Protein phosphatase 2A (PP2A) modulators and methods of use thereof

Abstract

The present disclosure relates, in part, to compounds that modulate protein phosphatase 2A (PP2A) activity. The compounds of the present disclosure are useful in the treatment, prevention and / or amelioration 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. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 395,026, filed on August 4, 2022, which is incorporated herein by reference in its entirety. Background of the Invention

[0004] Protein phosphatase 2A (PP2A) is one of the four major serine-threonine phosphatases involved in the negative regulation of cell growth and division. The 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 multiple cellular functions.

[0005] PP2A function may be associated with 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.

[0006] Therefore, there is a need in the art for chemical modulators of PP2A for treating, preventing and / or ameliorating PP2A-related pathologies and / or indications. The present disclosure satisfies this need. Summary of the invention

[0007] In one aspect, the present disclosure provides certain compounds of formula (I), or salts, solvates, enantiomers, diastereomers, isotopomers or tautomers thereof, wherein the substituents in (I) are defined elsewhere herein:

[0008]

[0009] In another aspect, the present disclosure provides certain compounds of formula (II) or salts, solvates, enantiomers, diastereomers, isotopomers or tautomers thereof, wherein the substituents in (II) are defined elsewhere herein:

[0010]

[0011] In another aspect, the present disclosure provides certain compounds of formula (III) or salts, solvates, enantiomers, diastereomers, isotopomers or tautomers thereof, wherein the substituents in (III) are defined elsewhere herein:

[0012]

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure (including compounds of formula (I), (II) and / or (III)) and at least one pharmaceutically acceptable carrier.

[0014] In another aspect, the present disclosure provides a method for treating, preventing and / or ameliorating a protein phosphatase 2A (PP2A)-related disease in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

[0015] In certain embodiments, the PP2A-associated disease is at least one selected from the group consisting of cancer, diabetes, autoimmune diseases, solid organ transplant rejection, graft-versus-host disease, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative diseases, and cardiac hypertrophy. DETAILED DESCRIPTION

[0016] Reference will now be made in detail to certain embodiments of the disclosed subject matter.While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0017] In this document, values ​​expressed in range format should be interpreted in a flexible manner to include not only the values ​​explicitly listed as the limits of the range, but also all individual values ​​or sub-ranges contained within the range, as if each value and sub-range were explicitly listed. For example, the range "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 sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. Unless otherwise specified, the expression "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise specified, the expression "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z".

[0018] In this document, unless the context clearly dictates otherwise, the terms "a", "an" or "the" are used to include one or more. Unless otherwise specified, the term "or" is used to refer to a non-exclusive "or". The expression "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B". In addition, it should be understood that the expressions or terms used herein (not otherwise defined) are for descriptive purposes only and not for limiting purposes. The use of any section headings is intended to aid in reading the document and should not be construed as limiting; information related to the section heading may appear within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if individually incorporated by reference.

[0019] In the methods described herein, the various actions may be performed in any order unless a time or order of operations is explicitly stated. In addition, specified actions may be performed simultaneously unless the claims explicitly state that they must be performed separately. For example, a claimed action to perform X and a claimed action to perform Y may be performed simultaneously in a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0020] definition

[0021] As used herein, the term "about" may allow a certain degree of variation in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or a limit of a stated range, and includes the exact stated value or range.

[0022] The term "acyl" refers to a carbonyl group attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle or any other moiety, wherein the atom attached to the carbonyl group is carbon. Examples of acyl groups include formyl, alkanoyl and aroyl. "Acetyl" refers to -C(O)CH 3 One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent molecular moiety remains at the carbonyl group. Examples include acetyl, benzoyl, propionyl, isobutyryl, tert-butyloxycarbonyl, benzyloxycarbonyl and the like.

[0023] The term "amido" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "amido" group is acetamido (CH 3 C(O)NH-).

[0024] The terms "administer / administering / administration" and the like as used herein 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 injections (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, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics (current edition); 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.

[0025] The term "alkoxy" as used herein refers to a group of linear, branched or cyclic configurations and combinations thereof having 1 to 6 carbon atoms connected to the parent structure by oxygen. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, sec-butoxy, isobutoxy, tert-butoxy, cyclohexyloxy and cycloheptyloxy.

[0026] In certain embodiments, the term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. 2 -C 6 "Alkenyl" refers to alkenyl moieties having 2 to 6 carbon atoms.

[0027] Examples of unsaturated olefinic groups include, but are not limited to, ethenyl (vinyl, -CH=CH 2 ), 1-propenyl (-CH=CH-CH 3 ), 2-propenyl (allyl, -CH-CH=CH 2 ), isopropenyl (1-methylvinyl, -C(CH 3 )=CH 2 ), butenyl, pentenyl and hexenyl.

[0028] As used herein, the term "alkenylene" refers to an alkene substituted at two or more positions, such as vinyl (-CH═CH-). Unless otherwise indicated, the term "alkenyl" may include "alkenylene" groups.

[0029] In certain embodiments, the term "alkyl" refers to a straight chain, branched chain, or cyclic hydrocarbon structure 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. As defined herein, an alkyl group may be optionally substituted.

[0030] 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, and branched chain alkyl groups include isopropyl, tert-butyl, isobutyl, sec-butyl, and neopentyl. In certain embodiments, the alkyl group is a saturated alkyl group having 2 to 6 carbon atoms. In certain embodiments, a straight or branched chain alkyl group has 6 or fewer carbon atoms in its backbone (e.g., a straight chain is C 1 -C 6 , the branch chain is C 3 -C 6 ).Term (C 1 -C 6 )Alkyl is understood to mean an alkyl group containing 1 to 6 carbon atoms.

[0031] The term "alkylamino" refers to an alkyl group attached to the parent molecular moiety through an amino group. The alkylamino group can be mono- or di-alkylated to form groups such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like.

[0032] The terms "alkylcarbonyl" and "alkoxycarbonyl" refer to -C(=O)alkyl or -C(=O)alkoxy, respectively.

[0033] The term "alkylthio" refers to an alkylthioether (alkyl-S-) group, wherein the term alkyl is as defined for alkyl, and wherein the sulfur may be mono- or di-oxidized. Examples of alkylthioether groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methylsulfonyl, ethylsulfinyl, and the like.

[0034] In certain embodiments, the term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. 2 -C 6 "Alkynyl" refers to alkynyl moieties having 2 to 6 carbon atoms.

[0035] Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (ethinyl, —C═CH) and 2-propynyl (propargyl, —CH 2 —C═CH).

[0036] The term "alkylene" refers to a straight or branched chain saturated hydrocarbon attached at two or more positions, such as a methylene (-CH2 Unless otherwise stated, the term "alkyl" may include "alkylene" groups.

[0037] Amide (carbamoyl, carbamoyl, aminocarbonyl, carboxamide) refers to, for example, -C(=O)NH 2 , -C(=O)NH(alkyl) or -C(=O)N(alkyl) 2 wherein the alkyl groups are independently amino substituents as defined for alkyl groups.

[0038] The term "amino" refers to -NH 2 .

[0039] As used herein, the terms "aryl" and "heteroaryl" refer to (i) phenyl (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N or S as defined for heterocycle; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N or S as defined for carbocycle or heterocycle; or (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N or S as defined for carbocycle or heterocycle. Aromatic 6- to 14-membered carbocycles include, but are not limited to, benzene, naphthalene, anthracene, indane, tetralin and fluorene, while 5- to 10-membered aromatic heterocycles include, but are not limited to, imidazole, pyridine, indole, thiophene, benzopyrone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole. As used herein, aryl and heteroaryl refer to residues in which one or more rings are aromatic, but not all rings need be aromatic.

[0040] The term "arylalkyl" as used herein refers to a substituent in which an aryl residue is attached to a parent structure via an alkyl group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, and the like. Heteroarylalkyl groups refer to substituents in which a heteroaryl residue is attached to a parent structure via an alkyl group. In certain embodiments, the alkyl group of an arylalkyl or heteroarylalkyl group is an alkyl group having 1 to 6 carbon atoms. Examples include, for example, pyridylmethyl, pyrimidylethyl, and the like.

[0041] The term "azido" as used herein refers to -N 3 .

[0042] 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 either from the nitrogen terminus or from the acid terminus and may be optionally substituted as defined herein.

[0043] As used herein, the term "carbonyl" refers to a -C(=O)- group, including formyl (-C(=O)H).

[0044] As used herein, the term "carboxy" refers to -C(=O)OH or the corresponding "carboxylate" anion, such as in a carboxylate salt.

[0045] The term "co-administration" refers to simultaneous administration by the same or different routes in the same formulation or two different formulations or sequential administration by the same or different routes. "Sequential" administration refers to a time difference of seconds, minutes, hours or days between the administration of two or more separate compounds.

[0046] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in the present disclosure. The administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single formulation (e.g., capsule or injection) with a fixed ratio of active ingredients or in multiple separate dosage forms of each active ingredient. In addition, the administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide a beneficial effect of the drug combination in treating the conditions or disorders described herein.

[0047] The term "comprising" used in this specification means including the subsequent features or actions, but does not exclude the existence of one or more other features or actions.

[0048] The term "cycloalkyl" or "carbocycle", used alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group, wherein each cyclic portion may contain 3 to 12 carbon atom ring members, and may optionally be a benzo-fused ring system, which is optionally substituted as defined herein. In certain embodiments, the cycloalkyl group contains 3 to 7 carbon atoms or 3 to 6 carbon atoms.

[0049] 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.

[0050] Examples of saturated monocyclic cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, methylcyclopropenyl, dimethylcyclopropenyl, methylcyclobutenyl, dimethylcyclobutenyl, methylcyclopentenyl, dimethylcyclopentenyl, and methylcyclohexenyl.

[0051] Examples of bicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, decahydronaphthyl, and the like. "Bicyclic" and "tricyclic" used with "cycloalkyl" are intended to include fused ring systems (e.g., decahydronaphthalene, octahydronaphthalene) as well as polycyclic (multi-centered) saturated or partially unsaturated types (including spirocyclic fused systems). Examples of bicyclic and tricyclic isomers are bicyclo[1,1,1]pentane, norbornane, camphor, adamantane, bicyclo[3,2,1]octane, and [4,4.1]-bicyclononane.

[0052] As used herein, the term "cyano," "nitrile," or "carbonitrile" refers to -CN.

[0053] The terms "diastereomer" and "diastereoisomer" are used interchangeably herein to refer to stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0054] As used herein, the term "disease" is generally synonymous with the terms "disorder" and "illness" (as in medical condition) and are used interchangeably because they all reflect an abnormal condition of the human or animal body or a part thereof, which impairs normal function, is usually manifested by distinctive signs and symptoms, and results in a shortened life or reduced quality of life for the human or animal.

[0055] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of at least one compound administered to achieve the desired result, such as alleviating one or more symptoms of the disease or disorder being treated to a certain extent. In some cases, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired change in the biological system. In particular cases, the result is a reduction in the growth, killing or induction of apoptosis of at least one abnormally proliferating cell (e.g., cancer cell). In some cases, an "effective amount" for therapeutic use is an amount required for a composition comprising a compound proposed herein to provide a clinically significant reduction in the disease. An appropriate "effective" amount in any individual case is determined by using any suitable technique (e.g., a dose escalation study).

[0056] As used herein, the term "ester", "carboxylate", "carboxylate ester" or "oxycarbonyl" refers to -C(=O)Oalkyl, wherein alkyl is an ester substituent as defined above for alkyl. Examples of ester groups include, but are not limited to -C(=O)OCH 3 , —C(=O)OCH 2 CH 3 , —C(=O)OC(CH 3 ) 3 and -C(=O)OPh.

[0057] As used herein, the term "halo" or "halogen", alone or in combination, refers to fluorine, chlorine, bromine or iodine. In certain embodiments, the halo can be fluorine or chlorine.

[0058] The term "haloalkoxy" refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0059] Term used herein " haloalkyl " refers to the alkyl with the implication as defined above, wherein one or more hydrogens are replaced by halogen. In certain embodiments, haloalkyl is monohaloalkyl, dihaloalkyl and polyhaloalkyl. The example of haloalkyl includes but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. " haloalkylene " refers to the haloalkyl connected at two or more positions. Examples include but are not limited to fluoromethylene (-CFH-), difluoromethylene (-CF 2 -) and chloromethylene (-CHCl-).

[0060] As used herein, the term "heteroarylene" refers to a divalent radical formed by removing two hydrogen atoms from one or more rings of a heteroaryl moiety, wherein the hydrogen atoms may be removed from the same or different rings (preferably the same ring), and each ring may be aromatic or non-aromatic.

[0061] The terms "heterocycle" and "heterocyclyl" are used interchangeably and refer to a cycloaliphatic or aromatic carbocyclic residue in which one to four carbons are replaced by heteroatoms selected from N, O and S. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In certain embodiments, the heterocycle is non-aromatic. In further embodiments, the heterocycle is aromatic.

[0062] 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, etc. Examples of heterocyclyl residues include, but are not limited to, piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidine, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl (also historically referred to as thienyl), benzothienyl, thiomorpholinyl, oxadiazolyl, triazolyl, and tetrahydroquinolinyl. It is worth noting that heteroaryl is a subset of heterocycles, where the heterocycle is aromatic. An oxygen heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygen as well as other heteroatoms. A sulfur heterocycle is a heterocycle containing at least one sulfur in the ring; it may contain additional sulfur, such as other heteroatoms. An oxygen heteroaryl is a subset of oxygen and other heteroatoms. An oxygen heteroaryl is a subset of oxygen heterocycles; examples include furan and oxazole. A sulfur heteroaryl is a subset of sulfur heterocycles; examples include, but are not limited to, thiophene and thiazine. A nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogen as well as other heteroatoms. Examples include, but are not limited to, piperidine, piperazine, morpholine, pyrrolidine, and thiomorpholine. A nitrogen heteroaryl is a subset of nitrogen heterocycles; examples include, but are not limited to, pyridine, pyrrole, and thiazole. Unless specifically prohibited, heterocyclic groups may be optionally substituted.

[0063] The term "hydroxy" refers to -OH.

[0064] As used herein, the term "increase" or the related terms "increased", "enhancement" or "enhanced" may refer to a statistically significant increase, while the term "reduced", "suppressed" or "inhibited" may refer to a statistically significant decrease. For the avoidance of doubt, an increase generally refers to an increase of at least 10% in a given parameter, and may encompass an increase of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99% or even 100% relative to a control, baseline or previous value. An inhibition generally refers to a decrease of at least 10% in a given parameter, and may encompass a decrease of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99% or even 100% relative to a control value.

[0065] The term "imino" as used herein refers to =N-.

[0066] The term "modulate" as used herein refers to increasing or decreasing the activity of PP2A. In certain embodiments, the compound according to one or more embodiments disclosed in this specification can increase the activity of a specific PP2A holoenzyme while reducing the activity of other PP2A heterotrimers.

[0067] The term "nitro" as used herein refers to -NO 2 .

[0068] The term "optionally substituted" can be used interchangeably with "unsubstituted or substituted". The term "substituted" refers to the replacement of one or more hydrogen atoms in a specific group with a specific group. In certain embodiments, 1, 2 or 3 hydrogen atoms are replaced by a specific group. In the case of alkyl and cycloalkyl, more than three hydrogen atoms can be replaced by fluorine. In certain embodiments, all available hydrogen atoms can be replaced by fluorine. Two substituents can be linked together to form a three- to seven-membered non-aromatic carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example, forming methylenedioxy or ethylenedioxy. In certain embodiments, the carbocyclic or heterocyclic ring formed is a fused ring or a spirocyclic ring.

[0069] The above groups (alone or as part of another substituent) may themselves be optionally substituted with one or more additional substituents selected from themselves and the following. In addition, the substituents listed below may themselves also be substituents.

[0070] The term "oxo" when referred to by itself as a substituent refers to a double-bonded oxygen (=0).

[0071] As used herein, the term "oxy" or "oxa" refers to -O-.

[0072] The term "patient" as used herein refers to all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs and rabbits. In some embodiments, the patient is a human.

[0073] The term "pharmaceutically acceptable salt" may refer to a salt prepared from a pharmaceutically acceptable non-toxic base or acid (including inorganic acids and bases and organic acids and bases). When the compound disclosed in this specification is basic, a salt may be prepared from a pharmaceutically acceptable non-toxic acid (including inorganic acids and organic acids). Suitable pharmaceutically acceptable acid addition salts of the compounds disclosed in the present specification include acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, ethanedisulfonic acid, ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, glucoheptanoic 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, naphthalenesulfonic 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, tautomeric acid, p-toluenesulfonic acid and the like. When the compound contains an acidic side chain, pharmaceutically acceptable base addition salts suitable for the compounds of the invention include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Further pharmaceutically acceptable salts include non-toxic ammonium cations and carboxylates, sulfonates and phosphonates anions attached to alkyl groups having 1 to 20 carbon atoms, when appropriate.

[0074] As used herein, the terms "prevent", "preventing", "prevention" and other grammatical equivalents include preventing other symptoms, preventing potential metabolic causes of symptoms, inhibiting a disease or disorder (e.g., preventing the development of a disease or disorder), and are intended to include prevention. These terms also include achieving a preventive benefit. To achieve a preventive effect, the composition is optionally administered to an individual at risk of developing a particular disease, an individual reporting one or more physiological symptoms of a disease, or an individual at risk of recurrence of a disease.

[0075] The term "stereoisomer" refers to compounds made up of the same atoms connected by the same bonds, but with different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0076] 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 proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via rearrangement of some of the bonding electrons. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the present invention.

[0077] As used herein, the terms "treat", "treating", "treatment" and other grammatical equivalents include alleviating, inhibiting or alleviating symptoms, alleviating or inhibiting the severity of symptoms of a disease or disorder, delaying its onset, delaying its recurrence, alleviating or ameliorating symptoms of a disease or disorder, ameliorating the underlying metabolic causes of symptoms, inhibiting a disease or disorder, such as arresting the development of a disease or disorder, alleviating a disease or disorder, causing regression of a disease or disorder, alleviating symptoms caused by a disease or disorder, or stopping symptoms of a disease or disorder. These terms also include achieving a therapeutic benefit. A therapeutic benefit refers to the elimination or amelioration of the underlying condition being treated, and / or the elimination or amelioration of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the individual.

[0078] Unless otherwise specified or described, the structure of the compound of one or more embodiments disclosed in this specification is also intended to include all stereoisomers (e.g., enantiomers, diastereomers, and cis-trans isomers) of the structure; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention as well as enantiomers, diastereomers, and cis-trans isomer (or conformational) mixtures are within the scope of the present invention. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to specify a specific configuration; therefore, any carbon-carbon double bond described herein as trans may be cis, trans, or a mixture of the two in any proportion. Unless otherwise specified, all tautomeric forms of the compounds of one or more embodiments disclosed in this specification are within the scope of the present disclosure. In addition, the disclosed compounds may exist in an unsolvated form as well as in a solvated form with a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). In general, the solvated forms are considered equivalent to the unsolvated forms.

[0079] Compound

[0080] In one aspect, the present disclosure provides a compound of formula (I) or a salt, solvate, enantiomer, diastereomer, isotopomer or tautomer thereof:

[0081]

[0082] in:

[0083] Ar is C 6 -C 10 Aryl or C 2 -C 10 Heteroaryl, which may be optionally substituted by at least one substituent selected from the group consisting of: 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 Halogenated alkoxy, C 2 -C 10 Heteroaryl, C 6 -C 10 Aryl, C 6 -C 10 Aryloxy, halogen, OH, N(R a )(R b )、CN、NO 2 、-C(=O)R a 、-C(=O)OR a and -C(=O)N(R a )(R b ),

[0084] Each C in Ar 6 -C 10 Aryl, C 2 -C 10 Heteroaryl or C 6 -C 10 The aryloxy substituents are independently optionally substituted with at least one substituent selected from the group consisting of: C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, F, Cl, Br, I, OH, CN, NO 2 、-C(=O)OR a and -C(=O)N(Ra )(R b ),and

[0085] The two vicinal substituents of Ar can be combined to form a 5- to 8-membered ring, which is connected to the C 6 -C 10 Aryl or C 2 -C 10 Heteroaryl fused;

[0086] R 1 Selected from the group consisting of:

[0087] R 2 is selected from the group consisting of: optionally substituted phenyl and optionally substituted C 2 -C 10 Heteroaryl,

[0088] Where R 2 Each optional substituent is at least one selected from the group consisting of halogen, OH, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl;

[0089] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h (if present) are each independently H,

[0090] Or from R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h The two geminal substituents selected in the formula (a) may be combined with the carbon atoms to which they are bonded to form an optionally substituted C 3 -C 8 Cycloalkyl;

[0091] R 4 is H;

[0092] R A Selected from the group consisting of: H and C 1-C 6 alkyl;

[0093] Each occurrence of R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl, benzyl and C 6 -C 10 aryl; and

[0094] Each occurrence of R b are independently selected from the group consisting of: H, optionally substituted C 1 -C 6 alkyl, optionally substituted benzyl, optionally substituted phenyl and optionally substituted naphthyl, wherein R b C 1 -C 6 The alkyl, benzyl, phenyl or naphthyl group is independently optionally substituted by at least one selected from the group consisting of: C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, halogen, OH, CN, NO 2 、C(=O)OR a and C(=O)N(R a )(R a ).

[0095] In certain embodiments, the compound of formula (I) is not selected from the group consisting of:

[0096] N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0097] N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0098] N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0099] N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide;

[0100] N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimide amide;

[0101] N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide;

[0102] N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimide amide;

[0103] N-(3-(4-Fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0104] N-(3-(4-Fluorophenyl)pyrrolidin-3-yl)-4-isopropoxybenzenesulfonamide;

[0105] N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-isopropoxypyridine-3-sulfonamide;

[0106] N-(3-(4-Fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimide amide;

[0107] N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide;

[0108] 3-amino-N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0109] 3-amino-N-(3-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0110] N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0111] N-(4-(3,4-dichlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0112] N-(4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0113] N-(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0114] N-(4-(4-Fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0115] N-(4-phenylpiperidin-4-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide;

[0116] N-(4-(4-chlorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide;

[0117] N-(4-(5-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0118] N-(4-(4-chlorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide;

[0119] N-(4-(5-chlorothiazol-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0120] N-(4-(4-Fluorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide;

[0121] N-(4-(3,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0122] N-(4-(2,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0123] N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0124] N-(4-(2,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0125] N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0126] N-(4-(5-chlorothien-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0127] N-(4-(4-chloro-2-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0128] N-(4-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0129] N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethyl)benzenesulfonamide;

[0130] 3-amino-N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; and

[0131] N-(4-(4-(difluoromethyl)phenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide.

[0132] In certain embodiments, R A For H.

[0133] In certain embodiments, R 1 for

[0134] In certain embodiments, R 2 is 4-fluorophenyl, which is further substituted by at least one additional substituent selected from the group consisting of halogen, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 2 -C 6 alkyl.

[0135] In certain embodiments, R 2 is 3-fluorophenyl, which is further substituted by at least one additional substituent selected from the group consisting of F, Br, OH, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0136] In certain embodiments, R 2 It is 3,4-difluorophenyl.

[0137] In certain embodiments, Ar is optionally substituted phenyl.

[0138] In certain embodiments, Ar is 4-methoxyphenyl, optionally further substituted with at least one additional substituent selected from the group consisting of halogen, NH 2 and C 1 -C 3 Alkoxy.

[0139] In certain embodiments, the compound is selected from the group consisting of:

[0140] N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0141] (S)-N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; and

[0142] (R)-N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide.

[0143] In certain embodiments, R 1 for

[0144] In certain embodiments, Ar is an optionally substituted phenyl or an optionally substituted pyridyl, wherein the optional substituent in Ar is at least one substituent selected from the group consisting of: C 1 -C 6 Halogenated alkoxy, C 1 -C 6 Alkoxy and -NH(C 1 -C 6 alkyl).

[0145] In certain embodiments, Ar is phenyl substituted with at least one substituent selected from the group consisting of trifluoromethoxy and methylamino.

[0146] In certain embodiments, Ar is

[0147] In certain embodiments, R 2 is a 3,5-disubstituted phenyl group, wherein each substituent is independently selected from the group consisting of halogen, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0148] In certain embodiments, R 2 is 4-chlorophenyl, which is further substituted by at least one substituent selected from the group consisting of Br, I, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0149] In certain embodiments, R 2 is 3-methylphenyl, which is further substituted by at least one substituent selected from the group consisting of halogen, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6alkyl.

[0150] In certain embodiments, R 2 is 3-pyridyl, which is optionally further substituted by at least one substituent selected from the group consisting of halogen, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0151] In certain embodiments, R 2 is 4-pyridyl, which is optionally further substituted by at least one substituent selected from the group consisting of halogen, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0152] In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for

[0153] In certain embodiments, Ar is

[0154] In certain embodiments, R 2 is selected from the group consisting of: 2-pyridyl, 3-pyridyl and 4-pyridyl, wherein the pyridyl is optionally substituted with at least one substituent selected from the group consisting of: halogen, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0155] In certain embodiments, R 2 is 3-fluorophenyl, which is optionally substituted by at least one substituent selected from the group consisting of halogen, C1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0156] In certain embodiments, R 2 is 4-fluorophenyl, which is further substituted by at least one substituent selected from the group consisting of halogen, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0157] In certain embodiments, R 2 for In certain embodiments, R 2 for

[0158] In certain embodiments, Ar is 4-trifluoromethoxyphenyl substituted with methylamino.

[0159] In certain embodiments, Ar is

[0160] In certain embodiments, R 2 is 4-chlorophenyl, which is optionally substituted by at least one substituent selected from the group consisting of halogen, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0161] In certain embodiments, R 2 for

[0162] In certain embodiments, the compound is selected from the group consisting of:

[0163] N-(4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0164] N-(4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0165] N-(4-(4-chloro-3-methylphenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0166] N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide;

[0167] N-(4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide;

[0168] N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(methylamino)-4-(trifluoromethoxy)benzenesulfonamide; and

[0169] N-(4-(2,5-dichloropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide.

[0170] In certain embodiments, R 1 for And two are selected from R 3 , R 3 '、R 4 , R 4 '、R 5 , R 5 '、R 6 and R 6 The geminal substituents of the group are combined with the atoms to which they are bonded to form a C 3 -C 8 Cycloalkyl.

[0171] In certain embodiments, R 1 for

[0172] In certain embodiments, R 2 is phenyl, which is optionally substituted by at least one substituent selected from the group consisting of halogen, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy and C 1 -C 6 alkyl.

[0173] In certain embodiments, R 2 It is phenyl.

[0174] In certain embodiments, Ar is optionally substituted phenyl.

[0175] In certain embodiments, Ar is

[0176] In certain embodiments, the compound is selected from the group consisting of:

[0177] N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide;

[0178] (S)-N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; and

[0179] (R)-N-(6-Phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide.

[0180] In another aspect, the present disclosure provides a compound of formula (II) or a salt, solvate, enantiomer, diastereomer, isotopomer or tautomer thereof:

[0181]

[0182] in:

[0183] Ar is C 6 -C 10 Aryl or C 2 -C 10 Heteroaryl, which may be optionally substituted by at least one substituent selected from the group consisting of: 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 Halogenated alkoxy, C 2 -C 10 Heteroaryl, C 6 -C 10 Aryl, C 6 -C 10 Aryloxy, halogen, OH, N(R a )(R b )、CN、NO 2、-C(=O)R a 、-C(=O)OR a and -C(=O)N(R a )(R a ),

[0184] Each C in Ar 6 -C 10 Aryl, C 2 -C 10 Heteroaryl or C 6 -C 10 The aryloxy substituents are independently optionally substituted with at least one substituent selected from the following group: 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

[0185] The two vicinal substituents of Ar can be combined to form a 5- to 8-membered ring, which is connected to the C 6 -C 10 Aryl or C 2 -C 10 Heteroaryl fused;

[0186] L is selected from the group consisting of: *-N(R B )S(=O) 2 -, *-C(=O)N(R B )- and optionally substituted C 2 -C 10 heteroarylene;

[0187] R 5 Selected from the group consisting of:

[0188] R 6 Selected from the group consisting of: optionally substituted C 6 -C 10 Aryl and optionally substituted C 2 -C 10 Heteroaryl,

[0189] Where R 6 Each optional substituent is at least one selected from the group consisting of halogen, C1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, -C(=O)OR a 、-S(=O) 2 (C 6 -C 10 Aryl) and -S(=O) 2 (C 2 -C 10 heteroaryl);

[0190] R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h (if present) are each independently selected from the group consisting of: 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 heterocyclic group, optionally substituted phenyl group and optionally substituted phenoxy group,

[0191] wherein each optional substituent is at least one selected from the group consisting of: C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, halogen, OH, C(=O)OR a and C(=O)N(R a )(R a ),

[0192] Among them, selected from R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7hThe two geminal substituents of may be combined with the carbon atom to which they are bonded to form a moiety selected from the group consisting of: an optionally substituted C 3 -C 8 Cycloalkyl and optionally substituted C 2 -C 10 Heterocyclic group,

[0193] Among them, selected from R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h The two vicinal substituents of may be combined with the carbon atom to which they are bonded to form a moiety selected from the group consisting of: an optionally substituted C 3 -C 8 Cycloalkyl, optionally substituted C 2 -C 10 heterocyclyl, and optionally substituted phenyl;

[0194] Among them, selected from R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h Two substituents separated by two to five carbon atoms may be combined with the carbon atoms to which they are bonded to form a moiety selected from the group consisting of: optionally substituted C 4 -C 7 Cycloalkyl and optionally substituted C 4 -C 8 Heterocyclic group;

[0195] R 8 Selected from the group consisting of: 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,

[0196] Wherein phenyl, benzyl or -S(=O) 2- Each optional substituent in the phenyl group is independently at least one selected from the group consisting of: F, Cl, Br, C 1 -C 3 Alkoxy, C 1-C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, hydroxy and -NH-C(=O)R a ;

[0197] R 9 Selected from the group consisting of: optionally substituted C 6 -C 10 Aryl and optionally substituted C 2 -C 10 Heteroaryl,

[0198] Where R 9 Each optional substituent is at least one selected from the group consisting of halogen, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, -C(=O)OR a 、-S(=O) 2 (C 6 -C 10 Aryl) and -S(=O) 2 (C 2 -C 10 heteroaryl);

[0199] R 10 Selected from the group consisting of: -(optionally substituted C 1 -C 6 Alkyl) (optionally substituted C 2 -C 12 Heterocycloalkyl) and optionally substituted C 1 -C 6 Aminoalkyl,

[0200] Where R 10 Each optional substituent is at least one selected from the group consisting of halogen, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl, -C(=O)OR a 、-S(=O) 2 (C 6 -C 10 Aryl) and -S(=O)2 (C 2 -C 10 heteroaryl);

[0201] R 11 is H;

[0202] R B is H;

[0203] Each occurrence of R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl, benzyl and C 6 -C 10 aryl; and

[0204] Each occurrence of R b are independently selected from the group consisting of: H, optionally substituted C 1 -C 6 alkyl, optionally substituted benzyl, optionally substituted phenyl and optionally substituted naphthyl, wherein R b C 1 -C 6 The alkyl, benzyl, phenyl or naphthyl group is independently optionally substituted by at least one selected from the group consisting of: C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, halogen, OH, CN, NO 2 、C(=O)OR a and C(=O)N(R a )(R a ).

[0205] In certain embodiments, the compound of formula (II) is selected from the group consisting of:

[0206]

[0207] Among them, R 12a , R 12b and R 12c (if present) are each independently selected from the group consisting of: C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3Haloalkoxy, halogen, OH, C(=O)OR a and C(=O)N(R a )(R a ).

[0208] In certain embodiments, R 12a , R 12b and R 12c In certain embodiments, at least one of R 12a , R 12b and R 12c Two of (if any) are H.

[0209] In certain embodiments, Ar is optionally substituted phenyl.

[0210] In certain embodiments, Ar is In certain embodiments, Ar is

[0211] In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least one of (if present) is H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least two of (if present) are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least three of (if present) are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least four of (if present) are H. In certain embodiments, R 7a , R 7b, R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least five of (if present) are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least six of (if present) are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least seven of (if present) are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h Each of them is H.

[0212] In certain embodiments, R 6 is phenyl optionally substituted by at least one halogen. 6 It is a phenyl group substituted by two halogens.

[0213] In certain embodiments, R 6 for In certain embodiments, R 6 for In certain embodiments, R 6 for

[0214] In certain embodiments, R 9 is phenyl optionally substituted by at least one halogen. 9 It is a phenyl group substituted by two halogens.

[0215] In certain embodiments, R 9 for In certain embodiments, R 9 for In certain embodiments, R 9 for

[0216] In certain embodiments, R 10 -CH 2 N(optionally substituted C 1 -C 6 alkyl) 2 .

[0217] In certain embodiments, R 10 -CH 2 NMe 2 .

[0218] In certain embodiments, the compound is selected from the group consisting of:

[0219] N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide;

[0220] (S)-N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide;

[0221] (R)-N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide;

[0222] N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide;

[0223] (S)-N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide;

[0224] (R)-N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide;

[0225] N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide;

[0226] (S)-N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide;

[0227] (R)-N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide;

[0228] 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine;

[0229] (S)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine;

[0230] (R)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine;

[0231] 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine;

[0232] (S)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine;

[0233] (R)-2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine;

[0234] 1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole;

[0235] (S)-1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole;

[0236] (R)-1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole;

[0237] 1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole;

[0238] (S)-1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole;

[0239] (R)-1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole; and

[0240] 4-Phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide.

[0241] In another aspect, the present disclosure provides a compound of formula (III) or a salt, solvate, enantiomer, diastereomer, isotopomer or tautomer thereof:

[0242]

[0243] in:

[0244] Ar is C 6 -C 10 Aryl or C 2 -C 10 Heteroaryl, which may be optionally substituted by at least one substituent selected from the group consisting of: 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 Halogenated alkoxy, C 2 -C 10 Heteroaryl, C 6 -C 10 Aryl, C 6 -C 10 Aryloxy, halogen, OH, N(R a )(R b )、CN、NO 2 、-C(=O)R a 、-C(=O)OR a and -C(=O)N(R a )(R a ),

[0245] Each C in Ar 6 -C 10 Aryl, C 2 -C 10 Heteroaryl or C 6 -C 10 The aryloxy substituents are independently optionally substituted with at least one substituent selected from the following group: 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 aand -C(=O)N(R a )(R a ),and

[0246] The two vicinal substituents of Ar can be combined to form a 5- to 8-membered ring, which is connected to the C 6 -C 10 Aryl or C 2 -C 10 Heteroaryl fused;

[0247] R 13 Selected from the group consisting of:

[0248] R 14a , R 14b , R 14c and R 14d Each independently selected from the group consisting of: C 6 -C 10 Aryl and optionally substituted C 2 -C 10 Heteroaryl,

[0249] Where R 14a , R 14b , R 14c and R 14d Each optional substituent is at least one selected from the group consisting of halogen, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Haloalkyl and -C(=O)OR a ;

[0250] R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 15i Each independently selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Halogenated alkoxy, C 1 -C3 Haloalkyl, -C(=O)OR a ;

[0251] R 16 is H;

[0252] R 17a , R 17b , R 17d , R 17e , R 17f , R 17g , R 17h , R 17i , R 17j , R 17k and R 17l (if present) are each independently selected from the group consisting of: H, halogen and C 2 -C 8 Heterocycloalkyl;

[0253] R 18a , R 18b , R 18c and R 18d Each independently selected from the group consisting of: H and C 1 -C 6 alkyl;

[0254] R 19 Selected from the group consisting of optionally substituted cyclohexyl and -CH 2 NMe 2 ;

[0255] X is selected from the group consisting of: -NR 16 -and-C(R 17k )(R 17l )-;

[0256] R C is H;

[0257] Each occurrence of R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl, benzyl and C 6 -C 10 aryl; and

[0258] Each occurrence of R b are independently selected from the group consisting of: H, optionally substituted C 1 -C 6 alkyl, optionally substituted benzyl, optionally substituted phenyl and optionally substituted naphthyl, wherein R b C 1 -C 6The alkyl, benzyl, phenyl or naphthyl group is independently optionally substituted by at least one selected from the group consisting of: C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, halogen, OH, CN, NO 2 、C(=O)OR a and C(=O)N(R a )(R a );

[0259] If R 13 for Then at least one of the following applies:

[0260] (a) Selected from R 17a , R 17b , R 17d , R 17e , R 17f , R 17g , R 17h , R 17i , R 17j , R 17k and R 17l At least one of (if present) is halogen, wherein said halogen is optionally F;

[0261] (b)R 14b is a phenyl group substituted by at least two fluorine atoms;

[0262] (c)R 14b is 4-chlorophenyl, and Ar is selected from the group consisting of a phenyl group optionally substituted with at least two substituents and a phenyl group optionally substituted with C 1 -C 6 an alkoxy-substituted pyridinyl group; and

[0263] (d) R 14b is 4-chlorophenyl, and Ar is not selected from the group consisting of 4-trifluoromethoxy and 6-trifluoromethoxy-3-pyridyl;

[0264] If R 13 for Then at least one of the following applies:

[0265] (a)R 14c is phenyl, and is selected from R 18a , R 18b , R 18c and R 18dOne, three or four of them are CH 3 ;and

[0266] (b)R 14c is phenyl, Ar is an optionally substituted pyridyl;

[0267] Among them, if R 13 for And R 19 CH 2 NMe 2 , then the compound of formula (III) is N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide; and

[0268] Among them, if R 13 for And R 19 is an optionally substituted cyclohexyl group, then at least one of the following applies:

[0269] (a) Ar is optionally substituted pyridyl; and

[0270] (b) Ar is replaced by at least one C 1 -C 6 Alkoxy substituents are substituted.

[0271] In certain embodiments, Ar is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridyl. In certain embodiments, Ar is phenyl, which is optionally substituted with at least one substituent selected from the group consisting of: C 1 -C 3 Haloalkoxy and N(R a )(R b In certain embodiments, Ar is phenyl, which is optionally substituted with at least one substituent selected from the group consisting of trifluoromethoxy and NH 2 .

[0272] In certain embodiments, Ar is In certain embodiments, Ar is

[0273] In certain embodiments, Ar is optionally substituted with at least one C 1 -C 6 In certain embodiments, Ar is substituted with at least one C 1 -C 6 3-pyridyl substituted with an alkoxy substituent.

[0274] In certain embodiments, Ar is

[0275] In certain embodiments, R 13 for In certain embodiments, R 13 for In certain embodiments, R 13 for

[0276] In certain embodiments, R 14a Selected from the group consisting of phenyl optionally substituted by at least one halogen and pyridinyl substituted by at least one halogen.

[0277] In certain embodiments, R 14a for In certain embodiments, R 14a for In certain embodiments, R 14a for

[0278] In certain embodiments, R 13 for

[0279] In certain embodiments, Ar is

[0280] In certain embodiments, R 14d It is cyclohexyl.

[0281] In certain embodiments, R 19 for

[0282] In certain embodiments, R 13 for

[0283] In certain embodiments, R 14b for In certain embodiments, R 14b for

[0284] In certain embodiments, Ar is In certain embodiments, Ar is In certain embodiments, Ar is In certain embodiments, Ar is

[0285] In certain embodiments, R 13 for In certain embodiments, R 13 for

[0286] In certain embodiments, selected from R 17e and R 17f At least one of the group consisting of is a halogen.

[0287] In certain embodiments, R 14b is phenyl substituted with at least one halogen. 14b for

[0288] In certain embodiments, Ar is 1 -C 6 Phenyl substituted with haloalkoxy.

[0289] In certain embodiments, Ar is

[0290] In certain embodiments, R 13 for

[0291] In certain embodiments, selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least one of the group consisting of is H. In certain embodiments, selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least two of the group consisting of are H. In certain embodiments, selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least three of the group consisting of are H. In certain embodiments, selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17jAt least four of the group consisting of are H. In certain embodiments, selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least five of the group consisting of are H. In certain embodiments, selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least six of the group consisting of are H. In certain embodiments, selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j At least seven of the group consisting of are H. In certain embodiments, R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i , and R 17j Each of them is H.

[0292] In certain embodiments, R 17i and R 17j are each independently H and are selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f At least one of the groups is C 2 -C 8 Heterocycloalkyl.

[0293] In certain embodiments, C 2 -C 8 Heterocycloalkyl is

[0294] In certain embodiments, Ar is

[0295] In certain embodiments, R 13 for

[0296] In certain embodiments, selected from R 18a , R 18b , R 18c and R 18d Two of the groups are C 1 -C 6 alkyl.

[0297] In certain embodiments, R 13 for

[0298] In certain embodiments, Ar is 1 -C 6 Alkoxy substituted pyridinyl.

[0299] In certain embodiments, Ar is

[0300] In certain embodiments, the compound is selected from the group consisting of:

[0301] N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0302] (R)-N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0303] (S)-N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0304] N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0305] (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0306] (S)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0307] N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0308] (S)-N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0309] (R)-N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0310] N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide;

[0311] (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide;

[0312] (S)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide;

[0313] 6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide;

[0314] (R)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide;

[0315] (S)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide;

[0316] N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0317] (R)-N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0318] (S)-N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0319] N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0320] (R)-N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0321] (S)-N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0322] N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide;

[0323] (R)-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide;

[0324] (S)-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide;

[0325] 3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0326] (R)-3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0327] (S)-3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0328] N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide;

[0329] (R)-N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide;

[0330] (S)-N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide;

[0331] N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide;

[0332] (R)-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide;

[0333] (S)-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide;

[0334] N-(1-(4-fluorophenyl)-2-(3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0335] N-((R)-1-(4-fluorophenyl)-2-((R)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0336] N-((R)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0337] N-((S)-1-(4-fluorophenyl)-2-((R)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0338] N-((S)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0339] N-(2-([1,3'-diazetidine]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0340] (S)-N-(2-([1,3'-diazetidine]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0341] (R)-N-(2-([1,3'-diazetidine]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0342] N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide;

[0343] (R)-N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide;

[0344] (S)-N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide;

[0345] N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide;

[0346] (R)-N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide;

[0347] (S)-N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide;

[0348] N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide;

[0349] (R)-N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide; and

[0350] (S)-N-(Cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide.

[0351] Salt

[0352] The compounds described herein can form salts with acids or bases, and such salts are also included in the present invention. The term "salt" includes addition salts of free acids or bases useful in the methods of the present invention. The term "pharmaceutically acceptable salt" refers to salts with toxicity characteristics within the range that can provide utility in pharmaceutical applications. In certain embodiments, these salts are pharmaceutically acceptable salts. Nevertheless, pharmaceutically unacceptable salts may have properties such as high crystallinity, which have practicality in the practice of the present invention, such as practicality in the synthesis, purification or formulation of compounds useful in the methods of the present invention.

[0353] Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of inorganic acids include sulfuric acid, 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 aliphatic, cycloaliphatic, aromatic, arylaliphatic, 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, pamoic acid (or pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, p-aminobenzenesulfonic 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., saccharate, sucrose salt). A salt may be composed of one molar equivalent, one molar equivalent, or multiple molar equivalents of the acid or base relative to any compound of the invention.

[0354] Suitable pharmaceutically acceptable base addition salts of the compounds of the invention include, for example, ammonium salts and metal 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'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N-methylglucamine) and procaine. All of these salts can be prepared from the corresponding compounds by, for example, reacting a suitable acid or base with the compound.

[0355] synthesis

[0356] The present invention further provides methods for preparing the compounds of the present invention. The compounds of the present teachings can be prepared according to the procedures outlined herein from commercially available starting materials, compounds known in the literature, or easily prepared intermediates, using standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for preparing organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or standard textbooks in the field.

[0357] It should be understood that when typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by conventional optimization procedures by those skilled in the art. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps provided may be altered in order to optimize the formation of the compounds described herein.

[0358] The methods described herein can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means (e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry) or by chromatography (e.g., high pressure liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC)).

[0359] The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups may be easily determined by those skilled in the art. The composition and chemical properties of protecting groups may be found in, for example, Greene et al., Protective Groups in Organic Synthesis, 2nd edition (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

[0360] The reactions or methods described herein can be carried out in a suitable solvent, which can be easily selected by a technician in the field of organic synthesis. Suitable solvents generally do not react substantially with reactants, intermediates and / or products at the temperature (i.e., the temperature range can be from the solvent solidification temperature to the boiling temperature) at which the reaction is carried out. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the specific reaction steps, a solvent suitable for the specific reaction steps can be selected.

[0361] In certain embodiments, the compounds synthesized using the methods described herein may contain one or more chiral carbon atoms, thereby producing two or more isomers. Absolute stereochemistry can be represented by wedge-shaped bonds (bold or parallel lines). In certain embodiments, the product formed in any of the reactions described may be a racemate. If a racemate is formed, the isomers constituting the racemate can be separated using any suitable chiral separation method known to those skilled in the art. Suitable chiral separation methods include, but are not limited to, supercritical fluid chromatography (SFC), chiral HPCL, crystallization, derivatization, or any combination thereof.

[0362] As used herein, "enantiomer I" or "diastereomer I" refers to the first enantiomer or diastereomer eluted from a chiral column under the specific chiral analysis conditions detailed for a specific compound; "enantiomer II" or "diastereomer II" refers to the second enantiomer or diastereomer eluted from a chiral column under the specific chiral analysis conditions detailed for a specific compound. Such nomenclature does not imply or confer any specific relative and / or absolute configuration of these compounds.

[0363] In certain embodiments, the separation of isomers formed in one or more separate reactions may require the formation of derivatives prior to chiral resolution. A non-limiting example of derivatization is the use of known protecting groups (e.g., esters, amides, carbamates, ethers, etc.) to protect one or more functional groups present in the compound, followed by separation of isomers by a suitable method. The desired compound is finally obtained by removing the protecting group.

[0364] The present disclosure provides compounds of formula (I), formula (II) and formula (III). Those skilled in the art will recognize that the techniques and / or methods for synthesizing compounds of formula (I) can be applied to synthesizing compounds of formula (II) or formula (III) in many cases, and vice versa.

[0365] In certain embodiments, the compounds of the present disclosure can be prepared according to the methods provided in Schemes 1-9, wherein X is a halogen, PG is a protecting group, v is an integer selected from 1 and 2, w is an integer selected from 0 and 1, and the definition of Ar is within the scope of the present invention. The substituent "R" is generally used herein to cover any substituent within the scope of the compounds of formula (I), (II) and / or (III). For example, in certain embodiments, R can be R 2 or R 6 In other embodiments, R may be H. In addition, positions indicated as unsubstituted may further comprise one or more substituents encompassed by compounds of formula (I), (II) and / or (III).

[0366]

[0367]

[0368] method

[0369] The present disclosure relates in part to a method for treating, preventing and / or ameliorating a protein phosphatase 2A (PP2A)-related disease in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds of the present disclosure or a pharmaceutical composition comprising any one of the compounds of the present disclosure and a pharmaceutically acceptable carrier.

[0370] In certain embodiments, the PP2A-associated disease is at least one selected from the group consisting of cancer, diabetes, autoimmune diseases, solid organ transplant rejection, graft-versus-host disease, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative diseases, and cardiac hypertrophy.

[0371] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.

[0372] The present disclosure also relates in part to the use of a compound according to one or more embodiments disclosed herein, such as a compound of formula (I), (II) or (III), a salt, solvate, enantiomer, diastereomer, isotopomer, tautomer or any mixture thereof as a drug for treating, preventing and / or ameliorating a disease or condition in a patient.

[0373] The compounds according to one or more embodiments disclosed in this specification may be modulators of PP2A. The compounds described herein may exhibit antiproliferative effects and may be used as monotherapy in cancer treatment and / or other indications described in this specification. In addition, they may be used in combination with other drugs to restore sensitivity to chemotherapy, targeted therapy, or immunotherapy to which resistance has developed.

[0374] In certain embodiments, the disease or disorder is improved by modulating PP2A. In certain embodiments, the disease or disorder is at least one selected from the group consisting of cancer, diabetes, autoimmune disease, solid organ transplant rejection, graft-versus-host disease, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative disease, and cardiac hypertrophy. In certain embodiments, the disease is cancer.

[0375] In certain embodiments, a therapeutically effective amount of a compound according to one or more embodiments disclosed in the present specification, such as a compound of formula (I), (II) or (III), a solvate, enantiomer, diastereomer, isotopomer, tautomer or pharmaceutically acceptable salt thereof is administered to a patient in need of treatment for a disease.

[0376] In certain embodiments, a method of treating cancer in a patient having a tumor expressing PP2A comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), (II) or (III), a solvate, enantiomer, diastereomer, isotopomer, tautomer, or pharmaceutically acceptable salt thereof.

[0377] In certain embodiments, a method of treating a malignant solid tumor in a patient in need thereof is provided, 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 cancer. In certain embodiments, the malignant tumor is a lymphoma. In certain embodiments, the malignant solid tumor is a sarcoma.

[0378] In certain embodiments, the cancer is bladder cancer, blood cancer, bone cancer, bone marrow cancer, brain cancer, breast cancer, colon cancer, esophageal cancer, gastrointestinal cancer, gum cancer, head cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, neck cancer, ovarian cancer, prostate cancer, skin cancer, stomach cancer, testicular cancer, tongue cancer, and / or uterine cancer. In addition, the cancer may be specifically at least one of the following histological types, but is not limited to these: malignant tumor; carcinoma; undifferentiated carcinoma; giant cell carcinoma or spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatricoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; malignant gastrinoma; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyps; adenocarcinoma, familial polyposis coli; solid carcinoma; malignant carcinoid tumor; branchial-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe cell carcinoma; oncocytic carcinoma; oncocytic adenocarcinoma; basophilic cell carcinoma; clear cell adenocarcinoma; granular cell carcinoma; Follicular adenocarcinoma; Papillary and follicular adenocarcinoma; Unencapsulated sclerosing carcinoma; Adrenocortical carcinoma; Endometrioid carcinoma; Carcinoma of skin appendages; Apocrine gland carcinoma; Sebaceous gland carcinoma; Cerumen gland carcinoma; Mucoepidermoid carcinoma; Cystadenocarcinoma; Papillary cystadenocarcinoma; Papillary serous cystadenocarcinoma; Mucinous cystadenocarcinoma; Mucinous adenocarcinoma; Signet ring cell carcinoma; Infiltrating ductal carcinoma; Medullary carcinoma; Lobular carcinoma; Inflammatory carcinoma; Paget's disease of the breast; Acinar cell carcinoma; Adenosquamous carcinoma; Adenocarcinoma with squamous metaplasia; Malignant thymoma; Malignant ovarian stromal tumor; Malignant thecoma; Malignant granulosa cell tumor; Malignant androgenic tumor; Sertoli cell carcinoma; Malignant Leydig cell tumor; Malignant lipid cell tumor; Malignant paraganglioma; Malignant breast Extraglandular paraganglioma; pheochromocytoma; angiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; malignant blue nevus; sarcoma; fibrosarcoma; malignant fibrous histiocytoma; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; malignant mixed tumor; mixed Müllerian tumor; Wilms tumor; hepatoblastoma; carcinosarcoma; malignant mesenchymal tumor; malignant Brenner tumor; malignant phyllodes tumor; synovial sarcoma; malignant mesothelioma; dysgerminoma; embryonal carcinoma; malignant teratoma; malignant ovarian goiter; villous mesonephroma; malignant mesonephroma; angiosarcoma; malignant hemangioendothelioma; Kaposi's sarcoma; malignant hemangiopericytoma; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; malignant chondroblastoma; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing's sarcoma; malignant odontogenic tumor; ameloblastic odontosarcoma; malignant ameloblastoma; ameloblastic fibrosarcoma; malignant pinealoma; chordoma; malignant glioma; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroglioma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma;neuroblastoma; retinoblastoma; olfactory neurogenic tumor; malignant meningioma; neurofibrosarcoma; malignant neurilemmary tumor; malignant granular cell tumor; malignant lymphoma; Hodgkin's disease; Hodgkin's disease; paragranuloma; malignant lymphoma, small lymphocytic; 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; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryocytic leukemia; myeloid sarcoma; and hairy cell leukemia. ;

[0379] In certain embodiments, the autoimmune disease is at least one of colitis, multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, acute pancreatitis, chronic pancreatitis, diabetes, insulin-dependent diabetes mellitus (IDDM or type I 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. , autoimmune diseases associated with silicone implants, Sjögren's syndrome, systemic lupus erythematosus (SLE), vasculitic syndromes (e.g., giant cell arteritis, Behcet's disease, and Wegener's granulomatosis), vitiligo, secondary hematologic manifestations of autoimmune diseases (e.g., anemia), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness (e.g., Meniere's disease), Goodpasture's syndrome, Graves' disease, HIV-associated autoimmune syndromes, and Guillain-Barré disease.

[0380] In certain embodiments, the neurodegenerative disease is Alzheimer's disease. In certain embodiments, the neurodegenerative disease is Parkinson's disease.

[0381] PP2A enzymes may be involved in the regulation of cellular transcription, cell cycle, and viral transformation. Many viruses, including cytomegalovirus, parainfluenza virus, DNA tumor virus, and HIV-1, use different methods to use PP2A to modify, control, or inactivate host cell activities. Therefore, the compounds according to one or more embodiments disclosed in this specification can also be further used in a method for treating viral infection in a patient by administering a therapeutically effective amount of the compound according to one or more embodiments disclosed in this specification to the patient. Examples of viruses that can cause viral infections that require treatment include, but are not limited to: polyomaviruses, such as John Cunningham virus (JCV), Simian virus 40 (SV40), or BK virus (BKV); influenza virus, 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.

[0382] The compound or pharmaceutical composition according to one or more embodiments disclosed in this specification may be further used in a method for treating beta coronavirus infection in a patient by administering a therapeutically effective amount of the compound or pharmaceutical composition according to one or more embodiments disclosed in this specification to the patient.

[0383] The compound according to one or more embodiments disclosed in this specification can be further used in the prevention of beta coronavirus infection in a patient by administering a preventively effective amount of the compound or pharmaceutical composition according to one or more embodiments disclosed in this specification to the patient.

[0384] The compound according to one or more embodiments disclosed in the present specification can be used for the manufacture of a medicament for treating or preventing betacoronavirus infection.

[0385] 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; initially referred to as nCoV-2019).

[0386] In certain embodiments, the betacoronavirus is SARS-CoV.

[0387] In certain embodiments, the betacoronavirus is SARS-CoV-2.

[0388] Serine / threonine phosphatases, including PP2A, may be involved in the regulation of synaptic plasticity. Reduced PP2A activity has been implicated in the maintenance of long-term potentiation (LTP) at synapses, and thus treatment with PP2A modulators described herein may reverse synaptic LTP. Abused psychostimulants such as cocaine and methamphetamine are associated with detrimental synaptic LTP, which may underlie addiction and relapse pathologies, and thus PP2A modulators described herein may be useful in the treatment of psychostimulant abuse.

[0389] Pharmaceutical compositions, formulations and routes of administration

[0390] The present disclosure also relates to a pharmaceutical composition comprising a compound according to one or more embodiments described in the present specification (eg, a compound of formula I, an enantiomer, a diastereomer, a tautomer or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.

[0391] In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), (II) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers thereof and optionally one or more other therapeutic ingredients. A carrier may be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and does not cause undue harm to the recipient thereof.

[0392] The pharmaceutical composition can be manufactured in any manner known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, embedding or compression processes. "Pharmaceutically acceptable carrier" may refer to an excipient, carrier or adjuvant that can be administered to a patient together with at least one therapeutic compound, which does not destroy the pharmacological activity of the therapeutic compound, and is generally safe, non-toxic, and has neither biological nor other adverse effects when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0393] Pharmaceutical preparations may include preparations suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, intranasal, rectal and topical (including skin, buccal, sublingual and intraocular) administration, although the most suitable route may depend on, for example, the recipient's illness and condition. The preparations may conveniently be in unit dosage form and may be prepared by any method well known in the pharmaceutical art. Typically, these methods include the step of combining a compound of formula (I), (II) or a pharmaceutically acceptable salt, ester, amide, solvate or enantiomer or diastereomer or tautomer thereof ("active ingredient") with a carrier constituting one or more auxiliary ingredients. In general, the preparation is prepared by uniformly and closely combining the active ingredient with a liquid carrier or a fine solid carrier or both, and then molding the product into the desired dosage form when necessary.

[0394] Formulations of the compounds of the present disclosure suitable for oral administration may be in the form of discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. The active ingredient may also be in the form of a pill, ointment or paste.

[0395] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers (e.g., glycerol or sorbitol). Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as a powder or granules) optionally mixed with a binder, an inert diluent or lubricant, a surfactant or a dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide a slow or controlled release of the active ingredient therein. The dosage of all oral preparations should be suitable for this mode of administration. Push-fit capsules can contain a mixture of active ingredients with fillers (e.g., lactose), binders (e.g., starches) and / or lubricants (e.g., talc or magnesium stearate) and optional stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or a liquid polyethylene glycol. In addition, stabilizers may also be added. The dragee cores are provided with suitable coatings. For this reason, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee coatings for identification or characterization of different combinations of active compound dosages.

[0396] The compounds of the present disclosure can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable preparations can be presented in unit doses, for example, in ampoules or in multi-dose containers, and preservatives are added. The composition can be in the form of a suspension, solution or emulsion, for example, in an oily or aqueous vehicle, and can contain formulations such as suspending agents, stabilizers and / or dispersants. The preparation can be present in unit doses or multi-dose containers, for example, sealed ampoules and vials, and can be stored in powder form or stored under freeze drying (lyophilization) conditions, only requiring immediate addition of sterile liquid carriers, such as saline or sterile pyrogen-free water, before use. Temporary injection solutions and suspensions can be prepared by sterile powders, granules and tablets of the aforementioned types.

[0397] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include 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 carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain a suitable stabilizer, or increase the solubility of the compound to allow the preparation of a medicament for a highly concentrated solution.

[0398] In addition to the previously described preparations, the compounds of the present disclosure can also be formulated as storage preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the compound can be formulated with a suitable polymeric material or hydrophobic material (e.g., formulated as an emulsion in an acceptable oil) or an ion exchange resin, or formulated as a slightly soluble derivative, for example, a slightly soluble salt.

[0399] For buccal or sublingual administration, the composition may take the form of tablets, lozenges, pastilles or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0400] 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.

[0401] In certain embodiments, the compounds disclosed herein can be administered topically, i.e., by non-systemic administration. This includes applying the compounds disclosed herein externally to the epidermis or oral cavity, and dropping the compounds into the ears, eyes, and noses so that the compounds do not enter the blood in large quantities. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0402] Preparations suitable for topical application include liquid or semi-liquid preparations suitable for permeating the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for application to the eyes, ears or noses. The active ingredient for topical application may account for, for example, 0.001% to 10% w / w (by weight) of the preparation. In certain embodiments, the active ingredient may account for up to 10% w / w. In other embodiments, its content may be less than 5% w / w. In certain embodiments, the active ingredient may account for 2% w / w to 5% w / w. In other embodiments, it may account for 0.1% to 1% w / w of the preparation.

[0403] For inhalation administration, the compounds disclosed herein can be conveniently delivered from an insufflator, atomizer pressurized pack or other convenient device for delivering an aerosol spray. The pressurized pack can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds disclosed herein can be in the form of a dry powder composition, such as a powder mixture of the compound and a suitable powder matrix (e.g., lactose or starch). The powder composition can be present in a unit dosage form, such as a capsule, cartridge, gelatin or blister package, wherein the powder can be administered by means of an insufflator or insufflator.

[0404] In particular, intranasal delivery can be used to deliver compounds to the central nervous system. Intranasal drug administration has been shown to be a non-invasive method for delivering neurotrophic factors and other therapeutic agents to the brain and spinal cord, bypassing the blood-brain barrier (BBB). It only takes a few minutes for drugs to be delivered from the nasal cavity to the central nervous system along the olfactory and trigeminal nerve pathways. Intranasal delivery occurs via an extracellular pathway and does not require the drug to bind to any receptors or undergo axonal transport. Intranasal delivery also targets nasal-associated lymphoid tissue (NALT) and deep cervical lymph nodes. In addition, high levels of intranasally administered therapeutics have been observed in the vascular walls and perivascular spaces of cerebral blood vessels. By using this intranasal approach on animal models, researchers have successfully reduced stroke damage, reversed neurodegeneration in Alzheimer's disease, reduced anxiety, improved memory, stimulated brain neurogenesis, and treated brain tumors.

[0405] In certain embodiments, unit dosage formulations are those containing an effective dose or an appropriate fraction thereof of an active ingredient.

[0406] It should 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.

[0407] Combination therapy

[0408] In some cases, it may be appropriate to administer at least one of the compounds of formula (I), (II) or (III) (enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient when receiving one of the compounds described herein to treat cancer is nausea, then co-administration of an antiemetic may be appropriate. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when used in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein together with another therapeutic agent (which also includes a treatment regimen) that also has a therapeutic benefit. By way of example only, in a cancer treatment involving administration of one of the compounds described herein, also providing another cancer therapeutic agent to the patient may produce an increased therapeutic benefit. In any event, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be an additive benefit of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0409] The compounds of the present invention may be particularly useful in combination with therapeutic agents and / or anticancer agents. Therefore, the present disclosure provides a combination of compounds of formula (I), (II) or (III) for simultaneous, separate or sequential administration in combination with therapeutic agents and / or anticancer agents. The compounds of the present disclosure and other anticancer agents may act additively or synergistically. The synergistic combination of the compounds of the present invention and another anticancer agent may allow the use of lower doses of one or both of these agents and / or lower frequency doses of the compounds of the present invention and one or both of other anticancer agents and / or lower frequency administration of these agents, which may reduce any toxicity associated with administering these agents to patients without reducing the efficacy of these agents in cancer treatment. In addition, the synergistic effect may improve the efficacy of these agents in cancer treatment and / or reduce any adverse or unnecessary side effects associated with the use of any one agent alone.

[0410] Therapeutic agents and / or anticancer agents can be administered according to treatment regimens known in the art. It will be clear to those skilled in the art that the administration of therapeutic agents and / or anticancer agents can vary according to the disease being treated and the known effects of the anticancer agent on the disease. In addition, according to the knowledge of a skilled clinician, the treatment regimen (e.g., dosage and administration time) can be changed according to the observed effects of the administered therapeutic agent (i.e., antitumor agent or radiation) on the patient and according to the observed disease response to the administered therapeutic agent and observed adverse reactions.

[0411] In certain embodiments, the compounds according to one or more embodiments disclosed in the specification, such as compounds of formula I, can be administered in combination with one or more agents selected from the following: aromatase inhibitors, antiestrogens, antiprogestins, antiandrogens or gonadorelin agonists, anti-inflammatory agents, antihistamines, anticancer agents, angiogenesis inhibitors, topoisomerase 1 and 2 inhibitors, microtubule active agents, alkylating agents, antitumor agents, antimetabolites, dacarbazine (DTIC), platinum-containing compounds, lipid or protein kinase targeting agents, protein or lipid phosphatase targeting agents, anti-angiogenic agents , agents that induce cell differentiation, bradykinin 1 receptor and angiotensin II antagonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokine or cytokine inhibitors, bisphosphonates, rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR agonists, HSP90 inhibitors, smoothened antagonists, Ras subtype inhibitors, telomerase inhibitors, protease inhibitors, metalloproteinase inhibitors, aminopeptidase inhibitors, immunomodulators, therapeutic antibodies and protein kinase inhibitors, such as tyrosine kinase or serine / threonine kinase inhibitors.

[0412] In certain embodiments, the combination of a compound of Formula I and an anticancer agent is for simultaneous, separate or sequential administration.

[0413] Those of ordinary skill in the art will be able to discern which combinations of agents are useful based on the specific properties of the drugs and the cancer involved. The categories of such agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents / cytostatics, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, cell proliferation and survival signal inhibitors, bisphosphonates, aromatase inhibitors, siRNA therapeutics, γ-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTK), agents that interfere with cell cycle checkpoints, PARP inhibitors, HDAC inhibitors, Smo antagonists (HH inhibitors), HSP90 inhibitors, CYP17 inhibitors, third generation AR antagonists, JAK inhibitors such as Ruxolitinib (trade name Jakafi) and BTK kinase inhibitors.

[0414] Anticancer agents suitable for combination therapy with the compounds disclosed herein include, but are not limited to:

[0415] 1) Alkaloids and natural product drugs, including microtubule inhibitors (e.g., vincristine, vinblastine, vindesine, vinorelbine, etc.), microtubule stabilizers (e.g., paclitaxel [Taxol], docetaxel, taxotere, etc.), and chromatin function inhibitors, including topoisomerase inhibitors, such as epipodophyllotoxins (e.g., etoposide [VP-161, teniposide [VM-261, etc.), and agents targeting topoisomerase I (e.g., camptothecin, topotecan (Hycamtin) and irinotecan [CPT-11], rubitecan (Orathecin), etc.);

[0416] 2) Covalent DNA binding agents [alkylating agents], including nitrogen mustards (e.g., mechloretharnine, chlormethine, chlorambucil, cyclophosphamide, estracit, ifosfamide, melphalan, etc.); alkyl sulfonates, such as busulfan [Myleran], nitrosoureas (e.g., carmustine or BCNU (bischloroethyl nitrosourea), fotemustine, lomustine and semustine, streptozotocin, etc.) and other alkylating agents (e.g., dacarbazine, procarbazine ethyleneimine / methylmelamine, triethylenemelamine (TEM), triethylenethiophosphoramide (thiotepa), hexamethylmelamine (HMM, hexamethylmelamine) and mitomycin, uramustine, etc.), including temozolomide (trade names Temodar and Temodal and Temcad), hexamethylmelamine (also known as hexalen) and mitomycin; and

[0417] 3) Non-covalent DNA-binding agents [antitumor antibiotics], including nucleic acid inhibitors (e.g., daunomycin [actinomycin D1, etc.), anthracyclines (e.g., daunorubicin [daunomycin and Cerubidine], doxorubicin [adriamycin], epirubicin (Ellence), idarubicin [idarubicin], valrubicin (Valstar), etc.), anthracenediones (e.g., anthracycline analogs, such as [mitoxantrone], etc.), bleomycin (Blenoxane), etc., amsacrine and plicamycin (mithramycin), daunomycin, mitomycin C.

[0418] In certain embodiments, a combination of a compound of formula (I), (II) or (III) and radiotherapy is used to treat a cancer patient. In certain embodiments, the method comprises administering a therapeutically effective amount of a compound of the present disclosure to a patient suffering from cancer, and adjuvanting the patient with an effective amount of radiotherapy. In certain embodiments, the compound is administered to a patient in need before, simultaneously with, or after radiotherapy.

[0419] In certain embodiments, the compound or pharmaceutical composition may further comprise or be administered in combination with one or more other antiviral agents, including but not limited to oseltamivir phosphate, zanamivir or Remdesivir, vidarabine, acyclovir, ganciclovir, valganciclovir, valacyclovir, cidofovir, famciclovir, ribavirin, amantadine, rimantadine, interferon, oseltamivir, palivizumab, rimantadine, zanamivir, nucleoside analog reverse transcriptase inhibitors (NRTIs), such as zidovudine, 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.

[0420] In certain embodiments, the compound or pharmaceutical composition 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.

[0421] Controlled release formulations and drug delivery systems

[0422] In certain embodiments, the compositions and / or formulations of the invention may be, but are not limited to, short term, rapid offset, and controlled, such as sustained release, delayed release, and pulsatile release formulations.

[0423] The term "sustained release" is used in its traditional sense to refer to a drug formulation that releases the drug gradually over a longer period of time and can (although not necessarily) result in blood concentrations of the drug remaining essentially constant over a longer period of time. This period of time may be as long as a month or more, and the release time should be longer than the same dose of the drug administered as a bolus.

[0424] For sustained release, the compound can be formulated with an appropriate polymer or hydrophobic material that provides the compound with sustained release properties. Thus, the compound used in the method of the invention can be administered in the form of microparticles, for example by injection, or in the form of a wafer or disc by implantation.

[0425] In certain embodiments of the invention, compounds useful in the invention are administered to a subject alone or in combination with another pharmaceutical agent using a sustained release formulation.

[0426] The term "delayed release" is used herein in its conventional sense to refer to a pharmaceutical formulation that begins to release the drug after a delay after administration, which delay may (although not necessarily) include a delay of about 10 minutes to about 12 hours.

[0427] The term "pulsatile release" is used herein in its conventional sense to refer to a drug formulation that provides for release of the drug in a manner that produces a pulsatile plasma profile of the drug following administration.

[0428] The term "immediate release" is used in its conventional sense to refer to a pharmaceutical formulation that provides release of the drug immediately after administration.

[0429] As used herein, short-term refers to any time period up to and including 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 after drug administration, and any or all full or partial increments thereof.

[0430] Administration / Dosage

[0431] The compound can be applied to animals at a frequency of several times a day, or can be applied to animals at a lower frequency, such as once a day, once a week, once every two weeks, once a month, or even lower frequency, such as once every few months or even once a year or less. It should be understood that, in non-limiting examples, the amount of the compound administered daily can be applied every day, every other day, every 2 days, every 3 days, every 4 days or every 5 days. For example, in the case of application every other day, 5 mg dosage can be started every day on Monday, the first subsequent 5 mg dosage every day is applied on Wednesday, the second subsequent 5 mg dosage every day is applied on Friday, and so on. The frequency of administration is obvious to those skilled in the art, and depends on many factors, such as but not limited to the type and severity of the disease treated and the type and age of the animal.

[0432] In certain embodiments, the compositions of the present invention are applied to the patient with a dosage of one to five times or more per day. In other embodiments, the dosage range of the compositions of the present invention applied to the patient includes but is not limited to once a day, once every two days, once every three days to once a week and once every two weeks. For those skilled in the art, it is apparent that the frequency of application of the various combination compositions of the present invention will vary depending on the subject, depending on many factors, including but not limited to age, disease to be treated or illness, sex, overall health and other factors. Therefore, the present invention should not be construed as being limited to any specific dosing regimen, and the precise dosage and compositions applied to any patient will be determined by the attending physician considering all other factors of the patient.

[0433] The compound according to one or more embodiments disclosed in this specification can be administered orally or by injection at a dosage of 0.1 to 500 mg / kg per day. The dosage range for adults is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in discrete units can conveniently contain a certain amount of one or more compounds that are effective at the dose or multiples thereof, for example, containing 5 mg to 500 mg, typically about 10 mg to 200 mg units.

[0434] The range of the compound of the present invention for administration can be from about 1 μg to about 7,500 mg, from about 20 μg to about 7,000 mg, from about 40 μg to about 6,500 mg, from about 80 μg to about 6,000 mg, from about 100 μg to about 5,500 mg, from about 200 μg to about 5,000 mg, from about 400 μg to about 4,000 mg, from about 800 μg to about 3,000 mg, from about 1 mg to about 2,500 mg, from about 2 mg to about 2,000 mg, from about 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.

[0435] In some embodiments, the dose of the compound of the invention is from about 0.5 μg to about 5,000 mg. In some embodiments, the dose 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 the 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.

[0436] 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.

[0437] The compounds of the present disclosure can be administered in a variety of ways, such as by oral administration, topical administration or injection. The exact amount of the compound administered to the patient will be the responsibility of the attending physician. The specific dosage level for any particular patient will depend on a variety of factors, including the activity, age, body weight, health status, sex, diet, administration time, administration route, excretion rate, drug combination, the exact illness being treated and the severity of the indication or illness being treated of the specific compound used. In addition, the administration route may vary depending on the condition and its severity.

[0438] Example

[0439] Various embodiments of the present application may be better understood with reference to the following examples provided by way of illustration.The scope of the present application is not limited to the examples given herein.

[0440] LCMS conditions

[0441] Method A: Waters Acquity UPLC system, using Waters Acquity UPLC CSH C18 (2.1x50mm), 1.7μm column, eluent including A=H 2 O + 0.05% TFA (v / v); and eluent B = CH 3 CN + 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 voltage: 0.8 kV; cone voltage: 10 V.

[0442] Method B: Waters Acquity UPLC system, using Waters Acquity UPLC CSH C18 (2.1x50mm), 1.7μm column, eluent including A=H 2 O + 0.05% TFA (v / v); and eluent B = CH 3 CN + 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 voltage: 0.8 kV; cone voltage: 15 V.

[0443] Method C: Acquity UPLC system, using Waters Acquity UPLC BEH C18 (2.1 x 50 mm), 1.7 μm column, eluent including A=H 2 O+AcONH 4( 10 mM); and eluent B = CH 3 CN. Oven temperature: 45℃; Gradient: t 0min =2% B; t 4min =90% B; t 4.5min =90% B; t 4.6min =2% B; t 5.5min =2% B (v / v). Flow rate: 0.8 mL / min. Electrospray ionization mode; capillary voltage: 3 kV; cone voltage: 15 / 30 V.

[0444] Method D: Waters Acquity UPLC system, using Waters Acquity UPLC CSH C18 (2.1x50mm), 1.7μm column, eluents include: eluent A = H 2 O + 0.02% HCOOH; and eluent B = CH 3 CN + 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. Negative electrospray ES-; capillary voltage: 3 kV; sample cone voltage: 15 / 30 V.

[0445] Method E: Waters Acquity UPLC system, using Waters Acquity UPLC CSH C18 (2.1x50mm), 1.7μm column, eluent includes: eluent A = H 2 O + 0.02% HCOOH; and eluent B = CH 3 CN + 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 voltage: 3 kV; sample cone voltage: 15 / 30 V.

[0446] Method F: Waters Acquity UPLC system, using Waters Acquity UPLC CSH C18 (2.1x50mm), 1.7μm column, eluents include: eluent A = H 2 O + 0.05% TFA; and eluent B = CH 3 CN + 0.035% TFA. 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 voltage: 3 kV; sample cone voltage: 15 / 30 V.

[0447] Example 1: N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide (1)

[0448]

[0449] Step 1: Synthesis of benzyl 3-(3,4-difluorophenyl)-3-hydroxypyrrolidine-1-carboxylate

[0450]

[0451] In a three-necked round-bottom flask equipped with a thermometer, an addition funnel and a reflux condenser, magnesium (222 mg, 9.12 mmol) and I 2 A suspension of the crystals in anhydrous THF (7 mL) was stirred at room temperature. A solution of 4-bromo-1,2-difluorobenzene (1,23 g, 6.39 mmol) in anhydrous THF (3 mL) was added to the addition funnel and a few drops were added to the reaction mixture. The orange suspension was stirred at 65 ° C until it changed color, and then the remaining solution was added dropwise. The mixture was stirred at 65 ° C for 1 hour and then cooled to 0 ° C. A solution of 3-oxopyrrolidine-1-carboxylic acid benzyl ester (1,0 g, 4.56 mmol) in anhydrous THF (3 mL) was added dropwise, and the mixture was stirred at 0 ° C for 1 hour and then stirred at room temperature overnight. With saturated NH 4 The reaction was quenched with Cl aqueous solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 10% to 70% of EtOAc in cyclohexane) to give the title compound as a yellow oil (802.6 mg, 50% yield, 95% purity, t r=0.89 min). LCMS (Method A): m / z found 334.3 [M+H] + .

[0452] Step 2: Synthesis of benzyl 3-(2-chloroacetamido)-3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate

[0453]

[0454] In a round-bottom flask under nitrogen, a solution of 3-(3,4-difluorophenyl)-3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (800 mg, 2.40 mmol) and 2-chloroacetonitrile (4.6 mL, 72.0 mmol) in anhydrous DCM (6 mL) was stirred at 0°C. 2,2,2-trifluoroacetic acid (4.6 mL, 60.0 mmol) was added dropwise, and the mixture was stirred at 0°C for 4 hours and then at room temperature overnight. The mixture was poured into ice water and saturated Na 2 CO 3 The aqueous solution was stirred until pH = 9. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as an orange oil (987.4 mg, yield 70%, purity 70%, t r =0.87 min). LCMS (Method A): m / z found 409.4 [M+H] + .

[0455] Step 3: Synthesis of benzyl 3-amino-3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate

[0456]

[0457] To a sealed tube was added benzyl 3-[(2-chloroacetyl)amino]-3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate (70%, 987 mg, 1.69 mmol) in a mixture of ethanol (23.8 mL) and acetic acid (4.8 mL) (ratio 5:1). Thiourea (98%, 171 mg, 2.20 mmol) was then added and the mixture was stirred at 80 °C overnight. The solution was cooled to room temperature and then diluted with DCM. Na 2 CO 3 The aqueous solution was stirred until pH = 9. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude oil was stirred in a small amount of Et 2 Dried 2M HCl / Et 2 O (8.4 mL, 16.9 mmol). The mixture was stirred at room temperature overnight. The solid was filtered and washed with Et 2O, and dried under reduced pressure at 45°C for 64 hours to obtain the hydrochloride of the title compound as an off-white powder (441.2 mg, yield 60%, purity 86%, t r =0.59 min). LCMS (Method A): m / z found 441.2 [M-HCl+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.89(s,3H),7.74(ddd,J=12.2,7.6,2.4Hz,1H),7.56(dtd,J=10.5,8.5, 6.5Hz,1H),7.47–7.28(m,6H),5.12(d,J=1.9Hz,2H),3.80–3.48(m,4H),2.63–2.42(m,2H).

[0458] Step 4: Synthesis of benzyl 3-(3,4-difluorophenyl)-3-((4-(trifluoromethoxy)phenyl)sulfonamido)pyrrolidine-1-carboxylate

[0459]

[0460] To a sealed vial was added benzyl 3-amino-3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate hydrochloride (86%, 200 mg, 0.466 mmol), DMAP (11 mg, 0.0933 mmol) and triethylamine (260 μL, 1.87 mmol) in DCM (4.4 mL). Then 4-(trifluoromethoxy)benzenesulfonyl chloride (98%, 81 μL, 0.466 mmol) was added and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was diluted with DCM and NH 4 Cl saturated aqueous solution. Separate the layers and extract the aqueous layer with DCM. Wash the combined organic layers with brine, dry over sodium sulfate, filter and concentrate. Triturate the crude residue with DCM. Filter the suspension, wash with DCM and dry under reduced pressure at 45 ° C for 4 hours to obtain the title compound as an off-white powder (125.1 mg, yield 46%, purity 97%, t r =0.99 min). LCMS (Method B): m / z found 579.3 [M+Na] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.63(d,J=5.6Hz,1H),7.47(dd,J=8.8,1.9Hz,2H),7.41 –7.34(m,4H),7.37–7.29(m,1H),7.29(d,J=8.5Hz,2H),7.14–6.98(m,1H) ,6.94(d,J=8.4Hz,0H),5.14–5.01(m,2H),4.13(dd,J=18.9,11.4Hz,1H), 3.57(dd,J=16.8,11.4Hz,1H), 3.54–3.31(m,1H), 2.69(d,J=13.8Hz,1H).

[0461] Step 5: Synthesis of N-(3-(3,4-difluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0462]

[0463] In a round-bottom flask, to a solution of benzyl 3-(3,4-difluorophenyl)-3-[[4-(trifluoromethoxy)phenyl]sulfonylamino]pyrrolidine-1-carboxylate (97%, 125 mg, 0.218 mmol) in ethanol (1.5 mL) was added Pd / C (10%, 23 mg, 0.0218 mmol), and the mixture was stirred under H 2 The mixture was stirred overnight under a 3% aqueous solution of ethyl acetate. The reaction mixture was filtered through a talc pad, washed with EtOH first, and then with hot EtOH. The two residues were combined and then purified by reverse phase flash chromatography (using a gradient of ACN from 0% to 100% in water (0.1% AcOH)). The desired fractions were combined and concentrated under reduced pressure. Salt exchange (acetate to hydrochloride) was performed with Amberlite IRA-410 (Cl), stirred at room temperature overnight, and then the resin was washed with MeOH. The filtrate was concentrated under reduced pressure to obtain the hydrochloride of the title compound as a white powder (12.6 mg, 12% yield, 99.5% purity, t r =1.73 minutes). LCMS (Method C): m / z found 422.9 [M-HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6)δppm8.17-9.17(m,2H)7.46(d,J=8.04Hz,2H)7.29(d,J=8.12Hz,2H)7.03-7.08(m,2H)6.95(m,J=4.20,4.20,2.70Hz,1H)3.91(br d,J=11.59Hz,1H)3.21-3.28(m,4H)2.72-2.78(m,1H)2.12(dt,J=13.39,9.22Hz,1H).

[0464] Example 2: N-(4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (2)

[0465]

[0466] Step 1: Synthesis of 1-benzyl-4-(3,5-difluorophenyl)piperidine-4-carbonitrile

[0467]

[0468] To a stirred solution of 4-(3,5-difluorophenyl)piperidine-4-carbonitrile (50%, 400 mg, 0.900 mmol) and benzaldehyde (0.18 mL, 1.80 mmol) in methanol (6 mL) at 25°C was added polymer-bound sodium cyanoborohydride (900 mg, 1.80 mmol). The reaction mixture was stirred at 25°C for 3 hours and filtered. The residue was washed with methanol and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 10% to 30% EtOAc in cyclohexane) to give the title compound as a colorless oil (439 mg, quantitative yield, purity 99%, t r =0.59 min). LCMS (Method A): m / z found 313.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.37–7.24(m,8H),3.57(s,2H),2.94(dt,J=12.5,3.3Hz,2H) ,2.32(td,J=12.2,2.2Hz,2H),2.16(dq,J=13.4,2.7Hz,2H),2.08–1.97(m,2H).

[0469] Step 2: Synthesis of 1-benzyl-4-(3,5-difluorophenyl)piperidine-4-carboxamide

[0470]

[0471] In a round-bottom flask, a mixture of 1-benzyl-4-(3,5-difluorophenyl)piperidine-4-carbonitrile (99%, 439 mg, 1.39 mmol) in water (1.4 mL) and sulfuric acid (5.6 mL, 0.104 mol) was stirred at 65 ° C for 45 minutes. The mixture was poured into ice water and basified with 10M NaOH (21 mL, 0.209 mol) to reach pH = 10-11. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as an orange oil (439 mg, yield 91%, purity 95%, t r =0.51 min). LCMS (Method A): m / z found 331.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.37–7.25(m,5H),7.13(d,J=9.2Hz,2H),7.06(dt,J=9.5,4.8Hz,3H) ,3.41(s,2H),2.60(s,2H),2.42(d,J=10.9Hz,2H),2.17(d,J=12.3Hz,2H),1.79(s,2H).

[0472] Step 3: Synthesis of 1-benzyl-4-(3,5-difluorophenyl)piperidin-4-amine

[0473]

[0474] To a stirred solution of 1-benzyl-4-(3,5-difluorophenyl)piperidine-4-carboxamide (95%, 439 mg, 1.26 mmol) in acetonitrile (3.1 mL) and water (3.1 mL) at room temperature was added [phenyl-(2,2,2-trifluoroacetyl)oxy-{3}-iodoalkyl] 2,2,2-trifluoroacetate (96%, 577 mg, 1.29 mmol). The reaction mixture was stirred at room temperature for 16 hours, and ACN was concentrated under reduced pressure. 1M HCl aqueous solution was added and the aqueous layer was washed with EtOAc. The aqueous layer was washed with saturated Na 2 CO 3 The aqueous solution was basified and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a white solid (249 mg, yield 61%, purity 93%, t r =0.41 min). LCMS (Method A): m / z found 303.4 [M+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)7.32(d,J=4.3Hz,4H),7.29–7.19(m,3H),7.02(tt,J=9.3,2.4H z,1H),3.49(s,2H),2.51–2.44(m,2H),1.97–1.76(m,4H),1.52(d,J=12.8Hz,2H).

[0475] Step 4: Synthesis of N-(1-benzyl-4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0476]

[0477] To a sealed vial was added 1-benzyl-4-(3,5-difluorophenyl)piperidin-4-amine (93%, 249 mg, 0.766 mmol), N,N-dimethylpyridin-4-amine (99%, 19 mg, 0.153 mmol) and triethylamine (0.43 mL, 3.06 mmol) in DCM (7 mL). 4-(Trifluoromethoxy)benzenesulfonyl chloride (98%, 0.13 mL, 0.766 mmol) was added and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was washed with DCM and saturated NH 4 Cl was diluted. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using MeOH (NH 3 0.7 M) in DCM (gradient from 0% to 10%) to afford the title compound as a pale yellow solid (345 mg, yield 86%, purity 100%, t r =0.73 min). LCMS (Method B): m / z found 527.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.05(s,1H),7.52–7.43(m,2H),7.37–7.20(m,7H),6.81–6.72(m,3H),3.47 (s,2H),2.61–2.52(m,2H),2.45(t,J=11.0Hz,2H),2.32(d,J=13.4Hz,2H),1.91–1.77(m,2H).

[0478] Step 5: Synthesis of N-(4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0479]

[0480] To a stirred solution of N-[1-benzyl-4-(3,5-difluorophenyl)-4-piperidinyl]-4-(trifluoromethoxy)benzenesulfonamide (345 mg, 0.655 mmol) and DIPEA (0.23 mL, 1.31 mmol) in DCM (4 mL) was added 1-chloroethyl chloroformate (95%, 0.15 mL, 1.31 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (4 mL) and the reaction mixture was stirred at 65 ° C for 16 hours. The reaction mixture was cooled to room temperature and quenched with water. EtOAc was added 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 product was purified by HPLC using MeOH (0.7N NH 3 The crude product was purified by flash chromatography on silica gel with a gradient of 1% to 15% ) in DCM. The desired fractions were concentrated and the residue was dissolved in minimal DCM and Et 2 2M HCl in O. Add Et 2 O, and the resulting suspension was filtered and washed with Et 2 O and dried under vacuum at 50°C for 12 h to give the hydrochloride salt of the title compound as a white powder (38 mg, yield 12%, purity 100%, t r =1.35 minutes). LCMS (Method D): m / z found 437.1 [M-HCl+H] + ; 1 H-NMR (DMSO-d 6 ,500MHz): δ(ppm)8.82(br s,2H),8.54(br s,1H),7.46-7.49(m,2H),7.29(d,J=7.8Hz,2H),6.78-6.85(m,3H),3.18-3.28(m,4H),2.51-2.58(m,2H),1.99-2.09(m,2H).

[0481] Example 3: N-(4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (3)

[0482]

[0483] Step 1: Synthesis of benzyl 4-(6-chloropyridin-3-yl)-4-cyanopiperidine-1-carboxylate

[0484]

[0485] To a stirred solution of benzylbis(2-bromoethyl)amine (284 mg, 0.883 mmol) and (6-chloropyridin-3-yl)acetonitrile (98%, 125 mg, 0.803 mmol) in anhydrous DMF (2.5 mL) was added sodium hydride (60%, 193 mg, 4.82 mmol) in portions under nitrogen at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then warmed to 60°C and stirred at this temperature overnight. The reaction mixture was allowed to cool to room temperature. The mixture was washed with saturated NH 4 The reaction mixture was quenched with Cl aqueous solution. EtOAc was added, each phase was separated, and the aqueous phase was extracted three times with EtOAc. The combined organic layer was washed with brine, dried with a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (using a gradient of 0% to 100% of EtOAc in heptane) to give the title compound as a yellow oil (206.9 mg, yield 83%, purity 99%, t r =0.52 min). LCMS (Method A): m / z found 312.3 [M+H] + ; 1 H-NMR (DMSO-d 6 , 400MHz): δ (ppm) 8.61 (d, J = 2.7Hz, 1H), 8.06 (dd, J = 8.5, 2.8Hz, 1H), 7.60 (d, J = 8.5Hz, 1H), 7.35 (d, J = 4.4Hz, 4H), 7.30–7.23 (m ,1H),3.58(s,2H),2.96(dt,J=12.7,3.2Hz,2H),2.34(td,J=12.2,2.2Hz,2H),2.18(dq,J=13.5,2.8Hz,2H),2.11–1.99(m,2H).

[0486] Step 2: Synthesis of 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxamide

[0487]

[0488] In a sealed tube, a mixture of 1-benzyl-4-(6-chloro-3-pyridyl)piperidine-4-carbonitrile (180 mg, 0.578 mmol) in sulfuric acid (2.3162 mL) and water (0.579 mL) was stirred at 65 ° C for 4 hours. The mixture was poured into ice water and basified to pH = 10 with 1 N NaOH aqueous solution. Water and DCM were added to obtain two homogeneous layers, and the aqueous layer was extracted twice with DCM. The combined organic layers were dried using a phase separator and concentrated under reduced pressure to give the title compound as a white solid (203.6 mg, quantitative yield, purity 95%, t r=0.46 min). LCMS (Method A): m / z found 330.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.40(d,J=2.6Hz,1H),7.81(dd,J=8.5,2.7Hz,1H),7.48(d,J=8.5Hz,1H),7.33–7.20(m,6H),7.08 (s,1H),3.42(s,2H),2.59(d,J=11.4Hz,2H),2.45(d,J=13.2Hz,2H),2.19(t,J=10.8Hz,2H),1.84(t,J=11.8Hz,2H).

[0489] Step 3: Synthesis of 1-benzyl-4-(6-chloropyridin-3-yl)piperidin-4-amine

[0490]

[0491] In a round-bottom flask, a solution of 1-benzyl-4-(6-chloro-3-pyridyl)piperidine-4-carboxamide (95%, 178 mg, 0.514 mmol) in acetonitrile (1.4 mL) and water (1.4 mL) was stirred at room temperature. [Bis(trifluoroacetyloxy)iodo]benzene (282 mg, 0.630 mmol) was added, and the mixture was stirred at 80 °C overnight. ACN was evaporated, then 1N HCl aqueous solution was added, and the mixture was washed twice with DCM. Saturated Na 2 CO 3 The aqueous solution was stirred until pH = 9. The aqueous layer was extracted three times with DCM, and the combined organic layers were washed with brine, filtered through a phase separator and concentrated under reduced pressure to afford the title compound as a yellow oil (117.6 mg, yield 71%, purity 94%, t r =0.39 min). LCMS (Method A): m / z found 302.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.56(d,J=2.6Hz,1H),7.99(dd,J=8.4,2.7Hz,1H),7.43(d,J=8.4Hz,1H),7.32(d, J=4.0Hz, 4H), 7.24 (ddd, J=8.8, 5.2, 3.6Hz, 1H), 3.50 (s, 2H), 1.96–1.90 (m, 2H), 1.63–1.54 (m, 2H).

[0492] Step 4: N-(1-benzyl-4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0493]

[0494] To a stirred solution of 1-benzyl-4-(6-chloro-3-pyridinyl)piperidin-4-amine (115 mg, 0.381 mmol) in DCM (2.5 mL) in a sealed vial were added triethylamine (0.16 mL, 1.14 mmol) and DMAP (4.7 mg, 0.0381 mmol) in sequence. 4-(Trifluoromethoxy)benzenesulfonyl chloride (0.071 mL, 0.419 mmol) was then added to the reaction mixture and stirred at 40 °C overnight. The reaction mixture was cooled to room temperature and washed with half-saturated NaHCO 3 The aqueous solution was quenched. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 2% to 10% MeOH in DCM) to give the title compound as a light yellow powder (160.1 mg, yield 76%, purity 95%, t r =0.68 min). LCMS (Method B): m / z found 526.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.22–8.15(m,2H),7.72–7.42(m,4H),7.33–7.24(m,7H),7.05(d,J= 8.4Hz, 1H), 3.45 (s, 2H), 2.44 (d, J = 10.5Hz, 2H), 2.34 (d, J = 13.9Hz, 2H), 1.93 (s, 2H).

[0495] Step 5: Synthesis of N-(4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0496]

[0497] To a stirred solution of N-[1-benzyl-4-(6-chloro-3-pyridinyl)-4-piperidinyl]-4-(trifluoromethoxy)benzenesulfonamide (155 mg, 0.295 mmol) in DCM (3.5 mL) was added 1-chloroethyl chloroformate (99%, 64 μL, 0.590 mmol) under nitrogen. The solution became cloudy and DIPEA (52 μL, 0.295 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (3.7 mL) and the reaction mixture was stirred at 65 °C for 4 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by flash chromatography on silica gel (using MeOH (0.7 N NH 3 ) in DCM (gradient from 2% to 15%). The residue was triturated in MeOH and filtered. The precipitate was suspended in 2M HCl / Et 2 O (1.5 mL, 2.95 mmol) for 4 h, filtered, and washed with Et 2 O, and vacuum dried at 40°C for 20 hours to obtain the hydrochloride of the title compound as a white powder (18 mg, yield 12%, purity 99.6%, 1.17 minutes). LCMS (method D): m / z found 436.1 [M-HCl+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δppm 1.99-2.16(m,2H)2.57(br d,J=13.94Hz,2H)3.18-3.27(m,4H)7.07(d,J=8.31Hz,1H)7.29(dd,J=8.80,0.73Hz,2H) 7.42-7.47(m,2H)7.51(dd,J=8.44,2.81Hz,1H)8.18(d,J=2.45Hz,1H)8.41-8.69(m,3H).

[0498] Example 4: N-(4-(4-chloro-3-methylphenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (4)

[0499]

[0500] Step 1: Synthesis of benzyl 4-(4-chloro-3-methylphenyl)-4-hydroxypiperidine-1-carboxylate

[0501]

[0502] In a round bottom flask, to a stirred solution of 0.5M bromo(4-chloro-3-methylphenyl)magnesium (20 mL, 10.1 mmol) in anhydrous THF (16 mL) was added dropwise a solution of benzyl 4-oxopiperidine-1-carboxylate (98%, 2.00 g, 8.40 mmol) in anhydrous THF (11 mL) under nitrogen at 0°C. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 20 hours. The mixture was poured into saturated NH 4 Cl aqueous solution and add EtOAc. Separate the layers. Extract the aqueous layer twice with EtOAc. Wash the combined organic layers with brine, dry over sodium sulfate, filter and concentrate under reduced pressure. The crude residue is purified by flash chromatography on silica gel (using a gradient of 0 to 8% of MeOH in DCM) to give the title compound as a yellow gum (1.98 g, yield 53.7%, purity 82%, t r = 0.97 min). LCMS (Method A); 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.45(dt,J=2.1,0.7Hz,1H),7.42–7.27(m,7H),5.16(s,1H),5.09(s,2H),3.93( d,J=12.9Hz,2H),3.20(s,2H),2.32(s,3H),1.82(td,J=13.1,4.7Hz,2H),1.57(d,J=13.3Hz,2H).

[0503] Step 2: Synthesis of benzyl 4-(4-chloro-3-methylphenyl)-4-(2-chloroacetamido)piperidine-1-carboxylate

[0504]

[0505] At 0°C, a round-bottom flask was charged with 4-(4-chloro-3-methyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (82%, 1.98 g, 4.51 mmol) and 2-chloroacetonitrile (8.6 mL, 0.135 mol) in anhydrous DCM (7.5 mL), and then 2,2,2-trifluoroacetic acid (8.6 mL, 0.113 mol) was added dropwise over 1 hour and stirred at the same temperature for 3 hours. The reaction mixture was poured into ice and washed with saturated NaHCO 3 The aqueous solution was quenched. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (using a gradient of 0% to 50% of EtOAc in heptane) to give the title compound as a white gum (1.33 g, yield 60.3%, purity 89%, t r=0.96 min). LCMS (Method A): m / z found 435.5 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.42(s,1H),7.42–7.34(m,4H),7.36–7.29(m,3H),7.18(dd,J=8.6,2.4Hz,1H),5.09(s,2H ), 4.12 (s, 2H), 3.92 (d, J = 13.3Hz, 2H), 3.09 (s, 3H), 2.31 (s, 3H), 2.28 (s, 1H), 1.80 (td, J = 13.1, 4.5Hz, 2H).

[0506] Step 3: Synthesis of benzyl 4-amino-4-(4-chloro-3-methylphenyl)piperidine-1-carboxylate

[0507]

[0508] To a sealed tube was added benzyl 4-[(2-chloroacetyl)amino]-4-(4-chloro-3-methyl-phenyl)piperidine-1-carboxylate (89%, 1.33 g, 2.72 mmol) in a mixture of ethanol (38.3 mL) and acetic acid (7.7 mL). Thiourea (98%, 275 mg, 3.53 mmol) was then added and the mixture was stirred at 80 °C overnight. The solution was cooled to room temperature and then diluted with DCM. Half-saturated Na 2 CO 3 The aqueous solution was stirred until pH = 9. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude oil was stirred in a small amount of Et 2 Dried 2M HCl / Et 2 O (14 mL, 27.2 mmol). The suspension was stirred at room temperature overnight and filtered. The residue was washed with Et 2 O and dried under reduced pressure at 45°C for 2 hours to obtain the title compound as a white powder (1.03 g, yield 84.3%, purity 88%, t r = 0.67 min). LCMS (Method A); 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.49(s,3H),7.63(d,J=2.4Hz,1H),7.53(d,J=8.5Hz,1H),7.46(dd,J=8.5,2.5Hz,1H),7.40–7. 30(m,5H),5.08(s,2H),3.79(d,J=13.7Hz,2H),3.13(bs,2H),2.47–2.38(m,2H),2.37(s,3H),2.05–1.94(m,2H).

[0509] Step 4: Synthesis of benzyl 4-(4-chloro-3-methylphenyl)-4-((4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate

[0510]

[0511] To a sealed vial was added 4-amino-4-(4-chloro-3-methyl-phenyl)piperidine-1-carboxylic acid benzyl ester hydrochloride (88%, 1.03 g, 2.29 mmol), DMAP (56 mg, 0.459 mmol) and triethylamine (1278 μL, 9.17 mmol) in DCM (21.6 mL). Then 4-(trifluoromethoxy)benzenesulfonyl chloride (467 μL, 2.75 mmol) was added and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was diluted with DCM and saturated NH 4 Cl aqueous solution. Separate the layers and extract the aqueous layer with DCM. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue is purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0% to 5%) to give the title compound as an off-white powder (1.24 g, yield 90%, purity 97%, t r =1.09 min). LCMS (Method A): m / z found 605.3 [M+Na] + ; 1 H-NMR (DMSO-d 6 , 400MHz): δ (ppm) 8.21 (s, 1H), 7.40–7.34 (m, 6H), 7.33–7.29 (m, 1H), 7.25–7.14 (m, 2H), 7.01–6.97 (m, 2H), 6.94 (dd, J = 8. 5,2.2Hz,1H),5.07(s,2H),3.78(d,J=13.5Hz,2H),3.33(bs,2H),2.38(d,J=13.7Hz,2H),2.05(s,3H),1.82–1.70(m,2H).

[0512] Step 5: N-(4-(4-chloro-3-methylphenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0513]

[0514] In a round bottom flask, to a stirred solution of 4-(4-chloro-3-methyl-phenyl)-4-[[4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylic acid benzyl ester (97%, 500 mg, 0.832 mmol) in anhydrous acetonitrile (4.6 mL) was added iodo(trimethyl)silane (97%, 366 μL, 2.50 mmol) under nitrogen and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (using (0.7N NH 3 / MeOH) in DCM with a gradient from 0 to 15%). The residue was dissolved in 2M HCl / Et 2 O (4.16 mL, 8.32 mmol) for 24 h, filtered and dried under reduced pressure. 2 CO 3 The aqueous solution was added to the solid, the suspension was stirred at room temperature for 3 hours and filtered. The residue was washed with water and dried under reduced pressure at 45°C for 48 hours. The solid was dissolved in 2H HCl / Et 2 O overnight, filtered, and washed with Et 2 O and dried under reduced pressure at 45°C to give the hydrochloride of the title compound as a white powder (13.8 mg, yield 3.6%, purity 97%, t r =1.52 minutes). LCMS (Method D): m / z found 449.1 [M-HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm1.92-2.01(m,2H)2.06(s,3H)2.51-2.57(m,2H)3.13-3.27(m,4H)6.94(dd,J=8.58,2.42Hz,1H)6.9 8(d,J=1.76Hz,1H)7.02(d,J=8.36Hz,1H)7.21(d,J=8.07Hz,2H)7.35(d,J=8.80Hz,2H)7.45-9.17(m,3H).

[0515] Example 5: N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide (5)

[0516]

[0517] Step 1: Synthesis of 1-benzyl-4-(5-chloropyridin-2-yl)piperidine-4-carbonitrile

[0518]

[0519] In a sealed tube, 2-bromo-5-chloropyridine (98%, 392 mg, 2.00 mmol) was added to a stirred solution of 1-benzylpiperidine-4-carbonitrile (440 mg, 2.20 mmol) in anhydrous toluene (10 mL) at room temperature under nitrogen. The reaction mixture was cooled to 0 ° C, and 1M sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (4.0 mL, 3.99 mmol) was added dropwise. The solution was stirred at 0 ° C for 4 hours, then quenched with saturated aqueous ammonium chloride to reach pH = 7 and DCM was added. The aqueous layer was extracted with DCM. The combined organic layer was filtered through a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of MeOH from 0% to 5% in DCM). The desired fractions were combined and concentrated under reduced pressure to give the title compound as a yellow oil (498 mg, yield 79%, purity 99%, t r =0.56 min). LCMS (Method A): m / z found 312.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,500MHz): δ(ppm)8.69(d,J=2.5Hz,1H),8.03(ddd,J=8.4,2.6,1.2Hz,1H),7.67(d,J=8.6Hz,1H),7.36–7.31(m, 4H), 7.26 (h, J=4.2Hz, 1H), 3.57 (s, 2H), 2.93 (d, J=12.0Hz, 2H), 2.33 (td, J=11.6, 3.4Hz, 2H), 2.18–2.06 (m, 4H).

[0520] Step 2: Synthesis of 1-benzyl-4-(5-chloropyridin-2-yl)piperidine-4-carboxamide

[0521]

[0522] In a round-bottom flask, a mixture of 1-benzyl-4-(5-chloro-2-pyridyl)piperidine-4-carbonitrile (498 mg, 1.60 mmol) in sulfuric acid (6.4 mL) and water (1.6 mL) was stirred at 65 ° C for 3 hours and 30 minutes. The mixture was poured into ice water and basified to pH = 11 (precipitation) with 30% NaOH aqueous solution (about 10 mL). Water and DCM were added, and the aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give the title compound as a white powder (491 mg, yield 93%, purity 100%, t r =0.5 min). LCMS (Method A): m / z found 330.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,500MHz): δ(ppm)8.57(d,J=2.5Hz,1H),7.88(dd,J=8.6,2.7Hz,1H),7.44(d,J=8.6Hz,1H),7.36–7.1 8(m,5H),7.05(d,J=39.6Hz,2H),3.38(s,2H),2.48–2.36(m,2H),2.36–2.17(m,4H),2.17–1.95(m,2H)

[0523] Step 3: Synthesis of 1-benzyl-4-(5-chloropyridin-2-yl)piperidin-4-amine

[0524]

[0525] In a round-bottom flask, a solution of 1-benzyl-4-(5-chloro-2-pyridyl)piperidine-4-carboxamide (491 mg, 1.49 mmol) in acetonitrile (3.4 mL) and water (3.4 mL) was stirred at room temperature. [Bis(trifluoroacetyloxy)iodo]benzene (96%, 680 mg, 1.52 mmol) was added, and the mixture was stirred at 60 ° C overnight, then at 80 ° C for 6 hours, and ACN was evaporated. 1N HCl aqueous solution was added, and the mixture was washed twice with DCM. Saturated Na 2 CO 3 The aqueous solution was stirred until pH = 9. The aqueous layer was extracted three times with DCM, and the combined organic layers were washed with brine, filtered through a phase separator and concentrated under reduced pressure to afford the title compound as an orange oil (416 mg, yield 90%, purity 97%, t r =0.41 min). LCMS (Method A): m / z found 302.3 [M+H] + ; 1 H-NMR (DMSO-d 6, 400MHz): δ (ppm) 8.55 (d, J = 2.5Hz, 1H), 7.87 (dd, J = 8.6, 2.6Hz, 1H), 7.70 (d, J = 8.6Hz, 1H), 7.32 (d, J = 4.4Hz, 4H), 7.24 (d dd,J=8.7,5.1,3.6Hz,1H),3.48(s,2H),2.51–2.43(m,4H),2.20–2.06(m,2H),1.97(s,2H),1.50(dq,J=13.2,3.2Hz,2H).

[0526] Step 4: Synthesis of N-(1-benzyl-4-(5-chloropyridin-2-yl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide

[0527]

[0528] In a sealed vial, triethylamine (0.14 mL, 0.994 mmol) and DMAP (4.0 mg, 0.0331 mmol) were added to a stirred solution of 1-benzyl-4-(5-chloro-2-pyridinyl)piperidin-4-amine (100 mg, 0.331 mmol) in DCM (2.2 mL) in sequence. 6-(Propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 90 mg, 0.364 mmol) was then added to the reaction mixture and stirred at 45 °C overnight and at 55 °C for 4 hours. The reaction mixture was cooled to room temperature and treated with half-saturated NaHCO 3 The aqueous solution was quenched. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 2% to 10% MeOH in DCM) to give the title compound as a light yellow oil (121 mg, yield 69%, purity 95%, t r =0.69 min). LCMS (Method A): m / z found 501.4 [M+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.20(d,J=2.6Hz,1H),8.03(s,1H),7.93(d,J=2.5Hz,1H),7.62(dd,J=8.6,2.6Hz,1H),7.56(dd,J=8.8,2.6Hz,1H),7.36–7. 20(m,6H),6.62(d,J=8.7Hz,1H),5.24(h,J=6.2Hz,1H),3.44(s,2H),2.44(s,4H),2.31(d,J=13.4Hz,2H),2.03(s,2H),1.31(d,J=6.1Hz,6H).

[0529] Step 5: Synthesis of N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0530]

[0531] To a stirred solution of N-[1-benzyl-4-(5-chloro-2-pyridinyl)-4-piperidinyl]-6-isopropoxy-pyridine-3-sulfonamide (120 mg, 0.240 mmol) in DCE (2.4 mL) was added 1-chloroethyl chloroformate (52 μL, 0.479 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 1 hour until a suspension was formed, then triethylamine (0.067 mL, 0.479 mmol) was added and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (2.4 mL) and the reaction mixture was stirred at 65 ° C for 4 hours. The mixture was concentrated, DCM and half-saturated NaHCO were added 3 The solution was stirred and the aqueous layer was extracted twice more with DCM. The combined organic layers were concentrated in vacuo and purified by reverse phase flash chromatography using a gradient of ACN in water from 0% to 100% (0.1% AcOH). The desired fractions were washed with half-saturated Na 2 CO 3 The solution was basified and extracted three times with DCM. The combined organic layers were dried through a phase separator and concentrated in vacuo. Diethyl ether (2 mL) and 2M hydrogen chloride (1.2 mL, 2.40 mmol) were added to the resulting white solid and stirred at room temperature for 4 hours, filtered, washed with diethyl ether and dried in vacuo at 40 °C for 20 hours. DCM and half-saturated Na 2 CO 3The solution was added to the solid, the aqueous layer was extracted twice more with DCM, and the organic layer was concentrated in vacuo. 2M hydrogen chloride / ether (0.12 mL, 0.240 mmol) was added, and the suspension was stirred at room temperature for 45 minutes, filtered, washed with ether and dried in vacuo at 45°C for 20 hours to give the title compound as a white powder (37 mg, 32% purity, 99.5% purity, t r =1.15 minutes). LCMS (Method D): m / z found 411.2 [M-2HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm 1.30(d,J=6.31Hz,6H)2.08-2.25(m,2H)2.54(br d,J=14.53Hz,2H)3.11-3.25(m,4H)5.23(quin,J=6.20Hz,1H)6.60(dd,J=8.80,0.59Hz,1H)7.31(d,J=8.66Hz,1H)7.53(dd,J= 8.66, 2.64Hz, 1H) 7.64 (dd, J = 8.58, 2.57Hz, 1H) 7.89-7.97 (m, 1H) 8.24 (dd, J = 2.49, 0.59Hz, 1H) 8.46 (s, 1H) 8.66-8.93 (m, 2H).

[0532] Example 6: N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide (6)

[0533]

[0534] Step 1: Synthesis of 6-oxo-4-azaspiro[2.5]octane-4-carboxylic acid benzyl ester

[0535]

[0536] In a round-bottom flask, DIPEA (1.7 mL, 9.57 mmol) and pyridine sulfur trioxide (700 mg, 4.40 mmol) in DMSO (2.8 mL) were added to a stirred solution of 6-hydroxy-4-azaspiro [2.5] octane-4-carboxylic acid benzyl ester (500 mg, 1.91 mmol) in DCM (2.5 mL) at 0 ° C. The reaction mixture was stirred for 2 hours at 0 ° C. The reaction mixture was quenched with water. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of EtOAc from 2% to 100% in cyclohexane) to give the title compound as a yellow oil (429 mg, yield 86%, purity 100%, t r =0.81 min). LCMS (Method B): m / z found 260.1 [M+H] + ; 1 H-NMR (400MHz, DMSO) δ7.49–7.23(m,5H),5.10(s,2H),4.02(s,2H),2.57–2.45(m,2H),1.87(t,J=6.8Hz,2H),1.08–0.98(m,2H),0.89–0.80(m,2H).

[0537] Step 2: Synthesis of 6-hydroxy-6-phenyl-4-azaspiro[2.5]octane-4-carboxylic acid benzyl ester

[0538]

[0539] To a solution of benzyl 6-oxo-4-azaspiro[2.5]octane-4-carboxylate (429 mg, 1.65 mmol) in anhydrous THF (5.5 mL) was added dropwise 1 M bromo(phenyl)magnesium solution in THF (2.0 mL, 1.99 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour and then at room temperature overnight. The mixture was heated to 40°C with saturated NH 4 The reaction was quenched with Cl aqueous solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 2% to 15% of MeOH in DCM) to give the title compound as a white solid (237.2 mg, 41% yield, 97% purity, t r =0.95 min). LCMS (Method A): m / z found 360.5 [M+Na] + ; 1H-NMR (400MHz, DMSO) δ7.60–7.50(m,2H),7.45–7.14(m,8H),5.26–4.87(m,3H),3.83(t,J=14.6Hz,1H),3.59(d,J=2.3Hz,1H),3.21(t,J=1 5.8Hz,1H),2.45(d,J=14.3Hz,1H),2.24–2.04(m,1H),1.77(td,J=7.4,4.7Hz,1H),1.11(s,1H),0.99–0.75(m,2H),0.57(d,J=23.8Hz,2H).

[0540] Step 3: Synthesis of 6-(2-chloroacetamido)-6-phenyl-4-azaspiro[2.5]octane-4-carboxylic acid benzyl ester

[0541]

[0542] In a round bottom flask under nitrogen, a solution of benzyl 6-hydroxy-6-phenyl-4-azaspiro[2.5]octane-4-carboxylate (237 mg, 0.702 mmol) and 2-chloroacetonitrile (1.3 mL, 21.1 mmol) in anhydrous DCM (1.8 mL) was stirred at 0°C. 2,2,2-trifluoroacetic acid (1.3 mL, 17.6 mmol) was added and the mixture was stirred at 0°C for 6 hours and at room temperature for 16 hours. The mixture was poured into ice water and saturated Na 2 CO 3 The aqueous solution was stirred until pH = 9. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (277.1 mg, yield 86%, purity 91%, t r =0.89 min). LCMS (Method A): m / z found 437.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,500MHz): δ(ppm)8.49(s,1H),7.50(d,J=2.2Hz,4H),7.41–7.29(m,7H),7.00(t,J=56.0Hz,1H),5.10(s,2 H), 4.13 (s, 2H), 3.94 (d, J = 13.2Hz, 2H), 3.12 (s, 2H), 2.33 (d, J = 13.4Hz, 2H), 1.84 (td, J = 13.1, 4.5Hz, 2H).

[0543] Step 4: Synthesis of 6-amino-6-phenyl-4-azaspiro[2.5]octane-4-carboxylic acid benzyl ester

[0544]

[0545] In a sealed tube, a solution of 6-[(2-chloroacetyl)amino]-6-phenyl-4-azaspiro[2.5]octane-4-carboxylic acid benzyl ester (275 mg, 0.666 mmol) in ethanol (4.3 mL) and acetic acid (870 μL) was stirred at room temperature, thiourea (66 mg, 0.866 mmol) was added, and the mixture was stirred at 50 ° C for 5 days and then at 70 ° C for 8 hours. The mixture was cooled to room temperature and poured into ice water. Saturated Na 2 CO 3 The aqueous solution was stirred until pH = 9, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in EtOAc. 2 O / MeOH 98 / 2 (3 mL) and 2M HCl / Et 2 O (666 μL, 1.33 mmol). Water was added to dissolve the oil, the layers were separated, and the mixture was washed with Et 2 O was added to the aqueous layer. 2 CO 3 The aqueous solution was stirred until pH = 9 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (140 mg, yield 48%, purity 78%, t r =0.62 min). LCMS (Method B): m / z found 337.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.62(s,3H),7.79(d,J=8.2Hz,2H),7.69(d,J=8.2Hz,2H),7.43–7.27(m,5H),7.09(t,J=55 .7Hz,1H),5.09(s,2H),3.81(d,J=13.7Hz,2H),3.19(s,2H),2.46(d,J=14.9Hz,2H),2.07(t,J=10.8Hz,2H).

[0546] Step 5: Synthesis of benzyl 6-phenyl-6-((4-(trifluoromethoxy)phenyl)sulfonamido)-4-azaspiro[2.5]octane-4-carboxylate

[0547]

[0548] In a sealed tube under nitrogen, a solution of benzyl 6-amino-6-phenyl-4-azaspiro[2.5]octane-4-carboxylate (78%, 140 mg, 0.325 mmol), triethylamine (181 μL, 1.30 mmol) and 4-dimethylaminopyridine (7.9 mg, 0.0649 mmol) in anhydrous DCM (2.6 mL) was stirred at room temperature. 4-(Trifluoromethoxy)benzenesulfonyl chloride (55 μL, 0.325 mmol) was added and the mixture was stirred at 40 °C for 16 hours. The mixture was washed with DCM and half-saturated NaHCO 3 The aqueous solution was diluted. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 50% of EtOAc in heptane) to give the title compound as a colorless oil (75 mg, yield 35%, purity 86%, t r =1.09 minutes). LCMS (Method A): m / z found 561.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.33–7.75(m,1H),7.57–6.61(m,12H),5.00(d,J=14.5Hz,2H ),4.02(s,2H),2.45–1.61(m,3H),1.25(s,2H),1.07–0.67(m,3H),0.59(s,1H).

[0549] Step 6: Synthesis of N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0550]

[0551] In a sealed tube under nitrogen, iodo(trimethyl)silane (57 μL, 0.401 mmol) was added to a stirred solution of 6-phenyl-6-[[4-(trifluoromethoxy)phenyl]sulfonylamino]-4-azaspiro[2.5]octane-4-carboxylic acid benzyl ester (75 mg, 0.134 mmol) in anhydrous acetonitrile (750 μL), and the solution was stirred at room temperature for 1 hour. The mixture was concentrated and HCl2N / Et 2 O. Add Et 2 O, and the suspension was stirred at room temperature for 30 minutes and filtered. The residue was washed with Et 2 O and dried under reduced pressure for 2 hours. 2 CO 3The mixture was partitioned between aqueous solution and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel using (MeOH + 2% NH 4 The desired fractions were concentrated and the residue was dissolved in Et 2 O. Add HCl 2N / Et 2 O (55 μL, 1.0 eq.) and stirred the solution at room temperature for 2 h. The solution was concentrated and the residue was stirred in pentane / Et 2 O 8 / 2 and the resulting suspension was filtered. 2 The residue was washed with 0.08 / 2 and dried under reduced pressure at 45°C for 16 hours to give the hydrochloride of the title compound as a white powder (25 mg, yield 40%, purity 100%, t r =1.34 min). LCMS (Method D): m / z found 427.2 [M-HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm 9.00-9.62(m,2H)8.58(s,1H)7.32-7.38(m,2H)7.15(dd,J=8.95,0.88Hz,2H)7.04-7.09(m,2H)6.98-7.03(m,1H)6.91-6.97(m,2H)4.10(br d,J=12.18Hz,1H)3.34-3.42(m,1H)2.51-2.58(m,2H)1.77-1.94(m,1H)1.20-1.28(m,1 H)1.06-1.14(m,1H)0.94-1.02(m,1H)0.83-0.90(m,1H)0.64(dt,J=9.65,6.03Hz,1H).

[0552] Example 7: N-(4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide (7)

[0553]

[0554] Step 1: Synthesis of 4-(3,4-difluorophenyl)piperidine-4-carbonitrile

[0555]

[0556] In a round-bottom flask under nitrogen, tert-butyl 4-cyano-4-(3,4-difluorophenyl)piperidine-1-carboxylate (95%, 3.00 g, 9.31 mmol) was added to a solution of Et 24M HCl / dioxane (23 mL, 93.1 mmol) was added to a 4% HCl / dioxane solution of 1% HCl (23 mL, 93.1 mmol), and the mixture was stirred at room temperature overnight. The suspension was filtered and washed with Et 2 O, and dried under reduced pressure at 45°C for 4 hours to obtain the hydrochloride of the title compound as a white powder (2.23 g, yield 78%, purity 85%, t r =0.49 min). LCMS (Method A): m / z found 223.3 [M-HCl+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)9.08(s,2H),7.69–7.63(m,1H),7.59(dt,J=10.6,8.8Hz,1H),7.42(dddd,J=8.4,4.0,2.5,1.4Hz,1H ), 3.49(dt,J=13.7,3.4Hz,2H), 3.09(td,J=13.2,2.8Hz,2H), 2.48–2.43(m,2H), 2.31(ddd,J=14.4,12.7,4.0Hz,2H).

[0557] Step 2: Synthesis of 1-benzyl-4-(3,4-difluorophenyl)piperidine-4-carbonitrile

[0558]

[0559] In a sealed tube, a suspension of 4-(3,4-difluorophenyl)piperidine-4-carbonitrile hydrochloride (85%, 2.23 g, 7.33 mmol) and potassium carbonate (2.53 g, 18.3 mmol) in ACN (19 mL) was stirred at room temperature under nitrogen. Bromomethylbenzene (98%, 1.1 mL, 8.79 mmol) was added and the mixture was stirred at 65 °C overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine and purified by Na 2 SO 4 The title compound was dried and concentrated under reduced pressure to give a colorless oil (2.5 g, yield 95%, purity 87%, t r =0.59 min). LCMS (Method B): m / z found 313.2 [M+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)7.67(ddd,J=12.3,7.6,2.4Hz,1H),7.51(dt,J=10.5,8.6 Hz,1H),7.42(dddd,J=8.7,3.9,2.4,1.3Hz,1H),7.34(d,J=4.3Hz,4H),7.26 (ddd,J=8.6,5.0,3.8Hz,1H),3.56(s,2H),2.94(dt,J=12.6,3.1Hz,2H),2. 31(td,J=12.2,2.3Hz,2H),2.14(dd,J=13.5,2.5Hz,2H),2.05–1.94(m,2H).

[0560] Step 3: Synthesis of 1-benzyl-4-(3,4-difluorophenyl)piperidine-4-carboxamide

[0561]

[0562] In a round-bottom flask, 1-benzyl-4-(3,4-difluorophenyl)piperidine-4-carbonitrile (87%, 2.50 g, 6.96 mmol) was placed in water (7 mL) and sulfuric acid (27.7 mL), and the mixture was stirred at 65 ° C for 1 hour. The mixture was poured into ice water and basified with 30% NaOH aqueous solution until pH = 10-11. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound as a white foam (2.0 g, yield 82%, purity 95%, t r =0.51 min). LCMS (Method A): m / z found 331.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.43–7.16(m,9H),7.01(s,1H),3.40(s,2H),2.60(d,J=11.2 Hz,2H),2.42(d,J=13.2Hz,2H),2.15(t,J=11.0Hz,2H),1.77(t,J=11.9Hz,2H)

[0563] Step 4: Synthesis of 1-benzyl-4-(3,4-difluorophenyl)piperidin-4-amine

[0564]

[0565] In a round-bottom flask, 1-benzyl-4-(3,4-difluorophenyl)piperidine-4-carboxamide (95%, 2.00 g, 5.75 mmol) was placed in a mixture of ACN (13.3 mL) and water (13.3 mL). [Phenyl-(2,2,2-trifluoroacetyl)oxy-{3}-iodoalkyl] 2,2,2-trifluoroacetate (97%, 2.55 g, 5.75 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The ACN was concentrated under reduced pressure. 1N HCl aqueous solution was added, and the aqueous layer was washed with DCM. The aqueous layer was washed with saturated Na 2 CO 3 The aqueous solution was basified and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a colorless oil (1.04 g, yield 59%, purity 95.3%, t r =0.85 min). LCMS (Method F): m / z found 303 [M+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δppm 7.52-7.67(m,1H)7.35(dd,J=7.09,1.47Hz,2H)7.28-7.33(m,4H)7.20-7.28(m,1H)3.49(s,2H)2.53(br s,2H)2.31-2.50(m,4H)1.81-2.06(m,2H)1.57(br d,J=12.47Hz,2H).

[0566] Step 5: Synthesis of N-(1-benzyl-4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide

[0567]

[0568] A sealed vial was charged with 1-benzyl-4-(3,4-difluorophenyl)piperidin-4-amine (95%, 200 mg, 0.630 mmol), DMAP (15 mg, 0.126 mmol) and triethylamine (351 μL, 2.52 mmol) in DCM (6 mL). Then 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 156 mg, 0.630 mmol) was added and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was diluted with DCM and NH 4Cl saturated aqueous solution. Separate the layers and extract the aqueous layer with DCM. The combined organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue is purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0% to 5%) to give the title compound as an off-white powder (224 mg, yield 63%, purity 90%, t r =0.70 min). LCMS (Method A): m / z found 502.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.87(s,1H),7.85(dd,J=2.5,0.7Hz,1H),7.55(dd,J=8.8,2.6Hz,1H),7.37–7.20(m,5H),7.13–6.97(m,3H),6.61(dd, J=8.7,0.7Hz,1H),5.20(hept,J=6.2Hz,1H),3.48(s,2H),2.51–2.46(m,4H),2.34(d,J=13.1Hz,2H),1.84(s,2H),1.28(d,J=6.2Hz,6H).

[0569] Step 6: Synthesis of N-(4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide

[0570]

[0571] In a round-bottom flask, Pd / C (10%, 86 mg, 0.0804 mmol) was added to a solution of N-[1-benzyl-4-(3,4-difluorophenyl)-4-piperidinyl]-6-isopropoxy-pyridine-3-sulfonamide (90%, 224 mg, 0.402 mmol) in methanol (2.7 mL), and the mixture was stirred under H 2 The reaction mixture was filtered through a talc pad and washed with EtOH. The filtrate was concentrated under reduced pressure and then washed with EtOH. 2 O (1.8 mL) and add 2N HCl / Et 2 O (1.0 mL, 2.01 mmol). The mixture was stirred at room temperature overnight. The suspension was filtered and washed with Et 2 O and dried under reduced pressure at 45°C for 64 hours. The solid was purified by reverse phase flash chromatography using a gradient of ACN in water from 0% to 100% (0.1% AcOH). The desired fractions were combined, concentrated under reduced pressure, diluted with DCM, and washed with saturated Na 2 CO 3The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The solid was diluted in a minimum amount of DCM and 2N HCl / Et 2 O (2 mL, 4.02 mmol), and the mixture was stirred at room temperature overnight. The suspension was filtered and the solid was washed with Et 2 O, and dried under reduced pressure at 45°C for 5 hours to obtain the dihydrochloride salt of the title compound as a white powder (48.9 mg, yield 25%, purity 99.4%, t r =1.66 min). LCMS (Method F): m / z found 412 [M-2HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm 8.83(br s,2H)8.37(s,1H)7.89(dd,J=2.64,0.59Hz,1H)7.56(dd,J=8.73,2.57Hz,1H)7.07-7.17(m ,2H)7.01(dt,J=5.72,2.71Hz,1H)6.61(dd,J=8.80,0.59Hz,1H)5.11-5.30(m,1H)3.22(br s, 4H) 2.57 (br d, J = 13.35Hz, 2H) 2.01 ( br s, 2H) 1.28 ( d, J = 6.16Hz, 6H).

[0572] Example 8: N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(methylamino)-4-(trifluoromethoxy)benzenesulfonamide (8)

[0573]

[0574] Step 1: Synthesis of tert-butyl 4-(4-chlorophenyl)-4-((3-nitro-4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate

[0575]

[0576] In a sealed tube under nitrogen, 3-nitro-4-(trifluoromethoxy)benzene-1-sulfonyl chloride (492 mg, 1.61 mmol) was added to a stirred solution of tert-butyl 4-amino-4-(4-chlorophenyl)piperidine-1-carboxylate (500 mg, 1.61 mmol), triethylamine (1.1 mL, 8.04 mmol) and 4-dimethylaminopyridine (39 mg, 0.322 mmol) in anhydrous DCM (10 mL), and the mixture was stirred at 40 °C for 16 h. The mixture was washed with DCM and half-saturated NaHCO 3Dilution. The aqueous layer was extracted with DCM, the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 50% EtOAc in heptane) to give the title compound as a yellow solid (388 mg, 40% yield, 98% purity, t r =1.07 min). LCMS (Method B): m / z found 480.1 [M-Boc+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.53(s,1H),7.88(d,J=2.2Hz,1H),7.72(dd,J=8.7,2.3Hz,1H),7.66(dd,J=8.7,1.5Hz,1H),7.16–7.07 (m,2H),7.03–6.95(m,2H),3.70(d,J=13.6Hz,2H),3.31(s,4H),2.39(d,J=13.6Hz,2H),1.87–1.65(m,2H),1.40(s,10H).

[0577] Step 2: Synthesis of tert-butyl 4-((3-amino-4-(trifluoromethoxy)phenyl)sulfonamido)-4-(4-chlorophenyl)piperidine-1-carboxylate

[0578]

[0579] In a sealed tube, a suspension of iron (205 mg, 3.68 mmol) and ammonium chloride (50 mg, 0.937 mmol) in ethanol (3.2 mL) and water (1.6 mL) was stirred at 70 ° C for 1 hour. A suspension of tert-butyl 4-(4-chlorophenyl)-4-[[3-nitro-4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (388 mg, 0.669 mmol) in ethanol (3.2 mL) was added, and the mixture was stirred at 80 ° C for 2 hours. The mixture was cooled to room temperature and filtered through a talc pad. The pad was washed with EtOH, and the filtrate was concentrated. The residue was dissolved in EtOAc and half-saturated NaHCO 3 The aqueous solution was added and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow solid (344 mg, purity 99%, yield 92%, t r =1.00 min). LCMS (Method A): m / z found 450.3 [M-Boc+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.04(s,1H),7.22–7.12(m,2H),7.11–7.02(m,2H),6.97(dd,J=8.6,1.6Hz,1H),6.78(d,J=2.3Hz,1H),6.53(d d,J=8.5,2.3Hz,1H),5.64(s,2H),3.76–3.56(m,2H),3.15(s,2H),2.29(d,J=13.5Hz,2H),1.70(t,J=11.1Hz,2H),1.39(s,10H).

[0580] Step 3: Synthesis of tert-butyl 4-(4-chlorophenyl)-4-((3-(methylamino)-4-(trifluoromethoxy)phenyl)sulfonamido)piperidine-1-carboxylate

[0581]

[0582] In a sealed tube, a solution of tert-butyl 4-[[3-amino-4-(trifluoromethoxy)phenyl]sulfonylamino]-4-(4-chlorophenyl)piperidine-1-carboxylate (150 mg, 0.273 mmol) and paraformaldehyde (9.0 mg, 0.300 mmol) in methanol (3 mL) and acetic acid (300 μL) was stirred at room temperature for 1 hour. Polymer-bound sodium cyanoborohydride (409 mg, 0.818 mmol) was added and the mixture was gently stirred at 55 °C for 22 hours. The mixture was filtered through dicalite, the residue was washed with MeOH, and the filtrate was concentrated. The resulting oil was dissolved in EtOAc. The organic layer was washed with half-saturated Na 2 CO 3 The mixture was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 60% EtOAc in heptane) to give the title compound as a white foam (100 mg, 58% yield, 90% purity, t r =1.04 min). LCMS (Method A): m / z found 586.4 [M+Na] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.04(s,1H),7.17–7.08(m,2H),7.04–6.95(m,3H),6.58(dd,J =8.4,2.2Hz,1H),6.46(d,J=2.2Hz,1H),6.02(d,J=4.8Hz,1H),3.68(d,J=13.4H z,2H),3.22(s,2H),2.75(s,1H),2.65(d,J=4.9Hz,3H),2.33(d,J=13.4Hz,2H), 1.70(t,J=11.3Hz,2H),1.39(s,10H),1.27(d,J=13.4Hz,2H),0.92–0.80(m,1H).

[0583] Step 4: Synthesis of N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(methylamino)-4-(trifluoromethoxy)benzenesulfonamide

[0584]

[0585] In a sealed tube under nitrogen, a solution of tert-butyl 4-(4-chlorophenyl)-4-[[3-(methylamino)-4-(trifluoromethoxy)phenyl]sulfonylamino]piperidine-1-carboxylate (90%, 100 mg, 0.160 mmol) in 1,4-dioxane (1 mL) was stirred at room temperature. 2M HCl / Et 2 O (798 μL, 1.60 mmol), and the mixture was stirred at room temperature for 22 hours. Additional 2M HCl / Et 2 O (399 μL, 0.798 mmol), and the mixture was stirred at room temperature for 22 hours. The mixture was concentrated to dryness, and the crude product was purified by reverse phase flash chromatography (using (ACN + 0.1% AcOH) in (H 2 The desired fractions were concentrated and the residue was dissolved in EtOAc and half-saturated Na 2 CO 3 The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in MeOH and 2M HCl / Et 2 O (130 μL, 4.0 eq.). The mixture was stirred at room temperature for 2 hours and concentrated. The residue was added to Et 2 O and the resulting suspension was filtered. The residue was washed with Et 2 O and dried under reduced pressure at 45°C for 64 hours to obtain the hydrochloride salt of the title compound as a white powder (23 mg, yield 28%, purity 99%, t r=1.35 minutes). LCMS (Method D): m / z found 464.1 [M-HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm 1.96-2.05(m,2H)2.54(br d,J=13.50Hz,2H)2.64(s,3H)3.21(br s,4H)5.95-6.13(m,1H)6.42(d,J=2.20Hz,1H)6.55(dd,J=8.44,2.27Hz,1H)7.01(d,J=8.66Hz,3H)7.08-7.14(m,2H)8.30(s,1H)8.79(br d,J=0.73Hz,2H).

[0586] Example 9: N-(4-(2,5-dichloropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide (9)

[0587]

[0588] Step 1: Synthesis of 1-benzyl-4-(2,5-dichloropyridin-4-yl)piperidine-4-carbonitrile

[0589]

[0590] To a stirred solution of 1-benzylpiperidine-4-carbonitrile (1.17 g, 5.85 mmol) in anhydrous toluene (15.2 mL) was added 1 M 1,1,1,3,3,3-hexamethyldisilazane sodium salt (11 mL, 10.6 mmol) dropwise in a sealed tube at 0°C under nitrogen. The reaction mixture was stirred for 15 minutes, then 2,4,5-trichloropyridine (97%, 1.00 g, 5.32 mmol) was added dropwise. The solution was stirred at 0°C for 2.5 hours, then saturated with NH 4 The mixture was quenched with aqueous Cl solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 10% to 100% of EtOAc in cyclohexane) to give the title compound as a brown oil (172.5 mg, 8% yield, 94% purity, t r =0.56 min). LCMS (Method A): m / z found 346.3 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d 6)δppm 8.59(s,1H)7.64(s,1H)7.30-7.36(m,4H)7.23-7.29(m,1H)3.57(s,2H)2. 97(brd,J=12.91Hz,2H)2.35-2.44(m,4H)2.07(td,J=12.76,3.52Hz,2H).

[0591] Step 2: Synthesis of 1-benzyl-4-(2,5-dichloropyridin-4-yl)piperidine-4-carboxamide

[0592]

[0593] In a sealed tube, a mixture of 1-benzyl-4-(2,5-dichloro-4-pyridyl)piperidine-4-carbonitrile (94%, 170 mg, 0.462 mmol) in sulfuric acid (1.8 mL) and water (0.5 mL) was stirred at 65 ° C for 4 hours. The mixture was poured into ice water and basified to pH = 10 with 1N NaOH aqueous solution. The aqueous layer was extracted three times with DCM. The combined organic layers were dried using a phase separator and concentrated under reduced pressure to give the title compound as a light brown foam (101.9 mg, yield 58%, purity 97%, t r =0.49 min). LCMS (Method A): m / z found 364.4 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 )δ8.40(s,1H),7.58(s,1H),7.36–7.19(m,5H),7.02(s,1H),6.88(s,1H),3.4 3(s,2H),2.58(t,J=8.3Hz,2H),2.34(t,J=8.7Hz,4H),2.09(d,J=3.2Hz,2H).

[0594] Step 3: Synthesis of 1-benzyl-4-(2,5-dichloropyridin-4-yl)piperidin-4-amine

[0595]

[0596] To a stirred solution of 1-benzyl-4-(2,5-dichloro-4-pyridinyl)piperidine-4-carboxamide (101 mg, 0.277 mmol) in acetonitrile (0.75 mL) and water (0.75 mL) was added [bis(trifluoroacetoxy)iodo]benzene (125 mg, 0.291 mmol). The mixture was stirred at room temperature overnight and the acetonitrile was removed under vacuum. 1M aqueous HCl was added to pH 1-2. The aqueous layer was washed twice with DCM. Saturated Na 2 CO 3The aqueous solution was added to the aqueous layer to pH 9. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, filtered through a phase separator and concentrated under reduced pressure to afford the title compound as an orange oil (61.5 mg, yield 64%, purity 98%, t r =0.44 min). LCMS (Method B): m / z found: [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 )δ8.38(s,1H),7.79(s,1H),7.32(d,J=5.0Hz,4H),7.29–7.20(m,1H),3.51(s,2H) ,2.65–2.51(m,4H),2.33(td,J=12.3,4.8Hz,2H),2.07(s,2H),1.66–1.51(m,2H).

[0597] Step 4: Synthesis of N-(1-benzyl-4-(2,5-difluoropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0598]

[0599] In a sealed vial, triethylamine (37 μL, 0.268 mmol) and 4-(trifluoromethoxy)benzenesulfonyl chloride (33 μL, 0.196 mmol) were added sequentially to a stirred solution of 1-benzyl-4-(2,5-dichloro-4-pyridyl)piperidin-4-amine (60 mg, 0.178 mmol) in DCM (1.2 mL) under nitrogen. The reaction mixture was stirred at room temperature overnight. Additional triethylamine (0.037 mL, 0.268 mmol) and 4-(trifluoromethoxy)benzenesulfonyl chloride (51 mg, 0.196 mmol) were added and the mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and washed with saturated NaHCO 3 The aqueous solution was quenched. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (using (0.7N NH 3 / MeOH) in DCM (gradient from 1% to 15%) to give the title compound as an orange oil (58.5 mg, yield 56%, purity 97%, t r =0.70 min). LCMS (Method B): m / z found 560.2 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6)δ8.46(s,1H),8.03(s,1H),7.64–7.56(m,2H),7.52(s,1H),7.44–7.35(m,2H),7.35–7.27(m,2H),7. 24(tt,J=6.3,1.2Hz,3H),3.40(s,2H),2.64–2.51(m,4H),2.26(t,J=11.1Hz,2H),2.03–1.81(m,2H).

[0600] Step 5: Synthesis of N-(4-(2,5-difluoropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide

[0601]

[0602] To a stirred solution of N-[1-benzyl-4-(2,5-dichloro-4-pyridinyl)-4-piperidinyl]-4-(trifluoromethoxy)benzenesulfonamide (58 mg, 0,104 mmol) in DCM (1.2 mL) was added 1-chloroethyl chloroformate (22 μL, 0.207 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (1.3 mL), and the reaction mixture was stirred at 65 °C for 16 hours. The reaction mixture was cooled to room temperature and then washed with saturated NaHCO 3 The aqueous solution was quenched. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (using (0.7N NH 3 The desired fractions were concentrated and purified by reverse phase preparative chromatography using a gradient of acetonitrile in water from 0% to 100% (0.1% AcOH in water). The desired fractions were combined and the acetonitrile was removed in vacuo. The aqueous layer was washed with saturated NaHCO 3 The aqueous solution was basified. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried with a phase separator, and concentrated under reduced pressure. The residue was dissolved in a minimum amount of MeOH. A 2M solution of hydrogen chloride in ether (0.15 mL, 0.300 mmol) was added, followed by ether (5 mL). The mixture was stirred at room temperature for 4 hours. The solid was filtered, washed with ether and dried overnight in vacuo at 50 ° C to give the hydrochloride salt of the title compound as a white powder (8.5 mg, yield 16%, purity 99.49%, t r =1.22 minutes). LCMS (Method D): m / z found 470.1 [M-HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d6 )δ8.79(br s,1H)8.71-8.77(m,2H)7.98(s,1H)7.53-7.57(m,3H)7.36(d,J=8.11Hz,2H)3.21-3.27(m,2H)3.15(br s,2H)2.81(br d,J=12.91Hz,2H)2.10(br t,J=11.66Hz,2H).

[0603] Example 10: N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (10)

[0604]

[0605] Step 1: Synthesis of tert-butyl 4-(phenyl((4-(trifluoromethoxy)phenyl)sulfonamido)methyl)piperidine-1-carboxylate

[0606]

[0607] To a stirred solution of tert-butyl 4-[amino(phenyl)methyl]piperidine-1-carboxylate (95%, 250 mg, 0.818 mmol) in anhydrous DCM (5.4522 mL) in a sealed vial were added triethylamine (0.34 mL, 2.45 mmol) and DMAP (10 mg, 0.0818 mmol) in sequence. 4-(Trifluoromethoxy)benzenesulfonyl chloride (0.17 mL, 0.981 mmol) was then added and the mixture was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature and washed with saturated Na 2 CO 3 The aqueous solution was quenched. The layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were purified by Na 2 SO 4 The crude residue was purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0% to 5%) to afford the title compound as an off-white powder (302 mg, yield 72%, purity 100%, t r =1.07 min). LCMS (Method A): m / z found 415.2 [M-Boc+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.37(d,J=9.1Hz,1H),7.60–7.52(m,2H),7.28–7.21(m,2H),7.03(d,J=1.8Hz,5H),4.01(t,J=8.8Hz,1H),3.92( d,J=13.1Hz,1H),3.79(d,J=13.2Hz,1H),2.58(s,1H),1.80(d,J=13.1Hz,1H),1.72–1.60(m,1H),1.36(s,10H),1.05–0.85(m,3H).

[0608] Step 2: Synthesis of N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide

[0609]

[0610] To a stirred solution of tert-butyl 4-[phenyl-[[4-(trifluoromethoxy)phenyl]sulfonylamino]methyl]piperidine-1-carboxylate (302 mg, 0.587 mmol) in anhydrous ether (1.4673 mL) was added 4M hydrogen chloride (1.5 mL, 5.87 mmol) in dioxane at room temperature under nitrogen in a round bottom flask and the reaction mixture was stirred overnight. The suspension was filtered and washed with Et 2 O, and dried in vacuo at 45°C overnight to give the hydrochloride salt of the title compound as an off-white powder (206.5 mg, yield 78%, t r =1.71 min). LCMS (Method F): m / z found 414.9 [M-HCl+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δppm 1.23(td,J=8.74,3.79Hz,2H)1.29-1.42(m,1H)1.74-1.90(m,1H)2.04(brdd,J=13.94,2.20Hz,1H)2.66-2.86(m,2H)3.15(br d,J=12.72Hz,1H)3.29(br s,1H)4.03(t,J=9.17Hz,1H)6.99-7.06(m,5H)7.22(d,J=8.07Hz,2H)7.55(d,J=8.80Hz,2H)8.25-8.41(m,1H)8.49(d,J=9.78Hz,1H)8.69(br d, J = 9.78 Hz, 1H).

[0611] Example 11: (R)-N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (11)

[0612]

[0613] N-(Phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (128 mg) was purified by chromatography on a Pirkle (R,R) Whelk-01 5 μm (250 x 21.1 mm) column using CO 2 / (MeOH+0.5% IPAm) 90 / 10 mobile phase for chiral separation and purification. The desired fractions were concentrated, diluted with DCM, and washed with saturated NaHCO 3 The solution was washed with brine. The organic layer was dried through a phase separator and concentrated. The free base was diluted in a minimum amount of DCM and HCl 2N / Et 2 O (2.0 equiv.). The mixture was stirred overnight, then filtered and washed with Et 2 O, and dried under reduced pressure at 45°C for 20 hours to obtain the hydrochloride of the title compound as a white powder (27.1 mg, yield 20%, purity 100%, t r =1.32 minutes). LCMS (Method D): m / z found 415.2 [M-HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm 1.16-1.28(m,2H)1.30-1.42(m,1H)1.76-1.87(m,1H)2.04(br dd,J=14.09,2.64Hz,1H)2.67-2.82(m,2H)3.11-3.18(m,1H)3.26-3.30(m,1H)4.02(t,J=9.17Hz,1H)6. 95-7.10(m,5H)7.21(dd,J=8.95,0.88Hz,2H)7.50-7.59(m,2H)8.08-8.82(m,2H)8.48(d,J=9.83Hz,1H).

[0614] Example 12: (S)-N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (12)

[0615]

[0616] N-(Phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (128 mg) was purified by chromatography on a Pirkle (R,R) Whelk-01 5 μm (250 x 21.1 mm) column using CO 2 / (MeOH+0.5% IPAm) 90 / 10 mobile phase for chiral separation and purification. The desired fractions were concentrated, diluted with DCM, and washed with saturated NaHCO 3 The solution was washed with brine. The organic layer was dried through a phase separator and concentrated. The free base was diluted in a minimum amount of DCM and HCl 2N / Et 2 O (2.0 equiv.). The mixture was stirred overnight, then filtered and washed with Et 2 O, and dried under reduced pressure at 45°C for 20 hours to obtain the hydrochloride of the title compound as a white powder (29.2 mg, yield 22%, purity 100%, t r =1.32 minutes). LCMS (Method D): m / z found 415.2 [M-HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm 1.14-1.29(m,2H)1.30-1.43(m,1H)1.76-1.86(m,1H)2.04(br dd,J=14.16,2.71Hz,1H)2.67-2.85(m,2H)3.15(br d,J=12.76Hz,1H)3.27-3.32(m,1H)4.03(t,J=9.17Hz,1H)6.97-7.11(m,5H )7.21(dd,J=8.88,0.81Hz,2H)7.50-7.61(m,2H)8.27-8.65(m,2H)8.48(br d,J=9.83Hz,1H).

[0617] Example 13: (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (13)

[0618]

[0619] Step 1: Synthesis of tert-butyl 4-((R)-(((R)-tert-butylsulfinyl)amino)(4-chlorophenyl)methyl)piperidine-1-carboxylate

[0620]

[0621] In a three-necked round-bottom flask equipped with a thermometer, a solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (1.00 g, 3.07 mmol) in anhydrous THF (15 mL) was stirred at 0°C under nitrogen. Next, 4-chlorophenylmagnesium bromide (3.7 mL, 3.68 mmol, 1 M) was added dropwise over 5 minutes, and the solution was stirred at room temperature for 16 hours. The mixture was stirred at 0°C and quenched by the dropwise addition of half-saturated NaHCO 3 The reaction mixture was quenched with an aqueous solution. The reactant was extracted twice with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 20% to 100% of EtOAc in heptane) to give the title compound as a white foam (545 mg, 38% yield, 97% purity, t r =0.98 min). LCMS (Method A): m / z found 451.4 [M+Na] + ; 1 H-NMR (DMSO-d 6 , 400MHz): δ (ppm) 7.38 (d, J = 0.7Hz, 4H), 5.58 (d, J = 9.8Hz, 1H), 4.07–3.74 (m, 3H), 3.32–3.19 (m, 1H), 2.63 (d, J = 36.5Hz, 2H), 1.91 (d,J=13.2Hz,1H),1.85–1.72(m,1H),1.46–1.32(m,11H),1.32–1.17(m,3H),1.10(s,12H),1.05–0.90(m,2H),0.90–0.82(m,1H).

[0622] Step 2: Synthesis of tert-butyl (R)-4-(amino(4-chlorophenyl)methyl)piperidine-1-carboxylate

[0623]

[0624] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(R)-[[(R)-tert-butylsulfinyl]amino]-(4-chlorophenyl)methyl]piperidine-1-carboxylate (650 mg, 1.52 mmol) in methanol (8 mL) was stirred at room temperature. 4M HCl / dioxane (417 μL, 1.67 mmol) was added and the mixture was stirred at room temperature for 45 minutes. Saturated Na 2 CO 3 The aqueous solution and water were added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH4 OH) in DCM (gradient from 0.4% to 7%) to afford the title compound as a colorless oil (325 mg, yield 66%, purity 100%, t r =0.65 min). LCMS (Method A): m / z found 325.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.40–7.27(m,4H),3.91(dd,J=34.8,13.2Hz,2H),3.56(d,J=7.0Hz,1H),2.52(s,2H),1.94(s, 2H),1.81–1.72(m,1H),1.52(dtd,J=11.6,7.7,3.5Hz,1H),1.37(s,10H),1.27–1.14(m,1H),1.10–0.85(m,2H).

[0625] Step 3: Synthesis of tert-butyl (R)-4-((4-chlorophenyl)((4-(trifluoromethoxy)phenyl)sulfonamido)methyl)piperidine-1-carboxylate

[0626]

[0627] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(R)-amino-(4-chlorophenyl)methyl]piperidine-1-carboxylate (100 mg, 0.308 mmol), triethylamine (172 μL, 1.23 mmol) and 4-dimethylaminopyridine (7.5 mg, 61.6 μmol) in anhydrous DCM (2 mL) was stirred at room temperature, 4-(trifluoromethoxy)benzenesulfonyl chloride (52 μL, 0.308 mmol) was added, and the mixture was stirred at 40 ° C for 16 hours. The mixture was washed with DCM and half-saturated NaHCO 3 The aqueous solution was diluted. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 50% of EtOAc in heptane) to give the title compound as a white solid (125 mg, yield 74%, purity 100%, t r =1.09 min). LCMS (Method A): m / z found 449.1 [M-Boc+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.42(s,1H),7.66–7.53(m,2H),7.36–7.21(m,2H),7.18–6.97(m,4H),4.17–3.63(m, 3H), 2.52 (s, 2H), 1.80 (d, J = 12.6Hz, 1H), 1.64 (q, J = 10.1Hz, 1H), 1.37 (s, 9H), 0.96 (d, J = 13.9Hz, 3H).

[0628] Step 4: Synthesis of (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide

[0629]

[0630] To a stirred solution of tert-butyl 4-[(R)-(4-chlorophenyl)-[[4-(trifluoromethoxy)phenyl]sulfonylamino]methyl]piperidine-1-carboxylate (120 mg, 0.219 mmol) in DCM (1.5 mL) was added 2M HCl / EtOH dropwise at 25 °C. 2 O (1.1 mL, 2.19 mmol). The reaction mixture was stirred at 25 °C for 16 h. Et 2 O, and the resulting suspension was filtered and washed with Et 2 O, and dried under vacuum at 50°C for 24 hours to obtain the hydrochloride salt of the title compound as a white powder (102 mg, yield 96%, purity 99.79%, t r =1.63 minutes). LCMS (Method D): m / z found 449.98 [M+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δppm 8.53(br d,J=9.78Hz,3H)7.52-7.67(m,2H)7.27(dd,J=8.80,0.98Hz,2H)7.08-7.13(m,2H)7.07(s,2H)4.07(t,J=9.17Hz,1H )3.07-3.30(m,2H)2.77(brd,J=2.93Hz,2H)1.94-2.09(m,1H)1.68-1.87(m,1H)1.28-1.41(m,1H)1.09-1.27(m,2H).

[0631] Example 14: (S)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (14)

[0632]

[0633] Step 1: Synthesis of tert-butyl 4-((S)-(((R)-tert-butylsulfinyl)amino)(4-chlorophenyl)methyl)piperidine-1-carboxylate

[0634]

[0635] In a three-necked round-bottom flask equipped with a thermometer, a solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (1.00 g, 3.07 mmol) in anhydrous THF (15 mL) was stirred at 0°C under nitrogen. 1M 4-chlorophenylmagnesium bromide (3.7 mL, 3.68 mmol) was added dropwise over 5 minutes, and the solution was stirred at room temperature for 16 hours. The mixture was stirred at 0°C and saturated NaHCO was added dropwise. 3 The reaction mixture was quenched with an aqueous solution. The reactant was extracted twice with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 20% to 100% of EtOAc in heptane) to give the title compound as a white foam (345 mg, yield 25%, purity 93%, t r =1.00 min). LCMS (Method A): m / z found 451.4 [M+Na] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.40–7.33(m,2H),7.33–7.26(m,2H),5.49(d,J=6.9Hz,1H),4.07–3.92(m,2H),3.87(d, J=13.3Hz,1H),2.52(s,2H),1.99(s,1H),1.87–1.73(m,1H),1.37(s,10H),1.23–1.09(m,2H),1.02(s,11H)

[0636] Step 2: Synthesis of tert-butyl (S)-4-(amino(4-chlorophenyl)methyl)piperidine-1-carboxylate

[0637]

[0638] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-[[(R)-tert-butylsulfinyl]amino]-(4-chlorophenyl)methyl]piperidine-1-carboxylate (510 mg, 1.19 mmol) in methanol (6 mL) was stirred at room temperature. 4M HCl / dioxane (327 μL, 1.31 mmol) was added and the mixture was stirred at room temperature for 45 minutes. Saturated Na 2CO 3 The aqueous solution and water were added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 0.4% to 7%) to afford the title compound as a colorless oil (282 mg, yield 73%, purity 100%, t r =0.65 min). LCMS (Method A): m / z found 325.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.43–7.23(m,4H),3.91(dd,J=34.8,13.0Hz,2H),3.56(d,J=7.0Hz,1H),2.52(s,2H), 1.94–1.69(m,3H),1.51(tdt,J=11.2,7.1,3.4Hz,1H),1.37(s,9H),1.29–1.14(m,1H),1.11–0.85(m,2H)

[0639] Step 3: Synthesis of tert-butyl (S)-4-((4-chlorophenyl)((4-(trifluoromethoxy)phenyl)sulfonamido)methyl)piperidine-1-carboxylate

[0640]

[0641] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-amino-(4-chlorophenyl)methyl]piperidine-1-carboxylate (100 mg, 0.308 mmol), triethylamine (172 μL, 1.23 mmol) and 4-dimethylaminopyridine (7.5 mg, 61.6 μmol) in anhydrous DCM (2 mL) was stirred at room temperature, 4-(trifluoromethoxy)benzenesulfonyl chloride (52 μL, 0.308 mmol) was added, and the mixture was stirred at 40 ° C for 16 hours. The mixture was washed with DCM and half-saturated NaHCO 3 The aqueous solution was diluted. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 50% of EtOAc in heptane) to give the title compound as a colorless oil (130 mg, yield 76%, purity 100%, t r =1.09 min). LCMS (Method A): m / z found 449.1 [M-Boc+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.42(s,1H),7.65–7.53(m,2H),7.36–7.23(m,2H),7.16–6.98(m,4H),4.17–3.67( m,3H),2.52(s,2H),1.80(d,J=13.1Hz,1H),1.64(q,J=10.4Hz,1H),1.37(s,9H),1.11–0.74(m,3H).

[0642] Step 4: Synthesis of (S)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide

[0643]

[0644] To a stirred solution of tert-butyl 4-[(S)-(4-chlorophenyl)-[[4-(trifluoromethoxy)phenyl]sulfonylamino]methyl]piperidine-1-carboxylate (125 mg, 0.228 mmol) in DCM (1.5 mL) was added 2M HCl / EtOH dropwise at 25 °C. 2 O (1.1 mL, 2.28 mmol). The reaction mixture was stirred at 25 °C for 2 h. Et 2 O, and the resulting suspension was filtered and washed with Et 2 O, and dried under vacuum at 50°C for 24 hours to obtain the title compound as a white powder (103 mg, yield 93%, purity 99.72%, t r = 1.63 min). LCMS (Method D); 1 H-NMR (500 MHz, DMSO-d 6 )δppm 1.17-1.29(m,2H)1.30-1.42(m,1H)1.73-1.87(m,1H)2.02(br dd,J=13.94,2.45Hz,1H)2.66-2.84(m,2H)3.09-3.20(m,1H)3.24-3.30(m,1H)4.07(t,J=9.1 7Hz, 1H) 7.02-7.14 (m, 4H) 7.26 (dd, J = 8.80, 0.98Hz, 2H) 7.53-7.62 (m, 2H) 8.28-8.76 (m, 3H).

[0645] Example 15: (S)-N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide (15)

[0646]

[0647] Step 1: Synthesis of tert-butyl (S,E)-4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate

[0648]

[0649] In a round-bottom flask under nitrogen, a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.7 g, 13.0 mmol) in anhydrous THF (12 mL) was stirred at room temperature. A solution of (S)-tert-butylsulfenamide (1.5 g, 12.4 mmol) in anhydrous THF (12 mL) was added, followed by titanium ethoxide (13 mL, 61.9 mmol), and the solution was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water (200 mL), the resulting suspension was stirred at room temperature for 10 minutes, and filtered through talc. The residue was washed with EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to give the title compound as a beige solid (3.8 g, yield 86%, purity 100%, t r =0.91 min). LCMS (Method B): m / z found 339.2 [M+Na] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.91(d,J=3.7Hz,1H),3.90(d,J=13.1Hz,2H),2.86(s,2 H), 2.75–2.64 (m, 1H), 1.84 (t, J = 11.8Hz, 2H), 1.39 (s, 11H), 1.10 (s, 9H).

[0650] Step 2: Synthesis of tert-butyl 4-((S)-(((S)-tert-butylsulfinyl)amino)(5-chloropyridin-2-yl)methyl)piperidine-1-carboxylate

[0651]

[0652] In a three-necked round-bottom flask equipped with a thermometer, 2-bromo-5-chloropyridine (912 mg, 4.74 mmol) was dissolved in anhydrous Et 2 O (30 mL) solution was stirred at -78 °C. 1.6 M butyl lithium (3.3 mL, 5.21 mmol) was added dropwise over 1 min, and the mixture was stirred at -78 °C for 1 h. 4-[(E)-[(S)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 4.74 mmol) was added dropwise over 3 min. 2O (12 mL) solution, and the solution was stirred at -78 °C for 2 h. The mixture was washed with saturated NH 4 The reaction mixture was quenched with aqueous Cl and washed with EtOAc and H 2 The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 90% EtOAc in heptane) to give the title compound as an off-white foam (280 mg, 13% yield, 94% purity, t r =0.94 min). LCMS (Method A): m / z found 430.4 [M+H] + ; 1 H-NMR (DMSO-d 6 , 400MHz): δ (ppm) 8.54 (d, J = 2.5Hz, 1H), 7.92 (dd, J = 8.4, 2.5Hz, 1H), 7.43 (d, J = 8.4Hz, 1H), 5.58 (d, J = 7.9Hz, 1H), 4.11 (t, J = 7.9Hz, 1H), 3.97(d,J=13.5Hz,1H),3.91–3.79(m,1H),2.75–2.53(m,2H),1.90(dd,J=15.1,10.8Hz,2H),1.37(s,9H),1.15–1.04(m,2H),1.01(s,9H).

[0653] Step 3: Synthesis of tert-butyl (S)-4-(amino(5-chloropyridin-2-yl)methyl)piperidine-1-carboxylate

[0654]

[0655] A solution of tert-butyl 4-[(S)-[[(S)-tert-butylsulfinyl]amino]-(5-chloro-2-pyridinyl)methyl]piperidine-1-carboxylate (280 mg, 0.612 mmol) in MeOH (3 mL) was stirred at room temperature. A 4M solution of HCl in dioxane (0.16 mL, 0.643 mmol) was added and the mixture was stirred at room temperature for 16 hours. Saturated Na 2 CO 3 The aqueous solution and water were added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 1% to 10%) to afford the title compound as a colorless oil (120 mg, yield 58%, purity 97%, t r=0.61 min). LCMS (Method A): m / z found 326.4 [M+H] + ; 1 H-NMR (DMSO-d 6 , 400MHz): δ (ppm) 8.54 (d, J = 2.5Hz, 1H), 7.86 (dd, J = 8.4, 2.5Hz, 1H), 7.43 (d, J = 8.4Hz, 1H), 3.91 (dd, J = 24.6, 13.3Hz, 2H), 3.6 4(d,J=6.4Hz,1H),2.58(s,2H),1.96(s,2H),1.69(tt,J=13.8,3.7Hz,2H),1.37(s,9H),1.25–1.18(m,1H),1.15–1.00(m,2H).

[0656] Step 4: Synthesis of (S)-tert-butyl 4-((5-chlorophenyl-2-yl)((4-(trifluoromethoxy)phenyl)sulfonamido)methyl)piperidine-1-carboxylate

[0657]

[0658] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-amino-(5-chloro-2-pyridinyl)methyl]piperidine-1-carboxylate (92%, 100 mg, 0.282 mmol), triethylamine (157 μL, 1.13 mmol) and 4-dimethylaminopyridine (1.7 mg, 0.0141 mmol) in anhydrous DCM (2 mL) was stirred at room temperature, then 4-(trifluoromethoxy)benzenesulfonyl chloride (97%, 49 μL, 0.282 mmol) was added and the mixture was stirred at 40 °C for 3.5 hours. The mixture was washed with DCM and half-saturated NaHCO 3 The aqueous solution was diluted. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 0% to 30% of EtOAc in heptane) to give the title compound as a white foam (107.3 mg, yield 69%, purity 100%, t r =1.05 min). LCMS (Method A): m / z found 450.3 [M-Boc+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.45(s,1H),8.31(d,J=2.5Hz,1H),7.76–7.44(m,3H),7.42–7.26(m,2H),7.15(d,J=8.4Hz,1H),4.1 6(d,J=8.1Hz,1H),3.85(dd,J=40.8,12.2Hz,2H),2.68(bs,2H),1.93–1.67(m,2H),1.37(s,9H),0.98(d,J=3.8Hz,3H).

[0659] Step 5: Synthesis of (S)-N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide

[0660]

[0661] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-(5-chloro-2-pyridinyl)-[[4-(trifluoromethoxy)phenyl]sulfonylamino]methyl]piperidine-1-carboxylate (107 mg, 0.195 mmol) in anhydrous DCM (1.3 mL) was stirred at room temperature. 2M HCl / Et 2 O (975 μL, 1.95 mmol), and the mixture was stirred at room temperature for 5 hours. 2 O diluted the mixture and filtered the suspension. The residue was washed with Et 2 O and dried under reduced pressure at 45°C overnight to give the hydrochloride of the title compound as a white powder (55 mg, yield 58%, purity 100%, t r =1.67 minutes). LCMS (Method D): m / z found 450.0 [M-H+HCl] + ; 1 H-NMR (DMSO-d 6 ,600MHz): δ(ppm)8.66(br d,J=10.3Hz,1H),8.56(d,J=9.8Hz,1H),8.26-8.34(m,2H),7.58-7.63(m,3H),7.30(d,J=8.2Hz,2H),7.17(dd,J=8.4 ,0.6Hz,1H),4.19(dd,J=9.8,8.3Hz,1H),3.10-3.31(m,2H),2.69-2.81(m,2H),1.90-1.98(m,2H),1.15-1.44(m,3H).

[0662] Example 16: (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide (16)

[0663]

[0664] Step 1: Synthesis of tert-butyl 4-((R)-(((R)-tert-butylsulfinyl)amino)(4-chlorophenyl)methyl)piperidine-1-carboxylate

[0665]

[0666] In a three-necked round-bottom flask equipped with a thermometer, a solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (1.00 g, 3.07 mmol) in anhydrous THF (15 mL) was stirred at 0°C under nitrogen. Next, 4-chlorophenylmagnesium bromide (3.7 mL, 3.68 mmol, 1 M) was added dropwise over 5 minutes, and the solution was stirred at room temperature for 16 hours. The mixture was stirred at 0°C and quenched by the dropwise addition of half-saturated NaHCO 3 The reaction mixture was quenched with an aqueous solution. The reactant was extracted twice with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 20% to 100% of EtOAc in heptane) to give the title compound as a white foam (545 mg, 38% yield, 97% purity, t r =0.98 min). LCMS (Method A): m / z found 451.4 [M+Na] + ; 1 H-NMR (DMSO-d 6 , 400MHz): δ (ppm) 7.38 (d, J = 0.7Hz, 4H), 5.58 (d, J = 9.8Hz, 1H), 4.07–3.74 (m, 3H), 3.32–3.19 (m, 1H), 2.63 (d, J = 36.5Hz, 2H), 1.91 (d,J=13.2Hz,1H),1.85–1.72(m,1H),1.46–1.32(m,11H),1.32–1.17(m,3H),1.10(s,12H),1.05–0.90(m,2H),0.90–0.82(m,1H).

[0667] Step 2: Synthesis of tert-butyl (R)-4-(amino(4-chlorophenyl)methyl)piperidine-1-carboxylate

[0668]

[0669] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(R)-[[(R)-tert-butylsulfinyl]amino]-(4-chlorophenyl)methyl]piperidine-1-carboxylate (650 mg, 1.52 mmol) in methanol (8 mL) was stirred at room temperature. 4M HCl / dioxane (417 μL, 1.67 mmol) was added and the mixture was stirred at room temperature for 45 minutes. Saturated Na 2 CO 3 The aqueous solution and water were added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 0.4% to 7%) to afford the title compound as a colorless oil (325 mg, yield 66%, purity 100%, t r =0.64 min). LCMS (Method A): m / z found 325.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.40–7.27(m,4H),3.91(dd,J=34.8,13.2Hz,2H),3.56(d,J=7.0Hz,1H),2.52(s,2H),1.94(s, 2H),1.81–1.72(m,1H),1.52(dtd,J=11.6,7.7,3.5Hz,1H),1.37(s,10H),1.27–1.14(m,1H),1.10–0.85(m,2H).

[0670] Step 3: Synthesis of tert-butyl (R)-4-((4-chlorophenyl)((6-isopropoxypyridine)-3-sulfonamido)methyl)piperidine-1-carboxylate

[0671]

[0672] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(R)-amino-(4-chlorophenyl)methyl]piperidine-1-carboxylate (100 mg, 0.308 mmol), triethylamine (172 μL, 1.23 mmol) and 4-dimethylaminopyridine (7.5 mg, 61.6 μmol) in anhydrous DCM (2 mL) was stirred at room temperature, 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (76 mg, 0.308 mmol) was added, and the mixture was stirred at 40 ° C for 16 hours. The mixture was washed with DCM and half-saturated NaHCO 3The aqueous solution was diluted. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 50% of EtOAc in heptane) to give the title compound as a colorless oil (165 mg, yield 89%, purity 87%, t r =1.06 min). LCMS (Method A): m / z found 546.5 [M+Na] + .

[0673] Step 4: Synthesis of (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide

[0674]

[0675] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(R)-(4-chlorophenyl)-[(6-isopropoxy-3-pyridinyl)sulfonylamino]methyl]piperidine-1-carboxylate (165 mg, 0.315 mmol) in anhydrous DCM (2 mL) was stirred at room temperature. 2M HCl / Et 2 O (1.6 mL, 3.15 mmol), and the mixture was stirred at room temperature for 16 h. 2 O diluted the mixture and filtered the suspension. The residue was washed with Et 2 O and dried under reduced pressure at 45°C for 16 hours to obtain the hydrochloride salt of the title compound as a white powder (102 mg, yield 63%, purity 97.5%, t r =1.32 minutes). LCMS (Method D): m / z found 424.2 [M-HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6)δppm 8.74-8.86(m,1H)8.45(d,J=9.98Hz,2H)8.12(dd,J=2.57,0.66Hz,1H)7.59-7.65(m,1H)7.06-7 .17(m,4H)6.57(dd,J=8.80,0.59Hz,1H)5.18(spt,J=6.19Hz,1H)4.06(t,J=9.32Hz,1H)3.29(br d,J=12.62Hz,1H)3.15(brd,J=12.47Hz,1H)2.64-2.85(m,2H)2.04(br d,J=12.47Hz,1H)1.71-1.85(m,1H)1.31-1.43(m,1H)1.26(dd,J=6.16,1.17Hz,7H)1.17-1.24(m,2H).

[0676] Example 17: (S)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide (17)

[0677]

[0678] Step 1: Synthesis of tert-butyl 4-((S)-(((R)-tert-butylsulfinyl)amino)(4-chlorophenyl)methyl)piperidine-1-carboxylate

[0679]

[0680] In a three-necked round-bottom flask equipped with a thermometer, a solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (1.00 g, 3.07 mmol) in anhydrous THF (15 mL) was stirred at 0°C under nitrogen. 1M 4-chlorophenylmagnesium bromide (3.7 mL, 3.68 mmol) was added dropwise over 5 minutes, and the solution was stirred at room temperature for 16 hours. The mixture was stirred at 0°C and saturated NaHCO was added dropwise. 3 The reaction mixture was quenched with an aqueous solution. The reactant was extracted twice with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 20% to 100% of EtOAc in heptane) to give the title compound as a white foam (345 mg, yield 25%, purity 93%, t r =1.00 min). LCMS (Method A): m / z found 451.4 [M+Na] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)7.40–7.33(m,2H),7.33–7.26(m,2H),5.49(d,J=6.9Hz,1H),4.07–3.92(m,2H),3.87(d,J =13.3Hz,1H),2.52(s,2H),1.99(s,1H),1.87–1.73(m,1H),1.37(s,10H),1.23–1.09(m,2H),1.02(s,11H).

[0681] Step 2: Synthesis of tert-butyl (S)-4-(amino(4-chlorophenyl)methyl)piperidine-1-carboxylate

[0682]

[0683] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-[[(R)-tert-butylsulfinyl]amino]-(4-chlorophenyl)methyl]piperidine-1-carboxylate (510 mg, 1.19 mmol) in methanol (6 mL) was stirred at room temperature. 4M HCl / dioxane (327 μL, 1.31 mmol) was added and the mixture was stirred at room temperature for 45 minutes. Saturated Na 2 CO 3 The aqueous solution and water were added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 0.4% to 7%) to afford the title compound as a colorless oil (282 mg, yield 73%, purity 100%, t r =0.65 min). LCMS (Method A): m / z found 325.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.43–7.23(m,4H),3.91(dd,J=34.8,13.0Hz,2H),3.56(d,J=7.0Hz,1H),2.52(s,2H),1 .94–1.69(m,3H),1.51(tdt,J=11.2,7.1,3.4Hz,1H),1.37(s,9H),1.29–1.14(m,1H),1.11–0.85(m,2H).

[0684] Step 3: Synthesis of tert-butyl (S)-4-((4-chlorophenyl)((6-isopropoxypyridine)-3-sulfonamido)methyl)piperidine-1-carboxylate

[0685]

[0686] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-amino-(4-chlorophenyl)methyl]piperidine-1-carboxylate (100 mg, 0.308 mmol), triethylamine (172 μL, 1.23 mmol) and 4-dimethylaminopyridine (7.5 mg, 61.6 μmol) in anhydrous DCM (2 mL) was stirred at room temperature, 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (76 mg, 0.308 mmol) was added, and the mixture was stirred at 40 ° C for 16 hours. The mixture was washed with DCM and half-saturated NaHCO 3 The aqueous solution was diluted. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 50% of EtOAc in heptane) to give the title compound as a colorless oil (165 mg, yield 95%, purity 93%, t r =1.06 min). LCMS (Method A): m / z found 546.4 [M+Na] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.32(d,J=8.3Hz,1H),8.13(dd,J=2.6,0.7Hz,1H),7.63(d d,J=8.8,2.6Hz,1H),7.20–7.01(m,4H),6.60(dd,J=8.8,0.7Hz,1H),5.20(he pt,J=6.2Hz,1H),4.14–3.68(m,3H),2.75–2.51(m,2H),1.84(d,J=12.7Hz,1H ), 1.63 (t, J = 10.7Hz, 1H), 1.37 (s, 9H), 1.32–1.26 (m, 6H), 1.09–0.90 (m, 3H).

[0687] Step 4: Synthesis of (S)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide

[0688]

[0689] In a sealed tube under nitrogen, a solution of tert-butyl 4-[(S)-(4-chlorophenyl)-[(6-isopropoxy-3-pyridinyl)sulfonylamino]methyl]piperidine-1-carboxylate (165 mg, 0.315 mmol) in anhydrous DCM (2 mL) was stirred at room temperature. 2M HCl / Et 2O (1.6 mL, 3.15 mmol), and the mixture was stirred at room temperature for 16 h. 2 O diluted the mixture and filtered the suspension. The residue was washed with Et 2 O and dried under reduced pressure at 45°C for 16 hours to obtain the dihydrochloride salt of the title compound as a white powder (110 mg, yield 67%, purity 96.3%, t r =1.33 minutes). LCMS (Method D): m / z found 424.2 [M-HCl+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δppm 1.21-1.30(m,8H)1.34-1.43(m,1H)1.75-1.83(m,1H)2.04(br d,J=12.96Hz,1H)2.68-2.81(m,2H)3.14(br d,J=12.47Hz,1H)3.29(brd,J=1.00Hz,1H)4.06(t,J=9.41Hz,1H)5.18(spt,J=6.19Hz,1H)6.57(d,J=8.80H z,1H)7.09-7.14(m,4H)7.62(dd,J=8.80,2.69Hz,1H)8.12(d,J=2.45Hz,1H)8.46(d,J=10.03Hz,1H)8.50(br d,J=10.52Hz,1H)8.86(br d,J=10.27Hz,1H).

[0690] Example 18: (R)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide (18)

[0691]

[0692] Step 1: Synthesis of tert-butyl 4-((R)-(((R)-tert-butylsulfinyl)amino)(phenyl)methyl)piperidine-1-carboxylate

[0693]

[0694] To a stirred solution of tert-butyl 4-[(E)-[(R)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (500 mg, 1.53 mmol) in anhydrous THF (7.5 mL) was added 1 M phenylmagnesium bromide (1.8 mL, 1.84 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours and then at 25°C for 12 hours. The mixture was heated to 40°C with saturated NH 4The reaction was quenched with aqueous Cl solution and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated Na 2 CO 3 The mixture was washed with water, then with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 10% to 80% EtOAc in cyclohexane) to give the title compound as a colorless oil (237 mg, 36% yield, 93% purity, t r =0.93 min). LCMS (Method A): m / z found 417.5 [M+Na] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.38–7.28(m,4H),7.26–7.19(m,1H),5.51(d,J=9.5Hz,1H),3.96(d,J=12.5Hz,1H),3.86(d,J=5.9Hz,1H),2.58(s,2H ),1.94–1.87(m,1H),1.87–1.74(m,1H),1.42–1.38(m,1H),1.37(s,10H),1.10(s,9H),1.09–1.03(m,1H),0.95(qd,J=12.6,4.4Hz,1H).

[0695] Step 2: Synthesis of tert-butyl (R)-4-(amino(phenyl)methyl)piperidine-1-carboxylate

[0696]

[0697] To a stirred solution of tert-butyl 4-[(R)-[[(R)-tert-butylsulfinyl]amino]-phenyl-methyl]piperidine-1-carboxylate (237 mg, 0.559 mmol) in methanol (3 mL) was added 4M HCl / dioxane (150 μL, 0.614 mmol) dropwise at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was washed with saturated Na 2 CO 3 The aqueous solution was basified and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (using MeOH (NH 3 0.7 M) in DCM (gradient from 1% to 15%) to afford the title compound as a colorless oil (76 mg, yield 46%, purity 98%, t r =0.6 min). LCMS (Method A): m / z found 291.2 [M+H] +; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.29(d,J=4.4Hz,4H),7.20(dt,J=8.7,4.1Hz,1H),3.96(d, J=13.2Hz,1H),3.86(d,J=13.3Hz,1H),3.54(d,J=7.1Hz,1H),2.57(s,2H),1. 90(s,2H),1.80(dt,J=13.0,2.9Hz,1H),1.54(tdt,J=11.2,7.0,3.5Hz,1H),1 .37(s,9H),1.22(dt,J=13.2,3.2Hz,1H),0.99(dqd,J=29.5,12.6,4.4Hz,2H).

[0698] Step 3: Synthesis of tert-butyl (R)-4-(((6-isopropoxypyridine)-3-sulfonamido)(phenyl)methyl)piperidine-1-carboxylate

[0699]

[0700] A sealed vial was charged with tert-butyl 4-[(R)-amino(phenyl)methyl]piperidine-1-carboxylate (76 mg, 0.256 mmol), DMAP (6.3 mg, 51, 3 μmol) and triethylamine (140 μL, 1.03 mmol) in DCM (2.3 mL). 6-(Propan-2-yloxy)pyridine-3-sulfonyl chloride (64 mg, 0.256 mmol) was then added and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was diluted with DCM and saturated NH 4 Cl aqueous solution. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine and purified by Na 2 SO 4 The crude residue was purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0% to 5%) to afford the title compound as a light orange solid (64.5 mg, yield 48%, purity 94%, t r =1.02 min). LCMS (Method A): m / z found 434.4 [M-tBu+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.28(d,J=9.5Hz,1H),8.15(d,J=2.6Hz,1H),7.59(dd,J=8.7,2.6H z,1H),7.08–7.01(m,5H),6.54(d,J=8.8Hz,1H),5.18(p,J=6.2Hz,1H),4.06–3.98(m ,1H),3.97–3.88(m,1H),3.86–3.73(m,1H),2.51(d,J=1.9Hz,1H),1.83(d,J=13.1Hz ,1H),1.66(s,1H),1.37(s,10H),1.24(dd,J=6.2,1.7Hz,6H),1.01(d,J=12.5Hz,3H).

[0701] Step 4: Synthesis of (R)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide

[0702]

[0703] To a stirred solution of tert-butyl 4-[(R)-[(6-isopropoxy-3-pyridinyl)sulfonylamino]-phenyl-methyl]piperidine-1-carboxylate (65 mg, 0.124 mmol) in DCM (1 mL) was added dropwise 2M HCl / Et 2 O (0.62 mL, 1.24 mmol). The reaction mixture was stirred at 25 °C for 4 h. Et 2 O, and the resulting suspension was filtered and washed with Et 2 O, and dried in vacuo at 50°C overnight to give the title compound as an off-white powder (45 mg, yield 81%, purity 95.33%, t r =1.32 minutes). LCMS (Method D): m / z found 390 [M+H] + ; 1 H-NMR (500 MHz, DMSO-d 6)δppm 8.54-8.70(m,1H)8.39(d,J=10.03Hz,1H)8.19-8.33(m,1H)8.15(d,J=2.69Hz,1H)7.58(dd,J=8.80,2 .69Hz,1H)7.07(s,5H)6.51(d,J=8.80Hz,1H)5.03-5.27(m,1H)4.03(dd,J=9.66,8.93Hz,1H)3.29(br s,1H)3.16(br d,J=11.74Hz,1H)2.65-2.90(m,2H)1.97-2.16(m,1H)1.74-1.87(m,1H)1.34-1.44(m,1H)1.24(dd,J=6.24,2.08Hz,8H).

[0704] Example 19: (S)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide (19)

[0705]

[0706] Step 1: Synthesis of tert-butyl (S,E)-4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate

[0707]

[0708] A solution of (S)-(-)-2-methyl-2-propylsulfenamide (1.00 g, 8.09 mmol) in THF (8 mL) and titanium ethoxide (8.8 mL, 40.4 mmol) were added sequentially to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1.81 g, 8.49 mmol) in THF (8 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and the suspension was filtered. The precipitate was extracted twice with EtOAc. The filtrate was extracted with EtOAc. The combined organic layer was filtered through MgSO 4 The residue was dried under vacuum to give the title compound as a pale yellow solid (2.23 g, yield 77%, purity 88%, t r =0.9 min). LCMS (Method A): m / z found 339.4 [M+Na] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)7.92(d,J=3.7Hz,1H),3.98–3.84(m,2H),2.87(s,2H),2.70(tq,J =11.1,3.8Hz,1H),1.90–1.72(m,2H),1.42–1.35(m,11H),1.11(s,6H),1.08(s,3H).

[0709] Step 2: Synthesis of tert-butyl 4-((S)-(((S)-tert-butylsulfinyl)amino)(phenyl)methyl)piperidine-1-carboxylate

[0710]

[0711] To a stirred solution of tert-butyl 4-[(E)-[(S)-tert-butylsulfinyl]iminomethyl]piperidine-1-carboxylate (88%, 500 mg, 1.39 mmol) in anhydrous THF (7 mL) was added 1 M phenylmagnesium bromide (1.5 mL, 1.53 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours and then at 25°C for 16 hours. The mixture was heated to 40°C with saturated NH 4 The reaction was quenched with aqueous Cl solution and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated Na 2 CO 3 The mixture was washed with water, then with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 10% to 70% EtOAc in cyclohexane) to give the title compound as a white solid (175 mg, 31% yield, 97% purity, t r =1.7 minutes). LCMS (Method B): m / z found 417.3 [M+Na] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.37–7.26(m,4H),7.22(t,J=7.0Hz,1H),5.51(d,J=9.5Hz,1H),4.14–3.72(m,3 H),2.73–2.43(m,1H),1.90(d,J=13.0Hz,1H),1.86–1.74(m,1H),1.37(s,9H),1.24–0.86(m,13H).

[0712] Step 3: Synthesis of tert-butyl 4-[(S)-amino(phenyl)methyl]piperidine-1-carboxylate

[0713]

[0714] To a stirred solution of tert-butyl 4-[(S)-[[(S)-tert-butylsulfinyl]amino]-phenyl-methyl]piperidine-1-carboxylate (171 mg, 0.420 mmol) in methanol (2 mL) was added 4M HCl / dioxane (120 μL, 0.462 mmol) dropwise at 25°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction was washed with saturated Na 2 CO 3 The aqueous solution was basified and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using MeOH (0.7 M NH 3 ) in DCM with a gradient from 1% to 15%) to afford the title compound as a colorless oil (93 mg, yield 68%, purity 89%, t r =0.6 min). LCMS (Method B): m / z found 291.2 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.29(d,J=4.4Hz,4H),7.24–7.15(m,1H),3.91(dd,J=38.3,13.1Hz,2H),3.53(d,J=7.1Hz,1H),2. 57(s,2H),1.93–1.69(m,3H),1.53(dtd,J=11.4,7.7,3.6Hz,1H),1.37(s,9H),1.27–1.16(m,1H),1.11–0.88(m,2H).

[0715] Step 4: Synthesis of tert-butyl (S)-4-(((6-isopropoxypyridine)-3-sulfonamido)(phenyl)methyl)piperidine-1-carboxylate

[0716]

[0717] A sealed vial was charged with tert-butyl 4-[(S)-amino(phenyl)methyl]piperidine-1-carboxylate (89%, 93 mg, 0.285 mmol), DMAP (7.0 mg, 57,0 μmol) and triethylamine (160 μL, 1.14 mmol) in DCM (2.5 mL). 6-(Propan-2-yloxy)pyridine-3-sulfonyl chloride (71 mg, 0.285 mmol) was then added and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was diluted with DCM and saturated NH 4 Cl aqueous solution. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine and purified by Na 2 SO4 The crude residue was purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0% to 5%) to afford the title compound as a white powder (63.6 mg, yield 45%, purity 99%, t r =1.02 min). LCMS (Method A): m / z found 434.5 [M-tBu+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.29(d,J=9.3Hz,1H),8.16(d,J=2.5Hz,1H),7.60(dd,J=8.8,2.6Hz ,1H),7.12–7.00(m,5H),6.55(d,J=8.8Hz,1H),5.18(p,J=6.2Hz,1H),4.02(t,J=8.8Hz ,1H),3.94(d,J=13.1Hz,1H),3.80(d,J=13.1Hz,1H),2.67(s,1H),1.84(d,J=13.2Hz,1 H),1.67(d,J=10.4Hz,1H),1.37(s,9H),1.25(dd,J=6.2,1.6Hz,6H),1.10–0.87(m,3H)

[0718] Step 5: Synthesis of (S)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide

[0719]

[0720] To a stirred solution of tert-butyl 4-[(S)-[(6-isopropoxy-3-pyridinyl)sulfonylamino]-phenyl-methyl]piperidine-1-carboxylate (64 mg, 0.129 mmol) in DCM (860 μL) was added dropwise 2M HCl / Et 2 O (640 μL, 1.29 mmol). The reaction mixture was stirred at 25 °C for 3 h. Et 2 O, and the resulting suspension was filtered and washed with Et 2 O, and dried in vacuo at 50°C overnight to give the hydrochloride of the title compound as a white powder (40 mg, yield 71%, purity 97.13%, t r =1.58 min). LCMS (Method F): m / z found 390 [M+H] + ; 1 H-NMR (500 MHz, DMSO-d 6)δppm 1.21-1.28(m,8H)1.31-1.41(m,1H)1.77-1.85(m,1H)2.01-2.08(m,1H)2.70-2.83(m,2H)3.16(br d,J=12.72Hz,1H)3.27-3.30(m,1H)4.01-4.06(m,1H)5.16(quin,J=6.17Hz,1H)6.52(d,J=8.80 Hz,1H)7.04-7.10(m,5H)7.58(dd,J=8.80,2.45Hz,1H)8.15(d,J=2.72Hz,1H)8.18-8.74(m,3H).

[0721] Example 20: N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (20)

[0722]

[0723] Step 1: Synthesis of tert-butyl 4-(2-(2,4-difluorophenyl)-2-oxoethyl)piperazine-1-carboxylate

[0724]

[0725] In a sealed tube, under nitrogen, a solution of tert-butyl piperazine-1-carboxylate (1.43 g, 7.66 mmol), triethylamine (652 μL, 4.68 mmol) and 2-bromo-1-(2,4-difluorophenyl)ethanone (1.00 g, 4.25 mmol) in DCM (9.4 mL) was stirred at room temperature. The mixture was stirred in an ice-water bath, and DMAP (26 mg, 0.213 mmol) was added. The cold bath was removed, and the mixture was stirred at room temperature for 16 hours. Half-saturated NaHCO was added. 3 The aqueous solution was added and the mixture was stirred at room temperature for 5 minutes. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 1% to 10%) to afford the title compound as an orange oil (1.13 mg, yield 51%, purity 66%, t r =0.55 min). LCMS (Method A): m / z found 341.4 [M+H] + ; 1H-NMR (400MHz, DMSO) δ7.93 (td, J=8.6, 6.7Hz, 1H), 7.41 (ddd, J=11.6, 9.3, 2.4Hz, 1H), 7.28 –7.19(m,1H),3.77(d,J=2.6Hz,2H),3.29(t,J=5.1Hz,4H),2.49–2.42(m,4H),1.40(s,9H).

[0726] Step 2: Synthesis of tert-butyl 4-(2-amino-2-(2,4-difluorophenyl)ethyl)piperazine-1-carboxylate

[0727]

[0728] In a sealed tube under nitrogen, polymer-bound sodium cyanoborohydride (3.34 g, 6.68 mmol) was added to a stirred solution of tert-butyl 4-[2-(2,4-difluorophenyl)-2-oxo-ethyl]piperazine-1-carboxylate (1.14 g, 3.34 mmol) and ammonium acetate (2.57 g, 33.4 mmol) in acetic acid (2 mL) and methanol (20.4 mL). The mixture was stirred at 50 °C overnight and filtered. The residue was washed with MeOH and the filtrate was concentrated and then dissolved in DCM and saturated NaHCO 3 The organic layer was washed with saturated NaHCO 3 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 (MeOH + 2% NH 4 OH) in DCM (gradient from 1% to 5%) to afford the title compound as a yellow oil (376.6 mg, yield 31%, purity 95%, t r =0.56 min). LCMS (Method A): m / z found 342.4 [M+H] + ; 1 H-NMR (400MHz, DMSO) δ7.64(td,J=8.6,6.8Hz,1H),7.13(ddd,J=10.8,9.4,2.6Hz,1H),7.06(t t, J=8.5, 1.7Hz, 1H), 4.32 (dd, J=8.7, 5.1Hz, 1H), 3.30 (s, 4H), 2.48–2.17 (m, 8H), 1.39 (s, 9H).

[0729] Step 3: Synthesis of tert-butyl 4-(2-(2,4-difluorophenyl)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)ethyl)piperazine-1-carboxylate

[0730]

[0731] To a stirred solution of tert-butyl 4-[2-amino-2-(2,4-difluorophenyl)ethyl]piperazine-1-carboxylate (150 mg, 0.439 mmol) in DCM (2.8 mL) was added triethylamine (92 μL, 0.659 mmol) and 4-(trifluoromethoxy)benzenesulfonyl chloride (82 μL, 0.483 mmol) in a sealed vial under nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NaHCO 3 The aqueous solution was quenched. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 0.7N ammonia in methanol / dichloromethane from 1% to 15%) to give the title compound as a light yellow solid (194 mg, yield 77%, purity 99.6%, t r =0.75 min). LCMS (Method B): m / z found 566.3 [M+H] + ; 1 H-NMR (400MHz, DMSO) δ8.47(s,1H),7.85–7.68(m,2H),7.45(dq,J=7.8,1.1Hz,2H),7.32(td,J=8.6,6.5Hz,1H),7.01(ddd,J=10.6,9.3,2. 5Hz,1H),6.95–6.84(m,1H),4.61(dd,J=8.6,5.8Hz,1H),3.20–2.94(m,4H),2.59(dd,J=13.0,8.8Hz,1H),2.39–2.10(m,5H),1.37(s,9H).

[0732] Step 4: Synthesis of N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide

[0733]

[0734] To a stirred solution of tert-butyl 4-[2-(2,4-difluorophenyl)-2-[[4-(trifluoromethoxy)phenyl]sulfonylamino]ethyl]piperazine-1-carboxylate (100%, 193 mg, 0.340 mmol) in 1,4-dioxane (2.3 mL) in a round bottom flask was added a 4M solution of hydrogen chloride in 1,4-dioxane (0.85 mL, 3.40 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours and then diluted with ether (31.5 mL). The reaction was stirred overnight. The solid was filtered and washed with Et 2O and dried in vacuo at 50°C overnight to give the dihydrochloride salt of the title compound as an off-white solid (142.7 mg, yield 77%, purity 99.47%, t r =1.36 min). LCMS (Method D): m / z found (600 MHz, DMSO-d 6 )δppm 8.63-9.41(m,3H)7.66(d,J=8.80Hz,2H)7.26-7.39(m,3H)6.90-6.99(m ,1H)6.82(td,J=8.51,2.49Hz,1H)4.72-5.02(m,1H)2.58-3.53(m,10H).

[0735] Example 21: N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (21)

[0736]

[0737] Step 1: Synthesis of tert-butyl 4-(2-(3,4-difluorophenyl)-2-oxoethyl)piperazine-1-carboxylate

[0738]

[0739] In a sealed tube, under nitrogen, a solution of tert-butyl piperazine-1-carboxylate (1.38 g, 7.43 mmol), triethylamine (633 μL, 4.54 mmol) and 2-bromo-1-(3,4-difluorophenyl)ethanone (97%, 1.00 g, 4.13 mmol) in DCM (9.1 mL) was stirred at room temperature. The mixture was stirred in an ice-water bath, and DMAP (25 mg, 0.206 mmol) was added. The cold bath was removed, and the mixture was stirred at room temperature for 16 hours. Half-saturated NaHCO was added. 3 The aqueous solution was added and the mixture was stirred at room temperature for 5 minutes. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 0.4% to 4%) to afford the title compound as a pale yellow solid (1.33 g, yield 86%, purity 91%, t r =0.56 min). LCMS (Method A): m / z found 341.4 [M+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)8.02(ddd,J=11.4,7.9,2.1Hz,1H),7.89(ddt,J=8.1,5.0,1.6H z,1H),7.60(dt,J=10.5,8.3Hz,1H),3.87(s,2H),2.50–2.43(m,4H),1.40(s,9H).

[0740] Step 2: Synthesis of tert-butyl 4-(2-amino-2-(3,4-difluorophenyl)ethyl)piperazine-1-carboxylate

[0741]

[0742] In a sealed tube under nitrogen, polymer-bound sodium cyanoborohydride (3.53 g, 7.06 mmol) was added to a stirred solution of tert-butyl 4-[2-(3,4-difluorophenyl)-2-oxo-ethyl]piperazine-1-carboxylate (91%, 1.32 g, 3.53 mmol) and ammonium acetate (2.72 g, 35.3 mmol) in acetic acid (2.2 mL) and methanol (21.6 mL). The mixture was stirred at 40 °C for 16 h and filtered. The residue was washed with MeOH and the filtrate was concentrated and then dissolved in DCM and saturated NaHCO 3 The organic layer was washed with saturated NaHCO 3 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 (MeOH + 2% NH 4 OH) in DCM from 1% to 5% gradient) to give the title compound as a yellow solid (746 mg, yield 55%, purity 90%, t r =0.59 min). LCMS (Method A): m / z found 342.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.43(ddd,J=12.3,8.1,2.1Hz,1H),7.34(dt,J=10.8,8.5Hz,1H),7.21(ddt,J=8.3,4.7,1.7H z,1H),4.04(dd,J=8.9,5.1Hz,1H),2.43(dt,J=10.7,5.1Hz,2H),2.37–2.22(m,4H),1.96(s,2H),1.40(s,9H).

[0743] Step 3: Synthesis of tert-butyl 4-(2-(3,4-difluorophenyl)-2-((4-(trifluoromethoxy)phenyl)sulfonamido)ethyl)piperazine-1-carboxylate

[0744]

[0745] To a stirred solution of tert-butyl 4-[2-amino-2-(3,4-difluorophenyl)ethyl]piperazine-1-carboxylate (90%, 150 mg, 0.395 mmol) in DCM (2.6 mL) was added triethylamine (83 μL, 0.593 mmol) and 4-(trifluoromethoxy)benzenesulfonyl chloride (97%, 0.069 mL, 0.395 mmol) in a sealed vial under nitrogen. The reaction mixture was stirred at room temperature for 64 h. The reaction mixture was washed with saturated NaHCO 3 The aqueous solution was quenched. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 0.7N ammonia in methanol / dichloromethane from 1% to 10%) to give the title compound as a white solid (200 mg, yield 82%, purity 92%, t r =0.75 min). LCMS (Method B): m / z found 566.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.32(s,1H),7.79–7.73(m,2H),7.48–7.40(m,2H),7.27–7.15(m,2H),7.08 –7.00(m,1H),4.41(dd,J=9.1,5.4Hz,1H),3.19–3.02(m,5H),2.34–2.18(m,3H),1.38(s,9H).

[0746] Step 4: Synthesis of N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide

[0747]

[0748] To a stirred solution of tert-butyl 4-[2-(3,4-difluorophenyl)-2-[[4-(trifluoromethoxy)phenyl]sulfonylamino]ethyl]piperazine-1-carboxylate (92%, 195 mg, 0.317) in 1,4-dioxane (2.1 mL) in a round bottom flask was added 4M hydrogen chloride in 1,4-dioxane (0.79 mL, 3.17 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours, additional 4M hydrogen chloride in 1,4-dioxane (0.79 mL, 3.17 mmol) was added, and the suspension was stirred overnight. Additional 4M hydrogen chloride in 1,4-dioxane (0.79 mL, 3.17 mmol) was added, the mixture was stirred for 6 hours, and then diluted with ether (29.4 mL). The reaction was stirred overnight. The solid was filtered and washed with Et 2 O and dried in vacuo at 50°C overnight to give the dihydrochloride salt of the title compound as a white solid (157.3 mg, yield 92%, purity 100%, t r =1.72 minutes). LCMS (Method D): m / z found 465.9 [M-2HCl+H] + ; 1 H-NMR (DMSO-d 6 ,600MHz): δ(ppm)8.95-9.60(m,2H),8.45-8.88(m,1H),7.55-7.77(m,2H),7.28-7.41(m,2H),7 .19-7.26(m,1H),7.10-7.18(m,1H),7.00-7.07(m,1H),4.52-4.89(m,1H),2.59-4.32(m,10H).

[0749] Example 22: N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide (22)

[0750]

[0751] Step 1: Synthesis of tert-butyl 4-(2-(4-chlorophenyl)-2-oxoethyl)piperazine-1-carboxylate

[0752]

[0753] In a sealed tube, under nitrogen, a solution of tert-butyl piperazine-1-carboxylate (1.44 g, 7.71 mmol), triethylamine (657 μL, 4.71 mmol) and 2-bromo-1-(4-chlorophenyl)ethanone (1.00 g, 4.28 mmol) in DCM (9.5 mL) was stirred at room temperature. The mixture was stirred in an ice-water bath, and DMAP (26 mg, 0.214 mmol) was added. The cold bath was removed, and the mixture was stirred at room temperature for 16 hours. Half-saturated NaHCO was added. 3 The aqueous solution was added and the mixture was stirred at room temperature for 5 minutes. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 1% to 10%) to afford the title compound as a yellow oil (1.4 g, yield 88%, purity 91%, t r =0.58 min). LCMS (Method A): m / z found 339.4 [M+H] + ; 1 H-NMR (400MHz, DMSO) δ8.03–7.96(m,2H),7.62–7.56(m,2H),3.87(s,2H),3.33-3.30(m,4H),2.49–2.41(m,4H),1.40(s,9H).

[0754] Step 2: Synthesis of tert-butyl 4-(2-amino-2-(4-chlorophenyl)ethyl)piperazine-1-carboxylate

[0755]

[0756] In a sealed tube under nitrogen, polymer-bound sodium cyanoborohydride (4.14 g, 8.29 mmol) was added to a stirred solution of tert-butyl 4-[2-(4-chlorophenyl)-2-oxo-ethyl]piperazine-1-carboxylate (1.40 g, 4.14 mmol) and ammonium acetate (3.19 g, 41.4 mmol) in acetic acid (2.54 mL) and methanol (25.4 mL). The mixture was stirred at 5 °C overnight and filtered. The residue was washed with MeOH and the filtrate was concentrated and then dissolved in DCM. The organic layer was washed with saturated NaHCO 3 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 (MeOH + 2% NH 4 OH) in DCM (gradient from 1% to 15%) to afford the title compound as a yellow oil (707 mg, yield 45%, purity 90%, tr =0.59 min). LCMS (Method A): m / z found 340.4 [M+H] + ; 1 H-NMR (400MHz, DMSO) δ7.44–7.37(m,2H),7.37–7.30(m,2H),4.04(dd,J=9.2,4.7Hz,1H),3.30(s,4H),2.48–2.21(m,6H),1.94(brs,2H),1.40(s,9H).

[0757] Step 3: Synthesis of tert-butyl 4-(2-(4-chlorophenyl)-2-((6-isopropoxypyridine)-3-sulfonamido)ethyl)piperidine-1-carboxylate

[0758]

[0759] In a sealed vial, triethylamine (92 μL, 0.662 mmol) and 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (114 mg, 0.485 mmol) were added sequentially to a stirred solution of tert-butyl 4-[2-amino-2-(4-chlorophenyl)ethyl]piperazine-1-carboxylate (150 mg, 0.441 mmol) in DCM (2.9 mL) under nitrogen. The reaction mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO 3 The reaction mixture was quenched with aqueous solution. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using (0.7N NH 3 / MeOH) in DCM (gradient from 1% to 15%) to afford the title compound as a pale yellow solid (185 mg, yield 77%, purity 99%, t r =0.75 min). LCMS (Method B): m / z found 539.3 [M+H] + ; 1 H-NMR (400MHz, DMSO) δ8.35(dd,J=2.6,0.7Hz,1H),8.22(s,1H),7.83(dd,J=8.8,2.6Hz,1H),7.30–7.19(m,4H),6.77(dd,J=8.8,0.7Hz,1H),5 .26(hept,J=6.2Hz,1H),4.38(dd,J=9.2,5.1Hz,1H),3.20–2.98(m,4H),2.55-2.50(m,1H),2.32–2.17(m,5H),1.37(s,9H),1.34–1.21(m,6H).

[0760] Step 4: Synthesis of N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide

[0761]

[0762] In a round bottom flask, to a stirred solution of tert-butyl 4-[2-(4-chlorophenyl)-2-[(6-isopropoxy-3-pyridyl)sulfonylamino]ethyl]piperazine-1-carboxylate (184 mg, 0.341 mmol) in 1,4-dioxane (2.3 mL) was added dropwise 4M hydrogen chloride in 1,4-dioxane (2.1 mL, 8.53 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with ether (31.6 mL). The reaction was stirred overnight. The solid was filtered and washed with Et 2 O and dried under vacuum at 50 °C overnight. 2 CO 3 The crude product was dissolved in 1,4-dioxane (2.27 mL) and 2M hydrogen chloride / ether (0.47 mL, 0.940 mmol) was added. Ether (23 mL) was added and the mixture was stirred for 1 hour. The solid was filtered and washed with Et 2 O and dried in vacuo at 50°C overnight to give the dihydrochloride salt of the title compound as an off-white solid (141 mg, yield 78%, purity 97.73%, t r =1.64 min). LCMS (Method F): m / z found 439 [M-2HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm 1.27(d,J=6.16Hz,6H)2.63-3.43(m,2H)3.72-4.79(m,9H)5.17-5.24(m,1H)6.66(br d,J=8.80Hz,1H)7.17-7.22(m,4H)7.73(br d,J=8.51Hz,1H)8.20(br s,1H)8.34-9.47(m,3H).

[0763] Example 23: 3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (23)

[0764]

[0765] Step 1: Synthesis of tert-butyl 4-(2-(4-chlorophenyl)-2-oxoethyl)piperazine-1-carboxylate

[0766]

[0767] In a sealed tube, under nitrogen, a solution of tert-butyl piperazine-1-carboxylate (1.44 g, 7.71 mmol), triethylamine (657 μL, 4.71 mmol) and 2-bromo-1-(4-chlorophenyl)ethanone (1.00 g, 4.28 mmol) in DCM (9.5 mL) was stirred at room temperature. The mixture was stirred in an ice-water bath, and DMAP (26 mg, 0.214 mmol) was added. The cold bath was removed, and the mixture was stirred at room temperature for 16 hours. Half-saturated NaHCO was added. 3 Aqueous solution, and the mixture was stirred at room temperature for 5 minutes. The aqueous layer was extracted twice with DCM. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 0% to 50% of EtOAc in cyclohexane) to obtain the title compound as a yellow powder (895 mg, yield 50%, purity 81%, t r =0.58 min). LCMS (Method A): m / z found 339.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.04–7.96(m,2H),7.63–7.55(m,2H),3.87(s,2H),3.33-3.30(m,4H),2.50–2.43(m,4H),1.40(s,9H).

[0768] Step 2: Synthesis of tert-butyl 4-(2-amino-2-(4-chlorophenyl)ethyl)piperazine-1-carboxylate

[0769]

[0770] In a sealed tube under nitrogen, polymer-bound sodium cyanoborohydride (2.14 g, 4.28 mmol) was added to a stirred solution of tert-butyl 4-[2-(4-dichlorophenyl)-2-oxo-ethyl]piperazine-1-carboxylate (81%, 895 mg, 2.14 mmol) and ammonium acetate (1.65 g, 21.4 mmol) in acetic acid (1.3 mL) and methanol (13.1 mL). The mixture was stirred at 65 °C overnight. The reaction mixture was filtered, washed with MeOH, and concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated NaHCO 3The reaction mixture was washed with water. The combined aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0% to 10%) to give the title compound as a yellow oil (411 mg, yield 54%, purity 96%, t r =0.60 min). LCMS (Method B): m / z found 340.2 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.42–7.38(m,2H),7.36–7.32(m,2H),4.05(dd,J=9.3,4.8Hz,1H),3.31 (s,4H),3.19–3.14(m,2H),2.44(dt,J=10.9,5.1Hz,2H),2.38–2.19(m,4H),1.39(s,9H).

[0771] Step 3: Synthesis of tert-butyl 4-(2-(4-chlorophenyl)-2-((3-nitro-4-(trifluoromethoxy)phenyl)sulfonamido)ethyl)piperazine-1-carboxylate

[0772]

[0773] A sealed vial was charged with tert-butyl 4-[2-amino-2-(4-chlorophenyl)ethyl]piperazine-1-carboxylate (200 mg, 0.565 mmol), 4-dimethylaminopyridine (14 mg, 0.113 mmol) and triethylamine (315 μL, 2.26 mmol) in DCM (5.3 mL), followed by 3-nitro-4-(trifluoromethoxy)benzene-1-sulfonyl chloride (173 mg, 0.565 mmol) and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was diluted with DCM and saturated NH 4 Cl aqueous solution. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine and purified by Na 2 SO 4 The crude residue was purified by flash chromatography on silica gel (using a gradient of 10% to 80% EtOAc in heptane) to afford the title compound as a yellow gum (123 mg, 34% yield, 97% purity, t r =0.77 min). LCMS (Method A): m / z found 609.4 [M+H] + ; 1 H-NMR (DMSO-d 6, 400MHz): δ (ppm) 8.69 (d, J = 8.0Hz, 1H), 8.28 (d, J = 2.3Hz, 1H), 8.05 (dd, J = 8.7, 2.3Hz, 1H), 7.83 (dq, J = 8.6, 1.5Hz, 1H), 7.21(s,4H),4.48(td,J=8.7,5.0Hz,1H),3.09(t,J=5.2Hz,2H),3.01(d,J=13.7Hz,2H),2.33–2.24(m,6H),1.37(s,9H).

[0774] Step 4: Synthesis of tert-butyl 4-(2-((3-amino-4-(trifluoromethoxy)phenyl)sulfonamido)-2-(4-chlorophenyl)ethyl)piperazine-1-carboxylate

[0775]

[0776] In a sealed tube, a suspension of iron (55 mg, 0.980 mmol) and ammonium chloride (15 mg, 0.274 mmol) in ethanol (1 mL) and water (0.5 mL) was stirred at 70 ° C for 1 hour. A solution of tert-butyl 4-[2-(4-chlorophenyl)-2-[[3-nitro-4-(trifluoromethoxy)phenyl]sulfonylamino]ethyl]piperazine-1-carboxylate (123 mg, 0.196 mmol) in ethanol (1 mL) was added and the mixture was stirred at 80 ° C for 5 hours. The mixture was cooled to room temperature and filtered through a talc pad. The pad was washed with EtOH and DCM, and the filtrate was concentrated. The residue was dissolved in DCM and saturated NaHCO 3 Aqueous solution. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse flash chromatography (using a gradient from 0% to 100% of ACN (0.1% AcOH) in water (0.1% AcOH)). The desired fractions were concentrated and washed with saturated Na 2 CO 3 The aqueous solution was basified and extracted with DCM. The combined organic layers were dried and concentrated through a phase separator to give the title compound as a yellow foam (74.3 mg, yield 65%, purity 99%, t r =0.73 min). LCMS (Method A): m / z found 579.3 [M+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)7.91(s,1H),7.32–7.22(m,4H),7.18(dd,J=8.9,1.9Hz,2H),6.86(dd,J=8.4,2.3Hz,1H),5.81(s,2H),4.26(s,1H) ,3.08(d,J=16.5Hz,4H),2.42(dd,J=13.0,9.1Hz,1H),2.25(dd,J=12.9,5.6Hz,1H),2.21(s,2H),2.13(d,J=7.0Hz,2H),1.36(s,9H)

[0777] Step 5: Synthesis of 3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide

[0778]

[0779] In a round-bottom flask, tert-butyl 4-[2-[[3-amino-4-(trifluoromethoxy)phenyl]sulfonylamino]-2-(4-chlorophenyl)ethyl]piperazine-1-carboxylate (74 mg, 0.127 mmol) was stirred in anhydrous 1,4-dioxane (1.2 mL). 4M HCl in dioxane (635 μL, 2.54 mmol) was added and the resulting suspension was stirred at room temperature overnight. The resulting residue was filtered and washed with Et 2 O and dried under vacuum at 45 °C for 4 h to give the dihydrochloride salt of the title compound as a beige powder (51.2 mg, yield 73%, purity 95.7%, t r =1.45 minutes). LCMS (Method D): m / z found: [M-2HCl+H] + ; 1 H-NMR (DMSO-d 6 ,500MHz)δ8.6-10.2(m,2H),8.31(br d,1H,J=4.6Hz),7.1-7.4(m,4H),6.9-7.1(m,2H),6.74(br d,1H,J=8.3Hz),4.8-6.4(m,2H),4.3-4.8(m,1H),2.6-3.4(m,10H).

[0780] Example 24: N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide (24)

[0781]

[0782] Step 1: Synthesis of tert-butyl 4-(2-(3,4-difluorophenyl)-2-((6-isopropoxypyridine)-3-sulfonamido)ethyl)piperidine-1-carboxylate

[0783]

[0784] To a stirred solution of tert-butyl 4-[2-amino-2-(3,4-difluorophenyl)ethyl]piperazine-1-carboxylate (90%, 150 mg, 0.395 mmol) in DCM (2.6 mL) was added triethylamine (83 μL, 0.593 mmol) and 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 98 mg, 0.395 mmol) in a sealed vial under nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NaHCO 3 The aqueous solution was quenched. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 0.7N ammonia in MeOH / DCM from 0% to 10%) to give the title compound as a white solid (180 mg, yield 80%, purity 96%, t r =0.74 min). LCMS (Method B): m / z found 541.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.34(d,J=2.5Hz,1H),8.24(s,1H),7.82(dd,J=8.8,2.5Hz,1H),7.31–7.19(m,2H),7.10–7.05(m,1H),6.77(d,J=8.9Hz ,1H),5.25(p,J=6.1Hz,1H),4.40(dd,J=9.1,5.3Hz,1H),3.22–2.99(m,4H),2.36–2.20(m,5H),1.38(s,8H),1.28(dd,J=6.2,4.5Hz,6H).

[0785] Step 2: Synthesis of N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide

[0786]

[0787] To a stirred solution of tert-butyl 4-[2-(3,4-difluorophenyl)-2-[(6-isopropoxy-3-pyridyl)sulfonylamino]ethyl]piperazine-1-carboxylate (210 mg, 0.388 mmol) in 1,4-dioxane (2.6 mL) in a round bottom flask was added a 4M solution of hydrogen chloride in 1,4-dioxane (0.79 mL, 3,88 mmol). The reaction mixture was stirred at room temperature overnight. Additional 4M solution of hydrogen chloride in 1,4-dioxane (0.79 mL, 3.88 mmol) was added and the suspension was stirred overnight. Additional 4M solution of hydrogen chloride in 1,4-dioxane (0.79 mL, 3.88 mmol) was added and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with ether (36 mL) and stirred at room temperature overnight. The solid was filtered and washed with Et 2 O, and dried under vacuum at 50°C for 64 hours to obtain the title compound as an off-white solid (144.6 mg, yield 70%, purity 96.49%). LCMS (Method D): m / z found 441 [M-2HCl+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δppm 1.27(t,J=5.75Hz,6H)2.65-3.41(m,7H)3.71-4.23(m,4H)4.52-4.82(m,1H)5.21(quin,J=6.17Hz,1H)6.69(d,J=8.80Hz,1H) 7.04-7.12(m,1H)7.17-7.34(m,2H)7.75(dd,J=8.80,2.69Hz,1H)8.22(d,J=2.45Hz,1H)8.37-8.80(m,1H)8.83-9.91(m,2H).

[0788] Example 25: (R)-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide (25)

[0789]

[0790] Under nitrogen, a sealed vial was charged with a solution of N-[(1R)-1-(4-chlorophenyl)-2-oxo-2-piperazin-1-yl-ethyl]-4-(trifluoromethoxy)benzenesulfonamide (94%, 950 mg, 1.87 mmol) in anhydrous THF (14.4 mL). A 2M solution of lithium aluminum hydride in THF (2.8 mL, 5.61 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. Water (0.10 mL, 5.61 mmol) was added dropwise at 0°C, followed by 5M sodium hydroxide (1.1 mL, 5.61 mmol) and water (0.30 mL, 16.8 mmol). The suspension was filtered and washed with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (using (0.7N NH 3 The residue was purified by reverse phase flash chromatography using a gradient of ACN in water from 0% to 100% (0.1% AcOH in water and ACN). The desired fractions were concentrated and the residue was dissolved in a minimum amount of DCM and 2M hydrogen chloride in Et 2 O (0.27 mL, 0.549 mmol) solution. Add Et 2 O and stirred the suspension for 2 h, then filtered and washed with Et 2 O and dried under vacuum to give the dihydrochloride salt of the title compound as a white powder (74 mg, yield 9%, purity 99.23%, t r =1.11 min). LCMS (Method D): m / z found 380.1 [M-HCl+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm 8.16-9.59(m,4H)7.61(br s,2H)7.47-7.54(m,1H)7.40(br s,2H)7.16-7.26(m,4H)3.79-5.15(m,7H)2.52-3.58(m,9H).

[0791] Example 26: N-((S)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (26)

[0792]

[0793] Step 1: Synthesis of N-((1S)-1-(4-fluorophenyl)-2-(3-fluoropiperidin-1-yl)-2-oxoethyl)-4-(trifluoromethoxy)benzenesulfonamide

[0794]

[0795] In a sealed tube under nitrogen, a solution of (2S)-2-(4-fluorophenyl)-2-[[4-(trifluoromethoxy)phenyl]sulfonylamino]acetic acid (92%, 150 mg, 0.351 mmol) in DCM (1.75 mL) was stirred at 0°C. DIPEA (0.092 mL, 0.526 mmol) and HATU (98%, 150 mg, 0.386 mmol) were added, and the mixture was stirred at 0°C for 10 minutes. 3-Fluoropiperidine (42 mg, 0.403 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was washed with saturated NH 4 Cl aqueous solution was quenched, and the aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 1% to 5% of MeOH in DCM) to obtain the title compound as a yellow solid (124 mg, yield 72%, purity 97%, t r =0.92 min). LCMS (Method B): m / z found 479 [M+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δ8.71–8.52(m,1H),7.79–7.71(m,2H),7.42–7.32(m,2H),7.32–7.22(m,2H),7.03–6.93(m,2H),5.50–5.39(m,1H) ,4.72–4.40(m,1H),3.96–3.74(m,1H),3.74–3.46(m,1H),3.29–2.93(m,2H),1.92–1.52(m,2H),1.52–0.96(m,2H).

[0796] Step 2: Synthesis of N-((S)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide

[0797]

[0798] A solution of N-[(1S)-1-(4-fluorophenyl)-2-(3-fluoro-1-piperidinyl)-2-oxo-ethyl]-4-(trifluoromethoxy)benzenesulfonamide (97%, 176 mg, 0.357 mmol) in DCM (2.3 mL) was stirred at 0°C. Chloro(trimethyl)silane (0.11 mL, 0.856 mmol) was added dropwise, and the mixture was stirred at 0°C for 30 minutes. 2M lithium aluminum hydride (0.50 mL, 0.999 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 hour and then at room temperature for 16 hours. The mixture was cooled to 0°C, and water (18 μL, 0.999 mmol) was added dropwise. The suspension was stirred at room temperature for 15 minutes, and 5M sodium hydroxide (20 μL, 0.999 mmol) was added dropwise. The suspension was stirred at room temperature for 15 minutes, and water (54 μL, 3.00 mmol) was added dropwise. The suspension was stirred at room temperature for 30 minutes and filtered through a pad of talc. The filtrate was washed with saturated Na 2 CO 3 The crude product was purified by flash chromatography on silica gel (using MeOH (NH 3 0.7N) in DCM with a gradient from 1% to 10%. The obtained mixture of diastereomers was purified by preparative SFC on a chiralpak IC column using 2 / (MeOH+0.5% IPAm) 95 / 5 was used as mobile phase for purification. The desired fractions were concentrated, the residue was dissolved in minimal DCM and 2N HCl / Et 2 O. Add Et 2 O, and the resulting suspension was filtered. The residue was washed with Et 2 O and dried under vacuum at 50°C for 12 h to give the hydrochloride salt of the title compound as a white powder (10 mg, yield 6%, purity 98.53%, t r =1.52 minutes). LCMS (Method D): m / z found 465 [M-HCl+H] + ; 1 H-NMR (500 MHz, DMSO-d 6)δppm1.58-2.20(m,4H)3.02-3.34(m,3H)3.42-3.84(m,3H)4.94(br t,J=8.68Hz,1H)5.05-5.33(m,1H)6.89(br t,J=8.44Hz,2H)7.19(br dd,J=8.19,5.50Hz,2H)7.28(br d,J=8.31Hz,2H)7.61(br d,J=8.56Hz,2H)8.77(br d,J=10.27Hz,1H)9.72-10.52(m,1H).

[0799] Example 27: (S)-N-(2-([1,3'-diazetidine]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide (27)

[0800]

[0801] Step 1: Synthesis of (S)-N-(2-([1,3'-diazetidine]-1'-yl)-1-(4-fluorophenyl)-2-oxoethyl)-4-(trifluoromethoxy)benzenesulfonamide

[0802]

[0803] In a round-bottom flask, to a solution of (2S)-2-(4-fluorophenyl)-2-[[4-(trifluoromethoxy)phenyl]sulfonylamino]acetic acid (200 mg, 0.509 mmol) in DCM (5.4 mL) were added DIPEA (1.3 mL, 7.63 mmol) and propanephosphonic anhydride (T3P) in DCM (50%, 0.98 mL, 2.03 mmol). Then 1-(azetidin-3-yl)azetidine ditrifluoroacetate (95%, 273 mg, 0.763 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NH 4 The solution was quenched with aqueous Cl solution and water was added. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated Na 2 CO 3 The mixture was washed with aqueous solution, then with brine, and then with anhydrous Na 2 SO 4 The crude residue was purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0 to 10%) to afford the title compound as a yellow gum (133.4 mg, 51% yield, 95% purity, t r =0.62 min). LCMS (Method A): m / z found 488.3 [M+H] + ;1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.74(d,J=7.8Hz,1H),7.78–7.70(m,21H),7.38(ddt,J=7.9,4.2,1.0Hz,2H),7.23 (ddd,J=8.7,5.5,3.1Hz,2H),6.97(td,J=8.9,7.0Hz,2H),4.97(t,J=8.2Hz,0.5H),4.23–4.15(m,0.5 H),3.97(dd,J=9.2,4.2Hz,0.5H),3.89–3.81(m,0H),3.72–3.57(m,1H),3.40(td,J=10.3,4.4Hz,1H ),3.32–3.11(m,1H),3.13–3.07(m,2H),2.98(t,J=7.0Hz,2H),2.04–1.94(m,1H),1.92–1.80(m,1H).

[0804] Step 2: Synthesis of (S)-N-(2-([1,3'-diazetidine]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide

[0805]

[0806] In a round-bottom flask under nitrogen, chloro(trimethyl)silane (84 μL, 0.657 mmol) was added to a solution of N-[(1S)-2-[3-(azetidin-1-yl)azetidin-1-yl]-1-(4-fluorophenyl)-2-oxo-ethyl]-4-(trifluoromethoxy)benzenesulfonamide (133 mg, 0.274 mmol) in anhydrous DCM (1 mL) at 0°C, and the mixture was stirred at this temperature for 30 minutes. 2M lithium aluminum hydride (0.38 mL, 0.766 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 hour, and then stirred at room temperature overnight. The reaction mixture was cooled to 0°, and water (40 μL) was added dropwise. The suspension was stirred for 15 minutes, and then 15% NaOH aqueous solution (40 μL) was added dropwise. The mixture was stirred at 0°C for 15 minutes, and then water (120 μL) was added. The suspension was stirred at room temperature for 30 minutes, then filtered through cardboard and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0% to 10%). The desired fractions were concentrated under reduced pressure. The resulting yellow powder was diluted in DCM and 2M HCl / Et was added. 2 O (0.27 mL, 0.547 mmol). The mixture was stirred at room temperature overnight, filtered, and washed with Et 2O and dried under reduced pressure at 45°C overnight to give the dihydrochloride salt of the title compound as a white powder (63.1 mg, yield 38%, purity 91.8%, t r =1.19 minutes). LCMS (Method D): m / z found 474.2 [M-2HCl+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δppm 12.34(br s,1H)10.62(br s,1H)2.03-2.42(m,2H)3.44-4.82(m,12H)6.89(t,J=1.00Hz,2H)7.16(br t,J=1.00Hz,2H)7.29(d,J=8.31Hz,2H)7.60(d,J=8.17Hz,2H)8.91(br s,1H)10.62(br s,1H).

[0807] Example 28: N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide (28)

[0808]

[0809] Step 1: Synthesis of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethan-1-one

[0810]

[0811] In a round-bottom flask, to a stirred solution of 2-bromo-1-(3,4-dichlorophenyl)ethanone (97%, 15.00 g, 54.3 mmol) in anhydrous DCM (108.61 mL) at 0°C under nitrogen, 2M dimethylamine in THF (49 mL, 97.7 mmol), triethylamine (8.3 mL, 59.7 mmol) and DMAP (332 mg, 2.72 mmol) were added in sequence. The reaction mixture was warmed and stirred at room temperature overnight. The reaction mixture was quenched with water (400 mL) and ethyl acetate (400 mL) was added. The aqueous layer was extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0% to 2%) to give the title compound as a brown oil (6.77 g, yield 54%, t r =0.51 min). LCMS (Method A): m / z found 232.1 [M+H] + ; 1 H-NMR (DMSO-d6 , 400MHz): δ (ppm) 8.18 (d, J = 2.0Hz, 1H), 7.94 (dd, J = 8.4, 2.1Hz, 1H), 7.80 (d, J = 8.4Hz, 1H), 3.75 (s, 2H), 2.24 (s, 6H).

[0812] Step 2: Synthesis of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethane-1-one oxime

[0813]

[0814] A sealed vial was charged with 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethanone (99%, 6.77 g, 28.9 mmol), hydroxylamine hydrochloride (4.01 g, 57.7 mmol) and DIPEA (11 mL, 60.6 mmol) in anhydrous ethanol (127.46 mL). The reaction mixture was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound as a brown oil (16.43 g, quantitative yield, purity 44%). LCMS (Method A): m / z found to be 247.1 [M+H] + .

[0815] Step 3: 1-(3,4-dichlorophenyl)-N 2 ,N 2 -Synthesis of dimethylethane-1,2-diamine

[0816]

[0817] In a three-necked round-bottom flask, to a stirred solution of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethanone oxime (44%, 16.43 g, 29.3 mmol) in anhydrous THF (128.52 mL) was added dropwise 2.4 M lithium aluminum hydride in THF (30 mL, 73.1 mmol) at 0°C under nitrogen over 40 minutes (the temperature did not exceed 8°C during the addition). The reaction mixture was stirred at an external temperature of 75°C (the temperature inside the mixture was 65°C) for 3 hours. The reaction mixture was cooled to 0°C, quenched with water (2.77 mL, the same weight as LAH, added dropwise), and then 1 M sodium hydroxide (2.8 mL, 2.78 mmol) and water (three times the weight of LAH) were added. The resulting heterogeneous mixture was stirred at room temperature overnight, then filtered and rinsed with THF. The organic layer was washed with anhydrous Na 2 SO 4 The crude product was purified by flash chromatography on silica gel using methanol (0.7 N NH 3) in dichloromethane (1% to 4% gradient). The desired fractions were combined and concentrated in vacuo to give the title compound as an orange oil (1.83 g, 48% yield, 100% purity). 1 H-NMR (400 MHz, DMSO-d 6 )δ7.64(d,J=1.9Hz,1H),7.54(dd,J=8.3,2.4Hz,1H),7.36(dt,J=8.3,2.0Hz,1H) ,3.98(dd,J=8.8,5.4Hz,1H),2.30–2.22(m,1H),2.21–2.14(m,7H),1.94(s,2H).

[0818] Step 4: Synthesis of 4-(3-(trifluoromethyl)phenoxy)benzenesulfonyl chloride

[0819]

[0820] In a three-necked round-bottom flask equipped with a thermometer, a solution of 4-[3-(trifluoromethyl)phenoxy]aniline (95%, 300 mg, 1.13 mmol) in TFA (3.8265 mL) was stirred at 0°C. Concentrated HCl (376 μL, 12.4 mmol) in water was added, and the mixture was stirred at 0°C for 5 minutes, and then a solution of sodium nitrite (98 mg, 1.41 mmol) in water (425 μL) was added dropwise over 5 minutes to keep the temperature below 0°C. The mixture was stirred at -5°C for 30 minutes to obtain Solution A.

[0821] In a separate three-necked round-bottom flask equipped with a thermometer, a solution of copper (II) chloride (77 mg, 0.574 mmol) and copper (I) chloride (3.4 mg, 0.0338 mmol) in acetic acid (3.8265 mL) and sulfurous acid (3.8 mL, 49.5 mmol) was stirred at -5 ° C. Solution A was added dropwise over about 5 minutes while keeping the temperature below 5 ° C. The mixture was stirred at 0 ° C for 5 minutes and then at room temperature for 1 hour. The mixture was stirred at 55 ° C for 5.5 hours and then at room temperature for 14 hours, then extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound as a black oil (150 mg, yield 39%). 1 H-NMR (DMSO-d 6 , 400MHz): δ (ppm) 7.69–7.59 (m, 3H), 7.50 (ddd, J = 9.1, 2.5, 1.6Hz, 1H), 7.33–7.28 (m, 2H), 7.05–6.99 (m, 2H).

[0822] Step 5: Synthesis of N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide

[0823]

[0824] In a sealed tube under nitrogen, a suspension of 4-[3-(trifluoromethyl)phenoxy]benzenesulfonyl chloride (150 mg, 0.445 mmol) in DCM (4 mL) was added to a stirred solution of 1-(3,4-dichlorophenyl)-N',N'-dimethyl-ethane-1,2-diamine (104 mg, 0.445 mmol) and triethylamine (248 μL, 1.78 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 3 days and poured into half-saturated NaHCO 3 The aqueous layer was extracted with DCM, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 The desired fractions were concentrated and purified by reverse phase chromatography using a gradient of (ACN + 0.2% AcOH) in (H2O + 0.2% AcOH) from 0% to 100%. The desired fractions were concentrated and the residue was dissolved in Et 2 O. The solution was added dropwise to a stirred HCl 2N / Et 2 O, and the suspension was stirred at room temperature for 16 hours. The suspension was filtered and the residue was washed with Et 2 O and dried under reduced pressure at 50°C for 16 hours to obtain the hydrochloride salt of the title compound as a white powder (16 mg, yield 6%, purity 99.7%, t r =1.85 minutes). LCMS (Method D): m / z found 533.2 [M-HCl+H] + ; 1 H-NMR (DMSO-d 6 ,500MHz)δ9.57(br s,1H),8.5-8.8(m,1H),7.7-7.8(m,1H),7.65(d,1H,J=7.8Hz),7.54(d,2H,J=8.8Hz),7.4-7.5(m,3H),7.25(br d,2H,J=8.3Hz),6.90(d,2H,J=8.8Hz),4.7-4.9(m,1H),3.1-3.5(m,2H),2.7-3.0(m,6H).

[0825] Example 29: N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide (29)

[0826]

[0827] In a sealed tube under nitrogen, a solution of 1-(2,2-dimethyl-1-phenylcyclopropyl)methanamine (95%, 150 mg, 0.813 mmol), 4-dimethylaminopyridine (20 mg, 0.163 mmol) and triethylamine (0.34 mL, 2.44 mmol) in anhydrous DCM (6 mL) was stirred at room temperature. 6-(Propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 0.22 g, 0.894 mmol) was added and the mixture was stirred at 40 °C for 16 hours. The mixture was washed with half-saturated NaHCO 3 The crude product was purified by flash chromatography on silica gel using (0.7 N NH 3 ) in DCM (gradient from 0% to 3%). The desired fractions were concentrated and the residue was mixed with Et 2 O. Add 2M HCl in Et 2 O (1.2 mL, 2.40 mmol) solution, and the resulting heterogeneous mixture was stirred at room temperature for 4 hours. The residue was filtered and washed with Et 2 O, and dried under reduced pressure at 40 ° C overnight. The title compound has melted. The resulting jelly is dissolved in MeOH and concentrated under reduced pressure. The residue is ground in pentane and stirred at room temperature for 2 hours. The heterogeneous mixture is filtered, washed with pentane and dried under reduced pressure at room temperature to obtain the title compound as a white solid (85.8 mg, yield 28%, purity 99.88%, t r = 2.87 minutes). LCMS (Method D): m / z found 375.2 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d 6 )δppm 0.62(s,3H)0.65(d,J=4.84Hz,1H)0.77(d,J=4.70Hz,1H)1.16(s,3H)1.31(dd,J =1.00Hz,6H)2.98(dd,J=13.06,5.87Hz,1H)3.19(dd,J=13.06,5.28Hz,1H)5.28( spt,J=6.19Hz,1H)6.76(dd,J=8.80,0.59Hz,1H)7.11-7.15(m,1H)7.17-7.21(m ,4H)7.47(t,J=5.65Hz,1H)7.77(dd,J=8.73,2.57Hz,1H)8.34(d,J=2.67Hz,1H).

[0828] Example 30: N-(Cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide (30)

[0829]

[0830] In a sealed tube under nitrogen, 6-(propan-2-yloxy)pyridine-3-sulfonyl chloride (95%, 144 mg, 0.580 mmol) was added to a stirred solution of cyclohexyl(3,5-dichlorophenyl)methanamine hydrochloride (95%, 150 mg, 0.484 mmol), triethylamine (337 μL, 2.42 mmol) and 4-dimethylaminopyridine (12 mg, 0.0967 mmol) in anhydrous DCM (4 mL) and stirred at 40 °C for 16 h. The mixture was washed with DCM and half-saturated NaHCO 3 The aqueous solution was diluted. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried over a phase separator, and concentrated. The crude product was purified by flash chromatography on silica gel (using (0.7N NH 3 ) in DCM with a gradient from 0% to 2%). The desired fractions were combined and concentrated to give the title compound as a white solid (205 mg, yield 91%, purity 99.64%, t r =3.29 minutes). LCMS (Method D): m / z found 457 [M+H] + ; 1 H-NMR(DMSO-d6,600MHz): δ(ppm)8.22(br d,J=6.6Hz,1H),8.16(dd,J=2.6,0.6Hz,1H),7.64(dd,J=8.8,2.6Hz,1H),7.21(t,J=1.9Hz,1H),7.10(d,J=1.9Hz,2H),6.63(dd,J=8.7, 0.7Hz,1H),5.20(quin,J=6.2Hz,1H),3.99-4.03(m,1H),1.51-1.94(m,4H),1.39-1.50(m,1H),1.27(d,J=6.2Hz,6H),0.73-1.19(m,6H)

[0831] Example 31: N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(trifluoromethoxy)benzamide (31)

[0832]

[0833] In a sealed tube, a mixture of 4-(trifluoromethoxy)benzoic acid (32 μL, 0.243 mmol), [2-amino-2-(3,4-dichlorophenyl)ethyl]dimethylamine (62 mg, 0.267 mmol), EDCI (70 mg, 0.364 mmol), HOBt (41 mg, 0.267 mmol) and triethylamine (101 μL, 0.728 mmol) in DMF (2 mL) was stirred at room temperature for 16 h. The mixture was poured into NH 4 Cl was added to a saturated aqueous solution and extracted three times with EtOAc. The combined organic layers were washed with saturated NaHCO 3 The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 1% to 10%). The desired fractions were concentrated and dissolved in Et 2 O. Add 2N HCl / Et 2 O, and the mixture was stirred at room temperature for 16 hours and concentrated. The residue was dried under reduced pressure at 45°C for 16 hours and triturated with pentane. The resulting suspension was filtered, the residue was washed with pentane and dried under reduced pressure at 45°C for 16 hours to obtain the hydrochloride of the title compound as a white powder (63 mg, yield 56%, purity 99.7%, t r =1.62 minutes). LCMS (Method E): m / z found 421.2 [M-HCl+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δ(ppm)=9.74(br s,1H),9.47(br d,J=8.3Hz,1H),8.19-8.10(m,2H),7.86(d,J=2.0Hz,1H),7.68(d,J=8.3Hz,1H),7.57-7.48(m,3H),5.59(br t,J=8.4Hz,1H),3.75(br t,J=12.1Hz,1H),3.44(br t,J=8.9Hz,1H),2.97-2.75(m,6H).

[0834] Example 32: N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-3-nitro-4-(trifluoromethoxy)benzamide (32)

[0835]

[0836] In a sealed tube, a mixture of 3-nitro-4-(trifluoromethoxy)benzoic acid (32 μL, 0.199 mmol), [2-amino-2-(3,4-dichlorophenyl)ethyl]dimethylamine (51 mg, 0.219 mmol), DIPEA (139 μL, 0.796 mmol) and 1-propanephosphonic acid cyclic anhydride (50%, 317 mg, 0.498 mmol) in DMF (1 mL) was stirred at room temperature for 16 h. The mixture was poured into half-saturated NaHCO 3 The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 The desired fractions were concentrated and the residue was dissolved in a minimum amount of Et 2 O, the resulting suspension was diluted with pentane, stirred at room temperature for 10 minutes and filtered. The residue was washed with pentane and dried under reduced pressure at 45°C for 16 hours to obtain the title compound as a white powder (43 mg, yield 46%, purity 99.3%, t r =1.84 min). LCMS (Method E): m / z found 465.9 [M+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δ9.13(d,J=7.8Hz,1H),8.65(d,J=2.2Hz,1H),8.33(dd,J=8.8,2.2Hz,1H),7.88(dd,J=8.7,1.3Hz,1H),7.71(d,J=2.0Hz,1H),7. 60(d,J=8.3Hz,1H),7.42(dd,J=8.3,2.0Hz,1H),5.26–5.02(m,1H),2.73(dd,J=12.5,9.3Hz,1H),2.49–2.40(m,1H),2.21(s,6H).

[0837] Example 33: N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide (33)

[0838]

[0839] Step 1: Synthesis of benzyl 3-(4-fluorophenyl)-3-hydroxypyrrolidine-1-carboxylate

[0840]

[0841] 3-(4-Chlorophenyl)pyrrolidin-3-ol hydrochloride (0.60 g, 2.56 mmol) and DIPEA (1.3 mL, 7.69 mmol) in anhydrous ACN (9 mL) were charged into a sealed vial. 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 saturated aqueous sodium bicarbonate solution (50 mL), and then ethyl acetate (50 mL) and water (20 mL) were added. The aqueous layer was extracted with ethyl acetate (1 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was ground in dichloromethane, filtered, washed with dichloromethane, and the resulting powder was then dried under vacuum at 50°C for 20 hours. The filtrate was purified by flash chromatography on silica gel (using a gradient of methanol in dichloromethane from 1% to 5%) to afford the title compound as a beige powder (848 mg, yield 100%, purity 100%, t r = 0.89 min). LCMS (Method A); 1 H-NMR (DMSO-d 6 , 400MHz): δ (ppm) 7.54 (d, J = 8.6 Hz, 2H), 7.46–7.26 (m, 7H), 5.55 (s, 1H), 5.10 (d, J = 9.8 Hz, 2H), 3.67–3.43 (m, 4H), 2.32–1.97 (m, 2H).

[0842] Step 2: Synthesis of benzyl 3-azido-3-(4-chlorophenyl)pyrrolidine-1-carboxylate

[0843]

[0844] At 0°C, a sealed vial was charged with 3-(4-chlorophenyl)-3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (759 mg, 2.29 mmol) in a mixture of TFA (8.4 mL) and water (1.33 mL). Sodium azide (1.04 g, 16.0 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. Dichloromethane (10 mL) and saturated sodium bicarbonate solution (15 mL) were added. The aqueous layer was extracted with dichloromethane (1 x 10 mL). The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (815 mg, yield 100%, purity 100%, t r = 1.03 min). LCMS (Method A); 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)7.60-7.48(m,4H),7.47-7.28(m,6H),5.12(s,2H),4.07-3. 88(m,1H),3.75–3.38(m,3H),2.58-2.52(m,1H),2.41(dt,J=22.4,11.8Hz,1H)

[0845] Step 3: Synthesis of benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate

[0846]

[0847] In a round bottom flask under nitrogen, triphenylphosphine (614 mg, 2.34 mmol) followed by 4-methylbenzenesulfonic acid hydrate (1.34 g, 7.02 mmol) were added to a stirred solution of 3-azido-3-(4-chlorophenyl)pyrrolidine-1-carboxylic acid benzyl ester (835 mg, 2.34 mmol) in THF (10 mL). The mixture was stirred at room temperature for 1.5 hours. The suspension was filtered, washed with THF (5 mL), and dried under vacuum for 18 hours to give the title compound as a white powder (890 mg, yield 74%, purity 100%, t r =1.04 min). LCMS (Method A): m / z found 331.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.51(s,3H),7.59–7.51(m,4H),7.50–7.46(m,2H),7.43–7.31(m,5H),7.11(d,J=7.9Hz,2H),5. 13(d,J=4.9Hz,2H),4.07(d,J=11.7Hz,1H),3.82–3.53(m,3H),2.53(s,1H),2.47(d,J=13.3Hz,1H),2.29(s,3H).

[0848] Step 4: Synthesis of benzyl 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylate

[0849]

[0850] In a sealed tube, 4-(trifluoromethoxy)benzenesulfonyl chloride (255 μL, 1.50 mmol) was added to a stirred solution of 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylic acid benzyl tosylate (688 mg, 1.37 mmol) and triethylamine (1.9 mL, 13.7 mmol) in DCM (20 mL). The reactants were stirred at room temperature for 3 days. Water (5 mL) was added, and the aqueous layer was extracted with dichloromethane (1×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of ethyl acetate in cyclohexane from 10% to 40%) to give the title compound as a yellow oil (162 mg, yield 36%, purity 100%, t r =0.62 min). LCMS (Method A): m / z found 331.2 [M+H] + .

[0851] Step 5: Synthesis of benzyl 3-(4-chlorophenyl)-3-(4-(trifluoromethoxy)benzamido)pyrrolidine-1-carboxylate

[0852]

[0853] In a sealed tube, a mixture of 3-amino-3-(4-chlorophenyl)pyrrolidine-1-formic acid benzyl ester (52 mg, 0.157 mmol), triethylamine (44 μL, 0.314 mmol), 1-hydroxybenzotriazole hydrate (72 mg, 0.472 mmol), 3-(ethyliminomethylamino)-N,N-dimethyl-propane-1-amine hydrochloride (39 mg, 0.204 mmol) and 4-(trifluoromethoxy)benzoic acid (36 mg, 0.173 mmol) in DMF (1.56 mL) was stirred at room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and dichloromethane (15 mL), and water (10 mL) was added. The aqueous layer was extracted with dichloromethane (1 x 10 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of methanol in dichloromethane from 0% to 5%) to afford the title compound as a beige powder (53.5 mg, yield 65%, purity 99%, t r =1.06 min). LCMS (Method A): m / z found (DMSO-d 6,400MHz): δ(ppm)9.00(s,1H),7.94(d,J=8.8Hz,2H),7.50–7.25(m,11H),5.10(d,J=3.7Hz,2H),4.16(dd,J =21.7,11.3Hz,1H),3.87(dd,J=24.0,11.4Hz,1H),3.64–3.34(m,2H),2.84–2.65(m,1H),2.41–2.21(m,1H).

[0854] Step 6: Synthesis of N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide

[0855]

[0856] In a round-bottom flask, to a stirred suspension of 3-(4-chlorophenyl)-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine-1-carboxylic acid benzyl ester (50 mg, 0.0964 mmol) in acetonitrile (1.75 mL) at room temperature was added iodo(trimethyl)silane (41 μL, 0.289 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 15% ammonia methanol in dichloromethane). The residue was triturated in methanol, filtered, washed with methanol (3 mL), and dried under vacuum at 70 ° C for 1 hour. The residue was then triturated in a 2M solution of hydrogen chloride in diethyl ether (482 μL, 0.964 mmol) for 2 hours, filtered, washed with diethyl ether, and dried under vacuum at 70 ° C for 16 hours to give the hydrochloride salt of the title compound as a white powder (32.6 mg, yield 80%, purity 99.6%, t r =1.37 min). LCMS (Method E): m / z found 385 [M+H] + ; 1 H-NMR (DMSO-d 6 ,600MHz): δ(ppm)9.37(br s,2H),8.98(s,1H),7.96-8.08(m,2H),7.45-7.50(m,4H),7.41-7.44(m,2H),4.18(dd,J=12.2,1. 0Hz,1H),3.63(d,J=12.2Hz,1H),3.38-3.49(m,2H),2.82-2.92(m,1H),2.21(dt,J=13.4,9.8Hz,1H

[0857] Example 34: 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine (34)

[0858]

[0859] Step 1: Synthesis of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethan-1-one

[0860]

[0861] In a round-bottom flask, at room temperature, under nitrogen, 2-bromo-1-(3,4-dichlorophenyl)ethanone (25.00g, 90.5mmol) was added to a stirred solution of 2M dimethylamine in THF (81mL, 0.163mol), triethylamine (14mL, 0.0996mol) and DMAP (553mg, 4.53mmol) in anhydrous DCM (200mL). The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was quenched with water (500mL), and EtOAc (800mL) was added. The water layer was extracted with EtOAc (2x 30mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 20% to 100% to afford the title compound as a brown oil (15.81 g, 70% yield, 93% purity, t r =0.52 min). LCMS (Method A): m / z found 232.1 [M+H] + ; 1 H-NMR (DMSO-d 6 , 400MHz): δ (ppm) 8.18 (d, J = 2.0Hz, 1H), 7.94 (dd, J = 8.4, 2.0Hz, 1H), 7.80 (d, J = 8.4Hz, 1H), 3.76 (s, 2H), 2.24 (s, 6H).

[0862] Step 2: Synthesis of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethane-1-ol

[0863]

[0864] To a stirred solution of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethanone (930 mg, 4.01 mmol) in methanol (15 mL) was added sodium borohydride (227 mg, 6.01 mmol) in a round bottom flask at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 1 hour and allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in DCM and half-saturated NaHCO 3 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 (MeOH + 2% NH 4 OH) in DCM (gradient from 1% to 10%) to afford the title compound as a brown oil (830 mg, yield 87%, purity 99%, t r =0.51 min). LCMS (Method A): m / z found 234.2 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.63–7.50(m,2H),7.34(ddd,J=8.3,2.0,0.5Hz,1H),5.26( d, J=4.1Hz, 1H), 4.66 (td, J=6.8, 3.9Hz, 1H), 2.48–2.30 (m, 2H), 2.19 (s, 6H).

[0865] Step 3: Synthesis of 2-chloro-2-(3,4-dichlorophenyl)-N,N-dimethylethane-1-amine

[0866]

[0867] In a sealed tube under nitrogen, a solution of thionyl chloride (3.3 mL, 45.7 mmol) in chloroform (8 mL) was added to a stirred solution of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethanol (1.07 g, 4.57 mmol) in chloroform (8 mL). The mixture was stirred at 70 °C for 1 hour and concentrated under reduced pressure to give the hydrochloride salt of the title compound as an orange solid (1.26 g, yield 95%, t r =0.58 min). LCMS (Method A): m / z found 252.1 [M-HCl+H] + ; 1 H-NMR (DMSO-d 6,400MHz): δ(ppm)9.98(s,1H),7.89(d,J=2.1Hz,1H),7.77(d,J=8.5Hz,1H),7.58(dd,J=8.4,2 .2Hz,1H),5.77(dt,J=8.5,3.8Hz,1H),4.07–3.89(m,1H),3.77(d,J=13.7Hz,1H),2.85(s,6H)

[0868] Step 4: Synthesis of 2-(4-bromo-1H-pyrazol-1-yl)-2-(3,4-dichlorophenyl)-N,N-dimethylethane-1-amine

[0869]

[0870] In a sealed tube under nitrogen, a suspension of 2-chloro-2-(3,4-dichlorophenyl)-N,N-dimethyl-ethylamine hydrochloride (250 mg, 0.865 mmol), 4-bromo-1H-pyrazole (130 mg, 0.865 mmol) and cesium carbonate (620 mg, 1.90 mmol) in anhydrous DMF (2.5 mL) was stirred at room temperature for 16 hours. The crude product was poured into half-saturated NaHCO 3 The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 1% to 5%) to afford the title compound as a beige oil (195 mg, yield 58%, purity 94%, t r =0.66 min). LCMS (Method A): m / z found 364.2 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.18(d,J=0.7Hz,1H),7.68–7.57(m,3H),7.36(dd,J=8.4,2.1Hz,1H),5.67( dd,J=9.4,5.9Hz,1H), 3.22(dd,J=12.9,9.5Hz,1H), 2.79(dd,J=13.0,5.9Hz,1H), 2.18(s,6H).

[0871] Step 5: Synthesis of 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethan-1-amine

[0872]

[0873] In a sealed tube, a solution of 2-(4-bromopyrazol-1-yl)-2-(3,4-dichlorophenyl)-N,N-dimethyl-ethylamine (100 mg, 0.275 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (57 mg, 0.275 mmol) and potassium carbonate (49 mg, 0.358 mmol) in 1,4-dioxane (4 mL) and water (800 μL) was degassed with argon for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) (10 mg, 0.0138 mmol) was added, the mixture was degassed for 5 minutes, and stirred at 100 °C for 22 hours. The mixture was poured into half-saturated NaHCO 3 The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 The desired fractions were concentrated and purified by reverse phase chromatography using (MeCN + 0.1% ACOH) in (H 2 The desired fractions were concentrated and the residue was dissolved in Et 2 O. The solution was added dropwise to a stirred 2N HCl / Et 2 O. The resulting paste was dissolved with MeOH, and the solution was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was triturated in pentane. The suspension was filtered, the residue was washed with pentane and dried under reduced pressure at 45°C for 64 hours to obtain the hydrochloride salt of the title compound as a white powder (30 mg, yield 22%, purity 98.9%, t r =1.89 min). LCMS (Method E): m / z found 444.2 [M-HCl+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δ9.67(br s,1H),8.47(s,1H),8.19(s,1H),7.70-7.75(m,4H),7.38(d,J=8.07Hz,2H),7.34(dd,J=2.08,8.44Hz,1H),6.21(br d,J=8.31Hz,1H),4.29-4.41(m,1H),3.85(br s,1H),2.67-2.93(m,6H).

[0874] Example 35: 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine (35)

[0875]

[0876] Step 1: Synthesis of 2-(4-bromo-1H-imidazol-1-yl)-2-(3,4-dichlorophenyl)-N,N-dimethylethane-1-amine

[0877]

[0878] In a sealed tube under nitrogen, a suspension of 2-chloro-2-(3,4-dichlorophenyl)-N,N-dimethyl-ethylamine hydrochloride (250 mg, 0.865 mmol), 4-bromo-1H-imidazole (127 mg, 0.865 mmol) and cesium carbonate (620 mg, 1.90 mmol) in anhydrous DMF (2.5 mL) was stirred at room temperature for 16 hours. The crude product was poured into half-saturated NaHCO 3 The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 OH) in DCM (gradient from 1% to 10%) to afford the title compound as a beige oil (200 mg, yield 55%, purity 87%, t r =0.58 min). LCMS (Method A): m / z found 364.2 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.84(d,J=1.5Hz,1H),7.73(d,J=2.1Hz,1H),7.65(d,J=8.4Hz,1H),7.56(d,J=1.5Hz,1H),7.40(dd,J =8.4, 2.1Hz, 1H), 5.60 (dd, J = 9.8, 6.0Hz, 1H), 3.20 (dd, J = 13.0, 9.8Hz, 1H), 2.76 (dd, J = 13.2, 6.2Hz, 1H), 2.19 (s, 6H).

[0879] Step 2: Synthesis of 2-(3,4-dichlorophenyl)-N,N-dimethyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)ethan-1-amine

[0880]

[0881] In a sealed tube, a solution of 2-(4-bromoimidazol-1-yl)-2-(3,4-dichlorophenyl)-N,N-dimethyl-ethylamine (100 mg, 0.275 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (57 mg, 0.275 mmol) and potassium carbonate (49 mg, 0.358 mmol) in 1,4-dioxane (4 mL) and water (800 μL) was degassed with argon for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) (10 mg, 0.0138 mmol) was added, the mixture was degassed for 5 minutes, and stirred at 100 °C for 22 hours. The mixture was poured into half-saturated NaHCO 3 The crude product was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 The desired fractions were concentrated and purified by reverse phase chromatography using (MeCN + 0.1% AcOH) in (H 2 The desired fractions were concentrated and the residue was dissolved in Et 2 O. The solution was added dropwise to a stirred 2N HCl / Et 2 O, and the resulting suspension was stirred at room temperature for 16 hours. The suspension was filtered and the residue was washed with Et 2 O and dried under reduced pressure at 45°C for 64 hours to obtain the hydrochloride salt of the title compound as a white powder (33 mg, yield 24%, purity 98.9%, t r =1.73 min). LCMS (Method E): m / z found 444.2 [M-HCl+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δ10.43(br s,1H),8.91(br s,1H),8.37(br s,1H),7.88-7.92(m,3H),7.76(d,J=8.56Hz,1H),7.45-7.50(m,3H),6.34(br d,J=9.29Hz,1H),4.47(br t,J=12.35Hz,1H),3.94(br d,J=12.47Hz,1H),2.91(br s,3H),2.82(brs,3H).

[0882] Example 36: 1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole (36)

[0883]

[0884] Step 1: Synthesis of benzyl 3-(4-chlorophenyl)-3-((2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrrolidine-1-carboxylate

[0885]

[0886] In a sealed tube under nitrogen, sodium carbonate (128 mg, 1.21 mmol) was added to a stirred solution of 3-amino-3-(4-chlorophenyl)pyrrolidine-1-carboxylic acid benzyl ester (100 mg, 0.302 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethanone (86 mg, 0.302 mmol) in anhydrous acetonitrile (10 mL). The mixture was stirred at 40 ° C for 6 hours and then at 60 ° C for 16 hours. Additional 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethanone (86 mg, 0.302 mmol) was added and the mixture was stirred at 40 ° C for 3 days and then cooled to 0 ° C. Water was added and the mixture was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of EtOAc in heptane from 5% to 40%) to afford the title compound as a yellow oil (80 mg, yield 42%, purity 85%, t r =0.87 min). LCMS (Method B): m / z found 533.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.06–7.92(m,2H),7.51–7.23(m,11H),5.09(s,2H),3.98–3.82(m,2H),3.82– 3.66(m,1H),3.62–3.35(m,3H),2.86(s,1H),2.44(s,1H),2.11(ddd,J=21.4,12.3,8.8Hz,1H).

[0887] Step 2: Synthesis of benzyl 3-(4-chlorophenyl)-3-(N-(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)formamido)pyrrolidine-1-carboxylate

[0888]

[0889] In a sealed tube under nitrogen, acetic anhydride (472 μL, 5.10 mmol) was stirred at 0°C. Formic acid (2.4 mL, 63.8 mmol) was added dropwise and the mixture was stirred at 0°C for 5 minutes. A solution of 3-(4-chlorophenyl)-3-[[2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl]amino]pyrrolidine-1-carboxylic acid benzyl ester (680 mg, 1.28 mmol) in anhydrous DCM (17 mL) was added dropwise and the mixture was stirred at room temperature for 16 hours. The mixture was poured into an ice-cold saturated aqueous sodium carbonate solution (pH = 9-10) and the mixture was stirred at room temperature for 5 minutes. 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 product was purified by flash chromatography on silica gel (using a gradient of EtOAc in heptane from 10% to 60%) to afford the title compound as a white foam (480 mg, yield 66%, purity 99%, t r =1.00 min). LCMS (Method A): m / z found 561.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.56(s,1H),8.13–8.00(m,2H),7.54–7.19(m,12H),5.15–5.04(m,2H),4.68–4.58(m,2H),4.16–3.9 6(m,2H),3.63(ddt,J=27.4,10.8,7.2Hz,1H),3.23(tt,J=11.1,7.0Hz,1H),2.68(p,J=6.8Hz,1H),2.62–2.51(m,1H).

[0890] Step 3: Synthesis of benzyl 3-(4-chlorophenyl)-3-(4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)pyrrolidine-1-carboxylate

[0891] In a sealed tube under nitrogen, ammonium formate (216 mg, 3.42 mmol) was added to a stirred solution of benzyl 3-(4-chlorophenyl)-3-[formyl-[2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl]amino]pyrrolidine-1-carboxylate (480 mg, 0.856 mmol) in acetic acid (5 mL). The mixture was stirred at 120 °C for 16 hours, cooled to room temperature, and poured into ice water. Half-saturated Na 2 CO 3The aqueous solution was added until pH = 9, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (using a gradient of 10% to 80% of EtOAc in heptane) to give the title compound as a yellow oil (320 mg, yield 66%, purity 97%, t r =0.85 min). LCMS (Method A): m / z found 542.3 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)8.15–7.93(m,2H),7.91–7.78(m,2H),7.55–7.14(m,11H),5.20–4.98(m,2H),4.60(dd,J=12.0,9. 2Hz,1H),4.16–3.95(m,1H),3.67–3.48(m,1H),3.48–3.32(m,1H),3.13(s,1H),2.72(ddd,J=22.3,16.5,8.6Hz,1H).

[0892] Step 4: Synthesis of 1-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-imidazole

[0893]

[0894] In a sealed tube under nitrogen, trimethylsilyl iodide (83 μL, 0.581 mmol) was added to a stirred solution of 3-(4-chlorophenyl)-3-[4-[4-(trifluoromethoxy)phenyl]imidazol-1-yl]pyrrolidine-1-carboxylic acid benzyl ester (315 mg, 0.581 mmol) in anhydrous acetonitrile (3 mL). The mixture was stirred at room temperature for 24 hours, and additional trimethylsilyl iodide (83 μL, 0.581 mmol) was added. The mixture was stirred at room temperature for 24 hours and concentrated to dryness. The residue was purified by flash chromatography on silica gel (using (MeOH + 2% NH 4 The desired fractions were concentrated and EtOH (gradient from 1% to 10%) was added to the residue. 2 O. The suspension was stirred at room temperature and HCl 2N / Et 2 The suspension was stirred at room temperature for 2 hours and filtered. The residue was washed with Et 2 O, and dried under reduced pressure at 45°C for 3 days. The solid was purified by reverse phase flash chromatography (using (ACN + 0.1% AcOH) in (H 2The desired fractions were concentrated and the residue was dissolved in DCM and half-saturated Na 2 CO 3 The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in MeOH (1 mL) and 2N HCl / Et 2 O (300 μL). The solution was stirred at room temperature for 16 hours and concentrated. The residue was added to Et 2 O and filtered. The residue was washed with Et 2 O and dried under reduced pressure at 45°C for 16 hours to obtain the dihydrochloride salt of the title compound as a white powder (107 mg, yield 38%, purity 99.8%, t r =1.53 minutes). LCMS (Method D): m / z found 408.2 [M-2HCl+H] + ; 1 H-NMR (DMSO-d 6 ,600MHz)δ9.7-10.4(m,2H),8.8-9.6(m,1H),8.46(br s,1H),7.8-8.1(m,2H),7.2-7.7(m,6H),4.68(br dd,1H,J=5.0,13.1Hz),3.7-4.1(m,1H),3.6-3.7(m,1H),3.42(br dd,1H,J=6.5,14.3Hz),3.30(brdd,1H,J=6.6,11.0Hz),2.7-2.9(m,1H).

[0895] Example 37: 1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole (37)

[0896]

[0897] Step 1: Synthesis of tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)-3-phenylpyrrolidine-1-carboxylate

[0898]

[0899] An ElectraSyn vial (5 mL, IKA) with a stir bar was charged with 1-[(tert-butoxy)carbonyl]-3-phenylpyrrolidine-3-carboxylic acid (95%, 184 mg, 0.600 mmol), 4-bromo-1H-pyrazole (98%, 30 mg, 0.200 mmol), N,N,N-tributylbutyl-1-ammonium hexafluorophosphate (58 mg, 0.150 mmol), Molecular sieves (100 mg), 2,4,6-trimethylpyridine (26 μL, 0.200 mmol) and DCM (3.0674 mL). An ElectraSyn vial cap equipped with an anode (graphite) and a cathode (Ni) was inserted into the mixture. After pre-stirring for 15 minutes, the reaction mixture was electrolyzed at a constant current of 10 mA for 3 hours. The ElectraSyn vial cap was removed and the electrodes were rinsed with DCM (2 mL). The resulting mixture was washed with 1M HCL (aq.) and water, dried over a phase separator, and concentrated in vacuo. The crude product was dissolved in a minimum amount of DCM and added to a large amount of Et 2 O. The resulting precipitate was filtered to give the starting N,N,N-tributylbutyl-1-ammonium hexafluorophosphate. The filtrate was concentrated (dark green oil) and purified by flash chromatography on silica gel (using a gradient of EtOAc in cyclohexane from 0% to 50%) to give the title compound as a yellow oil (20 mg, 23% yield, 92% purity, t r =1.02 min). LCMS (Method B): m / z found 336.2 [M-tBu+H] + ; 1 H-NMR (DMSO-d 6 ,400 MHz): δ(ppm)8.36(d,J=4.6 Hz,1H),7.64(d,J=3.9 Hz,1H),7.40–7.27(m,3H),7.22–7.13(m,2H),4.72(d,J=11.7 Hz,1H),3.80(dd,J=11.9,2.1 Hz,1H),3.54–3.34(m,1H),3.29–3.06(m,2H),2.64(ddd,J=13.4,9.4,5.5 Hz,1H),1.39(d,J=11.7 Hz,9H).

[0900] Step 2: Synthesis of tert-butyl 3-phenyl-3-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

[0901]

[0902] In a sealed tube, a solution of tert-butyl 3-(4-bromopyrazol-1-yl)-3-phenyl-pyrrolidine-1-carboxylate (20 mg, 0.0510 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (10 mg, 0.0510 mmol) and potassium carbonate (9.2 mg, 0.0663 mmol) in 1,4-dioxane (800 μL) and water (150 μL) was degassed with argon for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) (1.9 mg, 2.55 μmol) was added, the mixture was degassed for 5 minutes, and stirred at 100 °C for 22 hours. The mixture was poured into half-saturated NaHCO 3 The crude product was purified by flash chromatography on silica gel (using a gradient of 5% to 50% of EtOAc in heptane) to give the title compound as a white foam (30 mg, yield 68%, t r =1.11 min). LCMS (Method A): m / z found 474.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400 MHz): δ(ppm)8.64(s,1H),8.02(d,J=2.3 Hz,1H),7.79–7.68(m,2H),7.41–7.24(m,5H),7.24–7.14(m,2H),4.82–4.68(m,1H),3.86(dd,J=11.8,2.2 Hz,1H),3.51(q,J=10.0 Hz, 1H), 3.28–3.12 (m, 3H), 2.75–2.60 (m, 1H), 1.39 (d, J = 15.6 Hz, 9H).

[0903] Step 3: Synthesis of 1-(3-phenylpyrrolidin-3-yl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole

[0904]

[0905] In a sealed tube under nitrogen, 4M hydrogen chloride / dioxane (158 μL, 0.634 mmol) was added to a stirred solution of tert-butyl 3-phenyl-3-[4-[4-(trifluoromethoxy)phenyl]pyrazol-1-yl]pyrrolidine-1-carboxylate (30 mg, 0.0634 mmol) in 1,4-dioxane (300 μL) under nitrogen. The mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by reverse phase chromatography (using ACN + 0.1% AcOH in H 2The desired fractions were combined and the organic solvent was evaporated. Saturated NaHCO was added. 3 The aqueous solution was stirred until pH = 9, and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in Et 2 O and add 2N HCl in Et 2 O solution. The suspension was stirred at room temperature for 16 hours and concentrated. The residue was triturated in pentane and filtered. The residue was washed with pentane and dried under reduced pressure at 45°C for 16 hours to give the hydrochloride of the title compound as a white powder (9 mg, yield 34%, purity 98.6%, t r =1.96 min). LCMS (Method D): m / z found 374 [M+H] + ; 1 H-NMR (500 MHz, DMSO-d 6 )δppm 2.66-2.77(m,1H)3.13(td,J=11.49,6.60Hz,1H)3.37-3.45(m,1H)3.54-3.62(m,1H)3.77(d,J=12.47Hz,1H)4.74(dd,J=12.72,1 .47Hz, 1H) 7.23 (d, J = 7.09Hz, 2H) 7.37 (dd, J = 8.19, 6.48Hz, 5H) 7.74 (d, J = 8.80Hz, 2H) 8.11 (s, 1H) 8.64 (s, 1H) 9.17-9.81 (m, 2H).

[0906] Example 38: 4-phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide (38)

[0907]

[0908] Step 1: Synthesis of 1-phenyl-N-(4-(trifluoromethoxy)phenyl)methanesulfonamide

[0909]

[0910] In a sealed tube under nitrogen, phenylmethanesulfonyl chloride (98%, 500 mg, 2.57 mmol) was added to a stirred solution of 4-(trifluoromethoxy)aniline (382 μL, 2.83 mmol) and anhydrous pyridine (622 μL, 7.71 mmol) in anhydrous THF (7.3434 mL) at -5°C. The solution was stirred at 50°C for 20 hours and washed with half-saturated Na 2 CO 3The aqueous solution was diluted. The aqueous layer was extracted twice with DCM, filtered through a phase separator, filtered and concentrated. The crude product was dissolved in ether and pentane was added. The resulting solid was filtered and washed with pentane to give the title compound as a beige solid (603 mg, yield 71%, purity 100%, t r = 0.91 min). LCMS (Method A); 1 H-NMR (DMSO-d 6 ,500MHz): δ(ppm)10.05(s,1H),7.56–7.02(m,9H),4.51(s,2H).

[0911] Step 2: Synthesis of N-(4-methoxybenzyl)-1-phenyl-N-(4-(trifluoromethoxy)phenyl)methanesulfonamide

[0912]

[0913] To a stirred solution of 1-phenyl-N-[4-(trifluoromethoxy)phenyl]methanesulfonamide (99%, 603 mg, 1.80 mmol) and 1-(chloromethyl)-4-methoxy-benzene (0.27 mL, 1.98 mmol) in anhydrous DMF (6 mL) was added potassium carbonate (374 mg, 2.70 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 60 ° C overnight. Water and EtOAc were added to the mixture, the layers were separated, the organic layer was washed three times with brine, concentrated under reduced pressure, and purified by flash chromatography on silica gel (using a gradient of MeOH in DCM from 0% to 2%) to give the title compound as a yellow oil (840.5 mg, yield 98%, purity 95%, t r = 1.02 min). LCMS (Method A); 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.49–7.35(m,5H),7.34–7.24(m,4H),7.15–7.09(m,2H),6.86–6.76(m,2H),4.74(s,2H),4.65(s,2H),3.69(s,3H).

[0914] Step 3: Synthesis of 1-benzyl-N-(4-methoxybenzyl)-4-phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide

[0915]

[0916] To a stirred solution of N-[(4-methoxyphenyl)methyl]-1-phenyl-N-[4-(trifluoromethoxy)phenyl]methanesulfonamide (340 mg, 0.753 mmol) and benzylbis(2-bromoethyl)amine (242 mg, 0.753 mmol) in anhydrous THF (7.5 mL) at -15 °C under nitrogen was added 1 M NaHMDS (1.9 mL, 1.88 mmol). The reaction mixture was stirred at 0 °C for 2 hours, then slowly warmed to room temperature and stirred overnight. Additional 1 M NaHMDS (1.9 mL, 1.88 mmol) and benzyl-bis(2-bromoethyl)amine (242 mg, 0.753 mmol) were added at 0 °C, and the reaction mixture was stirred at 0 °C for 4 hours, then warmed to room temperature. The mixture was washed with saturated NH 4 Cl aqueous solution quenched, and extracted with EtOAc. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (using a gradient of 0% to 10% of MeOH in DCM) to obtain the title compound as an orange jelly (271 mg, yield 52%, purity 88%, t r =0.81 min). LCMS (Method B): m / z found 611.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.74–7.67(m,2H),7.45(dd,J=8.3,6.8Hz,2H),7.32–7.20(m,8H),7.17–7.09(m,2H),6.96–6.90(m,2H),6.76–6 .68(m,2H),4.22(s,2H),3.64(s,3H),3.31(s,2H),2.71(dd,J=21.0,12.4Hz,4H),2.27(t,J=12.4Hz,2H),1.84(t,J=11.7Hz,2H).

[0917] Step 4: Synthesis of N-(4-methoxybenzyl)-4-phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide

[0918]

[0919] To a stirred solution of 1-benzyl-N-[(4-methoxyphenyl)methyl]-4-phenyl-N-[4-(trifluoromethoxy)phenyl]piperidine-4-sulfonamide (88%, 241 mg, 0.347 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.12 mL, 0.695 mmol) in DCM (2.5 mL) was added 1-chloroethyl chloroformate (95%, 0.079 mL, 0.695 mmol) at 25 °C under nitrogen. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (2.5 mL) and the reaction mixture was stirred at 65 °C for 16 hours. The reaction mixture was cooled to room temperature and quenched with water. EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (using MeOH (0.7N NH 3 ) in dichloromethane with a gradient from 1% to 10%) to afford the title compound as a yellow powder (89 mg, yield 49%, purity 100%, t r =0.74 min). LCMS (Method A): m / z found 521.4 [M+H] + ; 1 H-NMR (DMSO-d 6 ,400MHz): δ(ppm)7.75(d,J=7.4Hz,2H),7.51(dd,J=8.4,6.5Hz,2H),7.45(t,J =7.2Hz,1H),7.31(d,J=9.0Hz,2H),7.18(d,J=8.5Hz,2H),6.93(d,J=8.8Hz,2H) ,6.73(d,J=8.8Hz,2H),4.20(s,2H),3.64(s,3H),3.27–3.19(m,2H),2.81(d,J =13.6Hz, 2H), 2.56 (s, 1H), 2.40 (t, J = 13.0Hz, 2H), 1.02 (dd, J = 6.1, 2.9Hz, 1H).

[0920] Step 5: Synthesis of 4-phenyl-N-(4-(trifluoromethoxy)phenyl)piperidine-4-sulfonamide

[0921]

[0922] To a stirred solution of N-[(4-methoxyphenyl)methyl]-4-phenyl-N-[4-(trifluoromethoxy)phenyl]piperidine-4-sulfonamide (100%, 89 mg, 0.171 mmol) in DCM (1 mL) at 25°C was added 2,2,2-trifluoroacetic acid (0.65 mL, 8.55 mmol) dropwise. The reaction mixture was stirred at 25°C for 1 hour. The reaction was washed with saturated Na 2 CO 3 The aqueous solution was basified and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (using M...

Claims

1. A compound of formula (I) or a salt, solvate, enantiomer, diastereomer, isotopomer or tautomer thereof: in: Ar is C6-C 10 Aryl or C2-C 10 heteroaryl, which may be optionally substituted by at least one substituent selected from the group consisting of 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-C6 10 Heteroaryl, C6-C 10 Aryl, C6-C 10 Aryloxy, halogen, OH, N(R a )(R b )、CN、NO2、-C(=O)R a 、-C(=O)OR a and -C(=O)N(R a )(R b ), Each C6-C 10 Aryl, C2-C 10 Heteroaryl or C6-C 10 The aryloxy substituents are independently optionally substituted with at least one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, F, Cl, Br, I, OH, CN, NO2, -C(=O)OR a and -C(=O)N(R a )(R b ),and The two vicinal substituents of Ar can be combined to form a 5- to 8-membered ring, and the ring is connected to the C6-C 10 Aryl or C2-C 10 Heteroaryl fused; R 1 Selected from the group consisting of: R 2 is selected from the group consisting of optionally substituted phenyl and optionally substituted C2-C 10 Heteroaryl, Where R 2 wherein each optional substituent is at least one selected from the group consisting of halogen, OH, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl; R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h (if present) are each independently H, Or from R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h The two geminal substituents selected in can be combined with the carbon atoms to which they are bonded to form an optionally substituted C3-C8 cycloalkyl group; R 4 is H; R A Selected from the group consisting of: H and C1-C6 alkyl; Each occurrence of R a are independently selected from the group consisting of: H, C1-C6 alkyl, benzyl and C6-C 10 Aryl; Each occurrence of R b are independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted phenyl and optionally substituted naphthyl, wherein R b The C1-C6 alkyl, benzyl, phenyl or naphthyl in the group is independently optionally substituted by at least one selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, CN, NO2, C(=O)OR a and C(=O)N(R a )(R a );and Wherein the compound of formula (I) is not selected from the group consisting of: N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimide amide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N'-methyl-4-(trifluoromethoxy)benzenesulfonimide amide; N-(3-(4-Fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-(4-Fluorophenyl)pyrrolidin-3-yl)-4-isopropoxybenzenesulfonamide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-6-isopropoxypyridine-3-sulfonamide; N-(3-(4-Fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonimide amide; N-(3-(4-chlorophenyl)pyrrolidin-3-yl)-N-methyl-4-(trifluoromethoxy)benzenesulfonamide; 3-amino-N-(3-(4-fluorophenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; 3-amino-N-(3-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(3,4-dichlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-phenylpiperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-Fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-phenylpiperidin-4-yl)-6-(trifluoromethoxy)pyridine-3-sulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide; N-(4-(5-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide; N-(4-(5-chlorothiazol-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-Fluorophenyl)piperidin-4-yl)-4-isopropoxybenzenesulfonamide; N-(4-(3,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(2,4-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(2,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(3-phenylpiperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(5-chlorothien-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chloro-2-fluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethyl)benzenesulfonamide; 3-amino-N-(4-(4-chlorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; and N-(4-(4-(difluoromethyl)phenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide.

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

3. The compound according to claim 1 or 2, wherein R 1 for 4. A compound as claimed in any one of claims 1 to 3, wherein at least one of the following applies: (a)R 2 is 4-fluorophenyl, which is further substituted by at least one additional substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C2-C6 alkyl; or (b)R 2 is 3-fluorophenyl, which is further substituted by at least one additional substituent selected from the group consisting of F, Br, OH, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl.

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

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

7. The compound of any one of claims 1 to 6, wherein Ar is 4-methoxyphenyl, optionally further substituted with at least one additional substituent selected from the group consisting of halogen, NH2 and C1-C3 alkoxy.

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

9. The compound of claim 1 or 2, wherein R 1 for 10. The compound of claim 9, wherein Ar is an optionally substituted phenyl or an optionally substituted pyridyl, wherein the optional substituent in Ar is at least one substituent selected from the group consisting of: C1-C6 haloalkoxy, C1-C6 alkoxy and -NH(C1-C6 alkyl).

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

12. The compound of claim 11, wherein Ar is 13. The compound of claim 12, wherein at least one of the following applies: (a)R 2 is 3,5-disubstituted phenyl, wherein each substituent is independently selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl; (b)R 2 is 4-chlorophenyl, which is further substituted by at least one substituent selected from the group consisting of Br, I, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl; (c)R 2 is 3-methylphenyl, which is further substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl; (d) R 2 is 3-pyridyl, which is optionally further substituted by at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl; and (e)R 2 is 4-pyridyl, which is optionally further substituted by at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl.

14. A compound as described in any one of claims 9 to 13, wherein R 2 Selected from the group consisting of:

15. The compound of claim 11, wherein Ar is 16. A compound as described in any one of claims 9-11 and 15, wherein at least one of the following applies: (a)R 2 Selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl, wherein the pyridyl is optionally substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl; (b)R 2 is 3-fluorophenyl, which is optionally substituted by at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl; or (c)R 2 is 4-fluorophenyl, which is further substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl.

17. A compound as described in any one of claims 9-11 and 15-16, wherein R 2 Selected from the group consisting of:

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

19. A compound as described in any one of claims 9-11 and 18, wherein Ar is 20. The compound of any one of claims 9-11 and 18-19, wherein R 2 is 4-chlorophenyl, which is optionally substituted with at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl.

21. A compound as described in any one of claims 9-11 and 18-20, wherein R 2 for 22. A compound as described in any one of claims 9-21, selected from the group consisting of: N-(4-(3,5-difluorophenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(6-chloropyridin-3-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(4-chloro-3-methylphenyl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide; N-(4-(5-chloropyridin-2-yl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide; N-(4-(3,4-difluorophenyl)piperidin-4-yl)-6-isopropoxypyridine-3-sulfonamide; N-(4-(4-chlorophenyl)piperidin-4-yl)-3-(methylamino)-4-(trifluoromethoxy)benzenesulfonamide; and N-(4-(2,5-dichloropyridin-4-yl)piperidin-4-yl)-4-(trifluoromethoxy)benzenesulfonamide.

23. The compound of claim 1 or 2, wherein R 1 for And two are selected from R 3 , R 3 '、R 4 , R 4 '、R 5 , R 5 '、R 6 and R 6 The geminal substituents forming the group are combined with the atoms to which they are bonded to form a C3-C8 cycloalkyl group.

24. A compound as described in any one of claims 1-2 and 23, wherein R 1 for 25. The compound of any one of claims 1-2 and 23-24, wherein R 2 is phenyl, which is optionally substituted by at least one substituent selected from the group consisting of halogen, C1-C3 haloalkoxy, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C6 alkyl.

26. A compound as described in any one of claims 1-2 and 23-25, wherein R 2 It is phenyl.

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

28. A compound as described in any one of claims 1-2 and 23-27, wherein Ar is 29. A compound as described in any one of claims 1-2 and 23-28, selected from the group consisting of: N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(6-phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide; and (R)-N-(6-Phenyl-4-azaspiro[2.5]octan-6-yl)-4-(trifluoromethoxy)benzenesulfonamide.

30. A compound of formula (II) or a salt, solvate, enantiomer, diastereomer, isotopomer or tautomer thereof: in: Ar is C6-C 10 Aryl or C2-C 10 heteroaryl, which may be optionally substituted by at least one substituent selected from the group consisting of 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-C6 10 Heteroaryl, C6-C 10 Aryl, C6-C 10 Aryloxy, halogen, OH, N(R a )(R b )、CN、NO2、-C(=O)R a 、-C(=O)OR a and -C(=O)N(R a )(R a ), Each C6-C 10 Aryl, C2-C 10 Heteroaryl or C6-C 10 The aryloxy substituents are independently optionally substituted with at least one substituent selected from the following group: 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 The two vicinal substituents of Ar can be combined to form a 5- to 8-membered ring, and the ring is connected to the C6-C 10 Aryl or C2-C 10 Heteroaryl fused; L is selected from the group consisting of: *-N(R B )S(=O)2-、*-C(=O)N(R B )- and optionally substituted C2-C 10 heteroarylene; R 5 Selected from the group consisting of: R 6 Selected from the group consisting of: optionally substituted C6-C 10 Aryl and optionally substituted C2-C 10 Heteroaryl, Where R 6 Each optional substituent is at least one selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -C(=O)OR a 、-S(=O)2(C6-C 10 Aryl) and -S(=O)2(C2-C 10 heteroaryl); R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h (if present) are each independently selected from the group consisting of H, C1-C6 alkyl, hydroxy, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 heterocyclyl, optionally substituted phenyl and optionally substituted phenoxy, wherein each optional substituent is at least one selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, halogen, OH, C(=O)OR a and C(=O)N(R a )(R a ), Among them, selected from R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h The two geminal substituents of may be combined with the carbon atom to which they are bonded to form a moiety selected from the group consisting of an optionally substituted C3-C8 cycloalkyl group and an optionally substituted C2-C 10 Heterocyclic group, Among them, selected from R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h The two vicinal substituents of can be combined with the carbon atom to which they are bonded to form a moiety selected from the group consisting of an optionally substituted C3-C8 cycloalkyl, an optionally substituted C2-C 10 heterocyclyl, and optionally substituted phenyl; Among them, selected from R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h Two substituents separated by two to five carbon atoms may be combined with the carbon atom to which they are bonded to form a moiety selected from the group consisting of an optionally substituted C4-C7 cycloalkyl and an optionally substituted C4-C8 heterocyclyl; R 8 Selected from the group consisting of: 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, Wherein phenyl, benzyl or -S(=O) 2- Each optional substituent in the phenyl group is independently at least one selected from the group consisting of F, Cl, Br, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, hydroxyl and -NH-C(=O)R a ; R 9 Selected from the group consisting of: optionally substituted C6-C 10 Aryl and optionally substituted C2-C 10 Heteroaryl, Where R 9 Each optional substituent is at least one selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -C(=O)OR a 、-S(=O)2(C6-C 10 Aryl) and -S(=O)2(C2-C 10 heteroaryl); R 10 Selected from the group consisting of: -(optionally substituted C1-C6 alkylene) (optionally substituted C2-C 12 heterocycloalkyl) and optionally substituted C1-C6 aminoalkyl, Where R 10 Each optional substituent is at least one selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -C(=O)OR a 、-S(=O)2(C6-C 10 Aryl) and -S(=O)2(C2-C 10 heteroaryl); R 11 is H; R B is H; Each occurrence of R a are independently selected from the group consisting of: H, C1-C6 alkyl, benzyl and C6-C 10 aryl; and Each occurrence of R b are independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted phenyl and optionally substituted naphthyl, wherein R b The C1-C6 alkyl, benzyl, phenyl or naphthyl in the group is independently optionally substituted by at least one selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, CN, NO2, C(=O)OR a and C(=O)N(R a )(R a ).

31. The compound of claim 30, selected from the group consisting of: in, R 12a , R 12b and R 12c (if present) are each independently selected from the group consisting of: 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 ).

32. The compound of claim 31, wherein at least one of the following applies: (a)R 12a , R 12b and R 12c At least one of (if present) is H; and (b)R 12a , R 12b and R 12c Two of (if any) are H.

33. A compound as described in any one of claims 30-32, wherein Ar is optionally substituted phenyl.

34. A compound as described in any one of claims 30-33, wherein Ar is selected from the group consisting of:

35. A compound as described in any one of claims 30-34, wherein at least one of the following applies: (a)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least one of (if any) is H; (b)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least two (if any) of are H; (c)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least three (if any) of them are H; (d) R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least four (if any) of them are H; (e)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least five (if any) of them are H; (f)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least six (if any) of them are H; (g)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h At least seven (if any) of (h)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h Each of (if present) is H.

36. A compound as described in any one of claims 30-35, wherein R 6 is phenyl optionally substituted by at least one halogen.

37. A compound as described in any one of claims 30-36, wherein R 6 It is a phenyl group substituted by two halogens.

38. A compound as described in any one of claims 30-37, wherein R 6 Selected from the group consisting of:

39. A compound as described in any one of claims 30-34, wherein R 9 is phenyl optionally substituted by at least one halogen.

40. A compound as described in any one of claims 30-34 and 39, wherein R 9 It is a phenyl group substituted by two halogens.

41. A compound as described in any one of claims 30-34 and 39-40, wherein R 9 Selected from the group consisting of:

42. A compound as described in any one of claims 30-34 and 39-41, wherein R 10 is -CH2N(optionally substituted C1-C6 alkyl)2.

43. A compound as described in any one of claims 30-34 and 39-42, wherein R 10 It is -CH2NMe2.

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

45. A compound of formula (III) or a salt, solvate, enantiomer, diastereomer, isotopomer or tautomer thereof: in: Ar is C6-C 10 Aryl or C2-C 10 heteroaryl, which may be optionally substituted by at least one substituent selected from the group consisting of 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-C6 10 Heteroaryl, C6-C 10 Aryl, C6-C 10 Aryloxy, halogen, OH, N(R a )(R b )、CN、NO2、-C(=O)R a 、-C(=O)OR a and -C(=O)N(R a )(R b ), Each C6-C 10 Aryl, C2-C 10 Heteroaryl or C6-C 10 The aryloxy substituents are independently optionally substituted with at least one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, F, Cl, Br, I, OH, CN, NO2, -C(=O)OR a and -C(=O)N(R a )(R b ),and The two vicinal substituents of Ar can be combined to form a 5- to 8-membered ring, and the ring is connected to the C6-C 10 Aryl or C2-C 10 Heteroaryl fused; R 13 Selected from the group consisting of: R 14a , R 14b , R 14c and R 14d Each independently selected from the group consisting of: C6-C 10 Aryl and optionally substituted C2-C 10 Heteroaryl, Where R 14a , R 14b , R 14c and R 14d Each optional substituent is at least one selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl and -C(=O)OR a ; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 15i Each is independently selected from the group consisting of: H, halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -C(=O)OR a ; R 16 is H; R 17a , R 17b , R 17d , R 17e , R 17f , R 17g , R 17h , R 17i , R 17j , R 17k and R 17l (if present) are each independently selected from the group consisting of: H, halogen, and C2-C8 heterocycloalkyl; R 18a , R 18b , R 18c and R 18d Each is independently selected from the group consisting of: H and C1-C6 alkyl; R 19 Selected from the group consisting of optionally substituted cyclohexyl and -CH2NMe2; X is selected from the group consisting of: -NR 16 -and-C(R 17k )(R 17l )-; R C is H; Each occurrence of R a are independently selected from the group consisting of: H, C1-C6 alkyl, benzyl and C6-C 10 aryl; and Each occurrence of R b are independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted phenyl and optionally substituted naphthyl, wherein R b The C1-C6 alkyl, benzyl, phenyl or naphthyl in the group is independently optionally substituted by at least one selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, CN, NO2, C(=O)OR a and C(=O)N(R a )(R a ); If R 13 for Then at least one of the following applies: (a) Selected from R 17a , R 17b , R 17d , R 17e , R 17f , R 17g , R 17h , R 17i , R 17j , R 17k and R 17l At least one of (if present) is halogen, wherein said halogen is optionally F; (b)R 14b is a phenyl group substituted by at least two fluorine atoms; (c)R 14b is 4-chlorophenyl, and Ar is selected from the group consisting of a phenyl group optionally substituted with at least two substituents and a pyridyl group optionally substituted with a C1-C6 alkoxy group; and (d) R 14b is 4-chlorophenyl, and Ar is not selected from the group consisting of 4-trifluoromethoxy and 6-trifluoromethoxy-3-pyridyl; If R 13 for Then at least one of the following applies: (a)R 14c is phenyl, and is selected from R 18a , R 18b , R 18c and R 18d One, three or four of are CH3; and (b)R 14c is phenyl, Ar is an optionally substituted pyridyl; Among them, if R 13 for And R 19 is CH2NMe2, then the compound of formula (III) is N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide; and Among them, if R 13 for And R 19 is an optionally substituted cyclohexyl group, then at least one of the following applies: (a) Ar is optionally substituted pyridyl; and (b) Ar is substituted with at least one C1-C6 alkoxy substituent.

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

47. as claimed in claim 45 or 46 described compounds, wherein Ar is phenyl, it is optionally substituted by at least one substituent selected from the group consisting of: C1-C3 haloalkoxy and N (R a )(R b ).

48. A compound as described in any one of claims 45-47, wherein Ar is phenyl optionally substituted by at least one substituent selected from the group consisting of trifluoromethoxy and NH2.

49. A compound as described in any one of claims 45-48, wherein Ar is selected from the group consisting of:

50. A compound as described in claim 45 or 46, wherein Ar is pyridinyl optionally substituted with at least one C1-C6 alkoxy substituent.

51. A compound as described in any one of claims 45-46 and 50, wherein Ar is 3-pyridyl substituted with at least one C1-C6 alkoxy substituent.

52. A compound as described in any one of claims 45-46 and 50-51, wherein Ar is 53. A compound as described in any one of claims 45-52, wherein R 13 for 54. A compound as described in any one of claims 45-53, wherein R 13 Selected from the group consisting of:

55. A compound as described in any one of claims 45-54, wherein R 14a Selected from the group consisting of phenyl optionally substituted by at least one halogen and pyridinyl substituted by at least one halogen.

56. A compound as described in any one of claims 45-55, wherein R 14a Selected from the group consisting of:

57. The compound of claim 45 or 46, wherein R 13 for 58. A compound as described in any one of claims 45-46 and 57, wherein Ar is 59. A compound as described in any one of claims 45-46 and 57-58, wherein R 14d It is cyclohexyl.

60. A compound as described in any one of claims 45-46 and 57-59, wherein R 19 for 61. The compound of claim 45 or 46, wherein R 13 for 62. The compound of claim 61, wherein R 14a Selected from the group consisting of:

63. The compound of claim 61 or 62, wherein Ar is selected from the group consisting of:

64. The compound of claim 45 or 46, wherein R 13 for 65. The compound of claim 64, wherein selected from R 17e and R 17f At least one of the group consisting of is a halogen.

66. A compound as described in any one of claims 45-46 and 64-65, wherein R 13 for 67. A compound as described in any one of claims 45-46 and 64-66, wherein R 14b is phenyl substituted by at least one halogen.

68. A compound as described in any one of claims 45-46 and 64-67, wherein R 14b for 69. A compound as described in any one of claims 45-46 and 64-68, wherein Ar is phenyl substituted with at least one C1-C6 alkoxy group.

70. A compound as described in any one of claims 45-46 and 64-69, wherein Ar is 71. The compound of claim 45 or 46, wherein R 13 for 72. The compound of claim 71, wherein at least one of the following applies: (a) Select from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i and R 17j At least one of the groups is H; (b) Selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i and R 17j At least two of the groups are H; (c) Selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i and R 17j At least three of the groups are H; (d) Selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i and R 17j At least four of the groups are H; (e) Select from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i and R 17j At least five of the groups are H; (f) Selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i and R 17j At least six of the groups are H; (g) Selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i and R 17j At least seven of the groups are H; (h)R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17i and R 17j Each of them is H.

73. The compound of claim 71 or 72, wherein R 17i and R 17j are each independently H and are selected from R 17a , R 17b , R 17c , R 17d , R 17e , R 17f At least one of the groups consisting of is a C2-C8 heterocycloalkyl group.

74. The compound of claim 73, wherein the C2-C8 heterocycloalkyl is 75. A compound as described in claims 71-74, wherein Ar is 76. The compound of claim 45 or 46, wherein R 13 for 77. A compound as described in any one of claims 45-46 and 76, wherein selected from R 18a , R 18b , R 18c and R 18d Two of the groups consist of C1-C6 alkyl groups.

78. A compound as described in any one of claims 45-46 and 76-77, wherein R 13 for 79. The compound of claim 78, wherein Ar is pyridyl substituted with at least one C1-C6 alkoxy group.

80. The compound of claim 78 or 79, wherein Ar is 81. A compound as described in any one of claims 45-80, selected from the group consisting of: N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(phenyl(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-((5-chloropyridin-2-yl)(piperidin-4-yl)methyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide; (R)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide; (S)-N-((4-chlorophenyl)(piperidin-4-yl)methyl)-6-isopropoxypyridine-3-sulfonamide; 6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide; (R)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide; (S)-6-isopropoxy-N-(phenyl(piperidin-4-yl)methyl)pyridine-3-sulfonamide; N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(1-(2,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide; (R)-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide; (S)-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide; 3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-3-amino-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide; (R)-N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide; (S)-N-(1-(3,4-difluorophenyl)-2-(piperazin-1-yl)ethyl)-6-isopropoxypyridine-3-sulfonamide; N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide; (R)-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide; (S)-N-(1-(4-chlorophenyl)-2-(piperazin-1-yl)ethyl)benzenesulfonamide; N-(1-(4-fluorophenyl)-2-(3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((R)-1-(4-fluorophenyl)-2-((R)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((R)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((S)-1-(4-fluorophenyl)-2-((R)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; N-((S)-1-(4-fluorophenyl)-2-((S)-3-fluoropiperidin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(2-([1,3'-diazetidine]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; (S)-N-(2-([1,3'-diazetidine]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; (R)-N-(2-([1,3'-diazetidine]-1'-yl)-1-(4-fluorophenyl)ethyl)-4-(trifluoromethoxy)benzenesulfonamide; N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide; (R)-N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide; (S)-N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide; N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide; (R)-N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide; (S)-N-((2,2-dimethyl-1-phenylcyclopropyl)methyl)-6-isopropoxypyridine-3-sulfonamide; N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide; (R)-N-(cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide; and (S)-N-(Cyclohexyl(3,5-dichlorophenyl)methyl)-6-isopropoxypyridine-3-sulfonamide.

82. A pharmaceutical composition comprising at least one compound as described in any one of claims 1-81 and at least one pharmaceutically acceptable carrier.

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

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

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

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

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