CN116806217A

CN116806217A - Substituted cyclic modulators of protein phosphatase 2A (PP 2A) and methods of use thereof

Info

Publication number: CN116806217A
Application number: CN202280010739.3A
Authority: CN
Inventors: G·L·特雷诺; M·O·拉巴尔格拉西亚; L·福尔莫斯; O·盖尔博韦特; F·卡丘西
Original assignee: Lapata Therapy Co
Current assignee: Lapata Therapy Co
Priority date: 2021-02-08
Filing date: 2022-02-07
Publication date: 2023-09-26

Abstract

The present disclosure relates in part to chemical modulators of protein phosphatase 2A (PP 2A). The compounds of the present disclosure are useful for treating, preventing and/or alleviating cancer, diabetes, autoimmune diseases, solid organ transplant rejection, graft-versus-host disease, chronic Obstructive Pulmonary Disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative diseases and cardiac hypertrophy.

Description

Substituted cyclic modulators of protein phosphatase 2A (PP 2A) and methods of use thereof

Cross Reference to Related Applications

According to 35U.S. c. ≡119 (e), the present application calls for priority of U.S. provisional patent application No. 63/146,789 filed on 8 th year 2 of 2021, U.S. provisional patent application No. 63/191,405 filed on 21 th year 5 of 2021, and U.S. provisional patent application No. 63/273,405 filed on 29 th year 10 of 2021, all of which are incorporated herein by reference in their entireties.

Background

Protein phosphatase 2A (PP 2A) is one of the four major serine threonine phosphatases and is involved in negative regulation of cell growth and division. PP2A holoenzyme is a heterotrimeric protein comprising structural subunit (a), catalytic subunit (C) and regulatory subunit (B). PP2A heterotrimeric protein phosphatase is a ubiquitous and conserved phosphatase with a broad substrate specificity and multiple cellular functions.

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.

Thus, there is a need in the art for PP2A chemical modulators for the treatment, prevention and/or amelioration of PP2A related pathologies and/or indications. The present disclosure addresses this need.

Disclosure of Invention

The present disclosure provides certain compounds of formula (I), or salts, solvates, enantiomers, diastereomers, isotopic isomers, or tautomers thereof, or any mixtures thereof, selected from (Ia), (Ib), (Ic), (Id), (Ie), and (If), wherein the substituents in (Ia), (Ib), (Ic), (Id), (Ie), and (If) are defined elsewhere herein:

the present disclosure further provides a pharmaceutical composition comprising at least one compound of the present disclosure. In certain embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

The present disclosure further provides methods of treating, preventing and/or alleviating PP 2A-related disorders in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of the present disclosure and/or at least one pharmaceutical composition of the present disclosure. In certain embodiments, the PP 2A-related disorder is selected from the group consisting of cancer, diabetes, autoimmune disease, solid organ transplant rejection, graft versus host disease, chronic Obstructive Pulmonary Disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative disease, and cardiac hypertrophy.

Detailed Description

Reference will now be made in detail to certain embodiments of the disclosed subject matter. Although the disclosed subject matter will be described in connection with the enumerated claims, it should be understood that the exemplary subject matter is not intended to limit the claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should be construed in a flexible manner to include not only the values explicitly recited as the limits of the range, but also to include all the individual values or sub-ranges encompassed within that range as if each value and sub-range is explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also the 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 indicated, the recitations "about X to Y" and "about X to about Y" have the same meaning. Also, unless otherwise indicated, a statement of "about X, Y or about Z" has the same meaning as "about X, about Y, or about Z".

In this document, the terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or" unless otherwise specified. It is stated that "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". Also, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description and not of limitation. The use of any section headings is to aid in reading the file and should not be construed as limiting; information related to chapter titles may appear inside or outside the particular chapter. All publications, patents, and patent documents mentioned in this document are incorporated by reference in their entirety as if individually incorporated by reference.

In the methods described herein, acts may be performed in any order, unless time or order of operations is explicitly recited. Furthermore, certain actions may be performed concurrently unless explicitly stated to be separate. For example, the claimed actions to perform X and the claimed actions to perform Y may occur simultaneously in a single operation, and the resulting process would fall within the literal scope of the claimed process.

Definition of the definition

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" means-C (O) CH ₃ A group. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen, or sulfur, so long as the point of attachment to the parent molecular moiety remains on the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.

As used herein, the term "amido" alone or in combination includes acyl groups attached to the parent moiety through an amino group. "Acylamido group An example of a "group" is acetamido (CH ₃ C(O)NH-)。

As used herein, the terms "administration," "administering," and the like refer to methods that can be used to deliver a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein, such as, for example, goodman and Gilman, the Pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, pharmaceutical Sciences (current edition), mack Publishing co., easton, pa. In certain embodiments, the compounds and compositions described herein are administered orally.

As used herein, the term "alkoxy" or "alkoxy" refers to a group having a straight, branched, or cyclic configuration of 1 to 6 carbon atoms, and combinations thereof, attached to a parent structure through oxygen. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclohexyloxy, and cycloheptyloxy.

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

Examples of unsaturated alkenyl groups include, but are not limited to, vinyl (vinyl), -CH ═ CH ₂ ) 1-propenyl (-CH ═ CH-CH) ₃ ) 2-propenyl (allyl, -CH-CH ═ CH) ₂ ) Propenyl (1-methyl vinyl, -C (CH) ₃ )═CH ₂ ) Butenyl, pentenyl and hexenyl.

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.

In one embodiment, the term "alkyl" refers to straight, branched, or cyclic hydrocarbon structures and combinations thereof, and may be saturated or unsaturated (e.g., partially unsaturated, fully unsaturated). Thus, the term "alkyl" includes alkenylene, alkynyl, cycloalkyl, and the like. Alkyl groups, as defined herein, may be optionally substituted.

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 examples of branched-chain alkyl groups include isopropyl, tert-butyl, isobutyl, sec-butyl, and neopentyl. In one embodiment, the alkyl group is a saturated alkyl group having 2 to 6 carbon atoms. In one embodiment, the linear or branched alkyl group has 6 or less carbon atoms in its backbone (e.g., the linear chain is C ₁ -C ₆ Branched chain is C ₃ -C ₆ ). Term (C) ₁ -C ₆ ) Alkyl is understood to mean alkyl having 1 to 6 carbon atoms.

The term "alkylamino" refers to an alkyl group attached to the parent molecular moiety through an amino group. Alkylamino groups may be mono-or di-alkylated to form groups such as, for example, N-methylamino, N-ethylamino, N-dimethylamino, N-ethylmethylamino.

The terms "alkylcarbonyl" and "alkoxycarbonyl" refer to-C (=o) alkyl or-C (=o) alkoxy, respectively.

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

In one embodiment, the term "alkynyl" refers to a compound having one or more carbon-carbon threeAlkyl of the bond. In one embodiment, the term "C ₂ -C ₆ Alkynyl "refers to an alkynyl moiety having 2 to 6 carbon atoms.

Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (ethynyl), -c=ch), and 2-propynyl (propargyl), -CH ₂ -C＝CH)。

The term "alkylene" refers to a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH) ₂ -). Unless otherwise indicated, the term "alkyl" may include "alkylene" groups.

Amido (carbamoyl), carbamoyl (carbamyl), carboxamide (aminocarbonyl), carboxamide (carboxamide)) are for example-C (=O) NH ₂ -C (=o) NH (alkyl) or-C (=o) N (alkyl) ₂ Wherein alkyl is independently an amino substituent as defined for alkyl.

The term "amino" refers to-NH ₂ 。

As used herein, the terms "aryl" and "heteroaryl" refer to (i) phenyl (or benzene) or a monocyclic 5-or 6-membered heteroaryl ring containing 1-4 heteroatoms selected from O, N or S, as defined for heterocycles; (ii) A bicyclic 9 or 10 membered aromatic or heteroaromatic ring system containing 0 to 4 heteroatoms selected from O, N or S, as defined for carbocyclic or heterocyclic rings; or (iii) a tricyclic 13 or 14 membered aromatic or heteroaromatic ring system containing 0 to 5 heteroatoms selected from O, N or S, as defined for carbocyclic or heterocyclic rings. Aromatic 6-to 14-membered carbocycles include, but are not limited to, benzene, naphthalene, anthracene, indane, tetrahydronaphthalene, and fluorene, and 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. Aryl and heteroaryl, as used herein, refer to residues in which one or more of the rings are aromatic, but not necessarily all of the rings.

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

As used herein, the term "azido" refers to-N ₃ 。

As used herein, the term "carbamate" refers to an ester of carbamic acid (-NHC (=o) O-), which may be attached to the parent molecular moiety from a nitrogen or acid terminus, and which may be optionally substituted as defined herein.

As used herein, the term "carbonyl" refers to a-C (=o) -group and includes formyl (C (=o) H).

As used herein, the term "carboxyl" or "carboxyl" refers to-C (=o) OH or the corresponding "carboxylate" anion such as in carboxylate.

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

The term "combination therapy (combination therapy)" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, such as in a single formulation (e.g., capsule or injection) having a fixed proportion of active ingredient or in multiple separate dosage forms of each active ingredient. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the benefit of the pharmaceutical combination in treating the condition or disorder described herein.

The term "comprising" as used in this specification is intended to include the feature(s) or act(s) thereinafter without excluding the existence of one or more additional features or acts.

The term "cycloalkyl" or alternatively "carbocycle" used alone or in combination refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety may contain 3 to 12 carbon atom ring members, and may optionally be an optionally substituted benzofused ring system as defined herein. In one embodiment, cycloalkyl groups contain 3 to 7 carbon atoms or 3 to 6 carbon atoms.

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.

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

Examples of bicyclic cycloalkyl groups 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 such as decalin, octahydronaphthalene, and polycyclic (multicentric) saturated or partially unsaturated types, including spiro-fused systems. Examples of the bicyclic and tricyclic isomers are bicyclo [1, 1] pentane, norbornane, camphor, adamantane, bicyclo [3,2,1] octane and [4,4.1] -bicyclononane.

As used herein, the term "cyano", "nitrile" or "nitrile" refers to-CN.

As used herein, the term "diastereoisomer" refers to stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

As used herein, the term "disease" is intended to be generally synonymous with the terms "disorder" and "condition" (as in medical conditions) and is used interchangeably as they both reflect abnormal conditions of impaired normal function of the human or animal body or a portion thereof, often manifested as obvious signs and symptoms, and result in reduced survival time or quality of life of the human or animal.

As used herein, the term "effective amount" or "therapeutically effective amount (therapeutically effective amount)" refers to an amount of at least one compound administered sufficient to achieve a desired result, e.g., in some degree of alleviation of one or more symptoms of the disease or disorder being treated. In some cases, the result is a reduction and/or alleviation of the signs, symptoms, or etiology of a disease, or any other desired change in a biological system. In certain instances, the result is reduced growth, killing or induction of apoptosis in at least one more abnormally proliferative cell, such as a cancer cell. In certain instances, an "effective amount" for therapeutic use is an amount of a composition comprising a compound described herein that is required to provide a clinically significant reduction in disease. In any individual case, the appropriate "effective" amount is determined using any suitable technique, such as a dose escalation study.

As used herein, the terms "ester", "carboxylate (carboxylic acid ester) or" oxycarbonyl "refer to a-C (=o) O alkyl group, wherein alkyl is an ester substituent defined for the alkyl group described above. 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.

As used herein, the term "halo" or "halogen" alone or in combination means fluorine, chlorine, bromine or iodine. In one embodiment, the halogen may be fluorine or chlorine.

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

As used herein, the term "haloalkyl" refers to an alkyl group having the meaning as defined above, wherein one or more hydrogens are replaced with halogen. In one embodiment, haloalkyl is mono-, di-and polyhaloalkyl. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include, but are not limited to, fluoromethylene (-CFH-), difluoromethylene (-CF) ₂ (-) and chloromethylene (-CHCl-).

The terms "heterocycle" and "heterocyclyl" are interchangeable and refer to a cycloaliphatic or aryl carbocyclic residue in which 1 to 4 carbons are substituted with heteroatoms selected from N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. In one embodiment, the heterocycle is non-aromatic. In a further embodiment, the heterocycle is aromatic.

Examples of heterocycles include, but are not limited to, aziridine, azetidine pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxane, benzodioxole (benzodioxole), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran, and the like. Examples of heterocyclyl residues include, but are not limited to, piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, tetrahydrothiazolyl, isothiazolyl, quinuclidinyl, isothiazolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl (also known in the past as phenylthio), benzothienyl, thiomorpholinyl, oxadiazolyl, triazolyl, and tetrahydroquinolinyl. It should be noted 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 and other heteroatoms. Oxaaryl is a subset of oxygen and other heteroatoms. Oxaaryl is a subset of the oxa-cyclic rings; examples include furan and oxazole. Thiaaryl is a subset of thia rings; examples include, but are not limited to, thiophenes and thiazines. An azacyclic ring is a heterocyclic ring 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. Azaaryl is a subset of nitrogen heterocycles; examples include, but are not limited to, pyridine, pyrrole, and thiazole. Unless specifically indicated, heterocyclic groups may be optionally substituted.

The term "hydroxy" refers to-OH.

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

As used herein, the term "imino" refers to =n-.

As used herein, the term "modulate" refers to increasing or decreasing the activity of PP 2A. In one embodiment, compounds according to one or more embodiments disclosed herein may increase the activity of a particular PP2A holoenzyme while decreasing the activity of other PP2A heterotrimers.

As used herein, the term "nitro" refers to-NO ₂ 。

The term "optionally substituted (optionally substituted)" may be used interchangeably with "unsubstituted or substituted (unsubstituted or substituted)". The term "substituted" refers to the substitution of one or more hydrogen atoms in a particular group with a particular group. In one embodiment, 1, 2 or 3 hydrogen atoms are substituted with a specific group. In the case of alkyl and cycloalkyl groups, more than three hydrogen atoms may be substituted with fluorine. In one embodiment, all available hydrogen atoms may be replaced by fluorine. The two substituents may be linked together to form a three to seven membered non-aromatic carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example to form methylenedioxy or ethylenedioxy. In one embodiment, the carbocycle or heterocycle formed is a fused ring or spiro ring.

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

When referred to as a substituent per se, the term "oxo" (oxy) refers to a double bond oxygen (=o).

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

As used herein, the term "patient" refers to all mammals including humans. Examples of patients include humans, cattle, dogs, cats, goats, sheep, pigs, and rabbits. In some embodiments, the patient is a human.

The term "pharmaceutically acceptable salt" may refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and inorganic bases, and organic acids and organic bases. When the compounds disclosed in this specification are basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts of the compounds disclosed in this 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, ethylenediamine tetraacetic acid, formic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, 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 (tannic), tartaric acid, teoclatic acid, p-toluenesulfonic acid, and the like. When the compounds contain acidic side chains, suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include, but are not limited to, metal salts or organic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc made from lysine, arginine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Other pharmaceutically acceptable salts include, if appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl groups having 1 to 20 carbon atoms.

The terms "prevention", "prevention" or "prevention" as used herein and other grammatical equivalents include preventing additional symptoms, preventing the underlying metabolic cause of the symptoms, inhibiting a disease or disorder, e.g., preventing the development of a disease or disorder, and are intended to include prophylaxis. These terms also include achieving a prophylactic benefit. For prophylactic benefit, 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 disease recurrence.

The term "stereoisomers" refers to compounds that are bound by the same atom through the same bond but have different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

As used herein, the terms "sulfonate", "sulfonic acid" and "sulfonic acid group (sulfonic)" refer to-SO ₃ The H group and its anion serve as sulfonic acid for salt formation.

As used herein, the term "sulfanyl" refers to-S-.

As used herein, the term "sulfinyl" refers to-S (=o) -.

As used herein, the term "sulfonyl" refers to-S (=o) ₂ -。

The term "sulfonamide" (sulfamoyl); sulfamide) refers to-S (=o) ₂ NH ₂ 、-S(＝O) ₂ NH (alkyl), -S (=O) ₂ N (alkyl) ₂ Wherein alkyl is independently an amino substituent as defined for alkylamino. Examples of sulfonamide groups include, but are not limited to, -S (=o) ₂ NH ₂ 、-S(＝O) ₂ NH(CH ₃ )、-S(＝O) ₂ N(CH ₃ ) ₂ 、-S(＝O) ₂ NH(CH ₂ CH ₃ )、-S(＝O) ₂ N(CH ₂ CH ₃ ) ₂ and-S (=o) ₂ NHPh。

The term "sulfonylimide" is understood to mean the group-NHS ((=O) (NR) ¹⁸ ))-。

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible by a low energy barrier. Some non-limiting examples of proton tautomers (also known as proton-transfer tautomers) include tautomers by proton transfer, such as keto-enol and imine-enamine isomerisation. Valence tautomers include interconversions by recombining some of the bonded electrons. Unless otherwise indicated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

As used herein, the terms "thia" and "thio" refer to an-S-group or ether in which oxygen is replaced by sulfur. Oxidized derivatives of thio, i.e., sulfinyl and sulfonyl, are included in the definition of thia and thio.

The terms "treatment", "treatment" or "treatment" and other grammatical equivalents as used herein include alleviating, inhibiting or alleviating a symptom, reducing or inhibiting the severity of a symptom, delaying the onset of a symptom, delaying the recurrence of a symptom, alleviating or ameliorating the underlying metabolic cause of a symptom, inhibiting a disease or disorder, e.g., preventing the development of a disease or disorder, alleviating the disease or disorder, causing regression of a disease or disorder, alleviating a disorder caused by a disease or disorder, or stopping the symptoms of a disease or disorder. The term further includes obtaining a therapeutic benefit. Therapeutic benefit refers to eradication or amelioration of the underlying disorder being treated, and/or eradication or amelioration of one or more physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual.

Unless otherwise indicated or described, structures of compounds according to one or more embodiments disclosed in this specification are also intended to include all stereoisomeric forms of the structures (e.g., enantiomers, diastereomers, and cis-trans isomers); for example, the R and S configuration, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers for each asymmetric center. Thus, single stereochemical isomers, as well as mixtures of enantiomers, diastereomers and cis-trans isomers (or conformations) of the compounds of the invention are within the scope of the present disclosure. The configuration of any carbon-carbon double bond present herein is selected for convenience only and is not intended to designate a particular configuration; thus, any carbon-carbon double bond described herein as trans may be cis, trans, or a mixture of both in any ratio. Unless otherwise indicated, all tautomeric forms of the compounds according to one or more embodiments disclosed in the present specification are within the scope of the present disclosure. Furthermore, the compounds of the present disclosure may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to unsolvated forms.

Compounds of formula (I)

In certain embodiments, the present disclosure relates to compounds of formula (I), or a salt, solvate, enantiomer, diastereomer, isotopic isomer, or tautomer thereof, selected from the group consisting of:

wherein:

ar is C ₆ -C ₁₀ Aryl or C ₂ -C ₁₀ Heteroaryl, which is selected from C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, C ₂ -C ₁₀ Heteroaryl, C ₆ -C ₁₀ Aryl, C ₆ -C ₁₀ Aryloxy, halogen, OH, NH ₂ ，CN、NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^a and-C (=O) N (R) ^a )(R ^a ) Optionally substituted with at least one substituent of (c),

wherein each C in Ar ₆ -C ₁₀ Aryl, C ₂ -C ₁₀ Heteroaryl or C ₆ -C ₁₀ Aryloxy substituents are independently selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, F, cl, br, I, OH, CN, NO ₂ 、-C(＝O)OR ^a and-C (=O) N (R) ^a )(R ^a ) Optionally substituted, and

wherein the two ortho substituents of Ar can combine to provide a 5-to 8-membered ring fused to Ar;

g is optionally substituted C ₃ -C ₈ Cycloalkyl group, which is selected from C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, phenyl, halogen, OH, NH ₂ ，CN、NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^a and-C (=O) N (R) ^a )(R ^a ) Optionally substituted with at least one substituent of (c),

wherein the phenyl group in G is selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, F, cl, br, I, OH, CN, NO ₂ 、-C(＝O)OR ^a and-C (=O) N (R) ^a )(R ^a ) Optionally substituted, and

wherein two substituents in G may combine to provide a C with G ₃ -C ₈ Cycloalkyl spiro union (spiro), fused or bridged C ₃ -C ₈ Cycloalkyl;

R ¹ selected from the group consisting of

R ² Selected from H, halogen, optionally substituted C ₁ -C ₆ Alkyl, optionally substituted phenyl, optionally substituted C ₃ -C ₆ Cycloalkyl, optionally substituted C ₂ -C ₁₀ Heterocyclyl, optionally substituted C ₁ -C ₆ Aminoalkyl, optionally substituted C ₁ -C ₆ Alkoxyalkyl, optionally substituted C ₁ -C ₆ Haloalkyl, optionally substituted C ₂ -C ₆ Alkynyl, -C (=o) OR ^a and-C (=O) N (R) ^a )(R ^a )，

Wherein R is ² Each optional substituent of (a) is selected from halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ Haloalkyl, -C (=o) OR ^a ，-S(＝O) ₂ -C ₆ -C ₁₀ Aryl and-S (=o) ₂ -C ₂ -C ₁₀ At least one of heteroaryl;

R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ and R is ⁸ ' each independently selected from H, C ₁ -C ₆ Alkyl, hydroxy, C ₁ -C ₄ Haloalkyl, optionally substituted C ₃ -C ₈ Cycloalkyl, optionally substituted C ₂ -C ₆ Heterocyclyl, optionally substituted phenyl and optionally substituted phenoxy,

wherein each optional substituent in the heterocyclyl, phenyl or phenoxy group is selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, halogen, OH, C (=o) OR ^a And C (=O) N (R) ^a )(R ^a ) At least one of the above-mentioned materials,

wherein is selected from R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ The two paired substituents of' may combine with the carbon atom to which they are bound to form a member selected from optionally substituted C ₃ -C ₈ Cycloalkyl and optionally substituted C ₂ -C ₁₀ The moiety(s) of the heterocyclic group,

wherein is selected from R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ The two ortho substituents of' may combine with the carbon atom to which they are bound to form a member selected from optionally substituted C ₃ -C ₈ Cycloalkyl, optionally substituted C ₂ -C ₁₀ A heterocyclyl and optionally substituted phenyl moiety;

wherein is selected from R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ ' two substituents, separated by 2 to 5 carbon atoms, which may combine with the carbon atom to which they are bound to form a member selected from optionally substituted C ₄ -C ₇ Cycloalkyl and optionally substituted C ₄ -C ₈ A portion of a heterocyclic group;

R ¹⁰ selected from 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 -an optionally substituted phenyl group, wherein,

wherein phenyl, benzyl or-S (=o) _2- Each optional substituent in the phenyl group is independently selected from F, cl, br, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ Haloalkyl, hydroxy and-NH-C (=o) R ^a At least one of (a) and (b);

R ^10’ Selected from substituted phenyl, substituted benzyl, -C (=o) -optionally substituted C ₁ -C ₆ Alkyl, wherein R is ^10’ Wherein the benzyl or phenyl group is selected from halogen, C ₁ -C ₃ Haloalkyl, OH and N (R) ^a )(R ^b ) Is substituted with at least one substituent of (a), and wherein R ^10’ Is substituted with at least one phenyl substituent;

y is selected from C (R) ^a )(R ^a )、C＝O、NR ¹⁰ 、NR ^10’ And the group consisting of O and O,

wherein if Y is C (R ^a )(R ^a ) And R is ² Is optionally substituted phenyl, ar comprises C substituted with at least one trifluoromethoxy substituent ₆ -C ₁₀ Aryl or C ₂ -C ₁₀ Heteroaryl;

z is selected from C= O, NR ¹⁰ 、NR ^10’ O and S;

R ^A is H or C ₁ -C ₆ An alkyl group;

R ^a each occurrence of (a) is independently selected from H, C ₁ -C ₆ Alkyl, benzyl and C ₆ -C ₁₀ An aryl group; and

R ^b independently selected from H, optionally substituted C ₁ -C ₆ Alkyl, optionally substituted benzyl, optionally substituted phenyl and optionally substituted naphthyl, wherein R ^b C in (C) ₁ -C ₆ Alkyl, benzyl, phenyl or naphthyl are independently selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, halogen, OR ^a 、CN、NO ₂ 、C(＝O)OR ^a And C (=O) N (R) ^a )(R ^a ) Optionally substituted at least one of (a);

wherein in (Ia), (Ib) and (Ic) at least one of the following applies:

a)R ² is phenyl or C ₂ -C ₁₀ Heteroaryl, wherein phenyl or heteroaryl is selected from halogen, OH, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy and C ₁ -C ₆ At least one substituent of the alkyl group is optionally substituted;

b)R ³ and R is ^3’ At least one of which is phenyl or C ₂ -C ₁₀ Heteroaryl, wherein phenyl or heteroaryl is selected from halogen, OH, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy and C ₁ -C ₆ At least one substituent in the alkyl group;

c)R ³ 、R ^3’ 、R ⁴ and R is ^4’ At least one of which is phenyl or C ₂ -C ₁₀ Heteroaryl, wherein phenyl or heteroaryl is selected from halogen, OH, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy and C ₁ -C ₆ At least one substituent of the alkyl group is optionally substituted, wherein one of Y and Z is present and is selected from c= O, NR ¹⁰ And O, wherein R ¹⁰ Selected from H, C ₃ -C ₆ Cycloalkyl, phenyl, optionally substituted benzyl, -C (=o) OR ^b 、-C(＝O)R ^b ，-S(＝O) ₂ -optionally substituted phenyl;

d) Selected from R ³ 、R ^3’ 、R ⁴ 、R ^4’ 、R ⁵ 、R ^5’ 、R ⁶ 、R ^6’ 、R ⁷ 、R ^7’ 、R ⁸ And R is ^8’ Is combined with the carbon atom to which they are bonded to form C ₃ -C ₈ Cycloalkyl or C ₂ -C ₆ Heterocyclyl wherein cycloalkyl or heterocyclyl is selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, halogen, N (R) ^a )(R ^a )、OR ^a 、C(＝O)R ^a 、C(＝O)OR ^a And C (=O) N (R) ^a )(R ^a ) Is substituted by at least one substituent group of the formula,

e) Selected from R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ The two ortho substituents of' combine with the carbon atom to which they are bound to form C ₃ -C ₈ Cycloalkyl, C ₂ -C ₁₀ Heterocyclyl or phenyl wherein cycloalkyl, heterocyclyl or phenyl is selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, halogen, OR ^a 、C(＝O)R ^a 、C(＝O)OR ^a And C (=O) N (R) ^a )(R ^a ) Is substituted by at least one substituent;

f) Selected from R ³ 、R ^3’ 、R ⁴ 、R ^4’ 、R ⁵ 、R ^5’ 、R ⁶ 、R ^6’ 、R ⁷ 、R ^7’ 、R ⁸ And R is ^8’ Is combined with the carbon atom to which they are bonded to form C ₃ -C ₈ Cycloalkyl or C ₂ -C ₆ Heterocyclyl, and is selected from R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ The two ortho substituents of' combine with the carbon atom to which they are bound to form C ₃ -C ₈ Cycloalkyl, C ₂ -C ₁₀ Heterocyclyl or phenyl wherein each of cycloalkyl, heterocyclyl or phenyl is independently selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, halogen, N (R) ^a )(R ^a )、OR ^a 、C(＝O)R ^a 、C(＝O)OR ^a And C (=O) N (R) ^a )(R ^a ) Optionally substituted with at least one substituent of (a);

g) Y is N (R) ^10’ ) And R is ⁴ 、R ^4’ 、R ⁶ And R is ^6’ Each, if present, is independently selected from H, C ₁ -C ₆ Alkyl, hydroxy, C ₁ -C ₄ Haloalkyl, phenyl and phenoxy;

h)R ² 、R ³ 、R ^3’ 、R ⁴ and R is ^4’ At least one of which is optionally substituted C ₃ -C ₈ Cycloalkyl or C ₂ -C ₁₀ Heterocyclyl wherein each optional substituent in cycloalkyl or heterocycloalkyl is independently selected from halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, OR ^a 、N(R ^a )(R ^b )、C(＝O)R ^a And C (=O) OR ^a The method comprises the steps of carrying out a first treatment on the surface of the And

i)R ² selected from optionally substituted C ₁ -C ₆ Haloalkyl, optionally substituted C ₂ -C ₆ Aminoalkyl and optionally substituted C ₂ -C ₆ Alkynyl, wherein R is ² Each optional substituent in the haloalkyl, aminoalkyl and alkynyl groups in (a) is selected from C ₁ -C ₆ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, halogen, C (=o) R ^a 、C(＝O)OR ^a 、C(＝O)N(R ^a )(R ^a )、S(＝O) ₂ -optionally substituted phenyl and S (=o) ₂ -optionally substituted C ₂ -C ₁₀ At least one of the heteroaryl groups.

In certain embodiments, C is substituted with at least one trifluoromethyl substituent ₆ -C ₁₀ Aryl or C ₂ -C ₁₀ Heteroaryl is trifluoromethylphenyl. In certain embodiments, the trifluoromethylphenyl group is 4-trifluoromethylphenyl.

In certain embodiments, the compound of formula (I) is selected from:

wherein:

R ⁹ each occurrence of (a) is independently selected from F, cl, br, C ₁ -C ₃ Alkoxy and C ₁ -C ₃ Haloalkoxy groups; and

n is an integer selected from 0, 1 and 2.

In certain embodiments, R ^A Is H. In certain embodiments, R ^A Is methyl.

In certain embodiments, the compound of formula (I) is selected from:

in certain embodiments, the compound of formula (I) is selected from:

/>

wherein:

n is an integer selected from 0, 1 and 2.

In certain embodiments, R ¹ Selected from the group consisting of />

Wherein R is ^a1 And R is ^a2 Each independently selected from F, cl, br, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy and C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^a1 Is F. In certain embodiments, R ^a1 Is Cl. In certain embodiments, R ^a1 Is Br. In certain embodiments, R ^a1 Is Me. In certain embodiments, R ^a1 Is CHF ₂ . In certain embodiments, R ^a1 Is CF (CF) ₃ . In certain embodiments, R ^a1 Is OMe. In certain embodiments, R ^a1 Is OEt. In certain embodiments, R ^a1 Is OCF ₃ . In certain embodiments, R ^a1 Is OCF ₂ H。

In certain embodiments, R ^a2 Is F. In certain embodiments, R ^a2 Is Cl. In certain embodiments, R ^a2 Is Br. In certain embodiments, R ^a2 Is Me. In certain embodiments, R ^a2 Is CHF ₂ . In certain embodiments, R ^a2 Is CF (CF) ₃ . In certain embodiments, R ^a2 Is OMe. In certain embodiments, R ^a2 Is OEt. In certain embodiments, R ^a2 Is OCF ₃ . In certain embodiments, R ^a2 Is OCF ₂ H。

In certain embodiments, ar is selected from

X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ Each independently selected from C ₁ -C ₆ Alkyl, F, cl, N (R) ^a )(R ^b )、OR ^b 、-C(＝O)OR ^a 、-C(＝O)N(R ^a )(R ^a )、NH ₂ 、OH、NO ₂ 、C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy and phenyl.

In certain embodiments, the compound of formula (I) is a compound of formula (Ia-1) or (Ia' -1), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-2) or (Ia' -2), wherein R ³ 、R ^3’ 、R ⁴ And R is ^4’ At least two of which are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-3) or (Ia' -3), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ And R is ⁵ At least four of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-4) or (Ia' -4), wherein R ³ And R is ^3’ At least one of which is H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-5) or (Ia' -5), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H. In some casesIn embodiments, the compound of formula (I) is a compound of formula (Ia-6) or (Ia' -6), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-7) or (Ia' -7), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ia-8) or (Ia' -8), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ At least ten of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-1) or (Ib' -1), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-2) or (Ib' -2), wherein R ³ 、R ^3’ 、R ⁴ And R is ^4’ At least two of which are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-3) or (Ib' -3), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ And R is ⁵ At least four of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-4) or (Ib' -4), wherein R ³ And R is ^3’ At least one of which is H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-5) or (Ib' -5), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-6) or (Ib' -6), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-7) or (Ib' -7), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ib-8) or (Ib' -8), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ At least ten of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-1) or (Ic' -1), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-2) or (Ic' -2), wherein R ³ 、R ^3’ 、R ⁴ And R is ^4’ At least two of which are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-3) or (Ic' -3), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ And R is ⁵ At least four of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-4) or (Ic' -4), wherein R ³ And R is ^3’ At least one of which is H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-5) or (Ic' -5), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-6) or (Ic' -6), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-7) or (Ic' -7), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ic-8) or (Ic' -8), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ At least ten of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Id-1), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (Ie-1), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H. In certain embodiments, the compound of formula (I) is a compound of formula (If-1), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H.

In certain embodiments, X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ Each of which, if present, is H.

In certain embodiments, X is present ¹ 、X ² 、X ³ And X ⁴ And X is ¹ 、X ² 、X ³ And X ⁴ At least one of which is H. In certain embodiments, X is present ¹ 、X ² 、X ³ And X ⁴ And X is ¹ 、X ² 、X ³ And X ⁴ At least two of which are H. In certain embodiments, X is present ¹ 、X ² 、X ³ And X ⁴ And X is ¹ 、X ² 、X ³ And X ⁴ At least three of which are H.

In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ And X ⁵ And X is ¹ 、X ² 、X ³ 、X ⁴ And X ⁵ At least one of which is H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ And X ⁵ And X is ¹ 、X ² 、X ³ 、X ⁴ And X ⁵ At least two of which are H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ And X ⁵ And X is ¹ 、X ² 、X ³ 、X ⁴ And X ⁵ At least three of which are H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ And X ⁵ And X is ¹ 、X ² 、X ³ 、X ⁴ And X ⁵ Is H.

In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ At least one of which is H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ At least two of which are H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ At least three of which are H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ Is H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ Is H.

In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least one of which is H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least two of which are H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least three of which are H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ Is H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ Is H. In certain embodiments, X is present ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ And X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ Is H.

In certain embodiments, X ¹ Is OCF ₃ . In certain embodiments, X ¹ Is thatIn certain embodiments, X ¹ Is CF (CF) ₃ . In certain embodiments, X ¹ Is NH ₂ . In certain embodiments, X ¹ Is O (CH) ₃ ) ₂ )。

In certain embodiments, X ² Is OCF ₃ . In some casesIn embodiments, X ² Is thatIn certain embodiments, X ² Is CF (CF) ₃ . In certain embodiments, X ² Is NH ₂ . In certain embodiments, X ² Is O (CH) ₃ ) ₂ )。/>

In certain embodiments, X ³ Is OCF ₃ . In certain embodiments, X ³ Is thatIn certain embodiments, X ³ Is CF (CF) ₃ . In certain embodiments, X ³ Is NH ₂ . In certain embodiments, X ³ Is O (CH) ₃ ) ₂ )。

In certain embodiments, X ⁴ Is OCF ₃ . In certain embodiments, X ⁴ Is thatIn certain embodiments, X ⁴ Is CF (CF) ₃ . In certain embodiments, X ⁴ Is NH ₂ . In certain embodiments, X ⁴ Is O (CH) ₃ ) ₂ )。

In certain embodiments, X ⁵ Is OCF ₃ . In certain embodiments, X ⁵ Is thatIn certain embodiments, X ⁵ Is CF (CF) ₃ . In certain embodiments, X ⁵ Is NH ₂ . In certain embodiments, X ⁵ Is O (CH) ₃ ) ₂ )。

In certain embodiments, X ⁶ Is OCF ₃ . In certain embodiments, X ⁶ Is thatIn certain embodiments, X ⁶ Is CF (CF) ₃ . In certain embodiments, X ⁶ Is NH ₂ . In certain embodiments, X ⁶ Is O (CH) ₃ ) ₂ )。

In certain embodiments, X ⁷ Is OCF ₃ . In certain embodiments, X ⁷ Is thatIn certain embodiments, X ⁷ Is CF (CF) ₃ . In certain embodiments, X ⁷ Is NH ₂ . In certain embodiments, X ⁷ Is O (CH) ₃ ) ₂ )。

In certain embodiments, ar isIn certain embodiments, ar is +.>In certain embodiments, ar is +.>In certain embodiments, ar is +.>In certain embodiments, ar is +.>In certain embodiments, ar is +.>In certain embodiments, ar isIn certain embodiments, ar is +.>In certain embodiments, ar is +.>In certain embodiments, ar is +.>In certain embodiments, ar isIn certain embodiments, ar is +.>In certain embodiments, ar isIn certain embodiments, ar is +. >

In certain embodiments, ar is 1-naphthyl. In certain embodiments, ar is 2-naphthyl. In certain embodiments, ar is 2-pyridyl. In certain embodiments, ar is 3-pyridyl. In certain embodiments, ar is 4-pyridyl.

In certain embodiments, G is:

wherein:

R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ and R is ^14’ Each independently selected from H, C ₁ -C ₆ Alkyl, C ₁ -C ₆ A haloalkyl group and an optionally substituted phenyl group,

wherein each optional substituent in the phenyl group is selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, halogen, OH, C (=o) OR ^a And C (=O) N (R) ^a )(R ^a ) At least one of, and

wherein R is ¹¹ And R is ¹³ Or R is ¹¹ And R is ^13’ Can optionally be combined with the atoms to which they are bonded to form C ₃ -C ₈ Cycloalkyl groups.

In certain embodiments, R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ At least one of which is H; in certain embodiments, R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ At least two of which are H. In certain embodiments, R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ At least three of which are H. In certain embodiments, R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ Is H. In certain embodiments, R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ Is H. In certain embodiments, R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ Is H. In certain embodiments, R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ Is H.

In certain embodiments, R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ At least one of them is CF ₃ 。

In certain embodiments, G is

In certain embodiments, R ² is-CH ₂ F. In certain embodiments, R ² is-C (=o) OEt. In certain embodiments, R ² Is Ph. In certain embodiments, R ² Is thatIn certain embodiments, R ² Is thatIn certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is thatIn certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is thatIn certain embodiments, R ² Is->In certain embodiments, R ² Is thatIn certain embodiments, R ² Is->In certain embodiments, R ² Is->In certain embodiments, R ² Is->

In certain embodiments, R ³ Is methyl. In certain embodiments, R ³ Is trifluoromethyl. In certain embodiments, R ³ Is a hydroxyl group. In certain embodiments, R ³ is-C (=o) OMe. In certain embodiments, R ³ Is Ph. In certain embodiments, R ³ Is thatIn certain embodiments, R ³ Is->In certain embodiments, R ³ Is->In certain embodiments, R ³ Is->In certain embodiments, R ³ Is thatIn certain embodiments, R ³ Is F.

In certain embodiments, R ³ Is methyl. In certain embodiments, R ³ Is trifluoromethyl. In certain embodiments, R ³ ' is a hydroxyl group. In certain embodiments, R ³ ' is-C (=o) OMe. In certain embodiments, R ³ ' is Ph. In certain embodiments, R ³ ' isAt a certain positionIn some embodiments, R ^3’ Is->In certain embodiments, R ³ Is->In certain embodiments, R ³ ' is->In certain embodiments, R ³ ' isIn certain embodiments, R ^3’ Is F.

In certain embodiments, R ⁴ Is methyl. In certain embodiments, R ⁴ Is trifluoromethyl. In certain embodiments, R ⁴ Is a hydroxyl group. In certain embodiments, R ⁴ is-C (=o) OMe. In certain embodiments, R ⁴ Is Ph. In certain embodiments, R ⁴ Is thatIn certain embodiments, R ⁴ Is->In certain embodiments, R ⁴ Is thatIn certain embodiments, R ⁴ Is->In certain embodiments, R ⁴ Is->In certain embodiments, R ⁴ Is F.

In certain embodiments, R ⁴ ' is methyl. In certain embodiments, R ⁴ ' is trifluoromethyl. In certain embodiments, R ⁴ ' is a hydroxyl group. In certain embodiments, R ⁴ ' is-C (=o) OMe. In certain embodiments, R ⁴ ' is Ph. In certain embodiments, R ⁴ ' isIn certain embodiments, R ^4’ Is->In certain embodiments, R ⁴ ' is->In certain embodiments, R ⁴ ' is->In certain embodiments, R ⁴ ' isIn certain embodiments, R ^4’ Is F.

In certain embodiments, R ⁵ Is methyl. In certain embodiments, R ⁵ Is trifluoromethyl. In certain embodiments, R ⁵ Is a hydroxyl group. In certain embodiments, R ⁵ is-C (=o) OMe. In certain embodiments, R ⁵ Is Ph. In certain embodiments, R ⁵ Is thatIn certain embodiments, R ⁵ Is->In certain embodiments, R ⁵ Is thatIn certain embodiments, R ⁵ Is->In certain embodiments, R ⁵ Is thatIn certain embodiments, R ⁵ Is F.

In certain embodiments, R ⁵ ' is methyl. In certain embodiments, R ⁵ ' is trifluoromethyl. In certain embodiments, R ⁵ ' is a hydroxyl group. In certain embodiments, R ⁵ ' is-C (=o) OMe. In certain embodiments, R ⁵ ' is Ph. In certain embodiments, R ⁵ ' isIn certain embodiments, R ^5’ Is->In certain embodiments, R ⁵ ' is->In certain embodiments, R ⁵ ' is->In certain embodiments, R ⁵ ' isIn certain embodiments, R ^5’ Is F.

In certain embodiments, R ⁶ Is methyl. In certain embodiments, R ⁶ Is trifluoromethyl. In certain embodiments, R ⁶ Is a hydroxyl group. In certain embodiments, R ⁶ is-C (=o) OMe. In certain embodiments, R ⁶ Is Ph. In certain embodiments, R ⁶ Is thatIn certain embodiments, R ⁶ Is->In certain embodiments, R ⁶ Is thatIn certain embodiments, R ⁶ Is->In certain embodiments, R ⁶ Is thatIn certain embodiments, R ⁶ Is F.

In certain embodiments, R ⁶ ' is methyl. In certain embodiments, R ⁶ ' is trifluoromethyl. In certain embodiments, R ⁶ ' is a hydroxyl group. In certain embodiments, R ⁶ ' is-C (=o) OMe. In certain embodiments, R ⁶ ' is Ph. In certain embodiments, R ⁶ ' isIn certain embodiments, R ^6’ Is->In certain embodiments, R ⁶ ' is->In certain embodiments, R ⁶ ' is->In certain embodiments, R ⁶ ' isIn certain embodiments, R ^6’ Is F.

In certain embodiments, R ⁷ Is methyl. In certain embodiments, R ⁷ Is trifluoromethyl. In certain embodiments, R ⁷ Is a hydroxyl group. In certain embodiments, R ⁷ is-C (=o) OMe. In certain embodiments, R ⁷ Is Ph. In certain embodiments, R ⁷ Is thatIn certain embodiments, R ⁷ Is->In certain embodiments, R ⁷ Is thatIn certain embodiments, R ⁷ Is->In certain embodiments, R ⁷ Is thatIn certain embodiments, R ⁷ Is F. />

In certain embodiments, R ⁷ ' is methyl. In certain embodiments, R ⁷ ' is trifluoromethyl. In certain embodiments, R ⁷ ' is a hydroxyl group. In certain embodiments, R ⁷ ' is-C (=o) OMe. In certain embodiments, R ⁷ ' is Ph. In certain embodiments, R ⁷ ' isIn certain embodiments, R ^7’ Is->In some embodiments of the present invention, in some embodiments,R ⁷ ' is->In certain embodiments, R ⁷ ' is->In certain embodiments, R ⁷ ' isIn certain embodiments, R ^7’ Is F.

In certain embodiments, R ⁸ Is methyl. In certain embodiments, R ⁸ Is trifluoromethyl. In certain embodiments, R ⁸ Is a hydroxyl group. In certain embodiments, R ⁸ is-C (=o) OMe. In certain embodiments, R ⁸ Is Ph. In certain embodiments, R ⁸ Is thatIn certain embodiments, R ⁸ Is->In certain embodiments, R ⁸ Is thatIn certain embodiments, R ⁸ Is->In certain embodiments, R ⁸ Is thatIn certain embodiments, R ⁸ Is F.

In certain embodiments, R ⁸ ' is methyl. In certain embodiments, R ⁸ ' is trifluoromethyl. In certain embodiments, R ⁸ ' is a hydroxyl group. In certain embodiments, R ⁸ ' is-C (=o) OMe. In certain embodiments, R ⁸ ' is Ph. In certain embodiments, R ⁸ ' isIn certain embodiments, R ^8’ Is->In certain embodiments, R ⁸ ' is->In certain embodiments, R ⁸ ' is->In certain embodiments, R ⁸ ' isIn certain embodiments, R ^8’ Is F.

In certain embodiments, Y is NR ¹⁰ . In certain embodiments, Y is NH.

In certain embodiments, R ¹⁰ Is H. In certain embodiments, R ¹⁰ Is methyl. In certain embodiments, R ¹⁰ Is 3-methylbutyl. In certain embodiments, R ¹⁰ Is tert-butyl. In certain embodiments, R ¹⁰ Is cyclopropyl. In certain embodiments, R ¹⁰ Is 3-oxetanyl. In certain embodiments, R ¹⁰ is-C (=O) CH ₂ CH(CH ₃ ) ₂ . In certain embodiments, R ¹⁰ is-C (=O) Ot-Bu. In certain embodiments, R ¹⁰ Is S (=O) ₂ Me. In certain embodiments, R ¹⁰ Is benzyl. In certain embodiments, R ¹⁰ Is thatIn certain embodiments, R ¹⁰ Is->In certain embodiments, R ¹⁰ Is->In certain embodiments, R ¹⁰ Is->In certain embodiments, R ¹⁰ Is->In certain embodiments, R ¹⁰ Is->In certain embodiments, R ¹⁰ Is thatIn certain embodiments, R ¹⁰ Is->In certain embodiments, R ¹⁰ Is that

In certain embodiments, Y is NR ^10’ 。

In certain embodiments, R ^10’ Is thatIn certain embodiments, R ^10’ Is thatIn certain embodiments, R ^10’ Is->In certain embodiments, R ^10’ Is thatIn certain embodiments, R ^10’ Is->In certain embodiments, R ^10’ Is that

In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In some embodimentsWherein R is ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In some embodiments of the present invention, in some embodiments,R ¹ is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In some embodimentsWherein R is ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is thatIn certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->In certain embodiments, R ¹ Is->

In certain embodiments, the present disclosure provides a compound of formula (II), or a salt, solvate, enantiomer, diastereomer, isotopic isomer, or tautomer thereof, selected from the group consisting of:

Wherein:

ar is C ₆ -C ₁₀ Aryl or C ₂ -C ₁₀ Heteroaryl, which is selected from C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, C ₂ -C ₁₀ Heteroaryl, C ₆ -C ₁₀ Aryl, C ₆ -C ₁₀ Aryloxy, halogen, OH, NH ₂ ，CN、NO ₂ 、-C(＝O)OR ^a and-C (=O) N (R) ^a )(R ^a ) Optionally substituted with at least one substituent of (c),

R ^A is H or C ₁ -C ₆ An alkyl group; and

R ¹ selected from the group consisting of/>

/>

In certain embodiments, R ^A Is H. In certain embodiments, R ^A Is methyl.

In certain embodiments, the compound of formula (II) is selected from:

/>

in certain embodiments, ar is selected from And

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ Each independently selected from C ₁ -C ₆ Alkyl, F, cl, N (R) ^a )(R ^b )、OR ^b 、-C(＝O)OR ^a 、-C(＝O)N(R ^a )(R ^a )、NH ₂ 、OH、NO ₂ 、C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy and phenyl.

In certain embodiments, X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least one of (a), if present, is O (CH) ₃ ) ₂ ). In certain embodiments, X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least one, if any, of OCFs ₃ . In certain embodiments, X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least one, if any, of

In certain embodiments, ar isIn certain embodiments, ar isIn certain embodiments, ar is +.>In certain embodiments, ar isIn certain embodiments, ar is +.>In certain embodiments, ar isIn certain embodiments, ar is +.>

In certain embodiments, the compound is selected from:

n- (6-fluoro-2, 2-dimethylbenzodihydropyran-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1- (tert-butyl) -2- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

4- (2- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) piperidine-1-carboxylic acid tert-butyl ester;

2- (1- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) pyrrolidine-1-carboxylic acid tert-butyl ester;

n- (6- (difluoromethoxy) -4-oxo-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1- (3-ethoxy-4-hydroxybenzyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

3- (fluoromethyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) pyrrolidine-1-carboxylic acid tert-butyl ester;

n- (1-cyclopropyl-2- (3, 4-difluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

N- (2-oxo-1- (3- (trifluoromethyl) benzyl) piperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (spiro [ chromane-2, 1' -cyclopent ] -4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1-benzyl-3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (3-fluoro-4-methoxyphenyl) tetrahydro-2H-pyran-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1- (3-chlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide;

methyl 3- (1- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopentyl) propionate;

n- (4, 6-dichloro-2, 3-dihydro-1H-inden-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n-2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro [3.4] oct-6-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (6-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1- (3-methoxyphenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (2- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1- (3, 4-dichlorophenyl) piperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

3, 5-dimethyl-N- ((1- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclohexyl) methyl) isoxazole-4-sulfonamide;

N- (1- (2-phenylbutyryl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

4- (trifluoromethoxy) -N- (1- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) benzenesulfonamide;

n- (2-ethyl-1- (m-tolyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1- (5-chloro-2-methoxyphenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (5, 8-difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (2- (4-chlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (2- (3, 4-dichlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1- (3-bromophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3- (4-chlorophenyl) azetidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3, 4-dichlorophenyl) azetidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (3, 4-dichlorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

N- (4-phenylpiperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

benzyl 3- (3, 4-dichlorophenyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) pyrrolidine-1-carboxylate;

n- (3- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

4- (4-chlorophenyl) -4- ((4- (trifluoromethoxy) phenyl) sulfamide) piperidine-1-carboxylic acid tert-butyl ester;

n- (1-benzyl-3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide;

n- (1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide;

n- (4- (4-chloro-3-fluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide;

n- (3- (4-chloro-3-fluorophenyl) azetidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (4-fluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4-phenylpiperidin-4-yl) -6- (trifluoromethoxy) pyridine-3-sulfonamide;

n- (1-methyl-4-phenylpiperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (4-chlorophenyl) piperidin-4-yl) -4-isopropoxy 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- (4- (5-fluoropyridin-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (bicyclo [1.1.1] piperidin-1-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (4-chlorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide;

n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -N' -methyl-4- (trifluoromethoxy) benzenesulfonimide amide;

n- (3- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

3- (4-chlorophenyl) -3- ((4- (trifluoromethoxy) phenyl) sulfamide) pyrrolidine-1-carboxylic acid tert-butyl ester;

n- (3- (4-chlorophenyl) -1- (oxetan-3-yl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3- (4-chlorophenyl) -1- (methylsulfonyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (5-chlorothiazol-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (4-fluorophenyl) piperidin-4-yl) -4-isopropoxy benzenesulfonamide;

n- (3- (4-chlorophenyl) -1-isopentylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

N- (4- (4-fluorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide;

n- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide;

racemic N- ((3 s,4 s) -3- (4-chlorophenyl) -4-fluoropyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6-isopropoxypyridine-3-sulfonamide;

n- (3- (4-chlorophenyl) -1- (3-methylbutanoyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (3, 4-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (2, 4-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -N-methyl-4- (trifluoromethoxy) benzenesulfonamide;

n- (3-phenyl-8-azabicyclo [3.2.1] oct-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (5-chloropyridin-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (2, 5-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1- (3, 4-dichlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

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

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

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

n- (4- (4-chloro-2-fluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (5-chloro-3-fluoropyridin-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n' - (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

n- (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethyl) benzenesulfonamide;

n- (4- (4-chlorophenyl) piperidin-4-yl) -3- (trifluoromethyl) bicyclo [1.1.1] pentane-1-sulfonamide;

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

n- (4- (4- (difluoromethyl) phenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

In certain embodiments, the compound is selected from:

(R) -N- (6-fluoro-2, 2-dimethylbenzodihydropyran-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((2R, 3R) -1- (tert-butyl) -2- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

N- ((2 r,3 s) -1- (tert-butyl) -2- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

4- ((1 r,2 r) -2- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) piperidine-1-carboxylic acid tert-butyl ester;

4- ((1 r,2 s) -2- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) piperidine-1-carboxylic acid tert-butyl ester;

(R) -tert-butyl 2- (1- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) pyrrolidine-1-carboxylate;

(R) -N- (6- (difluoromethoxy) -4-oxo-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -3- (fluoromethyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) pyrrolidine-1-carboxylic acid tert-butyl ester;

n- ((2R, 3R) -1-cyclopropyl-2- (3, 4-difluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((2R, 3S) -1-cyclopropyl-2- (3, 4-difluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (2-oxo-1- (3- (trifluoromethyl) benzyl) piperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (spiro [ chromane-2, 1' -cyclopent ] -4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (1-benzyl-3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (4, 6-dichloro-2, 3-dihydro-1H-inden-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((6 r,7 r) -2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro [3.4] oct-6-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((6 r,7 s) -2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro [3.4] oct-6-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (6-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((2R, 3R) -2- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((2R, 3S) -2- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (1- (3, 4-dichlorophenyl) piperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 r) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 s) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (1- (2-phenylbutyryl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -4- (trifluoromethoxy) -N- (1- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) benzenesulfonamide;

n- ((1 r,2 r) -2-ethyl-1- (m-tolyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 s) -2-ethyl-1- (m-tolyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (1- (5-chloro-2-methoxyphenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (5, 8-difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1R, 2R) -2- (4-chlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 s) -2- (4-chlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1R, 2R) -2- (3, 4-dichlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 s) -2- (3, 4-dichlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (1- (3-bromophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -benzyl 3- (3, 4-dichlorophenyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) pyrrolidine-1-carboxylic acid ester;

n- ((3R, 4R) -4- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((3R, 4S) -4- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (1-benzyl-3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide;

(R) -N- (1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide;

(R) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide;

(R) -N- ((R) -3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

(R) -N- ((S) -3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

(R) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6- (trifluoromethoxy) pyridine-3-sulfonamide;

(R) -N- ((R) -3- (4-chlorophenyl) pyrrolidin-3-yl) -N' -methyl-4- (trifluoromethoxy) benzenesulfonimide amide;

(R) -N- ((S) -3- (4-chlorophenyl) pyrrolidin-3-yl) -N' -methyl-4- (trifluoromethoxy) benzenesulfonimide amide;

(R) -N- (3- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -3- (4-chlorophenyl) -3- ((4- (trifluoromethoxy) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester;

(R) -N- (3- (4-chlorophenyl) -1- (oxetan-3-yl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3- (4-chlorophenyl) -1- (methylsulfonyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3- (4-chlorophenyl) -1-isopentylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide;

n- ((3R, 4R) -3- (4-chlorophenyl) -4-fluoropyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((3R, 4S) -3- (4-chlorophenyl) -4-fluoropyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6-isopropoxypyridine-3-sulfonamide;

(R) -N- (3- (4-chlorophenyl) -1- (3-methylbutanoyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- ((R) -3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

(R) -N- ((S) -3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

(R) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -N-methyl-4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -3-amino-N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide; and

(R) -3-amino-N- (3- (4-fluoro-3-methylphenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

Or a salt, solvate, isotopic isomer or tautomer thereof.

In certain embodiments, the compound is selected from:

(S) -N- (6-fluoro-2, 2-dimethylbenzodihydropyran-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((2 s,3 r) -1- (tert-butyl) -2- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((2 s,3 s) -1- (tert-butyl) -2- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

4- ((1 s,2 s) -2- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) piperidine-1-carboxylic acid tert-butyl ester;

4- ((1 s,2 r) -2- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) piperidine-1-carboxylic acid tert-butyl ester;

(S) -tert-butyl 2- (1- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) pyrrolidine-1-carboxylate;

(S) -N- (6- (difluoromethoxy) -4-oxo-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -3- (fluoromethyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) pyrrolidine-1-carboxylic acid tert-butyl ester;

n- ((2 s,3 s) -1-cyclopropyl-2- (3, 4-difluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((2 s,3 r) -1-cyclopropyl-2- (3, 4-difluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (2-oxo-1- (3- (trifluoromethyl) benzyl) piperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (spiro [ chromane-2, 1' -cyclopent ] -4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (1-benzyl-3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (4, 6-dichloro-2, 3-dihydro-1H-inden-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((6 s,7 s) -2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro [3.4] oct-6-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((6 s,7 r) -2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro [3.4] oct-6-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (6-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((2 s,3 s) -2- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((2 s,3 r) -2- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (1- (3, 4-dichlorophenyl) piperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 s) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 r) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (1- (2-phenylbutyryl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -4- (trifluoromethoxy) -N- (1- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) benzenesulfonamide;

n- ((1 s,2 s) -2-ethyl-1- (m-tolyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (1- (5-chloro-2-methoxyphenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (5, 8-difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 s) -2- (4-chlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 r) -2- (4-chlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 s) -2- (3, 4-dichlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 r) -2- (3, 4-dichlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (1- (3-bromophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -benzyl 3- (3, 4-dichlorophenyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) pyrrolidine-1-carboxylic acid ester;

N- ((3S, 4S) -4- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((3 s,4 r) -4- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (1-benzyl-3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide;

(S) -N- (1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide;

(S) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide;

(S) -N- ((S) -3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

(S) -N- ((R) -3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

(S) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6- (trifluoromethoxy) pyridine-3-sulfonamide;

(S) -N- ((S) -3- (4-chlorophenyl) pyrrolidin-3-yl) -N' -methyl-4- (trifluoromethoxy) benzenesulfonimide amide;

(S) -N- ((R) -3- (4-chlorophenyl) pyrrolidin-3-yl) -N' -methyl-4- (trifluoromethoxy) benzenesulfonimide amide;

(S) -N- (3- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -3- (4-chlorophenyl) -3- ((4- (trifluoromethoxy) phenyl) sulfamide) pyrrolidine-1-carboxylic acid tert-butyl ester;

(S) -N- (3- (4-chlorophenyl) -1- (oxetan-3-yl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3- (4-chlorophenyl) -1- (methylsulfonyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3- (4-chlorophenyl) -1-isopentylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide;

n- ((3S, 4S) -3- (4-chlorophenyl) -4-fluoropyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((3 s,4 r) -3- (4-chlorophenyl) -4-fluoropyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6-isopropoxypyridine-3-sulfonamide;

(S) -N- (3- (4-chlorophenyl) -1- (3-methylbutanoyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- ((S) -3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

(S) -N- ((R) -3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

(S) -N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -N-methyl-4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -3-amino-N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide; and

(S) -3-amino-N- (3- (4-fluoro-3-methylphenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

In certain embodiments, the compound is selected from:

n- (4- ((4- ((4- (trifluoromethoxy) phenyl) sulfamido) piperidin-1-yl) sulfonyl) phenyl) acetamide;

1- ((4- (trifluoromethoxy) phenyl) sulfamido) -2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester;

(1 r,2 r) -1- ((4- (trifluoromethoxy) phenyl) sulphonamido) -2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester;

(1 r,2 s) -1- ((4- (trifluoromethoxy) phenyl) sulfonamide) -2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester;

(1 s,2 s) -1- ((4- (trifluoromethoxy) phenyl) sulfamido) -2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester;

(1 s,2 r) -1- ((4- (trifluoromethoxy) phenyl) sulfamido) -2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester;

n- (2- (4-fluorophenoxy) cyclohexyl) -4- (trifluoromethoxy) benzenesulfonamide;

N- ((1R, 2R) -2- (4-fluorophenoxy) cyclohexyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 s) -2- (4-fluorophenoxy) cyclohexyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 s) -2- (4-fluorophenoxy) cyclohexyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 r) -2- (4-fluorophenoxy) cyclohexyl) -4- (trifluoromethoxy) benzenesulfonamide;

4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide;

(R) -4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide;

(S) -4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide;

4- (trifluoromethoxy) -N- ((1 r,3 r) -3, 4-trimethylcyclohexyl) benzenesulfonamide;

4- (trifluoromethoxy) -N- ((1 r,3 s) -3, 4-trimethylcyclohexyl) benzenesulfonamide;

4- (trifluoromethoxy) -N- ((1 s,3 s) -3, 4-trimethylcyclohexyl) benzenesulfonamide;

4- (trifluoromethoxy) -N- ((1 s,3 r) -3, 4-trimethylcyclohexyl) benzenesulfonamide;

n- (2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 r) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 s) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 s) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

N- ((1 s,2 r) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

1- ((4- (trifluoromethoxy) phenyl) sulfamido) -2, 3-dihydro-1H-indene-1-carboxylic acid ethyl ester;

(R) -1- ((4- (trifluoromethoxy) phenyl) sulfamido) -2, 3-dihydro-1H-indene-1-carboxylic acid ethyl ester;

(S) -1- ((4- (trifluoromethoxy) phenyl) sulfamido) -2, 3-dihydro-1H-indene-1-carboxylic acid ethyl ester;

3, 5-dimethyl-7- ((4- (trifluoromethoxy) phenyl) sulfonamide) adamantane-1-carboxylic acid methyl ester;

n- (2-benzyl octahydrocyclopenta [ c ] pyrrol-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (2-benzyloctahydrocyclopenta [ c ] pyrrol-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (2-benzyloctahydrocyclopenta [ c ] pyrrol-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

4- (trifluoromethoxy) -N- (4- (trifluoromethyl) -4,5,6, 7-tetrahydro-1H-indazol-6-yl) benzenesulfonamide;

4- (trifluoromethoxy) -N- ((4 r,6 r) -4- (trifluoromethyl) -4,5,6, 7-tetrahydro-1H-indazol-6-yl) benzenesulfonamide;

4- (trifluoromethoxy) -N- ((4 r,6 s) -4- (trifluoromethyl) -4,5,6, 7-tetrahydro-1H-indazol-6-yl) benzenesulfonamide;

4- (trifluoromethoxy) -N- ((4 s,6 s) -4- (trifluoromethyl) -4,5,6, 7-tetrahydro-1H-indazol-6-yl) benzenesulfonamide;

4- (trifluoromethoxy) -N- ((4 s,6 r) -4- (trifluoromethyl) -4,5,6, 7-tetrahydro-1H-indazol-6-yl) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

The compounds of the invention may have one or more stereocenters, and each stereocenter may exist independently in either the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic forms. The compounds described herein include racemic, optical, regioisomeric and stereoisomeric forms, or combinations thereof, having the therapeutically useful properties described herein. The preparation of the optically active form is effected in any suitable manner, including, as non-limiting examples, by resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. The compounds illustrated herein by the racemate further represent both enantiomers or mixtures thereof, or in the case where two or more chiral centers are present, all diastereomers or mixtures thereof.

In certain embodiments, the compounds of the present invention exist as tautomers. All tautomers are included within the scope of the compounds described herein.

The compounds described herein also include isotopically-labeled compounds, wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or atomic mass number different from the atomic mass or atomic mass number usually found in nature (i.e., an isotopic isomer). Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ³⁶ Cl、 ¹⁸ F、 ¹²³ I、 ¹²⁵ I、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³² P and ³⁵ s, S. In certain embodiments, substitution with heavier isotopes such as deuterium provides greater chemical stability. Isotopically-labeled compounds can be prepared by any suitable method or by using a suitable isotopically-labeled reagent in place of the method otherwise employing an unlabeled reagent.

In certain embodiments, the compounds described herein are labeled by other means, including but not limited to using chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the present invention may comprise any substituent or combination of substituents provided herein.

Salt

The compounds described herein may form salts with acids or bases, and such salts are included in the present invention. The term "salt" includes addition salts of free acids or bases useful in the methods of the invention. The term "pharmaceutically acceptable salt" refers to salts having toxicity characteristics within the range useful in pharmaceutical applications. In certain embodiments, the salt is a pharmaceutically acceptable salt. However, pharmaceutically unacceptable salts may have properties such as high crystallinity which have utility in the practice of the present invention, such as, for example, in the synthesis, purification or formulation of compounds useful in the methods of the present invention.

Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of the inorganic acid include sulfate, hydrogen sulfate (hydrogen sulfate), hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic 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, sulfanilic acid, 2-hydroxyethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, stearic acid, alginic acid, β -hydroxybutyric acid, salicylic acid, galactaric acid, glycerophosphonic acid and saccharin acid (e.g., saccharinate), sugar acid salt (saccharate)). Salts may be composed of 1 molar equivalent, 1 or more than 1 molar equivalent of the acid or base moiety relative to any of the compounds of the present invention.

Suitable pharmaceutically acceptable base addition salts of the compounds of the invention include, for example, ammonium salts and metal salts, including alkali, alkaline earth and transition metal salts, such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts prepared from basic amines such as, for example, 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 the appropriate acid or base with the compound.

Synthesis

The invention further provides a process for preparing the compounds of the invention. The compounds of the present teachings can be prepared from commercially available starting materials, compounds known in the literature, or readily prepared intermediates according to the procedures outlined herein by 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 are readily available from the relevant scientific literature or standard textbooks in the field.

It should be understood that other process conditions may be used where typical or preferred process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressures, etc.) are given unless otherwise indicated. The optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions may be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described herein.

The processes described herein may be monitored according to any suitable method known in the art. For example, product formation may be achieved by spectroscopic methods (spectroscopic means), such as nuclear magnetic resonance spectroscopy (e.g., ¹ h or ¹³ C) Infrared spectroscopy, spectrophotometry (e.g., ultraviolet visible), mass spectrometry, or by chromatography such as High Pressure Liquid Chromatography (HPLC), gas Chromatography (GC), gel Permeation Chromatography (GPC), or Thin Layer Chromatography (TLC).

The preparation of the compounds may involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of suitable protecting groups can be readily determined by one skilled in the art. The chemical nature of the protecting group can be found, for example, in Greene et al, protective Groups in Organic Synthesis, 2 nd edition (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

The reactions or methods described herein may be carried out in a suitable solvent that may be readily selected by one skilled in the art of organic synthesis. Suitable solvents are generally substantially nonreactive with the reactants, intermediates, and/or products at the temperature at which the reaction is carried out, i.e., at a temperature in the range of the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, an appropriate solvent for the particular reaction step may be selected.

In certain embodiments, compounds synthesized using the methods described herein may contain one or more chiral carbon atoms, thereby producing two or more isomers. Absolute stereochemistry may be described using wedge bonds (bold or parallel lines). In certain embodiments, the product formed in any of the reactions may be a racemate. If racemates are formed, any suitable chiral resolution method known to those skilled in the art may be used to isolate the isomers that make up the racemates. Suitable methods for chiral resolution include, but are not limited to, supercritical Fluid Chromatography (SFC), chiral HPCL, crystallization, derivatization, or any combination thereof.

As used herein, "enantiomer I" or "diastereomer I" refers to the first enantiomer or diastereomer that elutes from a chiral column under specific chiral analysis conditions detailed for a particular compound(s); "enantiomer II" or "diastereomer II" refers to the second enantiomer or diastereomer that elutes from a chiral column under specific chiral analysis conditions detailed for a particular compound(s). This nomenclature does not imply or impart any particular relative and/or absolute configuration to these compounds.

In certain embodiments, separation of the isomers formed in one or more separate reactions may require formation of the derivative prior to chiral resolution. Non-limiting examples of derivatization are protecting one or more functional groups present in the compound using known protecting groups (such as esters, amides, carbamates, ethers, etc.), and then isolating the isomers by suitable methods. The desired compound is finally obtained by removal of the protecting group.

The present disclosure provides compounds of formula (I) and formula (II). Those skilled in the art will recognize that in many cases the techniques and/or methods used to synthesize the compounds of formula (I) will be applicable to the synthesis of the compounds of formula (II), and vice versa.

In certain embodiments, the compounds of the present disclosure having the structure of formula (I) include sulfonamides of formula (Ia'), which may be prepared as described herein. Compounds of formula (Ia'), wherein Ar, A and R ² Defined within the scope of the present disclosure, prepared from the corresponding arylsulfonyl chloride 1-1 and amine 1-2 in the presence of a base and a solvent (scheme 1). A suitable base for sulfonylation is Et ₃ N. A suitable solvent for sulfonylation is CH ₂ Cl ₂ 。

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

In general, compounds of formula (Ia') can be prepared according to the synthetic method provided in scheme 2, which are compounds of formulae 2-6 wherein v is 1 or 2,w is 0 or 1 and R is selected from halogen, C ₁ -C ₃ Phenyl optionally substituted with at least one substituent of alkoxy and trifluoromethyl, X is a halogen selected from Cl and Br, and PG is a protecting group including, but not limited to, benzyl (Bn), t-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

As shown in scheme 2, the cyclic ammonium halide 2-1 can be protected with a suitable protecting group (e.g., t-butoxycarbonyl (Boc)) using a suitable protecting group precursor (e.g., di-t-butyl carbonate) to give the protected amine 2-2. Any of a variety of conditions/reagents may be used, including but not limited to: (a) TFA and NaN ₃ ；(b)BF ₃ ·Et ₂ O and TMS-N ₃ The method comprises the steps of carrying out a first treatment on the surface of the (c) DBU and Diphenylphosphorylazide (DPPA); and (d) SOCl ₂ Or MsCl and NaN ₃ To effect displacement of the tertiary alcohol of 2-2 with azide to give tertiary azide (tertiary azide) 2-3. Reduction of tertiary azide 2-3 to the corresponding amine 2-4 may be accomplished under suitable reaction conditions, including but not limited to, with PPh ₃ And p-toluenesulfonic acid (PTSA) treatment. Amine 2-4 may be sulfonylated to the corresponding sulfonamide 2-5 using an aryl sulfonamide and any of a number of suitable basic reaction conditions, including but not limited to: (a) Et (Et) ₃ N and DCM; (b) pyridine and THF; (c) pure (heat) pyridine; and (d) Et ₃ N, DMAP and DCM. Depending on the kind (identity) of the particular protecting group used, this is achieved by treatment with: (a) In the presence of dioxaneHCl in an alkane; (b) TMS-I in ACN; and (c) H in MeOH ₂ And Pd/C, removal of the Protecting Group (PG) can be achieved to give 2-6. In certain embodiments, the protecting group is Boc, removed using HCl in dioxane. In certain embodiments, the protecting group is Cbz and is removed using TMS-I in ACN.

Alternatively, as shown in scheme 3, compounds of formula 2-6 can be prepared from a diammonium halide 3-1, which can be protected with a suitable protecting group, such as t-butoxycarbonyl (Boc), using a suitable protecting group precursor, such as di-t-butyl carbonate, to provide directly the mono-protected amine 2-4. Compounds of formulas 2-6 may be prepared from the mono-protected amines 2-4 in the order described elsewhere herein.

Compounds of the present disclosure having the structure of formula (I) include sulfonylimide amides (sulfonimidamides) of formula (Ib ') or (Ic'), which may be prepared as described herein. Preparation of Compounds of formula (Ib ') or formula (Ic') wherein Ar, A, R are Ar, A, R from the corresponding arylsulfonyl chloride 1-1 and amine 1-2 ^a And R is ² Defined within the scope of this disclosure (scheme 4). Arylsulfonyl chloride 1-1 may be present in a suitable base such as NaHCO ₃ In the presence of a suitable reducing agent, e.g. Na ₂ SO ₃ Reduction to provide sulfinate 4-1. Sulfinate 4-1 may be chlorinated to the corresponding sulfinyl chloride 4-2 with a suitable chlorinating agent such as oxalyl chloride. Can be prepared in a suitable base such as Et ₃ Condensing thionyl chloride 4-2 with a suitable amine (e.g., 4-3) in the presence of N provides sulfenamide 4-4. The sulfenamides 4-4 can be converted to compounds of formula (Ib') by oxidation with a suitable oxidant, such as t-BuOCl, followed by condensation of the amines 1-2.

In certain embodiments, sulfiliminamide (Ib ') may undergo tautomerization to yield sulfiliminamide (Ic'). In certain embodiments, the sulfinamide (Ic ') may undergo tautomerization to give the sulfinamide (Ib'). In certain embodiments, the compounds of formulas (Ib ') and (Ic') may be present as a mixture.

In certain embodiments, an N-alkyl-sulfonamide of formula (Ia ') can be prepared from a sulfonamide of formula (Ia'), wherein R ^B Is C ₁ -C ₆ An alkyl group. In certain embodiments, compounds of formula (Ia ") are prepared from compounds of formula (Ia') by a modified Mitsunobu reaction (scheme 5). In certain embodiments, in the presence of phosphine ligands (non-limiting examples include PPh ₃ ) And treating the sulfonamide (Ia') with a dialkyl azodicarbonate (non-limiting examples include diethyl azodicarbonate (DEAD) and diisopropyl azodicarbonate (DIAD)) in the presence of a suitable primary or secondary alcohol.

As shown in scheme 6, tertiary alcohol 2-2 can be converted to alpha-haloamide 6-1 using a suitable acid, such as trifluoroacetic acid, with a suitable alpha-halonitrile, such as 2-chloroacetonitrile. Removal of the α -haloacyl moiety of 6-1 can be accomplished under suitable reaction conditions, including but not limited to treatment with thiourea in the presence of a suitable acid such as acetic acid at a suitable temperature (including but not limited to 80 ℃) to afford amine 2-4. Amine 2-4 may be sulfonylated to the corresponding sulfonamide 2-5 using an aryl sulfonamide and any of a number of suitable basic reaction conditions, including but not limited to: (a) Et (Et) ₃ N and DCM; (b) pyridine and THF; (c) pure pyridine; and (d) Et ₃ N, DMAP and DCM. Depending on the type of particular protecting group used, removal of the Protecting Group (PG) may be accomplished, as described elsewhere herein, yielding 2-6.

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As shown in scheme 7, secondary amine 7-1 can be reacted with a suitable base such as Et ₃ Protection with a suitable protecting group (PG') such as benzyl in the presence of N using a suitable alkylating agent such as benzyl bromide gives 7-2. In the presence of a suitable acid (including H ₂ SO ₄ ) Nitrile 7-2 can be hydrolyzed to amide 7-3 at a suitable temperature, e.g., 60 c. Hofmann rearrangement of amide 7-3 may be accomplished under suitable reaction conditions including, but not limited to, with a suitable halogenating agent such as [ bis (trifluoroacetoxy) iodide ]]Benzene treatment gives amine 7-4. Amine 7-4 may be sulfonylated to the corresponding sulfonamide 7-5 using an aryl sulfonamide and any of a number of suitable basic reaction conditions, including but not limited to: (a) Et (Et) ₃ N and DCM; (b) pyridine and THF; (c) pure pyridine; and (d) Et ₃ N, DMAP and DCM. Removal of the protecting group (PG') can be accomplished under suitable reaction conditions, including treatment with a suitable N-dealkylating reagent, including 1-chloroethyl carbonate, to give a range of 2-6.

Method

The present disclosure relates in part to methods of treating, preventing and/or ameliorating a PP 2A-related disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds of the present disclosure or a pharmaceutical composition comprising any of the compounds of the present disclosure and a pharmaceutically acceptable carrier.

In certain embodiments, at least one of the PP 2A-related diseases is selected from 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 subject is a mammal. In certain embodiments, the mammal is a human.

The present disclosure further relates in part to the use of a compound according to one or more embodiments disclosed herein, e.g., a compound of formula (I) or (II), a salt, a solvate, an enantiomer, a diastereomer, an isotopic isomer, a tautomer, or any mixture thereof, as a medicament for treating, preventing, and/or alleviating a disease or disorder in a patient.

Compounds according to one or more embodiments disclosed in the present specification may be modulators of PP 2A. The compounds described herein may exhibit antiproliferative effects and may be used as monotherapy in the treatment of cancer and/or the treatment of other indications described herein. In addition, they can be used in combination with other drugs to restore sensitivity to chemotherapy, targeted therapies, or immunotherapy that has developed resistance.

In certain embodiments, the disease or disorder is alleviated by modulation of PP 2A. In certain embodiments, the disease or disorder is at least one selected from cancer, diabetes, autoimmune disease, solid organ transplant rejection, graft versus host disease, chronic Obstructive Pulmonary Disease (COPD), non-alcoholic fatty liver disease, abdominal aortic aneurysm, chronic liver disease, heart failure, neurodegenerative disease, and cardiac hypertrophy. In one embodiment, the disease is cancer.

In certain embodiments, a therapeutically effective amount of a compound according to one or more embodiments disclosed herein, e.g., a compound of formula (I) or (II), solvates, enantiomers, diastereomers, isotopic isomers, tautomers, or pharmaceutically acceptable salts thereof, is administered to a patient in need of treatment of the disease.

In certain embodiments, a method of treating cancer in a patient having a tumor that expresses PP2A comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or (II), a solvate, enantiomer, diastereomer, isotopic isomer, tautomer, or pharmaceutically acceptable salt thereof.

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

In certain embodiments, the cancer is bladder cancer, blood 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. Furthermore, the cancer may be specifically at least one of the following histological types, but is not limited to these: neoplasms (malignant); cancer; cancer (undifferentiated); giant cell carcinoma or spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphatic epithelial cancer; basal cell carcinoma; hair mother cell carcinoma; transitional cell carcinoma (transitional cell carcinoma); papillary transitional cell carcinoma; adenocarcinomas; gastrinomas (malignant); bile duct cancer; hepatocellular carcinoma; combining hepatocellular carcinoma and cholangiocarcinoma; small Liang Xianai; adenoid cystic carcinoma; adenocarcinomas among adenomatous polyps; adenocarcinomas, familial polyposis coli; solid cancer; carcinoid (malignant); gill-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe cell carcinoma (chromophobe carcinoma); eosinophilic cancer; eosinophilic adenocarcinoma; basophilic granulocyte cancer; clear cell adenocarcinoma; granulosa cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; non-enveloped sclerotic cancers; adrenal cortex cancer; ovarian intimal carcinoma; skin accessory cancer; apocrine adenocarcinoma; sebaceous gland cancer; cerumen adenocarcinoma; epidermoid carcinoma of mucous; cystic adenocarcinoma; papillary cyst adenocarcinoma; papillary serous cystic adenocarcinoma; mucinous cystic adenocarcinoma; mucinous adenocarcinomas; printing ring cell carcinoma; invasive ductal carcinoma; medullary carcinoma; lobular carcinoma; inflammatory cancer; paget's disease (breast); acinar cell carcinoma; adenosquamous carcinoma; adenocarcinomas are accompanied by squamous metaplasia; thymoma (malignant); ovarian stromal tumor (malignant); membranous cell neoplasms (malignant); granuloma (malignant); male blastoma (malignant); support cell carcinoma (sertoli cell carcinoma); stromal cell tumor (malignant); lipid cell neoplasms (malignant); paragangliomas (malignant); extramammary paragangliomas (malignant); pheochromocytoma; hemangiosarcoma (glomannosarcoma); malignant melanoma; non-pigmented melanoma; superficial diffuse melanoma; malignant melanoma in giant pigmented nevi; epithelioid cell melanoma; blue nevi (malignant); sarcoma; fibrosarcoma; fibrohistiocytoma (malignant); myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; interstitial sarcoma; mixed tumors (malignant); miao Leguan (mullerian) mixed tumors; nephroblastoma; hepatoblastoma; carcinoma sarcoma; mesenchymal neoplasms (malignant); brenner (Brenner) tumor (malignant); phylliform tumors (malignant); synovial sarcoma; mesothelioma (malignant); a vegetative cell tumor; embryo cancer; teratomas (malignant); ovarian goiter (malignant); choriocarcinoma; malignant mesonephroma; hemangiosarcoma; vascular endothelial tumors (malignant); kaposi's sarcoma; vascular endothelial cell neoplasms (malignant); lymphangiosarcoma; osteosarcoma; a cortical bone sarcoma; chondrosarcoma; chondroblastoma (malignant); mesenchymal chondrosarcoma; bone giant cell tumor; ewing's sarcoma; odontogenic tumors (malignant); ameloblastic osteosarcoma; enameloblastoma (malignant); ameloblastic fibrosarcoma; pineal tumor (malignant); chordoma; glioma (malignant); ventricular tube membranoma; astrocytoma; plasmacytoma; fibroastrocytoma; astrocytoma; glioblastoma; oligodendrogliomas; oligodendroglioma; primitive neuroectoderm; cerebellar sarcoma; ganglion neuroblastoma; neuroblastoma; retinoblastoma; an olfactory neurogenic tumor; meningioma (malignant); neurofibrosarcoma; schwannoma (malignant); granuloma (malignant); malignant lymphoma; hodgkin's disease; hodgkin's; granuloma parades; malignant lymphoma, small lymphocytes; malignant lymphoma (large cell, diffuse); malignant lymphoma (follicular); mycosis fungoides; other specific non-hodgkin lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestine disease; leukemia; lymphocytic leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic granulocytic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryocyte leukemia; osteosarcoma; and hairy cell leukemia.

In certain embodiments, the autoimmune disease is colitis, multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, acute pancreatitis, chronic pancreatitis, diabetes, insulin dependent diabetes mellitus (IDDM or type 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, silica gel implant-related autoimmune disease, sjogren's Syndrome (SLE), systemic lupus erythema disease (SLE), vasculitis syndrome (e.g., giant cell arteritis, behcet's disease and Wegener's granulomatosis), vitiligo, secondary hematological manifestations of autoimmune diseases (e.g., anemia), drug-induced autoimmunity, hashimoto thyroiditis, pituitary inflammation, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness (e.g., meniere's disease), goodpasture's syndrome, graves ' disease, HIV-related autoimmune syndrome, and Gullain-Barre disease.

In certain embodiments, the neurodegenerative disease is alzheimer's disease. In certain embodiments, the neurodegenerative disease is parkinson's disease.

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, utilize PP2A to modify, control, or inactivate cellular activity of a host using different methods. Thus, compounds according to one or more embodiments disclosed herein may be further used in a method of treating a viral infection in a patient by administering to the patient a therapeutically effective amount of a compound according to one or more embodiments disclosed herein. Examples of viruses that may cause viral infections in need of treatment include, but are not limited to: polyomaviruses, such as john cunningan virus (John Cunningham Virus) (JCV), simian virus 40 (SV 40) or BK virus (BKV); influenza, human immunodeficiency Virus type 1 (HIV-1), human Papilloma Virus (HPV), adenovirus, epstein-Barr Virus (EBV), hepatitis C Virus (HCV), molluscum Contagiosum Virus (MCV); human T lymphocyte virus type 1 (HTLV-1), herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), hepatitis B virus, bovine papilloma virus (BPV-1), human T lymphocyte virus type 1, japanese encephalitis virus, respiratory Syncytial Virus (RSV) and West Nile virus.

The compounds or pharmaceutical compositions according to one or more embodiments disclosed in the present specification may further be used in a method of treating a β -coronavirus infection in a patient by administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to one or more embodiments disclosed in the present specification.

The compounds according to one or more embodiments disclosed in the present specification may be further used to prevent a beta coronavirus infection in a patient by administering to the patient a prophylactically effective amount of a compound or pharmaceutical composition according to one or more embodiments disclosed in the present specification.

The compounds according to one or more embodiments disclosed in the present specification may be used in the manufacture of a medicament for the treatment or prophylaxis of a beta coronavirus infection.

In certain embodiments, the beta coronavirus 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).

In certain embodiments, the beta coronavirus is SARS-CoV.

In certain embodiments, the beta coronavirus is SARS-CoV-2.

Serine/threonine phosphatases, including PP2A, may be involved in the regulation of synaptic plasticity. Reduced PP2A activity is associated with the maintenance of long term enhancement of synapses (LTP), and thus treatment with PP2A modulators (such as those described herein) may reverse synaptic LTP. Abuse of psychostimulants such as cocaine and methamphetamine are associated with deleterious synaptic LTPs, which may be the pathological basis for addiction and relapse, and thus the PP2A modulators described herein may be useful in the treatment of psychostimulant abuse.

Pharmaceutical compositions, formulations and routes of administration

The present disclosure also relates to pharmaceutical compositions comprising a compound according to one or more embodiments described in the present specification, e.g., a compound of formula I, an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical compositions comprise a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers therefor, and optionally one or more other therapeutic ingredients. The carrier may be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions may be prepared in any manner known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. A "pharmaceutically acceptable carrier" may refer to an excipient, carrier, or adjuvant that may be administered to a patient with at least one therapeutic compound, and which does not destroy its pharmacological activity and is generally safe, non-toxic, and neither biologically nor otherwise undesirable when administered at a dose sufficient to deliver a therapeutic amount of the compound.

Although the most suitable route may depend on, for example, the condition and disorder of the recipient, pharmaceutical formulations may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular and intramedullary), intraperitoneal, transmucosal, transdermal, intranasal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods comprise associating (association) a compound of formula (I), (II) or a pharmaceutically acceptable salt, ester, amide, solvate or enantiomer or diastereomer thereof ("active ingredient") with a carrier constituting one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

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

Pharmaceutical formulations for oral use include tablets, push-in capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be prepared by compression or moulding, optionally with the use of one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, inert diluent or lubricant, surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in a dosage suitable for such administration. Push-in capsules may contain the active ingredient in admixture with fillers (such as lactose), binders (such as starches) and/or lubricants (such as talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, 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 tablets or dragee coatings for identifying or characterizing different combinations of active compound doses.

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

Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation 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 suspending agent, for example sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds of the present disclosure may also be formulated as depot formulations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges or gels formulated in conventional manner. Such compositions may include flavoring-based active ingredients such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycols or other glycerides.

In one embodiment, the compounds disclosed herein may be administered topically, i.e., by non-systemic administration. This includes external application of the compounds disclosed herein to the epidermis or oral cavity and instillation of such compounds into the ear, eye and nose, such that the compounds do not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

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

For administration by inhalation, the compounds of the present disclosure may be conveniently delivered from an insufflator, nebulizer pressurizing bag, or other convenient means of delivering an aerosol spray. The pressurized pack may include a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of pressurized aerosols, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds disclosed herein may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be present in unit dosage form, such as a capsule, cartridge (cartridge), gelatin or blister pack, from which the powder may be administered by means of an inhaler or insufflator.

In particular, intranasal delivery may be used to deliver compounds to the CNS. Intranasal administration has been shown to be a non-invasive method of delivering neurotrophic factors and other therapeutic agents to the brain and spinal cord, bypassing the Blood Brain Barrier (BBB). Transmission from the nose to the CNS along the olfactory and trigeminal pathways occurs within minutes. Intranasal delivery occurs through an extracellular pathway and does not require drug binding to any receptor or axonal transport. Intranasal delivery is also directed to Nasal Associated Lymphoid Tissue (NALT) and deep-neck lymph nodes. In addition, high levels of intranasal administration of therapeutic agents are observed in the vessel wall and perivascular space of the cerebral vascular system (cerebroviculature). Using this intranasal approach in animal models, researchers have successfully reduced stroke damage, reversed the neurodegeneration of Alzheimer's disease, reduced anxiety, improved memory, stimulated brain neurogenesis, and treated brain tumors.

In one embodiment, unit dosage formulations are those containing an effective dose or an appropriate fraction thereof of the active ingredient.

It will be appreciated that in addition to the ingredients specifically mentioned above, the above formulations may include agents conventional in the art for the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

Combination therapy

In certain instances, it may be appropriate to administer at least one of the compounds of formula (I) or (II) (an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects a patient experiences when receiving one of the compounds used herein to treat cancer is nausea, then co-administration of an anti-emetic agent may be appropriate. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefits experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefits. By way of example only, in cancer treatments involving administration of one of the compounds described herein, increased therapeutic benefit may be produced by providing the patient with another cancer therapeutic agent. In any event, regardless of the disease, condition, or disorder being treated, the overall benefit experienced by the patient may be just the addition of the two therapeutic agents or the patient may experience a synergistic benefit.

The compounds of the present invention may be particularly useful in combination with therapeutic and/or anti-cancer agents. Accordingly, the present disclosure provides a combination of compounds of formula (I) or (II) for use in combination with a therapeutic and/or anticancer agent for simultaneous, separate or sequential administration. The compounds of the present disclosure and other anticancer agents may add or act synergistically. The synergistic combination of a compound of the present invention and another anticancer agent may allow for the use of lower doses of one or both of these agents and/or lower frequent doses of one or both of the compound of the present invention and the other anticancer agent, and/or less frequent administration of these agents may reduce any toxicity associated with administration of the agents to a patient without reducing the efficacy of the agents in treating cancer. Furthermore, synergistic effects may result in increased efficacy of these agents in treating cancer and/or reduce any adverse or undesirable side effects associated with the use of either agent alone.

The therapeutic and/or anticancer agent may be administered according to therapeutic regimens well known in the art. It will be apparent to those skilled in the art that the administration of the therapeutic and/or anticancer agent may vary depending on the disease being treated and the known effect of the anticancer agent on the disease. Furthermore, the treatment regimen (e.g., the dosage and time of administration) may vary according to the observed effect of the administered therapeutic agent (i.e., the antineoplastic agent or radiation) on the patient, and in view of the observed response of the disease to the administered therapeutic agent as well as the observed side effects, according to the knowledge of the skilled clinician.

In certain embodiments, a compound according to one or more embodiments disclosed herein, e.g., a compound of formula I, may be administered in combination with one or more agents selected from the group consisting of: aromatase inhibitors, antiestrogens, antiprogestins or gonadotrophin 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, antiangiogenic 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, smooth antagonists, ras isoforms inhibitors, telomerase inhibitors, protease inhibitors, metalloprotease inhibitors, aminopeptidase inhibitors, immunomodulators, therapeutic antibodies and protein kinase inhibitors such as tyrosine kinase or serine/threonine kinase inhibitors.

In certain embodiments, a combination of a compound of formula I and an anticancer agent is provided for simultaneous, separate or sequential administration.

One of ordinary skill in the art will be able to discern which combinations of agents will be useful based on the particular characteristics of the drug and the cancer involved. Classes of such agents include: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins/cytostatics, antiproliferatives, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, cell proliferation and survival signaling inhibitors, bisphosphonates, aromatase inhibitors, siRNA therapeutic agents, gamma secretase inhibitors, agents that interfere with Receptor Tyrosine Kinases (RTKs), agents that interfere with cell cycle checkpoints, PARP inhibitors, HDAC inhibitors, smo antagonists (HH inhibitors), HSP90 inhibitors, CYP17 inhibitors, third generation AR antagonists, JAK inhibitors such as ruxotinib (trade name Jakafi) and BTK kinase inhibitors.

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

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

2) Covalent DNA binding agents [ alkylating agents ], including nitrogen mustards (e.g., chloroethylamine, nitrogen mustards (chloroethane), chlorambucil, cyclophosphamide, estramustine (Emcyt, estracit), ifosfamide (ifosfamide), ifosfamide (Ifosphamide), melphalan (alkan), and the like); alkyl sulfonates such as busulfan [ mylaran ], nitrosoureas (e.g., carmustine or BCNU (bischloroethylnitrosourea), fotemustine lomustine (fotemustine Lomustine) and semustine, streptozotocin, etc.), and other alkylating agents (e.g., dacarbazine, procarbazine ethyleneimine (procarbazine ethylenimine)/methyl melamine, triethylene melamine (TEM), triethylenethiophosphamide (thiotepa), hexamethylmelamine (HMM, hexamethylmelamine) and mitomycin, uracil nitrogen mustard (uramcaline), etc.), including temozolomide (trade names Temodar and Temodar), hexamethylmelamine (also known as hexalen) and mitomycin; and

3) Non-covalent DNA binding agents [ antitumor antibiotics ], including nucleic acid inhibitors (e.g., dactinomycin [ actinomycin Dl, etc.), anthracyclines (e.g., daunorubicin (Daunorubicin) [ dactinomycin (Daunomycin) and Daunorubicin (Cerubidine) ], doxorubicin [ adrian ycin ], epirubicin (Ellence) and idarubicin [ Idamycin ], valrubicin (Valstar), etc.), anthracenediones (e.g., anthracycline analogs such as [ mitoxantrone ], etc.), bleomycin (bleomycin sulfate (Blenoxane), etc.), amsacrine (amsacrine) and plicamycin (Mithramycin), actinomycin, mitomycin C.

In certain embodiments, a patient suffering from cancer is treated with a combination of a compound of formula (I) or (II) and radiation therapy. In certain embodiments, the method comprises administering to a patient suffering from cancer a therapeutically effective amount of a compound of the present disclosure, and adjunctively treating the patient with an effective amount of a radiation therapeutic agent. In certain embodiments, the compound is administered to a patient in need thereof prior to, concurrently with, or after radiation therapy.

In one embodiment, 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, orAdefovir, abamectin, acyclovir, ganciclovir, valganciclovir, valacyclovir, cidofovir, famciclovir, ribavirin, amantadine, rimantadine (Rimantadine), interferon, oseltamivir, palivizumab, rimantadine (Rimantadine), zanamivir, nucleoside analog reverse transcriptase inhibitors (NRTI) such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, and abacavir, non-nucleoside reverse transcriptase inhibitors (NNRTI) such as nevirapine, delavirdine, and efavirenz, protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and other known antiviral compounds and formulations.

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

Controlled release formulation and drug delivery system:

in certain embodiments, the compositions and/or formulations of the present invention may be, but are not limited to, short-term, fast-compensating, and controlled, e.g., sustained release, delayed release, and pulsatile release formulations.

The term sustained release in its conventional sense refers to a pharmaceutical formulation that gradually releases a drug over an extended period of time, although not necessarily, resulting in a substantially constant blood level of the drug over an extended period of time. The period of time may be as long as one month or more and should be longer than the same amount of release administered as a bolus.

For sustained release, the compounds may be formulated with suitable polymers or hydrophobic materials that provide sustained release characteristics to the compound. Thus, the compounds used in the methods of the invention may be administered in particulate form, for example by injection, or by implantation in wafer or disc form.

In certain embodiments of the invention, a compound useful in the invention is administered to a subject using a slow release formulation, alone or in combination with another pharmaceutical formulation.

The term delayed release is used herein in its conventional sense to refer to a pharmaceutical formulation that provides an initial release of a drug after a certain delay following administration of the drug, and may include, although not necessarily, from about 10 minutes up to about 12 hours.

The term pulsatile release is used herein in its conventional sense to refer to a pharmaceutical formulation that provides drug release in a manner that produces a pulsatile plasma profile following drug administration.

The term immediate release in its conventional sense refers to a pharmaceutical formulation that provides for release of a drug immediately after administration of the drug.

As used herein, short term refers to any period of time following drug administration 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 and any or all full or partial increments thereof.

Administration/administration

The compound may be administered to the animal several times a day, or may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every few months, or even once a year or less. It will be appreciated that in non-limiting examples, the amount of compound administered per day may be administered once per day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, once every other day, a daily dose of 5mg may be started on monday, a first subsequent daily dose of 5mg administered on wednesday, a second subsequent daily dose of 5mg administered on friday, and so on. The frequency of dosage will be apparent to the skilled artisan and will depend on many factors such as, but not limited to, the type and severity of the disease being treated and the type and age of the animal.

In certain embodiments, the compositions of the present invention are administered to a patient at a dose in the range of 1-5 times or more per day. In other embodiments, the compositions of the present invention are administered to a patient in a dosage range that includes, but is not limited to, once daily, once every two days, once every three days to once a week, and once every two weeks. It will be apparent to those skilled in the art that the frequency of administration of the various compositions of the present invention will vary from subject to subject, depending on a number of factors including, but not limited to, age, disease or disorder to be treated, sex, general health and other factors. Thus, the present invention should not be construed as limited to any particular dosage regimen and the precise dosage and composition to be administered to any patient will be determined by the attending physician taking into account all other factors of the patient.

The compounds according to one or more embodiments disclosed in the present specification may be administered orally or by injection at a dose of 0.1 to 500mg/kg per day. The dosage range for adults is typically 5mg to 2 g/day. A tablet or other form of presentation provided in discrete units may conveniently contain an amount of one or more compounds effective at such doses or multiples thereof, for example, containing units of from 5mg to 500mg, typically from about 10mg to about 200 mg.

The compounds of the invention for administration may be within the following ranges: about 1 μg to about 7,500mg, about 20 μg to about 7,000mg, about 40 μg to about 6,500mg, about 80 μg to about 6,000mg, about 100 μg to about 5,500mg, about 200 μg to about 5,000mg, about 400 μg to about 4,000mg, about 800 μg to about 3,000mg, about 1mg to about 2,500mg, about 2mg to about 2,000mg, about 5mg to about 1,000mg, about 10mg to about 750mg, about 20mg to about 600mg, about 30mg to about 500mg, about 40mg to about 400mg, about 50mg to about 300mg, about 60mg to about 250mg, about 70mg to about 200mg, about 80mg to about 150mg, and any whole and partial increments therebetween.

In some embodiments, the dosage of the compounds of the present invention is about 0.5 μg and about 5,000mg. In some embodiments, the dosage of the compounds of the present invention used in the compositions described herein is less than about 5,000mg, or less than about 4,000mg, or less than about 3,000mg, or less than about 2,000mg, or less than about 1,000mg, or less than about 800mg, or less than about 600mg, or less than about 500mg, or less than about 200mg, or less than about 50mg. Similarly, in some embodiments, the dosage of the second compound as described herein is less than about 1,000mg, or less than about 800mg, or less than about 600mg, or less than about 500mg, or less than about 400mg, or less than about 300mg, or less than about 200mg, or less than about 100mg, or less than about 50mg, or less than about 40mg, or less than about 30mg, or less than about 25mg, or less than about 20mg, or less than about 15mg, or less than about 10mg, or less than about 5mg, or less than about 2mg, or less than about 1mg, or less than about 0.5mg, and any full and partial increments thereof.

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

The compounds of the present disclosure may be administered in a variety of ways, such as orally, topically or by injection. The precise amount of compound administered to the patient will be at the discretion of the attending physician. The specific dosage level for any particular patient will depend on a variety of factors including the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the precise disease being treated and the severity of the indication or disorder being treated. Furthermore, the route of administration may vary with the condition and severity thereof.

LCMS conditions

Method A: HPLC Alliance 2695 system using Gemini NX-C18 phenomenox (30X 2 mm), 3 μm column, eluent including eluent A=H ₂ O+0.05% TFA (v/v); and eluent b=ch ₃ Cn+0.035%tfa. Oven temperature: 55 ℃; gradient: t is t _0min ＝2％B；t _2.5min ＝98％B；t _3.5min ＝98％B；t _3.6min ＝2％B；t _5min =5%b (v/v). Flow rate: 0.9mL/min. Positively sprayed es+; capillary tube: 3.5kV; taper hole (cone) voltage: 15V.

Method B: waters Acquity UPLC System using Waters Acquity UPLC CSH C (50X 2.1 mm), 1.7 μm column, eluent comprising: eluent a=h ₂ O+0.02% HCOOH (v/v); and eluent b=ch ₃ CN+0.02% HCOOH (v/v). Oven temperature: 55 ℃; gradient: t is t _0min ＝0.2％B；t _4min＝ 98％B；t _4.5min ＝98％B；t _4.6min ＝2％B；t _5min =2%b. Flow rate: 1mL/min. Negative electrospraying ES-; capillary tube: 3kV; taper hole voltage: 15V.

Method C: waters Acquity UPLC System using Waters Acquity UPLC CSH C (2.1X150 mm), 1.7 μm column, eluent comprising: eluent a=h ₂ O+0.02% hcooh; and eluent b=ch ₃ Cn+0.02% hcooh. Oven temperature: 55 ℃; gradient: t is 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: 1mL/min. Electrospray ionization mode; capillary tube: 3kV; sample taper hole: 15/30V.

Method D: waters Acquity UPLC System using Waters Acquity UPLC CSH C (2.1X50 mm), 1.7 μm column, A=H ₂ O+0.05% TFA (v/v); and eluent b=ch ₃ CN+0.035％TFA. Oven temperature: 55 ℃; gradient: t is 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: 0.8mL/min. Positively sprayed es+; capillary tube: 0.8kV; taper hole voltage: 15V.

Method E: waters Acquity UPLC System using Waters Acquity UPLC CSH C (2.1X50 mm), 1.7 μm column, A=H ₂ O+0.05% TFA (v/v); and eluent b=ch ₃ Cn+0.035%tfa. Oven temperature: 55 ℃; gradient: t is 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: 0.8mL/min. Positively sprayed es+; capillary tube: 0.8kV; taper hole voltage: 10V.

Method F: waters Acquity UPLC System using Waters Acquity UPLC CSH C (2.1X100 mm), 1.7 μm column, A=H ₂ O+0.02% HCOOH (v/v); and b=ch ₃ Cn+0.02% hcooh. Oven temperature: 55 ℃; gradient: t is t _0min ＝2％B，t _15min ＝98％B，t _15.2min ＝2％B，t _18min =2%b (v/v). Flow rate: 0.7mL/min. Electrospray ionization mode; capillary tube: 3kV; sample taper hole: 15/30V.

Method G: waters Acquity UPLC System using Waters Acquity UPLC CSH C (2.1X50 mm), 1.7 μm column, A=H ₂ O+0.05% TFA (v/v); and eluent b=ch ₃ Cn+0.035%tfa. Oven temperature: 55 ℃; gradient: t is t _0min ＝2％B；t _2.4min ＝98％B；t _3.0min ＝98％B；t _3.03min ＝2％B；t _3.5min =2%b (v/v). Flow rate: 0.8mL/min. Positively sprayed es+; capillary tube: 0.8kV; taper hole voltage: 15V.

Method H: waters Acquity UPLC System using Waters Acquity UPLC CSH C (50X 2.1 mm), 1.7 μm column, eluent comprising: eluent a=h ₂ O+0.02% HCOOH (v/v); and eluent b=ch ₃ CN+0.02% HCOOH (v/v). Oven temperature: 55 ℃; gradient: t is t _0min ＝0.2％B；t _4min ＝98％B；t _4.5min ＝98％B；t _4.6min＝ 2％B；t _5min =2%b. Flow rate: 1mL/min. Negative electrospraying ES-; capillary tube: 3kV; sample taper hole: 15/30V.

Examples

Various embodiments of the present application may be better understood by reference to the following illustrative examples. The scope of the application is not limited to the examples given herein.

Example 1: synthesis of Compounds 1-34

Sulfonamide Synthesis procedure-Sulfonyl chloride and amine coupling

Each vial was filled with amine reagent (0.4221 mmol,1.1 eq) and Et ₃ N (1.5348 mmol,4eq, 214. Mu.L). A solution of 4- (trifluoromethoxy) benzenesulfonyl chloride in DCM (0.284 mmol,1.0eq,2mL,0.192 mmol/mL) was partitioned into each vial. The reaction mixture was stirred at 25 ℃ overnight. The reaction mixture was filtered on a 3mL ChemElut cartridge (pretreated with HCl 1M (3 mL)) and eluted with 2mL DCM. The fractions obtained were concentrated at room temperature under a nitrogen flow for 2 hours and then dried under vacuum at 40 ℃ overnight. Purification is carried out by SCX, PE-AX or flash chromatography, if necessary.

In certain embodiments, SCX is used: ISOLUTE-SCX (1 g,6 mL) cartridge. The cartridge was eluted with 10mL DCM and the crude product solution diluted in 1mL by gravity filtration. The cartridge was eluted twice with 4mL DCM, and 2mL 2N NH was used ₃ Is eluted once in MeOH. The desired fraction was concentrated under nitrogen flow at room temperature for 2 hours and then dried under vacuum at 40 ℃ overnight.

In certain embodiments, PE-AX is used: ISOLUTE-PE-AX (1 g,6 mL) cartridge. The cartridge was eluted with 10mL DCM and the crude product solution diluted in 1mL by gravity filtration. The cartridge was eluted twice with 4mL of 1.25N HCl in MeOH and once with 2mL of 1.25N HCl in MeOH. The desired fraction was concentrated under nitrogen flow at room temperature for 2 hours and then dried under vacuum at 40 ℃ overnight.

In certain embodiments, flash chromatography is used, wherein the crude product is purified by silica gel flash chromatography using a gradient of 2% to 10% MeOH in DCM. The desired fraction was concentrated under nitrogen flow at room temperature for 2 hours and then dried under vacuum at 40 ℃ overnight.

LCMS analysis was performed using method a unless otherwise indicated.

The following compounds were prepared according to the procedures and conditions provided herein:

n- (4- ((4- ((4- (trifluoromethoxy) phenyl) sulfamido) piperidin-1-yl) sulfonyl) phenyl) acetamide (1)

TABLE 1 analytical data for Compound 1

Starting material (amine): n- (4- ((4-aminopiperidin-1-yl) sulfonyl) phenyl) acetamide.

N- (1- (5-chloro-2-methoxyphenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (2)

TABLE 2 analytical data for Compound 2

Starting material (amine): 1- (5-chloro-2-methoxyphenyl) pyrrolidin-3-amine.

N- (1- (3-bromophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (3)

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TABLE 3 analytical data for Compound 3

Starting material (amine): 1- (3-bromophenyl) pyrrolidin-3-amine.

Cis 1- ((4- (trifluoromethoxy) phenyl) sulfamido) -2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester (4)

TABLE 4 analytical data for Compound 4

Starting material (amine): cis-1-amino-2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester hydrochloride.

N- (1- (3, 4-dichlorophenyl) piperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (5)

TABLE 5 analytical data for Compound 5

Starting material (amine): 1- (3, 4-dichlorophenyl) piperidin-3-amine.

4- (trifluoromethoxy) -N- (1- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) benzenesulfonamide (6)

TABLE 6 analytical data for Compound 6

Starting material (amine): 1- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-amine.

N- (2- (4-fluorophenoxy) cyclohexyl) -4- (trifluoromethoxy) benzenesulfonamide (7)

TABLE 7 analytical data for Compound 7

Starting material (amine): 2- (4-fluorophenoxy) cyclohex-1-amine.

4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide (8)

TABLE 8 analytical data for Compound 8

Starting material (amine): 3, 4-trimethylcyclohex-1-amine.

Trans N- (2- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (9)

TABLE 9 analytical data for Compound 9

Starting material (amine): trans 2- (4-chlorophenyl) -1-methylpyrrolidin-3-amine.

N- (5, 8-Difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (10)

TABLE 10 analytical data for Compound 10

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^a LCMS method B; starting material (amine): 5, 8-Difluorochroman-4-amines.

N- (4, 6-dichloro-2, 3-dihydro-1H-inden-1-yl) -4- (trifluoromethoxy) benzenesulfonamide (11)

TABLE 11 analytical data for Compound 11

^a LCMS method B; starting material (amine): 4, 6-dichloro-2, 3-dihydro-1H-inden-1-amine.

N- (6-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide (12)

TABLE 12 analytical data for Compound 12

^a LCMS method B; initiationSubstance (amine): 6-chloro-1, 2,3, 4-tetrahydronaphthalen-1-amine.

N- (2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide (13)

TABLE 13 analytical data for Compound 13

Starting material (amine): 2-phenylcyclohepta-1-amine.

N- (1- (3-chlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide (14)

TABLE 14 analytical data for Compound 14

Starting material (amine): 1- (3-chlorophenyl) cyclopent-1-amine.

N- (1- (3-methoxyphenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide (15)

TABLE 15 analytical data for Compound 15

Starting material (amine): 1- (3-methoxyphenyl) cyclopent-1-amine.

N- (2-oxo-1- (3- (trifluoromethyl) benzyl) piperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (16)

TABLE 16 analytical data for Compound 16

Starting material (amine): 3-amino-1- (3- (trifluoromethyl) benzyl) piperidin-2-one.

N- (1- (2-phenylbutyryl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (17)

TABLE 17 analytical data for Compound 17

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Starting material (amine): 1- (4-aminopiperidin-1-yl) -2-phenylbutan-1-one.

N- (spiro [ chromane-2, 1' -cyclopent ] -4-yl) -4- (trifluoromethoxy) benzenesulfonamide (18)

TABLE 18 analytical data for Compound 18

^a LCMS method B; starting material (amine): spiro [ chromane-2, 1' -cyclopentanes]-4-amine.

Methyl 3- (1- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopentyl) propionate (19)

TABLE 19 analytical data for Compound 19

Starting material (amine): methyl 3- (1-aminocyclopentyl) propionate.

1- ((4- (trifluoromethoxy) phenyl) sulfamido) -2, 3-dihydro-1H-indene-1-carboxylic acid ethyl ester (20)

TABLE 20 analytical data for Compound 20

Starting material (amine): 1-amino-2, 3-dihydro-1H-indene-1-carboxylic acid ethyl ester.

3, 5-dimethyl-7- ((4- (trifluoromethoxy) phenyl) sulfonamide) adamantane-1-carboxylic acid methyl ester (21)

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TABLE 21 analytical data for Compound 21

Starting material (amine): 3, 5-dimethyl-7- (methylamino) adamantane-1-carboxylic acid methyl ester.

N- (2-Benzylboropenta [ c ] pyrrol-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (22)

TABLE 22 analytical data for Compound 22

Starting material (amine): 2-benzyl octahydrocyclopenta [ c ] pyrrol-4-amine.

2- (1- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) pyrrolidine-1-carboxylic acid tert-butyl ester (23)

TABLE 23 analytical data for Compound 23

Starting material (amine): 2- (1-aminocyclopropyl) pyrrolidine-1-carboxylic acid tert-butyl ester.

Trans-4- (2- ((4- (trifluoromethoxy) phenyl) sulphonamido) cyclopropyl) piperidine-1-carboxylic acid tert-butyl ester (24)

TABLE 24 analytical data for Compound 24

Starting material (amine): trans-4- (2-aminocyclopropyl) piperidine-1-carboxylic acid tert-butyl ester.

N- (6- (difluoromethoxy) -4-oxo-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide (25)

TABLE 25 analytical data for Compound 25

Starting material (amine): 4-amino-7- (difluoromethoxy) -3, 4-dihydronaphthalen-1 (2H) -one.

4- (trifluoromethoxy) -N- (4- (trifluoromethyl) -4,5,6, 7-tetrahydro-1H-indazol-6-yl) benzenesulfonamide (26)

TABLE 26 analytical data for Compound 26

Starting material (amine): 4- (trifluoromethyl) -4,5,6, 7-tetrahydro-1H-indazol-6-amine.

(S) -N- (6-fluoro-2, 2-dimethylbenzodihydropyran-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (27)

TABLE 27 analytical data for Compound 27

Quantity (mg)	Yield (%)	Purity (%)	MS(m/z)	Observed ions ^a	r _t (min)
						120.1	68.7	92.11	418	[M-H] ^-	2.86

^a LCMS method B; starting material (amine): (S) -6-fluoro-2, 2-dimethylbenzodihydropyran-4-amine.

N- (2-ethyl-1- (m-tolyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide (28)

TABLE 28 analytical data for Compound 28

Starting material (amine): 2-ethyl-1- (m-tolyl) cyclopropyl-1-amine.

N- (4- (3-fluoro-4-methoxyphenyl) tetrahydro-2H-pyran-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (29)

TABLE 29 analytical data for Compound 29

^a LCMS method B; starting material (amine): 4- (3-fluoro-4-methoxyphenyl) tetrahydro-2H-pyran-4-amine.

N- (1- (3-ethoxy-4-hydroxybenzyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (30)

TABLE 30 analytical data for Compound 30

Starting material (amine): 4- ((4-aminopiperidin-1-yl) methyl) -2-ethoxyphenol.

Racemic N- ((6R, 7R) -2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro [3.4] oct-6-yl) -4- (trifluoromethoxy) benzenesulfonamide (31)

TABLE 31 analytical data for Compound 31

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Starting material (amine): rac (6 r,7 r) -7-amino-2-benzyl-1-isopropyl-2-azaspiro [3.4] oct-6-ol.

3- (fluoromethyl) -3- ((4- (trifluoromethoxy) phenyl) sulphonamido) pyrrolidine-1-carboxylic acid tert-butyl ester (32)

TABLE 32 analytical data for Compound 32

Starting material (amine): 3-amino-3- (fluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester.

3, 5-dimethyl-N- ((1- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclohexyl) methyl) isoxazole-4-sulfonamide (33)

TABLE 33 analytical data for Compound 33

Starting material (amine): n- ((1-aminocyclohexyl) methyl) -3, 5-dimethylisoxazole-4-sulfonamide.

Racemic N- ((2S, 3R) -1-cyclopropyl-2- (3, 4-difluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (34)

TABLE 34 analytical data for Compound 34

Starting material (amine): rac (2 s,3 r) -1-cyclopropyl-2- (3, 4-difluorophenyl) pyrrolidin-3-amine.

Example 2: n- (1-benzyl-3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (35)

4- (trifluoromethoxy) benzenesulfonyl chloride (35 μl,0.198 mmol) was added to a stirred solution of 1-benzyl-3-phenyl-pyrrolidin-3-amine (50 mg,0.198 mmol) and triethylamine (110 μl,0.793 mmol) in anhydrous DCM (2.1611 mL) in a sealed tube. The solution was stirred at room temperature for 20 hours. Water (10 mL) was added and the aqueous layer was extracted with dichloromethane (1X 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography using a gradient of 0% to 100% acetonitrile in water (0.1% acoh in water). The crude product was further purified by flash chromatography on silica gel using a gradient of 0% to 5% methanol in dichloromethane. The residue was triturated in 2M hydrogen chloride in diethyl ether (1.0 ml,2.00 mmol), filtered, washed with diethyl ether and dried under vacuum at 60 ℃ for 20 hours to give the title compound as a yellow oil (39.9 mg, 39% yield, 98.9% purity, t _r =1.63 min). LCMS (method C): m/z found 477[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ(ppm)10.55-11.48(m，1H)，8.45-9.18(m，1H)，7.44-7.70(m，5H)，7.25-7.40(m，2H)，7.10-7.20(m，2H)，6.94-7.05(m，5H)，4.38-4.60(m，2H)，3.41-4.22(m，4H)，2.93-3.06(m，1H)，2.18-2.28(m，1H)。

Example 3: n- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (36)

Step 1: synthesis of 3-amino-3-phenylpyrrolidine-1-carboxylic acid tert-butyl ester

In a sealed vial, to a stirred solution of 3-phenylpyrrolidin-3-amine (2 HCl) (100 mg,0.425 mmol) and triethylamine (0.24 mL,1.70 mmol) in DCM (4.2526 mL) was addedDi-tert-butyl dicarbonate (93 mg,0.425 mmol). The reaction mixture was stirred at room temperature overnight. Water and DCM were added and the aqueous layer was extracted twice with DCM. The organic layer was saturated with NH ₄ Cl solution was washed, then with saturated NaHCO ₃ The solution was washed with brine and then concentrated in vacuo to give the title compound as a colourless oil (99.5 mg, 86% yield, t) _r =0.55 min). LCMS (method D): m/z found 263.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)7.47(d，J＝7.6Hz，2H)，7.33(t，J＝7.6Hz，2H)，7.22(t，J＝7.3Hz，1H)，3.58–3.35(m，4H)，2.23–1.85(m，4H)，1.42(d，J＝4.4Hz，10H)。

Step 2: synthesis of tert-butyl 3-phenyl-3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] pyrrolidine-1-carboxylate

4- (trifluoromethoxy) benzenesulfonyl chloride (0.60 mL,3.53 mmol) was added to a stirred solution of tert-butyl 3-amino-3-phenylpyrrolidine-1-carboxylate (925 mg,3.53 mmol) and N, N-dimethylpyridine-4-amine (99%, 87mg, 0.704 mmol) in DCM (35.258 mL) under nitrogen in a sealed vial. The solution was stirred at room temperature for 4 hours with half saturated NaHCO ₃ And DCM solution, and the aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator, then concentrated in vacuo and purified by flash chromatography on silica gel using a gradient of 20% to 80% EtOAc in heptane to give the title compound as a white powder (1.371 g, 79% yield, t _r =1.00 min). LCMS (method E): m/z 509[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)8.53(d，J＝7.9Hz，1H)，7.38(dd，J＝8.7，1.6Hz，2H)，7.19(d，J＝7.4Hz，2H)，7.09–6.92(m，5H)，4.04(d，J＝11.4Hz，1H)，3.56–3.35(m，2H)，3.29(s，2H)，2.81–2.60(m，1H)，2.16(ddt，J＝21.2，12.5，8.4Hz，1H)，1.41(d，J＝4.6Hz，9H)。

Step 3: synthesis of N- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (36)

In a round bottom flask, 3-phenyl-3- [ [4- (trifluoromethoxy) phenyl ]]Sulfonylamino groups]A stirred solution of pyrrolidine-1-carboxylic acid tert-butyl ester (59 mg,0.121 mmol) in diethyl ether (1.8375 mL) was added a 2M solution of hydrogen chloride in diethyl ether (1.8 mL,3.64 mmol). The mixture was stirred at room temperature for 3 hours, then 4M hydrogen chloride in dioxane (1.8 ml,7.28 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, then sonicated in diethyl ether and filtered to give the hydrogen chloride salt of the title compound as a white powder (46 mg, 89% yield, 99.3% purity, t _r =1.29 min). LCMS (method C): m/z found 386.9[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，600MHz)：δ(ppm)9.02-9.59(m，2H)，8.46-8.83(m，1H)，7.34(d，J＝9.0Hz，2H)，7.16(d，J＝8.1Hz，2H)，7.00-7.06(m，3H)，6.92-6.99(m，2H)，4.13(d，J＝11.9Hz，1H)，3.34-3.45(m，3H)，2.85(ddd，J＝9.3，7.8，4.0Hz，1H)，2.14(dt，J＝13.2，9.8Hz，1H)。

Example 4: racemic N- ((2 s,3 r) -1- (tert-butyl) -2- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (37 and 38).

4- (trifluoromethoxy) benzenesulfonyl chloride (542 μl,3.20 mmol) was added to a stirred solution of rac (2 s,3 r) -1-tert-butyl-2- (4-chloro-3-fluorophenyl) pyrrolidin-3-amine (95%, 1.04 g,3.52 mmol) and triethylamine (1.8 mL,12.8 mmol) in DCM (12.816 mL) in a sealed tube. The solution was stirred at room temperature for 20 hours, then diluted with water and DCM. The aqueous layer was extracted twice with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Gradient 0.2% to 5% (MeOH+2% NH) ₄ OH) solution in DCMThe crude product was purified by flash chromatography on silica gel to give the racemic product as a white powder (1.14 g, 70.5% yield). Enantiomers were separated by chiral chromatography. A sample of the racemic mixture (125 mg) was dissolved in a mixture of i-PrOH (1.5 mL), meOH (1.5 mL) and ACN (2 mL) by sonication to provide a solution at a concentration of 25 mg/mL. The solution was filtered through a hydrophilic polypropylene filter (GHP, 0.45 μm). CO using 10% i-PrOH ₂ The solution was applied as mobile phase (Waters Prep SFC80, flow rate=50 mL/min, t=40 ℃, p=143 bar, UV detection at 210 nm), 20 sample solutions were applied to a Chiralpak IB column (250×20mm,5 μm) to give isolated enantiomers.

Enantiomer I (37): (338.1 mg, yield 21%, purity 100%, t) _r =1.82 min). LCMS (method C): m/z found 494[ M+H ]] ⁺ ； ¹ H ^- NMR(500MHz，DMSO-d ₆ )δ(ppm)8.07(s，1H)7.88(d，J＝8.80Hz，2H)7.49-7.59(m，2H)7.41(t，J＝8.07Hz，1H)7.22-7.30(m，1H)7.13-7.20(m，1H)4.05(m，J＝2.40Hz，1H)3.07-3.13(m，1H)2.92-3.05(m，2H)1.45-1.85(m，2H)0.91(s，9H)。

Enantiomer II (38): (287.0 mg, yield 18%, purity 100%, t) _r =1.82 min). LCMS (method C): m/z found 494[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ(ppm)8.04-8.15(m，1H)7.80-7.95(m，2H)7.50-7.64(m，2H)7.36-7.46(m，1H)7.22-7.31(m，1H)7.13-7.20(m，1H)4.05(m，J＝2.20Hz，1H)3.07-3.15(m，1H)2.89-3.06(m，2H)1.48-1.86(m，2H)0.91(s，9H)。

Example 5: n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (39)

Step 1: synthesis of 3- (4-chlorophenyl) -3-hydroxypyrrolidine-1-carboxylic acid benzyl ester

A sealed vial was charged with a solution of 3- (4-chlorophenyl) pyrrolidine-3-ol hydrochloride (0.60 g,2.56 mmol) and DIPEA (1.3 mL,7.69 mmol) in anhydrous acetonitrile (9 mL). Benzyl chloroformate (97%, 413. Mu.L, 2.82 mmol) was added dropwise at 0deg.C and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL). Ethyl acetate (50 mL) and water (20 mL) were then added. The aqueous layer was extracted with ethyl acetate (1X 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated in dichloromethane, filtered and washed with dichloromethane to give a white powder. The filtrate was purified by flash chromatography on silica gel using a gradient of 1% to 5% methanol in methylene chloride to give an off-white powder, which was added to the white powder and dried in vacuo at 50 ℃ for 20 hours to give the title compound (848 mg, yield 100%, t _r =0.89 min). LCMS (method E); ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)7.54(d，J＝8.6Hz，2H)，7.46–7.26(m，7H)，5.55(s，1H)，5.10(d，J＝9.8Hz，2H)，3.67–3.43(m，4H)，2.32–1.97(m，2H)。

step 2: synthesis of benzyl 3-azido-3- (4-chlorophenyl) pyrrolidine-1-carboxylate

A sealed vial was charged with a solution of 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) at 0deg.C. Sodium azide (1.04 g,16.0 mmol) was added at 0deg.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 (1X 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (815 mg, 100% yield, t _r＝ 1.03 min). LCMS (method E); 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)。

step 3: synthesis of benzyl 3-amino-3- (4-chlorophenyl) pyrrolidine-1-carboxylate

Triphenylphosphine (614 mg,2.34 mmol) and then 4-methylbenzenesulfonic acid hydrate (PTSA) (1.34 g,7.02 mmol) were added to a stirred solution of benzyl 3-azido-3- (4-chlorophenyl) pyrrolidine-1-carboxylate (835 mg,2.34 mmol) in THF (10 mL) under nitrogen in a round bottom flask. 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, 74% yield, t _r =1.04 min). LCMS (method E): 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)。

Step 4: synthesis of benzyl 3- (4-chlorophenyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) pyrrolidine-1-carboxylate

4- (trifluoromethoxy) benzenesulfonyl chloride (74 μl,0.437 mmol) was added to a stirred solution of benzyl 3-amino-3- (4-chlorophenyl) pyrrolidine-1-carboxylate (200 mg,0.398 mmol) and triethylamine (277 μl,1.99 mmol) in DCM (6.1538 mL) in a sealed tube. The solution was stirred at room temperature for 3 hours. Water (5 mL) was added and the aqueous layer was extracted with dichloromethane (1X 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, and subjected toDried 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% to 5% methanol in dichloromethane to give the title compound as a yellow powder (64.4 mg, 27% yield, t _r =1.03 min). LCMS (method E): m/z found 577.2[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)8.64(s，1H)，7.46–7.30(m，7H)，7.25(d，J＝8.3Hz，2H)，7.10–7.00(m，4H)，5.16–5.00(m，2H)，4.14(dd，J＝19.3，11.3Hz，1H)，3.66–3.32(m，3H)，2.69(d，J＝12.3Hz，1H)，2.37–2.07(m，1H)。

Step 5: synthesis of N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (39)

To N- [3- (4-chlorophenyl) -1- (2-phenoxyacetyl) pyrrolidin-3-yl at room temperature in a round bottom flask]A stirred suspension of 4- (trifluoromethoxy) benzenesulfonamide (90%, 435mg, 0.704 mmol) in acetonitrile (14 mL) was added iodo (trimethyl) silane (301. Mu.L, 2.12 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and then partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2X 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. Using a gradient of 2% to 10% (MeOH+2% NH) ₄ OH) the crude product was purified by flash chromatography on silica gel. The crude product was further purified by reverse phase flash chromatography using an aqueous solution of acetonitrile (+0.1% acoh) with a gradient of 0% to 100%. The residue was triturated in 4M hydrogen chloride in dioxane (1.8 ml,7.05 mmol) and diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 70 ℃ for 16 hours to give the hydrochloride salt of the title compound as an off-white powder (27.9 mg, 9% yield, 99.4% purity, t _r =1.38 min). LCMS (method C): m/z found 421.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)9.47(br s，2H)，8.69-8.99(m，1H)，7.40(d，J＝7.8Hz，2H)，7.22(d，J＝8.1Hz，2H)，7.00-7.08(m，4H)，4.12(br d，J＝12.0Hz，1H)，3.34-3.43(m，3H)，2.82-2.89(m，1H)，2.10-2.18(m，1H)。

Example 6:3- (3, 4-dichlorophenyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) pyrrolidine-1-carboxylic acid benzyl ester (40) and N- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (41)

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Step 1: synthesis of benzyl 3- (3, 4-dichlorophenyl) -3-hydroxypyrrolidine-1-carboxylate

A sealed vial was charged with a solution of 3- (3, 4-dichlorophenyl) pyrrolidine-3-ol hydrochloride (500 mg,1.86 mmol) and DIPEA (1.0 mL,5.73 mmol) in anhydrous acetonitrile (6.5 mL). Benzyl chloroformate (97%, 300 μl,2.05 mmol) was added dropwise at 0deg.C and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and ethyl acetate and water were added. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0% to 50% EtOAc in DCM to give the title compound as an off-white gum (638 mg, 91% yield, t _r =0.94 min). LCMS (method E); ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)7.76(d，J＝2.1Hz，1H)，7.61(dd，J＝8.4，3.7Hz，1H)，7.51(dd，J＝8.4，2.2Hz，1H)，7.42–7.26(m，5H)，5.69(s，1H)，5.13–5.07(m，2H)，3.67–3.44(m，4H)，2.36–2.19(m，1H)，2.04(dt，J＝13.0，6.6Hz，1H)。

step 2: 3-azido-3- (3, 4-dichlorophenyl) pyrrolidine-1-carboxylic acid benzyl ester

To a solution of 3- (3, 4-dichlorophenyl) -3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (356 mg,0.978 mmol) in anhydrous DCM (5 mL) in a sealed vial under nitrogen at 0deg.C was added azido (trimethyl) silane (260 μl,1.96 mmol) and boron trifluoride etherate (242 μl,1.96 mmol). The reaction mixture was allowed to warm to room temperature and stirred at that temperature for 2 days. The reaction mixture was taken up with saturated NaHCO ₃ The aqueous solution was quenched drop wise. EtOAc was added and the layers separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. Purification of the crude product by flash chromatography on silica gel using EtOAc in heptane with a gradient of 5% to 50%. The desired fractions were combined and concentrated to give the title compound as a colorless oil (299.8 mg, 38% yield, t _r =1.11 min). LCMS (method D); ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)7.84(t，J＝2.5Hz，1H)，7.79(t，J＝2.3Hz，1H)，7.73(dd，J＝8.4，4.9Hz，1H)，7.63(dd，J＝8.4，5.6Hz，1H)，7.52(ddd，J＝12.6，8.4，2.2Hz，2H)，7.46–7.30(m，11H)，6.58(dt，J＝10.4，2.0Hz，1H)，5.17–5.11(m，5H)，4.59–4.47(m，2H)，4.39–4.26(m，2H)，4.07–3.98(m，1H)，3.70–3.43(m，3H)，2.59–2.52(m，1H)，2.47–2.37(m，1H)。

step 3: synthesis of benzyl 3-amino-3- (3, 4-dichlorophenyl) pyrrolidine-1-carboxylate

Triphenylphosphine (121 mg,0.463 mmol) and then 4-methylbenzenesulfonic acid hydrate (PTSA) (262 mg,1.38 mmol) were added to a stirred solution of benzyl 3-azido-3- (3, 4-dichlorophenyl) pyrrolidine-1-carboxylate (50%, 360mg,0.460 mmol) in THF (2 mL) under nitrogen in a round bottom flask. The mixture was stirred at room temperature overnight. Passing the suspension through Filtration, washing with THF, and vacuum drying for 18 hours gave the title compound as a white powder (166.1 mg, 64% yield, t _r =0.67 min). LCMS (method D): m/z found 348.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)8.46(s，2H)，7.86–7.73(m，2H)，7.54–7.45(m，3H)，7.43–7.31(m，5H)，7.11(d，J＝7.8Hz，2H)，5.21–5.07(m，2H)，4.07(d，J＝11.8Hz，1H)，3.82–3.52(m，3H)，2.60–2.45(m，2H)，2.29(s，3H)。

Step 4: synthesis of benzyl 3- (3, 4-dichlorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] pyrrolidine-1-carboxylate (40)

To a stirred suspension of benzyl 3-amino-3- (3, 4-dichlorophenyl) pyrrolidine-1-carboxylate (128 mg,0.238 mmol) in DCM (2.4 mL) was added triethylamine (166. Mu.L, 1.19 mmol), 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 62. Mu.L, 0.358 mmol) and N, N-dimethylpyridine-4-amine (5.8 mg,0.0476 mmol) in sequence at room temperature in a vial. The reaction mixture was stirred at this temperature for 1 hour and then heated at 40 ℃ for 4 hours. The reaction mixture was taken up with DCM and saturated NaHCO ₃ Diluting the aqueous solution. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using 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 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a white foam (117.6 mg, 79% yield, t) _r =1.06 min). LCMS (method E): m/z found 611.2[ M+Na ]] ⁺ ； ¹ (DMSO-d ₆ ，400MHz)δ(ppm)8.67(s，1H)，7.55–6.99(m，12H)，5.17–4.98(m，2H)，4.22–3.98(m，1H)，3.70–3.33(m，3H)，2.76–2.60(m，1H)，2.37–2.10(m，1H)。

Step 5: n- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (41)

To 3- (3, 4-dichlorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] at room temperature in a round bottom flask]Sulfonylamino groups]A stirred solution of pyrrolidine-1-carboxylic acid benzyl ester (89 mg,0.150 mmol) in acetonitrile (2.8 mL) was added iodo (trimethyl) silane (64 μl,0.450 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. A gradient of 2% to 20% MeOH (0.7N NH was used ₃ ) The crude product was purified by flash chromatography on silica gel. The desired fractions were combined and concentrated. The residue was triturated in MeOH, filtered, washed with MeOH and diethyl ether and dried in vacuo at 45 ℃ for 18 hours to give the first crop of the title compound (crop) as a white powder (23.4 mg, 34% yield). The filtrate was combined with another fraction containing the title compound. The resulting powder was dissolved in a mixture of MeOH/DCM and the homogeneous solution was added to diethyl ether and stirred for 2 hours. The precipitate formed was filtered, washed with diethyl ether and pentane, dried in vacuo at 45 ℃ for 18 hours and the first crop was combined to give the title compound as a white powder (38.6 mg, 79% yield). The combined precipitate was further purified by reverse phase preparative chromatography (C18 AQ 15.5 g) using a gradient of 0% to 100% acetonitrile in water (0.1% acoh in both). The desired fractions were combined and concentrated. The residue was subjected to salt exchange (acetate with chloride) in HCl 2N diethyl ether and stirred at room temperature overnight. The suspension was filtered, washed with diethyl ether and pentane and dried at 45 ℃ for 18 hours to give the hydrochloride salt of the title compound as a white powder (25.4 mg, 34% yield, 95.1% purity, t _r =1.47 min). LCMS (method C): m/z found 455[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ(ppm)9.38–7.71(m，1H)，7.49(d，J＝8.8Hz，2H)，7.31–7.27(m，2H)，7.26(s，1H)，7.23(d，J＝2.2Hz，1H)，7.13(dd，J＝8.6，2.2Hz，1H)，3.44–3.37(m，J＝11.6，0.9Hz，1H)，3.29–3.21(m，1H)，3.03–2.93(m，1H)，2.90(d，J＝11.7Hz，1H)，2.86–2.79(m，1H)，2.49–2.44(m，1H)，2.07–1.97(m，1H)。

Example 7: racemic N- ((1R, 2S) -2- (4-chlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide (42)

In a round bottom flask in N ₂ 4- (trifluoromethoxy) benzenesulfonyl chloride (0.059 mL,0.349 mmol) was added to a stirred solution of rac (1R, 2S) -2- (4-chlorophenyl) cyclopropyl-1-amine hydrochloride (95%, 75mg,0.349 mmol) and triethylamine (0.19 mL,1.40 mmol) in anhydrous DCM (2.3273 mL). The solution was stirred at room temperature overnight and then DCM and half saturated NaHCO were added ₃ The solution was extracted twice with DCM. The combined organic layers were filtered through a phase separator, then concentrated in vacuo and purified by flash chromatography on silica gel using an isocratic eluent comprising 100% dcm to give the title compound as a white powder (111.1 mg, yield = 81%, purity 100%, t _r =2.71 min). LCMS (method C): m/z found 392[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ(ppm)8.32(d，J＝3.4Hz，1H)，7.87(d，J＝8.8Hz，2H)，7.59(d，J＝8.1Hz，2H)，7.25(d，J＝8.6Hz，2H)，6.92(d，J＝8.6Hz，2H)，2.39–2.23(m，1H)，1.95–1.74(m，1H)，1.23–1.03(m，2H)。

Example 8: n- (2- (3, 4-dichlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide (43 and 44)

Triethylamine (242. Mu.L, 1.74 mmol) was added to a stirred solution of 4- (trifluoromethoxy) benzenesulfonyl chloride (113 mg,0.435 mmol) and 2- (3, 4-dichlorophenyl) cyclopent-1-amine (100 mg,0.435 mmol) in DCM (2 mL) under nitrogen in a sealed tube. The solution was stirred at room temperature for 16 hours and poured into half saturated NaHCO ₃ In an aqueous solution. The aqueous layer was extracted twice with DCM. Salt for combined organic layersWashed with water, dried over sodium sulfate, filtered and concentrated. Gradient 1% to 5% (MeOH+2% NH) ₄ OH) the crude product was purified by flash chromatography on silica gel to give two fractions. The first fraction was concentrated and the residue was triturated in pentane. The obtained suspension was filtered and dried under reduced pressure at 45℃for 16 hours to give diastereomer I (racemate) of the title compound (43) as a white powder (42 mg, yield 21%, purity 98.9%, t) _r =3 min). LCMS (method C): m/z found 452.1[ M-H ]] ^- ； ¹ H-NMR(500MHz，DMSO-d ₆ ) Delta (ppm) 7.71-7.62 (m, 3H), 7.47-7.42 (m, 2H), 7.40 (d, j=8.3 hz, 1H), 7.35 (d, j=2.0 hz, 1H), 7.11 (dd, j=8.3, 2.0hz, 1H), 3.92-3.79 (m, 1H), 3.16-3.04 (m, 1H), 1.94-1.71 (m, 4H), 1.62-1.49 (m, 1H), 1.46-1.32 (m, 1H). The second fraction was concentrated and purified using a gradient of 0% to 100% (mecn+0.1% acoh) in (H ₂ O+0.1% acoh) was purified by reverse phase chromatography. The desired fractions were concentrated and the residue was taken up in DCM and half saturated NaHCO ₃ Diluting in water 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 triturated in pentane and then a few drops of Et were added ₂ O. The resulting suspension was filtered, the residue was washed with pentane and dried under reduced pressure at 45 ℃ for 64 hours to give diastereomer II (racemate) of the title compound (42) as a white powder (31 mg, yield 15%, purity 99.3%, t) _r =2.98 min). LCMS (method C): m/z found 452.2[ M-H ]] ^- ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ(ppm)8.07(s，1H)，7.66(d，J＝8.8Hz，2H)，7.39–7.31(m，4H)，7.10(dd，J＝8.3，2.0Hz，1H)，3.54(q，J＝8.5Hz，1H)，2.89–2.67(m，1H)，2.03–1.80(m，2H)，1.75–1.50(m，3H)，1.48–1.33(m，1H)。

Example 9: n- (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (45)

Step 1: synthesis of tert-butyl 4- (4-chlorophenyl) -4- ((4- (trifluoromethoxy) phenyl) sulfamido) piperidine-1-carboxylate

To a stirred suspension of tert-butyl 4-amino-4- (4-chlorophenyl) piperidine-1-carboxylate (200 mg,0.643 mmol) in DCM (6.4844 mL) was added triethylamine (0.45 mL,3.22 mmol), 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 168. Mu.L, 0.968 mmol) and N, N-dimethylpyridin-4-amine (16 mg,0.129 mmol) in sequence at room temperature in a vial. The reaction mixture was stirred at this temperature for 1 hour and then heated at 40 ℃ overnight. The reaction mixture was taken up with DCM and saturated NaHCO ₃ Diluting the aqueous solution. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a white foam (327.3 mg, 95.08% yield, 98.74% purity, t _r =1.06 min). LCMS (method E): m/z found 435.2[ M-Boc+H] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ(ppm)8.22(s，1H)，7.43–7.35(m，2H)，7.23(d，J＝8.1Hz，2H)，7.10(d，J＝8.7Hz，2H)，6.99(d，J＝8.6Hz，2H)，3.69(d，J＝13.4Hz，2H)，3.23(s，2H)，2.35(d，J＝13.5Hz，2H)，1.72(t，J＝10.4Hz，2H)，1.40(s，9H)。

Step 2: synthesis of N- (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (45)

To a stirred solution of 4M hydrogen chloride in dioxane (9.0 mL,36.0 mmol) in diethyl ether (20 mL) in a round bottom flask was added 4- (4-chlorophenyl) -4- [ [4- (trifluoromethoxy) phenyl ]]Sulfonyl groupAmino group]Tert-butyl piperidine-1-carboxylate (293 mg, 0.268 mmol). The mixture was stirred at room temperature overnight, then filtered and washed with diethyl ether to give the hydrochloride salt of the title compound as a white powder (190.5 mg, yield 73.799%, purity 100%, t _r =1.62 min). LCMS (method C): m/z found 434.8[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ(ppm)8.87-8.64(m，2H)，8.51(br s，1H)，7.37(d，J＝9.0Hz，2H)，7.22(d，J＝8.3Hz，2H)，7.12-7.06(m，2H)，7.04-6.97(m，2H)，3.27-3.14(m，4H)，2.57(br d，J＝13.7Hz，2H)，2.08-1.98(m，2H)。

Example 10: n- (3-Phenylazetidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (46)

Step 1: synthesis of tert-butyl 3-phenyl-3- ((4- (trifluoromethoxy) phenyl) sulfonamide) azetidine-1-carboxylate

A solution of 4- (trifluoromethoxy) benzenesulfonyl chloride (105 mg,0.403 mmol) in dry THF (500. Mu.L) was added to a stirred solution of 3-amino-3-phenylazetidine-1-carboxylic t-butyrate (100 mg,0.403 mmol) and pyridine (65. Mu.L, 0.805 mmol) in THF (1 mL) under nitrogen in a sealed tube. The mixture was stirred at room temperature for 16 hours, then with half saturated NaHCO ₃ The aqueous solution was diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Gradient 0.2% to 5% (MeOH+2% NH) ₄ OH) the crude product was purified by flash chromatography on silica gel to give the title compound as a white solid (92 mg, 48% yield, t _r =0.99 min). LCMS (method E): m/z found 417.3[ M-Boc+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)9.07(s，1H)，7.43–7.36(m，2H)，7.23(d，J＝8.0Hz，2H)，7.16–7.09(m，2H)，7.09–7.03(m，3H)，4.32–4.11(m，4H)，1.37(s，9H)。

Step 2: synthesis of N- (3-phenylazetidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (46)

A solution of 4M hydrogen chloride in dioxane (79. Mu.L, 0.317 mmol) was added to 3-phenyl-3- [ [4- (trifluoromethoxy) phenyl ] under nitrogen in a sealed tube]Sulfonylamino groups]Tert-butyl azetidine-1-carboxylate (100%, 30mg,0.0635 mmol) in 1, 4-dioxane (500 μl). The mixture was stirred at room temperature for 16 hours, and a further 4M hydrogen chloride solution in dioxane (159 μl,0.635 mmol) was added. The mixture was stirred at room temperature for 24 hours. The suspension was treated with Et ₂ O (2 mL) was diluted, stirred at room temperature for 2 hours, and then filtered. The residue was taken up in Et ₂ O-washing and drying under reduced pressure at 60℃for 64 hours gave the hydrochloride of the title compound as a white powder (23 mg, yield 88%, purity 99.8%, t) _r =1.17 min). LCMS (method C): m/z found 373[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ(ppm)8.5-10.3(m，3H)，7.32(d，2H，J＝8.8Hz)，7.17(d，2H，J＝8.1Hz)，7.0-7.1(m，5H)，4.41(s，4H)。

Example 11: n- (3- (4-chlorophenyl) azetidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (47)

Step 1: synthesis of benzyl 3- (4-chlorophenyl) -3-hydroxy-azetidine-1-carboxylate

Filling a sealed vial with a 3- (4-chlorophenyl) nitrogen heterocycleA solution of butane-3-ol 2,2 trifluoroacetate salt (500 mg,1.68 mmol) and DIPEA (1.2 mL,6.72 mmol) in anhydrous ACN (6 mL). Benzyl chloroformate (263 μl,1.85 mmol) was added dropwise at 0deg.C and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and ethyl acetate (15 mL) and water (10 mL) were added. The aqueous layer was extracted with ethyl acetate (1X 15 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 1% to 5% methanol in dichloromethane to give the title compound as an off-white powder (530 mg, purity 100%, yield 99%, t _r =0.90 min). LCMS (method E): m/z found 318.1[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.56–7.50(m，2H)，7.47–7.42(m，2H)，7.40–7.29(m，5H)，6.50(s，1H)，5.10(s，2H)，4.13(s，4H)。

Step 2: synthesis of benzyl 3- (4-chlorophenyl) -3-methylsulfonyloxy-azetidine-1-carboxylate

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To a stirred solution of 3- (4-chlorophenyl) -3-hydroxy-azetidine-1-carboxylic acid benzyl ester (100%, 460mg,1.45 mmol) in anhydrous DCM (8 mL) was added triethylamine (404. Mu.L, 2.90 mmol) and methanesulfonyl chloride (100%, 225. Mu.L, 2.90 mmol) in sequence at room temperature under nitrogen in a sealed vial. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound as a brown oil (585 mg, 92% purity, 94% yield, t) _r =1.01 min). LCMS (method D); ¹ H-NMR (chloroform-d, 400 MHz): delta (ppm) 7.44 (s, 4H), 7.39-7.28 (m, 5H), 5.10 (s, 2H), 4.72-4.47 (m, 4H), 2.55 (s, 3H).

Step 3: synthesis of benzyl 3-azido-3- (4-chlorophenyl) azetidine-1-carboxylate

A sealed vial was charged with a solution of 3- (4-chlorophenyl) -3-methylsulfonyloxy-azetidine-1-carboxylic acid benzyl ester (570 mg,1.44 mmol) in a mixture of anhydrous DCM (1.5 mL) and anhydrous DMF (8 mL). NaN was added at room temperature ₃ (281mg, 4.32 mmol) and the reaction mixture was stirred at 50℃for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (2 mL) and water (2 mL) and dichloromethane (5 mL) were added. The aqueous layer was extracted with dichloromethane (1X 3 mL). The combined organic layers were 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 40% ethyl acetate in cyclohexane to give the title compound as a yellow oil (279 mg, 100% purity, 57% yield, t _r =1.02 min). LCMS (method E): m/z found 343.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.63–7.45(m，4H)，7.42–7.23(m，5H)，5.08(d，J＝2.2Hz，2H)，4.79–4.17(m，4H)。

Step 4: synthesis of benzyl 3-amino-3- (4-chlorophenyl) azetidine-1-carboxylate

Triphenylphosphine (211 mg,0.805 mmol) and then 4-methylbenzenesulfonic acid (459 mg,2.42 mmol) were added to a stirred solution of benzyl 3-azido-3- (4-chlorophenyl) azetidine-1-carboxylate (276 mg,0.805 mmol) in THF (3.4 mL) under nitrogen in a round bottom flask. The mixture was stirred at room temperature for 1.5 hours. The suspension was filtered, washed with THF (5 mL) and dried in vacuo for 18 hours to give the title compound as a white powder (263 mg, 100% purity, 67% yield, t) _r =0.61 min). LCMS (method E): m/z found 317.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.88(s，3H)，7.61–7.52(m，4H)，7.51–7.45(m，2H)，7.42–7.30(m，5H)，7.11(d，J＝7.8Hz，2H)，5.10(s，2H)，4.36(t，J＝11.5Hz，4H)，2.29(s，3H)。

Step 5: synthesis of benzyl 3- (4-chlorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] azetidine-1-carboxylate

A sealed vial was charged under nitrogen with a solution of 3-amino-3- (4-chlorophenyl) azetidine-1-carboxylic acid benzyl ester 4-methylbenzenesulfonic acid (100 mg,0.205 mmol) and triethylamine (143 μl,1.02 mmol) in anhydrous DCM (4 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (38. Mu.L, 0.225 mmol) was added and the reaction mixture was stirred at room temperature for 22 hours and at 40℃for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and dichloromethane (5 mL) was added. The aqueous layer was extracted with dichloromethane (1X 5 mL). The combined organic layers were 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% to 5% methanol in dichloromethane to give the title compound as an off-white powder (86 mg, 92% purity, 72% yield, t _r =1.03 min). LCMS (method E): m/z found 541.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)9.17(s，1H)，7.44–7.30(m，7H)，7.26(d，J＝8.1Hz，2H)，7.18–7.06(m，4H)，5.05(s，2H)，4.34(s，4H)。

Step 6: synthesis of N- [3- (4-chlorophenyl) azetidin-3-yl ] -4- (trifluoromethoxy) benzenesulfonamide (47)

To 3- (4-chlorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] at room temperature in a round-bottomed flask]Sulfonylamino groups]A stirred suspension of benzyl azetidine-1-carboxylate (80 mg,0.148 mmol) in acetonitrile (3 mL) was added iodo (trimethyl) silane (63 μl,0.444 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Dichloromethane using ammonia methanol gradient of 4% to 15%The crude product was purified by flash chromatography on silica gel. The residue was purified by reverse phase flash chromatography using a gradient of 0% to 100% acetonitrile in water (+0.1% acoh in water). The residue was triturated in 4M HCl in diethyl ether (370 μl,1.48 mmol) for 3 hours, filtered, washed with diethyl ether and dried under vacuum at 70 ℃ for 16 hours to give the hydrochloride salt of the title compound as a white powder (28.5 mg, purity 100%, yield 44%, t _r =1.31 min). LCMS (method C): m/z found 407[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)9.17(s，1H)，7.44–7.30(m，7H)，7.26(d，J＝8.1Hz，2H)，7.18–7.06(m，4H)，5.05(s，2H)，4.34(s，4H)。

Example 12: n- (3, 4-dichlorophenyl) azetidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (48)

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Step 1: synthesis of benzyl 3- (3, 4-dichlorophenyl) -3-hydroxy-azetidine-1-carboxylate

To a stirred suspension of magnesium (113 mg,4.63 mmol) and iodine crystals (catalytic) in anhydrous THF (2 mL) was added several drops of a solution of 1-bromo-3, 4-dichlorobenzene (97%, 0.46mL,3.48 mmol) in anhydrous THF (1.5 mL) at room temperature in a three-necked round bottom flask. The reaction was heated at 50 ℃ until a discoloration (orange to yellow) was observed. Then, the remaining solution was added dropwise and stirred at this temperature for 1 hour (until magnesium was consumed). The reaction mixture was then cooled to 0deg.C and a solution of benzyl 3-oxoazetidine-1-carboxylate (95%, 500mg,2.31 mmol) in anhydrous THF (1.3 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Pouring the reaction mixture into saturated NH ₄ To the aqueous Cl solution and EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc. Combining the organic mattersThe layer was washed with saturated aqueous NaCl, 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% to 75% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (776.2 mg, purity 100%, yield 95%, t) _r =0.95 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.72(d，J＝2.2Hz，1H)，7.65(d，J＝8.4Hz，1H)，7.51(dd，J＝8.4，2.2Hz，1H)，7.42–7.36(m，4H)，7.36–7.31(m，1H)，6.63(s，1H)，5.10(s，2H)，4.22–4.08(m，4H)。

step 2: synthesis of benzyl 3- (3, 4-dichlorophenyl) -3-methylsulfonyloxy-azetidine-1-carboxylate

To a stirred solution of 3- (3, 4-dichlorophenyl) -3-hydroxy-azetidine-1-carboxylic acid benzyl ester (660 mg,1.87 mmol) in anhydrous DCM (9 mL) in a round bottom flask at 0deg.C under nitrogen was added triethylamine (1.0 mL,7.17 mmol) and methanesulfonyl chloride (100%, 290 μL,3.73 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow gum (137.5 mg). The crude product was used directly in the next step without any purification. ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.88(d，J＝2.2Hz，1H)，7.74(d，J＝8.4Hz，1H)，7.59(dd，J＝8.4，2.2Hz，1H)，7.40–7.29(m，5H)，5.08(s，2H)，4.59–4.49(m，4H)。

Step 3: synthesis of benzyl 3-azido-3- (3, 4-dichlorophenyl) azetidine-1-carboxylate

The sealed vial was charged with benzyl 3- (3, 4-dichlorophenyl) -3-methylsulfonyloxy-azetidine-1-carboxylate (806 mg,1.87 mmol) in anhydrous DMF (9.2492 mL) at 0deg.CSolution, and sodium azide (365 mg,5.62 mmol) was added. The reaction mixture was stirred at 50 ℃ for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (25 mL) and water (25 mL) and dichloromethane (50 mL) were added. The aqueous layer was extracted with dichloromethane (1X 50 mL). The combined organic layers were dried using a phase separator and concentrated under reduced pressure. Purification of the crude product by flash chromatography on silica gel using a gradient of 0% to 50% ethyl acetate in heptane afforded the title compound as a colourless oil (577.8 mg, purity 98%, yield 80.139%, t) _r =1.06 min). LCMS (method E); ¹ H-NMR (400 MHz, chloroform-d) delta 7.53-7.48 (m, 2H), 7.40-7.31 (m, 5H), 7.23 (dd, J=8.4, 2.3Hz, 1H), 5.14 (s, 2H), 4.35 (d, J=1.7 Hz, 4H).

Step 4: synthesis of benzyl 3-amino-3- (3, 4-dichlorophenyl) azetidine-1-carboxylate

Triphenylphosphine (426 mg,1.62 mmol) and then 4-methylbenzenesulfonic acid (920 mg,4.84 mmol) were added to a stirred solution of benzyl 3-azido-3- (3, 4-dichlorophenyl) azetidine-1-carboxylate (98%, 6271 mg,1.61 mmol) in THF (9 mL) under nitrogen in a round bottom flask. The mixture was stirred at room temperature for 2 hours. The suspension was filtered, washed with a small amount of THF and dried under vacuum for 18 hours to give the title compound as a white powder (596.2 mg, purity 100%, yield 70.624%, t) _r =0.65 min). LCMS (method E): m/z found 351.2[ M+H-pTSA] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.83(s，3H)，7.86–7.74(m，2H)，7.53(dd，J＝8.5，2.3Hz，1H)，7.50–7.44(m，2H)，7.44–7.29(m，5H)，7.11(d，J＝7.8Hz，2H)，5.10(s，2H)，4.44(s，2H)，4.32(d，J＝9.7Hz，2H)，2.29(s，3H)。

Step 5: synthesis of benzyl 3- (3, 4-dichlorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] azetidine-1-carboxylate

To a stirred suspension of 1- ((benzyloxy) carbonyl) -3- (3, 4-dichlorophenyl) azetidin-3-amine 4-methylbenzenesulfonate (202 mg, 0.383 mmol) in DCM (2.5 mL) was added triethylamine (269. Mu.L, 1.93 mmol), 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 101. Mu.L, 0.581 mmol) and N, N-dimethylpyridine-4-amine (4.8 mg,0.0397 mmol) in sequence at room temperature in a vial. The reaction mixture was heated at 40 ℃ and stirred at that temperature for 4 hours. The reaction mixture was cooled to room temperature and saturated NaHCO ₃ Diluting the aqueous solution. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 10% to 100% ethyl acetate in heptane. The desired fractions were combined and concentrated to give the title compound as a white solid (79 mg, purity 98%, yield 36%, t) _r =1.05 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ9.19(s，1H)，7.46–7.41(m，2H)，7.41–7.25(m，9H)，7.19(dd，J＝8.4，2.2Hz，1H)，5.06(s，2H)，4.40–4.29(m，4H)。

step 6: synthesis of N- [3- (3, 4-dichlorophenyl) azetidin-3-yl ] -4- (trifluoromethoxy) benzenesulfonamide (48)

To 3- (3, 4-dichlorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] at room temperature in a round bottom flask]Sulfonylamino groups]A stirred solution of benzyl azetidine-1-carboxylate (79 mg,0.137 mmol) in anhydrous ACN (2 mL) was added iodo (trimethyl) silane (58 μl,0.408 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was triturated in acetonitrile, filtered, washed with acetonitrile and dried under vacuum at room temperature overnight. To the residue were added water, triethylamine (96 μl,0.689 mmol) and methyltetrahydrofuran. The layers were separated. Organic matters are treated The layer was washed once more with water and triethylamine (96 μl,0.689 mmol). The combined organic layers were washed once with methyltetrahydrofuran. The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. Et by adding diethyl ether and 2M hydrogen chloride to the residue ₂ O solution (0.69 mL,1.37 mmol). The resulting suspension was stirred at room temperature overnight, filtered, washed with diethyl ether and dried under vacuum at 45 ℃ for 18 hours to give the hydrochloride salt of the title compound as a white powder (34.4 mg, purity 96.57%, yield 51%, t _r =1.64 min). LCMS (method C): m/z actual measurement 441[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ10.12–8.76(m，3H)，7.40(s，2H)，7.36–7.32(m，1H)，7.31–7.28(m，1H)，7.27–7.23(m，2H)，7.19–7.12(m，1H)，4.55–4.29(m，4H)。

Example 13: n- (4- (3, 4-dichlorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (49)

Step 1: synthesis of benzyl 4-oxopiperidine-1-carboxylate

To a stirred solution of piperidin-4-one hydrochloride (1:1) (98%, 3.00g,21.7 mmol) and DIPEA (23 mL,0.132 mol) in DCM (70 mL) was added benzyl chloroformate (6.2 mL,43.6 mmol) and DMAP (265 mg,2.17 mmol) at room temperature under nitrogen in a round bottom flask. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride. Dichloromethane and water were then added. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed once with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 10% to 75% ethyl acetate in cyclohexane to give the title compound as a yellow oil (3.89 g, purity 1 00%, yield 77%, t _r =0.71 min). LCMS (method D); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.43–7.35(m，4H)，7.37–7.30(m，1H)，5.13(s，2H)，3.70(t，J＝6.1Hz，4H)，2.40(t，J＝6.3Hz，4H)。

step 2: synthesis of 4- (3, 4-dichlorophenyl) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester

To a stirred suspension of magnesium (198 mg,8.15 mmol) and iodine crystals in anhydrous THF (6.8 mL) was added several drops of a solution of 1-bromo-3, 4-dichlorobenzene (97%, 823. Mu.L, 6.23 mmol) in anhydrous THF (3 mL) at room temperature in a three-necked round bottom flask under nitrogen. The reaction was heated at 50 ℃ until discoloration (orange to colorless) was observed. Then, the remaining solution was added dropwise and stirred at 50 ℃ for 1 hour (until magnesium was consumed). The reaction mixture was then cooled to 0deg.C and a solution of benzyl 4-oxopiperidine-1-carboxylate (1.00 g,4.29 mmol) in anhydrous THF (3 mL) was added dropwise at 0deg.C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous ammonium chloride solution. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 10% to 100% ethyl acetate in heptane to give the title compound as a white solid (1.04 g, purity 98%, yield 63%, t) _r =1.00 min). LCMS (method D); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.71(d，J＝2.1Hz，1H)，7.58(d，J＝8.5Hz，1H)，7.46(dd，J＝8.5，2.1Hz，1H)，7.40–7.36(m，4H)，7.36–7.30(m，1H)，5.36(s，1H)，5.10(s，2H)，3.95(dd，J＝13.4，3.3Hz，2H),3.28–3.09(m，2H)，1.86(td，J＝13.1，4.8Hz，2H)，1.57(d，J＝13.2Hz，2H)。

step 3: synthesis of benzyl 4-azido-4- (3, 4-dichlorophenyl) piperidine-1-carboxylate

In a three-necked round bottom flask, azido (trimethyl) silane (126. Mu.L, 0.949 mmol) and BF were charged at 0deg.C ₃ A solution of etherate (585. Mu.L, 4.74 mmol) in anhydrous DCM (2 mL) was added dropwise a solution of benzyl 4- (3, 4-dichlorophenyl) -4-hydroxy-piperidine-1-carboxylate (300 mg,0.789 mmol) in anhydrous DCM (3.6 mL). The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Pouring the reaction mixture into saturated NaHCO ₃ In aqueous solution (50 mL). The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure to give the title compound as a colorless oil (301.9 mg, purity 60%, yield 57%, t) _r =1.12 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ ) Delta 7.78 (d, j=2.3 hz, 1H), 7.72 (d, j=8.5 hz, 1H), 7.54 (dd, j=8.5, 2.3hz, 1H), 7.41-7.30 (m, 5H), 5.10 (s, 2H), 3.95 (d, j=13.3 hz, 2H), 3.30-3.07 (m, 2H), 2.06-1.94 (m, 4H). The product obtained is an inseparable mixture with 4- (3, 4-dichlorophenyl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester.

Step 4: synthesis of benzyl 4-amino-4- (3, 4-dichlorophenyl) piperidine-1-carboxylate

Triphenylphosphine (134 mg,0.512 mmol) and then p-toluenesulfonic acid (255 mg,1.34 mmol) were added to a stirred solution of a non-separable mixture of benzyl 4-azido-4- (3, 4-dichlorophenyl) piperidine-1-carboxylate (60%, 302mg,0.447 mmol) and benzyl 4- (3, 4-dichlorophenyl) -3, 6-dihydro-2H-pyridine-1-carboxylate (40%, 302mg,0.333 mmol) in THF (2.1 mL) under nitrogen in a round bottom flask. The mixture was stirred at room temperature overnight. The suspension was filtered and washed with a small amount of THF. The filtrate was concentrated and purified by reverse phase chromatography (C18) using a gradient of 0% to 100% acetonitrile in water (0.1% acoh in water and acetonitrileAq-100 g) was purified. The desired fractions were combined and concentrated to give the title compound as a colorless oil (84.9 mg, purity 84%, yield 42%, t) _r =0.67 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.86(d，J＝2.3Hz，1H)，7.72(d，J＝8.6Hz，1H)，7.57(dd，J＝8.6，2.3Hz，1H)，7.40–7.30(m，5H)，7.11(d，J＝7.8Hz，2H)，5.09(s，2H)，3.70–3.57(m，2H)，3.39–3.33(m，2H)，2.35–2.20(m，2H)，1.90–1.77(m，2H)。

step 5: synthesis of benzyl 4- (3, 4-dichlorophenyl) -4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

To a stirred suspension of benzyl 4-amino-4- (3, 4-dichlorophenyl) piperidine-1-carboxylate (84%, 87mg,0.192 mmol) in DCM (1.9 mL) was added triethylamine (134. Mu.L, 0.961 mmol), 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 50. Mu.L, 0.290 mmol) and N, N-dimethylpyridine-4-amine (2.4 mg,0.0198 mmol) in sequence at room temperature in a vial. The reaction mixture was stirred at this temperature for 1 hour and then heated at 40 ℃ overnight. The reaction mixture was cooled to room temperature and saturated NaHCO ₃ Diluting the aqueous solution. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. Purification of the crude product by flash chromatography on silica gel uses a gradient of 0.5% to 10% methanol in dichloromethane. The desired fractions were combined and concentrated to give the title compound as a colourless gum (51 mg, 93% purity, 41% yield, t) _r =1.08 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.28(s，1H)，7.46–7.41(m，2H)，7.40–7.29(m，5H)，7.28–7.22(m，4H)，7.13(dd，J＝8.5，2.2Hz，1H)，5.08(s，2H)，3.87–3.76(m，2H)，3.31–3.24(m，2H)，2.41–2.32(m，2H)，1.86–1.72(m，2H)。

step 6: synthesis of N- [4- (3, 4-dichlorophenyl) -4-piperidinyl ] -4- (trifluoromethoxy) benzenesulfonamide (49)

To 4- (3, 4-dichlorophenyl) -4- [ [4- (trifluoromethoxy) phenyl ] at room temperature in a round bottom flask]Sulfonylamino groups]A stirred solution of benzyl piperidine-1-carboxylate (51 mg,0.0845 mmol) in acetonitrile (1.3 mL) was added iodo (trimethyl) silane (36 μl,0.254 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The crude product was dry loaded onto celite and a gradient of 1% to 20% methanol (0.7N NH was used ₃ ) Is purified by flash chromatography on silica gel. The desired fractions were combined and washed with water and triethylamine (59 μl,0.423 mmol). The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative chromatography (C18 Aq30 g) using a gradient of 0% to 100% acetonitrile in water (0.1% acoh in both). The desired fractions were combined and concentrated. Et in diethyl ether followed by 2M hydrogen chloride ₂ The residue was salt exchanged (acetate with chlorohydrate) in O solution (0.43 mL,0.850 mmol) and stirred overnight at room temperature. The suspension was filtered, washed with diethyl ether and dried at 45 ℃ for the weekend to give the hydrochloride salt of the title compound as a white powder (20.4 mg, purity 99.75%, yield 48%, t _r =1.49 min). LCMS (method C): m/z found 469[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ8.70(br d，J＝0.7Hz，2H)，8.51(s，1H)，7.43(d，J＝8.8Hz，2H)，7.32–7.27(m，1H)，7.27–7.22(m，3H)，7.17–7.09(m，1H)，3.23(br d，J＝6.4Hz，4H)，2.54(br s，2H)，2.13–1.95(m，2H)。

Example 14: n- (4-phenylpiperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (50)

Step 1: synthesis of tert-butyl 4-phenyl-4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

A sealed vial was charged with tert-butyl 4-amino-4-phenylpiperidine-1-carboxylate (150 mg,0.543 mmol), DMAP (13 mg,0.109 mmol) and triethylamine (303. Mu.L, 2.17 mmol) in DCM (9 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (101. Mu.L, 0.597 mmol) was added and the reaction mixture was stirred at 40℃for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and water (15 mL) and dichloromethane (10 mL) were added. The aqueous layer was extracted with dichloromethane (1X 15 mL). The combined organic layers were 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% to 5% methanol in dichloromethane to give the title compound as a white powder (266 mg, purity 98%, yield 96%, t) _r =1.03 min). LCMS (method E): m/z observed value 523.3[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.16(s，1H)，7.40–7.30(m，2H)，7.17(d，J＝8.1Hz，2H)，7.08(dd，J＝7.7，1.8Hz，2H)，7.00–6.89(m，3H)，3.70(d，J＝13.4Hz，2H)，3.24(s，2H)，2.38(d，J＝13.6Hz，2H)，1.73(t，J＝10.5Hz，2H)，1.40(s，9H)。

Step 2: synthesis of N- (4-phenyl-4-piperidinyl) -4- (trifluoromethoxy) benzenesulfonamide

To a stirred solution of 2M hydrogen chloride in diethyl ether (15 mL,30.0 mmol) in a round bottom flask was added 4-phenyl-4- [ [4- (trifluoromethoxy) phenyl ]]Sulfonylamino groups]Tert-butyl piperidine-1-carboxylate (265 mg,0.529 mmol). The mixture was stirred at room temperature for 18 hours, then filtered and washed with diethyl ether to give the hydrochloride salt of the title compound as a white powder (175.8mg, purity 99.9%, yield 77%, t _r =1.71 min). LCMS (method C): m/z found 401.0[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ ，300K)δppm 8.79(br s，2H)，8.43(br s，1H)，7.28-7.36(m，2H)，7.12-7.19(m，2H)，7.04-7.10(m，2H)，6.91-7.03(m，3H)，3.12-3.29(m，4H)，2.59(br d，J＝13.7Hz，2H)，1.98-2.10(m，2H)。

Example 15: racemic N- ((3R, 4R) -4- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (51)

Step 1: synthesis of rac- (3R, 4S) -3- (3, 4-dichlorophenyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

A suspension of copper (I) (93 mg, 0.481 mmol) and iodine (25 mg,0.0972 mmol) in dry THF (18 mL) was stirred under nitrogen at room temperature in a three-necked round bottom flask equipped with thermometer and reflux condenser. A few drops of a solution of 1-bromo-3, 4-dichlorobenzene (2493. Mu.L, 19.4 mmol) in dry THF (18 mL) was added and the mixture stirred with gradual heating until the mixture was discolored (60 ℃). The remaining solution was added dropwise over 20 seconds and the mixture was stirred at 60 ℃ until the magnesium was consumed (30 min). The mixture was stirred at 0deg.C, magnesium (520 mg,21.4 mmol) was added, followed by dropwise addition of 6-oxa-3-azabicyclo [3.1.0 ] over 20 seconds ]A solution of tert-butyl hexane-3-carboxylate (1.80 g,9.72 mmol) in dry THF (9 mL). The mixture was stirred at room temperature for 2 hours and cooled to 0 ℃. The mixture was treated with saturated NH ₄ The aqueous Cl solution was quenched and extracted 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 5% to 30% EtOAc in heptane. The desired fraction was concentrated and a gradient of 0% to 100% was used(MeCN+0.2% AcOH) in (H) ₂ O+0.2% acoh) was purified by silica gel reverse phase chromatography. The desired fractions were combined and ACN evaporated. The mixture was treated with saturated NaHCO ₃ The aqueous solution was basified and extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (1.32 g, purity>95%, yield 24%, t _r =0.93 min). LCMS (method E): m/z found 276.1[ M-tBu+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.64–7.52(m，2H)，7.30(dd，J＝8.4，2.1Hz，1H)，5.34(d，J＝5.3Hz，1H)，4.22(p，J＝6.7Hz，1H)，3.71(dd，J＝10.6，7.8Hz，1H)，3.57(dd，J＝10.8，6.6Hz，1H)，3.31–3.24(m，1H)，3.24–3.11(m，1H)，3.11–2.96(m，1H)，1.41(d，J＝3.9Hz，9H)。

Step 2: synthesis of rac- (3R, 4S) -3- (3, 4-dichlorophenyl) -4-methylsulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of rac- (3R, 4S) -3- (3, 4-dichlorophenyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (100%, 470mg,1.41 mmol) and triethylamine (394. Mu.L, 2.83 mmol) in dry DCM (10 mL) was stirred at 0deg.C under nitrogen in a round bottom flask. Methanesulfonyl chloride (164 μl,2.12 mmol) was added dropwise and the mixture was stirred at 0 ℃ for 10min and at room temperature for 3 hours. The mixture was treated with saturated NaHCO ₃ The aqueous was washed twice, the combined aqueous layers were extracted with DCM, the combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound as a colourless oil (520 mg, purity 100%, yield 89%, t) _r =0.98 min). LCMS (method E): m/z found 310.1[ M-Boc+H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.70–7.57(m，2H)，7.34(dd，J＝8.4，2.0Hz，1H)，5.28(q，J＝5.6Hz，1H)，3.88–3.58(m，3H)，3.48–3.37(m，2H)，3.16(s，3H)，1.43(s，9H)。

Step 3: synthesis of rac- (3R, 4R) -3-azido-4- (3, 4-dichlorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Sodium azide (330 mg,5.07 mmol) was added to a stirred solution of rac- (3R, 4S) -3- (3, 4-dichlorophenyl) -4-methylsulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (520 mg,1.27 mmol) in dry DMF (5 mL) under nitrogen in a sealed tube. The mixture was stirred at 75℃for 23 hours. The mixture was cooled to room temperature and quenched with EtOAc and saturated NaHCO ₃ Diluting the aqueous solution. The organic layer was saturated with NaHCO ₃ The aqueous solution was washed, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using a gradient of 5% to 30% EtOAc in heptane to give the title compound as a colourless oil (335 mg, 100% purity, 74% yield, t) _r =1.09 min). LCMS (method E): m/z found 300.9[ M-tBu+H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.67–7.56(m，2H)，7.35(dd，J＝8.4，2.0Hz，1H)，4.63(t，J＝3.9Hz，1H)，3.79–3.66(m，2H)，3.65–3.53(m，1H)，3.53–3.41(m，2H)，1.43(s，9H)。

Step 4: synthesis of rac- (3R, 4R) -3-amino-4- (3, 4-dichlorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Polymer-bound triphenylphosphine (344 mg,1.03 mmol) was added to a stirred solution of rac- (3R, 4R) -3-azido-4- (3, 4-dichlorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (335 mg,0.938 mmol) in THF (5 mL) and water (2 mL) under nitrogen in a sealed tube. The solution was stirred at 45 ℃ for 16 hours and filtered. The residue was washed with DCM and the filtrate was dried over sodium sulfate, filtered and concentrated to give the title compound as a colourless oil (203 mg, purity 100%, yield 65%, t) _r =0.63 min). LCMS (method E):m/z found 275.1[ M-tBu+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.58(d，J＝8.3Hz，1H)，7.49(d，J＝3.4Hz，1H)，7.23(d，J＝8.0Hz，1H)，3.65–3.52(m，3H)，3.51–3.33(m，2H)，3.17–3.02(m，1H)，1.43(s，9H)。

Step 5: synthesis of rac- (3R, 4R) -3- (3, 4-dichlorophenyl) -4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] pyrrolidine-1-carboxylic acid tert-butyl ester

4- (trifluoromethoxy) benzenesulfonyl chloride (46 μl,0.272 mmol) was added to a stirred solution of rac- (3 r,4 r) -3-amino-4- (3, 4-dichlorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg,0.272 mmol), triethylamine (151 μl,1.09 mmol) and N, N-dimethylpyridin-4-amine (99%, 3.4mg,0.0272 mmol) in dry DCM (300 μl) under nitrogen in a sealed tube. The mixture was stirred at room temperature for 16 hours and poured into half saturated NaHCO ₃ Is a kind of medium. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Gradient 0.5% to 5% (MeOH+2% NH) was used ₄ OH) the crude product was purified by flash chromatography on silica gel to give the title compound as a white solid (98 mg, 99% purity, 64% yield, t _r =1.08 min). LCMS (method D): m/z found 499.1[ M-tBu+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.21–7.95(m，1H)，7.72(t，J＝8.4Hz，2H)，7.47(t，J＝7.6Hz，3H)，7.36–7.25(m，1H)，7.16–7.00(m，1H)，4.28–4.02(m，1H)，3.70–3.44(m，3H)，3.43–3.32(m，1H)，3.14–2.90(m，1H)，1.39(d，J＝18.2Hz，9H)。

Step 6: synthesis of N- [ rac- (3R, 4R) -4- (3, 4-dichlorophenyl) pyrrolidin-3-yl ] -4- (trifluoromethoxy) benzenesulfonamide

A solution of 4M hydrogen chloride in dioxane (1.7 mL,6.84 mmol) was added to rac- (3R, 4R) -3- (3, 4-dichlorophenyl) -4- [ [4- (trifluoromethoxy) phenyl ] in a sealed tube under nitrogen]Sulfonylamino groups]A stirred suspension of pyrrolidine-1-carboxylic acid tert-butyl ester (95 mg,0.171 mmol) in diethyl ether (2 mL). The mixture was stirred at room temperature for 16 hours, and methanol (1 mL) was added. The mixture was stirred at room temperature for 4 hours and concentrated. The residue was taken up in Et ₂ O was triturated and the suspension was filtered. The residue was taken up in Et ₂ O was washed and dried under reduced pressure at 60℃for 16 hours to give the hydrochloride salt of the title compound as a white powder. (76 mg, purity 100%, yield 90%, t) _r =1.5 min). LCMS (method C): m/z found 455.0[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，600MHz)δ9.43(br s，2H)，8.1-8.7(m，1H)，7.7-7.7(m，2H)，7.4-7.5(m，3H)，7.39(d，1H，J＝2.1Hz)，7.12(dd，1H，J＝2.2，8.4Hz)，4.33(br s，1H)，3.5-3.7(m，3H)，3.42(dd，1H，J＝6.2，12.5Hz)，3.02(dd，1H，J＝3.0，12.4Hz)。

Example 16: n- (3- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (52)

Step 1: synthesis of benzyl 3-oxopyrrolidine-1-carboxylate

To a stirred solution of pyrrolidin-3-one hydrochloride (1:1) (97%, 5.00g,39.9 mmol) and DIPEA (42 mL,0.239 mol) in DCM (200 mL) was added benzyl chloroformate (12 mL,83.8 mmol) and DMAP (487 mg,3.99 mmol) in a round bottom flask at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and dichloromethane (100 mL) and water (50 mL) were added. The aqueous layer was treated with dichloromethane (2X 25 mL)And (5) extracting. The combined organic layers were 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 20% to 100% ethyl acetate in cyclohexane to give the title compound as a yellow oil (4.59 g, purity 100%, yield 53%, t _r =0.68 min). LCMS (method E); ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.45–7.25(m，5H)，5.13(s，2H)，3.73(d，J＝24.2Hz，4H)，2.58(t，J＝7.2Hz，2H)。

step 2: synthesis of 3- (4-chloro-3-fluoro-phenyl) -3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester

To a stirred solution of 0.5M bromine (4-chloro-3-fluorophenyl) magnesium (5.3 mL,2.65 mmol) in nitrogen at 0 ℃ was added dropwise a solution of benzyl 3-oxopyrrolidine-1-carboxylate (97%, 500mg,2.21 mmol) in anhydrous THF (4.5 mL) in a three neck round bottom flask. The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Pouring the reaction mixture into saturated NH ₄ To the aqueous Cl solution and EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, 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% to 50% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a pale yellow oil (355.7 mg, purity 100%, yield 46%, t) _r =0.90 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.60–7.52(m，2H)，7.42–7.29(m，6H)，5.68(s，1H)，5.12–5.07(m，2H)，3.65–3.45(m，4H)，2.34–2.21(m，1H)，2.04(dt，J＝12.7，6.7Hz，1H)。

step 3: synthesis of benzyl 3-azido-3- (4-chloro-3-fluoro-phenyl) pyrrolidine-1-carboxylate

NaN was added to a stirred solution of benzyl 3- (4-chloro-3-fluoro-phenyl) -3-hydroxy-pyrrolidine-1-carboxylate (284 mg, 0.812 mmol) in a mixture of TFA (2.8 mL) and water (0.45 mL) in a round bottom flask at 0deg.C ₃ (372 mg,5.72 mmol). The reaction mixture was stirred at room temperature overnight. After this, the reaction mixture was heated at 50 ℃ for 8 hours. The reaction mixture was cooled to room temperature and slowly poured into saturated NaHCO ₃ Aqueous solution and ice. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 5% to 50% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a pale yellow oil (212.2 mg, 88% purity, 61% yield, t) _r =1.04 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.73–7.64(m，2H)，7.44–7.30(m，6H)，5.12(s，2H)，4.01(ddd，J＝10.0，7.5，3.1Hz，1H)，3.69–3.43(m，3H)，2.58–2.51(m，1H)，2.48–2.32(m，1H)。

step 4: synthesis of benzyl 3-amino-3- (4-chloro-3-fluoro-phenyl) pyrrolidine-1-carboxylate

Triphenylphosphine (150 mg, 0.578mmol) and 4-methylbenzenesulfonic acid (300 mg,1.58 mmol) were added to a stirred solution of benzyl 3-azido-3- (4-chloro-3-fluoro-phenyl) pyrrolidine-1-carboxylate (88%, 212mg,0.498 mmol) in THF (2.5 mL) under nitrogen in a round bottom flask. The mixture was stirred at room temperature overnight. The suspension was filtered, washed with a small amount of THF, then diethyl ether, and dried under vacuum for 72 hours to give the title compound as a white powder (210 mg, purity 98%, yield 79%, t) _r =0.62 min). LCMS (method E): m/z found 349.3[ M+H-pTSA]； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.52(s，3H)，7.73(q，J＝7.9Hz，1H)，7.64(dd，J＝10.8，2.2Hz，1H)，7.50–7.45(m，2H)，7.43–7.31(m，6H)，7.11(d，J＝7.9Hz，2H)，5.18–5.08(m，2H)，4.06(d，J＝11.7Hz，1H)，3.81–3.52(m，3H)，2.57–2.45(m，2H)，2.29(s，3H)。

Step 5: synthesis of benzyl 3- (4-chloro-3-fluoro-phenyl) -3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] pyrrolidine-1-carboxylate

To a stirred suspension of 3-amino-3- (4-chloro-3-fluoro-phenyl) pyrrolidine-1-carboxylic acid benzyl ester 4-methylbenzenesulfonic acid (80 mg,0.154 mmol) in DCM (1.5 mL) was added triethylamine (104 μl,0.746 mmol), 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 40 μl,0.231 mmol) and finally N, N-dimethylpyridine-4-amine (3.7 mg,0.0306 mmol) in sequence at room temperature in a sealed vial. The reaction mixture was stirred at this temperature for 1 hour, and then heated at 40 ℃ for 3 hours. The reaction mixture was cooled to room temperature and saturated NaHCO ₃ Diluting the aqueous solution. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The residue was triturated in DCM. Diethyl ether was added to the suspension and the suspension was stirred for 1 hour. The resulting suspension was filtered, washed with diethyl ether (+several drops of DCM) and dried in vacuo at 40℃for 16 h to give the title compound as a white powder (75.5 mg, 96% purity, 82% yield, t) _r =1.03 min). LCMS (method E): m/z found 595.2[ M+Na ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.68(d，J＝5.6Hz，1H)，7.49(dd，J＝8.7，1.4Hz，2H)，7.41–7.20(m，8H)，7.06–6.99(m，1H)，6.97(dd，J＝8.4，1.7Hz，1H)，5.15–5.01(m，2H)，4.12(dd，J＝20.4，11.5Hz,1H)，3.60(dd，J＝15.0，11.4Hz，1H)，3.54–3.33(m，2H)，2.77–2.62(m，1H)，2.35–2.13(m，1H)。

Step 6: synthesis of N- (3- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide

To 3- (4-chloro-3-fluoro-phenyl) -3- [ [4- (trifluoromethoxy) phenyl ] at room temperature in a round bottom flask under nitrogen]Sulfonylamino groups]A stirred solution of pyrrolidine-1-carboxylic acid benzyl ester (75 mg,0.130 mmol) in anhydrous acetonitrile (1.9 mL) was added iodo (trimethyl) silane (55 μl,0.386 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. A gradient of 2% to 20% MeOH (0.7N NH was used ₃ ) The crude product was purified by flash chromatography on silica gel. The desired fractions were combined and concentrated. The residue was purified by reverse phase preparative chromatography (C18 Aq 100 g) using a gradient of 0% to 100% acetonitrile in water (0.1% acoh in water and acetonitrile). The desired fractions were combined and concentrated. The residue was salted in diethyl ether and then Et with 2M hydrogen chloride was added ₂ O solution (0.65 mL,1.30 mmol) and stirred at room temperature for 2 hours. The suspension was filtered, washed with diethyl ether and dried at 45 ℃ for 18 hours to give the hydrochloride salt of the title compound as an off-white powder (32.3 mg, purity 98.43%, yield 51%, t _r =1.38 min). LCMS (method C): m/z found 439[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ9.68–9.17(m，2H)，8.81(br s，1H)，7.46(d，J＝8.8Hz，2H)，7.27(d，J＝8.3Hz，2H)，7.22(t，J＝8.1Hz，1H)，7.06(dd，J＝10.5，2.0Hz，1H)，6.97(dd，J＝8.4，1.8Hz，1H)，4.16–4.00(m，1H)，3.46–3.34(m，3H)，2.88–2.79(m，1H)，2.25–2.08(m，1H)。

Example 17:4- (4-chlorophenyl) -4- ((4- (trifluoromethoxy) phenyl) sulfamido) piperidine-1-carboxylic acid tert-butyl ester (53)

To a stirred suspension of tert-butyl 4-amino-4- (4-chlorophenyl) piperidine-1-carboxylate (200 mg,0.643 mmol) in DCM (6.4844 mL) in a vial at room temperature was added triethylamine (0.45 mL,3.22 mmol), 4- (trifluoro) in sequenceMethoxy) benzenesulfonyl chloride (98%, 168. Mu.L, 0.968 mmol) and DMAP (16 mg,0.129 mmol). The reaction mixture was stirred at this temperature for 1 hour and then heated at 40 ℃ overnight. The reaction mixture was taken up with DCM and saturated NaHCO ₃ Diluting the aqueous solution. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a white foam (327.3 mg, purity 98.74%, yield 95.08%, t) _r =3.0 min). The product may be further dried under reduced pressure at 45 ℃. LCMS (method C): m/z actual measurement 534[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，600MHz)δ8.21(s，1H)，7.38(d，2H，J＝8.9Hz)，7.22(d，2H，J＝8.1Hz)，7.09(d，2H，J＝8.8Hz)，6.98(d，2H，J＝8.8Hz)，3.68(br d，2H，J＝13.2Hz)，3.22(br d，2H，J＝2.3Hz)，2.34(br d，2H，J＝13.2Hz)，1.71(br t，2H，J＝10.6Hz)，1.39(s，9H)。

Example 18: n- (1-benzyl-3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide (54)

Step 1: synthesis of 1-benzyl pyrrolidin-3-one

To a stirred suspension of pyrrolidin-3-one hydrochloride (1:1) (97%, 5.00g,39.9 mmol) in a mixture of (bromomethyl) benzene (5.5 mL,46.3 mmol) in ethyl acetate (8.75 mL) and DCE (95 mL) was added triethylamine (14 mL,0.100 mol) at room temperature in a sealed vial and the reaction mixture was stirred overnight at 70 ℃. The reaction mixture was poured into water. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were dissolved in saturated sodium chlorideThe solution was washed, 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 2% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a yellow oil (2.43 g, purity 100%, yield 34.759%). ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.38–7.23(m，5H)，3.69(s，2H)，2.89–2.83(m，4H)，2.35(t，J＝6.9Hz，2H)。

Step 2: synthesis of 1-benzyl-3- (4-chlorophenyl) pyrrolidin-3-ol

To a stirred solution of 1M magnesium bromo (4-chlorophenyl) (3.1 mL,3.15 mmol) in anhydrous THF (11 mL) at 0deg.C in nitrogen was added a solution of 1-benzylpyrrolidin-3-one (500 mg,2.85 mmol) in a three-necked round bottom flask. The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. The reaction mixture was treated with saturated NH ₄ The aqueous Cl solution was quenched and EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, 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 2% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a brown oil (382.9 mg, 95% purity, 44.298% yield, t _r =0.58 min). LCMS (method D): m/z found 288.1[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.54–7.49(m，2H)，7.38–7.29(m，6H)，7.24(ddd，J＝9.3，4.1，1.9Hz，1H)，5.34(s，1H)，3.67(s，2H)，2.85–2.72(m，3H)，2.67(d，J＝9.7Hz，1H)，2.15–1.99(m，2H)。

Step 3: synthesis of 3-azido-1-benzyl-3- (4-chlorophenyl) pyrrolidine

In sealingIn a vial, azido (trimethyl) silane (0.86 mL,6.51 mmol) and BF were added to a solution of 1-benzyl-3- (4-chlorophenyl) pyrrolidin-3-ol (935 mg,3.25 mmol) in anhydrous DCM (16.414 mL) under nitrogen at 0deg.C ₃ Etherate (0.80 mL,6.51 mmol). The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. The reaction mixture was then stirred again at 40 ℃ overnight. Additional azido (trimethyl) silane (0.86 mL,6.51 mmol) and BF were added at 0deg.C ₃ Etherate (0.80 mL,6.51 mmol) and the reaction mixture was stirred at room temperature for 4 hours. Adding additional BF at 0 DEG C ₃ Etherate (0.80 mL,6.50 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was taken up with saturated NaHCO ₃ The aqueous solution was quenched drop wise (bubbling). DCM was added and the layers separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous sodium chloride, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 1% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title product (535 mg, purity 100%, yield 52.116%, t) _r =0.63 min). LCMS (method E): m/z found 313.2[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ7.45(d，J＝3.7Hz，4H)，7.39–7.29(m，4H)，7.25(dt，J＝5.5，2.8Hz，1H)，3.71(d，J＝3.3Hz，2H)，3.18(d，J＝10.2Hz，1H)，2.99(q，J＝7.7，7.0Hz，1H)，2.80(d，J＝10.2Hz，1H)，2.61(q，J＝7.9，7.4Hz，1H)，2.43–2.35(m，2H)。

Step 4: synthesis of 1-benzyl-3- (4-chlorophenyl) pyrrolidin-3-amine

Triphenylphosphine (452 mg,1.72 mmol) and then 4-methylbenzenesulfonic acid (976 mg,5.13 mmol) were added to a stirred solution of 3-azido-1-benzyl-3- (4-chlorophenyl) pyrrolidine (535 mg,1.71 mmol) in THF (10 mL) under nitrogen in a round bottom flask. The mixture was stirred at room temperature for 2.5 hours. The suspension was filtered, with small amounts of THF and Et ₂ O-washing and vacuum drying for 18 hours gave the title compound as a white powder (919 mg, purity 100%, yield 85.126%, t) _r =0.48 min). LCMS (method E): m/z observed 287.2[ M+H ] ] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.79(s，1H)，8.54(s，1H)，7.74–7.18(m，13H)，7.12(d，J＝7.8Hz，4H)，4.48(s，2H)，4.14(s，1H)，2.62(d，J＝41.2Hz，2H)，2.39(d，J＝47.9Hz，1H)，2.30(s，6H)。

Step 5: synthesis of N- (1-benzyl-3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide (54)

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In a vial, at room temperature, 4- [4- (trifluoromethyl) phenoxy ]]A stirred suspension of benzenesulfonyl chloride (107. Mu.L, 0.487 mmol) in DCM (15 mL) was added sequentially 1-benzyl-3- (4-chlorophenyl) pyrrolidin-3-amine; 4-Methylbenzenesulfonic acid (300 mg,0.475 mmol) and triethylamine (0.50 mL,3.59 mmol). The reaction mixture was stirred at this temperature overnight. The reaction mixture was taken up with DCM and saturated NaHCO ₃ Diluting the aqueous solution. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 50% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a white foam (132.8 mg, purity 96.02%, yield 47.596%, t) _r =2.01 min). The product may be dried under reduced pressure at 45 ℃. LCMS (method C): m/z found 587[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.40(s，1H)，7.82(d，J＝8.7Hz，2H)，7.47–7.38(m，2H)，7.33–7.13(m，12H)，7.00–6.93(m，2H)，3.65(s，2H)，3.16–3.03(m，2H)，2.64(t，J＝7.1Hz，2H)，2.18–2.08(m，1H)。

Example 19: n- (1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide (55)

Step 1: synthesis of 1-benzyl pyrrolidin-3-one

To a stirred suspension of pyrrolidin-3-one hydrochloride (1:1) (97%, 5.00g,39.9 mmol) in a mixture of ethyl acetate (8,75 mL) and DCE (95 mL) was added (bromomethyl) benzene (5.5 mL,46.3 mmol) and triethylamine (14 mL,0.100 mol) at room temperature in a sealed vial. The reaction mixture was stirred at 70 ℃ overnight. The reaction mixture was poured into water. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 2% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a yellow oil (2, 43g, purity 100%, yield 34%). ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.38–7.23(m，5H)，3.69(s，2H)，2.89–2.83(m，4H)，2.35(t，J＝6.9Hz，2H)。

Step 2: synthesis of 1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidin-3-ol

To a stirred suspension of magnesium (97 mg,3.99 mmol) and iodine crystals in dry THF (2.2 mL) was added several drops of a solution of 1-bromo-3, 4-dichlorobenzene (97%, 0.45mL,3.42 mmol) in dry THF at room temperature in a three-necked round bottom flask. The reaction was heated at 50 ℃ until decolorization (orange to yellow). Then, the remaining solution was added dropwise and stirred at this temperature for 1 hour (until magnesium was consumed). The reaction mixture was then cooled to room temperature and 1-benzyl-pyrrolidin-3-one (500 mg,2.85 mmol) was added dropwise over dry THF (1, 5 mL) Is a solution of (a) a solution of (b). The reaction mixture was stirred at this temperature overnight. Pouring the reaction mixture into saturated NH ₄ To the aqueous Cl solution and EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, 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% to 50% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as an orange oil (335.5 mg, purity 100%, yield 37%, t) _r =0.62 min). LCMS (method E): m/z found 322.2[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.71(d，J＝2.1Hz，1H)，7.57(d，J＝8.4Hz，1H)，7.48(dd，J＝8.4，2.1Hz，1H)，7.37–7.30(m，4H)，7.27–7.20(m，1H)，5.52(s，1H)，3.67(d，J＝1.8Hz，2H)，2.87–2.80(m，2H),2.73(q，J＝8.0Hz，1H)，2.64(d，J＝9.7Hz，1H)，2.15–1.99(m，2H)。

Step 3: synthesis of 3-azido-1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidine

In a sealed vial, a solution of 1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidin-3-ol (436 mg,1.35 mmol) in dry DCM (6, 8 mL) under nitrogen at 0deg.C was added azido (trimethyl) silane (360 μl,2.71 mmol) and BF ₃ Etherate (335. Mu.L, 2.71 mmol). The reaction mixture was warmed to 40 ℃ and stirred at that temperature overnight. Additional azido (trimethyl) silane (180. Mu.L, 1.36 mmol) and BF were added at room temperature ₃ Etherate (167 μl,1.35 mmol) and the reaction mixture was stirred at 40 ℃ for an additional night. Adding additional BF at room temperature ₃ Etherate (500 μl,4.05 mmol) and the reaction mixture was stirred at 40 ℃ for an additional night. The reaction mixture was taken up with saturated NaHCO ₃ The aqueous solution was quenched drop wise (bubbling). EtOAc was added and the layers separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. Gradient of 2% was usedThe crude product was purified by flash chromatography on silica gel to 75% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (276.9 mg, purity 100%, yield 59%, t) _r =0.68 min). LCMS (method E): m/z found 347.2[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.71(d，J＝2.2Hz，1H)，7.65(d，J＝8.5Hz，1H)，7.46(dd，J＝8.5，2.3Hz，1H)，7.37–7.31(m，4H)，7.26(ddd，J＝8.6，5.4，3.4Hz，1H)，3.72(d，J＝3.2Hz，2H)，3.19(d，J＝10.2Hz，1H)，3.03–2.94(m，1H)，2.83(d，J＝10.2Hz，1H)，2.68–2.59(m，1H)，2.41(t，J＝7.2Hz，2H)。

Step 4: synthesis of 1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidin-3-amine

Triphenylphosphine (264 mg,1.01 mmol) and then 4-methylbenzenesulfonic acid hydrate (569 mg,2.99 mmol) were added to a stirred solution of 3-azido-1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidine (347 mg,1.00 mmol) in THF (4, 4 mL) under nitrogen in a round bottom flask. The mixture was stirred at room temperature overnight. The suspension was filtered, washed with a minimum amount of THF and dried under vacuum for 18 hours to give the 4-methylbenzenesulfonate salt of the title compound as a white powder (601.1 mg, 98% purity, 89% yield, t _r =1.04 min). LCMS (method E): m/z found 321.2[ M+H ]] ⁺ ； ¹ H-NMR (400 MHz, methanol-d) ₄ )δ7.77(d，J＝2.4Hz，1H)，7.74–7.65(m，5H)，7.58–7.42(m，6H)，7.26(d，J＝8.0Hz，4H)，4.63–4.38(m，2H)，4.15–3.91(m，1H)，3.87–3.71(m，1H)，3.68–3.46(m，1H)，3.02–2.73(m，2H)，2.40(s，6H)。

Step 5: synthesis of N- (1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide (55)

To a stirred suspension of triethylamine (209 μl,1.50 mmol) and 1-benzyl-3- (3, 4-dichlorophenyl) pyrrolidin-3-amine 4-methylbenzenesulfonate (200 mg,0.300 mmol) in DCM (3,0046 ml) was added triethylamine (209 μl,1.50 mmol) at room temperature in a vial. The reaction mixture was stirred at room temperature overnight with half saturated NaHCO ₃ The solution and DCM were diluted and the aqueous layer was extracted twice with DCM. The combined organic layers were filtered through a phase separator, then concentrated in vacuo and concentrated using a gradient of 0% to 4% MeOH (0.7N NH ₃ ) Purification by flash chromatography on silica gel provided the title compound as a white powder (172 mg, 93.69% purity, 82% yield, t _r =2.10 min). LCMS (method C): m/z found 621[ M+H ]] ⁺ ；

¹ H-NMR(500MHz，DMSO-d ₆ )δ8.47(s，1H)，7.81(d，J＝8.8Hz，2H)，0.00(d，J＝9.0Hz，2H)，7.37(d，J＝8.3Hz，1H)，7.34–7.21(m，8H)，0.00(dd，J＝8.6，2.2Hz，1H)，6.95(d，J＝8.8Hz，2H)，3.64(s，2H)，3.18–2.97(m，2H)，2.71–2.55(m，2H)，2.47–2.42(m，1H)，2.18–2.09(m，1H)。

Example 20: n- (4- (4-chloro-3-fluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (56)

Step 1: synthesis of benzyl 4-oxopiperidine-1-carboxylate

To a stirred solution of piperidin-4-one hydrochloride (1:1) (98%, 3.00g,21.7 mmol) and DIPEA (23 mL,0.132 mol) in DCM (70 mL) was added benzyl chloroformate (6.2 mL,43.6 mmol) and DMAP (265 mg,2.17 mmol) at room temperature under nitrogen in a round bottom flask. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride And (5) extinguishing. Dichloromethane and water were then added. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed once with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 10% to 75% ethyl acetate in cyclohexane to give the title compound as a yellow oil (3.89 g, purity 100%, yield 77%, t _r =0.71 min). LCMS (method D); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.43–7.35(m，4H)，7.37–7.30(m，1H)，5.13(s，2H)，3.70(t，J＝6.1Hz，4H)，2.40(t，J＝6.3Hz，4H)。

step 2: synthesis of 4- (4-chloro-3-fluoro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester

To a stirred solution of benzyl 4-oxopiperidine-1-carboxylate (500 mg,2.14 mmol) in anhydrous THF (4.3 mL) was added dropwise a solution of 0.5M bromine (4-chloro-3-fluorophenyl) magnesium (5.2 mL,2.60 mmol) in nitrogen at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Pouring the reaction mixture into saturated NH ₄ To the aqueous Cl solution was added ethyl acetate. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, 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% ethyl acetate in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (239.4 mg, purity 100%, yield 31%, t) _r =0.94). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.55–7.46(m，2H)，7.39(d，J＝4.3Hz，4H)，7.34(ddd，J＝8.6，6.4，2.4Hz，2H)，5.35(s，1H)，5.10(s，2H)，3.94(d，J＝10.7Hz，2H)，3.30–3.11(m，2H)，1.86(td，J＝13.1，4.7Hz，3H)，1.58(d，J＝13.1Hz，2H)。

step 3: synthesis of benzyl 4-azido-4- (4-chloro-3-fluoro-phenyl) piperidine-1-carboxylate

In a three-necked round bottom flask, azido (trimethyl) silane (81. Mu.L, 0.613 mmol) and BF were charged at 0deg.C ₃ A solution of etherate (377. Mu.L, 3.06 mmol) in anhydrous DCM (0.74 mL) was added dropwise a solution of 4- (4-chloro-3-fluoro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester (185 mg,0.509 mmol) in anhydrous DCM (2.8 mL). The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Pouring the reaction mixture into saturated NaHCO ₃ In aqueous solution (30 mL). The aqueous layer was extracted three times with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure to give the title compound as a colorless oil (188.2 mg, purity 69%, yield 66%, t) _r =1.08 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.68(t，J＝8.2Hz，1H)，7.62(dd，J＝11.1，2.2Hz，1H)，7.45–7.28(m，6H)，5.10(s，2H)，4.00–3.88(m，2H)，3.29–3.08(m，2H)，2.08–1.93(m，4H)。

step 4: synthesis of benzyl 4-amino-4- (4-chloro-3-fluoro-phenyl) piperidine-1-carboxylate

Triphenylphosphine (150 mg, 0.578mmol) and then 4-methylbenzenesulfonic acid hydrate (300 mg,1.58 mmol) were added to a stirred solution of an inseparable mixture of benzyl 4-azido-4- (4-chloro-3-fluoro-phenyl) piperidine-1-carboxylate (69%, 188mg, 0.336 mmol) and benzyl 4- (4-chloro-3-fluoro-phenyl) -3, 6-dihydro-2H-pyridine-1-carboxylate (31%, 188mg,0.169 mmol) in THF (2.5 mL) under nitrogen in a round bottom flask. The mixture was stirred at room temperature overnight. The suspension was filtered and washed with a small amount of THF. The filtrate was concentrated. The crude product was purified by reverse phase chromatography (Redisep C18Aq-30 g) using a gradient of 0% to 100% acetonitrile in water (0.1% acoh in water and acetonitrile). The desired fractions were pooled and pooled Concentration gave the title compound as a colorless oil (66.4 mg, 86% purity, 47% yield, t) _r =0.65 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.73–7.65(m，2H)，7.50–7.43(m，1H)，7.42–7.30(m，5H)，7.11(d，J＝7.8Hz，2H)，5.09(s，2H)，3.77–3.59(m，2H)，3.30–3.19(m，2H)，2.40–2.24(m，2H)，1.90–1.79(m，2H)。

step 5: synthesis of benzyl 4- (4-chloro-3-fluoro-phenyl) -4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

To a stirred solution of 4-amino-4- (4-chloro-3-fluoro-phenyl) piperidine-1-carboxylic acid benzyl ester (74%, 66mg,0.135 mmol) in DCM (1.3 mL) was added triethylamine (94. Mu.L, 0.674 mmol), 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 35. Mu.L, 0.204 mmol) and N, N-dimethylpyridine-4-amine (1.7 mg,0.0139 mmol) in sequence at room temperature in a vial. The reaction mixture was heated at 40 ℃ and stirred at that temperature overnight. The reaction mixture was cooled to room temperature. The organic layer was saturated with NH ₄ Aqueous Cl solution is washed, then saturated NaHCO ₃ Aqueous solution and finally saturated aqueous NaCl solution. The organic layer was dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 10% to 100% ethyl acetate in heptane. The desired fractions were combined and concentrated to give the title compound as a colourless gum (34.9 mg, 94% purity, 41% yield, t) _r =1.05 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.29(s，1H)，7.47–7.42(m，2H)，7.41–7.34(m，4H)，7.34–7.29(m，1H)，7.26(d，J＝8.2Hz，2H)，7.23–7.16(m，1H)，7.06–6.95(m，2H)，5.08(s，2H)，3.81(d，J＝13.5Hz，2H)，3.32–3.21(m，2H)，2.36(d，J＝13.8Hz，2H)，1.84–1.71(m，2H)。

Step 6: n- (4- (4-chloro-3-fluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide

To 4- (4-chloro-3-fluoro-phenyl) -4- [ [4- (trifluoromethoxy) phenyl ] at room temperature in a round bottom flask]Sulfonylamino groups]Benzyl piperidine-1-carboxylate (35 mg,0.0595 mmol) in acetonitrile (0.86 mL) was stirred and iodo (trimethyl) silane (25 μl,0.178 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The crude product was dry loaded onto celite and a gradient of 1% to 20% MeOH (0.7N NH was used ₃ ) Is purified by flash chromatography on silica gel. The desired fractions were combined and washed with water and triethylamine (41 μl,0.297 mmol). The aqueous layer was extracted once with dichloromethane and methyltetrahydrofuran. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative chromatography (C18 Aq 15.5 g) using a gradient of 0% to 100% acetonitrile in water (0.1% acoh in both). The desired fractions were combined and concentrated. Salt exchange of the residue in diethyl ether followed by addition of Et of 2M hydrogen chloride ₂ O solution (0.30 mL,0.595 mmol) and stirred at room temperature overnight. The suspension was filtered, washed with diethyl ether and dried at 45 ℃ for 24 hours to give the hydrochloride salt of the title compound as a white powder (16.5 mg, purity 99.56%, yield 57%, t) _r =1.42 min). LCMS (method C): m/z actual measurement 453[ M+H ]] ⁺ ； ¹ H-NMR(600MHz，DMSO-d ₆ )δ8.83–8.59(m，2H)，8.51(s，1H)，7.47–7.39(m，2H)，7.28–7.25(m，2H)，7.23(s，1H)，7.06–7.02(m，1H)，7.01–6.95(m，1H)，3.27–3.17(m，4H)，2.60–2.52(m，2H)，2.08–1.97(m，2H)。

Example 21: n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide (57)

Step 1: synthesis of benzyl 3- (4-chlorophenyl) -3- [ [4- [4- (trifluoromethyl) phenoxy ] phenyl ] sulfonylamino ] pyrrolidine-1-carboxylate

A sealed vial was charged with a solution of 1- ((benzyloxy) carbonyl) -3- (4-chlorophenyl) pyrrolidine-3-ammonium-4-methylbenzenesulfonate (250 mg,0.497 mmol), 4-dimethylaminopyridine (12 mg,0.0994 mmol), and triethylamine (0.35 mL,2.49 mmol) in DCM (4.5968 mL). Adding 4- [4- (trifluoromethyl) phenoxy ]]Benzenesulfonyl chloride (0.13 ml,0.596 mmol) and the reaction mixture was stirred at 40 ℃ for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and dichloromethane was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium carbonate and then saturated aqueous sodium chloride, dried using a phase separator and concentrated under reduced pressure. The residue was triturated in MeOH, filtered, washed with MeOH and dried in vacuo for 18 hours. The filtrate was concentrated under reduced pressure. Microporous polystyrene resin (MP-TsOH) (746 mg,1.49 mmol) for pTsOH functionalization was stirred at room temperature as a solution of the mixture in methanol (20 mL) overnight. Additional MP-TsOH (497 mg,0.994 mmol) was added and the mixture was stirred at room temperature for 1 hour. The resin was filtered and washed with MeOH and DCM. The filtrate was concentrated under reduced pressure to give the title product as a colorless solid (250 mg, purity 98%, yield 78.12%, t) _r =1.11 min). LCMS (method D): m/z observed 653.3[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)8.50(d，J＝7.5Hz，1H)，7.83(d，J＝7.0Hz，2H)，7.76–7.65(m，2H)，7.36(ddd，J＝14.2，9.0，4.6Hz，6H)，7.28–7.04(m，8H)，6.93(d，J＝8.8Hz，2H)，5.07(d，J＝9.6Hz，2H)，4.14(dd，J＝29.2，11.1Hz，1H)，3.64–3.32(m，3H)，2.67(s，1H)，2.27–2.10(m，1H)

Step 2: synthesis of N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (4- (trifluoromethyl) phenoxy) benzenesulfonamide (57)

To a 3- (4-chlorophenyl) -3- [ [4- [4- (trifluoromethyl) phenoxy ] at room temperature in a round bottom flask]Phenyl group]Sulfonylamino groups]A stirred suspension of pyrrolidine-1-carboxylic acid benzyl ester (98%, 245mg,0.380 mmol) in dry acetonitrile (10 mL) was added iodo (trimethyl) silane (0.16 mL,1.14 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, and then 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 18% methanolic ammonia in dichloromethane. The desired fractions were combined and washed with water (30 mL) and triethylamine (0.53 mL,3.80 mmol). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated in methanol, filtered, washed with methanol and dried in vacuo for 18 hours. The solid obtained was triturated in 2M hydrogen chloride in diethyl ether (0.57 mL,1.14 mmol) for 2 hours, filtered, washed with diethyl ether, pentane and dried in vacuo at 45℃for 4 hours to give the HCl salt of the title compound as a white powder (79.1 mg, purity 99.72%, yield 38.87%, t) _r =1.97 min). LCMS (method C): m/z observations 497.1[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ9.42(br d，J＝2.0Hz，2H)，8.89–8.25(m，1H)，7.85(d，J＝8.6Hz，2H)，7.32(d，J＝8.8Hz，2H)，7.24(d，J＝8.6Hz，2H)，7.19–7.14(m，2H)，7.13–7.02(m，2H)，6.89(d，J＝8.8Hz，2H)，4.18–4.06(m，1H)，3.44–3.34(m，3H)，2.93–2.77(m，1H)，2.23–2.04(m，1H)。

Example 22: n- (3- (4-chloro-3-fluorophenyl) azetidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (58)

Step 1: synthesis of benzyl 3- (4-chloro-3-fluorophenyl) -3-hydroxyazetidine-1-carboxylate

To a stirred suspension of magnesium (113 mg,4.63 mmol) and a catalytic amount of iodine in anhydrous THF (2 mL) was added several drops of a solution of 4-bromo-1-chloro-2-fluorobenzene (98%, 430 μl,3.48 mmol) in anhydrous THF (1.5 mL) at room temperature in a three-necked round bottom flask. The reaction mixture was heated at 50 ℃ until discoloration (orange to yellow) was observed. Next, the remaining solution was added dropwise and stirred at this temperature for 1 hour (until magnesium was consumed). Then, the reaction mixture was cooled to 0 ℃ and a solution of benzyl 3-oxo-azetidine-1-carboxylate (95%, 500mg,2.31 mmol) in anhydrous THF (1.6 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, then the reaction mixture was poured into saturated NH ₄ To the aqueous Cl solution, etOAc was added. The layers were separated and the aqueous layer was then extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, 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% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (590.4 mg, purity 100%, yield 76%, t) _r =0.90 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.64–7.55(m，1H)，7.51(dd，J＝10.8，2.1Hz，1H)，7.42–7.36(m，5H)，7.36–7.30(m，1H)，6.63(s，1H)，5.10(s，2H)，4.26–4.05(m，4H)。

step 2: synthesis of 3- (4-chloro-3-fluoro-phenyl) -3-methylsulfonyloxy-azetidine-1-carboxylic acid benzyl ester

To a stirred solution of 3- (4-chloro-3-fluoro-phenyl) -3-hydroxy-azetidine-1-carboxylic acid benzyl ester (250 mg,0.745 mmol) in anhydrous DCM (3.5 mL) was added triethylamine (414 μl,2.97 mmol) and methanesulfonyl chloride (115 μl,1.49 mmol) at room temperature under nitrogen in a round bottom flask. The reaction mixture was stirred for 2 hours, and then the reaction mixture was concentrated under reduced pressure. The crude product was diluted in dichloromethane and washed with waterTwice. The organic layer was washed once with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure to give the title compound as a yellow oil (324 mg, purity 95%, yield 100%). The crude product was used directly in the next step without any purification. ¹ H-NMR (400 MHz, chloroform-d) delta 7.52-7.47 (m, 1H), 7.40-7.32 (m, 5H), 7.32-7.28 (m, 1H), 7.27-7.23 (m, 1H), 5.12 (s, 2H), 4.68 (d, J=11.2 Hz, 2H), 4.52-4.44 (m, 2H), 2.73 (s, 3H).

Step 3: synthesis of benzyl 3-azido-3- (4-chloro-3-fluoro-phenyl) azetidine-1-carboxylate

A sealed vial was charged with a solution of 3- (4-chloro-3-fluoro-phenyl) -3-methylsulfonyloxy-azetidine-1-carboxylic acid benzyl ester (95%, 155mg,0.356 mmol) in anhydrous DMF (1.78 mL) and then NaN was added at room temperature ₃ (28 mg,0.428 mmol) and the reaction mixture was stirred at 40℃overnight. The reaction mixture was cooled to room temperature, then water (20 mL) and EtOAc were added. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed once with water and once with saturated aqueous NaCl, 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 5% to 50% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (91.7 mg, purity 100%, yield 77%, t) _r =1.02 min). LCMS (method E): m/z found 317.2[ M-N ] ₃ +H] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.70(t，J＝8.1Hz，1H)，7.66(dd，J＝10.5，2.1Hz，1H)，7.42–7.30(m，6H)，5.07(s，2H)，4.46(d，J＝9.3Hz，2H)，4.27(d，J＝9.5Hz，2H)。

Step 4: synthesis of benzyl 3-amino-3- (4-chloro-3-fluorophenyl) azetidine-1-carboxylate

To a stirred solution of benzyl 3-azido-3- (4-chloro-3-fluoro-phenyl) azetidine-1-carboxylate (92 mg,0.254 mmol) in THF (1.4 mL) under nitrogen in a round bottom flask was added triphenylphosphine (67 mg,0.256 mmol) and 4-methylbenzenesulfonic acid hydrate (145 mg,0.763 mmol) in sequence. The mixture was stirred at room temperature overnight and the resulting suspension was filtered, washed with THF and dried under vacuum for 18 hours to give the p-toluenesulfonate salt of the title compound as a white powder (99 mg, purity 100%, yield 77%, t) _r =0.63 min). LCMS (method E): m/z found 335.2[ M+H-APTS] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.77(s，3H)，7.75(t，J＝8.1Hz，1H)，7.64(dd，J＝10.6，2.2Hz，1H)，7.50–7.44(m，2H)，7.43–7.31(m，6H)，7.11(d，J＝7.8Hz，2H)，5.10(s，2H)，4.53–4.37(m，2H)，4.32(d，J＝9.6Hz，2H)，2.29(s，3H)。

Step 5: synthesis of benzyl 3- (4-chloro-3-fluorophenyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) azetidine-1-carboxylate

To benzyl 3-amino-3- (4-chloro-3-fluoro-phenyl) azetidine-1-carboxylate at room temperature in a vial; a stirred suspension of 4-methylbenzenesulfonic acid (99 mg,0.195 mmol) in DCM (1.3 mL) was successively added triethylamine (136. Mu.L, 0.976 mmol), 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 51. Mu.L, 0.295 mmol) and N, N-dimethylpyridin-4-amine (2.5 mg,0.0201 mmol). The reaction mixture was stirred at 40 ℃ for 4 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was saturated with NH ₄ Washing with aqueous Cl solution once, and washing with saturated NaHCO ₃ The aqueous solution was washed once and once with saturated aqueous NaCl solution. The organic layer was dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 10% to 50% ethyl acetate in heptane. The desired fractions were combined and concentrated to give the title compound asWhite solid (65.3 mg, purity 100%, yield 60%, t) _r =1.02 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO-d ₆ )δ9.20(s，1H)，7.48–7.42(m，2H)，7.41–7.32(m，5H)，7.32–7.25(m，3H)，7.09(dd，J＝10.5，2.1Hz，1H)，7.05(dd，J＝8.4，2.1Hz，1H)，5.05(s，2H)，4.34(s，4H)。

step 6: synthesis of N- (3- (4-chloro-3-fluorophenyl) azetidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (58)

To 3- (4-chloro-3-fluoro-phenyl) -3- [ [4- (trifluoromethoxy) phenyl ] at room temperature in a round bottom flask]Sulfonylamino groups]A stirred solution of benzyl azetidine-1-carboxylate (65 mg,0.116 mmol) in acetonitrile (1.7 mL) was added iodo (trimethyl) silane (49 μl,0.346 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 2% to 20% methanol (+0.7n ammonia) in dichloromethane. The desired fractions were combined and water and triethylamine (81 μl,0.583 mmol) were added. The layers were separated and the aqueous layer was then extracted once with dichloromethane. The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. Et by adding diethyl ether and 2M hydrogen chloride to the residue ₂ O solution (0.60 mL,1.20 mmol). The suspension was stirred at room temperature overnight, filtered, washed with diethyl ether and dried in vacuo at 45 ℃ for 2 days to give the HCl salt of the title compound as a white powder (28.4 mg, 97.99% purity, 52% yield, t _r =1.57 min). LCMS (method C): m/z found 425[ M+H-HCl ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.98-9.94(m，3H)，7.42(d，J＝7.9Hz，2H)，7.25-7.31(m，3H)，7.12(br d，J＝9.9Hz，1H)，7.02(d，J＝8.2Hz，1H)，4.36-4.44(m，4H)。

Example 23: n- (4- (4-fluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (59)

Step 1: synthesis of tert-butyl 4- ((tert-butoxycarbonyl) amino) -4- (4-fluorophenyl) piperidine-1-carboxylate

To a stirred solution of 4- (4-fluorophenyl) piperidin-4-amine dihydrochloride (150 mg,0.561 mmol) and triethylamine (313 μl,2.25 mmol) in DCM (2 mL) was added tert-butoxycarbonyl tert-butyl carbonate (123 mg,0.561 mmol) in a sealed vial. The reaction mixture was stirred at room temperature overnight. Water (1 mL) and DCM (1 mL) were added, and the aqueous layer was extracted twice with DCM. The organic layer was saturated with NH ₄ Cl solution was washed, then with saturated NaHCO ₃ The solution was washed, filtered through a phase separator, and concentrated in vacuo to give the title compound as a colorless oil (142 mg, purity 81%, yield 70%, t) _r =0.58 min). LCMS (method E): m/z found 295.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)7.61–7.51(m，2H)，7.17–7.07(m，2H)，3.71(d，J＝12.4Hz，2H)，3.27(s，2H)，1.90(s，2H)，1.77(td，J＝12.7，12.1，4.6Hz，2H)，1.54(t，J＝9.9Hz，2H)，1.41(s，9H)。

Step 2: synthesis of tert-butyl 4- (4-fluorophenyl) -4- ((4- (trifluoromethoxy) phenyl) sulfamide) piperidine-1-carboxylate

A sealed vial was charged with a solution of tert-butyl 4-amino-4- (4-fluorophenyl) piperidine-1-carboxylate (70%, 146mg,0.347 mmol), N-dimethylpyridine-4-amine (8.5 mg,0.0694 mmol) and triethylamine (145 μl,1.04 mmol) in DCM (3 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (65 μl,0.382 mmol) was then added to the reaction mixture and stirred at 40 ℃ overnight. Will be reversed The mixture was treated with DCM and saturated NaHCO ₃ The aqueous solution was diluted and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. The desired fractions were combined and concentrated. The resulting white residue was purified by reverse phase preparative chromatography using a gradient of 0% to 100% acetonitrile in water (0.1% tfa in water and acetonitrile). The desired fractions were combined and concentrated to give the title compound as a white solid (114 mg, 96% purity, 61% yield, t) _r =1.02 min). LCMS (method E): m/z found 419.3[ M-Boc+H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)8.19(s，1H)，7.38(d，J＝8.8Hz，2H)，7.22(d，J＝8.2Hz，2H)，7.10(dd，J＝8.8，5.4Hz，2H)，6.73(t，J＝8.8Hz，2H)，3.70(d，J＝13.3Hz，2H)，3.24(s，2H)，2.37(d，J＝13.3Hz，2H)，1.71(t，J＝10.2Hz，2H)，1.40(s，9H)。

Step 3: synthesis of N- (4- (4-fluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (59)

To 4- (4-fluorophenyl) -4- [ [4- (trifluoromethoxy) phenyl ] at room temperature in a round bottom flask]Sulfonylamino groups]A stirred suspension of tert-butyl piperidine-1-carboxylate (96%, 114mg,0.211 mmol) in diethyl ether (2 mL) was added Et with 2M hydrogen chloride ₂ O solution (1.1 mL,2.20 mmol). The reaction mixture was stirred at room temperature overnight. The suspension was filtered, using Et ₂ O-washing and vacuum drying gave the HCl salt of the title compound as a white solid (89 mg, purity 98.32%, yield 93%, t) _r =1.27 min). LCMS (method B): m/z found 419.1[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ8.5-8.9(m，2H)，8.45(s，1H)，7.3-7.4(m，2H)，7.22(dd，2H，J＝0.9，8.9Hz)，7.10(dd，2H，J＝5.3，8.9Hz)，6.76(t，2H，J＝8.9Hz)，3.2-3.3(m，4H)，2.58(br d，2H，J＝13.4Hz)，1.9-2.1(m，2H)。

Example 24: n- (4-phenylpiperidin-4-yl) -6- (trifluoromethoxy) pyridine-3-sulfonamide (60)

Step 1: synthesis of 5- (benzylthio) -2- (trifluoromethoxy) pyridine

A sealed vial was charged with a solution of 5-bromo-2- (trifluoromethoxy) pyridine (95%, 1.00g,3.93 mmol) and DIPEA (1.4 mL,7.85 mmol) in anhydrous 1, 4-dioxane (13.086 mL). The reaction mixture was degassed with argon for 5min. Next, xanthene (227 mg,0.393 mmol), tris (dibenzylideneacetone) dipalladium (0) (180 mg,0.196 mmol) and benzyl mercaptan (922. Mu.L, 7.85 mmol) were added and the reaction mixture was stirred at 105℃for 3 hours. The mixture was cooled to room temperature, filtered over a celite pad, washed with dioxane and DCM, concentrated and purified by flash chromatography on silica gel using a gradient of 0 to 10% EtOAc in heptane to give the title compound as a pale yellow oil (1072 mg, 96% purity, 92% yield, t _r =1.03 min). LCMS (method D): m/z found 286.1[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)8.30–8.25(m，1H)，7.99(dd，J＝8.6，2.6Hz，1H)，7.36–7.21(m，6H)，4.31(s，2H)。

Step 2: synthesis of tert-butyl 4-phenyl-4- ((6- (trifluoromethoxy) pyridine) -3-sulfonamide) piperidine-1-carboxylate

To a stirred solution of 5-benzylsulfanyl-2- (trifluoromethoxy) pyridine (150 mg,0.526 mmol) in acetonitrile (4.41 mL) in a sealed vial at 0deg.C under nitrogen was added water (0) 1119 mL), acetic acid (0.1692 mL), and 1, 3-dichloro-5, 5-dimethyl-imidazolidine-2, 4-dione (207 mg,1.05 mmol). The reaction mixture was stirred at 0deg.C for 2 hours, then concentrated in vacuo at 0deg.C, dissolved in DCM (5 mL) and quenched with 10mL of 5% NaHCO ₃ Quenching. The organic layer was dried over a phase separator and a solution of tert-butyl 4-amino-4-phenylpiperidine-1-carboxylate (174 mg,0.631 mmol) and triethylamine (0.37 mL,2.63 mmol) in DCM (3 mL) was added dropwise and stirred overnight at 40 ℃. Adding half saturated NaHCO ₃ The solution was extracted twice with DCM. The combined organic layers were dried over a phase separator, concentrated in vacuo and purified by flash chromatography on silica gel using a gradient of 0% to 5% methanol in DCM. The obtained product was purified again by flash chromatography on silica gel using a gradient of 0% to 50% EtOAc in heptane to give the title compound as an off-white solid (16.2 mg, 91% purity, 5.59% yield, t _r LCMS (method E) =1.0 min): m/z found 402.3[ M-H+Boc] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)δ(ppm)8.35(s，1H)，8.05(d，J＝2.4Hz，1H)，7.73(dd，J＝8.6，2.5Hz，1H)，7.13–7.04(m，3H)，6.97(dd，J＝5.3，1.7Hz，3H)，3.72(d，J＝13.5Hz，2H)，2.42(d，J＝13.3Hz，2H)，1.76(t，J＝10.6Hz，2H)，1.40(s，9H)。

Step 3: synthesis of N- (4-phenylpiperidin-4-yl) -6- (trifluoromethoxy) pyridine-3-sulfonamide (60)

To a stirred solution of 4M hydrogen chloride in dioxane (0.20 mL,0.798 mmol) in diethyl ether (0.1996 mL) in a round bottom flask was added 4-phenyl-4- [ [6- (trifluoromethoxy) -3-pyridinyl ]Sulfonylamino groups]Piperidine-1-carboxylic acid tert-butyl ester (91%, 11mg,0.0200 mmol). The mixture was stirred at room temperature overnight, filtered, and taken up in Et ₂ O-washing and vacuum drying overnight at 45℃gave the HCl salt of the expected compound as a white powder (6.9 mg, purity 97.23%, yield 76.77%, t) _r =1.30 min). LCMS (method C): m/z found 402.0[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ(ppm)8.63(br s，3H)，8.05(d，J＝2.2Hz，1H)，7.73(dd，J＝8.7，2.6Hz，1H)，6.98-7.11(m，6H)，3.26(br d，J＝13.4Hz，4H)，2.62(br d，J＝13.9Hz，2H)，2.04(br s，2H)。

Example 25: n- (1-methyl-4-phenylpiperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (61)

Step 1: synthesis of tert-butyl 4-phenyl-4- ((4- (trifluoromethoxy) phenyl) sulfonamide) piperidine-1-carboxylate

A sealed vial was charged with tert-butyl 4-amino-4-phenylpiperidine-1-carboxylate (265 mg,0.959 mmol), DMAP (23 mg,0.192 mmol) and triethylamine (535. Mu.L, 3.84 mmol) in DCM (15 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (179. Mu.L, 1.05 mmol) was added and the reaction mixture was stirred at 40℃for 18 hours, then quenched by the addition of saturated aqueous ammonium chloride (5 mL), water (10 mL) and dichloromethane (10 mL). The aqueous layer was extracted with dichloromethane (1X 15 mL). The combined organic layers were 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% to 5% methanol in dichloromethane to give the title compound as a white powder (438 mg, 100% purity, 91% yield, t _r =1.03 min). LCMS (method E): m/z observed value 523.3[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.16(s，1H)，7.37–7.32(m，2H)，7.17(d，J＝8.0Hz，2H)，7.08(dd，J＝7.7，1.9Hz，2H)，7.00–6.89(m，3H)，3.70(d，J＝13.6Hz，2H)，3.24(s，2H)，2.38(d，J＝13.3Hz，2H)，1.73(t，J＝10.6Hz，2H)，1.40(s，9H)。

To a stirred solution of 2M hydrogen chloride in diethyl ether (25 mL,49.2 mmol) in a round bottom flask was added 4-phenyl-4- [ [4- (trifluoromethoxy) phenyl ]]Sulfonylamino groups]Tert-butyl piperidine-1-carboxylate (435 mg,0.869 mmol). The mixture was stirred at room temperature for 36 hours, then filtered, washed with diethyl ether and dried in vacuo at 50 ℃ for 3 days to give the HCl salt of the title compound as a white powder (345 mg, purity 100%, yield 91%, t _r =0.64 min). LCMS (method E): m/z actual measurement (DMSO-d ₆ ，400MHz)δ(ppm)8.81(s，2H)，8.45(s，1H)，7.38–7.27(m，2H)，7.16(d，J＝8.1Hz，2H)，7.07(dd，J＝8.0，1.6Hz，2H)，6.97(qd，J＝8.6，7.6，2.7Hz，3H)，3.24(d，J＝8.2Hz，4H)，2.60(d，J＝13.6Hz，2H)，2.16–1.95(m，2H)。

Step 3: synthesis of N- (1-methyl-4-phenylpiperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (61)

A solution of N- (4-phenyl-4-piperidinyl) -4- (trifluoromethoxy) benzenesulfonamide hydrochloride (100 mg,0.229 mmol) and formaldehyde (8.2 mg,0.275 mmol) in DCM (2.289 mL) and methanol (1 mL) was stirred at room temperature for 10min under nitrogen in a sealed vial. Triethylamine (0.035 mL,0.252 mmol) and acetic acid (0.026 mL,0.458 mmol) were added and the mixture was stirred at room temperature for 30min. Adding polymer-bound NaBH ₃ CN (229 mg,0.458 mmol) and the mixture was stirred at room temperature for 16 hours, then the mixture was filtered, the residue was washed with MeOH, the filtrate was concentrated and then a gradient of 5% to 10% (MeOH+2% NH) was used ₄ OH) in DCM was purified by flash chromatography on silica gel. The desired fractions were pooled and Et was added ₂ Et of O (5 mL) and HCl 2N ₂ O solution (5 mL). The mixture was stirred at room temperature overnight, filtered, and taken up in Et ₂ O-washing and then drying overnight at 45℃under vacuum gave the title compound as a white powder (77.2 mg, purity 100%, yield 75%, t) _r =1.25 min). LCMS (method B): m/z found 415[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)10.54(br s，1H)，8.41(s，1H)，7.32(br d，J＝8.6Hz，2H)，7.13(br d，J＝8.3Hz，2H)，7.06(br d，J＝7.3Hz，2H)，6.91-7.01(m，3H)，3.45(br d，J＝11.7Hz，2H)，3.32-3.39(m，2H)，2.60-2.98(m，5H)，2.08(br t，J＝12.3Hz，2H)。

Example 26: n- (4- (4-chlorophenyl) piperidin-4-yl) -4-isopropoxy-benzenesulfonamide (62)

Step 1: synthesis of tert-butyl 4- (4-chlorophenyl) -4- ((4-isopropoxyphenyl) sulfonamide) piperidine-1-carboxylate

A sealed vial was charged with a solution of tert-butyl 4-amino-4- (4-chlorophenyl) piperidine-1-carboxylate (75 mg,0.241 mmol) and triethylamine (101. Mu.L, 0.724 mmol) in DCM (2 mL). 4- (propan-2-yloxy) benzenesulfonyl chloride (98%, 64mg,0.265 mmol) was then added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then heated at 40 ℃ for 2 hours, and N, N-dimethylpyridine-4-amine (5.9 mg,0.0483 mmol) was added. The reaction mixture was stirred at 40 ℃ overnight. The reaction mixture was taken up with DCM and saturated NaHCO ₃ The aqueous solution was diluted and the layers separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as an off-white solid (82 mg, 98% purity, 65% yield, t) _r =1.05 min). LCMS (method E): m/z found 409.4[ M-Boc+H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.89(s，1H)，7.24–7.15(m，2H)，7.11(d，J＝8.7Hz，2H)，7.02(d，J＝8.7Hz，2H)，6.72(d，J＝8.9Hz，2H)，4.63(p，J＝6.0Hz，1H)，3.68(d，J＝13.2Hz，2H)，3.28–3.07(m，2H)，2.31(d，J＝13.9Hz，2H)，1.67(t，J＝10.4Hz，2H)，1.39(s，9H)，1.29(d，J＝6.0Hz，6H)。

Step 2: synthesis of N- (4- (4-chlorophenyl) piperidin-4-yl) -4-isopropoxy-benzenesulfonamide (62)

In a round-bottomed flask, 4- (4-chlorophenyl) -4- [ (4-isopropoxyphenyl) sulfonylamino was introduced under nitrogen at room temperature]A stirred suspension of tert-butyl piperidine-1-carboxylate (80 mg,0.157 mmol) in diethyl ether (1.5 mL) was added Et with 2M hydrogen chloride ₂ O solution (786. Mu.L, 1.57 mmol). The reaction mixture was stirred at room temperature overnight. Next, a 4M solution of 1, 4-dioxane (0.20 ml,0.786 mmol) of hydrogen chloride was added at room temperature and the reaction mixture was stirred at room temperature for 4 hours. The suspension was filtered, using Et ₂ O-washing and drying overnight at 40℃gave the HCl salt of the title compound as a white solid (47 mg, 99.73% purity, 67% yield, t) _r =1.56 min). LCMS (method C) m/z found 409[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ8.63(br s，2H)，8.10(s，1H)，7.16(d，2H，J＝8.8Hz)，7.1-7.1(m，2H)，7.0-7.1(m，2H)，6.70(d，2H，J＝9.0Hz)，4.62(quin，1H，J＝6.0Hz)，3.1-3.3(m，4H)，2.4-2.6(m，2H)，1.8-2.1(m，2H)，1.28(d，6H，J＝6.1Hz)。

Example 27: n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide (63)

Step 1: synthesis of sodium 4- (trifluoromethoxy) benzene sulfinate

In a round bottom flask equipped with a condenser, 4- (trifluoromethoxy) benzenesulfonyl chloride (0.65 mL,3.84 mmol), sodium sulfite (1081 mg,8.44 mmol) and NaHCO ₃ An aqueous solution (10 mL) of (0.71 g,8.44 mmol) was stirred at 65℃for 20 hours. The mixture was cooled to room temperature and then concentrated. Methanol (10 mL) was added to the residue and the suspension was stirred at room temperature for 2 hours and then filtered. The residue was washed with MeOH and the filtrate was concentrated to give the title compound as a white powder (430 mg, 45% yield, t _r =0.91 min). LCMS (method E); ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.56(d，J＝8.5Hz，2H)，7.28(d，J＝8.4Hz，2H)。

step 2: synthesis of 4- (trifluoromethoxy) benzene sulfinyl chloride

To a stirred suspension of sodium 4- (trifluoromethoxy) benzenesulfonate (430 mg,1.73 mmol) in anhydrous DCM (4.3173 mL) was added sequentially oxalyl chloride (0.23 mL,2.60 mmol) and anhydrous DMF (0.0173 mL) in a round bottom flask at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound as a white powder (1.23 g, purity 25%, yield 72%). This compound was used in the next step without further purification.

Step 3: synthesis of N- [ (3, 4-dimethoxyphenyl) methyl ] -4- (trifluoromethoxy) benzenesulfonamide

In a round bottom flask, 4- (trifluoromethoxy) benzene was sulfinated at room temperature under nitrogenA stirred suspension of acid chloride (25%, 1.10g,1.12 mmol) in anhydrous DCM (3.7473 mL) was added sequentially 1- (3, 4-dimethoxyphenyl) methylamine (98%, 0.26mL,1.69 mmol) and triethylamine (0.47 mL,3.37 mmol). The reaction mixture was stirred at room temperature for 20 hours. Water was added and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 5% methanol in dichloromethane and MeOH (0.7N NH ₃ ) Is purified once more in DCM. The desired fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (142 mg, 97% purity, 33% yield, t) _r =0.86 min). LCMS (method E): m/z found 376.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.90–7.70(m，2H)，7.70–7.43(m，2H)，7.19–7.09(m，1H)，6.84(d，J＝8.2Hz，1H)，6.80(d，J＝1.9Hz，1H)，6.73(dd，J＝8.2，2.0Hz，1H)，3.95(dd，J＝14.1，5.2Hz，1H)，3.71(d，J＝0.9Hz，7H)。

Step 4: synthesis of benzyl 3- (4-chlorophenyl) -3- [ [ N- [ (3, 4-dimethoxyphenyl) methyl ] -S- [4- (trifluoromethoxy) phenyl ] sulfonylimino ] amino ] pyrrolidine-1-carboxylate

N- [ (3, 4-Dimethoxyphenyl) methyl group was purged in a round bottom flask at 0deg.C under nitrogen]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (112 mg, 0.294 mmol) in tetrachloromethane (1.2 mL,12.8 mmol) was added t-butyl hypochlorite (0.040 mL,0.356 mmol). The reaction mixture was stirred in the dark at 0 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure at 2 ℃. The residue was dissolved in anhydrous THF (0.9292 mL), benzyl 3-amino-3- (4-chlorophenyl) pyrrolidine-1-carboxylate (108 mg,0.327 mmol), DIPEA (156 μl,0.891 mmol) and N, N-dimethylpyridine-4-amine (99%, 3.7mg,0.0297 mmol) were added in sequence, and the reaction mixture was stirred at 40 ℃ for 18 hours. The reaction mixture was cooled to room temperature and water (20 mL)) Quench and add ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. A gradient of 0% to 6% MeOH (0.7N NH ₃ ) The crude product was purified by flash chromatography on silica gel to give the title compound as a colorless oil (145 mg, 90% purity, 62% yield, t) _r =1.11 min). LCMS (method E): m/z found 704.1[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.79(d，J＝8.8Hz，2H)，7.34(dd，J＝9.0，4.5Hz，12H)，6.96–6.31(m，3H)，5.07(d，J＝4.3Hz，2H)，4.17–3.98(m，1H)，3.94–3.48(m，10H)，3.39(s，1H)，2.70–2.53(m，1H)，2.35–2.15(m，1H)。

Step 5: synthesis of benzyl 3- (4-chlorophenyl) -3- [ [ [4- (trifluoromethoxy) phenyl ] sulfonylimino ] amino ] pyrrolidine-1-carboxylate

To 3- (4-chlorophenyl) -3- [ [ N- [ (3, 4-dimethoxyphenyl) methyl ] in a round-bottomed flask at 0deg.C under nitrogen]S- [4- (trifluoromethoxy) phenyl ]]Sulfonimido group]Amino group]A stirred solution of pyrrolidine-1-carboxylic acid benzyl ester (145 mg,0.206 mmol) in a mixture of acetonitrile (2.75 mL) and water (1.38 mL) was added ammonium cerium nitrate (282 mg,0.515 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was diluted with water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution and dried over Na ₂ SO ₄ Dried, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel using a gradient of 2% to 10% MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as an off-white solid (77 mg, 91% purity, 61% yield, t) _r =0.97 min). LCMS (method E): m/z found 576.2; ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.10–6.47(m，14H)，5.15–4.95(m，2H)，4.84–3.36(m，5H)，2.94–2.54(m，1H)，2.30–1.86(m，1H)。

Step 6: synthesis of N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide (63)

In a sealed vial, 3- (4-chlorophenyl) -3- [ [ [4- (trifluoromethoxy) phenyl ]]Sulfonimido group]Amino group]A suspension of pyrrolidine-1-carboxylic acid benzyl ester (77 mg,0.139 mmol) in anhydrous CAN (3.4749 mL) was stirred at room temperature under nitrogen. Iodo (trimethyl) silane (83 mg,0.417 mmol) was added dropwise, the mixture stirred at room temperature for 1.5 hours, concentrated in vacuo and concentrated using a gradient of 2% to 15% MeOH (0.7N NH) ₃ ) Is purified by flash chromatography on silica gel. The desired fractions were combined, water and triethylamine (0.19 ml,1.39 mmol) were added, the aqueous layer was extracted twice with DCM, and the combined organic layers were concentrated in vacuo. The resulting oil was dissolved in diethyl ether, pentane was added and the resulting solid was filtered to give the expected compound as an off-white powder (24 mg, 92.9% purity, 38% yield, t _r =4.48 min). LCMS (method F): m/z actual measurement 420; ¹ H-NMR(DMSO-d6，600MHz)+TFA：δ(ppm)7.69-7.77(m，2H)，7.35(dd，J＝15.2，8.1Hz，2H)，7.13-7.26(m，4H)，3.81-4.04(m，1H)，3.12-3.66(m，3H)，2.69-2.89(m，1H)，2.13-2.32(m，1H)。

example 28: n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6- (trifluoromethoxy) pyridine-3-sulfonamide (64)

Magnesium (2.04 g,84.1 mmol) was added to a three-necked round bottom flask at room temperature under nitrogen l) and an stirred suspension of iodine crystals in anhydrous THF (90 mL) were added to a few drops of a solution of 1-bromo-4-chlorobenzene (12.28 g,64.2 mmol) in anhydrous THF (50 mL). The grignard reaction was heated at 50 ℃ until discoloration (orange to colorless) was observed. Then, the remaining solution was added dropwise and stirred at 50 ℃ for 1 hour (until magnesium was consumed). The reaction mixture was then cooled to 0deg.C and a solution of benzyl 3-oxopyrrolidine-1-carboxylate (97%, 10.00g,44.2 mmol) in anhydrous THF (50 mL) was added dropwise at 0deg.C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and then ethyl acetate (100 mL) and water (50 mL) were added. The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated in DCM, filtered, washed with a small amount of DCM and dried in vacuo. The filtrate was concentrated and purified by flash chromatography on silica gel using a gradient of 0% to 4% methanol in dichloromethane. The first residues of the desired fractions concentrated and separated were combined to give the title compound as an off-white solid (8.939 g, purity 100%, yield 60.9%, t _r =0.89 min). LCMS (method E): m/z found 332.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.59–7.49(m，2H)，7.45–7.25(m，7H)，5.56(s，1H)，5.09(d，J＝9.8Hz，2H)，3.67–3.39(m，4H)，2.30–2.16(m，1H)，2.04(dt，J＝12.7，6.4Hz，1H)。

To a solution of 3- (4-chlorophenyl) -3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (8.88 g,26.8 mmol) in anhydrous DCM (100 mL) in a round bottom flask at 0deg.C under nitrogen was added azido (trimethyl) silane (4.3 mL,32.1 mmol) and BF ₃ Etherate (20 mL,0.161 mol). The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Saturated sodium bicarbonate at 0deg.CAqueous solution (50 mL) the reaction mixture was quenched and then water (30 mL) and dichloromethane (50 mL) were added. The aqueous layer was extracted with DCM (2X 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried using a phase separator and concentrated under reduced pressure to give the title product as a brown oil (8.838 g, purity 70%, yield 64.8%, t _r =1.03 min). LCMS (method E): m/z found 357.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.61–7.48(m，5H)，7.47–7.28(m，9H)，6.45(d，J＝12.4Hz，0H)，5.15(d，J＝3.9Hz，1H)，5.12(s，2H)，4.58–4.43(m，1H)，4.38–4.23(m，1H)，4.02–3.95(m，1H)，3.70–3.42(m，3H)，2.59–2.51(m，1H)，2.40(dt，J＝22.5，11.8Hz，1H)。

Triphenylphosphine (4.22 g,16.1 mmol) and then 4-methylbenzenesulfonic acid hydrate (9.18 g,48.2 mmol) were added to a stirred solution of benzyl 3-azido-3- (4-chlorophenyl) pyrrolidine-1-carboxylate (70%, 8.83g,17.3 mmol) in THF (76.5 mL) at room temperature under nitrogen in a round bottom flask. The mixture was stirred at room temperature overnight. The suspension was filtered, washed with diethyl ether and dried under vacuum at 45 ℃ for 48 hours to give 4-methylbenzenesulfonate of the title compound as a white solid (6.68 g, purity 100%, yield 76.7%, t _r =0.62 min). LCMS (method E): m/z found 331.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.49(s，3H)，7.56(d，J＝7.0Hz，4H)，7.47(d，J＝8.1Hz，2H)，7.43–7.30(m，5H)，7.22–6.94(m，3H)，5.19–5.08(m，2H)，4.06(d，J＝12.1Hz，1H)，3.80–3.52(m，3H)，2.46(s，1H)，2.29(s，3H)。

Step 4: synthesis of benzyl 3- (4-chlorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] pyrrolidine-1-carboxylate

Charging a round bottom flask with benzyl 3-amino-3- (4-chlorophenyl) pyrrolidine-1-carboxylate; a solution of 4-methylbenzenesulfonic acid (6.41 g,12.7 mmol), triethylamine (14 mL,0.102 mol), and 4- (trifluoromethoxy) benzenesulfonyl chloride (2.6 mL,15.3 mmol) in DCM (117.86 mL). 4-dimethylaminopyridine (311 mg,2.55 mmol) was added and the reaction mixture was stirred at 40℃ (hot plate adjusted to 45 ℃) for 20 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution and methylene chloride. The layers were separated. The organic layer was saturated with NaHCO ₃ The aqueous solution was washed and then washed with saturated aqueous sodium chloride, dried using a phase separator and concentrated under reduced pressure. The residue was triturated in MeOH, filtered, washed with MeOH and dried in vacuo for 18 hours to give the title compound as a white powder (3.3 g, 97% purity, 45.3% yield, t _r =0.62 min). LCMS (method E); ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.79–7.67(m，0H)，7.52(dd，J＝8.5，1.5Hz，0H)，7.44–7.24(m，1H)，5.20–4.97(m，0H)，3.71–3.43(m，1H)。

step 5: synthesis of 5-benzylsulfanyl-2- (trifluoromethoxy) pyridine

The sealed vial was charged with 5-bromo-2- (trifluoromethoxy) pyridine (0.58 mL,4.13 mmol), pd ₂ (dba) ₃ (95%, 199mg,0.207 mmol) and (5-diphenylphosphino-9, 9-dimethyl-xanthen-4-yl) -diphenyl-phosphine (phosphane) (98%, 244mg,0.413 mmol) in degassed anhydrous 1, 4-dioxane-anhydrous (21 mL). Benzyl mercaptan (0.73 mL,6.20 mmol) was added and the reaction mixture was stirred at 105℃for 3 hours. The mixture was cooled to room temperature, filtered over a celite pad, washed with dioxane and DCM, and concentrated. The crude product was purified by flash silica gel chromatography over 10 column volumes using a gradient of 100% heptane to 10% etoac in heptane to give the title compound as an off-white solid (0).95g, purity 95%, yield 76.6%, t _r =1.08 min). LCMS (method E): m/z actual measurement 286[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.30–8.25(m，1H)，7.99(dd，J＝8.6，2.6Hz，1H)，7.36–7.21(m，6H)，4.31(s，2H)。

Step 6: synthesis of 6- (trifluoromethoxy) pyridine-3-sulfonyl chloride

To a stirred solution of 5-benzylsulfanyl-2- (trifluoromethoxy) pyridine (0.95 g,3.33 mmol) in acetonitrile (20 mL) was added sequentially water (1 mL) and acetic acid (1.5 mL) in a three-necked round bottom flask equipped with a thermometer at 0deg.C under nitrogen followed by the addition of 1, 3-dichloro-5, 5-dimethyl-imidazolidine-2, 4-dione (720 mg,3.66 mmol) in portions. The reaction mixture was stirred at 0deg.C for 2 hours, then concentrated in vacuo, dissolved in DCM and quenched with 10mL NaHCO at 0deg.C ₃ 5% quenching. The organic layer was separated and dried by a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of (100/0 to 1/1) heptane/DCM. The fractions were collected and the solvent removed in vacuo to give the title compound as a colourless oil (450 mg, 60% purity, 30.993%). ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.50(dd，J＝2.4，0.5Hz，1H)，8.13(dd，J＝8.4，2.4Hz，1H)，7.25(dd，J＝8.4，0.6Hz，1H)。

Step 7: synthesis of benzyl 3- (4-chlorophenyl) -3- [ [6- (trifluoromethoxy) -3-pyridyl ] sulfonylamino ] pyrrolidine-1-carboxylate

To a stirred suspension of 6- (trifluoromethoxy) pyridine-3-sulfonyl chloride (60%, 450mg,1.03 mmol) in anhydrous DCM (9 mL) was added N, N-dimethylpyridin-4-amine (99%, 21mg,0.172 mmol) and N, N-diethylamine (0.30 mL,2.15 mmol) in sequence in a round bottom flask equipped with a condenser, followed by the addition ofBenzyl 3-amino-3- (4-chlorophenyl) pyrrolidine-1-carboxylate (95%, 300mg,0.862 mmol) was added. The reaction mixture was stirred at reflux for 5 hours. The reaction was cooled at 25℃and the mixture was saturated with NH ₄ The Cl solution was quenched. The phases were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed once with water, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel over 20 column volumes using a gradient of 99/1 to 9/1 DCM/MeOH to give the title compound as an off-white solid (212 mg, purity 70%, yield 31%, t _r =1.96 min). LCMS (method G): m/z actual measurement 556[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ7.61(d，J＝8.6Hz，1H)，7.56–7.25(m，11H)，6.49–6.42(m，1H)，5.16–5.12(m，2H)，4.60–4.43(m，2H)，4.40–4.26(m，2H)，3.89–3.60(m，1H)。

Step 8: synthesis of N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6- (trifluoromethoxy) pyridine-3-sulfonamide (64)

To 3- (4-chlorophenyl) -3- [ [6- (trifluoromethoxy) -3-pyridinyl ] at 0deg.C under nitrogen]Sulfonylamino groups]Benzyl pyrrolidine-1-carboxylate (70%, 80mg,0.101 mmol) in acetonitrile (1.0 mL) was added iodo (trimethyl) silane (0.043 mL,0.302 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours and the solvent was removed in vacuo. Et with 1M hydrogen chloride ₂ O solution (0.30 mL,0.302 mmol) and the mixture was stirred at 25℃for 30min and the solvent was removed in vacuo. The crude product was purified by reverse phase preparative chromatography (C18 aq,25 g) using a gradient of 0% to 100% acetonitrile+0.1% acoh/water+0.1% acoh. The fractions were collected and the solvent was removed in vacuo. The residue was taken up in DCM and taken up in 1M NaHCO ₃ Washing the solution. The phases were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed once with water, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was dissolved in dioxane (1 mL) and 1M chlorine was addedEt of hydrogen sulfide ₂ O solution (0.30 mL,0.302 mmol). The mixture was stirred at 25℃for 1 hour. Dioxane and Et were removed in vacuo ₂ O. The residue was taken up in anhydrous Et ₂ Grinding in O, filtering, and using anhydrous Et ₂ O-washing and vacuum drying at 25℃for 16 hours gave the hydrochloride salt of the title compound as a white solid (11 mg, purity 94.81%, yield 23%, t) _r =1.2 min). LCMS (method H): m/z found 422[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，600MHz)δ9.47(br s，2H)，9.07(s，1H)，8.14(d，1H，J＝2.5Hz)，7.87(dd，1H，J＝2.6，8.6Hz)，7.15(dd，1H，J＝0.6，8.7Hz)，7.0-7.1(m，4H)，4.15(br d，1H，J＝11.7Hz)，3.41(br d，3H，J＝8.5Hz)，2.8-3.0(m，1H)，2.16(td，1H，J＝9.8，13.3Hz)。

Example 29: n- (4- (5-Fluoropyridin-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (65)

Step 1: synthesis of 1-benzyl-piperidin-4-one

To a stirred suspension of piperidin-4-one hydrochloride (98%, 3.00g,21.7 mmol) in acetonitrile (50 mL) in a sealed round bottom flask at room temperature was added K ₂ CO ₃ (7.49 g,54.2 mmol) and bromotoluene (3.1 mL,26.0 mmol). The reaction mixture was stirred at 60 ℃ overnight. The reaction mixture was poured into water. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 10% to 100% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a yellow liquid (2.49 g, purity 87%, yield 53%, t) _r =0.58 min). LCMS (method E); ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.38–7.25(m，5H)，3.61(s，2H)，2.68(t，J＝6.1Hz，4H)，2.35(t，J＝6.1Hz，4H)。

Step 2: synthesis of 1-benzylpiperidine-4-carbonitrile

To a stirred solution of 1-benzylpiperidin-4-one (87%, 1.00g,4.60 mmol) and 1- (isocyanomethylsulfonyl) -4-methyl-benzene (98%, 916mg,4.60 mmol) in DME (36.459 mL) was added dropwise a solution of KOT-Bu (1.03 g,9.19 mmol) dissolved in a mixture of 16mL DME and t-butanol 1:1 at 0deg.C in a round bottom flask. The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Water (50 mL) was added and the mixture was extracted three times with EtOAc (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 1% to 8% MeOH in DCM. The desired fractions were combined and concentrated under reduced pressure to give the title compound as a yellow oil (811.1 mg, purity 91%, yield 80%, t) _r =0.41 min). LCMS (method E): m/z found 201.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.37–7.20(m，5H)，3.46(s，2H)，2.86(tt，J＝8.4，4.3Hz，1H),2.52(d，J＝13.9Hz，2H)，2.25(t，J＝10.1Hz，2H)，1.85(ddt，J＝13.9，7.3，3.8Hz，2H)，1.75–1.63(m，2H)。

Step 3: synthesis of 1-benzyl-4- (5-fluoro-2-pyridyl) piperidine-4-carbonitrile

To a stirred solution of 1-benzylpiperidine-4-carbonitrile (91%, 810mg,3.68 mmol) in anhydrous toluene (36.80 mL) was added 2-bromo-5-fluoropyridine (98%, 661mg,3.68 mmol) at room temperature under nitrogen in a sealed tube. The reaction mixture was cooled to 0deg.C and added dropwise 1M NaHMDS (7.4 mL,7.36 mmol) was added. The solution was stirred at 0 ℃ for 1 hour and then at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride to reach pH 7, then EtOAc was added. The layers were separated and the aqueous layer 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 a gradient of 10% to 80% EtOAc in cyclohexane. The desired fractions were combined and concentrated under reduced pressure to give the desired product as an off-white solid (923.3 mg, 99% purity, 84% yield, t) _r =0.53 min). LCMS (method E): m/z found 296.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.63(d，J＝3.0Hz，1H)，7.84(td，J＝8.7，3.0Hz，1H)，7.71(dd，J＝8.8，4.2Hz，1H)，7.37–7.22(m，5H)，3.57(s，2H)，2.94(dt，J＝12.5，3.4Hz，2H)，2.33(td，J＝11.8，3.1Hz，2H)，2.18–2.07(m，4H)。

Step 4: synthesis of 1-benzyl-4- (5-fluoro-2-pyridyl) piperidine-4-carboxamide

1-benzyl-4- (5-fluoro-2-pyridinyl) piperidine-4-carbonitrile (99%, 200mg,0.670 mmol) in H in a sealed tube ₂ SO ₄ A mixture of (2.6853 mL) and water (0.6713 mL) was stirred at 65℃for 1.5 h. The mixture was poured into ice water and basified with 30% aqueous naoh to reach pH 10-11. 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 over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (198.9 mg, 99% purity, 94% yield, t) _r =0.47 min). LCMS (method D): m/z found 314.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)8.52(d，J＝3.0Hz，1H)，7.69(td，J＝8.8，3.1Hz，1H)，7.47(dd，J＝8.9，4.4Hz，1H)，7.37–7.19(m，5H)，7.03(d，J＝34.4Hz，2H)，3.39(s，2H)，2.44(s，1H)，2.39–2.20(m，2H)，2.06(d，J＝11.7Hz，2H)。

Step 5: synthesis of 1-benzyl-4- (5-fluoro-2-pyridyl) piperidin-4-amine

In a sealed tube, 1-benzyl-4- (5-fluoro-2-pyridinyl) piperidine-4-carboxamide (99%, 335mg,1.06 mmol) is charged and dissolved in acetonitrile (3.00 mL) and water (3.00 mL). Then charging [ bis (trifluoroacetoxy) iodide ]]Benzene (96%, 284 mg,1.08 mmol) and the reaction was stirred at room temperature overnight and at 80 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum overnight. The residue was dissolved in Et ₂ Et in O and 2M Hydrogen chloride ₂ O solution (11 mL,21.2 mmol). The suspension was stirred at room temperature for 2 hours, filtered and taken up with Et ₂ And (3) washing. The resulting gum was dissolved in MeOH and concentrated under reduced pressure. Pouring the residue into saturated Na ₂ CO ₃ In aqueous solution to reach pH 10 and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown oil (270 mg, 65% purity, 58% yield, t _r =0.45 min). LCMS (method D): m/z found 286.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.48(d，J＝2.9Hz，1H)，7.74–7.61(m，2H)，7.36–7.28(m，5H)，6.41(s，0H)，5.76(s，0H)，3.48(s，2H)，2.48(s，1H)，2.19–1.94(m，3H)，1.88(s，2H)，1.51(dq，J＝11.4，2.2Hz，2H)。

Step 6: synthesis of N- [ 1-benzyl-4- (5-fluoro-2-pyridyl) -4-piperidinyl ] -4- (trifluoromethoxy) benzenesulfonamide

A sealed vial was charged with 1-benzyl-4- (5-fluoro-2-pyridinyl) piperidin-4-amine (59%, 270mg, 0.5538 mmol) and triethylamine (0.39 mL,2.79 mmol) in DCM (5.1633 mL). Adding 4- (trifluoromethoxy) benzenesulfonyl chloride(98%, 116. Mu.L, 0.670 mmol) and 4-dimethylaminopyridine (14 mg,0.112 mmol) and the reaction mixture was stirred overnight at 40 ℃. The reaction mixture was quenched with saturated aqueous ammonium chloride and dichloromethane was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride, dried using 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. The desired fractions were combined and concentrated to give the title compound as an off-white foam (262.7 mg, purity 100%, yield 92%, t) _r =0.68 min). LCMS (method D): m/z found 510.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.12(s，1H)，8.09(d，J＝2.8Hz，1H)，7.50–7.41(m，2H)，7.36–7.20(m，9H)，3.42(s，2H)，2.42(s，3H)，2.32(d，J＝13.7Hz，2H)，2.04(s，2H)。

Step 7: synthesis of N- [4- (5-fluoro-2-pyridyl) -4-piperidinyl ] -4- (trifluoromethoxy) benzenesulfonamide

To a stirred solution of 1-chloroethyl carbonate (99%, 0.10mL,0.954 mmol) in DCE (12 mL) under nitrogen was added N- [ 1-benzyl-4- (5-fluoro-2-pyridinyl) -4-piperidinyl]4- (trifluoromethoxy) benzenesulfonamide (100%, 243mg,0.477 mmol). The reaction mixture was stirred at room temperature for 2 days, then concentrated under reduced pressure. The residue was dissolved in MeOH (12 mL) and the reaction mixture was stirred at 65 ℃ overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting white solid was triturated in a mixture of dichloromethane and methanol (95:5, 15 mL) and the resulting white powder was filtered and washed twice with a mixture of dichloromethane and methanol (95:5, 2 x 5 mL). The resulting solid was again triturated in a mixture of dichloromethane and methanol (95:5, 10 mL), the resulting powder was filtered, washed with a mixture of dichloromethane and methanol (95:5, 2 x 5 mL) and dried in vacuo at 45 ℃ to give the title compound as a white powder (132.8 mg, 99% purity, 66% yield, t _r =0.62 min). LCMS (method E): m/z found 420.4[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.52(s，2H)，8.14(d，J＝2.9Hz，1H)，7.45–7.40(m，2H)，7.36(dd，J＝8.6，2.9Hz，1H)，7.33–7.27(m，3H)，3.25–3.13(m，4H)，2.58–2.52(m，2H)，2.21–2.10(m，2H)。

Step 8: synthesis of N- (4- (5-fluoropyridin-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (65)

N- [4- (5-fluoro-2-pyridinyl) -4-piperidinyl in a round-bottomed flask at room temperature under nitrogen]4- (trifluoromethoxy) benzenesulfonamide (133 mg,0.317 mmol) in Et ₂ Stirred suspension in O (3.4 mL) was added Et with 2M HCl ₂ O solution (2.4 mL,4.80 mmol). After 10 min, meOH (3.4 mL) was added and the mixture was stirred at room temperature for 4 hours. The resulting suspension was filtered with Et ₂ O (3X 5 mL) was washed three times and dried at 45℃for 18 hours to give the hydrochloride salt of the title compound as a white powder (112.3 mg, purity 99.02%, yield 78%, t) _r =0.62 min). LCMS (method H): m/z found 420[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ8.77(br d，2H，J＝18.1Hz)，8.56(s，1H)，8.13(d，1H，J＝2.9Hz)，7.4-7.5(m，2H)，7.3-7.4(m，1H)，7.2-7.3(m，3H)，3.1-3.3(m，4H)，2.56(br d，2H，J＝14.2Hz)，2.1-2.2(m，2H)。

Example 30: n- (4- (bicyclo [1.1.1] pentan-1-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (66)

Step 1: synthesis of 4- (1-bicyclo [1.1.1] pentyl) -4-nitro-piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 2M Lithium Diisopropylamide (LDA) in THF/heptane (1.3 mL,2.52 mmol) was added dropwise a solution of tert-butyl 4-nitropiperidine-1-carboxylate (553 mg,2.40 mmol) in anhydrous THF (6 mL) in a three-necked flask at-78deg.C under nitrogen. The reaction mixture was stirred at-78 ℃ for 30min. Next, 0.5MZnCl was added at-78deg.C ₂ A solution in THF (6.0 mL,3.00 mmol). The reaction mixture was warmed to 0℃and stirred at 0℃for 5min, then 0.15M tricyclo [1.1.1.0 ] was added dropwise ^1,3 ]Pentane (8.0 mL,1.20 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours and allowed to slowly warm to room temperature. The reaction mixture was stirred at this temperature overnight. Saturated NH was added at 0deg.C ₄ Aqueous Cl (12 mL) and stirred at this temperature for 1 hour. Next, etOAc (20 mL) was added and the layers were separated. The aqueous layer was extracted twice with EtOAc (15 mL). Washing the combined organic layers with saturated NH ₄ Aqueous Cl (15 mL) was washed once and once with saturated aqueous sodium chloride (15 mL), taken over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 2% to 100% EtOAc in cyclohexane to give the title compound as a white solid (80.9 mg, 98% purity, 22% yield, t _r =1.03 min). LCMS (method E); ¹ H-NMR(400MHz，CDCl3)δ4.11–4.01(m，2H)，2.70(t，J＝13.1Hz，2H)，2.53(s，1H)，2.45(dq，J＝14.9，2.7Hz，2H)，1.72(s，6H)，1.62(td，J＝13.5，4.9Hz，2H)，1.45(s，9H)。

step 2: synthesis of tert-butyl 4-amino-4- (1-bicyclo [1.1.1] pentyl) piperidine-1-carboxylate

Filling a sealed vial with 4- (1-bicyclo [ 1.1.1)]Amyl) -4-nitro-piperidine-1-carboxylic acid tert-butyl ester (79 mg,0.267 mmol), NH ₄ A solution of Cl (57 mg,1.07 mmol) and iron (60 mg,1.07 mmol) in a mixture of water (0.5 mL) and MeOH (2 mL). The reaction mixture was warmed to 70 ℃ and stirred at that temperature for 3.5 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite, washed twice with MeOH and the filtrate concentrated under reduced pressure. The residue was dissolved in a mixture of dichloromethane (10 mL) and half-saturated aqueous sodium bicarbonate (10 mL) was added. The layers were separated and the aqueous layer was extracted with dichloromethane (2X 10 mL). The combined organic layers were washed once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride, dried using a phase separator, and concentrated under reduced pressure to give the title compound as an off-white solid (69.5 mg, 95% purity, 93% yield, t _r =0.58 min). LCMS (method E): m/z found 267.4[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ3.69(d，J＝12.8Hz，2H)，3.11–2.91(m，3H)，2.45(s，1H)，1.58(s，6H)，1.39(s，9H)，1.32–1.21(m，2H)，1.17–1.07(m，2H)。

Step 3: synthesis of tert-butyl 4- (1-bicyclo [1.1.1] pentyl) -4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

In a round bottom flask at room temperature to 4-amino-4- (1-bicyclo [ 1.1.1)]A stirred suspension of tert-butyl amyl) piperidine-1-carboxylate (67 mg,0.252 mmol) and pyridine (41. Mu.L, 0.503 mmol) in acetonitrile (2.5 mL) was added 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 52. Mu.L, 0.302 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with half-saturated aqueous ammonium chloride (10 mL) and then dichloromethane (15 mL) was added. The layers were separated. The aqueous layer was extracted twice with dichloromethane (10 mL). The combined organic layers were washed once with saturated aqueous ammonium chloride (10 mL), once with saturated aqueous sodium bicarbonate, once with saturated aqueous sodium chloride, dried using a phase separator, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography using a gradient of 0% to 10% methanolic ammonia (0.7N) in dichloromethane. The desired fractions were combined and concentrated under reduced pressure to give the title compound as an off-white solid Body (75.1 mg, purity 98%, yield 60%, t) _r =1.09 min). LCMS (method E): m/z found 513.4[ M+Na ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.01–7.90(m，2H)，7.64–7.53(m，2H)，7.51(s，1H)，3.58(d，J＝13.5Hz，2H)，2.55–2.52(m，2H)，2.39(s，1H)，1.85(d，J＝13.8Hz，2H)，1.33(s，9H)，1.28(ddd，J＝16.2，12.2，4.3Hz，2H)。

Step 4: synthesis of N- (4- (bicyclo [1.1.1] pentan-1-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (66)

In a round-bottomed flask, 4- (1-bicyclo [ 1.1.1) is charged under nitrogen at room temperature]Amyl) -4- [ [4- (trifluoromethoxy) phenyl]Sulfonylamino groups]Piperidine-1-carboxylic acid tert-butyl ester (75 mg,0.153 mmol) in Et ₂ A stirred solution of O (1.5 mL) was added 4M hydrogen chloride in dioxane (380. Mu.L, 1.52 mmol). The reaction mixture was stirred at this temperature. After 4 hours, et with 2M hydrogen chloride was added ₂ O solution (800. Mu.L, 1.60 mmol). The reaction mixture was stirred at room temperature for 40 hours. The resulting suspension was filtered, washed twice with diethyl ether (2×2 mL) and dried under vacuum at 45 ℃ for 18 hours to give the hydrochloride salt of the title compound as a white powder (56.8 mg, purity 100%, yield 87%, t _r =1.23 min). LCMS (method H): m/z found 391[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.36-8.52(m，2H)，7.98(d，J＝7.9Hz，2H)，7.71(s，1H)，7.62(d，J＝8.1Hz，2H)，3.10(br d，J＝12.5Hz，2H)，2.53-2.64(m，2H)，2.38(s，1H)，2.01(br d，J＝13.7Hz，2H)，1.61-1.70(m，2H)，1.57(s，6H)。

Example 31: n- (4- (4-chlorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide (67)

Step 1: synthesis of tert-butyl 4- (4-chlorophenyl) -4- [ (6-isopropoxy-3-pyridyl) sulfonylamino ] piperidine-1-carboxylate

A sealed vial was charged with tert-butyl 4-amino-4- (4-chlorophenyl) piperidine-1-carboxylate (95%, 75mg,0.229 mmol), N, N-dimethylpyridine-4-amine (5.6 mg,0.0458 mmol) and triethylamine (96 μl,0.688 mmol) in DCM (2.2807 mL). 6- (propan-2-yloxy) pyridine-3-sulfonyl chloride (95%, 47. Mu.L, 0.252 mmol) was added to the reaction mixture and stirred overnight at 40 ℃. Additional N, N-dimethylpyridin-4-amine (5.6 mg,0.0458 mmol), 6- (prop-2-yloxy) pyridine-3-sulfonyl chloride (95%, 28mg,0.115 mmol) and triethylamine (48 μl,0.344 mmol) were added at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and saturated NaHCO was added ₃ An aqueous solution. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as an off-white solid (75 mg, 96% purity, 62% yield, t) _r =1.09 min). LCMS (method E): m/z found 532.3[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.09(s，1H)，7.85(d，J＝2.6Hz，1H)，7.50(dd，J＝8.8，2.6Hz，1H)，7.11(d，J＝8.7Hz，2H)，7.03(d，J＝8.7Hz，2H)，6.55(d，J＝8.8Hz，1H)，5.23(hept，J＝6.2Hz，1H)，3.71(d，J＝13.3Hz，2H)，3.26(s，2H)，2.36(d，J＝13.5Hz，2H)，1.70(t，J＝10.6Hz，2H)，1.40(s，9H)，1.30(d，J＝6.2Hz，6H)。

Step 2: synthesis of N- (4- (4-chlorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide (67)

In a round-bottomed flask, 4- (4-chlorophenyl) -4- [ (6-isopropoxy-3-pyridinyl) sulfonylamino was placed in a flask at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (73 mg,0.143 mmol) in Et ₂ Stirred solution in O (2.269 mL) was added Et with 2M HCl ₂ O solution (0.72 mL,1.43 mmol). The reaction mixture was stirred at room temperature for 8 hours. Et with additional 2M HCl ₂ O solution (1.0 mL,2.00 mmol) and the reaction mixture was stirred at room temperature for 20 hours. Next, a solution of 4M HCl in 1, 4-dioxane (0.80 ml,3.20 mmol) was added and the reaction mixture was stirred at room temperature for 24 hours. The suspension was filtered, using Et ₂ O (5 mL) was washed and dried under vacuum at 50deg.C for 18 hours. The resulting powder was purified by reverse phase flash chromatography using a gradient of 0% to 100% acetonitrile in water (0.1% acoh in water and acetonitrile). Et in 2M HCl ₂ A solution of O (0.72 mL,1.43 mmol) was stirred for 2 hours and the resulting suspension was filtered off with Et ₂ O-washing and vacuum drying at 40℃for 3 days gave the title compound as a white powder (34 mg, purity 98.99%, yield 54%, t) _r =1.25 min). LCMS (method H): m/z found 410[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.70(br s，2H)，8.35(s，1H)，7.85(d，J＝2.4Hz，1H)，7.49(dd，J＝8.8，2.4Hz，1H)，7.05-7.15(m，4H)，6.55(d，J＝8.8Hz，1H)，5.22(spt，J＝6.2Hz，1H)，3.17-3.29(m，4H)，2.54-2.60(m，2H)，1.95-2.05(m，2H)，1.30(d，J＝6.4Hz，6H)。

Example 32: n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -N' -methyl-4- (trifluoromethoxy) benzenesulfonimide amide (68)

Step 1: synthesis of N-methyl-4- (trifluoromethoxy) benzene sulfinamide

To a stirred suspension of 4- (trifluoromethoxy) phenylsulfinyl chloride (95%, 300mg,1.17 mmol) in anhydrous DCM (3.8836 mL) was added a solution of 2M methylamine in THF (0.87 mL,1.75 mmol) and triethylamine (0.49 mL,3.50 mmol) in sequence at room temperature in a round bottom flask under nitrogen. The reaction mixture was stirred at room temperature for 20 hours. Water was added and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried by filtration through a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 6% methanol in dichloromethane to give the title compound as a pale yellow oil (151 mg, 92% purity, 50% yield, t _r =0.75 min). LCMS (method E): m/z found 240.1[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.76–7.69(m，2H)，7.59–7.53(m，2H)，6.63(q，J＝5.1Hz，1H)，2.26(d，J＝5.1Hz，3H)。

Step 2: synthesis of benzyl 3- (4-chlorophenyl) -3- [ [ N-methyl-S- [4- (trifluoromethoxy) phenyl ] sulfonylimino ] amino ] pyrrolidine-1-carboxylate

To a stirred solution of N-methyl-4- (trifluoromethoxy) benzenesulfonamide (100 mg,0.418 mmol) in tetrachloromethane (1.7 mL,18.1 mmol) in a sealed vial was added tert-butyl hypochlorite (0.057 mL,0.502 mmol) at 0deg.C under nitrogen. The reaction mixture was stirred in the dark at 0 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure at 2 ℃. The residue was dissolved in anhydrous THF (1.3076 mL), then benzyl 3-amino-3- (4-chlorophenyl) pyrrolidine-1-carboxylate (152 mg,0.460 mmol), DIPEA (219 μl,1.25 mmol) and N, N-dimethylpyridin-4-amine (99%, 5.2mg,0.0418 mmol) were added sequentially, and the reaction mixture was stirred at 40 ℃ for 18 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL) and EtOAc (20 mL) was added. The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. Using ladders MeOH (0.7 NNH) at a degree of 2% to 10% ₃ ) The crude product was purified by flash chromatography on silica gel with a gradient of 0% to 4% MeOH (0.7 NNH) ₃ ) Is purified once more in DCM to give the title compound as a pale yellow foam (112 mg, 96% purity, 45% yield, t) _r =1.05 min). LCMS (method E): m/z found 568.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.93–7.61(m，2H)，7.54–7.02(m，11H)，7.00–6.56(m，1H)，5.18–4.98(m，2H)，4.04(dd，J＝19.0，10.5Hz，1H)，3.79–3.49(m，2H)，3.49–3.37(m，1H)，2.65–2.53(m，1H)，2.32–1.85(m，4H)。

Step 3: synthesis of N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -N' -methyl-4- (trifluoromethoxy) benzenesulfonimide amide (68)

3- (4-chlorophenyl) -3- [ [ N-methyl-S- [4- (trifluoromethoxy) phenyl ] was sealed in a vial under nitrogen]Sulfonimido group]Amino group]A solution of pyrrolidine-1-carboxylic acid benzyl ester (96%, 112mg,0.189 mmol) in acetonitrile (1.8929 mL) was stirred at room temperature. Next, iodo (trimethyl) silane (0.081 mL, 0.618 mmol) was added and the mixture was stirred at room temperature for 1 hour. MeOH (0.092 ml,2.27 mmol) was added at 0 ℃, the mixture stirred at room temperature for 1 hour, concentrated in vacuo, and concentrated using a gradient of 0% to 8% MeOH (0.7N NH) ₃ ) Is purified by flash chromatography on silica gel. The desired fractions were pooled and treated with saturated Na ₂ CO ₃ The solution was washed, filtered through a phase separator and concentrated in vacuo. Et with addition of 2M HCl ₂ O solution (0.95 mL,1.89 mmol) and the mixture was stirred at room temperature overnight, filtered, and taken up in Et ₂ O-washing and drying overnight at 45℃under vacuum gave the bis (HCl) salt of the title compound as an off-white powder (23.3 mg, purity 98.86%, yield 26%, t _r =1.41 min). LCMS (method H): m/z [ M+H ]] ⁺ ；(DMSO-d ₆ ，500MHz)δ9.1-9.7(m，2H)，7.8-8.0(m，2H)，7.2-7.6(m，6H)，6.6-7.2(m，1H)，3.7-4.3(m，1H)，3.4-3.7(m，2H)，3.1-3.3(m，1H)，2.7-2.8(m，1H)，2.0-2.3(m，4H)。

Example 33: n- (3- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (69)

N- [3- (4-chlorophenyl) pyrrolidin-3-yl was placed in a sealed vial under nitrogen]A solution of 4- (trifluoromethoxy) benzenesulfonamide hydrochloride (60 mg,0.131 mmol) and formaldehyde (4.7 mg,0.157 mmol) in DCM (1.3 mL) and MeOH (0.6 mL) was stirred at room temperature for 10min. Next, et is added ₃ N (20. Mu.L, 0.144 mmol) and AcOH (19. Mu.L, 0.328 mmol) and the mixture was stirred at room temperature for 30min. Adding polymer-bound NaBH ₃ CN (131 mg,0.262 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was filtered, the residue was washed with dichloromethane and methanol, the filtrate was concentrated and purified by flash chromatography on silica gel using a gradient of 2% to 10% methanolic ammonia in dichloromethane. Et in 2M HCl ₂ O solution (656. Mu.L, 1.31 mmol) was triturated, filtered and taken up in Et ₂ O-washing and vacuum drying at 50℃for 18 hours gave the title compound as a white powder (47.4 mg, purity 99.86%, yield 77%, t) _r =1.36 min). LCMS (method H): m/z found 435.1[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)10.32-11.03(m，1H)，8.74-9.21(m，1H)，7.40(d，J＝8.8Hz，2H)，7.23(d，J＝8.3Hz，2H)，7.03(s，4H)，3.33-4.71(m，3H)，3.14-3.28(m，1H)，2.77-3.07(m，4H)，2.21-2.42(m，1H)。

Example 34: n- (3- (4-chlorophenyl) -1-methylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (70)

In a sealed vial, N- [3- (4-chlorophenyl) pyrrolidin-3-yl]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide hydrochloride (50 mg,0.109 mmol) and triethylamine (76. Mu.L, 0.547 mmol) in DCM (1 mL) was added di-tert-butyl dicarbonate (25 mg,0.115 mmol). The reaction mixture was stirred at room temperature for 18 hours. Water and dichloromethane were added. The aqueous layer was extracted with dichloromethane (2X 5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 3% methanol in dichloromethane. The residue was triturated in pentane, filtered, washed with pentane and dried in vacuo at 50 ℃ for 4 days to give the title compound as a colourless oil (45.3 mg, 98.4% purity, 78.3% yield, t _r =2.87 min). LCMS (method H): m/z found 519[ M-H ]] ^- ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ8.59(br s，1H)，7.42(d，2H，J＝8.6Hz)，7.24(br d，2H，J＝7.1Hz)，7.04(d，4H，J＝1.2Hz)，4.01(dd，1H，J＝7.8，11.0Hz)，3.3-3.5(m，2H)，3.2-3.3(m，1H)，2.6-2.8(m，1H)，2.0-2.3(m，1H)，1.40(d，9H，J＝5.1Hz)。

Example 35: n- (3- (4-chlorophenyl) -1- (oxetan-3-yl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (71)

To N- [3- (4-chlorophenyl) pyrrolidin-3-yl under nitrogen in a sealed vial]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (100 mg,0.238 mmol) in MeOH (2.3763 mL) was added oxetan-3-one (0.030 mL, 0.475mmol) and acetic acid (0.027 mL, 0.475mmol) and the mixture was stirred at room temperature for 30min. Adding polymer-bound NaBH ₃ CN (238 mg,0.475 mmol) and the mixture was stirred at room temperature overnight. The mixture was filtered, the residue was washed with MeOH and EtOAc, the filtrate was concentrated, and the crude product was purified by flash chromatography on silica gel using a gradient of 0% to 10% MeOH in DCM. The desired fractions were pooled and concentrated in vacuo. Et is used for the obtained solid ₂ O was triturated, filtered, and dried under vacuum at 45℃for 72 hours to give the title productThe product was a white powder (70.7 mg, purity 98.9%, yield 62%, t _r =1.49 min). LCMS (method H): m/z found 477[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ8.57–8.19(m，1H)，7.49–7.44(m，2H)，7.27(d，J＝8.1Hz，2H)，7.15–7.11(m，2H)，7.03(d，J＝8.6Hz，2H)，4.62–4.26(m，5H)，3.81–3.66(m，1H)，3.20–2.90(m，2H)，2.77–2.60(m，2H)，2.17–2.08(m，1H)。

Example 36: n- (3- (4-chlorophenyl) -1- (methylsulfonyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (72)

In a vial, N- [3- (4-chlorophenyl) pyrrolidin-3-yl at room temperature]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (98%, 70mg,0.163 mmol) in DCM (1.6466 mL) was added triethylamine (114. Mu.L, 0.815 mmol) and methanesulfonyl chloride (15. Mu.L, 0.196 mmol) in sequence. The reaction mixture was stirred at room temperature overnight. Additional N, N-dimethylpyridin-4-amine (99%, 4.0mg,0.0326 mmol) was added and the reaction mixture was stirred at room temperature for 4.5 hours. The reaction mixture was then heated at 40 ℃ overnight. The reaction mixture was diluted with DCM and saturated NaHCO was added ₃ An aqueous solution. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. The desired fractions were combined and concentrated to give the desired product as a colourless oil. Addition of Et ₂ O and filtering the precipitate formed and using Et ₂ And (3) washing. The precipitate was combined and dried in vacuo at 45 ℃ for 18 hours to give the desired compound as a white powder (41.8 mg, purity 97.77%, yield 50.25%, t) _r =2.37 min). LCMS (method H): m/z found 499.1[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ8.61(s，1H)，7.43–7.36(m，2H)，7.23(d，J＝8.1Hz，2H)，7.07–6.96(m，4H)，4.08(dd，J＝10.6，1.3Hz，1H)，3.52(d，J＝10.6Hz，1H)，3.46(td，J＝9.5，6.8Hz，1H)，3.39(td，J＝8.9，2.7Hz，1H)，2.97(s，3H)，2.77(dd，J＝12.9，6.2Hz，1H)，2.21(dt，J＝12.8，8.9Hz，1H)。

Example 37: n- (4- (5-Chlorothiazol-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (73)

Step 1: synthesis of tert-butyl 4-carbamoyl-4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

To a stirred solution of tert-butyl 4-amino-4-carbamoyl-piperidine-1-carboxylate (95%, 1.50g,5.86 mmol) in DCM (51 mL) was added triethylamine (3.3 mL,23.4 mmol), DMAP (99%, 145mg,1.17 mmol) and 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 1.2mL,7.03 mmol) in sequence at room temperature in a screw vial. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL), then water (20 mL) and DCM were added. The aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 1% to 5% ammonia MeOH in DCM to give the title compound as an off-white powder (2.46 g, 100% purity, 90% yield, t _r =0.83 min). LCMS (method E): m/z found 368.3[ M-C (=O) OtBu+H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.96(s，1H)，7.95–7.90(m，2H)，7.60–7.52(m，2H)，7.02(d，J＝38.9Hz，2H)，3.49–3.35(m，2H)，2.87(ddd，J＝13.4，9.2，3.8Hz，2H)，1.86–1.65(m，4H)，1.35(s，9H)。

Step 2: synthesis of tert-butyl 4-thiocarbamoyl-4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

The sealed vials were sequentially filled with 4-carbamoyl-4- [ [4- (trifluoromethoxy) phenyl ]]Sulfonylamino groups]A solution of tert-butyl piperidine-1-carboxylate (0.80 g,1.71 mmol) and Lawesson's reagent (97%, 356 mg,0.856 mmol) in dry THF (12 mL). The reaction mixture was stirred at 60 ℃ for 20 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (5 mL) and water (15 mL) and dichloromethane (15 mL) were added. The aqueous layer was extracted with dichloromethane (15 mL). The combined organic layers were washed with saturated aqueous sodium chloride, 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% to 5% methanol in dichloromethane to give the title compound as a white powder (548 mg, purity 100%, yield 66%, t _r =0.91 min). LCMS (method E): m/z found 384.3[ M-C (=O) OtBu+H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)9.72(s，1H)，8.60(s，1H)，8.06(s，1H)，7.96–7.89(m，2H)，7.58–7.51(m，2H)，3.57(d，J＝13.3Hz，2H)，2.71(t，J＝12.5Hz，2H)，2.00(d，J＝13.8Hz，2H)，1.93(d，J＝12.7Hz，3H)，1.35(s，9H)。

Step 3: synthesis of tert-butyl 4-thiazol-2-yl-4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

Filling a sealed vial with 4-thiocarbamoyl-4- [ [4- (trifluoromethoxy) phenyl ]]Sulfonylamino groups]A solution of tert-butyl piperidine-1-carboxylate (98%, 515mg,1.04 mmol) and chloroacetaldehyde (50% in water) (269. Mu.L, 2.09 mmol) in acetone (20 mL). The reaction mixture was stirred at 60 ℃ for 18 hours. The reaction mixture was cooled to room temperature, and water (10 mL) and EtOAc (10 mL) were added. The aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with saturated aqueous sodium chlorideThe solution was washed, 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 4% methanol in dichloromethane to give the title compound as a white powder (128 mg, 97% purity, 23% yield, t _r =0.98 min). LCMS (method E): m/z found 508.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.60(s，1H)，7.68–7.56(m，2H)，7.47(d，J＝3.2Hz，1H)，7.42–7.40(m，2H)，7.38(t，J＝1.1Hz，1H)，3.49(dt，J＝13.6，4.5Hz，2H)，3.17(t，J＝11.4Hz，2H)，2.28(d，J＝14.1Hz，2H)，2.05–1.95(m，2H)，1.38(s，9H)。

Step 4: synthesis of tert-butyl 4- (5-chlorothiazol-2-yl) -4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

Filling a sealed vial with 4-thiazol-2-yl-4- [ [4- (trifluoromethoxy) phenyl ]]Sulfonylamino groups]A solution of tert-butyl piperidine-1-carboxylate (97%, 275mg,0.526 mmol) and N-chlorosuccinimide (77 mg,0.578 mmol) in anhydrous DMF (13.75 mL). The reaction mixture was stirred at room temperature for 18 hours. Additional N-chlorosuccinimide (70 mg,0.526 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (5 mL) and water (10 mL) and ethyl acetate (10 mL) were added. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 10% to 40% ethyl acetate in cyclohexane to give the title compound as a white powder (93.1 mg, 97% purity, 32% yield, t _r =1.06 min). LCMS (method E): m/z found [ M-tBu+H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.69(s，1H)，7.74–7.66(m，2H)，7.48–7.43(m，2H)，7.41(s，1H)，3.50(dt，J＝13.8，4.6Hz，2H)，3.13(t，J＝11.7Hz，2H)，2.22(d，J＝13.7Hz，2H)，2.04–1.90(m，2H)，1.38(s，9H)。

Step 5: synthesis of N- (4- (5-chlorothiazol-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (73)

A solution of 4M hydrogen chloride in dioxane (803. Mu.L, 3.21 mmol) was added to 4- (5-chlorothiazol-2-yl) -4- [4- (trifluoromethoxy) phenyl ] in a sealed tube under nitrogen]Sulfonylamino groups]Tert-butyl piperidine-1-carboxylate (87 mg,0.161 mmol) was in a stirred solution of dried 1, 4-dioxane (870 μl). The solution was stirred at room temperature for 2 hours. MeOH was added to dissolve the resulting suspension, and the mixture was concentrated. The residue was sonicated in MeOH (3 mL) and the suspension was added drop wise to stirred Et ₂ O (30 mL). The suspension was stirred at room temperature for 30min and then filtered. The residue was taken up in Et ₂ O-washing and drying under reduced pressure at 45℃gave the hydrochloride of the title compound as a white powder (70 mg, purity 96.1%, yield 87%, t) _r =1.21 min). LCMS (method H): m/z found 442[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ8.92(s，3H)，7.6-7.8(m，2H)，7.4-7.5(m，3H)，3.14(br s，4H)，2.4-2.5(m，2H)，2.28(ddd，2H，J＝4.3，9.7，14.4Hz)。

Example 38: n- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (74)

Step 1: synthesis of 3- (4-fluorophenyl) -3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester

In a three-necked round bottom flask, magnesium was added to the flask at room temperature under nitrogen 106mg,4.36 mmol) and iodine (a crystal) in dry THF (3.41 mL) were added to a solution of a few drops of 1-bromo-4-fluorobenzene (95%, 576mg,3.13 mmol) in dry THF (1.47 mL). The reaction mixture was then heated at 60 ℃, followed by the addition of a few drops of the previous solution until discoloration (orange to colorless) of the reaction mixture was observed. Then, the remaining solution was added dropwise at 60 ℃ and the reaction was stirred at 60 ℃ for 1 hour. After this time, the reaction mixture was cooled to 0deg.C and a solution of benzyl 3-oxopyrrolidine-1-carboxylate (98%, 500mg,2.23 mmol) in anhydrous THF (1.47 mL) was added dropwise. Then, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ℃ and quenched dropwise (10 mL) with saturated aqueous ammonium chloride. EtOAc (5 mL) was added and the two layers were stirred at room temperature overnight. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography with solid precipitate using a gradient of 20% to 100% EtOAc in heptane. The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as an off-white solid (381.5 mg, 91% purity, 49% yield, t) _r =0.86 min). LCMS (method E): m/z found 316.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.60–7.50(m，2H)，7.44–7.27(m，5H)，7.17(ddd，J＝12.7，7.5，3.8Hz，2H)，5.52(d，J＝1.9Hz，1H)，5.10(d，J＝9.5Hz，2H)，3.64–3.45(m，4H)，2.25(dq，J＝12.0，9.1Hz，1H)，2.05(dtd，J＝12.7，6.2，3.1Hz，1H)。

Step 2: synthesis of benzyl 3- [ (2-chloroacetyl) amino ] -3- (4-fluorophenyl) pyrrolidine-1-carboxylate

Into a sealed vial was charged successively 3- (4-fluorophenyl) -3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (91%, 380mg,1.10 mmol), chloroacetonitrile (7.0 mL,0.111 mol) and trifluoroacetic acid (2.1 mL,27.4 mmol). The reaction mixture was stirred at room temperatureMix for 1 hour. The reaction mixture was poured into water at 0 ℃ and quenched with saturated aqueous sodium bicarbonate until pH 9. The aqueous layer was extracted with dichloromethane. The combined organic layers were 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% to 5% methanol in dichloromethane to give the title compound as a pale yellow solid (205.7 mg, 96% purity, 46% yield, t _r =0.87 min). LCMS (method E): m/z found 391.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.80(d，J＝3.6Hz，1H)，7.44–7.29(m，7H)，7.15(dtt，J＝8.9，6.3，3.0Hz，2H)，5.15–5.04(m，2H)，4.13–3.91(m，3H)，3.67(dd，J＝27.7，11.3Hz，1H)，3.46(ddd，J＝19.3，8.7，5.2Hz，2H)，2.67–2.53(m，1H)，2.34–2.17(m，1H)。

Step 3: synthesis of benzyl 3-amino-3- (4-fluorophenyl) pyrrolidine-1-carboxylate

Filling a sealed vial with 3- [ (2-chloroacetyl) amino]A solution of benzyl 3- (4-fluorophenyl) pyrrolidine-1-carboxylate (96%, 205mg,0.504 mmol) and thiourea (50 mg, 0.015 mmol) in a mixture of EtOH (4.19 mL) and acetic acid (0.84 mL). The reaction mixture was stirred at 80 ℃ overnight. The reaction mixture was diluted in DCM and saturated NaHCO was added ₃ Aqueous solution (up to pH 9 aqueous phase). The aqueous layer was extracted twice with DCM and the combined organic layers were washed with brine, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 8% MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as a yellow oil (151.9 mg, purity 90%, yield 86%, t) _r =0.60 min). LCMS (method E): m/z found 315.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.56–7.48(m，2H)，7.41–7.27(m，5H)，7.13(ddd，J＝9.0，7.9，4.9Hz，2H)，5.09(d，J＝5.5Hz，2H)，3.67–3.40(m，4H)，2.22–1.93(m，4H)。

Step 4: synthesis of benzyl 3- (4-fluorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] pyrrolidine-1-carboxylate

A sealed vial was charged with benzyl 3-amino-3- (4-fluorophenyl) pyrrolidine-1-carboxylate (75 mg,0.239 mmol), 4-dimethylaminopyridine (5.8 mg,0.0477 mmol) and triethylamine (0.17 mL,1.19 mmol) in DCM (2.2067 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (49. Mu.L, 0.286 mmol) was added and the reaction mixture was stirred at 40℃for 20 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and dichloromethane was added. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride, dried using a phase separator, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as a yellow solid (113.9 mg, 97% purity, 86% yield, t) _r =1.00 min). LCMS (method D): m/z found 561.3[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.60(s，1H)，7.46–7.30(m，7H)，7.28–7.21(m，2H)，7.08(ddd，J＝8.8，5.3，1.1Hz，2H)，6.79(td，J＝8.8，5.0Hz，2H)，5.14–5.02(m，2H)，4.16(dd，J＝17.3，11.3Hz，1H)，3.63–3.32(m，3H)，2.81–2.65(m，1H)，2.28–2.11(m，1H)。

Step 5: synthesis of N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (74)

To 3- (4-fluorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] at room temperature in a round bottom flask]Sulfonylamino groups]A stirred suspension of pyrrolidine-1-carboxylic acid benzyl ester (97%, 114mg,0.205 mmol) in dry CAN (5.2877 mL) was added iodo (trimethyl) Silane (88. Mu.L, 0.615 mmol). The reaction mixture was stirred at room temperature for 30min. Next, the reaction mixture was concentrated under reduced pressure. Et in 2M HCl ₂ O solution (2.5 mL,5.00 mmol) and Et ₂ O (5 mL) was stirred for 30min, then MeOH (0.2 mL) was added. The mixture was stirred at room temperature for 2 hours, filtered, and treated with Et ₂ O was washed and pentane and dried in vacuo at 45℃for 2 hours. The residue was suspended in MeOH (5 mL) and 7M ammonia MeOH (0.20 mL,1.40 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was triturated in a mixture of water (8 mL), DCM (8 mL) and MeOH (0.8 mL) and stirred at room temperature for 30min. Saturated aqueous sodium carbonate solution was added to reach pH 9. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried using a phase separator and concentrated under reduced pressure. Et in 2M HCl ₂ O solution (2.1 mL,4.10 mmol) and Et ₂ O (2 mL) was again milled for 2 hours and concentrated under reduced pressure. The beige solid was dissolved in a small amount of MeOH and poured into Et ₂ O. The precipitated product was filtered off with Et ₂ O-rinse and vacuum drying at 45℃for 24 hours afforded the hydrochloride salt as an off-white solid (49.3 mg, purity 99.62%, yield 54%, t) _r =1.22 min). LCMS (method H): m/z found 405.2[ M+H ]] ⁺ ； ¹ H-NMR(600MHz，DMSO-d ₆ )δppm 9.80(m，2H)，9.00(m，1H)，7.42(m，2H)，7.21(d，J＝8.1Hz，2H)，7.11(m，2H)，6.75(t，J＝8.8Hz，2H)，4.13(dd，J＝12.0，1.2Hz，1H)，3.39(m，3H)，2.94(m，1H)，2.11(dt，J＝13.1，9.7Hz，1H)。

Example 39: n- (4- (4-fluorophenyl) piperidin-4-yl) -4-isopropoxy benzenesulfonamide (75)

Step 1: synthesis of tert-butyl 4-amino-4- (4-fluorophenyl) piperidine-1-carboxylate

To a stirred solution of 4- (4-fluorophenyl) piperidin-4-amine dihydrochloride (150 mg,0.561 mmol) and triethylamine (313 μl,2.25 mmol) in DCM (2.7 mL) was added tert-butoxycarbonyl tert-butyl carbonate (110 mg,0.505 mmol) in a sealed vial. The reaction mixture was stirred at room temperature overnight. Water and DCM were added and the aqueous layer was extracted twice with DCM. The organic layer was saturated with NH ₄ Cl solution was washed, then with saturated NaHCO ₃ The solution was washed, filtered through a phase separator, and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 5% to 15% methanolic ammonia in DCM. The desired fractions were combined and concentrated to give the title compound as a colorless oil (112 mg, purity 82%, yield 55.6%, t) _r =0.60 min). LCMS (method E): m/z found 295.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.61–7.49(m，2H)，7.17–7.06(m，2H)，3.71(d，J＝12.5Hz，2H)，3.27(s，2H)，1.86(s，2H)，1.77(td，J＝12.9，4.6Hz，2H)，1.53(d，J＝11.8Hz，2H)，1.41(s，9H)。

Step 2: synthesis of tert-butyl 4- (4-fluorophenyl) -4- [ (4-isopropoxyphenyl) sulfonylamino ] piperidine-1-carboxylate

To a stirred solution of tert-butyl 4-amino-4- (4-fluorophenyl) piperidine-1-carboxylate (82%, 112mg,0.312 mmol) in DCM (2.7 mL) was added triethylamine (130. Mu.L, 0.936 mmol), 4- (propan-2-yloxy) benzenesulfonyl chloride (98%, 54. Mu.L, 0.343 mmol) and N, N-dimethylpyridine-4-amine (7.6 mg,0.0624 mmol) in sequence at room temperature in a sealed vial. The reaction mixture was stirred at 40 ℃ overnight. The reaction mixture was taken up with DCM and saturated NaHCO ₃ Diluting the aqueous solution. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. Will be of the required levelFractions were combined and concentrated. The resulting white residue was again purified by reverse phase preparative chromatography using a gradient of 0% to 100% acetonitrile in water (0.1% tfa in water and acetonitrile). The desired fractions were combined and concentrated to give the title compound as a white solid (97.8 mg, purity 100%, yield 63.6%, t) _r =1.02 min). LCMS (method E): m/z found 515.4[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.85(s，1H)，7.23–7.07(m，4H)，6.83–6.65(m，4H)，4.66–4.56(m，1H)，3.68(d，J＝13.0Hz，2H)，3.20(s，2H)，2.32(d，J＝13.0Hz，2H)，1.68(t，J＝10.6Hz，2H)，1.39(s，9H)，1.27(d，J＝6.0Hz，6H)。

Step 3: synthesis of N- (4- (4-fluorophenyl) piperidin-4-yl) -4-isopropoxy benzenesulfonamide (75)

In a round bottom flask at room temperature to 4- (4-fluorophenyl) -4- [ (4-isopropoxyphenyl) sulfonylamino]Piperidine-1-carboxylic acid tert-butyl ester (98 mg, 0.199mmol) in Et ₂ Stirred suspension in O (1.88 mL) was added Et with 2M HCl ₂ O solution (1.0 mL,2.07 mmol). The reaction mixture was stirred at room temperature overnight. Additional 4M HCl in 1, 4-dioxane (0.50 mL,1.99 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. Additional 4M HCl in 1, 4-dioxane (0.99 ml,3.97 mmol) was added and the reaction mixture was stirred at room temperature overnight. The suspension was filtered, using Et ₂ O-washing and vacuum drying at 45℃gave the title compound as a white solid (75.6 mg, purity 100%, yield 88.8%, t) _r =1.19 min). LCMS (method H): m/z found 393.2[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δppm 1.27(d，J＝6.11Hz，6H)1.95-2.04(m，2H)2.51-2.56(m，2H)3.17-3.24(m，4H)4.60(spt，J＝6.03Hz，1H)6.70(d，J＝7.93Hz，2H)6.80(t，J＝8.33Hz，2H)7.09-7.14(m，1H)7.14-7.18(m，1H)8.09(s，1H)8.80(br s，2H)。

Example 40: n- (3- (4-chlorophenyl) -1-isopentylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (76)

Step 1: synthesis of N- [3- (4-chlorophenyl) -1- (3-methylbutanoyl) pyrrolidin-3-yl ] -4- (trifluoromethoxy) benzenesulfonamide

To N- [3- (4-chlorophenyl) pyrrolidin-3-yl at 0deg.C ]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (150 mg,0.356 mmol) and DIPEA (249. Mu.L, 1.43 mmol) in DCM (3.2 mL) was added dropwise 3-methylbutyryl chloride (48. Mu.L, 0.392 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL). Water (5 mL) and methylene chloride (10 mL) were then added. The layers were separated. The aqueous layer was extracted twice with dichloromethane (2X 10 mL). The combined organic layers were washed once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 10% methanol in dichloromethane. The residue was dissolved in 2mL of dichloromethane, then in diethyl ether (4 mL) and pentane (4 mL). The resulting suspension was filtered, washed with pentane and dried in vacuo at 45 ℃ for 18 hours to give the title compound as a white powder (147.9 mg, purity 98.77%, yield 82%, t) _r =2.62 min). LCMS (method H): m/z found 505[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δppm 0.87-0.93(m，6H)1.95-2.04(m，1H)2.04-2.28(m，3H)2.61-2.81(m，1H)3.48(s，3H)4.13-4.23(m，1H)7.04-7.11(m，4H)7.25(ddd，J＝8.86，4.10，0.73Hz，2H)7.40-7.45(m，2H)8.59(s，1H)。

Step 2: synthesis of N- (3- (4-chlorophenyl) -1-isopentylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (76)

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N- [3- (4-chlorophenyl) -1- (3-methylbutanoyl) pyrrolidin-3-yl was placed in a sealed tube under nitrogen]A solution of 4- (trifluoromethoxy) benzenesulfonamide (97 mg,0.193 mmol) in dry THF (1.8 mL) was stirred at 0deg.C. Dropwise adding 2M BH ₃ ·SMe ₂ (289. Mu.L, 0.578 mmol) and the mixture was stirred at room temperature for 1 hour and at 60℃for 4 hours. The mixture was stirred at 0deg.C and MeOH (1.5 mL) was added dropwise. The mixture was stirred at 0deg.C for 15min, then 4N aqueous HCl (1.5 mL) was added. The mixture was stirred at 60 ℃ for 1 hour and then cooled to 0 ℃. The mixture was basified with 4N aqueous NaOH (2 ml, ph 12.5) and extracted three times with DCM. The combined organic layers were washed once with saturated aqueous sodium chloride, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 1% to 10% methanol in dichloromethane. The desired fractions were combined and concentrated under reduced pressure. The resulting white solid was diluted in Et ₂ O and Et with 2M HCl ₂ O solution (0.96 mL,1.93 mmol). The mixture was stirred at room temperature for 3 hours, and the resulting suspension was filtered, washed twice with diethyl ether and dried under vacuum at 45 ℃ for 18 hours to give the hydrochloride salt of the title compound as a white powder (68.9 mg, purity 100%, yield 68%, t) _r =1.69 min). LCMS (method H): m/z found 491.2[ M+H ]] ⁺ ； ¹ H-NMR(600MHz，DMSO-d ₆ )δppm 0.87-0.95(m，6H)1.53-1.69(m，3H)2.16-2.37(m，1H)2.78-3.03(m，1H)3.20-3.28(m，2H)3.33-3.39(m，1H)3.41-3.83(m，2H)4.00-4.52(m，1H)7.01-7.10(m，4H)7.19-7.26(m，2H)7.40(d，J＝8.66Hz，2H)8.82-9.08(m，1H)10.31-11.05(m，1H)。

Example 41: n- (4- (4-fluorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide (77)

To a stirred solution of 4- (4-fluorophenyl) piperidin-4-amine dihydrochloride (150 mg,0.561 mmol) and triethylamine (313 μl,2.25 mmol) in DCM (2 mL) was added tert-butoxycarbonyl tert-butyl carbonate (123 mg,0.561 mmol) in a sealed vial. The reaction mixture was stirred at room temperature overnight. Water (5 mL) and DCM (5 mL) were added and the layers were separated. The aqueous layer was extracted twice with DCM (2X 10 mL). The combined organic layers were treated with saturated NH ₄ Cl solution (10 mL) followed by saturated NaHCO ₃ The solution (10 mL) was washed and finally washed with saturated aqueous sodium chloride. The organic layer was filtered using a phase separator and then concentrated under reduced pressure to give the title compound as a colorless oil (163 mg, purity 82%, yield 81%, t) _r =0.60 min). LCMS (method E): m/z found 295.3[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO)δ7.59–7.51(m，2H)，7.16–7.07(m，2H)，3.70(d，J＝13.0Hz，2H)，3.30–3.09(m，2H)，2.09–2.04(m，2H)，1.78(ddd，J＝13.3，11.8，4.6Hz，2H)，1.58–1.50(m，2H)，1.41(s，9H)。

Step 2: synthesis of tert-butyl 4- (4-fluorophenyl) -4- [ (6-isopropoxy-3-pyridyl) sulfonylamino ] piperidine-1-carboxylate

To a stirred solution of tert-butyl 4-amino-4- (4-fluorophenyl) piperidine-1-carboxylate (82%, 80mg,0.223 mmol), triethylamine (93 μl,0.669 mmol) and N, N-dimethylpyridine-4-amine (5.4 mg,0.0446 mmol) in DCM (1.5 mL) was added 6- (prop-2-yloxy) pyridine-3-sulfonyl chloride (95%, 61mg,0.245 mmol). The reaction mixture was stirred at 40 ℃ overnight. Additional 6- (propan-2-yloxy) pyridine-3-sulfonyl chloride (95%, 28mg,0.112 mmol), triethylamine (47. Mu.L, 0.334 mmol) and N, N were added at room temperature Lutidine-4-amine (2.7 mg,0.0223 mmol) and the reaction mixture was stirred at 40 ℃ for another 6 hours. The reaction mixture was cooled to room temperature, diluted with DCM (10 mL) and saturated aqueous ammonium chloride solution (10 mL) was added. The layers were separated. The organic layer was washed once with saturated aqueous sodium bicarbonate (10 mL) and once with saturated aqueous sodium chloride (10 mL), dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0.5% to 10% methanol in dichloromethane. The desired fractions were combined and concentrated under reduced pressure to give the title compound as a colorless oil (112.4 mg, purity 96%, yield 98%, t) _r =1.04 min). LCMS (method E): m/z found 516.3[ M+Na ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.05(s，1H)，7.82(d，J＝2.5Hz，1H)，7.51(dd，J＝8.7，2.7Hz，1H)，7.17–7.09(m，2H)，6.85–6.74(m，2H)，6.56(d，J＝9.0Hz，1H)，5.20(hept，J＝6.1Hz，1H)，3.71(d，J＝13.3Hz，2H)，3.27(m，2H)，2.38(d，J＝13.5Hz，2H)，1.71(s，2H)，1.40(s，9H)，1.29(d，J＝6.1Hz，6H)。

Step 3: synthesis of N- (4- (4-fluorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide (77)

In a round bottom flask, 4- (4-fluorophenyl) -4- [ (6-isopropoxy-3-pyridinyl) sulfonylamino]Piperidine-1-carboxylic acid tert-butyl ester (112 mg,0.226 mmol) in Et ₂ A stirred solution in O (0.55 mL) was added to Et of 4M HCl ₂ O solution (0.65 mL,2.60 mmol). The mixture was stirred at room temperature overnight, then filtered and taken up in Et ₂ O (2X 2 mL) was washed twice. The resulting white powder was dissolved in a small amount of MeOH and slowly poured into Et ₂ O (20 mL). The suspension was stirred at room temperature for 2 hours, then filtered, and taken up in Et ₂ O (2X 2 mL) was washed twice and dried in vacuo at 45℃for 18 hours to give the hydrochloride salt of the title compound as a white powder (78.1 mg, purity 97.7%, yield 79%, t) _r =1.15 min). LCMS (method H): m/z found 394[M+H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ8.75(br s，2H)，8.33(br s，1H)，7.82(d，1H，J＝2.4Hz)，7.51(dd，1H，J＝2.4，8.8Hz)，7.14(dd，2H，J＝5.4，8.8Hz)，6.83(t，2H，J＝8.8Hz)，6.56(d，1H，J＝8.8Hz)，5.19(spt，1H，J＝6.2Hz)，3.1-3.3(m，4H)，2.58(br d，2H，J＝13.7Hz)，1.8-2.2(m，2H)，1.28(d，6H，J＝6.4Hz)。

Example 42: n- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide (78)

Step 1: synthesis of benzyl 3- (4-fluorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] pyrrolidine-1-carboxylate

A sealed vial was charged with benzyl 3-amino-3- (4-fluorophenyl) pyrrolidine-1-carboxylate (75 mg,0.239 mmol), 4-dimethylaminopyridine (5.8 mg,0.0477 mmol) and triethylamine (0.17 mL,1.19 mmol) in DCM (2.2067 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (49. Mu.L, 0.286 mmol) was added and the reaction mixture was stirred at 40℃for 20 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and dichloromethane was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as a yellow solid (113.9 mg, 97% purity, 86% yield, t) _r =1.00 min). LCMS (method D): m/z found 561.3[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.60(s，1H)，7.46–7.30(m，7H)，7.28–7.21(m，2H)，7.08(ddd，J＝8.8，5.3，1.1Hz，2H)，6.79(td，J＝8.8，5.0Hz，2H)，5.14–5.02(m，2H)，4.16(dd，J＝17.3，11.3Hz，1H)，3.63–3.32(m，3H)，2.81–2.65(m，1H)，2.28–2.11(m，1H)。

Step 2: synthesis of N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy-benzenesulfonamide (78)

In a round bottom flask at room temperature to 3- (4-fluorophenyl) -3- [ (4-isopropoxyphenyl) sulfonylamino]A stirred suspension of pyrrolidine-1-carboxylic acid benzyl ester (97%, 85mg,0.162 mmol) in anhydrous ACN (4.1651 mL) was added iodo (trimethyl) silane (69 μl,0.485 mmol). The reaction mixture was stirred at room temperature for 30min. The reaction mixture was concentrated under reduced pressure. Et in 2M HCl ₂ O solution (2.5 mL,5.00 mmol) and Et ₂ O (5 mL) was triturated for 30min, then MeOH (0.2 mL) was added and the mixture stirred at room temperature for 2 h, filtered, and taken up in Et ₂ O and pentane were washed and dried in vacuo at 45℃for 2 hours. The residue was suspended in MeOH (5 mL) and 7M ammonia in MeOH (0.20 mL,1.40 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was triturated between water (8 mL), DCM (8 mL) and MeOH (0.8 mL) and stirred at room temperature for 30min. Saturated aqueous sodium carbonate solution was added to reach pH 9. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The residue was taken up in 2M hydrogen chloride in diethyl ether (2.0 mL,4.00 mmol) and Et ₂ O (2 mL) was again milled for 2 hours and concentrated under reduced pressure. The pink gum was dissolved in a small amount of MeOH and poured into Et ₂ O. The precipitated product was filtered, rinsed with a small amount of diethyl ether, and dried in vacuo at 45 ℃ for 24 hours to give the hydrochloride salt of the title compound as a pale pink solid (16.8 mg, 94.49% purity, 24% yield, t _r =1.14 min). LCMS (method H): m/z found 379.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，600MHz)：δ(ppm)8.65-9.69(m，2H)，8.19-8.49(m，1H)，7.14-7.22(m，2H)，7.09(dd，J＝8.8，5.4Hz，2H)，6.81(t，J＝8.8Hz，2H)，6.70(d，J＝8.9Hz，2H)，4.61(dt，J＝12.0，6.0Hz，1H)，4.05(br d，J＝11.4Hz，1H)，3.35-3.42(m，2H)，3.28-3.31(m，1H)，2.78-2.86(m，1H)，2.04-2.15(m，1H)，1.26(dd，J＝6.0，0.7Hz，6H)。

Example 43: n- ((3S, 4S) -3- (4-chlorophenyl) -4-fluoropyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (79)

Step 1: synthesis of 3- (4-chlorophenyl) -2, 5-dihydropyrrole-1-carboxylic acid benzyl ester

To a solution of benzyl 3- (4-chlorophenyl) -3-hydroxy-pyrrolidine-1-carboxylate (9.64 g,29.1 mmol) in anhydrous DCM (150 mL) in a round bottom flask at 0deg.C under nitrogen was added azido (trimethyl) silane (4.6 mL,34.9 mmol) and BF ₃ ·Et ₂ O (22 mL,0.174 mol). The reaction mixture was allowed to warm to room temperature and stirred at that temperature for 20 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) at 0 ℃ then water (30 mL) and DCM (20 mL) were added. The aqueous layer was extracted once with DCM (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of benzyl 3-azido-3- (4-chlorophenyl) pyrrolidine-1-carboxylate and benzyl 3- (4-chlorophenyl) -2, 5-dihydropyrrole-1-carboxylate, which was used in the next step without further purification (9.99 g, purity 62%, t _r =1.03 min). LCMS (method E): m/z found 314.2[ M+H ]] ⁺ 。

Triphenylphosphine (4.55 g,17.4 mmol) and then p-toluenesulfonic acid hydrate (9.91 g,52.1 mmol) were added to a stirred solution of a mixture of benzyl 3-azido-3- (4-chlorophenyl) pyrrolidine-1-carboxylate and benzyl 3- (4-chlorophenyl) -2, 5-dihydropyrrole-1-carboxylate (62%, 9.99g,17.4 mmol) in THF (75 mL) under nitrogen in a round bottom flask at room temperature. The mixture was stirred at room temperature for 16 hours. The suspension was filtered, using TWashing with HF (25 mL) and drying in vacuo at 40℃for 3 days afforded the pTsOH salt of benzyl 3-amino-3- (4-chlorophenyl) pyrrolidine-1-carboxylate as a white powder (7.09 g, 80% yield). The filtrate was then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 100% dichloromethane in isocratic mode to give the title compound as a white powder (1.1 g, 99% purity, 20% yield, t _r =1.03 min). LCMS (method E): m/z found 314.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.57–7.48(m，2H)，7.47–7.28(m，7H)，6.46(d，J＝12.3Hz，1H)，5.15(d，J＝3.6Hz，2H)，4.41(dd，J＝77.5，22.6Hz，4H)。

Step 3: synthesis of rac- (3R, 4R) -3-amino-3- (4-chlorophenyl) -4-fluoro-pyrrolidine-1-carboxylic acid benzyl ester

To a stirred solution of 3- (4-chlorophenyl) -2, 5-dihydropyrrole-1-carboxylic acid benzyl ester (1.0 g,3.19 mmol) in anhydrous ACN (40 mL) at 0deg.C was added 1- (chloromethyl) -4-fluoro-1, 4-diazabicyclo [2.2.2 ]Octane ditetrafluoroborate (98%, 3.0g,8.30 mmol). The reaction mixture was stirred at 0 ℃ for 15 minutes and warmed at 25 ℃ for 16 hours. With saturated NaHCO ₃ The solution and DCM absorbed the residue. The phases were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed once with water, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography (C18 aq 50 g) using an aqueous solution of acetonitrile with a gradient of 0% to 100% (both solvents containing 0.1% acoh). Remove solvent and use saturated NaHCO ₃ The solution and DCM absorbed the residue. The phases were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were taken up over Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure gave the title compound (220 mg, purity 62%, yield 12%, t) _r =0.65 min). LCMS (method D): m/z found 349.3[ M+H ]] ⁺ 。

Step 4: synthesis of racemic (3R, 4R) -3- (4-chlorophenyl) -4-fluoro-3- ((4- (trifluoromethoxy) phenyl) sulfamido) pyrrolidine-1-carboxylic acid benzyl ester

To a stirred suspension of rac- (3 r,4 r) -3-amino-3- (4-chlorophenyl) -4-fluoro-pyrrolidine-1-carboxylic acid benzyl ester (136 mg, 0.399mmol) in anhydrous DCM (4.0 mL) was added N, N-diethylamine (0.11 mL,0.782 mmol) and N, N-dimethylpyridin-4-amine (24 mg,0.196 mmol) in sequence followed by 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 0.10mL,0.587 mmol) in a round bottom flask equipped with a condenser. The reaction mixture was stirred at reflux for 5 hours. The reaction was cooled to 25℃and the mixture was saturated with NH ₄ The Cl solution was quenched. The phases were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed once with water, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 1% to 10% MeOH in DCM to give the title compound as a mixture of enantiomers (120 mg, purity 90%, yield 48%, t _r =1.05 min). LCMS (method D): m/z found 573.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.85(d，J＝5.6Hz，1H)，7.23-7.43(m，9H)，7.02-7.12(m，4H)，5.62-5.81(m，1H)，5.04-5.16(m，2H)，4.44-4.55(m，1H)，3.86-4.06(m，1H)，3.50-3.81(m，2H)。

Step 5: synthesis of rac-N- ((3S, 4S) -3- (4-chlorophenyl) -4-fluoropyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (79)

In a round bottom flask at room temperature to rac- (3R, 4R) -3- (4-chlorophenyl) -4-fluoro-3- [ [4- (trifluoromethoxy) phenyl ]]Sulfonylamino groups]A stirred solution of pyrrolidine-1-carboxylic acid benzyl ester (130 mg,0.227 mmol) in CAN (3.036 mL) was added iodo (trimethyl) silane (97 μl,0.681 mmol). The reaction mixture was allowed to stand at room temperatureStirred for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. Using a gradient of 0% to 7% MeOH and 2% NH ₄ The crude product was purified by flash chromatography on silica gel in DCM. The desired fractions were combined and then water, triethylamine (158 μl,1.13 mmol) and Na were added ₂ CO ₃ Solution (2N, pH 10-12). The phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The resulting off-white solid was resuspended in Et ₂ O and adding Et of 1MHCl ₂ O solution (2.3 mL,2.27 mmol). The suspension was stirred at room temperature overnight, filtered, and taken up in Et ₂ O-washing and drying at 45℃for 24 hours gave the hydrochloride of the title compound as a white powder (49 mg, purity 97.4%, yield 45%, t) _r =1.41 min). LCMS (method H): m/z 439[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，600MHz)：δ(ppm)9.51-10.55(m，2H)，9.20(br s，1H)，7.39-7.45(m，2H)，7.23(d，J＝8.2Hz，2H)，7.07-7.10(m，2H)，6.99-7.07(m，2H)，5.78-5.92(m，1H)，4.49(d，J＝12.3Hz，1H)，3.79-3.91(m，1H)，3.65-3.75(m，1H)，3.55(dd，J＝12.3，2.3Hz，1H)。

Example 44: n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6-isopropoxypyridine-3-sulfonamide (80)

Step 1: synthesis of benzyl 3- (4-chlorophenyl) -3- [ (6-isopropoxy-3-pyridyl) sulfonylamino ] pyrrolidine-1-carboxylate

To a stirred solution of benzyl 3-amino-3- (4-chlorophenyl) pyrrolidine-1-carboxylate (100 mg,0.303 mmol) in DCM (2.0 mL) was added 6- (propan-2-yloxy) pyridine-3-sulfonyl chloride (95%, 90mg, 0.264 mmol) and N, N-dimethylpyridin-4-amine (7.4 mg,0.0607 mmol) and triethylamine (92.14)7mg,0.9106 mmol). The reaction mixture was stirred at 40 ℃ overnight. The reaction mixture was cooled to room temperature, diluted with DCM (13 mL) and saturated aqueous ammonium chloride (13 mL) was added. The layers were separated. The organic layer was washed once with saturated aqueous sodium bicarbonate (13 mL) and once with saturated aqueous sodium chloride (13 mL), taken up in Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 1.5% methanol in dichloromethane. The desired fractions were combined and concentrated under reduced pressure to give the title compound as a white powder (139 mg, purity 98%, yield 85%, t) _r =1.03 min). LCMS (method D): m/z found 530.04[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.49(s，1H)，7.90(t，J＝2.9Hz，1H)，7.56(ddd，J＝8.8，2.7，1.3Hz，1H)，7.44–7.29(m，5H)，7.10(d，J＝4.2Hz，4H)，6.59(dd，J＝8.8，2.3Hz，1H)，5.29–5.17(m，1H)，5.14–5.01(m，2H)，4.20–4.08(m，1H)，3.63–3.33(m，3H)，2.74–2.69(m，1H)，2.24–2.11(m，1H)，1.30(d，J＝6.2Hz，6H)。

Step 2: synthesis of N- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6-isopropoxypyridine-3-sulfonamide (80)

In a round-bottomed flask, 3- (4-chlorophenyl) -3- [ (6-isopropoxy-3-pyridinyl) sulfonylamino was placed under nitrogen at room temperature]A stirred solution of pyrrolidine-1-carboxylic acid benzyl ester (131 mg,0.247 mmol) in dry CAN (4.9 mL) was added iodo (trimethyl) silane (106 μl,0.741 mmol). The reaction mixture was stirred at this temperature for 1.5 hours and concentrated under reduced pressure. The residue was dissolved in a small amount of ACN and poured into Et ₂ O. The resulting suspension was stirred for 1 hour, filtered, and taken up in Et ₂ O was washed and dried at 45℃for 1 hour. The residue was then stirred in a mixture of dichloromethane (10 mL) and half-saturated aqueous sodium carbonate (10 mL). The homogeneous mixture was stirred for 1 hour and then partitioned. The aqueous layer was extracted twice with dichloromethane (10 mL). Will be combined The organic layer of (2) was washed once with a saturated aqueous sodium hydrogencarbonate solution and once with a saturated aqueous sodium chloride solution, dried using a phase separator, and concentrated under reduced pressure. The residue was suspended in Et ₂ O (3 mL) and then Et with 2M HCl ₂ O solution (1.3 mL,2.60 mmol). The suspension was stirred for 3 hours, filtered and dried at 45 ℃ for 18 hours to give the hydrochloride salt of the title compound as an off-white powder (68.4 mg, purity 94.63%, yield 61%, t) _r =5.24 min). LCMS (method F): m/z found 396[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δppm 1.30(t，J＝6.24Hz，6H)2.13(dt，J＝13.20，9.78Hz，1H)2.88(dt，J＝13.45，3.79Hz，1H)3.32-3.44(m，3H)4.12(br dd，J＝11.98，6.11Hz，1H)5.23(spt，J＝6.19Hz，1H)6.56(d，J＝8.31Hz，1H)7.06-7.12(m，4H)7.56(dd，J＝8.80，2.45Hz，1H)7.86(d，J＝2.20Hz，1H)8.70(s，1H)9.44-9.65(m，2H)。

Example 45: n- (3- (4-chlorophenyl) -1- (3-methylbutanoyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (81)

To N- [3- (4-chlorophenyl) pyrrolidin-3-yl at 0deg.C]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (150 mg,0.356 mmol) and DIPEA (249. Mu.L, 1.43 mmol) in DCM (3.2 mL) was added dropwise 3-methylbutyryl chloride (48. Mu.L, 0.392 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and then water (5 mL) and dichloromethane (10 mL) were added. The layers were separated and the aqueous layer was extracted with DCM (2X 10 mL). The combined organic layers were washed once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 10% methanol in dichloromethane. The residue was dissolved in 2mL of dichloromethane, then in diethyl ether (4 mL) and pentane (4 mL). The resulting suspension was filtered, washed with pentane and dried in vacuo at 45℃for 18 hours, The title compound was obtained as a white powder (147.9 mg, purity 98.77%, yield 82%, t) _r =2.62 min). LCMS (method H): m/z found 505[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δppm 0.87-0.93(m，6H)1.95-2.04(m，1H)2.04-2.28(m，3H)2.61-2.81(m，1H)3.48(s，3H)4.13-4.23(m，1H)7.04-7.11(m，4H)7.25(ddd，J＝8.86，4.10，0.73Hz，2H)7.40-7.45(m，2H)8.59(s，1H)。

Example 46: n- (4- (3, 4-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (82)

Step 1: synthesis of 1-tert-butoxycarbonyl-4- (3, 4-difluorophenyl) piperidine-4-carboxylic acid

To a stirred suspension of tert-butyl 4-cyano-4- (3, 4-difluorophenyl) piperidine-1-carboxylate (95%, 200mg,0.589 mmol) in ethanol (4.3 mL) was added NaOH (1.2 mL,11.8 mmol) at room temperature in a sealed tube. The reaction mixture was stirred at 80 ℃ overnight. The mixture was poured into an ice water solution and acidified with a saturated aqueous potassium hydrogen sulfate solution to achieve ph=3. The precipitate formed was filtered, washed with water and dried under reduced pressure at 50℃for 4 hours to give the title compound as a brown solid (191.6 mg, 94% purity, 90% yield, t) _r =0.92 min). LCMS (method E): m/z found 242.3[ M+H-Boc] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)12.89(s，1H)，7.54–7.35(m，2H)，7.30–7.17(m，1H)，3.77(dt，J＝4.0，13.9Hz，2H)，2.98(s，2H)，2.40–2.25(m，2H)，1.72(ddd，J＝4.2，11.0，13.4Hz，2H)，1.39(s，9H)。

Step 2: synthesis of tert-butyl 4- [ [ 1-tert-butoxycarbonyl-4- (3, 4-difluorophenyl) -4-piperidinyl ] carbamoylamino ] -4- (3, 4-difluorophenyl) piperidine-1-carboxylate

To a stirred solution of 1-tert-butoxycarbonyl-4- (3, 4-difluorophenyl) piperidine-4-carboxylic acid (94%, 130mg,0.358 mmol) in tert-butanol (3.6 mL) was added sequentially diphenylphosphorus azide (diphenyl phosphorazidate) (100. Mu.L, 0.465 mmol) and triethylamine (100. Mu.L, 0.716 mmol) in a sealed tube at room temperature under nitrogen. The reaction mixture was stirred at 90 ℃ overnight. The reaction mixture was cooled to room temperature and quenched with water, then DCM was added. 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 1% to 8% MeOH in DCM. The desired fractions were combined and concentrated under reduced pressure to give the title compound as a yellow oil (90 mg, 94% purity, 54% yield, t) _r =1.09 min). LCMS (method E): m/z found 651.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)7.39–7.24(m，4H)，7.17(dt，J＝10.6，3.4Hz，2H)，6.50(s，2H)，3.84(d，J＝13.2Hz，4H)，3.01(s，5H)，2.08(d，J＝13.1Hz，4H)，1.72(td，J＝13.0，4.5Hz，4H)，1.42(s，18H)。

Step 3: synthesis of tert-butyl 4-amino-4- (3, 4-difluorophenyl) piperidine-1-carboxylate

Filling a sealed vial with 4- [ [ 1-tert-butoxycarbonyl-4- (3, 4-difluorophenyl) -4-piperidinyl]Carbamoyl amino groups]-tert-butyl 4- (3, 4-difluorophenyl) piperidine-1-carboxylate (94%, 90mg,0.130 mmol) and N- (2-aminoethyl) ethane-1, 2-diamine (0.42 mL,3.90 mmol). The reaction mixture was warmed up to 130 ℃ and stirred at that temperature overnight. The reaction mixture was then warmed up to 140 ℃ for 4 hours and stirred at room temperature for 2 days. Additional N- (2-aminoethyl) ethane-1, 2-diamine (0.49 mL,4.55 mmol) was added at room temperature and the reaction was mixedThe mixture was stirred at 140℃for 3 hours. The reaction mixture was cooled to room temperature, and then methylene chloride and a saturated aqueous solution of ammonium chloride were added. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed once with saturated aqueous ammonium chloride, once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride, dried using a phase separator and concentrated in vacuo to give the title compound as a pale yellow oil (30.6 mg, 70% purity, 27% yield, t _r =0.61 min). LCMS (method D): m/z found 313.2[ M+H ]] ⁺ ；(DMSO，400MHz)：δ(ppm)7.64–7.54(m，1H)，7.38–7.29(m，2H)，3.73(d，J＝13.0Hz，2H)，1.94(d，J＝23.8Hz，2H)，1.76(ddd，J＝13.2，12.0，4.7Hz，2H)，1.51(dq，J＝13.6，2.8Hz，2H)，1.41(s，9H)。

Step 4: synthesis of tert-butyl 4- (3, 4-difluorophenyl) -4- ((4- (trifluoromethoxy) phenyl) sulfonamide) piperidine-1-carboxylate

A sealed vial was charged with a mixture of tert-butyl 4-amino-4- (3, 4-difluorophenyl) piperidine-1-carboxylate (90%, 35mg,0.101 mmol), triethylamine (70. Mu.L, 0.504 mmol) and 4-dimethylaminopyridine (2.5 mg,0.0202 mmol) in DCM (0.9328 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 21. Mu.L, 0.121 mmol) was then added and the reaction mixture was stirred at 40℃for 2 days. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (10 mL). Dichloromethane (10 mL) was then added and the layers separated. The aqueous layer was extracted once with dichloromethane (10 mL). The combined organic layers were washed once with saturated aqueous sodium bicarbonate (10 mL) and once with saturated aqueous sodium chloride (10 mL), dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 10% methanol in dichloromethane. The desired fractions were combined and concentrated under reduced pressure to give the desired compound as a white solid (17.5 mg, 97% purity, 31% yield, t) _r =1.05 min). LCMS (method E); ¹ H-NMR(400MHz，DMSO)δ8.21(s，1H)，7.47–7.41(m，2H)，7.31–7.25(m，2H)，7.08–6.93(m，3H)，3.72(d，J＝13.3Hz，2H)，3.28–3.14(m，3H)，2.39–2.30(m，2H)，1.71(t，J＝11.9Hz，2H)，1.40(s，9H)。

step 5: synthesis of N- (4- (3, 4-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (82)

To 4- (3, 4-difluorophenyl) -4- [ [4- (trifluoromethoxy) phenyl ] in a round-bottomed flask at room temperature under nitrogen]Sulfonylamino groups]A stirred suspension of tert-butyl piperidine-1-carboxylate (30 mg,0.0565 mmol) in diethyl ether (0.14 mL) was added to a solution of 4MHCl in 1, 4-dioxane (0.14 mL,0.560 mmol). The reaction mixture was stirred at this temperature overnight. The resulting suspension was filtered, washed three times with diethyl ether (3×3 mL) and dried at 45 ℃ for 24 hours to give the hydrochloride salt of the title compound as a white powder (21 mg, purity 98.25%, yield 77%, t) _r =1.31 min). LCMS (method H): m/z found 437[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，600MHz)δ8.71(br s，2H)，8.48(s，1H)，7.4-7.5(m，2H)，7.27(d，2H，J＝8.2Hz)，6.8-7.1(m，3H)，3.23(br s，4H)，2.56(br d，2H，J＝13.6Hz)，1.8-2.2(m，2H)。

Example 47: n- (4- (2, 4-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (83)

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Step 1: synthesis of 4- (2, 4-difluorophenyl) piperidine-4-carbonitrile

To 4-cyano-4- (2, 4-difluorophenyl) piperidine-1-carboxylic acid tert-butyl ester (95)A stirred solution of%250 mg,0.737 mmol) in diethyl ether (1.8501 mL) was added 4M hydrogen chloride in dioxane (1.8 mL,7.37 mmol). The mixture was stirred at room temperature for 2 days, then filtered, washed twice with diethyl ether and dried under vacuum at 45 ℃ for 18 hours to give the hydrochloride salt of the title compound as a white powder (186 mg, 98% purity, 96% yield, t _r =0.48 min). LCMS (method D): m/z found 223.1[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO)δ9.12(s，2H)，7.57(td，J＝9.0，6.2Hz，1H)，7.47(ddd，J＝12.1，9.0，2.7Hz，1H)，7.28–7.19(m，1H)，3.51(dt，J＝13.9，3.4Hz，2H)，3.13(td，J＝13.2，2.7Hz，2H)，2.48(m，2H)，2.31(td，J＝13.7，4.0Hz，2H)。

Step 2: synthesis of 1-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carbonitrile

To a stirred suspension of 4- (2, 4-difluorophenyl) piperidine-4-carbonitrile hydrochloride (98%, 186mg, 0.704 mmol) in CAN (1.6248 mL) in a sealed tube at room temperature was added bromotoluene (0.10 mL,0.846 mmol) and K ₂ CO ₃ (0.24 g,1.76 mmol). The reaction mixture was stirred at 65 ℃ overnight. The reaction mixture was poured into water. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride, 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 5% to 80% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a colorless oil (140.2 mg, purity 98%, yield 62.4%, t) _r =0.58 min). LCMS (method D): m/z found 313.2 [ M+H ]] ⁺ ； ¹ H-NMR (DMSO，400 MHz)：δ (ppm)7.55(td，J＝9.1，6.3Hz，1H)，7.46–7.31(m，5H)，7.27(ddd，J＝8.7，5.2，3.5Hz，1H)，7.17(td，J＝8.2，2.5Hz，1H)，3.57(s，2H)，2.95(dt，J＝12.7，3.3Hz，2H)，2.35(td，J＝12.2，2.1Hz，2H)，2.23(dd，J＝13.3，2.5Hz，2H)，2.09–1.96(m，2H)。

Step 3: synthesis of 1-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carboxamide

1-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carbonitrile (98%, 138mg,0.433 mmol) in H in a round bottom flask ₂ SO ₄ A mixture of (1.7343 mL) and water (0.4336 mL) was stirred at 65℃for 1 hour. The mixture was poured into ice water and basified with 30% aqueous naoh to achieve ph=10-11. 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 over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless oil (150.6 mg, purity 87%, yield 91.6%, t) _r =0.51 min). The crude product was used directly in the next step without any purification. LCMS (method E): m/z found 331.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)7.46(td，J＝9.1，6.5Hz，1H)，7.36–7.20(m，5H)，7.15(ddd，J＝12.2，9.2，2.8Hz，1H)，7.11–7.02(m，1H)，6.95(d，J＝18.8Hz，2H)，5.77(s，0H)，3.41(s，2H)，2.45(s，2H)，2.41–2.28(m，4H)，2.02–1.89(m，2H)。

Step 4: synthesis of 1-benzyl-4- (2, 4-difluorophenyl) piperidin-4-amine

A sealed tube was charged with 1-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carboxamide (87%, 147mg, 0.3838 mmol) and dissolved in ACN (1.0997 mL) and water (1.0997 mL). Bis (trifluoroacetoxy) iodobenzene (96%, 177mg,0.396 mmol) was then charged and the reaction stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum overnight. The residue was dissolved in Et ₂ Et in O and 2M Hydrogen chloride ₂ O solution (1.9 mL,3.88 mmol). The suspension was stirred at room temperature overnight, filtered and taken up with Et ₂ And (3) washing. Will be spentThe gum was dissolved in MeOH and concentrated under reduced pressure. Pouring the residue into saturated Na ₂ CO ₃ In aqueous solution to achieve ph=10, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a pale pink oil (103.1 mg, 83% purity, 72.9% yield, t _r =0.42 min). LCMS (method D): m/z found 303.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)7.62(td，J＝9.3，6.9Hz，1H)，7.38–7.20(m，5H)，7.13(ddd，J＝12.9，9.2，2.7Hz，1H)，7.02(td，J＝8.5，2.7Hz，1H)，3.49(s，2H)，2.53(d，J＝2.9Hz，2H)，2.10(dt，J＝13.1，8.0Hz，2H)，1.81(s，2H)，1.56(d，J＝12.9Hz，2H)。

Step 5: synthesis of N- (1-benzyl-4- (2, 4-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide

A round bottom flask was charged with a solution of 1-benzyl-4- (2, 4-difluorophenyl) piperidin-4-amine (83%, 103mg,0.283 mmol) and triethylamine (0.16 mL,1.12 mmol) in DCM (2.6 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (57. Mu.L, 0.334 mmol) and N, N-dimethylpyridin-4-amine (6.9 mg,0.0565 mmol) were then added and the reaction mixture stirred at 40℃overnight. The reaction mixture was diluted with DCM and saturated NH was added ₄ Aqueous Cl solution. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated NaHCO ₃ The aqueous solution was washed, then brine was used, dried using a phase separator and concentrated under reduced pressure. The crude product (150 mg) was purified by flash chromatography on silica gel using a gradient of 0% to 5% MeOH in DCM. The desired fractions were combined and concentrated under reduced pressure to give the title compound as an off-white solid (120.4 mg, 99% purity, 80.1% yield, t _r =0.71 min). LCMS (method D): m/z found 527.2[ M+H ]] ⁺ ； ¹ H-NMR(CDCl ₃ ，400MHz)：δ(ppm)7.48–7.17(m，8H)，7.01(d，J＝8.4Hz，2H)，6.78–6.69(m，1H)，6.14(ddd，J＝12.9，8.5，2.7Hz，1H)，4.90(s，1H)，3.53(d，J＝20.2Hz，2H)，2.88–2.39(m，6H)，2.05(s，2H)。

Step 6: n- (4- (2, 4-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (83)

To N- [ 1-benzyl-4- (2, 4-difluorophenyl) -4-piperidinyl in nitrogen]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (99%, 116mg,0.218 mmol) in DCE (0.3635 mL) was added 1-chloroethyl carbonate (62 mg, 0.433 mmol). The reaction mixture was stirred at room temperature overnight. Then, the suspension was concentrated under reduced pressure. The residue was dissolved in methanol (0.3635 mL) and the reaction mixture was stirred at 65 ℃ for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting off-white solid was triturated overnight in a mixture of dichloromethane and methanol (95:5, 7 ml) and the resulting white powder was filtered, washed twice with DCM and once with a mixture of dichloromethane and methanol (95:5). The resulting white powder was triturated once more in a mixture of dichloromethane and methanol (95:5, 5 ml) for 2 hours and the resulting powder was filtered, washed twice with a mixture of dichloromethane and methanol (95:5) and dried in vacuo at 45 ℃ for 1 hour. The white powder was triturated in diethyl ether (1 mL) and a 2M solution of hydrogen chloride in diethyl ether (0.55 mL,1.09 mmol) was added. The mixture was stirred at room temperature overnight, filtered and dried under vacuum at 45 ℃ overnight to give the hydrochloride salt of the title compound as a white powder (40.5 mg, purity 95.65%, yield 37.6%, t _r =1.36 min). LCMS (method H): m/z found 437[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ8.79(br s，2H)，8.58(s，1H)，7.41–7.37(m，3H)，7.36–7.31(m，1H)，7.28(d，J＝8.1Hz，2H)，6.93(td，J＝8.4，2.7Hz，1H)，6.49–6.33(m，1H)，3.25(br d，J＝6.1Hz，5H)，2.15–1.96(m，2H)。

Example 48: n- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide (84)

Step 1: synthesis of benzyl 3- ((N' - (3, 4-dimethoxybenzyl) -4- (trifluoromethoxy) phenyl) sulfonamide imidoamide (sulfonoa midimidamido)) -3- (4-fluorophenyl) pyrrolidine-1-carboxylate

N- [ (3, 4-Dimethoxyphenyl) methyl group was purged in a round bottom flask at 0deg.C under nitrogen]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (250 mg,0.666 mmol) in tetrachloromethane (2.5 mL,26.0 mmol) was added t-butyl hypochlorite (0.11 mL,0.932 mmol). The reaction mixture was stirred in the dark at 0 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure at 2 ℃. The residue was dissolved in anhydrous THF (2.0833 mL), benzyl 3-amino-3- (4-fluorophenyl) pyrrolidine-1-carboxylate (230 mg,0.733 mmol), DIPEA (349 μl,2.00 mmol) and N, N-dimethylpyridin-4-amine (99%, 8.2mg,0.0666 mmol) were added in sequence, and the reaction mixture was stirred at 40 ℃ for 4 hours and at room temperature for 40 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL) and ethyl acetate (20 mL) was added. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. A gradient of 0% to 8% MeOH (0.7N NH ₃ ) The crude product was purified by flash chromatography on silica gel to give the expected compound as a yellow oil (230 mg, 81% purity, 41% yield, t _r =1.07 min). LCMS (method D): m/z found 688.4[ M+H ]] ⁺ 。

Step 2: synthesis of benzyl 3- (4-chlorophenyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide imidoyl) pyrrolidine-1-carboxylate

In a round bottom flask, 3- [ [ N- [ (3, 4-dimethoxyphenyl) methyl ] is charged under nitrogen at 0deg.C]S- [4- (trifluoromethoxy) phenyl ]]Sulfonimido group]Amino group]A stirred solution of benzyl 3- (4-fluorophenyl) pyrrolidine-1-carboxylate (81%, 230mg, 0.271mmol) in a mixture of ACN (3.612 mL) and water (1.806 mL) was added cerium (IV) ammonium nitrate (371 mg,0.677 mmol). The reaction mixture was stirred at 0 ℃ for 2.5 hours. The reaction mixture was diluted with water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution and dried over Na ₂ SO ₄ Dried, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel using a gradient of 2% to 10% MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as an off-white solid (109 mg, 90% purity, 65% yield, t _r =0.92 min). LCMS (method D): m/z found 538.2[ M+H ] ] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)8.20–6.50(m，14H)，5.16–4.98(m，2H)，4.66(s，1H)，4.36–3.82(m，1H)，3.80–3.37(m，3H)，3.05–2.58(m，1H)，2.31–1.95(m，1H)。

Step 3: synthesis of N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide (84)

3- (4-fluorophenyl) -3- [ [ [4- (trifluoromethoxy) phenyl ] in a sealed vial under nitrogen]Sulfonimido group]Amino group]A solution of pyrrolidine-1-carboxylic acid benzyl ester (90%, 110mg,0.184 mmol) in CAN (1.8418 mL) was stirred at room temperature, then iodo (trimethyl) silane (0.079 mL,0.553 mmol) was added to the pale yellow suspension, and the resulting orange solution was stirred at room temperature for 2 hours. Additional iodo (trimethyl) silane (0.039 ml,0.276 mmol) was added and the mixture was stirred for 1 hour. Methanol (0.13 mL,3.32 mmol) was added at 0deg.C, the mixture stirred at room temperature for 1 hour, concentrated in vacuo and concentrated using a gradient of 0% to 8% MeOH (0.7N NH) ₃ ) Is purified by flash chromatography on silica gel.The desired fractions were pooled and treated with saturated Na ₂ CO ₃ The solution was washed, filtered through a phase separator and concentrated in vacuo. The residue was taken up in Et ₂ O was triturated and filtered to give the desired product as a white powder (48 mg, 99.25% purity, 64% yield, t) _r =1.41 min). LCMS (method H): m/z found 434[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ9.1-9.7(m，2H)，7.8-8.0(m，2H)，7.2-7.6(m，6H)，6.6-7.2(m，1H)，3.7-4.3(m，1H)，3.4-3.7(m，2H)，3.1-3.3(m，1H)，2.7-2.8(m，1H)，2.0-2.3(m，4H)。

Example 49: n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -N-methyl-4- (trifluoromethoxy) benzenesulfonamide (85)

Step 1: synthesis of tert-butyl 3- (4-chlorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] pyrrolidine-1-carboxylate

In a sealed vial, N- [3- (4-chlorophenyl) pyrrolidin-3-yl]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (100 mg,0.238 mmol) and triethylamine (0.13 mL,0.951 mmol) in DCM (1 mL) was added di-tert-butyl dicarbonate (54 mg,0.250 mmol). The reaction mixture was stirred at room temperature overnight. Water and dichloromethane were added and the layers separated. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were then extracted with saturated NaHCO ₃ The solution was washed once with saturated aqueous NaCl, filtered through a phase separator, and then concentrated under vacuum pressure to give the title compound as a colorless oil (129.1 mg, 95% purity, 99% yield, t) _r =1.03 min). LCMS (method E): m/z found 543.2[ M+Na ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.60(d，J＝9.0Hz，1H)，7.43(d，J＝8.8Hz，2H)，7.25(d，J＝7.8Hz，2H)，7.07–7.03(m，4H)，4.02(dd，J＝11.0，6.0Hz，1H)，3.52–3.35(m，2H)，3.31–3.24(m，1H)，2.76–2.61(m，1H)，2.23–2.07(m，1H)，1.41(d，J＝3.9Hz，9H)。

Step 2: synthesis of tert-butyl 3- (4-chlorophenyl) -3- ((N-methyl-4- (trifluoromethoxy) phenyl) sulfamide) pyrrolidine-1-carboxylate

3- (4-chlorophenyl) -3- [ [4- (trifluoromethoxy) phenyl ] was placed in a sealed tube under nitrogen]Sulfonylamino groups]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (123 mg,0.237 mmol) in dry THF (2.2 mL) was stirred at 0deg.C. Dry methanol (14. Mu.L, 0.355 mmol), triphenylphosphine (93 mg,0.355 mmol) and diisopropylazodicarbonate (70. Mu.L, 0.355 mmol) were added and the mixture was stirred at room temperature overnight. Adding half saturated NaHCO ₃ 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 100% ethyl acetate in heptane. The desired fraction was concentrated to give the title compound as a colourless gum (188.9 mg, purity 63%, yield 94%, t) _r =1.08 min). LCMS (method E): m/z found 557.2[ M+Na ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ8.87(s，2H)，7.55(dd，J＝8.9，3.4Hz，2H)，7.40–7.35(m，2H)，7.34–7.25(m，4H)，4.26(t，J＝12.8Hz，1H)，3.71(t，J＝11.0Hz，1H)，3.30–3.21(m，1H)，3.05(s，3H)，2.88–2.74(m，1H)，2.70–2.55(m，1H)，2.50–2.42(m，1H)，1.38(d，J＝24.4Hz，9H)。

Step 3: synthesis of N- [3- (4-chlorophenyl) pyrrolidin-3-yl ] -N-methyl-4- (trifluoromethoxy) benzenesulfonamide (85)

In a round bottom flask, dioxane was dissolved into 4M hydrogen chlorideA stirred solution of the solution (0.60 mL,2.40 mmol) in diethyl ether (2 mL) was added 3- (4-chlorophenyl) -3- [ methyl- [4- (trifluoromethoxy) phenyl ]]Sulfonyl-amino groups]Pyrrolidine-1-carboxylic acid tert-butyl ester (63%, 189mg,0.222 mmol). The mixture was stirred at room temperature overnight. Next, the reaction mixture was concentrated, and then methanol and 0.7N ammonia were added. The resulting precipitate was filtered, and the filtrate was concentrated and purified by flash silica gel chromatography using a gradient of 2% to 20% methanol in dichloromethane with 0.7N ammonia. The desired fractions were combined and concentrated. The resulting gum was purified by reverse phase preparative chromatography (redisep. C18aq15.5 g) using a gradient of 0% to 100% acetonitrile in water (0.1%AcOH in both eluants). The desired fractions were combined and the organic solvent was removed. The aqueous layer was treated with saturated NaHCO ₃ The aqueous solution was neutralized, and then dichloromethane and a few drops of methanol were added. The layers were separated. The aqueous layer was washed twice with dichloromethane, over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was triturated in pentane, filtered, washed with pentane and dried in vacuo at 40 ℃ for 18 hours to give the expected compound as a white powder (15.1 mg, 99.36% purity, 16% yield, t _r =1.91 min). LCMS (method C): m/z found 435[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δ7.65(d，J＝9.0Hz，2H)，7.45–7.35(m，4H)，7.28(s，2H)，3.44–3.34(m，1H)，3.33–3.31(m，1H)，3.25–3.19(m，1H)，3.00(s，3H)，2.87–2.77(m，1H)，2.72–2.61(m，1H)，2.43–2.29(m，2H)。

Example 50: n- (3-phenyl-8-azabicyclo [3.2.1] oct-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (86)

Step 1: synthesis of 8-benzyl-8-azabicyclo [3.2.1] octan-3-one

In a sealed round bottom flask, 8-azabicyclo [3.2.1] at room temperature]A stirred suspension of octyl-3-ketone hydrochloride (1:1) (98%, 2.00g,12.1 mmol) in acetonitrile (30 mL) was added K ₂ CO ₃ (4.19 g,30.3 mmol) and bromotoluene (1.8 mL,15.2 mmol). The reaction mixture was stirred at 60 ℃ overnight. The reaction mixture was poured into water. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was taken up in Et ₂ Grinding in O. The resulting suspension was filtered and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using a gradient of 10% to 50% EtOAc in heptane. The desired fractions were combined and concentrated to give the title compound as a pale yellow liquid (2.362 g, purity 98%, yield 88.664%, t) _r =0.41 min). LCMS (method D): m/z found 216.2[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO)δ7.43(ddt，J＝7.5，1.3，0.7Hz，2H)，7.39–7.32(m，2H)，7.28–7.23(m，1H)，3.77(s，2H)，3.48–3.37(m，2H)，2.67(dd，J＝15.8，4.4Hz，2H)，2.10–1.96(m，4H)，1.58–1.42(m，2H)。

Step 2: synthesis of 8-benzyl-8-azabicyclo [3.2.1] octane-3-carbonitrile

To 8-benzyl-8-azabicyclo [3.2.1] at 0deg.C in a sealed round bottom flask]A stirred solution of octyl-3-ketone (98%, 1.30g,5.92 mmol) and 1- (isocyanomethylsulfonyl) -4-methyl-benzene (98%, 1.18g,5.92 mmol) in DME (35 mL) was added dropwise to a solution of potassium tert-butoxide (1328 mg,11.8 mmol) dissolved in a 1:1 mixture of tert-butanol (9 mL) and DME (9 mL). The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Water was added and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. A gradient of 0.5% to 2% MeOH (0.7N NH was used ₃ ) Is prepared by flash chromatographyThe crude product was purified. The desired fractions were combined and concentrated under reduced pressure to give the title compound as a yellow oil (698 mg, purity 84%, yield 44%, t) _r =0.43 min). LCMS (method D): m/z found 227.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)7.38–7.32(m，3H)，7.32–7.28(m，1H)，7.26–7.20(m，1H)，3.48(s，2H)，3.12(p，J＝2.9Hz，2H)，3.01(tt，J＝11.9，6.3Hz，1H)，1.98–1.87(m，2H)，1.85–1.69(m，4H)，1.62–1.57(m，2H)。

Step 3: synthesis of 8-benzyl-3-phenyl-8-azabicyclo [3.2.1] octane-3-carbonitrile

In a sealed vial, at room temperature, at N ₂ Intermediate 8-benzyl-8-azabicyclo [3.2.1]A stirred solution of octane-3-carbonitrile (250 mg,1.10 mmol) and fluorobenzene (99%, 2.6mL,27.6 mmol) was added 1M [ bis (trimethylsilyl) amino ]]Potassium in THF (2.2 mL,2.21 mmol). The reaction mixture was stirred at room temperature for 10min. The reaction mixture was then irradiated at 100℃for 18min. Pouring the reaction mixture into saturated NH ₄ In Cl solution (50 mL) and extracted twice with EtOAc. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel using a gradient of 10% to 50% EtOAc in heptane to give the title compound as a white solid (220 mg, purity 100%, yield 66%, t _r =0.58 min). LCMS (method D): m/z found 303.2 [ M+H ]] ⁺ ； ¹ H-NMR (DMSO，400 MHz)：δ (ppm)7.69–7.08(m，10H)，3.55(s，2H)，3.33–3.26(m，2H)，2.39–2.27(m，2H)，2.27–2.05(m，6H)。

Step 4: synthesis of 8-benzyl-3-phenyl-8-azabicyclo [3.2.1] octane-3-carboxamide

In a round bottom flask, 8-benzyl-3-phenyl-8-nitrogenHeterobicyclo [3.2.1]Octane-3-carbonitrile (235 mg,0.777 mmol) in H ₂ SO ₄ A mixture of (3.0325 mL) and water (0.7581 mL) was stirred at 65℃for 2 hours and 80℃for 1 hour. The mixture was poured into ice water and basified with 30% aqueous naoh to achieve ph=10-11. 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 over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (264 mg, 87% purity, 92% yield, t _r =0.51 min). LCMS (method E): m/z found 321.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)7.40–7.24(m，9H)，7.19(dt，J＝14.2，7.1Hz，2H)，6.88(s，1H)，3.46(s，2H)，3.13(s，2H)，2.93(d，J＝13.4Hz，2H)，1.87(dd，J＝9.6，6.1Hz，6H)。

Step 5: synthesis of 8-benzyl-3-phenyl-8-azabicyclo [3.2.1] oct-3-amine

Filling 8-benzyl-3-phenyl-8-azabicyclo [3.2.1] in sealed tube]Octane-3-carboxamide (87%, 264mg, 0.719 mmol) and was dissolved in acetonitrile (2.0307 mL) and water (2.0307 mL). Then charging [ bis (trifluoroacetoxy) iodide ]]Benzene (96%, 328mg,0.731 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Adding saturated Na ₂ CO ₃ And the aqueous layer was extracted twice with DCM. The combined organic layers were concentrated under reduced pressure and Et was then added ₂ Et of O (4 mL) and 2M HCl ₂ O solution (3.6 mL,7.17 mmol). The suspension was stirred at room temperature for 2 hours, filtered and taken up in Et ₂ And (3) washing. The resulting solid was dried in vacuo at 45℃for 2 hours to give the dihydrochloride of the title compound as an off-white solid (239 mg, 97% purity, 88.528% yield, t) _r =0.39 min). LCMS (method E): m/z found 393.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)10.79(s，1H)，8.60(s，3H)，7.72(dd，J＝6.6，3.0Hz，2H)，7.67–7.57(m，2H)，7.51–7.35(m，6H)，4.25(d，J＝6.1Hz，2H)，3.95(d，J＝5.4Hz，2H)，2.87(dd，J＝16.1，3.7Hz，2H)，2.73(d，J＝15.8Hz，2H)，2.56(s，2H)，2.35(d，J＝9.8Hz，2H)。

Step 6: synthesis of N- (8-benzyl-3-phenyl-8-azabicyclo [3.2.1] oct-3-yl) -4- (trifluoromethoxy) benzenesulfonamide

A round bottom flask was charged with 8-benzyl-3-phenyl-8-azabicyclo [3.2.1]Octan-3-amine; a solution of the dihydrochloride compound (239 mg, 0.650 mmol) and triethylamine (0.46 mL,3.27 mmol) in DCM (4 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (0.11 mL, 0.254 mmol) and N, N-dimethylpyridin-4-amine (16 mg,0.131 mmol) were then added to the reaction mixture and stirred at 40℃overnight. The reaction mixture was diluted with DCM and half saturated Na was added ₂ CO ₃ An aqueous solution. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over a phase separator and concentrated in vacuo. Anhydrous acetonitrile (4 mL) and pyridine (0.11 mL,1.31 mmol) were added under nitrogen. The mixture was added and stirred at room temperature overnight. The mixture was filtered and the solid was washed with ACN and dissolved in half-saturated Na ₂ CO ₃ Solution and DCM. The aqueous layer was extracted once with DCM and the combined organic layers were dried using a phase separator and concentrated under reduced pressure to give the title compound as a yellow solid (169 mg, 100% purity, 50% yield, t _r =0.73 min). LCMS (method E): m/z found 517.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)7.85(s，1H)，7.37–7.16(m，7H)，7.14–7.06(m，2H)，6.99(dd，J＝6.6，3.1Hz，2H)，6.90–6.79(m，3H)，3.50(s，2H)，3.21(s，2H)，2.75(d，J＝13.8Hz，2H)，2.36–2.25(m，2H)，2.12–1.90(m，4H)。

Step 7: synthesis of N- (3-phenyl-8-azabicyclo [3.2.1] oct-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (86)

N- (8-benzyl-3-phenyl-8-azabicyclo [ 3.2.1)]A suspension of oct-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (92%, 180mg,0.321 mmol) in a mixture of THF (1.6028 mL), ethanol (1.6028 mL) and methanol (20 mL). The resulting homogeneous solution was purged with argon. Palladium on carbon catalyst (10 wt%,34mg,0.0321 mmol) was added and the reaction mixture was stirred under hydrogen overnight. The solution was filtered through a pad of celite and the resulting solution was concentrated under reduced pressure. The resulting crude product was dissolved in methanol (20 mL) and purged with argon. Palladium on carbon (10 wt%,34mg,0.0321 mmol) was added and the reaction mixture was stirred under hydrogen for 24 hours. The solution was filtered through a pad of celite and the resulting filtrate was concentrated under reduced pressure to provide a solid. Diethyl ether (3 mL) was added to the solid to form a suspension, and 2M HCl (1.6 mL,3.21 mmol) was added. The resulting suspension was stirred at room temperature overnight. The residue was filtered and washed with diethyl ether to give the hydrochloride of the title compound as a grey solid (90 mg, purity 98.06%, yield 61%, t) _r =1.28 min). LCMS (method H): m/z found 427.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，600MHz)：δ(ppm)8.48-9.19(m，2H)，8.30(s，1H)，7.26-7.31(m，2H)，7.09-7.14(m，2H)，6.95-7.00(m，2H)，6.86-6.92(m，3H)，3.95-4.28(m，2H)，2.98(br d，J＝13.8Hz，2H)，2.52(br d，J＝8.4Hz，2H)，2.21(br d，J＝14.2Hz，2H)，1.98-2.10(m，2H)。

Example 51: n- (4- (5-chloropyridin-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (87)

Step 1: synthesis of 1-benzyl-4- (5-chloro-2-pyridinyl) piperidine-4-carbonitrile

To 1-benzylpiperidine-4-carbonitrile at room temperature under nitrogen(91%, 224mg,1.02 mmol) in dry toluene (10.185 mL) was added 2-bromo-5-chloropyridine (98%, 200mg,1.02 mmol). The reaction mixture was cooled to 0deg.C and 2M sodium 1, 3-hexamethyldisilazane (discolazan-2-ide) (1.0 mL,2.04 mmol) was added dropwise. The reaction mixture was stirred at 0 ℃ for 1 hour, then at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride to achieve ph=7 and EtOAc was added. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (column) using a gradient of 10% (EtOAc in cyclohexane) to 30% EtOAc in cyclohexane. The desired fractions were combined and concentrated under reduced pressure to give the title compound as a colorless solid (270 mg, purity 100%, yield 85%, t) _r =0.55 min). LCMS (method E): m/z found 312.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)8.69(d，J＝2.2Hz，1H)，8.04(dd，J＝8.6，2.6Hz，2H)，7.72–7.64(m，2H)，7.34(d，J＝4.4Hz，6H)，7.32–7.22(m，2H)，3.57(s，3H)，2.94(dt，J＝12.5，3.4Hz，4H)，2.33(ddd，J＝12.2，10.8，3.8Hz，4H)，2.20–2.05(m，7H)。

Step 2: synthesis of 1-benzyl-4- (5-chloro-2-pyridinyl) piperidine-4-carboxamide

1-benzyl-4- (5-chloro-2-pyridinyl) piperidine-4-carbonitrile (100%, 270mg,0.866 mmol) in H in a sealed tube ₂ SO ₄ A mixture of (3.4685 mL) and water (0.8671 mL) was stirred overnight at 65 ℃. The mixture was poured into ice water and basified with 30% aqueous naoh to achieve ph=10-11. 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 over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a white powder (276.3 mg, purity 98%, yield 94.81%, t _r =0.51 min). LCMS (method E): m/z found 330.4[ M+H ]] ⁺ ； ¹ H-NMR (400 mhz, dmso) δ8.58 (d, j=2.5 hz, 1H), 7.89 (dd, j=8.6, 2.6hz, 1H), 7.45 (d, j=8.6 hz, 1H), 7.37-7.19 (m, 5H), 7.09 (s, 1H), 7.02 (s, 1H), 3.39 (s, 2H), 2.43 (s, 2H), 2.30 (dt, j=21.7, 11.7hz, 4H), 2.06 (s, 2H). The crude product was used in the next step without further purification.

Step 3: synthesis of 1-benzyl-4- (5-chloro-2-pyridinyl) piperidin-4-amine

A sealed tube was charged with 1-benzyl-4- (5-chloro-2-pyridinyl) piperidine-4-carboxamide (275 mg,0.834 mmol) and dissolved in acetonitrile (2.4 mL) and water (2.4 mL). The flask was charged with [ bis (trifluoroacetoxy) iodo ] ]Benzene (96%, 3831 mg,0.850 mmol) and the reaction was stirred at room temperature for 16 hours, then at 40℃for 4 hours. Additional [ bis (trifluoroacetoxy) iodo [ benzene (96%, 374mg,0.834 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in Et ₂ O and Et with 2M HCl ₂ O solution (4.2 mL,8.34 mmol). The suspension was stirred at room temperature for 18 hours, filtered and washed with diethyl ether and dried in vacuo at 50 ℃ for 4 hours to give the hydrochloride salt of the title compound as an off-white powder (245 mg, purity 49%, yield 43%, t _r =0.42 min). LCMS (method D): m/z found 302.3[ M+H ]] ⁺ 。

Step 4: synthesis of N- [ 1-benzyl-4- (5-chloro-2-pyridinyl) -4-piperidinyl ] -4- (trifluoromethoxy) benzenesulfonamide

A sealed vial was charged with a solution of 1-benzyl-4- (5-chloro-2-pyridinyl) piperidin-4-amine hydrochloride (50%, 248 mg, 0.365 mmol), triethylamine (153. Mu.L, 1.10 mmol) and DMAP (8.8 mg,0.0724 mmol) in DCM (2.5 mL). Then 4- (trifluoromethoxy) benzeneSulfonyl chloride (74 μl,0.436 mmol) was added to the reaction mixture and stirred at 40 ℃ for 16 hours. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (4 mL), then water (10 mL) and dichloromethane (10 mL) were added. The aqueous layer was extracted with dichloromethane (2X 10 mL). The combined organic layers were 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% to 5% MeOH in DCM to give the title compound as a brown powder (51 mg, 84% purity, 27% yield, t _r =0.71 min). LCMS (method E): m/z found 526.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)8.20–8.14(m，1H)，7.60(dd，J＝8.5，2.5Hz，1H)，7.52–7.43(m，2H)，7.36–7.22(m，9H)，3.41(s，2H)，2.46–2.20(m，6H)，2.05(s，2H)。

Step 5: synthesis of N- (4- (5-chloropyridin-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (87)

To a stirred solution of 1-chloroethyl carbonate (99%, 17. Mu.L, 0.160 mmol) in DCE (2 mL) under nitrogen was added N- [ 1-benzyl-4- (5-chloro-2-pyridinyl) -4-piperidinyl]4- (trifluoromethoxy) benzenesulfonamide (84%, 50mg,0.0799 mmol). The reaction mixture was stirred at room temperature for 16 hours. Additional 1-chloroethyl carbonate (99%, 17 μl,0.160 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 6 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and the reaction mixture was stirred at 65 ℃ for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was triturated in dichloromethane, filtered, washed with dichloromethane, and dried in vacuo. The resulting precipitate was purified by flash chromatography on silica gel using a gradient of 2% to 15% methanolic ammonia in dichloromethane. The residue was triturated in 2M hydrogen chloride in diethyl ether (399 μl,0.799 mmol) for 4 hours, filtered, washed with diethyl ether, and dried under vacuum at 50 ℃ for 20 hours to give the title compound Hydrochloride of the material as a white powder (8.7 mg, purity 96.2%, yield 22%, t) _r =1.22 min). LCMS (method H): m/z found 436[ M+H ]] ⁺ ； ¹ H-NMR(600MHz，DMSO-d ₆ )δppm 8.70(m，2H)，8.58(s，1H)，8.20(dd，J＝2.5，0.6Hz，1H)，7.58(dd，J＝8.5，2.6Hz，1H)，7.43(d，J＝8.9Hz，2H)，7.28(td，J＝8.7，0.7Hz，3H)，3.15(m，4H)，2.53(br d，J＝1.2Hz，2H)，2.19(m，2H)。

Example 52: n- (4- (2, 5-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (88)

Step 1: synthesis of 4- (2, 5-difluorophenyl) piperidine-4-carbonitrile

A sealed vial was charged with tert-butyl 4-cyano-4- (2, 5-difluorophenyl) piperidine-1-carboxylate (95%, 300mg,0.884 mmol) and a solution of 4M HCl in 1, 4-dioxane (3.3 mL,13.3 mmol) in diethyl ether (2.28 mL) in sequence under nitrogen. The reaction mixture was stirred at room temperature for 18 hours. The suspension was filtered, washed with diethyl ether (10 mL) and dried in vacuo at 50 ℃ for 7 hours to give the hydrochloride salt of the title compound as an off-white powder (271 mg, 80% purity, 95% yield, t _r =0.46 min). LCMS (method E): m/z found 223.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)9.19(s，2H)，7.51–7.36(m，3H)，3.51(dt，J＝13.6，3.2Hz，2H)，3.13(td，J＝13.4，2.7Hz，2H)，2.55–2.52(m，2H)，2.40–2.26(m，2H)。

Step 2: synthesis of 1-benzyl-4- (2, 5-difluorophenyl) piperidine-4-carbonitrile

To a stirred solution of 4- (2, 5-difluorophenyl) piperidine-4-carbonitrile hydrochloride (80%, 265mg, 0.630 mmol) in DMF (2 mL) was added bromotoluene (146. Mu.L, 1.23 mmol) and triethylamine (343. Mu.L, 2.46 mmol) at room temperature in a sealed tube. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL) and then water (10 mL) and DCM (10 mL) were added. The aqueous layer was extracted with dichloromethane (2X 5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the crude product by flash chromatography on silica gel using a gradient of 0% to 20% ethyl acetate in cyclohexane afforded the title compound as a colourless oil (278 mg, purity 100%, yield 93%, t) _r =0.57 min). LCMS (method E): m/z found 313.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)7.45–7.21(m，8H)，3.57(s，2H)，2.95(dt，J＝12.7，3.2Hz，2H)，2.36(td，J＝12.3，2.2Hz，2H)，2.24(dq，J＝13.3，2.7Hz，2H)，2.07–1.99(m，2H)。

Step 3: synthesis of 1-benzyl-4- (2, 5-difluorophenyl) piperidine-4-carboxamide

1-benzyl-4- (2, 5-difluorophenyl) piperidine-4-carbonitrile (86%, 274 mg,0.765 mmol) was reacted in H in a round bottom flask ₂ SO ₄ The mixture of (3 mL) and water (0.76. Mu.L) was stirred at 65℃for 1 hour. The mixture was poured into ice water and basified with 30% aqueous naoh to achieve ph=10-11. 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 over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white gum (278 mg, purity 81%, yield 89%, t) _r =0.50 min). LCMS (method E): m/z found 331.4[ M+H ]] ⁺ ； ¹ H-NMR (DMSO, 400 MHz): delta (ppm) 7.36-7.11 (m, 8H), 6.95 (d, j=13.2 hz, 2H), 3.42 (s, 2H), 2.46 (s, 1H), 2.43-2.29 (m, 5H), 1.95 (ddd, j=13.0, 9.2,3.6hz, 2H). The product was used in the next step without further purificationAnd (3) step (c).

Step 4: synthesis of 1-benzyl-4- (2, 5-difluorophenyl) piperidin-4-amine

Into the sealed tube was charged 1-benzyl-4- (2, 5-difluorophenyl) piperidine-4-carboxamide (81%, 278mg,0.682 mmol) followed by acetonitrile (1.931 mL) and water (1.931 mL). Next, [ bis (trifluoroacetoxy) iodo ] was added ]Benzene (96%, 311mg,0.695 mmol) and the reaction was stirred at room temperature for 2 hours. Acetonitrile was evaporated, then saturated aqueous sodium bicarbonate (5 mL), water (5 mL) and dichloromethane (10 mL) were added. The aqueous layer was extracted with dichloromethane (2X 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in diethyl ether (4 mL) and Et with 2M hydrogen chloride was added ₂ O solution (3.4 mL,6.82 mmol). The reaction mixture was stirred at room temperature for 2 hours, filtered, washed with diethyl ether and dried in vacuo at 50 ℃ for 3 days to give the hydrochloride salt of the title compound as an off-white powder (293 mg, purity 70%, yield 100%, t _r =0.40 min). LCMS (method E): m/z found 303.4[ M+H ]] ⁺ 。

Step 5: synthesis of N- [ 1-benzyl-4- (2, 5-difluorophenyl) -4-piperidinyl ] -4- (trifluoromethoxy) benzenesulfonamide

A sealed vial was charged with a solution of 1-benzyl-4- (2, 5-difluorophenyl) piperidin-4-amine hydrochloride (100%, 290mg,0.959 mmol), N-dimethylpyridin-4-amine (99%, 24mg,0.192 mmol) and triethylamine (0.53 mL,3.84 mmol) in DCM (9 mL) in sequence. 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 0.25mL,1.44 mmol) was then added to the reaction mixture and stirred at 40℃for 4 hours. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The layers were separated. The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate Filtered, and concentrated under reduced pressure. The resulting yellow oil was triturated in a minimum amount of MeOH at 0 ℃. The precipitate was filtered, washed twice with MeOH, and dried in vacuo at 45 ℃ for 18 hours to give the title compound as a white powder (106.6 mg). The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel using a gradient of 0% to 5% methanol in dichloromethane. The desired fractions were combined and concentrated. The solid was dried in vacuo at 45 ℃ for 18 hours to give the title compound as an off-white solid (153 mg, purity 100%, yield 30.3%, t _r =0.72 min). LCMS (method E): m/z found 527.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)8.20(s，1H)，7.50–7.42(m，2H)，7.37–7.20(m，7H)，7.09(ddd，J＝9.8，6.3，3.2Hz，1H)，6.90(ddt，J＝10.6，7.1，3.2Hz，1H)，6.51(ddd，J＝11.6，9.0，4.8Hz，1H)，3.46(s，2H)，2.63–2.51(m，2H)，2.51–2.38(m，4H)，1.90(s，2H)。

Step 6: synthesis of N- (4- (2, 5-difluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (88)

To N- [ 1-benzyl-4- (2, 5-difluorophenyl) -4-piperidinyl in nitrogen]A stirred suspension of 4- (trifluoromethoxy) benzenesulfonamide (260 mg,0.494 mmol) in DCE (1.5094 mL) was added 1-chloroethylcarbonate (95%, 112. Mu.L, 0.988 mmol). The reaction mixture was stirred at room temperature overnight. The suspension was concentrated under reduced pressure. The residue was dissolved in MeOH (1.5094 mL) and the mixture was stirred at 65 ℃ for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting off-white solid was triturated in a mixture of dichloromethane and methanol (95:5, 10 mL) for 1 hour, then the resulting white powder was filtered and washed twice with DCM and dried in vacuo at 45 ℃ for about 72 hours. The white powder was triturated with diethyl ether (4 mL) and then 2M HCl (2.0 mL,4.00 mmol) was added. The mixture was stirred at room temperature overnight, filtered and dried under vacuum at 45 c overnight to give the hydrochloride salt of the title compound as a white powder (88 mg, Purity 95.84%, yield 36.6%, t _r =1.23 min). LCMS (method C): m/z found 437[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.86(br s，2H)，8.60(s，1H)，7.40-7.47(m，2H)，7.26-7.32(m，2H)，7.13(ddd，J＝9.8，6.4，3.2Hz，1H)，6.95(ddt，J＝8.9，7.3，3.5Hz，1H)，6.55(ddd，J＝11.7，9.0，4.8Hz，1H)，3.23(br d，J＝6.6Hz，4H)，2.67(br d，J＝12.7Hz，2H)，2.02-2.15(m，2H)。

Example 53: n- (1- (3, 4-dichlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide (89)

Step 1: synthesis of 1- (3, 4-dichlorophenyl) cyclopropyl-1-amine

Ti (O-iPr) was added to a stirred solution of 3, 4-dichlorobenzonitrile (98%, 200mg,1.14 mmol) in diethyl ether (12 mL) at-70℃in dry three-necked round bottom flask under argon ₄ (371. Mu.L, 1.25 mmol) and 3M ethyl magnesium bromide (0.76 mL,2.28 mmol). The reaction mixture was stirred at-70 ℃ for 10min, and then warmed to room temperature and stirred at room temperature for 1 hour. BF is then carried out ₃ OEt (281. Mu.L, 2.28 mmol) was added to the mixture and stirred at room temperature for 1 hour. The reaction mixture was acidified with 1M aqueous HCl (3.5 mL) and Et was added ₂ O (10 mL). 10% aqueous NaOH (11 mL) was added to the resultant to clarify the phase, and the aqueous phase was treated with Et ₂ And O extraction. The combined organic layers were 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 0.2% to 5% MeOH in DCM. The desired fractions were combined and concentrated to give the title compound as an orange oil (48.8 mg, 85% purity, 18% yield, t _r =0.53 min). LCMS (method E): m/z found 202.1[ M+H ]] ⁺ ； ¹ H-NMR(400MHz，DMSO-d ₆ )δ(ppm)：7.61(d，J＝2.3Hz，1H)，7.49(d，J＝8.5Hz，1H)，7.19(dd，J＝8.5，2.3Hz，1H)，2.45(s，2H)，1.01(d，J＝8.2Hz，2H)，0.95(d，J＝8.2Hz，2H)。

Step 2: synthesis of N- (1- (3, 4-dichlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide (89)

4- (trifluoromethoxy) benzenesulfonyl chloride (97%, 38. Mu.L, 0.217 mmol) was added to 1- (3, 4-dichlorophenyl) cyclopropylamine (85%, 47mg,0.196 mmol) and Et in a sealed tube ₃ N (82. Mu.L, 0.588 mmol) in DCM (2 mL). The solution was stirred at room temperature for 18 hours. Additional Et was added at room temperature ₃ N (27. Mu.L, 0.196 mmol) and 4- (trifluoromethoxy) benzenesulfonyl chloride (97%, 17. Mu.L, 0.0980 mmol) and the reaction mixture was stirred for 18 hours. Water (5 mL) was added and the aqueous layer extracted with DCM (2X 10 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 5% to 40% ethyl acetate in heptane to give the title compound as a yellow solid (37.6 mg, purity 99.31%, yield 45%, t) _r =2.74 min). LCMS (method H): m/z found 424.1[ M-H ]] ^- ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.71-9.29(m，1H)，7.60-7.71(m，2H)，7.32-7.41(m，2H)，7.30(d，J＝8.6Hz，1H)，7.26-7.28(m，1H)，7.07(dd，J＝8.3，2.2Hz，1H)，1.05-1.23(m，4H)。

Example 54: n- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (90)

Step 1: synthesis of benzyl 3-hydroxy-3-phenylpiperidine-1-carboxylate

Et to 3M phenylmagnesium bromide in a three neck round bottom flask at 3℃under nitrogen ₂ A stirred solution of O solution (1.7 mL,5.10 mmol) in dry THF (8 mL) was added dropwise to a solution of benzyl 3-oxopiperidine-1-carboxylate (98%, 0.83mL,4.20 mmol) in dry THF (5.5 mL). The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Pouring saturated NH into the reaction mixture ₄ Aqueous Cl (10 mL) and EtOAc (10 mL) were added. The layers were separated. The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product (1.38 g) was placed in DCM (0.7 mL, 5V) and sonicated. The resulting homogeneous solution was added in portions to 27mL of pentane (20V) and the mixture was triturated. The homogeneous mixture was stirred for 1 hour after precipitation was observed. The solid was then filtered and washed with pentane and dried in vacuo at 45 ℃ in an oven to give the desired compound as a yellow solid (961 mg, purity 90%, yield 66%, t _r =0.89 min). LCMS (method D): m/z found 312.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.56–7.49(m，2H)，7.39–7.29(m，7H)，7.28–7.18(m，1H)，5.08(d，J＝12.4Hz，3H)，3.96(d，J＝13.2Hz，1H)，3.74(d，J＝13.2Hz，1H)，3.23(dd，J＝33.2，15.0Hz，1H)，3.11–2.82(m，1H)，2.05–1.82(m，2H)，1.72(d，J＝12.9Hz，1H)，1.46(d，J＝12.3Hz，1H)。

Step 2: synthesis of benzyl 3- [ (2-chloroacetyl) amino ] -3-phenyl-piperidine-1-carboxylate

A round bottom flask was charged with a solution of 3-hydroxy-3-phenyl-piperidine-1-carboxylic acid benzyl ester (90%, 961mg,2.78 mmol) in DCM (4.8 mL) and 2-chloroacetonitrile (5.3 mL,83.3 mmol) at 0deg.C. Trifluoroacetic acid (5.3 mL,69.4 mmol) was added dropwise for 1 hour and the reaction stirred at 0deg.C for 6 hours When (1). The reaction mixture was poured into ice and quenched with saturated aqueous sodium bicarbonate (ph=9). The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried using a phase separator and concentrated under reduced pressure to give the title compound as a yellow oil (1.063 g, 50% purity, 50% yield, t _r =0.91 min). LCMS (method D): m/z found 387.2min [ M+H ]] ⁺ . The crude product was used without further purification.

Step 3: synthesis of 3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester

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Into a round bottom flask was charged 3- [ (2-chloroacetyl) amino ]]A solution of benzyl 3-phenyl-piperidine-1-carboxylate (50%, 1.06g,1.37 mmol) in a mixture of EtOH (12.5 mL) and AcOH (2.5 mL) (5:1 ratio) was added thiourea (0.14 g,1.79 mmol). The reaction mixture was stirred at 80℃for 4 hours. The reaction mixture was cooled to room temperature and stirred at room temperature for 2 days, then heated at 80 ℃ for 5 hours, and cooled to room temperature. The mixture was diluted in DCM and saturated Na was added ₂ CO ₃ The aqueous solution was until ph=9 was reached. The aqueous layer was extracted twice with DCM and the combined organic layers were washed with brine, dried using a phase separator and concentrated under reduced pressure. The resulting gum was dissolved in Et ₂ O and Et with 2M HCl ₂ O solution (6.9 mL,13.7 mmol). The mixture was stirred at room temperature overnight. The precipitate formed was filtered off with Et ₂ O was washed and dried in vacuo at 45℃for 2 hours. A minimum amount of methanol was added to the solid. The resulting homogeneous solution was added to a large amount of Et ₂ O, and the mixture was stirred at room temperature for 4 hours. The precipitate formed was filtered off with Et ₂ O-washing and drying overnight at 45℃under vacuum gave the hydrochloride of the title compound as an off-white solid (372 mg, purity 98%, yield 77%, t) _r =0.60 min). LCMS (method D): m/z found 311.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.60(s，3H)，7.61(d，J＝7.4Hz，2H)，7.47–7.30(m，8H)，5.12(s，2H)，4.05(s，1H)，3.85(d，J＝13.7Hz，1H)，3.55(s，1H)，3.38(td，J＝8.3，4.0Hz，1H)，2.32–2.22(m，1H)，2.13(d，J＝9.3Hz，1H)，1.81(s，1H)，1.47(s，1H)。

Step 4: synthesis of benzyl 3-phenyl-3- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

A sealed vial was charged with 3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester hydrochloride (98%, 150mg,0.424 mmol), N, N-dimethylpyridine-4-amine (10 mg,0.0848 mmol) and triethylamine (236 μl,1.70 mmol) in DCM (4 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (86 μl,0.509 mmol) was then added to the reaction mixture and stirred at 40 ℃ overnight. The reaction mixture was taken up with DCM and saturated NH ₄ The Cl aqueous solution was diluted. The layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 2% MeOH in DCM. The desired fractions were combined and concentrated. The desired fractions were combined and concentrated to give the title compound as a white solid (150 mg, 97% purity, 66% yield, t) _r =1.05 min). LCMS (method E): m/z found 557.3[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.25(s，1H)，7.32(d，J＝8.5Hz，7H)，7.23–7.13(m，2H)，7.10(s，2H)，6.98(t，J＝7.2Hz，1H)，6.90(s，2H)，5.13(d，J＝45.2Hz，2H)，4.49(d，J＝13.5Hz，1H)，3.58(d，J＝53.0Hz，2H)，3.22(s，1H)，2.22(s，1H)，2.09(s，1H)，1.64(s，1H)，1.14(s，1H)。

Step 5: synthesis of N- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (90)

In a four-necked round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, 3-phenyl-3- [ [4- (trifluoromethoxy) phenyl ] was added under nitrogen at room temperature]Sulfonylamino groups]A stirred suspension of benzyl piperidine-1-carboxylate (97%, 150mg,0.272 mmol) in dry ACN (4 mL). Iodo (trimethyl) silane (119 μl,0.838 mmol) was added for 3min, the mixture was stirred at room temperature for 1.5 hours, and concentrated. Et with 2M HCl ₂ O solution (777. Mu.L, 1.55 mmol) then Et ₂ O (2 mL) was added to the residue and the suspension was stirred at room temperature for 2.5 hours. MeOH (124 μl) was added and the mixture was stirred at room temperature for 1 hour and filtered. The residue was taken up in Et ₂ O was washed and dried under reduced pressure at 45℃overnight. The residue was dissolved in MeOH (2 mL) and then 7N NH ₃ To the stirred solution (from a clear yellow to a colorless solution) was added MeOH (124 μl). The resulting solution was stirred at room temperature for 2 hours and concentrated. The residue was added to a stirred mixture of water (3 mL), DCM (1.5 mL), and MeOH (51. Mu.L). Next, saturated Na was added ₂ CO ₃ Aqueous (4 mL) until ph=8-9 is reached. The mixture was stirred at room temperature overnight and the layers were separated. The combined organic layers were washed with saturated aqueous NaCl, dried using a phase separator and concentrated in vacuo to give the title compound as a white powder (78 mg, purity 100%, yield 72%, t) _r =0.64 min). LCMS (method E): m/z found 401.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.90(s，1H)，7.43–7.34(m，2H)，7.21(dq，J＝7.8，1.1Hz，2H)，7.15–7.05(m，2H)，7.03–6.91(m，3H)，3.18(dd，J＝13.2，2.3Hz，1H)，2.87–2.79(m，1H)，2.73(d，J＝13.2Hz，1H)，2.47(d，J＝21.4Hz，2H)，2.08(s，1H)，1.89(ddd，J＝13.5，11.0，3.7Hz，1H)，1.74–1.60(m，1H)，1.35(dd，J＝11.2，6.7Hz，1H)。

To N- (3-phenyl-3-piperidinyl) -4- (trifluoromethoxy) benzenesulfonamide (78 mg,0.195 mmol) in Et at room temperature in a round bottom flask ₂ A stirred solution in O (2 mL) was added Et with 2M HCl ₂ O solution (974. Mu.L, 1.95 mmol). The reaction mixture was stirred at room temperature overnight. The suspension was filtered, using Et ₂ O-washing and vacuum drying overnight at 45℃gave the hydrochloride salt of the title compound as a white solid (80 mg, purity 99.29%, yield 94%, t) _r =1.21 min). LCMS (method H): m/z found 401.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，600MHz)：δ(ppm)9.50(br s，1H)，8.54(s，1H)，8.29(br s，1H)，7.34(d，J＝8.1Hz，2H)，7.14(d，J＝8.5Hz，2H)，6.97-7.03(m，3H)，6.92-6.96(m，2H)，4.07(br d，J＝12.5Hz，1H)，3.38(br d，J＝12.8Hz，1H)，3.24(br d，J＝12.0Hz，1H)，2.90-2.96(m，1H)，2.44(br d，J＝11.2Hz，1H)，2.05-2.13(m，1H)，1.71-1.80(m，2H)。

Example 55: n- (4- (5-chlorothien-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (91)

Step 1: synthesis of 4- (5-chloro-2-thienyl) -4-cyano-piperidine-1-carboxylic acid tert-butyl ester

A sealed vial was charged under argon with a solution of tert-butyl 4-cyano-4- (thiophen-2-yl) piperidine-1-carboxylate (370 mg,1.27 mmol) in anhydrous DMF (7.3 mL). A solution of N-chlorosuccinimide (203 mg,1.52 mmol) in anhydrous DMF (2.5 mL) was added dropwise at room temperature and the reaction mixture was stirred at room temperature in the dark for 3 days. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (2 mL), and water (2 mL) and dichloromethane (5 mL) were added. The aqueous layer was extracted with dichloromethane (2X 5 mL). The combined organic layers were 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% to 20% ethyl acetate in cyclohexane to give the title compound as a yellow oil (360 mg, 99% purity, 86% yield, t) _r =1.03 min). LCMS (method D); ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.18–7.09(m，2H)，4.09–3.99(m，2H)，3.02(s，2H)，2.28(dq，J＝13.5，2.8Hz，2H)，1.90(ddd，J＝13.5，12.0，4.3Hz，2H)，1.42(s，9H)。

step 2: synthesis of 4- (5-chloro-2-thienyl) piperidine-4-carbonitrile

Into a sealed vial under nitrogen was charged successively 4- (5-chloro-2-thienyl) -4-cyano-piperidine-1-carboxylic acid tert-butyl ester (355 mg,1.09 mmol) and Et with 2M HCl ₂ O solution (4.3 mL,8.69 mmol) in Et ₂ O (3 mL). The reaction mixture was stirred at room temperature for 18 hours. An additional 4M HCl in 1, 4-dioxane (4.1 mL,16.3 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 6 hours. The suspension was filtered, using Et ₂ O (10 mL) and vacuum drying at 50deg.C for 16 hours gave the hydrochloride salt of the title compound as a white powder (254 mg, 100% purity, 89% yield, t) _r =0.49 min). LCMS (method E): m/z found 227.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)9.19(s，2H)，7.18(d，J＝4.0Hz，1H)，7.16(d，J＝4.0Hz，1H)，3.44(dt，J＝13.8，3.7Hz，2H)，3.08(ddd，J＝13.5，12.2，2.9Hz，2H)，2.60–2.51(m，4H)，2.31(ddd，J＝14.2，12.2，4.0Hz，2H)。

Step 3: synthesis of 1-benzyl-4- (5-chloro-2-thienyl) piperidine-4-carbonitrile

To a stirred solution of 4- (5-chloro-2-thienyl) piperidine-4-carbonitrile hydrochloride (254 mg,0.965 mmol) in DMF (2.3 mL) in a sealed tube at room temperature was added benzyl bromide (138. Mu.L, 1.16 mmol) and Et ₃ N (404. Mu.L, 2.90 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL) and water (10 mL) and dichloromethane (10 mL) were added. The aqueous layer was treated with dichloromethane (2X 5 mL) ) And (5) extracting. The combined organic layers were 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% to 20% ethyl acetate in cyclohexane to give the title compound as a colourless oil (285 mg, 100% purity, 93% yield, t _r =0.61 min). LCMS (method E): m/z found 317.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.39–7.22(m，5H)，7.12(d，J＝3.9Hz，1H)，7.10(d，J＝3.9Hz，1H)，3.55(s，2H)，2.89(dt，J＝13.1，3.4Hz，2H)，2.35–2.20(m，4H)，2.04–1.92(m，2H)。

Step 4: synthesis of 1-benzyl-4- (5-chloro-2-thienyl) piperidine-4-carboxamide

1-benzyl-4- (5-chloro-2-thienyl) piperidine-4-carbonitrile (270 mg, 0.850 mmol) in a round bottom flask at 0deg.C ₂ SO ₄ A mixture of (3.6097 mL) and water (0.9024 mL) was stirred at 60℃for 16 h. The mixture was cooled to 0 ℃ and basified with 30% aqueous naoh to reach ph=11. Water and DCM were added and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a pink gum (152 mg, 75% purity, 40% yield, t) _r =0.54 min). LCMS (method E): m/z found 335.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ 400 MHz): delta (ppm) 7.35-7.20 (m, 5H), 6.97 (d, j=3.9 hz, 1H), 6.82 (d, j=3.8 hz, 1H), 3.55 (s, 1H), 3.41 (s, 2H), 2.52 (s, 2H), 2.41-2.14 (m, 4H), 1.87 (d, j=12.2 hz, 2H). The batch was used in the next step without further purification.

Step 5: synthesis of 1-benzyl-4- (5-chloro-2-thienyl) piperidin-4-amine

In sealingThe tube was charged with 1-benzyl-4- (5-chloro-2-thienyl) piperidine-4-carboxamide (75%, 150mg,0.336 mmol) and dissolved in ACN (1 mL) and water (1 mL). Then [ bis (trifluoroacetoxy) iodo]Benzene (96%, 154mg, 0.343mmol) was charged to the reaction vessel and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate (5 mL) was added and the aqueous layer was extracted twice with dichloromethane (2X 10 mL). The combined organic layers were concentrated under reduced pressure and Et was then added ₂ Et of O (4 mL) and 2M HCl ₂ O solution (0.93 mL,1.86 mmol). The suspension was stirred at room temperature for 2 hours, filtered and taken up with Et ₂ O-washing and vacuum drying at 50deg.C for 20 hours gave the hydrochloride salt of the title compound as an off-white powder (145 mg, purity 30%, yield 38%, t) _r =0.44 min). LCMS (method E): m/z 307.3[ M+H ]] ⁺ 。

Step 6: synthesis of N- [ 1-benzyl-4- (5-chloro-2-thienyl) -4-piperidinyl ] -4- (trifluoromethoxy) benzenesulfonamide

A sealed vial was charged with a solution of 1-benzyl-4- (5-chloro-2-thienyl) piperidin-4-amine hydrochloride (30%, 137mg,0.120 mmol), triethylamine (100. Mu.L, 0.718 mmol) and DMAP (7.3 mg,0.0599 mmol) in DCM (2 mL). 4- (trifluoromethoxy) benzenesulfonyl chloride (61. Mu.L, 0.359 mmol) was then added to the reaction mixture and stirred at 40℃for 16 hours. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (4 mL). Water (10 mL) and methylene chloride (10 mL) were added. The aqueous layer was extracted with dichloromethane (2X 10 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (5 mL), 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% to 5% methanol in dichloromethane to give the title compound as an off-white powder (38 mg, 100% purity, 60% yield, t _r =0.74 min). LCMS (method E): m/z found 531.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.17(s，1H)，7.62–7.54(m，2H)，7.39–7.20(m，7H)，6.65(d，J＝3.9Hz，1H)，6.60(d，J＝3.9Hz，1H)，3.42(s，2H)，2.42(s，5H)，2.27(d，J＝13.6Hz，2H)，1.98(s，2H)。

Step 7: synthesis of N- (4- (5-chlorothien-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (91)

To a stirred solution of 1-chloroethylcarbonate (99%, 23. Mu.L, 0.215 mmol) in DCE (1.8 mL) under nitrogen was added N- [ 1-benzyl-4- (5-chloro-2-thienyl) -4-piperidinyl]4- (trifluoromethoxy) benzenesulfonamide (38 mg,0.0716 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (1.8 mL) and the reaction mixture was stirred at 65 ℃ for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was triturated in dichloromethane, filtered, washed with dichloromethane and dried in vacuo. The resulting precipitate was purified by flash chromatography on silica gel using a gradient of 2% to 15% methanolic ammonia in dichloromethane. Et in 2M HCl ₂ Grinding in O solution (358. Mu.L, 0.716 mmol) for 16 hours, filtering and using Et ₂ O-washing and vacuum drying at 50deg.C for 3 days gave the hydrochloride salt of the title compound as a white powder (15.7 mg, purity 99.2%, yield 46%, t) _r =1.4 min). LCMS (method H): m/z found 441.1[ M+H ] ] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δppm2.14(ddd，J＝14.37，10.33，4.16Hz，2H)2.50-2.53(m，2H)3.12-3.23(m，4H)6.61(d，J＝3.91Hz，1H)6.70(d，J＝3.91Hz，1H)7.35(d，J＝8.01Hz，2H)7.57(d，J＝7.88Hz，2H)8.55(br s，1H)8.83(br s，2H)。

Example 56: 3-amino-N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (92)

Step 1: synthesis of benzyl 3- [ [ 3-amino-4- (trifluoromethoxy) phenyl ] sulfonylamino ] -3- (4-fluorophenyl) pyrrolidine-1-carboxylate

In a sealed tube, iron (50 mg,0.895 mmol) and NH ₄ A suspension of Cl (12 mg,0.228 mmol) in EtOH (1.1 mL) and water (360. Mu.L) was stirred at 70℃for 1 hour. Adding 3- (4-fluorophenyl) -3- [ [ 3-nitro-4- (trifluoromethoxy) phenyl group]Sulfonylamino groups]Pyrrolidine-1-carboxylic acid benzyl ester (95 mg,0.163 mmol) and the mixture was stirred at 80 ℃ for 1 hour. The mixture was cooled to room temperature and filtered through a pad of celite. The pad was washed with DCM and the filtrate was diluted with water and DCM. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (83 mg, 99% purity, 91% yield, t) _r =0.95 min). LCMS (method E): m/z found 554.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)8.40(s，1H)，7.45–7.24(m，5H)，7.18–7.03(m，2H)，6.95(ddd，J＝8.5，3.2，1.6Hz，1H)，6.89–6.69(m，3H)，6.51(ddd，J＝8.5，3.5，2.3Hz，1H)，5.65(d，J＝2.9Hz，2H)，5.17–4.98(m，2H)，4.11(dd，J＝16.9，11.2Hz，1H)，3.65–3.34(m，3H)，2.78–2.59(m，1H)，2.17(ddt，J＝17.6，12.5，8.4Hz，1H)。

Step 2: synthesis of 3-amino-N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (92)

Iodo (trimethyl) silane (63 μL,0.445 mmol) was added to 3- [ [ 3-amino-4- (trifluoromethoxy) phenyl ] in a sealed tube under nitrogen ]Sulfonylamino groups]A stirred mixture of benzyl 3- (4-fluorophenyl) pyrrolidine-1-carboxylate (99%, 83mg,0.148 mmol) in dry acetonitrile (2 mL). The mixture is mixedStirred at room temperature for 1.5 hours and then at 0 ℃. MeOH (72 μl,1.78 mmol) was added and the suspension stirred at 0 ℃ for 1 hour and concentrated. Gradient 1% to 16% (MeOH+2% NH) ₄ OH) in DCM the crude product was purified by flash chromatography on silica gel. The desired fractions were concentrated and dissolved in MeOH. Et with HCl 2N added dropwise ₂ O solution and the mixture was stirred at room temperature for 1 hour. The suspension was filtered and the residue was taken up in Et ₂ O-washing and drying under reduced pressure at 45℃for 16 hours gave the hydrochloride of the title compound as a white powder (16.8 mg, purity 99.4%, yield 24%, t) _r =1.03 min). LCMS (method H): m/z found 420.2[ M+H ]] ⁺ ； ¹ H-NMR(600MHz，DMSO-d ₆ )δ9.59–9.18(m，2H)，8.46(s，1H)，7.10(dd，J＝8.5，5.3Hz，2H)，6.92(d，J＝7.9Hz，1H)，6.79(t，J＝8.7Hz，2H)，6.67(d，J＝2.3Hz，1H)，6.48(dd，J＝8.5，2.3Hz，1H)，5.97–5.13(m，2H)，4.08(br dd，J＝11.8，5.9Hz，1H)，3.36–3.31(m，3H)，2.88–2.75(m，1H)，2.13(dt，J＝13.2，9.8Hz，1H)。

Example 57: 3-amino-N- (3- (4-fluoro-3-methylphenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (93)

Step 1: synthesis of 3- (4-fluoro-3-methyl-phenyl) -3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester

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Magnesium (266 mg,10.9 mmol) and crystal I were stirred at room temperature under nitrogen in a three-necked round bottom flask equipped with thermometer, addition funnel and reflux condenser ₂ A suspension in dry THF (8.4 mL). The addition funnel was charged with a solution of 4-bromo-1-fluoro-2-methylbenzene (970 μl,7.63 mmol) in dry THF (3.6 mL) and several drops were added to the reaction mixture. The orange suspension was stirred at 65℃untilTo color change and the remaining solution was added dropwise. The mixture was stirred at 65 ℃ for 1 hour and cooled to 0 ℃. A solution of benzyl 3-oxopyrrolidine-1-carboxylate (1200 mg,5.47 mmol) in dry THF (3.6 mL) was added dropwise at 0deg.C and the mixture stirred at 0deg.C for 1 hr. Dropwise addition of saturated NH ₄ Aqueous Cl followed by dropwise addition of EtOAc. The mixture was stirred at room temperature for 16 hours to dissolve the remaining Mg, and the aqueous layer was extracted 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 5% MeOH in DCM to give the title compound as a colourless oil (1322 mg, purity 65%, yield 48%, t _r =0.91 min). LCMS (method D): m/z found 330.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.46–7.27(m，7H)，7.09(ddd，J＝9.8，8.6，3.8Hz，1H)，5.45(d，J＝1.8Hz，1H)，5.16–5.04(m，2H)，3.65–3.41(m，4H)，2.24(t，J＝2.5Hz，4H)，2.03(dt，J＝12.9，6.7Hz，1H)。

Step 2: synthesis of benzyl 3- [ (2-chloroacetyl) amino ] -3- (4-fluoro-3-methyl-phenyl) pyrrolidine-1-carboxylate

2, 2-trifluoro-acetic acid (7.8 mL,0.102 mol) was added dropwise to a stirred solution of 3- (4-fluoro-3-methyl-phenyl) -3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (1343 mg,4.08 mmol) and 2-chloroacetonitrile (7.7 mL,0.122 mol) in DCM (7.2016 mL) in a round bottom flask at 0deg.C. The mixture was stirred at 0 ℃ for 6 hours and poured into ice. Adding saturated Na ₂ CO ₃ The aqueous solution was brought to ph=9 and the mixture was extracted twice with DCM. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated to give a mixture of the title compounds as an oil (1.4 g, purity 50%, yield 43%, t _r =0.91 min). LCMS (method D): m/z found 405.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.76(d，J＝3.7Hz，1H)，7.50–7.23(m，10H)，7.23–7.00(m，2H)，5.23–4.98(m，4H)，4.50(d，J＝20.7Hz，1H)，4.30(d，J＝23.7Hz，1H)，4.12–3.92(m，2H)，3.65(dd，J＝25.9，11.3Hz，1H)，3.45(ddd，J＝17.2，8.9，5.6Hz，2H)，2.70–2.52(m，1H)，2.39–2.13(m，4H)。

Step 3: synthesis of benzyl 3-amino-3- (4-fluoro-3-methyl-phenyl) pyrrolidine-1-carboxylate

Thiourea (171 mg,2.25 mmol) was added to 3- [ (2-chloroacetyl) amino group in a sealed tube]-benzyl 3- (4-fluoro-3-methyl-phenyl) pyrrolidine-1-carboxylate (50%, 1.40g,1.73 mmol) in a stirred solution of EtOH (12.5 mL) and AcOH (2.5 mL). The mixture was stirred at 80 ℃ for 16 hours and poured into water. Adding saturated Na ₂ CO ₃ The aqueous solution was brought to ph=9 and the mixture was extracted three times with DCM. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in Et ₂ O+meoh, and Et with 2M HCl added ₂ O solution (8.6 mL,17.3 mmol). The mixture was stirred at room temperature for 16 hours, filtered and dried under vacuum to give the hydrochloride salt of the title compound as an off-white solid (478 mg, 95% purity, 76% yield, t) _r =0.62 min). LCMS (method E): m/z found 329.2[ M+H ] ] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.71(s，3H)，7.52(d，J＝5.9Hz，1H)，7.45–7.29(m，6H)，7.24(td，J＝9.1，5.9Hz，1H)，5.13(d，J＝2.3Hz，2H)，4.09(dd，J＝11.9，6.8Hz，1H)，3.82–3.49(m，3H)，2.59(t，J＝10.2Hz，1H)，2.49–2.39(m，1H)，2.27(t，J＝2.5Hz，3H)。

Step 4: synthesis of benzyl 3- (4-fluoro-3-methyl-phenyl) -3- [ [ 3-nitro-4- (trifluoromethoxy) phenyl ] sulfonylamino ] pyrrolidine-1-carboxylate

A solution of 3-amino-3- (4-fluoro-3-methyl-phenyl) pyrrolidine-1-carboxylic acid benzyl ester hydrochloride (178 mg,1.31 mmol), triethylamine (913. Mu.L, 6.55 mmol) and 4-dimethylaminopyridine (32 mg,0.262 mmol) in dry DCM (11 mL) was stirred at room temperature under nitrogen in a sealed tube. Next, 3-nitro-4- (trifluoromethoxy) benzene-1-sulfonyl chloride (400 mg,1.31 mmol) was added dropwise and the mixture was stirred at 40℃for 16 hours. The mixture was washed with DCM and half saturated NaHCO ₃ Diluting the aqueous solution. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using a gradient of 20% to 70% EtOAc in heptane to give the title compound as a yellow solid. (170 mg, purity)>90%, yield 21%, t _r =1.04 min). LCMS (method D): m/z found 598.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.84(s，1H)，7.90(dd，J＝8.8，2.2Hz，1H)，7.82–7.62(m，2H)，7.47–7.25(m，5H)，7.04–6.82(m，2H)，6.71(q，J＝8.4Hz，1H)，5.11(d，J＝2.3Hz，2H)，4.22(dd，J＝17.4，11.2Hz，1H)，3.51(ddd，J＝36.2，19.1，10.2Hz，3H)，2.78(s，1H)，2.29–2.08(m，1H)，1.99(dd，J＝4.5，1.8Hz，3H)。

Step 5: synthesis of N- [3- (4-fluoro-3-methyl-phenyl) pyrrolidin-3-yl ] -3-nitro-4- (trifluoromethoxy) benzenesulfonamide

Iodo (trimethyl) silane (121 μl,0.853 mmol) was added to 3- (4-fluoro-3-methyl-phenyl) -3- [ 3-nitro-4- (trifluoromethoxy) phenyl ] in a sealed tube under nitrogen ]Sulfonylamino groups]A stirred mixture of pyrrolidine-1-carboxylic acid benzyl ester (170 mg,0.284 mmol) in dry acetonitrile (3.4 mL). The mixture was stirred at room temperature for 1 hour and concentrated. Gradient 1% to 10% (MeOH+2% NH) ₄ OH) purification of the crude product by flash chromatography on silica gel to give the title compound as a yellow solid [ (]24mg, purity 76%, yield 13%, t _r =0.67 min). LCMS (method E): m/z found 464.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.95–7.62(m，2H)，7.48–7.17(m，1H)，7.12–6.82(m，2H)，6.80–6.60(m，1H)，3.72–3.41(m，1H)，3.11(dt，J＝10.5，7.9Hz，1H)，2.98–2.78(m，2H)，2.60(ddd，J＝11.8，7.8，3.6Hz，1H)，2.08–1.87(m，3H)。

Step 6: synthesis of 3-amino-N- [3- (4-fluoro-3-methyl-phenyl) pyrrolidin-3-yl ] -4- (trifluoromethoxy) benzenesulfonamide (93)

In a sealed tube, iron (16 mg,0.284 mmol) and NH ₄ A suspension of Cl (3.9 mg,0.0725 mmol) in EtOH (350. Mu.L) and water (115. Mu.L) was stirred at 70℃for 1 hour. Adding N- [3- (4-fluoro-3-methyl-phenyl) pyrrolidin-3-yl]A solution of 3-nitro-4- (trifluoromethoxy) benzenesulfonamide (24 mg,0.0518 mmol) in EtOH (350. Mu.L) and the mixture was stirred at 80℃for 45min. The mixture was cooled to room temperature and filtered through a pad of celite. The pad was washed with EtOH and DCM and the filtrate was concentrated. The residue was dissolved in DCM and water, and 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 flash chromatography on silica gel using a gradient of 2% to 20% MeOH in DCM. The desired fractions were concentrated and Et ₂ O was added to the residue. Et with 2N HCl ₂ The O solution was added to the residue and the suspension was stirred at room temperature for 16 hours and filtered. The residue was taken up in Et ₂ O-washing and drying under reduced pressure at 45℃for 16 hours gave the title compound as a white powder (5 mg, purity 95.5%, yield 19%, t) _r =1.22 min). LCMS (method H): m/z found 434.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.87-9.25(m，2H)，7.59-7.84(m，2H)，7.36(br d，J＝8.3Hz，2H)，7.00-7.27(m，4H)，3.12-3.55(m，4H)，2.51-2.80(m，2H)，1.72-2.25(m，2H)。

Example 58: n- (4- (4-chloro-2-fluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (94)

Step 1: synthesis of 4- (4-chloro-2-fluoro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester

A solution of 4- (4-chloro-2-fluorophenyl) piperidine-4-hydrochloride (500 mg,1.88 mmol) and triethylamine (1.0 mL,7.51 mmol) in MeOH (5 mL) was stirred at 0deg.C under nitrogen in a round bottom flask. Benzyl chloroformate (265 μl,1.88 mmol) was added dropwise and the mixture was stirred at room temperature for 16 hours. The mixture was treated with half saturated NaHCO ₃ And DCM dilution. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using a gradient of 0.4% to 5% MeOH in DCM to give the title compound as a colourless oil (150 mg, 98% purity, 21% yield, t _r =1.7 min). LCMS (method E): m/z found 364.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.65(t，J＝8.7Hz，1H)，7.44–7.26(m，7H)，5.50(s，1H)，5.11(s，2H)，4.00–3.86(m，2H)，3.26(d，J＝23.4Hz，2H)，2.03(td，J＝13.1，4.8Hz，2H)，1.59(d，J＝13.3Hz，2H)。

Step 2: synthesis of benzyl 4- [ (2-chloroacetyl) amino ] -4- (4-chloro-2-fluoro-phenyl) piperidine-1-carboxylate

TFA (789. Mu.L, 10.3 mmol) was added to 4- (4-chloro-2-fluoro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester (150 mg,0.412 mmol) and 2-propenoic acid benzyl ester (150 mg,0.412 mmol) under nitrogen in a sealed tube at 0deg.CA stirred solution of chloroacetonitrile (783. Mu.L, 12.4 mmol) in dry DCM (730. Mu.L). The mixture was stirred at 0 ℃ for 7 hours and then at room temperature for 16 hours. The mixture was poured into ice and saturated Na was added ₂ CO ₃ Aqueous solution until ph=10. The mixture was extracted twice with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a colourless oil (175 mg, 80% purity, 77% yield, t) _r =0.95 min). LCMS (method E): m/z found 439.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.58(s，1H)，7.46–7.29(m，7H)，7.24(dd，J＝8.5，2.3Hz，1H)，5.10(s，2H)，4.09(s，2H)，3.92(d，J＝13.5Hz，2H)，3.16(s，2H)，2.45(d，J＝13.3Hz，2H)，1.88(td，J＝13.0，4.4Hz，2H)。

Step 3: synthesis of benzyl 4-amino-4- (4-chloro-2-fluoro-phenyl) piperidine-1-carboxylate

In a sealed tube, 4- [ (2-chloroacetyl) amino group]A solution of benzyl 4- (4-chloro-2-fluoro-phenyl) piperidine-1-carboxylate (175 mg,0.398 mmol) in EtOH (2.6 mL) and AcOH (530. Mu.L) was stirred at room temperature. Thiourea (39 mg,0.518 mmol) was added and the mixture was stirred at 80℃for 16 h and poured into ice. Adding saturated Na ₂ CO ₃ The aqueous solution was brought to ph=9 and the mixture 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 (120 mg, purity 90%, yield 83%, t _r =0.65 min). LCMS (method E): m/z found 363.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)7.63(dd，J＝9.3，8.6Hz，1H)，7.44–7.19(m，7H)，5.10(s，2H)，3.82(d，J＝13.3Hz，2H)，3.39(s，2H)，2.47–2.06(m，2H)，2.06–1.92(m，2H)，1.58(d，J＝13.1Hz，2H)，1.30–1.13(m，1H)。

Step 4: synthesis of benzyl 4- (4-chloro-2-fluoro-phenyl) -4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

A solution of benzyl 4-amino-4- (4-chloro-2-fluoro-phenyl) piperidine-1-carboxylate (115 mg,0.317 mmol), triethylamine (221. Mu.L, 1.58 mmol) and 4-dimethylaminopyridine (7.7 mg,0.0634 mmol) in dry DCM (2 mL) was stirred at room temperature under nitrogen in a sealed tube. 4- (trifluoromethoxy) benzenesulfonyl chloride (98%, 84mg,0.317 mmol) was added dropwise and the mixture was stirred at 40℃for 16 hours. The mixture was washed with DCM and half saturated NaHCO ₃ And (5) diluting. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using a gradient of 20% to 70% EtOAc in heptane to give the title compound as a white solid (60 mg, 99% purity, 31% yield, t _r =1.08 min). LCMS (method E): m/z found 609.3[ M+Na] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.84(s，1H)，7.90(dd，J＝8.8，2.2Hz，1H)，7.82–7.62(m，2H)，7.47–7.25(m，5H)，7.04–6.82(m，2H)，6.71(q，J＝8.4Hz，1H)，5.11(d，J＝2.3Hz，2H)，4.22(dd，J＝17.4，11.2Hz，1H)，3.51(ddd，J＝36.2，19.1，10.2Hz，3H)，2.78(s，1H)，2.29–2.08(m，1H)，1.99(dd，J＝4.5，1.8Hz，3H)。

Step 5: synthesis of N- (4- (4-chloro-2-fluorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (94)

Iodo (trimethyl) silane (44 μl,0.307 mmol) was added to 4- (4-chloro-2-fluoro-phenyl) -4- [ [4- (trifluoromethoxy) phenyl ] under nitrogen]Sulfonylamino groups]Benzyl piperidine-1-carboxylate (60 mg,0.102 mmol) was added to a stirred solution. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in ACN and concentrated. Will remain behindThe material was dissolved in DCM/MeOH 9/1 and half saturated Na ₂ CO ₃ In an aqueous solution. The organic layer was treated with half saturated NaHCO ₃ The aqueous solution was washed twice, washed with brine, dried over sodium sulfate, filtered and concentrated. Et is added to ₂ O was added to the residue followed by Et with 2N HCl ₂ O solution. The suspension was stirred at room temperature for 16 hours and filtered. The residue was taken up in Et ₂ O-washing and drying under reduced pressure at 45℃for 16 hours gave the hydrochloride of the title compound as a white powder (31 mg, purity 96.5%, yield 59%, t) _r =1.45 min). LCMS (method H): m/z found 453.1[ M+H ]] ⁺ ； ¹ H-NMR(600MHz，DMSO-d ₆ )δ8.75(br s，2H)，8.61(s，1H)，7.43–7.36(m，2H)，7.35–7.29(m，1H)，7.27(d，J＝8.1Hz，2H)，7.15(dd，J＝8.4，2.1Hz，1H)，6.61(dd，J＝12.0，2.2Hz，1H)，3.28–3.16(m，4H)，2.74–2.62(m，2H)，2.15–1.96(m，2H)。

Example 59: n- (4- (5-chloro-3-fluoropyridin-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (95)

Step 1: synthesis of 1-benzyl-4- (5-chloro-3-fluoro-2-pyridinyl) piperidine-4-carbonitrile

To a stirred solution of 1-benzylpiperidine-4-carbonitrile (300 mg,1.50 mmol) in anhydrous toluene (14.979 mL) was added 2-bromo-5-chloro-3-fluoropyridine (98%, 322mg,1.50 mmol) at room temperature under nitrogen in a sealed tube. The reaction mixture was cooled to 0deg.C and 1M sodium 1, 3-hexamethyldisilazane (NaHMDS) (3.0 mL,3.00 mmol) was added dropwise. The solution was stirred at 0deg.C for 1 hour, then saturated NH ₄ The aqueous Cl solution was quenched to ph=7 and DCM was added. The aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. DCM dissolution using a gradient of 2% to 6% MeOHThe crude product was purified by flash chromatography on silica gel. The desired fractions were combined and concentrated under reduced pressure to give the title compound as a pale yellow solid (222 mg, 96% purity, 43% yield, t) _r =0.57 min). LCMS (method E): m/z found 330.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.58(dd，J＝2.1，0.9Hz，1H)，8.24(dd，J＝11.2，2.0Hz，1H)，7.33(d，J＝4.9Hz，4H)，7.30–7.22(m，1H)，3.56(s，2H)，2.98–2.89(m，2H)，2.36(td，J＝11.9，2.9Hz，2H)，2.25–2.10(m，4H)。

Step 2: synthesis of 1-benzyl-4- (5-chloro-3-fluoro-2-pyridinyl) piperidine-4-carboxamide

1-benzyl-4- (5-chloro-3-fluoro-2-pyridinyl) piperidine-4-carbonitrile (282 mg,0.855 mmol) in H in a round bottom flask ₂ SO ₄ The mixture of (3.425 mL) and water (0.8563 mL) was stirred at 65deg.C for 3.5 hours. The mixture was poured into ice water and basified (about 10 mL) with 30% aqueous naoh to reach ph=10 (precipitation). Water and DCM were added and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, filtered through a phase separator and concentrated under reduced pressure to give the title compound as a white powder (247 mg, purity 95%, yield 79%, t) _r =0.50). LCMS (method E): m/z found 348.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.51(dd，J＝2.1，1.0Hz，1H)，7.99(dd，J＝11.2，2.1Hz，1H)，7.34–7.20(m，5H)，6.98(d，J＝12.5Hz，2H)，3.37(s，2H)，2.52(d，J＝4.0Hz，1H)，2.48(s，1H)，2.29(dd，J＝11.3，5.7Hz，2H)，2.20(t，J＝5.5Hz，4H)。

Step 3: synthesis of 1-benzyl-4- (5-chloro-3-fluoro-2-pyridinyl) piperidin-4-amine

In a round bottom flaskA solution of 1-benzyl-4- (5-chloro-3-fluoro-2-pyridinyl) piperidine-4-carboxamide (247 mg,0.710 mmol) in acetonitrile (1.6423 mL) and water (1.6423 mL) was stirred at room temperature. Adding [ bis (trifluoroacetoxy) iodide ]]Benzene (96%, 324mg,0.724 mmol) and the mixture was stirred at room temperature overnight, then ACN was evaporated. 1N aqueous HCl was added and the mixture was washed twice with DCM. Saturated Na ₂ CO ₃ The aqueous layer was added to the aqueous solution until ph=10. The aqueous layer was extracted three times with DCM, the combined organic layers were washed with brine, filtered through a phase separator and concentrated under reduced pressure to give the title compound as a pale yellow oil (205 mg, purity 91%, yield 82%, t) _r =0.42 min). LCMS (method D): m/z found 320.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.47–8.42(m，1H)，7.98(dd，J＝11.9，2.1Hz，1H)，7.33–7.28(m，4H)，7.23(ddd，J＝8.6，5.6，2.5Hz，1H)，3.46(s，2H)，2.56(td，J＝10.8，2.9Hz，2H)，2.49–2.39(m，2H)，2.16(ddd，J＝13.8，10.3，3.9Hz，2H)，1.99(d，J＝34.5Hz，2H)，1.67(dt，J＝13.1，3.2Hz，2H)。

Step 4: synthesis of N- [ 1-benzyl-4- (5-chloro-3-fluoro-2-pyridyl) -4-piperidinyl ] -4- (trifluoromethoxy) benzenesulfonamide

To a stirred solution of 1-benzyl-4- (5-chloro-3-fluoro-2-pyridinyl) piperidin-4-amine (200 mg,0.625 mmol) in DCM (4.1693 mL) was added triethylamine (0.26 mL,1.88 mmol) and DMAP (7.6 mg,0.0625 mmol) in sequence in a sealed vial. 4- (trifluoromethoxy) benzenesulfonyl chloride (0.13 mL,0.754 mmol) was then added to the reaction mixture and stirred at 40℃overnight. The reaction mixture was cooled to room temperature and taken up with half-saturated Na ₂ CO ₃ Quenching with water solution. The layers were separated. The aqueous layer was extracted once with DCM. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 2% to 10% MeOH in DCM to give the desired compound as an off-white powder (250 mg,purity 98%, yield 72%, t _r =0.71 min). LCMS (method E): m/z found 544.3[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，500MHz)：δ(ppm)8.37(s，1H)，8.34–8.28(m，1H)，7.53–7.48(m，2H)，7.46(dd，J＝11.4，2.1Hz，1H)，7.37–7.28(m，4H)，7.27–7.20(m，3H)，3.40(s，2H)，2.36(d，J＝46.7Hz，6H)，2.10(s，2H)。

Step 5: synthesis of N- (4- (5-chloro-3-fluoropyridin-2-yl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (95)

To N- [ 1-benzyl-4- (5-chloro-3-fluoro-2-pyridinyl) -4-piperidinyl in nitrogen]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (250 mg,0.460 mmol) in DCE (5.7449 mL) was added 1-chloroethyl carbonate (99%, 100. Mu.L, 0.919 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (5.7449 mL) and the reaction mixture was stirred at 65 ℃ for 16 hours. The reaction mixture was cooled to room temperature and filtered. The solid was washed twice with a minimum of MeOH. The filtrate and solids were combined, concentrated in vacuo and concentrated using a gradient of 2% to 15% MeOH (0.7N NH ₃ ) Is purified by flash chromatography on silica gel. Et in 2M HCl ₂ Trituration in O solution (2.3 mL,4.60 mmol) for 4 hours, filtration and washing with diethyl ether and drying under vacuum at 40℃for 20 hours afforded the hydrochloride salt of the title compound as a white powder (135 mg, purity 98.77%, yield 60%, t) _r =1.3 min). LCMS (method H): m/z found 454.1[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.80(br s，2H)，8.76(s，1H)，8.35(s，1H)，7.42-7.52(m，3H)，7.34(d，J＝8.6Hz，2H)，3.16(br s，4H)，2.52-2.58(m，2H)，2.17-2.33(m，2H)。

Example 60: n' - (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonimide amide (96)

Step 1: synthesis of tert-butyl 4- (4-chlorophenyl) -4- [ [ N- [ (3, 4-dimethoxyphenyl) methyl ] -S- [4- (trifluoromethoxy) phenyl ] sulfonylimino ] amino ] piperidine-1-carboxylate

N- [ (3, 4-Dimethoxyphenyl) methyl group was purged in a round bottom flask at 0deg.C under nitrogen]A stirred solution of 4- (trifluoromethoxy) benzenesulfonamide (250 mg,0.666 mmol) in tetrachloromethane (2.5 mL,26.0 mmol) was added t-butyl hypochlorite (0.11 mL,0.932 mmol). The reaction mixture was stirred in the dark at 0 ℃ for 2 hours. The solution was concentrated under reduced pressure at 20 ℃. The residue was dissolved in anhydrous THF (2.0833 mL) and tert-butyl 4-amino-4- (4-chlorophenyl) piperidine-1-carboxylate (228 mg,0.733 mmol), DIPEA (349 μl,2.00 mmol) and N, N-dimethylpyridine-4-amine (99%, 8.2mg,0.0666 mmol) were added sequentially. The reaction mixture was stirred at 40 ℃ overnight. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and EtOAc (20 mL) was added. The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. A gradient of 0.4% to 5% MeOH (0.7N NH was used ₃ ) The crude product was purified by flash chromatography on silica gel to give the title compound as a white foam (235 mg, 89% purity, 46% yield, t) _r =1.12 min). LCMS (method D): m/z found 684.5[ M+H ]] ⁺ ； ¹ H-NMR(DMSO，400MHz)：δ(ppm)7.81(d，J＝9.0Hz，2H)，7.60–7.32(m，5H)，7.26–7.22(m，2H)，7.02–6.96(m，1H)，6.75(d，J＝8.3Hz，1H)，6.61(d，J＝2.2Hz，1H)，6.47(d，J＝8.0Hz，1H)，3.74–3.68(m，6H)，3.64(s，3H)，3.40(s，2H)，2.22(d，J＝13.0Hz，2H)，1.80–1.65(m，2H)，1.39(s，9H)。

Step 2: synthesis of benzyl 3- (4-chlorophenyl) -3- [ [ [4- (trifluoromethoxy) phenyl ] sulfonylimino ] amino ] pyrrolidine-1-carboxylate

To 4- (4-chlorophenyl) -4- [ [ N- [ (3, 4-dimethoxyphenyl) methyl ] in a round-bottomed flask at 0deg.C under nitrogen]S- [4- (trifluoromethoxy) phenyl ]]Sulfonimido group]Amino group]A stirred solution of tert-butyl piperidine-1-carboxylate (278 mg,0.407 mmol) in a mixture of acetonitrile (5.2899 mL) and water (2.645 mL) was added (NH 4) 2Ce (NO 3) ₆ (552 mg,0.988 mmol). The reaction mixture was stirred at 0 ℃ for 3 hours. The reaction mixture was diluted with water. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution and dried over Na ₂ SO ₄ Dried, filtered, concentrated under reduced pressure and concentrated using a gradient of 0% to 6% MeOH (0.7N NH ₃ ) Is purified by flash chromatography on silica gel. The desired fractions were combined and concentrated. The resulting yellow viscous solid was sonicated in diethyl ether and filtered to give the title compound as a white solid (124 mg, 99% purity, 40% yield, t) _r =0.96 min). LCMS (method E): m/z found 534.2[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.09–6.35(m，9H)，4.59(s，1H)，3.70(d，J＝39.0Hz，2H)，3.31(s，2H)，2.64(d，J＝24.5Hz，1H)，2.21(s，1H)，1.60(d，J＝93.6Hz，2H)，1.40(s，9H)。

Step 3: synthesis of 4- (4-chlorophenyl) -N- [ [4- (trifluoromethoxy) phenyl ] sulfonylimino ] piperidin-4-amine (96)

To 4- (4-chlorophenyl) -4- [ [ [4- (trifluoromethoxy) phenyl ] at room temperature under nitrogen]Sulfonimido group]Amino group]Piperidine-1-carboxylic acid tert-butyl ester (99%, 88mg,0.163 mmol) in Et ₂ A stirred suspension in O (1.6315 mL) was added 4M HCl in 1, 4-dioxane (0.41 mL,1.63 mmol). The resulting solution was stirred at room temperatureAfter 3 hours of stirring, an additional 4M HCl in 1, 4-dioxane (0.41 mL,1.63 mmol) was added and the resulting colorless solution was stirred at room temperature overnight. The white suspension obtained was filtered, washed with diethyl ether and dried in vacuo at 40 ℃ for 2 days and at 55 ℃ for 1 day to give the hydrochloride salt of the title compound as a white powder (50.6 mg, purity 100%, yield 70%, t _r =1.32 min). LCMS (method H): m/z found 434[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.87-9.25(m，2H)，7.59-7.84(m，2H)，7.36(br d，J＝8.3Hz，2H)，7.00-7.27(m，4H)，3.12-3.55(m，4H)，2.51-2.80(m，2H)，1.72-2.25(m，2H)。

Example 61: n- (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethyl) benzenesulfonamide (97)

Step 1: synthesis of tert-butyl 4- (4-chlorophenyl) -4- [ [4- (trifluoromethyl) phenyl ] sulfonylamino ] piperidine-1-carboxylate

A sealed vial was charged with a solution of tert-butyl 4-amino-4- (4-chlorophenyl) piperidine-1-carboxylate (200 mg,0.643 mmol), DMAP (16 mg,0.129 mmol) and triethylamine (359. Mu.L, 2.57 mmol) in DCM (10 mL). 4- (trifluoromethyl) benzenesulfonyl chloride (98%, 177mg, 0.706 mmol) was added and the reaction mixture was stirred at 40℃for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (6 mL) and water (3 mL) and dichloromethane (2 mL) were added. The organic layer was dried by using a phase separator and evaporated to dryness. The crude product was precipitated in DCM (1 mL) to give the title compound as a white powder (160 mg, purity 100%, yield 47.9%, t) _r =2.01 min). LCMS (method G): m/z found 419.3[ M-tBu-CO ] ₂ +H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.32(s，1H)，7.59(d，J＝8.4Hz，2H)，7.45(d，J＝8.2Hz，2H)，7.05(d，J＝8.7Hz，2H)，6.92(d，J＝8.7Hz，2H)，3.70(d，J＝13.4Hz，2H)，3.25(s，2H)，2.37(d，J＝13.5Hz，2H)，1.73(t，J＝10.5Hz，2H)。

Step 2: synthesis of N- (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethyl) benzenesulfonamide (97)

In a sealed tube, 4- (4-chlorophenyl) -4- [ [4- (trifluoromethyl) phenyl ]]Sulfonylamino groups]Piperidine-1-carboxylic acid tert-butyl ester (100%, 160mg,0.308 mmol) in Et ₂ A white heterogeneous stirred suspension in O (1.5 mL) was added to Et of 2M HCl ₂ O solution (4.6 mL,9.25 mmol). The mixture was stirred at room temperature for 18 hours. A solution of 4M HCl in 1, 4-dioxane (1.2 mL,4.62 mmol) was added. The mixture was stirred at room temperature for 18 hours. A solution of 4M HCl in 1, 4-dioxane (0.39 mL,1.54 mmol) was added at room temperature. The mixture was stirred at room temperature for 5 days and then filtered and taken up with Et ₂ O (1 mL) to give the hydrochloride salt of the title compound as a white powder (109 mg, purity 100%, yield 77.6%, t) _r =1.74 min). LCMS (method H): m/z found 419[ M+H ]] ⁺ ； ¹ H-NMR(600MHz，DMSO-d ₆ )δppm 8.85(br s，2H)8.63(br s，1H)7.58(d，J＝8.36Hz，2H)7.44(d，J＝8.22Hz，2H)7.05(d，J＝8.66Hz，2H)6.94(d，J＝8.80Hz，2H)3.15-3.28(m，4H)2.58(br d，J＝13.50Hz，2H)1.93-2.15(m，2H)。

Example 62: n- (4- (4-chlorophenyl) piperidin-4-yl) -3- (trifluoromethyl) bicyclo [1.1.1] pentane-1-sulfonamide (98)

Step 1: synthesis of tert-butyl 4- (4-chlorophenyl) -4- [ [3- (trifluoromethyl) -1-bicyclo [1.1.1] pentyl ] sulfonylamino ] piperidine-1-carboxylate

A sealed vial was charged with a solution of tert-butyl 4-amino-4- (4-chlorophenyl) piperidine-1-carboxylate (200 mg,0.643 mmol), DMAP (16 mg,0.129 mmol) and triethylamine (359. Mu.L, 2.57 mmol) in DCM (10 mL). Adding 3- (trifluoromethyl) bicyclo [1.1.1 ]Pentane-1-sulfonyl chloride (95%, 175mg, 0.706 mmol) and the reaction mixture was stirred at 40 ℃ for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (6 mL) and water (3 mL) and dichloromethane (2 mL) were added. The organic layer was dried using a phase separator and evaporated to dryness. The crude product was purified by flash chromatography on silica gel using a gradient of 0% to 100% EtOAc in heptane to give the title compound as a white powder (36 mg, 100% purity, 11% yield, t _r =1.95 min). LCMS (method G): m/z found 409.2[ M-CO ] ₂ tBu+H] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δppm 1.39(s，9H)1.77-1.90(m，2H)1.96(s，6H)2.24-2.40(m，2H)3.20-3.30(m，2H)3.58(dt，J＝13.51，4.00Hz，2H)7.44-7.48(m，2H)7.50-7.55(m，2H)7.77(s，1H)。

Step 2: synthesis of N- (4- (4-chlorophenyl) piperidin-4-yl) -3- (trifluoromethyl) bicyclo [1.1.1] pentane-1-sulfonamide (98)

In a sealed tube, 4- (4-chlorophenyl) -4- [ [3- (trifluoromethyl) -1-bicyclo [1.1.1]Amyl group]Sulfonylamino groups]Piperidine-1-carboxylic acid tert-butyl ester (36 mg,0.0707 mmol) in Et ₂ A white, homogeneously stirred solution in O (1 mL) was added 4M HCl in 1, 4-dioxane (0.35 mL,1.41 mmol). The mixture was stirred at room temperature for 5 days. A solution of 4M HCl in 1, 4-dioxane (0.35 mL,1.41 mmol) was added. The mixture was stirred at room temperature for 18 hours. A solution of 4M HCl in 1, 4-dioxane (0.21 mL,0.849 mmol) was added at room temperature. The mixture was stirred at room temperature for 18 hours, then 4M HCl in 1, 4-dioxane (0.21 ml,0.849 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered And use Et ₂ O (1 mL) to give the hydrochloride salt as a white powder (15.5 mg, purity 99.2%, yield 48.8%, t) _r =1.28 min). LCMS (method H): m/z found 409.1[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)δ8.75(br s，2H)，8.05(s，1H)，7.53(d，4H，J＝2.7Hz)，3.1-3.3(m，4H)，2.5-2.6(m，2H)，2.1-2.2(m，2H)，1.96(s，6H)。

Example 63: 3-amino-N- (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (99)

Step 1: synthesis of tert-butyl 4- (4-chlorophenyl) -4- [ [ 3-nitro-4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

3-nitro-4- (trifluoromethoxy) benzene-1-sulfonyl chloride (98 mg,0.322 mmol) was added to a stirred solution of tert-butyl 4-amino-4- (4-chlorophenyl) piperidine-1-carboxylate (100 mg,0.322 mmol), triethylamine (224 μl,1.61 mmol) and 4-dimethylaminopyridine (7.9 mg,0.0643 mmol) in dry DCM (2 mL) under nitrogen in a sealed tube and stirred at 40 ℃ for 16 hours. The mixture was washed with DCM and half saturated NaHCO ₃ And (5) diluting. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification of crude product by flash chromatography on silica gel using a gradient of 0.4% to 5% (meoh+2% nh) ₄ OH) in DCM to give the title compound as a yellow solid (88 mg, 93% purity, 43% yield, t) _r =1.06 min). LCMS (method E): m/z found 480.3[ M-CO ₂ tBu+H] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.53(s，1H)，7.88(d，J＝2.3Hz，1H)，7.72(dd，J＝8.7，2.3Hz，1H)，7.65(dq，J＝8.7，1.5Hz，1H)，7.17–7.06(m，2H)，7.04–6.95(m，2H)，3.69(d，J＝13.5Hz，2H)，3.43–3.15(m，4H)，2.39(d，J＝13.7Hz，2H)，1.76(t，J＝11.7Hz，2H)，1.40(s，10H)。

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

In a sealed tube, a suspension of iron (43 mg,0.776 mmol) and ammonium chloride (11 mg,0.198 mmol) in EtOH (1 mL) and water (500. Mu.L) was stirred at 70℃for 1 hour. Adding 4- (4-chlorophenyl) -4- [ [ 3-nitro-4- (trifluoromethoxy) phenyl group]Sulfonylamino groups]A solution of tert-butyl piperidine-1-carboxylate (93%, 88mg,0.141 mmol) in EtOH (1 mL) and the mixture was stirred at 80℃for 2 h. The mixture was cooled to room temperature and filtered through a pad of celite. The pad was washed with EtOH and DCM and the filtrate was concentrated. The residue was dissolved in DCM and half saturated NaHCO ₃ The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Using a gradient of 0.4% to 6% (MeOH+2% NH) ₄ The residue was purified by flash chromatography on silica gel from a solution of OH) in DCM to give the expected product as a white solid (65 mg, 98% purity, 82% yield, t _r =1.01 min). LCMS (method E): m/z found 572.3[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)8.03(s，1H)，7.19–7.14(m，2H)，7.08–7.03(m，2H)，6.96(dd，J＝8.5，1.6Hz，1H)，6.78(d，J＝2.3Hz，1H)，6.52(dd，J＝8.5，2.3Hz，1H)，5.63(s，2H)，3.66(d，J＝13.2Hz，2H)，3.14(s，2H)，2.29(d，J＝13.4Hz，2H)，1.69(t，J＝12.7Hz，2H)，1.38(s，9H)。

Step 3: synthesis of 3-amino-N- (4- (4-chlorophenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (99)

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A solution of 4M HCl in 1, 4-dioxane (591. Mu.L, 2.36 mmol) was added to 4- [ [ 3-amino-4- (trifluoromethoxy) phenyl ] in a sealed tube under nitrogen]Sulfonylamino groups]-tert-butyl 4- (4-chlorophenyl) piperidine-1-carboxylate (65 mg,0.118 mmol) in a stirred solution of dried 1, 4-dioxane (1 mL). The mixture was stirred at room temperature for 16 hours and concentrated. The residue was dissolved in hot MeOH and gently stirred Et was added dropwise ₂ O. The resulting suspension was stirred at room temperature for 1 hour and filtered, and the residue was taken up in Et ₂ O-washing and drying under reduced pressure at 45℃for 16 hours gave the hydrochloride of the title compound as a white powder (35 mg, purity 98.4%, yield 59%, t) _r =1.25 min). LCMS (method H): m/z found 450.1[ M+H ]] ⁺ ； ¹ H-NMR(600MHz，DMSO-d6)δppm 8.54-8.73(m，2H)8.24(s，1H)7.11-7.15(m，2H)7.05-7.09(m，2H)6.93(dd，J＝8.58，1.39Hz，1H)6.73(d，J＝2.35Hz，1H)6.47(dd，J＝8.51，2.35Hz，1H)5.64(s，2H)3.14-3.25(m，4H)2.52(br d，J＝1.61Hz，1H)1.95-2.04(m，2H)。

Example 64: n- (4- (4- (difluoromethyl) phenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (100)

Step 1: synthesis of benzyl 4- [4- (difluoromethyl) phenyl ] -4-hydroxy-piperidine-1-carboxylate

A solution of 1-bromo-4- (difluoromethyl) benzene (1.00 g,4.83 mmol) in dry THF (10 mL) was stirred under nitrogen at-78deg.C in a three-neck round bottom flask equipped with a thermometer. 1.6M butyllithium (3.3 mL,5.31 mmol) was added dropwise and the mixture stirred at-78deg.C for 1 hour. A solution of benzyl 4-oxopiperidine-1-carboxylate (1.13 g,4.83 mmol) in dry THF (5 mL) was added dropwise and the mixture stirred at-78deg.C for 1 hour and at room temperature for 1 hour. The mixture is used Saturated NH ₄ The aqueous Cl solution was quenched and extracted three times with EtOAc. The combined organic layers were 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 yellow oil. (1.44 g, purity 80%, yield 66%, t) _r =0.89 min). LCMS (method E): m/z found 362.4[ M+H ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，500MHz)：δ(ppm)7.62(d，J＝8.0Hz，2H)，7.52(d，J＝8.1Hz，2H)，7.42–7.28(m，6H)，7.00(t，J＝56.0Hz，1H)，5.25(s，1H)，5.11(d，J＝12.2Hz，3H)，3.95(dd，J＝12.4，4.0Hz，2H)，3.23(s，2H)，1.86(td，J＝13.1，4.7Hz，2H)，1.60(d，J＝13.2Hz，2H)。

Step 2: synthesis of benzyl 4- [ (2-chloroacetyl) amino ] -4- [4- (difluoromethyl) phenyl ] piperidine-1-carboxylate

/>

4- [4- (difluoromethyl) phenyl ] under nitrogen in a round bottom flask]A solution of benzyl 4-hydroxy-piperidine-1-carboxylate (80%, 1.44g,3.19 mmol) and 2-chloroacetonitrile (6.1 mL,95.6 mmol) in dry DCM (8 mL) was stirred at 0deg.C. 2, 2-trifluoroacetic acid (6.1 mL,79.7 mmol) was added and the green mixture was stirred at 0deg.C for 6 hours and at room temperature for 16 hours. The mixture was poured into ice water and saturated Na was added ₂ CO ₃ Aqueous solution 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 oil (1.67 g, 60% purity, 71% yield, t _r =0.89 min). LCMS (method E): 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，2H)，4.13(s，2H)，3.94(d，J＝13.2Hz，2H)，3.12(s，2H)，2.33(d，J＝13.4Hz，2H)，1.84(td，J＝13.1，4.5Hz，2H)。

Step 3: synthesis of benzyl 4-amino-4- [4- (difluoromethyl) phenyl ] piperidine-1-carboxylate

In a sealed tube, 4- [ (2-chloroacetyl) amino group]-4- [4- (difluoromethyl) phenyl]A solution of benzyl piperidine-1-carboxylate (1.67 g,3.82 mmol) in EtOH (25 mL) and AcOH (5 mL) was stirred at room temperature. Thiourea (378 mg,4.97 mmol) was added and the mixture was stirred at 80℃for 16 hours and poured into ice water. Adding saturated Na ₂ CO ₃ The aqueous solution was brought to ph=9 and the mixture was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was taken up in Et ₂ Stirred in O/MeOH 95/5 (15 mL) and added dropwise to 2M HCl/Et ₂ O (3.8 mL,7.65 mmol). The resulting suspension was stirred at room temperature for 64 hours and filtered. The residue was taken up in Et ₂ O-washing and drying under reduced pressure at 45℃for 4 hours gave the hydrochloride of the title compound as a yellow powder (790 mg, purity 100%, yield 52%, t) _r =0.63 min). LCMS (method D): m/z found 361.2[ 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)。

Step 4: synthesis of benzyl 4- [4- (difluoromethyl) phenyl ] -4- [ [4- (trifluoromethoxy) phenyl ] sulfonylamino ] piperidine-1-carboxylate

4-amino-4- [4- (difluoromethyl) phenyl ] was placed in a sealed tube under nitrogen ]A solution of piperidine-1-carboxylic acid benzyl ester hydrochloride (200 mg,0.504 mmol), triethylamine (281. Mu.L, 2.02 mmol) and 4-dimethylaminopyridine (12 mg,0.101 mmol) in dry DCM (4 mL) was stirred at room temperature.Next, 4- (trifluoromethoxy) benzenesulfonyl chloride (86. Mu.L, 0.504 mmol) was added and the mixture was stirred at 40℃for 16 hours. The mixture was washed with DCM and half saturated NaHCO ₃ Diluting the 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 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 white solid (210 mg, 100% purity, 71% yield, t _r =1.01 min). LCMS (method E): m/z found 607.3[ M+Na ]] ⁺ ； ¹ H-NMR(DMSO-d ₆ ，400MHz)：δ(ppm)8.29(s，1H)，7.43–7.27(m，7H)，7.27–7.11(m，6H)，6.84(t，J＝55.9Hz，1H)，5.08(s，2H)，3.89–3.71(m，2H)，3.31(s，3H)，2.41(d，J＝13.6Hz，2H)，1.92–1.71(m，2H)。

Step 5: synthesis of N- (4- (4- (difluoromethyl) phenyl) piperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide (100)

In a round bottom flask under nitrogen was added iodo (trimethyl) silane (51 μl,0.359 mmol) to 4- [4- (difluoromethyl) phenyl]-4- [ [4- (trifluoromethoxy) phenyl ]]Sulfonylamino groups]Benzyl piperidine-1-carboxylate (210 mg, 0.319 mmol) in dry ACN (2 mL) and the solution was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was triturated in DCM/MeOH 9/1 (3 mL). The suspension was stirred at room temperature for 10min and filtered. The residue was washed with DCM and dried under reduced pressure at 45 ℃ for 2 hours. Adding half saturated Na ₂ CO ₃ Aqueous solution (10 mL) and the suspension was stirred at room temperature for 16 hours and filtered. The residue was washed with water and dried under reduced pressure at 45 ℃ for 4 hours. Addition of Et ₂ O/MeOH 95/5 (2 mL) and 2M HCl/Et ₂ O (198. Mu.L, 0.395 mmol) and the suspension was stirred at room temperature for 16 hours. The suspension was treated with Et ₂ O (2 mL) was diluted, filtered, and the residue was taken up in Et ₂ O-washing and drying under reduced pressure at 45℃for 64 hours gave the hydrochloride salt of the title compound as whiteColor powder (87 mg, 99.5% purity, 49% yield, t) _r =1.37 min). LCMS (method H): m/z found 451.2[ M+H ]] ⁺ ； ¹ H-NMR(500MHz，DMSO-d ₆ )δppm 2.02-2.13(m，2H)2.61(br d，J＝13.45Hz，2H)3.18-3.29(m，4H)6.84(t，J＝55.75Hz，1H)7.12-7.16(m，2H)7.16-7.20(m，2H)7.20-7.24(m，2H)7.33(d，J＝7.80Hz，2H)8.56(s，1H)8.89(br s，2H)。

Example 65: cell viability assay

LNCaP cell line

LNCaP cell lines were used for cell viability assays. LNCaP cells were seeded in 96-well plates at a density of 5000 cells per well. After 24 hours of plating, cells were treated with increasing doses of 1 μm to 80 μm of compounds 1-100. After 48 hours, the relative cell numbers were analyzed according to the manufacturer's instructions using the 3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) assay (Promega).

HCC1937 cell line

HCC1937 cells were plated in 96-well plates at a density of 10,000 cells per well. After overnight incubation, cells were treated with the following concentrations of compounds 1-100: 80. 40, 20, 10, 5, 2.5, 1.25. Mu.M. Compound concentrations were prepared from 80mM starter stock by serial dilution in RPMI. After 48 hours of compound treatment, cell viability was assessed using the Promega CellTiter aqueous one-time proliferation assay (Promega G3582, MTS assay) according to the manufacturer's protocol.

Cell viability data were analyzed using GraphPad Prism software. Logarithmic conversion and nonlinear regression (curve fitting) analysis was performed on the values using log (inhibitor) and response-variable slope (four parameters) and bottom limit to zero. The results are provided in table 35. The GI's provided in Table 35, unless otherwise noted ₅₀ The values correspond to LNCaP cell viability assays.

TABLE 35 cell viability assay data for Compounds 1-100

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^a GI ₅₀ Values correspond to HCC1937 cell line assay

The embodiments described above may be used in any combination with each other. Several embodiments may be combined together to form another embodiment. The product, method or use related to the present invention may comprise at least one of the embodiments described above. It should be appreciated that the benefits and advantages described above may relate to one embodiment or may relate to several embodiments. Embodiments are not limited to embodiments that solve any or all of the problems or embodiments that have any or all of the benefits and advantages. It will be further understood that reference to "an" item refers to one or more of those items.

It is obvious to a person skilled in the art that as the technology advances, the basic idea of the invention can be implemented in various ways. Accordingly, the present invention and its embodiments are not limited to the above examples; rather, they may vary within the scope of the claims.

The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the application. Thus, it should be understood that while the application has been described with respect to specific embodiments and optional features, modification and variation of the compositions, methods and concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this application as embodiments thereof.

Detailed description of the illustrated embodiments

The following exemplary embodiments are provided, the numbering of which should not be construed as specifying a level of importance:

embodiment 1 provides a compound of formula (I), or a salt, solvate, enantiomer, diastereomer, isotopic isomer, or tautomer thereof, selected from the group consisting of:

wherein:

ar is C ₆ -C ₁₀ Aryl or C ₂ -C ₁₀ Heteroaryl, which is selected from C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, C ₂ -C ₁₀ Heteroaryl, C ₆ -C ₁₀ Aryl, C ₆ -C ₁₀ Aryloxy, halogen, OH, NH ₂ 、CN、NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^a and-C (=O) N (R) ^a )(R ^a ) Optionally substituted with at least one substituent of (c),

wherein two substituents in G may combine to provide a C with G ₃ -C ₈ Cycloalkyl spiro or bridged C ₃ -C ₈ Cycloalkyl;

R ¹ selected from the group consisting of

wherein is selected from R ³ 、R ^3’ 、R ⁴ 、R ^4’ 、R ⁵ 、R ^5’ 、R ⁶ 、R ^6’ 、R ⁷ 、R ⁸ And R is ^8’ Separated by 2 to 5 carbon atoms, can combine with the carbon atoms to which they are bonded to form a member selected from optionally substituted C ₄ -C ₇ Cycloalkyl and optionally substituted C ₄ -C ₈ A portion of a heterocyclic group;

R ^10’ selected from phenyl, benzyl and-C (=o) -C ₁ -C ₆ Alkyl, wherein R is ^10’ Wherein the benzyl or phenyl group is selected from halogen, C ₁ -C ₃ Haloalkyl, OH and N (R) ^a )(R ^b ) Is substituted with at least one substituent of (a), and wherein R ^10’ Is substituted with at least one phenyl substituent;

z is selected from C= O, NR ¹⁰ 、NR ^10’ O and S;

R ^A Is H or C ₁ -C ₆ An alkyl group;

R ^b independently selected from H, optionally substituted C ₁ -C ₆ Alkyl, optionally substituted benzyl, optionally substituted phenyl and optionally substituted naphthyl, wherein R ^b C in (C) ₁ -C ₆ Alkyl, benzyl, phenyl or naphthyl are independently selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, halogen, OH, CN, NO ₂ 、C(＝O)OR ^a And C (=O) N (R) ^a )(R ^a ) Optionally substituted at least one of (a);

wherein in (Ia), (Ib) and (Ic) at least one of the following applies:

c)R ³ 、R ^3’ 、R ⁴ and R is ^4’ At least one of which is phenyl or C ₂ -C ₁₀ Heteroaryl, wherein phenyl or heteroaryl is selected from halogen, OH, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy and C ₁ -C ₆ At least one substituent of the alkyl group is optionally substituted, wherein one of Y and Z is present, and And one of Y and Z is selected from c= O, NR ¹⁰ And O, wherein R ¹⁰ Selected from H, C ₃ -C ₆ Cycloalkyl, phenyl, optionally substituted benzyl, -C (=o) OR ^b 、-C(＝O)R ^b ，-S(＝O) ₂ -optionally substituted phenyl;

i)R ² selected from optionally substituted C ₁ -C ₆ Haloalkyl, optionally substituted C ₂ -C ₆ Aminoalkyl and optionally substituted C ₂ -C ₆ Alkynyl, wherein R is ² Each optional substituent in the haloalkyl, aminoalkyl and alkynyl groups in (a) is selected from C ₁ -C ₆ Alkyl, C ₁ -C ₃ HaloalkanesRadical, C ₁ -C ₃ Haloalkoxy, halogen, C (=o) R ^a 、C(＝O)OR ^a 、C(＝O)N(R ^a )(R ^a )、S(＝O) ₂ -optionally substituted phenyl and S (=o) ₂ -optionally substituted C ₂ -C ₁₀ At least one of the heteroaryl groups.

Embodiment 2 provides the compound of embodiment 1, wherein the compound of formula (I) is selected from:

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wherein:

n is an integer selected from 0, 1 and 2.

Embodiment 3 provides the compound of embodiment 1 or 2, wherein R ^A Selected from H and Me.

Embodiment 4 provides the compound of embodiment 1 or 3, wherein R ¹ Selected from the group consisting of />

Embodiment 5 provides the compound of any one of embodiments 1-4, wherein Ar is selected from

Embodiment 6 provides a compound of any one of embodiments 1-3 and 5, wherein at least one of the following is applicable:

(a) The compound of formula (I) is a compound of formula (Ia-1), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H;

(b) The compound of formula (I) is a compound of formula (Ia-2), wherein R ³ 、R ^3’ 、R ⁴ And R is ^4’ At least two of which are H;

(c) The compound of formula (I) is a compound of formula (Ia-3), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ And R is ⁵ At least four of' are H;

(d) The compound of formula (I) is a compound of formula (Ia-4), wherein R ³ And R is ^3’ At least one of which is H;

(e) The compound of formula (I) is a compound of formula (Ia-5), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H;

(f) The compound of formula (I) is a compound of formula (Ia-6), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H;

(g) The compound of formula (I) is a compound of formula (Ia-7), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H;

(h) The compound of formula (I) is a compound of formula (Ia-8) wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ At least ten of' are H;

(i) The compound of formula (I) is a compound of formula (Ib-1), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H;

(j) The compound of formula (I) is a compound of formula (Ib-2), wherein R ³ 、R ^3’ 、R ⁴ And R is ^4’ At least two of which are H;

(k) The compound of formula (I) is a compound of formula (Ib-3), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ And R is ⁵ At least four of' are H;

(l) The compound of formula (I) is a compound of formula (Ib-4) wherein R ³ And R is ^3’ At least one of which is H;

(m) the compound of formula (I) is a compound of formula (Ib-5), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H;

(n) the compound of formula (I) is a compound of formula (Ib-6), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H;

(o) the compound of formula (I) is a compound of formula (Ib-7), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H;

(p) the compound of formula (I) is a compound of formula (Ib-8), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ At least ten of' are H;

(q) the compound of formula (I) is a compound of formula (Ic-1) wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H;

(R) the compound of formula (I) is a compound of formula (Ic-2), wherein R ³ 、R ^3’ 、R ⁴ And R is ^4’ At least two of which are H;

(s) the compound of formula (I) is a compound of formula (Ic-3), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ And R is ⁵ At least four of' are H;

(t) the compound of formula (I) is a compound of formula (Ic-4), wherein R ³ And R is ^3’ At least one of which is H;

(u) the compound of formula (I) is a compound of formula (Ic-5), wherein R ³ 、R ³ '、R ⁴ And R is ⁴ At least two of' are H;

(v) The compound of formula (I) is a compound of formula (Ic-6) wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H;

(w) the compound of formula (I) is a compound of formula (Ic-7), wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H;

(x) The compound of formula (I) is a compound of formula (Ic-8) wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ 、R ⁶ '、R ⁷ 、R ⁷ '、R ⁸ And R is ⁸ At least ten of' are H;

(y) the compound of formula (I) is a compound of formula (Id-1) wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H;

(z) the compound of formula (I) is a compound of formula (Ie-1) wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H; and

(aa) the compound of formula (I) is a compound of formula (If-1) wherein R ³ 、R ³ '、R ⁴ 、R ⁴ '、R ⁵ 、R ⁵ '、R ⁶ And R is ⁶ At least six of' are H.

Embodiment 7 provides the compound of any one of embodiments 5-6, wherein X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least one, if any, selected from CF ₃ 、NH ₂ ，O(CH(CH ₃ ) ₂ )、OCF ₃ And

embodiment 8 provides the compound of any one of embodiments 1-7, wherein Ar is selected from

Embodiment 9 provides the compound of embodiment 1 or 2, wherein G is:

wherein:

Embodiment 10 provides the compound of embodiment 9, wherein at least one of the following applies:

(a)R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ and R is ^14’ At least one of which is H;

(b)R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ and R is ^14’ At least two of which are H;

(c)R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ and R is ^14’ At least three of (a) are H;

(d)R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ and R is ^14’ At least four of which are H;

(e)R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ and R is ^14’ At least five of (a) is H;

(f)R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ and R is ^14’ At least six of which are H; and

(a)R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ and R is ^14’ Is H.

Embodiment 11 provides the compound of embodiment 9 or 10, wherein R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ At least one of them is CF ₃ 。

Embodiment 12 provides the compound of any one of embodiments 1-2 and 10-11, wherein G is

Embodiment 13 provides the compound of any one of embodiments 1-3 and 5-12, wherein R ² Selected from:

-CH ₂ F、-C(＝O)OEt、Ph、

embodiment 14 provides a compound of any one of embodiments 1-3 and 5-13, wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ And R is ^8' At least one, if any, selected from:

methyl, trifluoromethyl, hydroxy, fluoro, -C (=O) OMe, ph,

Embodiment 15 provides a compound of any one of embodiments 1-14, wherein Y is NR ¹⁰ 。

Embodiment 16 provides the compound of embodiment 15, wherein R ¹⁰ Selected from H, methyl, 3-methylbutyl, tert-butyl, cyclopropyl, 3-oxetanyl, -C (=O) CH ₂ CH(CH ₃ ) ₂ 、-C(＝O)Ot-Bu、S(＝O) ₂ Me, benzyl group,

Embodiment 17 provides a compound of any one of embodiments 1-14, wherein Y is NR ^10’ 。

Embodiment 18 provides the compound of embodiment 17, wherein R ^10’ Selected from the group consisting of/>

Embodiment 19 provides the compound of any one of embodiments 1, 3, and 9-12, wherein R ¹ Selected from the group consisting of

/>

Embodiment 20 provides a compound of formula (II), or a salt, solvate, enantiomer, diastereomer, isotopic isomer, or tautomer thereof, selected from the group consisting of:

wherein:

R ^A is H or C ₁ -C ₆ An alkyl group; and

R ¹ selected from the group consisting of

/>

Embodiment 21 provides the compound of embodiment 20, wherein R ^A Is H or Me.

Embodiment 22 provides the compound of embodiment 20 or 21, wherein Ar is selected from/>

And

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ Each independently selected from C ₁ -C ₆ Alkyl, F, cl, N (R) ^a )(R ^b )、OR ^b 、-C(＝O)OR ^a 、-C(＝O)N(R ^a )(R ^a )、NH ₂ 、OH、NO ₂ ，C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy and phenyl.

Embodiment 23 provides a compound of any one of embodiments 20-22, wherein X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least one, if any, selected from CF ₃ 、NH ₂ 、O(CH(CH ₃ ) ₂ )、OCF ₃ And

embodiment 24 provides a compound of any one of embodiments 20-23, wherein Ar is selected from

Embodiment 25 provides a compound of embodiment 1 selected from the group consisting of:

N- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (1- (3-chlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide;

N- (5, 8-difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (2- (4-chlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4-phenylpiperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4-phenylpiperidin-4-yl) -6- (trifluoromethoxy) pyridine-3-sulfonamide;

n- (1-methyl-4-phenylpiperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (4-chlorophenyl) piperidin-4-yl) -4-isopropoxy benzenesulfonamide;

n- (4- (4-chlorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide;

n- (4- (4-fluorophenyl) piperidin-4-yl) -4-isopropoxy benzenesulfonamide;

n- (4- (4-fluorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide;

n- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide;

n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6-isopropoxypyridine-3-sulfonamide;

n- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

Embodiment 26 provides a compound of embodiment 1 selected from the group consisting of:

(R) -N- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (5, 8-difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide;

(R) -N- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

Embodiment 27 provides a compound of embodiment 1 selected from the group consisting of:

(S) -N- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 r) -2-ethyl-1- (m-tolyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (5, 8-difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide;

(S) -N- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

Embodiment 28 provides a compound selected from the group consisting of:

n- (2- (4-fluorophenoxy) cyclohexyl) -4- (trifluoromethoxy) benzenesulfonamide;

4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide;

(R) -4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide;

(S) -4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide;

n- (2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 r) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 s) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 s) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 r) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

4- (trifluoromethoxy) -N- ((4 s,6 s) -4- (trifluoromethyl) -4,5,6, 7-tetrahydro-1H-indazol-6-yl) benzenesulfonamide; and

or a salt, solvate, isotopic isomer or tautomer thereof.

Embodiment 29 provides a pharmaceutical composition comprising at least one compound of any one of embodiments 1-28 and at least one pharmaceutically acceptable carrier.

Embodiment 30 provides a method of treating, preventing and/or alleviating a PP 2A-associated disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-28 or a pharmaceutical composition of embodiment 29.

Embodiment 31 provides the method of embodiment 30, wherein the PP 2A-related 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.

Embodiment 32 provides the method of embodiment 30 or 31, wherein the subject is a mammal.

Embodiment 33 provides the method of embodiment 32, wherein the mammal is a human.

The disclosures of each patent, patent application, and publication cited herein are hereby incorporated by reference in their entirety. Although the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and modifications of the invention can be devised by those skilled in the art without departing from the true spirit and scope of the invention. It is intended that the following claims be interpreted to embrace all such embodiments and equivalent variations.

Claims

1. A compound of formula (I), or a salt, solvate, enantiomer, diastereomer, isotopic isomer, or tautomer thereof, selected from the group consisting of:

Wherein:

g is optionally substituted C ₃ -C ₈ Cycloalkyl group, which is selected from C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, phenyl, halogen, OH, NH ₂ 、CN、NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^a and-C (=O) N (R) ^a )(R ^a ) Optionally substituted with at least one substituent of (c),

R ¹ selected from the group consisting of

Wherein R is ² Each optional substituent of (a) is selected from halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ Haloalkyl, -C (=o) OR ^a 、-S(＝O) ₂ -C ₆ -C ₁₀ Aryl and-S (=o) ₂ -C ₂ -C ₁₀ At least one of heteroaryl;

R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ and R is ^8' Each independently selected from H, C ₁ -C ₆ Alkyl, hydroxy, C ₁ -C ₄ Haloalkyl, optionally substituted C ₃ -C ₈ Cycloalkyl, optionally substituted C ₂ -C ₆ Heterocyclyl, optionally substituted phenyl and optionally substituted phenoxy,

wherein is selected from R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ And R is ^8' May combine with the carbon atom to which they are bonded to form a member selected from optionally substituted C ₃ -C ₈ Cycloalkyl and optionally substituted C ₂ -C ₁₀ The moiety(s) of the heterocyclic group,

wherein is selected from R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ And R is ^8' May combine with the carbon atom to which they are bound to form a member selected from optionally substituted C ₃ -C ₈ Cycloalkyl, optionally substituted C ₂ -C ₁₀ A heterocyclyl and optionally substituted phenyl moiety;

wherein the phenyl, benzyl or-S (=o) _2- Each optional substituent in the phenyl group is independently selected from F, cl, br, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ Haloalkyl, hydroxy and-NH-C (=o) R ^a At least one of (a) and (b);

z is selected from C= O, NR ¹⁰ 、NR ^10’ O and S;

R ^A is H or C ₁ -C ₆ An alkyl group;

wherein in (Ia), (Ib) and (Ic) at least one of the following applies:

b)R ³ and R is ^3’ At least one of which is phenyl or C ₂ -C ₁₀ Heteroaryl, wherein phenyl or heteroaryl is selected from halogen, OH, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ HaloalkanesRadical, C ₁ -C ₃ Alkoxy and C ₁ -C ₆ At least one substituent in the alkyl group;

c)R ³ 、R ^3’ 、R ⁴ And R is ^4’ At least one of which is phenyl or C ₂ -C ₁₀ Heteroaryl, wherein phenyl or heteroaryl is selected from halogen, OH, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy and C ₁ -C ₆ At least one substituent of the alkyl group is optionally substituted, wherein one of Y and Z is present and is selected from c= O, NR ¹⁰ And O, wherein R ¹⁰ Selected from H, C ₃ -C ₆ Cycloalkyl, phenyl, optionally substituted benzyl, -C (=o) OR ^b 、-C(＝O)R ^b 、-S(＝O) ₂ -optionally substituted phenyl;

d) Selected from R ³ 、R ^3’ 、R ⁴ 、R ^4’ 、R ⁵ 、R ^5’ 、R ⁶ 、R ^6’ 、R ⁷ 、R ^7’ 、R ⁸ And R is ^8’ Is combined with the carbon atom to which they are bonded to form C ₃ -C ₈ Cycloalkyl or C ₂ -C ₆ A heterocyclic group, wherein the cycloalkyl or heterocyclic group is selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, halogen, N (R) ^a )(R ^a )、OR ^a 、C(＝O)R ^a 、C(＝O)OR ^a And C (=O) N (R) ^a )(R ^a ) Is substituted by at least one substituent group of the formula,

e) Selected from R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ And R is ^8' Is combined with the carbon atom to which they are bound to form C ₃ -C ₈ Cycloalkyl, C ₂ -C ₁₀ Heterocyclyl or phenyl wherein the cycloalkyl, heterocyclyl or phenyl is selected from C ₁ -C ₃ Alkyl group、C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, halogen, OR ^a 、C(＝O)R ^a 、C(＝O)OR ^a And C (=O) N (R) ^a )(R ^a ) Is substituted by at least one substituent;

f) Selected from R ³ 、R ^3’ 、R ⁴ 、R ^4’ 、R ⁵ 、R ^5’ 、R ⁶ 、R ^6’ 、R ⁷ 、R ^7’ 、R ⁸ And R is ^8’ Is combined with the carbon atom to which they are bonded to form C ₃ -C ₈ Cycloalkyl or C ₂ -C ₆ Heterocyclyl and is selected from R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ And R is ^8' Is combined with the carbon atom to which they are bound to form C ₃ -C ₈ Cycloalkyl, C ₂ -C ₁₀ Heterocyclyl or phenyl wherein each of said cycloalkyl, heterocyclyl or phenyl is independently selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, halogen, N (R) ^a )(R ^a )、OR ^a 、C(＝O)R ^a 、C(＝O)OR ^a And C (=O) N (R) ^a )(R ^a ) Optionally substituted with at least one substituent of (a);

h)R ² 、R ³ 、R ^3’ 、R ⁴ and R is ^4’ At least one of which is optionally substituted C ₃ -C ₈ Cycloalkyl or C ₂ -C ₁₀ Heterocyclyl wherein each optional substituent in the cycloalkyl or heterocycloalkyl is independently selected from halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, OR ^a 、N(R ^a )(R ^b )、C(＝O)R ^a And C (=O) OR ^a The method comprises the steps of carrying out a first treatment on the surface of the And

2. The compound of claim 1, wherein the compound of formula (I) is selected from:

wherein:

n is an integer selected from 0, 1 and 2.

3. The compound according to claim 1 or 2, wherein R ^A Selected from H and Me.

4. A method according to claim 1 or 3, whereinR ¹ Selected from the group consisting of

5. The compound according to any one of claims 1-4, wherein Ar is selected from

6. The compound according to any one of claims 1-3 and 5, wherein at least one of the following is applicable:

(a) The compound of formula (I) is a compound of formula (Ia-1), wherein R ³ 、R ^3' 、R ⁴ And R is ^4' Is to of (a)At least two are H;

(c) The compound of formula (I) is a compound of formula (Ia-3), wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ And R is ^5' At least four of which are H;

(e) The compound of formula (I) is a compound of formula (Ia-5), wherein R ³ 、R ^3' 、R ⁴ And R is ^4' At least two of which are H;

(f) The compound of formula (I) is a compound of formula (Ia-6), wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ And R is ^6' At least six of which are H;

(g) The compound of formula (I) is a compound of formula (Ia-7), wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ And R is ^6' At least six of which are H;

(h) The compound of formula (I) is a compound of formula (Ia-8) wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ And R is ^8' Is H;

(i) The compound of formula (I) is a compound of formula (Ib-1), wherein R ³ 、R ^3' 、R ⁴ And R is ^4' At least two of which are H;

(k) The compound of formula (I) is a compound of formula (Ib-3), wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ And R is ^5' At least four of which are H;

(m) the compound of formula (I) is a compound of formula (Ib-5), wherein R ³ 、R ^3' 、R ⁴ And R is ^4' At least two of which are H;

(n) the compound of formula (I) is a compound of formula (Ib-6), wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ And R is ^6' At least six of which are H;

(o) the compound of formula (I) is a compound of formula (Ib-7), wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ And R is ^6' At least six of which are H;

(p) the compound of formula (I) is a compound of formula (Ib-8), wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ And R is ^8' Is H;

(q) the compound of formula (I) is a compound of formula (Ic-1) wherein R ³ 、R ^3' 、R ⁴ And R is ^4' At least two of which are H;

(s) the compound of formula (I) is a compound of formula (Ic-3), wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ And R is ^5' At least four of which are H;

(u) the compound of formula (I) is of formula (Ic-5)A compound wherein R is ³ 、R ^3' 、R ⁴ And R is ^4' At least two of which are H;

(v) The compound of formula (I) is a compound of formula (Ic-6) wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ And R is ^6' At least six of which are H;

(w) the compound of formula (I) is a compound of formula (Ic-7), wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ And R is ^6' At least six of which are H;

(x) The compound of formula (I) is a compound of formula (Ic-8) wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ And R is ^8' Is H;

(y) the compound of formula (I) is a compound of formula (Id-1) wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ And R is ^6' At least six of which are H;

(z) the compound of formula (I) is a compound of formula (Ie-1) wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ And R is ^6' At least six of which are H; and

(aa) the compound of formula (I) is a compound of formula (If-1) wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ And R is ^6' Is H.

7. The compound of any one of claims 5-6, wherein X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least one, if any, selected from CF ₃ 、NH ₂ 、O(CH(CH ₃ ) ₂ )、OCF ₃ And

8. the compound according to any one of claims 1-7, wherein Ar is selected from

9. The compound of claim 1 or 2, wherein G is:

wherein:

10. The compound of claim 9, wherein at least one of the following is applicable:

11. The compound according to claim 9 or 10, wherein R ¹¹ 、R ¹² 、R ^12’ 、R ¹³ 、R ^13’ 、R ¹⁴ And R is ^14’ At least one of them is CF ₃ 。

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

13. The compound of any one of claims 1-3 and 5-12, wherein R ² Selected from:

-CH ₂ F、-C(＝O)OEt、Ph、

14. the compound of any one of claims 1-3 and 5-13, wherein R ³ 、R ^3' 、R ⁴ 、R ^4' 、R ⁵ 、R ^5' 、R ⁶ 、R ^6' 、R ⁷ 、R ^7' 、R ⁸ And R is ^8' At least one, if any, selected from:

methyl, trifluoromethyl, hydroxy, fluoro, -C (=O) OMe, ph,

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

16. The compound of claim 15, wherein R ¹⁰ Selected from H, methyl, 3-methylbutyl, tert-butyl, cyclopropyl, 3-oxetanyl, -C (=O) CH ₂ CH(CH ₃ ) ₂ 、-C(＝O)Ot-Bu、S(＝O) ₂ Me, benzyl group,

17. According to the weightsThe compound of any one of claims 1-14, wherein Y is NR ^10’ 。

18. The compound of claim 17, wherein R ^10’ Selected from the group consisting of

19. The compound of any one of claims 1, 3 and 9-12, wherein R ¹ Selected from the group consisting of />

/>

20. A compound of formula (II), or a salt, solvate, enantiomer, diastereomer, isotopic isomer, or tautomer thereof, selected from the group consisting of:

/>

wherein:

R ^A is H or C ₁ -C ₆ An alkyl group; and

R ¹ selected from the group consisting of />

/>

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

22. The compound of claim 20 or 21, wherein Ar is selected from And

23. The compound of any one of claims 20-22, wherein X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ And X ⁷ At least one, if any, selected from CF ₃ 、NH ₂ 、O(CH(CH ₃ ) ₂ )、OCF ₃ And

24. the compound of any one of claims 20-23, wherein Ar is selected from

25. The compound of claim 1, selected from the group consisting of:

n- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

N- (1- (3-chlorophenyl) cyclopentyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (5, 8-difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

N- (2- (4-chlorophenyl) cyclopropyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4-phenylpiperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4-phenylpiperidin-4-yl) -6- (trifluoromethoxy) pyridine-3-sulfonamide;

n- (1-methyl-4-phenylpiperidin-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- (4- (4-chlorophenyl) piperidin-4-yl) -4-isopropoxy benzenesulfonamide;

n- (4- (4-chlorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide;

n- (4- (4-fluorophenyl) piperidin-4-yl) -4-isopropoxy benzenesulfonamide;

n- (4- (4-fluorophenyl) piperidin-4-yl) -6-isopropoxypyridine-3-sulfonamide;

n- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide;

n- (3- (4-chlorophenyl) pyrrolidin-3-yl) -6-isopropoxypyridine-3-sulfonamide;

n- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

26. The compound of claim 1, selected from the group consisting of:

n- ((2 r,3 s) -1- (tert-butyl) -2- (4-chloro-3-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide; 4- ((1 r,2 r) -2- ((4- (trifluoromethoxy) phenyl) sulfonamide) cyclopropyl) piperidine-1-carboxylic acid tert-butyl ester;

(R) -N- (6- (difluoromethoxy) -4-oxo-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide; (R) -3- (fluoromethyl) -3- ((4- (trifluoromethoxy) phenyl) sulfonamide) pyrrolidine-1-carboxylic acid tert-butyl ester;

(R) -N- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((6 r,7 s) -2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro [3.4] oct-6-yl) -4- (trifluoromethoxy) benzenesulfonamide; (R) -N- (6-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (5, 8-difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(R) -N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide;

(R) -N- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

27. The compound of claim 1, selected from the group consisting of:

(S) -N- (3-phenylpyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

N- ((6 s,7 r) -2-benzyl-7-hydroxy-1-isopropyl-2-azaspiro [3.4] oct-6-yl) -4- (trifluoromethoxy) benzenesulfonamide; (S) -N- (6-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (5, 8-difluorochroman-4-yl) -4- (trifluoromethoxy) benzenesulfonamide;

(S) -N- (3- (4-fluorophenyl) pyrrolidin-3-yl) -4-isopropoxy benzenesulfonamide;

(S) -N- (3- (4-chlorophenyl) -1- (3-methylbutanoyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide; (S) -N- ((S) -3- (4-fluorophenyl) pyrrolidin-3-yl) -4- (trifluoromethoxy) benzenesulfonimide amide;

(S) -N- (3-phenylpiperidin-3-yl) -4- (trifluoromethoxy) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

28. A compound selected from the group consisting of:

n- (2- (4-fluorophenoxy) cyclohexyl) -4- (trifluoromethoxy) benzenesulfonamide;

4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide;

(R) -4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide;

(S) -4- (trifluoromethoxy) -N- (3, 4-trimethylcyclohexyl) benzenesulfonamide;

n- (2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 r) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 r,2 s) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 s) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

n- ((1 s,2 r) -2-phenylcycloheptyl) -4- (trifluoromethoxy) benzenesulfonamide;

or a salt, solvate, isotopic isomer or tautomer thereof.

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

30. A method of treating, preventing and/or alleviating a PP 2A-related disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-28 or a pharmaceutical composition according to claim 29.

31. The method of claim 30, wherein at least one of the PP 2A-related diseases is selected from 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.

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

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