Aromatic compounds for use as protein phosphatase 2A (PP2A) modulators

Abstract

The present disclosure relates to compounds of formula (I) that modulate the activity of protein phosphatase 2A (PP2A). The compounds of the disclosure are useful for the treatment, prevention, and / or amelioration of cancer, diabetes, autoimmune diseases, solid organ transplant rejection, graft-versus-host disease, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative diseases, and cardiac hypertrophy. JPEG2025525943000339.jpg18170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 395,026, filed August 4, 2022, which is incorporated by reference herein in its entirety. [Background technology]

[0002] Protein phosphatase 2A (PP2A) is one of four major serine-threonine phosphatases and is involved in the negative control of cell growth and division. PP2A holoenzyme is a heterotrimeric protein containing a structural subunit (A), a catalytic subunit (C), and a regulatory subunit (B). PP2A heterotrimeric protein phosphatase is a ubiquitous, conserved phosphatase with broad substrate specificity and diverse cellular functions.

[0003] The function of PP2A may be involved in a variety of pathologies and indications, including, but not limited to, cancer, diabetes, autoimmune diseases, solid organ transplant rejection, graft-versus-host disease, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative diseases, and / or cardiac hypertrophy.

[0004] Thus, there is a need in the art for chemical modulators of PP2A for the treatment, prevention, and / or amelioration of PP2A-related pathologies and / or indications. The present disclosure addresses that need. Summary of the Invention [Problem to be solved by the invention]

[0005] In one aspect, the disclosure provides certain compounds of formula (I), or salts, solvates, enantiomers, diastereoisomers, isotopologues, or tautomers thereof, wherein the substituents in (I) are as defined elsewhere herein. [ka]

[0006] In another aspect, the disclosure provides certain compounds of formula (II), or salts, solvates, enantiomers, diastereoisomers, isotopologues, or tautomers thereof, wherein the substituents in (II) are defined elsewhere herein: [ka]

[0007] In another aspect, the disclosure provides certain compounds of formula (III), or salts, solvates, enantiomers, diastereoisomers, isotopologues, or tautomers thereof, wherein the substituents in (III) are defined elsewhere herein: [ka]

[0008] In another aspect, the present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure, including compounds of formula (I), (II), and / or (III), and at least one pharmaceutically acceptable carrier.

[0009] In another aspect, the present disclosure provides methods for treating, preventing, and / or ameliorating a protein phosphatase 2A (PP2A)-associated disorder in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

[0010] In certain embodiments, the PP2A-related disease is at least one selected from the group consisting of cancer, diabetes, autoimmune diseases, solid organ transplant rejection, graft-versus-host disease, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative diseases, and cardiac hypertrophy. DETAILED DESCRIPTION OF THE INVENTION

[0011] Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0012] Throughout this document, values expressed in range format should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of that range, but also all individual numerical values or subranges within that range, as if each numerical value and subrange were explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also individual values (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the stated range. The term "about X to Y" has the same meaning as "about X to about Y" unless otherwise indicated. Similarly, the term "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise indicated.

[0013] In this document, the terms "a," "an," or "the" are used to include one or more unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or" unless otherwise indicated. The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B." It should further be understood that phrases and terms employed herein and not otherwise defined are for descriptive purposes and should not be considered limiting. Any use of section headings is intended to aid in the reading of the document and is not to be construed as limiting. Information associated with a section heading may occur within or outside that particular section. All publications, patents, and patent documents referenced in this document are incorporated herein by reference in their entirety, as if individually incorporated by reference.

[0014] In the methods described herein, acts may be performed in any order unless a temporal or operational sequence is explicitly recited. Furthermore, certain acts may be performed simultaneously unless express claim language dictates otherwise. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in a single operation, and the resulting process is within the context of the claimed process.

[0015] definition As used herein, the term "about" may allow for a degree of variation in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or boundary of a stated range, and includes the exact stated value or range.

[0016] The term "acyl" means a carbonyl bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety, where the atom bonded to the carbonyl is carbon. Examples of acyl groups include formyl, alkanoyl, and aroyl. An "acetyl" group refers to a -C(O)CH group. One or more carbons in the acyl residue can be replaced by nitrogen, oxygen, or sulfur as long as the point of attachment to the parent molecular moiety remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.

[0017] The term "acylamino," as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CHC(O)NH-).

[0018] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. For example, they are discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.: Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In certain embodiments, the compounds and compositions described herein are administered orally.

[0019] The terms "alkoxy" or "alkoxyl," as used herein, refer to groups of 1 to 6 carbon atoms of a linear, branched, or cyclic configuration and combinations thereof, attached to the parent structure through an oxygen. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, sec-butoxy, isobutoxy, tert-butoxy, cyclohexyloxy, and cycloheptyloxy.

[0020] In certain embodiments, the term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. In certain embodiments, the term "C2-C6 alkenyl" refers to an alkenyl moiety having 2 to 6 carbon atoms.

[0021] Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH), 1-propenyl (-CH=CH-CH), 2-propenyl (allyl, -CH-CH=CH), isopropenyl (1-methylvinyl, -C(CH)=CH), butenyl, pentenyl, and hexenyl.

[0022] As used herein, the term "alkenylene" refers to an alkene substituted at two or more positions, such as ethenyl (-CH=CH-). Unless otherwise specified, the term "alkenyl" can include "alkenylene" groups.

[0023] In certain embodiments, the term "alkyl" refers to linear, branched, or cyclic hydrocarbon structures and combinations thereof, and can be saturated or unsaturated (e.g., partially unsaturated, fully unsaturated). Thus, the term "alkyl" includes the sub-classes alkenyl, alkynyl, cycloalkyl, etc. Alkyl groups can be optionally substituted as defined herein.

[0024] Examples of saturated straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl, as well as branched-chain alkyls. Examples of groups include isopropyl, tert-butyl, isobutyl, sec-butyl, and neopentyl. In certain embodiments, alkyl is a saturated alkyl having 2 to 6 carbon atoms. In certain embodiments, a straight-chain or branched-chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C1-C6 for straight chains, C3-C6 for branched chains). The term (C1-C6) alkyl may be understood to refer to an alkyl group containing 1 to 6 carbon atoms.

[0025] The term "alkylamino" means an alkyl group attached to the parent molecular moiety through an amino group. The alkylamino groups can be mono- or di-alkylated to form, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like groups.

[0026] The terms "alkylcarbonyl" and "alkoxycarbonyl" mean -C(=O)alkyl or -C(=O)alkoxy, respectively.

[0027] The term "alkylthio" refers to an alkyl thioether (alkyl-S-) group, where the term alkyl is as defined for an alkyl group and the sulfur can be singly or doubly oxidized. Examples of alkyl thioether groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.

[0028] In certain embodiments, the term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. In certain embodiments, the term "C2-C6 alkynyl" refers to an alkynyl moiety having 2 to 6 carbon atoms.

[0029] Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (ethynyl, -C≡CH) and 2-propynyl (propargyl, -CH2-C≡CH).

[0030] The term "alkylene" means a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH-). Unless otherwise specified, the term "alkyl" can include "alkylene" groups.

[0031] Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamido) means a group such as -C(=O)NH, -C(=O)NH(alkyl), or -C(=O)N(alkyl), where the alkyl groups are independently amino substituents as defined for an alkyl group.

[0032] The term "amino" means --NH.sub.2.

[0033] The terms "aryl" and "heteroaryl," as used herein, refer to (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from O, N, or S as defined for a heterocycle; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0 to 4 heteroatoms selected from O, N, or S as defined for a carbocycle or heterocycle; or (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0 to 5 heteroatoms selected from O, N, or S as defined for a carbocycle or heterocycle. Aromatic 6- to 14-membered carbocyclic rings include, but are not limited to, benzene, naphthalene, anthracene, indane, tetralin, and fluorene, and 5- to 10-membered aromatic heterocycles include, but are not limited to, imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole, and pyrazole. As used herein, aryl and heteroaryl refer to residues in which one or more rings are aromatic, but not all are required to be aromatic.

[0034] As used herein, the term "arylalkyl" refers to a substituent in which an aryl residue is attached to a parent structure via an alkyl. Examples of arylalkyl include, but are not limited to, benzyl, phenethyl, and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to a parent structure via an alkyl. In certain embodiments, the alkyl group of the arylalkyl or heteroarylalkyl is an alkyl group of 1 to 6 carbons. Examples include, for example, pyridinylmethyl, pyrimidinylethyl, and the like.

[0035] The term "azido" as used herein refers to -N3.

[0036] The term "carbamate," as used herein, refers to an ester of carbamic acid (-NHC(=O)O-), which may be attached to the parent molecular moiety through either the nitrogen or the acid terminus, and may be optionally substituted as defined herein.

[0037] As used herein, "carbonyl" refers to the group -C(=O)- and includes formyl (-C(=O)H).

[0038] The term "carboxyl" or "carboxy" as used herein refers to -C(=O)OH or the corresponding "carboxylate" anion, e.g., in a carboxylic acid salt. The term "co-administration" refers to simultaneous administration in the same formulation or in two different formulations via the same or different route, or sequential administration by the same or different route. "Sequential" administration means a time difference of a few seconds, minutes, hours, or days between the administration of two or more separate compounds.

[0039] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration encompasses co-administration of these therapeutic agents substantially simultaneously, e.g., in a single formulation (e.g., capsule or injection) having a fixed ratio of active ingredients, or in multiple separate dosage forms for each active ingredient. Furthermore, such administration also encompasses sequential use of each type of therapeutic agent. In either case, the treatment regimen provides the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0040] The term "comprising" is used herein to mean including the feature(s) or act(s) that follows it without excluding the presence of one or more additional features or acts.

[0041] The terms "cycloalkyl" or alternatively "carbocycle," alone or in combination, refer to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, each cyclic moiety of which can contain 3 to 12 carbon atom ring members, and which can optionally be a benzo-fused ring system, optionally substituted as defined herein. In certain embodiments, a cycloalkyl contains 3 to 7 carbon atoms or 3 to 6 carbon atoms.

[0042] Examples of saturated monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl), methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, and the like.

[0043] Examples of saturated monocyclic cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, methylcyclopropenyl, dimethylcyclopropenyl, methylcyclobutenyl, dimethylcyclobutenyl, methylcyclopentenyl, dimethylcyclopentenyl, methylcyclohexenyl, and the like.

[0044] Examples of bicyclic cycloalkyl groups include, but are not limited to, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, decalinyl, and the like. "Bicyclic" and "tricyclic," when used in conjunction with "cycloalkyl," are intended to include both fused ring systems such as decahydronaphthalene, octahydronaphthalene, and the like, as well as polycyclic (multi-center) saturated or partially unsaturated forms, including spiro-fused ring systems. Examples of bicyclic and tricyclic isomers are bicyclo[1,1,1]pentane, norbornane, camphor, adamantane, bicyclo[3,2,1]octane, and [4,4.1]-bicyclononane.

[0045] The term "cyano," "nitrile," or "carbonitrile" as used herein means --CN.

[0046] The terms "diastereomer" and "diastereoisomer" are used interchangeably herein and refer to stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0047] The term "disease" as used herein is generally intended to be synonymous and is used interchangeably with the terms "disorder" and "condition" (as in medical condition), all of which reflect an abnormal condition of the human or animal body or one of its parts that impairs the normal functioning, usually manifested by distinct signs and symptoms, and which reduces the duration or quality of life of the human or animal.

[0048] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of at least one compound administered to achieve a desired result, e.g., to alleviate to some extent one or more symptoms of the disease or condition being treated. In certain instances, the result is reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. In certain instances, the result is a reduction in proliferation, killing, or induction of apoptosis in at least one abnormally proliferating cell, e.g., a cancer cell. In certain instances, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as described herein required to produce a clinically significant reduction in disease. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0049] The term "ester," "carboxylate," "carboxylic acid ester," or "oxycarbonyl," as used herein, means -C(=O)Oalkyl, where alkyl is an ester substituent as defined above for alkyl. Examples of ester groups include, but are not limited to, -C(=O)OCH, -C(=O)OCHCH, -C(=O)OC(CH), and -C(=O)OPh.

[0050] The term "halo" or "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine, and iodine. In certain embodiments, halo can be fluorine or chlorine.

[0051] The term "haloalkoxy" means a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0052] The term "haloalkyl" as used herein refers to an alkyl radical having the meaning defined above, in which one or more hydrogen atoms are replaced with halogen atoms. In certain embodiments, haloalkyl is a monohaloalkyl, dihaloalkyl, and polyhaloalkyl group. Examples of haloalkyl radicals include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include, but are not limited to, fluoromethylene (-CFH-), difluoromethylene (-CF2-), and chloromethylene (-CHCl-).

[0053] As used herein, the term "heteroarylene" refers to a divalent radical formed by removing two hydrogen atoms from one or more rings of a heteroaryl moiety, where the hydrogen atoms can be removed from the same or different rings (preferably the same ring), and each of these rings can be aromatic or non-aromatic.

[0054] The terms "heterocycle" and, interchangeably, "heterocyclyl" refer to an alicyclic or aryl carbocyclic residue in which one to four carbons are replaced by heteroatoms selected from the group consisting of N, O, and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. In certain embodiments, the heterocycle is non-aromatic. In further embodiments, the heterocycle is aromatic.

[0055] Examples of heterocycles include, but are not limited to, aziridine, azetidine, pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxane, benzodioxole, tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran, and the like. Examples of heterocyclyl residues include, but are not limited to, piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (historically also called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl, and tetrahydroquinolinyl. Note that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic. Oxygen heterocycle is a heterocycle containing at least one oxygen atom in the ring, and may contain additional oxygen atoms and other heteroatoms. Sulfur heterocycles are heterocycles containing at least one sulfur atom in the ring and may contain additional sulfur atoms as other heteroatoms. Oxygen heteroaryls are a subset of oxygen heterocycles. Oxygen heteroaryls are a subset of oxygen heterocycles, and examples include furan and oxazole. Sulfur heteroaryls are a subset of sulfur heterocycles, and examples include, but are not limited to, thiophene and thiazine. Nitrogen heterocycles are heterocycles containing at least one nitrogen atom in the ring and may contain additional nitrogen atoms and other heteroatoms. Examples include, but are not limited to, piperidine, piperazine, morpholine, pyrrolidine, and thiomorpholine. Nitrogen heteroaryls are a subset of nitrogen heterocycles, and examples include, but are not limited to, pyridine, pyrrole, and thiazole. Heterocyclic groups may be optionally substituted unless specifically prohibited.

[0056] As used herein, the term "hydroxy" means --OH.

[0057] As used herein, the term "increase" or the related terms "increased," "enhance," or "enhanced" may refer to a statistically significant increase, and the terms "decreased," "suppressed," or "inhibited" may refer to a statistically significant decrease. For the avoidance of doubt, an increase generally refers to at least a 10% increase in a given parameter and may include at least a 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or even 100% increase relative to a control, baseline, or prior value. Inhibition generally refers to at least a 10% decrease in a given parameter and may include at least a 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or even 100% decrease relative to a control value.

[0058] The term "imino" as used herein means =N-.

[0059] As used herein, the term "modulate" refers to increasing or decreasing the activity of PP2A. In certain embodiments, a compound according to one or more embodiments disclosed herein may increase the activity of a particular PP2A holoenzyme while decreasing the activity of other PP2A heterotrimers.

[0060] The term "nitro" as used herein means --NO.sub.2.

[0061] The term "optionally substituted" can be used interchangeably with "unsubstituted or substituted." The term "substituted" refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. In certain embodiments, one, two, or three hydrogen atoms are replaced with a specified radical. In the case of alkyl and cycloalkyl, more than three hydrogen atoms can be replaced by fluorine. In certain embodiments, all available hydrogen atoms can be replaced by fluorine. Two substituents can be joined together to form a 3- to 7-membered non-aromatic carbocyclic or heterocyclic ring consisting of 0-3 heteroatoms, for example, methylenedioxy or ethylenedioxy. In certain embodiments, the formed carbocyclic or heterocyclic ring is a fused ring or a spiro ring.

[0062] The above groups, whether alone or as part of another substituent, may themselves be optionally substituted with one or more groups selected from themselves and the additional substituents listed below. Additionally, the substituents listed below may themselves be substituents.

[0063] The term "oxo," when referred to as a substituent by itself, refers to a double-bonded oxygen (=O).

[0064] The term "oxy" or "oxa" as used herein means --O--.

[0065] As used herein, the term "patient" refers to any mammal, including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. In some embodiments, the patient is a human.

[0066] The term "pharmaceutically acceptable salts" can refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. When the compounds disclosed herein are basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Suitable pharmaceutically acceptable acid addition salts of the compounds disclosed herein include acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid (besylate), benzoic acid, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, ethanedisulfonic acid, ethanesulfonic acid, ethylenediaminetetraacetate, formate, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydrobromide, and the like. Acids suitable for the addition of bases include hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthylenesulfonic acid, nitric acid, oleic acid, pamoic acid, pantothenic acid, phosphoric acid, pivalic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, theocratic acid, p-toluenesulfonic acid, etc. Suitable pharmaceutically acceptable base addition salts for compounds of the invention, when the compound contains an acidic side chain, include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium cations and anions of carboxylates, sulfonates, and phosphonates attached to alkyls having 1 to 20 carbon atoms.

[0067] As used herein, the terms "prevent," "preventing," or "prevention," and other grammatical equivalents, include and are intended to include preventing additional symptoms, preventing the underlying metabolic cause of symptoms, suppressing a disease or condition, e.g., inhibiting the onset of a disease or condition. The term further includes achieving a prophylactic benefit. In a prophylactic benefit, the composition is optionally administered to an individual at risk of developing a particular disease, reporting one or more physiological symptoms of a disease, or at risk of recurrence of the disease.

[0068] The term "stereoisomers" refers to compounds composed of the same atoms joined by the same bonds but with different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0069] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. Some non-limiting examples of 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 via reorganization of some of the bonding electrons. Unless otherwise specified, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

[0070] The terms "treat," "treating," and "treatment," and other grammatical equivalents, include alleviating, inhibiting, or reducing symptoms; reducing the severity of or inhibiting symptoms of a disease or condition; delaying its onset; delaying its recurrence; attenuating or ameliorating itself; ameliorating the underlying metabolic cause of a symptom; inhibiting a disease or condition, e.g., preventing the onset of a disease or condition; relieving a disease or condition; causing regression of a disease or condition; alleviating symptoms caused by a disease or condition; or arresting the symptoms of a disease or condition. The term further includes achieving a therapeutic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated and / or the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the individual.

[0071] Unless otherwise stated or depicted, the structures of the compounds according to one or more embodiments disclosed herein are intended to include all stereoisomeric (e.g., enantiomeric, diastereomeric, and cis-trans isomeric) forms of the structures, including, for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers of the compounds as well as enantiomeric, diastereomeric, and cis-trans isomeric (or conformational) mixtures are within the scope of the invention. The configuration of any carbon-carbon double bond appearing herein has been selected for convenience only and is not intended to designate a particular configuration. Thus, a carbon-carbon double bond arbitrarily depicted herein as trans can be cis, trans, or a mixture of the two in any ratio. Unless otherwise specified, all tautomeric forms of the compounds according to one or more embodiments disclosed herein are within the scope of the disclosure. Additionally, the compounds of the present disclosure can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In general, the solvated forms are considered to be the same as the unsolvated forms.

[0072] compound In one aspect, the disclosure provides a compound of formula (I), or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof: [ka] During the ceremony, Ar is C6~C 10 Aryl or C2-C 10 Heteroaryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C 10 Heteroaryl, C6-C 10 Aryl, C6-C 10 Aryloxy, halogen, OH, N(R a )(R b ), CN, NO2, -C(=O)R a , -C(=O)OR a , and -C(=O)N(R a )(R b and optionally substituted with at least one substituent selected from the group consisting of: Each C6 to C in Ar 10 Aryl, C2-C 10 Heteroaryl or C6-C 10 The aryloxy substituents are independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, F, Cl, Br, I, OH, CN, NO2, -C(=O)OR a , and -C(=O)N(R a )(R b and optionally substituted with at least one substituent selected from the group consisting of: The two adjacent substituents of Ar combine to form C6-C 10 Aryl or C2-C 10 may provide a 5- to 8-membered ring fused with a heteroaryl; R 1 but, [ka] is selected from the group consisting of R 2 optionally substituted phenyl and optionally substituted C-C 10 heteroaryl; R 2 wherein each optional substituent is at least one selected from the group consisting of halogen, OH, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl; R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , and R 3h are, if present, each independently H; or R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , and R 3h two geminal substituents selected from: may combine with the carbon atoms to which they are attached to form an optionally substituted C3-C8 cycloalkyl; R 4 is H, R A is selected from the group consisting of H and C1-C6 alkyl; R a each occurrence of is independently selected from H, C1-C6 alkyl, benzyl, and C6-C 10 aryl; R b is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl; and R bwherein the C1-C6 alkyl, benzyl, phenyl, or naphthyl is independently C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, CN, NO2, C(=O)OR a , and C(=O)N(R a )(R a ) is optionally substituted with at least one selected from the group consisting of:

[0073] In certain embodiments, the compound of formula (I) is not selected from the group consisting of: N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimidamide, N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-isopropoxybenzenesulfonamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-isopropoxypyridine-3-sulfonamide, N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide, 3-amino-N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, 3-amino-N-(3-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(3,4-dichlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-phenylpiperidin-4-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide, N-(4-(5-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide, N-(4-(5-chlorothiazol-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-fluorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide, N-(4-(3,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(2,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(2,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(5-chlorothiophen-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chloro-2-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethyl)benzenesulfonamide, 3-amino-N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, and N-(4-(4-(difluoromethyl)phenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide.

[0074] In certain embodiments, R A is H.

[0075] In certain embodiments, R 1 but, [ka] is.

[0076] In certain embodiments, R 2 is 4-fluorophenyl further substituted with at least one additional substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C2-C6 alkyl.

[0077] In certain embodiments, R 2 is 3-fluorophenyl further substituted with at least one additional substituent selected from the group consisting of F, Br, OH, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0078] In certain embodiments, R 2 is 3,4-difluorophenyl.

[0079] In certain embodiments, Ar is optionally substituted phenyl.

[0080] In certain embodiments, Ar is 4-methoxyphenyl optionally further substituted with at least one additional substituent selected from the group consisting of halogen, NH2, and C1-C3 alkoxy.

[0081] In certain embodiments, the compound is N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, and (R)—N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide is selected from the group consisting of:

[0082] In certain embodiments, R 1 but, [ka] is.

[0083] In certain embodiments, Ar is optionally substituted phenyl or optionally substituted pyridyl, and the optional substituents on Ar are at least one substituent selected from the group consisting of C-C haloalkoxy, C-C alkoxy, and —NH(C-C alkyl).

[0084] In certain embodiments, Ar is phenyl substituted with at least one substituent selected from the group consisting of trifluoromethoxy and methylamino.

[0085] In certain embodiments, Ar is [ka] is.

[0086] In certain embodiments, R 2 is 3,5-disubstituted phenyl, each substituent independently selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0087] In certain embodiments, R 2 is 4-chlorophenyl further substituted with at least one substituent selected from the group consisting of Br, I, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0088] In certain embodiments, R 2is 3-methylphenyl further substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0089] In certain embodiments, R 2 is 3-pyridyl optionally further substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0090] In certain embodiments, R 2 is 4-pyridyl optionally further substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0091] In certain embodiments, R 2 but, [ka] In certain embodiments, R 2 but, [ka] In certain embodiments, R 2 but, [ka] In certain embodiments, R 2 but, [ka] is.

[0092] In certain embodiments, Ar is [ka] is.

[0093] In certain embodiments, R 2 is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl, wherein the pyridyl is optionally substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0094] In certain embodiments, R 2 is 3-fluorophenyl optionally substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0095] In certain embodiments, R 2 is 4-fluorophenyl further substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0096] In certain embodiments, R 2 but, [ka] In certain embodiments, R 2 but, [ka] is.

[0097] In certain embodiments, Ar is methylamino substituted 4-trifluoromethoxyphenyl.

[0098] In certain embodiments, Ar is [ka] is.

[0099] In certain embodiments, R 2 is 4-chlorophenyl optionally substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0100] In certain embodiments, R 2 but, [ka] is.

[0101] In certain embodiments, the compound is N-(4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chloro-3-methylphenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide, N-(4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(methylamino)-4-(trifluoromethoxy)benzenesulfonamide, and N-(4-(2,5-dichloropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide is selected from the group consisting of:

[0102] In certain embodiments, R 1 but, [ka] and R 3 , R 3’ , R 4 , R 4’ , R 5 , R 5’ , R 6 , and R 6’ and two geminal substituents selected from the group consisting of: which, together with the atoms to which they are attached, form a C3-C8 cycloalkyl.

[0103] In certain embodiments, R 1 but, [ka] is.

[0104] In certain embodiments, R 2 is phenyl optionally substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl.

[0105] In certain embodiments, R 2 is phenyl.

[0106] In certain embodiments, Ar is optionally substituted phenyl.

[0107] In certain embodiments, Ar is [ka] is.

[0108] In certain embodiments, the compound is N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide, and (R)-N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide is selected from the group consisting of:

[0109] In another aspect, the disclosure provides a compound of formula (II), or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof: [ka] During the ceremony, Ar is C6~C 10 Aryl or C2-C 10 Heteroaryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C 10 Heteroaryl, C6-C 10 Aryl, C6-C 10 Aryloxy, halogen, OH, N(R a )(R b ), CN, NO2, -C(=O)R a , -C(=O)OR a , and -C(=O)N(R a )(R a Optionally substituted with at least one substituent selected from the group consisting of: Each C6 to C in Ar 10 Aryl, C2-C 10 Heteroaryl or C6-C 10 The aryloxy substituents are independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, F, Cl, Br, I, OH, CN, NO2, -C(=O)OR a , and -C(=O)N(R a )(R a and optionally substituted with at least one substituent selected from the group consisting of: The two adjacent substituents of Ar combine to form C6-C 10Aryl or C2-C 10 may provide a 5- to 8-membered ring fused with a heteroaryl; L is *-N(R B )S(=O)2-, *-C(=O)N(R B )- and optionally substituted C2-C 10 heteroarylene; R 5 is selected from the group consisting of: [ka] R 6 optionally substituted C6 to C 10 Aryl and optionally substituted C-C 10 heteroaryl; R 6 wherein each optional substituent is halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —C(═O)OR a , -S(=O)2(C6~C 10 aryl), and -S(=O)2(C2-C 10 heteroaryl), R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h each, if present, is independently selected from the group consisting of H, C1-C6 alkyl, hydroxyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 heterocyclyl, optionally substituted phenyl, and optionally substituted phenoxy; Each optional substituent is selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, C(=O)OR a , and C(=O)N(R a )(R aand at least one selected from the group consisting of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h two geminal substituents selected from, taken together with the carbon atoms to which they are attached, form optionally substituted C3-C8 cycloalkyl and optionally substituted C2-C 10 heterocyclyl, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h two adjacent substituents selected from, taken together with the carbon atoms to which they are attached, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C 10 may form a moiety selected from the group consisting of heterocyclyl, and optionally substituted phenyl, Separated by 2 to 5 carbon atoms, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h two substituents selected from may combine with the carbon atoms to which they are attached to form a moiety selected from the group consisting of optionally substituted C4-C7 cycloalkyl and optionally substituted C4-C8 heterocyclyl; R 8 is H, C1-C6 alkyl, C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted benzyl, -C(=O)OR b , -C(=O)R b and —S(═O)2-optionally substituted phenyl; Each optional substituent in phenyl, benzyl, or -S(=O)2-phenyl is independently F, Cl, Br, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, hydroxyl, and -NH-C(=O)R a and at least one selected from the group consisting of: R 9 optionally substituted C6 to C 10 Aryl and optionally substituted C-C 10 heteroaryl; R 9 wherein each optional substituent is halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —C(═O)OR a , -S(=O)2(C6~C 10 aryl), and -S(=O)2(C2-C 10 heteroaryl), R 10 is -(optionally substituted C1-C6 alkyl)(optionally substituted C2-C 12 heterocycloalkyl), and optionally substituted C1-C6 aminoalkyl; R 10 wherein each optional substituent is halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —C(═O)OR a , -S(=O)2(C6~C 10 aryl), and -S(=O)2(C2-C 10 heteroaryl), R 11 is H, R B is H, R a each occurrence of is independently selected from H, C1-C6 alkyl, benzyl, and C6-C 10 aryl; R bis independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl; and R b wherein the C1-C6 alkyl, benzyl, phenyl, or naphthyl is independently C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, CN, NO2, C(=O)OR a , and C(=O)N(R a )(R a ) is optionally substituted with at least one selected from the group consisting of:

[0110] In certain embodiments, the compound of formula (II) is: [ka] (In the formula, R 12a , R 12b , and R 12c When present, each independently represents C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, C(=O)ORa, and C(=O)N(R a )(R a )) is selected from the group consisting of:

[0111] In certain embodiments, R 12a , R 12b , and R 12c When present, at least one of R 12a , R 12b , and R 12c Two of, if present, are H.

[0112] In certain embodiments, Ar is optionally substituted phenyl.

[0113] In certain embodiments, Ar is [ka] In certain embodiments, Ar is [ka] is.

[0114] In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h When present, at least one of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h When present, at least two of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h When present, at least three of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h When present, at least four of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h When present, at least five of R 7a , R 7b , R 7c, R 7d , R 7e , R 7f , R 7g , and R 7h When present, at least six of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h When present, at least seven of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h Each of, if present, is H.

[0115] In certain embodiments, R 6 is phenyl optionally substituted with at least one halogen. In certain embodiments, R 6 is a phenyl substituted with two halogens.

[0116] In certain embodiments, R 6 but, [ka] In certain embodiments, R 6 but, [ka] In certain embodiments, R 6 but, [ka] is.

[0117] In certain embodiments, R 9is phenyl optionally substituted with at least one halogen. In certain embodiments, R 9 is a phenyl substituted with two halogens.

[0118] In certain embodiments, R 9 but, [ka] In certain embodiments, R 9 but, [ka] In certain embodiments, R 9 but, [ka] is.

[0119] In certain embodiments, R 10 is —CH 2 N(optionally substituted C 1 -C 6 alkyl) 2 .

[0120] In certain embodiments, R 10 is -CH2NMe2.

[0121] In certain embodiments, the compound is: N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide, (S)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide, (R)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide, N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide, (S)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide, (R)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide, (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide, (R)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide, 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine, (S)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine, (R)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine, 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine, (S)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine, (R)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine, 1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole, (S)-1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole, (R)-1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole, 1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole, (S)-1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole, (R)-1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole, and 4-Phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide is selected from the group consisting of:

[0122] In another aspect, the disclosure provides a compound of formula (III), or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof: [ka] During the ceremony, Ar is C6~C 10 Aryl or C2-C 10 Heteroaryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C 10 Heteroaryl, C6-C 10 Aryl, C6-C 10 Aryloxy, halogen, OH, N(R a )(R b ), CN, NO2, -C(=O)R a , -C(=O)OR a , and -C(=O)N(R a )(R aand optionally substituted with at least one substituent selected from the group consisting of: Each C6 to C in Ar 10 Aryl, C2-C 10 Heteroaryl or C6-C 10 The aryloxy substituents are independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, F, Cl, Br, I, OH, CN, NO2, -C(=O)OR a , and -C(=O)N(R a )(R a and optionally substituted with at least one selected from the group consisting of: The two adjacent substituents of Ar combine to form C6-C 10 Aryl or C2-C 10 may provide a 5- to 8-membered ring fused with a heteroaryl; R 13 but, [ka] R 14a , R 14b , R 14c , and R 14d However, each independently, C6~C 10 Aryl and optionally substituted C-C 10 heteroaryl; R 14a , R 14b , R 14c , and R 14d wherein each optional substituent is selected from halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, and —C(═O)OR a and at least one selected from the group consisting of: R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 15ieach independently represents H, halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -C(=O)OR a is selected from the group consisting of R 16 is H, R 17a , R 17b , R 17d , R 17e , R 17f , R 17g , R 17h , R 17i , R 17j , R 17k , and R 17l are, if present, each independently selected from the group consisting of H, halogen, and C2-C8 heterocycloalkyl; R 18a , R 18b , R 18c , and R 18d are each independently selected from the group consisting of H and C1-C6 alkyl; R 19 is selected from the group consisting of optionally substituted cyclohexyl and —CHNMe; X is -NR 16 - and -C(R 17k )(R 17l )-, R C is H, R a each occurrence of is independently selected from H, C1-C6 alkyl, benzyl, and C6-C 10 aryl; R b is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl; and R b wherein C1-C6 alkyl, benzyl, phenyl, or naphthyl is independently C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, CN, NO2, C(=O)OR a, and C(=O)N(R a )(R a and optionally substituted with at least one selected from the group consisting of: R 13 but, [ka] , then at least one of the following applies: (a)R 17a , R 17b , R 17d , R 17e , R 17f , R 17g , R 17h , R 17i , R 17j , R 17k , and R 17l when present, is halogen, said halogen optionally being F; (b)R 14b is phenyl substituted with at least two fluorine atoms, (c)R 14b is 4-chlorophenyl, and Ar is selected from the group consisting of phenyl optionally substituted with at least two substituents, and pyridyl optionally substituted with C1-C6 alkoxy; (d)R 14b is 4-chlorophenyl and Ar is not selected from the group consisting of 4-trifluoromethoxy and 6-trifluoromethoxy-3-pyridyl; R 13 but [ka] , then at least one of the following applies: (a)R 14c is phenyl, and R 18a , R 18b , R 18c , and R 18d one, three, or four selected from are CH3; (b)R 14cis phenyl and Ar is optionally substituted pyridyl; R 13 but, [ka] and R 19 is CHNMe, the compound of formula (III) is N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide; R 13 but, [ka] and R 19 When is optionally substituted cyclohexyl, at least one of the following applies: (a) Ar is optionally substituted pyridyl; (b) Ar is substituted with at least one C1-C6 alkoxy substituent.

[0123] In certain embodiments, Ar is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridyl. In certain embodiments, Ar is selected from the group consisting of C1-C3 haloalkoxy and N(R a )(R b In certain embodiments, Ar is phenyl optionally substituted with at least one substituent selected from the group consisting of trifluoromethoxy, and NH.

[0124] In certain embodiments, Ar is [ka] In certain embodiments, Ar is [ka] is.

[0125] In certain embodiments, Ar is pyridyl optionally substituted with at least one C1-C6 alkoxy substituent. In certain embodiments, Ar is 3-pyridyl substituted with at least one C1-C6 alkoxy substituent.

[0126] In certain embodiments, Ar is [ka] is.

[0127] In certain embodiments, R 13 but, [ka] In certain embodiments, R 13 but, [ka] In certain embodiments, R 13 but, [ka] is.

[0128] In certain embodiments, R 14a is selected from the group consisting of phenyl optionally substituted with at least one halogen, and pyridyl substituted with at least one halogen.

[0129] In certain embodiments, R 14a but, [ka] In certain embodiments, R 14a but, [ka] In certain embodiments, R 14a but, [ka] is.

[0130] In certain embodiments, R 13 but, [ka] is.

[0131] In certain embodiments, Ar is [ka] is.

[0132] In certain embodiments, R 14d is cyclohexyl.

[0133] In certain embodiments, R 19 but, [ka] is.

[0134] In certain embodiments, R 13 but, [ka] is.

[0135] In certain embodiments, R 14b but, [ka] In certain embodiments, R 14b but, [ka] is.

[0136] In certain embodiments, Ar is [ka] In certain embodiments, Ar is [ka] In certain embodiments, Ar is [ka] In certain embodiments, Ar is [ka] is.

[0137] In certain embodiments, R 13 but, [ka] In certain embodiments, R 13 but, [ka] is.

[0138] In certain embodiments, R 17e and R 17f At least one selected from the group consisting of is a halogen.

[0139] In certain embodiments, R 14b is phenyl substituted with at least one halogen. 14b but, [ka] is.

[0140] In certain embodiments, Ar is phenyl substituted with at least one C1-C6 haloalkoxy.

[0141] In certain embodiments, Ar is [ka] is.

[0142] In certain embodiments, R 13 but, [ka] is.

[0143] In certain embodiments, R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least one selected from the group consisting of is H. In certain embodiments, R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least two selected from the group consisting of are H. In certain embodiments, R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j and R are H. In certain embodiments, R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least four selected from the group consisting of are H. In certain embodiments, R 17a , R 17b , R 17c , R 17d , R 17e , R 17f, R 17i , and R 17j At least five selected from the group consisting of are H. In certain embodiments, R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least six selected from the group consisting of are H. In certain embodiments, R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least seven selected from the group consisting of are H. In certain embodiments, R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j Each of these is H.

[0144] In certain embodiments, R 17i and R 17j are each independently H, and R 17a , R 17b , R 17c , R 17d , R 17e , R 17f At least one selected from the group consisting of is a C2-C8 heterocycloalkyl.

[0145] In certain embodiments, the C2-C8 heterocycloalkyl is: [ka] is.

[0146] In certain embodiments, Ar is [ka] is.

[0147] In certain embodiments, R 13 but, [ka] is.

[0148] In certain embodiments, R 18a , R 18b , R 18c , and R 18d Two selected from the group consisting of are C1-C6 alkyl.

[0149] In certain embodiments, R 13 but, [ka] is.

[0150] In certain embodiments, Ar is pyridyl substituted with at least one C1-C6 alkoxy.

[0151] In certain embodiments, Ar is [ka] is.

[0152] In certain embodiments, the compound is: N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide, (R)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide, (S)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide, 6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide, (R)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide, (S)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide, N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, (R)—N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, (S)—N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, 3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)-3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)-3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, (R)—N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, (S)—N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide, (R)—N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide, (S)—N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide, N-(1-(4-fluorophenyl)-2-(3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((R)-1-(4-fluorophenyl)-2-((R)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((R)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((S)-1-(4-fluorophenyl)-2-((R)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((S)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(2-([1,3'-biazetidin]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(2-([1,3′-biazetidin]-1′-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-(2-([1,3′-biazetidin]-1′-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide, (R)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide, (S)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide, N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide, (R)—N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide, (S)—N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide, N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide, (R)-N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide, and (S)-N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide is selected from the group consisting of:

[0153] salt The compounds described herein can form salts with acids or bases, and such salts are included in the present invention. The term "salt" encompasses addition salts of free acids or free bases that are useful in the methods of the present invention. The term "pharmaceutically acceptable salt" refers to a salt that has a toxicity profile within a range that provides usefulness in pharmaceutical applications. In certain embodiments, the salt is a pharmaceutically acceptable salt. A pharmaceutically unacceptable salt may still have properties such as high crystallinity, which have utility in the practice of the present invention, such as usefulness in the process of synthesizing, purifying, or formulating compounds useful in the methods of the present invention.

[0154] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include sulfate, hydrogen sulfate, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids can be selected from the aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclylic, carboxylic, and sulfonic acid classes of organic acids, including formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, and embonic acid. (or pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantoenoic acid, sulfanilic acid, 2-hydroxyethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, stearic acid, arginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, galacturonic acid, glycerophosphate, and saccharin (e.g., saccharinate, saccharate). Salts may be comprised of 1, 1, or more than 1 molar equivalent of acid or base fraction relative to any compound of the invention.

[0155] Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, ammonium salts and metal salts, including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts prepared from basic amines such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N-methylglucamine), and procaine. All of these salts can be prepared from the corresponding compound, for example, by reacting the appropriate acid or base with the compound.

[0156] synthesis The present invention further provides processes for preparing the compounds of the present teachings. The compounds of the present teachings can be prepared according to the procedures outlined herein from commercially available starting materials, compounds known in the literature, or easily prepared intermediates by using standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field.

[0157] It will be understood that while typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.

[0158] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by high pressure liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC). Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes. The reactions or processes described herein can be carried out in a suitable solvent, which can be easily selected by one skilled in the art of organic synthesis. A suitable solvent typically does not substantially react with the reactants, intermediates, and / or products at the temperature at which the reaction is carried out, i.e., a temperature that can range from the freezing temperature of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for that particular reaction step can be selected.

[0159] In certain embodiments, compounds synthesized using the methods described herein contain one or more chiral carbon atoms, which may give rise to two or more isomers. Absolute stereochemistry may be depicted using a wedge bond (bold or parallel). In certain embodiments, the product formed in any of the reactions described may be racemic. If a racemate is formed, the isomers that make up the racemate may be separated using any suitable method for chiral resolution known to those skilled in the art. Suitable methods for chiral resolution include, but are not limited to, supercritical fluid chromatography (SFC), chiral HPLC, crystallization, derivatization, or any combination thereof.

[0160] As used herein, "enantiomer I" or "diastereomer I" refers to the first enantiomer or diastereomer eluted from a chiral column under the specific chiral analytical conditions detailed for the particular compound(s), and "enantiomer II" or "diastereomer II" refers to the second enantiomer or diastereomer eluted from a chiral column under the specific chiral analytical conditions detailed for the particular compound(s). Such nomenclature does not imply or confer a particular relative and / or absolute configuration of any of these compounds.

[0161] In certain embodiments, the separation of isomers formed in one or more separate reactions may require the formation of derivatives prior to chiral resolution. A non-limiting example of derivatization is to protect one or more functional groups present in the compound using known protecting groups (e.g., esters, amides, carbamates, ethers, etc.), followed by separation of the isomers by a suitable method. The desired compound is finally obtained by removing the protecting group.

[0162] The present disclosure provides compounds of Formula (I), Formula (II), and Formula (III). One of ordinary skill in the art will recognize that techniques and / or methods for synthesizing compounds of Formula (I) will often be applicable to synthesizing compounds of Formula (II) or Formula (III), and vice versa.

[0163] In certain embodiments, compounds of the present disclosure can be prepared as provided in Schemes 1-9, where X is a halogen, PG is a protecting group, v is an integer selected from the group consisting of 1 and 2, w is an integer selected from the group consisting of 0 and 1, and Ar is as defined within the scope of the present invention. The substituent "R" is used generally herein to encompass any substituent within the scope of compounds of formula (I), (II), and / or (III). For example, in certain embodiments, R is R 2 or R 6In other embodiments, R can be H. Additionally, positions depicted without substitution may further include one or more substituents encompassed in compounds of formula (I), (II), and / or (III). [ka] [ka] [ka]

[0164] method The present disclosure relates, in part, to a method for treating, preventing, and / or ameliorating a protein phosphatase 2A (PP2A)-associated disease in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds of the present disclosure, or a pharmaceutical composition comprising any one of the compounds of the present disclosure and a pharmaceutically acceptable carrier.

[0165] In certain embodiments, the PP2A-related disease is at least one selected from the group consisting of cancer, diabetes, autoimmune diseases, solid organ transplant rejection, graft-versus-host disease, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative diseases, and cardiac hypertrophy.

[0166] In certain embodiments, the subject is a mammal, hi certain embodiments, the mammal is a human.

[0167] The present disclosure further relates, in part, to the use of a compound according to one or more embodiments disclosed herein, e.g., a compound of Formula (I), (II), or (III), a salt, solvate, enantiomer, diastereomer, isotopologue, tautomer, or any mixture thereof, for use as a medicament for treating, preventing, and / or ameliorating a disease or condition in a patient. The compounds according to one or more embodiments disclosed herein may be modulators of PP2A. The compounds described herein may exhibit antiproliferative effects and may be useful as monotherapy in the treatment of cancer and / or other indications described herein. Furthermore, they may be used in combination with other drugs to restore sensitivity to chemotherapy, targeted therapy, or immunotherapy to which resistance has developed.

[0168] In certain embodiments, the disease or condition is ameliorated by regulating PP2A. In certain embodiments, the disease or condition is at least one selected from the group consisting of cancer, diabetes, autoimmune disease, solid organ transplant rejection, graft-versus-host disease, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative disease, and cardiac hypertrophy. In certain embodiments, the disease is cancer.

[0169] In certain embodiments, a patient in need of treatment for a disease is administered a therapeutically effective amount of a compound according to one or more embodiments disclosed herein, e.g., a compound of Formula (I), (II), or (III), a solvate, enantiomer, diastereomer, isotopologue, tautomer, or a pharmaceutically acceptable salt thereof.

[0170] In certain embodiments, a method for treating cancer in a patient having a tumor that expresses PP2A comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), a solvate, enantiomer, diastereomer, isotopologue, tautomer, or a pharmaceutically acceptable salt thereof.

[0171] In certain embodiments, provided are methods for treating a malignant solid tumor in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, the malignant solid tumor is a carcinoma. In certain embodiments, the malignant tumor is a lymphoma. In certain embodiments, the malignant solid tumor is a sarcoma.

[0172] In certain embodiments, the cancer is of the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal tract, gums, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testes, tongue, and / or uterus. Furthermore, the cancer may specifically be of at least one of the following histological types, but is not limited to: neoplasia, malignant, carcinoma, undifferentiated carcinoma, giant cell or spindle cell carcinoma, small cell carcinoma, papillary carcinoma, squamous cell carcinoma, lymphoepithelial carcinoma, basal cell carcinoma, pleural matrix carcinoma, transitional cell carcinoma, papillary transitional cell carcinoma, adenocarcinoma, malignant gastrinoma, cholangiocarcinoma, hepatocellular carcinoma, mixed hepatocellular carcinoma and cholangiocarcinoma, trabecular adenocarcinoma, adenoid cystic carcinoma, adenocarcinoma within adenomatous polyps, adenocarcinoma, familial polyposis coli, solid tumors, malignant carcinoid tumor, branched alveolar adenocarcinoma, papillary adenocarcinoma, chromophobe carcinoma, eosinophilic carcinoma, eosinophilic adenocarcinoma, basophilic carcinoma, clear cell adenocarcinoma, granular cell carcinoma, follicular adenocarcinoma, papillary and follicular adenocarcinoma, non-encapsulated sclerosing carcinoma, adrenocortical carcinoma, endometrial carcinoma, carcinoma of the skin adnexa, apocrine adenocarcinoma, sebaceous adenocarcinoma, ceruminous adenocarcinoma, mucoepidermoid carcinoma, cystadenocarcinoma, papillary cystadenocarcinoma, serous papillary cystadenocarcinoma, mucinous cystadenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, invasive duct carcinoma, medullary carcinoma, lobular carcinoma, inflammatory carcinoma, Paget's disease of mammals, pancreatic acinar cell carcinoma, adenosquamous carcinoma, squamous metaplastic adenocarcinoma, thymoma, malignant, malignant ovarian stromal tumor, coma, malignant, malignant granulomatous cell tumor;Malignant androblastoma, Sertoli cell carcinoma, malignant Leydig cell tumor, malignant lipid cell tumor, malignant paraganglioma, malignant extramammary paraganglioma, pheochromocytoma, glomus sarcoma, malignant melanoma, black melanoma, superficial spreading melanoma, malignant melanoma in giant pigmented nevus, epithelial cell melanoma, malignant blue nevus, sarcoma, fibrosarcoma, malignant fibrous histiocytoma, myxosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, stromal sarcoma, mixed malignant tumors Tumors, Müllerian mixed tumor, nephroblastoma, hepatoblastoma, carcinosarcoma, malignant mesenchymoma, malignant Brenner tumor, malignant phyllodes tumor, synovial sarcoma, malignant mesothelioma, dysgerminoma, germinoma, malignant teratoma, malignant ovarian stroma, choriocarcinoma, malignant mesonephroma, hematosarcoma, malignant hemangioendothelioma, Kaposi's sarcoma, malignant hemangiopericytoma, lymphangiosarcoma, osteosarcoma, juxtacortical osteosarcoma, chondrosarcoma, malignant chondroblastoma, mesenchymal chondrosarcoma, giant cell tumor of bone, Ewing's sarcoma, malignant odontogenic tumor, red blastoma Spheroid gingival tumor, malignant erythroblastoma, erythroblastic fibrosarcoma, malignant pinealoma, spondyloma, malignant glioma, ependymoma, astrocytoma, protoplasmic astrocytoma, fibrous astrocytoma, astroblastoma, glioblastoma, oligodendroglioma, oligodendroglioma, primitive neuroectodermal, cerebellar sarcoma, ganglioneuroblastoma, neuroblastoma, retinoblastoma, olfactory neurogenic tumor, malignant meningioma, neurofibrosarcoma, malignant neurilemmoma, malignant granular cell tumor, malignant lymphoma, Hodgkin's disease, Hodgkin's, paragranuloma , malignant lymphoma, small lymphocytic, malignant lymphoma, diffuse large cell, follicular lymphoma, mycosis fungoides, other specified non-Hodgkin's lymphoma, malignant histiocytosis, multiple myeloma, mast cell sarcoma, immunoproliferative small intestinal disease, leukemia, lymphocytic leukemia, plasma cell leukemia, erythrocytosis, lymphosarcoma cell leukemia, myeloid leukemia, basophilic leukemia, eosinophilic leukemia, monocytic leukemia, mast cell leukemia, megakaryoblastic leukemia, myeloid sarcoma, and hairy cell leukemia;

[0173] In certain embodiments, the autoimmune disease is selected from the group consisting of colitis, multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, acute pancreatitis, chronic pancreatitis, diabetes, insulin-dependent diabetes mellitus (IDDM or type 1 diabetes), insulitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune hemolytic syndrome, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, reactive arthritis, ankylosing spondylitis, silicone implant-associated autoimmune leukemia, and leukemia. and at least one of immune disorders, Sjogren's syndrome, systemic lupus erythematosus (SLE), vasculitis syndromes (e.g., giant cell arteritis, Behcet's disease, and Wegener's granulomatosis), vitiligo, hematological manifestations secondary to autoimmune diseases (e.g., anemia), drug-induced autoimmunity, Hashimoto's disease, hypophysitis, idiopathic thrombocytopenic abscess, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune hearing loss (e.g., Meniere's disease), Gutpasture's syndrome, Grubbs' disease, HIV-associated autoimmune syndrome, and Guillain-Barré disease.

[0174] In certain embodiments, the neurodegenerative disease is Alzheimer's disease, hi certain embodiments, the neurodegenerative disease is Parkinson's disease.

[0175] PP2A enzymes may be involved in the regulation of cell transcription, cell cycle, and viral transformation. Many viruses, including cytomegalovirus, parainfluenza, DNA tumor viruses, and HIV-1, exploit PP2A using different approaches to modify, control, or inactivate host cellular activity. Therefore, a compound according to one or more embodiments disclosed herein can further be used in a method for treating a viral infection in a patient by administering a therapeutically effective amount of a compound according to one or more embodiments disclosed herein to the patient. Examples of viruses that may cause the viral infections to be treated include, but are not limited to, polyomaviruses such as John Cunningham virus (JCV), simian virus 40 (SV40), or BK virus (BKV), influenza, human immunodeficiency virus type 1 (HIV-1), human papillomavirus (HPV), adenovirus, Epstein-Barr virus (EBV), hepatitis C virus (HCV), molluscum contagiosum virus (MCV), human T-cell leukemia virus type 1 (HTLV-1), herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), hepatitis B virus, bovine papillomavirus (BPV-1), human T-cell leukemia virus type 1, Japanese encephalitis virus, respiratory syncytial virus (RSV), and West Nile virus.

[0176] The compounds or pharmaceutical compositions according to one or more embodiments disclosed herein may further be used in a method for treating a betacoronavirus infection in a patient by administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to one or more embodiments disclosed herein.

[0177] The compounds according to one or more embodiments disclosed herein may further be used in preventing betacoronavirus infection in a patient by administering to the patient a prophylactically effective amount of a compound or pharmaceutical composition according to one or more embodiments disclosed herein.

[0178] The compounds according to one or more embodiments disclosed herein can be used in the manufacture of a medicament for the treatment or prevention of a betacoronavirus infection.

[0179] In certain embodiments, the betacoronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus SARS-CoV, Middle East respiratory syndrome MERS-CoV, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, originally known as nCoV-2019).

[0180] In certain embodiments, the betacoronavirus is SARS-CoV.

[0181] In certain embodiments, the betacoronavirus is SARS-CoV-2.

[0182] Serine / threonine phosphatases, including PP2A, may be involved in the regulation of synaptic plasticity. Reduced PP2A activity is associated with the maintenance of synaptic long-term potentiation (LTP), and therefore, treatment with PP2A modulators, such as those described herein, can reverse synaptic LTP. Because psychostimulant drugs of abuse, such as cocaine and methamphetamine, are associated with adverse synaptic LTP, which may underlie the pathology of addiction and relapse, the PP2A modulators described herein may be useful as treatments for psychostimulant drug abuse.

[0183] Pharmaceutical compositions, formulations and routes of administration The present disclosure also relates to a pharmaceutical composition comprising a compound according to one or more embodiments described herein, e.g., a compound of Formula I, an enantiomer, diastereomer, tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0184] In certain embodiments, pharmaceutical compositions comprise a compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutical carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0185] Pharmaceutical compositions can be prepared by any method known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes. A "pharmaceutically acceptable carrier" can refer to an excipient, carrier, or adjuvant that can be administered to a patient together with at least one therapeutic compound, does not impair its pharmacological activity when administered in a dosage sufficient to deliver a therapeutic amount of the compound, and is generally safe, non-toxic, and biologically or otherwise unnecessary.

[0186] Pharmaceutical formulations may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, intranasal, rectal, and topical (including cutaneous, buccal, sublingual, and ocular) administration, although the optimal route may depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In general, these methods include the step of bringing into association a compound of Formula (I), (II), or a pharmaceutically acceptable salt, ester, amide, solvate, or enantiomer or diastereomer or tautomer thereof (the "active ingredient") with the carrier, which constitutes one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0187] Formulations of the compounds of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0188] Orally usable compositions include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surface-active agent, or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or engraved and may be formulated to provide slow or controlled release of the active ingredient therein. All formulations intended for oral administration should be in dosages suitable for such administration. Push-fit capsules may contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. Dragee cores may be provided with suitable coatings. For this purpose, concentrated sugar solutions may optionally be used, which may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0189] The compounds of the present disclosure can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Injectable formulations can be provided in unit dosage form, such as ampoules, or in multi-dose containers with added preservatives. The compositions can take forms such as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The formulations can be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in powder form or freeze-dried (lyophilized) requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0190] Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0191] In addition to the formulations described above, the compound of the present disclosure can also be formulated as depot preparation.Such long-acting preparations can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Therefore, for example, the compound can be formulated with suitable polymer or hydrophobic material (for example, as an emulsion in acceptable oil) or ion exchange resin, or as a poorly soluble derivative, for example, as a poorly soluble salt.

[0192] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may contain the active ingredient in a flavored base such as sucrose and acacia, or tragacanth.

[0193] The compositions may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides. In certain embodiments, the compounds disclosed herein may be administered topically, i.e., non-systemically. This includes externally applying the compounds disclosed herein to the epidermis or buccal cavity, as well as instilling such compounds into the ear, eye, and nose so that the compounds do not enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0194] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for administration to the eye, ear, or nose. The active ingredient for topical administration may comprise, for example, 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, the composition may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, the active ingredient may comprise 0.1% to 1% w / w of the formulation.

[0195] For administration by inhalation, the compounds disclosed herein can be conveniently delivered from an insufflator, a nebulizer pressurized pack, or other convenient means for delivering an aerosol spray. The pressurized pack can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds disclosed herein can be in the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition can be provided in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered with the aid of an inhaler or insufflator.

[0196] In particular, intranasal delivery can be useful for delivering compounds to the CNS. Intranasal drug administration has been shown to be a noninvasive method for bypassing the blood-brain barrier (BBB) to deliver neurotrophins and other therapeutic agents to the brain and spinal cord. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal pathways. Intranasal delivery occurs via an extracellular route and does not require the drug to bind to any receptors or undergo axonal transport. Intranasal delivery also targets the nasal-associated lymphoid tissue (NALT) and deep cervical lymph nodes. Furthermore, intranasally administered therapeutic agents are found at high levels in the blood vessel walls and perivascular spaces of the cerebral vasculature. Using this intranasal method in animal models, researchers have successfully reduced stroke damage, reversed Alzheimer's disease neurodegeneration, reduced anxiety, improved memory, stimulated neurogenesis, and treated brain tumors.

[0197] In certain embodiments, unit dosage formulations contain an effective dose or an appropriate fraction thereof of the active ingredient.

[0198] It will be understood that the above formulations may include, in addition to the ingredients particularly mentioned above, other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0199] Combination therapy In certain cases, it may be appropriate to administer at least one compound of Formula (I), (II), or (III) (or an enantiomer, diastereoisomer, tautomer, or pharmaceutically acceptable salt thereof) in combination with another therapeutic agent. By way of example only, if nausea is one of the side effects experienced by a patient when administered one of the compounds herein for the treatment of cancer, it may be appropriate to administer an antiemetic agent in combination. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., an adjuvant may have minimal therapeutic effect by itself, but in combination with another therapeutic agent, improves the overall therapeutic effect for the patient). Alternatively, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (including a treatment regimen) that also has a therapeutic effect. By way of example only, in a cancer treatment that includes the administration of one of the compounds described herein, an increased therapeutic effect may be achieved by also providing the patient with another cancer therapeutic agent. In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be merely additive of the two therapeutic agents, or the patient may experience a synergistic benefit. The present compounds may be particularly useful in combination with therapeutic and / or anti-cancer agents. Accordingly, the present disclosure provides combinations of compounds of Formula (I), (II), or (III) used in combination with therapeutic and / or anti-cancer agents for simultaneous, separate, or sequential administration. The compounds of the present disclosure and other anti-cancer agents may act additively or synergistically. A synergistic combination of a compound of the present invention with another anti-cancer agent may allow for the use of lower doses of one or both of these agents, and / or less frequent use of the compound and one or both of the other anti-cancer agent, and / or may reduce any toxicity associated with administering the agents to a patient without reducing the effectiveness of the agents in treating cancer. Furthermore, synergistic effects may result in improved efficacy of these agents in treating cancer and / or reduced adverse or undesirable side effects associated with the use of either agent alone.

[0200] The therapeutic agent and / or anti-cancer agent can be administered according to treatment protocols well known in the art. As will be apparent to those skilled in the art, the administration of the therapeutic agent and / or anti-cancer agent can vary depending on the disease being treated and the known effects of the anti-cancer agent on that disease. Furthermore, according to the knowledge of a skilled clinician, the treatment protocol (e.g., dosage and frequency of administration) can be modified taking into account the effect of the administered therapeutic agent (i.e., anti-tumor agent or radiation) on the patient, the observed response of the disease to the administered therapeutic agent, and any observed side effects.

[0201] In certain embodiments, the compounds according to one or more embodiments disclosed herein, e.g., compounds of Formula I, are selected from the group consisting of aromatase inhibitors, antiestrogens, antiprogesterones, antiandrogens, or gonadorelin agonists, anti-inflammatory agents, antihistamines, anticancer agents, angiogenesis inhibitors, topoisomerase 1 and 2 inhibitors, microtubule activators, alkylating agents, antitumor agents, antimetabolites, dacarbazine (DTIC), platinum-containing compounds, lipid or protein kinase targeting agents, protein or lipid phosphatase targeting agents, antiangiogenic agents, agents that induce cell differentiation, bradykinin 1 receptor and angiotensin II antagonists. The compound may be administered in combination with one or more agents selected from the group consisting of agonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokine or cytokine inhibitors, bisphosphanates, rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR agonists, HSP90 inhibitors, smoothened antagonists, inhibitors of Ras isoforms, telomerase inhibitors, protease inhibitors, metalloproteinase inhibitors, aminopeptidase inhibitors, immunomodulators, therapeutic antibodies, and protein kinase inhibitors, e.g., tyrosine kinase or serine / threonine kinase inhibitors.

[0202] In certain embodiments, a combination of a compound of Formula I and an anti-cancer agent is provided for simultaneous, separate, or sequential administration.

[0203] Those skilled in the art can identify which drug combinations are useful based on the specific characteristics of the drugs and the cancer involved. Such drug classes include estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, gamma-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), agents that interfere with cell cycle checkpoints, PARP inhibitors, HDAC inhibitors, Smo antagonists (HH inhibitors), HSP90 inhibitors, CYP17 inhibitors, third-generation AR antagonists, JAK inhibitors, such as ruxolitinib (trade name Jkafi), and BTK kinase inhibitors.

[0204] Anti-cancer agents suitable for use in combination therapy with the compounds disclosed herein include, but are not limited to: 1) chromatin function inhibitors, including alkaloid and natural product drugs, including microtubule inhibitors (e.g., vincristine, vinblastine, vindesine, and vinorelbine), microtubule stabilizers (e.g., paclitaxel [Taxol], docetaxel, and taxotere), and topoisomerase inhibitors, such as epipodophyllotoxins (e.g., etoposide [VP-161] and teniposide [VM-261]), and drugs that target topoisomerase I (e.g., camptothecin, topotecan (hycamtin), and irinotecan [CPT-11], rubican (oratecin), etc.); 2) Covalent DNA binders [alkylating agents], including nitrogen mustards (e.g., mechloretharine, chloromethine, chlorambucil, cyclophosphamide, estramustine (Encyte, Estracit), ifosfamide, melphalan (Alkeran), etc.), alkylsulfonates such as busulfan [Myleran], nitrosoureas (e.g., carmustine or BCNU (bis-chloroethylnitrosourea), fotemustine, lomustine, and and semustine, streptozocin, etc.), as well as other alkylating agents (e.g., dacarbazine, procarbazine ethyleneimine / methylmelamine, triethylenemelamine (TEM)), triethylenethiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine), and temozolomide (trade names Temodar, Temodal, and Temcad), altretamine (also Hexalen), and mitomycin, including uramustine, etc., and 3) Non-covalent DNA binders [antineoplastic antibiotics], including nucleic acid inhibitors (e.g., dactinomycin [actinomycin D1], etc.), anthracyclines (e.g., daunorubicin [daunomycin, and cerubicin], doxorubicin [adriamycin], epirubicin (Ellence), and idarubicin [idamycin], valrubicin (Valstar), etc.), anthracenediones (e.g., anthracycline analogs such as [mitoxantrone]), bleomycin (blenoxane), etc., ansacrines and plicamycin (mithramycin), dactinomycin, mitomycin C.

[0205] In certain embodiments, cancer patients are treated with a compound of Formula (I), (II), or (III) in combination with radiation therapy. In certain embodiments, the method comprises administering to the cancer patient a therapeutically effective amount of a compound of the present disclosure and treating the patient with an adjunctively effective amount of radiation therapy. In certain embodiments, the compound is administered to a patient in need thereof before, simultaneously with, or after radiation treatment.

[0206] In certain embodiments, the compound or pharmaceutical composition may further comprise or be administered in combination with one or more other antiviral agents, including, but not limited to, oseltamivir phosphate, zaamivir or Virazole®, remdesivir, vidarabine, acyclovir, ganciclovir, valganciclovir, valacyclovir, cidofovir, famciclovir, ribavirin, amantadine, rimantadine, interferon, oseltamivir, palivizumab, rimantadine, zanamivir, nucleoside analog reverse transcriptase inhibitors (NRTIs), e.g., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, and non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as abacavir, nevirapine, delavirdine, and efavirenz, protease inhibitors, such as sacquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and other known antiviral compounds and formulations.

[0207] In certain embodiments, the compounds or pharmaceutical compositions may be co-administered with one or more antiviral agents. The compounds or pharmaceutical compositions of the invention may be administered in any order.

[0208] Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the compositions and / or formulations of the present invention may be short-term, immediate offset, and controlled, including, but not limited to, sustained release, delayed release, and pulsed release formulations.

[0209] The term sustained release is used in its conventional sense to refer to a drug formulation that provides sustained release of drug over an extended period of time and that may, but does not necessarily, result in substantially constant blood drug levels over an extended time frame, which may be as long as or longer than one month and should be a longer release than the same amount of drug administered in bolus form.

[0210] For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compounds. Thus, the compounds for use in the methods of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or disks by implantation.

[0211] In certain embodiments of the present invention, the compounds useful within the present invention are administered to a subject, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0212] The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides an initial release of drug after some delay following drug administration, which may, but is not necessarily, include a delay of from about 10 minutes up to about 12 hours.

[0213] The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a manner as to result in a pulsatile plasma profile of the drug following drug administration.

[0214] The term immediate release is used in its conventional sense to refer to a drug formulation that provides release of the drug immediately after drug administration.

[0215] As used herein, short-term refers to any period of time after drug administration of up to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof.

[0216] Administration / Dosage The compound may be administered to animals at a frequency such as several times a day, or less frequently, such as once a day, once a week, once every two weeks, once a month, or even once every few months or even less frequently, such as once a year or less. It is understood that the amount of compound administered per day can be administered, in non-limiting examples, every day, every other day, every two days, every three days, every four days, or every five days. For example, in every other day administration, a 5 mg dose per day may be administered starting on Monday, the first subsequent 5 mg dose per day may be administered on Wednesday, the second subsequent 5 mg dose per day may be administered on Friday, etc. The frequency of administration is readily apparent to those skilled in the art and depends on several factors, such as, but not limited to, the type and severity of the disease being treated, and the type and age of the animal.

[0217] In certain embodiments, the compositions of the present invention are administered to a patient in dosages ranging from 1 to 5 or more times per day. In other embodiments, the compositions of the present invention are administered to a patient in dosage ranges including, but not limited to, daily, once every two or three days, to once a week, and once every two weeks. It will be readily apparent to those skilled in the art that the frequency of administration of various combinations of the compositions of the present invention will vary for each subject depending on many factors, including, but not limited to, age, disease or disorder being treated, sex, overall health, and other factors. Therefore, the present invention should not be construed as limited to any particular dosage regimen, and the exact dosage and composition to be administered to any patient will be determined by the attending physician, taking into account all other factors related to the patient.

[0218] The compounds according to one or more embodiments disclosed herein may be administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adult humans is generally 5 mg to 2 g per day. Tablets or other presentation forms provided in discrete units may conveniently contain an effective amount of one or more compounds at such doses, or an equivalent multiple thereof, e.g., units containing 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0219] The compounds of the present invention for administration may be administered in the following dosages: about 1 μg to about 7,500 mg, about 20 μg to about 7,000 mg, about 40 μg to about 6,500 mg, about 80 μg to about 6,000 mg, about 100 μg to about 5,500 mg, about 200 μg to about 5,000 mg, about 400 μg to about 4,000 mg, about 800 μg to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg to about 2,500 mg, about 3 mg to about 3,000 mg, about 4 mg to about 4,000 mg, about 5 mg to about 5,000 mg, about 6 mg to about 6,000 mg, about 7 mg to about 7,500 mg, about 8 mg to about 9,000 mg, about 9 mg to about 10,000 mg, about 10 mg to about 12,000 mg, about 10 mg to about 14,000 mg, about 10 mg to about 16,000 mg, about 10 mg to about 18,000 mg, about 10 mg to about 24,000 mg, about 10 mg to about 26,000 mg, about 10 mg to about 28,000 mg, about 10 mg to about 28,000 mg, about 10 mg to about 28,000 mg, about 10 mg to about 29,000 mg, about 10 mg to about 3 ... The dose may range from about 1,000 mg, about 5 mg to about 1,000 mg, about 10 mg to about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 150 mg, and any and all whole or partial increments therebetween.

[0220] In some embodiments, the dosage of the compound of the invention is from about 0.5 μg to about 5,000 mg. In some embodiments, the dosage of the compound of the invention used in the compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of a second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments therebetween.

[0221] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0222] The compounds of the present disclosure can be administered in various ways, for example, orally, topically, or by injection. The exact amount of compound administered to a patient is the responsibility of the attending physician. The specific dose level for any particular patient depends on various factors, including the activity of the specific compound used, the patient's age, weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, the exact disorder being treated, and the severity of the symptoms or condition being treated. In addition, the administration route may vary depending on the condition and its severity. [Example]

[0223] Various embodiments of the present application may be better understood by reference to the following examples, which are provided by way of illustration and not intended to limit the scope of the present application to the examples provided herein.

[0224] LCMS conditions Method A: Waters Acquity UPLC system using a Waters Acquity UPLC CSH C18 (2.1 x 50 mm), 1.7 μm column, eluent A = H2O + 0.05% TFA (v / v), and eluent B = CH3CN + 0.035% TFA. Oven temperature: 55 °C, gradient: t 0分 =2%B, t 1分 =98%B, t 1.5分 =98%B, t 1.52分 =2%B, t 1.7分 = 2% B (v / v). Flow rate: 0.8 mL / min. Positive electrospray ES+, capillary: 0.8 kV, cone voltage: 10 V. Method B: Waters Acquity UPLC system using a Waters Acquity UPLC CSH C18 (2.1 × 50 mm), 1.7 μm column, eluent A = H2O + 0.05% TFA (v / v), and eluent B = CH3CN + 0.035% TFA. Oven temperature: 55 °C, gradient: t 0分 =2%B, t 1分 =98%B, t 1.5分 =98%B, t 1.52分 =2%B, t 1.7分= 2% B (v / v). Flow rate: 0.8 mL / min. Positive electrospray ES+, capillary: 0.8 kV, cone voltage: 15 V. Method C: Acquity UPLC system using a Waters Acquity UPLC BEH C18 (2.1 x 50 mm), 1.7 μm column, eluent A = H2O + AcONH4 (10 mM), and eluent B = CH3CN. Oven temperature: 45 °C, gradient: t 0分 =2%B, t 4分 =90%B, t 4.5分 =90%B, t 4.6分 =2%B, t 5.5分 = 2% B (v / v). Flow rate: 0.8 mL / min. Electrospray ionization mode, capillary: 3 kV, cone voltage: 15 / 30 V. Method D: Waters Acquity UPLC system using a Waters Acquity UPLC CSH C18 (2.1 x 50 mm), 1.7 μm column, eluent A = H2O + 0.02% HCOOH, and eluent B = CH3CN + 0.02% HCOOH. Oven temperature: 55 °C, gradient: t 0分 =2%B, t 4分 =98%B, t 4.5分 =98%B, t 4.6分 = 2%B, and t 5.0分 = 2% B (v / v). Flow rate: 1 mL / min. Negative electrospray ES-, capillary: 3 kV, sample cone: 15 / 30 V. Method E: Waters Acquity UPLC system using a Waters Acquity UPLC CSH C18 (2.1 x 50 mm), 1.7 μm column, eluent A = H2O + 0.02% HCOOH, and eluent B = CH3CN + 0.02% HCOOH. Oven temperature: 55 °C, gradient: t 0分 =2%B, t 4分 =98%B, t 4.5分 =98%B, t 4.6分 = 2%B, and t 5.0分 = 2% B (v / v). Flow rate: 1 mL / min. Electrospray ionization mode, capillary: 3 kV, sample cone: 15 / 30 V. Method F: Waters Acquity UPLC system using a Waters Acquity UPLC CSH C18 (2.1 x 50 mm), 1.7 μm column, eluent A = H2O + 0.05% TFA, and eluent B = CH3CN + 0.035% TFA. Oven temperature: 55 °C, gradient: t 0分 =2%B, t 4分 =98%B, t 4.5分 =98%B, t 4.6分 = 2%B, and t 5.0分 = 2% B (v / v). Flow rate: 1 mL / min. Electrospray ionization mode, capillary: 3 kV, sample cone: 15 / 30 V.

[0225] Example 1: N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (1) [ka] Step 1: Synthesis of benzyl 3-(3,4-difluorophenyl)-3-hydroxypyrrolidine-1-carboxylate [ka] A suspension of magnesium (222 mg, 9.12 mmol) and crystals of I2 in anhydrous THF (7 mL) was stirred at room temperature under nitrogen in a three-necked round-bottom flask equipped with a thermometer, an addition funnel, and a reflux condenser. A solution of 4-bromo-1,2-difluorobenzene (1.23 g, 6.39 mmol) in anhydrous THF (3 mL) was added to the addition funnel, and a few drops were added to the reaction mixture. The orange suspension was stirred at 65 °C until discoloration occurred, and the remaining solution was added dropwise. The mixture was stirred at 65 °C for 1 h and then cooled to 0 °C. A solution of benzyl 3-oxopyrrolidine-1-carboxylate (1.0 g, 4.56 mmol) in anhydrous THF (3 mL) was added dropwise, and the mixture was stirred at 0 °C for 1 h and then at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 10% to 70% EtOAc in cyclohexane to give the title compound as a yellow oil (802.6 mg, 50% yield, 95% purity, t r =0.89 min). LCMS (Method A): m / z found 334.3 [M+H] + .

[0226] Step 2: Synthesis of benzyl 3-(2-chloroacetamido)-3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate [ka] In a round-bottom flask under nitrogen, a solution of benzyl 3-(3,4-difluorophenyl)-3-hydroxy-pyrrolidine-1-carboxylate (800 mg, 2.40 mmol) and 2-chloroacetonitrile (4.6 mL, 72.0 mmol) in dry DCM was stirred at 0 °C. 2,2,2-Trifluoroacetic acid (4.6 mL, 60.0 mmol) was added dropwise, and the mixture was stirred at 0 °C for 4 h and at room temperature overnight. The mixture was poured into ice water, and saturated aqueous Na2CO3 was added until pH = 9. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as an orange oil (987.4 mg, 70% yield, 70% purity, t r =0.87 min). LCMS (Method A): m / z found 409.4 [M+H] + .

[0227] Step 3: Synthesis of benzyl 3-amino-3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate [ka] To a sealed tube was added benzyl 3-[(2-chloroacetyl)amino]-3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate (70%, 987 mg, 1.69 mmol) in a mixture of ethanol (23.8 mL) and acetic acid (4.8 mL) (5:1 ratio). Thiourea (98%, 171 mg, 2.20 mmol) was then added, and the mixture was stirred at 80 °C overnight. The solution was cooled to room temperature and then diluted with DCM. Aqueous NaCO was added until pH = 9. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude oil was diluted with a small amount of EtO, and 2 M HCl / EtO (8.4 mL, 16.9 mmol) was added. The mixture was stirred at room temperature overnight. The solid was filtered, washed with Et2O, and dried under reduced pressure at 45 °C for 64 h to give the hydrochloride salt of the title compound as an off-white powder (441.2 mg, 60% yield, 86% purity, t r=0.59 min). LCMS (Method A): m / z found 441.2 [M-HCl+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.89 (s,3H),7.74 (dddd,J=12.2,7.6,2.4 Hz,1H),7.56 (dtd,J=10.5,8.5 ,6.5 Hz,1H),7.47 - 7.28 (m,6H),5.12 (d,J=1.9 Hz,2H),3.80 - 3.48 (m,4H),2.63 - 2.42 (m,2H).

[0228] Step 4: Synthesis of benzyl 3-(3,4-difluorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate [ka] To a sealed vial was added benzyl 3-amino-3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate hydrochloride (86%, 200 mg, 0.466 mmol), DMAP (11 mg, 0.0933 mmol), and triethylamine (260 μL, 1.87 mmol) in DCM (4.4 mL). 4-(Trifluoromethoxy)benzenesulfonyl chloride (98%, 81 μL, 0.466 mmol) was then added, and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was diluted with DCM, and saturated aqueous NH4Cl was added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was triturated with DCM. The suspension was filtered, washed with DCM, and dried under reduced pressure at 45° C. for 4 hours to give the title compound as an off-white powder (125.1 mg, 46% yield, 97% purity, t r =0.99 min). LCMS (Method B): m / z found 579.3 [M+Na] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.63 (d,J=5.6 Hz,1H),7.47 (dd,J=8.8,1.9 Hz,2H),7.41~7.34 (m, 4H), 7.37 - 7.29 (m, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.14 - 6.98 (m, 1H), 6.94 (d, J=8.4 Hz, 0H), 5.14 - 5.01 (m) ,2H),4.13 (dd,J=18.9,11.4 Hz,1H),3.57 (dd,J=16.8,11.4 Hz,1H),3.54 - 3.31 (m,1H),2.69 (d,J=13.8 Hz,1H).

[0229] Step 5: Synthesis of N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a solution of benzyl 3-(3,4-difluorophenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate (97%, 125 mg, 0.218 mmol) in ethanol (1.5 mL) in a round-bottom flask, Pd / C (10%, 23 mg, 0.0218 mmol) was added, and the mixture was stirred overnight under an H atmosphere. The reaction mixture was filtered over a talc pad and washed first with EtOH and then with warm EtOH. Both residues were combined and purified by reverse-phase flash chromatography using a gradient of 0% to 100% ACN in water (0.1% AcOH). The desired fractions were combined and concentrated under reduced pressure. Salt exchange (acetate to hydrochloride) was performed on Amberlite IRA-410(Cl) and stirred overnight at room temperature. The resin was then washed with MeOH. The filtrate was concentrated under reduced pressure to give the hydrochloride salt of the title compound as a white powder (12.6 mg, 12% yield, 99.5% purity, t r =1.73 minutes). LCMS (Method C): m / z actual value 422.9 [M-HCl+H] + ; 1H-NMR (600 MHz,DMSO-d6) δ ppm 8.17 - 9.17 (m,2 H) 7.46 (d,J=8.04 Hz,2 H) 7.29 (d,J=8.12 Hz,2 H) 7.03 - 7.08 (m, 2 H) 6.95 (m, J=4.20, 4.20, 2.70 Hz, 1 H) 3.91 (br d, J=11.59 Hz, 1 H) 3.21 - 3.28 (m, 4 H) 2.72 - 2.78 (m , 1H) 2.12 (dt, J=13.39, 9.22 Hz, 1 H).

[0230] Example 2: N-(4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (2) [ka] Step 1: Synthesis of 1-benzyl-4-(3,5-difluorophenyl)piperidine-4-carbonitrile [ka] To a stirred solution of 4-(3,5-difluorophenyl)piperidine-4-carbonitrile (50%, 400 mg, 0.900 mmol) and benzaldehyde (0.18 mL, 1.80 mmol) in methanol (6 mL) at 25 °C was added polymer-bound sodium cyanoborohydride (900 mg, 1.80 mmol). The reaction mixture was stirred at 25 °C for 3 h and filtered. The residue was washed with methanol, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 10% to 30% EtOAc in cyclohexane to give the title compound as a colorless oil (439 mg, quantitative yield, 99% purity, t r =0.59 min). LCMS (Method A): m / z found 313.4 [M+H] + ; 1H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.37 - 7.24 (m, 8H), 3.57 (s, 2H), 2.94 (dt, J=12.5, 3.3 Hz, 2H), 2.32 ( td,J=12.2,2.2Hz,2H),2.16(dq,J=13.4,2.7Hz,2H),2.08-1.97(m,2H).

[0231] Step 2: Synthesis of 1-benzyl-4-(3,5-difluorophenyl)piperidine-4-carboxamide [ka] In a round-bottom flask, a mixture of 1-benzyl-4-(3,5-difluorophenyl)piperidine-4-carbonitrile (99%, 439 mg, 1.39 mmol) in water (1.4 mL) and sulfuric acid (5.6 mL, 0.104 mol) was stirred at 65 °C for 45 min. The mixture was poured into ice water and basified with 10 M NaOH (21 mL, 0.209 mol) to reach pH = 10-11. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as an orange oil (439 mg, 91% yield, 95% purity, t r =0.51 min). LCMS (Method A): m / z found 331.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.37 - 7.25 (m, 5H), 7.13 (d, J=9.2 Hz, 2H), 7.06 (dt, J=9.5, 4.8 Hz, 3H), 3.41 (s, 2H), 2.60 (s, 2H), 2.42 (d, J=10.9 Hz, 2H), 2.17 (d, J=12.3 Hz, 2H), 1.79 (s, 2H).

[0232] Step 3: Synthesis of 1-benzyl-4-(3,5-difluorophenyl)piperidin-4-amine [ka] To a stirred solution of 1-benzyl-4-(3,5-difluorophenyl)piperidine-4-carboxamide (95%, 439 mg, 1.26 mmol) in acetonitrile (3.1 mL) and water (3.1 mL) at room temperature, [phenyl-(2,2,2-trifluoroacetyl)oxy-{3}-iodanyl]2,2,2-trifluoroacetic acid (96%, 577 mg, 1.29 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature, and the ACN was concentrated under reduced pressure. 1 M aqueous HCl was added, and the aqueous layer was washed with EtOAc. The aqueous layer was basified with saturated aqueous Na2CO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a white solid (249 mg, 61% yield, 93% purity, t r =0.41 min). LCMS (Method A): m / z found 303.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.32 (d, J=4.3 Hz, 4H), 7.29 - 7.19 (m, 3H), 7.02 (tt, J=9.3, 2.4 Hz, 1H), 3.49 (s, 2H), 2.51 - 2.44 (m, 2H), 1.97 - 1.76 (m, 4H), 1.52 (d, J=12.8 Hz, 2H).

[0233] Step 4: Synthesis of N-(1-benzyl-4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a sealed vial was added 1-benzyl-4-(3,5-difluorophenyl)piperidin-4-amine (93%, 249 mg, 0.766 mmol), N,N-dimethylpyridin-4-amine (99%, 19 mg, 0.153 mmol), and triethylamine (0.43 mL, 3.06 mmol) in DCM (7 mL). 4-(Trifluoromethoxy)benzenesulfonyl chloride (98%, 0.13 mL, 0.766 mmol) was added, and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was diluted with DCM and saturated aqueous NH4Cl solution. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 0% to 10% MeOH (0.7M in NH3) in DCM to give the title compound as a pale yellow solid (345 mg, 86% yield, 100% purity, t r =0.73 min). LCMS (Method B): m / z found 527.3 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.05 (s, 1H), 7.52 - 7.43 (m, 2H), 7.37 - 7.20 (m, 7H), 6.81 - 6.72 (m, 3H) ),3.47 (s, 2H),2.61 - 2.52 (m,2H),2.45 (t, J=11.0 Hz, 2H),2.32 (d, J=13.4 Hz, 2H), 1.91 - 1.77 (m, 2H).

[0234] Step 5: Synthesis of N-(4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of N-[1-benzyl-4-(3,5-difluorophenyl)-4-piperidyl]-4-(trifluoromethoxy)benzenesulfonamide (345 mg, 0.655 mmol) and DIPEA (0.23 mL, 1.31 mmol) in DCM (4 mL) under nitrogen, 1-chloroethyl carbonochloridate (95%, 0.15 mL, 1.31 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (4 mL), and the mixture was stirred at 65° C. for 16 hours. The reaction mixture was cooled to room temperature and quenched with water. EtOAc was added, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a 1% to 15% gradient of MeOH (0.7 N NH) in DCM. The desired fractions were concentrated, the residue was dissolved in a minimum amount of DCM, and HCl 2M in EtO was added dropwise. EtO was added, and the resulting suspension was filtered, washed with EtO, and dried under vacuum at 50 °C for 12 h to give the hydrochloride salt of the title compound as a white powder (38 mg, 12% yield, 100% purity, t r =1.35 min). LCMS (Method D): m / z found 437.1 [M-HCl+H] + ; 1 H-NMR (DMSO-d6,500 MHz): δ (ppm) 8.82 (br s,2H),8.54 (br s,1H),7.46-7.49 (m,2H),7.29 (d,J=7.8 Hz, 2H),6.78-6.85 (m, 3H),3.18-3.28 (m, 4H), 2.51-2.58 (m, 2H), 1.99-2.09 (m, 2H).

[0235] Example 3: N-(4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (3) [ka] Step 1: Synthesis of benzyl 4-(6-chloropyridin-3-yl)-4-cyanopiperidine-1-carboxylate [ka] To a stirred solution of benzylbis(2-bromoethyl)amine (284 mg, 0.883 mmol) and (6-chloropyridin-3-yl)acetonitrile (98%, 125 mg, 0.803 mmol) in dry DMF (2.5 mL) at 0 °C was added sodium hydride (60%, 193 mg, 4.82 mmol) in portions. The reaction mixture was stirred at room temperature for 1 h, then warmed to 60 °C and stirred at this temperature overnight. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl. EtOAc was added, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with brine, dried using a phase separator, and concentrated under vacuum. The crude material was purified by silica gel flash chromatography using a gradient of 0% to 100% EtOAc in heptane to give the title compound as a yellow oil (206.9 mg, 83% yield, 99% purity, t r =0.52 min). LCMS (Method A): m / z found 312.3 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.61 (d, J=2.7 Hz, 1H), 8.06 (dd, J=8.5, 2.8 Hz, 1H), 7.60 (d, J= 8.5 Hz, 1H), 7.35 (d, J=4.4 Hz, 4H), 7.30 - 7.23 (m, 1H), 3.58 (s, 2H), 2.96 (dt, J=12.7, 3.2 Hz, 2H), 2.34 (dt, J=12.7, 3.2 Hz, 2H) td,J=12.2,2.2Hz,2H),2.18(dq,J=13.5,2.8Hz,2H),2.11-1.99(m,2H).

[0236] Step 2: Synthesis of 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxamide [ka] In a sealed tube, a mixture of 1-benzyl-4-(6-chloro-3-pyridyl)piperidine-4-carbonitrile (180 mg, 0.578 mmol) in sulfuric acid (2.3162 mL) and water (0.579 mL) was stirred at 65° C. for 4 hours. The mixture was poured into ice water and basified with 1N aqueous NaOH to pH=10. Water and DCM were added to obtain two homogeneous layers, and the aqueous layer was extracted twice with DCM. The combined organic layers were dried using a phase separator and concentrated under reduced pressure to give the title compound as a white solid (203.6 mg, quantitative yield, 95% purity, t r =0.46 min). LCMS (Method A): m / z found 330.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.40 (d, J=2.6 Hz, 1H), 7.81 (dd, J=8.5, 2.7 Hz, 1H), 7.48 (d, J= 8.5 Hz, 1H), 7.33 - 7.20 (m, 6H), 7.08 (s, 1H), 3.42 (s, 2H), 2.59 (d, J=11.4 Hz, 2H), 2.45 (d, J=13.2 Hz, 2H),2.19 (t, J=10.8 Hz, 2H), 1.84 (t, J=11.8 Hz, 2H).

[0237] Step 3: Synthesis of 1-benzyl-4-(6-chloropyridin-3-yl)piperidin-4-amine [ka] In a round-bottom flask, a solution of 1-benzyl-4-(6-chloro-3-pyridyl)piperidine-4-carboxamide (95%, 178 mg, 0.514 mmol) in acetonitrile (1.4 mL) and water (1.4 mL) was stirred at room temperature. [Bis(trifluoroacetoxy)iodo]benzene (282 mg, 0.630 mmol) was added, and the mixture was stirred at 80 °C overnight. The ACN was evaporated, then 1N aqueous HCl was added, and the mixture was washed twice with DCM. Saturated aqueous Na2CO3 was added to the aqueous layer until pH = 9. The aqueous layer was extracted three times with DCM, and the combined organic layers were washed with brine, filtered through a phase separator, and concentrated under reduced pressure to give the title compound as a yellow oil (117.6 mg, 71% yield, 94% purity, t r =0.39 min). LCMS (Method A): m / z found 302.3 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.56 (d, J=2.6 Hz, 1H), 7.99 (dd, J=8.4, 2.7 Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.32 (d, J=4.0 Hz, 4H), 7.24 (dddd, J=8.8, 5.2, 3.6 Hz, 1H), 3.50 (s, 2H), 1.96 - 1.90 (m, 2H),1.63-1.54(m,2H).

[0238] Step 4: N-(1-benzyl-4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of 1-benzyl-4-(6-chloro-3-pyridyl)piperidin-4-amine (115 mg, 0.381 mmol) in DCM (2.5 mL) in a sealed vial, triethylamine (0.16 mL, 1.14 mmol) and DMAP (4.7 mg, 0.0381 mmol) were added sequentially. 4-(Trifluoromethoxy)benzenesulfonyl chloride (0.071 mL, 0.419 mmol) was then added to the reaction mixture, which was stirred at 40 °C overnight. The reaction mixture was cooled to room temperature and quenched with half-saturated aqueous NaHCO3 solution. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 2% to 10% MeOH in DCM to give the title compound as a light yellow powder (160.1 mg, 76% yield, 95% purity, t r =0.68 min). LCMS (Method B): m / z found 526.3 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.22 - 8.15 (m,2H),7.72 - 7.42 (m,4H),7.33 - 7.24 (m,7H),7.05 (d,J =8.4Hz,1H),3.45(s,2H),2.44(d,J=10.5Hz,2H),2.34(d,J=13.9Hz,2H),1.93(s,2H).

[0239] Step 5: Synthesis of N-(4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of N-[1-benzyl-4-(6-chloro-3-pyridyl)-4-piperidyl]-4-(trifluoromethoxy)benzenesulfonamide (155 mg, 0.295 mmol) in DCM (3.5 mL) under nitrogen, 1-chloroethyl carbonochloridate (99%, 64 μL, 0.590 mmol) was added. The solution became cloudy, and DIPEA (52 μL, 0.295 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (3.7 mL), and the reaction mixture was stirred at 65° C. for 4 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by silica gel flash chromatography using a gradient of 2% to 15% MeOH (0.7 N NH) in DCM. The residue was triturated with MeOH and filtered. The precipitate was suspended in 2M HCl / EtO (1.5 mL, 2.95 mmol) for 4 h, filtered, washed with EtO, and dried under vacuum at 40 °C for 20 h to give the hydrochloride salt of the title compound as a white powder (18 mg, 12% yield, 99.6% purity, 1.17 min). LCMS (Method D): m / z found 436.1 [M-HCl+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ ppm 1.99 - 2.16 (m,2 H) 2.57 (br d,J=13.94 Hz,2 H) 3.18 - 3.27 (m,4 H) 7.07 (d, J=8.31Hz,1H)7.29(dd,J=8.80,0.73Hz,2H)7.42-7.47(m,2H)7.51(dd,J=8.44,2.81Hz,1H)8.18(d,J) =2.45Hz,1H)8.41-8.69(m,3H).

[0240] Example 4: N-(4-(4-chloro-3-methylphenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (4) [ka] Step 1: Synthesis of benzyl 4-(4-chloro-3-methylphenyl)-4-hydroxypiperidine-1-carboxylate [ka] To a stirred solution of 0.5 M bromo(4-chloro-3-methylphenyl)magnesium (20 mL, 10.1 mmol) in dry THF (16 mL) in a round-bottom flask under nitrogen was added a solution of benzyl 4-oxopiperidine-1-carboxylate (98%, 2.00 g, 8.40 mmol) in dry THF (11 mL) dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 20 h. The mixture was poured into saturated aqueous NH4Cl and EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography using a gradient of 0 to 8% MeOH in DCM to give the title compound as a yellow gum (1.98 g, 53.7% yield, 82% purity, t r =0.97 min) by LCMS (Method A); 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.45 (dt,J=2.1,0.7 Hz,1H),7.42 - 7.27 (m,7H),5.16 (s,1H),5.09 ( s, 2H), 3.93 (d, J=12.9 Hz, 2H), 3.20 (s, 2H), 2.32 (s, 3H), 1.82 (td, J=13.1, 4.7 Hz, 2H), 1.57 (d, J =13.3Hz,2H).

[0241] Step 2: Synthesis of benzyl 4-(4-chloro-3-methylphenyl)-4-(2-chloroacetamido)piperidine-1-carboxylate [ka] To a round-bottom flask, benzyl 4-(4-chloro-3-methyl-phenyl)-4-hydroxy-piperidine-1-carboxylate (82%, 1.98 g, 4.51 mmol) and 2-chloroacetonitrile (8.6 mL, 0.135 mol) in dry DCM (7.5 mL) were added at 0 °C. Then, 2,2,2-trifluoroacetic acid (8.6 mL, 0.113 mol) was added dropwise over 1 h and stirred at the same temperature for 3 h. The reaction mixture was poured into ice and quenched with saturated aqueous NaHCO3 solution. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography using a gradient of 0 to 50% EtOAc in heptane to give the title compound as a white gum (1.33 g, 60.3% yield, 89% purity, t r =0.96 min). LCMS (Method A): m / z found 435.5 [M+H] + ; 1H -NMR (DMSO-d6,400 MHz): δ (ppm) 8.42 (s,1H),7.42 - 7.34 (m,4H),7.36 - 7.29 (m,3H),7.18 (dd,J=8.6) ,2.4 Hz,1H),5.09 (s,2H),4.12 (s,2H),3.92 (d,J=13.3 Hz,2H),3.09 (s,3H),2.31 (s,3H),2.28 (s, 1H), 1.80 (td, J=13.1, 4.5 Hz, 2H).

[0242] Step 3: Synthesis of benzyl 4-amino-4-(4-chloro-3-methylphenyl)piperidine-1-carboxylate [ka] To a sealed tube was added benzyl 4-[(2-chloroacetyl)amino]-4-(4-chloro-3-methyl-phenyl)piperidine-1-carboxylate (89%, 1.33 g, 2.72 mmol) in a mixture of ethanol (38.3 mL) and acetic acid (7.7 mL). Thiourea (98%, 275 mg, 3.53 mmol) was then added, and the mixture was stirred at 80 °C overnight. The solution was cooled to room temperature and then diluted with DCM. Half-saturated aqueous NaCO solution was added until pH = 9. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude oil was diluted with a small amount of EtO, and 2 M HCl / EtO (14 mL, 27.2 mmol) was added. The suspension was stirred at room temperature overnight and filtered. The residue was washed with Et2O and dried under reduced pressure at 45 °C for 2 hours to obtain the title compound as a white powder (1.03 g, yield 84.3%, purity 88%, t r =0.67 min) LCMS (Method A); 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.49 (s,3H),7.63 (d,J=2.4 Hz,1H),7.53 (d,J=8.5 Hz,1H),7.46 (dd,J=8.5,2.5Hz,1H),7.40 - 7.30 (m,5H),5.08 (s,2H),3.79 (d,J=13.7Hz,2H),3.13 (bs,2H),2.47 - 2.38 (m, 2H), 2.37 (s, 3H), 2.05 - 1.94 (m, 2H).

[0243] Step 4: Synthesis of benzyl 4-(4-chloro-3-methylphenyl)-4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate [ka] To a sealed vial was added benzyl 4-amino-4-(4-chloro-3-methyl-phenyl)piperidine-1-carboxylate hydrochloride (88%, 1.03 g, 2.29 mmol), DMAP (56 mg, 0.459 mmol), and triethylamine (1278 μL, 9.17 mmol) in DCM (21.6 mL). 4-(Trifluoromethoxy)benzenesulfonyl chloride (467 μL, 2.75 mmol) was then added, and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was diluted with DCM, and saturated aqueous NH4Cl was added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel flash chromatography using a gradient of 0% to 5% MeOH in DCM to give the title compound as an off-white powder (1.24 g, 90% yield, 97% purity, t r = 1.09 min). LCMS (Method A): m / z found 605.3 [M+Na] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.21 (s, 1H), 7.40 - 7.34 (m, 6H), 7.33 - 7.29 (m, 1H), 7.25 - 7.14 (m, 2H) ),7.01 - 6.97 (m,2H),6.94 (dd,J=8.5,2.2 Hz,1H),5.07 (s,2H),3.78 (d,J=13.5 Hz,2H),3.33 (bs,2H) , 2.38 (d, J=13.7 Hz, 2H), 2.05 (s, 3H), 1.82 - 1.70 (m, 2H).

[0244] Step 5: Synthesis of N-(4-(4-chloro-3-methylphenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of benzyl 4-(4-chloro-3-methyl-phenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (97%, 500 mg, 0.832 mmol) in dry acetonitrile (4.6 mL) in a round-bottom flask under nitrogen, iodo(trimethyl)silane (97%, 366 μL, 2.50 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography using a gradient of 0 to 15% (0.7 N NH3 / MeOH) in DCM. The residue was triturated with 2 M HCl / Et2O (4.16 mL, 8.32 mmol) for 24 h, filtered, and dried under reduced pressure. Saturated aqueous Na2CO3 was added to the solid, and the suspension was stirred at room temperature for 3 h and filtered. The residue was washed with water and dried under reduced pressure at 45 °C for 48 h. The solid was triturated in 2H HCl / Et2O overnight, filtered, washed with Et2O, and dried under vacuum at 45 °C to give the hydrochloride salt of the title compound as a white powder (13.8 mg, 3.6% yield, 97% purity, t r =1.52 min). LCMS (Method D): m / z found 449.1 [M-HCl+H] + ; 1 H-NMR (600 MHz,DMSO-d6) δ ppm 1.92 - 2.01 (m,2 H) 2.06 (s,3 H) 2.51 - 2.57 (m,2 H) 3.13 - 3.27 (m,4 H) 6.94 (dd,J=8.58,2.42Hz,1H)6.98(d,J=1.76Hz,1H)7.02(d,J=8.36Hz,1H)7.21(d,J=8.07Hz,2H)7.35 (d,J=8.80Hz,2H)7.45-9.17(m,3H).

[0245] Example 5: N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide (5) [ka] Step 1: Synthesis of 1-benzyl-4-(5-chloropyridin-2-yl)piperidine-4-carbonitrile [ka] To a stirred solution of 1-benzylpiperidine-4-carbonitrile (440 mg, 2.20 mmol) in dry toluene (10 mL) at room temperature in a sealed tube under nitrogen was added 2-bromo-5-chloropyridine (98%, 392 mg, 2.00 mmol). The reaction mixture was cooled to 0°C, and 1 M sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (4.0 mL, 3.99 mmol) was added dropwise. The solution was stirred at 0°C for 4 hours, then quenched with saturated aqueous ammonium chloride to pH = 7, and DCM was added. The aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 0% to 5% MeOH / DCM. The desired fractions were combined and concentrated under reduced pressure to give the title compound as a yellow oil (498 mg, 79% yield, 99% purity, t r =0.56 min). LCMS (Method A): m / z found 312.3 [M+H] + ; 1 H-NMR (DMSO-d6,500 MHz): δ (ppm) 8.69 (d,J=2.5 Hz,1H),8.03 (ddd,J=8.4,2.6,1.2 Hz,1H),7.67 (d, J=8.6 Hz, 1H), 7.36 - 7.31 (m, 4H), 7.26 (h, J=4.2 Hz, 1H), 3.57 (s, 2H), 2.93 (d, J=12.0 Hz, 2H), 2.33 (d, J=12.0 Hz, 2H) td, J=11.6, 3.4 Hz, 2H), 2.18 - 2.06 (m, 4H).

[0246] Step 2: Synthesis of 1-benzyl-4-(5-chloropyridin-2-yl)piperidine-4-carboxamide [ka] In a round-bottom flask, a mixture of 1-benzyl-4-(5-chloro-2-pyridyl)piperidine-4-carbonitrile (498 mg, 1.60 mmol) in sulfuric acid (6.4 mL) and water (1.6 mL) was stirred at 65° C. for 3 hours and 30 minutes. The mixture was poured into ice water and basified with 30% aqueous NaOH (approximately 10 mL) until a pH of 11 was reached (precipitation). Water and DCM were added, and the aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give the title compound as a white powder (491 mg, 93% yield, 100% purity, t r =0.5 min). LCMS (Method A): m / z found 330.3 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz): δ (ppm) 8.57 (d, J=2.5 Hz, 1H), 7.88 (dd, J=8.6, 2.7 Hz, 1H), 7.44 (d, J= 8.6 Hz, 1H), 7.36 - 7.18 (m, 5H), 7.05 (d, J=39.6 Hz, 2H), 3.38 (s, 2H), 2.48 - 2.36 (m, 2H), 2.36 - 2.17 (m, 4H) ), 2.17 - 1.95 (m, 2H)

[0247] Step 3: Synthesis of 1-benzyl-4-(5-chloropyridin-2-yl)piperidin-4-amine [ka] A solution of 1-benzyl-4-(5-chloro-2-pyridyl)piperidine-4-carboxamide (491 mg, 1.49 mmol) in acetonitrile (3.4 mL) and water (3.4 mL) was stirred in a round-bottom flask at room temperature. [Bis(trifluoroacetoxy)iodo]benzene (96%, 680 mg, 1.52 mmol) was added, and the mixture was stirred at 60° C. overnight and then at 80° C. for 6 hours, and the ACN was evaporated. 1N aqueous HCl was added, and the mixture was washed twice with DCM. Saturated aqueous NaCO was added to the aqueous layer until pH = 9. The aqueous layer was extracted three times with DCM, and the combined organic layers were washed with brine, filtered through a phase separator, and concentrated under reduced pressure to give the title compound as an orange oil (416 mg, 90% yield, 97% purity, t r =0.41). LCMS (Method A): m / z found 302.3 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.55 (d, J=2.5 Hz, 1H), 7.87 (dd, J=8.6, 2.6 Hz, 1H), 7.70 (d, J= 8.6 Hz, 1H), 7.32 (d, J=4.4 Hz, 4H), 7.24 (dddd, J=8.7, 5.1, 3.6 Hz, 1H), 3.48 (s, 2H), 2.51-2.43 (m, 4H),2.20 - 2.06 (m, 2H), 1.97 (s, 2H), 1.50 (dq, J=13.2, 3.2 Hz, 2H).

[0248] Step 4: Synthesis of N-(1-benzyl-4-(5-chloropyridin-2-yl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide [ka] To a stirred solution of 1-benzyl-4-(5-chloro-2-pyridyl)piperidin-4-amine (100 mg, 0.331 mmol) in DCM (2.2 mL) in a sealed vial, triethylamine (0.14 mL, 0.994 mmol) and DMAP (4.0 mg, 0.0331 mmol) were added sequentially. 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 90 mg, 0.364 mmol) was then added to the reaction mixture, which was stirred at 45° C. overnight and at 55° C. for 4 hours. The reaction mixture was cooled to room temperature and quenched with half-saturated aqueous NaHCO solution. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 2% to 10% MeOH / DCM to give the title compound as a pale yellow oil (121 mg, 69% yield, 95% purity, t r =0.69 min). LCMS (Method A): m / z found 501.4 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.20 (d,J=2.6 Hz,1H),8.03 (s,1H),7.93 (d,J=2.5 Hz,1H),7.62 (dd, J=8.6, 2.6 Hz, 1H), 7.56 (dd, J=8.8, 2.6 Hz, 1H), 7.36 - 7.20 (m, 6H), 6.62 (d, J=8.7 Hz, 1H), 5.24 (h, J=6.2 Hz, 1H), 3.44 (s, 2H), 2.44 (s, 4H), 2.31 (d, J=13.4 Hz, 2H), 2.03 (s, 2H), 1.31 (d, J=6.1 Hz,6H).

[0249] Step 5: Synthesis of N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of N-[1-benzyl-4-(5-chloro-2-pyridyl)-4-piperidyl]-6-isopropoxy-pyridine-3-sulfonamide (120 mg, 0.240 mmol) in DCE (2.4 mL) under nitrogen, 1-chloroethyl carbonochloridate (52 μL, 0.479 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour until a suspension formed. Triethylamine (0.067 mL, 0.479 mmol) was then added, and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (2.4 mL), and the reaction mixture was stirred at 65° C. for 4 hours. The mixture was concentrated, DCM and half-saturated NaHCO3 solution were added, and the aqueous layer was extracted twice more with DCM. The combined organic layers were concentrated in vacuo and purified by reverse-phase flash chromatography using a gradient of 0% to 100% (0.1% AcOH) ACN / water. The desired fraction was basified with half-saturated Na2CO3 solution and extracted three times with DCM. The combined organic layers were dried on a phase separator and concentrated in vacuo. Diethyl ether (2 mL) and 2 M hydrogen chloride (1.2 mL, 2.40 mmol) were added to the resulting white solid, stirred at room temperature for 4 hours, filtered, washed with diethyl ether, and dried under vacuum at 40 °C for 20 hours. DCM and half-saturated Na2CO3 solution were added to the solid, the aqueous layer was extracted twice more with DCM, and the organic layer was concentrated in vacuo. 2 M hydrogen chloride in diethyl ether (0.12 mL, 0.240 mmol) was added, the suspension was stirred at room temperature for 45 minutes, filtered, washed with diethyl ether, and dried under vacuum at 45 °C for 20 hours to give the title compound as a white powder (37 mg, 32% purity, 99.5% t r =1.15 min). LCMS (Method D): m / z found 411.2 [M-2HCl+H] + ; 1H-NMR (600 MHz,DMSO-d6) δ ppm 1.30 (d,J=6.31 Hz,6 H) 2.08 - 2.25 (m,2 H) 2.54 (br d,J=14.53 Hz,2 H) 3.11 - 3.25 (m,4 H) 5.23 (quintet, J=6.20 Hz,1 H) 6.60 (dd,J=8.80,0.59 Hz,1 H) 7.31 (d,J=8.66 Hz,1 H) 7.53 (dd, J=8.66,2.64Hz,1H) 7.64 (dd,J=8.58,2.57Hz,1H) 7.89 - 7.97 (m,1H) 8.24 (dd,J=2.49,0.59Hz,1H) 8.46 (s, 1H) 8.66 - 8.93 (m,2H).

[0250] Example 6: N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide (6) [ka] Step 1: Synthesis of benzyl 6-oxo-4-azaspiro[2.5]octane-4-carboxylate [ka] To a stirred solution of benzyl 6-hydroxy-4-azaspiro[2.5]octane-4-carboxylate (500 mg, 1.91 mmol) in DCM (2.5 mL) in a round-bottom flask at 0 °C, DIPEA (1.7 mL, 9.57 mmol) was added sequentially, followed by a solution of sulfur trioxide pyridine (700 mg, 4.40 mmol) in DMSO (2.8 mL). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 2% to 100% EtOAc / cyclohexane to give the title compound as a yellow oil (429 mg, 86% yield, 100% purity, t r=0.81). LCMS (Method B): m / z found 260.1 [M+H] + ; 1 H-NMR (400 MHz,DMSO) δ 7.49 - 7.23 (m,5H),5.10 (s,2H),4.02 (s,2H),2.57 - 2.45 (m,2H),1.87 (t,J=6.8) Hz,2H),1.08 - 0.98 (m,2H),0.89 - 0.80 (m,2H).

[0251] Step 2: Synthesis of benzyl 6-hydroxy-6-phenyl-4-azaspiro[2.5]octane-4-carboxylate [ka] To a solution of benzyl 6-oxo-4-azaspiro[2.5]octane-4-carboxylate (429 mg, 1.65 mmol) in dry THF (5.5 mL) at 0 °C was added 1 M bromo(phenyl)magnesium in THF (2.0 mL, 1.99 mmol) dropwise. The mixture was stirred at 0 °C for 1 h and then at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 2% to 15% MeOH / DCM to give the title compound as a white solid (237.2 mg, 41% yield, 97% purity, t r =0.95 min). LCMS (Method A): m / z found 360.5 [M+Na] + ; 1H-NMR (400 MHz,DMSO) δ 7.60 - 7.50 (m,2H),7.45 - 7.14 (m,8H),5.26 - 4.87 (m,3H),3.83 (t,J=14.6 Hz,1H),3.59 (d, J = 2.3 Hz, 1H), 3.21 (t, J = 15.8 Hz, 1H), 2.45 (d, J = 14.3 Hz, 1H), 2.24 - 2.04 (m, 1H), 1.77 (td, J = 7.4, 4.7 Hz, 1H), 1.11 (s, 1H), 0.99 - 0.75 (m, 2H), 0.57 (d, J = 23.8 Hz, 2H).

[0252] Step 3: Synthesis of benzyl 6-(2-chloroacetamido)-6-phenyl-4-azaspiro[2.5]octane-4-carboxylate [ka] In a round-bottom flask under nitrogen, a solution of benzyl 6-hydroxy-6-phenyl-4-azaspiro[2.5]octane-4-carboxylate (237 mg, 0.702 mmol) and 2-chloroacetonitrile (1.3 mL, 21.1 mmol) in dry DCM (1.8 mL) was stirred at 0 °C. 2,2,2-Trifluoroacetic acid (1.3 mL, 17.6 mmol) was added, and the mixture was stirred at 0 °C for 6 h and at room temperature for 16 h. The mixture was poured into ice water, and saturated aqueous Na2CO3 was added until pH = 9. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a yellow solid (277.1 mg, 86% yield, 91% purity, t r =0.89 min). LCMS (Method A): m / z found 437.3 [M+H] + ; 1H-NMR (DMSO-d6,500 MHz): δ (ppm) 8.49 (s,1H),7.50 (d,J=2.2 Hz,4H),7.41~7.29 (m,7H),7.00 (t, J=56.0Hz,1H),5.10(s,2H),4.13(s,2H),3.94(d,J=13.2Hz,2H),3.12(s,2H),2.33(d,J=13.4Hz, 2H), 1.84 (td, J=13.1, 4.5 Hz, 2H).

[0253] Step 4: Synthesis of benzyl 6-amino-6-phenyl-4-azaspiro[2.5]octane-4-carboxylate [ka] A solution of benzyl 6-[(2-chloroacetyl)amino]-6-phenyl-4-azaspiro[2.5]octane-4-carboxylate (275 mg, 0.666 mmol) in ethanol (4.3 mL) and acetic acid (870 μL) was stirred at room temperature in a sealed tube. Thiourea (66 mg, 0.866 mmol) was added, and the mixture was stirred at 50° C. for 5 days and then at 70° C. for 8 hours. The mixture was allowed to cool to room temperature and poured into ice water. Saturated aqueous NaCO solution was added until pH = 9, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was dissolved in EtO / MeOH 98 / 2 (3 mL), and 2 M HCl / EtO (666 μL, 1.33 mmol) was added dropwise. Water was added to dissolve the oil, the layers were separated, and the aqueous layer was washed with EtO. Saturated aqueous Na2CO3 was added to the aqueous layer until pH = 9, which was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a yellow oil (140 mg, 48% yield, 78% purity, t r =0.62 min). LCMS (Method B): m / z found 337.4 [M+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.62 (s,3H),7.79 (d,J=8.2 Hz,2H),7.69 (d,J=8.2 Hz,2H),7.43 - 7.27 (m,5H),7.09 (t,J=55.7 Hz,1H),5.09 (s,2H),3.81 (d,J=13.7Hz,2H),3.19 (s,2H),2.46 (d, J=14.9Hz,2H),2.07(t,J=10.8Hz,2H).

[0254] Step 5: Synthesis of benzyl 6-phenyl-6-((4-(trifluoromethoxy)phenyl)sulfonamido)-4-azaspiro[2.5]octane-4-carboxylate [ka] Benzyl 6-amino-6-phenyl-4-azaspiro[2.5]octane-4-carboxylate (78%, 140 mg, 0.325 mmol), triethylamine (181 μL, 1.30 mmol), and 4-dimethylaminopyridine (7.9 mg, 0.0649 mmol) were stirred in anhydrous DCM (2.6 mL) in a sealed tube under nitrogen at room temperature. 4-(Trifluoromethoxy)benzenesulfonyl chloride (55 μL, 0.325 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The mixture was diluted with DCM and half-saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 5% to 50% EtOAc / heptane to give the title compound as a colorless oil (75 mg, 35% yield, 86% purity, t r =1.09 min). LCMS (Method A): m / z found 561.3 [M+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.33 - 7.75 (m,1H),7.57 - 6.61 (m,12H),5.00 (d,J=14.5 Hz,2H),4.02 (s, 2H), 2.45 - 1.61 (m, 3H), 1.25 (s, 2H), 1.07 - 0.67 (m, 3H), 0.59 (s, 1H).

[0255] Step 6: Synthesis of N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] In a sealed tube under nitrogen, iodo(trimethyl)silane (57 μL, 0.401 mmol) was added to a solution of benzyl 6-phenyl-6-[[4-(trifluoromethoxy)phenyl]sulfonylamino]-4-azaspiro[2.5]octane-4-carboxylate (75 mg, 0.134 mmol) in dry acetonitrile (750 μL), and the solution was stirred at room temperature for 1 h. The mixture was concentrated, and HCl 2N / EtO was added. EtO was added, and the suspension was stirred at room temperature for 30 min and filtered. The residue was washed with EtO and dried under reduced pressure for 2 h. The solid was partitioned between half-saturated aqueous NaCO3 and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography using a gradient of 0.4% to 6% (MeOH + 2% NH4OH) / DCM. The desired fractions were concentrated, and the residue was dissolved in EtO. HCl 2N / EtO (55 μL, 1.0 equiv.) was added dropwise, and the solution was stirred at room temperature for 2 h. The solution was concentrated, the residue was triturated with pentane / EtO 8 / 2, and the resulting suspension was filtered. The residue was washed with pentane / EtO 8 / 2 and dried under reduced pressure at 45 °C for 16 h to give the hydrochloride salt of the title compound as a white powder (25 mg, 40% yield, 100% purity, t r =1.34 min). LCMS (Method D): m / z found 427.2 [M-HCl+H] + ; 1H-NMR (600 MHz,DMSO-d6) δ ppm 9.00 - 9.62 (m,2 H) 8.58 (s,1 H) 7.32 - 7.38 (m,2 H) 7.15 (dd,J=8.95,0.88 Hz) ,2H) 7.04~7.09 (m,2H) 6.98~7.03 (m,1H) 6.91~6.97 (m,2H) 4.10 (br d,J=12.18 Hz,1 H) 3.34~3.42 (m, 1H) 2.51 - 2.58 (m, 2H) 1.77 - 1.94 (m, 1H) 1.20 - 1.28 (m, 1H) 1.06 - 1.14 (m, 1H) 0.94 - 1.02 (m, 1H) 0.83 - 0.90 (m,1 H) 0.64 (dt,J=9.65,6.03 Hz,1 H).

[0256] Example 7: N-(4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide (7) [ka] Step 1: Synthesis of 4-(3,4-difluorophenyl)piperidine-4-carbonitrile [ka] To a solution of tert-butyl 4-cyano-4-(3,4-difluorophenyl)piperidine-1-carboxylate (95%, 3.00 g, 9.31 mmol) in EtO (23.1 mL) in a round-bottom flask under nitrogen, 4 M HCl / dioxane (23 mL, 93.1 mmol) was added and the mixture was stirred at room temperature overnight. The suspension was filtered, washed with EtO, and dried under reduced pressure at 45 °C for 4 h to give the hydrochloride salt of the title compound as a white powder (2.23 g, 78% yield, 85% purity, t r =0.49 min). LCMS (Method A): m / z found 223.3 [M-HCl+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 9.08 (s,2H),7.69 - 7.63 (m,1H),7.59 (dt,J=10.6,8.8 Hz,1H),7.42 ( dddd,J=8.4,4.0,2.5,1.4 Hz,1H),3.49 (dt,J=13.7,3.4 Hz,2H),3.09 (td,J=13.2,2.8 Hz,2H),2.48 - 2.43 (m, 2H),2.31 (ddd,J=14.4,12.7,4.0 Hz,2H).

[0257] Step 2: Synthesis of 1-benzyl-4-(3,4-difluorophenyl)piperidine-4-carbonitrile [ka] In a sealed tube, a suspension of 4-(3,4-difluorophenyl)piperidine-4-carbonitrile hydrochloride (85%, 2.23 g, 7.33 mmol) and potassium carbonate (2.53 g, 18.3 mmol) in ACN (19 mL) was stirred at room temperature under nitrogen. Bromomethylbenzene (98%, 1.1 mL, 8.79 mmol) was added, and the mixture was stirred at 65 °C overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO and concentrated under reduced pressure to give the title compound as a colorless oil (2.5 g, 95% yield, 87% purity, t r =0.59 min). LCMS (Method B): m / z found 313.2 [M+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.67 (ddd,J=12.3,7.6,2.4 Hz,1H),7.51 (dt,J=10.5,8.6 Hz,1H),7.42 (dddd,J=8.7,3.9,2.4,1.3 Hz,1H),7.34 (d,J=4.3 Hz,4H),7.26 (dddd,J=8.6,5.0,3.8 Hz,1H),3.56 (s,2H) ,2.94 (dt, J=12.6, 3.1 Hz, 2H),2.31 (td, J=12.2, 2.3 Hz, 2H),2.14 (dd, J=13.5, 2.5Hz, 2H), 2.05 - 1.94 (m, 2H).

[0258] Step 3: Synthesis of 1-benzyl-4-(3,4-difluorophenyl)piperidine-4-carboxamide [ka] In a round-bottom flask, 1-benzyl-4-(3,4-difluorophenyl)piperidine-4-carbonitrile (87%, 2.50 g, 6.96 mmol) was placed in water (7 mL) and sulfuric acid (27.7 mL), and the mixture was stirred at 65° C. for 1 h. The mixture was poured into ice water and basified with 30% aqueous NaOH to pH=10-11. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound as a white foam (2.0 g, 82% yield, 95% purity, t r =0.51 min). LCMS (Method A): m / z found 331.4 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.43 - 7.16 (m,9H),7.01 (s,1H),3.40 (s,2H),2.60 (d,J=11.2 Hz, 2H),2.42 (d, J=13.2 Hz, 2H),2.15 (t, J=11.0 Hz, 2H), 1.77 (t, J=11.9 Hz, 2H)

[0259] Step 4: Synthesis of 1-benzyl-4-(3,4-difluorophenyl)piperidin-4-amine [ka] In a round-bottom flask, 1-benzyl-4-(3,4-difluorophenyl)piperidine-4-carboxamide (95%, 2.00 g, 5.75 mmol) was placed in a mixture of ACN (13.3 mL) and water (13.3 mL). [Phenyl-(2,2,2-trifluoroacetyl)oxy-{3}-iodanyl] 2,2,2-trifluoroacetate (97%, 2.55 g, 5.75 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The ACN was concentrated under reduced pressure. 1N aqueous HCl was added, and the aqueous layer was washed with DCM. The aqueous layer was basified with saturated aqueous Na2CO3 and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a colorless oil (1.04 g, 59% yield, 95.3% purity, t r =0.85 min). LCMS (Method F): m / z found 303 [M+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ ppm 7.52 - 7.67 (m,1 H) 7.35 (dd,J=7.09,1.47 Hz,2 H) 7.28 - 7.33 (m,4 H) 7.20 - 7.28 (m,1 H) 3.49 (s,2 H) 2.53 (br s,2 H) 2.31 - 2.50 (m,4 H) 1.81 - 2.06 (m,2 H) 1.57 (br d,J=12.47 Hz,2 H).

[0260] Step 5: Synthesis of N-(1-benzyl-4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide [ka] To a sealed vial was added 1-benzyl-4-(3,4-difluorophenyl)piperidin-4-amine (95%, 200 mg, 0.630 mmol), DMAP (15 mg, 0.126 mmol), and triethylamine (351 μL, 2.52 mmol) in DCM (6 mL). 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 156 mg, 0.630 mmol) was then added, and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was diluted with DCM, and saturated aqueous NH4Cl was added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel flash chromatography using a gradient of 0% to 5% MeOH / DCM to give the title compound as an off-white powder (224 mg, 63% yield, 90% purity, t r =0.70 min). LCMS (Method A): m / z found 502.4 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.87 (s,1H),7.85 (dd,J=2.5,0.7 Hz,1H),7.55 (dd,J=8.8,2.6 Hz, 1H), 7.37 - 7.20 (m, 5H), 7.13 - 6.97 (m, 3H), 6.61 (dd, J=8.7, 0.7 Hz, 1H), 5.20 (septet, J=6.2 Hz, 1H), 3.48 (s) , 2H), 2.51 - 2.46 (m, 4H), 2.34 (d, J=13.1 Hz, 2H), 1.84 (s, 2H), 1.28 (d, J=6.2 Hz, 6H).

[0261] Step 6: Synthesis of N-(4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide [ka] To a solution of N-[1-benzyl-4-(3,4-difluorophenyl)-4-piperidyl]-6-isopropoxy-pyridine-3-sulfonamide (90%, 224 mg, 0.402 mmol) in methanol (2.7 mL) in a round-bottom flask, Pd / C (10%, 86 mg, 0.0804 mmol) was added, and the mixture was stirred under an H atmosphere for 5 hours. The reaction mixture was filtered through a talc pad and washed with EtOH. The filtrate was concentrated under reduced pressure, then diluted in EtO (1.8 mL), and 2 N HCl / EtO (1.0 mL, 2.01 mmol) was added. The mixture was stirred overnight at room temperature. The suspension was filtered, washed with EtO, and dried under reduced pressure at 45 °C for 64 hours. The solid was purified by reverse-phase flash chromatography using a gradient of 0% to 100% (0.1% AcOH) ACN / water. The desired fractions were combined, concentrated under reduced pressure, diluted with DCM, and washed with saturated aqueous Na2CO3. The combined organic layers were dried through a phase separator and concentrated under reduced pressure. The solid was diluted with a minimum amount of DCM, 2N HCl / Et2O (2 mL, 4.02 mmol) was added, and the mixture was stirred at room temperature overnight. The suspension was filtered, the solid was washed with Et2O, and dried under reduced pressure at 45 °C for 5 h to give the dihydrochloride salt of the title compound as a white powder (48.9 mg, 25% yield, 99.4% purity, t r =1.66 min). LCMS (Method F): m / z found 412 [M-2HCl+H] + ; 1 H-NMR (600 MHz,DMSO-d6) δ ppm 8.83 (br s,2 H) 8.37 (s,1 H) 7.89 (dd,J=2.64,0.59 Hz,1 H) 7.56 (dd,J= 8.73,2.57Hz,1H) 7.07 - 7.17 (m,2 H) 7.01 (dt,J=5.72,2.71 Hz,1 H) 6.61 (dd,J=8.80,0.59 Hz,1 H) 5.11 - 5.30 (m , 1 H) 3.22 (br s, 4 H) 2.57 (br d, J=13.35 Hz, 2 H) 2.01 (br s, 2 H) 1.28 (d, J=6.16 Hz, 6 H).

[0262] Example 8: N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(methylamino)-4-(trifluoromethoxy)benzenesulfonamide (8) [ka] Step 1: Synthesis of tert-butyl 4-(4-chlorophenyl)-4-((3-nitro-4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate [ka] In a sealed tube under nitrogen, 3-nitro-4-(trifluoromethoxy)benzene-1-sulfonyl chloride (492 mg, 1.61 mmol) was added to a stirred solution of tert-butyl 4-amino-4-(4-chlorophenyl)piperidine-1-carboxylate (500 mg, 1.61 mmol), triethylamine (1.1 mL, 8.04 mmol), and 4-dimethylaminopyridine (39 mg, 0.322 mmol) in anhydrous DCM (10 mL), and the mixture was stirred at 40 °C for 16 h. The mixture was diluted with DCM and half-saturated NaHCO. The aqueous layer was extracted with DCM, and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 5% to 50% EtOAc / heptane to give the title compound as a yellow solid (388 mg, 40% yield, 98% purity, t r = 1.07 min). LCMS (Method B): m / z found 480.1 [M-Boc+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.53 (s,1H),7.88 (d,J=2.2 Hz,1H),7.72 (dd,J=8.7,2.3 Hz,1H) ,7.66 (dd,J=8.7,1.5 Hz,1H),7.16 - 7.07 (m,2H),7.03 - 6.95 (m,2H),3.70 (d,J=13.6 Hz,2H),3.31 (s,4H) ), 2.39 (d, J=13.6 Hz, 2H), 1.87 - 1.65 (m, 2H), 1.40 (s, 10H).

[0263] Step 2: Synthesis of tert-butyl 4-((3-amino-4-(trifluoromethoxy)phenyl)sulfonamido)-4-(4-chlorophenyl)piperidine-1-carboxylate [ka] In a sealed tube, a suspension of iron (205 mg, 3.68 mmol) and ammonium chloride (50 mg, 0.937 mmol) in ethanol (3.2 mL) and water (1.6 mL) was stirred at 70 °C for 1 h. A suspension of tert-butyl 4-(4-chlorophenyl)-4-[[3-nitro-4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (388 mg, 0.669 mmol) in ethanol (3.2 mL) was added, and the mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and filtered through a pad of talc powder. The pad was washed with EtOH, and the filtrate was concentrated. The residue was dissolved in EtOAc and half-saturated aqueous NaHCO3, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a yellow oil (344 mg, 99% purity, 92% yield, t r =1.00 min). LCMS (Method A): m / z found 450.3 [M-Boc+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.04 (s,1H),7.22 - 7.12 (m,2H),7.11 - 7.02 (m,2H),6.97 (dd,J=8.6) ,1.6 Hz, 1H),6.78 (d, J=2.3 Hz, 1H),6.53 (dd, J=8.5, 2.3 Hz, 1H), 5.64 (s, 2H), 3.76 - 3.56 (m, 2H), 3.15 (s, 2H), 2.29 (d, J=13.5 Hz, 2H), 1.70 (t, J=11.1 Hz, 2H), 1.39 (s, 10H).

[0264] Step 3: Synthesis of tert-butyl 4-(4-chlorophenyl)-4-((3-(methylamino)-4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate [ka] In a sealed tube, a solution of tert-butyl 4-[[3-amino-4-(trifluoromethoxy)phenyl]sulfonylamino]-4-(4-chlorophenyl)piperidine-1-carboxylate (150 mg, 0.273 mmol) and paraformaldehyde (9.0 mg, 0.300 mmol) in methanol (3 mL) and acetic acid (300 μL) was stirred at room temperature for 1 h. Polymer-bound sodium cyanoborohydride (409 mg, 0.818 mmol) was added, and the mixture was gently stirred at 55 °C for 22 h. The mixture was filtered through dicalite, the residue was washed with MeOH, and the filtrate was concentrated. The resulting oil was dissolved in EtOAc. The organic layer was washed with half-saturated Na2CO3, brine, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 5% to 60% EtOAc / heptane to give the title compound as a white foam (100 mg, 58% yield, 90% purity, t r = 1.04 min). LCMS (Method A): m / z found 586.4 [M+Na] + ; 1H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.04 (s, 1H), 7.17 - 7.08 (m, 2H), 7.04 - 6.95 (m, 3H), 6.58 (dd, J=8.4) ,2.2 Hz,1H),6.46 (d,J=2.2 Hz,1H),6.02 (d,J=4.8 Hz,1H),3.68 (d,J=13.4 Hz,2H),3.22 (s,2H),2.75 (s, 1H), 2.65 (d, J=4.9 Hz, 3H), 2.33 (d, J=13.4 Hz, 2H), 1.70 (t, J=11.3 Hz, 2H), 1.39 (s, 10H), 1.27 (d, J=13.4 Hz, 2H), 0.92 - 0.80 (m, 1H).

[0265] Step 4: Synthesis of N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(methylamino)-4-(trifluoromethoxy)benzenesulfonamide [ka] A solution of tert-butyl 4-(4-chlorophenyl)-4-[[3-(methylamino)-4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (90%, 100 mg, 0.160 mmol) in 1,4-dioxane (1 mL) was stirred at room temperature in a sealed tube under nitrogen. 2 M HCl / EtO (798 μL, 1.60 mmol) was added, and the mixture was stirred at room temperature for 22 h. Additional 2 M HCl / EtO (399 μL, 0.798 mmol) was added, and the mixture was stirred at room temperature for 22 h. The mixture was concentrated to dryness, and the crude material was purified by reverse-phase flash chromatography using a gradient of 0% to 100% (ACN + 0.1% AcOH) / (H2O + 0.1% AcOH). The desired fractions were concentrated, and the residue was dissolved in EtOAc and half-saturated aqueous Na2CO3. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in MeOH, and 2M HCl / EtO (130 μL, 4.0 equiv.) was added. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was triturated with EtO, and the resulting suspension was filtered. The residue was washed with EtO and dried under reduced pressure at 45° C. for 64 hours to give the hydrochloride salt of the title compound as a white powder (23 mg, 28% yield, 99% purity, t r =1.35 min). LCMS (Method D): m / z found 464.1 [M-HCl+H] + ; 1 H-NMR (600 MHz,DMSO-d6) δ ppm 1.96 - 2.05 (m,2 H) 2.54 (br d,J=13.50 Hz,2 H) 2.64 (s,3 H) 3.21 (br s,4 H) 5.95 - 6.13 (m, 1 H) 6.42 (d, J=2.20 Hz, 1 H) 6.55 (dd, J=8.44, 2.27 Hz, 1 H) 7.01 (d, J=8.66 Hz, 3 H) 7.08 - 7.14 (m, 2 H) 8.30 (s, 1 H) 8.79 (br d, J=0.73 Hz, 2 H).

[0266] Example 9: N-(4-(2,5-dichloropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (9) [ka] Step 1: Synthesis of 1-benzyl-4-(2,5-dichloropyridin-4-yl)piperidine-4-carbonitrile [ka] To a stirred solution of 1-benzylpiperidine-4-carbonitrile (1.17 g, 5.85 mmol) in anhydrous toluene (15.2 mL) in a sealed tube under nitrogen at 0° C. was added 1 M sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (11 mL, 10.6 mmol) dropwise. The reaction mixture was stirred for 15 minutes, and then 2,4,5-trichloropyridine (97%, 1.00 g, 5.32 mmol) was added dropwise. The solution was stirred at 0° C. for 2.5 hours and then quenched with saturated aqueous NH4Cl. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 10% to 100% EtOAc / cyclohexane to give the title compound as a brown oil (172.5 mg, 8% yield, 94% purity, t r =0.56 min). LCMS (Method A): m / z found 346.3 [M+H] + ; 1 H-NMR (600 MHz,DMSO-d6) δ ppm 8.59 (s,1 H) 7.64 (s,1 H) 7.30 - 7.36 (m,4 H) 7.23 - 7.29 (m,1 H) 3.57 (s , 2 H) 2.97 (br d, J=12.91 Hz, 2 H) 2.35 - 2.44 (m, 4 H) 2.07 (td, J=12.76, 3.52 Hz, 2 H).

[0267] Step 2: Synthesis of 1-benzyl-4-(2,5-dichloropyridin-4-yl)piperidine-4-carboxamide [ka] In a sealed tube, a mixture of 1-benzyl-4-(2,5-dichloro-4-pyridyl)piperidine-4-carbonitrile (94%, 170 mg, 0.462 mmol) in sulfuric acid (1.8 mL) and water (0.5 mL) was stirred at 65° C. for 4 hours. The mixture was poured into ice water and basified with 1N aqueous NaOH solution to reach pH=10. The aqueous layer was extracted three times with DCM. The combined organic layers were dried using a phase separator and concentrated under reduced pressure to give the title compound as a light brown foam (101.9 mg, 58% yield, 97% purity, t r =0.49 min). LCMS (Method A): m / z found 364.4 [M+H] + ; 1 H-NMR (400 MHz,DMSO-d6) δ 8.40 (s,1H),7.58 (s,1H),7.36 - 7.19 (m,5H),7.02 (s,1H),6.88 (s,1H) ,3.43 (s, 2H),2.58 (t, J=8.3 Hz, 2H), 2.34 (t, J = 8.7 Hz, 4H), 2.09 (d, J = 3.2 Hz, 2H).

[0268] Step 3: Synthesis of 1-benzyl-4-(2,5-dichloropyridin-4-yl)piperidin-4-amine [ka] To a stirred solution of 1-benzyl-4-(2,5-dichloro-4-pyridyl)piperidine-4-carboxamide (101 mg, 0.277 mmol) in acetonitrile (0.75 mL) and water (0.75 mL) was added [bis(trifluoroacetoxy)iodo]benzene (125 mg, 0.291 mmol). The mixture was stirred at room temperature overnight, and the acetonitrile was removed under vacuum. 1 M aqueous HCl was added to reach a pH of 1-2. The aqueous layer was extracted twice with DCM. Saturated aqueous NaCO was added to the aqueous layer to reach a pH of 9. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, filtered through a phase separator, and concentrated under reduced pressure to give the title compound as an orange oil (61.5 mg, 64% yield, 98% purity, t r =0.44 min). LCMS (Method B): m / z found [M+H] + ; 1 H-NMR (400 MHz,DMSO-d6) δ 8.38 (s,1H),7.79 (s,1H),7.32 (d,J=5.0 Hz,4H),7.29 - 7.20 (m,1H),3.51 (s, 2H), 2.65 - 2.51 (m, 4H), 2.33 (td, J = 12.3, 4.8 Hz, 2H), 2.07 (s, 2H), 1.66 - 1.51 (m, 2H).

[0269] Step 4: Synthesis of N-(1-benzyl-4-(2,5-dichloropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of 1-benzyl-4-(2,5-dichloro-4-pyridyl)piperidin-4-amine (60 mg, 0.178 mmol) in DCM (1.2 mL) in a sealed vial under nitrogen, triethylamine (37 μL, 0.268 mmol) and 4-(trifluoromethoxy)benzenesulfonyl chloride (33 μL, 0.196 mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight. Additional triethylamine (0.037 mL, 0.268 mmol) and 4-(trifluoromethoxy)benzenesulfonyl chloride (51 mg, 0.196 mmol) were added, and the mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 15% (0.7N NH3 / MeOH) / DCM to give the title compound as an orange oil (58.5 mg, 56% yield, 97% purity, t r =0.70 min). LCMS (Method B): m / z found 560.2 [M+H] + ; 1 H-NMR (400 MHz,DMSO-d6) δ 8.46 (s,1H),8.03 (s,1H),7.64 - 7.56 (m,2H),7.52 (s,1H),7.44 - 7.35 (m, 2H), 7.35 - 7.27 (m, 2H), 7.24 (tt, J=6.3, 1.2 Hz, 3H), 3.40 (s, 2H), 2.64 - 2.51 (m, 4H), 2.26 (t, J = 11.1 Hz), 2H), 2.03 - 1.81 (m, 2H).

[0270] Step 5: Synthesis of N-(4-(2,5-dichloropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of N-[1-benzyl-4-(2,5-dichloro-4-pyridyl)-4-piperidyl]-4-(trifluoromethoxy)benzenesulfonamide (58 mg, 0.104 mmol) in DCM (1.2 mL) under nitrogen, 1-chloroethyl carbonochloridate (22 μL, 0.207 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (1.3 mL), and the reaction mixture was stirred at 65° C. for 16 hours. The reaction mixture was then cooled to room temperature and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 20% (0.7 N NH3 / MeOH) / DCM. The desired fractions were concentrated and purified by reverse-phase preparative chromatography using a gradient of 0% to 100% acetonitrile / water (0.1% aqueous AcOH). The desired fractions were combined and the acetonitrile was removed under vacuum. The aqueous layer was basified with saturated aqueous NaHCO3. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried using a phase separator, and concentrated under reduced pressure. The residue was dissolved in a minimum amount of MeOH. 2M hydrogen chloride in diethyl ether (0.15 mL, 0.300 mmol) was added, followed by diethyl ether (5 mL). The mixture was stirred at room temperature for 4 hours. The solid was filtered, washed with diethyl ether, and dried overnight under vacuum at 50 °C to give the hydrochloride salt of the title compound as a white powder (8.5 mg, 16% yield, 99.49% purity, t r =1.22 min). LCMS (Method D): m / z found 470.1 [M-HCl+H] + ; 1H-NMR (600 MHz,DMSO-d6) δ 8.79 (br s,1 H) 8.71 - 8.77 (m,2 H) 7.98 (s,1 H) 7.53 - 7.57 (m,3 H) 7.36 (d ,J=8.11Hz,2H) 3.21 - 3.27 (m,2H) 3.15 (br s,2H) 2.81 (br d,J=12.91Hz,2H) 2.10 (br t,J=11.66Hz,2H).

[0271] Example 10: N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (10) [ka] Step 1: Synthesis of tert-butyl 4-(phenyl((4-(trifluoromethoxy)phenyl)sulfonamido)methyl)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[amino(phenyl)methyl]piperidine-1-carboxylate (95%, 250 mg, 0.818 mmol) in dry DCM (5.4522 mL) in a sealed vial, triethylamine (0.34 mL, 2.45 mmol) and DMAP (10 mg, 0.0818 mmol) were added sequentially. 4-(Trifluoromethoxy)benzenesulfonyl chloride (0.17 mL, 0.981 mmol) was then added, and the mixture was stirred at 45° C. overnight. The reaction mixture was cooled to room temperature and quenched with saturated aqueous Na2CO3 solution. The layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography using a gradient of 0% to 5% MeOH / DCM to give the title compound as an off-white powder (302 mg, 72% yield, 100% purity, t r = 1.07 min). LCMS (Method A): m / z found 415.2 [M-Boc+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.37 (d,J=9.1 Hz,1H),7.60 - 7.52 (m,2H),7.28 - 7.21 (m,2H),7.03 (d, J=1.8 Hz, 5H), 4.01 (t, J=8.8 Hz, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.79 (d, J=13.2 Hz, 1H), 2.58 (s, 1H), 1.80 (d, J=13.1 Hz, 1H), 1.72 - 1.60 (m, 1H), 1.36 (s, 10H), 1.05 - 0.85 (m, 3H).

[0272] Step 2: Synthesis of N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of tert-butyl 4-[phenyl-[[4-(trifluoromethoxy)phenyl]sulfonylamino]methyl]piperidine-1-carboxylate (302 mg, 0.587 mmol) in dry diethyl ether (1.4673 mL) in a round-bottom flask under nitrogen at room temperature was added a solution of 4 M hydrogen chloride in dioxane (1.5 mL, 5.87 mmol), and the reaction mixture was stirred overnight. The suspension was filtered, washed with EtO, and dried under vacuum at 45 °C overnight to give the hydrochloride salt of the title compound as an off-white powder (206.5 mg, 78% yield, t r =1.71 min). LCMS (Method F): m / z found 414.9 [M-HCl+H] + ; 1H-NMR (500 MHz,DMSO-d6) δ ppm 1.23 (td,J=8.74,3.79 Hz,2 H) 1.29 - 1.42 (m,1 H) 1.74 - 1.90 (m,1 H) 2.04 (br dd,J=13.94,2.20Hz,1H)2.66-2.86(m,2H)3.15(br d,J=12.72Hz,1H)3.29(br s,1H)4.03(t,J=9.17Hz) ,1H) 6.99 - 7.06 (m,5 H) 7.22 (d,J=8.07 Hz,2 H) 7.55 (d,J=8.80 Hz,2 H) 8.25 - 8.41 (m,1 H) 8.49 (d, J=9.78Hz,1H) 8.69(br d,J=9.78Hz,1H).

[0273] Example 11: (R)—N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (11) [ka] N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (128 mg) was purified by chiral separation on a Pirkle® Whelk-01 5 μm (250 × 21.1 mm) column using a mobile phase of CO₂ / (MeOH + 0.5% IPAm) 90 / 10. The desired fractions were concentrated, diluted with DCM, and washed with saturated NaHCO₃ solution and brine. The organic layer was dried and concentrated on a phase separator. The free base was diluted with a minimum amount of DCM, and HCl 2N / Et₂O (2.0 equiv.) was added. The mixture was stirred overnight, then filtered, washed with Et₂O, and dried under reduced pressure at 45°C for 20 hours to give the hydrochloride salt of the title compound as a white powder (27.1 mg, 20% yield, 100% purity, t r =1.32 min). LCMS (Method D): m / z found 415.2 [M-HCl+H] + ; 1H-NMR (600 MHz,DMSO-d6) δ ppm 1.16 - 1.28 (m,2 H) 1.30 - 1.42 (m,1 H) 1.76 - 1.87 (m,1 H) 2.04 (br dd,J=14.09 ,2.64Hz,1H) 2.67-2.82(m,2H)3.11-3.18(m,1H)3.26-3.30(m,1H)4.02(t,J=9.17Hz,1H)6.95-7.10(m, 5 H) 7.21 (dd, J=8.95, 0.88 Hz, 2 H) 7.50 - 7.59 (m, 2 H) 8.08 - 8.82 (m, 2 H) 8.48 (d, J=9.83 Hz, 1 H).

[0274] Example 12: (S)—N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (12) [ka] N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (128 mg) was purified by chiral separation on a Pirkle® Whelk-01 5 μm (250 × 21.1 mm) column using a mobile phase of CO₂ / (MeOH + 0.5% IPAm) 90 / 10. The desired fractions were concentrated, diluted with DCM, and washed with saturated NaHCO₃ solution and brine. The organic layer was dried on a phase separator and concentrated. The free base was diluted with a minimum amount of DCM and HCl 2N / Et₂O (2.0 equiv.) was added. The mixture was stirred overnight, then filtered, washed with Et₂O, and dried under reduced pressure at 45°C for 20 hours to give the hydrochloride salt of the title compound as a white powder (29.2 mg, 22% yield, 100% purity, t r =1.32 min). LCMS (Method D): m / z found 415.2 [M-HCl+H] + ; 1H-NMR (600 MHz,DMSO-d6) δ ppm 1.14 - 1.29 (m,2 H) 1.30 - 1.43 (m,1 H) 1.76 - 1.86 (m,1 H) 2.04 (br dd,J=14.16 ,2.71Hz,1H) 2.67-2.85(m,2H) 3.15(br d,J=12.76Hz,1H) 3.27-3.32(m,1H) 4.03(t,J=9.17Hz,1H) 6.97 - 7.11 (m, 5 H) 7.21 (dd, J=8.88, 0.81 Hz, 2 H) 7.50 - 7.61 (m, 2 H) 8.27 - 8.65 (m, 2 H) 8.48 (br d, J=9.83 Hz), 1H).

[0275] Example 13: (R)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (13) [ka] Step 1: Synthesis of tert-butyl 4-((R)-(((R)-tert-butylsulfinyl)amino)(4-chlorophenyl)methyl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (1.00 g, 3.07 mmol) in anhydrous THF (15 mL) was stirred at 0 °C under nitrogen in a three-necked round-bottom flask equipped with a thermometer. 4-Chlorophenylmagnesium bromide (3.7 mL, 3.68 mmol, 1 M) was then added dropwise over 5 min, and the solution was stirred at room temperature for 16 h. The mixture was stirred at 0 °C and quenched by the dropwise addition of half-saturated aqueous NaHCO3. The mixture was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 20% to 100% EtOAc / heptane to give the title compound as a white foam (545 mg, 38% yield, 97% purity, t r =0.98 min). LCMS (Method A): m / z found 451.4 [M+Na] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.38 (d, J=0.7 Hz, 4H), 5.58 (d, J=9.8 Hz, 1H), 4.07 - 3.74 (m, 3H) ,3.32 - 3.19 (m,1H),2.63 (d,J=36.5 Hz,2H),1.91 (d,J=13.2 Hz,1H),1.85 - 1.72 (m,1H),1.46 - 1.32 (m,11H) ), 1.32 - 1.17 (m, 3H), 1.10 (s, 12H), 1.05 - 0.90 (m, 2H), 0.90 - 0.82 (m, 1H).

[0276] Step 2: Synthesis of tert-butyl (R)-4-(amino(4-chlorophenyl)methyl)piperidine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(R)-[[(R)-tert-butylsulfinyl]amino]-(4-chlorophenyl)methyl]piperidine-1-carboxylate (650 mg, 1.52 mmol) in methanol (8 mL) was stirred at room temperature. 4 M HCl / dioxane (417 μL, 1.67 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. Saturated aqueous NaCO and water were added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 0.4% to 7% (MeOH + 2% NHOH) / DCM to give the title compound as a colorless oil (325 mg, 66% yield, 100% purity, t r =0.65 min). LCMS (Method A): m / z found 325.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.40 - 7.27 (m, 4H), 3.91 (dd, J=34.8, 13.2 Hz, 2H), 3.56 (d, J=7.0 Hz, 1H), 2.52 (s, 2H), 1.94 (s, 2H), 1.81 - 1.72 (m, 1H), 1.52 (dtd, J=11.6, 7.7, 3.5 Hz, 1H), 1.37 (s, 10H), 1.27 -1.14(m,1H),1.10-0.85(m,2H).

[0277] Step 3: Synthesis of tert-butyl (R)-4-((4-chlorophenyl)((4-(trifluoromethoxy)phenyl)sulfonamido)methyl)piperidine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(R)-amino-(4-chlorophenyl)methyl]piperidine-1-carboxylate (100 mg, 0.308 mmol), triethylamine (172 μL, 1.23 mmol), and 4-dimethylaminopyridine (7.5 mg, 61.6 μmol) in dry DCM (2 mL) was stirred at room temperature. 4-(Trifluoromethoxy)benzenesulfonyl chloride (52 μL, 0.308 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The mixture was diluted with DCM and half-saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 5% to 50% EtOAc / heptane to give the title compound as a white solid (125 mg, 74% yield, 100% purity, t r = 1.09 min). LCMS (Method A): m / z found 449.1 [M-Boc+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.42 (s, 1H), 7.66 - 7.53 (m, 2H), 7.36 - 7.21 (m, 2H), 7.18 - 6.97 (m, 4H) ), 4.17 - 3.63 (m, 3H), 2.52 (s, 2H), 1.80 (d, J=12.6 Hz, 1H), 1.64 (q, J=10.1 Hz, 1H), 1.37 (s, 9H), 0.96 (d,J=13.9Hz,3H).

[0278] Step 4: Synthesis of (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of tert-butyl 4-[(R)-(4-chlorophenyl)-[[4-(trifluoromethoxy)phenyl]sulfonylamino]methyl]piperidine-1-carboxylate (120 mg, 0.219 mmol) in DCM (1.5 mL) at 25 °C was added 2 M HCl / EtO (1.1 mL, 2.19 mmol) dropwise. The reaction mixture was stirred at 25 °C for 16 h. EtO was added and the formed suspension was filtered, washed with EtO, and dried under vacuum at 50 °C for 24 h to give the hydrochloride salt of the title compound as a white powder (102 mg, 96% yield, 99.79% purity, t r =1.63 min). LCMS (Method D): m / z found 449.98 [M+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ ppm 8.53 (br d,J=9.78 Hz,3 H) 7.52 - 7.67 (m,2 H) 7.27 (dd,J=8.80,0.98 Hz,2 H) ) 7.08 - 7.13 (m,2 H) 7.07 (s,2 H) 4.07 (t,J=9.17 Hz,1 H) 3.07 - 3.30 (m,2 H) 2.77 (br d,J=2.93 Hz,2 H) ) 1.94 - 2.09 (m,1 H) 1.68 - 1.87 (m,1 H) 1.28 - 1.41 (m,1 H) 1.09 - 1.27 (m,2 H).

[0279] Example 14: (S)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (14) [ka] Step 1: Synthesis of tert-butyl 4-((S)-(((R)-tert-butylsulfinyl)amino)(4-chlorophenyl)methyl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (1.00 g, 3.07 mmol) in dry THF (15 mL) was stirred at 0 °C under nitrogen in a three-necked round-bottom flask equipped with a thermometer. 1 M 4-chlorophenylmagnesium bromide (3.7 mL, 3.68 mmol) was added dropwise over 5 min, and the solution was stirred at room temperature for 16 h. The mixture was stirred at 0 °C and quenched by the dropwise addition of saturated aqueous NaHCO3. The mixture was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 20% to 100% EtOAc / heptane to give the title compound as a white foam (345 mg, 25% yield, 93% purity, t r =1.00 min). LCMS (Method A): m / z found 451.4 [M+Na] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.40 - 7.33 (m, 2H), 7.33 - 7.26 (m, 2H), 5.49 (d, J=6.9 Hz, 1H), 4.07 - 3.92 (m, 2H), 3.87 (d, J=13.3 Hz, 1H), 2.52 (s, 2H), 1.99 (s, 1H), 1.87 - 1.73 (m, 1H), 1.37 (s, 10H), 1.23 - 1.09 (m,2H),1.02 (s,11H)

[0280] Step 2: Synthesis of tert-butyl (S)-4-(amino(4-chlorophenyl)methyl)piperidine-1-carboxylate [ka] In a sealed tube under nitrogen, tert-butyl 4-[(S)-[[(R)-tert-butylsulfinyl]amino]-(4-chlorophenyl)methyl]piperidine-1-carboxylate (510 mg, 1.19 mmol) in methanol (6 mL) was stirred at room temperature. 4 M HCl / dioxane (327 μL, 1.31 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. Saturated aqueous NaCO and water were added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 0.4% to 7% (MeOH + 2% NHOH) / DCM to give the title compound as a colorless oil (282 mg, 73% yield, 100% purity, t r =0.65 min). LCMS (Method A): m / z found 325.4 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.43 - 7.23 (m,4H),3.91 (dd,J=34.8,13.0 Hz,2H),3.56 (d,J=7.0 Hz, 1H), 2.52 (s, 2H), 1.94 - 1.69 (m, 3H), 1.51 (tdt, J=11.2, 7.1, 3.4 Hz, 1H), 1.37 (s, 9H), 1.29 - 1.14 (m, 1H),1.11-0.85 (m,2H)

[0281] Step 3: Synthesis of tert-butyl (S)-4-((4-chlorophenyl)((4-(trifluoromethoxy)phenyl)sulfonamido)methyl)piperidine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-amino-(4-chlorophenyl)methyl]piperidine-1-carboxylate (100 mg, 0.308 mmol), triethylamine (172 μL, 1.23 mmol), and 4-dimethylaminopyridine (7.5 mg, 61.6 μmol) in dry DCM (2 mL) was stirred at room temperature. 4-(Trifluoromethoxy)benzenesulfonyl chloride (52 μL, 0.308 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The mixture was diluted with DCM and half-saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 5% to 50% EtOAc / heptane to give the title compound as a colorless oil (130 mg, 76% yield, 100% purity, t r =1.09 min). LCMS (Method A): m / z found 449.1 [M-Boc+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.42 (s, 1H), 7.65 - 7.53 (m, 2H), 7.36 - 7.23 (m, 2H), 7.16 - 6.98 (m, 4H), 4.17 - 3.67 (m, 3H), 2.52 (s, 2H), 1.80 (d, J=13.1 Hz, 1H), 1.64 (q, J=10.4 Hz, 1H), 1.37 (s, 9H), 1.11 - 0.74 (m, 3H).

[0282] Step 4: Synthesis of (S)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of tert-butyl 4-[(S)-(4-chlorophenyl)-[[4-(trifluoromethoxy)phenyl]sulfonylamino]methyl]piperidine-1-carboxylate (125 mg, 0.228 mmol) in DCM (1.5 mL) at 25 °C was added 2 M HCl / EtO (1.1 mL, 2.28 mmol) dropwise. The reaction mixture was stirred at 25 °C for 2 h. EtO was added and the formed suspension was filtered, washed with EtO, and dried under vacuum at 50 °C for 24 h to give the title compound as a white powder (103 mg, 93% yield, 99.72% purity, t r = 1.63 min). LCMS (Method D) 1 H-NMR (500 MHz,DMSO-d6) δ ppm 1.17 - 1.29 (m,2 H) 1.30 - 1.42 (m,1 H) 1.73 - 1.87 (m,1 H) 2.02 (br dd,J=13.94 ,2.45Hz,1H) 2.66-2.84(m,2H)3.09-3.20(m,1H)3.24-3.30(m,1H)4.07(t,J=9.17Hz,1H)7.02-7.14( m, 4 H) 7.26 (dd, J=8.80, 0.98 Hz, 2 H) 7.53 - 7.62 (m, 2 H) 8.28 - 8.76 (m, 3 H).

[0283] Example 15: (S)—N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (15) [ka] Step 1: Synthesis of tert-butyl (S,E)-4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate [ka] In a round-bottom flask under nitrogen, a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.7 g, 13.0 mmol) in dry THF (12 mL) was stirred at room temperature. A solution of (S)-tert-butylsulfinamide (1.5 g, 12.4 mmol) in dry THF (12 mL) was then added, followed by titanium ethoxide (13 mL, 61.9 mmol), and the solution was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water (200 mL), and the resulting suspension was stirred at room temperature for 10 minutes and filtered through talc. The residue was washed with EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. 、 Filtration and concentration gave the title compound as a beige solid (3.8 g, 86% yield, 100% purity, t r =0.91 min). LCMS (Method B): m / z found 339.2 [M+Na] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.91 (d, J=3.7 Hz, 1H), 3.90 (d, J=13.1 Hz, 2H), 2.86 (s, 2H), 2.75 - 2.64 (m, 1H), 1.84 (t, J=11.8 Hz, 2H), 1.39 (s, 11H), 1.10 (s, 9H).

[0284] Step 2: Synthesis of tert-butyl 4-((S)-(((S)-tert-butylsulfinyl)amino)(5-chloropyridin-2-yl)methyl)piperidine-1-carboxylate [ka] A solution of 2-bromo-5-chloropyridine (912 mg, 4.74 mmol) in anhydrous EtO (30 mL) was stirred at −78 °C under nitrogen in a three-necked round-bottom flask equipped with a thermometer. 1.6 M butyllithium (3.3 mL, 5.21 mmol) was added dropwise over 1 min, and the mixture was stirred at −78 °C for 1 h. A solution of tert-butyl 4-[(E)-[(S)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (1.50 g, 4.74 mmol) in anhydrous EtO (12 mL) was added dropwise over 3 min. The solution was stirred at −78 °C for 2 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc and HO. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 5% to 90% EtOAc / heptane to give the title compound as an off-white foam (280 mg, 13% yield, 94% purity, t r =0.94 min). LCMS (Method A): m / z found 430.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.54 (d, J=2.5 Hz, 1H), 7.92 (dd, J=8.4, 2.5 Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 5.58 (d, J=7.9 Hz, 1H), 4.11 (t, J=7.9 Hz, 1H), 3.97 (d, J=13.5 Hz, 1H), 3.91 - 3.79 (m, 1H),2.75 - 2.53 (m,2H),1.90 (dd,J=15.1,10.8 Hz,2H),1.37 (s,9H),1.15 - 1.04 (m,2H),1.01 (s,9H).

[0285] Step 3: Synthesis of tert-butyl (S)-4-(amino(5-chloropyridin-2-yl)methyl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-[(S)-[[(S)-tert-butylsulfinyl]amino]-(5-chloro-2-pyridyl)methyl]piperidine-1-carboxylate (280 mg, 0.612 mmol) in MeOH (3 mL) was stirred at room temperature. 4 M HCl in dioxane (0.16 mL, 0.643 mmol) was added, and the mixture was stirred at room temperature for 16 h. Saturated aqueous Na2CO3 and water were added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 10% (MeOH + 2% NH4OH) / DCM to give the title compound as a colorless oil (120 mg, 58% yield, 97% purity, t r =0.61 min). LCMS (Method A): m / z found 326.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.54 (d, J=2.5 Hz, 1H), 7.86 (dd, J=8.4, 2.5 Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 3.91 (dd, J=24.6, 13.3 Hz, 2H), 3.64 (d, J=6.4 Hz, 1H), 2.58 (s, 2H), 1.96 (s, 2H), 1.69 (tt, J=13.8,3.7Hz,2H),1.37(s,9H),1.25-1.18(m,1H),1.15-1.00(m,2H).

[0286] Step 4: Synthesis of tert-butyl (S)-4-((5-chloropyridin-2-yl)((4-(trifluoromethoxy)phenyl)sulfonamido)methyl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-[(S)-amino-(5-chloro-2-pyridyl)methyl]piperidine-1-carboxylate (92%, 100 mg, 0.282 mmol), triethylamine (157 μL, 1.13 mmol), and 4-dimethylaminopyridine (1.7 mg, 0.0141 mmol) in dry DCM (2 mL) was stirred at room temperature in a sealed tube under nitrogen. 4-(trifluoromethoxy)benzenesulfonyl chloride (97%, 49 μL, 0.282 mmol) was then added, and the mixture was stirred at 40° C. for 3.5 h. The mixture was diluted with DCM and half-saturated aqueous NaHCO solution. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 0% to 30% EtOAc / heptane to give the title compound as a white foam (107.3 mg, 69% yield, 100% purity, t r =1.05 min). LCMS (Method A): m / z found 450.3 [M-Boc+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.45 (s, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.76 - 7.44 (m, 3H), 7.42 - 7.26 ( m,2H),7.15 (d,J=8.4 Hz,1H),4.16 (d,J=8.1 Hz,1H),3.85 (dd,J=40.8,12.2 Hz,2H),2.68 (bs,2H),1.93 - 1.67 (m,2H),1.37 (s,9H),0.98 (d,J=3.8 Hz,3H).

[0287] Step 5: Synthesis of (S)—N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-(5-chloro-2-pyridyl)-[[4-(trifluoromethoxy)phenyl]sulfonylamino]methyl]piperidine-1-carboxylate (107 mg, 0.195 mmol) in dry DCM (1.3 mL) was stirred at room temperature. 2 M HCl / EtO (975 μL, 1.95 mmol) was added, and the mixture was stirred at room temperature for 5 h. The mixture was diluted with EtO, and the suspension was filtered. The residue was washed with EtO and dried overnight at 45 °C under reduced pressure to give the hydrochloride salt of the title compound as a white powder (55 mg, 58% yield, 100% purity, t r =1.67 min). LCMS (Method D): m / z found 450.0 [M-H+HCl] + ; 1 H-NMR (DMSO-d6, 600 MHz): δ (ppm) 8.66 (br d, J = 10.3 Hz, 1H), 8.56 (d, J = 9.8 Hz, 1H), 8.26-8.34 (m, 2H) ),7.58-7.63 (m,3H),7.30 (d,J=8.2 Hz,2H),7.17 (dd,J= 8.4,0.6 Hz,1H),4.19 (dd,J= 9.8,8.3 Hz,1H) ,3.10-3.31 (m,2H),2.69-2.81 (m,2H),1.90-1.98 (m,2H),1.15-1.44 (m,3H).

[0288] Example 16: (R)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide (16) [ka] Step 1: Synthesis of tert-butyl 4-((R)-(((R)-tert-butylsulfinyl)amino)(4-chlorophenyl)methyl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (1.00 g, 3.07 mmol) in dry THF (15 mL) was stirred at 0 °C under nitrogen in a three-necked round-bottom flask equipped with a thermometer. 4-Chlorophenylmagnesium bromide (3.7 mL, 3.68 mmol, 1 M) was then added dropwise over 5 min, and the solution was stirred at room temperature for 16 h. The mixture was stirred at 0 °C and quenched by the dropwise addition of half-saturated aqueous NaHCO3. The mixture was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 20% to 100% EtOAc / heptane to give the title compound as a white foam (545 mg, 38% yield, 97% purity, t r =0.98 min). LCMS (Method A): m / z found 451.4 [M+Na] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.38 (d, J=0.7 Hz, 4H), 5.58 (d, J=9.8 Hz, 1H), 4.07 - 3.74 (m, 3H) ,3.32 - 3.19 (m,1H),2.63 (d,J=36.5 Hz,2H),1.91 (d,J=13.2 Hz,1H),1.85 - 1.72 (m,1H),1.46 - 1.32 (m,11H) ), 1.32 - 1.17 (m, 3H), 1.10 (s, 12H), 1.05 - 0.90 (m, 2H), 0.90 - 0.82 (m, 1H).

[0289] Step 2: Synthesis of tert-butyl (R)-4-(amino(4-chlorophenyl)methyl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-[(R)-[[(R)-tert-butylsulfinyl]amino]-(4-chlorophenyl)methyl]piperidine-1-carboxylate (650 mg, 1.52 mmol) in methanol (8 mL) was stirred at room temperature in a sealed tube under nitrogen. 4 M HCl / dioxane (417 μL, 1.67 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. Saturated aqueous NaCO and water were added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 0.4% to 7% (MeOH + 2% NHOH) / DCM to give the title compound as a colorless oil (325 mg, 66% yield, 100% purity, t r =0.64 min). LCMS (Method A): m / z found 325.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.40 - 7.27 (m, 4H), 3.91 (dd, J=34.8, 13.2 Hz, 2H), 3.56 (d, J=7.0 Hz, 1H), 2.52 (s, 2H), 1.94 (s, 2H), 1.81 - 1.72 (m, 1H), 1.52 (dtd, J=11.6, 7.7, 3.5 Hz, 1H), 1.37 (s, 10H), 1.27 -1.14(m,1H),1.10-0.85(m,2H).

[0290] Step 3: Synthesis of tert-butyl (R)-4-((4-chlorophenyl)((6-isopropoxypyridine)-3-sulfonamido)methyl)piperidine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(R)-amino-(4-chlorophenyl)methyl]piperidine-1-carboxylate (100 mg, 0.308 mmol), triethylamine (172 μL, 1.23 mmol), and 4-dimethylaminopyridine (7.5 mg, 61.6 μmol) in dry DCM (2 mL) was stirred at room temperature. 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (76 mg, 0.308 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The mixture was diluted with DCM and half-saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 5% to 50% EtOAc / heptane to give the title compound as a colorless oil (165 mg, 89% yield, 87% purity, t r = 1.06 min). LCMS (Method A): m / z found 546.5 [M+Na] + .

[0291] Step 4: Synthesis of (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide [ka] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(R)-(4-chlorophenyl)-[(6-isopropoxy-3-pyridyl)sulfonylamino]methyl]piperidine-1-carboxylate (165 mg, 0.315 mol) in dry DCM (2 mL) was stirred at room temperature. 2 M HCl / EtO (1.6 mL, 3.15 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with EtO, and the suspension was filtered. The residue was washed with EtO and dried under reduced pressure at 45 °C for 16 h to give the hydrochloride salt of the title compound as a white powder (102 mg, 63% yield, 97.5% purity, t r =1.32 min). LCMS (Method D): m / z found 424.2 [M-HCl+H] + ; 1H-NMR (600 MHz,DMSO-d6) δ ppm 8.74 - 8.86 (m,1 H) 8.45 (d,J=9.98 Hz,2 H) 8.12 (dd,J=2.57,0.66 Hz,1 H) 7.59 - 7.65 (m,1 H) 7.06 - 7.17 (m,4 H) 6.57 (dd,J=8.80,0.59 Hz,1 H) 5.18 (septet,J=6.19 Hz,1 H) 4.06 (t,J=9.32Hz,1H)3.29(brd,J=12.62Hz,1H) 3.15(brd,J=12.47Hz,1H) 2.64-2.85(m,2H) 2.04(brd,J=12.47Hz) ,1H) 1.71 - 1.85 (m,1 H) 1.31 - 1.43 (m,1 H) 1.26 (dd,J=6.16,1.17 Hz,7 H) 1.17 - 1.24 (m,2 H).

[0292] Example 17: (S)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide (17) [ka] Step 1: Synthesis of tert-butyl 4-((S)-(((R)-tert-butylsulfinyl)amino)(4-chlorophenyl)methyl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (1.00 g, 3.07 mmol) in dry THF (15 mL) was stirred at 0 °C under nitrogen in a three-necked round-bottom flask equipped with a thermometer. 1 M 4-chlorophenylmagnesium bromide (3.7 mL, 3.68 mmol) was added dropwise over 5 min, and the solution was stirred at room temperature for 16 h. The mixture was stirred at 0 °C and quenched by the dropwise addition of saturated aqueous NaHCO3. The mixture was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 20% to 100% EtOAc / heptane to give the title compound as a white foam (345 mg, 25% yield, 93% purity, t r =1.00 min). LCMS (Method A): m / z Found 451.4 [M+Na] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.40 - 7.33 (m, 2H), 7.33 - 7.26 (m, 2H), 5.49 (d, J=6.9 Hz, 1H), 4.07 - 3.92 (m, 2H), 3.87 (d, J=13.3 Hz, 1H), 2.52 (s, 2H), 1.99 (s, 1H), 1.87 - 1.73 (m, 1H), 1.37 (s, 10H), 1.23 - 1.09 (m, 2H), 1.02 (s, 11H).

[0293] Step 2: Synthesis of tert-butyl (S)-4-(amino(4-chlorophenyl)methyl)piperidine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-[[(R)-tert-butylsulfinyl]amino]-(4-chlorophenyl)methyl]piperidine-1-carboxylate (510 mg, 1.19 mmol) in methanol (6 mL) was stirred at room temperature. 4 M HCl / dioxane (327 μL, 1.31 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. Saturated aqueous NaCO and water were added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 0.4% to 7% (MeOH + 2% NHOH) / DCM to give the title compound as a colorless oil (282 mg, 73% yield, 100% purity, t r =0.65 min). LCMS (Method A): m / z found 325.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.43 - 7.23 (m, 4H), 3.91 (dd, J=34.8, 13.0 Hz, 2H), 3.56 (d, J=7.0 Hz, 1H), 2.52 (s, 2H), 1.94 - 1.69 (m, 3H), 1.51 (tdt, J=11.2, 7.1, 3.4 Hz, 1H), 1.37 (s, 9H), 1.29 - 1.14 (m, 1H), 1.11 - 0.85 (m, 2H).

[0294] Step 3: Synthesis of tert-butyl (S)-4-((4-chlorophenyl)((6-isopropoxypyridine)-3-sulfonamido)methyl)piperidine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-amino-(4-chlorophenyl)methyl]piperidine-1-carboxylate (100 mg, 0.308 mmol), triethylamine (172 μL, 1.23 mmol), and 4-dimethylaminopyridine (7.5 mg, 61.6 μmol) in dry DCM (2 mL) was stirred at room temperature. 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (76 mg, 0.308 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The mixture was diluted with DCM and half-saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 5% to 50% EtOAc / heptane to give the title compound as a colorless oil (165 mg, 95% yield, 93% purity, t r = 1.06 min). LCMS (Method A): m / z found 546.4 [M+Na] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.32 (d, J=8.3 Hz, 1H), 8.13 (dd, J=2.6, 0.7 Hz, 1H), 7.63 (dd, J= 8.8, 2.6 Hz, 1H), 7.20 - 7.01 (m, 4H), 6.60 (dd, J=8.8, 0.7 Hz, 1H), 5.20 (septet, J=6.2 Hz, 1H), 4.14 - 3.68 (m, 3H) ),2.75 - 2.51 (m,2H),1.84 (d,J=12.7 Hz,1H),1.63 (t,J=10.7Hz,1H),1.37 (s,9H),1.32 - 1.26 (m,6H),1.09~0.90(m,3H).

[0295] Step 4: Synthesis of (S)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide [ka] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-(4-chlorophenyl)-[(6-isopropoxy-3-pyridyl)sulfonylamino]methyl]piperidine-1-carboxylate (165 mg, 0.315 mmol) in dry DCM (2 mL) was stirred at room temperature. 2 M HCl / EtO (1.6 mL, 3.15 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtO, and the suspension was filtered. The residue was washed with EtO and dried under reduced pressure at 45 °C for 16 hours to give the dihydrochloride salt of the title compound as a white powder (110 mg, 67% yield, 96.3% purity, t r =1.33 min). LCMS (Method D): m / z found 424.2 [M-HCl+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ ppm 1.21 - 1.30 (m,8 H) 1.34 - 1.43 (m,1 H) 1.75 - 1.83 (m,1 H) 2.04 (br d,J=12.96 Hz,1 H) 2.68 - 2.81 (m,2 H) 3.14 (br d,J=12.47 Hz,1 H) 3.29 (br d,J=1.00 Hz,1 H) 4.06 (t,J=9.41 Hz,1 5.18 (septet, J=6.19 Hz, 1 H) 6.57 (d, J=8.80 Hz, 1 H) 7.09 - 7.14 (m, 4 H) 7.62 (dd, J=8.80, 2.69 Hz, 1H) 8.12 (d,J=2.45Hz,1H)8.46(d,J=10.03Hz,1H)8.50(brd,J=10.52Hz,1H)8.86(brd,J=10.27Hz,1H).

[0296] Example 18: (R)-6-Isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide (18) [ka] Step 1: Synthesis of tert-butyl 4-((R)-(((R)-tert-butylsulfinyl)amino)(phenyl)methyl)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (500 mg, 1.53 mmol) in anhydrous THF (7.5 mL) at 0 °C was added 1 M phenylmagnesium bromide (1.8 mL, 1.84 mmol) dropwise. The reaction mixture was stirred at 0 °C for 2 h and then at 25 °C for 12 h. The reaction was quenched with saturated aqueous NH4Cl, and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated aqueous Na2CO3, then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 10% to 80% EtOAc / cyclohexane to give the title compound as a colorless oil (237 mg, 36% yield, 93% purity, t r =0.93 min). LCMS (Method A): m / z found 417.5 [M+Na] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.38 - 7.28 (m,4H),7.26 - 7.19 (m,1H),5.51 (d,J=9.5 Hz,1H),3.96 (d,J=12.5 Hz,1H),3.86 (d,J=5.9 Hz,1H),2.58 (s,2H),1.94 - 1.87 (m,1H),1.87 - 1.74 (m,1H),1.42 - 1.38 (m, 1H), 1.37 (s, 10H), 1.10 (s, 9H), 1.09 - 1.03 (m, 1H), 0.95 (qd, J=12.6, 4.4 Hz, 1H).

[0297] Step 2: Synthesis of tert-butyl (R)-4-(amino(phenyl)methyl)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[(R)-[[(R)-tert-butylsulfinyl]amino]-phenyl-methyl]piperidine-1-carboxylate (237 mg, 0.559 mmol) in methanol (3 mL) at 25 °C was added dropwise 4 M HCl / dioxane (150 μL, 0.614 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was basified with saturated aqueous Na2CO3, and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography using a gradient of 1% to 15% MeOH (0.7 M in NH3) / DCM to give the title compound as a colorless oil (76 mg, 46% yield, 98% purity, t r =0.6 min). LCMS (Method A): m / z found 291.2 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.29 (d, J=4.4 Hz, 4H), 7.20 (dt, J=8.7, 4.1 Hz, 1H), 3.96 (d, J=13.2 Hz, 1H), 3.86 (d, J=13.3 Hz, 1H), 3.54 (d, J=7.1 Hz, 1H), 2.57 (s, 2H), 1.90 (s, 2H), 1.80 (dt, J= 13.0, 2.9 Hz, 1H), 1.54 (tdt, J=11.2, 7.0, 3.5 Hz, 1H), 1.37 (s, 9H), 1.22 (dt, J=13.2, 3.2 Hz, 1H), 0.99 (dqd, J =29.5,12.6,4.4Hz,2H).

[0298] Step 3: Synthesis of tert-butyl (R)-4-(((6-isopropoxypyridine)-3-sulfonamido)(phenyl)methyl)piperidine-1-carboxylate [ka] In a sealed vial, tert-butyl 4-[(R)-amino(phenyl)methyl]piperidine-1-carboxylate (76 mg, 0.256 mmol), DMAP (6.3 mg, 51.3 μmol), and triethylamine (140 μL, 1.03 mmol) were added in DCM (2.3 mL). 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (64 mg, 0.256 mmol) was then added, and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was diluted with DCM, and saturated aqueous NH4Cl was added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel flash chromatography using a gradient of 0% to 5% MeOH / DCM to give the title compound as a pale orange solid (64.5 mg, 48% yield, 94% purity, t r = 1.02 min). LCMS (Method A): m / z found 434.4 [M-tBu+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.28 (d, J=9.5 Hz, 1H), 8.15 (d, J=2.6 Hz, 1H), 7.59 (dd, J=8.7, 2.6 Hz, 1H), 7.08 - 7.01 (m, 5H), 6.54 (d, J=8.8 Hz, 1H), 5.18 (p, J=6.2 Hz, 1H), 4.06 - 3.98 (m, 1H), 3.97 - 3.88 (m, 1H), 3.86 - 3.73 (m, 1H), 2.51 (d, J=1.9 Hz, 1H), 1.83 (d, J=13.1 Hz, 1H), 1.66 (s, 1H), 1.37 (s) ,10H),1.24 (dd,J=6.2,1.7Hz,6H),1.01 (d,J=12.5Hz,3H).

[0299] Step 4: Synthesis of (R)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide [ka] To a stirred solution of tert-butyl 4-[(R)-[(6-isopropoxy-3-pyridyl)sulfonylamino]-phenyl-methyl]piperidine-1-carboxylate (65 mg, 0.124 mmol) in DCM (1 mL) at 25 °C was added 2 M HCl / EtO (0.62 mL, 1.24 mmol) dropwise. The reaction mixture was stirred at 25 °C for 4 h. EtO was added and the formed suspension was filtered, washed with EtO, and dried under vacuum at 50 °C overnight to give the title compound as an off-white powder (45 mg, 81% yield, 95.33% purity, t r =1.32 min). LCMS (Method D): m / z found 390 [M+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ ppm 8.54 - 8.70 (m,1 H) 8.39 (d,J=10.03 Hz,1 H) 8.19 - 8.33 (m,1 H) 8.15 (d,J =2.69Hz,1H)7.58(dd,J=8.80,2.69Hz,1H)7.07(s,5H)6.51(d,J=8.80Hz,1H)5.03-5.27(m,1H)4.03 (dd,J=9.66,8.93 Hz,1 H) 3.29 (br s,1 H) 3.16 (br d,J=11.74 Hz,1 H) 2.65 - 2.90 (m,2 H) 1.97 - 2.16 (m,1 H) 1.74 - 1.87 (m,1 H) 1.34 - 1.44 (m,1 H) 1.24 (dd,J=6.24,2.08 Hz,8 H).

[0300] Example 19: (S)-6-Isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide (19) [ka] Step 1: Synthesis of tert-butyl (S,E)-4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate [ka] A solution of (S)-(-)-2-methyl-2-propanesulfinamide (1.00 g, 8.09 mmol) in THF (8 mL) and titanium ethoxide (8.8 mL, 40.4 mmol) was added successively to tert-butyl 4-formylpiperidine-1-carboxylate (1.81 g, 8.49 mmol) in THF (8 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and the suspension was filtered. The precipitate was extracted twice with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dried under vacuum to give the title compound as a pale yellow solid (2.23 g, 77% yield, 88% purity, t r =0.9 min). LCMS (Method A): m / z found 339.4 [M+Na] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.92 (d,J=3.7 Hz,1H),3.98 - 3.84 (m,2H),2.87 (s,2H),2.70 (tq, J=11.1,3.8Hz,1H),1.90-1.72(m,2H),1.42-1.35(m,11H),1.11(s,6H),1.08(s,3H).

[0301] Step 2: Synthesis of tert-butyl 4-((S)-(((S)-tert-butylsulfinyl)amino)(phenyl)methyl)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[(E)-[(S)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (88%, 500 mg, 1.39 mmol) in anhydrous THF (7 mL) at 0 °C was added 1 M phenylmagnesium bromide (1.5 mL, 1.53 mmol) dropwise. The reaction mixture was stirred at 0 °C for 2 h and then at 25 °C for 16 h. The reaction was quenched with saturated aqueous NH4Cl, and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated aqueous Na2CO3, then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 10% to 70% EtOAc / cyclohexane to give the title compound as a white solid (175 mg, 31% yield, 97% purity, t r =1.7 min). LCMS (Method B): m / z found 417.3 [M+Na] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.37 - 7.26 (m, 4H), 7.22 (t, J=7.0 Hz, 1H), 5.51 (d, J=9.5 Hz, 1H) ,4.14-3.72(m,3H),2.73-2.43(m,1H),1.90(d,J=13.0Hz,1H),1.86-1.74(m,1H),1.37(s,9H),1.24-0.86 (m,13H).

[0302] Step 3: Synthesis of tert-butyl 4-[(S)-amino(phenyl)methyl]piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[(S)-[[(S)-tert-butylsulfinyl]amino]-phenyl-methyl]piperidine-1-carboxylate (171 mg, 0.420 mmol) in methanol (2 mL) at 25 °C was added 4 M HCl / dioxane (120 μL, 0.462 mmol) dropwise. The reaction mixture was stirred at 25 °C for 3 h. The reaction was basified with saturated aqueous Na2CO3 and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 15% MeOH (0.7 M in NH3) / DCM to give the title compound as a colorless oil (93 mg, 68% yield, 89% purity, t r =0.6 min). LCMS (Method B): m / z found 291.2 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.29 (d, J=4.4 Hz, 4H), 7.24 - 7.15 (m, 1H), 3.91 (dd, J=38.3, 13.1 Hz, 2H), 3.53 (d, J=7.1 Hz, 1H), 2.57 (s, 2H), 1.93 - 1.69 (m, 3H), 1.53 (dtd, J=11.4, 7.7, 3.6 Hz, 1H), 1.37 (s, 9H), 1.27 - 1.16 (m, 1H), 1.11 - 0.88 (m, 2H).

[0303] Step 4: Synthesis of tert-butyl (S)-4-(((6-isopropoxypyridine)-3-sulfonamido)(phenyl)methyl)piperidine-1-carboxylate [ka] To a sealed vial was added tert-butyl 4-[(S)-amino(phenyl)methyl]piperidine-1-carboxylate (89%, 93 mg, 0.285 mmol), DMAP (7.0 mg, 57.0 μmol), and triethylamine (160 μL, 1.14 mmol) in DCM (2.5 mL). 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (71 mg, 0.285 mmol) was then added, and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was diluted with DCM, and saturated aqueous NH4Cl was added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel flash chromatography using a gradient of 0% to 5% MeOH / DCM to give the title compound as a white powder (63.6 mg, 45% yield, 99% purity, t r = 1.02 min). LCMS (Method A): m / z found 434.5 [M-tBu+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.29 (d,J=9.3 Hz,1H),8.16 (d,J=2.5 Hz,1H),7.60 (dd,J=8.8, 2.6 Hz, 1H), 7.12 - 7.00 (m, 5H), 6.55 (d, J=8.8 Hz, 1H), 5.18 (p, J=6.2 Hz, 1H), 4.02 (t, J=8.8 Hz, 1H) ,3.94 (d, J=13.1Hz, 1H), 3.80 (d, J=13.1Hz, 1H), 2.67 (s, 1H), 1.84 (d, J=13.2Hz, 1H), 1.67 (d, J=13.1Hz, 1H) 10.4 Hz,1H),1.37 (s,9H),1.25 (dd,J=6.2,1.6 Hz,6H),1.10 - 0.87 (m,3H)

[0304] Step 5: Synthesis of (S)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide [ka] To a stirred solution of tert-butyl 4-[(S)-[(6-isopropoxy-3-pyridyl)sulfonylamino]-phenyl-methyl]piperidine-1-carboxylate (64 mg, 0.129 mmol) in DCM (860 μL) at 25 °C was added 2 M HCl / EtO (640 μL, 1.29 mmol) dropwise. The reaction mixture was stirred at 25 °C for 3 h. EtO was added and the formed suspension was filtered, washed with EtO, and dried under vacuum at 50 °C overnight to give the hydrochloride salt of the title compound as a white powder (40 mg, 71% yield, 97.13% purity, t r =1.58 min). LCMS (Method F): m / z found 390 [M+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ ppm 1.21 - 1.28 (m,8 H) 1.31 - 1.41 (m,1 H) 1.77 - 1.85 (m,1 H) 2.01 - 2.08 (m,1 H) ) 2.70 - 2.83 (m,2 H) 3.16 (br d,J=12.72 Hz,1 H) 3.27 - 3.30 (m,1 H) 4.01 - 4.06 (m,1 H) 5.16 (quintet, J=6.17 Hz, 1H) 6.52 (d, J=8.80Hz, 1H) 7.04 - 7.10 (m, 5H) 7.58 (dd, J=8.80, 2.45Hz, 1H) 8.15 (d, J=2.72Hz, 1H) 8.18-8.74(m,3H).

[0305] Example 20: N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (20) [ka] Step 1: Synthesis of tert-butyl 4-(2-(2,4-difluorophenyl)-2-oxoethyl)piperazine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl piperazine-1-carboxylate (1.43 g, 7.66 mmol), triethylamine (652 μL, 4.68 mmol), and 2-bromo-1-(2,4-difluorophenyl)ethanone (1.00 g, 4.25 mmol) in DCM (9.4 mL) was stirred at room temperature. The mixture was stirred in a cold bath, and DMAP (26 mg, 0.213 mmol) was added. The cold bath was removed, and the mixture was stirred at room temperature for 16 hours. Half-saturated aqueous NaHCO3 was added, and the mixture was stirred at room temperature for 5 minutes. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 10% (MeOH + 2% NH4OH) / DCM to give the title compound as an orange oil (1.13 g, 51% yield, 66% purity, t r =0.55 min). LCMS (Method A): m / z found 341.4 [M+H] + ; 1 H-NMR (400 MHz,DMSO) δ 7.93 (td,J=8.6,6.7 Hz,1H),7.41 (dddd,J=11.6,9.3,2.4 Hz,1H),7.28 - 7.19 (m,1H),3.77 (d, J = 2.6 Hz, 2H), 3.29 (t, J = 5.1 Hz, 4H), 2.49 - 2.42 (m, 4H), 1.40 (s, 9H).

[0306] Step 2: Synthesis of tert-butyl 4-(2-amino-2-(2,4-difluorophenyl)ethyl)piperazine-1-carboxylate [ka] In a sealed tube under nitrogen, polymer-bound sodium cyanoborohydride (3.34 g, 6.68 mmol) was added to a stirred solution of tert-butyl 4-[2-(2-(2,4-difluorophenyl)-2-oxo-ethyl]piperazine-1-carboxylate (1.14 g, 3.34 mmol) and ammonium acetate (2.57 g, 33.4 mmol) in acetic acid (2 mL) and methanol (20.4 mL). The mixture was stirred at 50° C. overnight and filtered. The residue was dissolved in MeOH The filtrate was concentrated and then dissolved in DCM and saturated aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, and the combined aqueous layers were then extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 5% (MeOH + 2% NH4OH) / DCM to give the title compound as a yellow oil (376.6 mg, 31% yield, 95% purity, t r =0.56 min). LCMS (Method A): m / z found 342.4 [M+H] + ; 1 H-NMR (400 MHz,DMSO) δ 7.64 (td,J=8.6,6.8 Hz,1H),7.13 (ddd,J= 10.8,9.4,2.6 Hz,1H),7.06 (tt,J= 8.5,1.7 Hz, 1H), 4.32 (dd, J=8.7, 5.1 Hz, 1H), 3.30 (s, 4H), 2.48 - 2.17 (m, 8H), 1.39 (s, 9H).

[0307] Step 3: Synthesis of tert-butyl 4-(2-(2,4-difluorophenyl)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)ethyl)piperazine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-amino-2-(2,4-difluorophenyl)ethyl]piperazine-1-carboxylate (150 mg, 0.439 mmol) in DCM (2.8 mL) in a sealed vial under nitrogen, triethylamine (92 μL, 0.659 mmol) and 4-(trifluoromethoxy)benzenesulfonyl chloride (82 μL, 0.483 mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO3. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 15% 0.7 N ammonia in methanol / dichloromethane to give the title compound (194 mg, 77% yield, 99.6% purity, t r =0.75 min). LCMS (Method B): m / z found 566.3 [M+H] + ; 1 H-NMR (400 MHz,DMSO) δ 8.47 (s,1H),7.85 - 7.68 (m,2H),7.45 (dq,J=7.8,1.1 Hz,2H),7.32 (td,J= 8.6,6.5 Hz, 1H), 7.01 (ddd, J = 10.6, 9.3, 2.5 Hz, 1H), 6.95 - 6.84 (m, 1H), 4.61 (dd, J = 8.6, 5.8 Hz, 1H), 3.20 - 2.94 (m, 4H), 2.59 (dd, J=13.0, 8.8 Hz, 1H), 2.39 - 2.10 (m, 5H), 1.37 (s, 9H).

[0308] Step 4: Synthesis of N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of tert-butyl 4-[2-(2,4-difluorophenyl)-2-[[4-(trifluoromethoxy)phenyl]sulfonylamino]ethyl]piperazine-1-carboxylate (100%, 193 mg, 0.340 mmol) in 1,4-dioxane (2.3 mL) in a round-bottom flask was added 4 M hydrogen chloride in 1,4-dioxane (0.85 mL, 3.40 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours and then diluted with diethyl ether (31.5 mL). The reaction was stirred overnight. The solid was filtered, washed with EtO, and dried under vacuum at 50 °C overnight to give the dihydrochloride salt of the title compound as an off-white solid (142.7 mg, 77% yield, 99.47% purity, t r = 1.36 min). LCMS (Method D): m / z found (600 MHz, DMSO-d6) δ ppm 8.63 - 9.41 (m, 3 H) 7.66 (d, J = 8.80 Hz, 2 H) 7.26 - 7.39 (m, 3 H) 6.90 - 6.99 (m, 1 H) 6.82 (td, J = 8.51, 2.49 Hz, 1 H) 4.72 - 5.02 (m, 1 H) 2.58 - 3.53 (m, 10 H).

[0309] Example 21: N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (21) [ka] Step 1: Synthesis of tert-butyl 4-(2-(3,4-difluorophenyl)-2-oxoethyl)piperazine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl piperazine-1-carboxylate (1.38 g, 7.43 mmol), triethylamine (633 μL, 4.54 mmol), and 2-bromo-1-(3,4-difluorophenyl)ethanone (97%, 1.00 g, 4.13 mmol) in DCM (9.1 mL) was stirred at room temperature. The mixture was stirred in a cold bath, and DMAP (25 mg, 0.206 mmol) was added. The cold bath was removed, and the mixture was stirred at room temperature for 16 hours. Half-saturated aqueous NaHCO3 was added, and the mixture was stirred at room temperature for 5 minutes. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 0.4% to 4% (MeOH + 2% NH4OH) / DCM to give the title compound as a pale yellow solid (1.33 g, 86% yield, 91% purity, t r =0.56 min). LCMS (Method A): m / z found 341.4 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.02 (ddd,J=11.4,7.9,2.1 Hz,1H),7.89 (ddt,J=8.1,5.0,1.6 Hz,1H),7.60 (dt, J=10.5, 8.3 Hz, 1H), 3.87 (s, 2H), 2.50 - 2.43 (m, 4H), 1.40 (s, 9H).

[0310] Step 2: Synthesis of tert-butyl 4-(2-amino-2-(3,4-difluorophenyl)ethyl)piperazine-1-carboxylate [ka] In a sealed tube under nitrogen, polymer-bound sodium cyanoborohydride (3.53 g, 7.06 mmol) was added to a stirred solution of tert-butyl 4-[2-(3,4-difluorophenyl)-2-oxoethyl]piperazine-1-carboxylate (91%, 1.32 g, 3.53 mmol) and ammonium acetate (2.72 g, 35.3 mmol) in acetic acid (2.2 mL) and methanol (21.6 mL). The mixture was stirred at 40 °C for 16 h and filtered. The residue was washed with MeOH, and the filtrate was concentrated and then dissolved in DCM and saturated aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, and the combined aqueous layers were then extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 5% (MeOH + 2% NH4OH) / DCM to give the title compound as a yellow solid (746 mg, 55% yield, 90% purity, t r =0.59 min). LCMS (Method A): m / z found 342.4 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.43 (ddd,J=12.3,8.1,2.1 Hz,1H),7.34 (dt,J=10.8,8.5 Hz,1H),7.21 ( ddt,J=8.3,4.7,1.7Hz,1H),4.04(dd,J=8.9,5.1Hz,1H),2.43(dt,J=10.7,5.1Hz,2H),2.37-2.22(m,4H),1.96 (s,2H),1.40 (s,9H).

[0311] Step 3: Synthesis of tert-butyl 4-(2-(3,4-difluorophenyl)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)ethyl)piperazine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-amino-2-(3,4-difluorophenyl)ethyl]piperazine-1-carboxylate (90%, 150 mg, 0.395 mmol) in DCM (2.6 mL) in a sealed vial under nitrogen, triethylamine (83 μL, 0.593 mmol) and 4-(trifluoromethoxy)benzenesulfonyl chloride (97%, 0.069 mL, 0.395 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 64 h. The reaction mixture was quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 10% 0.7 N ammonia in methanol / dichloromethane to give the title compound as a white solid (200 mg, 82% yield, 92% purity, t r =0.75 min). LCMS (Method B): m / z found 566.3 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.32 (s, 1H), 7.79 - 7.73 (m, 2H), 7.48 - 7.40 (m, 2H), 7.27 - 7.15 (m, 2H) ), 7.08 - 7.00 (m, 1H), 4.41 (dd, J=9.1, 5.4 Hz, 1H), 3.19 - 3.02 (m, 5H), 2.34 - 2.18 (m, 3H), 1.38 (s, 9H).

[0312] Step 4: Synthesis of N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a stirred solution of tert-butyl 4-[2-(3,4-difluorophenyl)-2-[[4-(trifluoromethoxy)phenyl]sulfonylamino]ethyl]piperazine-1-carboxylate (92%, 195 mg, 0.317 mmol) in 1,4-dioxane (2.1 mL) in a round-bottom flask, 4 M hydrogen chloride in 1,4-dioxane (0.79 mL, 3.17 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and additional 4 M hydrogen chloride in 1,4-dioxane (0.79 mL, 3.17 mmol) was added, and the suspension was stirred overnight. Additional 4 M hydrogen chloride in 1,4-dioxane (0.79 mL, 3.17 mmol) was added, and the mixture was stirred for 6 hours and then diluted with diethyl ether (29.4 mL). The reaction was stirred overnight. The solid was filtered, washed with Et2O, and dried under vacuum at 50 °C overnight to give the dihydrochloride salt of the title compound as a white solid (157.3 mg, 92% yield, 100% purity, t r =1.72 min). LCMS (Method D): m / z found 465.9 [M-2HCl+H] + ; 1 H-NMR (DMSO-d6,600 MHz): δ (ppm) 8.95-9.60 (m,2H),8.45-8.88 (m,1H),7.55-7.77 (m,2H),7.28-7.41 (m,2H),7.19-7.26 (m,1H),7.10-7.18 (m,1H),7.00-7.07 (m,1H),4.52-4.89 (m,1H),2.59-4.32 (m,10H).

[0313] Example 22: N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide (22) [ka] Step 1: Synthesis of tert-butyl 4-(2-(4-chlorophenyl)-2-oxoethyl)piperazine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl piperazine-1-carboxylate (1.44 g, 7.71 mmol), triethylamine (657 μL, 4.71 mmol), and 2-bromo-1-(4-chlorophenyl)ethanone (1.00 g, 4.28 mmol) in DCM (9.5 mL) was stirred at room temperature. The mixture was stirred in a cold bath, and DMAP (26 mg, 0.214 mmol) was added. The cold bath was removed, and the mixture was stirred at room temperature for 16 h. Half-saturated aqueous NaHCO3 was added, and the mixture was stirred at room temperature for 5 min. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 10% (MeOH + 2% NH4OH) / DCM to give the title compound as a yellow oil (1.4 g, 88% yield, 91% purity, t r =0.58 min). LCMS (Method A): m / z found 339.4 [M+H] + ; 1 H-NMR (400 MHz,DMSO) δ 8.03 - 7.96 (m,2H),7.62 - 7.56 (m,2H),3.87 (s,2H),3.33-3.30 (m,4H),2.49 - 2.41 (m, 4H), 1.40 (s, 9H).

[0314] Step 2: Synthesis of tert-butyl 4-(2-amino-2-(4-chlorophenyl)ethyl)piperazine-1-carboxylate [ka] In a sealed tube under nitrogen, polymer-bound sodium cyanoborohydride (4.14 g, 8.29 mmol) was added to a stirred solution of tert-butyl 4-[2-(4-chlorophenyl)-2-oxoethyl]piperazine-1-carboxylate (1.40 g, 4.14 mmol) and ammonium acetate (3.19 g, 41.4 mmol) in acetic acid (2.54 mL) and methanol (25.4 mL). The mixture was stirred overnight at 5 °C and filtered. The residue was washed with MeOH, and the filtrate was concentrated and then dissolved in DCM. The organic layer was washed with saturated aqueous NaHCO3, and the combined aqueous layers were then extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 15% (MeOH + 2% NH4OH) / DCM to give the title compound as a yellow oil (707 mg, 45% yield, 90% purity, t r =0.59 min). LCMS (Method A): m / z found 340.4 [M+H] + ; 1 H-NMR (400 MHz,DMSO) δ 7.44 - 7.37 (m,2H),7.37 - 7.30 (m,2H),4.04 (dd,J=9.2,4.7 Hz,1H),3.30 (s,4H),2.48 - 2.21 (m, 6H), 1.94 (brs, 2H), 1.40 (s, 9H).

[0315] Step 3: Synthesis of tert-butyl 4-(2-(4-chlorophenyl)-2-((6-isopropoxypyridine)-3-sulfonamido)ethyl)piperazine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-amino-2-(4-chlorophenyl)ethyl]piperazine-1-carboxylate (150 mg, 0.441 mmol) in DCM (2.9 mL) in a sealed vial under nitrogen, triethylamine (92 μL, 0.662 mmol) and 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (114 mg, 0.485 mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 15% (0.7 N NH3 / MeOH) to give the title compound as a pale yellow solid (185 mg, 77% yield, 99% purity, t r =0.75 min). LCMS (Method B): m / z found 539.3 [M+H] + ; 1 H-NMR (400 MHz,DMSO) δ 8.35 (dd,J=2.6,0.7 Hz,1H),8.22 (s,1H),7.83 (dd,J= 8.8,2.6 Hz,1H),7.30 - 7.19 (dd,J=8.8,2.6 Hz,1H) m,4H),6.77 (dd,J=8.8,0.7 Hz,1H),5.26 (septet,J=6.2 Hz,1H),4.38 (dd,J = 9.2,5.1 Hz,1H),3.20 - 2.98 (m, 4H), 2.55-2.50 (m, 1H), 2.32 - 2.17 (m, 5H), 1.37 (s, 9H), 1.34 - 1.21 (m, 6H).

[0316] Step 4: Synthesis of N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide [ka] To a stirred solution of tert-butyl 4-[2-(4-chlorophenyl)-2-[(6-isopropoxy-3-pyridyl)sulfonylamino]ethyl]piperazine-1-carboxylate (184 mg, 0.341 mmol)) in 1,4-dioxane (2.3 mL) in a round-bottom flask was added 4 M hydrogen chloride in 1,4-dioxane (2.1 mL, 8.53 mmol) dropwise. The reaction mixture was stirred at room temperature overnight and then diluted with diethyl ether (31.6 mL). The reaction was stirred overnight. The solid was filtered, washed with EtO, and dried under vacuum at 50 °C overnight. The solid was partitioned between half-saturated aqueous NaCO and DCM. The organic layer was dried using a phase separator and concentrated under reduced pressure. The crude material was dissolved in 1,4-dioxane (2.27 mL) and 2 M hydrogen chloride in diethyl ether (0.47 mL, 0.940 mmol) was added. Diethyl ether (23 mL) was added and the mixture was stirred for 1 h. The solid was filtered, washed with EtO, and dried under vacuum at 50 °C overnight to give the dihydrochloride salt of the title compound as an off-white solid (141 mg, 78% yield, 97.73% purity, t r =1.64 min). LCMS (Method F): m / z found 439 [M-2HCl+H] + ; 1 H-NMR (600 MHz,DMSO-d6) δ ppm 1.27 (d,J=6.16 Hz,6 H) 2.63 - 3.43 (m,2 H) 3.72 - 4.79 (m,9 H) 5.17 - 5.24 (m , 1H) 6.66 (br d, J=8.80 Hz, 1 H) 7.17 - 7.22 (m, 4 H) 7.73 (br d, J=8.51 Hz, 1 H) 8.20 (br s, 1 H) 8.34 - 9.47 (m, 3 H).

[0317] Example 23: 3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (23) [ka] Step 1: Synthesis of tert-butyl 4-(2-(4-chlorophenyl)-2-oxoethyl)piperazine-1-carboxylate [ka] In a sealed tube under nitrogen, a solution of tert-butyl piperazine-1-carboxylate (1.44 g, 7.71 mmol), triethylamine (657 μL, 4.71 mmol), and 2-bromo-1-(4-chlorophenyl)ethanone (1.00 g, 4.28 mmol) in DCM (9.5 mL) was stirred at room temperature. The mixture was stirred in a cold bath, and DMAP (26 mg, 0.214 mmol) was added. The cold bath was removed, and the mixture was stirred at room temperature for 16 h. Half-saturated aqueous NaHCO3 was added, and the mixture was stirred at room temperature for 5 min. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 0% to 50% EtOAc / cyclohexane to give the title compound as a yellow powder (895 mg, 50% yield, 81% purity, t r =0.58 min). LCMS (Method A): m / z found 339.4 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.04 - 7.96 (m,2H),7.63 - 7.55 (m,2H),3.87 (s,2H),3.33-3.30 (m,4H) ),2.50-2.43(m,4H),1.40(s,9H).

[0318] Step 2: Synthesis of tert-butyl 4-(2-amino-2-(4-chlorophenyl)ethyl)piperazine-1-carboxylate [ka] In a sealed tube under nitrogen, polymer-bound sodium cyanoborohydride (2.14 g, 4.28 mmol) was added to a stirred solution of tert-butyl 4-[2-(4-chlorophenyl)-2-oxoethyl]piperazine-1-carboxylate (81%, 895 mg, 2.14 mmol) and ammonium acetate (1.65 g, 21.4 mmol) in acetic acid (1.3 mL) and methanol (13.1 mL). The mixture was stirred at 65 °C overnight. The reaction mixture was filtered, washed with MeOH, and concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated aqueous NaHCO3. The combined aqueous layers were extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 0% to 10% MeOH / DCM to give the title compound as a yellow oil (411 mg, 54% yield, 96% purity, t r =0.60 min). LCMS (Method B): m / z found 340.2 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.42 - 7.38 (m,2H),7.36 - 7.32 (m,2H),4.05 (dd,J=9.3,4.8 Hz,1H),3.31 (s, 4H), 3.19 - 3.14 (m, 2H), 2.44 (dt, J=10.9, 5.1 Hz, 2H), 2.38 - 2.19 (m, 4H), 1.39 (s, 9H).

[0319] Step 3: Synthesis of tert-butyl 4-(2-(4-chlorophenyl)-2-((3-nitro-4-(trifluoromethoxy)phenyl)sulfonamido)ethyl)piperazine-1-carboxylate [ka] To a sealed vial was added tert-butyl 4-[2-amino-2-(4-chlorophenyl)ethyl]piperazine-1-carboxylate (200 mg, 0.565 mmol), 4-dimethylaminopyridine (14 mg, 0.113 mmol), and triethylamine (315 μL, 2.26 mmol) in DCM (5.3 mL). 3-Nitro-4-(trifluoromethoxy)benzene-1-sulfonyl chloride (173 mg, 0.565 mmol) was then added, and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was diluted with DCM, and saturated aqueous NH4Cl was added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel flash chromatography using a gradient of 10-80% EtOAc / heptane to give the title compound as a yellow gum (123 mg, 34% yield, 97% purity, t r =0.77 min). LCMS (Method A): m / z found 609.4 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.69 (d, J=8.0 Hz, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.05 (dd, J=8.7, 2.3 Hz, 1H), 7.83 (dq, J=8.6, 1.5 Hz, 1H), 7.21 (s, 4H), 4.48 (td, J=8.7, 5.0 Hz, 1H), 3.09 (t, J=5.2 Hz, 2H), 3.01 (d, J=13.7 Hz, 2H), 2.33 - 2.24 (m, 6H), 1.37 (s, 9H).

[0320] Step 4: Synthesis of tert-butyl 4-(2-((3-amino-4-(trifluoromethoxy)phenyl)sulfonamido)-2-(4-chlorophenyl)ethyl)piperazine-1-carboxylate [ka] In a sealed tube, a suspension of iron (55 mg, 0.980 mmol) and ammonium chloride (15 mg, 0.274 mmol) in ethanol (1 mL) and water (0.5 mL) was stirred at 70 °C for 1 h. A solution of tert-butyl 4-[2-(4-chlorophenyl)-2-[[3-nitro-4-(trifluoromethoxy)phenyl]sulfonylamino]ethyl]piperazine-1-carboxylate (123 mg, 0.196 mmol) in ethanol (1 mL) was added, and the mixture was stirred at 80 °C for 5 h. The mixture was cooled to room temperature and filtered through a talc pad. The pad was washed with EtOH and DCM, and the filtrate was concentrated. The residue was dissolved in DCM and saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse flash chromatography using a gradient of 0% to 100% ACN (0.1% AcOH) / water (0.1% AcOH). The desired fractions were concentrated, basified with saturated aqueous Na2CO3, and extracted with DCM. The combined organic layers were dried on a phase separator and concentrated to give the title compound as a yellow foam (74.3 mg, 65% yield, 99% purity, t r =0.73 min). LCMS (Method A): m / z found 579.3 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.91 (s, 1H), 7.32 - 7.22 (m, 4H), 7.18 (dd, J=8.9, 1.9 Hz, 2H), 6.86 ( dd,J=8.4,2.3Hz,1H),5.81(s,2H),4.26(s,1H),3.08(d,J=16.5Hz,4H),2.42(dd,J=13.0,9.1Hz,1H) ),2.25 (dd,J=12.9,5.6 Hz,1H),2.21 (s,2H),2.13 (d,J=7.0 Hz,2H),1.36 (s,9H)

[0321] Step 5: Synthesis of 3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] In a round-bottom flask, tert-butyl 4-[2-[[3-amino-4-(trifluoromethoxy)phenyl]sulfonylamino]-2-(4-chlorophenyl)ethyl]piperazine-1-carboxylate (74 mg, 0.127 mmol) was stirred in anhydrous 1,4-dioxane (1.2 mL). 4 M HCl in dioxane (635 μL, 2.54 mmol) was added, and the resulting suspension was stirred at room temperature overnight. The resulting residue was filtered, washed with EtO, and dried under vacuum at 45 °C for 4 h to give the dihydrochloride salt of the title compound as a beige powder (51.2 mg, 73% yield, 95.7% purity, t r =1.45 min). LCMS (Method D): m / z found [M-2HCl+H] + ; 1 H-NMR (DMSO-d6,500 MHz) δ 8.6-10.2 (m,2H),8.31 (br d,1H,J=4.6 Hz),7.1-7.4 (m,4H),6.9-7.1 (m, ,2H),6.74 (br d,1H,J=8.3 Hz),4.8-6.4 (m,2H),4.3-4.8 (m,1H),2.6-3.4 (m,10H).

[0322] Example 24: N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide (24) [ka] Step 1: Synthesis of tert-butyl 4-(2-(3,4-difluorophenyl)-2-((6-isopropoxypyridine)-3-sulfonamido)ethyl)piperazine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-amino-2-(3,4-difluorophenyl)ethyl]piperazine-1-carboxylate (90%, 150 mg, 0.395 mmol) in DCM (2.6 mL) in a sealed vial under nitrogen, triethylamine (83 μL, 0.593 mmol) and 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 98 mg, 0.395 mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 10% 0.7 N ammonia in MeOH / DCM to give the title compound as a white solid (180 mg, 80% yield, 96% purity, t r =0.74 min). LCMS (Method B): m / z found 541.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.34 (d, J=2.5 Hz, 1H), 8.24 (s, 1H), 7.82 (dd, J=8.8, 2.5 Hz, 1H) ,7.31 - 7.19 (m,2H),7.10 - 7.05 (m,1H),6.77 (d,J=8.9 Hz,1H),5.25 (p,J=6.1 Hz,1H),4.40 (dd,J=9.1 ,5.3Hz,1H),3.22-2.99(m,4H),2.36-2.20(m,5H),1.38(s,8H),1.28(dd,J=6.2,4.5Hz,6H).

[0323] Step 2: Synthesis of N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide [ka] To a stirred solution of tert-butyl 4-[2-(3,4-difluorophenyl)-2-[(6-isopropoxy-3-pyridyl)sulfonylamino]ethyl]piperazine-1-carboxylate (210 mg, 0.388 mmol) in 1,4-dioxane (2.6 mL) in a round-bottom flask was added dropwise 4 M hydrogen chloride in 1,4-dioxane (0.79 mL, 3.88 mmol). The reaction mixture was stirred at room temperature overnight. Additional 4 M hydrogen chloride in 1,4-dioxane (0.79 mL, 3.88 mmol) was added, and the suspension was stirred overnight. Additional 4 M hydrogen chloride in 1,4-dioxane (0.79 mL, 3.88 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with diethyl ether (36 mL) and stirred at room temperature overnight. The solid was filtered, washed with EtO, and dried under vacuum at 50° C. for 64 hours to give the title compound as an off-white solid (144.6 mg, 70% yield, 96.49% purity). LCMS (Method D): m / z found 441 [M-2HCl+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ ppm 1.27 (t,J=5.75 Hz,6 H) 2.65 - 3.41 (m,7 H) 3.71 - 4.23 (m,4 H) 4.52 - 4.82 (m ,1H) 5.21 (quintet, J=6.17Hz,1H) 6.69 (d,J=8.80Hz,1H) 7.04 - 7.12 (m,1H) 7.17 - 7.34 (m,2H) 7.75 (dd,J=8.80,2.69Hz,1H)8.22(d,J=2.45Hz,1H)8.37-8.80(m,1H)8.83-9.91(m,2H).

[0324] Example 25: (R)—N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide (25) [ka] To a sealed vial was added N-[(1R)-1-(4-chlorophenyl)-2-oxo-2-piperazin-1-yl-ethyl]-4-(trifluoromethoxy)benzenesulfonamide (94%, 950 mg, 1.87 mmol) in dry THF (14.4 mL) under nitrogen. 2 M lithium aluminum hydride in THF (2.8 mL, 5.61 mmol) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature for 12 hours. Water (0.10 mL, 5.61 mmol) was added dropwise at 0° C., followed by 5 M sodium hydroxide (1.1 mL, 5.61 mmol) and water (0.30 mL, 16.8 mmol). The suspension was filtered and washed with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 10% (0.7 N NH3 / MeOH) / DCM. The residue was purified by reverse flash chromatography using a gradient of 0% to 100% (0.1% AcOH and ACN in water) ACN / water. The desired fractions were concentrated, the residue was dissolved in a minimum amount of DCM, and 2 M hydrogen chloride in Et2O (0.27 mL, 0.549 mmol) was added. Et2O was added, and the suspension was stirred for 2 h, then filtered, washed with Et2O, and dried under vacuum to give the dihydrochloride salt of the title compound as a white powder (74 mg, 9% yield, 99.23% purity, t r =1.11 min). LCMS (Method D): m / z found 380.1 [M-HCl+H] + ; 1 H-NMR (600 MHz,DMSO-d6) δ ppm 8.16 - 9.59 (m,4 H) 7.61 (br s,2 H) 7.47 - 7.54 (m,1 H) 7.40 (br s,2 H) 7.16 -7.26(m,4H)3.79-5.15(m,7H)2.52-3.58(m,9H).

[0325] Example 26: N-((S)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (26) [ka] Step 1: Synthesis of N-((1S)-1-(4-fluorophenyl)-2-(3-fluoropiperidin-1-yl)-2-oxoethyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] In a sealed tube under nitrogen, a solution of (2S)-2-(4-fluorophenyl)-2-[[4-(trifluoromethoxy)phenyl]sulfonylamino]acetic acid (92%, 150 mg, 0.351 mmol) in DCM (1.75 mL) was stirred at 0 °C. DIPEA (0.092 mL, 0.526 mmol) and HATU (98%, 150 mg, 0.386 mmol) were added, and the mixture was stirred at 0 °C for 10 min. 3-Fluoropiperidine (42 mg, 0.403 mmol) was added, and the mixture was stirred at room temperature for 4 h. The mixture was quenched with saturated aqueous NH4Cl, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 5% MeOH / DCM to give the title compound as a yellow solid (124 mg, 72% yield, 97% purity, t r =0.92 min). LCMS (Method B): m / z found 479 [M+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ 8.71 - 8.52 (m,1H),7.79 - 7.71 (m,2H),7.42 - 7.32 (m,2H),7.32 - 7.22 (m,2H),7.03~6.93(m,2H),5.50~5.39(m,1H),4.72~4.40(m,1H),3.96~3.74(m,1H),3.74~3.46(m,1H),3.29~2.93(m,, 2H), 1.92 - 1.52 (m, 2H), 1.52 - 0.96 (m, 2H).

[0326] Step 2: Synthesis of N-((S)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] A solution of N-[(1S)-1-(4-fluorophenyl)-2-(3-fluoro-1-piperidyl)-2-oxo-ethyl]-4-(trifluoromethoxy)benzenesulfonamide (97%, 176 mg, 0.357 mmol) in DCM (2.3 mL) was stirred at 0 °C. Chloro(trimethyl)silane (0.11 mL, 0.856 mmol) was added dropwise, and the mixture was stirred at 0 °C for 30 minutes. 2 M lithium aluminum hydride (0.50 mL, 0.999 mmol) was added dropwise, and the mixture was stirred at 0 °C for 1 hour and then at room temperature for 16 hours. The mixture was cooled to 0 °C, and water (18 μL, 0.999 mmol) was added dropwise. The suspension was stirred at room temperature for 15 minutes, and 5 M sodium hydroxide (20 μL, 0.999 mmol) was added dropwise. The suspension was stirred at room temperature for 15 minutes, and water (54 μL, 3.00 mmol) was added dropwise. The suspension was stirred at room temperature for 30 minutes and filtered through a talc pad. The filtrate was washed with saturated aqueous Na2CO3 and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 10% MeOH (0.7 N NH3) / DCM. The resulting mixture of diastereoisomers was purified by preparative SFC on a chiralpak IC column using CO2 / (MeOH + 0.5% IPAm) 95 / 5 as the mobile phase. The desired fractions were concentrated, and the residue was dissolved in a minimum amount of DCM, and 2 N HCl / Et2O was added dropwise. Et2O was added, and the resulting suspension was filtered. The residue was washed with EtO and dried under vacuum at 50 °C for 12 h to give the hydrochloride salt of the title compound as a white powder (10 mg, 6% yield, 98.53% purity, t r =1.52 min). LCMS (Method D): m / z found 465 [M-HCl+H] + ; 1H-NMR (500 MHz,DMSO-d6) δ ppm 1.58 - 2.20 (m,4 H) 3.02 - 3.34 (m,3 H) 3.42 - 3.84 (m,3 H) 4.94 (br t,J=8.68) Hz,1 H) 5.05 - 5.33 (m,1 H) 6.89 (br t,J=8.44 Hz,2 H) 7.19 (br dd,J=8.19,5.50 Hz,2 H) 7.28 (br d,J=8.31 Hz, 2 H) 7.61 (br d, J=8.56 Hz, 2 H) 8.77 (br d, J=10.27 Hz, 1 H) 9.72 - 10.52 (m, 1 H).

[0327] Example 27: (S)—N-(2-([1,3′-biazetidin]-1′-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (27) [ka] Step 1: Synthesis of (S)-N-(2-([1,3'-biazetidin]-1'-yl)-1-(4-fluorophenyl)-2-oxoethyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a solution of (2S)-2-(4-fluorophenyl)-2-[[4-(trifluoromethoxy)phenyl]sulfonylamino]acetic acid (200 mg, 0.509 mmol) in DCM (5.4 mL) in a round-bottom flask, DIPEA (1.3 mL, 7.63 mmol) and propanephosphonic anhydride (T3P) in DCM (50%, 0.98 mL, 2.03 mmol) were added sequentially. 1-(azetidin-3-yl)azetidine ditrifluoroacetate (95%, 273 mg, 0.763 mmol) was then added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NH4Cl, and water was added. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous Na2CO3, then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography using a gradient of 0 to 10% MeOH / DCM to give the title compound as a yellow foam (133.4 mg, 51% yield, 95% purity, t r =0.62 min). LCMS (Method A): m / z found 488.3 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.74 (d, J=7.8 Hz, 1H), 7.78 - 7.70 (m, 21H), 7.38 (ddt, J=7.9, 4.2, 1.0 Hz, 2H), 7.23 (ddd, J=8.7, 5.5, 3.1 Hz, 2H), 6.97 (td, J=8.9, 7.0 Hz, 2H), 4.97 (t, J=8.2 Hz, 0.5H), 4.23 - 4.15 (m, 0.5H), 3.97 (dd, J=9.2, 4.2 Hz, 0.5H), 3.89 - 3.81 (m, 0H), 3.72 - 3.57 (m, 1H), 3.40 (td, J=10.3, 4.4) Hz, 1H), 3.32 - 3.11 (m, 1H), 3.13 - 3.07 (m, 2H), 2.98 (t, J=7.0 Hz, 2H), 2.04 - 1.94 (m, 1H), 1.92 - 1.80 (m, 1H).

[0328] Step 2: Synthesis of (S)-N-(2-([1,3'-biazetidin]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide [ka] To a solution of N-[(1S)-2-[3-(azetidin-1-yl)azetidin-1-yl]-1-(4-fluorophenyl)-2-oxo-ethyl]-4-(trifluoromethoxy)benzenesulfonamide (133 mg, 0.274 mmol) in anhydrous DCM (1 mL) in a round-bottom flask under nitrogen, chloro(trimethyl)silane (84 μL, 0.657 mmol) was added, and the mixture was stirred at this temperature for 30 minutes. 2 M lithium aluminum hydride (0.38 mL, 0.766 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 hour and then at room temperature overnight. The reaction mixture was cooled to 0°C, and water (40 μL) was added dropwise. The suspension was stirred for 15 minutes, and 15% aqueous NaOH (40 μL) was added dropwise. The mixture was stirred at 0°C for 15 minutes, and water (120 μL) was added. The suspension was stirred at room temperature for 30 minutes, then filtered through cardboard and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography using a gradient of 0 to 10% MeOH / DCM. The desired fractions were concentrated under reduced pressure. The resulting yellow powder was diluted with DCM and 2 M HCl / EtO (0.27 mL, 0.547 mmol) was added. The mixture was stirred overnight at room temperature, filtered, washed with EtO, and dried overnight under reduced pressure at 45 °C to give the dihydrochloride salt of the title compound as a white powder (63.1 mg, 38% yield, 91.8% purity, t r =1.19 min). LCMS (Method D): m / z found 474.2 [M-2HCl+H] + ; 1H-NMR (500 MHz,DMSO-d6) δ ppm 12.34 (br s,1 H) 10.62 (br s,1 H) 2.03 - 2.42 (m,2 H) 3.44 - 4.82 (m,12 H) 6.89 (t,J=1.00Hz,2H)7.16(brt,J=1.00Hz,2H)7.29(d,J=8.31Hz,2H)7.60(d,J=8.17Hz,2H)8.91(br s,1H) 10.62(br s,1H).

[0329] Example 28: N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide (28) [ka] Step 1: Synthesis of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethan-1-one [ka] To a stirred solution of 2-bromo-1-(3,4-dichlorophenyl)ethanone (97%, 15.00 g, 54.3 mmol) in anhydrous DCM (108.61 mL) in a round-bottom flask under nitrogen at 0° C., 2 M dimethylamine in THF (49 mL, 97.7 mmol), triethylamine (8.3 mL, 59.7 mmol), and DMAP (332 mg, 2.72 mmol) were added sequentially. The reaction mixture was warmed and stirred at room temperature overnight. The reaction mixture was quenched with water (400 mL), and ethyl acetate (400 mL) was added. The aqueous layer was extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 0% to 2% MeOH / DCM to give the title compound as a brown oil (6.77 g, 54% yield, t r =0.51 min). LCMS (Method A): m / z found 232.1 [M+H] + ; 1H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.18 (d, J=2.0 Hz, 1H), 7.94 (dd, J=8.4, 2.1 Hz, 1H), 7.80 (d, J= 8.4Hz,1H),3.75 (s,2H),2.24 (s,6H).

[0330] Step 2: Synthesis of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethan-1-one oxime [ka] To a sealed vial was added 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethanone (99%, 6.77 g, 28.9 mmol), hydroxylamine hydrochloride (4.01 g, 57.7 mmol), and DIPEA (11 mL, 60.6 mmol) in anhydrous ethanol (127.46 mL). The reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum to give the title compound as a brown oil (16.43 g, quantitative yield, 44% purity). LCMS (Method A): m / z 247.1 [M+H]+.

[0331] Step 3: 1-(3,4-dichlorophenyl) - N 2 ,N 2- Synthesis of dimethylethane-1,2-diamine [ka] To a stirred solution of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethanone oxime (44%, 16.43 g, 29.3 mmol) in anhydrous THF (128.52 mL) in a three-necked round-bottom flask at 0° C. under nitrogen, 2.4 M lithium aluminum hydride in THF (30 mL, 73.1 mmol) was added dropwise over 40 minutes at 7° C. (the temperature did not exceed 8° C. during the addition). The reaction mixture was stirred at an external temperature of 75° C. (65° C. in the mixture) for 3 hours. The reaction mixture was cooled to 0° C. and quenched with water (2.77 mL, equal weight to LAH, added dropwise), followed by the addition of 1 M sodium hydroxide (2.8 mL, 2.78 mmol) and water (three times the weight of LAH). The resulting heterogeneous mixture was stirred overnight at room temperature and then filtered and rinsed with THF. The filtrate was dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 4% methanol (0.7 N NH) / dichloromethane. The desired fractions were combined and concentrated in vacuo to give the title compound as an orange oil (1.83 g, 48% yield, 100% purity). 1 H-NMR (400 MHz,DMSO-d6) δ 7.64 (d,J=1.9 Hz,1H),7.54 (dd,J= 8.3,2.4 Hz,1H),7.36 (dt,J= 8.3,2.0 Hz) , 1H), 3.98 (dd, J = 8.8, 5.4 Hz, 1H), 2.30 - 2.22 (m, 1H), 2.21 - 2.14 (m, 7H), 1.94 (s, 2H).

[0332] Step 4: Synthesis of 4-(3-(trifluoromethyl)phenoxy)benzenesulfonyl chloride [ka] In a three-necked round-bottom flask equipped with a thermometer, a solution of 4-[3-(trifluoromethyl)phenoxy]aniline (95%, 300 mg, 1.13 mmol) in TFA (3.8265 mL) was stirred at 0° C. Concentrated aqueous HCl (376 μL, 12.4 mmol) was added, the mixture was stirred at 0° C. for 5 minutes, and then a solution of sodium nitrite (98 mg, 1.41 mmol) in water (425 μL) was added dropwise over 5 minutes to keep the temperature below 0° C. The mixture was stirred at −5° C. for 30 minutes to give solution A.

[0333] In a separate three-necked round-bottom flask equipped with a thermometer, a solution of copper(II) dichloride (77 mg, 0.574 mmol) and copper(I) chloride (3.4 mg, 0.0338 mmol) in acetic acid (3.8265 mL) and sulfuric acid (3.8 mL, 49.5 mmol) was stirred at −5° C. Solution A was added dropwise over approximately 5 minutes, maintaining the temperature below 5° C. The mixture was stirred at 0° C. for 5 minutes and then at room temperature for 1 hour. The mixture was stirred at 55° C. for 5.5 hours and then at room temperature for 14 hours, after which it was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the title compound as a black oil (150 mg, 39% yield). 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.69 - 7.59 (m, 3H), 7.50 (ddd, J=9.1, 2.5, 1.6 Hz, 1H), 7.33 - 7.28 (m, 2H) ),7.05-6.99(m,2H).

[0334] Step 5: Synthesis of N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide [ka] In a sealed tube under nitrogen, a suspension of 4-[3-(trifluoromethyl)phenoxy]benzenesulfonyl chloride (150 mg, 0.445 mmol) in DCM (1 mL) was added to a stirred solution of 1-(3,4-dichlorophenyl)-N',N'-dimethyl-ethane-1,2-diamine (104 mg, 0.445 mmol) and triethylamine (248 μL, 1.78 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 3 days and poured into half-saturated aqueous NaHCO3 solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 0.2% to 5% (MeOH + 2% NH4OH) / DCM. The desired fractions were concentrated and purified by reverse chromatography using a gradient of 0% to 100% (ACN + 0.2% AcOH) / (H2O + 0.2% AcOH). The desired fractions were concentrated and the residue was dissolved in Et2O. The solution was added dropwise to stirred 2N HCl / Et2O and the suspension was stirred at room temperature for 16 hours. The suspension was filtered, the residue was washed with Et2O and dried under reduced pressure at 50 °C for 16 hours to give the hydrochloride salt of the title compound as a white powder (16 mg, 6% yield, 99.7% purity, t r =1.85 min). LCMS (Method D): m / z found 533.2 [M-HCl+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ 9.57 (br s, 1H), 8.5-8.8 (m, 1H), 7.7-7.8 (m, 1H), 7.65 (d, 1H, J=7.8 Hz) ),7.54 (d, 2H, J=8.8 Hz),7.4-7.5 (m, 3H),7.25 (br d, 2H, J=8.3 Hz),6.90 (d, 2H, J=8.8 Hz),4.7- 4.9 (m,1H),3.1-3.5 (m,2H),2.7-3.0 (m,6H).

[0335] Example 29: N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide (29) [ka] A solution of 1-(2,2-dimethyl-1-phenylcyclopropyl)methanamine (95%, 150 mg, 0.813 mmol), 4-dimethylaminopyridine (20 mg, 0.163 mmol), and triethylamine (0.34 mL, 2.44 mmol) in dry DCM (6 mL) was stirred at room temperature in a sealed tube under nitrogen. 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 0.22 g, 0.894 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The mixture was washed with half-saturated aqueous NaHCO, water, and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 0% to 3% MeOH (0.7 N NH) in DCM. The desired fractions were concentrated, and the residue was triturated with EtO. 2M Hydrogen chloride in EtO (1.2 mL, 2.40 mmol) was added, and the resulting heterogeneous mixture was stirred at room temperature for 4 hours. The residue was filtered, washed with EtO, and dried under reduced pressure at 40°C overnight. The title compound melted. The resulting gum was dissolved in MeOH and concentrated under reduced pressure. The residue was triturated with pentane and stirred at room temperature for 2 hours. The heterogeneous mixture was filtered, washed with pentane, and dried under reduced pressure at room temperature to give the title compound as a white solid (85.8 mg, 28% yield, 99.88% purity, t r =2.87 min). LCMS (Method D): m / z found 375.2 [M+H] + ; 1H-NMR (600 MHz,DMSO-d6) δ ppm 0.62 (s,3 H) 0.65 (d,J=4.84 Hz,1 H) 0.77 (d,J=4.70 Hz,1 H) 1.16 (s, 3H) 1.31 (dd, J=1.00Hz, 6H) 2.98 (dd, J=13.06, 5.87Hz, 1H) 3.19 (dd, J=13.06, 5.28Hz, 1H) 5.28 (Septet, J=6.19) Hz,1 H) 6.76 (dd,J=8.80,0.59 Hz,1 H) 7.11 - 7.15 (m,1 H) 7.17 - 7.21 (m,4H) 7.47 (t,J=5.65 Hz,1H) 7.77 (dd, J=8.73, 2.57Hz, 1H) 8.34 (d, J=2.67Hz, 1H).

[0336] Example 30: N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide (30) [ka] In a sealed tube under nitrogen, 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 144 mg, 0.580 mmol) was added to a stirred solution of cyclohexyl(3,5-dichlorophenyl)methanamine hydrochloride (95%, 150 mg, 0.484 mmol), triethylamine (337 μL, 2.42 mmol), and 4-dimethylaminopyridine (12 mg, 0.0967 mmol) in anhydrous DCM (4 mL) and stirred at 40 °C for 16 h. The mixture was diluted with DCM and half-saturated aqueous NaHCO3. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried on a phase separator, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 0% to 2% MeOH (0.7 N NH3) / DCM. The desired fractions were combined and concentrated to give the title compound as a white solid (205 mg, 91% yield, 99.64% purity, t r =3.29 min). LCMS (Method D): m / z found 457 [M+H] + ;1 H-NMR (DMSO-d6,600 MHz): δ (ppm) 8.22 (br d,J=6.6 Hz,1H),8.16 (dd,J= 2.6,0.6 Hz,1H),7.64 (dd,J= 8.8, 2.6 Hz, 1H), 7.21 (t, J = 1.9 Hz, 1H), 7.10 (d, J = 1.9 Hz, 2H), 6.63 (dd, J = 8.7, 0.7 Hz, 1H), 5.20 (quintet, J=6.2Hz,1H),3.99-4.03(m,1H),1.51-1.94(m,4H),1.39-1.50(m,1H),1.27(d,J=6.2Hz,6H),0.73-1.19 (m,6H)

[0337] Example 31: N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide (31) [ka] A mixture of 4-(trifluoromethoxy)benzoic acid (32 μL, 0.243 mmol), [2-amino-2-(3,4-dichlorophenyl)ethyl]dimethylamine (62 mg, 0.267 mmol), EDCI (70 mg, 0.364 mmol), HOBt (41 mg, 0.267 mmol), and triethylamine (101 μL, 0.728 mmol) in DMF (2 mL) was stirred at room temperature for 16 h in a sealed tube. The mixture was poured into saturated aqueous NH4Cl and extracted three times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, then brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 10% (MeOH + 2% NH4OH) / DCM. The desired fractions were concentrated and dissolved in Et2O. 2N HCl / EtO was added, and the mixture was stirred at room temperature for 16 hours and concentrated. The residue was dried under reduced pressure at 45°C for 16 hours and triturated with pentane. The resulting suspension was filtered, and the residue was washed with pentane and dried under reduced pressure at 45°C for 16 hours to give the hydrochloride salt of the title compound as a white powder (63 mg, 56% yield, 99.7% purity, tr =1.62 min). LCMS (Method E): m / z found 421.2 [M-HCl+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ (ppm) = 9.74 (br s,1H),9.47 (br d,J=8.3 Hz,1H),8.19 - 8.10 (m,2H),7.86 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.57 - 7.48 (m, 3H), 5.59 (br t, J = 8.4 Hz, 1H), 3.75 (br t, J = 12.1 Hz, 1H), 3.44 (br t, J = 8.9 Hz, 1H), 2.97 - 2.75 (m, 6H).

[0338] Example 32: N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide (32) [ka] A mixture of 3-nitro-4-(trifluoromethoxy)benzoic acid (32 μL, 0.199 mmol), [2-amino-2-(3,4-dichlorophenyl)ethyl]dimethylamine (51 mg, 0.219 mmol), DIPEA (139 μL, 0.796 mmol), and 1-propanephosphonic acid cyclic anhydride (50%, 317 mg, 0.498 mmol) in DMF (1 mL) was stirred at room temperature for 16 h in a sealed tube. The mixture was poured into semi-saturated aqueous NaHCO and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 10% (MeOH + 2% NHOH) / DCM. The desired fractions were concentrated, and the residue was dissolved in a minimal amount of EtO. The resulting suspension was diluted with pentane, stirred at room temperature for 10 min, and filtered. The residue was washed with pentane and dried under reduced pressure at 45°C for 16 hours to give the title compound as a white powder (43 mg, yield 46%, purity 99.3%, tr =1.84 min). LCMS (Method E): m / z found 465.9 [M+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ 9.13 (d,J=7.8 Hz,1H),8.65 (d,J= 2.2 Hz,1H),8.33 (dd,J= 8.8,2.2 Hz,1H) ),7.88 (dd, J = 8.7,1.3 Hz,1H),7.71 (d,J = 2.0 Hz,1H),7.60 (d,J = 8.3 Hz,1H),7.42 (dd,J = 8.3,2.0 Hz), 1H), 5.26 - 5.02 (m, 1H), 2.73 (dd, J = 12.5, 9.3 Hz, 1H), 2.49 - 2.40 (m, 1H), 2.21 (s, 6H).

[0339] Example 33: N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide (33) [ka] Step 1: Synthesis of benzyl 3-(4-chlorophenyl)-3-hydroxypyrrolidine-1-carboxylate [ka] In a sealed vial, 3-(4-chlorophenyl)pyrrolidin-3-ol hydrochloride (0.60 g, 2.56 mmol) and DIPEA (1.3 mL, 7.69 mmol) were added in anhydrous ACN (9 mL). Benzyl chloroformate (97%, 413 μL, 2.82 mmol) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (50 mL), followed by the addition of ethyl acetate (50 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated in dichloromethane, filtered, washed with dichloromethane, and the resulting powder was then dried under vacuum at 50° C. for 20 hours. The filtrate was purified by silica gel flash chromatography using a gradient of 1% to 5% methanol / dichloromethane to give the title compound as a beige powder (848 mg, 100% yield, 100% purity, t r =0.89 min). LCMS (Method A) 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.54 (d,J=8.6 Hz,2H),7.46 - 7.26 (m,7H),5.55 (s,1H),5.10 (d, J=9.8Hz,2H),3.67-3.43(m,4H),2.32-1.97(m,2H).

[0340] Step 2: Synthesis of benzyl 3-azido-3-(4-chlorophenyl)pyrrolidine-1-carboxylate [ka] In a sealed vial, benzyl 3-(4-chlorophenyl)-3-hydroxy-pyrrolidine-1-carboxylate (759 mg, 2.29 mmol) in a mixture of TFA (8.4 mL) and water (1.33 mL) was added at 0° C. Sodium azide (1.04 g, 16.0 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. Dichloromethane (10 mL) and saturated sodium bicarbonate solution (15 mL) were added. The aqueous layer was extracted with dichloromethane (1×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (815 mg, 100% yield, 100% purity, t r = 1.03 min). LCMS (Method A) 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.60 - 7.48 (m,4H),7.47 - 7.28 (m,6H),5.12 (s,2H),4.07 - 3.88 (m,1H) ),3.75 - 3.38 (m,3H),2.58 - 2.52 (m,1H),2.41 (dt,J=22.4,11.8 Hz,1H)

[0341] Step 3: Synthesis of benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate [ka] In a round-bottom flask under nitrogen, triphenylphosphine (614 mg, 2.34 mmol) was added followed by 4-methylbenzenesulfonic acid hydrate (1.34 g, 7.02 mmol) to a stirred solution of benzyl 3-azido-3-(4-chlorophenyl)pyrrolidine-1-carboxylate (835 mg, 2.34 mmol) in THF (10 mL). The mixture was stirred at room temperature for 1.5 h. The suspension was filtered, washed with THF (5 mL), and dried under vacuum for 18 h to give the title compound as a white powder (890 mg, 74% yield, 100% purity, t r = 1.04 min). LCMS (Method A): m / z found 331.3 [M+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.51 (s,3H),7.59 - 7.51 (m,4H),7.50 - 7.46 (m,2H),7.43 - 7.31 (m,5H) ),7.11 (d, J=7.9 Hz, 2H), 5.13 (d, J=4.9 Hz, 2H), 4.07 (d, J=11.7 Hz, 1H), 3.82 - 3.53 (m, 3H), 2.53 (s, 1H), 2.47 (d, J=13.3 Hz, 1H), 2.29 (s, 3H).

[0342] Step 4: Synthesis of benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate [ka] In a sealed tube, 4-(trifluoromethoxy)benzenesulfonyl chloride (255 μL, 1.50 mmol) was added to a stirred solution of benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate tosylate (688 mg, 1.37 mmol) and triethylamine (1.9 mL, 13.7 mmol) in DCM (20 mL). The solution was stirred at room temperature for 3 h. Water (5 mL) was added, and the aqueous layer was extracted with dichloromethane (1×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 10% to 40% ethyl acetate / cyclohexane to give the title compound as a yellow oil (162 mg, 36% yield, 100% purity, t r =0.62 min). LCMS (Method A): m / z 331.2 [M+H] + .

[0343] Step 5: Synthesis of benzyl 3-(4-chlorophenyl)-3-(4-(trifluoromethoxy)benzamido)pyrrolidine-1-carboxylate [ka] In a sealed tube, benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate (52 mg, 0.157 mmol), triethylamine (44 μL, 0.314 mmol), 1-hydroxybenzotriazole hydrate (72 mg, 0.472 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (39 mg, 0.204 mmol), and 4-(trifluoromethoxy)benzoic acid (36 mg, 0.173 mmol) in DMF (1.56 mL) were stirred at room temperature for 24 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (5 mL) and dichloromethane (15 mL), and water (10 mL) was added. The aqueous layer was extracted with dichloromethane (1 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 0% to 5% methanol / dichloromethane to give the title compound as a beige powder (53.5 mg, 65% yield, 99% purity, t r = 1.06 min). LCMS (Method A): m / z actual value (DMSO-d6, 400 MHz): δ (ppm) 9.00 (s, 1H), 7.94 (d, J=8.8 Hz, 2H), 7.50 - 7.25 (m, 11H) ),5.10 (d, J=3.7 Hz, 2H), 4.16 (dd, J=21.7, 11.3 Hz, 1H), 3.87 (dd, J=24.0, 11.4 Hz, 1H), 3.64 - 3.34 (m, 2H), 2.84-2.65(m,1H),2.41-2.21(m,1H).

[0344] Step 6: Synthesis of N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide [ka] To a stirred suspension of benzyl 3-(4-chlorophenyl)-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine-1-carboxylate (50 mg, 0.0964 mmol) in acetonitrile (1.75 mL) at room temperature in a round-bottom flask was added iodo(trimethyl)silane (41 μL, 0.289 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 5% to 15% ammonia in methanol / dichloromethane. The residue was triturated with methanol, filtered, washed with methanol (3 mL), and dried under vacuum at 70° C. for 1 hour. The residue was then triturated with 2 M hydrogen chloride in diethyl ether (482 μL, 0.964 mmol) for 2 h, filtered, washed with diethyl ether, and dried under vacuum at 70° C. for 16 h to give the hydrochloride salt of the title compound as a white powder (32.6 mg, 80% yield, 99.6% purity, t r =1.37 min). LCMS (Method E): m / z found 385 [M+H] + ; 1 H-NMR (DMSO-d6,600 MHz): δ (ppm) 9.37 (br s,2H),8.98 (s,1H),7.96-8.08 (m,2H),7.45-7.50 (m,4H) ,7.41-7.44 (m,2H),4.18 (dd,J=12.2,1.0 Hz,1H),3.63 (d,J=12.2 Hz,1H),3.38-3.49 (m,2H),2.82-2.92 (m,1H),2.21 (dt,J=13.4,9.8 Hz,1H

[0345] Example 34: 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine (34) [ka] Step 1: Synthesis of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethan-1-one [ka] To a stirred solution of 2-bromo-1-(3,4-dichlorophenyl)ethanone (25.00 g, 90.5 mmol) in dry DCM (200 mL) in a round-bottom flask under nitrogen at room temperature, 2 M dimethylamine in THF (81 mL, 0.163 mol), triethylamine (14 mL, 0.0996 mol), and DMAP (553 mg, 4.53 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (500 mL), and EtOAc (800 mL) was added. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a gradient of 20% to 100% EtOAc / cyclohexane to give the title compound as a brown oil (15.81 g, 70% yield, 93% purity, t r =0.52 min). LCMS (Method A): m / z found 232.1 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.18 (d, J=2.0 Hz, 1H), 7.94 (dd, J=8.4, 2.0 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 3.76 (s, 2H), 2.24 (s, 6H).

[0346] Step 2: Synthesis of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethan-1-ol [ka] To a stirred solution of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethanone (930 mg, 4.01 mmol) in methanol (15 mL) in a round-bottom flask under nitrogen at 0 °C was added sodium borohydride (227 mg, 6.01 mmol). The reaction mixture was stirred at 0 °C for 1 h and warmed to room temperature. The reaction mixture was stirred at room temperature for 1 h and concentrated. The residue was dissolved in DCM and half-saturated aqueous NaHCO3. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 10% (MeOH + 2% NH4OH) / DCM to give the title compound as a brown oil (830 mg, 87% yield, 99% purity, t r =0.51 min). LCMS (Method A): m / z found 234.2 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.63 - 7.50 (m, 2H), 7.34 (ddd, J=8.3, 2.0, 0.5 Hz, 1H), 5.26 (d, J=4.1 Hz, 1H), 4.66 (td, J=6.8, 3.9 Hz, 1H), 2.48 - 2.30 (m, 2H), 2.19 (s, 6H).

[0347] Step 3: Synthesis of 2-chloro-2-(3,4-dichlorophenyl)-N,N-dimethylethan-1-amine [ka] In a sealed tube under nitrogen, a solution of thionyl chloride (3.3 mL, 45.7 mmol) in chloroform (8 mL) was added to a stirred solution of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethanol (1.07 g, 4.57 mmol) in chloroform (8 mL). The mixture was stirred at 70° C. for 1 h and concentrated under reduced pressure to give the hydrochloride salt of the title compound as an orange solid (1.26 g, 95% yield, t r =0.58 min). LCMS (Method A): m / z found 252.1 [M-HCl+H]+ ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 9.98 (s,1H),7.89 (d,J=2.1 Hz,1H),7.77 (d,J=8.5 Hz,1H),7.58 (dd,J=8.4,2.2Hz,1H),5.77(dt,J=8.5,3.8Hz,1H),4.07-3.89(m,1H),3.77(d,J=13.7Hz,1H),2.85(s, 6H)

[0348] Step 4: Synthesis of 2-(4-bromo-1H-pyrazol-1-yl)-2-(3,4-dichlorophenyl)-N,N-dimethylethan-1-amine [ka] In a sealed tube under nitrogen, a suspension of 2-chloro-2-(3,4-dichlorophenyl)-N,N-dimethyl-ethanamine hydrochloride (250 mg, 0.865 mmol), 4-bromo-1H-pyrazole (130 mg, 0.865 mmol), and cesium carbonate (620 mg, 1.90 mmol) in dry DMF (2.5 mL) was stirred at room temperature for 16 h. The crude material was poured into half-saturated aqueous NaHCO solution, and the aqueous layer was extracted three times with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 5% (MeOH + 2% NHOH) / DCM to give the title compound as a beige oil (195 mg, 58% yield, 94% purity, t r =0.66 min). LCMS (Method A): m / z found 364.2 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.18 (d, J=0.7 Hz, 1H), 7.68 - 7.57 (m, 3H), 7.36 (dd, J=8.4, 2.1 Hz, 1H),5.67 (dd,J=9.4,5.9 Hz,1H),3.22 (dd,J=12.9,9.5 Hz,1H),2.79 (dd,J=13.0,5.9 Hz,1H),2.18 (s,6H).

[0349] Step 5: Synthesis of 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine [ka] In a sealed tube, a solution of 2-(4-bromopyrazol-1-yl)-2-(3,4-dichlorophenyl)-N,N-dimethyl-ethanamine (100 mg, 0.275 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (57 mg, 0.275 mmol), and potassium carbonate (49 mg, 0.358 mmol) in 1,4-dioxane (4 mL) and water (800 μL) was degassed with argon for 10 minutes. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (10 mg, 0.0138 mmol) was added, and the mixture was degassed for 5 minutes and stirred at 100° C. for 22 hours. The mixture was poured into half-saturated aqueous NaHCO solution, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 5% (MeOH + 2% NH4OH) / DCM. The desired fractions were concentrated and purified by reverse-phase chromatography using a gradient of (MeCN + 0.1% ACOH) / (H2O + 0.1% AcOH). The desired fractions were concentrated and the residue was dissolved in Et2O. The solution was added dropwise to stirred 2N HCl / Et2O. The resulting paste was dissolved with MeOH and the solution was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was triturated with pentane. The suspension was filtered, the residue was washed with pentane and dried under reduced pressure at 45 °C for 64 hours to give the hydrochloride salt of the title compound as a white powder (30 mg, 22% yield, 98.9% purity, t r =1.89 min). LCMS (Method E): m / z found 444.2 [M-HCl+H] + ; 1H-NMR (500 MHz,DMSO-d6) δ 9.67 (br s,1H),8.47 (s,1H),8.19 (s,1H),7.70-7.75 (m,4H),7.38 (d,J =8.07Hz,2H),7.34(dd,J=2.08,8.44Hz,1H),6.21(br d,J=8.31Hz,1H),4.29-4.41(m,1H),3.85(br s,1H),2.67-2.93 (m,6H).

[0350] Example 35: 2-(3,4-dichlorophenyl)-N,N-dimethyl 2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine (35) [ka] Step 1: Synthesis of 2-(4-bromo-1H-imidazol-1-yl)-2-(3,4-dichlorophenyl)-N,N-dimethylethan-1-amine [ka] In a nitrogen-sealed tube, a suspension of 2-chloro-2-(3,4-dichlorophenyl)-N,N-dimethyl-ethanamine hydrochloride (250 mg, 0.865 mmol), 4-bromo-1H-imidazole (127 mg, 0.865 mmol), and cesium carbonate (620 mg, 1.90 mmol) in dry DMF (2.5 mL) was stirred at room temperature for 16 h. The crude material was poured into half-saturated aqueous NaHCO solution, and the aqueous layer was then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 10% (MeOH + 2% NHOH) / DCM to give the title compound as a beige oil (200 mg, 55% yield, 87% purity, t r =0.58 min). LCMS (Method A): m / z found 364.2 [M+H] + ; 1H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.84 (d, J=1.5 Hz, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.65 (d, J=8.4 Hz) ,1H),7.56 (d,J=1.5 Hz,1H),7.40 (dd,J=8.4,2.1 Hz,1H),5.60 (dd,J=9.8,6.0 Hz,1H),3.20 (dd,J=8.4,2.1 Hz,1H),5.60 (dd,J=9.8,6.0 Hz,1H),13.0, 9.8 Hz, 1H), 2.76 (dd, J=13.2, 6.2 Hz, 1H), 2.19 (s, 6H).

[0351] Step 2: Synthesis of 2-(3,4-dichlorophenyl)-N,N-dimethyl 2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine [ka] In a sealed tube, a solution of 2-(4-bromoimidazol-1-yl)-2-(3,4-dichlorophenyl)-N,N-dimethyl-ethanamine (100 mg, 0.275 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (57 mg, 0.275 mmol), and potassium carbonate (49 mg, 0.358 mmol) in 1,4-dioxane (4 mL) and water (800 μL) was degassed with argon for 10 minutes. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (10 mg, 0.0138 mmol) was added, and the mixture was degassed for 5 minutes and stirred at 100° C. for 22 hours. The mixture was poured into half-saturated aqueous NaHCO solution, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 1% to 10% (MeOH + 2% NH4OH) / DCM. The desired fractions were concentrated and purified by reverse-phase chromatography using a gradient of 0% to 100% (MeCN + 0.1% AcOH) / (H2O + 0.1% AcOH). The desired fractions were concentrated and the residue was dissolved in Et2O. The solution was added dropwise to stirred 2N HCl / Et2O, and the resulting suspension was stirred at room temperature for 16 hours. The suspension was filtered, and the residue was washed with Et2O and dried under reduced pressure at 45 °C for 64 hours to give the hydrochloride salt of the title compound as a white powder (33 mg, 24% yield, 98.9% purity, t r =1.73 min). LCMS (Method E): m / z found 444.2 [M-HCl+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ 10.43 (br s,1H),8.91 (br s,1H),8.37 (br s,1H),7.88-7.92 (m,3H),7.76 (d ,J=8.56Hz,1H),7.45-7.50(m,3H),6.34(brd,J=9.29Hz,1H),4.47(brt,J=12.35Hz,1H),3.94(brd,J =12.47Hz,1H),2.91(brs,3H),2.82(brs,3H).

[0352] Example 36: 1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole (36) [ka] Step 1: Synthesis of benzyl 3-(4-chlorophenyl)-3-((2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrrolidine-1-carboxylate [ka] In a sealed tube under nitrogen, sodium carbonate (128 mg, 1.21 mmol) was added to a stirred solution of benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate (100 mg, 0.302 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethanone (86 mg, 0.302 mmol) in anhydrous acetonitrile (10 mL). The mixture was stirred at 40° C. for 6 hours and then at 60° C. for 16 hours. Additional 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethanone (86 mg, 0.302 mmol) was added, and the mixture was stirred at 40° C. for 3 days and then cooled to 0° C. Water was added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 5% to 40% EtOAc / heptane to give the title compound as a yellow oil (80 mg, 42% yield, 85% purity, t r =0.87 min). LCMS (Method B): m / z found 533.3 [M+H] + ; 1H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.06 - 7.92 (m, 2H), 7.51 - 7.23 (m, 11H), 5.09 (s, 2H), 3.98 - 3.82 (m, 2H) ), 3.82 - 3.66 (m, 1H), 3.62 - 3.35 (m, 3H), 2.86 (s, 1H), 2.44 (s, 1H), 2.11 (dddd, J=21.4, 12.3, 8.8 Hz, 1H).

[0353] Step 2: Synthesis of benzyl 3-(4-chlorophenyl)-3-(N-(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)formamido)pyrrolidine-1-carboxylate [ka] Acetic anhydride (472 μL, 5.10 mmol) was stirred at 0°C in a sealed tube under nitrogen. Formic acid (2.4 mL, 63.8 mmol) was added dropwise, and the mixture was stirred at 0°C for 5 min. A solution of benzyl 3-(4-chlorophenyl)-3-[[2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl]amino]pyrrolidine-1-carboxylate (680 mg, 1.28 mmol) in dry DCM (17 mL) was added dropwise, and the mixture was stirred at room temperature for 16 h. The mixture was poured into ice-saturated aqueous sodium carbonate (pH = 9-10), and the mixture was stirred at room temperature for 5 min. The aqueous layer was extracted twice with DCM, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 10% to 60% EtOAc / heptane to give the title compound as a white foam (480 mg, 66% yield, 99% purity, t r =1.00 min). LCMS (Method A): m / z found 561.4 [M+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.56 (s,1H),8.13 - 8.00 (m,2H),7.54 - 7.19 (m,12H),5.15 - 5.04 (m,2H) ),4.68~4.58 (m,2H),4.16 - 3.96 (m,2H),3.63 (ddt,J=27.4,10.8,7.2 Hz,1H),3.23 (tt,J=11.1,7.0 Hz,1H),2.68 (p, J=6.8 Hz, 1H), 2.62 - 2.51 (m, 1H).

[0354] Step 3: Synthesis of benzyl 3-(4-chlorophenyl)-3-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)pyrrolidine-1-carboxylate [ka] In a sealed tube under nitrogen, ammonium formate (216 mg, 3.42 mmol) was added to a solution of benzyl 3-(4-chlorophenyl)-3-[formyl-[2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl]amino]pyrrolidine-1-carboxylate (480 mg, 0.856 mmol) in acetic acid (5 mL). The mixture was stirred at 120 °C for 16 h, cooled to room temperature, and poured into ice water. Half-saturated aqueous Na2CO3 was added until pH = 9, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using a gradient of 10% to 80% EtOAc / heptane to give the title compound as a yellow oil (320 mg, 66% yield, 97% purity, t r =0.85 min). LCMS (Method A): m / z found 542.3 [M+H] + ; 1H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.15 - 7.93 (m,2H),7.91 - 7.78 (m,2H),7.55 - 7.14 (m,11H),5.20 - 4.98 (m, 2H), 4.60 (dd, J=12.0, 9.2 Hz, 1H), 4.16 - 3.95 (m, 1H), 3.67 - 3.48 (m, 1H), 3.48 - 3.32 (m, 1H), 3.13 (s, 1H) ),2.72 (ddd, J=22.3, 16.5, 8.6 Hz, 1H).

[0355] Step 4: Synthesis of 1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole [ka] In a sealed tube under nitrogen, iodotrimethylsilane (83 μL, 0.581 mmol) was added to a stirred solution of benzyl 3-(4-chlorophenyl)-3-[4-[4-(trifluoromethoxy)phenyl]imidazol-1-yl]pyrrolidine-1-carboxylate (315 mg, 0.581 mmol) in dry acetonitrile (3 mL). The mixture was stirred at room temperature for 24 hours, and additional iodotrimethylsilane (83 μL, 0.581 mmol) was added. The mixture was stirred at room temperature for 24 hours and concentrated to dryness. The residue was purified by silica gel flash chromatography using a gradient of 1% to 10% (MeOH + 2% NH4OH) / DCM. The desired fractions were concentrated, and Et2O was added to the residue. The suspension was stirred at room temperature, and 2N HCl / Et2O was added. The suspension was stirred at room temperature for 2 hours and filtered. The residue was washed with Et2O and dried under reduced pressure at 45 °C for 3 days. The solid was purified by reverse-phase flash chromatography using a gradient of 0% to 100% (ACN + 0.1% AcOH) / (H2O + 0.1% AcOH). The desired fractions were concentrated, and the residue was dissolved in DCM and half-saturated aqueous Na2CO3. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in MeOH (1 mL), and 2N HCl / Et2O (300 μL) was added. The solution was stirred at room temperature for 16 hours and concentrated. The residue was triturated with Et2O and filtered. The residue was washed with Et2O and dried under reduced pressure at 45 °C for 16 hours to give the dihydrochloride salt of the title compound as a white powder (107 mg, 38% yield, 99.8% purity, t r =1.53 min). LCMS (Method D): m / z found 408.2 [M-2HCl+H] + ; 1H-NMR (DMSO-d6,600 MHz) δ 9.7-10.4 (m,2H),8.8-9.6 (m,1H),8.46 (br s,1H),7.8-8.1 (m,2H),7.2 -7.7 (m, 6H), 4.68 (br dd, 1H, J=5.0, 13.1Hz), 3.7-4.1 (m, 1H), 3.6-3.7 (m, 1H), 3.42 (br dd, 1H, J= 6.5, 14.3 Hz), 3.30 (br dd, 1H, J=6.6, 11.0 Hz), 2.7-2.9 (m, 1H).

[0356] Example 37: 1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole (37) [ka] Step 1: Synthesis of tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)-3-phenylpyrrolidine-1-carboxylate [ka] To an ElectraSyn vial (5 mL, IKA) equipped with a stir bar, 1-[(tert-butoxy)carbonyl]-3-phenylpyrrolidine-3-carboxylic acid (95%, 184 mg, 0.600 mmol), 4-bromo-1H-pyrazole (98%, 30 mg, 0.200 mmol), N,N,N-tributylbutan-1-aminium hexafluorophosphate (58 mg, 0.150 mmol), 3 Å molecular sieves (100 mg), 2,4,6-trimethylpyridine (26 μL, 0.200 mmol), and DCM (3.0674 mL) were added. An ElectraSyn vial cap equipped with an anode (graphite) and cathode (Ni) was inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolyzed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed and the electrode was rinsed with DCM (2 mL). The resulting mixture was washed with 1 M HCl (aq), water, dried on a phase separator, and concentrated in vacuo. The crude material was dissolved in a minimum amount of DCM and added to a large amount of EtO. The resulting precipitate was filtered to give the starting material, N,N,N-tributylbutan-1-aminium hexafluorophosphate. The filtrate was concentrated (dark green oil) and purified by silica gel flash chromatography using a gradient of 0% to 50% EtOAc / cyclohexane to give the title compound as a yellow oil (20 mg, 23% yield, 92% purity, t r = 1.02 min). LCMS (Method B): m / z found 336.2 [M-tBu+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 8.36 (d, J=4.6 Hz, 1H), 7.64 (d, J=3.9 Hz, 1H), 7.40 - 7.27 (m, 3H) ,7.22 - 7.13 (m,2H),4.72 (d,J=11.7 Hz,1H),3.80 (dd,J=11.9,2.1 Hz,1H),3.54 - 3.34 (m,1H),3.29 - 3.06 (m), 2H), 2.64 (ddd, J=13.4, 9.4, 5.5 Hz, 1H), 1.39 (d, J=11.7 Hz, 9H).

[0357] Step 2: Synthesis of tert-butyl 3-phenyl-3-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [ka] In a sealed tube, a solution of tert-butyl 3-(4-bromopyrazol-1-yl)-3-phenyl-pyrrolidine-1-carboxylate (20 mg, 0.0510 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (10 mg, 0.0510 mmol), and potassium carbonate (9.2 mg, 0.0663 mmol) in 1,4-dioxane (800 μL) and water (150 μL) was degassed with argon for 10 minutes. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.9 mg, 2.55 μmol) was added, and the mixture was degassed for 5 minutes and stirred at 100° C. for 22 hours. The mixture was poured into half-saturated aqueous NaHCO solution, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 5% to 50% EtOAc / heptane to give the title compound as a white foam (30 mg, 68% yield, t r = 1.11 min). LCMS (Method A): m / z found 474.4 [M+H] + ; 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 8.64 (s,1H),8.02 (d,J=2.3 Hz,1H),7.79 - 7.68 (m,2H),7.41 - 7.24 (m,5H),7.24 - 7.14 (m,2H),4.82 - 4.68 (m,1H),3.86 (dd,J=11.8,2.2 Hz,1H),3.51 (q,J=10.0 Hz,1H),3.28 - 3.12 (m, 3H), 2.75 - 2.60 (m, 1H), 1.39 (d, J=15.6 Hz, 9H).

[0358] Step 3: Synthesis of 1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole [ka] In a sealed tube under nitrogen, 4 M hydrogen chloride / dioxane (158 μL, 0.634 mmol) was added to a stirred solution of tert-butyl 3-phenyl-3-[4-[4-(trifluoromethoxy)phenyl]pyrazol-1-yl]pyrrolidine-1-carboxylate (30 mg, 0.0634 mmol) in 1,4-dioxane (300 μL) under nitrogen. The mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by reverse-phase chromatography using a gradient of 0% to 100% ACN + 0.1% AcOH / H2O + 0.1% AcOH. The desired fractions were combined and the organic solvent was evaporated. Saturated aqueous NaHCO3 was added until pH = 9, and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in Et2O, and 2 N HCl in Et2O was added. The suspension was stirred at room temperature for 16 hours and concentrated. The residue was triturated with pentane and filtered. The residue was washed with pentane and dried under reduced pressure at 45° C. for 16 hours to give the hydrochloride salt of the title compound as a white powder (9 mg, 34% yield, 98.6% purity, t r =1.96 min). LCMS (Method D): m / z found 374 [M+H] + ; 1 H-NMR (500 MHz,DMSO-d6) δ ppm 2.66 - 2.77 (m,1 H) 3.13 (td,J=11.49,6.60 Hz,1 H) 3.37 - 3.45 (m,1 H) 3.54 - 3.62 (m, 1 H) 3.77 (d, J=12.47 Hz, 1 H) 4.74 (dd, J=12.72, 1.47 Hz, 1 H) 7.23 (d, J=7.09 Hz, 2 H) 7.37 (dd, J=8.19, 6.48 Hz, 5 H) 7.74 (d, J=8.80 Hz, 2 H) 8.11 (s, 1 H) 8.64 (s, 1H) 9.17 - 9.81 (m, 2 H).

[0359] Example 38: 4-phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide (38) [ka] Step 1: Synthesis of 1-phenyl-N-(4-(trifluoromethoxy)phenyl)methanesulfonamide [ka] In a sealed tube under nitrogen at 5°C, phenylmethanesulfonyl chloride (98%, 500 mg, 2.57 mmol) was added to a stirred solution of 4-(trifluoromethoxy)aniline (382 μL, 2.83 mmol) and anhydrous pyridine (622 μL, 7.71 mmol) in anhydrous THF (7.3434 mL). The solution was stirred at 50°C for 20 h and diluted with a half-saturated aqueous solution of Na2CO3. The aqueous layer was extracted twice with DCM, filtered through a phase separator, and concentrated. The crude material was dissolved in diethyl ether and pentane was added. The resulting solid was filtered and washed with pentane to give the title compound as a beige solid (603 mg, 71% yield, 100% purity, t r =0.91 min). LCMS (Method A) 1 H-NMR (DMSO-d6, 500 MHz): δ (ppm) 10.05 (s, 1H), 7.56 - 7.02 (m, 9H), 4.51 (s, 2H).

[0360] Step 2: Synthesis of N-(4-methoxybenzyl)-1-phenyl-N-(4-(trifluoromethoxy)phenyl)methanesulfonamide [ka] To a stirred solution of 1-phenyl-N-[4-(trifluoromethoxy)phenyl]methanesulfonamide (99%, 603 mg, 1.80 mmol) and 1-(chloromethyl)-4-methoxy-benzene (0.27 mL, 1.98 mmol) in dry DMF (6 mL) at room temperature under nitrogen, potassium carbonate (374 mg, 2.70 mmol) was added. The reaction mixture was stirred at 60° C. overnight. Water and EtOAc were added to the mixture, the layers were separated, and the organic layer was washed three times with brine, concentrated under reduced pressure, and purified by silica gel flash chromatography using a gradient of 0% to 2% MeOH / DCM to give the title compound as a yellow oil (840.5 mg, 98% yield, 95% purity, t r = 1.02 min). LCMS (Method A) 1 H-NMR (DMSO-d6,400 MHz): δ (ppm) 7.49 - 7.35 (m,5H),7.34 - 7.24 (m,4H),7.15 - 7.09 (m,2H),6.86 - 6.76 (m, , 2H), 4.74 (s, 2H), 4.65 (s, 2H), 3.69 (s, 3H).

[0361] Step 3: Synthesis of 1-benzyl-N-(4-methoxybenzyl)-4-phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide [ka] To a stirred solution of N-[(4-methoxyphenyl)methyl]-1-phenyl-N-[4-(trifluoromethoxy)phenyl]methanesulfonamide (340 mg, 0.753 mmol) and benzyl bis(2-bromoethyl)amine (242 mg, 0.753 mmol) in anhydrous THF (7.5 mL) at −15° C. under nitrogen, 1 M NaHMDS (1.9 mL, 1.88 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours, then slowly warmed to room temperature and stirred overnight. Additional 1 M NaHMDS (1.9 mL, 1.88 mmol) and benzyl bis(2-bromoethyl)amine (242 mg, 0.753 mmol) were added at 0° C., and the reaction mixture was stirred at 0° C. for 4 hours, then warmed to room temperature. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed with brine, dried over aqueous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography using a gradient of 0% to 10% MeOH / DCM to give the title compound as an orange gum (271 mg, 52% yield, 88% purity, t r =0.81 min). LCMS (Method B): m / z found 611.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.74 - 7.67 (m, 2H), 7.45 (dd, J=8.3, 6.8 Hz, 2H), 7.32 - 7.20 (m, 8H),7.17 - 7.09 (m,2H),6.96 - 6.90 (m,2H),6.76 - 6.68 (m,2H),4.22 (s,2H),3.64 (s,3H),3.31 (s,2H),2.71 (s,2H) dd,J=21.0,12.4Hz,4H),2.27(t,J=12.4Hz,2H),1.84(t,J=11.7Hz,2H).

[0362] Step 4: Synthesis of N-(4-methoxybenzyl)-4-phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide [ka] To a stirred solution of 1-benzyl-N-[(4-methoxyphenyl)methyl]-4-phenyl-N-[4-(trifluoromethoxy)phenyl]piperidine-4-sulfonamide (88%, 241 mg, 0.347 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.12 mL, 0.695 mmol) in DCM (2.5 mL) at 25° C. under nitrogen, 1-chloroethyl carbonochloridate (95%, 0.079 mL, 0.695 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (2.5 mL), and the reaction mixture was stirred at 65° C. for 16 hours. The reaction mixture was cooled to room temperature and quenched with water. EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of 1% to 10% MeOH (0.7N NH) / dichloromethane to give the title compound as a yellow powder (89 mg, 49% yield, 100% purity, t r =0.74 min). LCMS (Method A): m / z found 521.4 [M+H] + ; 1 H-NMR (DMSO-d6, 400 MHz): δ (ppm) 7.75 (d, J=7.4 Hz, 2H), 7.51 (dd, J=8.4, 6.5 Hz, 2H), 7.45 (t, J= 7.2 Hz, 1H), 7.31 (d, J=9.0 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.8 Hz) ,2H),4.20 (s, 2H),3.64 (s, 3H),3.27 - 3.19 (m, 2H),2.81 (d, J=13.6 Hz, 2H), 2.56 (s, 1H), 2.40 (t, J=13.0Hz,2H),1.02(dd,J=6.1,2.9Hz,1H).

[0363] Step 5: Synthesis of 4-phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide [ka] To a stirred solution of N-[(4-methoxyphenyl)methyl]-4-phenyl-N-[4-(trifluoromethoxy)phenyl]piperidine-4-sulfonamide (100%, 89 mg, 0.171 mmol) in DCM (1 mL) at 25 °C was added 2,2,2-trifluoroacetic acid (0.65 mL, 8.55 mmol) dropwise. The reaction mixture was stirred at 25 °C for 1 h. The reaction was basified with saturated aqueous Na2CO3, and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography using a gradient of 1% to 15% MeOH (0.7 M in NH3) / DCM to give the product. The product was dissolved in a minimal amount of DCM, and 2 M HCl in ether was added dropwise. Et2O was added and the precipitate formed was filtered, washed with Et2O and dried under vacuum at 50 °C to give the hydrochloride salt of the title compound as a white powder (21 mg, 28% yield, 100% purity, t r =1.30 min). LCMS (Method D): m / z found 401.2 [M-HCl+H] + ; 1 H-NMR (600 MHz,DMSO-d6) δ ppm 2.50 - 2.56 (m,4 H) 2.86 (br d,J=12.18 Hz,2 H) 3.32 - 3.40 (m,2 H) 6.92 (d, J=8.12Hz,2H)7.06(d,J=8.28Hz,2H)7.28-7.32(m,3H)7.48-7.52(m,2H)8.75(brs,2H)10.14(brs, 1H).

[0364] Example 39: Cell viability assay LNCaP cell line The LNCaP cell line was used for cell viability assays. LNCaP cells were plated in 96-well plates at a density of 5,000 cells per well. 24 h after plating, cells were treated with increasing doses of compounds (e.g., comp...

Claims

1. A compound of formula (I) or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof: 【Chemical 1】 (In the formula, Ar is C ６ ~C １０ Aryl or C ２ ~C １０ Heteroaryl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Hydroxyalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C ２ ~C １０ Heteroaryl, C ６ ~C １０ Aryl, C ６ ~C １０ Aryloxy, halogen, OH, N(R ａ ) (R ｂ ), CN, NO ２ , -C(=O)R ａ , -C(=O)OR ａ , and —C(═O)N(R ａ ) (R ｂ and optionally substituted with at least one substituent selected from the group consisting of: Each C in Ar ６ ~C １０ Aryl, C ２ ~C １０ Heteroaryl, or C ６ ~C １０ The aryloxy substituents are independently selected from the group consisting of C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, F, Cl, Br, I, OH, CN, NO ２ , -C(=O)OR ａ , and —C(═O)N(R ａ ) (R ｂ and optionally substituted with at least one substituent selected from the group consisting of: The two adjacent substituents of Ar combine to form a C ６ ~C １０ Aryl or C ２ ~C １０ A 5- to 8-membered ring fused to the heteroaryl may be provided; R １ but, 【Chemistry 2】 is selected from the group consisting of R ２ optionally substituted phenyl and optionally substituted C ２ ~C １０ heteroaryl; R ２ wherein each optional substituent is halogen, OH, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ alkyl, R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ３ｅ , R ３ｆ , R ３ｇ , and R ３ｈ is, if present, independently at each occurrence H; or R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ３ｅ , R ３ｆ , R ３ｇ , and R ３ｈ Two geminal substituents selected from, taken together with the carbon atoms to which they are attached, form an optionally substituted C ３ ~C ８ can form a cycloalkyl, R ４ is H, R Ａ However, H and C １ ~C ６ is selected from the group consisting of alkyl, R ａ Each occurrence of １ ~C ６ Alkyl, benzyl, and C ６ ~C １０ aryl; R ｂ each occurrence of is independently selected from H, optionally substituted C １ ~C ６ is selected from the group consisting of alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl; R ｂ The C in １ ~C ６ alkyl, benzyl, phenyl, or naphthyl are independently C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, halogen, OH, CN, NO ２ , C(=O)OR ａ , and C(═O)N(R ａ ) (R ａ and optionally substituted with at least one selected from the group consisting of: The compound of formula (I) is N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimidamide, N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-isopropoxybenzenesulfonamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-isopropoxypyridine-3-sulfonamide, N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide, 3-amino-N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, 3-amino-N-(3-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(3,4-dichlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-phenylpiperidin-4-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide, N-(4-(5-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide, N-(4-(5-chlorothiazol-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-fluorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide, N-(4-(3,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(2,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(2,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(5-chlorothiophen-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chloro-2-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethyl)benzenesulfonamide, 3-amino-N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, and N-(4-(4-(difluoromethyl)phenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (not selected from the group consisting of:

2. R Ａ The compound of claim 1 , wherein is H.

3. R １ but, 【Chemistry 3】 3. The compound according to claim 1 or 2, wherein

4. (a) R ２ But halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C ２ -C ６ 4-fluorophenyl further substituted with at least one additional substituent selected from the group consisting of alkyl; or (b) R ２ F, Br, OH, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ 4. The compound according to claim 1, wherein one of the following applies: 3-fluorophenyl further substituted with at least one additional substituent selected from the group consisting of alkyl.

5. R ２ The compound according to any one of claims 1 to 4, wherein is 3,4-difluorophenyl.

6. 6. The compound of any one of claims 1 to 5, wherein Ar is optionally substituted phenyl.

7. Ar is a halogen, NH ２ , and C １ ~C ３ 7. The compound of any one of claims 1 to 6, which is 4-methoxyphenyl optionally further substituted with at least one additional substituent selected from the group consisting of alkoxy.

8. N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide, and (R)—N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide 8. The compound of any one of claims 1 to 7, selected from the group consisting of:

9. R １ but, 【Chemistry 4】 3. The compound according to claim 1 or 2, wherein

10. Ar is optionally substituted phenyl or optionally substituted pyridyl, and the optional substituents on Ar are C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, and —NH(C １ ~C ６ 10. The compound of claim 9, wherein at least one substituent is selected from the group consisting of: alkyl.

11. 11. The compound of claim 9 or 10, wherein Ar is phenyl substituted with at least one substituent selected from the group consisting of trifluoromethoxy and methylamino.

12. Ar is, 【Chemistry 5】 12. The compound of claim 11, wherein:

13. (a) R ２ is 3,5-disubstituted phenyl, and each substituent is independently selected from halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ being selected from the group consisting of alkyl; (b) R ２ But, Br, I, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ 4-chlorophenyl further substituted with at least one substituent selected from the group consisting of alkyl; (c) R ２ But halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ 3-methylphenyl further substituted with at least one substituent selected from the group consisting of alkyl; (d) R ２ But halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ 3-pyridyl optionally further substituted with at least one substituent selected from the group consisting of alkyl; and (e) R ２ But halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ and 4-pyridyl optionally further substituted with at least one substituent selected from the group consisting of alkyl.

14. In the formula, R ２ but, 【Chemistry 6】 14. The compound of any one of claims 9 to 13, selected from the group consisting of:

15. Ar is, 【Chemistry 7】 12. The compound of claim 11, wherein:

16. (a) R ２ is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl, wherein the pyridyl is selected from the group consisting of halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ optionally substituted with at least one substituent selected from the group consisting of alkyl; (b) R ２ But halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ 3-fluorophenyl optionally substituted with at least one substituent selected from the group consisting of alkyl; or (c) R ２ But halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ 4-fluorophenyl further substituted with at least one substituent selected from the group consisting of alkyl.

17. R ２ but, 【Chemistry 8】 17. The compound of any one of claims 9 to 11, 15 and 16, selected from the group consisting of:

18. The compound of any one of claims 9 to 11, wherein Ar is methylamino substituted 4-trifluoromethoxyphenyl.

19. Ar is, 【Chemistry 9】 19. The compound of any one of claims 9 to 11 and 18, wherein:

20. R ２ But halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ 20. The compound of any one of claims 9 to 11, 18 and 19, which is 4-chlorophenyl optionally substituted with at least one substituent selected from the group consisting of alkyl.

21. R ２ but, 【Chemistry 10】 21. The compound of any one of claims 9 to 11 and 18 to 20, wherein

22. below: N-(4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(4-chloro-3-methylphenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide, N-(4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide, N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(methylamino)-4-(trifluoromethoxy)benzenesulfonamide, and N-(4-(2,5-dichloropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide 22. The compound of any one of claims 9 to 21, selected from the group consisting of:

23. R １ but, 【Chemistry 11】 and R ３ , R ３’ , R ４ , R ４’ , R ５ , R ５’ , R ６ , and R ６’ and two geminal substituents selected from the group consisting of: ３ ~C ８ 3. The compound of claim 1 or 2, which forms a cycloalkyl.

24. R １ but, 【Chemistry 12】 24. The compound of any one of claims 1 to 2 and 23, wherein

25. R ２ But halogen, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ６ 25. The compound of any one of claims 1, 2, 23 and 24, which is phenyl optionally substituted with at least one substituent selected from the group consisting of alkyl.

26. R ２ 26. The compound of any one of claims 1, 2 and 23-25, wherein is phenyl.

27. 27. The compound of any one of claims 1, 2, and 23-26, wherein Ar is optionally substituted phenyl.

28. Ar is, 【Chemistry 13】 28. The compound of any one of claims 1, 2 and 23 to 27, wherein

29. below: N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide, and (R)—N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide 30. The compound of any one of claims 1, 2 and 23 to 28, selected from the group consisting of:

30. A compound of formula (II) or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof: 【Chemistry 14】 (In the formula, Ar is C ６ ~C １０ Aryl or C ２ ~C １０ Heteroaryl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Hydroxyalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C ２ ~C １０ Heteroaryl, C ６ ~C １０ Aryl, C ６ ~C １０ Aryloxy, halogen, OH, N(R ａ ) (R ｂ ), CN, NO ２ , -C(=O)R ａ , -C(=O)OR ａ , and —C(═O)N(R ａ ) (R ａ and optionally substituted with at least one substituent selected from the group consisting of: Each C in Ar ６ ~C １０ Aryl, C ２ ~C １０ Heteroaryl, or C ６ ~C １０ The aryloxy substituents are independently selected from the group consisting of C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, F, Cl, Br, I, OH, CN, NO ２ , -C(=O)OR ａ , and —C(═O)N(R ａ ) (R ａ and optionally substituted with at least one substituent selected from the group consisting of: The two adjacent substituents of Ar combine to form a C ６ ~C １０ Aryl or C ２ ~C １０ A 5- to 8-membered ring fused to the heteroaryl may be provided; L is *-N(R Ｂ ) S(=O) ２ -, *-C(=O)N(R Ｂ )- and optionally substituted C ２ ~C １０ heteroarylene; R ５ but, 【Chemistry 15】 is selected from the group consisting of R ６ is optionally substituted C ６ ~C １０ Aryl and optionally substituted C ２ ~C １０ heteroaryl; R ６ wherein each optional substituent in １ ~C ６ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, —C(═O)OR ａ , -S(=O) ２ (C ６ ~C １０ aryl), and —S(═O) ２ (C ２ ~C １０ heteroaryl), R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are, when present, each independently H, C １ ~C ６ Alkyl, hydroxyl, C １ ~C ４ Haloalkyl, optionally substituted C ３ ~C ８ Cycloalkyl, optionally substituted C ２ ~C ６ selected from the group consisting of heterocyclyl, optionally substituted phenyl, and optionally substituted phenoxy; Each optional substituent is C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, halogen, OH, C(=O)OR ａ , and C(═O)N(R ａ ) (R ａ and at least one selected from the group consisting of R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ Two geminal substituents selected from, taken together with the carbon atoms to which they are attached, form an optionally substituted C ３ ~C ８ Cycloalkyl and optionally substituted C ２ ~C １０ heterocyclyl, R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ Two adjacent substituents selected from, taken together with the carbon atoms to which they are attached, form an optionally substituted C ３ ~C ８ Cycloalkyl, optionally substituted C ２ ~C １０ may form a moiety selected from the group consisting of heterocyclyl, and optionally substituted phenyl, R are separated by 2 to 5 carbon atoms ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ Two substituents selected from, taken together with the carbon atom to which they are attached, form an optionally substituted C ４ ~C ７ Cycloalkyl and optionally substituted C ４ ~C ８ heterocyclyl, R ８ But H, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, optionally substituted phenyl, optionally substituted benzyl, —C(═O)OR ｂ , -C(=O)R ｂ , and -S(=O) ２ - optionally substituted phenyl, Phenyl, benzyl, or —S(═O) ２ -each optional substituent on phenyl is independently F, Cl, Br, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, hydroxyl, and —NH—C(═O)R ａ At least one selected from the group consisting of: R ９ is optionally substituted C ６ ~C １０ Aryl, and optionally substituted C ２ ~C １０ heteroaryl; R ９ wherein each optional substituent in １ ~C ６ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, —C(═O)OR ａ , -S(=O) ２ (C ６ ~C １０ aryl), and —S(═O) ２ (C ２ ~C １０ heteroaryl), R １０ is -(optionally substituted C １ ~C ６ alkyl) (optionally substituted C ２ ~C １２ heterocycloalkyl), and optionally substituted C １ ~C ６ aminoalkyl; R １０ wherein each optional substituent in １ ~C ６ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, —C(═O)OR ａ , -S(=O) ２ (C ６ ~C １０ aryl), and —S(═O) ２ (C ２ ~C １０ heteroaryl), R １１ is H, R Ｂ is H, R ａ Each occurrence of １ ~C ６ Alkyl, benzyl, and C ６ ~C １０ aryl; R ｂ each occurrence of is independently selected from H, optionally substituted C １ ~C ６ is selected from the group consisting of alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl; R ｂ The C in １ ~C ６ alkyl, benzyl, phenyl, or naphthyl are independently C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, halogen, OH, CN, NO ２ , C(=O)OR ａ , and C(═O)N(R ａ ) (R ａ ) optionally substituted with at least one selected from the group consisting of:

31. 31. The compound of claim 30, selected from the group consisting of: 【Chemistry 16】 (In the formula, R １２ａ , R １２ｂ , and R １２ｃ are present, each independently, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, halogen, OH, C(═O)ORa, and C(═O)N(R ａ ) (R ａ ) selected from the group consisting of:

32. (a) R １２ａ , R １２ｂ , and R １２ｃ is H, if present; and (b) R １２ａ , R １２ｂ , and R １２ｃ and two of, when present, are H.

33. 33. The compound of any one of claims 30 to 32, wherein Ar is optionally substituted phenyl.

34. Ar is, 【Chemistry 17】 34. The compound of any one of claims 30 to 33, selected from the group consisting of:

35. (a) R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ is H, when present; (b) R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ and at least two of, when present, are H; (c) R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are H, when present; (d) R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are H, when present; (e) R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are H, when present; (f) R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are H, when present; (g) R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ are H, if present; and (h) R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , and R ７ｈ and each, when present, is H.

36. R ６ 36. The compound of any one of claims 30 to 35, wherein is phenyl optionally substituted with at least one halogen.

37. R ６ 37. The compound of any one of claims 30 to 36, wherein is phenyl substituted with two halogens.

38. R ６ but, 【Chemistry 18】 38. The compound of any one of claims 30 to 37, selected from the group consisting of:

39. R ９ 35. The compound of any one of claims 30 to 34, wherein is phenyl optionally substituted with at least one halogen.

40. R ９ 40. The compound of any one of claims 30 to 34, and 39, wherein is phenyl substituted with two halogens.

41. R ９ but, 【Chemistry 19】 41. The compound of any one of claims 30 to 34, 39 and 40, selected from the group consisting of:

42. R １０ But -CH ２ N (optionally substituted C １ ~C ６ alkyl) ２ 42. The compound of any one of claims 30 to 34 and 39 to 41, wherein

43. R １０ But -CH ２ NMe ２ 43. The compound of any one of claims 30 to 34 and 39 to 42, wherein

44. below: N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide, (S)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide, (R)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide, N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide, (S)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide, (R)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide, N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide, (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide, (R)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide, 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine, (S)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine, (R)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine, 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine, (S)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine, (R)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine, 1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole, (S)-1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole, (R)-1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole, 1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole, (S)-1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole, (R)-1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole, and 4-phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide 44. The compound of any one of claims 30 to 43, selected from the group consisting of:

45. A compound of formula (III) or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof: 【Chemistry 20】 (In the formula, Ar is C ６ ~C １０ Aryl or C ２ ~C １０ Heteroaryl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Hydroxyalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C ２ ~C １０ Heteroaryl, C ６ ~C １０ Aryl, C ６ ~C １０ Aryloxy, halogen, OH, N(R ａ ) (R ｂ ), CN, NO ２ , -C(=O)R ａ , -C(=O)OR ａ , and —C(═O)N(R ａ ) (R ｂ and optionally substituted with at least one substituent selected from the group consisting of: Each C in Ar ６ ~C １０ Aryl, C ２ ~C １０ Heteroaryl, or C ６ ~C １０ The aryloxy substituents are independently selected from the group consisting of C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, F, Cl, Br, I, OH, CN, NO ２ , -C(=O)OR ａ , and —C(═O)N(R ａ ) (R ｂ and optionally substituted with at least one substituent selected from the group consisting of: The two adjacent substituents of Ar combine to form a C ６ ~C １０ Aryl or C ２ ~C １０ A 5- to 8-membered ring fused to the heteroaryl may be provided; R １３ but, 【Chemical 21】 is selected from the group consisting of R １４ａ , R １４ｂ , R １４ｃ , and R １４ｄ However, each independently, C ６ ~C １０ Aryl and optionally substituted C ２ ~C １０ heteroaryl; R １４ａ , R １４ｂ , R １４ｃ , and R １４ｄ wherein each optional substituent in １ ~C ６ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, and —C(═O)OR ａ At least one selected from the group consisting of: R １５ａ , R １５ｂ , R １５ｃ , R １５ｄ , R １５ｅ , R １５ｆ , R １５ｇ , R １５ｈ , R １５ｉ are each independently H, halogen, C １ ~C ６ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, C １ ~C ３ Haloalkyl, —C(═O)OR ａ is selected from the group consisting of R １６ is H, R １７ａ , R １７ｂ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｇ , R １７ｈ , R １７ｉ , R １７ｊ , R １７ｋ , and R １７ｌ are, when present, each independently H, halogen, and C ２ ~C ８ heterocycloalkyl; R １８ａ , R １８ｂ , R １８ｃ , and R １８ｄ However, H and C １ ~C ６ independently selected from the group consisting of alkyl, R １９ is optionally substituted cyclohexyl and —CH ２ NMe ２ is selected from the group consisting of X is -NR １６ - and -C(R １７ｋ ) (R １７ｌ )- is selected from the group consisting of R Ｃ is H, R ａ Each occurrence of １ ~C ６ Alkyl, benzyl, and C ６ ~C １０ aryl; R ｂ each occurrence of is independently selected from H, optionally substituted C １ ~C ６ is selected from the group consisting of alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl; R ｂ C in １ ~C ６ alkyl, benzyl, phenyl, or naphthyl are independently C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, halogen, OH, CN, NO ２ , C(=O)OR ａ , and C(═O)N(R ａ ) (R ａ and optionally substituted with at least one selected from the group consisting of: R １３ but, 【Chemical 22】 If , then at least one of the following applies: (a) R １７ａ , R １７ｂ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｇ , R １７ｈ , R １７ｉ , R １７ｊ , R １７ｋ , and R １７ｌ when present, is halogen, said halogen optionally being F; (b) R １４ｂ is phenyl substituted with at least two fluorine atoms; (c) R １４ｂ is 4-chlorophenyl, Ar is phenyl optionally substituted with at least two substituents, and C １ ~C ６ pyridyl optionally substituted with alkoxy; (d) R １４ｂ is 4-chlorophenyl and Ar is not selected from the group consisting of 4-trifluoromethoxy and 6-trifluoromethoxy-3-pyridyl; R １３ but, 【Chemical 23】 If , then at least one of the following applies: (a) R １４ｃ is phenyl, and R １８ａ , R １８ｂ , R １８ｃ , and R １８ｄ one, three, or four selected from ３ and (b) R １４ｃ is phenyl and Ar is optionally substituted pyridyl; R １３ but, 【Chemistry 24】 and R １９ But CH ２ NMe ２ then the compound of formula (III) is N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide; R １３ but, 【Chemistry 25】 and R １９ When is optionally substituted cyclohexyl, at least one of the following applies: (a) Ar is optionally substituted pyridyl; (b) Ar is at least one C １ ~C ６ substituted with an alkoxy substituent).

46. 46. The compound of claim 45, wherein Ar is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridyl.

47. Ar is C １ ~C ３ Haloalkoxy and N(R ａ ) (R ｂ 47. The compound of claim 45 or 46, wherein the compound is phenyl optionally substituted with at least one substituent selected from the group consisting of:

48. Ar is trifluoromethoxy, and NH ２ 48. The compound of any one of claims 45 to 47, which is phenyl optionally substituted with at least one substituent selected from the group consisting of:

49. Ar is, 【Chemical 26】 49. The compound of any one of claims 45 to 48, selected from the group consisting of:

50. Ar is at least one C １ ~C ６ 47. The compound of claim 45 or 46, which is pyridyl optionally substituted with an alkoxy substituent.

51. Ar is at least one C １ ~C ６ 51. The compound of any one of claims 45, 46 and 50, which is a 3-pyridyl substituted with an alkoxy substituent.

52. Ar is, 【Chemical 27】 52. The compound of any one of claims 45, 46, 50 and 51, wherein

53. R １３ but, 【Chemical 28】 53. The compound of any one of claims 45 to 52, wherein:

54. R １３ but, 【Chemical Formula 29】 54. The compound of any one of claims 45 to 53, selected from the group consisting of:

55. R １４ａ 55. The compound of any one of claims 45 to 54, wherein is selected from the group consisting of phenyl optionally substituted with at least one halogen, and pyridyl substituted with at least one halogen.

56. R １４ａ but, 【Chemistry 30】 56. The compound of any one of claims 45 to 55, selected from the group consisting of:

57. R １３ but, 【Chemical 31】 47. The compound of claim 45 or 46, wherein:

58. Ar is, 【Chemical 32】 58. The compound of any one of claims 45, 46 and 57, wherein:

59. R １４ｄ 60. The compound of any one of claims 45, 46, 57 and 58, wherein is cyclohexyl.

60. R １９ but, 【Chemical 33】 60. The compound of any one of claims 45, 46 and 57-59, wherein

61. R １３ but, 【Chemical 34】 47. The compound of claim 45 or 46, wherein:

62. R １４ｂ but, 【Chemistry 35】 62. The compound of claim 61, selected from the group consisting of:

63. Ar is, 【Chemical 36】 63. The compound of claim 61 or 62, selected from the group consisting of:

64. R １３ but, 【Chemical 37】 47. The compound of claim 45 or 46, wherein:

65. R １７ｅ and R １７ｆ 65. The compound of claim 64, wherein at least one selected from the group consisting of is halogen.

66. R １３ but, 【Chemical Formula 38】 66. The compound of any one of claims 45, 46, 64 and 65, wherein

67. R １４ｂ 67. The compound of any one of claims 45, 46 and 64-66, wherein is phenyl substituted with at least one halogen.

68. R １４ｂ but, 【Chemical 39】 68. The compound of any one of claims 45, 46 and 64 to 67, wherein

69. Ar is at least one C １ ~C ６ 69. The compound of any one of claims 45, 46 and 64-68, which is phenyl substituted with haloalkoxy.

70. Ar is, 【Chemistry 40】 70. The compound of any one of claims 45, 46 and 64 to 69, wherein

71. R １３ but, 【Chemistry 41】 47. The compound of claim 45 or 46, wherein:

72. (a) R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｉ , and R １７ｊ at least one selected from the group consisting of: (b) R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｉ , and R １７ｊ at least two selected from the group consisting of: (c) R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｉ , and R １７ｊ at least three selected from the group consisting of: (d) R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｉ , and R １７ｊ at least four selected from the group consisting of: (e) R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｉ , and R １７ｊ at least five selected from the group consisting of: (f) R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｉ , and R １７ｊ at least six selected from the group consisting of: (g) R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｉ , and R １７ｊ at least seven selected from the group consisting of are H; and (h) R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ , R １７ｅ , R １７ｆ , R １７ｉ , and R １７ｊ and each of the following applies:

73. R １７ｉ and R １７ｊ are each independently H, and R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ , R １７ｅ , R １７ｆ At least one selected from the group consisting of ２ ~C ８ 73. The compound of claim 71 or 72, which is heterocycloalkyl.

74. Said C ２ ~C ８ Heterocycloalkyl is 【Chemistry 42】 74. The compound of claim 73, wherein:

75. Ar is, 【Chemistry 43】 75. The compound of any one of claims 71 to 74, wherein:

76. R １３ but, 【Chemical 44】 47. The compound of claim 45 or 46, wherein:

77. R １８ａ , R １８ｂ , R １８ｃ , and R １８ｄ Two selected from the group consisting of C １ ~C ６ 77. The compound of any one of claims 45, 46 and 76, which is alkyl.

78. R １３ but, 【Chemistry 45】 80. The compound of any one of claims 45, 46, 76 and 77, wherein:

79. Ar is at least one C １ ~C ６ 79. The compound of claim 78, which is pyridyl substituted with alkoxy.

80. Ar is, 【Chemistry 46】 80. The compound of claim 78 or 79, wherein:

81. below: N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide, (R)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide, (S)—N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide, 6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide, (R)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide, (S)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide, N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, (R)—N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, (S)—N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, 3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)-3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)-3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, (R)—N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, (S)—N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide, N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide, (R)—N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide, (S)—N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide, N-(1-(4-fluorophenyl)-2-(3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((R)-1-(4-fluorophenyl)-2-((R)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((R)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((S)-1-(4-fluorophenyl)-2-((R)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-((S)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(2-([1,3'-biazetidin]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (S)—N-(2-([1,3′-biazetidin]-1′-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, (R)—N-(2-([1,3′-biazetidin]-1′-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide, N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide, (R)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide, (S)—N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide, N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide, (R)—N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide, (S)—N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide, N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide, (R)—N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide, and (S)—N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide, 81. The compound of any one of claims 45 to 80, selected from the group consisting of:

82. 82. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 81 and at least one pharmaceutically acceptable carrier.

83. A method for treating, preventing, and / or ameliorating a protein phosphatase 2A (PP2A)-associated disease in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in any one of claims 1 to 81, or a pharmaceutical composition described in claim 82.

84. The method of claim 83, wherein the PP2A-associated disease is at least one selected from the group consisting of cancer, diabetes, autoimmune diseases, solid organ transplant rejection, graft-versus-host disease, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative diseases, and cardiac hypertrophy.

85. 85. The method of claim 83 or 84, wherein the subject is a mammal.

86. 86. The method of claim 85, wherein the mammal is a human.

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