Substituted Cyclic Modulators of Protein Phosphatase 2A (PP2A) and Methods Using the Same

Abstract

The present disclosure relates, in part, to chemical modulators of protein phosphatase 2A (PP2A).The compounds of the present disclosure are useful in treating, preventing, and / or ameliorating 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.

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 / 146,789, filed February 8, 2021, U.S. Provisional Patent Application No. 63 / 191,405, filed May 21, 2021, and U.S. Provisional Patent Application No. 63 / 273,405, filed October 29, 2021, all of which are incorporated by reference herein in their entirety. [Background technology]

[0002] Background of the Invention Protein phosphatase 2A (PP2A) is one of four major serine-threonine phosphatases and has been implicated in the negative regulation 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 and conserved phosphatase with broad substrate specificity and diverse cellular functions.

[0003] The function of PP2A can be implicated 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-associated pathologies and / or indications. The present disclosure addresses this need. Summary of the Invention

[0005] The present disclosure provides certain compounds of formula (I), selected from the group consisting of (Ia), (Ib), (Ic), (Id), (Ie), and (If), or salts, solvates, enantiomers, diastereoisomers, isotopologues, or tautomers thereof, or any mixture thereof, wherein the substituents in (Ia), (Ib), (Ic), (Id), (Ie), and (If) are defined elsewhere herein. TIFF2024508687000001.tif36128

[0006] The present disclosure further provides pharmaceutical compositions comprising at least one compound of the present disclosure. In certain embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0007] The present disclosure further provides a method for treating, preventing, and / or ameliorating a PP2A-related disease in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of the present disclosure and / or at least one pharmaceutical composition of the present disclosure. In certain embodiments, the PP2A-related disease is 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. DETAILED DESCRIPTION OF THE INVENTION

[0008] Detailed Description of the Invention Reference will now be made in detail to certain aspects 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 illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0009] Throughout this specification, values ​​expressed in range format should be interpreted flexibly to include not only the numerical values ​​explicitly stated 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 stated. For example, a range such as "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 phrase "about X to Y" has the same meaning as "about X to about Y" unless otherwise indicated. Similarly, the phrase "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise indicated.

[0010] As used herein, 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 phrases "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." Furthermore, any expressions or terms employed herein and not specifically defined should be understood to be for purposes of description only, not limitation. Any use of section headings is intended to aid in the reading of the document and should not be construed as limiting; information associated with a section heading may be found within or outside that particular section. All publications, patents, and patent documents mentioned herein are incorporated by reference in their entirety, as if individually incorporated by reference.

[0011] In the methods described herein, acts may be performed in any order unless a temporal or operational order is explicitly recited. Furthermore, specified acts may be performed simultaneously unless the claim language explicitly recites them as being performed separately. 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 would be encompassed within the process language of the claim.

[0012] definition The term "acyl" refers to 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.

[0013] 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-).

[0014] 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 biological site of 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, as discussed, for example, 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.

[0015] The terms "alkoxy" or "alkoxyl," as used herein, refer to groups of from 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, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, sec-butoxy, isobutoxy, tert-butoxy, cyclohexyloxy, and cycloheptyloxy.

[0016] In one embodiment, the term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. In one embodiment, the term "C2-C6 alkenyl" refers to an alkenyl moiety having from 2 to 6 carbon atoms.

[0017] 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.

[0018] 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 an "alkenylene" group.

[0019] In one embodiment, the term "alkyl" refers to linear, branched, or cyclic hydrocarbon structures and combinations thereof, and may be saturated or unsaturated (e.g., partially unsaturated, fully unsaturated). Thus, the term "alkyl" includes subclasses such as alkenyl, alkynyl, cycloalkyl, etc. Alkyl groups may be optionally substituted as defined herein.

[0020] 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, while branched-chain alkyl groups include isopropyl, tert-butyl, isobutyl, sec-butyl, and neopentyl. In one embodiment, the alkyl is a saturated alkyl having 2 to 6 carbon atoms. In one embodiment, a straight-chain or branched-chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C1-C6 for straight chain, C3-C6 for branched chain). The term (C1-C6) alkyl may be understood to refer to an alkyl group containing 1 to 6 carbon atoms.

[0021] The term "alkylamino" means an alkyl group attached to the parent molecular moiety through an amino group. The alkylamino group can be mono- or di-alkylated to form, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like groups.

[0022] The terms "alkylcarbonyl" and "alkoxycarbonyl" mean -C(=O)alkyl or -C(=O)alkoxy, respectively.

[0023] The term "alkylthio" means an alkyl thioether (alkyl-S-) group, where the term alkyl is as defined for an alkyl group and the sulfur can be oxidized with one or two oxygens. Examples of alkyl thioether groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0024] In one embodiment, the term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. In one embodiment, the term "C2-C6 alkynyl" refers to an alkynyl moiety having from 2 to 6 carbon atoms.

[0025] Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C=CH) and 2-propynyl (propargyl, -CH2-C=CH).

[0026] The term "alkylene" means a straight or branched chain saturated hydrocarbon bonded at two or more positions, such as methylene (-CH-). Unless otherwise noted, the term "alkyl" can include "alkylene" groups.

[0027] 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 alkyl groups.

[0028] The term "amino" means --NH.sub.2.

[0029] The terms "aryl" and "heteroaryl," as used herein, refer to (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring 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 heterocyclic rings 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 necessarily all.

[0030] 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 an arylalkyl or heteroarylalkyl is an alkyl group containing 1 to 6 carbon atoms. Examples include, for example, pyridinylmethyl, pyrimidinylethyl, and the like.

[0031] The term "azido" as used herein means -N3.

[0032] 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 from either the nitrogen or the acid terminus, and may be substituted as defined herein.

[0033] As used herein, the term "carbonyl" refers to the group -C(=O)- and includes formyl (-C(=O)H).

[0034] The term "carboxyl" or "carboxy" as used herein refers to --C(.dbd.O)OH, or the corresponding "carboxylate" anion as in carboxylic acid salts.

[0035] The term "co-administered" refers to simultaneous administration in the same formulation or in two different formulations via the same or different routes, or sequential administration by the same or different routes. By "sequential" administration, it is meant that there is a time difference of seconds, minutes, hours, or days between the administration of two or more separate compounds.

[0036] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in this disclosure. Such administration includes the simultaneous administration of these therapeutic agents in a substantially simultaneous manner, such as in a single formulation (e.g., a capsule or injection) in which the ratio of active ingredients is constant, or in multiple separate dosage forms for each active ingredient. Furthermore, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0037] The term "comprising" is used herein to mean including the feature or act that follows it without excluding the presence of one or more further features or acts.

[0038] The terms "cycloalkyl" or alternatively "carbocycle," alone or in combination, mean a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, wherein each cyclic moiety can contain 3 to 12 carbon atom ring members, which can be an optionally substituted benzo-fused ring system as defined herein. In one embodiment, a cycloalkyl contains 3 to 7 carbon atoms or 3 to 6 carbon atoms.

[0039] Examples of saturated monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl), methylcyclopentyl, dimethylcyclopentyl, and methylcyclohexyl.

[0040] Examples of saturated monocyclic cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, methylcyclopropenyl, dimethylcyclopropenyl, methylcyclobutenyl, dimethylcyclobutenyl, methylcyclopentenyl, dimethylcyclopentenyl, and methylcyclohexenyl.

[0041] 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, and polycyclic (multi-center), saturated or partially unsaturated types, including spirocyclic fused systems. Examples of isomers of the bicyclic and tricyclic types are bicyclo[1,1,1]pentane, norbornane, camphor, adamantane, bicyclo[3,2,1]octane, and [4,4.1]-bicyclononane.

[0042] As used herein, the term "cyano," "nitrile," or "carbonitrile" refers to --CN.

[0043] As used herein, the term "diastereomers" refers to stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0044] As used herein, the term "disease" is intended to be generally synonymous with, and is used interchangeably with, the terms "disorder" and "condition" (e.g., pathology), in that both reflect an abnormal condition of the human or animal body or one of its parts that impairs normal function, is typically manifested by characteristic signs and symptoms, and causes a decrease in the length or quality of life of the human or animal.

[0045] 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, for example, to alleviate to some extent one or more symptoms of the disease or condition being treated.In certain cases, the result is the reduction and / or alleviation of the signs, symptoms, or causes of disease, or any other desired change in a biological system.In specific cases, the result is the reduction of growth, death, or induction of apoptosis of at least one abnormally proliferating cell, such as a cancer cell.In certain cases, the "effective amount" for therapeutic use is the amount of a composition comprising a compound described herein that is required to cause a clinically significant reduction in disease.The appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0046] As used herein, the term "ester," "carboxylate," "carboxylic acid ester," or "oxycarbonyl" refers to -C(=O)Oalkyl, where alkyl is an ester substituent as defined for alkyl above. Examples of ester groups include, but are not limited to, -C(=O)OCH, -C(=O)OCHCH, -C(=O)OC(CH), and -C(=O)OPh.

[0047] The term "halo" or "halogen," as used herein, alone or in combination, means fluorine, chlorine, bromine, or iodine. In one embodiment, halo can be fluorine or chlorine.

[0048] The term "haloalkoxy" means a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0049] The term "haloalkyl" as used herein refers to an alkyl radical having the meaning defined above in which one or more hydrogens have been replaced with halogen. In one embodiment, 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-).

[0050] 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 be oxidized, and the nitrogen heteroatom may be quaternized. In one embodiment, the heterocycle is non-aromatic. In a further embodiment, the heterocycle is aromatic.

[0051] 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 heterocycles in which the heterocycle is aromatic. An oxygen heterocycle is a heterocycle containing at least one oxygen atom in the ring and may contain additional oxygen atoms or other heteroatoms. A sulfur heterocycle is a heterocycle containing at least one sulfur atom in the ring and may contain additional sulfur atoms as other heteroatoms. Oxygen heteroaryl is a subset of oxygen as the other heteroatom. Oxygen heteroaryl is a subset of oxygen heterocycle, examples of which include furan and oxazole. Sulfur heteroaryl is a subset of sulfur heterocycle, examples of which include, but are not limited to, thiophene and thiazine. Nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring and may contain additional nitrogen or other heteroatoms. Examples of which include, but are not limited to, piperidine, piperazine, morpholine, pyrrolidine, and thiomorpholine. Nitrogen heteroaryl is a subset of nitrogen heterocycle, examples of which include, but are not limited to, pyridine, pyrrole, and thiazole. Heterocyclic groups may be substituted unless specifically prohibited.

[0052] The term "hydroxy" means --OH.

[0053] As used herein, the term "increase" or the related terms "increased," "improve," or "improved" can refer to a statistically significant increase, and the terms "decreased," "suppressed," or "inhibited" can 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 compared to a control, baseline, or historical 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 compared to a control value.

[0054] The term "imino" as used herein means =N-.

[0055] As used herein, the term "modulate" means to increase or decrease the activity of PP2A. In one embodiment, 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.

[0056] As used herein, the term "nitro" means --NO.sub.2.

[0057] The term "optionally substituted" may 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 one embodiment, one, two, or three hydrogen atoms are replaced with a specified radical. For alkyl and cycloalkyl, more than three hydrogen atoms may be replaced with fluorine. In one embodiment, all available hydrogen atoms may be replaced with fluorine. Two substituents may combine to form a 3-7 membered non-aromatic carbocyclic or heterocyclic ring consisting of 0-3 heteroatoms, for example, methylenedioxy or ethylenedioxy. In one embodiment, the formed carbocyclic or heterocyclic ring is a fused or spirocyclic ring.

[0058] The above groups, either alone or as part of another substituent, can themselves be substituted with one or more groups selected from themselves and the additional substituents listed below. Additionally, the substituents listed below can themselves be substituents.

[0059] The term "oxo," when referring to a substituent itself, refers to a double-bonded oxygen (=O).

[0060] The term "oxy" or "oxa" as used herein means --O--.

[0061] 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 human.

[0062] 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 and organic acids. Suitable pharmaceutically acceptable acid addition salts for 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, ethylenediaminetetraacetic acid, formic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydrobromic acid, 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, teoclatic acid, p-toluenesulfonic acid, etc. If the compound contains an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the invention include, but are not limited to, metallic 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 non-toxic ammonium cations, and carboxylate, sulfonate, and phosphonate anions, where appropriate, attached to an alkyl having 1 to 20 carbon atoms.

[0063] As used herein, the terms "prevent," "preventing," or "prevention," and other grammatical equivalents, include preventing further symptoms, preventing the underlying metabolic causes of symptoms, inhibiting a disease or condition, for example, stopping the progression of a disease or condition, and are intended to include prevention.The term also includes achieving preventive benefits.With regard to preventive benefits, the composition may be administered to individuals at risk of developing a particular disease, individuals who report one or more physiological symptoms of the disease, or individuals at risk of disease recurrence.

[0064] The term "stereoisomer" refers to compounds made up of the same atoms joined by the same bonds but having different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0065] As used herein, the terms "sulfonate," "sulfonic acid," and "sulfonic" refer to the -SO3H group and its anion when sulfonic acid is used to form a salt.

[0066] The term "sulfanyl" as used herein means --S--.

[0067] The term "sulfinyl" as used herein means --S(.dbd.O)--.

[0068] The term "sulfonyl" as used herein means -S(=O)2-.

[0069] The term "sulfonamido" (sulfinamoyl; sulfonic acid amide; sulfonamide) means -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, where alkyl is independently an amino substituent as defined for the alkylamino group. Examples of sulfonamido groups include, but are not limited to, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3), -S(=O)2NH(CH2CH3), -S(=O)2N(CH2CH3), and -S(=O)2NHPh.

[0070] The term "sulfonimidamide" refers to the group -NHS((=O)(NR 18 ))- can be understood to refer to.

[0071] 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 isomerism. Valence tautomers include interconversions via rearrangement of some of the bonding electrons. Unless otherwise specified, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

[0072] As used herein, the terms "thia" and "thio" refer to the group -S- or ethers where the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0073] The terms "treat," "treating," or "treatment," as used herein, and other grammatical equivalents, include alleviating, inhibiting, or alleviating symptoms, reducing or inhibiting the severity of symptoms of a disease or condition, delaying its onset, delaying its recurrence, ameliorating or alleviating it, alleviating the underlying metabolic cause of symptoms, inhibiting a disease or condition, for example, stopping the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving conditions caused by a disease or condition, or stopping the symptoms of a disease or condition. The term also includes achieving a therapeutic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated and / or the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the individual.

[0074] Unless otherwise stated or depicted, a structure of a compound according to one or more embodiments disclosed herein is also intended to include all stereoisomeric (e.g., enantiomers, diastereomers, and cis-trans isomers) forms of the structure, e.g., R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and cis-trans isomeric (or conformational) mixtures of the present compounds are within the scope of the present disclosure. The configuration of any carbon-carbon double bond depicted herein as trans has been selected for convenience only and is not intended to designate a particular configuration; thus, a carbon-carbon double bond conveniently depicted herein as trans may be cis, trans, or a mixture of the two in any ratio. Unless otherwise stated, all tautomeric forms of a compound according to one or more embodiments disclosed herein are within the scope of the present disclosure. Furthermore, the compounds of the present disclosure can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0075] compound In certain aspects, the present disclosure provides TIFF2024508687000002.tif35128, or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof, selected from the group consisting of: 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, NH2, CN, NO2, -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 C6 to C in Ar 10 Aryl, C2-C 10 Heteroaryl, or C6-C 10 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: Two vicinal substituents of Ar may together provide a 5- to 8-membered ring fused to Ar; G is an optionally substituted C3-C8 cycloalkyl, which is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, halogen, OH, NH2, CN, NO2, and -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: The phenyl in G is 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: Two substituents on G may together provide a C3-C8 cycloalkyl that is spiro, fused, or bridged with the C3-C8 cycloalkyl on G; R 1 teeth Selected from the group consisting of TIFF2024508687000003.tif24151; R 2 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 Heterocyclyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C2-C6 alkynyl, -C(=O)OR a , and -C(=O)N(R a )(R a ) selected from the group consisting of R 2 Each optional substituent in 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 at least one selected from the group consisting of heteroaryl; R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' are each 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 on heterocyclyl, phenyl, or phenoxy is 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 a and at least one selected from the group consisting of R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two geminal substituents selected from the group consisting of, together with the carbon atoms to which they are attached, optionally substituted C3-C8 cycloalkyl and optionally substituted C2-C 10 heterocyclyl, R 3 , R 3' , R 4 , R 4' , R5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two vicinal substituents selected from the above, taken together with the carbon atoms to which they are attached, form an optionally substituted C3-C8 cycloalkyl, an optionally substituted C2-C 10 may form a moiety selected from the group consisting of heterocyclyl, and optionally substituted phenyl; R separated by 2 to 5 carbon atoms 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' two substituents selected from may, together with the carbon atoms to which they are attached, form a moiety selected from the group consisting of optionally substituted C4-C7 cycloalkyl and optionally substituted C4-C8 heterocyclyl; R 10 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 on 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 at least one selected from the group consisting of: R 10' is selected from the group consisting of substituted phenyl, substituted benzyl, and —C(═O)-optionally substituted C1-C6 alkyl; R 10'Benzyl or phenyl in the formula (I) are halogen, C1-C3 haloalkyl, OH, and N(R a )(R b ) and R 10' wherein the alkyl is substituted with at least one phenyl substituent; Y is C(R a )(R a ), C=O, NR 10 , N.R. 10' and O, Y is C(R a )(R a ) and R 2 When is an optionally substituted phenyl, Ar is a C-C substituted with at least one trifluoromethoxy substituent. 10 Aryl or C2-C 10 Contains heteroaryl; Z is C=O, NR 10 , N.R. 10' , O, and S; R A is H or C1-C6 alkyl; R a is independently in each occurrence H, C1-C6 alkyl, benzyl, and C6-C 10 aryl; R b is independently selected at each occurrence from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl; R b In the formula (I), C1-C6 alkyl, benzyl, phenyl, or naphthyl is independently C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OR a , CN, NO2, C(=O)OR a , and C(=O)N(R a )(R a ) may be substituted with at least one selected from the group consisting of: In (Ia), (Ib), and (Ic), at least one of the following applies: a) R 2 is phenyl or C2-C 10 heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, OH, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl; b) R 3 and R 3' At least one of the following is phenyl or C2-C 10 heteroaryl, wherein the phenyl or heteroaryl is substituted with at least one substituent selected from the group consisting of halogen, OH, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl; c) R 3 , R 3' , R 4 , and R 4' At least one of the following is phenyl or C2-C 10 heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, OH, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C6 alkyl; one of Y and Z is present; and one of Y and Z is C═O, NR 10 and O, 10 is H, C3-C6 cycloalkyl, phenyl, optionally substituted benzyl, -C(=O)OR b , -C(=O)R b , -S(=O)2- optionally substituted phenyl; d) R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R8 , and R 8' two geminal substituents selected from the group consisting of, taken together with the carbon atoms to which they are attached, form a C3-C8 cycloalkyl or a C2-C6 heterocyclyl, and the cycloalkyl or heterocyclyl is selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, halogen, N(R a )(R a ), OR a , C(=O)R a , C(=O)OR a , and C(=O)N(R a )(R a ) substituted with at least one substituent selected from the group consisting of: e) R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two vicinal substituents selected from the above, taken together with the carbon atoms to which they are attached, form a C3-C8 cycloalkyl, a C2-C 10 and forming a cycloalkyl, heterocyclyl, or phenyl, wherein the cycloalkyl, heterocyclyl, or phenyl is selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, halogen, OR a , C(=O)R a , C(=O)OR a , and C(=O)N(R a )(R a ) substituted with at least one substituent selected from the group consisting of: f) R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R8' two geminal substituents selected from, taken together with the carbon atoms to which they are attached, form a C3-C8 cycloalkyl or a C2-C6 heterocyclyl; R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two vicinal substituents selected from the above, taken together with the carbon atoms to which they are attached, form a C3-C8 cycloalkyl, a C2-C 10 cycloalkyl, heterocyclyl, or phenyl, each of which independently is C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, halogen, N(R a )(R a ), OR a , C(=O)R a , C(=O)OR a , and C(=O)N(R a )(R a Optionally, the alkyl group may be substituted with at least one substituent selected from the group consisting of: g) Y is N(R 10' ) and R 4 , R 4' , R 6 , and R 6' each, if present, is independently selected from the group consisting of H, C1-C6 alkyl, hydroxyl, C1-C4 haloalkyl, phenyl, and phenoxy; h) R 2 , R 3 , R 3' , R 4 , and R 4' At least one of the groups is optionally substituted C3-C8 cycloalkyl or C2-C 10heterocyclyl, and each optional substituent on the cycloalkyl or heterocycloalkyl is independently selected from halogen, C1-C6 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, OR a , N(R a )(R b ), C(=O)R a , and C(=O)OR a selected from the group consisting of: i) R 2 is selected from the group consisting of optionally substituted C1-C6 haloalkyl, optionally substituted C2-C6 aminoalkyl, and optionally substituted C2-C6 alkynyl; R 2 The optional substituents of haloalkyl, aminoalkyl, and alkynyl in a , C(=O)OR a , C(=O)N(R a )(R a ), S(=O)2-optionally substituted phenyl and S(=O)2-optionally substituted C2-C 10 and at least one selected from the group consisting of heteroaryl.

[0076] In certain embodiments, a C6-C substituted with at least one trifluoromethyl substituent 10 Aryl or C2-C 10 Heteroaryl is trifluoromethylphenyl. In certain embodiments, trifluoromethylphenyl is 4-trifluoromethylphenyl.

[0077] In certain embodiments, the compound of formula (I) is TIFF2024508687000004.tif227145TIFF2024508687000005.tif23148; During the ceremony R 9 is independently selected at each occurrence from the group consisting of F, Cl, Br, C1-C3 alkoxy, and C1-C3 haloalkoxy; and n is an integer selected from the group consisting of 0, 1, and 2.

[0078] In certain embodiments, R A is H. In certain embodiments, R A is methyl.

[0079] In certain embodiments, the compound of formula (I) is TIFF2024508687000006.tif16128.

[0080] In certain embodiments, the compound of formula (I) is TIFF2024508687000007.tif108148TIFF2024508687000008.tif144154; During the ceremony R 9 is independently selected at each occurrence from the group consisting of F, Cl, Br, C1-C3 alkoxy, and C1-C3 haloalkoxy; and n is an integer selected from the group consisting of 0, 1, and 2.

[0081] In certain embodiments, R 1 teeth TIFF2024508687000009.tif26128TIFF2024508687000010.tif219147TIFF2024508687000011.tif21128; During the ceremony R a1 and R a2 are each independently selected from the group consisting of F, Cl, Br, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy.

[0082] In certain embodiments, R a1 is F. In certain embodiments, R a1 is Cl. In certain embodiments, R a1 is Br. In certain embodiments, R a1 is Me. In certain embodiments, Ra1 is CHF2. In certain embodiments, R a1 is CF3. In certain embodiments, R a1 is OMe. In certain embodiments, R a1 is OEt. In certain embodiments, R a1 is OCF3. In certain embodiments, R a1 is OCF2H.

[0083] In certain embodiments, R a2 is F. In certain embodiments, R a2 is Cl. In certain embodiments, R a2 is Br. In certain embodiments, R a2 is Me. In certain embodiments, R a2 is CHF2. In certain embodiments, R a2 is CF3. In certain embodiments, R a2 is OMe. In certain embodiments, R a2 is OEt. In certain embodiments, R a2 is OCF3. In certain embodiments, R a2 is OCF2H.

[0084] In certain embodiments, Ar is TIFF2024508687000012.tif54137, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently C1-C6 alkyl, F, Cl, N(R a )(R b ), OR b , -C(=O)OR a , -C(=O)N(R a )(R a ), NH2, OH, NO2, C1-C3 haloalkyl, C1-C3 haloalkoxy, and phenyl.

[0085] In certain embodiments, the compound of formula (I) is a compound of formula (Ia-1) or (Ia'-1), wherein R 3 , R 3' , R 4 , and R 4' and at least two of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-2) or (Ia'-2), wherein R 3 , R 3' , R 4 , and R 4' and at least two of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-3) or (Ia'-3), wherein R 3 , R 3' , R 4 , R 4' , R 5 , and R 5' At least four of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-4) or (Ia'-4), wherein R 3 and R 3' and at least one of R is H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-5) or (Ia'-5), wherein R 3 , R 3' , R 4 , and R 4' and at least two of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-6) or (Ia'-6), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least six of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-7) or (Ia'-7), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6'At least six of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-8) or (Ia'-8), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' At least 10 of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-1) or (Ib'-1), wherein R 3 , R 3' , R 4 , and R 4' and at least two of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-2) or (Ib'-2), wherein R 3 , R 3' , R 4 , and R 4' and at least two of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-3) or (Ib'-3), wherein R 3 , R 3' , R 4 , R 4' , R 5 , and R 5' At least four of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-4) or (Ib'-4), wherein R 3 and R 3' and at least one of R is H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-5) or (Ib'-5), wherein R 3 , R 3' , R 4 , and R 4' and at least two of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-6) or (Ib'-6), wherein R 3 , R 3' , R 4 , R 4' , R 5, R 5' , R 6 , and R 6' At least six of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-7) or (Ib'-7), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least six of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-8) or (Ib'-8), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' At least 10 of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-1) or (Ic'-1), wherein R 3 , R 3' , R 4 , and R 4' and at least two of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-2) or (Ic'-2), wherein R 3 , R 3' , R 4 , and R 4' and at least two of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-3) or (Ic'-3), wherein R 3 , R 3' , R 4 , R 4' , R 5 , and R 5' At least four of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-4) or (Ic'-4), wherein R 3 and R 3'and at least one of R is H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-5) or (Ic'-5), wherein R 3 , R 3' , R 4 , and R 4' and at least two of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-6) or (Ic'-6), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least six of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-7) or (Ic'-7), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least six of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-8) or (Ic'-8), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' At least 10 of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Id-1), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least six of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ie-1), wherein R 3 , R 3' , R4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least six of R are H. In certain embodiments, the compound of formula (I) is a compound of formula (If-1), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least six of them are H.

[0086] In certain embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 Each of, if present, is H.

[0087] In certain embodiments, X 1 , X 2 , X 3 , and X 4 exists and X 1 , X 2 , X 3 , and X 4 At least one of X is H. In certain embodiments, 1 , X 2 , X 3 , and X 4 exists and X 1 , X 2 , X 3 , and X 4 At least two of X are H. In certain embodiments, 1 , X 2 , X 3 , and X 4 exists and X 1 , X 2 , X 3 , and X 4 At least three of them are H.

[0088] In certain embodiments, X 1 , X 2 , X 3 , X 4 , and X 5 exists and X 1 , X 2 , X 3 , X 4 , and X 5 At least one of X is H. In certain embodiments, 1 , X 2 , X 3 , X 4 , and X 5 exists and X 1 , X 2 , X 3 , X 4 , and X 5 At least two of X are H. In certain embodiments, 1 , X 2 , X 3 , X 4 , and X 5 exists and X 1 , X 2 , X 3 , X 4 , and X 5 At least three of X are H. In certain embodiments, 1 , X 2 , X 3 , X 4 , and X 5 exists and X 1 , X 2 , X 3 , X 4 , and X 5 At least four of them are H.

[0089] In certain embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 exists and X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 At least one of X is H. In certain embodiments,1 , X 2 , X 3 , X 4 , X 5 , and X 6 exists and X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 At least two of X are H. In certain embodiments, 1 , X 2 , X 3 , X 4 , X 5 , and X 6 exists and X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 At least three of X are H. In certain embodiments, 1 , X 2 , X 3 , X 4 , X 5 , and X 6 exists and X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 At least four of X are H. In certain embodiments, 1 , X 2 , X 3 , X 4 , X 5 , and X 6 exists and X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 At least five of them are H.

[0090] In certain embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7exists and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 At least one of X is H. In certain embodiments, 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 exists and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 At least two of X are H. In certain embodiments, 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 exists and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 At least three of X are H. In certain embodiments, 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 exists and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 At least four of X are H. In certain embodiments, 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 exists and X 1 , X2 , X 3 , X 4 , X 5 , X 6 , and X 7 At least five of X are H. In certain embodiments, 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 exists and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 At least six of them are H.

[0091] In certain embodiments, X 1 is OCF3. In certain embodiments, X 1 teeth TIFF2024508687000013.tif20128. In certain embodiments, X 1 is CF3. In certain embodiments, X 1 is NH2. In certain embodiments, X 1 is O(CH(CH3)2). In certain embodiments, X 2 is OCF3. In certain embodiments, X 2 teeth TIFF2024508687000014.tif20128. In certain embodiments, X 2 is CF3. In certain embodiments, X 2 is NH2. In certain embodiments, X 2 is O(CH(CH3)2). In certain embodiments, X 3 is OCF3. In certain embodiments, X 3 teeth TIFF2024508687000015.tif20128. In certain embodiments, X 3 is CF3. In certain embodiments, X 3 is NH2. In certain embodiments, X 3 is O(CH(CH3)2). In certain embodiments, X4 is OCF3. In certain embodiments, X 4 teeth TIFF2024508687000016.tif20128. In certain embodiments, X 4 is CF3. In certain embodiments, X 4 is NH2. In certain embodiments, X 4 is O(CH(CH3)2). In certain embodiments, X 5 is OCF3. In certain embodiments, X 5 teeth TIFF2024508687000017.tif20128. In certain embodiments, X 5 is CF3. In certain embodiments, X 5 is NH2. In certain embodiments, X 5 is O(CH(CH3)2). In certain embodiments, X 6 is OCF3. In certain embodiments, X 6 teeth TIFF2024508687000018.tif20128. In certain embodiments, X 6 is CF3. In certain embodiments, X 6 is NH2. In certain embodiments, X 6 is O(CH(CH3)2). In certain embodiments, X 7 is OCF3. In certain embodiments, X 7 teeth TIFF2024508687000019.tif20128. In certain embodiments, X 7 is CF3. In certain embodiments, X 7 is NH2. In certain embodiments, X 7 is O(CH(CH3)2).

[0092] In certain embodiments, Ar is TIFF2024508687000020.tif9128. In certain embodiments, Ar is TIFF2024508687000021.tif15128. In certain embodiments, Ar is TIFF2024508687000022.tif15128. In certain embodiments, Ar is TIFF2024508687000023.tif15128. In certain embodiments, Ar is TIFF2024508687000024.tif15128. In certain embodiments, Ar is TIFF2024508687000025.tif20128. In certain embodiments, Ar is TIFF2024508687000026.tif20128. In certain embodiments, Ar is TIFF2024508687000027.tif11128. In certain embodiments, Ar is TIFF2024508687000028.tif23128. In certain embodiments, Ar is TIFF2024508687000029.tif14128. In certain embodiments, Ar is TIFF2024508687000030.tif9128. In certain embodiments, Ar is TIFF2024508687000031.tif10128. In certain embodiments, Ar is TIFF2024508687000032.tif13128. In certain embodiments, Ar is The file is TIFF2024508687000033.tif12128.

[0093] In certain embodiments, Ar is 1-naphthyl. In certain embodiments, Ar is 2-naphthyl. In certain embodiments, Ar is 2-pyridyl. In certain embodiments, Ar is 3-pyridyl. In certain embodiments, Ar is 4-pyridyl.

[0094] In certain embodiments, G is TIFF2024508687000034.tif19128, During the ceremony R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14'are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, and optionally substituted phenyl; Each optional substituent on phenyl is 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 a and at least one selected from the group consisting of R 11 and R 13 , or R 11 and R 13' may be taken together with the atom to which they are attached to form a C3-C8 cycloalkyl.

[0095] In certain embodiments, R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' at least one of R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' At least two of R are H. In certain embodiments, 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' At least three of R are H. In certain embodiments, 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' At least four of R are H. In certain embodiments, 11 , R 12 , R 12' , R 13 , R 13' , R14 , and R 14' At least five of R are H. In certain embodiments, 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' At least six of R are H. In certain embodiments, 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' Each of is H.

[0096] In certain embodiments, R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' At least one of them is CF3.

[0097] In certain embodiments, G is The file is TIFF2024508687000035.tif7128.

[0098] In certain embodiments, R 2 is —CHF. In certain embodiments, R 2 is —C(═O)OEt. In certain embodiments, R 2 is Ph. In certain embodiments, R 2 teeth TIFF2024508687000036.tif11128. In certain embodiments, R 2 teeth TIFF2024508687000037.tif9128. In certain embodiments, R 2 teeth TIFF2024508687000038.tif11128. In certain embodiments, R 2 teeth TIFF2024508687000039.tif11128. In certain embodiments, R2 teeth TIFF2024508687000040.tif14128. In certain embodiments, R 2 teeth TIFF2024508687000041.tif13128. In certain embodiments, R 2 teeth TIFF2024508687000042.tif13128. In certain embodiments, R 2 teeth TIFF2024508687000043.tif14128. In certain embodiments, R 2 teeth TIFF2024508687000044.tif14128. In certain embodiments, R 2 teeth TIFF2024508687000045.tif14128. In certain embodiments, R 2 teeth TIFF2024508687000046.tif14128. In certain embodiments, R 2 teeth TIFF2024508687000047.tif15128. In certain embodiments, R 2 teeth TIFF2024508687000048.tif20128. In certain embodiments, R 2 teeth TIFF2024508687000049.tif14128. In certain embodiments, R 2 teeth TIFF2024508687000050.tif14128. In certain embodiments, R 2 teeth TIFF2024508687000051.tif14128. In certain embodiments, R 2 teeth TIFF2024508687000052.tif18128. In certain embodiments, R 2 teeth TIFF2024508687000053.tif18128. In certain embodiments, R 2 teeth TIFF2024508687000054.tif10128. In certain embodiments, R 2 teeth TIFF2024508687000055.tif10128. In certain embodiments, R 2 teeth TIFF2024508687000056.tif10128. In certain embodiments, R 2 teeth TIFF2024508687000057.tif13128. In certain embodiments, R 2 teeth TIFF2024508687000058.tif7128.

[0099] In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is trifluoromethyl. In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 3 is —C(═O)OMe. In certain embodiments, R 3 is Ph. In certain embodiments, R 3 teeth TIFF2024508687000059.tif11128. In certain embodiments, R 3 teeth TIFF2024508687000060.tif14128. In certain embodiments, R 3 teeth TIFF2024508687000061.tif14128. In certain embodiments, R 3 teeth TIFF2024508687000062.tif13128. In certain embodiments, R 3 teeth TIFF2024508687000063.tif12128. In certain embodiments, R 3 is F.

[0100] In certain embodiments, R 3' is methyl. In certain embodiments, R 3' is trifluoromethyl. In certain embodiments, R3' is hydroxyl. In certain embodiments, R 3' is —C(═O)OMe. In certain embodiments, R 3' is Ph. In certain embodiments, R 3' teeth TIFF2024508687000064.tif11128. In certain embodiments, R 3' teeth TIFF2024508687000065.tif13128. In certain embodiments, R 3' teeth TIFF2024508687000066.tif13128. In certain embodiments, R 3' teeth TIFF2024508687000067.tif14128. In certain embodiments, R 3' teeth TIFF2024508687000068.tif12128. In certain embodiments, R 3' is F.

[0101] In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is trifluoromethyl. In certain embodiments, R 4 is hydroxyl. In certain embodiments, R 4 is —C(═O)OMe. In certain embodiments, R 4 is Ph. In certain embodiments, R 4 teeth TIFF2024508687000069.tif11128. In certain embodiments, R 4 teeth TIFF2024508687000070.tif14128. In certain embodiments, R 4 teeth TIFF2024508687000071.tif14128. In certain embodiments, R 4 teeth TIFF2024508687000072.tif14128. In certain embodiments, R 4 teeth TIFF2024508687000073.tif12128. In certain embodiments, R 4 is F.

[0102] In certain embodiments, R 4' is methyl. In certain embodiments, R 4' is trifluoromethyl. In certain embodiments, R 4' is hydroxyl. In certain embodiments, R 4' is —C(═O)OMe. In certain embodiments, R 4' is Ph. In certain embodiments, R 4' teeth TIFF2024508687000074.tif11128. In certain embodiments, R 4' teeth TIFF2024508687000075.tif14128. In certain embodiments, R 4' teeth TIFF2024508687000076.tif14128. In certain embodiments, R 4' teeth TIFF2024508687000077.tif14128. In certain embodiments, R 4' teeth TIFF2024508687000078.tif12128. In certain embodiments, R 4' is F.

[0103] In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is trifluoromethyl. In certain embodiments, R 5 is hydroxyl. In certain embodiments, R 5 is —C(═O)OMe. In certain embodiments, R 5 is Ph. In certain embodiments, R 5 teeth TIFF2024508687000079.tif11128. In certain embodiments, R 5 teeth TIFF2024508687000080.tif14128. In certain embodiments, R 5 teeth TIFF2024508687000081.tif14128. In certain embodiments, R 5 teeth TIFF2024508687000082.tif14128. In certain embodiments, R 5 teeth TIFF2024508687000083.tif12128. In certain embodiments, R 5 is F.

[0104] In certain embodiments, R 5' is methyl. In certain embodiments, R 5' is trifluoromethyl. In certain embodiments, R 5' is hydroxyl. In certain embodiments, R 5' is —C(═O)OMe. In certain embodiments, R 5' is Ph. In certain embodiments, R 5' teeth TIFF2024508687000084.tif11128. In certain embodiments, R 5' teeth TIFF2024508687000085.tif14128. In certain embodiments, R 5' teeth TIFF2024508687000086.tif14128. In certain embodiments, R 5' teeth TIFF2024508687000087.tif14128. In certain embodiments, R 5' teeth TIFF2024508687000088.tif12128. In certain embodiments, R 5' is F.

[0105] In certain embodiments, R 6 is methyl. In certain embodiments, R 6 is trifluoromethyl. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 is —C(═O)OMe. In certain embodiments, R 6 is Ph. In certain embodiments, R6 teeth TIFF2024508687000089.tif11128. In certain embodiments, R 6 teeth TIFF2024508687000090.tif14128. In certain embodiments, R 6 teeth TIFF2024508687000091.tif14128. In certain embodiments, R 6 teeth TIFF2024508687000092.tif14128. In certain embodiments, R 6 teeth TIFF2024508687000093.tif12128. In certain embodiments, R 6 is F.

[0106] In certain embodiments, R 6' is methyl. In certain embodiments, R 6' is trifluoromethyl. In certain embodiments, R 6' is hydroxyl. In certain embodiments, R 6' is —C(═O)OMe. In certain embodiments, R 6' is Ph. In certain embodiments, R 6' teeth TIFF2024508687000094.tif11128. In certain embodiments, R 6' teeth TIFF2024508687000095.tif14128. In certain embodiments, R 6' teeth TIFF2024508687000096.tif13128. In certain embodiments, R 6' teeth TIFF2024508687000097.tif14128. In certain embodiments, R 6' teeth TIFF2024508687000098.tif12128. In certain embodiments, R 6' is F.

[0107] In certain embodiments, R 7is methyl. In certain embodiments, R 7 is trifluoromethyl. In certain embodiments, R 7 is hydroxyl. In certain embodiments, R 7 is —C(═O)OMe. In certain embodiments, R 7 is Ph. In certain embodiments, R 7 teeth TIFF2024508687000099.tif11128. In certain embodiments, R 7 teeth TIFF2024508687000100.tif14128. In certain embodiments, R 7 teeth TIFF2024508687000101.tif14128. In certain embodiments, R 7 teeth TIFF2024508687000102.tif13128. In certain embodiments, R 7 teeth TIFF2024508687000103.tif12128. In certain embodiments, R 7 is F.

[0108] In certain embodiments, R 7' is methyl. In certain embodiments, R 7' is trifluoromethyl. In certain embodiments, R 7' is hydroxyl. In certain embodiments, R 7' is —C(═O)OMe. In certain embodiments, R 7' is Ph. In certain embodiments, R 7' teeth TIFF2024508687000104.tif11128. In certain embodiments, R 7' teeth TIFF2024508687000105.tif13128. In certain embodiments, R 7' teeth TIFF2024508687000106.tif14128. In certain embodiments, R 7' teeth TIFF2024508687000107.tif14128. In certain embodiments, R 7' teeth TIFF2024508687000108.tif12128. In certain embodiments, R 7' is F.

[0109] In certain embodiments, R 8 is methyl. In certain embodiments, R 8 is trifluoromethyl. In certain embodiments, R 8 is hydroxyl. In certain embodiments, R 8 is —C(═O)OMe. In certain embodiments, R 8 is Ph. In certain embodiments, R 8 teeth TIFF2024508687000109.tif11128. In certain embodiments, R 8 teeth TIFF2024508687000110.tif14128. In certain embodiments, R 8 teeth TIFF2024508687000111.tif13128. In certain embodiments, R 8 teeth TIFF2024508687000112.tif13128. In certain embodiments, R 8 teeth TIFF2024508687000113.tif12128. In certain embodiments, R 8 is F.

[0110] In certain embodiments, R 8' is methyl. In certain embodiments, R 8' is trifluoromethyl. In certain embodiments, R 8' is hydroxyl. In certain embodiments, R 8' is —C(═O)OMe. In certain embodiments, R 8' is Ph. In certain embodiments, R 8' teeth TIFF2024508687000114.tif11128. In certain embodiments, R 8' teeth TIFF2024508687000115.tif13128. In certain embodiments, R 8' teeth TIFF2024508687000116.tif14128. In certain embodiments, R 8' teeth TIFF2024508687000117.tif14128. In certain embodiments, R 8' teeth TIFF2024508687000118.tif12128. In certain embodiments, R 8' is F.

[0111] In certain embodiments, Y is NR 10 In certain embodiments, Y is NH.

[0112] In certain embodiments, R 10 is H. In certain embodiments, R 10 is methyl. In certain embodiments, R 10 is 3-methylbutyl. In certain embodiments, R 10 is tert-butyl. In certain embodiments, R 10 is cyclopropyl. In certain embodiments, R 10 is 3-oxetanyl. In certain embodiments, R 10 is —C(═O)CHCH(CH). In certain embodiments, R 10 is —C(═O)Ot-Bu. In certain embodiments, R 10 is S(=O)Me. In certain embodiments, R 10 is benzyl. In certain embodiments, R 10 teeth TIFF2024508687000119.tif16128. In certain embodiments, R 10 teeth TIFF2024508687000120.tif12128. In certain embodiments, R 10 teeth TIFF2024508687000121.tif14128. In certain embodiments, R 10 teeth TIFF2024508687000122.tif20128. In certain embodiments, R 10 teeth TIFF2024508687000123.tif18128. In certain embodiments, R 10 teeth TIFF2024508687000124.tif14128. In certain embodiments, R 10 teeth TIFF2024508687000125.tif16128. In certain embodiments, R 10 teeth TIFF2024508687000126.tif18128. In certain embodiments, R 10 teeth The file is TIFF2024508687000127.tif17128.

[0113] In certain embodiments, Y is NR 10' is.

[0114] In certain embodiments, R 10' teeth TIFF2024508687000128.tif16128. In certain embodiments, R 10' teeth TIFF2024508687000129.tif12128. In certain embodiments, R 10' teeth TIFF2024508687000130.tif14128. In certain embodiments, R 10' teeth TIFF2024508687000131.tif20128. In certain embodiments, R 10' teeth TIFF2024508687000132.tif13128. In certain embodiments, R 10' teeth TIFF2024508687000133.tif18128.

[0115] In certain embodiments, R 1 teeth TIFF2024508687000134.tif25128. In certain embodiments, R 1 teeth TIFF2024508687000135.tif23128. In certain embodiments, R 1 teeth TIFF2024508687000136.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000137.tif20128. In certain embodiments, R 1 teeth TIFF2024508687000138.tif20128. In certain embodiments, R 1 teeth TIFF2024508687000139.tif20128. In certain embodiments, R 1 teeth TIFF2024508687000140.tif20128. In certain embodiments, R 1 teeth TIFF2024508687000141.tif20128. In certain embodiments, R 1 teeth TIFF2024508687000142.tif20128. In certain embodiments, R 1 teeth TIFF2024508687000143.tif20128. In certain embodiments, R 1 teeth TIFF2024508687000144.tif23128. In certain embodiments, R 1 teeth TIFF2024508687000145.tif22128. In certain embodiments, R 1 teeth TIFF2024508687000146.tif20128. In certain embodiments, R 1 teeth TIFF2024508687000147.tif20128. In certain embodiments, R 1 teeth TIFF2024508687000148.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000149.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000150.tif26128. In certain embodiments, R 1 teeth TIFF2024508687000151.tif23128. In certain embodiments, R 1 teeth TIFF2024508687000152.tif23128. In certain embodiments, R 1 teeth TIFF2024508687000153.tif23128. In certain embodiments, R 1 teeth TIFF2024508687000154.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000155.tif18128. In certain embodiments, R 1 teeth TIFF2024508687000156.tif26128. In certain embodiments, R 1 teeth TIFF2024508687000157.tif25128. In certain embodiments, R 1 teeth TIFF2024508687000158.tif34128. In certain embodiments, R 1 teeth TIFF2024508687000159.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000160.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000161.tif19128. In certain embodiments, R 1 teeth TIFF2024508687000162.tif25128. In certain embodiments, R 1 teeth TIFF2024508687000163.tif34128. In certain embodiments, R 1 teeth TIFF2024508687000164.tif16128. In certain embodiments, R 1 teeth TIFF2024508687000165.tif17128. In certain embodiments, R 1 teeth TIFF2024508687000166.tif18128. In certain embodiments, R 1 teeth TIFF2024508687000167.tif26128. In certain embodiments, R 1 teeth TIFF2024508687000168.tif26128. In certain embodiments, R 1 teeth TIFF2024508687000169.tif23128. In certain embodiments, R 1 teeth TIFF2024508687000170.tif30128. In certain embodiments, R 1 teeth TIFF2024508687000171.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000172.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000173.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000174.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000175.tif23128. In certain embodiments, R 1 teeth TIFF2024508687000176.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000177.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000178.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000179.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000180.tif39128. In certain embodiments, R 1 teeth TIFF2024508687000181.tif21128. In certain embodiments, R 1 teeth TIFF2024508687000182.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000183.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000184.tif26128. In certain embodiments, R 1 teeth TIFF2024508687000185.tif26128. In certain embodiments, R 1 teeth TIFF2024508687000186.tif23128. In certain embodiments, R 1 teeth TIFF2024508687000187.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000188.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000189.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000190.tif22128. In certain embodiments, R 1 teeth TIFF2024508687000191.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000192.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000193.tif27128. In certain embodiments, R 1 teeth TIFF2024508687000194.tif30128. In certain embodiments, R 1 teeth TIFF2024508687000195.tif31128. In certain embodiments, R 1 teeth TIFF2024508687000196.tif38128. In certain embodiments, R 1 teeth TIFF2024508687000197.tif34128. In certain embodiments, R 1 teeth TIFF2024508687000198.tif39128. In certain embodiments, R 1 teeth TIFF2024508687000199.tif39128. In certain embodiments, R 1 teeth TIFF2024508687000200.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000201.tif27128. In certain embodiments, R 1 teeth TIFF2024508687000202.tif27128. In certain embodiments, R 1 teeth TIFF2024508687000203.tif27128. In certain embodiments, R 1 teeth TIFF2024508687000204.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000205.tif27128. In certain embodiments, R 1 teeth TIFF2024508687000206.tif27128. In certain embodiments, R 1 teeth TIFF2024508687000207.tif37128. In certain embodiments, R 1 teeth TIFF2024508687000208.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000209.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000210.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000211.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000212.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000213.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000214.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000215.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000216.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000217.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000218.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000219.tif28128. In certain embodiments, R 1 teeth TIFF2024508687000220.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000221.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000222.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000223.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000224.tif29128. In certain embodiments, R 1 teeth TIFF2024508687000225.tif24128. In certain embodiments, R 1 teeth TIFF2024508687000226.tif19128. In certain embodiments, R 1 teeth TIFF2024508687000227.tif27128. In certain embodiments, R 1 teeth TIFF2024508687000228.tif15128. In certain embodiments, R 1 teeth TIFF2024508687000229.tif16128.

[0116] In certain aspects, the present disclosure provides TIFF2024508687000230.tif17128, or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof; During the ceremony Ar is C6-C10 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, NH2, 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: Each C6 to C in Ar 10 Aryl, C2-C 10 Heteroaryl, or C6-C 10 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: Two vicinal substituents of Ar may together provide a 5- to 8-membered ring fused to Ar; R A is H or C1-C6 alkyl; and R 1 teeth TIFF2024508687000231.tif145146 TIFF2024508687000232.tif212148 TIFF2024508687000233.tif221149 TIFF2024508687000234.tif58129.

[0117] In certain embodiments, R A is H. In certain embodiments, R A is methyl.

[0118] In certain embodiments, the compound of formula (II) TIFF2024508687000235.tif17128.

[0119] In certain embodiments, Ar is TIFF2024508687000236.tif54137; In the formula, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently C1-C6 alkyl, F, Cl, N(R a )(R b ), OR b , -C(=O)OR a , -C(=O)N(R a )(R a ), NH2, OH, NO2, C1-C3 haloalkyl, C1-C3 haloalkoxy, and phenyl.

[0120] In certain embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 When present, at least one of X is O(CH(CH3)2). 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 When present, at least one of X is OCF3. 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 If at least one of The file is TIFF2024508687000237.tif20128.

[0121] In certain embodiments, Ar is TIFF2024508687000238.tif14128. In certain embodiments, Ar is TIFF2024508687000239.tif9128. In certain embodiments, Ar is TIFF2024508687000240.tif13128. In certain embodiments, Ar is TIFF2024508687000241.tif11128. In certain embodiments, Ar is TIFF2024508687000242.tif10128. In certain embodiments, Ar is TIFF2024508687000243.tif13128. In certain embodiments, Ar is The file is TIFF2024508687000244.tif23128.

[0122] In certain embodiments, the compound is N-(6-fluoro-2,2-dimethylchroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 4-(2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; tert-Butyl 2-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)pyrrolidine-1-carboxylate; N-(6-(difluoromethoxy)-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3-ethoxy-4-hydroxybenzyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 3-(fluoromethyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate; N-(1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(2-oxo-1-(3-(trifluoromethyl)benzyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(spiro[chroman-2,1'-cyclopentan]-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-benzyl-3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(3-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3-chlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; Methyl 3-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopentyl)propiolate; N-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3-methoxyphenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3,4-dichlorophenyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; 3,5-dimethyl-N-((1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclohexyl)methyl)isoxazole-4-sulfonamide; N-(1-(2-phenylbutanoyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; 4-(trifluoromethoxy)-N-(1-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)benzenesulfonamide; N-(2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(5-chloro-2-methoxyphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(5,8-difluorochroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3-bromophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)azetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(3,4-dichlorophenyl)azetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(3,4-dichlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; 3-(3,4-dichlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate benzyl; N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 4-(4-chlorophenyl)-4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate; N-(1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; N-(1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; N-(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; N-(3-(4-chloro-3-fluorophenyl)azetidin-3-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-(1-methyl-4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide; N-(4-(5-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(bicyclo[1.1.1]pentan-1-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; N-(3-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 3-(4-chlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate; N-(3-(4-chlorophenyl)-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)-1-(methylsulfonyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(5-chlorothiazol-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-fluorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide; N-(3-(4-chlorophenyl)-1-isopentylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-fluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide; N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-isopropoxybenzenesulfonamide; rac N-((3S,4S)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-isopropoxypyridine-3-sulfonamide; N-(3-(4-chlorophenyl)-1-(3-methylbutanoyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(3,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(2,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide; N-(3-phenyl-8-azabicyclo[3.2.1]octan-3-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-(1-(3,4-dichlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(5-chlorothiophen-2-yl)piperidin-4-yl)-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-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-(trifluoromethoxy)benzenesulfonimidamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethyl)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-sulfonamide; 3-amino-N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; and N-(4-(4-(difluoromethyl)phenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide or a salt, solvate, isotope, or tautomer thereof.

[0123] In certain embodiments, the compound is (R)-N-(6-fluoro-2,2-dimethylchroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3R)-1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3S)-1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 4-((1R,2R)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; tert-Butyl 4-((1R,2S)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; (R)-tert-butyl 2-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)pyrrolidine-1-carboxylate; (R)-N-(6-(difluoromethoxy)-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-tert-butyl 3-(fluoromethyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate; N-((2R,3R)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3S)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(2-oxo-1-(3-(trifluoromethyl)benzyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(spiro[chroman-2,1'-cyclopentan]-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(1-benzyl-3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((6R,7R)-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((6R,7S)-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3R)-2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3S)-2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-(3,4-dichlorophenyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2R)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-(2-phenylbutanoyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-4-(trifluoromethoxy)-N-(1-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)benzenesulfonamide; N-((1R,2R)-2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-(5-chloro-2-methoxyphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(5,8-difluorochroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2R)-2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2R)-2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-(3-bromophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-3-(3,4-dichlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate benzyl; N-((3R,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((3R,4S)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (R)—N-(1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (R)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (R)-N-((R)-3-(4-chlorophenyl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (R)-N-((S)-3-(4-chlorophenyl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (R)—N-(3-(4-chlorophenyl)pyridin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide; (R)-N-((R)-3-(4-chlorophenyl)irolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; (R)-N-((S)-3-(4-chlorophenyl)irolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; (R)—N-(3-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-tert-butyl 3-(4-chlorophenyl)-3-((4-(trifluoromethoxy)phenyl)pyrrolidine)pyrrolidine-1-carboxylate; (R)—N-(3-(4-chlorophenyl)-1-(oxetan-3-yl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-chlorophenyl)-1-(methylsulfonyl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-fluorophenyl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-chlorophenyl)-1-isopentylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(3-(4-fluorophenyl)irolidin-3-yl)-4-isopropoxybenzenesulfonamide; N-((3R,4R)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((3R,4S)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(3-(4-chlorophenyl)pyridine-3-yl)-6-isopropoxypyridine-3-sulfonamide; (R)—N-(3-(4-chlorophenyl)-1-(3-methylbutanoyl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-((R)-3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (R)-N-((S)-3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (R)-N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-3-amino-N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; and (R)-3-amino-N-(3-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide or a salt, solvate, isotope, or tautomer thereof.

[0124] In certain embodiments, the compound is (S)-N-(6-fluoro-2,2-dimethylchroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3R)-1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3S)-1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 4-((1S,2S)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; tert-Butyl 4-((1S,2R)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; (S)-tert-butyl 2-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)pyrrolidine-1-carboxylate; (S)—N-(6-(difluoromethoxy)-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-tert-butyl 3-(fluoromethyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate; N-((2S,3S)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3R)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(2-oxo-1-(3-(trifluoromethyl)benzyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(spiro[chroman-2,1'-cyclopentan]-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-benzyl-3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((6S,7S)-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((6S,7R)-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3S)-2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3R)-2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-(3,4-dichlorophenyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2R)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-(2-phenylbutanoyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-4-(trifluoromethoxy)-N-(1-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)benzenesulfonamide; N-((1S,2S)-2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-(5-chloro-2-methoxyphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(5,8-difluorochroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2R)-2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2R)-2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-(3-bromophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-3-(3,4-dichlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate benzyl; N-((3S,4S)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((3S,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (S)—N-(1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (S)-N-((S)-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-((R)-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide; (S)-N-((S)-3-(4-chlorophenyl)pyrrolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-((R)-3-(4-chlorophenyl)pyrrolidin-3-yl)-N′-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-(3-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-tert-butyl 3-(4-chlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate; (S)—N-(3-(4-chlorophenyl)-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)-1-(methylsulfonyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)-1-isopentylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-isopropoxybenzenesulfonamide; N-((3S,4S)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((3S,4R)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-isopropoxypyridine-3-sulfonamide; (S)—N-(3-(4-chlorophenyl)-1-(3-methylbutanoyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-((S)-3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-((R)-3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-3-amino-N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; and (S)-3-Amino-N-(3-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide or a salt, solvate, isotope, or tautomer thereof.

[0125] In certain embodiments, the compound is N-(4-((4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidin-1-yl)sulfonyl)phenyl)acetamide; 1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl ester; (1R,2R)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl; (1R,2S)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl; (1S,2S)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl; (1S,2R)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl; N-(2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2R)-2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2R)-2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; 4-(trifluoromethoxy)-N-(3,4,4-trimethylcyclohexyl)benzenesulfonamide; (R)-4-(trifluoromethoxy)-N-(3,4,4-trimethylcyclohexyl)benzenesulfonamide; (S)-4-(trifluoromethoxy)-N-(3,4,4-trimethylcyclohexyl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((1R,3R)-3,4,4-trimethylcyclohexyl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((1R,3S)-3,4,4-trimethylcyclohexyl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((1S,3S)-3,4,4-trimethylcyclohexyl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((1S,3R)-3,4,4-trimethylcyclohexyl)benzenesulfonamide; N-(2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2R)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2R)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; 1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-1-carboxylate ethyl; (R)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-1-carboxylate ethyl; (S)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-1-carboxylate ethyl; 3,5-dimethyl-7-((4-(trifluoromethoxy)phenyl)sulfonamido)adamantane-1-carboxylate methyl ester; N-(2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; 4-(trifluoromethoxy)-N-(4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((4R,6R)-4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((4R,6S)-4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((4S,6S)-4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide; 4-(Trifluoromethoxy)-N-((4S,6R)-4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide or a salt, solvate, isotope, or tautomer thereof.

[0126] The compounds of the invention may have one or more stereocenters, and each stereocenter may independently exist in either the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic form. The compounds described herein include racemic, optically active, regioisomeric, and stereoisomeric forms, or combinations thereof, that possess the therapeutically useful properties described herein. Preparation of optically active forms can be accomplished in any suitable manner, including, but not limited to, resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. Compounds depicted herein by racemic formulas further represent either or a mixture of two enantiomers, or, if two or more chiral centers are present, all diastereomers or mixtures thereof.

[0127] In certain embodiments, compounds of the invention exist as tautomers, and all tautomers are included within the scope of the compounds described herein.

[0128] The compounds described herein also include isotopically labeled compounds in which one or more atoms have been replaced with an atom having the same atomic number but an atomic mass or mass number different from that normally found in nature (e.g., isotopologues). Examples of isotopes suitable for incorporation into the compounds described herein are: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, and 35Isotopically labeled compounds are prepared by any suitable method or process in which an appropriate isotopically labeled reagent is substituted for the otherwise employed non-labeled reagent.

[0129] In certain aspects, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0130] In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. Compounds of the invention may contain any substituent or combination of substituents provided herein.

[0131] 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 bases useful in the methods of the invention. The term "pharmaceutically acceptable salt" refers to a salt that has a toxicity profile within a range that makes it useful in pharmaceutical applications. In certain embodiments, the salt is a pharmaceutically acceptable salt. Salts that are not pharmaceutically acceptable may still have properties such as high crystallinity and have utility in the practice of the present invention, for example, in the process of synthesizing, purifying, or formulating compounds useful in the methods of the invention.

[0132] Suitable pharmaceutically acceptable acid addition salts may 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 may be selected from the aliphatic, alicyclic, aromatic, aromatic fatty acid, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, examples of which include 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, ethylenediamine diacetic ... Examples of suitable salts include carboxylic acid (i.e., pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, sulfanilic acid, 2-hydroxyethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, galacturonic acid, glycerophosphonic acid, and saccharin (e.g., saccharinate, saccharate). The salts may contain less than, one molar equivalent, or more than one molar equivalent of acid or base relative to any compound of the invention.

[0133] Suitable pharmaceutically acceptable base addition salts of the compounds of the invention include, for example, ammonium salts and metallic salts, including alkali metal, alkaline earth metal and transition metal salts, such as calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as N,N'-dibenzylethylene-diamine, 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.

[0134] synthesis The present invention further provides methods for preparing the compounds of the present invention. The compounds of the present teachings can be prepared from commercially available starting materials, compounds known in the literature, or easily prepared intermediates by employing standard synthetic methods and procedures known to those skilled in the art according to the procedures outlined herein. 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.

[0135] Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it is understood that 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 procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied in order to optimize the formation of the compounds described herein.

[0136] 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 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography, such as high performance liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0137] The preparation of compounds may involve the protection and deprotection of various chemical groups.The need for protection and deprotection and the selection of suitable protecting groups can be easily determined by those 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, which is incorporated herein by reference in its entirety for all purposes.

[0138] The reactions or processes described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents are typically substantially non-reactive with reactants, intermediates, and / or products at the temperature at which the reaction is carried out, i.e., the temperature can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of more than one solvent.A suitable solvent for a particular reaction step can be selected depending on the particular reaction step.

[0139] In certain embodiments, compounds synthesized using the methods described herein may contain one or more chiral carbon atoms, resulting in two or more isomers. Absolute stereochemistry may be represented using a wedge bond (bold or horizontal). In certain embodiments, the product formed in any of the reactions described may be racemic. When 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 separation include, but are not limited to, supercritical fluid chromatography (SFC), chiral HPLC, crystallization, derivatization, or any combination thereof.

[0140] As used herein, "enantiomer I" or "diastereomer I" refers to the first enantiomer or diastereomer that elutes from a chiral column under specific chiral analytical conditions specified for the specified compound; "enantiomer II" or "diastereomer II" refers to the second enantiomer or diastereomer that elutes from a chiral column under specific chiral analytical conditions specified for the specified compound. Such nomenclature does not imply or confer any particular relative and / or absolute configurations of these compounds.

[0141] In certain embodiments, 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 with known protecting groups (esters, amides, carbamates, ethers, etc.), followed by separation of the isomers by a suitable method. The desired compound is finally obtained via removal of the protecting group.

[0142] The present disclosure provides compounds of Formula (I) and Formula (II). Those skilled in the art will recognize that techniques and / or methods for the synthesis of compounds of Formula (I) are often applicable to the synthesis of compounds of Formula (II), and vice versa.

[0143] In certain embodiments, compounds of the present disclosure having the structure of formula (I) include sulfonamides of formula (Ia'), which can be prepared as described herein. Ar, A, and R 2 Compounds of formula (Ia'), where Ia is defined within the scope of this disclosure, are prepared from the corresponding arylsulfonyl chloride 1-1 and amine 1-2 in the presence of a base and a solvent (Scheme 1). A suitable base for sulfonylation is EtN. A suitable solvent for sulfonylation is CHCl. TIFF2024508687000245.tif27128

[0144] In certain embodiments, the arylsulfonyl halide (1-1) and / or amine (1-2) compounds are each commercially available. In other embodiments, at least one of the arylsulfonyl halide and amine is synthesized using synthetic methods known to those skilled in the art.

[0145] Generally, compounds of formula (Ia'), which are compounds of formula 2-6, where v is 1 or 2, w is 0 or 1, R is phenyl optionally substituted with at least one substituent selected from the group consisting of halogen, C1-C3 alkoxy, and trifluoromethyl, X is halogen selected from the group consisting of Cl and Br, and PG is a protecting group including, but not limited to, benzyl (Bn), tert-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz), can be prepared according to the synthesis provided in Scheme 2. TIFF2024508687000246.tif43145

[0146] As shown in Scheme 2, cyclic ammonium halide 2-1 can be protected with a suitable protecting group, such as tert-butyloxycarbonyl (Boc), using a suitable protecting group precursor (e.g., di-tert-butyl carbonate) to afford protected amine 2-2. Displacement of the tertiary alcohol of 2-2 with an azide to afford tertiary azide 2-3 can be achieved by any of a number of conditions / reagents, including, but not limited to, (a) TFA and NaN; (b) BF·EtO and TMS-N; (c) DBU and diphenylphosphoryl azide (DPPA); and (d) SOCl or MsCl and NaN. Reduction of tertiary azide 2-3 to the corresponding amine 2-4 can be achieved under suitable reaction conditions, including, but not limited to, treatment with PPh and paratoluenesulfonic acid (PTSA). Amine 2-4 can be sulfonylated to the corresponding sulfonamide 2-5 using arylsulfonamides under any of a number of suitable basic reaction conditions, including, but not limited to, (a) EtN and DCM; (b) pyridine and THF; (c) neat pyridine; and (d) EtN, DMAP, and DCM. Removal of the protecting group (PG) to give 2-6 can be achieved by treatment with (a) HCl in dioxane; (b) TMS-I in ACN; and (c) Pd / C in H and MeOH, depending on the specific protecting group employed. In certain embodiments, the protecting group is Boc and is removed with HCl in dioxane. In certain embodiments, the protecting group is Cbz and is removed with TMS-I in ACN.

[0147] Alternatively, as shown in Scheme 3, compounds of formula 2-6 can be prepared from diammonium halide salt 3-1, which can be protected with a suitable protecting group, such as tert-butyloxycarbonyl (Boc), using a suitable protecting group precursor (e.g., di-tert-butyl carbonate) to directly afford the mono-protected amine 2-4. Compounds of formula 2-6 can be prepared from the mono-protected amine 2-4 following the sequences described elsewhere herein. TIFF2024508687000247.tif48146

[0148] Compounds of the present disclosure having the structure of formula (I) include sulfonimide amides of formula (Ib') or formula (Ic'), which can be prepared as described herein. a , and R 2 Compounds of formula (Ib') or (Ic'), as defined within the scope of this disclosure, can be prepared from the corresponding arylsulfonyl chloride 1-1 and amine 1-2 (Scheme 4). The arylsulfonyl chloride 1-1 can be reduced with a suitable reducing agent, such as Na2SO3, in the presence of a suitable base, such as NaHCO3, to give sulfinate 4-1. The sulfinate 4-1 can be chlorinated to the corresponding sulfinyl chloride 4-2 with a suitable chlorinating agent, such as oxalyl chloride. The sulfinyl chloride 4-2 can be condensed with a suitable amine (e.g., 4-3) in the presence of a suitable base, such as Et3N, to give sulfinamide 4-4. The sulfinamide 4-4 can be converted to a compound of formula (Ib') by oxidation with a suitable oxidizing agent, such as t-BuOCl, followed by condensation with amine 1-2.

[0149] In certain embodiments, sulfinimidamide (Ib') may tautomerize to provide sulfinimidamide (Ic'). In certain embodiments, sulfinimidamide (Ic') may tautomerize to provide sulfinimidamide (Ib'). In certain embodiments, compounds of formula (Ib') and (Ic') may exist as a mixture. TIFF2024508687000248.tif50147

[0150] In certain embodiments, R BN-Alkyl-sulfonamides of formula (Ia"), where R is C1-C6 alkyl, can be prepared from sulfonamides of formula (Ia'). In certain embodiments, compounds of formula (Ia") are prepared from compounds of formula (Ia') by a modified Mitsunobu reaction (Scheme 5). In certain embodiments, sulfonamides (Ia') are treated with dialkyl azodicarboxylates, non-limiting examples of which include diethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate (DIAD), in the presence of a phosphine ligand, non-limiting examples of which include PPh3, and a suitable primary or secondary alcohol. TIFF2024508687000249.tif27128

[0151] As shown in Scheme 6, tertiary alcohol 2-2 can be converted to α-haloamide 6-1 with a suitable α-halonitrile, such as 2-chloroacetonitrile, using a suitable acid, such as trifluoroacetic acid. Removal of the α-haloacyl moiety of 6-1 can be achieved under suitable reaction conditions, including, but not limited to, treatment with thiourea in the presence of a suitable acid, such as acetic acid, at a suitable temperature, including, but not limited to, 80°C, to provide amine 2-4. Amine 2-4 can be sulfonylated to the corresponding sulfonamide 2-5 with an arylsulfonamide and any of a number of suitable basic reaction conditions, including, but not limited to, (a) EtN and DCM; (b) pyridine and THF; (c) neat pyridine; and (d) EtN, DMAP, and DCM. Removal of the protecting group (PG) to provide 2-6 can be achieved depending on the specific type of protecting group employed, as described elsewhere herein. TIFF2024508687000250.tif57142

[0152] As shown in Scheme 7, secondary amine 7-1 can be protected with a suitable protecting group (PG'), such as benzyl, using a suitable alkylating agent, such as benzyl bromide, in the presence of a suitable base, such as EtN, to give 7-2. Nitrile 7-2 can be hydrolyzed to amide 7-3 in the presence of a suitable acid, including HSO, at a suitable temperature, such as 60 °C. Hoffmann rearrangement of amide 7-3 can be achieved under suitable reaction conditions, including, but not limited to, treatment with a suitable halogenating reagent, such as [bis(trifluoroacetoxy)iodo]benzene, to give amine 7-4. Amine 7-4 can be sulfonylated to the corresponding sulfonamide 7-5 using an arylsulfonamide under any of a number of suitable basic reaction conditions, including, but not limited to, (a) EtN and DCM; (b) pyridine and THF; (c) neat pyridine; and (d) EtN, DMAP, and DCM. Removal of the protecting group (PG') to give 2-6 can be achieved under suitable reaction conditions, including treatment with a suitable N-dealkylating reagent, including 1-chloroethyl chloroformate. TIFF2024508687000251.tif48146

[0153] method The present disclosure relates, in part, to a method of treating, preventing, and / or ameliorating a PP2A-associated disease in a subject, 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.

[0154] 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.

[0155] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.

[0156] 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) or (II), a salt, a solvate, an enantiomer, a diastereomer, an isotopologue, a tautomer, or any mixture thereof, for use as a medicament for treating, preventing, and / or ameliorating a disease or condition in a patient.

[0157] The compounds according to one or more embodiments disclosed herein can be modulators of PP2A. The compounds described herein can exhibit antiproliferative effects and can be useful as monotherapy in cancer treatment and / or in the treatment of other indications described herein. Furthermore, they can be used in combination with other drugs to restore sensitivity to chemotherapy, targeted therapy, or immunotherapy to which resistance has developed.

[0158] In certain embodiments, disease or condition is ameliorated by regulating PP2A.In certain embodiments, 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 one embodiment, disease is cancer.

[0159] 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) or (II), a solvate, an enantiomer, a diastereomer, an isotopologue, a tautomer, or a pharmaceutically acceptable salt thereof.

[0160] In certain embodiments, a method of 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) or (II), solvate, enantiomer, diastereomer, isotopologue, tautomer, or a pharmaceutically acceptable salt thereof.

[0161] In certain embodiments, provided is a method 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.

[0162] In certain embodiments, the cancer is cancer of the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal tract, gums, head, kidney, liver, lung, nasopharynx, neck, ovaries, 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; carcinoma, undifferentiated; giant cell or spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; calcifying epithelioma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; mixed hepatocellular and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyps; adenocarcinoma, familial adenomatous polyposis; solid tumor; carcinoid tumor, malignant; bronchioloalveolar adenocarcinoma; Papillary adenocarcinoma; chromophobe carcinoma; eosinophil carcinoma; eosinophil carcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; Cystoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; invasive ductal carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget's disease, breast; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma with squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; Cell tumors, malignant; Androblastoma, malignant; Sertoli cell carcinoma; Leydig cell tumor, malignant; Lipid cell tumor, malignant; Paraganglioma, malignant; Extramammary paraganglioma, malignant; Pheochromocytoma; Glomerular sarcoma; Malignant melanoma; Amelanotic melanoma; Superficial spreading melanoma; Malignant melanoma in giant pigmented nevus; Epithelioid cell melanoma; Blue nevus, malignant; Sarcoma; Fibrosarcoma; Fibrous histiocytoma, malignant; Myxosarcoma; Liposarcoma; Leiomyosarcoma; Rhabdomyosarcoma; Embryonic rhabdomyosarcoma; Alveolar rhabdomyosarcoma; Stromal sarcoma; Mixed tumors, malignant; Mixed Müllerian tumor; Nephroblastoma; Hepatoblastoma; Carcinosarcoma; Mesenchymoma, malignant; Brenner tumor, malignant; Phyllodes tumor, malignant; Synovial sarcoma; Mesothelioma, malignant; Dysembryopathies; Embryonal carcinoma; Teratoma, malignant; Ovarian ventricle, malignant; Choriocarcinoma; Mesonephroma, malignant; Angiosarcoma; Hemangioendothelioma, malignant; Kaposi's sarcoma; Hemangiopericytoma, malignant; Lymphangiosarcoma; Osteosarcoma; Juxtacortical osteosarcoma; Chondrosarcoma; Chondroblastoma, malignant; Mesenchymal chondrosarcoma; Giant cell tumor of bone; Ewing's sarcoma; Odontogenic tumor, malignant; Ameloblastic epithelial sarcoma; Ameloblastoma, malignant; Ameloblastic fibrosarcoma; Pinealoma, malignant; Chordoma; Glioma, malignant;Ependymoma; astrocytoma; protoplasmic astrocytoma; fibrous astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroglioma; undifferentiated neuroectodermal tumor; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory tumor; meningioma, malignant; neurofibrosarcoma; schwannoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's; paragranuloma; malignant lymphoma, small cell; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; 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; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

[0163] In certain embodiments, the autoimmune disease is 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 disease, Sjogren's disease syndrome, systemic lupus erythematosus (SLE), vasculitis syndrome (e.g., giant cell arteritis, Behcet's disease & Wegener's granulomatosis), vitiligo, hematological findings secondary to autoimmune disease (e.g., anemia), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune hearing loss (e.g., Meniere's disease), Goodpasture's syndrome, Graves' disease, HIV-associated autoimmune syndrome, and Guillain-Barré syndrome.

[0164] In certain embodiments, the neurodegenerative disease is Alzheimer's disease. In certain embodiments, the neurodegenerative disease is Parkinson's disease.

[0165] 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, utilize PP2A using various approaches to modify, control, or inactivate host cellular activity. Therefore, the compounds according to one or more embodiments disclosed herein may further be used in methods for treating viral infections in patients by administering to the patient a therapeutically effective amount of a compound according to one or more embodiments disclosed herein. Examples of viruses that may cause the viral infection 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-lymphotropic virus type 1 (HTLV-1), herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), hepatitis B virus, bovine papillomavirus (BPV-1), human T-cell lymphotropic virus type 1, Japanese encephalitis virus, respiratory syncytial virus (RSV), and West Nile virus.

[0166] A compound or pharmaceutical composition 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.

[0167] The compounds according to one or more embodiments disclosed herein may further be used to prevent 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.

[0168] The compounds according to one or more embodiments disclosed herein can be used for the manufacture of a medicament for the treatment or prevention of a betacoronavirus infection.

[0169] 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).

[0170] In a particular embodiment, the betacoronavirus is SARS-CoV.

[0171] In certain embodiments, the betacoronavirus is SARS-CoV-2.

[0172] Serine / threonine phosphatases, including PP2A, may be involved in the regulation of synaptic plasticity. Decreased PP2A activity is associated with the maintenance of synaptic long-term potentiation (LTP), and treatment with PP2A modulators as described herein can reverse synaptic LTP. Because abuse of psychostimulant drugs such as cocaine and methamphetamine is associated with deleterious synaptic LTP, which may underlie addiction and relapse, the PP2A modulators described herein may be useful as treatments for psychostimulant drug abuse.

[0173] 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, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0174] 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. A carrier may be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0175] Pharmaceutical compositions can be prepared in any manner known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, 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 not biologically or otherwise undesirable.

[0176] 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 vary depending, 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. Typically, 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.

[0177] 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 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.

[0178] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft 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, surfactant, 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 scored and may be formulated to provide delayed or controlled release of the active ingredient therein. All formulations intended for oral administration should be in a dosage suitable for such administration. Push-fit capsules may contain the active ingredient in combination 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, active compounds can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol.In addition, stabilizers can be added.Sugary tablet cores are provided with suitable coatings.For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.For identification or to characterize different combinations of active compound dosages, dyes or pigments can be added to tablets or sugar-coated tablet coatings.

[0179] The compounds of the present disclosure can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations can be provided in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The formulations can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in powder or freeze-dried (lyophilized) form, requiring only the addition of a sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0180] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of active compounds, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and 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, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0181] In addition to the formulation described above, the compound of the present disclosure can also be formulated as sustained-release preparation.This long-acting formulation 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 emulsion in acceptable oil) or ion exchange resin, or as poorly soluble derivative, for example, as poorly soluble salt.

[0182] 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.

[0183] The compounds 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.

[0184] In one embodiment, the compound disclosed herein can be administered locally, that is, by non-systemic administration.This includes applying the compound disclosed herein to the epidermis or buccal cavity, and dropping such compound into ear, eye and nose, so that the compound does not enter bloodstream significantly.In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0185] 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, for example, comprise 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, it 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, it may comprise 0.1% to 1% w / w of the formulation.

[0186] For administration by inhalation, the compounds of the present disclosure can be conveniently delivered from an inhaler, a nebulizer pressurized pack, or other convenient means of delivering an aerosol spray.Pressurized packs can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases.In the case of pressurized aerosols, 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 mixture of the compound and a suitable powder base, such as lactose or starch.The powder composition can be provided in a unit dosage form, for example, a capsule, cartridge, gelatin, or blister pack, in which the powder can be administered with the aid of an inhaler or insufflator.

[0187] Intranasal delivery can be particularly 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 nasopharynx-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.

[0188] In one embodiment, the unit dosage formulation contains an effective dose, or an appropriate fraction thereof, of the active ingredient.

[0189] It will be understood that in addition to the ingredients particularly mentioned above, the formulations described above may include 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.

[0190] Combination therapy In certain cases, it may be appropriate to administer at least one compound of Formula (I) or (II) (enantiomer, diastereomer, tautomer, or a 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 receiving one of the compounds herein for the treatment of cancer, it may be appropriate to administer an antiemetic in combination. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be improved by administering an adjuvant (i.e., the adjuvant itself may have minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic effect on the patient is improved). 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 therapeutic benefit. By way of example only, in cancer treatment involving the administration of one of the compounds described herein, providing the patient with another cancer therapeutic agent may also result in an increased therapeutic benefit. In either case, regardless of the disease, disorder, or condition being treated, the benefit experienced by the patient overall may simply be additive of the two therapeutic agents, or the patient may experience a synergistic effect.

[0191] The present compounds may be particularly useful in combination with therapeutic agents and / or anticancer agents. Thus, the present disclosure provides combinations of compounds of formula (I) or (II) used in combination with therapeutic agents and / or anticancer agents for simultaneous, separate, or sequential administration. The compounds of the present disclosure and the other anticancer agents can act additively or synergistically. A synergistic combination of the present compounds with another anticancer agent may allow for the use of lower doses of one or both of these agents, and / or less frequent administration of the present compounds and one or both of the other anticancer agents, and / or less frequent administration of the agents may reduce any toxicity associated with administering the agents to patients without reducing the effectiveness of the agents in treating cancer. Furthermore, a synergistic effect 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.

[0192] Therapeutic agents and / or anti-cancer agents can be administered according to treatment protocols well known in the art. It will be apparent to those skilled in the art that the administration of therapeutic agents and / or anti-cancer agents can be varied 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, treatment protocols (e.g., dosage and frequency of administration) can be varied taking into account the observed effects of the administered therapeutic agent (i.e., anti-neoplastic agent or radiation) on the patient, and taking into account the observed disease response and observed side effects to the administered therapeutic agent.

[0193] 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, antineoplastic 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 I. The compound may be administered in combination with one or more agents selected from: I antagonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokine or cytokine inhibitors, bisphosphanates, rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR agonists, HSP90 inhibitors, smoothened antagonists, Ras isoform inhibitors, telomerase inhibitors, protease inhibitors, metalloproteinase inhibitors, aminopeptidase inhibitors, immunomodulators, therapeutic antibodies, and protein kinase inhibitors, e.g., tyrosine kinase or serine / threonine kinase inhibitors.

[0194] In certain embodiments, a combination of a compound of Formula I and an anti-cancer agent is provided for simultaneous, separate, or sequential administration.

[0195] Those skilled in the art will be able to determine which combination of drugs is useful based on the specific characteristics of the drug and the cancer involved.These drug classes include: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenylprotein 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 therapeutic agents, gamma-secretase inhibitors, receptor tyrosine kinase (RTK) interfering agents, cell cycle checkpoint interfering agents, PARP inhibitors, HDAC inhibitors, Smo antagonists (HH inhibitors), HSP90 inhibitors, CYP17 inhibitors, third-generation AR antagonists, JAK inhibitors, such as ruxolitinib (trade name Jakavi), and BTK kinase inhibitors.

[0196] Anti-cancer agents suitable for use in combination therapy with the compounds disclosed herein include, but are not limited to: 1) alkaloid and natural product drugs, including microtubule inhibitors (e.g., vincristine, vinblastine, and vindesine, and vinorelbine, etc.), microtubule stabilizers (e.g., paclitaxel [Taxol], docetaxel, taxotere, etc.), and topoisomerase inhibitors, e.g., chromatin function inhibitors, including epipodophyllotoxins (e.g., etoposide [VP-161 and teniposide [VM-261], etc.) and agents targeting topoisomerase I (e.g., camptothecin, topotecan (hycamtin) and irinotecan [CPT-11], rubitecan (oracecin), etc.); 2) Nitrogen mustards (e.g., mechlorethamine, chlormethine, chlorambucil, cyclophosphamide, estramustine (Emcyte, Estracyt), ifosfamide, melphalan (Alkeran), etc.); alkyl sulfonates such as busulfan (Myleran), nitrosoureas (e.g., carmustine or BCNU (bischloroethylnitrosourea), fotemustine Covalent DNA binders [alkylating agents], including lomustine, semustine, streptozocin, etc., and other alkylating agents, including temozolomide (trade names Temodar and Temodar and Temcad), altretamine (also known as hexalen), and mitomycin (e.g., dacarbazine, procarbazine ethyleneimine / methylmelamine, triethylenemelamine (TEM), triethylenethiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine), and mitomycin, uramustine, etc.); and 3) Noncovalent DNA binders [antineoplastic antibiotics], including nucleic acid inhibitors (e.g., dactinomycin [actinomycin D1], anthracyclines (e.g., daunorubicin [daunomycin and cerubicin], doxorubicin [adrianaysin], epirubicin (erence), and idarubicin [idamycin], valrubicin (barstar), etc.), anthracenediones (e.g., anthracycline analogs such as [mitoxantrone]), bleomycin (blenoxane), amsacrine and plicamycin (mithramycin), dactinomycin, and mitomycin C.

[0197] In certain embodiments, a patient with cancer is treated with a compound of Formula (I) or (II) in combination with radiation therapy. In certain embodiments, the method comprises administering a therapeutically effective amount of a compound of the present disclosure to a patient with cancer, and adjunctively treating the patient with an 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.

[0198] In one embodiment, the compound or pharmaceutical composition is selected from the group consisting of oseltamivir phosphate, zanamivir or Virazol®, 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, It may further comprise or be administered in combination with one or more other antiviral agents, including, but not limited to, didanosine, zalcitabine, stavudine, lamivudine, and abacavir, non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine, delavirdine, and efavirenz, protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and other known antiviral compounds and preparations.

[0199] In one embodiment, the compounds or pharmaceutical compositions may be co-administered with one or more antiviral agents. The compounds or pharmaceutical compositions of the present invention may be administered in any order.

[0200] Controlled-Release Formulations and Drug Delivery Systems In certain embodiments, the compositions and / or formulations of the present invention may be, but are not limited to, short-release formulations, rapid-offset formulations, or controlled-release formulations, including sustained-release, delayed-release, and pulsed-release formulations.

[0201] The term sustained release is used in its conventional sense to refer to a drug formulation that provides gradual release of drug over an extended period of time, resulting in substantially, but not necessarily, constant blood levels of drug over an extended period of time, which may be as long as one month or more and should result in a longer release than would be obtained if the same amount of drug were administered in bolus form.

[0202] For sustained release, the compounds may be formulated with a suitable polymeric or hydrophobic material that provides sustained release properties to the compound. Thus, compounds for use in the methods of the invention may be administered in the form of microparticles, for example, by injection, or by implantation in the form of a wafer or disk.

[0203] In certain embodiments of the invention, compounds useful within the invention are administered to a subject, either alone or in combination with other drugs, using sustained release formulations.

[0204] The term delayed release is used herein in its conventional sense to refer to drug formulations that provide an initial release of drug after some delay following drug administration, which may, but need not, include a delay of from about 10 minutes up to about 12 hours.

[0205] The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of drug in a manner that results in a pulsatile plasma profile of the drug following drug administration.

[0206] The term immediate release is used in its conventional sense to refer to a drug formulation that provides release of drug immediately after drug administration.

[0207] As used herein, short-term refers to any period of time of 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 or less after drug administration, and any or all whole or partial increments thereof.

[0208] Administration / Dosage The compound can be administered to animals several times a day, or less frequently, for example, once a day, once a week, once every two weeks, once a month, or even less frequently, for example, once every few months or once a year or less.It is understood that the amount of compound administered per day can be, for example, administered every day, every other day, every two days, every three days, every four days, or every five days, in non-limiting examples.For example, in alternate-day administration, a dose of 5 mg per day can be started on Monday, the first subsequent dose of 5 mg per day can be administered on Wednesday, and the second subsequent dose of 5 mg per day can be administered on Friday.The frequency of administration is readily apparent to those skilled in the art and varies depending on many factors, including but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.

[0209] In certain embodiments, the compositions of the 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 invention are administered to a patient in dosage ranges including, but not limited to, once daily, every 2 days, or every 3 days to once weekly and once every two weeks. It will be readily apparent to those skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from subject to subject depending on many factors, including, but not limited to, age, disease or disorder being treated, sex, general health, and other factors. Thus, the invention should not be construed as limited to any particular dosing regimen, and the precise dosage and composition administered to any patient will be determined by the attending physician, taking into account all other factors relevant to the patient.

[0210] The compounds according to one or more embodiments disclosed herein may be administered orally or via injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adults is generally 5 mg to 2 g per day. Tablets or other dosage forms provided as individual units may conveniently contain a fixed amount of one or more compounds, such as an effective dose or a multiple thereof, for example, a unit containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

[0211] For administration, the compounds of the invention may be administered in doses of 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 2,000 mg, about The range may be from 5 mg to about 1,000 mg, from about 10 mg to about 750 mg, from about 20 mg to about 600 mg, from about 30 mg to about 500 mg, from about 40 mg to about 400 mg, from about 50 mg to about 300 mg, from about 60 mg to about 250 mg, from about 70 mg to about 200 mg, from about 80 mg to about 150 mg, and any and all whole or partial increments therebetween.

[0212] 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 thereof.

[0213] The amount of active ingredient that may 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.

[0214] 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 will be the responsibility of the attending physician.The specific dosage level for any particular patient will vary depending on various factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, the exact disease being treated, and the severity of the indication or condition being treated.In addition, the administration route can vary depending on the condition and its severity.

[0215] LCMS conditions Method A: HPLC Alliance 2695 system employing a Gemini NX-C18 Phenomenex (30 × 2 mm), 3 μm column, with eluents containing eluent A = H2O + 0.05% TFA (v / v) and eluent B = CH3CN + 0.035% TFA. Oven temperature: 55 °C; gradient: t 0min =2%B;t 2.5min =98%B;t 3.5min =98%B;t 3.6min =2%B;t 5min = 5% B (v / v). Flow rate: 0.9 mL / min. Positive electrospray ES+; capillary: 3.5 kV; cone voltage: 15 V.

[0216] Method B: A Waters Acquity UPLC system employing a Waters Acquity UPLC CSH C18 (50 × 2.1 mm), 1.7 μm column, with eluents containing eluent A = HO + 0.02% HCOOH (v / v) and eluent B = CH3CN + 0.02% HCOOH (v / v). Oven temperature: 55 °C; gradient: t 0min =0.2%B;t 4min =98%B;t 4.5min =98%B;t 4.6min =2%B;t 5min = 2% B. Flow rate: 1 mL / min. Negative electrospray ES-; capillary: 3 kV; cone voltage: 15 V.

[0217] Method C: Waters Acquity UPLC system employing a Waters Acquity UPLC CSH C18 (2.1 × 50 mm), 1.7 μm column, with eluents containing eluent A = HO + 0.02% HCOOH and eluent B = CH3CN + 0.02% HCOOH. Oven temperature: 55 °C; gradient: t 0min =2%B;t 4min =98%B;t 4.5min =98%B;t 4.6min = 2%B; and t 5.0min = 2% B (v / v). Flow rate: 1 mL / min. Electrospray ionization mode; capillary: 3 kV; sample cone: 15 / 30 V.

[0218] Method D: Waters Acquity UPLC system employing a Waters Acquity UPLC CSH C18 (2.1 × 50 mm), 1.7 μm column, A = H2O + 0.05% TFA (v / v) and eluent B = CH3CN + 0.035% TFA. Oven temperature: 55 °C; gradient: t 0min =2%B;t 1min =98%B;t 1.5min =98%B;t 1.52min =2%B;t 1.7min = 2% B (v / v). Flow rate: 0.8 mL / min. Positive electrospray ES+; capillary: 0.8 kV; cone voltage: 15 V.

[0219] Method E: Waters Acquity UPLC system employing a Waters Acquity UPLC CSH C18 (2.1 × 50 mm), 1.7 μm column, A = HO + 0.05% TFA (v / v) and eluent B = CH3CN + 0.035% TFA. Oven temperature: 55 °C; gradient: t 0min =2%B;t 1min =98%B;t 1.5min =98%B;t 1.52min =2%B;t 1.7min = 2% B (v / v). Flow rate: 0.8 mL / min. Positive electrospray ES+; capillary: 0.8 kV; cone voltage: 10 V.

[0220] Method F: Waters Acquity UPLC system with A = HO + 0.02% HCOOH (v / v) and B = CHCN + 0.02% HCOOH, employing a Waters Acquity UPLC CSH C18 (2.1 x 100 mm), 1.7 μm column. Oven temperature: 55 °C; gradient: t 0min =2%B, t 15min =98%B, t 15.2min =2%B, t 18min = 2% B (v / v). Flow rate: 0.7 mL / min. Electrospray ionization mode; capillary: 3 kV; sample cone: 15 / 30 V.

[0221] Method G: Waters Acquity UPLC system employing a Waters Acquity UPLC CSH C18 (2.1 × 50 mm), 1.7 μm column, A = H2O + 0.05% TFA (v / v) and eluent B = CH3CN + 0.035% TFA. Oven temperature: 55 °C; gradient: t 0min =2%B;t 2.4min =98%B;t 3.0min =98%B;t 3.03min =2%B;t 3.5min = 2% B (v / v). Flow rate: 0.8 mL / min. Positive electrospray ES+; capillary: 0.8 kV; cone voltage: 15 V.

[0222] Method H: Waters Acquity UPLC system employing a Waters Acquity UPLC CSH C18 (50 × 2.1 mm), 1.7 μm column, with eluents containing eluent A = HO + 0.02% HCOOH (v / v) and eluent B = CH3CN + 0.02% HCOOH (v / v). Oven temperature: 55 °C; gradient: t 0min =0.2%B;t 4min =98%B;t 4.5min =98%B;t 4.6min =2%B;t 5min = 2% B. Flow rate: 1 mL / min. Negative electrospray ES-; capillary: 3 kV; sample cone: 15 / 30 V. [Example]

[0223] Various aspects of the present application can be better understood by reference to the following examples, which are presented by way of illustration, and the scope of the present application is not limited to the examples given herein.

[0224] Example 1: Synthesis of Compounds 1-34 Synthetic Procedure for Sulfonamides - Coupling of Sulfonyl Chlorides and Amines Each vial was charged with the amine reagent (0.4221 mmol, 1.1 eq) and EtN (1.5348 mmol, 4 eq, 214 μL). A solution of 4-(trifluoromethoxy)benzenesulfonyl chloride in DCM (0.384 mmol, 1.0 eq, 2 mL, 0.192 mmol / mL) was dispensed into each vial. The reaction mixture was stirred overnight at 25 °C. The reaction mixture was filtered through a 3 mL ChemElut cartridge (pre-treated with HCl 1 M (3 mL)) and eluted with 2 mL of DCM. The resulting fractions were concentrated under a stream of nitrogen for 2 h at room temperature and then dried under vacuum at 40 °C overnight. Purification was performed by SCX, PE-AX, or flash chromatography, if necessary.

[0225] In a specific embodiment, an SCX: ISOLUTE - SCX (1 g, 6 mL) cartridge was used. The cartridge was eluted with 10 mL of DCM, and then 1 mL of diluted crude solution was filtered by gravity. The cartridge was eluted twice with 4 mL of DCM and once with 2 mL of 2N NH3 in MeOH. The desired fractions were concentrated under a stream of nitrogen at room temperature for 2 hours and then dried under vacuum at 40 °C overnight.

[0226] In a specific embodiment, a PE-AX: ISOLUTE - PE-AX (1 g, 6 mL) cartridge was used. The cartridge was eluted with 10 mL of DCM, and then 1 mL of the diluted crude solution was filtered by gravity. The cartridge was eluted twice with 4 mL of 1.25 N HCl in MeOH and once with 2 mL of 1.25 N HCl in MeOH. The desired fractions were concentrated under a stream of nitrogen at room temperature for 2 hours and then vacuum dried at 40°C overnight.

[0227] In certain embodiments, flash chromatography was used to purify the crude product by flash chromatography on silica gel using a gradient of 2% to 10% MeOH in DCM. The desired fractions were concentrated under a stream of nitrogen at room temperature for 2 hours and then dried under vacuum at 40° C. overnight.

[0228] LCMS analyses were performed using Method A unless otherwise indicated.

[0229] The following compounds were prepared according to the procedures and conditions provided herein.

[0230] N-(4-((4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidin-1-yl)sulfonyl)phenyl)acetamide (1) TIFF2024508687000252.tif23128

[0231] Table 1: Analytical data for compound 1 TIFF2024508687000253.tif22150 Starting material (amine): N-(4-((4-aminopiperidin-1-yl)sulfonyl)phenyl)acetamide.

[0232] N-(1-(5-chloro-2-methoxyphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (2) TIFF2024508687000254.tif33128

[0233] Table 2: Analytical data for compound 2 TIFF2024508687000255.tif22150 Starting material (amine): 1-(5-chloro-2-methoxyphenyl)pyrrolidin-3-amine.

[0234] N-(1-(3-bromophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (3) TIFF2024508687000256.tif21128

[0235] Table 3: Analytical data for compound 3 TIFF2024508687000257.tif22150 Starting material (amine): 1-(3-bromophenyl)pyrrolidin-3-amine.

[0236] Cis 1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl (4) TIFF2024508687000258.tif21128

[0237] Table 4: Analytical data for compound 4 TIFF2024508687000259.tif22150 Starting material (amine): cis 1-amino-2,3-dihydro-1H-indene-2-carboxylate methyl hydrochloride.

[0238] N-(1-(3,4-dichlorophenyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (5) TIFF2024508687000260.tif23128

[0239] Table 5: Analytical data for compound 5 TIFF2024508687000261.tif22150 Starting material (amine): 1-(3,4-dichlorophenyl)piperidin-3-amine.

[0240] 4-(trifluoromethoxy)-N-(1-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)benzenesulfonamide (6) TIFF2024508687000262.tif27128

[0241] Table 6: Analytical data for compound 6 TIFF2024508687000263.tif22150 Starting material (amine): 1-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-amine.

[0242] N-(2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide (7) TIFF2024508687000264.tif30128

[0243] Table 7: Analytical data for compound 7 TIFF2024508687000265.tif22150 Starting material (amine): 2-(4-fluorophenoxy)cyclohexane-1-amine.

[0244] 4-(Trifluoromethoxy)-N-(3,4,4-trimethylcyclohexyl)benzenesulfonamide (8) TIFF2024508687000266.tif18128

[0245] Table 8: Analytical data for compound 8 TIFF2024508687000267.tif22150 Starting material (amine): 3,4,4-trimethylcyclohexane-1-amine.

[0246] trans N-(2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (9) TIFF2024508687000268.tif25128

[0247] Table 9: Analytical data for compound 9 TIFF2024508687000269.tif22150 Starting material (amine): trans 2-(4-chlorophenyl)-1-methylpyrrolidin-3-amine.

[0248] N-(5,8-difluorochroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (10) TIFF2024508687000270.tif21128

[0249] Table 10: Analytical data for compound 10 TIFF2024508687000271.tif21150 a LCMS Method B; Starting material (amine): 5,8-difluorochroman-4-amine.

[0250] N-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethoxy)benzenesulfonamide (11) TIFF2024508687000272.tif27128

[0251] Table 11: Analytical data for compound 11 TIFF2024508687000273.tif22150 a LCMS Method B; Starting material (amine): 4,6-dichloro-2,3-dihydro-1H-inden-1-amine.

[0252] N-(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide (12) TIFF2024508687000274.tif30128

[0253] Table 12: Analytical data for compound 12 TIFF2024508687000275.tif22150 a LCMS Method B; Starting material (amine): 6-chloro-1,2,3,4-tetrahydronaphthalen-1-amine.

[0254] N-(2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide (13) TIFF2024508687000276.tif28128

[0255] Table 13: Analytical data for compound 13 TIFF2024508687000277.tif22150 Starting material (amine): 2-phenylcycloheptan-1-amine.

[0256] N-(1-(3-chlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide (14) TIFF2024508687000278.tif26128

[0257] Table 14: Analytical data for compound 14 TIFF2024508687000279.tif22150 Starting material (amine): 1-(3-chlorophenyl)cyclopentan-1-amine.

[0258] N-(1-(3-methoxyphenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide (15) TIFF2024508687000280.tif29128

[0259] Table 15: Analytical data for compound 15 TIFF2024508687000281.tif22150 Starting material (amine): 1-(3-methoxyphenyl)cyclopentan-1-amine.

[0260] N-(2-oxo-1-(3-(trifluoromethyl)benzyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (16) TIFF2024508687000282.tif19128

[0261] Table 16: Analytical data for compound 16 TIFF2024508687000283.tif22150 Starting material (amine): 3-amino-1-(3-(trifluoromethyl)benzyl)piperidin-2-one.

[0262] N-(1-(2-phenylbutanoyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (17) TIFF2024508687000284.tif23128

[0263] Table 17: Analytical data for compound 17 TIFF2024508687000285.tif22150 Starting material (amine): 1-(4-aminopiperidin-1-yl)-2-phenylbutan-1-one.

[0264] N-(spiro[chroman-2,1'-cyclopentan]-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (18) TIFF2024508687000286.tif31128

[0265] Table 18: Analytical data for compound 18 TIFF2024508687000287.tif22150 a LCMS Method B; Starting material (amine): spiro[chroman-2,1'-cyclopentane]-4-amine.

[0266] Methyl 3-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopentyl)propiolate (19) TIFF2024508687000288.tif28128

[0267] Table 19: Analytical data for compound 19 TIFF2024508687000289.tif22150 Starting material (amine): methyl 3-(1-aminocyclopentyl)propiolate.

[0268] 1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-1-carboxylate ethyl ester (20) TIFF2024508687000290.tif28128

[0269] Table 20: Analytical data for compound 20 TIFF2024508687000291.tif22150 Starting material (amine): ethyl 1-amino-2,3-dihydro-1H-indene-1-carboxylate.

[0270] Methyl 3,5-dimethyl-7-((4-(trifluoromethoxy)phenyl)sulfonamido)adamantane-1-carboxylate (21) TIFF2024508687000292.tif21128

[0271] Table 21: Analytical data for compound 21 TIFF2024508687000293.tif22150 Starting material (amine): methyl 3,5-dimethyl-7-(methylamino)adamantane-1-carboxylate.

[0272] N-(2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (22) TIFF2024508687000294.tif21128

[0273] Table 22: Analytical data for compound 22 TIFF2024508687000295.tif22150 Starting material (amine): 2-benzyloctahydrocyclopenta[c]pyrrol-4-amine.

[0274] tert-Butyl 2-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)pyrrolidine-1-carboxylate (23) TIFF2024508687000296.tif26128

[0275] Table 23: Analytical data for compound 23 TIFF2024508687000297.tif22150 Starting material (amine): tert-butyl 2-(1-aminocyclopropyl)pyrrolidine-1-carboxylate.

[0276] trans tert-butyl 4-(2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate (24) TIFF2024508687000298.tif25128

[0277] Table 24: Analytical data for compound 24 TIFF2024508687000299.tif22150 Starting material (amine): tert-butyl trans 4-(2-aminocyclopropyl)piperidine-1-carboxylate.

[0278] N-(6-(difluoromethoxy)-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide (25) TIFF2024508687000300.tif25128

[0279] Table 25: Analytical data for compound 25 TIFF2024508687000301.tif22150 Starting material (amine): 4-amino-7-(difluoromethoxy)-3,4-dihydronaphthalen-1(2H)-one.

[0280] 4-(Trifluoromethoxy)-N-(4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide (26) TIFF2024508687000302.tif25128

[0281] Table 26: Analytical data for compound 26 TIFF2024508687000303.tif22150 Starting material (amine): 4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-amine.

[0282] (S)-N-(6-fluoro-2,2-dimethylchroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (27) TIFF2024508687000304.tif29128

[0283] Table 27: Analytical data for compound 27 TIFF2024508687000305.tif22150 a LCMS Method B; Starting material (amine): (S)-6-fluoro-2,2-dimethylchroman-4-amine.

[0284] N-(2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide (28) TIFF2024508687000306.tif28128

[0285] Table 28: Analytical data for compound 28 TIFF2024508687000307.tif22150 Starting material (amine): 2-ethyl-1-(m-tolyl)cyclopropan-1-amine.

[0286] N-(4-(3-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (29) TIFF2024508687000308.tif34128

[0287] Table 29: Analytical data for compound 29 TIFF2024508687000309.tif22150 a LCMS Method B; Starting material (amine): 4-(3-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-amine.

[0288] N-(1-(3-ethoxy-4-hydroxybenzyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (30) TIFF2024508687000310.tif16128

[0289] Table 30: Analytical data for compound 30 TIFF2024508687000311.tif22150 Starting material (amine): 4-((4-aminopiperidin-1-yl)methyl)-2-ethoxyphenol.

[0290] rac N-((6R,7R)-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide (31) TIFF2024508687000312.tif23128

[0291] Table 31: Analytical data for compound 31 TIFF2024508687000313.tif56150 Starting material (amine): rac (6R,7R)-7-amino-2-benzyl-1-isopropyl-2-azaspiro[3.4]octan-6-ol.

[0292] tert-Butyl 3-(fluoromethyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate (32) TIFF2024508687000314.tif26128

[0293] Table 32: Analytical data for compound 32 TIFF2024508687000315.tif22150 Starting material (amine): tert-butyl 3-amino-3-(fluoromethyl)pyrrolidine-1-carboxylate.

[0294] 3,5-Dimethyl-N-((1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclohexyl)methyl)isoxazole-4-sulfonamide (33) TIFF2024508687000316.tif36128

[0295] Table 33: Analytical data for compound 33 TIFF2024508687000317.tif22150 Starting material (amine): N-((1-aminocyclohexyl)methyl)-3,5-dimethylisoxazole-4-sulfonamide.

[0296] rac N-((2S,3R)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (34) TIFF2024508687000318.tif28128

[0297] Table 34: Analytical data for compound 34 TIFF2024508687000319.tif22150 Starting material (amine): rac (2S,3R)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-amine.

[0298] Example 2: N-(1-benzyl-3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (35) TIFF2024508687000320.tif28128 In a sealed tube, 4-(trifluoromethoxy)benzenesulfonyl chloride (35 μL, 0.198 mmol) was added to a stirred solution of 1-benzyl-3-phenyl-pyrrolidin-3-amine (50 mg, 0.198 mmol) and triethylamine (110 μL, 0.793 mmol) in anhydrous DCM (2.1611 mL). The solution was stirred at room temperature for 20 h. Water (10 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 reverse-phase chromatography using a gradient of 0% to 100% acetonitrile in water (0.1% AcOH in water). The crude material was further purified by flash chromatography on silica gel using a gradient of 0% to 5% methanol in dichloromethane. The residue was triturated with 2 M hydrogen chloride in diethyl ether (1.0 mL, 2.00 mmol), filtered, washed with diethyl ether, and dried under vacuum at 60 °C for 20 h to give the title compound as a yellow oil (39.9 mg, 39% yield, 98.9% purity, t r =1.63min). LCMS (Method C): m / z measurement value 477 [M+H] + ; TIFF2024508687000321.tif25146

[0299] Example 3: N-(3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (36) TIFF2024508687000322.tif53146

[0300] Step 1: Synthesis of tert-butyl 3-amino-3-phenylpyrrolidine-1-carboxylate TIFF2024508687000323.tif21128 To a stirred solution of 3-phenylpyrrolidin-3-amine·(2HCl) (100 mg, 0.425 mmol) and triethylamine (0.24 mL, 1.70 mmol) in DCM (4.2526 mL) in a sealed vial, di-tert-butyl dicarbonate (93 mg, 0.425 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water and DCM were added, and the aqueous layer was extracted twice with DCM. The organic layer was washed with a saturated solution of NH₄Cl, then a saturated solution of NaHCO₃, brine, and then concentrated in vacuo to give the title compound as a colorless oil (99.5 mg, 86% yield, t r =0.55 min). LCMS (Method D): m / z measured 263.2 [M+H] + ; TIFF2024508687000324.tif18147

[0301] Step 2: Synthesis of tert-butyl 3-phenyl-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate TIFF2024508687000325.tif36128 To a stirred solution of tert-butyl 3-amino-3-phenylpyrrolidine-1-carboxylate (925 mg, 3.53 mmol) and N,N-dimethylpyridin-4-amine (99%, 87 mg, 0.705 mmol) in DCM (35.258 mL) in a sealed vial under nitrogen was added 4-(trifluoromethoxy)benzenesulfonyl chloride (0.60 mL, 3.53 mmol). The solution was stirred at room temperature for 4 h, diluted with a half-saturated solution of NaHCO3 and DCM, and the aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator, then concentrated in vacuo and purified by flash chromatography on silica gel using a 20% to 80% gradient of EtOAc in heptane to afford the title compound as a white powder (1.371 g, 79% yield, t r =1.00min). LCMS (Method E): m / z 509[M+H] + ; TIFF2024508687000326.tif25150

[0302] Step 3: Synthesis of N-(3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (36) TIFF2024508687000327.tif26128 To a stirred solution of tert-butyl 3-phenyl-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate (59 mg, 0.121 mmol) in diethyl ether (1.8375 mL) in a round-bottom flask was added 2 M hydrogen chloride in diethyl ether (1.8 mL, 3.64 mmol). The mixture was stirred at room temperature for 3 hours, then 4 M hydrogen chloride in dioxane (1.8 mL, 7.28 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, then sonicated in diethyl ether and filtered to give the hydrochloride salt of the title compound as a white powder (46 mg, 89% yield, 99.3% purity, t r = 1.29 min). LCMS (Method C): m / z measured 386.9 [M+H] + ; TIFF2024508687000328.tif25150

[0303] Example 4: rac N-((2S,3R)-1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (37 and 38) TIFF2024508687000329.tif26146 In a sealed tube, 4-(trifluoromethoxy)benzenesulfonyl chloride (542 μL, 3.20 mmol) was added to a stirred solution of racemic (2S,3R)-1-tert-butyl-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-amine (95%, 1.004 g, 3.52 mmol) and triethylamine (1.8 mL, 12.8 mmol) in DCM (12.816 mL). The solution was stirred at room temperature for 20 hours and then diluted with water and DCM. 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 flash chromatography on silica gel using a 0.2% to 5% gradient of (MeOH + 2% NH4OH) in DCM to give the racemic product as a white powder (1.14 g, 70.5% yield). The enantiomers were separated by chiral chromatography. A sample (125 mg) of the racemic mixture was dissolved by sonication in a mixture of i-PrOH (1.5 mL), MeOH (1.5 mL), and ACN (2 mL) to give a solution with a concentration of 25 mg / mL. The solution was filtered through a hydrophilic polypropylene filter (GHP, 0.45 μm). The separated enantiomers were obtained by 20 injections of the sample solution onto a Chiralpak IB column (250 × 20 mm, 5 μm) using 10% i-PrOH in CO2 as the mobile phase (Waters Prep SFC80, flow rate = 50 mL / min, T = 40 °C, P = 143 bar, UV detection at 210 nm). Enantiomer I (37): (338.1 mg, yield 21%, purity 100%, t r = 1.82 min). LCMS (Method C): m / z measured 494 [M+H] + ; TIFF2024508687000330.tif25149 Enantiomer II (38): (287.0 mg, yield 18%, purity 100%, t r = 1.82 min). LCMS (Method C): m / z measured 494 [M+H] + ; TIFF2024508687000331.tif25149

[0304] Example 5: N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (39) TIFF2024508687000332.tif53146

[0305] Step 1: Synthesis of benzyl 3-(4-chlorophenyl)-3-hydroxypyrrolidine-1-carboxylate TIFF2024508687000333.tif21128 A sealed vial was charged with 3-(4-chlorophenyl)pyrrolidin-3-ol hydrochloride (0.60 g, 2.56 mmol) and DIPEA (1.3 mL, 7.69 mmol) in anhydrous acetonitrile (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). Ethyl acetate (50 mL) and water (20 mL) were then added. The aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was triturated in dichloromethane, filtered, and washed with dichloromethane to give a white powder. The filtrate was purified by flash chromatography on silica gel using a gradient of 1% to 5% of methanol in dichloromethane to give a beige powder, which was added to the white powder and dried under vacuum at 50 °C for 20 h to give the title compound (848 mg, 100% yield, t r =0.89min). LCMS (Method E); TIFF2024508687000334.tif18146

[0306] Step 2: Synthesis of benzyl 3-azido-3-(4-chlorophenyl)pyrrolidine-1-carboxylate TIFF2024508687000335.tif23128 A sealed vial was charged with 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) 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 h. Dichloromethane (10 mL) and a saturated solution of sodium bicarbonate (15 mL) were added. The aqueous layer was extracted with dichloromethane (1 × 10 mL). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (815 mg, 100% yield, t r =1.03min). LCMS (Method E); TIFF2024508687000336.tif18142

[0307] Step 3: Synthesis of benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate TIFF2024508687000337.tif13128 In a round-bottom flask under nitrogen, triphenylphosphine (614 mg, 2.34 mmol) followed by 4-methylbenzenesulfonic acid hydrate (PTSA) (1.34 g, 7.02 mmol) was added 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, t r = 1.04 min). LCMS (Method E): m / z measured 331.3 [M+H] + ; TIFF2024508687000338.tif18144

[0308] Step 4: Synthesis of benzyl 3-(4-chlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate TIFF2024508687000339.tif38128 In a sealed tube, 4-(trifluoromethoxy)benzenesulfonyl chloride (74 μL, 0.437 mmol) was added to a stirred solution of benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate (200 mg, 0.398 mmol) and triethylamine (277 μL, 1.99 mmol) in DCM (6.1538 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 a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 0% to 5% gradient of methanol in dichloromethane to afford the title compound as a yellow powder (64.4 mg, 27% yield, t r = 1.03 min). LCMS (Method E): m / z measured 577.2 [M+Na] + ; TIFF2024508687000340.tif25143

[0309] Step 5: Synthesis of N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (39) TIFF2024508687000341.tif33128 In a round-bottom flask, iodo(trimethyl)silane (301 μL, 2.12 mmol) was added to a stirred suspension of N-[3-(4-chlorophenyl)-1-(2-phenoxyacetyl)pyrrolidin-3-yl]-4-(trifluoromethoxy)benzenesulfonamide (90%, 435 mg, 0.705 mmol) in acetonitrile (14 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and then partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2 × 25 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 flash chromatography on silica gel using a 2% to 10% gradient of (MeOH + 2% NH4OH) in dichloromethane. The crude material was further purified by reverse-phase flash chromatography using a gradient of 0% to 100% acetonitrile in water (+0.1% AcOH). The residue was triturated with 4 M hydrogen chloride in dioxane (1.8 mL, 7.05 mmol) and diethyl ether, 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 an off-white powder (27.9 mg, 9% yield, 99.4% purity, t r =1.38min). LCMS (Method C): m / z measurement value 421.2 [M+H] + ; TIFF2024508687000342.tif18148

[0310] Example 6: Benzyl 3-(3,4-dichlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate (40) and N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (41) TIFF2024508687000343.tif53146

[0311] Step 1: Synthesis of benzyl 3-(3,4-dichlorophenyl)-3-hydroxypyrrolidine-1-carboxylate TIFF2024508687000344.tif21128 A sealed vial was charged with 3-(3,4-dichlorophenyl)pyrrolidin-3-ol hydrochloride (500 mg, 1.86 mmol) and DIPEA (1.0 mL, 5.73 mmol) in anhydrous acetonitrile (6.5 mL). Benzyl chloroformate (97%, 300 μL, 2.05 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate and water were added. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a 0% to 50% gradient of EtOAc in DCM to afford the title compound as a beige gum (638 mg, 91% yield, t r =0.94min). LCMS (Method E); TIFF2024508687000345.tif25148

[0312] Step 2: Benzyl 3-azido-3-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate TIFF2024508687000346.tif23128 To a solution of benzyl 3-(3,4-dichlorophenyl)-3-hydroxy-pyrrolidine-1-carboxylate (358 mg, 0.978 mmol) in anhydrous DCM (5 mL) at 0 °C under nitrogen in a sealed vial, azido(trimethyl)silane (260 μL, 1.96 mmol) and boron trifluoride etherate (242 μL, 1.96 mmol) were added. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 2 days. The reaction mixture was quenched by the dropwise addition of a saturated aqueous solution of NaHCO3. EtOAc was added, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 5% to 50% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (299.8 mg, 38% yield, t r =1.11min). LCMS (Method D); TIFF2024508687000347.tif32148

[0313] Step 3: Synthesis of benzyl 3-amino-3-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate TIFF2024508687000348.tif17128 In a round-bottom flask under nitrogen, triphenylphosphine (121 mg, 0.463 mmol) followed by 4-methylbenzenesulfonic acid hydrate (PTSA) (262 mg, 1.38 mmol) was added to a stirred solution of benzyl 3-azido-3-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (50%, 360 mg, 0.460 mmol) in THF (2 mL). The mixture was stirred at room temperature overnight. The suspension was filtered, washed with THF, and dried under vacuum for 18 hours to give the title compound as a white powder (166.1 mg, 64% yield, t r =0.67 min). LCMS (Method D): m / z measured 348.2 [M+H] + ; TIFF2024508687000349.tif18146

[0314] Step 4: Synthesis of benzyl 3-(3,4-dichlorophenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate (40) TIFF2024508687000350.tif38128

[0315] To a stirred suspension of benzyl 3-amino-3-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (128 mg, 0.238 mmol) in DCM (2.4 mL) at room temperature in a vial, triethylamine (166 μL, 1.19 mmol), 4-(trifluoromethoxy)benzenesulfonyl chloride (98%, 62 μL, 0.358 mmol), and N,N-dimethylpyridin-4-amine (5.8 mg, 0.0476 mmol) were added sequentially. The reaction mixture was stirred at this temperature for 1 h and then heated at 40 °C for 4 h. The reaction mixture was diluted with DCM and a saturated aqueous solution of NaHCO3. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 2% to 100% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a white foam (117.6 mg, 79% yield, t r = 1.06 min). LCMS (Method E): m / z measured 611.2 [M+Na] + ; TIFF2024508687000351.tif11147

[0316] Step 5: N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (41) TIFF2024508687000352.tif33128 In a round-bottom flask, iodo(trimethyl)silane (64 μL, 0.450 mmol) was added to a stirred solution of benzyl 3-(3,4-dichlorophenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate (89 mg, 0.150 mmol) in acetonitrile (2.8 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum. The crude material was purified by flash chromatography on silica gel using a 2% to 20% gradient of MeOH (0.7 N NH3) in DCM. The desired fractions were combined and concentrated. The residue was triturated with MeOH, filtered, washed with MeOH and diethyl ether, and dried under vacuum at 45°C for 18 hours to give the first crop of the title compound as a white powder (23.4 mg, 34% yield). The filtrate was combined with another fraction containing the title compound. The resulting powder was dissolved in a mixture of MeOH / DCM, and the homogeneous solution was added to diethyl ether and stirred for 2 hours. The precipitate that formed was filtered, washed with diethyl ether and pentane, and dried under vacuum at 45°C for 18 hours. Combined with the first crop, the title compound was obtained as a white powder (38.6 mg, 79% yield). The combined precipitates were further purified by reverse-phase preparative chromatography (C18 AQ 15.5 g) using a 0% to 100% gradient of acetonitrile in water (both 0.1% AcOH). The desired fractions were combined and concentrated. The residue was salt exchanged (acetate to chloride) in 2N HCl in diethyl ether and stirred overnight at room temperature. The suspension was filtered, washed with diethyl ether and pentane, and dried at 45 °C for 18 h to give the hydrochloride salt of the title compound as a white powder (25.4 mg, 34% yield, 95.1% purity, t r =1.47min). LCMS (Method C): m / z measurement value 455 [M+H] + ; TIFF2024508687000353.tif32149

[0317] Example 7: rac N-((1R,2S)-2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide (42) 4-(Trifluoromethoxy)benzenesulfonyl chloride (0.059 mL, 0.349 mmol) was added to a stirred solution of racemic (1R,2S)-2-(4-chlorophenyl)cyclopropan-1-amine hydrochloride (95%, 75 mg, 0.349 mmol) and triethylamine (0.19 mL, 1.40 mmol) in anhydrous DCM (2.3273 mL) in a round-bottom flask under TIFF2024508687000354.tif27128N2. The solution was stirred overnight at room temperature, and then DCM and a half-saturated solution of NaHCO3 were added. The aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator, then concentrated in vacuo and purified by flash chromatography on silica gel using an isocratic eluent containing 100% DCM to afford the title compound as a white powder (111.1 mg, 81% yield, 100% purity, t r =2.71min). LCMS (Method C): m / z measurement value 392 [M+H] + ; TIFF2024508687000355.tif18144

[0318] Example 8: N-(2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide (43 and 44) TIFF2024508687000356.tif20148 In a sealed tube under nitrogen, triethylamine (242 μL, 1.74 mmol) was added to a stirred solution of 4-(trifluoromethoxy)benzenesulfonyl chloride (113 mg, 0.435 mmol) and 2-(3,4-dichlorophenyl)cyclopentan-1-amine (100 mg, 0.435 mmol) in DCM (2 mL). The solution was stirred at room temperature for 16 h and poured into 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 product was purified by flash chromatography on silica gel using a 1% to 5% gradient of (MeOH + 2% NH4OH) in DCM to give two fractions. The first fraction was concentrated, and the residue was triturated with pentane. The resulting suspension was filtered and dried under reduced pressure at 45° C. for 16 hours to give the diastereomer I (racemic) of the title compound (43) as a white powder (42 mg, 21% yield, 98.9% purity, t r =3min). LCMS (Method C): m / z measurement value 452.1 [MH] - ; The second fraction was concentrated and purified by reverse-phase chromatography using a 0% to 100% gradient of (MeCN + 0.1% AcOH) in (H2O + 0.1% AcOH). The desired fractions were concentrated, and the residue 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 residue was triturated with pentane, followed by the addition of a few drops of Et2O. The resulting suspension was filtered, and the residue was washed with pentane and dried under reduced pressure at 45 °C for 64 h to afford diastereomer II (racemic) of the title compound (42) as a white powder (31 mg, 15% yield, 99.3% purity, t r = 2.98 min). LCMS (Method C): m / z measured 452.2 [M−H] - ; TIFF2024508687000358.tif18148

[0319] Example 9: N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (45) TIFF2024508687000359.tif38146

[0320] Step 1: Synthesis of tert-butyl 4-(4-chlorophenyl)-4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate To a stirred suspension of tert-butyl 4-amino-4-(4-chlorophenyl)piperidine-1-carboxylate (200 mg, 0.643 mmol) in DCM (6.4844 mL) at room temperature in a vial, triethylamine (0.45 mL, 3.22 mmol), 4-(trifluoromethoxy)benzenesulfonyl chloride (98%, 168 μL, 0.968 mmol), and N,N-dimethylpyridin-4-amine (16 mg, 0.129 mmol) were added sequentially. The reaction mixture was stirred at this temperature for 1 h and then heated at 40 °C overnight. The reaction mixture was diluted with DCM and a saturated aqueous solution of NaHCO3. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a white foam (327.3 mg, 95.08% yield, 98.74% purity, t r = 1.06 min). LCMS (Method E): m / z measured 435.2 [M-Boc+H] + ; TIFF2024508687000361.tif18147

[0321] Step 2: Synthesis of N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (45) TIFF2024508687000362.tif32128 To a stirred solution of 4 M hydrogen chloride in dioxane (9.0 mL, 36.0 mmol) in diethyl ether (20 mL) in a round-bottom flask was added tert-butyl 4-(4-chlorophenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (293 mg, 0.548 mmol). The mixture was stirred at room temperature overnight, then filtered and washed with diethyl ether to give the hydrochloride salt of the title compound as a white powder (190.5 mg, 73.799% yield, 100% purity, t r = 1.62 min). LCMS (Method C): m / z measured 434.8 [M+H] + ; TIFF2024508687000363.tif25147

[0322] Example 10: N-(3-phenylazetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (46) TIFF2024508687000364.tif27145

[0323] Step 1: Synthesis of tert-butyl 3-phenyl-3-((4-(trifluoromethoxy)phenyl)sulfonamido)azetidine-1-carboxylate TIFF2024508687000365.tif28128 In a sealed tube under nitrogen, a solution of 4-(trifluoromethoxy)benzenesulfonyl chloride (105 mg, 0.403 mmol) in dry THF (500 μL) was added to a stirred solution of tert-butyl 3-amino-3-phenylazetidine-1-carboxylate (100 mg, 0.403 mmol) and pyridine (65 μL, 0.805 mmol) in THF (1 mL). The mixture was stirred at room temperature for 16 h and then diluted with half-saturated aqueous NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel using a 0.2% to 5% gradient of (MeOH + 2% NH4OH) in DCM to afford the title compound as a white solid (92 mg, 48% yield, t r =0.99 min). LCMS (Method E): m / z measured 417.3 [M-Boc+H] + ; TIFF2024508687000366.tif11150

[0324] Step 2: Synthesis of N-(3-phenylazetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (46) TIFF2024508687000367.tif25128 In a sealed tube under nitrogen, 4 M hydrogen chloride in dioxane (79 μL, 0.317 mmol) was added to a stirred solution of tert-butyl 3-phenyl-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]azetidine-1-carboxylate (100%, 30 mg, 0.0635 mmol) in 1,4-dioxane (500 μL). The mixture was stirred at room temperature for 16 hours, and additional 4 M hydrogen chloride in dioxane (159 μL, 0.635 mmol) was added. The mixture was stirred at room temperature for 24 hours. The suspension was diluted with EtO (2 mL), stirred at room temperature for 2 hours, and then filtered. The residue was washed with EtO and dried under reduced pressure at 60 °C for 64 hours to give the hydrochloride salt of the title compound as a white powder (23 mg, 88% yield, 99.8% purity, t r= 1.17 min). LCMS (Method C): m / z measured 373 [M+H] + ; TIFF2024508687000368.tif18148

[0325] Example 11: N-(3-(4-chlorophenyl)azetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (47) TIFF2024508687000369.tif31128

[0326] Step 1: Synthesis of benzyl 3-(4-chlorophenyl)-3-hydroxy-azetidine-1-carboxylate TIFF2024508687000370.tif19128 2,2,2-Trifluoroacetic acid 3-(4-chlorophenyl)azetidinium-3-ol (500 mg, 1.68 mmol) and DIPEA (1.2 mL, 6.72 mmol) in anhydrous ACN (6 mL) were charged to a sealed vial. Benzyl chloroformate (263 μL, 1.85 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 ammonium chloride (15 mL), and ethyl acetate (15 mL) and water (10 mL) were added. The aqueous layer was extracted with ethyl acetate (1 × 15 mL). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 1% to 5% of methanol in dichloromethane to give the title compound as a beige powder (530 mg, 100% purity, 99% yield, t r =0.90 min). LCMS (Method E): m / z measured 318.1 [M+H] + ; TIFF2024508687000371.tif18147

[0327] Step 2: Synthesis of benzyl 3-(4-chlorophenyl)-3-methylsulfonyloxy-azetidine-1-carboxylate TIFF2024508687000372.tif30128 To a stirred solution of benzyl 3-(4-chlorophenyl)-3-hydroxy-azetidine-1-carboxylate (100%, 460 mg, 1.45 mmol) in anhydrous DCM (8 mL) at room temperature under nitrogen in a sealed vial, triethylamine (404 μL, 2.90 mmol) and methanesulfonyl chloride (100%, 225 μL, 2.90 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum to afford the title compound as a brown oil (585 mg, 92% purity, 94% yield, t r =1.01min). LCMS (Method D); TIFF2024508687000373.tif11128

[0328] Step 3: Synthesis of benzyl 3-azido-3-(4-chlorophenyl)azetidine-1-carboxylate TIFF2024508687000374.tif30128 A sealed vial was charged with benzyl 3-(4-chlorophenyl)-3-methylsulfonyloxy-azetidine-1-carboxylate (570 mg, 1.44 mmol) in a mixture of anhydrous DCM (1.5 mL) and anhydrous DMF (8 mL). NaN3 (281 mg, 4.32 mmol) was added at room temperature, and the reaction mixture was stirred at 50 °C for 18 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (2 mL), and water (2 mL) and dichloromethane (5 mL) were added. The aqueous layer was extracted with dichloromethane (1 × 3 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 10% to 40% gradient of ethyl acetate in cyclohexane to give the title compound as a yellow oil (279 mg, 100% pure, 57% yield, t r = 1.02 min). LCMS (Method E): m / z measured 343.3 [M+H] + ; TIFF2024508687000375.tif11128

[0329] Step 4: Synthesis of benzyl 3-amino-3-(4-chlorophenyl)azetidine-1-carboxylate TIFF2024508687000376.tif18128 In a round-bottom flask under nitrogen, triphenylphosphine (211 mg, 0.805 mmol) followed by 4-methylbenzenesulfonic acid (459 mg, 2.42 mmol) was added to a stirred solution of benzyl 3-azido-3-(4-chlorophenyl)azetidine-1-carboxylate (276 mg, 0.805 mmol) in THF (3.4 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 (263 mg, 100% purity, 67% yield, t r =0.61 min). LCMS (Method E): m / z measured 317.2 [M+H] + ; TIFF2024508687000377.tif18147

[0330] Step 5: Synthesis of benzyl 3-(4-chlorophenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]azetidine-1-carboxylate TIFF2024508687000378.tif30128 A sealed vial under nitrogen was charged with 3-amino-3-(4-chlorophenyl)azetidine-1-carboxylate, benzyl 4-methylbenzenesulfonate (100 mg, 0.205 mmol) and triethylamine (143 μL, 1.02 mmol) in anhydrous DCM (4 mL). 4-(Trifluoromethoxy)benzenesulfonyl chloride (38 μL, 0.225 mmol) was added, and the reaction mixture was stirred at room temperature for 22 hours and at 40 °C for 3 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (10 mL), and dichloromethane (5 mL) was added. The aqueous layer was extracted with dichloromethane (1 × 5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 5% of methanol in dichloromethane to give the title compound as a beige powder (86 mg, 92% purity, 72% yield, t r= 1.03 min). LCMS (Method E): m / z measured 541.2 [M+H] + ; TIFF2024508687000379.tif11135

[0331] Step 6: Synthesis of N-[3-(4-chlorophenyl)azetidin-3-yl]-4-(trifluoromethoxy)benzenesulfonamide (47) TIFF2024508687000380.tif28128 To a stirred suspension of benzyl 3-(4-chlorophenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]azetidine-1-carboxylate (80 mg, 0.148 mmol) in acetonitrile (3 mL) at room temperature in a round-bottom flask was added iodo(trimethyl)silane (63 μL, 0.444 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 4% to 15% gradient of ammoniacal methanol in dichloromethane. The residue was purified by reverse-phase flash chromatography using a 0% to 100% gradient of acetonitrile in water (+ 0.1% AcOH in water). The residue was triturated with 4 M HCl in diethyl ether (370 μL, 1.48 mmol) for 3 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 (28.5 mg, 100% yield, 44% purity, t r =1.31min). LCMS (Method C): m / z measurement value 407 [M+H] + ; TIFF2024508687000381.tif11128

[0332] Example 12: N-(3-(3,4-dichlorophenyl)azetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (48) TIFF2024508687000382.tif29128

[0333] Step 1: Synthesis of benzyl 3-(3,4-dichlorophenyl)-3-hydroxy-azetidine-1-carboxylate TIFF2024508687000383.tif21128 In a three-neck round-bottom flask, a few drops of a solution of 1-bromo-3,4-dichlorobenzene (97%, 0.46 mL, 3.48 mmol) in anhydrous THF (1.5 mL) were added to a stirred suspension of magnesium (113 mg, 4.63 mmol) and iodine crystals (catalyst) in anhydrous THF (2 mL) at room temperature under nitrogen. The reaction was heated at 50 °C until a color change (orange to yellow) was observed. The remainder of the solution was then added dropwise and stirred at this temperature for 1 h (until the magnesium was consumed). The reaction mixture was then cooled to 0 °C, and a solution of benzyl 3-oxoazetidine-1-carboxylate (95%, 500 mg, 2.31 mmol) in anhydrous THF (1.3 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 75% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (776.2 mg, 100% pure, 95% yield, t r =0.95min). LCMS (Method E); TIFF2024508687000384.tif18145

[0334] Step 2: Synthesis of benzyl 3-(3,4-dichlorophenyl)-3-methylsulfonyloxy-azetidine-1-carboxylate TIFF2024508687000385.tif30128 To a stirred solution of benzyl 3-(3,4-dichlorophenyl)-3-hydroxyazetidine-1-carboxylate (660 mg, 1.87 mmol) in anhydrous DCM (9 mL) at 0 °C under nitrogen in a round-bottom flask, triethylamine (1.0 mL, 7.17 mmol) and methanesulfonyl chloride (100%, 290 μL, 3.73 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow gum (137.5 mg). The crude material was used directly in the next step without any purification. TIFF2024508687000386.tif11144

[0335] Step 3: Synthesis of benzyl 3-azido-3-(3,4-dichlorophenyl)azetidine-1-carboxylate TIFF2024508687000387.tif30128 A sealed vial was charged with benzyl 3-(3,4-dichlorophenyl)-3-methylsulfonyloxy-azetidine-1-carboxylate (806 mg, 1.87 mmol) in a mixture of anhydrous DMF (9.2492 mL) and sodium azide (365 mg, 5.62 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 18 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (25 mL), and water (25 mL) and dichloromethane (50 mL) were added. The aqueous layer was extracted with dichloromethane (1 × 50 mL). The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 50% ethyl acetate in heptane to give the title compound as a colorless oil (577.8 mg, 98% purity, 80.139% yield, t r =1.06min). LCMS (Method E); TIFF2024508687000388.tif18143

[0336] Step 4: Synthesis of benzyl 3-amino-3-(3,4-dichlorophenyl)azetidine-1-carboxylate TIFF2024508687000389.tif21128 In a round-bottom flask under nitrogen, triphenylphosphine (426 mg, 1.62 mmol) followed by 4-methylbenzenesulfonic acid (920 mg, 4.84 mmol) was added to a stirred solution of benzyl 3-azido-3-(3,4-dichlorophenyl)azetidine-1-carboxylate (98%, 621 mg, 1.61 mmol) in THF (9 mL). The mixture was stirred at room temperature for 2 hours. The suspension was filtered, washed with a little THF, and dried under vacuum for 18 hours to give the title compound as a white powder (596.2 mg, 100% purity, 70.624% yield, t r =0.65min). LCMS (Method E): m / z measurement value 351.2 [M+H-pTSA] + ; TIFF2024508687000390.tif18149

[0337] Step 5: Synthesis of benzyl 3-(3,4-dichlorophenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]azetidine-1-carboxylate To a stirred suspension of 1-((benzyloxy)carbonyl)-3-(3,4-dichlorophenyl)azetidin-3-aminium 4-methylbenzenesulfonate (202 mg, 0.386 mmol) in DCM (2.5 mL) at room temperature in a vial, triethylamine (269 μL, 1.93 mmol), 4-(trifluoromethoxy)benzenesulfonyl chloride (98%, 101 μL, 0.581 mmol), and N,N-dimethylpyridin-4-amine (4.8 mg, 0.0397 mmol) were added sequentially. The reaction mixture was heated to 40 °C and stirred at this temperature for 4 h. The reaction mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 10% to 100% ethyl acetate in heptane. The desired fractions were combined and concentrated to give the title compound as a white solid (79 mg, 98% purity, 36% yield, t r =1.05min). LCMS (Method E); TIFF2024508687000392.tif18145

[0338] Step 6: Synthesis of N-[3-(3,4-dichlorophenyl)azetidin-3-yl]-4-(trifluoromethoxy)benzenesulfonamide (48) TIFF2024508687000393.tif28128 In a round-bottom flask, iodo(trimethyl)silane (58 μL, 0.408 mmol) was added to a stirred solution of benzyl 3-(3,4-dichlorophenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]azetidine-1-carboxylate (79 mg, 0.137 mmol) in anhydrous ACN (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum. The residue was triturated with acetonitrile, filtered, washed with acetonitrile, and dried under vacuum at room temperature overnight. Water, triethylamine (96 μL, 0.689 mmol), and methyltetrahydrofuran were added to the residue. The layers were separated. The organic layer was washed once more with water and triethylamine (96 μL, 0.689 mmol). The combined aqueous layers were washed once with methyltetrahydrofuran. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Diethyl ether and 2 M hydrogen chloride in Et2O (0.69 mL, 1.37 mmol) were added to the residue. The resulting suspension was stirred overnight at room temperature, filtered, washed with diethyl ether, and dried under vacuum at 45 °C for 18 hours to give the hydrochloride salt of the title compound as a white powder (34.4 mg, purity 96.57%, yield 51%, t r =1.64min). LCMS (Method C): m / z measurement value 441 [M+H] + ; TIFF2024508687000394.tif11145

[0339] Example 13: N-(4-(3,4-dichlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (49) TIFF2024508687000395.tif32128

[0340] Step 1: Synthesis of benzyl 4-oxopiperidine-1-carboxylate TIFF2024508687000396.tif17128 To a stirred solution of piperidin-4-one hydrochloride (1:1) (98%, 3.00 g, 21.7 mmol) and DIPEA (23 mL, 0.132 mol) in DCM (70 mL) at room temperature under nitrogen in a round-bottom flask, benzyl chloroformate (6.2 mL, 43.6 mmol) and DMAP (265 mg, 2.17 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. Dichloromethane and water were then added. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed once with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 10% to 75% ethyl acetate in cyclohexane to give the title compound as a yellow oil (3.89 g, 100% purity, 77% yield, t r =0.71min). LCMS (Method D); TIFF2024508687000397.tif18145

[0341] Step 2: Synthesis of benzyl 4-(3,4-dichlorophenyl)-4-hydroxy-piperidine-1-carboxylate TIFF2024508687000398.tif25128 In a three-neck round-bottom flask, a few drops of a solution of 1-bromo-3,4-dichlorobenzene (97%, 823 μL, 6.23 mmol) in anhydrous THF (3 mL) were added to a stirred suspension of magnesium (198 mg, 8.15 mmol) and iodine crystals in anhydrous THF (6.8 mL) at room temperature under nitrogen. The reaction was heated at 50 °C until discoloration (orange to colorless) was observed. The remainder of the solution was then added dropwise and stirred at 50 °C for 1 h (until the magnesium was consumed). The reaction mixture was then cooled to 0 °C, and a solution of benzyl 4-oxopiperidine-1-carboxylate (1.00 g, 4.29 mmol) in anhydrous THF (3 mL) was added dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted three times with ethyl acetate. 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 flash chromatography on silica gel using a gradient of 10% to 100% ethyl acetate in heptane to give the title compound as a white solid (1.04 g, 98% purity, 63% yield, t r =1.00min). LCMS (Method D); TIFF2024508687000399.tif25150

[0342] Step 3: Synthesis of benzyl 4-azido-4-(3,4-dichlorophenyl)piperidine-1-carboxylate TIFF2024508687000400.tif31128 In a three-necked round-bottom flask, a solution of benzyl 4-(3,4-dichlorophenyl)-4-hydroxy-piperidine-1-carboxylate (300 mg, 0.789 mmol) in anhydrous DCM (3.6 mL) was added dropwise to a solution of azido(trimethyl)silane (126 μL, 0.949 mmol) and BF etherate (585 μL, 4.74 mmol) in anhydrous DCM (2 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction mixture was poured into a saturated aqueous solution of NaHCO (50 mL). The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure to give the title compound as a colorless oil (301.9 mg, 60% purity, 57% yield, t r =1.12min). LCMS (Method E); TIFF2024508687000401.tif18142 The product was obtained as an inseparable mixture with benzyl 4-(3,4-dichlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate.

[0343] Step 4: Synthesis of benzyl 4-amino-4-(3,4-dichlorophenyl)piperidine-1-carboxylate TIFF2024508687000402.tif25128 In a round-bottom flask under nitrogen, triphenylphosphine (134 mg, 0.512 mmol) and then p-toluenesulfonic acid (255 mg, 1.34 mmol) were added to a stirred solution of an inseparable mixture of benzyl 4-azido-4-(3,4-dichlorophenyl)piperidine-1-carboxylate (60%, 302 mg, 0.447 mmol) and benzyl 4-(3,4-dichlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (40%, 302 mg, 0.333 mmol) in THF (2.1 mL). The mixture was stirred overnight at room temperature. The suspension was filtered and washed with a little THF. The filtrate was concentrated and purified by reverse-phase chromatography (C18Aq - 100g) using a gradient of 0% to 100% acetonitrile in water (0.1% AcOH in water and acetonitrile). The desired fractions were combined and concentrated to give the title compound as a colorless oil (84.9mg, 84% purity, 42% yield, t r =0.67min). LCMS (Method E); TIFF2024508687000403.tif25148

[0344] Step 5: Synthesis of benzyl 4-(3,4-dichlorophenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate To a stirred suspension of benzyl 4-amino-4-(3,4-dichlorophenyl)piperidine-1-carboxylate (84%, 87 mg, 0.192 mmol) in DCM (1.9 mL) at room temperature in a vial, triethylamine (134 μL, 0.961 mmol), 4-(trifluoromethoxy)benzenesulfonyl chloride (98%, 50 μL, 0.290 mmol), and N,N-dimethylpyridin-4-amine (2.4 mg, 0.0198 mmol) were added sequentially. The reaction mixture was stirred at this temperature for 1 h and then heated at 40 °C overnight. The reaction mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0.5% to 10% methanol in dichloromethane. The desired fractions were combined and concentrated to give the title compound as a colorless gum (51 mg, 93% purity, 41% yield, t r =1.08min). LCMS (Method E); TIFF2024508687000405.tif18146

[0345] Step 6: Synthesis of N-[4-(3,4-dichlorophenyl)-4-piperidyl]-4-(trifluoromethoxy)benzenesulfonamide (49) To a stirred solution of benzyl 4-(3,4-dichlorophenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (51 mg, 0.0845 mmol) in acetonitrile (1.3 mL) at room temperature in a round-bottom flask was added iodo(trimethyl)silane (36 μL, 0.254 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum. The crude material was dry-loaded onto decalite and purified by flash chromatography on silica gel using a 1% to 20% gradient of methanol (0.7 N NH3) in dichloromethane. The desired fractions were combined and washed with water and triethylamine (59 μL, 0.423 mmol). The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative chromatography (C18Aq 30 g) using a gradient of 0% to 100% acetonitrile in water (0.1% AcOH in both). The desired fractions were combined and concentrated. Salt exchange of the residue (acetate to hydrochloride) was carried out in diethyl ether, followed by the addition of a 2 M solution of hydrogen chloride in Et2O (0.43 mL, 0.850 mmol) and stirring overnight at room temperature. The suspension was filtered, washed with diethyl ether, and dried at 45 °C over the weekend to give the hydrochloride salt of the title compound as a white powder (20.4 mg, 99.75% purity, 48% yield, t r = 1.49 min). LCMS (Method C): m / z measured 469 [M+H] + ; TIFF2024508687000407.tif25146

[0346] Example 14: N-(4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (50) TIFF2024508687000408.tif25128

[0347] Step 1: Synthesis of tert-butyl 4-phenyl-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate TIFF2024508687000409.tif39128 A sealed vial was charged with tert-butyl 4-amino-4-phenylpiperidine-1-carboxylate (150 mg, 0.543 mmol), DMAP (13 mg, 0.109 mmol), and triethylamine (303 μL, 2.17 mmol) in DCM (9 mL). 4-(Trifluoromethoxy)benzenesulfonyl chloride (101 μL, 0.597 mmol) was added, and the reaction mixture was stirred at 40 °C for 18 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (5 mL), and water (15 mL) and dichloromethane (10 mL) were added. The aqueous layer was extracted with dichloromethane (1 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 5% of methanol in dichloromethane to give the title compound as a white powder (266 mg, 98% purity, 96% yield, t r = 1.03 min). LCMS (Method E): m / z measured 523.3 [M+Na] + ; TIFF2024508687000410.tif26149

[0348] Step 2: Synthesis of N-(4-phenyl-4-piperidyl)-4-(trifluoromethoxy)benzenesulfonamide TIFF2024508687000411.tif28128 To a stirred solution of 2 M hydrogen chloride in diethyl ether (15 mL, 30.0 mmol) in a round-bottom flask was added tert-butyl 4-phenyl-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (265 mg, 0.529 mmol). The mixture was stirred at room temperature for 18 hours, then filtered and washed with diethyl ether to give the hydrochloride salt of the title compound as a white powder (175.8 mg, 99.9% yield, 77% purity, t r=1.71min). LCMS (Method C): m / z measurement value 401.0 [M+H] + ; TIFF2024508687000412.tif25149

[0349] Example 15: rac N-((3R,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (51) TIFF2024508687000413.tif28128

[0350] Step 1: Synthesis of tert-butyl rac-(3R,4S)-3-(3,4-dichlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate TIFF2024508687000414.tif21128 In a three-necked round-bottom flask equipped with a thermometer and reflux condenser under nitrogen, a suspension of copper(I) iodide (93 mg, 0.486 mmol) and iodine (25 mg, 0.0972 mmol) in dry THF (18 mL) was stirred at room temperature. A few drops of a solution of 1-bromo-3,4-dichlorobenzene (2493 μL, 19.4 mmol) in dry THF (18 mL) were added, and the mixture was stirred with gradual heating (60 °C) until the mixture discolored. The remainder of the solution was added dropwise over 20 seconds, and the mixture was stirred at 60 °C until the magnesium was consumed (30 min). The mixture was stirred at 0°C, and magnesium (520 mg, 21.4 mmol) was added, followed by the dropwise addition of a solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.80 g, 9.72 mmol) in dry THF (9 mL) over 20 seconds. The mixture was stirred at room temperature for 2 hours and cooled to 0°C. The mixture was quenched with saturated aqueous NH4Cl and 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 flash chromatography on silica gel using a 5% to 30% gradient of EtOAc in heptane. The desired fractions were concentrated and purified by reverse-phase chromatography on silica gel using a 0% to 100% gradient of (MeCN + 0.2% AcOH) in (HO + 0.2% AcOH). The desired fractions were combined, and the ACN was evaporated. The mixture was basified with aqueous saturated NaHCO and extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a white foam (1.32 g, purity >95%, yield 24%, t r =0.93 min). LCMS (Method E): m / z measured 276.1 [M-tBu+H] + ; TIFF2024508687000415.tif32145

[0351] Step 2: Synthesis of tert-butyl rac-(3R,4S)-3-(3,4-dichlorophenyl)-4-methylsulfonyloxy-pyrrolidine-1-carboxylate TIFF2024508687000416.tif26128 In a round-bottom flask under nitrogen, a solution of tert-butyl rac-(3R,4S)-3-(3,4-dichlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (100%, 470 mg, 1.41 mmol) and triethylamine (394 μL, 2.83 mmol) in dry DCM (10 mL) was stirred at 0 °C. Methanesulfonyl chloride (164 μL, 2.12 mmol) was added dropwise, and the mixture was stirred at 0 °C for 10 min and at room temperature for 3 h. The mixture was washed twice with saturated aqueous NaHCO3, the combined aqueous layer was extracted with DCM, and the combined organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound as a colorless oil (520 mg, 100% pure, 89% yield, t r =0.98 min). LCMS (Method E): m / z measured 310.1 [M-Boc+H] + ; TIFF2024508687000417.tif18148

[0352] Step 3: Synthesis of tert-butyl rac-(3R,4R)-3-azido-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate TIFF2024508687000418.tif21128 In a sealed tube under nitrogen, sodium azide (330 mg, 5.07 mmol) was added to a stirred solution of tert-butyl rac-(3R,4S)-3-(3,4-dichlorophenyl)-4-methylsulfonyloxy-pyrrolidine-1-carboxylate (520 mg, 1.27 mmol) in dry DMF (5 mL). The mixture was stirred at 75 °C for 23 h. The mixture was cooled to room temperature and diluted with EtOAc and saturated aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel using a 5% to 30% gradient of EtOAc in heptane to afford the title compound as a colorless oil (335 mg, 100% pure, 74% yield, t r = 1.09 min). LCMS (Method E): m / z measured 300.9 [M-tBu+H] + ; TIFF2024508687000419.tif18147

[0353] Step 4: Synthesis of tert-butyl rac-(3R,4R)-3-amino-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate TIFF2024508687000420.tif21128 In a sealed tube under nitrogen, polymer-bound triphenylphosphine (344 mg, 1.03 mmol) was added to a stirred solution of tert-butyl rac-(3R,4R)-3-azido-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (335 mg, 0.938 mmol) in THF (5 mL) and water (2 mL). The solution was stirred at 45 °C for 16 h and filtered. The residue was washed with DCM, and the filtrate was dried over sodium sulfate, filtered, and concentrated to give the title compound as a colorless oil (203 mg, 100% pure, 65% yield, t r =0.63 min). LCMS (Method E): m / z measured 275.1 [M-tBu+H] + ; TIFF2024508687000421.tif18144

[0354] Step 5: Synthesis of tert-butyl rac-(3R,4R)-3-(3,4-dichlorophenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate TIFF2024508687000422.tif26128 To a stirred solution of tert-butyl rac-(3R,4R)-3-amino-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (90 mg, 0.272 mmol), triethylamine (151 μL, 1.09 mmol), and N,N-dimethylpyridin-4-amine (99%, 3.4 mg, 0.0272 mmol) in dry DCM (300 μL) in a sealed tube under nitrogen was added 4-(trifluoromethoxy)benzenesulfonyl chloride (46 μL, 0.272 mmol). The mixture was stirred at room temperature for 16 h and poured into half-saturated NaHCO3. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel using a 0.5% to 5% gradient of (MeOH + 2% NH4OH) in DCM to give the title compound as a white solid (98 mg, 99% purity, 64% yield, t r = 1.08 min). LCMS (Method D): m / z measured value 499.1 [M-tBu+H] + ; TIFF2024508687000423.tif25150

[0355] Step 6: Synthesis of N-[rac-(3R,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl]-4-(trifluoromethoxy)benzenesulfonamide TIFF2024508687000424.tif28128 In a sealed tube under nitrogen, 4 M hydrogen chloride in dioxane (1.7 mL, 6.84 mmol) was added to a stirred suspension of tert-butyl rac-(3R,4R)-3-(3,4-dichlorophenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate (95 mg, 0.171 mmol) in diethyl ether (2 mL). The mixture was stirred at room temperature for 16 hours, and methanol (1 mL) was added. The mixture was stirred at room temperature for 4 hours and concentrated. The residue was triturated with EtO, and the suspension was filtered. The residue was washed with EtO and dried under reduced pressure at 60 °C for 16 hours to give the hydrochloride salt of the title compound as a white powder. (76 mg, 100% purity, 90% yield, t r =1.5min). LCMS (Method C): m / z measurement value 455.0 [M+H] + ; TIFF2024508687000425.tif18143

[0356] Example 16: N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (52) TIFF2024508687000426.tif27128

[0357] Step 1: Synthesis of benzyl 3-oxopyrrolidine-1-carboxylate TIFF2024508687000427.tif15128 To a stirred solution of pyrrolidin-3-one hydrochloride (1:1) (97%, 5.00 g, 39.9 mmol) and DIPEA (42 mL, 0.239 mol) in DCM (200 mL) at room temperature under nitrogen in a round-bottom flask, benzyl chloroformate (12 mL, 83.8 mmol) and DMAP (487 mg, 3.99 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), and dichloromethane (100 mL) and water (50 mL) were added. The aqueous layer was extracted with dichloromethane (2 × 25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 20% to 100% ethyl acetate in cyclohexane to give the title compound as a yellow oil (4.59 g, 100% purity, 53% yield, t r =0.68min). LCMS (Method E); TIFF2024508687000428.tif11128

[0358] Step 2: Synthesis of benzyl 3-(4-chloro-3-fluoro-phenyl)-3-hydroxy-pyrrolidine-1-carboxylate TIFF2024508687000429.tif19128 In a three-neck round-bottom flask, a solution of benzyl 3-oxopyrrolidine-1-carboxylate (97%, 500 mg, 2.21 mmol) in anhydrous THF (4.5 mL) was added dropwise to a stirred solution of 0.5 M bromo(4-chloro-3-fluorophenyl)magnesium (5.3 mL, 2.65 mmol) at 0 °C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction mixture was poured into a saturated aqueous solution of NH4Cl, and EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 0% to 50% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a pale yellow oil (355.7 mg, 100% purity, 46% yield, t r =0.90min). LCMS (Method E); TIFF2024508687000430.tif18148

[0359] Step 3: Synthesis of benzyl 3-azido-3-(4-chloro-3-fluoro-phenyl)pyrrolidine-1-carboxylate TIFF2024508687000431.tif23128 To a stirred solution of benzyl 3-(4-chloro-3-fluoro-phenyl)-3-hydroxy-pyrrolidine-1-carboxylate (286 mg, 0.818 mmol) in a mixture of TFA (2.8 mL) and water (0.45 mL) at 0 °C in a round-bottom flask was added NaN (372 mg, 5.72 mmol). The reaction mixture was stirred at room temperature overnight. After this time, the reaction mixture was heated at 50 °C for 8 h. The reaction mixture was cooled to room temperature and slowly poured into a saturated aqueous solution of NaHCO and ice. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 5% to 50% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a pale yellow oil (212.2 mg, 88% purity, 61% yield, t r =1.04min). LCMS (Method E); TIFF2024508687000432.tif18147

[0360] Step 4: Synthesis of benzyl 3-amino-3-(4-chloro-3-fluoro-phenyl)pyrrolidine-1-carboxylate TIFF2024508687000433.tif19128 In a round-bottom flask under nitrogen, triphenylphosphine (150 mg, 0.572 mmol) and 4-methylbenzenesulfonic acid (300 mg, 1.58 mmol) were added to a stirred solution of benzyl 3-azido-3-(4-chloro-3-fluoro-phenyl)pyrrolidine-1-carboxylate (88%, 212 mg, 0.498 mmol) in THF (2.5 mL). The mixture was stirred at room temperature overnight. The suspension was filtered, washed with a few drops of THF, then diethyl ether, and dried under vacuum for 72 h to afford the title compound as a white powder (210 mg, 98% purity, 79% yield, t r =0.62min). LCMS (Method E): m / z measurement 349.3 [M+H-pTSA]; TIFF2024508687000434.tif25148

[0361] Step 5: Synthesis of benzyl 3-(4-chloro-3-fluoro-phenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate TIFF2024508687000435.tif44128 To a stirred suspension of 3-amino-3-(4-chloro-3-fluoro-phenyl)pyrrolidine-1-carboxylate benzyl 4-methylbenzenesulfonate (80 mg, 0.154 mmol) in DCM (1.5 mL) at room temperature in a sealed vial, triethylamine (104 μL, 0.746 mmol), 4-(trifluoromethoxy)benzenesulfonyl chloride (98%, 40 μL, 0.231 mmol), and finally N,N-dimethylpyridin-4-amine (3.7 mg, 0.0306 mmol) were added sequentially. The reaction mixture was stirred at this temperature for 1 h and then heated at 40 °C for 3 h. The reaction mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The residue was triturated with DCM. Diethyl ether was added to the suspension, and the suspension was stirred for 1 hour. The resulting suspension was filtered, washed with diethyl ether (+ a few drops of DCM), and dried under vacuum at 40° C. for 16 hours to give the title compound as a white powder (75.5 mg, 96% purity, 82% yield, t r = 1.03 min). LCMS (Method E): m / z measured 595.2 [M+Na] + ; TIFF2024508687000436.tif32148

[0362] Step 6: Synthesis of N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide TIFF2024508687000437.tif27128 In a round-bottom flask under nitrogen, iodo(trimethyl)silane (55 μL, 0.386 mmol) was added to a stirred solution of benzyl 3-(4-chloro-3-fluoro-phenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate (75 mg, 0.130 mmol) in anhydrous acetonitrile (1.9 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum. The crude material was purified by flash chromatography on silica gel using a 2% to 20% gradient of MeOH (0.7 N NH) in DCM. The desired fractions were combined and concentrated. The residue was purified by reverse-phase preparative chromatography (C18Aq 100 g) using a gradient of 0% to 100% acetonitrile in water (0.1% AcOH in water and acetonitrile). The desired fractions were combined and concentrated. The residue was salt exchanged in diethyl ether, followed by the addition of a 2 M solution of hydrogen chloride in EtO (0.65 mL, 1.30 mmol) and stirring at room temperature for 2 hours. The suspension was filtered, washed with diethyl ether, and dried at 45 °C for 18 hours to give the hydrochloride salt of the title compound as an off-white powder (32.3 mg, 98.43% purity, 51% yield, t r =1.38min). LCMS (Method C): m / z measurement value 439 [M+H] + ; TIFF2024508687000438.tif25145

[0363] Example 17: tert-Butyl 4-(4-chlorophenyl)-4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate (53) To a stirred suspension of tert-butyl 4-amino-4-(4-chlorophenyl)piperidine-1-carboxylate (200 mg, 0.643 mmol) in DCM (6.4844 mL) at room temperature in a vial, triethylamine (0.45 mL, 3.22 mmol), 4-(trifluoromethoxy)benzenesulfonyl chloride (98%, 168 μL, 0.968 mmol), and DMAP (16 mg, 0.129 mmol) were added sequentially. The reaction mixture was stirred at this temperature for 1 h and then heated at 40 °C overnight. The reaction mixture was diluted with DCM and a saturated aqueous solution of NaHCO3. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a white foam (327.3 mg, 98.74% purity, 95.08% yield, t r =3.0 min). The product may be further dried under reduced pressure at 45° C. LCMS (Method C): m / z measured 534 [M+H] + ; TIFF2024508687000440.tif25147

[0364] Example 18: N-(1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide (54) TIFF2024508687000441.tif26128

[0365] Step 1: Synthesis of 1-benzylpyrrolidin-3-one TIFF2024508687000442.tif11128 To a stirred suspension of pyrrolidin-3-one hydrochloride (1:1) (97%, 5.00 g, 39.9 mmol) in a mixture of (bromomethyl)benzene (5.5 mL, 46.3 mmol) and DCE (95 mL) in ethyl acetate (8.75 mL) at room temperature in a sealed vial, triethylamine (14 mL, 0.100 mol) was added, and the reaction mixture was stirred at 70 °C overnight. The reaction mixture was poured into water. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 2% to 100% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a yellow oil (2.43 g, 100% purity, 34.759% yield). TIFF2024508687000443.tif11147

[0366] Step 2: Synthesis of 1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-ol TIFF2024508687000444.tif19128 In a three-necked round-bottom flask, a solution of 1-benzylpyrrolidin-3-one (500 mg, 2.85 mmol) was added to a stirred solution of 1 M bromo(4-chlorophenyl)magnesium (3.1 mL, 3.15 mmol) in anhydrous THF (11 mL) at 0 °C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl, and EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 2% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a brown oil (382.9 mg, 95% pure, 44.298% yield, t r =0.58 min). LCMS (Method D): m / z measured 288.1 [M+H] + ; TIFF2024508687000445.tif18149

[0367] Step 3: Synthesis of 3-azido-1-benzyl-3-(4-chlorophenyl)pyrrolidine TIFF2024508687000446.tif19128 In a sealed vial, azido(trimethyl)silane (0.86 mL, 6.51 mmol) and BF3 etherate (0.80 mL, 6.51 mmol) were added to a solution of 1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-ol (935 mg, 3.25 mmol) in anhydrous DCM (16.414 mL) at 0 °C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction mixture was then stirred once more at 40 °C overnight. Additional azido(trimethyl)silane (0.86 mL, 6.51 mmol) and BF3 etherate (0.80 mL, 6.51 mmol) were added at 0 °C, and the reaction mixture was stirred at room temperature for 4 h. Additional BF3 etherate (0.80 mL, 6.50 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by dropwise addition of saturated aqueous NaHCO3 (foaming occurred). DCM was added, and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous sodium chloride, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 1% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title product (535 mg, 100% pure, 52.116% yield, t r =0.63 min). LCMS (Method E): m / z measured 313.2 [M+H] + ; TIFF2024508687000447.tif25149

[0368] Step 4: Synthesis of 1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-amine TIFF2024508687000448.tif18128 In a round-bottom flask under nitrogen, triphenylphosphine (452 ​​mg, 1.72 mmol) followed by 4-methylbenzenesulfonic acid (976 mg, 5.13 mmol) was added to a stirred solution of 3-azido-1-benzyl-3-(4-chlorophenyl)pyrrolidine (535 mg, 1.71 mmol) in THF (10 mL). The mixture was stirred at room temperature for 2.5 h. The suspension was filtered, washed with a few drops of THF and EtO, and dried under vacuum for 18 h to afford the title compound as a white powder (919 mg, 100% purity, 85.126% yield, t r =0.48 min). LCMS (Method E): m / z measured 287.2 [M+H] + ; TIFF2024508687000449.tif18149

[0369] Step 5: Synthesis of N-(1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide (54) TIFF2024508687000450.tif26128 To a stirred suspension of 4-[4-(trifluoromethyl)phenoxy]benzenesulfonyl chloride (107 μL, 0.487 mmol) in DCM (15 mL) at room temperature in a vial, 1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-amine; 4-methylbenzenesulfonic acid (300 mg, 0.475 mmol), and triethylamine (0.50 mL, 3.59 mmol) were added sequentially. The reaction mixture was stirred at this temperature overnight. The reaction mixture was diluted with DCM and a saturated aqueous solution of NaHCO3. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 0% to 50% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a white foam (132.8 mg, purity 96.02%, yield 47.596%, t r= 2.01 min). The product may be dried under reduced pressure at 45°C. LCMS (Method C): m / z measured 587 [M+H] + ; TIFF2024508687000451.tif18150

[0370] Example 19: N-(1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide (55) TIFF2024508687000452.tif26128

[0371] Step 1: Synthesis of 1-benzylpyrrolidin-3-one TIFF2024508687000453.tif11128 To a stirred suspension of pyrrolidin-3-one hydrochloride (1:1) (97%, 5.00 g, 39.9 mmol) in a mixture of ethyl acetate (8.75 mL) and DCE (95 mL) at room temperature in a sealed vial, (bromomethyl)benzene (5.5 mL, 46.3 mmol) and triethylamine (14 mL, 0.100 mol) were added. The reaction mixture was stirred at 70 °C overnight. The reaction mixture was poured into water. The layers were separated. The aqueous layer was extracted twice with DCM. 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 flash chromatography on silica gel using a gradient of 2% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a yellow oil (2.43 g, 100% purity, 34% yield). TIFF2024508687000454.tif11147

[0372] Step 2: Synthesis of 1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-ol TIFF2024508687000455.tif18128 In a three-neck round-bottom flask, a few drops of a solution of 1-bromo-3,4-dichlorobenzene (97%, 0.45 mL, 3.42 mmol) in dry THF were added to a stirred suspension of magnesium (97 mg, 3.99 mmol) and iodine crystals in dry THF (2.2 mL) at room temperature under nitrogen. The reaction was heated at 50 °C until discoloration (orange to yellow) occurred. The remainder of the solution was then added dropwise and stirred at this temperature for 1 h (until the magnesium was consumed). The reaction mixture was then cooled to room temperature, and a solution of 1-benzylpyrrolidin-3-one (500 mg, 2.85 mmol) in dry THF (1.5 mL) was added dropwise. The reaction mixture was stirred at this temperature overnight. The reaction mixture was poured into a saturated aqueous solution of NH4Cl, and EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 0% to 50% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as an orange oil (335.5 mg, 100% pure, 37% yield, t r =0.62 min). LCMS (Method E): m / z measured 322.2 [M+H] + ; TIFF2024508687000456.tif25149

[0373] Step 3: Synthesis of 3-azido-1-benzyl-3-(3,4-dichlorophenyl)pyrrolidine TIFF2024508687000457.tif18128 To a solution of 1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-ol (436 mg, 1.35 mmol) in dry DCM (6.8 mL) at 0 °C under nitrogen in a sealed vial, azido(trimethyl)silane (360 μL, 2.71 mmol) and BF etherate (335 μL, 2.71 mmol) were added. The reaction mixture was warmed to 40 °C and stirred at this temperature overnight. Additional azido(trimethyl)silane (180 μL, 1.36 mmol) and BF etherate (167 μL, 1.35 mmol) were added at room temperature, and the reaction mixture was stirred at 40 °C overnight. Additional BF etherate (500 μL, 4.05 mmol) was added at room temperature, and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was quenched by dropwise addition of a saturated aqueous solution of NaHCO3 (foaming occurred). EtOAc was added and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 2% to 75% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (276.9 mg, 100% pure, 59% yield, t r =0.68 min). LCMS (Method E): m / z measured 347.2 [M+H] + ; TIFF2024508687000458.tif32149

[0374] Step 4: Synthesis of 1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-amine TIFF2024508687000459.tif19128 In a round-bottom flask under nitrogen, triphenylphosphine (264 mg, 1.01 mmol) followed by 4-methylbenzenesulfonic acid hydrate (569 mg, 2.99 mmol) was added to a stirred solution of 3-azido-1-benzyl-3-(3,4-dichlorophenyl)pyrrolidine (347 mg, 1.00 mmol) in THF (4.4 mL). The mixture was stirred at room temperature overnight. The suspension was filtered, washed with minimal THF, and dried under vacuum for 18 hours to afford the 4-methylbenzenesulfonic acid salt of the title compound as a white powder (601.1 mg, 98% purity, 89% yield, t r = 1.04 min). LCMS (Method E): m / z measured 321.2 [M+H] + ; TIFF2024508687000460.tif25154

[0375] Step 5: Synthesis of N-(1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide (55) To a stirred suspension of triethylamine (209 μL, 1.50 mmol) and 1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-aminium 4-methylbenzenesulfonate (200 mg, 0.300 mmol) in DCM (3,0046 mL) at room temperature in a vial, triethylamine (209 μL, 1.50 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with a half-saturated solution of NaHCO and DCM, and the aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator, then concentrated in vacuo and purified by flash chromatography on silica gel using a 0% to 4% gradient of MeOH (0.7 N NH) in DCM to afford the title compound as a white powder (172 mg, 93.69% purity, 82% yield, t r = 2.10 min). LCMS (Method C): m / z measured 621 [M+H] + ; TIFF2024508687000462.tif25150

[0376] Example 20: N-(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (56) TIFF2024508687000463.tif32128

[0377] Step 1: Synthesis of benzyl 4-oxopiperidine-1-carboxylate TIFF2024508687000464.tif17128 To a stirred solution of piperidin-4-one hydrochloride (1:1) (98%, 3.00 g, 21.7 mmol) and DIPEA (23 mL, 0.132 mol) in DCM (70 mL) at room temperature under nitrogen in a round-bottom flask, benzyl chloroformate (6.2 mL, 43.6 mmol) and DMAP (265 mg, 2.17 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. Dichloromethane and water were then added. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed once with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 10% to 75% ethyl acetate in cyclohexane to give the title compound as a yellow oil (3.89 g, 100% purity, 77% yield, t r =0.71min). LCMS (Method D); TIFF2024508687000465.tif18145

[0378] Step 2: Synthesis of benzyl 4-(4-chloro-3-fluoro-phenyl)-4-hydroxy-piperidine-1-carboxylate TIFF2024508687000466.tif25128 In a three-neck round-bottom flask, a 0.5 M solution of bromo(4-chloro-3-fluorophenyl)magnesium (5.2 mL, 2.60 mmol) was added dropwise to a stirred solution of benzyl 4-oxopiperidine-1-carboxylate (500 mg, 2.14 mmol) in anhydrous THF (4.3 mL) at 0 °C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction mixture was poured into a saturated aqueous solution of NH4Cl, and ethyl acetate was added. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 10% to 100% ethyl acetate in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (239.4 mg, 100% purity, 31% yield, t r =0.94). LCMS (Method E); TIFF2024508687000467.tif25145

[0379] Step 3: Synthesis of benzyl 4-azido-4-(4-chloro-3-fluoro-phenyl)piperidine-1-carboxylate TIFF2024508687000468.tif31128 In a three-necked round-bottom flask, a solution of benzyl 4-(4-chloro-3-fluoro-phenyl)-4-hydroxy-piperidine-1-carboxylate (185 mg, 0.509 mmol) in anhydrous DCM (2.8 mL) was added dropwise to a solution of azido(trimethyl)silane (81 μL, 0.613 mmol) and BF etherate (377 μL, 3.06 mmol) in anhydrous DCM (0.74 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction mixture was poured into a saturated aqueous solution of NaHCO (30 mL). The aqueous layer was extracted three times with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure to give the title compound as a colorless oil (188.2 mg, 69% purity, 66% yield, t r =1.08min). LCMS (Method E); TIFF2024508687000469.tif18143

[0380] Step 4: Synthesis of benzyl 4-amino-4-(4-chloro-3-fluoro-phenyl)piperidine-1-carboxylate TIFF2024508687000470.tif25128 In a round-bottom flask under nitrogen, triphenylphosphine (150 mg, 0.572 mmol) followed by 4-methylbenzenesulfonic acid hydrate (300 mg, 1.58 mmol) was added to a stirred solution of an inseparable mixture of benzyl 4-azido-4-(4-chloro-3-fluoro-phenyl)piperidine-1-carboxylate (69%, 188 mg, 0.334 mmol) and benzyl 4-(4-chloro-3-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (31%, 188 mg, 0.169 mmol) in THF (2.5 mL). The mixture was stirred overnight at room temperature. The suspension was filtered and washed with a few drops of THF. The filtrate was concentrated. The crude material was purified by reverse phase chromatography (Redisep C18Aq - 30g) using a gradient of 0% to 100% acetonitrile in water (0.1% AcOH in water and acetonitrile). The desired fractions were combined and concentrated to give the title compound as a colorless oil (66.4mg, 86% purity, 47% yield, t r =0.65min). LCMS (Method E); TIFF2024508687000471.tif18146

[0381] Step 5: Synthesis of benzyl 4-(4-chloro-3-fluoro-phenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate To a stirred solution of benzyl 4-amino-4-(4-chloro-3-fluoro-phenyl)piperidine-1-carboxylate (74%, 66 mg, 0.135 mmol) in DCM (1.3 mL) at room temperature in a vial, triethylamine (94 μL, 0.674 mmol), 4-(trifluoromethoxy)benzenesulfonyl chloride (98%, 35 μL, 0.204 mmol), and N,N-dimethylpyridin-4-amine (1.7 mg, 0.0139 mmol) were added sequentially. The reaction mixture was heated to 40 °C and stirred at this temperature overnight. The reaction mixture was cooled to room temperature. The organic layer was washed with a saturated aqueous solution of NH4Cl, then a saturated aqueous solution of NaHCO3, and finally a saturated aqueous solution of NaCl. The organic layer was dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 10% to 100% ethyl acetate in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless gum (34.9 mg, 94% purity, 41% yield, t r =1.05min). LCMS (Method E); TIFF2024508687000473.tif25144

[0382] Step 6: N-(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide To a stirred solution of benzyl 4-(4-chloro-3-fluoro-phenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (35 mg, 0.0595 mmol) in acetonitrile (0.86 mL) at room temperature in a round-bottom flask was added iodo(trimethyl)silane (25 μL, 0.178 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum. The crude material was dry-loaded onto decalite and purified by flash chromatography on silica gel using a 1% to 20% gradient of MeOH (0.7 N NH) in DCM. The desired fractions were combined and washed with water and triethylamine (41 μL, 0.297 mmol). The aqueous layer was extracted once with dichloromethane and methyltetrahydrofuran. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative chromatography (C18Aq - 15.5 g) using a gradient of 0% to 100% acetonitrile in water (0.1% AcOH in both). The desired fractions were combined and concentrated. Salt exchange of the residue was carried out in diethyl ether, followed by the addition of a 2 M solution of hydrogen chloride in Et2O (0.30 mL, 0.595 mmol) and stirring overnight at room temperature. The suspension was filtered, washed with diethyl ether, and dried at 45 °C for 24 h to give the hydrochloride salt of the title compound as a white powder (16.5 mg, 99.56% purity, 57% yield, t r = 1.42 min). LCMS (Method C): m / z measured 453 [M+H] + ; TIFF2024508687000475.tif18146

[0383] Example 21: N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide (57) TIFF2024508687000476.tif26128

[0384] Step 1: Synthesis of benzyl 3-(4-chlorophenyl)-3-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonylamino]pyrrolidine-1-carboxylate A sealed vial was charged with 1-((benzyloxy)carbonyl)-3-(4-chlorophenyl)pyrrolidin-3-aminium-4-methylbenzenesulfonate (250 mg, 0.497 mmol), 4-dimethylaminopyridine (12 mg, 0.0994 mmol), and triethylamine (0.35 mL, 2.49 mmol) in DCM (4.5968 mL). 4-[4-(trifluoromethyl)phenoxy]benzenesulfonyl chloride (0.13 mL, 0.596 mmol) was added, and the reaction mixture was stirred at 40 °C for 24 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and dichloromethane was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium carbonate followed by a saturated aqueous solution of sodium chloride, dried using a phase separator, and concentrated under reduced pressure. The residue was triturated with MeOH, filtered, washed with MeOH, and dried under vacuum for 18 hours. The filtrate was concentrated under reduced pressure. A solution of this mixture in methanol (20 mL) was stirred overnight at room temperature with pTsOH-functionalized microporous polystyrene resin (MP-TsOH) (746 mg, 1.49 mmol). Additional MP-TsOH (497 mg, 0.994 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The resin was filtered and washed with MeOH and DCM. The filtrate was concentrated under reduced pressure to give the title product as a colorless solid (250 mg, 98% purity, 78.12% yield, t r = 1.11 min). LCMS (Method D): m / z measured 653.3 [M+Na] + ; TIFF2024508687000478.tif32148

[0385] Step 2: Synthesis of N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide (57) To a stirred suspension of benzyl 3-(4-chlorophenyl)-3-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonylamino]pyrrolidine-1-carboxylate (98%, 245 mg, 0.380 mmol) in anhydrous acetonitrile (10 mL) at room temperature in a round-bottom flask was added iodo(trimethyl)silane (0.16 mL, 1.14 mmol). The reaction mixture was stirred at room temperature for 1.5 h, and then the reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 5% to 18% gradient of ammoniacal methanol in dichloromethane. The desired fractions were combined and washed with water (30 mL) and triethylamine (0.53 mL, 3.80 mmol). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with methanol, filtered, washed with methanol, and dried under vacuum for 18 hours. The resulting solid was triturated with 2 M hydrogen chloride in diethyl ether (0.57 mL, 1.14 mmol) for 2 hours, filtered, rinsed with diethyl ether, pentane, and dried under vacuum at 45 °C for 4 hours to give the HCl salt of the title compound as a white powder (79.1 mg, 99.72% purity, 38.87% yield, t r = 1.97 min). LCMS (Method C): m / z measured 497.1 [M+H] + ; TIFF2024508687000480.tif32146

[0386] Example 22: N-(3-(4-chloro-3-fluorophenyl)azetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (58) TIFF2024508687000481.tif28128

[0387] Step 1: Synthesis of benzyl 3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine-1-carboxylate To a stirred suspension of magnesium (113 mg, 4.63 mmol) and a catalytic amount of iodine in anhydrous THF (2 mL) at room temperature under nitrogen in a three-neck round-bottom flask, a few drops of a solution of 4-bromo-1-chloro-2-fluorobenzene (98%, 430 μL, 3.48 mmol) in anhydrous THF (1.5 mL) were added. The reaction mixture was heated at 50 °C until discoloration (orange to yellow) was observed. The remainder of the solution was then added dropwise and stirred at this temperature for 1 h (until the magnesium was consumed). The reaction mixture was then cooled to 0 °C, and a solution of benzyl 3-oxoazetidine-1-carboxylate (95%, 500 mg, 2.31 mmol) in anhydrous THF (1.6 mL) was added dropwise. After stirring the reaction mixture at room temperature for 3 h, the reaction mixture was poured into a saturated aqueous solution of NH₄Cl, and EtOAc was added. The layers were separated, and the aqueous layer was then extracted twice with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 10% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (590.4 mg, 100% purity, 76% yield, t r =0.90min). LCMS (Method E); TIFF2024508687000483.tif18145

[0388] Step 2: Synthesis of benzyl 3-(4-chloro-3-fluoro-phenyl)-3-methylsulfonyloxy-azetidine-1-carboxylate TIFF2024508687000484.tif30128 In a round-bottom flask, triethylamine (414 μL, 2.97 mmol) and methanesulfonyl chloride (115 μL, 1.49 mmol) were added to a stirred solution of benzyl 3-(4-chloro-3-fluoro-phenyl)-3-hydroxy-azetidine-1-carboxylate (250 mg, 0.745 mmol) in anhydrous DCM (3.5 mL) at room temperature under nitrogen. The reaction mixture was stirred for 2 hours, and then the reaction mixture was concentrated under reduced pressure. The crude material was diluted with dichloromethane and washed twice with water. The organic layer was washed once with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure to give the title compound as a yellow oil (324 mg, 95% purity, 100% yield). The crude material was used directly in the next step without any purification. TIFF2024508687000485.tif18153

[0389] Step 3: Synthesis of benzyl 3-azido-3-(4-chloro-3-fluoro-phenyl)azetidine-1-carboxylate A sealed vial was charged with benzyl 3-(4-chloro-3-fluoro-phenyl)-3-methylsulfonyloxy-azetidine-1-carboxylate (95%, 155 mg, 0.356 mmol) in anhydrous DMF (1.78 mL). NaN3 (28 mg, 0.428 mmol) was then added at room temperature, and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was cooled to room temperature, and then water (20 mL) and EtOAc were added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed once with water and once with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 5% to 50% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (91.7 mg, 100% purity, 77% yield, t r = 1.02 min). LCMS (Method E): m / z measured 317.2 [M-N3+H] + ; TIFF2024508687000487.tif18146

[0390] Step 4: Synthesis of benzyl 3-amino-3-(4-chloro-3-fluorophenyl)azetidine-1-carboxylate TIFF2024508687000488.tif21128 In a round-bottom flask under nitrogen, triphenylphosphine (67 mg, 0.256 mmol) and 4-methylbenzenesulfonic acid hydrate (145 mg, 0.763 mmol) were added sequentially to a stirred solution of benzyl 3-azido-3-(4-chloro-3-fluoro-phenyl)azetidine-1-carboxylate (92 mg, 0.254 mmol) in THF (1.4 mL). The mixture was stirred at room temperature overnight, and the resulting suspension was filtered, washed with THF, and dried under vacuum for 18 h to afford the p-toluenesulfonic acid salt of the title compound as a white powder (99 mg, 100% purity, 77% yield, t r =0.63 min). LCMS (Method E): m / z measured 335.2 [M+H-APTS] + ; TIFF2024508687000489.tif18148

[0391] Step 5: Synthesis of benzyl 3-(4-chloro-3-fluorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)azetidine-1-carboxylate To a stirred suspension of benzyl 3-amino-3-(4-chloro-3-fluoro-phenyl)azetidine-1-carboxylate; 4-methylbenzenesulfonic acid (99 mg, 0.195 mmol) in DCM (1.3 mL) at room temperature in a vial, triethylamine (136 μL, 0.976 mmol), 4-(trifluoromethoxy)benzenesulfonyl chloride (98%, 51 μL, 0.295 mmol), and N,N-dimethylpyridin-4-amine (2.5 mg, 0.0201 mmol) were added sequentially. The reaction mixture was stirred at 40 °C for 4 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed once with a saturated aqueous solution of NH4Cl, once with a saturated aqueous solution of NaHCO3, and once with a saturated aqueous solution of NaCl. The organic layer was dried using a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 10% to 50% ethyl acetate in heptane. The desired fractions were combined and concentrated to give the title compound as a white solid (65.3 mg, 100% purity, 60% yield, t r = 1.02 min). LCMS (Method E); TIFF2024508687000491.tif18145

[0392] Step 6: Synthesis of N-(3-(4-chloro-3-fluorophenyl)azetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (58) TIFF2024508687000492.tif28128 In a round-bottom flask, iodo(trimethyl)silane (49 μL, 0.346 mmol) was added to a stirred solution of benzyl 3-(4-chloro-3-fluoro-phenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]azetidine-1-carboxylate (65 mg, 0.116 mmol) in acetonitrile (1.7 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 2% to 20% gradient of methanol (+0.7 N ammonia) in dichloromethane. The desired fractions were combined, and water and triethylamine (81 μL, 0.583 mmol) were added. The layers were separated, and the aqueous layer was then extracted once with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. To the residue was added diethyl ether and 2 M hydrogen chloride in EtO (0.60 mL, 1.20 mmol). The suspension was stirred at room temperature overnight, filtered, washed with diethyl ether, and dried under vacuum at 45 °C for 2 days to give the HCl salt of the title compound as a white powder (28.4 mg, purity 97.99%, yield 52%, t r =1.57min). LCMS (Method C): m / z measurement value 425 [M+H-HCl] + ; TIFF2024508687000493.tif18145

[0393] Example 23: N-(4-(4-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (59) TIFF2024508687000494.tif32128

[0394] Step 1: Synthesis of tert-butyl 4-((tert-butoxycarbonyl)amino)-4-(4-fluorophenyl)piperidine-1-carboxylate TIFF2024508687000495.tif33128 To a stirred solution of 4-(4-fluorophenyl)piperidin-4-amine dihydrochloride (150 mg, 0.561 mmol) and triethylamine (313 μL, 2.25 mmol) in DCM (2 mL) in a sealed vial, tert-butoxycarbonyl tert-butyl carbonate (123 mg, 0.561 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water (1 mL) and DCM (1 mL) were added, and the aqueous layer was extracted twice with DCM. The organic layer was washed with a saturated solution of NH4Cl followed by a saturated solution of NaHCO3, filtered through a phase separator, and concentrated in vacuo to give the title compound as a colorless oil (142 mg, 81% purity, 70% yield, t r =0.58 min). LCMS (Method E): m / z measured 295.3 [M+H] + ; TIFF2024508687000496.tif25147

[0395] Step 2: Synthesis of tert-butyl 4-(4-fluorophenyl)-4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate TIFF2024508687000497.tif45128 A sealed vial was charged with tert-butyl 4-amino-4-(4-fluorophenyl)piperidine-1-carboxylate (70%, 146 mg, 0.347 mmol), N,N-dimethylpyridin-4-amine (8.5 mg, 0.0694 mmol), and triethylamine (145 μL, 1.04 mmol) in DCM (3 mL). 4-(Trifluoromethoxy)benzenesulfonyl chloride (65 μL, 0.382 mmol) was then added to the reaction mixture, which was stirred at 40 °C overnight. The reaction mixture was diluted with DCM and a saturated aqueous solution of NaHCO3, and the layers were then separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. The desired fractions were combined and concentrated. The resulting white residue was purified by reverse-phase preparative chromatography using a gradient of 0% to 100% acetonitrile in water (0.1% TFA in water and acetonitrile). The desired fractions were combined and concentrated to give the title compound as a white solid (114 mg, 96% purity, 61% yield, t r = 1.02 min). LCMS (Method E): m / z measured 419.3 [M-Boc+H] + ; TIFF2024508687000498.tif25149

[0396] Step 3: Synthesis of N-(4-(4-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (59) TIFF2024508687000499.tif32128 To a stirred suspension of tert-butyl 4-(4-fluorophenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (96%, 114 mg, 0.211 mmol) in diethyl ether (2 mL) at room temperature in a round-bottom flask was added 2 M hydrogen chloride in EtO (1.1 mL, 2.20 mmol). The reaction mixture was stirred at room temperature overnight. The suspension was filtered, washed with EtO, and dried under vacuum to afford the HCl salt of the title compound as a white solid (89 mg, 98.32% purity, 93% yield, t r =1.27min). LCMS (Method B): m / z measurement value 419.1 [M+H] + ; TIFF2024508687000500.tif18149

[0397] Example 24: N-(4-phenylpiperidin-4-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide (60) TIFF2024508687000501.tif27128

[0398] Step 1: Synthesis of 5-(benzylthio)-2-(trifluoromethoxy)pyridine A sealed vial was charged with 5-bromo-2-(trifluoromethoxy)pyridine (95%, 1.00 g, 3.93 mmol) and DIPEA (1.4 mL, 7.85 mmol) in anhydrous 1,4-dioxane (13.086 mL). The reaction mixture was degassed with argon for 5 min. Next, Xantphos (227 mg, 0.393 mmol), tris(dibenzylideneacetone)dipalladium(0) (180 mg, 0.196 mmol), and benzyl mercaptan (922 μL, 7.85 mmol) were added, and the reaction mixture was stirred at 105 °C for 3 h. The mixture was cooled to room temperature, filtered through a pad of decalite, washed with dioxane and DCM, concentrated, and purified by flash chromatography on silica gel using a 0% to 10% gradient of EtOAc in heptane to give the title compound as a pale yellow oil (1072 mg, 96% purity, 92% yield, t r = 1.03 min). LCMS (Method D): m / z measured 286.1 [M+H] + ; TIFF2024508687000503.tif18149

[0399] Step 2: Synthesis of tert-butyl 4-phenyl-4-((6-(trifluoromethoxy)pyridine)-3-sulfonamido)piperidine-1-carboxylate TIFF2024508687000504.tif38128 In a sealed vial, to a stirred solution of 5-benzylsulfanyl-2-(trifluoromethoxy)pyridine (150 mg, 0.526 mmol) in acetonitrile (4.41 mL) at 0° C. under nitrogen was added water (0.1119 mL), acetic acid (0.1692 mL), and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (207 mg, 1.05 mmol) sequentially. The reaction mixture was stirred at 0° C. for 2 h, then concentrated in vacuo, dissolved in DCM (5 mL), and quenched with 5% NaHCO (10 mL) at 0° C. The organic layer was dried over a phase separator and added dropwise to a solution of tert-butyl 4-amino-4-phenylpiperidine-1-carboxylate (174 mg, 0.631 mmol) and triethylamine (0.37 mL, 2.63 mmol) in DCM (3 mL) and stirred at 40 °C overnight. A semi-saturated solution of NaHCO was added, and the mixture was extracted twice with DCM. The combined organic layers were dried over a phase separator, concentrated in vacuo, and purified by flash chromatography on silica gel using a gradient of 0% to 5% methanol in DCM. The resulting product was repurified by flash chromatography on silica gel using a gradient of 0% to 50% EtOAc in heptane to give the title compound as a beige solid (16.2 mg, 91% purity, 5.59% yield, t r = 1.0 min). LCMS (Method E): m / z measured 402.3 [M-H+Boc] + ; TIFF2024508687000505.tif18144

[0400] Step 3: Synthesis of N-(4-phenylpiperidin-4-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide (60) TIFF2024508687000506.tif27128 To a stirred solution of 4 M hydrogen chloride in dioxane (0.20 mL, 0.798 mmol) in diethyl ether (0.1996 mL) in a round-bottom flask was added tert-butyl 4-phenyl-4-[[6-(trifluoromethoxy)-3-pyridyl]sulfonylamino]piperidine-1-carboxylate (91%, 11 mg, 0.0200 mmol). The mixture was stirred overnight at room temperature, filtered, washed with EtO, and dried overnight under vacuum at 45 °C to give the HCl salt of the expected compound as a white powder (6.9 mg, 97.23% purity, 76.77% yield, t r =1.30min). LCMS (Method C): m / z measurement value 402.0 [M+H] + ; TIFF2024508687000507.tif18149

[0401] Example 25: N-(1-methyl-4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (61) TIFF2024508687000508.tif29128

[0402] Step 1: Synthesis of tert-butyl 4-phenyl-4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate TIFF2024508687000509.tif36128 A sealed vial was charged with tert-butyl 4-amino-4-phenylpiperidine-1-carboxylate (265 mg, 0.959 mmol), DMAP (23 mg, 0.192 mmol), and triethylamine (535 μL, 3.84 mmol) in DCM (15 mL). 4-(Trifluoromethoxy)benzenesulfonyl chloride (179 μL, 1.05 mmol) was added, and the reaction mixture was stirred at 40 °C for 18 h. The reaction mixture was then quenched by the addition of a saturated aqueous solution of ammonium chloride (5 mL), water (10 mL), and dichloromethane (10 mL). The aqueous layer was extracted with dichloromethane (1 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 5% of methanol in dichloromethane to give the title compound as a white powder (438 mg, 100% purity, 91% yield, t r = 1.03 min). LCMS (Method E): m / z measured 523.3 [M+Na] + ; TIFF2024508687000510.tif25149

[0403] Step 2: Synthesis of N-(4-phenyl-4-piperidyl)-4-(trifluoromethoxy)benzenesulfonamide TIFF2024508687000511.tif27128 To a stirred solution of 2 M hydrogen chloride in diethyl ether (25 mL, 49.2 mmol) in a round-bottom flask was added tert-butyl 4-phenyl-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (435 mg, 0.869 mmol). The mixture was stirred at room temperature for 36 h, then filtered, washed with diethyl ether, and dried under vacuum at 50 °C for 3 days to give the HCl salt of the title compound as a white powder (345 mg, 100% purity, 91% yield, t r =0.64 min). LCMS (Method E): m / z measured value TIFF2024508687000512.tif18148

[0404] Step 3: Synthesis of N-(1-methyl-4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (61) In a sealed vial under nitrogen, a solution of N-(4-phenyl-4-piperidyl)-4-(trifluoromethoxy)benzenesulfonamide hydrochloride (100 mg, 0.229 mmol) and formaldehyde (8.2 mg, 0.275 mmol) in DCM (2.289 mL) and methanol (1 mL) was stirred at room temperature for 10 min. Triethylamine (0.035 mL, 0.252 mmol) and acetic acid (0.026 mL, 0.458 mmol) were added, and the mixture was stirred at room temperature for 30 min. Polymer-bound NaBHCN (229 mg, 0.458 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was then filtered, the residue washed with MeOH, and the filtrate was concentrated and then purified by flash chromatography on silica gel using a 5% to 10% gradient of (MeOH + 2% NHOH) in DCM. The desired fractions were collected, and EtO (5 mL) and 2 N HCl in EtO (5 mL) were added. The mixture was stirred overnight at room temperature, filtered, washed with EtO, and then dried overnight under vacuum at 45 °C to give the title compound as a white powder (77.2 mg, 100% pure, 75% yield, t r =1.25min). LCMS (Method B): m / z measurement value 415 [M+H] + ; TIFF2024508687000514.tif25150

[0405] Example 26: N-(4-(4-chlorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide (62) TIFF2024508687000515.tif32128

[0406] Step 1: Synthesis of tert-butyl 4-(4-chlorophenyl)-4-((4-isopropoxyphenyl)sulfonamido)piperidine-1-carboxylate TIFF2024508687000516.tif45128 A sealed vial was charged with tert-butyl 4-amino-4-(4-chlorophenyl)piperidine-1-carboxylate (75 mg, 0.241 mmol) and triethylamine (101 μL, 0.724 mmol) in DCM (2 mL). 4-(propan-2-yloxy)benzenesulfonyl chloride (98%, 64 mg, 0.265 mmol) was then added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then heated at 40°C for 2 hours, and N,N-dimethylpyridin-4-amine (5.9 mg, 0.0483 mmol) was added. The reaction mixture was stirred at 40°C overnight. The reaction mixture was diluted with DCM and a saturated aqueous solution of NaHCO3, and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as an off-white solid (82 mg, 98% purity, 65% yield, t r = 1.05 min). LCMS (Method E): m / z measured 409.4 [M-Boc+H] + ; TIFF2024508687000517.tif25148

[0407] Step 2: Synthesis of N-(4-(4-chlorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide (62) TIFF2024508687000518.tif32128 To a stirred suspension of tert-butyl 4-(4-chlorophenyl)-4-[(4-isopropoxyphenyl)sulfonylamino]piperidine-1-carboxylate (80 mg, 0.157 mmol) in diethyl ether (1.5 mL) at room temperature under nitrogen in a round-bottom flask was added 2 M hydrogen chloride in EtO (786 μL, 1.57 mmol). The reaction mixture was stirred overnight at room temperature. Next, 4 M hydrogen chloride in 1,4-dioxane (0.20 mL, 0.786 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 4 h. The suspension was filtered, washed with EtO, and dried overnight at 40 °C to give the HCl salt of the title compound as a white solid (47 mg, 99.73% purity, 67% yield, t r =1.56min). LCMS (Method C) m / z measurement value 409 [M+H] + ; TIFF2024508687000519.tif25149

[0408] Example 27: N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimide amide (63) TIFF2024508687000520.tif33128

[0409] Step 1: Synthesis of sodium 4-(trifluoromethoxy)benzenesulfinate TIFF2024508687000521.tif18128 In a round-bottom flask equipped with a condenser, a solution of 4-(trifluoromethoxy)benzenesulfonyl chloride (0.65 mL, 3.84 mmol), sodium sulfite (1081 mg, 8.44 mmol), and NaHCO3 (0.71 g, 8.44 mmol) in water (10 mL) was stirred at 65 °C for 20 h. The mixture was cooled to room temperature and concentrated. Methanol (10 mL) was added to the residue, and the suspension was stirred at room temperature for 2 h and then filtered. The residue was washed with MeOH, and the filtrate was concentrated to give the title compound as a white powder (430 mg, 45% yield, t r =0.91min). LCMS (Method E); TIFF2024508687000522.tif11128

[0410] Step 2: Synthesis of 4-(trifluoromethoxy)benzenesulfinyl chloride TIFF2024508687000523.tif18128 In a round-bottom flask, oxalyl dichloride (0.23 mL, 2.60 mmol) and anhydrous DMF (0.0173 mL) were added sequentially to a stirred suspension of sodium 4-(trifluoromethoxy)benzenesulfinate (430 mg, 1.73 mmol) in anhydrous DCM (4.3173 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and dried under vacuum to give the title compound as a white powder (1.23 g, 25% purity, 72% yield). The compound was used in the next step without further purification.

[0411] Step 3: Synthesis of N-[(3,4-dimethoxyphenyl)methyl]-4-(trifluoromethoxy)benzenesulfinamide TIFF2024508687000524.tif18128 In a round-bottom flask, to a stirred suspension of 4-(trifluoromethoxy)benzenesulfinyl chloride (25%, 1.10 g, 1.12 mmol) in anhydrous DCM (3.7473 mL) at room temperature under nitrogen, 1-(3,4-dimethoxyphenyl)methanamine (98%, 0.26 mL, 1.69 mmol) and triethylamine (0.47 mL, 3.37 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 20 hours. Water was added, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 0% to 5% gradient of methanol in dichloromethane and another 0% to 5% gradient of MeOH (0.7 N NH3) in DCM. The desired fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (142 mg, 97% purity, 33% yield, t r =0.86 min). LCMS (Method E): m / z measured 376.2 [M+H] + ; TIFF2024508687000525.tif25149

[0412] Step 4: Synthesis of benzyl 3-(4-chlorophenyl)-3-[[N-[(3,4-dimethoxyphenyl)methyl]-S-[4-(trifluoromethoxy)phenyl]sulfonimidoyl]amino]pyrrolidine-1-carboxylate TIFF2024508687000526.tif37128 To a stirred solution of N-[(3,4-dimethoxyphenyl)methyl]-4-(trifluoromethoxy)benzenesulfinamide (112 mg, 0.297 mmol) in tetrachloromethane (1.2 mL, 12.8 mmol) in a round-bottom flask at 0°C under nitrogen was added tert-butyl hypochlorite (0.040 mL, 0.356 mmol). The reaction mixture was stirred in the dark at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure at 2°C. The residue was dissolved in anhydrous THF (0.9292 mL), and benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate (108 mg, 0.327 mmol), DIPEA (156 μL, 0.891 mmol), and N,N-dimethylpyridin-4-amine (99%, 3.7 mg, 0.0297 mmol) were added sequentially, and the reaction mixture was stirred at 40° C. for 18 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and ethyl acetate (20 mL) was added. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 0% to 6% gradient of MeOH (0.7 N NH) in DCM to give the title compound as a colorless oil (145 mg, 90% pure, 62% yield, t r = 1.11 min). LCMS (Method E): m / z measured 704.1 [M+H] + ; TIFF2024508687000527.tif25148

[0413] Step 5: Synthesis of benzyl 3-(4-chlorophenyl)-3-[[[4-(trifluoromethoxy)phenyl]sulfonimidoyl]amino]pyrrolidine-1-carboxylate To a stirred solution of benzyl 3-(4-chlorophenyl)-3-[[N-[(3,4-dimethoxyphenyl)methyl]-S-[4-(trifluoromethoxy)phenyl]sulfonimidoyl]amino]pyrrolidine-1-carboxylate (145 mg, 0.206 mmol) in a mixture of acetonitrile (2.75 mL) and water (1.38 mL) at 0 °C under nitrogen in a round-bottom flask was added cerium ammonium nitrate (282 mg, 0.515 mmol). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography on silica gel using a 2% to 10% gradient of MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as an off-white solid (77 mg, 91% purity, 61% yield, t r =0.97 min). LCMS (Method E): m / z measured 576.2; TIFF2024508687000529.tif11143

[0414] Step 6: Synthesis of N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimide amide (63) In a sealed vial, a suspension of benzyl 3-(4-chlorophenyl)-3-[[[4-(trifluoromethoxy)phenyl]sulfonimidoyl]amino]pyrrolidine-1-carboxylate (77 mg, 0.139 mmol) in anhydrous ACN (3.4749 mL) was stirred at room temperature under nitrogen. Iodo(trimethyl)silane (83 mg, 0.417 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 h, concentrated in vacuo, and purified by flash chromatography on silica gel using a 2% to 15% gradient of MeOH (0.7 N NH) in DCM. The desired fractions were combined, water and triethylamine (0.19 mL, 1.39 mmol) were added, the aqueous layer was extracted twice with DCM, and the combined organic layers were concentrated in vacuo. The resulting oil was dissolved in diethyl ether, pentane was added, and the resulting solid was filtered to give the expected compound as an off-white powder (24 mg, purity 92.9%, yield 38%, t r = 4.48 min). LCMS (Method F): m / z measured value 420; TIFF2024508687000531.tif18144

[0415] Example 28: N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide (64) TIFF2024508687000532.tif33128

[0416] Step 1: Synthesis of benzyl 3-(4-chlorophenyl)-3-hydroxypyrrolidine-1-carboxylate In a three-neck round-bottom flask, a few drops of a solution of 1-bromo-4-chlorobenzene (12.28 g, 64.2 mmol) in anhydrous THF (50 mL) were added to a stirred suspension of magnesium (2.04 g, 84.1 mmol) and iodine crystals in anhydrous THF (90 mL) at room temperature under nitrogen. The Grignard reaction was heated at 50 °C until discoloration (orange to colorless) was observed. The remainder of the solution was then added dropwise and stirred at 50 °C for 1 h (until the magnesium was consumed). The reaction mixture was then cooled to 0 °C, and a solution of benzyl 3-oxopyrrolidine-1-carboxylate (97%, 10.00 g, 44.2 mmol) in anhydrous THF (50 mL) was added dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), followed by the addition of ethyl acetate (100 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with DCM, filtered, washed with a few drops of DCM, and dried under vacuum. The filtrate was concentrated and purified by flash chromatography on silica gel using a gradient of 0% to 4% methanol in dichloromethane. The desired fractions were concentrated and combined with the first residue isolated to give the title compound as a beige solid (8.939 g, 100% pure, 60.9% yield, t r =0.89 min). LCMS (Method E): m / z measured 332.3 [M+H] + ; TIFF2024508687000534.tif18147

[0417] Step 2: Synthesis of benzyl 3-azido-3-(4-chlorophenyl)pyrrolidine-1-carboxylate TIFF2024508687000535.tif23128 Azido(trimethyl)silane (4.3 mL, 32.1 mmol) and BF etherate (20 mL, 0.161 mol) were added to a solution of benzyl 3-(4-chlorophenyl)-3-hydroxy-pyrrolidine-1-carboxylate (8.88 g, 26.8 mmol) in anhydrous DCM (100 mL) at 0 °C under nitrogen in a round-bottom flask. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) at 0 °C, followed by the addition of water (30 mL) and dichloromethane (50 mL). The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried using a phase separator, and concentrated under reduced pressure to give the title product as a brown oil (8.838 g, 70% purity, 64.8% yield, t r = 1.03 min). LCMS (Method E): m / z measured 357.4 [M+H] + ; TIFF2024508687000536.tif25148

[0418] Step 3: Synthesis of benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate TIFF2024508687000537.tif20128 In a round-bottom flask under nitrogen, triphenylphosphine (4.22 g, 16.1 mmol) followed by 4-methylbenzenesulfonic acid hydrate (9.18 g, 48.2 mmol) was added to a stirred solution of benzyl 3-azido-3-(4-chlorophenyl)pyrrolidine-1-carboxylate (70%, 8.83 g, 17.3 mmol) in THF (76.5 mL) at room temperature. The mixture was stirred overnight at room temperature. The suspension was filtered, washed with diethyl ether, and dried under vacuum at 45 °C for 48 hours to give the 4-methylbenzenesulfonic acid salt of the title compound as a white solid (6.68 g, 100% pure, 76.7% yield, t r =0.62 min). LCMS (Method E): m / z measured 331.3 [M+H] + ; TIFF2024508687000538.tif18148

[0419] Step 4: Synthesis of benzyl 3-(4-chlorophenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate A round-bottom flask was charged with benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate; 4-methylbenzenesulfonic acid (6.41 g, 12.7 mmol), triethylamine (14 mL, 0.102 mol), and 4-(trifluoromethoxy)benzenesulfonyl chloride (2.6 mL, 15.3 mmol) in DCM (117.86 mL). 4-Dimethylaminopyridine (311 mg, 2.55 mmol) was added, and the reaction mixture was stirred at 40 °C (hot plate adjusted to 45 °C) for 20 h. A saturated aqueous solution of ammonium chloride and dichloromethane were poured into the reaction mixture. The layers were separated. The organic layer was washed with a saturated aqueous solution of NaHCO3, then with a saturated aqueous solution of sodium chloride, dried using a phase separator, and concentrated under reduced pressure. The residue was triturated with MeOH, filtered, washed with MeOH, and dried under vacuum for 18 hours to give the title compound as a white powder (3.3 g, 97% purity, 45.3% yield, t r =0.62min). LCMS (Method E); TIFF2024508687000540.tif11138

[0420] Step 5: Synthesis of 5-benzylsulfanyl-2-(trifluoromethoxy)pyridine A sealed vial was charged with 5-bromo-2-(trifluoromethoxy)pyridine (0.58 mL, 4.13 mmol), Pd2(dba)3 (95%, 199 mg, 0.207 mmol), and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (98%, 244 mg, 0.413 mmol) in degassed anhydrous 1,4-dioxane anhydride (21 mL). Benzyl mercaptan (0.73 mL, 6.20 mmol) was added, and the reaction mixture was stirred at 105 °C for 3 h. The mixture was cooled to room temperature, filtered through a pad of decalite, washed with dioxane and DCM, and concentrated. The crude material was purified by flash silica gel chromatography using a gradient of 100% heptane to 10% EtOAc in heptane over 10 column volumes to give the title compound as a beige solid (0.95 g, 95% purity, 76.6% yield, t r = 1.08 min). LCMS (Method E): m / z measured 286 [M+H] + ; TIFF2024508687000542.tif18142

[0421] Step 6: Synthesis of 6-(trifluoromethoxy)pyridine-3-sulfonyl chloride To a stirred solution of 5-benzylsulfanyl-2-(trifluoromethoxy)pyridine (0.95 g, 3.33 mmol) in acetonitrile (20 mL) at 0 °C under nitrogen in a three-neck round-bottom flask equipped with a thermometer, water (1 mL) and acetic acid (1.5 mL) were added sequentially, followed by the portionwise addition of 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (722 mg, 3.66 mmol). The reaction mixture was stirred at 0 °C for 2 h, then concentrated in vacuo, dissolved in DCM, and quenched with 10 mL of 5% NaHCO3 at 0 °C. The organic layer was separated, dried on a phase separator, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of heptane / DCM (100 / 0 to 1 / 1). The fractions were collected and the solvent removed under vacuum to give the title compound as a colorless oil (450 mg, 60% purity, 30.993% yield). TIFF2024508687000544.tif18146

[0422] Step 7: Synthesis of benzyl 3-(4-chlorophenyl)-3-[[6-(trifluoromethoxy)-3-pyridyl]sulfonylamino]pyrrolidine-1-carboxylate To a stirred suspension of 6-(trifluoromethoxy)pyridine-3-sulfonyl chloride (60%, 450 mg, 1.03 mmol) in anhydrous DCM (9 mL) in a round-bottom flask equipped with a condenser, N,N-dimethylpyridin-4-amine (99%, 21 mg, 0.172 mmol) and N,N-diethylethanamine (0.30 mL, 2.15 mmol) were added sequentially, followed by benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate (95%, 300 mg, 0.862 mmol). The reaction mixture was stirred at reflux for 5 h. The reaction was cooled to 25 °C, and the mixture was quenched with a saturated solution of NH4Cl. The phases were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed once with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography using a gradient of DCM / MeOH 99 / 1 to 9 / 1 over 20 column volumes to afford the title compound as a beige solid (212 mg, 70% purity, 31% yield, t r = 1.96 min). LCMS (Method G): m / z measured 556 [M+H] + ; TIFF2024508687000546.tif18149

[0423] Step 8: Synthesis of N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide (64) TIFF2024508687000547.tif33128 Under nitrogen, iodo(trimethyl)silane (0.043 mL, 0.302 mmol) was added to a stirred solution of benzyl 3-(4-chlorophenyl)-3-[[6-(trifluoromethoxy)-3-pyridyl]sulfonylamino]pyrrolidine-1-carboxylate (70%, 80 mg, 0.101 mmol) in acetonitrile (1.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, and the solvent was removed in vacuo. 1 M hydrogen chloride in EtO (0.30 mL, 0.302 mmol) was added, the mixture was stirred at 25 °C for 30 min, and the solvent was removed in vacuo. The crude material was purified by reverse-phase preparative chromatography (C18aq, 25 g) using a gradient of acetonitrile + 0.1% AcOH / water + 0.1% AcOH from 0% to 100%. The fractions were collected and the solvent removed in vacuo. The residue was taken up in DCM and washed with a 1 M solution of NaHCO3. The phases were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed once with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in dioxane (1 mL) and 1 M hydrogen chloride in Et2O (0.30 mL, 0.302 mmol) was added. The mixture was stirred at 25 °C for 1 h. Dioxane and Et2O were removed in vacuo. The residue was triturated with anhydrous Et2O, filtered, washed with anhydrous Et2O and dried under vacuum at 25 °C for 16 h to give the hydrochloride salt of the title compound as a white solid (11 mg, 94.81% purity, 23% yield, t r = 1.2 min). LCMS (Method H): m / z measured 422 [M+H] + ; TIFF2024508687000548.tif18148

[0424] Example 29: N-(4-(5-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (65) TIFF2024508687000549.tif28128

[0425] Step 1: Synthesis of 1-benzylpiperidin-4-one TIFF2024508687000550.tif12128 To a stirred suspension of piperidin-4-one hydrochloride (98%, 3.00 g, 21.7 mmol) in acetonitrile (50 mL) at room temperature in a sealed round-bottom flask was added K2CO3 (7.49 g, 54.2 mmol) and bromomethylbenzene (3.1 mL, 26.0 mmol). The reaction mixture was stirred at 60 °C overnight. The reaction mixture was poured into water. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 10% to 100% gradient of EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a yellow liquid (2.49 g, 87% purity, 53% yield, t r =0.58min). LCMS (Method E); TIFF2024508687000551.tif18142

[0426] Step 2: Synthesis of 1-benzylpiperidine-4-carbonitrile To a stirred solution of 1-benzylpiperidin-4-one (87%, 1.00 g, 4.60 mmol) and 1-(isocyanomethylsulfonyl)-4-methyl-benzene (98%, 916 mg, 4.60 mmol) in DME (36.459 mL) at 0 °C in a round-bottom flask was added a solution of K₄t-Bu (1.03 g, 9.19 mmol) dissolved in 16 mL of a 1:1 mixture of DME and tert-butyl alcohol dropwise. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. Water (50 mL) was added, and the mixture was extracted three times with EtOAc (30 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 flash chromatography using a gradient of 1% to 8% MeOH in DCM. The desired fractions were combined and concentrated under reduced pressure to give the title compound as a yellow oil (811.1 mg, 91% purity, 80% yield, t r=0.41 min). LCMS (Method E): m / z measured 201.3 [M+H] + ; TIFF2024508687000553.tif18143

[0427] Step 3: Synthesis of 1-benzyl-4-(5-fluoro-2-pyridyl)piperidine-4-carbonitrile TIFF2024508687000554.tif26128 In a sealed tube, 2-bromo-5-fluoropyridine (98%, 661 mg, 3.68 mmol) was added to a stirred solution of 1-benzylpiperidine-4-carbonitrile (91%, 810 mg, 3.68 mmol) in anhydrous toluene (36.80 mL) at room temperature under nitrogen. The reaction mixture was cooled to 0 °C, and 1 M NaHMDS (7.4 mL, 7.36 mmol) was added dropwise. The solution was stirred at 0 °C for 1 h and then at room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride to reach pH 7, and then EtOAc was added. The layers were separated, 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 material was purified by flash chromatography on silica gel using a 10% to 80% gradient of EtOAc in cyclohexane. The desired fractions were combined and concentrated under reduced pressure to give the expected product as an off-white solid (923.3 mg, 99% purity, 84% yield, t r =0.53 min). LCMS (Method E): m / z measured 296.4 [M+H] + ; TIFF2024508687000555.tif25150

[0428] Step 4: Synthesis of 1-benzyl-4-(5-fluoro-2-pyridyl)piperidine-4-carboxamide TIFF2024508687000556.tif27128 In a sealed tube, a mixture of 1-benzyl-4-(5-fluoro-2-pyridyl)piperidine-4-carbonitrile (99%, 200 mg, 0.670 mmol) in H2SO4 (2.6853 mL) and water (0.6713 mL) was stirred at 65 °C for 1.5 h. The mixture was poured into ice water and basified with aqueous 30% NaOH to reach a pH of 10-11. Water and DCM were added to obtain two homogenous layers, and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a white solid (198.9 mg, 99% purity, 94% yield, t r =0.47 min). LCMS (Method D): m / z measured 314.2 [M+H] + ; TIFF2024508687000557.tif18143

[0429] Step 5: Synthesis of 1-benzyl-4-(5-fluoro-2-pyridyl)piperidin-4-amine TIFF2024508687000558.tif19128 In a sealed tube, 1-benzyl-4-(5-fluoro-2-pyridyl)piperidine-4-carboxamide (99%, 335 mg, 1.06 mmol) was charged and dissolved in acetonitrile (3.00 mL) and water (3.00 mL). [Bis(trifluoroacetoxy)iodo]benzene (96%, 484 mg, 1.08 mmol) was then added, and the reaction was stirred at room temperature overnight and at 80 °C for 4 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum overnight. The residue was dissolved in EtO, and 2 M hydrogen chloride in EtO (11 mL, 21.2 mmol) was added. The suspension was stirred at room temperature for 2 hours, filtered, and washed with EtO. The resulting gum was dissolved in MeOH and concentrated under reduced pressure. The residue was poured into a saturated aqueous solution of Na2CO3 to reach pH 10, and 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 to give the title compound as a brown oil (270 mg, 65% purity, 58% yield, t r =0.45 min). LCMS (Method D): m / z measured 286.2 [M+H]+ ; TIFF2024508687000559.tif18143

[0430] Step 6: Synthesis of N-[1-benzyl-4-(5-fluoro-2-pyridyl)-4-piperidyl]-4-(trifluoromethoxy)benzenesulfonamide TIFF2024508687000560.tif37128 A sealed vial was charged with 1-benzyl-4-(5-fluoro-2-pyridyl)piperidin-4-amine (59%, 270 mg, 0.558 mmol) and triethylamine (0.39 mL, 2.79 mmol) in DCM (5.1633 mL). 4-(Trifluoromethoxy)benzenesulfonyl chloride (98%, 116 μL, 0.670 mmol) and 4-dimethylaminopyridine (14 mg, 0.112 mmol) were added, and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and dichloromethane was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried using a phase separator, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 2% to 10% gradient of MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as an off-white foam (262.7 mg, 100% purity, 92% yield, t r =0.68 min). LCMS (Method D): m / z measured 510.2 [M+H] + ; TIFF2024508687000561.tif18149

[0431] Step 7: Synthesis of N-[4-(5-fluoro-2-pyridyl)-4-piperidyl]-4-(trifluoromethoxy)benzenesulfonamide TIFF2024508687000562.tif34128 To a stirred solution of 1-chloroethyl chloroformate (99%, 0.10 mL, 0.954 mmol) in DCE (12 mL) under nitrogen was added N-[1-benzyl-4-(5-fluoro-2-pyridyl)-4-piperidyl]-4-(trifluoromethoxy)benzenesulfonamide (100%, 243 mg, 0.477 mmol). The reaction mixture was stirred at room temperature for 2 days and then concentrated under reduced pressure. The residue was dissolved in MeOH (12 mL), and the reaction mixture was stirred at 65 °C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting white solid was triturated with a mixture of dichloromethane and methanol (95:5, 15 mL), and the resultin...

Claims

1. A compound of formula (I) or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof, selected from the group consisting of: During the ceremony Ar is C 6 ~C 10 Aryl or C 2 ~C 10 Heteroaryl, which is 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, NH 2 , 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 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 Two vicinal substituents of Ar may together provide a 5- to 8-membered ring fused to Ar; G is an optionally substituted C 3 ~C 8 Cycloalkyl, which is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, phenyl, halogen, OH, NH 2 , 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 Phenyl in G is 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 substituents in G together form the C in G 3 ~C 8 C that is spiro, fused, or bridged with cycloalkyl 3 ~C 8 Cycloalkyl may be provided; R 1 teeth selected from the group consisting of: R 2 is H, halogen, optionally substituted C 1 ~C 6 Alkyl, optionally substituted phenyl, optionally substituted C 3 ~C 6 Cycloalkyl, optionally substituted C 2 ~C 10 Heterocyclyl, optionally substituted C 1 ~C 6 Aminoalkyl, optionally substituted C 1 ~C 6 Alkoxyalkyl, optionally substituted C 1 ~C 6 Haloalkyl, optionally substituted C 2 ~C 6 Alkynyl, -C(=O)OR a , and -C(=O)N(R a )(R a ) selected from the group consisting of R 2 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 at least one selected from the group consisting of heteroaryl; R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' are 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 on heterocyclyl, phenyl, or phenoxy 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 ) at least one selected from the group consisting of R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two geminal substituents selected from the group consisting of, together with the carbon atom to which they are attached, an optionally substituted C 3 ~C 8 Cycloalkyl and optionally substituted C 2 ~C 10 heterocyclyl, R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two vicinal substituents selected from the following, taken together with the carbon atom to which they are attached, may form an optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 2 ~C 10 heterocyclyl, and optionally substituted phenyl; R separated by 2 to 5 carbon atoms 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 8 , and R 8' Two substituents selected from the group consisting of optionally substituted C 4 ~C 7 Cycloalkyl and optionally substituted C 4 ~C 8 heterocyclyl; R 10 is 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 10' is phenyl, benzyl, and -C(=O)-C 1 ~C 6 alkyl; R 10' Benzyl or phenyl in is halogen, C 1 ~C 3 Haloalkyl, OH, and N(R a )(R b ) substituted with at least one substituent selected from the group consisting of R 10' wherein the alkyl is substituted with at least one phenyl substituent; Y is C(R a )(R a ), C=O, NR 10 , N.R. 10' and O, Y is C(R a )(R a ) and R 2 When is an optionally substituted phenyl, Ar is a C substituted with at least one trifluoromethoxy substituent. 6 ~C 10 Aryl or C 2 ~C 10 Contains heteroaryl; Z is C=O, NR 10 , N.R. 10' , O, and S; R A is H or C 1 ~C 6 is alkyl; R a are independently H, C 1 ~C 6 Alkyl, benzyl, and C 6 ~C 10 aryl; R b is independently at each occurrence H, optionally substituted C 1 ~C 6 R is selected from the group consisting of alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl; 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 ) may be substituted with at least one selected from the group consisting of; In (Ia), (Ib), and (Ic): a) R 2 is phenyl or C 2 ~C 10 Heteroaryl, wherein the phenyl or heteroaryl is selected from the group consisting of halogen, OH, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, and C 1 ~C 6 may be substituted with at least one substituent selected from the group consisting of alkyl; b) R 3 and R 3' At least one of the following is phenyl or C 2 ~C 10 Heteroaryl, wherein the phenyl or heteroaryl is selected from the group consisting of halogen, OH, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, and C 1 ~C 6 substituted with at least one substituent selected from the group consisting of alkyl; c) R 3 , R 3' , R 4 , and R 4' At least one of the following is phenyl or C 2 ~C 10 Heteroaryl, wherein the phenyl or heteroaryl is selected from the group consisting of halogen, OH, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, and C 1 ~C 6 alkyl, wherein one of Y and Z is present and one of Y and Z is C=O, NR 10 and O; R 10 is H, C 3 ~C 6 Cycloalkyl, phenyl, optionally substituted benzyl, -C(=O)OR b , -C(=O)R b , -S(=O) 2 - optionally substituted phenyl; d) R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two geminal substituents selected from, together with the carbon atom to which they are attached, form C 3 ~C 8 Cycloalkyl or C 2 ~C 6 heterocyclyl, the cycloalkyl or heterocyclyl being C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Haloalkoxy, halogen, N(R a )(R a ), OR a , C(=O)R a , C(=O)OR a , and C(=O)N(R a )(R a ) substituted with at least one substituent selected from the group consisting of: e) R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two vicinal substituents selected from, together with the carbon atom to which they are attached, form C 3 ~C 8 Cycloalkyl, C 2 ~C 10 heterocyclyl, or phenyl, wherein the cycloalkyl, heterocyclyl, or phenyl is C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Haloalkoxy, halogen, OR a , C(=O)R a , C(=O)OR a , and C(=O)N(R a )(R a ) substituted with at least one substituent selected from the group consisting of: f) R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two geminal substituents selected from, together with the carbon atom to which they are attached, form C 3 ~C 8 Cycloalkyl or C 2 ~C 6 Form a heterocyclyl, R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' Two vicinal substituents selected from, together with the carbon atom to which they are attached, form C 3 ~C 8 Cycloalkyl, C 2 ~C 10 heterocyclyl, or phenyl, each of which is independently C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Haloalkoxy, halogen, N(R a )(R a ), OR a , C(=O)R a , C(=O)OR a , and C(=O)N(R a )(R a ) may be substituted with at least one substituent selected from the group consisting of g) Y is N(R 10' ) and R 4 , R 4' , R 6 , and R 6' each, if present, independently represents H, C 1 ~C 6 Alkyl, Hydroxyl, C 1 ~C 4 Selected from the group consisting of haloalkyl, phenyl, and phenoxy; h) R 2 , R 3 , R 3' , R 4 , and R 4' At least one of the optionally substituted C 3 ~C 8 Cycloalkyl or C 2 ~C 10 heterocyclyl, and each optional substituent on the cycloalkyl or heterocycloalkyl is independently halogen, C 1 ~C 6 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Haloalkoxy, OR a , N(R a )(R b ), C(=O)R a , and C(=O)OR a selected from the group consisting of: i) R 2 is an optionally substituted C 1 ~C 6 Haloalkyl, optionally substituted C 2 ~C 6 Aminoalkyl and optionally substituted C 2 ~C 6 alkynyl; R 2 Each of the optional haloalkyl, aminoalkyl, and alkynyl substituents in 1 ~C 6 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Haloalkoxy, halogen, C(=O)R a , C(=O)OR a , C(=O)N(R a )(R a ), S(=O) 2 -Optionally substituted phenyl and S(=O) 2 -Optionally substituted C 2 ~C 10 At least one selected from the group consisting of heteroaryl At least one of the following applies: The compound, or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof.

2. The compound of formula (I) is selected from the group consisting of During the ceremony R 9 are independently F, Cl, Br, and C at each occurrence. 1 ~C 3 Alkoxy, and C 1 ~C 3 haloalkoxy; and n is an integer selected from the group consisting of 0, 1, and 2; 2. The compound of claim 1.

3. R A 3. The compound of claim 1 or 2, wherein is selected from the group consisting of H and Me.

4. R 1 but is selected from the group consisting of During the ceremony R a1 and R a2 are independently F, Cl, Br, and C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, and C 1 ~C 3 haloalkoxy, 4. A compound according to claim 1 or 3.

5. Ar is selected from the group consisting of During the ceremony X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently C 1 ~C 6 Alkyl, F, Cl, N(R a )(R b ), OR b , -C(=O)OR a , -C(=O)N(R a )(R a ), N.H. 2 , OH, NO 2 , C 1 ~C 3 Haloalkyl, C 1 ~C 3 haloalkoxy, and phenyl; A compound according to any one of claims 1 to 4.

6. The compound according to any one of claims 1 to 3 and 5, wherein at least one of the following applies: (a) The compound of formula (I) is a compound of formula (Ia-1), wherein R 3 , R 3' , R 4 , and R 4' at least two of are H; (b) The compound of formula (I) is a compound of formula (Ia-2), wherein R 3 , R 3' , R 4 , and R 4' at least two of are H; (c) The compound of formula (I) is a compound of formula (Ia-3), wherein R 3 , R 3' , R 4 , R 4' , R 5 , and R 5' At least four of are H; (d) The compound of formula (I) is a compound of formula (Ia-4), wherein R 3 and R 3' at least one of is H; (e) The compound of formula (I) is a compound of formula (Ia-5), wherein R 3 , R 3' , R 4 , and R 4' at least two of are H; (f) The compound of formula (I) is a compound of formula (Ia-6), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least 6 of are H; (g) The compound of formula (I) is a compound of formula (Ia-7), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least 6 of are H; (h) The compound of formula (I) is a compound of formula (Ia-8), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' At least 10 of are H; (i) The compound of formula (I) is a compound of formula (Ib-1), wherein R 3 , R 3' , R 4 , and R 4' at least two of are H; (j) The compound of formula (I) is a compound of formula (Ib-2), wherein R 3 , R 3' , R 4 , and R 4' at least two of are H; (k) The compound of formula (I) is a compound of formula (Ib-3), wherein R 3 , R 3' , R 4 , R 4' , R 5 , and R 5' At least four of are H; (l) The compound of formula (I) is a compound of formula (Ib-4), wherein R 3 and R 3' at least one of is H; (m) The compound of formula (I) is a compound of formula (Ib-5), wherein R 3 , R 3' , R 4 , and R 4' at least two of are H; (n) The compound of formula (I) is a compound of formula (Ib-6), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least 6 of are H; (o) The compound of formula (I) is a compound of formula (Ib-7), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least 6 of are H; (p) The compound of formula (I) is a compound of formula (Ib-8), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' At least 10 of are H; (q) The compound of formula (I) is a compound of formula (Ic-1), wherein R 3 , R 3' , R 4 , and R 4' at least two of are H; (r) the compound of formula (I) is a compound of formula (Ic-2), wherein R 3 , R 3' , R 4 , and R 4' at least two of are H; (s) The compound of formula (I) is a compound of formula (Ic-3), wherein R 3 , R 3' , R 4 , R 4' , R 5 , and R 5' At least four of are H; (t) The compound of formula (I) is a compound of formula (Ic-4), wherein R 3 and R 3' at least one of is H; (u) The compound of formula (I) is a compound of formula (Ic-5), wherein R 3 , R 3' , R 4 , and R 4' at least two of are H; (v) The compound of formula (I) is a compound of formula (Ic-6), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least 6 of are H; (w) The compound of formula (I) is a compound of formula (Ic-7), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least 6 of are H; (x) The compound of formula (I) is a compound of formula (Ic-8), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' At least 10 of are H; (y) The compound of formula (I) is a compound of formula (Id-1), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least 6 of are H; (z) The compound of formula (I) is a compound of formula (Ie-1), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' at least 6 of are H; and (aa) The compound of formula (I) is a compound of formula (If-1), wherein R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , and R 6' At least six of them are H.

7. X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 If at least one of the following is present, CF 3 , N.H. 2 , O(CH(CH 3 ) 2 ), OCF 3 , and The compound according to any one of claims 5 to 6, selected from the group consisting of:

8. Ar The compound according to any one of claims 1 to 7, selected from the group consisting of:

9. G and During the ceremony R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' are independently H, C 1 ~C 6 Alkyl, C 1 ~C 6 haloalkyl, and optionally substituted phenyl; Each optional substituent on phenyl 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 ) at least one selected from the group consisting of R 11 and R 13 , or R 11 and R 13' together with the atoms to which they are attached, C 3 ~C 8 may form a cycloalkyl, 3. A compound according to claim 1 or 2.

10. The compound of claim 9, wherein at least one of the following is true: (a) R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' at least one of is H; (b) R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' at least two of are H; (c) R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' At least three of are H; (d) R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' At least four of are H; (e) R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' At least five of are H; (f) R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' at least 6 of are H; and (g) R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' Each of is H.

11. R 11 , R 12 , R 12' , R 13 , R 13' , R 14 , and R 14' At least one of the following is CF 3 11. The compound of claim 9 or 10, wherein

12. G The compound of any one of claims 1-2 and 10-11,

13. R 2 が-CH 2 F、-C(=O)OEt、Ph、 The compound according to any one of claims 1 to 3 and 5 to 12, selected from the group consisting of:

14. R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 6' , R 7 , R 7' , R 8 , and R 8' When at least one of the following is present, it is selected from the group consisting of methyl, trifluoromethyl, hydroxyl, fluorine, -C(=O)OMe, Ph, The compound according to any one of claims 1 to 3 and 5 to 13, selected from the group consisting of:

15. Y is NR 10 15. The compound of any one of claims 1 to 14, wherein

16. R 10 is H, methyl, 3-methylbutyl, tert-butyl, cyclopropyl, 3-oxetanyl, -C(=O)CH 2 CH(CH 3 ) 2 , -C(=O)Ot-Bu, S(=O) 2 Me, Benzyl, 16. The compound of claim 15, selected from the group consisting of:

17. Y is NR 10' 15. The compound of any one of claims 1 to 14, wherein

18. R 10' but 18. The compound of claim 17, selected from the group consisting of:

19. R 1 but The compound of any one of claims 1, 3, and 9-12, selected from the group consisting of:

20. A compound of formula (II) selected from the group consisting of: During the ceremony Ar is C 6 ~C 10 Aryl or C 2 ~C 10 Heteroaryl, which is 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, NH 2 , 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 Each C in Ar 6 ~C 10 Aryl, C 2 ~C 10 Heteroaryl, or C 6 ~C 10 The aryloxy substituents are independently 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 Two vicinal substituents of Ar may together provide a 5- to 8-membered ring fused to Ar; R A is H or C 1 ~C 6 is alkyl; and R 1 teeth Selected from the group consisting of: The compound, or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof.

21. R A 21. The compound of claim 20, wherein is H or Me.

22. Ar is selected from the group consisting of During the ceremony X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently C 1 ~C 6 Alkyl, F, Cl, N(R a )(R b ), OR b , -C(=O)OR a , -C(=O)N(R a )(R a ), N.H. 2 , OH, NO 2 , C 1 ~C 3 Haloalkyl, C 1 ~C 3 haloalkoxy, and phenyl; 22. A compound according to claim 20 or 21.

23. X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 If at least one of the following is present, CF 3 , N.H. 2 , O(CH(CH 3 ) 2 ), OCF 3 , and The compound according to any one of claims 20 to 22, selected from the group consisting of:

24. Ar The compound according to any one of claims 20 to 23, selected from the group consisting of:

25. N-(6-fluoro-2,2-dimethylchroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 4-(2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; tert-Butyl 2-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)pyrrolidine-1-carboxylate; N-(6-(difluoromethoxy)-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3-ethoxy-4-hydroxybenzyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 3-(fluoromethyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate; N-(1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(2-oxo-1-(3-(trifluoromethyl)benzyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(spiro[chroman-2,1'-cyclopentan]-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-benzyl-3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(3-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3-chlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; Methyl 3-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopentyl)propiolate; N-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3-methoxyphenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3,4-dichlorophenyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; 3,5-dimethyl-N-((1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclohexyl)methyl)isoxazole-4-sulfonamide; N-(1-(2-phenylbutanoyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; 4-(trifluoromethoxy)-N-(1-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)benzenesulfonamide; N-(2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(5-chloro-2-methoxyphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(5,8-difluorochroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3-bromophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)azetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(3,4-dichlorophenyl)azetidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(3,4-dichlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; 3-(3,4-dichlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate benzyl; N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 4-(4-chlorophenyl)-4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate; N-(1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; N-(1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; N-(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; N-(3-(4-chloro-3-fluorophenyl)azetidin-3-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-(1-methyl-4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide; N-(4-(5-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(bicyclo[1.1.1]pentan-1-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; N-(3-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-butyl 3-(4-chlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate; N-(3-(4-chlorophenyl)-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)-1-(methylsulfonyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(5-chlorothiazol-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-fluorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide; N-(3-(4-chlorophenyl)-1-isopentylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-fluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide; N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-isopropoxybenzenesulfonamide; rac N-((3S,4S)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-isopropoxypyridine-3-sulfonamide; N-(3-(4-chlorophenyl)-1-(3-methylbutanoyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(3,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(2,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide; N-(3-phenyl-8-azabicyclo[3.2.1]octan-3-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-(1-(3,4-dichlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(5-chlorothiophen-2-yl)piperidin-4-yl)-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-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-(trifluoromethoxy)benzenesulfonimidamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethyl)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-sulfonamide; 3-amino-N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; and N-(4-(4-(difluoromethyl)phenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide 2. The compound of claim 1, selected from the group consisting of: or a salt, solvate, isotopologue, or tautomer thereof.

26. (R)-N-(6-fluoro-2,2-dimethylchroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3R)-1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3S)-1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 4-((1R,2R)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; tert-Butyl 4-((1R,2S)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; (R)-tert-butyl 2-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)pyrrolidine-1-carboxylate; (R)—N-(6-(difluoromethoxy)-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-tert-butyl 3-(fluoromethyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate; N-((2R,3R)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3S)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(2-oxo-1-(3-(trifluoromethyl)benzyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(spiro[chroman-2,1'-cyclopentan]-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-benzyl-3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((6R,7R)-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((6R,7S)-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3R)-2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2R,3S)-2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-(3,4-dichlorophenyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-(2-phenylbutanoyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-4-(trifluoromethoxy)-N-(1-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)benzenesulfonamide; N-((1R,2R)-2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-(5-chloro-2-methoxyphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(5,8-difluorochroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2R)-2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2R)-2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-(3-bromophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-3-(3,4-dichlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate benzyl; N-((3R,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((3R,4S)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (R)—N-(1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (R)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (R)-N-((R)-3-(4-chlorophenyl)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (R)—N-((S)-3-(4-chlorophenyl)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (R)—N-(3-(4-chlorophenyl)pyridine-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide; (R)-N-((R)-3-(4-chlorophenyl)irolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; (R)-N-((S)-3-(4-chlorophenyl)pyridin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; (R)—N-(3-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-tert-butyl 3-(4-chlorophenyl)-3-((4-(trifluoromethoxy)phenyl)pyrrolidine)pyrrolidine-1-carboxylate; (R)—N-(3-(4-chlorophenyl)-1-(oxetan-3-yl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-chlorophenyl)-1-(methylsulfonyl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-fluorophenyl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-chlorophenyl)-1-isopentylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-fluorophenyl)pyridin-3-yl)-4-isopropoxybenzenesulfonamide; N-((3R,4R)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((3R,4S)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-(4-chlorophenyl)pyridine-3-yl)-6-isopropoxypyridine-3-sulfonamide; (R)—N-(3-(4-chlorophenyl)-1-(3-methylbutanoyl)irolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-((R)-3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (R)—N-((S)-3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (R)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide; (R)—N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-3-amino-N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; and (R)-3-Amino-N-(3-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide 2. The compound of claim 1, selected from the group consisting of: or a salt, solvate, isotopologue, or tautomer thereof.

27. (S)—N-(6-fluoro-2,2-dimethylchroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3S)-1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3R)-1-(tert-butyl)-2-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; tert-Butyl 4-((1S,2S)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; tert-Butyl 4-((1S,2R)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)piperidine-1-carboxylate; (S)-tert-butyl 2-(1-((4-(trifluoromethoxy)phenyl)sulfonamido)cyclopropyl)pyrrolidine-1-carboxylate; (S)—N-(6-(difluoromethoxy)-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-tert-butyl 3-(fluoromethyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate; N-((2S,3S)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3R)-1-cyclopropyl-2-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(2-oxo-1-(3-(trifluoromethyl)benzyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(spiro[chroman-2,1'-cyclopentan]-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-benzyl-3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-phenylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((6S,7S)-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((6S,7R)-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro[3.4]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3S)-2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((2S,3R)-2-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-(3,4-dichlorophenyl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-(2-phenylbutanoyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-4-(trifluoromethoxy)-N-(1-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)benzenesulfonamide; N-((1S,2S)-2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2R)-2-ethyl-1-(m-tolyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-(5-chloro-2-methoxyphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(5,8-difluorochroman-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2R)-2-(4-chlorophenyl)cyclopropyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-(3,4-dichlorophenyl)cyclopentyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-(3-bromophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-3-(3,4-dichlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate benzyl; N-((3S,4S)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((3S,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(1-benzyl-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (S)—N-(1-benzyl-3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; (S)—N-((S)-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-((R)-3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide; (S)—N-((S)-3-(4-chlorophenyl)pyrrolidin-3-yl)-N′-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-((R)-3-(4-chlorophenyl)pyrrolidin-3-yl)-N′-methyl-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-(3-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-3-(4-chlorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate tert-butyl; (S)—N-(3-(4-chlorophenyl)-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)-1-(methylsulfonyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)-1-isopentylpyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-isopropoxybenzenesulfonamide; N-((3S,4S)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-((3S,4R)-3-(4-chlorophenyl)-4-fluoropyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-isopropoxypyridine-3-sulfonamide; (S)—N-(3-(4-chlorophenyl)-1-(3-methylbutanoyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-((S)-3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-((R)-3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimidamide; (S)—N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-3-amino-N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; and (S)-3-Amino-N-(3-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide 2. The compound of claim 1, selected from the group consisting of: or a salt, solvate, isotopologue, or tautomer thereof.

28. N-(4-((4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidin-1-yl)sulfonyl)phenyl)acetamide; 1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl; (1R,2R)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl; (1R,2S)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl; (1S,2S)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl; (1S,2R)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-2-carboxylate methyl; N-(2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2R)-2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2R)-2-(4-fluorophenoxy)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide; 4-(trifluoromethoxy)-N-(3,4,4-trimethylcyclohexyl)benzenesulfonamide; (R)-4-(trifluoromethoxy)-N-(3,4,4-trimethylcyclohexyl)benzenesulfonamide; (S)-4-(trifluoromethoxy)-N-(3,4,4-trimethylcyclohexyl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((1R,3R)-3,4,4-trimethylcyclohexyl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((1R,3S)-3,4,4-trimethylcyclohexyl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((1S,3S)-3,4,4-trimethylcyclohexyl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((1S,3R)-3,4,4-trimethylcyclohexyl)benzenesulfonamide; N-(2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2R)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1R,2S)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2S)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((1S,2R)-2-phenylcycloheptyl)-4-(trifluoromethoxy)benzenesulfonamide; Ethyl 1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-1-carboxylate; (R)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-1-carboxylate ethyl; (S)-1-((4-(trifluoromethoxy)phenyl)sulfonamido)-2,3-dihydro-1H-indene-1-carboxylate ethyl; Methyl 3,5-dimethyl-7-((4-(trifluoromethoxy)phenyl)sulfonamido)adamantane-1-carboxylate; N-(2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)—N-(2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; 4-(trifluoromethoxy)-N-(4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((4R,6R)-4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((4R,6S)-4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide; 4-(trifluoromethoxy)-N-((4S,6S)-4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide; and 4-(Trifluoromethoxy)-N-((4S,6R)-4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)benzenesulfonamide or a salt, solvate, isotopologue, or tautomer thereof.

29. 29. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 28 and at least one pharma- ceutically acceptable carrier.

30. A pharmaceutical composition for treating, preventing, and / or ameliorating a PP2A-related disease in a subject, comprising a therapeutically effective amount of a compound described in any one of claims 1 to 28.

31. The pharmaceutical composition of claim 30, wherein 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), nonalcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative diseases, and cardiac hypertrophy.

32. 32. The pharmaceutical composition of claim 30 or 31, wherein the subject is a mammal.

33. 33. The pharmaceutical composition of claim 32, wherein the mammal is a human.

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