC. The sequence was repeated twice more to yield the title compound (113 mg, 0.15 mmol, 90% Yield) as an oil, which was used without further purification. Step 4: Synthesis of 1-(3-(3,6-dichloropyridazin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-phenylpiperidin-2- oneTo a vial equipped with a stir bar, tris[2-(2-pyridyl)phenyl]iridium (1.5 mg, 0.002 mmol, 0.02 equiv.), Cu(acac)2(18 mg, 0.07 mmol, 0.6 equiv.), 4-phenylpiperidin-2-one (20 mg, 0.11 mmol, 1 equiv.), and 1,4-dioxane (2 mL) were added followed by DBU (43 mg, 0.043 mL, 0.29 mmol, 2.5 equiv.). The solution was sparged with N2for 5 minutes, then placed in front of blue LEDs and stirred for 1 hour. At this time, the mixture was diluted with iPrOAc and washed three times with brine. The organic fraction were dried over MgSO4, filtered, and concentrated. Purification via column chromatography gave 1-[3-(3,6-dichloropyridazin-4-yl)-1- bicyclo[1.1.1]pentanyl]-4-phenyl-piperidin-2-one (13 mg, 0.03 mmol, 29% Yield) as a white solid. LCMS (ESI) [M+H]+= 388.100 / 390.100 (5:3) Step 5: Synthesis of 4-phenyl-1-(3-(pyridazin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex.40)To a vial equipped with a stir bar add, Pd(dppf)Cl2(4 mg, 0.005 mmol, 0.15 equiv) and THF (0.5 mL) were added. The reaction was degassed with N2for 2 minutes, then 1-(3-(3,6- P38594-WOdichloropyridazin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-phenylpiperidin-2-one (13 mg, 0.03 mmol, 1 equiv), TMEDA (17 uL, 13 mg, 3.4 equiv) and sodium borohydride (4.3 mg, 0.12 mmol, 3.4 equiv) were added. The mixture was strired at room temperature until complete consumption of the starting materials was confirmed by LCMS analysis. Upon completion, the reaction was quenched with sat. aq. NH4Cl and extracted with DCM (3x). The combined organic fractions were dried over MgSO4, filtered, and concentrated. Purification via column chromatography (0 to 10% MeOH in DCM) afforded 4-phenyl-1-(3- pyridazin-4-yl-1-bicyclo[1.1.1]pentanyl)piperidin-2-one (Example 32, 2.7 mg, 0.0085 mmol, 25% Yield) as a white solid. Submitted as the racemate. Example 32:1H NMR (400 MHz, MeOD) δ 9.14 (s, 1H), 9.09 (d, J = 5.5 Hz, 1H), 7.66 – 7.58 (m, 1H), 7.39 – 7.16 (m, 5H), 3.53 – 3.42 (m, 2H), 3.18 – 3.06 (m, 1H), 2.63 – 2.44 (m, 2H), 2.60 (s, 6H), 2.20 – 2.09 (m, 1H), 2.08 – 1.96 (m, 1H). LCMS (ESI) [M+H]+= 320.2. Examples 33a and 33bStep 1: Synthesis of 4-(4-chloro-3-fluorophenyl)tetrahydro-2H-pyran-2-oneTo a solution of 5,6-dihydro-2H-pyran-2-one (4.39 mL, 50.97 mmol), 4-chloro-3- fluorophenylboronicacid (13.33 g, 76.45 mmol), BINAP (6.35 g, 10.19 mmol) and [Rh(COD)Cl]2(2.51 g, 5.1 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was added KOH (2.86 g, 50.97 mmol) at room temperature. Then the resulting mixture was stirred at 80oC for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was diluted with brine (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous P38594-WONa2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica, 15% EtOAc in petroleum ether) to afford 4-(4-chloro-3-fluorophenyl)tetrahydro-2H-pyran-2-one (5.1 g, 44% yield) as a white oil. LCMS: (ESI, m / z) [M+H]+= 229.1 Step 2: Synthesis of methyl 3-(4-chloro-3-fluorophenyl)-5-iodopentanoateTo a solution of 4-(4-chloro-3-fluoro-phenyl)tetrahydropyran-2-one (2.50 g, 10.93 mmol) and NaI (4.10 g, 27.33 mmol) in DCM (35 mL) was added TMSCl (3.30 mL, 27.33 mmol) dropwise at 0oC under nitrogen atmosphere. After stirring at 0oC for 10 min, to the mixture was added MeOH (1.33 mL, 32.80 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 10% ethyl acetate in petroleum ether) to afford methyl 3-(4-chloro-3- fluorophenyl)-5-iodopentanoate (2.1 g, 52% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz): δ 7.35 (t, J = 8.0 Hz, 1H), 7.05 - 6.92 (m, 2H), 3.61 (s, 3H), 3.35 - 3.24 (m, 1H), 3.10 - 3.02 (m, 1H), 2.85 - 2.76 (m, 1H), 2.67 - 2.56 (m, 2H), 2.27 - 1.99 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 370.9 Step 3: Synthesis of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-oneTo a solution of methyl 3-(4-chloro-3-fluoro-phenyl)-5-iodo-pentanoate (500 mg, 1.35 mmol) and 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (318 mg, 1.62 mmol) in DMA (5 mL) was added K2CO3(757 mg, 5.40 mmol). The reaction was stirred at 60oC for 1 h and then heated to 100oC for 16 hours. After cooling to room temperature, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. P38594-WOThe residue was by flash column chromatography (SiO2, 50% ethyl acetate in petroleum ether) to afford 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (200 mg, 40% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 371.0 Step 4: Chiral Separation of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-one (Ex.33a & 33b).4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (200 mg) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um), Supercritical CO2 / i-PrOH + 0.1% NH4OH = 55 / 45; 80 mL / min) to afford 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex. 33a, peak 1, Rt = 3.084 min, 19.7 mg, 10% yield) and 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex. 33b, peak 2, Rt = 3.223 min, 23.8 mg, 12% yield) both as white solids. Example 33a:1H NMR (DMSO-d6, 400 MHz): δ 8.50 (d, J = 5.6 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.39 -7.32 (m, 1H), 7.26 (d, J = 5.6 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 3.44 - 3.35 (m, 2H), 3.17 - 3.06 (m, 1H), 2.46 - 2.42 (m, 2H), 2.41 (s, 6H), 2.08 - 1.85 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 371.2 Example 33b:1H NMR (DMSO-d6, 400 MHz): δ 8.49 (d, J = 5.6 Hz, 2H), 7.53 (t, J = 8.0 Hz,, 1H), 7.38 (d, J = 10.8 Hz, 1H), 7.26 (d, J = 5.6 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 3.47 - 3.36 (m, 2H), 3.15 - 3.03 (m, 1H), 2.47 - 2.42 (m, 2H), 2.41 (s, 6H), 2.06 - 1.85 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 371.2 Examples 34a and 34bP38594-WOTo a mixture of (3,4-difluorophenyl)boronic acid (11.27 g, 71.36 mmol), 5,6-dihydro-2H- pyran-2-one (5.0 g, 50.97 mmol) and [Rh(COD)Cl]2(1.26 g, 2.55 mmol) in 1,4-dioxane (100 mL) was added a solution of KOH (2.86 g, 50.97 mmol) in water (10 mL) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was extracted with ethyl Acetate (100 x 3 mL). 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, 25% ethyl acetate in petroleum ether) to give 4- (3,4-difluorophenyl)tetrahydro-2H-pyran-2-one (8.4 g, 78% yield) as colorless oil.1H NMR (CDCl3, 400 MHz): δ 7.18 - 7.11 (m, 1H), 7.05 - 7.00 (m, 1H), 6.95 - 6.92 (m, 1H), 4.56 - 4.46 (m, 1H), 4.41 - 4.35 (m, 1H), 3.26 - 3.18 (m, 1H), 2.94 - 2.87 (m, 1H), 2.59 - 2.50 (m, 1H), 2.24 - 2.14 (m, 1H), 2.03 - 1.91 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 213.1 Step 2: Synthesis of methyl 3-(3,4-difluorophenyl)-5-iodopentanoateTo a solution of 4-(3,4-difluorophenyl)tetrahydro-2H-pyran-2-one (8.4 g, 39.59 mmol) and NaI (14.83 g, 98.97 mmol) in DCM (150 mL) was added TMSCl (11.95 mL, 98.97 mmol) dropwise at 0oC under nitrogen atmosphere. After stirring at 0oC for 10 min, to the mixture was added MeOH (4.81 mL, 118.76 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated Na2S2SO3solution (30 mL) and extracted with DCM (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, 6% ethyl acetate in petroleum ether) to afford methyl 3-(3,4-difluorophenyl)-5-iodopentanoate (8.26 g, 59% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz): δ 7.15 - 7.08 (m, 1H), 7.08 - 7.00 (m, 1H), 6.98 - 6.94 (m, 1H), 3.61 (s, 3H), 3.33 - 3.22 (m, 1H), 3.09 - 3.04 (m, 1H), 2.86 - 2.76 (m, 1H), 2.68 - 2.55 (m, 2H), 2.25 - 2.14 (m, 1H), 2.10 - 1.99 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 355.0 P38594-WOStep 3: Synthesis of 4-(3,4-difluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2- oneTo a stirred solution of methyl 3-(3,4-difluorophenyl)-5-iodopentanoate (750 mg, 2.12 mmol) and 3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-amine (617 mg, 2.54 mmol) in DMA (10 mL) was added K2CO3(1.17 g, 8.47 mmol). The mixture was stirred at 100oC for 16 hours. After cooling to room temperature, the mixture was quenched with water (20 mL) and 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 by flash column chromatography (SiO2, 20% EE (EtOAc / EtOH = 3:1) in petroleum ether) to yield 4-(3,4-difluorophenyl)-1-(3-(pyridin- 4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (350 mg, 47% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+= 355.1 Step 4: Chiral Separation of 4-(3,4-Difluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-4-(3,4-Difluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (180 mg, 0.51 mmol) was separated by chiral SFC (Chiralpak AY (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 85 / 15; 150 mL / min) to afford 4-(3,4-difluorophenyl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex. 34a, peak 1, Rt = 3.719 min, 32.1 mg, 18% yield) and 4-(3,4-difluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 34b, peak 2, Rt =3.786 min, 21.2 mg, 12% yield) both as white solids. Example 34a:1H NMR (DMSO-d6, 400 MHz): δ 8.49 (d, J = 6.0 Hz, 2H), 7.44 - 7.32 (m, 2H), 7.28 - 7.23 (m, 2H), 7.15 - 7.10 (m, 1H), 3.42 - 3.33 (m, 2H), 3.13 - 3.05 (m, 1H), 2.47 - 2.37 (m, 8H), 2.05 - 1.85 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 355.1. Example 34b:1H NMR (DMSO-d6, 400 MHz): δ = 8.49 (d, J = 4.8 Hz, 2H), 7.43 - 7.33 (m, 2H), 7.28 - 7.23 (m, 2H), 7.16 - 7.10 (m, 1H), 3.42 - 3.34 (m, 2H), 3.14 - 3.04 (m, 1H), 2.44 - 2.35 (m, 8H), 2.04 - 1.85 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 355.1. P38594-WOExamples 35a and 35b4-(6-Fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex. 36a and Ex. 36b by replacing 5-bromo-2- chloro-3-fluoro-pyridine with 5-bromo-2-fluoropyridine in step 1. Step 2: Chiral Separation of 4-(6-Fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin- 2-one (Ex 35a & 35b) 4-(6-Fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (108 mg, 0.32 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 70 / 30; 150 mL / min) to give 4-(6-fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan- 1-yl)piperidin-2-one (Ex 35a, peak 1, Rt = 1.316 min, 42 mg, 39% yield) and 4-(6-fluoropyridin-3-yl)-1-(3- (pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 35b, peak 2, Rt = 1.737 min, 37 mg, 34% yield) both as white solids. Example 35a:1H NMR (DMSO-d6, 400 MHz): δ 8.50 (d, J = 6.0 Hz, 2H), 8.16 (d, J = 2.4 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.31 - 7.23 (m, 2H), 7.18 - 7.13 (m, 1H), 3.44 - 3.35 (m, 2H), 3.22 - 3.11 (m, 1H), 2.48 - 2.38 (m, 8H), 2.07 - 1.90 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 338.2 Example 35b:1H NMR (DMSO-d6, 400 MHz): δ 8.54 - 8.46 (m, 2H), 8.16 (d, J = 1.6 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.29 - 7.23 (m, 2H), 7.18 - 7.13 (m, 1H), 3.45 - 3.35 (m, 2H), 3.22 - 3.11 (m, 1H), 2.48 - 2.38 (m, 8H), 2.07 - 1.90 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 338.1 Examples 36a and 36bP38594-WOStep 1: Synthesis of 4-(6-chloro-5-fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-oneA solution of 4-hydroxy-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (200 mg, 0.77 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC, 490 mg, 1.24 mmol) in t-BuOMe (4 mL) was stirred at room temperature for 5 minutes under nitrogen atmosphere. Then pyridine (0.1 mL, 1.24 mmol) in t-BuOMe (2 mL) was added dropwise at room temperature over the course of 5 minutes. The resulting solution was stirred at room temperature for 20 minutes under nitrogen atmosphere, a pink solid precipitated out during this time. Then the solution was filtered and the filtrate was added into another mixture of 5-bromo-2-chloro-3-fluoro- pyridine (155 mg, 0.74 mmol), NiBr2·dtbbpy (27 mg, 0.06 mmol), quinuclidine (144 mg, 1.29 mmol), phthalimide (43 mg, 0.30 mmol) and Ir(ppy)2(dtbbpy)PF6(10 mg, 0.01 mmol) in DMA (2 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). 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 (silica gel, 80 to 100% ethyl acetate in petroleum ether) to afford 4-(6-chloro-5- fluoropyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (140 mg, 49% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+= 372.0 Step 2: Chiral Separation of 4-(6-Chloro-5-fluoro-3-pyridyl)-1-[3-(4-pyridyl)-1-P38594-WO4-(6-Chloro-5-fluoro-3-pyridyl)-1-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentanyl]piperidin-2-one (140 mg, 0.38 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 65 / 35; 80 mL / min) to afford 4-(6-chloro-5-fluoro-3- pyridyl)-1-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentanyl]piperidin-2-one (Ex.36a, peak 1, Rt = 1.890 min, 35 mg, 24% yield) and 4-(6-chloro-5-fluoro-3-pyridyl)-1-[3-(4-pyridyl)-1- bicyclo[1.1.1]pentanyl]piperidin-2-one (Ex 36b, peak 2, Rt = 2.091 min, 38 mg, 27% yield) both as white solids. Example 36a:1H NMR (DMSO-d6, 400 MHz): δ 8.50 (dd, J = 1.6, 4.4 Hz, 2H), 8.26 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 2.0, 9.6 Hz, 1H), 7.26 (dd, J = 1.6, 4.4 Hz, 2H), 3.47 - 3.36 (m, 2H), 3.27 - 3.16 (m, 1H), 2.49 - 2.46 (m, 2H), 2.41 (s, 6H), 2.10 - 1.90 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 372.1 Example 36b:1H NMR (DMSO-d6, 400 MHz): δ 8.50 (dd, J = 1.6, 4.4 Hz, 2H), 8.26 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 2.0, 9.6 Hz, 1H), 7.26 (dd, J = 1.6, 4.4 Hz, 2H), 3.47 - 3.36 (m, 2H), 3.27 - 3.16 (m, 1H), 2.49 - 2.46 (m, 2H), 2.41 (s, 6H), 2.10 - 1.91 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 372.1 Examples 37a and 37bStep 1: 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin- 2-one was prepared using the general procedure described for the preparation of Ex 36a and Ex 36b by replacing 5-bromo-2-chloro-3-fluoro-pyridine with 5-bromo-2-(trifluoromethyl)pyrimidine in Step 1. Step 2: Chiral Separation of 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(2- (trifluoromethyl)pyrimidin-5-yl)piperidin-2-one (Ex.37a & 37b) 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin- 2-one (53 mg, 0.14 mmol) was separated by chiral SFC (Cellulose-2 (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 50 / 50; 150 mL / min) to afford 1-(3-(pyridin-4- P38594-WOyl)bicyclo[1.1.1]pentan-1-yl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin-2-one (Ex. 37a, peak 1, Rt = 1.412 min, 25 mg, 47% yield) and 1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(2- (trifluoromethyl)pyrimidin-5-yl)piperidin-2-one (Ex 37b, peak 2, Rt = 2.065 min, 22 mg, 41% yield) both as white solids. Example 37a:1H NMR (DMSO-d6, 400 MHz): δ 9.04 (s, 2H), 8.50 (d, J = 6.0 Hz, 2H), 7.27 (dd, J = 1.6, 4.4 Hz, 2H), 3.50 - 3.44 (m, 1H), 3.43 - 3.39 (m, 1H), 3.31 - 3.25 (m, 1H), 2.58 (d, J = 8.8 Hz, 2H), 2.46 - 2.39 (m, 6H), 2.18 - 1.97 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 389.2 Example 37b:1H NMR (DMSO-d6, 400 MHz): δ 9.04 (s, 2H), 8.50 (d, J = 6.0 Hz, 2H), 7.27 (d, J = 6.0 Hz, 2H), 3.50 - 3.43 (m, 1H), 3.42 - 3.39 (m, 1H), 3.31 - 3.26 (m, 1H), 2.58 (d, J = 8.8 Hz, 2H), 2.46 - 2.39 (m, 6H), 2.18 - 1.98 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 389.2 Examples 38a and 38bStep 1: Synthesis of 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(6-(trifluoromethyl)pyridin-3- yl)piperidin-2-one 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)piperidin-2- one was prepared using the general procedure described for the preparation of Ex. 36a and Ex.36b by replacing 5-bromo-2-chloro-3-fluoro-pyridine with 5-bromo-2-(trifluoromethyl)pyridine in Step 1. Step 2: Chiral Separation of 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(6- (trifluoromethyl)pyridin-3-yl)piperidin-2-one (Ex.38a & 38b) 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)piperidin-2- one (80 mg, 0.21 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 70 / 30; 70 mL / min) to afford 1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)piperidin-2-one (Ex. 38a, peak 1, Rt = 2.966 min, 21.8 mg, 27% yield) and 1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(6- (trifluoromethyl)pyridin-3-yl)piperidin-2-one (Ex 38b, peak 2, Rt = 3.210 min, 21 mg, 26% yield) both as white solids. P38594-WOExample 38a:1H NMR (DMSO-d6, 400 MHz): δ 8.73 (d, J = 1.6 Hz, 1H), 8.50 (dd, J = 1.6, 4.4 Hz, 2H), 8.02 (dd, J = 1.6, 8.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 1.6, 4.4 Hz, 2H), 3.47 - 3.40 (m, 2H), 3.31 - 3.23 (m, 1H), 2.54 - 2.50 (m, 2H), 2.42 (s, 6H), 2.13 - 1.95 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 388.0. Example 38b:1H NMR (DMSO-d6, 400 MHz): δ 8.73 (d, J = 1.6 Hz, 1H), 8.50 (d, J = 6.0 Hz, 2H), 8.02 (dd, J = 1.6, 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 4.4 Hz, 2H), 3.47 - 3.36 (m, 2H), 3.30 - 3.23 (m, 1H), 2.57 - 2.51 (m, 2H), 2.45 - 2.38 (m, 6H), 2.12 - 1.96 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 388.1. Examples 39a and 39bA solution of 4-bromo-1H-pyrazole (5.0 g, 34 mmol) and K2CO3(14.1 g, 102 mmol) in DMF (50 mL) was added 4-fluoropyridine hydrochloride (6.82 g, 51 mmol). The reaction mixture was stirred at 100oC for 16 hours. After cooling to room temperature, the reaction mixture was poured into H2O (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0-20% ethyl acetate in petroleum ether) to afford 4-(4- bromopyrazol-1-yl)pyridine (4.8 g, 63% yield) as a white solid.1H NMR (DMSO-d6, 400 MHz): δ 9.01 (s, 1H), 8.68 - 8.64 (m, 2H), 8.00 (s, 1H), 7.86 - 7.82 (m, 2H). Step 2: Synthesis of afford 4-(3,4-difluorophenyl)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-one P38594-WOTo a mixture of 4-(4-bromopyrazol-1-yl)pyridine (424 mg,1.89 mmol), 4-(3,4- difluorophenyl)piperidin-2-one (400 mg, 1.89 mmol) in 1,4-dioxane (4 mL) was added DMEDA (0.04 mL, 0.38 mmol), CuI (72 mg, 0.38 mmol) and K2CO3(785 mg, 5.68 mmol). The mixture was stirred at 110oC 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, 50-70% ethyl acetate in petroleum ether) to afford 4- (3,4-difluorophenyl)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-one (400 mg, 60% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+= 371.0 Step 3: Chiral Separation of 4-(3,4-Difluorophenyl)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-4-(3,4-Difluorophenyl)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-one (400 mg, mmol) was separated by chiral SFC (Chiralpak IC (250 × 30 mm, 5 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 75 / 25; 50 mL / min) to give peak 1 (150 mg crude) and peak 2 (150 mg crude). The peak 1 was purified by reverse phase chromatography (acetonitrile: 47-77% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4-(3,4-difluorophenyl)-1-(1-(pyridin-4-yl)-1H- pyrazol-4-yl)piperidin-2-one (Ex.39a, peak 1, Rt = 3.017 min, 96.7 mg, 24% yield) as a white solid. Example 39a:1H NMR (DMSO-d6, 400 MHz): δ 8.87 (s, 1H), 8.65 - 8.61 (m, 2H), 8.26 (s, 1H), 7.88 - 7.84 (m, 2H), 7.51 - 7.36 (m, 2H), 7.21 - 7.16 (m, 1H), 3.85 - 3.75 (m, 2H), 3.28 - 3.22 (m, 1H), 2.72 - 2.64 (m, 2H), 2.20 - 2.09 (m, 2H). LCMS: (ESI, m / z) [M+H] = 355.1 P38594-WOThe peak 2 was purified by reverse phase chromatography (acetonitrile: 47-77% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 4-(3,4-difluorophenyl)-1-(1-(pyridin-4-yl)-1H- pyrazol-4-yl)piperidin-2-one (Ex 39b, peak 2, Rt = 3.567 min, 101.1 mg, 25% yield) as a white solid. Example 39b:1H NMR (DMSO-d6, 400 MHz): δ 8.87 (s, 1H), 8.65 - 8.61 (m, 2H), 8.26 (s, 1H), 7.88 - 7.84 (m, 2H), 7.51 - 7.36 (m, 2H), 7.21 - 7.16 (m, 1H), 3.85 - 3.75 (m, 2H), 3.28 - 3.22 (m, 1H), 2.74 - 2.65 (m, 2H), 2.20 - 2.09 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 355.0 Examples 40a and 40bTo a mixture of 3-bromo-1H-pyrazole (2.0 g, 13.61 mmol) and K2CO3(5.64 g, 40.82 mmol) in DMF (50 mL) was added and 4-fluoropyridine hydrochloride (2.72 g, 20.41 mmol). The mixture was stirred at 100oC for 12 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (45 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 20% EtOAc in petroleum ether) to give 4-(3-bromopyrazol-1-yl)pyridine (1.4 g, 46% yield) as a yellow solid.1H NMR (DMSO-d6, 400 MHz): δ 8.72 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 5.6 Hz, 2H), 7.82 (d, J = 6.4 Hz, 2H), 6.81 (d, J = 2.8 Hz, 1H). LCMS: (ESI, m / z) [M+H]+= 223.9 Step 2: Synthesis of 4-(4-chloro-3-fluorophenyl)-1-(1-(pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-2-one P38594-WOTo a mixture of 4-(3-bromo-1H-pyrazol-1-yl)pyridine (300 mg, 1.34 mmol), 4-(4-chloro-3- fluorophenyl)piperidin-2-one (335 mg, 1.47 mmol) in 1,4-dioxane (8 mL) was added DMEDA (0.03 mL, 0.27 mmol), CuI (51 mg, 0.27 mmol) and K2CO3(555 mg, 4.02 mmol). The mixture was stirred at 110oC for 24 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 reverse phase chromatography (acetonitrile: 43-63% / 0.05% NH4OH + 10 mM NH4HCO3in water) to give 4- (4-chloro-3-fluorophenyl)-1-(1-(pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-2-one (110 mg, 22% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 371.0 Step 3: Chiral Separation of 4-(4-Chloro-3-fluorophenyl)-1-(1-(pyridin-4-yl)-1H-pyrazol-3-4-(4-Chloro-3-fluorophenyl)-1-(1-(pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-2-one (110 mg, 0.30 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to give 4-(4-chloro-3-fluorophenyl)-1-(1-(pyridin- 4-yl)-1H-pyrazol-3-yl)piperidin-2-one (Ex.40a, peak 1, Rt = 1.446 min, 32.6 mg, 29% yield) and 4- (4-chloro-3-fluorophenyl)-1-(1-(pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-2-one (Ex.40b, peak 2, Rt = 1.969 min, 31.4 mg, 28% yield) both as a white solid. Ex 40b was inactive in both of the assays. Example 40a:1H NMR (DMSO-d6, 400 MHz): δ 8.66 (d, J = 2.8 Hz, 1H), 8.64 - 8.58 (m, 2H), 7.85 - 7.77 (m, 2H), 7.56 (t, J = 8.4 Hz, 1H), 7.46 - 7.43 (m, 1H), 7.23 - 7.21 (m, 1H), 7.08 (d, J = 2.8 Hz, 1H), 4.23 - 4.13 (m, 1H), 3.92 - 3.80 (m, 1H), 3.29 - 3.25 (m, 1H), 2.76 - 2.68 (m, 2H), 2.23 - 2.04 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 371.0 P38594-WOExample 40b:1H NMR (DMSO-d6, 400 MHz): δ 8.66 (d, J = 2.8 Hz, 1H), 8.61 (d, J = 6.0 Hz, 2H), 7.86 - 7.77 (m, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 2.8 Hz, 1H), 4.25 - 4.13 (m, 1H), 3.89 - 3.82 (m, 1H), 3.32 - 3.25 (m, 1H), 2.79 - 2.67 (m, 2H), 2.25 - 2.05 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 371.0 Examples 41a and 41bStep 1: Synthesis of 4-(6-fluoropyridin-3-yl)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-oneA solution of 4-hydroxy-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-one (200 mg, 0.77 mmol) and NHC (490 mg, 1.24 mmol) in dioxane (3 mL) and DMA (0.2 mL) was stirred at room temperature for 5 minutes under nitrogen atmosphere. Then pyridine (0.33 mL, 4.12 mmol) in Dioxane (1 mL) was added dropwise over the course of 5 minutes. The resulting solution was stirred at room temperature for 20 minutes under nitrogen atmosphere. A pink solid precipitated out during this time. Then the solution was filtered and the filtrate was added into another mixture of 5-bromo- 2-fluoropyridine (135 mg, 0.77 mmol), NiBr2·dtbbpy (28 mg, 0.06 mmol), phthalimide (45 mg, 0.31 mmol), quinuclidine (149 mg, 1.34 mmol) and Ir(ppy)2(dtbbpy)PF6(11 mg, 0.01 mmol) in DMA (2 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 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 reverse phase chromatography (acetonitrile: 25-55% / 0.05% NH4OH + 10 mM NH4HCO3in water) P38594-WOto afford 4-(6-fluoropyridin-3-yl)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-one (25 mg, 10% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 338.1 Step 2: Chiral Separation of 4-(6-Fluoropyridin-3-yl)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-4-(6-Fluoropyridin-3-yl)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-one (45 mg, 0.13 mmol) was separated by chiral SFC (Chiralpak IH (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 50 / 50; 100 mL / min) to afford 4-(6-fluoropyridin-3-yl)-1-(1-(pyridin-4-yl)- 1H-pyrazol-4-yl)piperidin-2-one (Ex.41a, peak 1, Rt = 1.460 min, 25.3 mg, 45% yield) and 4-(6- fluoropyridin-3-yl)-1-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)piperidin-2-one (Ex 41b, peak 2, Rt = 2.095 min, 20.2 mg, 44% yield) both as white solids. Example 41a:1H NMR (DMSO-d6, 400 MHz): δ 8.87 (s, 1H), 8.63 (d, J = 5.6 Hz, 2H), 8.26 (s, 1H), 8.22 (s, 1H), 8.05 - 7.95 (m, 1H), 7.86 (d, J = 5.6 Hz, 2H), 7.18 (dd, J = 2.4, 8.4 Hz, 1H), 3.92 - 3.72 (m, 2H), 3.33 - 3.27 (m, 1H), 2.79 - 2.65 (m, 2H), 2.25 - 2.10 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 338.2 Example 41b:1H NMR (DMSO-d6, 400 MHz): δ 8.87 (s, 1H), 8.63 (d, J = 5.6 Hz, 2H), 8.26 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.05 - 7.95 (m, 1H), 7.86 (d, J = 6.0 Hz, 2H), 7.18 (dd, J = 2.8, 8.4 Hz, 1H), 3.91 - 3.76 (m, 2H), 3.34 - 3.26 (m, 1H), 2.79 - 2.66 (m, 2H), 2.25 - 2.11 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 338.1 P38594-WOStep 1: Synthesis of tert-butyl 4-(4-chloro-3-fluoro-phenyl)-3-fluoro-2-oxo-piperidine-1-carboxylateTo a solution of tert-butyl 4-(4-chloro-3-fluoro-phenyl)-2-oxo-piperidine-1-carboxylate (1.0 g, 3.05 mmol) in THF (10 mL) was added LDA (2 M, 1.83 mL, 3.66 mmol) at -78 °C dropwise under nitrogen atmosphere. After stirring at -78 °C for 0.5 hour, a solution of NFSI (1.06 g, 3.36 mmol) in THF (5 mL) was added dropwise at -78 °C. After stirring at -78 °C for 1 hour, the reaction was quenched with saturated ammonium chloride solution (10 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with brine (20 mL), and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (SiO2, 20% ethyl acetate in petroleum ether) to afford tert-butyl 4-(4-chloro- 3-fluoro-phenyl)-3-fluoro-2-oxo-piperidine-1-carboxylate (650 mg, 62% yield) as a white solid. LCMS: (ESI, m / z) [M+H-56]+= 290.0P38594-WOA solution of tert-butyl 4-(4-chloro-3-fluoro-phenyl)-3-fluoro-2-oxo-piperidine-1-carboxylate (650 mg, 1.88 mmol) in 5% TFA / HFIP solution (8 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL), and then was adjusted to pH = 8 with saturated NaHCO3solution. The aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 4-(4-chloro-3-fluoro- phenyl)-3-fluoro-piperidin-2-one (450 mg, 97% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 246.1 Step 3: Synthesis of 4-(4-chloro-3-fluorophenyl)-3-fluoro-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-oneTo a mixture of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (346 mg, 0.98 mmol), 4-(4-chloro-3-fluoro-phenyl)-3-fluoro-piperidin-2-one (200 mg, 0.81 mmol) in 1,4-dioxane (8 mL) was added DMEDA (26 uL, 0.24 mmol), CuI (31 mg, 0.16 mmol) and potassium carbonate (337 mg, 2.44 mmol) was added under nitrogen atmosphere. Then the mixture was stirred at 110 °C for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography (SiO2, 30 to 35% ethyl acetate in petroleum ether) to afford 4-(4-chloro-3-fluorophenyl)-3-fluoro-1- (3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (347 mg, 82% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 519.2 Step 4: Synthesis of 4-(4-chloro-3-fluorophenyl)-3-fluoro-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one P38594-WOA solution of 4-(4-chloro-3-fluorophenyl)-3-fluoro-1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (660 mg, 1.27 mmol) in 10% TFA / HFIP solution (10 mL) was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (8 mL), and then treated with aqueous saturated NaHCO3until pH = 8. 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. The crude was purified by reverse phase chromatography (acetonitrile: 45-75% / 0.05% NH4OH + 10 mM NH4HCO3 in water) to afford 4-(4-chloro-3-fluorophenyl)-3- fluoro-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (350 mg, 70% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 389.1 Step 5: Chiral Separation of 4-(4-chloro-3-fluorophenyl)-3-fluoro-1-(3-(pyridin-4-yl)-1H-pyrazol-5-4-(4-chloro-3-fluorophenyl)-3-fluoro-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (350 mg, 0.90 mmol) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 55 / 45; 80 mL / min) to afford cis-4-(4-chloro-3- fluorophenyl)-3-fluoro-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (peak 1, 40 mg crude) and trans-4-(4-chloro-3-fluorophenyl)-3-fluoro-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex. 42b, peak 2, Rt = 3.108 min, 113 mg, 32% yield) and a mixture of peak 3 and peak 4 (160 mg) as white solid. The peak 1 was purified by reverse phase chromatography (acetonitrile: 48-78% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford cis-4-(4-chloro-3-fluorophenyl)-3-fluoro-1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex. 42a, peak 1, Rt = 1.878 min, 26 mg, 7% yield) as a white solid. The peak 3 was separated by chiral SFC (Chiralcel OJ (250 mm x 30 mm, 10 um), P38594-WOSupercritical CO2 / i-PrOH + 0.1% NH4OH = 55 / 45; 80 mL / min) to afford trans-4-(4-chloro-3- fluorophenyl)-3-fluoro-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 42c, peak 3, Rt = 3.787 min, 95 mg, 27% yield) as a white solid. The peak 4 was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 50 / 50; 80 mL / min) to afford cis-4-(4-chloro-3-fluorophenyl)-3-fluoro-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 42d, peak 4, Rt = 4.396 min, 20 mg, 6% yield) as a white solid. Their relative configurations were confirmed by 2D NMR. Example 42a:1H NMR (DMSO-d6, 400 MHz): δ 13.51 (s, 1H), 8.65 (d, J = 4.4 Hz, 2H), 7.74 (d, J = 5.2 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 10.4 Hz, 1H), 7.33 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 5.22 (dd, J = 3.2, 47.6 Hz, 1H), 4.17 - 4.04 (m, 1H), 3.91 - 3.81 (m, 1H), 3.80 - 3.65 (m, 1H), 2.40 - 2.31 (m, 1H), 2.26 - 2.17 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 389.0 Example 42b:1H NMR (DMSO-d6, 400 MHz): δ 13.47 (br s, 1H), 8.65 (d, J = 5.6 Hz, 2H), 7.74 (d, J = 5.6 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 10.4 Hz, 1H), 7.33 - 7.26 (m, 2H), 5.37 (dd, J = 11.2, 47.6 Hz, 1H), 4.14 - 4.03 (m, 1H), 3.97 - 3.84 (m, 1H), 3.63 - 3.47 (m, 1H), 2.36 - 2.24 (m, 1H), 2.22 - 2.11 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 389.0 Example 42c:1H NMR (DMSO-d6, 400 MHz): δ 13.47 (br s, 1H), 8.65 (d, J = 5.2 Hz, 2H), 7.74 (d, J = 5.6 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.35 - 7.26 (m, 2H), 5.37 (dd, J = 11.2, 47.6 Hz, 1H), 4.15 - 4.03 (m, 1H), 3.95 - 3.84 (m, 1H), 3.61 - 3.48 (m, 1H), 2.34 - 2.24 (m, 1H), 2.20 - 2.11 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 389.0 Example 42d:1H NMR (DMSO-d6, 400 MHz): δ 13.49 (br s, 1H), 8.64 (d, J = 6.0 Hz, 2H), 7.75 (d, J = 6.0 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.33 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 5.22 (dd, J = 3.2, 47.2 Hz, 1H), 4.18 - 4.02 (m, 1H), 3.91 - 3.81 (m, 1H), 3.80 - 3.66 (m, 1H), 2.43 - 2.29 (m, 1H), 2.26 - 2.17 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 389.1 Examples 43a and 43bStep 1: Synthesis of 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine P38594-WOA mixture of 4-bromo-3-cyclopropyl-pyridine (5.0 g, 25.2 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.7 g, 30.3 mmol), Pd(dppf)Cl2(1.85 g, 2.5 mmol), KOAc (7.43 g, 75.7 mmol) in 1,4-dioxane (100 mL) was stirred at 90oC for 4 hours under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was used directly in the next step. Step 2: Synthesis of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3- cyclopropylpyridineTo the above solution was added 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole (8.7 g, 24.5 mmol) in 1,4-dioxane (100 mL) and water (5 mL), K2CO3(10.1 g, 73.4 mmol), Pd(dppf)Cl2(1.79 g, 2.5 mmol). The mixture was at 110oC for 2 hours under nitrogen atmosphere. After cooling to room temperature, the was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0-17% ethyl acetate in petroleum ether) to give 4-(5-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3-cyclopropylpyridine (9 g, 93% yield) as brown liquid. LCMS: (ESI, m / z) [M+H]+= 394.1 Step 3: Synthesis of 4-(4-chloro-3-fluorophenyl)-1-(3-(3-cyclopropylpyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one P38594-WO4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3- cyclopropylpyridine (600 mg, 1.5 mmol), 4-(4-chloro-3-fluoro-phenyl)piperidin-2-one (416 mg, 1.8 mmol) in 1,4-dioxane (15 mL) was added DMEDA (0.05 mL, 0.5 mmol), CuI (58 mg, 0.3 mmol) and K2CO3(526 mg, 3.8 mmol). Then the mixture was stirred at 110oC for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and under reduced pressure. The crude was purified by flash column chromatography (SiO2, 0-12% EE (25% ethanol in ethyl acetate) in petroleum ether) to afford 4-(4-chloro-3-fluorophenyl)-1-(3-(3-cyclopropylpyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (250 mg, 30% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 541.3 Step 4: Synthesis of 4-(4-chloro-3-fluorophenyl)-1-(3-(3-cyclopropylpyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-oneA mixture of 4-(4-chloro-3-fluorophenyl)-1-(3-(3-cyclopropylpyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one (270 mg, 0.50 mmol) in 5% TFA / HFIP (10 mL) was stirred at room temperature for 3 hours. The mixture was concentrated and adjust to pH=8 with saturated aqueous NaHCO3solution. The resulting solution was purified by reverse phase chromatography (acetonitrile: 48-78% / 0.05% NH4OH + 10 mM NH4HCO3 in water) to give 4- (4-chloro-3-fluorophenyl)-1-(3-(3-cyclopropylpyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (60 mg, 29% yield) as white powder. LCMS: (ESI, m / z) [M+H]+= 411.1 P38594-WOStep 5: Chiral Separation of 4-(4-Chloro-3-fluorophenyl)-1-(3-(3-cyclopropylpyridin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (Ex.43a & 43b)4-(4-Chloro-3-fluorophenyl)-1-(3-(3-cyclopropylpyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2- one (60 mg, 0.15 mmol) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 um); Supercritical CO2 / EtOH + 0.1% NH4OH = 40 / 60; 80 mL / min) to give 4-(4-chloro-3-fluorophenyl)- 1-(3-(3-cyclopropylpyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex. 43a, peak 1, Rt = 1.728 min, 17.9 mg, 30% yield) and 4-(4-chloro-3-fluorophenyl)-1-(3-(3-cyclopropylpyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one (Ex 43b, peak 2, Rt = 2.397 min, 24.5 mg, 41% yield) both as white solids. Example 43a:1H NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 8.47 (d, J = 4.4 Hz, 1H), 8.38 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.29 - 7.18 (m, 2H), 4.15 - 4.03 (m, 1H), 3.86 - 3.78 (m, 1H), 3.29 - 3.25 (m, 1H), 2.76 - 2.65 (m, 2H), 2.22 - 2.03 (m, 3H), 1.02 - 0.95 (m, 2H), 0.84 - 0.77 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 411.1 Example 43b:1H NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 8.47 (d, J = 4.4 Hz, 1H), 8.38 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.29 - 7.18 (m, 2H), 4.15 - 4.03 (m, 1H), 3.85 - 3.77 (m, 1H), 3.29 - 3.25 (m, 1H), 2.76 - 2.65 (m, 2H), 2.22 - 2.00 (m, 3H), 1.02 - 0.94 (m, 2H), 0.84 - 0.77 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 411.1 Examples 44a and 44bStep 1 — 2: Synthesis of 4-(3-Fluoro-4-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one P38594-WO4-(3-Fluoro-4-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and 9b by replacing (2- fluorophenyl)boronic acid with (3-fluoro-4-(trifluoromethyl)phenyl)boronic acid in Step 1. Step 3: Chiral Separation of 4-(3-Fluoro-4-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-4-(3-Fluoro-4-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (160 mg, 0.40 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 40 / 60; 80 mL / min) to afford 4-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 44a, peak 1, Rt = 1.771 min, 25 mg, 16% yield) and 4-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (Ex 44b, peak 2, Rt = 2.493 min, 20.1 mg, 13% yield) both as white solids. Example 44a:1H NMR (DMSO-d6, 400 MHz): 13.35 (s, 1H), 8.83 (d, J = 4.4 Hz, 2H), 7.81 - 7.70 (m, 3H), 7.55 (d, J = 12.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.28 (br s, 1H), 4.17 - 3.99 (m, 1H), 3.88 - 3.76 (m, 1H), 3.45 - 3.39 (m, 1H), 2.80 - 2.69 (m, 2H), 2.28 - 2.02 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 405.0 Example 44b:1H NMR (DMSO-d6, 400 MHz): 13.35 (s, 1H), 8.83 (d, J = 4.4 Hz, 2H), 7.81 - 7.70 (m, 3H), 7.55 (d, J = 12.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.28 (br s, 1H), 4.20 - 4.01 (m, 1H), 3.90 - 3.73 (m, 1H), 3.46 - 3.39 (m, 1H), 2.81 - 2.69 (m, 2H), 2.26 - 2.04 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 405.0 P38594-WOExample 45Step 1: Synthesis of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrileTo a stirred solution of 3,5-dibromo-1H-pyrazole-4-carbonitrile (2 g, 7.97 mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 229 mg, 9.57 mmol) at 0oC under nitrogen atmosphere. After stirring at 0oC for 30 min, SEM-Cl (2 mL, 11.96 mmol) was slowly added. Then the mixture was stirred at room temperature for 2 h. The reaction was quenched with NH4Cl (10 ml) at 0oC and diluted with H2O (10 mL), then 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 in vacuum. The residue was purified by by flash column chromatography (SiO2, 0 - 3% ethyl acetate in petroleum ether) to afford 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (2.5 g, 82% yield) as colorless oil. Step 2: Synthesis of 5-bromo-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carbonitrileP38594-WOTo a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (2.35 g, 6.17 mmol) and pyridin-4-ylboronic acid (833 mg, 6.78 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added Pd(dppf)Cl2(451 mg, 0.62 mmol) and K2CO3(2.56 g, 18.5 mmol). The mixture was stirred at 100oC for 2 h under nitrogen atmosphere. The mixture was concentrated in vacuum and the residue was purified by flash column chromatography (SiO2, 0 - 10% ethyl acetate in petroleum ether) to afford 5-bromo-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole-4-carbonitrile (1.1 g, 47% yield) as a purple solid. LCMS: (ESI, m / z) [M+H]+= 379.0 Step 3: Synthesis of 5-(4-(4-chloro-3-fluorophenyl)-2-oxopiperidin-1-yl)-3-(pyridin-4-yl)-1-((2-To a solution of 5-bromo-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-carbonitrile (500 mg, 1.32 mmol) and 4-(4-chloro-3-fluorophenyl)piperidin-2-one (360 mg, 1.58 mmol) in 1,4-dioxane (8 mL) was added K3PO4(0.33mL, 3.95mmol) and BrettPhos Pd G3 (120 mg, 0.13 mmol). The mixture was stirred at 100oC for 2 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuum. The residue was purified by flash column chromatography (SiO2, 0-60% ethyl acetate in petroleum ether) to afford 40 mg crude product, which was further purified by pre-TLC (50% ethyl acetate in petroleum ether) to afford 5-(4-(4-chloro-3-fluorophenyl)-2-oxopiperidin-1-yl)-3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (20 mg, 3% yield) as yellow oil. LCMS: (ESI, m / z) [M+H]+= 526.1 Step 4: Synthesis of 5-(4-(4-chloro-3-fluorophenyl)-2-oxopiperidin-1-yl)-3-(pyridin-4-yl)-1H-P38594-WOA solution of 5-(4-(4-chloro-3-fluorophenyl)-2-oxopiperidin-1-yl)-3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (20 mg, 0.04 mmol) in 5% TFA in HFIP (2 mL) was stirred at room temperature for 3 h. The mixture was pH adjusted to 8 with saturated NaHCO3at 0 °C, then extracted by DCM (30 mL x 3). The combined organic layers was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography (acetonitrile: 23-53% / 0.05% NH4OH + 10 mM NH4HCO3in water) to afford 5-(4- (4-chloro-3-fluorophenyl)-2-oxopiperidin-1-yl)-3-(pyridin-4-yl)-1H-pyrazole-4-carbonitrile (6.3 mg, 41% yield) as a white solid. Example 45:1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 6.0 Hz, 2H), 7.85 - 7.76 (m, 2H), 7.56 (t, J = 8.4 Hz, 1H), 7.51 -7.45 (m, 1H), 7.28 - 7.24 (m, 1H), 3.95 - 3.77 (m, 2H), 3.37 - 3.41 (m, 1H), 2.78 -2.71 (m, 2H), 2.21 - 2.10 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 396.0 Example 46Step 1: Synthesis of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4- (2,2,2-trifluoroethyl)piperidin-2-oneTo a mixture of 1,1,1-trifluoro-2-iodoethane (250 mg, 1.19 mmol), 1-(3-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5,6-dihydropyridin-2(1H)-one (500 mg, 1.35 mmol) in MeCN (20 mL) and water (2 mL) was added 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (100 mg, 0.13 mmol) and TEA (0.38 mL, 2.72 mmol). The mixture was purged with nitrogen atmosphere and then sealed. The mixture was placed in the integrated photoreactor (450 nm LED light) for 16 hours. The reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0 - 30% EE (EtOAc:EtOH = 3:1) in petroleum ether) to afford 1-(3- (pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-(2,2,2-trifluoroethyl)piperidin- 2-one (400 mg crude, 13% purity) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 455.3 P38594-WOStep 2: Synthesis of 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(2,2,2-trifluoroethyl)piperidin-2-one (Ex. 46)A solution of 1-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4- (2,2,2-trifluoroethyl)piperidin-2-one (800 mg crued) in 5% TFA / HFIP solution (10 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to remove TFA. Then the reaction residue was poured into water (5 mL), and then treated with aqueous saturated NaHCO3until pH = 8. The mixture was extracted with DCM (3 x 10 mL). The combined organic phases were 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 NH4HCO3in water) to give 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(2,2,2- trifluoroethyl)piperidin-2-one (20.8 mg, 2% yield over two steps) as a yellow oil. Example 46:1H NMR (DMSO-d6, 400 MHz): δ 13.31 (s, 1H), 8.62 (d, J = 4.0 Hz, 2H), 7.71 (d, J = 4.4 Hz, 2H), 7.25 (s, 1H), 4.12 - 3.94 (m, 1H), 3.77 - 3.66 (m, 1H), 2.68 - 2.56 (m, 1H), 2.49 - 2.19 (m, 4H), 2.13 - 2.02 (m, 1H), 1.72 (s, 1H). LCMS: (ESI, m / z) [M+H]+= 325.1 Examples 47a and 47bStep 1 — 2: 1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,4,5-trifluorophenyl)piperidin-2-oneP38594-WO1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,4,5-trifluorophenyl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and 9b by replacing (2- fluorophenyl)boronic acid with (3,4,5-trifluorophenyl)boronic acid in Step 1. Step 3: Chiral Separation of 1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,4,5-trifluorophenyl)piperidin- 2-one (Ex 47a & 47b)1-(3-(Pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,4,5-trifluorophenyl)piperidin-2-one (90 mg, 0.24 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / i- PrOH + 0.1% NH4OH = 50 / 50; 80 mL / min) to afford 1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,4,5- trifluorophenyl)piperidin-2-one (Ex. 47a, peak 1, Rt = 2.271 min, 26.9 mg, 30% yield) and 1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)-4-(3,4,5-trifluorophenyl)piperidin-2-one (Ex. 47b, peak 2, Rt = 2.690 min, 28.0 mg, 31% yield) both as white solid. Example 47a:1H NMR (DMSO-d6, 400 MHz): δ 13.35 (s, 1H), 8.63 (d, J = 4.0 Hz, 2H), 7.72 (d, J = 4.4 Hz, 2H), 7.36 (dd, J = 9.2, 6.8 Hz, 2H), 7.27 (s, 1H), 4.13 - 4.01 (m, 1 H), 3.82 - 3.70 (m, 1H), 3.29 -3.18 (m, 1H), 2.78 - 2.63 (m, 2H), 2.21 - 1.99 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 373.1 Example 47b:1H NMR (DMSO-d6, 400 MHz): δ 13.36 (s, 1H), 8.64 (d, J = 4.0 Hz, 2H), 7.73 (d, J = 4.4 Hz, 2H), 7.37 (dd, J = 9.2, 6.8 Hz, 2H), 7.28 (s, 1H), 4.13 - 4.01 (m, 1 H), 3.83 - 3.71 (m, 1H), 3.29 -3.18 (m, 1H), 2.78 - 2.63 (m, 2H), 2.21 - 1.99 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 373.1 Examples 48a and 48bP38594-WOStep 1 — 2: Synthesis of 4-(4-Chloro-3,5-difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)piperidin-2-one4-(4-Chloro-3,5-difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and Ex 9b by replacing (2-fluorophenyl)boronic acid with (4-chloro-3,5-difluorophenyl)boronic acid in Step 1. Step 3: Chiral Separation of 4-(4-Chloro-3,5-difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-4-(4-Chloro-3,5-difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (160 mg, 0.41 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / i-PrOH + 0.1% NH4OH = 45 / 55; 80 mL / min) to afford 4-(4-chloro-3,5-difluorophenyl)-1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 48a, peak 1, Rt = 2.493 min, 40 mg, 25% yield) and 4-(4-chloro-3,5-difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 48b, peak 2, Rt = 2.944 min, 50.9 mg, 32% yield) both as white solids. Example 48a:1H NMR (DMSO-d6, 400 MHz): δ 13.34 (br s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.77 - 7.69 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.27 (s, 1H), 4.13 - 3.98 (m, 1H), 3.83 - 3.71 (m, Hz, 1H), 2.76 -2.65 (m, 2H), 2.22 - 2.01 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 389.0 Example 48b:1H NMR (DMSO-d6, 400 MHz): δ 13.36 (br s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 4.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.20 (s, 1H), 4.13 - 4.00 (m, 1H), 3.83 - 3.71 (m, Hz, 1H), 2.73 -2.60 (m, 2H), 2.22 - 2.01 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 389.0 P38594-WOExamples 49a and 49b4-(2,4-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and Ex 9b by replacing (2- fluorophenyl)boronic acid with (2,4-difluorophenyl)boronic acid in Step 1. Step 3: Chiral Separation of 4-(2,4-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-4-(2,4-Difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (47 mg, 0.13 mmol) was separated by chiral SFC (Chiralcel OD (250 mm x 30 mm, 10 um), Supercritical CO2 / i- PrOH + 0.1% NH4OH = 65 / 35; 150 mL / min) to 4-(2,4-difluorophenyl)-1-(3-(pyridin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (Ex 49a, peak 1, Rt = 2.341 min, 15 mg, 31% yield) and 4-(2,4- difluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 49b, peak 2, Rt = 2.808 min, 14 mg, 30% yield) both as white solids. Example 49a:1H NMR (DMSO-d6, 400 MHz): δ 13.36 (br s, 1H), 8.63 (d, J = 5.2 Hz, 2H), 7.73 (d, J = 5.2 Hz, 2H), 7.50 - 7.39 (m, 1H), 7.33 - 7.17 (m, 2H), 7.15 - 7.02 (m, 1H), 4.12 - 3.99 (m, 1H), 3.88 - 3.74 (m, 1H), 3.52 - 3.44 (m, 1H), 2.75 - 2.65 (m, 2H), 2.18 - 2.01 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 355.2 Example 49b:1H NMR (DMSO-d6, 400 MHz): δ 13.37 (br s, 1H), 8.63 (d, J = 5.2 Hz, 2H), 7.73 (d, J = 5.6 Hz, 2H), 7.53 - 7.39 (m, 1H), 7.33 - 7.18 (m, 2H), 7.15 - 7.01 (m, 1H), 4.12 - 3.99 (m, P38594-WO1H), 3.90 - 3.76 (m, 1H), 3.56 - 3.42 (m, 1H), 2.75 - 2.65 (m, 2H), 2.18 - 2.01 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 355.2Step 1 — 2: Synthesis of 4-(3-Chloro-4-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin- 2-one4-(3-Chloro-4-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 9a and Ex 9b by replacing (2-fluorophenyl)boronic acid with (3-chloro-4-fluorophenyl)boronic acid in Step 1. Step 3: Chiral Separation of 4-(3-Chloro-4-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-4-(3-Chloro-4-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (50 mg, 0.13 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / i-PrOH + 0.1% NH4OH = 45 / 55; 80 mL / min) to afford 4-(3-chloro-4-fluorophenyl)-1-(3- (pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 50a, peak 1, Rt = 1.149 min, 12.0 mg, 24% yield) and 4-(3-chloro-4-fluorophenyl)-1-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one (Ex 50b, peak 2, Rt = 1.823 min, 11.7 mg, 23% yield) both as white solids. P38594-WOExample 50a:1H NMR (DMSO-d6, 400 MHz): δ 13.35 (br s, 1H), 8.62 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 5.6 Hz, 2H), 7.59 (d, J = 7.2 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.28 (s, 1H), 4.14 - 4.02 (m, 1H), 3.86 - 3.73 (m, 1H), 3.31 - 3.22 (m, 1H), 2.77 - 2.65 (m, 2H), 2.22 - 2.03 (m, 2H). LCMS: (ESI, m / z) [M+Na]+= 393.1 Example 50b:1H NMR (DMSO-d6, 400 MHz): δ 13.34 (br s, 1H), 8.62 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 5.6 Hz, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.23 (s, 1H), 4.11 - 3.97 (m, 1H), 3.86 - 3.73 (m, 1H), 3.31 - 3.22 (m, 1H), 2.76 - 2.64 (m, 2H), 2.22 - 2.03 (m, 2H). LCMS: (ESI, m / z) [M+Na]+= 393.2 Example 51 Step 1: Synthesis of 4-phenyl-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidine-2,6-dione (Ex 51)To a solution of 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetic acid salt (50 mg, 0.13 mmol, 1 equiv.) and 4-phenyloxane-2,6-dione (26 mg, 0.13 mmol, 1.0 equiv.) in tetrahydrofuran (1.3 mL, 0.1 M) was added triethylamine (55 µL, 0.39 mmol, 3.0 equiv.). Resulting solution was stirred at room temperature for 2 hour. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added acetic anhydride (640 uL, 0.2 M) and sodium acetate (14 mg, 0.17 mmol, 1.3 equiv.) and resulting solution was stirred at 140 °C for 2 hour. The product mixture was cooled to room temperature and was added water (3 mL) and stirred in ice bath. To the mixture was slowly added 5N sodium hydroxide solution until pH is neutral. Resulting solution was extracted with isopropyl acetate (5 mL) for 3 times. Organic layers were combined and dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by prep HPLC (XSelect CSH Prep C18, 50 × 30 mm, 5 µm; 0.1% formic acid in water / acetonitrile using a gradient of 5-85% acetonitrile to; 60 mL / min, 25 °C) to afford 4-phenyl-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidine-2,6-dione (24 mg, 57%) as a colorless solid.1H NMR (400 MHz, DMSO) δ 8.53 – 8.47 (m, 2H), 7.39 – 7.27 (m, 4H), 7.30 – 7.21 (m, 3H), 3.49 – 3.33 (m, 1H), 2.94 (dd, J = 16.6, 11.7 Hz, 2H), 2.79 (dd, J = 16.6, 4.3 Hz, 2H), 2.60 (s, 6H). LCMS: (ESI, m / z) [M+H]+= 333.1601. P38594-WOExample 52 Step1: Synthesis of 4-(4-chlorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidine-2,6- dione (Ex 52)To a solution of 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetic acid salt (60 mg, 0.22 mmol, 1 equiv.) and 4-(4-chlorophenyl)dihydro-2H-pyran-2,6(3H)-dione (51 mg, 0.22 mmol, 1.0 equiv.) in tetrahydrofuran (2.2 mL, 0.1 M) was added triethylamine (64 µL, 0.46 mmol, 3.0 equiv.). Resulting solution was stirred at room temperature for 2 hour. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added acetic anhydride (770 uL, 0.2 M) and sodium acetate (16 mg, 0.20 mmol, 1.3 equiv.) and resulting solution was stirred at 140 °C for 2 hours. The product mixture was cooled to room temperature and was added water (3 mL) and stirred in ice bath. To the mixture was slowly added 5N sodium hydroxide solution until pH is neutral. Resulting solution was extracted with isopropyl acetate (5 mL) for 3 times. Organic layers were combined and dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by prep HPLC (XSelect CSH Prep C18, 50 × 30 mm, 5 µm; 0.1% ammonium hydroxide in water / acetonitrile using a gradient of 30-70% acetonitrileto; 60 mL / min, 25 °C) to afford 4-(4- chlorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidine-2,6-dione (35 mg, 62%) as a colorless solid.1H NMR (400 MHz, DMSO) δ 8.52 – 8.45 (m, 2H), 7.45 – 7.37 (m, 2H), 7.37 – 7.30 (m, 2H), 7.30 – 7.24 (m, 2H), 3.45 (tt, J = 11.7, 4.2 Hz, 1H), 2.93 (dd, J = 16.6, 11.8 Hz, 2H), 2.83 – 2.72 (m, 2H), 2.60 (s, 6H). LCMS: (ESI, m / z) [M+H]+= 367.1209 P38594-WOExamples 53a, 53b, 53c, and 53dTo a round bottom flask equipped with a stir bar add (E)-3-(3,4-difluorophenyl)prop-2-enoic acid (5000 mg, 27 mmol, 1 equiv.) and MeOH (50 mL) followed by a few drops of sulfuric acid. The mixture was heated to 60 °C. The mixture was stirred until complete consumption of the starting materials was confirmed by LCMS analysis. At this time, the reaction was cooled to room temperature and amberlyst A21 (free base) was added to remove residual acid. The mixture was stirred for 1 hour, then filtered and concentrated. This afforded methyl (E)-3-(3,4-difluorophenyl)prop-2-enoate (5130 mg, 26 mmol, 95% Yield) as a white powder which was used without further purification.1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 16.0 Hz, 1H), 7.34 (ddd, J = 11.0, 7.6, 2.1 Hz, 1H), 7.25 – 7.11 (m, 2H), 6.35 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H).To a round bottom flask equipped with a stir bar add methyl (E)-3-(3,4-difluorophenyl)prop-2-enoate (5130 mg, 26 mmol, 1 equiv.) and diethyl ether (50 mL). The flask was cooled to 0 °C and then LAH (2950 mg, 78 mmol, 3 equiv.) was added slowly portion-wise. The mixture was stirred at this temperature until complete consumption of the starting materials was confirmed by LCMS analysis. At this time, the reaction was slowly quenched with aqueous Rochelle salt solution, followed by 1M NaOH (aq). The reaction mixture was diluted with a mixture of heptane and iPrOAc (1:3) and stirred vigorously for 5 minutes after which the reaction was allowed to stand at room temperature overnight. The organic fraction was decanted into an Erlenmeyer flask and the aqueous phase was transferred to a separatory funnel. The aqueous mixture was extracted 3x with 3:1 P38594-WOiPrOAc:heptane. The combined organic fractions were dried over MgSO4, filtered, and concentrated. This afforded (E)-3-(3,4-difluorophenyl)prop-2-en-1-ol (4370 mg, 26 mmol, 99% yield) as an oil which was used without further purification.1H NMR (400 MHz, CDCl3) δ 7.23 – 7.14 (m, 1H), 7.14 – 7.03 (m, 2H), 6.54 (d, J = 15.9 Hz, 1H), 6.28 (dt, J = 15.9, 5.5 Hz, 1H), 4.32 (dd, J = 5.5, 1.6 Hz, 2H).To a round bottom flask equipped with a stir bar, the crude alcohol from the previous step was added to DCM (100 mL) followed by TEA (2881 mg, 3.97 mL, 28 mmol, 1.1 equiv.). The mixture was cooled to 0 °C and acetyl chloride (2235 mg, 2.03 mL, 28 mmol, 1.1 equiv.) was added slowly dropwise. The mixture was allowed to warm to room temperature. The mixture was then stirred until complete consumption of the starting materials was confirmed by LCMS analysis. At this time, the mixture was washed with sat. aq. NH4Cl followed by sat. aq. NaHCO3and brine. The organic fraction was dried over MgSO4, filtered, and concentrated. Purification via column (0-20% iPrOAc in heptane) gave [(E)-3-(3,4-difluorophenyl)allyl] acetate (2200 mg, 10.4 mmol, 40% yield) as an oil.1H NMR (400 MHz, CDCl3) δ 7.20 (ddd, J = 11.1, 7.4, 1.6 Hz, 1H), 7.15 – 7.06 (m, 2H), 6.56 (d, J = 15.9 Hz, 1H), 6.20 (dt, J = 15.9, 6.3 Hz, 1H), 4.74 (d, J = 6.3 Hz, 2H), 2.10 (s, 3H). Step 4: Synthesis of 3-(3,4-difluorophenyl)pent-4-enoic acidIn a round bottom flask, the allylic acetate starting material (2200 mg, 10.4 mmol, 1 equiv.) was dissolved in toluene and concentrated to remove water via azeotrope. In the same flask, the dried material was diluted with THF (43 mL) and a stir bar was added. The solution was cooled to -78 °C and then TMSCl (2253 mg, 2.64 mL, 21 mmol, 2 equiv.) was added slowly dropwise. Immediately following this addition, KHMDS (1M in THF) (16000 mg, 17 mL, 15.5 mmol, 1.5 equiv.) was added slowly dropwise. The reaction was stirred at this temperature for 2 hours, then warmed to room temperature and subsequently reflux for 2.5 hours. The reaction was cooled to room temperature and then quenched with sat. aq. NaHCO3and diluted with diethyl ether. The mixture was extracted three times with 1 M NaOH (aq). The combined aqueous layers were acidified to pH = 2 with 2M HCl (aq) and then extracted four times with DCM. The combined DCM fractions were dried over MgSO4, filtered, and concentrated to afford 3-(3,4-difluorophenyl)pent-4-enoic acid (1800 mg, 8.5 mmol, 82% yield) as a yellow oil which was used without further purification. P38594-WO1H NMR (400 MHz, CDCl3) δ 7.09 (dt, J = 9.7, 8.3 Hz, 1H), 7.02 (ddd, J = 11.1, 7.6, 2.2 Hz, 1H), 6.98 – 6.89 (m, 1H), 5.99 – 5.82 (m, 1H), 5.18 – 4.99 (m, 2H), 3.83 (q, J = 7.4 Hz, 1H), 2.78 (dd, J = 15.8, 7.5 Hz, 1H), 2.69 (dd, J = 16.1, 8.2 Hz, 1H). Step 5: cis- and trans-4-(3,4-difluorophenyl)-5-(iodomethyl)dihydrofuran-2(3H)-oneThe alkene starting material was split into two portions for iodolactonization following protocols from this reference: Org. Biomol. Chem., 2013, 11, 1280-1285 Procedure to favor trans isomer: To a vial equipped with a stir bar, 3-(3,4-difluorophenyl)pent-4-enoic acid (700 mg, 3.3 mmol, 1 equiv.) and ACN (13 mL) were added followed by iodine (25.13 mg, 9.9 mmol, 3 equiv.). The mixture was protected from light and stirred at room temperature for 3 hours, then added sat. aq. NaHCO3(7 mL) and stirred an additional hour. On completion, the mixture was diluted with diethyl ether and washed with aq Na2S2O3until the organic layer was colorless. The organic fraction were dried over MgSO4, filtered, and concentrated. Purification via column (10-50% iPrOAc in heptane gradient) gave trans-4-(3,4-difluorophenyl)-5- (iodomethyl)dihydrofuran-2(3H)-one (285 mg, 0.84 mmol, 25% yield) and cis-4-(3,4-difluorophenyl)-5- (iodomethyl)dihydrofuran-2(3H)-one (450 mg, 1.3 mmol, 40% yield). Note: on this scale the reaction is not selective at room temperature, possibly due to exotherm. Running at smaller scale gave higher selectivity, possibly the reaction must be cooled at this scale. Procedure to favor cis isomer: To a vial equipped with a stir bar, 3-(3,4-difluorophenyl)pent-4-enoic acid (700 mg, 3.3 mmol, 1 equiv.) and chloroform (13 mL) were added followed by a solution of sodium bicarbonate (554 mg, 6.6 mmol, 2 equiv.) in water (13 mL). The mixture was cooled to 0 °C while stirring, I2(1675 mg, 6.6 mmol, 2 equiv.) was added and the reaction was protected from light. The mixture was stirred until complete consumption of the starting materials was confirmed by LCMS analysis. On completion, the mixture was diluted with ether and washed with aq Na2S2O3until the organic layer was colorless. The organic fraction was dried over MgSO4, filtered, and concentrated. Purification via column (10-50% iPrOAc in heptane gradient) gave cis-4-(3,4-difluorophenyl)-5- (iodomethyl)dihydrofuran-2(3H)-one (450 mg, 1.3 mmol, 40% yield) and trans-4-(3,4-difluorophenyl)-5- (iodomethyl)dihydrofuran-2(3H)-one (166 mg, 0.43 mmol, 13% yield) Trans isomer:1H NMR (400 MHz, CDCl3) δ 7.19 (dt, J = 9.9, 8.3 Hz, 1H), 7.09 (ddd, J = 10.8, 7.3, 2.3 Hz, 1H), 7.00 (ddt, J = 8.2, 3.8, 1.8 Hz, 1H), 4.29 (dt, J = 6.9, 4.8 Hz, 1H), 3.53 (td, J = 9.1, 6.9 Hz, 1H), 3.46 (dd, J = 11.2, 5.2 Hz, 1H), 3.34 (dd, J = 11.2, 4.2 Hz, 1H), 3.09 (dd, J = 18.0, 9.2 Hz, 1H), 2.74 (dd, J = 18.0, 9.0 Hz, 1H). Cis Isomer: P38594-WO1H NMR (400 MHz, CDCl3) δ 7.17 (dt, J = 9.9, 8.3 Hz, 1H), 7.08 (ddd, J = 10.9, 7.3, 2.3 Hz, 1H), 7.01 – 6.91 (m, 1H), 4.92 (dt, J = 8.5, 5.9 Hz, 1H), 3.87 (ddd, J = 8.6, 5.8, 2.8 Hz, 1H), 3.18 (dd, J = 10.3, 5.9 Hz, 1H), 3.09 (dd, J = 17.7, 8.6 Hz, 1H), 2.77 (dd, J = 17.7, 2.8 Hz, 1H), 2.68 (dd, J = 10.3, 8.5 Hz, 1H). Relative stereochemistry was assigned by analogy to: Org. Biomol. Chem., 2013, 11, 1280-1285 Step 6A: trans-4-(3,4-difluorophenyl)-5-hydroxy-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-oneTo a vial equipped with a stir bar, cis-4-(3,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-2-one (450 mg, 1.3 mmol, 1 equiv.), 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine dihydrochloride (326 mg, 1.4 mmol, 1.05 equiv.), and K2CO3 (736 mg, 5.3 mmol, 4 equiv.) were added followed by MeOH (2.7 mL). The mixture was stirred at 50 °C overnight. At this time 1 mL of MeOH was added and the mixture was heated to 70 °C. After prolonged reaction time the conversion was not improved and the reaction was allowed to cool to room temperature. The mixture was filtered and concentrated, then purified via column (0 to 10% MeOH in DCM) to give the title compound (110 mg, 0.3 mmol, 22% Yield) as a white solid (racemic). Chiral SFC (Chiralpak IA column, 20% MeOH [0.1% NH4OH modifier] in CO2isocratic 20%, flow rate 70 ml / min) afforded 41.9 mg of the fast-eluting enantiomer (Ex 53a, 76% recovery) and 37.3 mg of the slow-eluting enantiomer (Ex 53b, 68% recovery) Example 53a:1H NMR (400 MHz, DMSO) δ 8.53 – 8.47 (m, 2H), 7.42 – 7.30 (m, 2H), 7.29 – 7.23 (m, 2H), 7.14 – 7.07 (m, 1H), 5.16 (d, J = 5.6 Hz, 1H), 4.07 – 3.95 (m, 1H), 3.41 (dd, J = 11.7, 5.2 Hz, 1H), 3.11 (dd, J = 11.7, 8.3 Hz, 1H), 3.02 (td, J = 10.1, 6.0 Hz, 1H), 2.58 – 2.43 (m, 2H), 2.40 (s, 6H). LCMS [M+H]+= 371.16 Example 53b:1H NMR (400 MHz, DMSO) δ 8.53 – 8.47 (m, 2H), 7.42 – 7.30 (m, 2H), 7.29 – 7.23 (m, 2H), 7.13 – 7.07 (m, 1H), 5.16 (d, J = 5.5 Hz, 1H), 4.07 – 3.95 (m, 1H), 3.41 (dd, J = 11.7, 5.2 Hz, 1H), 3.11 (dd, J = 11.8, 8.3 Hz, 1H), 3.02 (td, J = 10.0, 6.0 Hz, 1H), 2.54 – 2.42 (m, 2H), 2.40 (s, 6H). LCMS [M+H]+= 371.16 Step 6B: cis-4-(3,4-difluorophenyl)-5-hydroxy-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-oneTo a vial equipped with a stir bar, trans-4-(3,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-2-one (450 mg, 1.3 mmol, 1 equiv.), 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine dihydrochloride (326 mg, 1.4 mmol, 1.05 equiv.), and K2CO3(736 mg, 5.3 mmol, 4 equiv.) were added followed by MeOH (2.7 mL). The mixture was stirred at 60 °C overnight. At this time the mixture was diluted with DCM and filtered through celite. The filtrate was concentrated and purified via column chromatography (1-10% MeOH in DCM gradient) to afford P38594-WOcis-4-(3,4-difluorophenyl)-5-hydroxy-1-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentanyl]piperidin-2-one (55 mg, 0.15 mmol, 11% Yield) as a white solid. Chiral SFC (Chiralpak IK column, 25% MeOH [0.1% NH4OH modifier] in CO2isocratic 25%, flow rate 70 ml / min) afforded 8.0 mg of the fast-eluting enantiomer (Ex 34c, 29% recovery) and 9.4 mg of the slow-eluting enantiomer (Ex 53d, 34% recovery). Example 53c:1H NMR (400 MHz, DMSO) δ 8.53 – 8.47 (m, 2H), 7.44 – 7.30 (m, 2H), 7.30 – 7.24 (m, 2H), 7.21 – 7.12 (m, 1H), 5.24 (d, J = 3.8 Hz, 1H), 4.08 (s, 1H), 3.55 – 3.37 (m, 1H), 3.1 – 3.3 (m, 2H), 2.70 (dd, J = 16.8, 12.7 Hz, 1H), 2.45 – 2.27 (m, 7H). LCMS [M+H]+= 371.16 Example 53d:1H NMR (400 MHz, DMSO) δ 8.59 – 8.38 (m, 2H), 7.46 – 7.31 (m, 2H), 7.31 – 7.24 (m, 2H), 7.21 – 7.11 (m, 1H), 5.24 (d, J = 3.8 Hz, 1H), 4.08 (s, 1H), 3.51 (dd, J = 12.5, 3.1 Hz, 1H), 3.30 – 3.20 (m, 2H), 2.70 (dd, J = 16.8, 12.7 Hz, 1H), 2.45 – 2.36 (m, 6H), 2.32 (dd, J = 16.9, 5.4 Hz, 1H). LCMS [M+H]+= 371.16 Example 54 Step 1: Synthesis of 1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(4- (trifluoromethyl)phenyl)piperidine-2,6-dione (Ex.54)To a solution of 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetic acid salt (50 mg, 0.13 mmol, 1 equiv.) and 4-(4-(trifluoromethyl)phenyl)dihydro-2H-pyran-2,6(3H)-dione (34 mg, 0.13 mmol, 1.0 equiv.) in tetrahydrofuran (1.3 mL, 0.1 M) was added triethylamine (53 µL, 0.38 mmol, 3.0 equiv.). Resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added acetic anhydride (640 uL, 0.2 M) and sodium acetate (14 mg, 0.17 mmol, 1.3 equiv.) and resulting solution was stirred at 140 °C for 2 hours. The product mixture was cooled to room temperature and diluted with water (3 mL) and stirred in ice bath. To the mixture was slowly added 5N sodium hydroxide solution until pH was neutral. Resulting solution was extracted with isopropyl acetate (5 mL) for 3 times. Organic layers were combined and dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by prep HPLC (XSelect CSH Prep C18, 50 × 30 mm, 5 µm; 0.1% P38594-WOformic acid in water / acetonitrile using a gradient of 5-85%; 60 mL / min, 25 °C) to afford 1-(3- (pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(4-(trifluoromethyl)phenyl)piperidine-2,6-dione (31 mg, 61%) as a colorless solid.1H NMR (400 MHz, DMSO) δ 8.50 (d, J = 5.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 4.9 Hz, 2H), 3.58 (tt, J = 11.7, 4.3 Hz, 1H), 2.99 (dd, J = 16.6, 12.0 Hz, 2H), 2.83 (dd, J = 16.5, 4.3 Hz, 2H), 2.61 (s, 6H). LCMS: (ESI, m / z) [M+H]+= 401.1485 Example 55 Step 1: Synthesis of 4-(4-chloro-3-fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-To a solution of 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetic acid salt (69 mg, 0.18 mmol, 1 equiv.) and 4-(4-chloro-3-fluorophenyl)dihydro-2H-pyran-2,6(3H)-dione (45 mg, 0.18 mmol, 1.0 equiv.) in tetrahydrofuran (1.8 mL, 0.1 M) was added triethylamine (75 µL, 0.54 mmol, 3.0 equiv.). Resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added acetic anhydride (890 uL, 0.2 M) and sodium acetate (19 mg, 0.23 mmol, 1.3 equiv.) and resulting solution was stirred at 140 °C for 2 hours. The product mixture was cooled to room temperature and diluted with water (3 mL) and stirred in ice bath. To the mixture was slowly added 5N sodium hydroxide solution until pH was neutral. Resulting solution was extracted with isopropyl acetate (5 mL) for 3 times. Organic layers were combined and dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by prep HPLC (Triart C18, 50 × 30 mm, 5 µm; 0.1% formic acid in water / acetonitrile using a gradient of 20-60%; 60 mL / min, 25 °C) to 4-(4-chloro-3-fluorophenyl)- 1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidine-2,6-dione (48 mg, 70%) as a colorless solid.1H NMR (400 MHz, DMSO) δ 8.53 – 8.47 (m, 2H), 7.57 (t, J = 8.1 Hz, 1H), 7.52 – 7.32 (m, 1H), 7.30 – 7.24 (m, 2H), 7.22 – 7.11 (m, 1H), 3.49 (tt, J = 12.0, 4.3 Hz, 1H), 3.00 – 2.88 (m, 2H), 2.84 – 2.74 (m, 2H), 2.60 (s, 6H). LCMS: (ESI, m / z) [M+H]+= 385.1110 P38594-WOExample 56 Step 1: Synthesis of 4-(4-fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidine-2,6- dione (Ex 56)To a solution of 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetic acid salt (57 mg, 0.15 mmol, 1 equiv.) and 4-(4-fluorophenyl)dihydro-2H-pyran-2,6(3H)-dione (36 mg, 0.16 mmol, 1.1 equiv.) in tetrahydrofuran (1.5 mL, 0.1 M) was added triethylamine (62 µL, 0.44 mmol, 3.0 equiv.). Resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added acetic anhydride (735 uL, 0.2 M) and sodium acetate (16 mg, 0.19 mmol, 1.3 equiv.) and resulting solution was stirred at 140 °C for 2 hours. The product mixture was cooled to room temperature and diluted with water (3 mL) and stirred in ice bath. To the mixture was slowly added 5N sodium hydroxide solution until pH was neutral. Resulting solution was extracted with isopropyl acetate (5 mL) for 3 times. Organic layers were combined and dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by prep HPLC (Gemini-NX C18, 50 × 30 mm, 5 µm; 0.1% formic acid in water / acetonitrile using a gradient of 5-85%; 60 mL / min, 25 °C) to 4-(4-fluorophenyl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidine-2,6-dione (40 mg, 78%) as a colorless solid.1H NMR (400 MHz, DMSO) δ 8.53 – 8.47 (m, 2H), 7.35 (qd, J = 6.1, 2.5 Hz, 2H), 7.33 – 7.25 (m, 2H), 7.23 – 7.13 (m, 2H), 3.45 (tt, J = 12.0, 4.0 Hz, 1H), 2.93 (dd, J = 16.6, 11.9 Hz, 2H), 2.78 (dd, J = 16.5, 4.3 Hz, 2H), 2.61 (s, 6H). LCMS: (ESI, m / z) [M+H]+= 351.1504 Example 57 Step 1: Synthesis of 1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(6-(trifluoromethyl)pyridin-3- yl)piperidine-2,6-dione (Ex 57) P38594-WOTo a solution of 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetic acid salt (55 mg, 0.14 mmol, 1 equiv.) and 4-(6-(trifluoromethyl)pyridin-3-yl)dihydro-2H-pyran-2,6(3H)-dione (40 mg, 0.16 mmol, 1.1 equiv.) in tetrahydrofuran (1.4 mL, 0.1 M) was added triethylamine (59 µL, 0.42 mmol, 3.0 equiv.). Resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added acetic anhydride (700 uL, 0.2 M) and sodium acetate (15 mg, 0.18 mmol, 1.3 equiv.) and resulting solution was stirred at 140 °C for 2 hours. The product mixture was cooled to room temperature and diluted with water (3 mL) and stirred in ice bath. To the mixture was slowly added 5N sodium hydroxide solution until pH was neutral. Resulting solution was extracted with isopropyl acetate (5 mL) for 3 times. Organic layers were combined and dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by prep HPLC (XSelect CSH Prep C18, 50 × 30 mm, 5 µm; 0.1% formic acid in water / acetonitrile using a gradient of 5-50%; 60 mL / min, 25 °C) to afford 1-(3- (pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)piperidine-2,6-dione (48 mg, 85%) as a colorless solid.1H NMR (400 MHz, DMSO) δ 8.76 (d, J = 2.2 Hz, 1H), 8.54 – 8.48 (m, 2H), 8.04 (dd, J = 8.3, 2.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.32 – 7.26 (m, 2H), 3.67 (tt, J = 12.3, 4.3 Hz, 1H), 3.04 (ddt, J = 17.0, 12.4, 1.3 Hz, 2H), 2.93 – 2.83 (m, 2H), 2.62 (s, 6H). LCMS: (ESI, m / z) [M+H]+= 402.1435 Example 584-(4-Fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 36a and Ex 36b by replacing 5-bromo-2-chloro-3-fluoro-pyridine with 5-bromo-2-(trifluoromethyl)pyridine in Step 1. The crude was purified by reverse phase chromatography (acetonitrile: 46-76% / 10 mM NH4HCO3 in water) to obtain 4-(3-fluorophenyl)-1-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentanyl]piperidin-2-one (54 mg, 21% yield) as a white solid. P38594-WO1H NMR (DMSO-d6, 400 MHz): δ 8.50 (dd, J =1.6, 4.4 Hz, 2H), 7.31 (dd, J = 2.8, 8.4 Hz, 2H), 7.28 - 7.23 (m, 2H), 7.14 (t, J = 9.2 Hz, 2H), 3.43 - 3.34 (m, 2H), 3.14 - 3.02 (m, 1H), 2.45 - 2.37 (m, 8H), 2.05 - 1.84 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 337.2 Example 59a and 59b Step 1: Synthesis of 4-(6-(Difluoromethyl)pyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin- 2-one4-(6-(Difluoromethyl)pyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 36a and 36b by replacing 5-bromo-2- chloro-3-fluoro-pyridine with 5-bromo-2-(difluoromethyl)pyridine in step 1. Step 2: Chiral Separation of 4-(6-(Difluoromethyl)pyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-one (Ex 59a & 59b) 4-(6-(Difluoromethyl)pyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (76 mg, 0.21 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to afford 4-(6-(difluoromethyl)pyridin-3-yl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex. 59a, peak 1, Rt = 1.753 min, 17.8 mg, 23% yield) and 4-(6- (difluoromethyl)pyridin-3-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 59b peak 2, Rt = 2.165 min, 19.7 mg, 26% yield) both as white solids. Example 59a:1H NMR (DMSO-d6, 400 MHz): δ 8.64 (s, 1H), 8.50 (d, J = 4.8 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 5.2 Hz, 2H), 6.93 (t, J = 55.2 Hz, 1H), 3.47 - 3.34 (m, 4H), 3.28 - 3.17 (m, 1H), 2.55 - 2.50 (m, 2 H), 2.46 - 2.39 (m, 6H), 2.11 - 1.93 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 370.1 Example 59b:1H NMR (DMSO-d6, 400 MHz): δ 8.64 (s, 1H), 8.50 (d, J = 4.8 Hz, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 5.2 Hz, 2H), 6.93 (t, J = 55.2 Hz, 1H), 3.47 - 3.34 (m, 2H), 3.28 - 3.18 (m, 1H), 2.55 - 2.50 (m, 2 H), 2.46 - 2.38 (m, 6H), 2.12 - 1.94 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 370.1 P38594-WOExamples 60a and 60b Step 1: Synthesis of 4-(5-Fluoropyridin-2-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2- one4-(5-Fluoropyridin-2-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 36a and 36b by replacing 5- bromo-2-chloro-3-fluoro-pyridine with 2-bromo-5-fluoropyridine in Step 1. Step 2: Chiral Separation of 4-(5-Fluoropyridin-2-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-one (Ex 60a & 60b) 4-(5-Fluoropyridin-2-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (60 mg, 0.18 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 55 / 45; 80 mL / min) to afford 4-(5-fluoropyridin-2-yl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 60a, peak 1, Rt = 1.888 min, 21 mg, 35% yield) and 4-(5-fluoropyridin-2-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 60b, peak 2, Rt = 2.111 min, 20 mg, 33% yield) both as white solids. Example 60a:1H NMR (400 MHz, DMSO-d6) δ 8.55 - 8.45 (m, 3H), 7.72 - 7.66 (m, 1H), 7.43 (dd, J = 4.4, 8.4 Hz, 1H), 7.26 (dd, J = 1.6, 4.4 Hz, 2H), 3.44 - 3.24 (m, 3H), 2.60 - 2.55 (m, 2H), 2.40 (s, 6H), 2.16 - 2.05 (m, 1H), 1.97 - 1.85 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 338.1 Example 60b:1H NMR (400 MHz, DMSO-d6) δ 8.55 - 8.45 (m, 3H), 7.72 - 7.66 (m, 1H), 7.43 (dd, J = 4.4, 8.8 Hz, 1H), 7.26 (dd, J = 1.6, 4.4 Hz, 2H), 3.44 - 3.22 (m, 3H), 2.56 - 2.52 (m, 2H), 2.40 (s, 6H), 2.15 - 2.06 (m, 1H), 1.96 - 1.85 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 338.1 Examples 61 Step 1: Synthesis of 4-(3,5-difluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidine- 2,6-dione (Ex.61) P38594-WOTo a solution of 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetic acid salt (53 mg, 0.14 mmol, 1 equiv.) and 4-(3,5-difluorophenyl)dihydro-2H-pyran-2,6(3H)-dione (95 mg, 0.41 mmol, 1.1 equiv.) in tetrahydrofuran (1.4 mL, 0.1 M) was added triethylamine (57 µL, 0.41 mmol, 3.0 equiv.). Resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added acetic anhydride (680 uL, 0.2 M) and sodium acetate (15 mg, 0.18 mmol, 1.3 equiv.) and resulting solution was stirred at 140 °C for 2 hours. The product mixture was cooled to room temperature and diluted with water (3 mL) and stirred in ice bath. To the mixture was slowly added 5N sodium hydroxide solution until pH was neutral. Resulting solution was extracted with isopropyl acetate (5 mL) for 3 times. Organic layers were combined and dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by prep HPLC (XSelect CSH Prep C18, 50 × 30 mm, 5 µm; 0.1% ammonium hydroxide in water / acetonitrile using a gradient of 30-70%; 60 mL / min, 25 °C) to afford 4-(3,5-difluorophenyl)- 1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidine-2,6-dione (8 mg, 16%) as a colorless solid.1H NMR (400 MHz, DMSO) δ 8.53 – 8.47 (m, 2H), 7.31 – 7.25 (m, 2H), 7.18 – 7.08 (m, 2H), 7.11 – 7.05 (m, 1H), 3.50 (tt, J = 12.1, 4.3 Hz, 1H), 2.95 (dd, J = 16.6, 12.2 Hz, 2H), 2.81 (dd, J = 16.7, 4.3 Hz, 2H), 2.61 (s, 6H). LCMS: (ESI, m / z) [M+H]+= 369.1416 Example 62 Step 1: Synthesis of 1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(3,4,5-trifluorophenyl)piperidine-2,6-dione (Ex 62)To a solution of 3-(4-pyridyl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetic acid salt (57 mg, 0.15 mmol, 1 equiv.) and 4-(3,4,5-trifluorophenyl)dihydro-2H-pyran-2,6(3H)-dione (40 mg, 0.16 mmol, 1.1 equiv.) in tetrahydrofuran (1.5 mL, 0.1 M) was added triethylamine (62 µL, 0.44 mmol, 3.0 equiv.). Resulting solution P38594-WOwas stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added acetic anhydride (740 uL, 0.2 M) and sodium acetate (16 mg, 0.19 mmol, 1.3 equiv.) and resulting solution was stirred at 140 °C for 2 hours. The product mixture was cooled to room temperature and diluted with water (3 mL) and stirred in ice bath. To the mixture was slowly added 5N sodium hydroxide solution until pH was neutral. Resulting solution was extracted with isopropyl acetate (5 mL) for 3 times. Organic layers were combined and dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by prep HPLC (XSelect CSH Prep C18, 50 × 30 mm, 5 µm; 0.1% formic acid in water / acetonitrile using a gradient of 5-50%; 60 mL / min, 25 °C) to afford 1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)-4-(3,4,5-trifluorophenyl)piperidine-2,6-dione (29 mg, 51%) as a colorless solid.1H NMR (400 MHz, DMSO) δ 8.53 – 8.47 (m, 2H), 7.39 – 7.24 (m, 4H), 3.49 (tt, J = 12.3, 4.3 Hz, 1H), 2.93 (ddt, J = 16.9, 12.3, 1.4 Hz, 2H), 2.85 – 2.75 (m, 2H), 2.61 (s, 6H). LCMS: (ESI, m / z) [M+H]+= 387.1319 Examples 63a and 63bStep 1: Synthesis of 4-(2-(Difluoromethyl)pyrimidin-5-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-one 4-(2-(Difluoromethyl)pyrimidin-5-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin- 2-one was prepared using the general procedure described for the preparation of Ex 63a and Ex 36b by replacing 5-bromo-2-chloro-3-fluoro-pyridine with 5-bromo-2-(difluoromethyl)pyrimidine in Step 1. Step 2: Chiral Separation of 4-(2-(Difluoromethyl)pyrimidin-5-yl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex.63a & 63b) 4-(2-(Difluoromethyl)pyrimidin-5-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin- 2-one (47 mg, 0.13 mmol) was separated by chiral SFC (Cellulose-2 (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 45 / 55; 150 mL / min) to afford 4-(2- (difluoromethyl)pyrimidin-5-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 63a, peak 1, Rt = 2.355 min, 16.7 mg, 36% yield) and 4-(2-(difluoromethyl)pyrimidin-5-yl)-1-(3- P38594-WO(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 63b, peak 2, Rt = 3.449 min, 15.8 mg, 34% yield) both as white solids. Example 63a:1H NMR (CDCl3, 400 MHz): δ 8.76 (s, 2H), 8.54 (d, J = 5.6 Hz, 2H), 7.19 - 7.12 (m, 2H), 6.68 (t, J = 54.4 Hz, 1H), 3.57 - 3.40 (m, 2H), 3.30 - 3.17 (m, 1H), 2.86 - 2.73 (m, 1H), 2.61 - 2.53 (m, 1H), 2.51 (s, 6H), 2.32 - 2.19 (m, 1H), 2.16 - 1.99 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 371.0 Example 63b:1H NMR (CDCl3, 400 MHz): δ 8.76 (s, 2H), 8.55 (d, J = 5.6 Hz, 2H), 7.15 (d, J = 6.0 Hz, 2H), 6.68 (t, J = 54.4 Hz, 1H), 3.57 - 3.40 (m, 2H), 3.30 - 3.18 (m, 1H), 2.86 - 2.73 (m,1H), 2.61 - 2.53 (m, 1H), 2.51 (s, 6H), 2.30 - 2.20 (m, 1H), 2.17 - 2.01 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 371.2Step 1: Synthesis of 4-(Isothiazol-5-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one 4-(Isothiazol-5-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 36a and Ex 36b by replacing 5- bromo-2-chloro-3-fluoro-pyridine with 5-bromoisothiazole in step 1. Step 2: Chiral Separation of 4-(Isothiazol-5-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-one (Ex 64a & 64b) 4-(Isothiazol-5-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (100 mg, 0.31 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to afford 4-(isothiazol-5-yl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 64a, peak 1, Rt = 1.939 min, 18.9 mg, 19% yield) as a white solid and 30 mg crude peak. The crude peak2 was further seperated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to afford 4-(isothiazol-5-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 64b, peak 2, Rt = 2.170 min, 23.8 mg, 24% yield) as a white solid. P38594-WOExample 64a:1H NMR (DMSO-d6, 400 MHz): δ 8.53 - 8.45 (m, 3H), 7.30 (s, 1H), 7.28 - 7.23 (m, 2H), 3.67 - 3.56 (m, 1H), 3.41 - 3.35 (m, 2H), 2.72 - 2.64 (m, 1H), 2.48 - 2.42 (m, 1H), 2.41 - 2.36 (s, 6H), 2.28 - 2.17 (m, 1H), 2.00 - 1.87 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 325.9 Example 64b:1H NMR (DMSO-d6, 400 MHz): δ 8.56 - 8.45 (m, 3H), 7.30 (d, J = 0.8 Hz, 1H), 7.28 - 7.21 (m, 2H), 3.67 - 3.55 (m, 1H), 3.44 - 3.34 (m, 2H), 2.72 - 2.64 (m, 1H), 2.47 - 2.42 (m, 1H), 2.41 - 2.36 (m, 6H), 2.27 - 2.16 (m, 1H), 2.00 - 1.86 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 326.1 Examples 65a and 65bStep 1: Synthesis of 4-(3-Fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one 4-(3-Fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 36a and Ex 36b by replacing 5-bromo-2-chloro-3-fluoro-pyridine with 1-bromo-3-fluorobenzene in step 1. Step 2: Chiral Separation of 4-(3-Fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-one (Ex 65a & 65b) 4-(3-Fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (50 mg, 0.15 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 70 / 30; 80 mL / min) to afford 4-(3-fluorophenyl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 65a, peak 1, Rt = 1.794 min, 22 mg, 43% yield) and 4-(3-fluorophenyl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 65b, peak 2, Rt = 1.988 min, 20 mg, 40% yield) both as white solid. Example 65a:1H NMR (DMSO-d6, 400 MHz): δ 8.50 (d, J = 6.0 Hz, 2H), 7.41 - 7.32 (m, 1H), 7.29 - 7.23 (m, 2H), 7.19 - 7.10 (m, 2H), 7.08 - 7.01 (m, 1H), 3.42 - 3.37 (m, 2H), 3.17 - 3.04 (m, 1H), 2.47 - 2.36 (m, 8H), 2.07 - 1.86 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 337.2 P38594-WOExample 65b:1H NMR (DMSO-d6, 400 MHz): δ 8.49 (d, J = 4.8 Hz, 2H), 7.41 - 7.32 (m, 1H), 7.26 (d, J = 5.2 Hz, 2H), 7.19 - 7.10 (m, 2H), 7.09 - 7.00 (m, 1H), 3.44 - 3.37 (m, 2H), 3.16 - 3.04 (m, 1H), 2.46 - 2.34 (m, 8H), 2.08 - 1.85 (m, 2H). LCMS: (ESI, m / z) [M+H]+= 337.2 Examples 66a and 66bStep 1: Synthesis of 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(2-(trifluoromethyl)thiazol-5- yl)piperidin-2-one 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(2-(trifluoromethyl)thiazol-5-yl)piperidin-2- one was prepared using the general procedure described for the preparation of Ex 36a and Ex 36b by replacing 5-bromo-2-chloro-3-fluoro-pyridine with 5-bromo-2-(trifluoromethyl)thiazole in step 1. Step 2: Chiral Separation of 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(2- (trifluoromethyl)thiazol-5-yl)piperidin-2-one (Ex.66a & 66b) 1-(3-(Pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(2-(trifluoromethyl)thiazol-5-yl)piperidin-2- one (60 mg, 0.15 mmol) was separated by chiral SFC (Chiralcel IC (250 mm x 30 mm, 10 um), Supercritical CO2 / i-PrOH + 0.1% NH4OH = 55 / 45; 80 mL / min) to 1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)-4-(2-(trifluoromethyl)thiazol-5-yl)piperidin-2-one (Ex 66a, peak 1, Rt = 2.418 min, 17.2 mg, 28% yield) and 1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-4-(2- (trifluoromethyl)thiazol-5-yl)piperidin-2-one (Ex 66b, peak 2, Rt = 3.006 min, 20.2 mg, 33%) both as white solids. Example 66a:1H NMR (DMSO-d6, 400 MHz): δ 8.49 (d, J = 5.6 Hz, 2H), 8.00 (s, 1H), 7.26 (d, J = 6.0 Hz, 2H), 3.67 - 3.56 (m, 1H), 3.43 - 3.38 (m, 2H), 2.74 - 2.65 (m, 1H), 2.54 -2.51 (m, 1H), 2.41 (s, 6H), 2.29 - 2.20 (m, 1H), 2.02 - 1.90 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 394.0 Example 66b:1H NMR (DMSO-d6, 400 MHz): δ 8.49 (d, J = 6.0 Hz, 2H), 8.00 (s, 1H), 7.28 - 7.24 (m, 2H), 3.67 - 3.56 (m, 1H), 3.43 - 3.38 (m, 2H), 2.74 - 2.66 (m, 1H), 2.54 -2.50 (m, 1H), 2.40 (s, 6H), 2.29 - 2.20 (m, 1H), 2.02 - 1.89 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 394.1. P38594-WOExamples 67a and 67bStep 1: Synthesis of 4-(2-Fluoropyridin-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin- 2-one 4-(2-Fluoropyridin-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 36a and Ex 36b by replacing 5-bromo-2-chloro-3-fluoro-pyridine with 4-bromo-2-fluoropyridine in step 1. Step 2: Chiral Separation of 4-(2-fluoropyridin-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-one (Ex 67a & 67b) 4-(2-fluoropyridin-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (77 mg, 0.23 mmol) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 55 / 45; 80 mL / min) to give 4-(2-fluoropyridin-4-yl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 67a, peak 1, Rt = 3.902 min, 26 mg, 33% yield) and 4-(2-fluoropyridin-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 67b, peak 2, Rt = 4.541 min, 26 mg, 33% yield) both as white solids. Example 67a:1H NMR (CDCl3, 400 MHz): δ 8.55 (d, J = 3.6 Hz, 2H), 8.20 (d, J = 5.2 Hz, 1H), 7.17 (d, J = 5.6 Hz, 2H), 7.04 (d, J = 5.2 Hz, 1H), 6.78 (s, 1H), 3.52 - 3.35 (m, 2H), 3.22 - 3.08 (m, 1H), 2.80 - 2.67 (m, 1H), 2.51 (s, 6H), 2.50 - 2.44 (m, 1H), 2.26 - 2.14 (m, 1H), 2.05 - 1.92 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 338.1 Example 67b:1H NMR (DMSO-d6, 400 MHz): δ 8.50 (d, J = 5.6 Hz, 2H), 8.18 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.28 - 7.23 (m, 2H), 7.13 (s, 1H), 3.45 - 3.37 (m, 2H), 3.25 - 3.14 (m, 1H), 2.49 - 2.44 (m, 2H), 2.41 (s, 6H), 2.13 - 2.03 (m, 1H), 2.02 - 1.87 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 338.1 P38594-WOExamples 68a and 68bStep 1: Synthesis of 4-(Isothiazol-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one 4-(Isothiazol-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one was prepared using the general procedure described for the preparation of Ex 36a and Ex 36b by replacing 5- bromo-2-chloro-3-fluoro-pyridine with 4-bromoisothiazole in step 1. Step 2: Chiral Separation of 4-(Isothiazol-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1- yl)piperidin-2-one (Ex.68a & 68b) 4-(Isothiazol-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (130 mg, 0.35 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH4OH = 40 / 60; 80 mL / min) to give 4-(isothiazol-4-yl)-1-(3-(pyridin-4- yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 68a, peak 1, Rt = 2.238m min, 35 mg, 23% yield) and 4-(isothiazol-4-yl)-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-2-one (Ex 68b, peak 2, Rt = 2.902 min, 34 mg, 21% yield) both as white solids. Example 68a:1H NMR (DMSO-d6, 400 MHz): δ 8.79 (s, 1H), 8.58 (s, 1H), 8.49 (d, J = 5.6 Hz, 2H), 7.25 (d, J = 6.0 Hz, 2H), 3.38 - 3.25 (m, 3H), 2.66 - 2.57 (m, 1H), 2.48 - 2.43 (m, 1H), 2.40 (s, 6H), 2.21 - 2.11 (m, 1H), 1.97 - 1.82 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 326.1 Example 68b:1H NMR (DMSO-d6, 400 MHz): δ 8.79 (s, 1H), 8.58 (s, 1H), 8.49 (d, J = 5.2 Hz, 2H), 7.26 (d, J = 6.0 Hz, 2H), 3.38 - 3.22 (m, 3H), 2.67 - 2.56 (m, 1H), 2.48 - 2.43 (m, 1H), 2.40 (s, 6H), 2.23 - 2.11 (m, 1H), 1.96 - 1.82 (m, 1H). LCMS: (ESI, m / z) [M+H]+= 325.9 Examples 69a and 69bP38594-WOStep 1: Synthesis of 4-(2-Oxo-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-4-yl)benzonitrile 4-(2-Oxo-1-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)piperidin-4-yl)benzonitrile was prepared using the general procedure described for the preparation of Ex 36a an...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof; wherein:X1is CR7or N; X2is CR4, CHR4, or N; X3is absent, CH, CH2, NH, or S; X4is N, CH2, CH, NH, O, or S; X5is CR8; Y is absent, CR5R6, or CH2CH2, wherein R5and R6are independently H, OH, CN, halo, C1-6alkyl, or C1-6cycloalkyl, or R5and R6, taken together with the carbon to which they are bonded, form a C3-6cycloalkyl; Z is CH or N; one of Q1and Q2is N and the other is CR4; one of Q3and Q4is N and the other is CR4; or Q3and Q4are CR4; R1ais H or C1-6alkyl; R1bis selected from C6-10aryl, 5- to 10-membered heteroaryl, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, bicyclo[1.1.1]pentan-1-yl, and C1-6alkyl substituted with C6-10aryl or C1-6haloalkoxy; 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 C1-6alkyl, halo, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl; or P38594-WOR1aand R1btaken together with the carbon to which they are bonded, form a C3-6cycloalkyl; R1cis H, F, or C1-6alkyl; R2is H, OH, CN, oxo or C1-6alkyl; R3is selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R4is H, halo, cyano, C1-6haloalkyl, or C1-6hydroxyalkyl; R7and R8are 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 X1is CR7; X2is CHR4; X3is absent or CH2; X4is CH2or O; X5is CR8; and R7and R8form 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 X1is CR7; X2is CHR4; X3is absent; X4is CH2; X5is CR8; and R7and R8form 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 X1is CR7; X2is CHR4; X3is CH2; X4is O; P38594-WOX5is CR8; and R7and R8form 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 R4is H.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected fromwherein: X1is C or N; X2is CR4or N; X3is CH, NH, or S; and X4is N, CH, NH, or S.

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. P38594-WO9. The compound of claim 6, having Formula V10. The compound of claim 6, having Formula (Va):or a pharmaceutically acceptable salt thereof.

11. The compound of claim 6, wherein Ringor a pharmaceutically acceptable salt thereof.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X1is C; X2is N; X3is NH; and X4is N.

13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X1is C; X2is CR4; X3is NH; and X4is N.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X1is N; X2is CR4; X3is CH; and X4is N. P38594-WO15. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X1is C; X2is CR4; X3is S; and X4is N.

16. The compound of any one of claims 13-15, or a pharmaceutically acceptable salt thereof, wherein R4is H.

17. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X1is N; X2is N; X3is CH; and X4is N.

18. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein X1is N; X2is N; X3is CH; and X4is CH.

19. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein X1is C; X2is N; X3is NH; and X4is CH.

20. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from ,21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R4is H, halo, or C1-6hydroxyalkyl.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R4is H.

23. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from P38594-WO, 24. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from25. The compound of claim 11, having Formula IIa:or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R4is H.

27. The compound of claim 11, having Formula IIb:or a pharmaceutically acceptable salt thereof.

28. The compound of claim 11, having Formula IIc: P38594-WOIIc, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 11, having Formula IId:IId, or a pharmaceutically acceptable salt thereof.

30. The compound of claim 11, having Formula IIe:IIe, or a pharmaceutically acceptable salt thereof.

31. The compound of claim 11, having Formula IIf:or a pharmaceutically acceptable salt thereof.

32. The compound of claim 11, having Formula IIg: P38594-WOor a pharmaceutically acceptable salt thereof. The compound of claim 6, wherein Ringcompound has Formula II:or a pharmaceutically acceptable salt thereof.

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

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

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R3is H.

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

38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein Y is CH2CH2.

39. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein Y is CR5R6. P38594-WO40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R5and R6are independently H, OH, CN, or halo.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R5and R6are H.

42. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R5is H and R6is OH or CN.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein R2is H, OH, CN, oxo or methyl.

44. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R2is H.

45. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein R1ais H or methyl.

46. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein R1ais H.

47. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein R1aand R1btaken together with the carbon to which they are bonded, form a C3-6cycloalkyl.

48. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R1bis selected from C6-10aryl, 5- to 10-membered heteroaryl, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and C1-6alkyl substituted with C6-10aryl or C1-6haloalkoxy; wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, halo, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R1bis selected from C6-10aryl and 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, halo, C1-6alkoxy, and C1-6haloalkyl.

50. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R1bis selected from P38594-WO,, wherein each R9is independently selected fromC1-6alkyl, halo, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl; and p is 0, 1, 2, 3, or 4.

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R1bis selected fromP38594-WO52. The compound of claim 50 or 51, or a pharmaceutically acceptable salt thereof, wherein each R9is independently selected from C1-6alkyl, halo, C1-6haloalkyl, and C1-6alkoxy.

53. The compound of claim 50 or 51, or a pharmaceutically acceptable salt thereof, wherein each R9is independently selected from methyl, halo, C1haloalkyl, and methoxy.

54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein R1cis H.

55. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein R1cis F.

56. The compound of claim 1, having Formula IIIa, IIIb, or IIIc:P38594-WOor a pharmaceutically acceptable salt thereof, wherein R6is H, OH, or CN.

57. The compound of claim 1, having Formula (IIId):or a pharmaceutically acceptable salt thereof.

58. The compound of claim 1, having Formula IVa, IVb, or IVc:P38594-WOor a pharmaceutically acceptable salt thereof, wherein R6is H, OH, or CN.

59. The compound of claim 1, having Formula (IVd):or a pharmaceutically acceptable salt thereof.

60. The compound of claim 1, having Formula (Va), (Vb), (Vc), (Vd), (Ve) or (Vf)or a pharmaceutically acceptable salt thereof. P38594-WO61. The compound of claim 59 or 60, or a pharmaceutically acceptable salt thereof, wherein R1ais H and R1bis selected from C6-10aryl and 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, halo, and C1-6haloalkyl.

62. The compound of claim 61, 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.

63. The compound of claim 1, having a formula selected from:or a pharmaceutically acceptable salt thereof.

64. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein R4is H.

65. The compound of claims 63 or 64, or a pharmaceutically acceptable salt thereof, wherein R1cis H or F.

66. The compound of claim 1, having a formula selected from: P38594-WOor a pharmaceutically acceptable salt thereof.

67. The compound of claim 1, having a formula selected from:P38594-WOor a pharmaceutically acceptable salt thereof.or a pharmaceutically acceptable salt thereof.

69. The compound of claim 1, having a formula selected from: P38594-WOor a pharmaceutically acceptable salt thereof.or a pharmaceutically acceptable salt thereof. P38594-WO71. The compound of claim 1, having a formula selected from:or a pharmaceutically acceptable salt thereof.

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

73. A pharmaceutical composition comprising the compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

74. The pharmaceutical composition of claim 73, wherein the pharmaceutical composition is formulated for oral administration.

75. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition is formulated for injection.

76. 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 1-70, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 73-75.

77. The method of claim 76, wherein the individual is a human.

78. The method of claim 75 or 76, wherein the individual (i) has a condition characterized by axonal degeneration or (ii) is at risk of developing a condition characterized by axonal degeneration. P38594-WO79. 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 1-70, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 73-75.

80. The method of claim 78, wherein the neurodegenerative disease is selected from ALS, CIPN, peripheral neuropathy, and MS.

81. The method of any one of claims 72-80, wherein the administering is via the oral route.

82. The method of any one of claims 72-80, wherein the administering is via injection.

83. A method of inhibiting SARM1 comprising contacting a biological sample with a therapeutically effective amount of the compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 73-75. P38594-WO

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