HK1210146B

HK1210146B - Substituted sulfonamide compounds

Info

Publication number: HK1210146B
Application number: HK15110828.0A
Authority: HK
Inventors: 克里斯蒂娜‧E‧布拉泽顿-普里斯; 陈慧芬; 陈少清; 陈智; 肖恩‧戴维‧埃里克森; 安东尼‧埃斯特拉德; 金庆镇; 李宏举; 艾伦‧约翰‧勒韦伊; 约瑟夫‧P‧利丝卡托斯; 钱义民; 苏松塞; 彼得‧米夏埃尔‧沃库利希; 伊林
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2012-09-27
Filing date: 2013-09-26
Publication date: 2018-05-04

Description

Substituted sulfonamide compounds

Technical Field

The present invention relates to substituted sulfonamide compounds, their preparation, pharmaceutical compositions containing them and their use as Transient Receptor Potential (TRP) channel antagonists.

Background

TRP channels are a class of ion channels found in the plasma membrane of a variety of human (or other animal) cell types. There are at least 28 known human TRP channels, which are divided into many families or groups based on sequence homology and function. TRPA1 is a non-selective cation-conducting channel that regulates membrane potential through sodium, potassium and calcium currents. TRPA1 has been shown to be highly expressed in human dorsal root ganglion neurons and peripheral sensory nerves. In humans, TRPA1 is activated by many reactive compounds such as acrolein, allyl isothiocyanate, ozone, and non-reactive compounds such as nicotine and menthol and is therefore considered to act as a 'chemical sensor'.

Many known TRPA1 agonists are stimulators that cause pain, irritation, and neurogenic inflammation in humans and other animals. Therefore, it would be expected that TRPA1 antagonists or agents that block the biological effects of TRPA1 channel activators would be useful in the treatment of diseases such as asthma and exacerbations thereof, chronic cough and related diseases, as well as in the treatment of acute and chronic pain. Recently, it has also been shown that products of tissue injury and oxidative stress, such as 4-hydroxynonenal and related compounds, activate the TRPA1 channel. This finding provides an additional rationale for the efficacy of small molecule TRPA1 antagonists in the treatment of diseases associated with tissue damage, oxidative stress and bronchial smooth muscle contraction such as asthma, Chronic Obstructive Pulmonary Disease (COPD), occupational asthma, and virus-induced lung inflammation. Furthermore, recent findings have correlated activation of the TRPA1 channel with increased Pain perception (Kosugi et al, J. Neurosci 27, (2007) 4443-; wei et al, Neurosci Lett 479(2010) 253-)) provides an additional rationale for the efficacy of small molecule TRPA1 inhibitors in the treatment of pain disorders.

Summary of The Invention

The present invention provides a compound of the invention which is a compound of formula (I):

wherein:

x, Y, Z are independently of one another C, CH or N;

R¹is unsubstituted phenyl, phenyl mono-or di-substituted independently by halogen or-CN, an unsubstituted five-or six-membered heteroaromatic ring or a five-or six-membered heteroaromatic ring substituted by lower alkyl, halogen or haloalkyl;

R²selected from the group consisting of hydrogen, deuterium, lower alkyl, haloalkyl, cycloalkyl, alkoxy, oxetanyl, phenyl and five or six membered heteroaromatic rings, wherein said lower alkyl, haloalkyl, cycloalkyl, alkoxy or oxetanyl is optionally substituted with deuterium and wherein said phenyl and said five or six membered heteroaromatic rings are each independently optionally substituted with lower alkyl, haloalkyl, deuterium or halogen;

R³and R^3′Each independently selected from the group consisting of hydrogen, deuterium, haloalkyl, cycloalkyl and lower alkyl, wherein said haloalkyl, cycloalkyl and lower alkyl are optionally substituted with deuterium, F, Cl, Br, hydroxy or alkoxy; or R³And R^3′Together with the carbon to which they are attached form a 3, 4,5 or 6-membered cycloalkyl group optionally substituted with deuterium, F, Cl, Br, hydroxy or alkoxy;

R⁴is hydrogen or lower alkyl;

R⁵is trifluoromethyl-phenyl, trifluoromethyl-pyridyl, trifluoromethyl-pyridazinyl, trifluoromethyl-pyrimidinyl, azetidino, pyrrolidino, cycloalkyl, piperidino,pyrrolidino-pyrimidinyl, heterocycle-pyrimidinyl, heterocycle-pyridinyl, heterocycle-pyridazinyl, heterocycle-pyrazinyl, cycloalkyl-pyrimidinyl, cycloalkyl-pyridinyl, cycloalkyl-pyridazinyl, cycloalkyl-pyrazinyl, or trifluoromethyl-pyrazinyl, wherein any azetidinyl, pyrrolidino, cycloalkyl, heterocycle, and piperidino are optionally substituted with lower alkyl, halogen, trifluoromethyl, trifluoromethoxy, or trifluoromethylthio; and is

R⁶Is hydrogen, halogen or alkoxy;

or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.

The present invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a respiratory disease.

The present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a respiratory disease.

The present invention also provides a method of treating a respiratory disease in a mammal, comprising administering to the mammal a compound of the present invention or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for modulating TRPA1 activity.

In another embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or condition mediated by TRPA1 activity. Within aspects of this embodiment, the disease or condition is pain, itch, an inflammatory disease, an inner ear disease, fever or another thermoregulatory disease, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disease, chronic obstructive pulmonary disease, incontinence, or a disease associated with reduced blood flow to the CNS or CNS hypoxia. Within certain aspects of this embodiment, the disease or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disease.

In another embodiment, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by TRPA1 activity. Within aspects of this embodiment, the disease or condition is pain, itch, an inflammatory disease, an inner ear disease, fever or another thermoregulatory disease, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disease, chronic obstructive pulmonary disease, incontinence, or a disease associated with reduced blood flow to the Central Nervous System (CNS) or CNS hypoxia. Within aspects of this embodiment, the disease or disorder is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disease.

In another embodiment, the present invention provides a method of modulating TRPA1 activity comprising contacting TRPA1 with a compound of the present invention or a salt thereof.

In another embodiment, the present invention provides a method of treating a disease or condition mediated by TRPA1 activity in a mammal, comprising administering to the mammal a compound of the present invention or a pharmaceutically acceptable salt thereof. Within certain aspects of this embodiment, the disease or condition is pain, itch, an inflammatory disease, an inner ear disease, fever or another thermoregulatory disease, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disease, chronic obstructive pulmonary disease, incontinence, or a disease associated with reduced blood flow to the CNS or CNS hypoxia. Within certain aspects of this embodiment, the disease or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disease.

The invention also provides the invention as described herein.

Detailed Description

Definition of

Unless otherwise indicated, the following specific terms and expressions used in the specification and claims are defined as follows:

the term "moiety" refers to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds, thereby forming part of a molecule. For example, the variable R of the formula (I)¹To R⁶Refers to a moiety attached to the core structure of formula (I) by a covalent bond.

With respect to a particular moiety having one or more hydrogen atoms, the term "substituted" refers to the fact that at least one hydrogen atom of the moiety is replaced with another substituent or moiety. For example, the term "lower alkyl substituted by halogen" refers to the fact that one or more hydrogen atoms of a lower alkyl (as defined below) are replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.).

The term "alkyl" refers to an aliphatic straight or branched chain saturated hydrocarbon moiety having from 1 to 20 carbon atoms. In particular embodiments the alkyl group has 1 to 10 carbon atoms.

The term "lower alkyl" refers to an alkyl moiety having from 1 to 7 carbon atoms. In particular embodiments, lower alkyl has 1 to 4 carbon atoms and in other particular embodiments, lower alkyl has 1 to 3 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

The term "alkoxy" denotes a group of formula-O-R ', wherein R' is alkyl. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.

"aryl" means a monovalent cyclic aromatic moiety having a mono-, bi-, or tricyclic aromatic ring. The aryl group may be optionally substituted as defined above. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenyleneSulfide group, diphenylsulfonyl group, diphenylisopropylidene group, benzodiAlkyl, benzofuranyl, benzodioxyl, benzopyranyl, benzoAzinyl radical, benzoOxazinonyl, benzopiperidinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like, including partially hydrogenated derivatives thereof, each optionally substituted.

The term "heteroaryl" denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms comprising 1, 2,3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl,an azole group, a thiazole group, a triazole group,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azaRadical, diazaBasic group, heteroAzolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolylAzolyl, benzisoylAzolyl, benzothiazolyl, benzisothiazolyl, benzoOxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

The terms "halo", "halogen" and "halide", which may be used interchangeably, refer to the substituents fluorine, chlorine, bromine, or iodine.

The term "haloalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by the same or different halogen atoms, in particular fluorine atoms. Examples of haloalkyl include monofluoro-, difluoro-or trifluoromethyl, -ethyl or-propyl, such as 3, 3, 3-trifluoropropyl, 2-fluoroethyl, 2, 2, 2-trifluoroethyl, fluoromethyl, or trifluoromethyl.

"cycloalkyl" means a monovalent saturated carbocyclic moiety having a mono-or bicyclic ring and 3 to 10 carbon atoms. The cycloalkyl moiety may be optionally substituted with one or more substituents. In particular embodiments, the cycloalkyl group contains 3 to 8 carbon atoms. In other particular embodiments, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl).

"heterocycle" means a saturated or partially unsaturated 4-to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety having one or more heteroatoms in the ring selected from oxygen, nitrogen, and sulfur. When used in relation to a ring atom of a heterocyclic ring, the nitrogen or sulfur may also be in oxidized form, and the nitrogen may be substituted with one or more alkyl groups. The heterocyclic ring may beAttached to its pendant group at any heteroatom or carbon atom, results in a stable structure and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, bisAlkyl, dioxolane, diazaOxygen nitrogen base, oxygen nitrogen heteroRadical, S-N-azaMorpholinyl, and quinuclidinyl. The term heterocycle also includes groups in which the heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo [2.2.1]Heptyl, octahydroindolyl, or tetrahydroquinolinyl.

Unless otherwise specified, the term "hydrogen" or "hydrogen" refers to a moiety of a hydrogen atom (-H) and is not H₂。

Unless otherwise indicated, the term "compound of the formula" or "compound of a formula" or "compounds of a formula" refers to any compound selected from the class of compounds defined by the formula (including any pharmaceutically acceptable salt or ester of any such compound, if not otherwise specified).

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological utility and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts may be formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, N-acetylcysteine and the like. In addition, salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins, and the like.

The compounds of the present invention may exist in the form of pharmaceutically acceptable salts. The compounds of the invention may also be present in the form of pharmaceutically acceptable esters, i.e. the methyl and ethyl esters of the acids of formula (I) to be used as prodrugs. The compounds of the present invention may also be solvated, i.e. hydrated. The solvation may be carried out during the preparation process or may for example take place as a result of the hygroscopic nature of the initially anhydrous compound of formula (I).

Compounds having the same molecular formula but differing in their nature or order of incorporation of their atoms or arrangement of their atoms in space are referred to as "isomers". Isomers in which the atoms are arranged differently in space are referred to as "stereoisomers". Diastereomers are stereoisomers that have opposite configurations at one or more chiral centers, which are not enantiomers. Stereoisomers with one or more asymmetric centers that are nonsuperimposable mirror images of each other are referred to as "enantiomers". When the compounds have asymmetric centers, for example, if the carbon atoms are bound to four different groups, enantiomeric pairs are possible. Enantiomers can be characterized by the absolute configuration of an asymmetric center or centers and described by the R-and S-ordering rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and are referred to as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers, respectively). The chiral compounds may exist as individual enantiomers or as mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures". In certain embodiments, the compounds are enriched in at least about 90% by weight of a single diastereomer or enantiomer. In other embodiments, the compounds are enriched in at least about 95%, 98%, or 99% by weight of a single diastereomer or enantiomer.

Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., isolated enantiomers) are intended to be included within the scope of the present invention.

The term "therapeutically effective amount" of a compound means an amount of the compound effective to prevent, alleviate or ameliorate symptoms of a disease or prolong the survival of the subject to be treated. Determination of a therapeutically effective amount is within the skill of the art. The therapeutically effective amount or dose of the compounds according to the invention may vary within limits and may be determined in a manner known in the art. The dosage will be adjusted as needed for the individual in each particular case, including the particular compound administered, the route of administration, the condition being treated, and the patient being treated. Generally, in the case of oral or parenteral administration to an adult human weighing about 70Kg, a daily dose of about 0.1mg to about 5,000mg, 1mg to about 1,000mg, or 1mg to 100mg may be appropriate, although the lower and upper limits may be exceeded as indicated by evidence when necessary. The daily dose may be administered in a single dose or in divided doses, or for parenteral administration it may be administered in a continuous infusion.

The term "pharmaceutically acceptable carrier" is intended to include any and all materials compatible with pharmaceutical administration, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except to the extent that any conventional media or agent is incompatible with the active compound, its use in the compositions of the invention is contemplated. Supplementary active compounds may also be incorporated into the compositions.

Useful pharmaceutical carriers for preparing compositions thereof may be solid, liquid or gaseous; thus, the compositions may take the form of tablets, pills, capsules, suppositories, powders, enteric coated or otherwise protected formulations (e.g., bound to ion exchange resins or packaged in lipoprotein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carrier may be selected from various oils, including petroleum, animal, vegetable or synthetic origin oils, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions (when isotonic with blood). For example, formulations for intravenous administration include sterile aqueous solutions of the active ingredient prepared by dissolving the solid active ingredient in water to produce an aqueous solution and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, anhydrous skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may be added with conventional pharmaceutical additives such as preservatives, stabilizers, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable Pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, e.w. martin. In any event, such compositions will contain an effective amount of the active compound together with a suitable carrier to prepare a suitable dosage form for proper administration to a recipient.

In the practice of the methods of the present invention, an effective amount of any one of the compounds of the present invention or any combination of the compounds of the present invention or pharmaceutically acceptable salts or esters thereof, is administered by any of the usual and acceptable methods known in the art, either alone or in combination. The compounds or compositions can thus be administered orally (e.g., buccal), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppository or lotion), transdermally (e.g., skin electroporation), or by inhalation (e.g., by aerosol), and in solid, liquid, or gaseous dosage forms, including tablets and suspensions. The administration can be in a single unit dosage form for continuous treatment or as a single dose therapy at will. The therapeutic composition may also be in the form of an oil emulsion or dispersion along with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained release composition for subcutaneous or intramuscular administration.

Compound (I)

In one aspect of the invention, there is provided as a first embodiment (embodiment "E1") of the invention a compound of formula I as described hereinafter:

wherein:

x, Y, Z are independently of one another C, CH or N;

R¹is unsubstituted phenyl, phenyl mono-or di-substituted independently by halogen or-CN, unsubstituted five-or six-membered heteroaromatic ring or a five-or six-membered heteroaromatic ring substituted by lower alkyl, halogen, or haloalkyl;

R²selected from the group consisting of hydrogen, deuterium, lower alkyl, haloalkyl, cycloalkyl, alkoxy, oxetanyl, phenyl and five or six membered heteroaromatic rings, wherein said lower alkyl, haloalkyl, cycloalkyl, alkoxy or oxetanyl is optionally substituted with deuterium, and wherein said phenyl and said five or six membered heteroaromatic rings are each independently optionally substituted with lower alkyl, haloalkyl, deuterium or halogen;

R³and R^3′Each independently selected from hydrogen; deuterium; a haloalkyl group; cycloalkyl and lower alkylWherein said haloalkyl, cycloalkyl and lower alkyl are optionally substituted with deuterium, F, Cl, Br, hydroxy or alkoxy; or R³And R^3′Together with the carbon to which they are attached form a 3, 4,5 or 6 membered cycloalkyl group optionally substituted with deuterium, F, Cl, Br, hydroxy or alkoxy;

R⁴is hydrogen or lower alkyl;

R⁵is trifluoromethyl-phenyl, trifluoromethyl-pyridyl, trifluoromethyl-pyridazinyl, trifluoromethyl-pyrimidinyl, azetidino, pyrrolidino, cycloalkyl, piperidino, pyrrolidino-pyrimidinyl, heterocycle-pyrimidinyl, heterocycle-pyridyl, heterocycle-pyridazinyl, heterocycle-pyrazinyl, cycloalkyl-pyrimidinyl, cycloalkyl-pyridyl, cycloalkyl-pyridazinyl, cycloalkyl-pyrazinyl, or trifluoromethyl-pyrazinyl, wherein any azetidinyl, pyrrolidino, cycloalkyl, heterocycle, and piperidino is optionally substituted with lower alkyl, halo, trifluoromethyl, trifluoromethoxy, or trifluoromethylthio; and is

R⁶Is hydrogen, halogen or alkoxy,

or a pharmaceutically acceptable salt thereof.

To understand, R⁵And R⁶Each is attached to a carbon atom, and when R is⁵And/or R⁶When attached to one or more of X, Y or Z, then R⁵And/or R⁶The one or more X, Y or Z attached is C.

Other embodiments of the invention (e.g., E2-E25) are set forth below

E2: a compound according to E1, wherein X, Y and Z are independently of each other C or CH.

E3: a compound according to E1, wherein one of X, Y or Z is N and the others are independently of each other C or CH.

E4: a compound according to E1, wherein two of X, Y or Z are N and the other is C or CH.

E5: a compound according to any one of E1-E4, wherein R¹Is unsubstituted phenyl, pyrazinyl, pyridyl or thienyl.

E6: a compound according to any one of E1-E4, wherein R¹Is phenyl optionally substituted by cyano, F or Cl, pyrazinyl optionally substituted by F or Cl, pyridinyl optionally substituted by F or Cl, pyrazole optionally substituted by F or Cl, or thienyl optionally substituted by F or Cl.

E7: a compound according to any one of E1-E4, wherein R¹Is phenyl substituted by F or Cl, pyrazinyl substituted by F or Cl, pyridinyl substituted by F or Cl, or thienyl substituted by F or Cl.

E8: a compound according to any one of E1-E7, wherein R²Is hydrogen.

E8.1: a compound according to any one of E1-E7, wherein R²Optionally substituted with phenylpyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

E8.2: a compound according to any one of E1-E7, wherein R²Is deuterium.

E9: a compound according to any one of E1-E7, wherein R²Is methyl, -CH₂CF₃Ethyl, hydroxyethyl, propyl, hydroxypropyl, cyclopropyl, isopropyl, methoxy-ethyl, tert-butyl, oxetan-3-ylmethyl or oxetanyl.

E10: a compound according to any one of E1-E7, wherein R²Is methyl, -CH₂CF₃Ethyl, hydroxy-ethyl, 2-hydroxypropyl, cyclopropyl, isopropyl, 2-methoxyethyl, tert-butyl, methoxymethyl, oxetan-3-ylmethyl, 4-fluorophenyl, or 3-oxetanyl.

E11: a compound according to any one of E1-E10, wherein R³And R^3′Are all hydrogen.

E11.1: according to E1-E10A compound of formula (I) wherein R³And R^3’Are all deuterium.

E12: a compound according to any one of E1-E10, wherein R³Or R^3′One of which is hydrogen and the other is methyl, tert-butyl, cyclopropyl, -CH₂OH or-CH₂OCH₃。

E13: a compound according to any one of E1-E10, wherein R³Or R^3′One is hydrogen, deuterium or methyl and the other is hydrogen, methyl, isopropyl, cyclopropyl, hydroxymethyl, methoxymethyl, or deuterium; or R³And R^3′Together with the carbon to which they are attached form a 3-membered cycloalkyl group.

E14: a compound according to any one of E1-E13, wherein R⁴Is hydrogen.

E15: a compound according to any one of E1-E13, wherein R⁴Is methyl.

E16: a compound according to any one of E1 and E5-E15, wherein:

selected from:

e17: a compound according to any one of E1-E16, wherein R⁵Is trifluoromethyl-phenyl.

E18: a compound according to any one of E1-E16, wherein R⁵Is 4-trifluoromethyl-pyridinyl, trifluoromethyl-pyridazinyl, trifluoromethyl-pyrimidinyl or trifluoromethyl-pyrazinyl.

E19: a compound according to any one of E1-E16, wherein R⁵Is trifluoromethylphenyl, 5-trifluoromethylpyridin-2-yl, 6-trisFluoromethylpyridin-3-yl, 6-trifluoromethylpyridazin-3-yl, 2-trifluoromethylpyrimidin-5-yl, 5-trifluoromethylpyrazin-2-yl, pyrrolidino, cyclopropyl, 4, 4-difluoropiperidino, 4-trifluoromethylpiperidino, 2- (2-methylpyrrolidinio) pyrimidin-5-yl or 4-trifluoromethylcyclohex-1-ene.

E20: a compound according to any one of E1-E16, wherein R⁵Is trifluoromethyl-phenyl, trifluoromethyl-pyridyl, trifluoromethyl-pyridazinyl, trifluoromethyl-pyrimidinyl, azetidino, pyrrolidino, piperidino, pyrrolidino-pyrimidinyl, or trifluoromethyl-pyrazinyl, wherein any azetidinyl, pyrrolidino, cycloalkyl, heterocycle, and piperidino is optionally substituted with lower alkyl, halogen, or trifluoromethyl.

E21: a compound according to any one of E1-E20, wherein R⁶Is hydrogen.

E22: a compound according to any one of E1-E20, wherein R⁶Is F or methoxy.

E23: a compound according to any one of E1-E20, wherein R⁶Is halogen or alkoxy.

E23: a compound according to any one of E1 and E5-E15, wherein:

selected from:

e24: a compound according to E1, wherein the compound is:

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

(S) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide;

2- (4-fluoro-benzenesulfonylamino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

(R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide;

(S) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-methyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -butyramide;

(R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-methyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -butyramide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -2-methyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (6-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (2-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (5-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) - (2, 2, 2-trifluoro-ethyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (6-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (5-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (4-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (3' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-propyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ cyclopropyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2-cyclopropyl-2- (4-fluoro-benzenesulfonylamino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (5-chloro-thiophene-2-sulfonyl) -methyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ methyl- (thiophene-2-sulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) - (2-methoxy-ethyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ tert-butyl- (4-fluoro-benzenesulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

(S) -2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -propionamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (4' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (3' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (6-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (5-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (4-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

(R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -propionamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (5-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (5-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (5-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (6-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (6-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-hydroxy-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide;

(S) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-methoxy-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide;

2- (benzenesulfonyl-isopropyl-amino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -oxetan-3-ylmethyl-amino ] -N- (4 '-trifluoro-3-ylmethyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (6-trifluoromethyl- [3, 4 '] bipyridinyl-2' -ylmethyl) -acetamide;

2- [ isopropyl- (pyridine-3-sulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [5- (4-trifluoromethyl-phenyl) -pyridin-3-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (6 '-trifluoromethyl- [2, 3' ] bipyridinyl-4-ylmethyl) -acetamide;

2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [2- (4-trifluoromethyl-phenyl) -pyridin-4-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -oxetan-3-yl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [ 3-fluoro-5- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -acetamide;

2- [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (2-cyano-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (6-trifluoromethyl-pyridazin-3-yl) -benzyl ] -acetamide;

2- [ isopropyl- (pyrazine-2-sulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl ] -acetamide;

2- [ (3, 4-difluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [ 4-fluoro-3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl ] -acetamide; or

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (5-trifluoromethyl-pyrazin-2-yl) -benzyl ] -acetamide;

2- [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino ] -N- [3- (5-trifluoromethyl-pyrazin-2-yl) -benzyl ] -acetamide;

2- [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino ] -N- [3- (6-trifluoromethyl-pyridazin-3-yl) -benzyl ] -acetamide;

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [2- (2-trifluoromethyl-pyrimidin-5-yl) -pyridin-4-ylmethyl ] -acetamide;

2- [ (5-chloro-thiophene-2-sulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide;

2- [ (5-chloro-thiophene-2-sulfonyl) -isopropyl-amino ] -N- [6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4-ylmethyl ] -acetamide; or

2- (4-fluoro-N- (4-fluorophenyl) phenylsulfonamido) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) acetamide.

E25: in another embodiment, the present invention provides a compound according to E1, wherein the compound is:

2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- (3- (pyrrolidin-1-yl) benzyl) acetamide;

n- (3-cyclopropylbenzyl) -2- (4-fluoro-N-isopropylphenylsulfonamido) acetamide;

r) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- (3- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) benzyl) acetamide;

(S) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- (3- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) benzyl) acetamide;

2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-4-yl) methyl) acetamide;

n- ((6- (4, 4-difluoropiperidin-1-yl) pyrimidin-4-yl) methyl) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) acetamide;

2- (N-isopropyl-1-methyl-1H-pyrazole-3-sulfonamide) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide;

2, 2-dideuterio-2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) acetamide;

1- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) cyclopropanecarboxamide;

(6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl-2- (4-fluoro-N-isopropylbenzenesulfonylamino) acetate; or

2- [ N- (prop-2-yl) (4-fluorobenzene) sulfonylamino ] -N- ([6- [4- (trifluoromethyl) cyclohex-1-en-1-yl ] pyrimidin-4-yl ] methyl) acetamide;

or a salt thereof.

In one embodiment, the present invention provides a compound of formula (I) which is a compound of formula (Ia):

wherein:

a) x, Y, Z are independently of one another C or N;

b) r1 is unsubstituted phenyl, phenyl mono-or di-substituted independently with halogen or-CN, an unsubstituted five-or six-membered heteroaromatic ring or a five-or six-membered heteroaromatic ring substituted with halogen;

c) r2 is hydrogen, unsubstituted lower alkyl, haloalkyl, lower alkyl substituted by-OH or oxetanyl, cycloalkyl, alkoxy or oxetanyl;

d) r3, R3' are independently from each other hydrogen, unsubstituted lower alkyl, cycloalkyl substituted by alkoxy or lower alkyl;

e) r4 is hydrogen or lower alkyl;

f) r5 is trifluoromethyl-phenyl, trifluoromethyl-pyridyl, trifluoromethyl-pyridazinyl, trifluoromethyl-pyrimidinyl or trifluoromethyl-pyrazinyl; and is

g) R6 is hydrogen, halogen or alkoxy,

h) or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound according to formula (Ia) wherein X, Y and Z are C.

In another embodiment, the invention provides a compound according to formula (Ia) wherein one of X, Y or Z is N and the other is C.

In another embodiment, the invention provides a compound according to formula (Ia) wherein two of X, Y or Z are N and the other is C.

In another embodiment, the invention provides a compound according to formula (Ia) wherein R1 is unsubstituted phenyl, pyrazinyl, pyridinyl or thienyl.

In another embodiment, the invention provides a compound according to formula (Ia) wherein R1 is phenyl substituted with F or Cl, pyrazinyl substituted with F or Cl, pyridinyl substituted with F or Cl, or thienyl substituted with F or Cl.

In another embodiment, the invention provides a compound according to formula (Ia) wherein R2 is hydrogen.

In another embodiment, the present invention provides a compound according to formula (Ia) wherein R2 is methyl, -CH₂CF₃Ethyl, hydroxy-ethyl, propyl, hydroxy-propyl, cyclopropyl, isopropyl, methoxy-ethyl, tert-butyl, oxetan-3-ylmethyl or oxetanyl.

In another embodiment, the present invention provides a compound according to formula (Ia) wherein R3 and R3' are both hydrogen.

In another embodiment, the present invention provides a compound according to formula (Ia) wherein one of R3 or R3' is hydrogen and the other is methyl, tert-butyl, cyclopropyl, -CH₂OH or-CH₂OCH₃。

In another embodiment, the invention provides a compound according to formula (Ia) wherein R4 is hydrogen.

In another embodiment, the present invention provides a compound according to formula (Ia) wherein R4 is methyl.

In another embodiment, the present invention provides a compound according to formula (Ia) wherein R5 is trifluoromethyl-phenyl.

In another embodiment, the invention provides a compound according to formula (Ia) wherein R5 is trifluoromethyl-pyridinyl, trifluoromethyl-pyridazinyl, trifluoromethyl-pyrimidinyl or trifluoromethyl-pyrazinyl.

In another embodiment, the invention provides a compound according to formula (Ia) wherein R6 is hydrogen.

In another embodiment, the invention provides a compound according to formula (Ia) wherein R6 is F or methoxy.

In another embodiment, the present invention provides a compound:

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [ 4-fluoro-3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl ] -acetamide;

2- [ (5-chloro-thiophene-2-sulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide; or

2- [ (5-chloro-thiophene-2-sulfonyl) -isopropyl-amino ] -N- [6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4-ylmethyl ] -acetamide;

or a salt thereof.

In another embodiment of the invention, the compounds of formula (I) are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present invention. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,²H，³H，¹¹C，¹³C，¹⁴C，¹³N，¹⁵N，¹⁵O，¹⁷O，¹⁸O，³¹P，³²P，³⁵S，¹⁸F，³⁶Cl，¹²³i, and¹²⁵I. these isotopically labeled compounds will be useful for determining or measuring the efficacy of the compounds by characterizing, for example, the site or pattern of action on an ion channel, or the binding affinity to a pharmacologically important ion channel, particularly the site of action on TRPA 1. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioisotope, are useful in drug and/or matrix tissue distribution studies. Radioisotope tritium, i.e.³H, and carbon-14, i.e.,¹⁴c, which is particularly useful for this purpose in view of its ease of incorporation and ready detection method. For example, the compound of formula (I) may be enriched in 1, 2,5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

With heavier isotopes such as deuterium, i.e.²H replacement may provide certain therapeutic advantages resulting from better metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. As illustrated in example 83, compounds of the invention include compounds of formula (I) wherein R³And/or R³' deuterium enrichment exceeds normal natural abundance. For example, R³And/or R³' may each be independently enriched with 1, 2,5, 10, 25, 50, 75, 90, 95 or 99 percent deuterium.

Using positron emitting isotopes, e.g.¹¹C，¹⁸F，¹⁵O and¹³n substitution, can be used in Positron Emission Tomography (PET) studies for detecting substrate receptor occupancy. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the examples set forth below, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent used previously.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I) and a pharmaceutically acceptable carrier.

In addition to salt forms, the present invention provides compounds in prodrug form. As used herein, the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir, the prodrug may be slowly converted to a compound of the invention with a suitable enzyme or chemical agent.

Prodrugs of the invention include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently linked through an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of a compound of the invention. The amino acid residues include, but are not limited to, 20 naturally occurring amino acids generally represented by three-letter symbols and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosine (demosine), isodesmosine (isodemosine), γ -carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline (norvaline), β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, p-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Other types of prodrugs are also included. For example, the free carboxyl groups of the compounds of the invention may be derivatized as amides or alkyl esters. As another example, compounds of the invention containing a free hydroxyl group can be derivatized into prodrugs by converting the hydroxyl group to a group such as, but not limited to, phosphate, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethoxymethoxycarbonyl, as described in Fleisher, d. et al, (1996) Improved oral drug delivery: solvability associations by the use of the drugs Advanced Drug Delivery Reviews, 19: 115, as outlined in. Also included are carbamate prodrugs of hydroxy and amino groups, as well as carbonate prodrugs of hydroxy groups, sulfonate esters and sulfate esters. Also included are derivatives of hydroxyl groups as (acyloxy) methyl ethers and (acyloxy) ethyl ethers, wherein the acyl group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functionalities, or wherein the acyl group is an amino acid ester as described above. Prodrugs of this type are described in j.med.chem., (1996), 39: 10, to be described. More specific examples include those using a compound such as (C)_1-6) Alkanoyloxymethyl, 1- ((C)_1-6) Alkanoyloxy) ethyl, 1-methyl-1- ((C)_1-6) Alkanoyloxy) ethyl group, (C)_1-6) Alkoxycarbonyloxymethyl, N- (C)_1-6) Alkoxycarbonylaminomethyl, succinyl, (C)_1-6) Alkanoyl, α -amino (C)_1-4) Alkanoyl, aroyl and α -aminoacyl, or α -aminoacyl- α -aminoacyl in place of a hydrogen atom of an alcohol group, wherein each α -aminoacyl is independently selected from a naturally occurring L-amino acid, P (O), (OH)₂，-P(O)(O(C_1-6) Alkyl radical)₂Or a glycosyl group (a group derived from a carbohydrate by removal of the hydroxyl group in the hemiacetal form).

For further examples of prodrug derivatives, see, e.g., a) Design of produgs, editors, h.bundgaard, (Elsevier, 1985) and Methods in Enzymology, vol.42, p.309-396, k.widder, et al editors (Academic Press, 1985); b) a Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 "Design and Application of Prodrugs," H.Bundgaardp.113-191 (1991); c) bundgaard, Advanced Drug Delivery Reviews, 8: 1-38 (1992); d) bundgaard et al, Journal of Pharmaceutical Sciences, 77: 285 (1988); and e) n.kakeya et al, chem.pharm.bull, 32: 692(1984), each of which is specifically incorporated herein by reference.

Furthermore, the present invention provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced by the metabolism of a specified compound or salt thereof in the body. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound.

The metabolites are typically radiolabeled by preparing the compounds of the invention (e.g.,¹⁴c or³H) Isotopes, which are parenterally administered to an animal such as a rat, mouse, guinea pig, monkey, or to a human in detectable doses (e.g., greater than about 0.5mg/kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and their conversion products to be isolated from urine, blood or other biological samples for identification. These products are easily isolated because they are labeled (others are isolated by using antibodies that are capable of binding epitopes retained in the metabolites). Metabolite structure is determined in a conventional manner, e.g., by MS, LC/MS or NMR analysis. Typically, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites, so long as they are not otherwise found in vivo, are useful in diagnostic assays for the therapeutic dosing of the compounds of the present invention.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Pharmaceutical compositions and administration

In addition to one or more of the compounds (or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof) provided above, the present invention also provides compositions and medicaments comprising a compound of formula I, or embodiments thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. The compositions of the invention may be used to selectively inhibit TRPA1 in a patient (e.g., a human).

In addition to one or more of the compounds (or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof) provided above, the present invention also provides a pharmaceutical composition comprising a compound of formula I, or an embodiment thereof, and at least one pharmaceutically acceptable carrier. The compositions of the invention may be used to selectively inhibit TRPA1 in a patient (e.g., a human).

The term "composition," as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

In one embodiment, the present invention provides a pharmaceutical composition (or medicament) comprising a compound of formula I or embodiments thereof, and stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof) and a pharmaceutically acceptable carrier, diluent or excipient. In another embodiment, the invention provides the preparation of a composition (or medicament) comprising a compound of the invention. In another embodiment, the present invention provides for administering a compound of formula I or an embodiment thereof and a composition comprising a compound of formula I or an embodiment thereof to a patient in need thereof (e.g., a human patient).

The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to the practitioner. The effective amount of the compound to be administered will be governed by such considerations and is the minimum amount required to inhibit TRPA1 activity, as required for the prevention or treatment of an undesirable disease or condition, such as, for example, pain. For example, such an amount may be lower than an amount that is toxic to normal cells, or the mammal as a whole.

In one embodiment, a therapeutically effective amount of a compound of the invention administered parenterally will be in the range of about 0.01-100mg/kg per dose, alternatively about, e.g., 0.1 to 20mg/kg of patient body weight per day, with a typical initial range of 0.3 to 15mg/kg per day of the compound used. In certain embodiments, the daily dose is given as a single daily dose or as divided doses two to six times per day, or in sustained release form. In the case of a 70kg adult male, the total daily dose will generally be from about 7mg to about 1,400 mg. The dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

The compounds of the invention may be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, gels, patches and the like. Such compositions may contain ingredients conventional in pharmaceutical formulations, for example, diluents, carriers, pH adjusting agents, sweeteners, fillers and other active agents.

The compounds of the invention may be administered in any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for topical treatment, intralesional administration. Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional or subcutaneous administration.

Compositions comprising a compound of formula I or embodiments thereof are typically formulated as pharmaceutical compositions according to standard pharmaceutical practice. Typical formulations are prepared by mixing a compound of the invention with a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard c, et al, Ansel's Pharmaceutical Dosage Forms and Drug delivery systems, philiadelphia: lippincott, Williams&Wilkins, 2004; gennaro, Alfonso r., et al Remington: the Science and Practice of pharmacy Philadelphia: lippincott, Williams&Wilkins, 2000: and Rowe, Raymond C.handbook of Pharmaceutical excipients Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, masking agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide the elegant appearance of a drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the preparation of a drug product (i.e., a medicament). Suitable carriers, diluents and excipients are well known to those skilled in the art and include buffers such as phosphates, citrates and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; quaternary ammonium chloride hexahydrocarbide; benzalkonium chloride, benzalkonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl parabens; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone(ii) a Amino acids such as glycine, glutamine, aspartic acid, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants such as TWEEN^TM，PLURONICS^TMOr polyethylene glycol (PEG). The active pharmaceutical ingredients of the present invention (e.g., a compound of formula I or embodiments thereof) may also be embedded in, for example, microcapsules prepared by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or macroemulsions. This technique is described in Remington: the Science and Practice of Pharmacy: remington the science and Practice of Pharmacy (2005), 21 st edition, Lippincott Williams&Wilkins, Philidelphia, PA. The particular carrier, diluent or excipient employed will depend upon the mode and purpose of administration of the compounds of the present invention. Solvents are generally selected based on solvents that one of skill in the art would consider safe for administration to mammals (GRAS). Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and the like, and mixtures thereof. Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include

Sustained release formulations of the compounds of the invention (e.g., a compound of formula I or an embodiment thereof) may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I, or an embodiment thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methacrylate), or poly (vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919)) Copolymers of L-glutamic acid and γ -ethyl-L-glutamate (Sidman et al, Biopolymers 22: 547, 1983), non-degradable ethylene vinyl acetate (Langer et al, j.biomed.mater.res.15: 167, 1981), degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT^TM(injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolyl acetate) and poly-D- (-) -3-hydroxybutyric acid (EP133,988A). Sustained release compositions also include liposome-entrapped compounds, which can be prepared by methods known per se (Epstein et al, Proc. Natl. Acad. Sci. U.S. A.82: 3688, 1985; Hwang et al, Proc. Natl. Acad. Sci. U.S. A.77: 4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A). Typically, liposomes are small (about 200-800 angstroms) monolithic in shape, with lipid content greater than about 30 mol% cholesterol, and the proportions selected are adjusted for optimal treatment.

The formulations include those suitable for the routes of administration detailed herein. The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical arts. Typically in Remington: the Science and practice of Pharmacy: the techniques and formulations are found in Remington the Science and Practice of Pharmacy (2005), 21 st edition, Lippincott Williams & Wilkins, Philidelphia, Pa. Such methods include the step of bringing into association the active ingredient with the carrier which consists of one or more additional ingredients.

In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents or excipients or finely divided solid carriers, diluents or excipients, or both, and then, if necessary, shaping the product. Typical formulations are prepared by mixing a compound of the invention with a carrier, diluent or excipient. The formulations may be prepared using conventional dissolution and mixing procedures. For example, the base drug substance (i.e., a compound of the invention or a stable form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above.

In one embodiment, the compound of formula I or embodiments thereof may be formulated by mixing at ambient temperature at an appropriate pH and in the desired purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to recipients at the dosages and concentrations employed in the galenic administration form. The pH of the formulation depends primarily on the particular use and concentration of the compound, but is preferably anywhere in the range of about 3 to about 8. In one embodiment, the compound of formula I (or embodiments thereof) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula I or embodiments thereof is sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

Formulations of a compound of the invention (e.g., a compound of formula I or embodiments thereof) suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of a compound of the invention.

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, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or marked and optionally formulated so as to provide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs may be prepared for oral use. Formulations of the compounds of the present invention (e.g., compounds of formula I or embodiments thereof) intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more chemical agents including sweetening agents, flavoring agents, coloring agents, preserving agents in order to provide the desired formulation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained release effect over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Examples of suitable oral administration forms are tablets containing about 1mg, 5mg, 10mg, 25mg, 30mg, 50mg, 80mg, 100mg, 150mg, 250mg, 300mg and 500mg of a compound of the invention complexed with about 90-30mg of anhydrous lactose, about 5-40mg of croscarmellose sodium, about 5-30mg polyvinylpyrrolidone (PVP) K30, and about 1-10mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition may be dried using conventional equipment, granulated, mixed with magnesium stearate and compressed into tablet form. An example of an aerosol formulation may be prepared by dissolving a compound, for example 5-400mg of a compound of the invention, in a suitable buffer, for example phosphate buffer, and, if desired, adding an isotonic agent (tonicifier), for example a salt such as sodium chloride. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

For the treatment of the eye or other external tissues, e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream in an oil-in-water cream base. If desired, the aqueous phase of the cream base may include polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups such as propylene glycol, butane 1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycols (including PEG 400) and mixtures thereof. The topical formulations may include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas, as desired. Examples of such penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsion of the invention may be constituted by known ingredients in a known manner. Although the phase may comprise emulsifiers only, it comprises, as required, a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both oil and fat. Emulsifiers form, with or without stabilizers, the so-called emulsifying waxes, and said waxes, together with oils and fats, form the so-called emulsifying ointment base, which forms the oily dispersed phase of cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include60，80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glycerol monostearate and sodium lauryl sulfate.

In one aspect of topical application, it is desirable to administer an effective amount of a pharmaceutical composition according to the invention to a target area, e.g., a skin surface adjacent to a peripheral neuron to be treated, a mucosal membrane, etc. This amount will generally range from about 0.0001mg to about 1g of a compound of the invention per application, depending on the area to be treated, whether it is diagnostic, prophylactic or therapeutic use, the severity of the symptoms, and the nature of the topical carrier used. Preferred topical formulations are ointments, wherein about 0.001 to about 50mg of active ingredient is used per cc of ointment base. The pharmaceutical composition may be formulated as a transdermal composition or transdermal delivery device ("patch"). Such compositions include, for example, a backing, an active compound reservoir, a control film, a liner, and a contact adhesive. Such transdermal patches may be used to provide continuous pulsatility, or on-demand delivery of the compounds of the present invention.

Aqueous suspensions of the compounds of the invention (e.g., a compound of formula I or embodiments thereof) contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia, and dispersing or wetting agents such as naturally-occurring phosphatides (e.g., lecithin), condensation products of an alkylene oxide with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose or saccharin.

The formulations of the compounds of the invention (e.g., a compound of formula I or embodiments thereof) may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. The suspensions may be prepared according to known techniques using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol, or as a lyophilized powder. Acceptable carriers and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time release formulation intended for oral administration to humans may contain from about 1 to 1000mg of the active substance, complexed with a suitable and convenient amount of carrier material which may vary from about 5 to about 95% (weight: weight) of the total composition. The pharmaceutical composition can be prepared to readily provide a measurable amount for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μ g of active ingredient per mL of solution, so that infusion into a suitable volume at a rate of about 30mL/hr may occur.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, 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.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration to the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository using a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have a particle size, for example, in the range of 0.1 to 500 microns (including particle sizes in increments of microns such as 0.5, 1, 30 microns, 35 microns, etc. in the range of 0.1 and 500 microns), which are administered by rapid inhalation through the nasal passages or by oral inhalation to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment of the diseases described below.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dose formulations are those containing a daily dose or unit daily sub-dose of the active ingredient, as listed above, or an appropriate fraction thereof.

Certain embodiments of the present invention provide compounds of formula I (or embodiments thereof) to cross the blood-brain barrier when the binding target is located in the brain. Certain neurodegenerative diseases are associated with an increase in blood brain barrier permeability, such that the compounds of formula I (or embodiments thereof) can be readily introduced into the brain. While the blood brain barrier is still intact, there are a variety of methods known in the art for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel-based methods.

Physical methods of transporting a compound of formula I (or embodiments thereof) across the blood-brain barrier include, but are not limited to, completely avoiding the blood-brain barrier or by creating an opening in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al, Gene Therapy 9: 398-^TM，GuildfordPharmaceutical)。

Methods of creating openings in a barrier include, but are not limited to, sonication (see, e.g., U.S. patent publication No. 2002/0038086), osmotic pressure (e.g., by application of hypertonic mannitol (Neuwelt, e.a., immunization of the blood-Brain barrier and its management, volumes 1 and 2, Plenum Press, n.y., 1989)), and permeabilization by, e.g., bradykinin or penetrant a-7 (see, e.g., U.S. patent nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

Lipid-based methods of transporting a compound of formula I (or embodiments thereof) across the blood-brain barrier include, but are not limited to, encapsulating a compound of formula I (or embodiments thereof) into a liposome coupled to an antibody-binding fragment that binds to a receptor on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. patent application publication No. 2002/0025313), and coating a compound of formula I (or embodiments thereof) in low-density lipoprotein particles (see, e.g., U.S. patent application publication No. 2004/0204354) or apolipoprotein E (see, e.g., U.S. patent application publication No. 2004/0131692).

Receptor and channel-based methods of transporting compounds of formula I (or embodiments thereof) across the blood-brain barrier include, but are not limited to, increasing the permeability of the blood-brain barrier using glucocorticoid blockers (see, e.g., U.S. patent application publication nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. patent application publication No. 2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. patent application publication No. 2003/0073713); coating a compound of formula I (or an embodiment thereof) with transferrin and modulating the activity of one or more transferrin receptors (see, e.g., U.S. patent application publication No. 2003/0129186), and cationized antibodies (see, e.g., U.S. patent No. 5,004,697).

For intracerebral use, in certain embodiments, the compound may be administered continuously by injection into the reservoir of the CNS, although bolus injections may be acceptable. The inhibitor may be administered intracerebroventricularly or otherwise introduced into the CNS or spinal fluid. Administration may be by use of an indwelling catheter and a continuous administration means such as a pump, or it may be by implantation, for example, intracerebral implantation of a slow release carrier. More specifically, the inhibitor may be injected via a long-term implanted cannula or with the aid of an osmotic micro-pump. Subcutaneous pumps are available which deliver proteins through the tubules into the ventricles of the brain. The highly complex pump can be refilled through the skin and its delivery rate can be set without surgery. Examples of suitable administration regimens and delivery systems comprising subcutaneous pump devices or continuous intraventricular perfusion through a fully implanted drug delivery system are those for administering dopamine, dopamine agonists, and cholinergic agonists to alzheimer's patients and parkinson's disease animal models, such as Harbaugh, j.neuraltrans.suppl.24: 271, 1987; and DeYebrenes et al, Mov.Disord.2: 143, 1987.

The compounds of formula I (or embodiments thereof) for use in the present invention are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to the practitioner. The compounds of formula I (or embodiments thereof) need not be, but are optionally, formulated with one or more agents currently used for the prevention or treatment of the disease under consideration. The effective amount of such other agents will depend on the amount of the compound of the invention present in the formulation, the type of disease or treatment, and other factors discussed above.

These are generally used at the same dosage and by the route of administration as described herein, or about 1 to 99% of the dosage described herein, or at any dosage and by any route that is empirically/clinically determined to be appropriate.

For the prevention or treatment of disease, the appropriate dosage of a compound of formula I (or embodiments thereof) (either alone or in combination with other agents) will depend upon the disease to be treated, the nature of the compound, the severity and course of the disease, whether the compound is administered for prophylactic or therapeutic purposes, previous therapy, the patient's clinical history and response to the compound, and the judgment of the attending physician. The compounds are suitable for administration to a patient at one time or over a series of treatments. Depending on the type and severity of the disease, about 1 μ g/kg to 15mg/kg (e.g., 0.1mg/kg-10mg/kg) of the compound may be an initial candidate dose for administration to a patient, possibly, for example, by one or more divided administrations, or by continuous perfusion. A typical daily dosage may range from about 1. mu.g kg to over 100mg/kg, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, treatment will generally continue until the desired suppression of disease symptoms occurs. An exemplary dose of the compound of formula I (or embodiments thereof) will range from about 0.05mg/kg to about 10 mg/kg. Thus, one or more doses of about 0.5mg/kg, 2.0mg/kg, 4.0mg/kg, or 10mg/kg (or any combination thereof) may be administered to a patient. Such doses may be administered intermittently, e.g., weekly or every three weeks (e.g., such that the patient receives about two to about twenty, or, e.g., about six doses of the antibody). An initial higher loading dose may be administered followed by one or more lower doses. An exemplary dosing regimen comprises administration of an initial loading dose of about 4mg/kg, followed by a weekly maintenance dose of about 2mg kg of the compound. However, other dosage regimens may be used. The progress of the treatment is readily monitored by conventional techniques and assays.

Other typical daily dosages may range from, for example, about 1g/kg up to 100mg/kg or more (e.g., about 1 μ g kg to 1mg/kg, about 1 μ g/kg to about 5mg/kg, about 1mg kg to 10mg/kg, about 5mg/kg to about 200mg/kg, about 50mg/kg to about 150mg/mg, about 100mg/kg to about 500mg/kg, about 100mg/kg to about 400mg/kg, and about 200mg/kg to about 400mg/kg), depending on the factors mentioned above. Typically, the clinician will administer the compound until a dosage is reached that results in an improvement, or preferably elimination, of one or more symptoms of the disease or disorder being treated. The course of the treatment is readily monitored by routine assays. One or more agents provided herein can be administered together or at different times (e.g., one agent is administered followed by a second agent). One or more agents can be administered to a subject using different techniques (e.g., one agent can be administered orally while a second agent is administered by intramuscular injection or intranasally). One or more agents may be administered such that the one or more agents simultaneously have a pharmacological effect in the subject. Alternatively, one or more agents may be administered such that the pharmacological activity of the first administered agent is ineffective prior to administration of the one or more second administered agents (e.g., 1, 2,3, or 4 second administered agents).

Indications and treatment methods

Representative compounds of the invention have been shown to modulate TRPA1 activity. Accordingly, the compounds of the present invention are useful for the treatment of diseases and conditions mediated by TRPA1 activity. Such diseases or conditions include, but are not limited to: pain (acute, chronic, inflammatory, or neuropathic pain); itch or various inflammatory diseases; inner ear diseases; fever or other thermoregulatory disorders; tracheobronchial or diaphragmatic dysfunction; gastrointestinal or urinary tract disorders; chronic obstructive pulmonary disease; (ii) incontinence; and diseases associated with reduced blood flow to the CNS or CNS hypoxia.

In particular embodiments, the compounds of the present invention may be administered to treat pain, including but not limited to neuropathic and inflammatory pain, among others. Certain types of pain may be considered a disease or condition, while other types may be considered symptoms of a different disease or condition, and pain may include a different etiology. Exemplary types of pain that can be treated with TRPA 1-modulators according to the present invention include pain associated with, caused by, or caused by: osteoarthritis, rotator cuff disease (rotator cuff disorders), arthritis (e.g., rheumatoid arthritis or inflammatory arthritis; see, Barton et al, exp. mol. Pathol.2006, 81 (2)), 166-, bursitis, tennis elbow (tendonitis), thrown elbow (pitcher's elbow), patellar tendonitis (patellar tendonitis), repetitive strain (repetitive strain in), myofascial syndrome (myofacial syndrome), muscle strain (muscle strain), myositis (myositis), temporomandibular joint disease (temporomandibular joint disease), amputation (amputation), low back pain (low back pain), spinal cord injury, neck pain, acute neck sprain (whiplash), cystspasm (bladderspasms), Gl tract disease, cystitis (cystitis), interstitial cystitis (interstitial cystitis), cholecystitis (cholecystitis), urinary tract infection, urinary tract colic (renal colic 385), urinary tract colic (renal colic), herpes (herpetic), herpes (otitis), otitis media (otitis media, etc.), esophageal pain (esophageal pain), esophageal spasm (esophageal spasms), abdominal diseases, gastroesophageal reflux disease (gastroesophageal reflux disease), pancreatitis (pancreatitis), enteritis (enterititis), irritable bowel disease (irritable bowewel disorder), inflammatory bowel disease, Crohn's disease, ulcerative colitis (ulcerative colitis), colonic swelling (colodistension), abdominal constriction (abdominal constriction), diverticular disease (divaricatiolosis), ventriculitis (invertebral inflammation), enteropathogenic qi (intestinal gas), hemorrhoids (hemorrhoidal disease), anal fissures (anal fistula), rectal disease, prostatitis (prostatitis), epididymitis (epyitis), testicular pain (cutaneous pain), genital herpes (genital pain), genital herpes (vaginal herpes), vaginal herpes (vaginal herpes simplex pelvic pain), vaginal herpes (infection), pleurisy, pericarditis, non-cardiac chest pain (non-cardiac pain), contusions, abrasions, skin incisions (skinning), Honore, p, et al, J pharmacological Exp ther, 2005, 314, 410-21, post-operative pain (stomatic pain), peripheral neuropathy (cutaneous neuropathy), central neuropathy (thoracic neuropathy), diabetic neuropathy (diabetic neuropathy), acute herpes zoster neuralgia (acute herpetic neuralgia), post herpetic neuralgia (post-herpetic neuralgia), trigeminal neuralgia (trigeminal neuralgia), pharyngeal neuralgia (glossogenic neuralgia), atypical neuralgia, facial neuralgia, cervical spondylosis (cervical spondylotic neuralgia), cervical spondylotic neuropathy (sciatic neuropathy), cervical spondylosis (sciatic neuropathy), cervical spondylosis (sciatic nerve plexus neuropathy (sciatic neuropathy), cervical spondylosis (sciatic neuropathy (sciatic nerve), cervical spondylosis (sciatic nerve plexus neuralgia (sciatic nerve), cervical spondylosis (sciatic nerve, lumbar plexus disease (lumbar plexus), neurodegenerative disorders, occipital neuralgia (occipital neuralgia), intercostal neuralgia (intercostal neuralgia), supraorbital neuralgia (supraorbital neuralgia), inguinal neuralgia (inguinal neuralgia), paresthesia (mercial paresthesia), genital neuralgia (genital neuralgia), carpal tunnel syndrome (carpal tunnel syndrome), Morton's neuroma, post-mastectomy syndrome (post-mastectomy syndrome), post-thoracotomy syndrome (post-morto-syndroyn), polio-palsy post-phase syndrome (post-iopol syndrome), lan-Barre syndrome (Gumbun-bary syndrome), renal artery syndrome (syndrome), neurodegenerative disorders (coronary artery syndrome, et al) (visceral hyperalgesia, coronary artery J.304), visceral hyperalgesia, coronary hyperalgesia, et al, visceral hyperalgesia, coronary hyperalgesia, et al, visceral hyperalgesia, 1. 304. 2003. or similar, thalamic Pain (thalamic Pain), cancer (e.g., Pain caused by cancer, including osteolytic sarcoma (osteolytic sarcoma), Pain caused by cancer treatment with radiation or chemotherapy, or Pain caused by nerve or bone damage associated with cancer (see, Menendez, l. et al, neurosci.lett.2005 (393) (1), 70-73; Asai, h. et al, Pain 2005, 117, 19-29), or bone destruction Pain (see, Ghilardi, j.r. et al, j.neurosci.2005, 25, 3126-31)), infection, or metabolic disease. In addition, the compounds may be used to treat pain indications such as visceral pain (visceral pain), ocular pain (ocula pain), thermal pain (thermal pain), dental pain (dental pain), pain caused by capsaicin (and other symptomatic conditions caused by capsaicin such as cough, tearing, and bronchospasm).

In another particular embodiment, the compounds of the invention may be administered for the treatment of itch, which may arise from a variety of sources, such as skin disorders or inflammatory diseases.

In another particular embodiment, the compounds of the invention may be administered to treat inflammatory diseases, including conditions selected from the group consisting of: renal or hepatobiliary disorders, immune disorders, drug reactions and unknown/emergent conditions. Inflammatory diseases that may be treated with the agents of the invention include, for example, inflammatory bowel disease (lBO), crohn's disease, and ulcerative colitis (ulcerative colitis) (Geppetti, p. et al, br. j. pharmacal.2004, 141, 1313-20; Yiangou, y. et al, Lancet2001, 357, 1338-39; Kimball, e.s. et al, neuroastrolol.motif, 2004, 16, 811), osteoarthritis (Szabo, a. et al, j. pharmacal.exp.ther.2005, 314, 111-.

In another particular embodiment, the compounds of the present invention may be administered to treat inner ear diseases. Such conditions include, for example, auditory hypersensitivity (hyperacusis), tinnitus (tinitus), vestibular hypersensitivity (vestibular hypersensitivity), and episodic vertigo (episodic vertigo).

In another specific embodiment, the compounds of the invention may be administered to treat tracheobronchial and diaphragm dysfunction, including, for example, asthma and allergy-related immune responses (Agopyan, N. et al, am. J. physiol. Lung CellMol. physiol. physiol.2004, 286, L563-72; Agopyan, N. et al, Toxicol. Appl. Pharmacal.2003, 192, 21-35), cough (e.g., acute or chronic cough, or cough induced by stimulation from gastroesophageal reflux disease; see, Lalloo, U.G. et al, J.Appl. physiol.1995, 79(4), 1082-7), bronchospasm (bronchyspaasm), chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and hiccups (singultus).

In another specific embodiment, the compounds of the invention may be administered to treat gastrointestinal and urinary tract disorders such as overactive bladder (bladder overactivity), inflammatory hyperalgesia (inflammatory hyperalgesia), hyperreflexia of the urinary bladder (viral hyperreflexia of the urinary bladder), hemorrhagic cystitis (hemorrhagic cystitis) (Dinis, p. et al, J Neurosci, 2004, 24, 11253-11263), interstitial cystitis (scutplant, a. et al, Neurosci letters, 2005, 381, 42-46), inflammatory prostate diseases, prostatitis (prostatitis) (sanz, m. et al, Eur J physical, 515, spasm, 20-27), nausea, emesis, intestinal distress, inflating (bladder distress), urinary incontinence (urinary incontinence).

In another particular embodiment, the compounds of the invention may be administered to treat conditions associated with reduced blood flow to the CNS or CNS hypoxia. Such conditions include, for example, head trauma (head trauma), spinal cord injury (spino surgery), thromboembolic or hemorrhagic stroke (thrombo-embonic or hemorrhagic stroke), transient ischemic attacks (transient ischemic attacks), cerebral vasospasm (cerebral vasospasm), hypoglycemia (hyperglycaemia), cardiac arrest (cardiac arrest), status epilepticus (status epilepticus), perinatal asphyxia (perinatal asphyxia), alzheimer's disease, and huntington's disease.

In other embodiments, the compounds of the invention may be administered to treat other diseases, disorders, or conditions mediated by TRPA1 activity, such as: anxiety disorders (anxiety); disorders of learning or memory; eye-related disorders (such as glaucoma (glaucoma), vision loss (vision loss), increased intraocular pressure (intercrasular pressure), and conjunctivitis); baldness (e.g., by stimulating hair growth); diabetes (including insulin-resistant diabetes or diabetes mediated by insulin sensitivity or secretion); obesity (e.g., through appetite suppression); dyspepsia (dyspepsia); biliary colic; renal colic; bladder pain syndrome (pain bladder rider syndrome); esophagitis (inflamed esophageal); upper respiratory disease; urinary incontinence; acute cystitis; and venom stinging (e.g., sea, snake, or insect bites or stings, including jellyfish, spider, or mink (stingray) venom stinging).

In a particular embodiment, the compounds of the invention are administered to treat pain (including but not limited to acute, chronic, neuropathic, and inflammatory pain), arthritis, itch, cough, asthma, or inflammatory bowel disease.

In another embodiment, the present invention provides a method of treating neuropathic pain or inflammatory pain, said method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to formula (I).

In another embodiment, the present invention provides a method of treating a respiratory disease selected from Chronic Obstructive Pulmonary Disease (COPD), asthma, allergic rhinitis and bronchospasm, said method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to formula (I).

In one embodiment, the present invention provides a compound of formula (I) as described in any one of E1-E25 above, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

In another embodiment, the present invention provides a compound of formula (I) as described in any one of E1-E25 above, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a respiratory disease.

In another embodiment, the present invention provides the use of a compound of formula (I) as described in any one of E1-E25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a respiratory disease.

In another embodiment, the present invention provides a method of treating a respiratory disease in a mammal, the method comprising administering to the mammal a compound of formula (I) as described in any one of E1-E25 above, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of formula (I) as described in any one of E1-E25 above, or a pharmaceutically acceptable salt thereof, for use in modulating TRPA1 activity.

In another embodiment, the present invention provides a compound of formula (I) as described in any one of E1-E25 above, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition mediated by TRPA1 activity. Within aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic, and inflammatory pain), itch, an inflammatory disease, an inner ear disease, fever or another thermoregulatory disease, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disease, chronic obstructive pulmonary disease, incontinence, or a disease associated with reduced blood flow to the CNS or CNS hypoxia. Within certain aspects of this embodiment, wherein the disease or condition is pain (including but not limited to acute, chronic, neuropathic, and inflammatory pain), arthritis, itch, cough, asthma, inflammatory bowel disease, or inner ear disease.

In another embodiment, the present invention provides the use of a compound of formula (I) as described in any one of E1 to E25 above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by TRPA1 activity. Within aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic, and inflammatory pain), itch, an inflammatory disease, an inner ear disease, fever or another thermoregulatory disease, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disease, chronic obstructive pulmonary disease, incontinence, or a disease associated with reduced blood flow to the CNS or CNS hypoxia. Within aspects of this embodiment, the disease or disorder is pain (including but not limited to acute, chronic, neuropathic, and inflammatory pain), arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disease.

In another embodiment, the present invention provides a method of modulating TRPA1 activity comprising contacting TRPA1 with a compound of formula (I) described in any one of E1 to E25 or a salt thereof.

In another embodiment, the present invention provides a method of treating a disease or disorder mediated by TRPA1 activity in a mammal, the method comprising administering to the mammal a compound of formula (I) as described in any one of E1 to E25 or a pharmaceutically acceptable salt thereof. Within certain aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic, and inflammatory pain), itch, an inflammatory disease, an inner ear disease, fever or another thermoregulatory disease, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disease, chronic obstructive pulmonary disease, incontinence, or a disease associated with reduced blood flow to the CNS or CNS hypoxia. Within certain aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic, and inflammatory pain), arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disease.

Combination therapy

In the treatment of ion channel-mediated diseases and conditions, the compounds of the present invention may be usefully combined with or as any combination of one or more other compounds of the present invention or one or more other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, including but not limited to:

opioid analgesics, for example morphine, heroin, cocaine, oxymorphone, levorphanol allylate (levalophan), oxycodone, codeine, dihydrocodeine, propoxyphene, nalmefene, fentanyl (fentanyl), hydrocodone, hydromorphone, meripide, methadone, nalprofen (nalorphine), naloxone (naloxone), naltrexone (naltrexone), buprenorphine (buprenorphine), butorphanol (buthenol), nalbuphine (nalbarbitane) and tebucine (pentazocine);

non-opioid analgesics, e.g., acementoniphen, salicylates (e.g., aspirin);

non-steroidal anti-inflammatory drugs (NSAIDs), for example ibuprofen (ibuprophen), naproxen (naproxen), fenoprofen (fenoprofen), ketoprofen (ketoprofen), celecoxib (celecoxib), diclofenac (diclofenac), diflunisal (diflusinal), etodolac (etodolac), fenbufen (fenbufen), fenoprofen (fenoprofen), flufenamic acid (flufenisal), flurbiprofen (flurbiprofen), ibuprofen (ibuprofen), indomethacin (indomethacin), ketoprofen (ketorolac), meclofenamic acid (meclofenamic acid), mefenamic acid (mefenamic acid), meloxicam (meloxicam), nabumetone (naprofen, naproxen (nifluminisone), nifluminisone (flufenamic acid), nifluminide (nitroflurbiprofen (flurazone),oxaprozin (oxaprozin), phenylbutazone, piroxicam, sulfasalazine (sulfasalazine), sulindac (sulindac), tolmetin (tolmetin) and zomepirac;

antispasmodics, e.g. carbamazepineOxcarbazepine (oxcarbazepine), lamotrigine (lamotrigine), sodium valproate (valproate), topiramate (topiramate), gabapentin (gabapentin) and pranopalinGabalin (pregabalin);

Antidepressants such as tricyclic antidepressants, e.g., amitriptyline, clomipramine, despramine, imipramine and nortriptyline;

COX-2 selective inhibitors, for example, celecoxib (celecoxib), rofecoxib (rofecoxib), parecoxib (parecoxib), valdecoxib (valdecoxib), deracoxib (deracoxib), etoricoxib (etoricoxib), and lumiracoxib (lumiracoxib);

α -adrenergic substances, for example, doxazosin (doxazosin), tamsulosin (tamsulosin), clonidine (clonidine), guanfacine (guanfacine), dexmetamidine, modafinil (modafinil), and 4-amino-6, 7-dimethoxy-2- (5-methanesulfonamido-1, 2,3, 4-tetrahydroisoquinolin-2-yl) -5- (2-pyridyl) quinazoline;

barbiturate sedatives, such as amobarbital (amobarbital), amobarbital (aprobarbital), sec-barbital (butababarbital), butabarbital (butarbital), phenobarbital (mephobarbital), methabarbital (methabarbital), methohexital (methohexital), pentobarbital (pentobarbital), phenobarbital (phenobarbital), secobarbital (secobarbital), tabbarbital (talbarbital), theomyll and thiobarbital (thiobarbital);

tachykinin (tacchykinin) (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as, for example, (R, 9R) -7- [3, 5-bis (trifluoromethyl) benzyl) ] -8, 9, 10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1, 4] diazocino [2, 1-g ] [1, 7] -naphthyridine-6-13-dione (TAK-637), 5- [ [2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethylphenyl ] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] -methyl ] -1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), aprepitant (aprepitant), lanepitant (lanepitant), dapitant (dapitant) or 3- [ [ 2-methoxy 5- (trifluoromethoxy) phenyl ] -methylamino ] -2-phenylpiperidine (2S, 3S);

coal tar analgesics, especially paracetamol;

serotonin (serotonin) reuptake inhibitors, for example, paroxetine (parooxetine), sertraline (sertraline), norfluoxetine (norfluoxetine) (fluoxetine) demethyl metabolite), desmethylsertraline as metabolite,' 3-fluvoxamine (fluvoxamine), paroxetine (parooxetine), citalopram (citalopram), citalopram metabolite desmethylcitalopram, escitalopram (escitalopram), d, l-fenfluramine (fenfluramine), femoxetine (femoxetine), eformin (ifoxetine), cyano duloxetine (cyadothite), ritoxetine (oxepine), dapoxetine (dapoxetine), nefazodone (nefazodone), citalopram (cycloxeine), troxacillin (troloxapine) and fluxolone (fluxolone);

norepinephrine (noradrenaline) reuptake inhibitors, for example, maprotiline (maprotiline), lofepramine (lofepramine), mirtazapine (mirtazapine), oxaprotiline (oxaprotiline), fezolamide (fezolamine), tomoxetine (tomoxetine), mianserin (miansein), bupropion (buprpion), the bupropion metabolite hydroxyamphetane, nomifensine (nomifensine) and viloxazine (viloxazine)) In particular selective norepinephrine reuptake inhibitors such as reboxetine, especially (S, S) -reboxetine, and venlafaxine duloxetine antipsychotic sedatives/anxiolytics;

Bis-serotonin-norepinephrine reuptake inhibitors such as venlafaxine, venlafaxine metabolites O-desmethylvenlafaxine, clomipramine metabolites desmethylclomipramine, duloxetine, milnacipran and imipramine;

acetylcholinesterase inhibitors such as donepezil (donepezil);

5-HT3 antagonists such as ondansetron;

metabotropic glutamate receptor (mGluR) antagonists;

local anesthetics such as mexiletine (mexiletine) and lidocaine (lidocaine);

corticosteroids such as dexamethasone (dexamethasone);

antiarrhythmic drugs, such as mexiletine and phenytoin (phenytoin);

muscarinic antagonists, for example tolterodine (tolterodine), propiverine (propiverine), trospium chloride (tropsium t chloride), darifenacin (darifenacin), solifenacin (solifenacin), tilmicoline (temiverine) and ipratropium (ipratropium);

cannabinoids;

capsaicin receptor agonists (e.g., a super-capsaicin (resiniferatoxin)) or antagonists (e.g., capsazepine);

sedatives, such as glutethimide, meprobamate, methaqualone, and antipyrine dichloride (dichlorphenazone);

anxiolytics such as benzodiazepinesThe class of the user is a generic class,

antidepressants such as mirtazapine (mirtazapine),

external preparations (e.g., lidocaine (lidocaine), capsaicin (capsacin) and super-capsaicin);

muscle relaxants such as benzodiazepinesClass i, baclofen (baclofen), carisoprodol (carisoprodol), chlorzoxazone (chlorr)zoxazone), cyclobenzaprine (cyclobenzapine), methocarbamol (methocarbamol) and orphenylidine;

antihistamines or H1 antagonists;

an NMDA receptor antagonist;

5-HT receptor agonists/antagonists;

PDEV inhibitors;

·

cholinergic (nicotinic) analgesics;

alpha-2-ligand;

prostaglandin E2 subtype antagonists;

leukotriene B4 antagonist;

5-lipoxygenase inhibitors; and

5-HT3 antagonists.

"combination" as used herein refers to any mixture or permutation of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agents. Unless otherwise clarified herein, "combination" may include the delivery of a compound of the invention with one or more therapeutic agents, either simultaneously or sequentially. Unless otherwise clear from the context, "combination" may include dosage forms of the compounds of the invention with another therapeutic agent. Unless otherwise clear herein, "combination" may include the route of administration of a compound of the invention with another therapeutic agent. Unless otherwise clear herein, a "combination" may include a formulation of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

In another embodiment, provided is the invention described above.

General preparation of Compounds of formula I

The starting materials and Reagents for preparing these compounds are generally available from commercial suppliers such as aldrich chemical co, or by methods known to those skilled in the art, according to methods described in references such as Fieser and Fieser's Reagents for Organic Synthesis; wiley & Sons: new York, 1991, volume 1-15; rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Vol.1-5 and desiccation; and Organic Reactions, Wiley & Sons: new York, 1991, volume 1-40.

The following synthetic reaction schemes are only illustrative of some of the methods by which the compounds of the present invention can be synthesized, and various modifications of these synthetic reaction schemes are possible and will be suggested to those skilled in the art having reference to the disclosure contained in this application.

If desired, starting materials and intermediates of the synthetic reaction schemes can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such substances can be characterized using conventional methods including physical constants and spectral data.

Unless indicated to the contrary, the reactions described herein are preferably carried out under an inert atmosphere at atmospheric pressure, at a reaction temperature of from about-78 ℃ to about 150 ℃, more preferably from about 0 ℃ to about 125 ℃, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 ℃.

The compounds of the present invention may be prepared by any number of conventional methods. For example, they can be prepared according to the procedures outlined in schemes 1 to 4 below.

Scheme 1

According toScheme 1, R²-the substituted amino acid can be reacted with a sulfonyl chloride to produce a sulfonamide carboxylic acid of formula 2. This conversion is well documented in the chemical literature and known to those skilled in the art. It is carried out under a variety of reaction conditions, for example, the amino acid and sulfonyl chloride may be incorporated into an aprotic solvent such as dichloromethane and treated with an excess of a base such as triethylamine or potassium carbonate. Alternatively, the two reactants may be stirred in solution in pyridine or a related polar, basic solvent to effect coupling. Plural and large number of R²Substituted amino acids can be purchased from commercial sources. Examples include sarcosine, 2- (prop-2-ylamino) acetic acid, 2- (ethylamino) -propionic acid, N-methyl-L-serine, and 2- [ (prop-2-yl) amino]Propionic acid. Similarly, many sulfonyl chlorides are available from commercial sources, including benzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 3, 4-dichlorobenzenesulfonyl chloride, pyridine-3-sulfonyl chloride, 2-chloropyridine-5-sulfonyl chloride, 3-cyanobenzenesulfonyl chloride, and 2-thiazolesulfonyl chloride. The intermediate of formula 2 can then be coupled to the amine of formula 3 by a variety of well-established methods to obtain the compound of formula 1. For example, the acid and amine can be combined in a solvent such as dimethylformamide and any number of peptide coupling reagents such as 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethylureaMethylphosphonium hexafluorophosphate (methanaminium) or bromo-tris-pyrrolidinophosAnd (4) treating hexafluorophosphate.

Scheme 2

Alternatively, the compounds of the invention may be prepared according to the procedures outlined in scheme 2. According to this scheme, the sulfonamides of formula 5 can be prepared according to well-established procedures by combining compounds containing R¹With a sulfonyl chloride containing R²Easily of aminesThe preparation method comprises the following steps. For example, sulfonyl chloride may be added to R²-a solution of an amine and an organic base such as triethylamine in a polar, aprotic solvent such as THF. Alternatively, the reagents may be combined in a moderately basic solvent such as pyridine. Containing R²The amines of (a) are readily available from commercial sources including methylamine, ethylamine, isopropylamine, cyclopropylamine, ethanolamine, 1-amino-2-propanol. If containing R²Containing a remote functional group, e.g., 3-aminocyclobutane, the remote amine can be used, for example, as described in "Protective Groups in organic Synthesis" [ T.W.Greene and P.G.M.Wuts, 3 rd edition, John Wiley and Sons, N.Y.1999]α -bromoacetamide of formula 6 is conveniently prepared by combining an amine of formula 3 with 2-bromoacyl chloride a wide variety of 2-bromo and 2-chloroacetyl chlorides are commercially available including 2-bromopropionyl chloride, bromoacetyl chloride, chloroacetyl chloride, 2-bromobutyryl chloride and α -bromoisovaleryl chloride.

Scheme 3

As shown in scheme 3, intermediates of general structure 3 can be synthesized by well-established methods. For example, a central aromatic ring and R⁵The bond between can be generated by a number of effective metal-catalyzed coupling methods, such as the method known as Suzuki coupling. In this embodiment, either of the two groups to be attached may be a boronic acid or ester or a halogen/pseudo-halogen. The other coupling partner will then be halogen/pseudo-halogen or boronic acid/ester respectively. The conditions under which the coupling is carried out include in a mixture of polar solvents such as bisHeating boric acid and aryl halide in the presence of an organic or inorganic base such as triethylamine or potassium carbonate in an alkane/water with a palladium catalyst such as tetrakis [ triphenylphosphine ]]Palladium or palladium (II) acetate.

Many of the starting materials of formulas 4a and 4b are commercially available. For example, 2-chloro-6- (trifluoromethoxy) -4-pyridinemethylamine, 2-bromo-4-pyridinemethylamine hydrochloride, (3, 6-dichloropyridazin-4-yl) methylamine, 4-aminomethyl-6-chloropyrimidine, (3-aminomethylphenyl) boronic acid hydrochloride, 5- (aminomethyl) -2-fluorophenylboronic acid, HCl, [5- (aminomethyl) -2-methylphenyl ] boronic acid, (5-bromopyridin-3-yl) methylamine, 3- (aminomethyl) -5-bromopyridin-2-ol, (5-bromo-2-chloro-pyridin-3-yl) -methylamine hydrochloride, (4-bromopyridin-2-yl) methylamine, (4-bromo-6- (trifluoromethyl) pyridin-2-yl) methylamine, 2-bromo-4-pyridylethylamine, (2-bromo-5-chloropyridin-4-yl) methylamine.

Scheme 4

The compounds of the invention, where X ═ Z ═ N, can be prepared by known methods for the synthesis of pyrimidines. For example, they can be prepared by the procedures outlined in scheme 4, wherein an aryl ketone ester is reacted with an amidine or suitable equivalent to produce a 4-aryl pyrimidinone. The intermediate may then be chlorinated under established conditions, such as heating in phosphorus oxychloride. The chloride may then be converted to a nitrile by a number of well known methods and subsequently reduced to an aminomethyl group. For example, chloropyrimidine can be heated in a polar solvent such as DMSO with potassium cyanide to obtain cyanopyrimidine. Alternatively, chloropyrimidine may be treated with zinc cyanide and a catalytic amount of a transition metal catalyst such as tetrakis [ triphenylphosphine ] palladium in a polar solvent such as N-methylpyrrolidone or THF. The nitrile is then reduced by dissolving it in a polar solvent such as ethanol and treating it with a catalytic amount of a metal catalyst such as palladium on carbon and shaking under an atmosphere or pressure of hydrogen, e.g., 60 psi.

Examples

Although certain exemplary embodiments are described and recited herein, the compounds of the present invention can be prepared according to the methods generally described herein and/or by methods available to those of ordinary skill in the art using appropriate starting materials.

The intermediates and the final compounds are purified by flash chromatography and/or by reverse phase preparative HPLC (high performance liquid chromatography). Unless otherwise stated, (1) Biotage SP1 was used^TMSystem and Quad 12/25 Cartidge Module (from BiotageAB), (2) ISCOChromatography apparatus (from Teledyne Isco, Inc.), or (3)IntelliFlash280^TMChromatography instruments (a subsidiary from Analogix inc., Varian inc.) perform flash chromatography. Unless otherwise indicated, the silica gel brand and pore size used were: (1) KP-SIL^TMParticle size: 40-60 microns (from Biotage AB); (2) silica gel CAS accession number: 63231-67-4, particle size: 47-60 microns; or (3) ZCX from qingdao haiyang Chemical co., Ltd, pore size: 200-300 meshes or 300-400 meshes. Using from Waters CorpDelta-Prep^TMA 3000HPLC system performs reverse phase preparative HPLC using one or more of the following columns: varian from Varian, IncC-18 column (10 μm, 20X 150mm), Xbridge from Waters corporation^TMPrep C₁₈Column (5 μm, OBD)^TM20 × 100mm), or SunFire from Waters corporation^TMPrep C₁₈Column (5 μm, OBD)^TM30×100mm)。

Use ofZQ^TM4000 (from Waters corporation),Quattro micro^TMan API (from Waters corporation),platform II (a division of Micromass, Waters),II FTICR, with a 4.7 Tesla magnet (from Bruker corporation),2795-ZQ^TM2000 (from Waters Corp.), or MDS Sciex^TMAPI-2000^TMn API (from MDS Inc.) was subjected to Mass Spectrometry (MS) or High Resolution Mass Spectrometry (HRMS). Unless otherwise stated, mass spectrometry data typically only indicate parent ions. MS or HRMS data are provided for the specific intermediate or compound indicated.

Using a composition all from Varian IncMercury300NMR spectrometer (obtained at 300 MHz)¹H NMR spectrum) andinova400NMR spectrometer (obtained at 400 MHz)¹H NMR spectrum) was performed. NMR data is provided for the particular intermediate or compound indicated.

All reactions involving air sensitive reagents were carried out under an inert atmosphere. Unless otherwise stated, reagents were used as received from commercial suppliers.

Example 1

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

The suspension (3-aminomethylphenyl) boronic acid hydrochloride (5.0g, 27mmol), potassium phosphate (17.2g, 81mmol), and 1-bromo-4- (trifluoromethyl) benzene were combined in 5/1 dimethoxyethane/water (100mL) at 25 ℃ and purged with nitrogen. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (2.0mg, 1.73mmol)) and then sealed and heated to 120 ℃ for 16 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (5-8% CH)₃OH/2％Et₃N in CH₂Cl₂In (e) to provide C- (4' -trifluoromethyl-biphenyl-3-yl) -methylamine as an oil. MH + ═ 252.

A solution of (4' -trifluoromethyl-biphenyl-3-yl) -methylamine (200mg, 796. mu. mol) and 2- (tert-butoxycarbonyl (methyl) amino) acetic acid (226mg, 1.19mmol) in DMF (3mL) was treated with HATU (605mg, 1.59mmol) at 25 ℃. The reaction mixture was stirred for 14 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded heavy oil, which was dissolved in 50/50 CH₂Cl₂In trifluoroacetic acid. The resulting solution was stirred for 1h, after which the volatiles were removed under reduced pressure. The resulting residue was suspended in 0.5M aqueous potassium carbonate and the suspension was washed with CH₂Cl₂The extraction was performed twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2- (methylamino) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide (190mg, 74%) as a heavy oil.

2- (methylammonium) at 25 DEG.CYl) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide (190mg, 0.59. mu. mol) and triethylamine (99. mu.L, 707. mu. mol) in CH₂Cl₂(3mL) was treated with 4-fluorobenzene-1-sulfonyl chloride (103mg, 531. mu. mol). After 1h, the reaction mixture was concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (188mg, 66%) as a white solid. MH + ═ 481.

Example 2

(S) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide

A solution of (4' - (trifluoromethyl) biphenyl-3-yl) methylamine (150mg, 0.6mmol), (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionic acid (121mg, 0.6mmol) and N, N-diisopropylethylamine (300 μ L, 1.8mmol) in DMF (2.5mL) was treated with HATU (227mg, 0.6 mmol). The reaction mixture was stirred for 16 h. The reaction mixture was then diluted with brine (25mL) and extracted twice with ethyl acetate. Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated in vacuo. Flash chromatography (5% CH)₃OH in CH₂Cl₂In (b), methyl- { (S) -1- [ (4' -trifluoromethyl-biphenyl-3-ylmethyl) -carbamoyl is provided]-ethyl } -carbamic acid tert-butyl ester (280mg) as heavy oil. MH + ═ 437.0

Reacting methyl- { (S) -1- [ (4' -trifluoromethyl-biphenyl-3-ylmethyl) -carbamoyl]-Ethyl } -carbamic acid tert-butyl ester (280mg, crude) in CH₂Cl₂The solution in (5.0mL) was treated with trifluoroacetic acid (410. mu.L). The solution was stirred for 17h, after which all volatiles were removed under reduced pressure to give (S) -2-methylamino-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide; trifluoro-acetic acid-containing compound (290 mg).MH+＝336.8

(S) -2-methylamino-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide; trifluoroacetic acid-containing compound (290mg), triethylamine (230. mu.L, 1.66mmol) in CH₂Cl₂(5mL) was treated with 4-fluorobenzenesulfonyl chloride (107mg, 0.55mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was then concentrated under reduced pressure and the crude material was purified by silica gel chromatography (40% ethyl acetate in hexanes) to afford (S) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- (4 '-trifluoromethyl-biphenyl-3-ylmethyl) -propionamide (95mg, 32% from (4' - (trifluoromethyl) biphenyl-3-yl) methylamine) as a white solid. MH + ═ 493.6

Example 3

2- (4-fluoro-benzenesulfonylamino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

(R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide was prepared according to the method described in example 2 using N-Boc glycine as starting material. MH + ═ 464.8

Example 4

(R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide

(R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide was prepared according to the method described in example 2 using (R) -2- (tert-butoxycarbonyl-methyl-amino) -propionic acid. MH + ═ 493.0

Example 5

(S) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-methyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -butyramide

(S) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-methyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -butyramide is prepared according to the method as described in example 2 using (S) -2- (tert-butoxycarbonyl-methyl-amino) -3-methyl-butyric acid. MH + ═ 521.0

Example 6

(R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-methyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -butyramide

(R) -2- [ (4-fluorobenzenesulfonyl) -methyl-amino ] -3-methyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -butyramide is prepared according to the method as described in example 2 using (R) -2- (tert-butoxycarbonyl-methyl-amino) -3-methyl-butyric acid. MH + ═ 521.2

Example 7

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -2-methyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide

In a 10mL pear-shaped flask, 2- (tert-butoxycarbonyl (methyl) amino) -2-methylpropanoic acid (300mg, 1.38mmol, Eq: 1.00), (4' - (trifluoromethyl) biphenyl-3-yl) methylamine (347mg, 1.38mmol, Eq: 1.00) and DIPEA (535mg, 723. mu.l, 4.14mmol, Eq: 3) were combined with DMF (2.00mL) to give a colorless solution. HATU (525mg, 1.38mmol, Eq: 1.00) was added and stirred at 25 ℃ overnight. The reaction was checked by LC-MS. MH + (-100) was found to be 350 (lacking Boc group). The reaction mixture was diluted with brine and water and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with brine and water, dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. The crude material was purified by flash chromatography (silica gel, 40+ g, 0% to 10% CH)₃OH/CH₂Cl₂Having 3% NH₄OH) to afford 2-methyl-2- (methylamino) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) propionamide (60mg, 9.6%) as a waxy solid.

In a 10mL round bottom flask, 2-methyl-2- (methylamino) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) propionamide (50mg, 143. mu. mol, Eq: 1.00) was reacted with CH₂Cl₂(2ml) were combined to give a colorless solution. Triethylamine (21.7mg, 29.8. mu.l, 214. mu. mol, Eq: 1.5) and 4-fluorobenzene-1-sulfonyl chloride (27.8mg, 143. mu. mol, Eq: 1.00) were added and stirred at 25 ℃ for 2 h. The crude reaction mixture was concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate to 10% ethyl acetate/dichloromethane) afforded 2- [ (4-fluorobenzenesulfonyl) -methyl-amino]-2-methyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide (26mg, 34%) as a white solid. MH + ═ 509.

Example 8

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (6-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

4-fluoro-3- (4, 4,5, 5-tetramethyl- [1, 3, 2] at 25 DEG C]A solution of dioxaborolan-2-yl) -benzylamine (1.00g, 3.98mmol), 1-bromo-4-trifluoromethyl-benzene (0.90g, 3.98mmol) and dipotassium hydrogen phosphate (2.54g, 11.9mmol) in 5/1 dimethoxyethane/water (12mL) was purged with nitrogen and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (230mg, 199. mu. mol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (10% CH)₃OH/1％NH₄OH in ethyl acetate) afforded C- (6-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (160mg, 15%) as a light oil.

C- (6-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (32.7mg, 121. mu. mol) and [ (4-fluoro-benzenesulfonyl) -methyl-amino-at 25 ℃ C]-acetic acid (30mg, 121. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (46.1mg, 121. mu. mol). N, N-diisopropylethylamine (31.4mg, 243. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- (6-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (33.5mg, 55%) as a white solid.

MH+＝498.9。

Example 9

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (2-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A solution of 3- (aminomethyl) -2-fluorophenylboronic acid hydrochloride (1.00g, 4.87mmol), 1-bromo-4-trifluoromethyl-benzene (1.10g, 4.87mmol) and dipotassium hydrogen phosphate (3.10g, 14.6mmol) in 5/1 dimethoxyethane/water (12mL) was purged with nitrogen and evacuated three times at 25 ℃. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (281mg, 243. mu. mol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (10% CH)₃OH/1％NH₄OH in ethyl acetate) to afford C- (2-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (120mg, 9%) as a light oil. M + H269.9.

C- (2-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (38.1mg, 142 μmol) and [ (4-fluoro-benzenesulfonyl) -methyl-amino-acid at 25 ℃]-acetic acid (35mg, 142. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (53.8mg, 142. mu. mol). N, N-diisopropylethylamine (36.6mg, 283. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- (2-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (36.8mg, 52%) as a white solid. MH + ═ 498.9.

Example 10

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide

A solution of 4- (aminomethyl) -phenylboronic acid hydrochloride (2.50g, 13.3mmol), 1-bromo-4-trifluoromethyl-benzene (3.99g, 13.3mmol) and dipotassium hydrogen phosphate (2.83g, 13.3mmol) in 5/1 dimethoxyethane/water (12mL) at 25 deg.C was purged with nitrogen and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (759mg, 665. mu. mol) and subsequently sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (10% CH)₃OH/1％NH₄OH in ethyl acetate) to afford C- (4' -trifluoromethyl-biphenyl-3-yl) -methylamine (2.1g, 66%) as a light oil.

C- (4' -trifluoromethyl-biphenyl-4-yl) -methylamine (30.5mg, 121. mu. mol) and [ (4-fluoro-benzenesulfonyl) -methyl-amino-acid at 25 ℃]-acetic acid (30mg, 121. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (46.1mg, 121. mu. mol). N, N-diisopropylethylamine (31.4mg, 243. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- (4' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide (32.8mg, 56%) as a white solid. MH + ═ 481.0.

Example 11

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (5-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A solution of 4,4, 5, 5-tetramethyl-2- (4-trifluoromethyl-phenyl) - [1, 3, 2] dioxaborolane (1.00g, 3.68mmol), 3-bromo-5-fluoro-benzonitrile (0.74g, 3.68mmol) and potassium carbonate (0.51g, 3.68mmol) in DMF (5mL) was purged with nitrogen and evacuated three times at 25 ℃. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (212mg, 184 μmol), and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 5-fluoro-4' -trifluoromethyl-biphenyl-3-carbonitrile (820mg, 84%) as a white solid.

A solution of 5-fluoro-4' -trifluoromethyl-biphenyl-3-carbonitrile (620mg, 2.34mmol), and 10% palladium on carbon (0.12g, 0.12mmol) in ethanol (10mL) was stirred at 25 deg.C under 50psi of hydrogen pressure for 3 h. Filtration, followed by concentration in vacuo, yielded C- (5-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (500mg, 79%) as a brown oil. M + H270.0.

C- (5-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (38.1mg, 142. mu. mol) and [ (4-fluoro-benzenesulfonyl) -methyl-amino-at 25 ℃ C]-acetic acid (35mg, 142. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (53.8mg, 142. mu. mol). N, N-diisopropylethylamine (36.6mg, 283. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄In aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- (5-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (37.5mg, 53%) as a white solidAnd (3) a body. MH + ═ 498.9.

Example 12

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (4-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A solution of 4,4, 5, 5-tetramethyl-2- (4-trifluoromethyl-phenyl) - [1, 3, 2] dioxaborolane (1.00g, 3.68mmol), 5-bromo-2-fluoro-benzonitrile (0.74g, 3.68mmol) and potassium carbonate (0.51g, 3.68mmol) in DMF (5mL) was purged with nitrogen and evacuated three times at 25 ℃. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (212mg, 184 μmol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 4-fluoro-4' -trifluoromethyl-biphenyl-3-carbonitrile (360mg, 37%) as a white solid.

A solution of 4-fluoro-4' -trifluoromethyl-biphenyl-3-carbonitrile (360mg, 1.36mmol), and 10% palladium on carbon (68mg, 0.068mmol) in ethanol (10mL) was stirred at 25 deg.C under 50psi of hydrogen pressure for 3 h. Filtration, followed by concentration in vacuo, yielded C- (4-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (300mg, 82%) as a brown oil. M + H270.0.

C- (4-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (32.7mg, 121 μmol) and [ (4-fluoro-benzenesulfonyl) -methyl-amino group at 25 ℃]-acetic acid (30mg, 121. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (46.1mg, 121. mu. mol). N, N-diisopropylethylamine (31.4mg, 243. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- (4-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (27.4mg, 45%) as a white solid. MH + ═ 498.9.

Example 13

2- [ (4-fluoro-benzenesulfonyl) - (2, 2, 2-trifluoro-ethyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

To (4' - (trifluoromethyl) biphenyl-3-yl) methylamine (500mg, 1.99mmol) and pyridine (644. mu.l, 7.96mmol) in CH at 5 deg.C₂Cl₂(25mL) solution 2-Bromoacetyl chloride (313mg, 1.99mmol) in CH was added₂Cl₂(5 ml). The reaction mixture was stirred at 5 ℃ for 15min and then at room temperature for 1 h. Adding CH₂Cl₂And water. The organic layer was washed with 2NHCl, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 2-bromo-N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide (690mg, 89%) as a white solid which was used directly in the next step without further purification. MH⁺＝373。

To a solution of 2, 2, 2-trifluoroethylamine (373mg, 3.77mmol) in pyridine (5mL) was added 4-fluorobenzene-1-sulfonyl chloride (734mg, 3.77 mmol). The reaction mixture was stirred at room temperature for 12 h. After removal of the solvent, water was added. The pH was adjusted to acidity using 1N HCl. The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4-fluoro-N- (2, 2, 2-trifluoroethyl) benzenesulfonamide (970mg, 100%) as a white solid which was purified without further purificationAnd then used in the next step. MH^-＝256。

To a solution of 4-fluoro-N- (2, 2, 2-trifluoroethyl) benzenesulfonamide (30mg, 117 μmol) and 2-bromo-N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide (43.4mg, 117 μmol) in DMF (2ml) was added cesium carbonate (114mg, 350 μmol). The reaction mixture was stirred at room temperature for 12 h. Ethyl acetate and water were added. The organic layer was washed with 1N HCl, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) - (2, 2, 2-trifluoro-ethyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (56mg, 88%) as a white solid. MH + ═ 549.

Example 14

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (6-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

C- (6-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 8 (30.9mg, 115. mu. mol) and [ ethyl- (4-fluoro-benzenesulfonyl) -amino at 25 ℃ C]-acetic acid (30.0mg, 115. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (43.7mg, 115. mu. mol). N, N-diisopropylethylamine (29.7mg, 230. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ Ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- (6-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (15.3mg, 26%) as a white solid. MH + ═ 512.9.

Example 15

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (5-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

C- (5-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 11 (30.9mg, 115. mu. mol) and [ ethyl- (4-fluoro-benzenesulfonyl) -amino at 25 ℃ C]-acetic acid (30.0mg, 115. mu. mol) in CH₂Cl₂A solution (5mL) was treated with HATU (43.7mg, 115. mu. mol). N, N-diisopropylethylamine (29.7mg, 230. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ Ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- (5-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (32.0mg, 54%) as a white solid. MH + ═ 512.9.

Example 16

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (4-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

C- (4-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 12 (30.9mg, 115. mu. mol) and [ ethyl- (4-fluoro-benzenesulfonyl) -amino at 25 ℃ C]-acetic acid (30.0mg, 115. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (43.7mg, 115. mu. mol). Adding N, N-diisopropylethylamine (29.7 mg)230. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ Ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- (4-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (28.1mg, 48%) as a white solid. MH + ═ 512.9.

Example 17

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide

C- (4' -trifluoromethyl-biphenyl-4-yl) -methylamine from example 10 (28.8mg, 115. mu. mol) and [ ethyl- (4-fluoro-benzenesulfonyl) -amino at 25 ℃ C]-acetic acid (30mg, 115. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (43.7mg, 115. mu. mol). N, N-diisopropylethylamine (29.7mg, 230. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ Ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- (4' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide (47.9mg, 84%) as a white solid. MH + ═ 494.9.

Example 18

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (3' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide

A solution of 4- (aminomethyl) -phenylboronic acid hydrochloride (1.0g, 5.34mmol), 1-bromo-3-trifluoromethyl-benzene (1.2g, 5.34mmol) and dipotassium hydrogen phosphate (3.4g, 16.0mmol) in 5/1 dimethoxyethane/water (12mL) was purged with nitrogen and evacuated three times at 25 ℃. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (308mg, 267 μmol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (10% CH)₃OH/1％NH₄OH in ethyl acetate) afforded C- (3' -trifluoromethyl-biphenyl-4-yl) -methylamine (180mg, 13%) as a light oil.

C- (3' -trifluoromethyl-biphenyl-4-yl) -methylamine (28.8mg, 115. mu. mol) and [ ethyl- (4-fluoro-benzenesulfonyl) -amino at 25 ℃ C]-acetic acid (30mg, 115. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (43.7mg, 115. mu. mol). N, N-diisopropylethylamine (29.7mg, 230. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ Ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- (3' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide (29.0mg, 51%) as a white solid. MH + ═ 494.9.

Example 19

2- [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A suspension of potassium carbonate (45g, 326mmol) and 2-aminoethanol (4.0g, 65.5mmol) was combined in acetonitrile (200ml) and cooled to 5 ℃ with mechanical stirring. Ethyl 2-bromoacetate (10.9g, 65.5mmol) in acetonitrile (40ml) was added over 1hr and stirred at 5 ℃ for an additional 1 hr. The suspension was filtered through celite and concentrated in vacuo. The residue was treated with 50% ethyl acetate/hexanes and filtered through celite and concentrated in vacuo to afford (2-hydroxy-ethylamino) -ethyl acetate as a heavy oil (-8 g).¹H NMR(400MHz，DMSO_d6)＝4.16(q，2H)，4.14(s，3H)，1.22(t，2H)ppm。

(2-hydroxy-ethylamino) -acetic acid ethyl ester (4.0g, 27.2mmol) and triethylamine (3.79ml, 27.2mmol) were combined with THF and cooled to 0 deg.C. 4-fluoro-benzenesulfonyl chloride (5.52g, 29.9mmol) in THF (40ml) was added slowly and the reaction was stirred at ambient for 14 hr. The suspension was filtered through celite and concentrated in vacuo to afford [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino ] -methyl-tert-butyl-phenyl]-ethyl acetate as a white solid.¹H NMR(400MHz，DMSO_d6)_□＝7.93(m，2H)，7.44(t，2H)，4.75(m，1H)，4.19(s，3H)，4.08(q，2H)，3.52(m，2H)，3.24(t，2H)1.18(t，2H)ppm。

Reacting [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino]Ethyl acetate (340mg, 1.11mmol) dissolved in bisAlkane (5ml) and treated with a solution of potassium hydroxide (300mg, 4.5mmol) dissolved in 4ml water. Stirring for 1hr and removing di in vacuoAn alkane. With 2N H₃PO₄The pH was adjusted to 4 and the aqueous phase was washed with 20% THF/CH₂Cl₂And (4) extracting. The organics were dried (MgSO)₄) And areConcentration in vacuo afforded [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino]Acetic acid as a white solid.¹H NMR(400MHz，DMSO_d6)_□□□7.89(m，2H)，7.45(t，2H)，4.70(br，1H)，4.08(s，3H)，3.51(t，2H)，3.27(t，2H)ppm。

Reacting [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino]Acetic acid in DMF (8ml) and CH₂Cl₂(4ml) in a mixture and cooled to 5 ℃. EDC (91.3mg, 4.76mmol) was added followed by (4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 1 (109mg, 4.33 mmol). It was stirred at ambient temperature for 14hr and concentrated in vacuo. The residue was purified by flash chromatography (40-50% ethyl acetate/hexanes) to afford 2- [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino]-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide as a white solid. MH + ═ 511.

Example 20

2- [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-propyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A solution of triethylamine (7.8ml, 56mmol) and 1-aminopropan-2-ol (3.5g, 46.6mmol) was combined in THF (150ml) and cooled to 5 ℃ with mechanical stirring. Methyl 2-bromoacetate (7.84g, 51.3mmol) in THF (50ml) was added over 1hr and stirred at 15 deg.C for another 3 hr. The suspension was filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate to 10% methanol/CH)₂Cl₂) Purification provided (2-hydroxy-propylamino) -acetic acid methyl ester.¹H NMR(400MHz，DMSO_d6)＝4.5(d，1H)，4.14(s，3H)，3.62(s，3H)，3.4(m，2H)，3.36(d，2H)1.01(d，3H)ppm。

Cooling of (2-hydroxy-propylamino) -acetic acid methyl ester(1.2g, 1.2mmol) and triethylamine (3.4ml, 24mmol) in CH₂Cl₂The solution of (1). Will CH₂Cl₂4-fluoro-benzenesulfonyl chloride (1.6g, 8.15mmol) in (20ml) was added slowly and stirred at 20 ℃ for 14 h. The suspension was filtered over celite, concentrated in vacuo, and the residue was purified by flash chromatography to give 1.8g of [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-propyl) -amino group]-methyl acetate as a white solid. MH + ═ 306.

Reacting [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-propyl) -amino]-methyl acetate (900mg, 2.95mmol) dissolved in bisAlkane (15ml) and treated with a solution of potassium hydroxide (827mg, 14.7mmol) dissolved in 8ml of water. Stirring for 1hr and removing di in vacuoAn alkane. With 2N H₃PO₄The pH was adjusted to 3. The opaque aqueous phase was washed with 10% THF/CH₂Cl₂And (4) extracting. The organics were dried (MgSO)₄) And concentrated in vacuo to afford [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-propyl) -amino [ (-4-fluoro-benzenesulfonyl) - (2-hydroxy-propyl) -amino ]]-acetic acid, as a solid.¹H NMR(400MHz，DMSO_d6)＝7.90(m，2H)，7.42(t，2H)，4.75(br，1H)，4.10(m，2H)，3.78(m，1H)，3.22(m，1H)，3.05(m，1H)，1.02(d，3H)ppm。

A solution of [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-propyl) -amino ] -acetic acid (60mg, 2.06mmol) in DMF (8ml) was cooled to 5 ℃. EDC (79mg, 4.12mmol) was added, followed by (4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 1 (52mg, 2.06 mmol). It was stirred at ambient temperature for 14hr and concentrated in vacuo. The residue was purified by flash chromatography (50-100% ethyl acetate/hexanes) to afford 2- [ (4-fluoro-benzenesulfonyl) - (2-hydroxypropyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide as a white solid. MH + 525.

Example 21

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

A solution of 4- (trifluoromethyl) phenylboronic acid (5.0g, 25.8mmol), 4, 6-dichloropyrimidine (3.92g, 25.8mmol), bis (triphenylphosphine) palladium (II) dichloride (362mg, 516. mu. mol) and sodium carbonate (8.2g, 77.4mmol, Eq: 3) in a three-solvent mixture of 50mL DME, 7.5mL ethanol and 7.5mL water was heated at 130 ℃ for 7 h. After cooling to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2SO 4. Filtration, followed by removal of volatiles under reduced pressure, yielded a dark red solid. The mixture was purified by flash chromatography (5% diethyl ether in hexanes) to give 4-chloro-6- (4-trifluoromethyl-phenyl) -pyrimidine (2.76g) as a white solid.

4-chloro-6- (4- (trifluoromethyl) phenyl) pyrimidine (2.55g, 9.86mmol) was dissolved in CH₃CN (50ml) and cooled to 0 ℃. Tetrabutylammonium cyanide (4.55g, 16.9mmol) and DABCO (3.32g, 29.6mmol) were added and the reaction mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was then adsorbed on a small amount of silica gel and purified by flash column (0-20% EtOAc over 35min) to give 6- (4- (trifluoromethyl) phenyl) pyrimidine-4-carbonitrile as a white solid (2.26 g; 92%).

To a solution of 6- (4- (trifluoromethyl) phenyl) pyrimidine-4-carbonitrile (1.5g, 6.02mmol) in ethanol (50ml) was added palladium on carbon (10% Pd/C) (0.7g, 658. mu. mol). The reaction was carried out under hydrogen atmosphere (55psi) for 3 h. The reaction mixture was filtered through a pad of celite and concentrated to give 6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl) methylamine (1.2g, 79%) as a dark brown oil.

A solution of [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -acetic acid (50mg, 202. mu. mol), (6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methylamine (51.2mg, 202. mu. mol), 1H-benzo [ d ] [1, 2, 3] triazol-1-ol hydrate (1.55mg, 10.1. mu. mol) and triethylamine (123mg, 169. mu.L, 1.21mmol) was dissolved in dichloromethane (2mL) and stirred at room temperature for 10 min. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (77.5mg, 404. mu. mol) was then added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated. The residue was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (gradient of 0-10% methanol in dichloromethane over 20min) afforded 2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide as a white powder (40mg, 41%) after lyophilization.

Example 22

2- [ cyclopropyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

To a solution of 2- (tert-butoxycarbonyl (cyclopropyl) amino) acetic acid (100mg, 465. mu. mol), (4' - (trifluoromethyl) biphenyl-3-yl) methylamine (128mg, 511. mu. mol), 1-hydroxybenzotriazole hydrate (78.3mg, 511. mu. mol) and N, N-diisopropylethylamine (243. mu.L, 1.39mmol) in DMF (4mL) was added HBPYU (220mg, 511. mu. mol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude tert-butyl cyclopropyl (2-oxo-2- ((4' - (trifluoromethyl) biphenyl-3-yl) methylamino) ethyl) carbamate (208mg, 100%) as a colorless oil which was used in the next step without further purification. MH + ═ 449.

Cyclopropyl (2-oxo-2- ((4' - (trifluoromethyl) biphenyl-3-yl) methylamino) ethyl) Tert-butyl carbamate (208mg, 464. mu. mol) in 4M HClThe solution in alkane solution (6mL, 24.0mmol) was stirred at room temperature for 2 h. After removal of the solvent by a rotary evaporator, water was added. The aqueous layer was neutralized with saturated sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield crude 2- (cyclopropylamino) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide (164mg, 102%) as a colorless oil which was used in the next step without further purification. MH + 349.

To a solution of 2- (cyclopropylamino) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide (162mg, 465. mu. mol) and N, N-diisopropylethylamine (259. mu.l, 1.86mmol) in CH₂Cl₂(8ml) 4-fluorobenzene-1-sulphonyl chloride (90.5mg, 465. mu. mol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with 1N HCl, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (80/20 to 60/40 hexanes/ethyl acetate) afforded 2- [ cyclopropyl- (4-fluoro-benzenesulfonyl) -amino]-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (194mg, 82%) as a white solid. MH + ═ 507.

Example 23

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

To a solution of 2- (tert-butoxycarbonyl (ethyl) amino) acetic acid (50mg, 246. mu. mol), (4' - (trifluoromethyl) biphenyl-3-yl) methylamine (68.0mg, 271. mu. mol) from example 1, 1-hydroxybenzotriazole hydrate (41.4mg, 271. mu. mol) and N, N-diisopropylethylamine (129. mu.L, 738. mu. mol) in DMF (2mL) was added HBPYU (117mg, 271. mu. mol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude tert-butyl ethyl (2-oxo-2- ((4' - (trifluoromethyl) biphenyl-3-yl) methylamino) ethyl) carbamate (107mg, 100%) as a colorless oil which was used in the next step without further purification. MH + ═ 437.

Ethyl (2-oxo-2- ((4' - (trifluoromethyl) biphenyl-3-yl) methylamino) ethyl) carbamic acid tert-butyl ester (107mg, 245. mu. mol) in 4M HCl in bisThe solution in alkane solution (6mL, 24.0mmol) was stirred at room temperature for 2 h. After removal of the solvent by a rotary evaporator, water was added. The aqueous layer was neutralized with saturated sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield crude 2- (ethylamino) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide (83mg, 101%) as a colorless oil, which was used in the next step without further purification. MH + ═ 337.

To 2- (ethylamino) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide (81mg, 241. mu. mol) and triethylamine (134. mu.l, 963. mu. mol) in CH₂Cl₂(8ml) 4-fluorobenzene-1-sulphonyl chloride (46.9mg, 241. mu. mol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with 1N HCl, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (60/40 to 50/50 hexanes/ethyl acetate) afforded 2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (194mg, 82%) as a white solid. MH + ═ 495.

Example 24

2-cyclopropyl-2- (4-fluoro-benzenesulfonylamino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

To a solution of 2- (tert-butoxycarbonylamino) -2-cyclopropylacetic acid (50mg, 232. mu. mol), (4' - (trifluoromethyl) biphenyl-3-yl) methylamine (64.2mg, 256. mu. mol), 1-hydroxybenzotriazole hydrate (39.1mg, 256. mu. mol) and N, N-diisopropylethylamine (122. mu.L, 697. mu. mol) in DMF (2mL) was added HBPYU (110mg, 256. mu. mol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield crude tert-butyl 1-cyclopropyl-2-oxo-2- ((4' - (trifluoromethyl) biphenyl-3-yl) methylamino) ethylcarbamate (104mg, 100%) as a white foam which was used directly in the next step without further purification. MH + ═ 449.

Tert-butyl 1-cyclopropyl-2-oxo-2- ((4' - (trifluoromethyl) biphenyl-3-yl) methylamino) ethylcarbamate (104mg, 232. mu. mol) in bis (4M) HClThe solution in alkane solution (6mL, 24.0mmol) was stirred at room temperature for 2 h. After removal of the solvent by a rotary evaporator, water was added. The aqueous layer was neutralized with saturated sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude 2-amino-2-cyclopropyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (80mg, 99%) as a colorless oil, which was used in the next step without further purification. MH + ═ 337.

To 2-amino-2-cyclopropyl-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (80mg, 230. mu. mol) and triethylamine (128. mu.l, 919. mu. mol) in CH₂Cl₂(4ml) 4-fluorobenzene-1-sulphonyl chloride (44.7mg, 230. mu. mol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with 1N HCl, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (60/40 to 50/50 hexanes/ethyl acetate) afforded 2-cyclopropyl-2- (4-fluoro-benzenesulfonylamino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (90mg, 82%) as a white solid. MH + ═ 507.

Example 25

2- [ (5-chloro-thiophene-2-sulfonyl) -methyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To a solution of 2- (tert-butoxycarbonyl (methyl) amino) acetic acid (82.2mg, 434. mu. mol), [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -methylamine from example 21 (100mg, 395. mu. mol), 1-hydroxybenzotriazole hydrate (66.5mg, 434. mu. mol) and N, N-diisopropylethylamine (207. mu.L, 1.18mmol) in DMF (2mL) was added HBTU (165mg, 434. mu. mol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield crude tert-butyl methyl (2-oxo-2- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methylamino) ethyl) carbamate (170mg, 101%) as a white solid which was used directly in the next step without further purification. MH + 425.

Methyl (2-oxo-2- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methylamino) ethyl) carbamic acid tert-butyl ester (168mg, 396. mu. mol) in 4M HCl in bisDissolution in an alkane solution (6mL, 24.0mmol)The solution was stirred at room temperature for 2 h. After removal of the solvent by a rotary evaporator, water was added. The aqueous layer was neutralized with saturated sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield crude 2- (methylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (123mg, 96%) as a light brown solid which was used in the next step without further purification. MH + ═ 325.

To 2- (methylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (84mg, 259. mu. mol) and N, N-diisopropylethylamine (136. mu.l, 777. mu. mol) in CH₂Cl₂(3ml) 5-chlorothiophene-2-sulfonyl chloride (56.2mg, 259. mu. mol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with 1N HCl, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 2- [ (5-chloro-thiophene-2-sulfonyl) -methyl-amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (58mg, 44%) as a white solid. MH + 505.

Example 26

2- [ methyl- (thiophene-2-sulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To 2- (methylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (84mg, 259. mu. mol) (from example 25, step b) and N, N-diisopropylethylamine (136. mu.l, 777. mu. mol) in CH₂Cl₂(3ml) thiophene-2-sulfonyl chloride (47.3mg, 259. mu. mol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with 1N HCl, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressureFiltered and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 2- [ methyl- (thiophene-2-sulfonyl) -amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (56mg, 46%) as a white solid. MH + ═ 471.

Example 27

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To a solution of 2- (tert-butoxycarbonyl (isopropyl) amino) acetic acid (660mg, 3.04mmol), [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -methylamine hydrochloride from example 21 (800mg, 2.76mmol), 1-hydroxybenzotriazole hydrate (465mg, 3.04mmol) and N, N-diisopropylethylamine (1.93mL, 11.0mmol) in DMF (15mL) was added HBTU (1.15g, 3.04 mmol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 to 0/100 hexanes/ethyl acetate) afforded isopropyl- ({ [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -carbamoyl } -methyl) -carbamic acid tert-butyl ester (900mg, 72%) as a white solid. MH + ═ 453.

Reacting isopropyl- ({ [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]-carbamoyl } -methyl) -carbamic acid tert-butyl ester (800mg, 1.77mmol) in 4M HClThe solution in alkane solution (20mL, 80.1mmol) was stirred at room temperature for 2 h. After removal of the solvent by a rotary evaporator, water was added. The aqueous layer was neutralized with saturated sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo,to give 2-isopropylamino-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (630mg, 101%) as a pale yellow solid. MH + ═ 353.

To a mixture of 2- (isopropylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (400mg, 1.14mmol) and N, N-diisopropylethylamine (595. mu.l, 3.41mmol) in CH₂Cl₂(10ml) 4-fluorobenzene-1-sulphonyl chloride (243mg, 1.25mmol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (10/90 to 0/100 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]-acetamide (400mg, 69%) as a white solid. MH + ═ 511.

Example 28

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To a solution of 2- (tert-butoxycarbonyl (ethyl) amino) acetic acid (44.1mg, 217 μmol), [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -methylamine from example 21 (50mg, 197 μmol), 1-hydroxybenzotriazole hydrate (33.3mg, 217 μmol) and N, N-diisopropylethylamine (103 μ L, 592 μmol) in DMF (2mL) was added HBTU (82.4mg, 217 μmol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded tert-butyl ethyl (2-oxo-2- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methylamino) ethyl) carbamate (50mg, 58%) as a light yellow oil. MH + ═ 439.

Tert-butyl ethyl (2-oxo-2- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methylamino) ethyl) carbamate (50mg, 114. mu. mol) in 4M HClThe solution in alkane solution (5mL, 20.0mmol) was stirred at room temperature for 2 h. After removal of the solvent by a rotary evaporator, water was added. The aqueous layer was neutralized with saturated sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2- (ethylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (35mg, 91%) as a light yellow solid. MH + ═ 339.

To 2- (ethylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (35mg, 103. mu. mol) and N, N-diisopropylethylamine (72.3. mu.l, 414. mu. mol) in CH₂Cl₂(4ml) 4-fluorobenzene-1-sulphonyl chloride (20.1mg, 103. mu. mol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (30mg, 58%) as a white solid. MH + ═ 497.

Example 29

2- [ (4-fluoro-benzenesulfonyl) - (2-methoxy-ethyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To a mixture of 2-methoxyethylamine (2.33ml, 26.6mmol) and potassium carbonate (14.7g, 107mmol) in acetonitrile (50ml) was added dropwise a solution of methyl bromoacetate (4.07g, 26.6mmol) in acetonitrile (50ml) at 0 ℃ over 1 h. After stirring at 0 ℃ for another hour, the solids were removed by celite filtration. The filtrate was concentrated. The residue was dissolved in diethyl ether and the solid was removed by filtration. The filtrate was concentrated to give crude methyl 2- (2-methoxyethylamino) acetate (3.4g, 87%) as a colorless oil, which was used in the next step without further purification.

To methyl 2- (2-methoxyethylamino) acetate (300mg, 2.04mmol) and N, N-diisopropylethylamine (712. mu.l, 4.08mmol) in CH₂Cl₂(8ml) 4-fluorobenzene-1-sulphonyl chloride (397mg, 2.04mmol) was added to the solution. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (100/0 to 60/40 hexanes/ethyl acetate) afforded methyl 2- (4-fluoro-N- (2-methoxyethyl) phenylsulfonamido) acetate (390mg, 63%) as a white solid. MH + ═ 306.

To a solution of methyl 2- (4-fluoro-N- (2-methoxyethyl) phenylsulfonamido) acetate (390mg, 1.28mmol) in THF (5mL) was added 1N LiOH (5mL, 5.01mmol) in water. The mixture was stirred for 1 h. The pH was adjusted dropwise to 4 with 2N HCl. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2- (4-fluoro-N- (2-methoxyethyl) phenylsulfonamido) acetic acid (370mg, 99%) as a white solid, which was used in the next step without further purification. MH + ═ 292.

To a solution of 2- (4-fluoro-N- (2-methoxyethyl) phenylsulfonamido) acetic acid (31.6mg, 109. mu. mol), [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -methylamine (25mg, 98.7. mu. mol), 1-hydroxybenzotriazole hydrate (16.6mg, 109. mu. mol) and N, N-diisopropylethylamine (69.0. mu.l, 395. mu. mol) from example 21 in DMF (2mL) was added HBTU (41.2mg, 109. mu. mol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (0/100 to 40/60 THF/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) - (2-methoxy-ethyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide (39mg, 75%) as a white solid. MH + ═ 527.

Example 30

2- [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] acetamide

To a solution of 2- (4-fluoro-N- (2-hydroxyethyl) phenylsulfonamido) acetic acid (32.8mg, 118. mu. mol), [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -methylamine (30mg, 118. mu. mol), 1-hydroxybenzotriazole hydrate (20.0mg, 130. mu. mol) and N, N-diisopropylethylamine (82.8. mu.l, 474. mu. mol) in DMF (4ml) was added HBTU (49.4mg, 130. mu. mol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (0/100 to 50/50 THF/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) - (2-hydroxy-ethyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide (25mg, 41%) as a white solid. MH + ═ 513.

Example 31

2- [ tert-butyl- (4-fluoro-benzenesulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To a solution of tert-butylamine (3.82g, 52.3mmol) in acetonitrile (30mL) at 0 ℃ was added dropwise a solution of methyl bromoacetate (2g, 13.1mmol) in acetonitrile (10 mL). The reaction was stirred at rt for an additional 4 h. After removal of the solids by filtration, the filtrate was concentrated and the residue was dissolved in diethyl ether. The solid was removed by filtration. The filtrate was concentrated to give tert-butylamino-acetic acid methyl ester (0.8g, 42%) as a colorless oil, which was used in the next step without further purification.

To tert-butylamino-acetic acid methyl ester (100mg, 689. mu. mol) and N, N-diisopropylethylamine (241. mu.l, 1.38mmol) in CH₂Cl₂(8ml) 4-fluorobenzene-1-sulphonyl chloride (174mg, 895. mu. mol) was added. DMAP (16.8mg, 138. mu. mol) was then added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (100/0 to 60/40 hexanes/ethyl acetate) afforded methyl 2- (N-tert-butyl-4-fluorophenylsulfonamide) acetate (150mg, 72%) as a colorless oil. MH + 304.

To a solution of methyl 2- (N-tert-butyl-4-fluorophenylsulphonamido) acetate (100mg, 330. mu. mol) in THF (2mL) was added 1N LiOH (1.32mL, 1.32mmol) in water. The mixture was stirred for 1 h. The pH was adjusted to 4 with 2N HCl. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2- (N-tert-butyl-4-fluorophenylsulfonamide) acetic acid (70mg, 73%) as a white solid, which was used in the next step without further purification. MH + 290.

To a solution of 2- (N-tert-butyl-4-fluorophenylsulphonamido) acetic acid (41.1mg, 142. mu. mol), [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -methylamine from example 21 (30mg, 118. mu. mol), 1-hydroxybenzotriazole hydrate (20.0mg, 130. mu. mol) and N, N-diisopropylethylamine (82.8. mu.l, 474. mu. mol) in DMF (2ml) was added HBTU (49.4mg, 130. mu. mol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (0/100 to 70/30 hexanes/ethyl acetate) afforded 2- [ tert-butyl- (4-fluoro-benzenesulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide (30mg, 48%) as a white solid. MH + 525.

Example 32

(S) -2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -propionamide

To a solution of (S) -2- (4-fluoro-N-isopropylbenzenesulfonamido) propionic acid (34.3mg, 118. mu. mol), [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -methylamine (30mg, 118. mu. mol), 1-hydroxybenzotriazole hydrate (20.0mg, 130. mu. mol) and N, N-diisopropylethylamine (82.8. mu.l, 474. mu. mol) from example 21 in DMF (2ml) was added HBTU (49.4mg, 130. mu. mol). The reaction mixture was stirred for 2 h. Ethyl acetate was added. The organic layer was washed with 1M citric acid, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (100/0 to 70/30 hexanes/ethyl acetate) afforded (S) -2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -propionamide (34mg, 55%) as a white solid. MH + 525.

Example 33

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (4' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide

C- (4' -trifluoromethyl-biphenyl-4-yl) -methylamine from example 17 (18.3mg, 73 μmol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino group at 25 ℃]-BAcid (20mg, 73. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (27.6mg, 73. mu. mol). N, N-diisopropylethylamine (18.8mg, 145. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (4' trifluoromethyl-biphenyl-4-ylmethyl) -acetamide (29mg, 79%) as a white solid. MH + ═ 509.0.

Example 34

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (3' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide

C- (3' -trifluoromethyl-biphenyl-4-yl) -methylamine from example 18 (18.3mg, 73 μmol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino group at 25 ℃]-acetic acid (20mg, 73. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (27.6mg, 73. mu. mol). N, N-diisopropylethylamine (18.8mg, 145. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (3' -trifluoromethyl-biphenyl-4-ylmethyl) -acetamide (8.3mg, 23%) as a white solid. MH + ═ 509.0.

Example 35

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (6-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

C- (6-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 8 (19.6mg, 73 μmol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino group at 25 ℃]-acetic acid (20mg, 73. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (27.6mg, 73. mu. mol). N, N-diisopropylethylamine (18.8mg, 146. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (6-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (9.3mg, 24%) as a white solid. MH + ═ 527.0.

Example 36

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (5-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

C- (5-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 11 (19.6mg, 73 μmol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (20mg, 73. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (27.6mg, 73. mu. mol) at 25 ℃. N, N-diisopropylethylamine (18.8mg, 146. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. Subsequently mixing the reactionThe mixture was poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (5-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (22.2mg, 58%) as a white solid. MH + ═ 527.0.

Example 37

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (4-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

C- (4-fluoro-4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 12 (19.6mg, 73 μmol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (20mg, 73. mu. mol) in CH₂Cl₂A solution (5mL) was treated with HATU (27.6mg, 73. mu. mol) at 25 ℃. N, N-diisopropylethylamine (18.8mg, 146. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (4-fluoro-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (24.0mg, 63%) as a white solid. MH + ═ 527.0.

Example 38

(R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -propionamide

6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl) -methylamine from example 21 (29.1mg, 115. mu. mol) and (R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]Propionic acid (30mg, 115. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (43.7mg, 115. mu. mol) at 25 ℃. N, N-diisopropylethylamine (29.7mg, 230. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded (R) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Propionamide (20.2mg, 35%) as a white solid. MH + ═ 496.9.

Example 39

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

C- (4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 1 (27.4mg, 109 μmol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate,filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (39.1mg, 71%) as a white solid. MH + ═ 509.0.

Example 40

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -acetamide

A solution of 3- (aminomethyl) -phenylboronic acid hydrochloride (2g, 10.7mmol), 2-chloro-5-trifluoromethyl-pyridine (1.94g, 10.7mmol) and cesium carbonate (10.5g, 32.1mmol) in 5/1 dimethoxyethane/water (12mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (618mg, 535. mu. mol) and then sealed and heated to 85 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (10% CH)₃OH/1％NH₄OH in ethyl acetate) afforded 3- (5-trifluoromethyl-pyridin-2-yl) -benzylamine (1.2g, 42%) as a light oil. MH + ═ 253.0

3- (5-trifluoromethyl-pyridin-2-yl) -benzylamine (18.3mg, 73. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (20.0mg, 73. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (27.6mg, 73. mu. mol) at 25 ℃. N, N-diisopropylethylamine (18.8mg, 145. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuoAnd (5) concentrating. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl]Acetamide (27.5mg, 74%) as a white solid. MH + 510.3.

EXAMPLE 41

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -acetamide

3- (5-trifluoromethyl-pyridin-2-yl) -benzylamine (20.4mg, 81. mu. mol) and [ (4-fluoro-benzenesulfonyl) -methyl-amino]Acetic acid (20.0mg, 81. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (30.8mg, 81. mu. mol) at 25 ℃. N, N-diisopropylethylamine (20.9mg, 162. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl]Acetamide (20.5mg, 53%) as a white solid. MH + ═ 482.1.

Example 42

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -acetamide

3- (5-trifluoromethyl-pyridin-2-yl) -benzylamine (19.3)mg, 77. mu. mol) and [ ethyl- (4-fluoro-benzenesulfonyl) -amino]-acetic acid (20.0mg, 77. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (29.1mg, 77. mu. mol) at 25 ℃. N, N-diisopropylethylamine (19.8mg, 154. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ Ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl]Acetamide (31.7mg, 84%) as a white solid. MH + 496.1.

Example 43

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -N- (5-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A solution of 4,4, 5, 5-tetramethyl-2- (4-trifluoromethyl-phenyl) - [1, 3, 2] dioxaborolane (1.00g, 3.68mmol), 3-bromo-5-methoxy-benzonitrile (0.78g, 3.68mmol) and potassium carbonate (0.51g, 3.68mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (212mg, 184 μmol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 5-methoxy-4' -trifluoromethyl-biphenyl-3-carbonitrile (0.70g, 69%) as a white solid.

A solution of 5-methoxy-4' -trifluoromethyl-biphenyl-3-carbonitrile (0.70g, 2.52mmol), and 10% palladium on carbon (134mg, 0.126mmol) in ethanol (10mL) was stirred at 25 ℃ under 50psi hydrogen pressure for 3 h. Filtration followed by concentration in vacuo yielded C- (5-methoxy-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (500mg, 70%) as a brown oil. M + H281.9.

Mixing C- (5-methoxy-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (22.8mg, 81. mu. mol) and [ (4-fluoro-benzenesulfonyl) -methyl-amino]-acetic acid (20mg, 81. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (30.8mg, 81. mu. mol) at 25 ℃. N, N-diisopropyl-ethylamine (20.9mg, 162. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2- [ (4-fluoro-benzenesulfonyl) -methyl-amino]-N- (5-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (19.2mg, 47%) as a white solid. MH + ═ 510.9.

Example 44

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (5-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

Mixing C- (5-methoxy-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (21.5mg, 77. mu. mol) and [ ethyl- (4-fluoro-benzenesulfonyl) -amino]-acetic acid (20mg, 77. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (29.1mg, 77. mu. mol) at 25 ℃. N, N-diisopropylethylamine (19.8mg, 154. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water andwashed once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ Ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- (5-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (18.8mg, 47%) as a white solid. MH + ═ 525.0.

Example 45

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (5-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

Mixing C- (5-methoxy-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (20.4mg, 73. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (20mg, 73. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (27.6mg, 73. mu. mol) at 25 ℃. N, N-diisopropylethylamine (18.8mg, 146. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (5-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (25.3mg, 65%) as a white solid. MH + ═ 539.0.

Example 46

2- [ ethyl- (4-fluoro-benzenesulfonyl) -amino ] -N- (6-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A solution of 4,4, 5, 5-tetramethyl-2- (4-trifluoromethyl-phenyl) - [1, 3, 2] dioxaborolane (1.00g, 3.68mmol), 3-bromo-4-methoxy-benzonitrile (0.78g, 3.68mmol) and potassium carbonate (0.51g, 3.68mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (212mg, 184 μmol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 6-methoxy-4' -trifluoromethyl-biphenyl-3-carbonitrile (0.80g, 79%) as a white solid.

A solution of 6-methoxy-4' -trifluoromethyl-biphenyl-3-carbonitrile (0.70g, 2.52mmol), and 10% palladium on carbon (134mg, 0.126mmol) in ethanol (10mL) was stirred at 25 ℃ under 50psi hydrogen pressure for 3 h. Filtration, followed by concentration in vacuo, yielded C- (6-methoxy-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (500mg, 70%) as a brown oil. M + H281.9.

Mixing C- (6-methoxy-4' -trifluoromethyl-biphenyl-3-yl) -methylamine (32.3mg, 115. mu. mol) and [ ethyl- (4-fluoro-benzenesulfonyl) -amino]-acetic acid (30mg, 115. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (43.7mg, 115. mu. mol) at 25 ℃. N, N-diisopropylethylamine (29.7mg, 230. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ Ethyl- (4-fluoro-benzenesulfonyl) -amino]-N- (6-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (16.2mg, 27%) as a white solid. MH + 525.1.

Example 47

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (6-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

C- (6-methoxy-4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 46 (81.7mg, 291 μmol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (80mg, 291. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (110mg, 291. mu. mol) at 25 ℃. N, N-diisopropylethylamine (75.1mg, 581. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (6-methoxy-4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (34.2mg, 22%) as a white solid. MH + ═ 539.0.

Example 48

2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

C- (4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 1 (27.4mg, 109 μmol) and [ (3-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. Adding N, N-diisopropylEthylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (43.8mg, 79%) as a white solid. MH + ═ 509.2.

Example 49

2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

The C- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl radical from example 21]-methylamine (27.6mg, 109 μmol) and [ (3-fluoro-benzenesulfonyl) -isopropyl-amino ]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (21.8mg, 39%) as a white solid. MH + ═ 511.1.

Example 50

2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -acetamide

3- (5-trifluoromethyl-pyridin-2-yl) -benzylamine from example 43 (27.5mg, 109. mu. mol) and [ (3-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.7mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl]Acetamide (26.1mg, 47%) as a white solid. MH + 510.2.

Example 51

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-hydroxy-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide

2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-hydroxy-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide was prepared according to the method described in example 2 using 2- (tert-butoxycarbonyl-methyl-amino) -3-hydroxy-propionic acid. MH + ═ 510.9

Example 52

(S) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino ] -3-methoxy-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide

A solution of (4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 1 (229mg, 912. mu. mol) and (S) -2-tert-butoxycarbonylamino-3-methoxy-propionic acid (200mg, 912. mu. mol) and N, N-diisopropylethylamine (478. mu.L, 2.74mmol) in DMF (6mL) was treated with HATU (694mg, 1.82mmol) at 25 ℃. The reaction mixture was stirred for 14 h. The reaction mixture was then poured into saturated NH₄Aqueous Cl and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded (S) -2-tert-butoxycarbonylamino-3-methoxy-propionic acid 4' -trifluoromethyl-biphenyl-3-ylmethyl ester (260mg) as a heavy oil. MH + ═ 453.0

(S) -2-tert-Butoxycarbonylamino-3-methoxy-propionic acid 4' -trifluoromethyl-biphenyl-3-ylmethyl ester was dissolved in 50/50CH₂Cl₂Trifluoroacetic acid (6 mL). The resulting solution was stirred for 1h, after which all volatiles were removed under reduced pressure. The resulting residue was suspended in 0.1M aqueous NaOH and the suspension was washed with CH₂Cl₂Extraction was carried out three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a heavy oil, which was dissolved in CH₂Cl₂And treated with N, N-diisopropylethylamine (197. mu.L, 1.13mmol) and 4-fluorobenzenesulfonyl chloride (110mg, 564. mu. mol). The reaction mixture was stirred at 25 ℃ for 3 hours, after which the volatiles were removed under reduced pressure. (S) -2- (4-fluorophenylsulfonylamino) -3-methoxy-propionic acid 4' -trifluoromethyl-biphenyl-3-ylmethyl ester (181mg, 63%) was isolated by chromatography (30-50% ethyl acetate in hexanes).

Dissolution of (S) -2- (4-fluorobenzenesulfonylamino) -3-methoxy-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide (155mg, 304. mu. mol) in DMF (3mL)The solution was treated with potassium carbonate (126mg, 911. mu. mol) and iodomethane (21. mu.L, 334. mu. mol). After 14h, the reaction mixture was poured into saturated NH₄Aqueous Cl and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and once with brine. The combined organic phases were over MgSO₄Dry, filter and remove all volatiles under reduced pressure. (S) -2- [ (4-fluoro-benzenesulfonyl) -methyl-amino-2- [ (4-fluoro-benzenesulfonyl) -methyl ] -amino-was isolated by flash chromatography (50/50 ethyl acetate/hexanes)]-3-methoxy-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -propionamide (142mg, 89%) as white foam. MH + (525.1)

Example 53

2- (benzenesulfonyl-isopropyl-amino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A solution of triethylamine (7.8ml, 56mmol) and isopropylamine (3.5g, 46.6mmol) were combined in THF (150ml) and cooled to 5 ℃ with mechanical stirring. Tert-butyl bromoacetate (7.84g, 51.3mmol) in THF (50ml) was added over 1h and stirred at 15 ℃ for another 3 h. The suspension was filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate to 10% methanol/CH)₂Cl₂) Purification provided isopropylamino-acetic acid tert-butyl ester.¹H NMR(400MHz，CDCl₃)＝3.37(s，2H)，2.82(m，1H)，1.49(s，9H)，1.09(d，6H)ppm。

Isopropylamino-acetic acid tert-butyl ester (400mg, 2.31mmol) and triethylamine (645ul, 24mmol) in CH₂Cl₂(10ml) solution with CH₂Cl₂Benzenesulfonyl chloride (450mg, 2.54mmol) in (10ml) was treated and stirred at 20 ℃ for 4 h. The suspension was filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography (10-40% ethyl acetate/hexanes) to afford (benzenesulfonyl-isopropyl-amino) -acetic acid tert-butyl ester as an oilAnd (4) forming a substance.¹H NMR(400MHz，CDCl₃)＝7.6-7.9(m，5H)，3.92(s，2H)3.90(m，1H)，1.44(s，9H)，0.96(d，6H)ppm。

(benzenesulfonyl-isopropyl-amino) -acetic acid tert-butyl ester (300mg, 1.0mmol) in dioxaneSolutions in alkane (3ml) were treated with 4.0M HCl/bisAlkane (1.2ml, 4.8mmol) and stirred for 14 h. It was concentrated in vacuo to afford (benzenesulfonyl-isopropyl-amino) -acetic acid as a white solid.¹H NMR(400MHz，DMSO_d6)＝7.60-7.92(m，5H)，3.93(s，2H)，3.88(m，1H)，0.96(d，6H)ppm。

(benzenesulfonyl-isopropyl-amino) -acetic acid (50mg, 1.94mmol) in CH₂Cl₂(8ml) the solution was combined with HATU (110mg, 2.89mmol) and sunitinib (41ul, 2.33 mmol). This was followed by the addition of (4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 1 (40mg, 1.79 mmol). The solution was stirred at ambient temperature for 16hr and concentrated in vacuo. The residue was purified by flash chromatography (25-50% ethyl acetate/hexanes) to afford 2- (benzenesulfonyl-isopropyl-amino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide as a white solid. MH + 491.

Example 54

2- [ (4-fluoro-benzenesulfonyl) -oxetan-3-ylmethyl-amino ] -N- (4 '-trifluoro-3-ylmethyl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A solution of oxetan-3-yl-methanol (500mg, 5.68mmol) in pyridine (5ml)Treated with p-toluenesulfonyl chloride (1.2g, 6.3 mmol) and stirred at ambient temperature for 4h the solution was diluted with 50% ethyl acetate/hexane solution (50ml) and filtered the solution was concentrated in vacuo and washed with 1N HCl, brine, dried (MgSO)₄) And concentrated in vacuo to afford toluene-4-sulfonic acid oxetan-3-ylmethyl ester as an oil.¹H NMR(400MHz，CDCl₃)＝7.73(d，2H)，7.38(d，2H)，4.68(t，2H)，4.24(t，2H)，4.18(d，2H)，3.22(m，1H)，2.41(s，3H)ppm。

A solution of toluene-4-sulfonic acid oxetan-3-ylmethyl ester (500mg, 2.2mmol) and amino-acetic acid methyl ester hydrochloride (950mg, 7.6mmol) in acetonitrile (10ml) was reacted with NaHCO₃(1.32g, 15.8mmol) were combined and stirred at 50-55 ℃ for 16 h. The mixture was diluted with ether and filtered through celite) and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate, then 10% methanol/CH)₂Cl₂) Purification to provide [ (oxetan-3-ylmethyl) -amino]-methyl acetate, oil.¹H NMR(400MHz，CDCl₃)＝4.75(t，2H)，4.45(t，2H)，3.78(s，3H)，3.48(d，2H)，3.12(M，1H)ppm。

Reacting [ (oxetan-3-ylmethyl) -amino group]Methyl acetate (150mg, 9.42mmol), 4-fluoro-benzenesulfonyl chloride (238mg, 1.23mmol), Schniphylline (500. mu.l, 28.5mmol), DMAP (57.6mg, 4.7mmol) in CH₂Cl₂The solution in (20ml) was stirred at ambient temperature for 4 h. The solvent was concentrated in vacuo and purified by flash chromatography (60-100% ethyl acetate/hexanes) to provide [ (4-fluoro-benzenesulfonyl) -oxetan-3-ylmethyl-amino]-methyl acetate, as a solid.¹H NMR(400MHz，DMSO_d6)＝7.93(m，2H)，7.47(t，2H)，4.53(t，2H)，4.22(t，2H)，4.16(s，2H)，3.48(d，2H)，3.31(s，3H)，3.17(m，1H)ppm。

Reacting [ (4-fluoro-benzenesulfonyl) -oxetan-3-ylmethyl-amino]-methyl acetate (100mg, 3.15mmol) solution in bisAlkane (7 ml). This solution was combined with a solution of potassium hydroxide (100mg, 18.8mmol) dissolved in water (4 ml). It was stirred at ambient temperature for 3h and the solvent was concentrated in vacuo to-3 ml. The solution was diluted with water (15ml) and 2N H₃PO₄Acidification followed by CH₂Cl₂And (4) extracting. Will CH₂Cl₂Solution drying (MgSO)₄) And concentrated in vacuo to afford [ (4-fluoro-benzenesulfonyl) -oxetan-3-ylmethyl-amino ] solid]-acetic acid. MH-302.

Reacting [ (4-fluoro-benzenesulfonyl) -oxetan-3-ylmethyl-amino]-solution of acetic acid (80mg, 2.64mmol) dissolved in CH₂Cl₂(15 ml). HATU (191mg, 5.0mmol) and sunitinib base (92. mu.l, 5.3mmol) were added and the solution was stirred for 5 min. To this was then added (4' -trifluoromethyl-biphenyl-3-yl) -methylamine from example 1 (66.3mg, 2.64 mmol). It was stirred at ambient temperature for 16hr and concentrated in vacuo. The residue was purified by flash chromatography (60-90% ethyl acetate/hexanes) to afford 2- [ (4-fluoro-benzenesulfonyl) -oxetan-3-ylmethyl-amino]-N- (4' -trifluoro-3-ylmethyl-amino group]-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide as a white solid. MH- ═ 535.

Example 55

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (6-trifluoromethyl- [3, 4 '] bipyridinyl-2' -ylmethyl) -acetamide

A solution of 6- (trifluoromethyl) pyridin-3-ylboronic acid (1.04g, 5.46mmol), 4-bromo-pyridine-2-carbonitrile (1.00g, 5.46mmol) and potassium carbonate (0.76g, 5.46mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (316mg, 273. mu. mol), and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 6-trifluoromethyl- [3, 4 '] bipyridinyl-2' -carbonitrile (0.90g, 66%) as a white solid. MH + ═ 249.9.

A solution of 6-trifluoromethyl- [3, 4 '] bipyridinyl-2' -carbonitrile (0.90g, 3.61mmol), and 10% palladium on carbon (192mg, 0.181mmol) in ethanol (10mL) was stirred at 25 ℃ under 50psi hydrogen pressure for 3 h. Filtration, followed by concentration in vacuo, yielded C- (6-trifluoromethyl- [3, 4 '] bipyridinyl-2' -yl) -methylamine (600mg, 66%) as a brown oil. MH + ═ 253.9.

Mixing C- (6-trifluoromethyl- [3, 4']Bipyridin-2' -yl) -methylamine (27.6mg, 109. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (6-trifluoromethyl- [3, 4']Bipyridin-2' -ylmethyl) -acetamide (25.4mg, 46%) as a white solid. MH + ═ 511.1.

Example 56

2- [ isopropyl- (pyridine-3-sulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

Reacting isopropyl- ({ [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]-carbamoyl } -methyl) -carbamic acid tert-butyl ester (800mg, 1.77mmol) in 4M HClThe solution in alkane solution (20mL, 80.1mmol) was stirred at room temperature for 2 h. After removal of the solvent by a rotary evaporator, water was added. The aqueous layer was neutralized with saturated sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-isopropylamino-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (630mg, 101%) as a pale yellow solid. MH + ═ 353.

To 2- (isopropylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (30mg, 85.1. mu. mol) and N, N-diisopropylethylamine (44.6. mu.L, 255. mu. mol) in CH₂Cl₂(3ml) pyridine-3-sulfonyl chloride (15.1mg, 85.1. mu. mol) was added to the solution. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 2- [ isopropyl- (pyridine-3-sulfonyl) -amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]-an acetamide (27mg,64%) as a white solid. MH + ═ 494.

Example 57

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [5- (4-trifluoromethyl-phenyl) -pyridin-3-ylmethyl ] -acetamide

A solution of 4, 4, 5, 5-tetramethyl-2- (4-trifluoromethyl-phenyl) - [1, 3, 2] dioxaborolane (743mg, 2.73mmol), 5-bromo-nicotinonitrile (500mg, 2.73mmol) and potassium carbonate (358mg, 2.73mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (158mg, 137. mu. mol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 5- (4-trifluoromethyl-phenyl) -nicotinonitrile (0.48g, 71%) as a white solid. MH + ═ 248.9.

A solution of 5- (4-trifluoromethyl-phenyl) -nicotinonitrile (0.48g, 1.93mmol), and 10% palladium on carbon (103mg, 0.097mmol) in ethanol (10mL) was stirred at 25 ℃ under 50psi of hydrogen pressure for 3 h. Filtration, followed by concentration in vacuo, yielded C- [5- (4-trifluoromethyl-phenyl) -pyridin-3-yl ] -methylamine (360mg, 74%) as a brown oil. M + H252.9.

Reacting C- [5- (4-trifluoromethyl-phenyl) -pyridin-3-yl]-methylamine (27.5mg, 109. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [5- (4-trifluoromethyl-phenyl) -pyridin-3-ylmethyl]Acetamide (30.7mg, 55%) as a white solid. MH + ═ 509.9.

Example 58

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- (6 '-trifluoromethyl- [2, 3' ] bipyridinyl-4-ylmethyl) -acetamide

2-Chloroisononitrile (1.89g, 13.7mmol), 6- (trifluoromethyl) pyridin-3-ylboronic acid (2.9g, 15.2mmol) and potassium carbonate (4.2g, 30.4mmol) dissolved in 60ml of water were combined with butanol (60ml) and bubbled with nitrogen for 10 min. Bis (triphenylphosphine) palladium (II) dichloride (533mg, 759 μmol) was added and the mixture was stirred at 85 ℃ for 3 h. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified by flash chromatography (40% ethyl acetate/hexanes) to afford 6 '-trifluoromethyl- [2, 3' ] bipyridinyl-4-carbonitrile. MH + ═ 250.

Mixing 6 '-trifluoromethyl- [2, 3']A solution of bipyridine-4-carbonitrile (100mg, 4.0mmol) in ethanol (20mL) was treated with 5% palladium on carbon (43 mg). It was hydrogenated in a Parr shaker at 50psi and 25 ℃ for 2 h. Filtered and concentrated in vacuo to afford (6 '-trifluoromethyl- [2, 3']Bipyridin-4-yl) -methylamine.¹H NMR(400MHz，DMSO_d6)＝9.43(d，1H)，8.76(d，1H)，8.68(d，1H)，8.09(m，1H)，8.03(d，1H)，7.47(d，1H)，3.86(s，2H)ppm。

Reacting [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid in CH₂Cl₂(8ml) solution inCombine with HATU (137mg, 3.6mmol) and suniting (105ul, 6.0mmol) and stir for 5 min. Followed by (6 '-trifluoromethyl- [2, 3']Bipyridin-4-yl) -methylamine (51mg, 2.0 mmol). The solution was stirred at 25 ℃ for 16hr and concentrated in vacuo. The residue was purified by flash chromatography (80-100% ethyl acetate/hexanes) to afford 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- (6 '-trifluoromethyl- [2, 3']Bipyridin-4-ylmethyl) -acetamide. MH + ═ 511.

Example 59

2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [2- (4-trifluoromethyl-phenyl) -pyridin-4-ylmethyl ] -acetamide

A solution of 4- (trifluoromethyl) phenylboronic acid (519mg, 2.73mmol), 2-bromo-isonicotinic acid nitrile (500mg, 2.73mmol) and potassium carbonate (358mg, 2.73mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (158mg, 137. mu. mol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, yielded a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 2- (4-trifluoromethyl-phenyl) -isonicotinonitrile (0.38g, 56%) as a white solid. MH + (248.9)

A solution of 2- (4-trifluoromethyl-phenyl) -isonicotinonitrile (0.38g, 1.53mmol), and 10% palladium on carbon (82mg, 0.077mmol) in ethanol (10mL) was stirred at 25 ℃ under 50psi of hydrogen pressure for 3 h. Filtration, followed by concentration in vacuo, yielded C- [2- (4-trifluoromethyl-phenyl) -pyridin-4-yl ] -methylamine (250mg, 65%) as a brown oil. MH + ═ 252.9.

Reacting 3- (5-trifluoromethyl-pyridin-2-yl) -benzylamine(36.6mg, 145. mu. mol) and [ (3-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (40mg, 145. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (55.2mg, 145. mu. mol) at 25 ℃. N, N-diisopropylethylamine (37.6mg, 291. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (3-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [2- (4-trifluoromethyl-phenyl) -pyridin-4-ylmethyl]Acetamide (51.5mg, 70%) as a white solid. MH + 510.0.

Example 60

2- [ (4-fluoro-benzenesulfonyl) -oxetan-3-yl-amino ] -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide

A solution of 2-bromo-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide from example 13 (55mg, 1.5mmol) and oxetan-3-amine (65mg, 8.9mmol) in THF (2ml) was stirred at 25 ℃ for 14 h. It was diluted with ether, filtered through celite and concentrated in vacuo to afford 2- (oxetan-3-ylamino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide.¹H NMR(400MHz，DMSO_d6)＝8.38(t，1H)，7.84(q，4H)，7.62(m，3H)，7.46(t，1H)，7.33(d，1H)，4.6(m，2H)，4.38(d，2H)，3.97(m，2H)3.88(m，1H)，3.95(d，2H)ppm。MH+＝365。

2- (Oxetan-3-ylamino) -N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide (50mg, 1.4mmol) and Schnixin base (120uL, 6.9mmol) in CH₂Cl₂(8ml) solution with DMAP ((8.4mg, 0.6)8mmol) and 4-fluorobenzene-1-sulfonyl chloride (37mg, 1.9mmol) were combined and stirred at 25 ℃ for 4 h. The solution was purified by flash chromatography (60% ethyl acetate/hexane) to afford 2- [ (4-fluoro-benzenesulfonyl) -oxetan-3-yl-amino]-N- (4' -trifluoromethyl-biphenyl-3-ylmethyl) -acetamide as a white solid. MH + ═ 523.

Example 61

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4-ylmethyl ] -acetamide

A solution of 6- (trifluoromethyl) -pyridin-3-ylboronic acid (Ark Pharm, Inc.) (2.54g, 13.3mmol) and 4, 6-dichloropyrimidine (2.2g, 14.4mmol) in 15% ethanol/tert-butanol (140ml) was combined with a solution of potassium phosphate (6.27g, 29.5mmol) dissolved in water (60ml) while adding N₂Bubbling. Bis (triphenylphosphine) palladium (II) dichloride (622mg, 886 μmol) was added and the well stirred mixture was heated to 85 ℃ for 3h and cooled. The organic phase was separated, diluted with ether (50ml) and washed with 50% brine/water solution. The organics were dried (MgSO)₄) Filtered and concentrated in vacuo to give a solid. The mixture of isomers was separated by flash chromatography (15-20% ethyl acetate/hexane) to afford-400 mg of 4-chloro-6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidine as a solid. MH + 260.

A solution of 4-chloro-6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidine (400mg, 1.54mmol) and triethylamine (312mg, 3.1mmol) in acetonitrile (10ml) was combined with tetrabutylammonium cyanide (410mg, 1.54mmol) and brought to 75 ℃ for 1 h. It was cooled, diluted with ether and washed with 50% brine/water. The organics were dried (MgSO)₄) Filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10% to 15% ethyl acetate/hexanes) to afford 6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidine-4-carbonitrile.MH+＝251。

A solution of 6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidine-4-carbonitrile (100mg, 0.4mmol) was combined with 5% palladium on carbon (400mg) in ethanol (20 ml). It was reduced in a Parr shaker over 4h at 25 ℃ under 50psi of hydrogen. Filtration and concentration in vacuo afforded C- [6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4-yl]-methylamine, as a solid.¹HNMR(400MHz，DMSO_d6)＝9.53(s，1H)，9.41(s，1H)，8.83(d，1H)，8.54(s，1H)，8.17(d，1H)，4.34(m，2H)ppm。

Coupling of C- [6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4-yl ] -methylamine (23mg, 0.09mmol) with 2- (4-fluoro-N-isopropylbenzenesulfonylamino) acetic acid (25mg, 0.09mmol) in the manner described in example 58 provided 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4-ylmethyl ] -acetamide. MH + ═ 512.

Example 62

4' - (trifluoromethyl) biphenyl-3-yl) methylamine (500mg, 1.99mmol) from example 1 and pyridine (644. mu.l, 7.96mmol) in CH at 5 deg.C₂Cl₂(25mL) solution 2-Bromoacetyl chloride (313mg, 1.99mmol) in CH was added₂Cl₂(5 ml). The reaction mixture was stirred at 5 ℃ for 15min and then at room temperature for 1 h. Adding CH₂Cl₂And water. The organic layer was washed with 2N HCl, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 2-bromo-N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide (690mg, 89%) as a white solid which was used directly in the next step without further purification. MH + ═ 373.

To a solution of 2, 2, 2-trifluoroethylamine (373mg, 3.77mmol) in pyridine (5mL) was added 4-fluorobenzene-1-sulfonyl chloride (734mg, 3.77 mmol). The reaction mixture was stirred at room temperature for 12 h. After removal of the solvent, water was added. The pH was adjusted to acidity using 1N HCl. The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4-fluoro-N- (2, 2, 2-trifluoroethyl) benzenesulfonamide (970mg, 100%) as a white solid, which was used in the next step without further purification. MH^-＝256。

Example 63

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [ 3-fluoro-5- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -acetamide

A solution of 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) pyridine (669mg, 2.45mmol), (3-bromo-5-fluorophenyl) methylamine (500mg, 2.45mmol) and potassium carbonate (0.34g, 2.45mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (142mg, 123 μmol), and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo yielded 3-fluoro-5- (6-trifluoromethyl-pyridin-3-yl) -benzylamine (0.55g, 83%) as a brown solid. M + H270.8

3-fluoro-5- (6-trifluoromethyl-pyridin-3-yl) -benzylamine (33.1mg, 131. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [ 3-fluoro-5- (6-trifluoromethyl-pyridin-3-yl) -benzyl]Acetamide (52.3mg, 91%) as a white solid. MH + ═ 528.0.

Example 64

2- [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To 2- (isopropylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (30mg, 85.1. mu. mol) and N, N-diisopropylethylamine (44.6. mu.L, 255. mu. mol) in CH₂Cl₂(3ml) 6-chloropyridine-3-sulfonyl chloride (21.7mg, 102. mu. mol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium carbonate and brine, over anhydrous sodium sulfateDried, filtered and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 2- [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (22mg, 49%) as a white solid. MH + ═ 528.

Example 65

2- [ (2-cyano-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To 2- (isopropylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (30mg, 85.1. mu. mol) and N, N-diisopropylethylamine (44.6. mu.L, 255. mu. mol) in CH₂Cl₂(3ml) 2-Cyanobenzenesulfonyl chloride (20.6mg, 102. mu. mol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 2- [ (2-cyano-benzenesulfonyl) -isopropyl-amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (30mg, 68%) as a white solid. MH + ═ 518.

Example 66

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (6-trifluoromethyl-pyridazin-3-yl) -benzyl ] -acetamide

A solution of 3- [ (tert-butoxycarbonylamino) methyl ] phenylboronic acid (500mg, 1.99mmol), 3-chloro-6- (trifluoromethyl) pyridazine (363mg, 1.99mmol) and potassium carbonate (0.28g, 1.99mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (115mg, 100. mu. mol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo yielded [3- (6-trifluoromethyl-pyridazin-3-yl) -benzyl ] -carbamic acid tert-butyl ester (0.65g, 92%) as a brown solid.

Reacting [3- (6-trifluoromethyl-pyridazin-3-yl) -benzyl]-tert-butyl carbamate (0.65g, 1.84mmol) in CH₂Cl₂The solution in (5mL) was treated with trifluoroacetic acid (2.1g, 18.4mmol) and then stirred at 25 ℃ for 3 h. The solution was concentrated in vacuo to give 3- (6-trifluoromethyl-pyridazin-3-yl) -benzylamine (450mg, 97%) as a brown oil. M + H253.9.

3- (6-trifluoromethyl-pyridazin-3-yl) -benzylamine (27.6mg, 109. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [3- (6-trifluoromethyl-pyridazin-3-yl) -benzyl]Acetamide (15.2mg, 27%) as a white solid. MH + ═ 511.0.

Example 67

2- [ isopropyl- (pyrazine-2-sulfonyl) -amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To a solution of sodium sulfite (3.86g, 30.6mmol) in water (20mL) was added 2-fluoropyrazine (2g, 20.4 mmol). It was stirred under pressure at 150 ℃ overnight. After removal of the solvent, the solid was dried to give crude pyrazine-2-sulfonic acid sodium salt as a white solid (6g), which was used directly in the next step without further purification.

To a suspension of crude pyrazine-2-sulfonic acid sodium salt (3.71g) in thionyl chloride (32.6g, 20mL, 274mmol) was added DMF (0.3mL, 3.87 mmol). It was stirred under reflux for 5 h. After removal of the solids by filtration, the filtrate was concentrated to give crude pyrazine-2-sulfonyl chloride as a red liquid (2g), which was used directly in the next step without further purification.

To 2- (isopropylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (30mg, 85.1. mu. mol) from example 27 and N, N-diisopropylethylamine (44.6. mu.L, 255. mu. mol) in CH₂Cl₂(3ml) crude pyrazine-2-sulfonyl chloride (45.6mg) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 2- [ isopropyl- (pyrazine-2-sulfonyl) -amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (2mg, 5%) as a white solid. MH + ═ 495.

Example 68

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl ] -acetamide

A solution of 3- [ (tert-butoxycarbonylamino) methyl ] phenylboronic acid (500mg, 1.99mmol), 5-bromo-2- (trifluoromethyl) pyrimidine (452mg, 1.99mmol) and potassium carbonate (0.28g, 1.99mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) -palladium (0) (115mg, 100 μmol), and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo yielded [3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl ] -carbamic acid tert-butyl ester (0.50g, 71%) as a brown solid. MH + ═ 354.0.

Reacting [3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl]-tert-butyl carbamate (0.50g, 1.42mmol) in CH₂Cl₂The solution in (5mL) was treated with trifluoroacetic acid (1.6g, 14.2mmol) and then stirred at 25 ℃ for 3 h. The solution was concentrated in vacuo to give 3- (2-trifluoromethyl-pyrimidin-5-yl) -benzylamine (320mg, 89%) as a brown oil. M + H254.0.

3- (2-trifluoromethyl-pyrimidin-5-yl) -benzylamine (27.6mg, 109. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl]Acetamide (27.5mg, 49%) as a white solid. MH + ═ 510.9.

Example 69

2- [ (3, 4-difluoro-benzenesulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

To 2- (isopropylamino) -N- ((6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methyl) acetamide (30mg, 85.1. mu. mol) and N, N-diisopropylethylamine (44.6. mu.L, 255. mu. mol) in CH₂Cl₂(3ml) 3, 4-difluorobenzenesulfonyl chloride (27.2mg, 128. mu. mol) was added. It was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 to 20/80 hexanes/ethyl acetate) afforded 2- [ (3, 4-difluoro-benzenesulfonyl) -isopropyl-amino]-N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl]Acetamide (28mg, 63%) as a white solid. MH + ═ 529.

Example 70

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [ 4-fluoro-3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl ] -acetamide

5- (aminomethyl) -2-fluorophenylboronic acid hydrochloride (2.0g, 9.74mmol), di-tert-butyldicarbonate (2.55g, 11.7mmol) and triethylamine (1.97g, 19.5mmol) are added to CH₃The solution in OH (10mL) was stirred at 25 ℃ for 3 h. The reaction mixture was poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo yielded 5- [ (tert-butoxycarbonylamino) methyl]2-Fluorophenylboronic acid (2.40g, 92%) as a brown solid.

A solution of 5- [ (tert-butoxycarbonylamino) methyl ] -2-fluorophenylboronic acid (500mg, 1.86mmol), 5-bromo-2- (trifluoromethyl) pyrimidine (422mg, 1.86mmol) and potassium carbonate (0.26g, 1.86mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) -palladium (0) (107mg, 93 μmol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo yielded [ 4-fluoro-3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl ] -carbamic acid tert-butyl ester (500mg, 73%) as a white solid. MH + ═ 372.0.

Reacting [ 4-fluoro-3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl]-carbamic acid tert-butyl ester (0.50g, 1.35mmol) in CH₂Cl₂The solution in (5mL) was treated with trifluoroacetic acid (1.5g, 13.5mmol) and then stirred at 25 ℃ for 3 h. The solution was concentrated in vacuo to give 4-fluoro-3- (2-trifluoromethyl-pyrimidin-5-yl) -benzylamine (350mg, 96%) as a brown oil. M + H272.0.

4-fluoro-3- (2-trifluoromethyl-pyrimidin-5-yl) -benzylamine (29.6mg, 109. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [ 4-fluoro-3- (2-trifluoromethyl-pyrimidin-5-yl) -benzyl]Acetamide (20.3mg, 35%) as a white solid. MH + ═ 529.0.

Example 71

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [3- (5-trifluoromethyl-pyrazin-2-yl) -benzyl ] -acetamide

A solution of 3- [ (tert-butoxycarbonylamino) methyl ] phenylboronic acid (500mg, 1.99mmol), 2-chloro-5-trifluoromethyl-pyrazine (363mg, 1.99mmol) and potassium carbonate (0.28g, 1.99mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (115mg, 100. mu. mol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo yielded [3- (5-trifluoromethyl-pyrazin-2-yl) -benzyl ] -carbamic acid tert-butyl ester (0.65g, 92%) as a brown solid.

Reacting [3- (5-trifluoromethyl-pyrazin-2-yl) -benzyl]-carbamic acid tert-butyl ester (0.65g, 1.70mmol) in CH₂Cl₂The solution in (5mL) was treated with trifluoroacetic acid (1.9g, 17.0mmol) and then stirred at 25 ℃ for 3 h. The solution was concentrated in vacuo to give 3- (5-trifluoromethyl-pyrazin-2-yl) -benzylamine (380mg, 88%) as a brown oil.

3- (5-trifluoromethyl-pyrazin-2-yl) -benzylamine (27.6mg, 109. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [3- (5-trifluoromethyl-pyrazin-2-yl) -benzyl]Acetamide (20.0mg, 36%) as a white solid. MH + ═ 511.0.

Example 72

2- [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino ] -N- [3- (5-trifluoromethyl-pyrazin-2-yl) -benzyl ] -acetamide

Reacting [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino]-acetic acid (30.0mg, 102 μmol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (26mg, 102. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (39.0mg, 102. mu. mol) at 25 ℃. N, N-diisopropylethylamine (26.5mg, 205. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino]-N- [3- (5-trifluoromethyl-pyrazin-2-yl) -benzyl]Acetamide (28.9mg, 53%) as a white solid. M + H528.0.

Example 73

2- [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino ] -N- [3- (6-trifluoromethyl-pyridazin-3-yl) -benzyl ] -acetamide

3- (6-trifluoromethyl-pyridazin-3-yl) -benzylamine (30.0mg, 102. mu. mol) and [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino]Acetic acid (26.0mg, 102. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (39.0mg, 102. mu. mol) at 25 ℃. Adding N, N-diisopropylethylamine (26.5mg, 2)05. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2- [ (6-chloro-pyridine-3-sulfonyl) -isopropyl-amino]-N- [3- (6-trifluoromethyl-pyridazin-3-yl) -benzyl]Acetamide (20.3mg, 38%) as a white solid. M + H528.0.

Example 74

2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino ] -N- [2- (2-trifluoromethyl-pyrimidin-5-yl) -pyridin-4-ylmethyl ] -acetamide

A solution of (2-bromo-pyridin-4-ylmethyl) -carbamic acid tert-butyl ester (300mg, 1.04mmol), 2- (trifluoromethyl) pyrimidin-5-ylboronic acid (200mg, 1.04mmol) and potassium carbonate (0.14g, 1.04mmol) in DMF (5mL) was purged with nitrogen at 25 ℃ and evacuated three times. The solution was then treated with tetrakis (triphenylphosphine) palladium (0) (60mg, 52. mu. mol) and then sealed and heated to 120 ℃ for 14 h. The reaction mixture was cooled to 25 ℃, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration, followed by concentration in vacuo yielded [2- (2-trifluoromethyl-pyrimidin-5-yl) -pyridin-4-ylmethyl ] -carbamic acid tert-butyl ester (50mg, 14%) as a brown solid. M + H355.0.

Reacting [2- (2-trifluoromethyl-pyrimidin-5-yl) -pyridin-4-ylmethyl]-carbamic acid tert-butyl ester (50mg, 141. mu. mol) in CH₂Cl₂A solution in (5mL) was treated with TFA (161mg, 1.41mmol) and then stirred at 25 ℃ for 3 h. The solution was concentrated in vacuo to give C- [2- (2-trifluoromethyl-pyrimidin-5-yl) -pyridin-4-yl]-methylamine (320mg,89%) as a brown oil. M + H254.9.

Reacting C- [2- (2-trifluoromethyl-pyrimidin-5-yl) -pyridin-4-yl]-methylamine (27.7mg, 109. mu. mol) and [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-acetic acid (30mg, 109. mu. mol) in CH₂Cl₂The solution in (5mL) was treated with HATU (41.4mg, 109. mu. mol) at 25 ℃. N, N-diisopropylethylamine (28.2mg, 218. mu. mol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2M KHSO₄Aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 Hexane/EtOAc) afforded 2- [ (4-fluoro-benzenesulfonyl) -isopropyl-amino]-N- [2- (2-trifluoromethyl-pyrimidin-5-yl) -pyridin-4-ylmethyl]Acetamide (44.1mg, 79%) as a white solid. M + H512.2.

Example 75

2- [ (5-chloro-thiophene-2-sulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide

2- (5-chloro-N-isopropylthiophene-2-sulfonamide) acetic acid (70.6mg, 237. mu. mol, Eq: 1.00), HATU (180mg, 474. mu. mol, Eq: 2.00) and sunitinib base (122mg, 166. mu.l, 948. mu. mol, Eq: 4.00) were combined with DCM (6ml) at 20 ℃ and stirred for 10 min. (6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) methylamine hydrochloride (60mg, 237. mu. mol, Eq: 1.00) was added and stirring continued for 14 h. The crude material was purified by flash chromatography (80-90% ethyl acetate/hexanes) to afford 2- [ (5-chloro-thiophene-2-sulfonyl) -isopropyl-amino ] -N- [6- (4-trifluoromethyl-phenyl) -pyrimidin-4-ylmethyl ] -acetamide as a solid. MH + ═ 534.

Example 76

2- [ (5-chloro-thiophene-2-sulfonyl) -isopropyl-amino ] -N- [6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4-ylmethyl ] -acetamide

2- (5-chloro-N-isopropylthiophene-2-sulfonylamino) acetic acid (64.4mg, 216. mu. mol, Eq: 1.10), HATU (150mg, 393. mu. mol, Eq: 2.00) and N-ethyl-N-isopropylpropan-2-amine (102mg, 787. mu. mol, Eq: 4.00) were reacted with CH₂CH₂(6ml) were combined and stirred at 20 ℃ for 10 min. (6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methylamine (50mg, 197. mu. mol, Eq: 1.00.) HCl was added and stirred for 5 h. The crude material was purified by flash chromatography (80-90% ethyl acetate/hexanes) to afford 2- [ (5-chloro-thiophene-2-sulfonyl) -isopropyl-amino]-N- [6- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4-ylmethyl]-an acetamide. MH + ═ 535.

Example 77

2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- (3- (pyrrolidin-1-yl) benzyl) acetamide

3- (pyrrolidin-1-yl) benzonitrile. A250-mL single-neck round bottom flask equipped with a magnetic stir bar and reflux condenser was charged with 3-chlorobenzonitrile (2.0g, 14.60mmol), pyrrolidine (1.6g, 21.90mmol), Pd₂(dba)₃(67mg，0.073mmol)，xantphos(84mg，0.15mmol)，Cs₂CO₃(9.5g, 29.14mmol) and bisAlkane (60 mL). The system was subjected to 3 cycles of vacuum/argon rinse and heated at 100 ℃ for 5 h. Will be provided withThe mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 10: 1PE/EA to afford the title compound (1.3g, 52%) as a pale yellow solid. MS-ESI: [ M + H ]]⁺73.1

(3- (pyrrolidin-1-yl) phenyl) methylamine. A50-mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with 3- (pyrrolidin-1-yl) benzonitrile (500mg, 2.91mmol), Pd/C (75mg, 10%), concentrated HCl (1 drop), and CH₃OH (10 mL). The system was subjected to 3 cycles of vacuum/hydrogen rinse and room temperature at H₂Stirring for 5 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (460mg, 90%) which was used in the next step without purification. MS-ESI: [ M + H ]]⁺177.1

2- (isopropylamino) acetic acid methyl ester. A500-mL single-neck round-bottom flask equipped with a magnetic stir bar was charged with propan-2-amine (5.0g, 84.75mmol), K₂CO₃(35.09g, 254.25mmol), and CH₃CN (90 mL). The mixture was stirred at 0 ℃ for 30 minutes. And subsequently reacting CH at 0 ℃ over a period of 1h₃Methyl 2-bromoacetate (12.88g, 84.75mmol) in CN (50mL) was added slowly. The mixture was stirred at 0 ℃ for an additional 1 h. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was sonicated in ether and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to give a colorless oil (8.1g, 73%), which was used in the next step without further purification.

Methyl 2- (4-fluoro-N-isopropylphenylsulfonamido) acetate. A250-mL single-necked round bottom flask equipped with a magnetic stir bar was charged with methyl 2- (isopropylamino) acetate (3.50g, 26.72mmol), 4-fluorobenzene-1-sulfonyl chloride (5.18g, 26.72mmol), DIPEA (5.20g, 40.08mmol), DMAP (122mg, 1.0mmol), and CH₂Cl₂(90 mL). The mixture was stirred at room temperature for 2 h. The solvent was subsequently removed under reduced pressure. The residue was purified by silica gel column chromatography using a 1: 3PE/EA to afford the title compound (5.0g, 65%) as a white solid. MS-ESI: [ M + H ]]⁺290.1

2- (4-fluoro-N-isopropylphenylsulfonamido) acetic acid. A250-mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with methyl 2- (4-fluoro-N-isopropylbenzenesulfonylamino) acetate (3.0g, 10.38mmol), LiOH (2.47g, 103.80mmol), THF (50mL), and H₂O (5 mL). The mixture was stirred at room temperature for 1h and concentrated under reduced pressure. The residue is taken up with H₂O (10mL) and then the resulting mixture was adjusted to pH 4 with 1N HCl. The mixture was extracted with ethyl acetate and the combined organic layers were concentrated under reduced pressure to give the crude title compound (1.5g, 53%) which was used directly in the next step without any further purification. MS-ESI: [ M + H ]]⁺276.1

2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- (3- (pyrrolidin-1-yl) benzyl) acetamide. A50-mL single-neck round-bottom flask equipped with a magnetic stir bar was charged with 2- (4-fluoro-N-isopropylbenzenesulfonylamino) acetic acid (100mg, 0.36mmol), (3- (pyrrolidin-1-yl) phenyl) methylamine (63mg, 0.36mmol), HATU (274mg, 0.72mmol), TEA (0.3mL), and CH₂Cl₂(10 mL). The mixture was stirred at room temperature for 1h and 2% KHSO was added₄And (3) solution. The resulting mixture was extracted with DCM. The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC to provide the title compound as a white solid (45mg, 46%). MS-ESI: [ M + H ]]⁺434.1.¹H NMR(500MHz，CDCl₃)7.85-7.82(m，2H)，7.20-7.16(m，3H)，6.84(s，1H)，6.57-6.47(m，3H)，4.44(d，J＝5.5Hz，2H)，4.23-4.18(m，1H)，3.73(s，2H)，3.28-3.26(m，4H)，2.00-1.97(m，4H)，0.98(d，J＝6.5Hz，6H)。

Example 78

N- (3-cyclopropylbenzyl) -2- (4-fluoro-N-isopropylphenylsulphonylamino) acetamide

N- (3-bromobenzyl) -2- (4-fluoro-N-isopropylphenylsulfonamido) acetamide. A250-mL single-neck round-bottom flask equipped with a magnetic stir bar was charged with 2- (4-fluoro-N-isopropylbenzenesulfonylamino) acetic acid (1.0g, 3.64mmol), (3-bromophenyl) methylamine (690mg, 3.64mmol), HATU (2.76g, 7.28mmol), TEA (3mL), and CH₂Cl₂(50 mL). The mixture was stirred at room temperature for 2h and 2% KHSO was added₄And (3) solution. The resulting mixture was extracted with DCM. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 3: 1PE/EA to afford the title compound as a white solid (960mg, 60%). MS-ESI: [ M + H ]]⁺443.1。

N- (3-cyclopropylbenzyl) -2- (4-fluoro-N-isopropylphenylsulphonylamino) acetamide. A50-mL single-neck round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with N- (3-bromobenzyl) -2- (4-fluoro-N-isopropylphenyl-sulfonamido) acetamide (150mg, 0.33mmol, 1.0eq.), cyclopropylboronic acid (146mg, 1.69mmol, 5.0eq.), PCy₃(38mg，0.14mmol，0.4eq.)，Pd(OAc)₂(15mg，0.067mmol，0.2eq.)，K₃PO₄(210mg, 0.99mmol, 3.0eq.), toluene (6mL), and H₂O (0.5 mL). After three cycles of vacuum/argon flushing, the mixture was heated at 100 ℃ for 10 h. It was cooled to room temperature and filtered through a pad of celite. The filtrate was evaporated under reduced pressure and the residue was purified by reverse phase prep-HPLC to give the title compound (65mg, 48%) as a white solid. MS-ESI: [ M + H ]]⁺405.1。¹H NMR(500MHz，DMSO-d₆)8.36-8.34(m，1H)，8.06-8.03(m，2H)，7.45-7.42(m，2H)，7.19-7.16(m，1H)，7.04-7.02(m，1H)，6.98-6.95(m，2H)，4.28(d，J＝6.0Hz，2H)，3.87-3.85(m，overlap，3H)，1.88-1.86(m，1H)，0.94-0.90(m，8H)，0.65-0.63(m，2H)

Example 79

(R) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- (3- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) benzyl) acetamide and (S) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- (3- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) benzyl) acetamide

(+, -) -5-bromo-2- (2-methylpyrrolidin-1-yl) pyrimidine. A500-mL round bottom flask equipped with a magnetic stirrer and reflux condenser was charged with 5-bromo-2-chloropyrimidine (13.6g, 70.4mmol, 1.0eq.), 2-methyl-pyrrolidine hydrochloride (10.5g, 86.8mmol, 1.2eq.), K₂CO₃(22.4g, 154.8mmol, 2.2eq.) and CH₃CN (150 mL). The reaction was heated at reflux for 48 h. After which it was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 1: 3EA/PE afforded the racemic title compound 15g (yield, 88%) as a white solid. MS-ESI: [ M + H ]]⁺242.1。

(+, -) -2- (2-methylpyrrolidin-1-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine. A250-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with racemic 5-bromo-2- (2-methylpyrrolidin-1-yl) pyrimidine (6.0g, 24.8mmol, 1.0eq.), Pin₂B₂(18.9g，74.4mmol，3.0eq.)，Pd₂(dba)₃(11.1g, 1.24mmol, 0.05eq.), x-phos (1.1g, 2.48mmol, 0.1eq.), KOAc (7.3g, 74.4mmol, 3.0eq.), and diAlkane (100 mL). After three cycles of vacuum/argon flushing, the mixture was heated at 70 ℃ for 3 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with petroleum to afford 6.1g of crude racemic title compound as a yellow solid, which was used directly in the next step.

MS-ESI：[M+H]⁺290.0

(+, -) -2- (4-fluoro-N-isopropylphenylsulfonamido) -N- (3- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) benzyl) acetamide. A50-mL single-neck round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with racemic 2- (2-methylpyrrolidin-1-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (270mg, 0.93mmol, 1.4eq.), N- (3-bromobenzyl) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) -acetamide (300mg, 0.67mmol, 1.0eq.), Pd (dppf) Cl₂(35mg，0.033mmol，0.05eq.)，K₃PO₄(424mg，2.0mmol，3.0eq.)，CH₃CN (10mL), and H₂O (2 mL). After three cycles of vacuum/argon flushing, the mixture was heated at 85 ℃ for 3 h. It was cooled to room temperature and filtered through a pad of celite. The filtrate was evaporated under reduced pressure and the residue was purified by reverse phase preparative-HPLC to give a racemic mixture of the title compound (265mg, 54%) as a white solid. After chiral resolution, two enantiomers were obtained in amounts of 21mg and 27mg, respectively (absolute stereochemistry is arbitrarily specified).

MS-ESI：[M+H]⁺526.2。

(R) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- (3- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) benzyl) acetamide.¹H NMR(500MHz，CDCl₃) Faster eluting isomer: 8.60-8.59(m, 2H), 7.90-7.87(m, 2H), 7.45-7.42(m, 3H), 7.30-7.29(m, 1H), 7.24-7.21(m, 2H), 7.05-7.04(m, 1H), 4.59(d, J ═ 6.0Hz, 2H), 4.38-4.26(m, 2H), 3.77(s, 2H), 3.76-3.74(m, 1H), 3.61-3.59(m, 1H), 2.15-2.02(m, 3H), 1.80-1.77(m, 1H), 1.31(d, J ═ 6.5Hz, 3H), 1.01(d, J ═ 6.5Hz, 6H).

(S) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- (3- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) benzyl) acetamide.¹H NMR(500MHz，CDCl₃) The slower eluting isomer: 8.60-8.59(m, 2H), 7.90-7.87(m, 2H), 7.46-7.42(m, 3H), 7.30-7.29(m, 1H), 7.24-7.21(m, 2H), 7.04-7.03(m, 1H), 4.59(d, J ═ 6.0Hz, 2H), 4.38-4.25(m, 2H), 3.77(s, 2H), 3.76-3.74(m, 1H), 3.62-3.60(m, 1H), 2.16-2.03(m, 3H), 1.80-1.77(m, 1H), (m, 2H), (m, 1H), and (m, 3H)m，1H)，1.31(d，J＝6.0Hz，3H)，1.01(d，J＝6.5Hz，6H)。

Example 80

2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-4-yl) methyl) acetamide

4-chloro-6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidine. A mixture of 4, 6-dichloropyrimidine (1.48g, 10mmol), DIPEA (2.58g, 20mmol) and 4- (trifluoromethyl) piperidine hydrochloride (1.89g, 10mmol) in 15mL of water was stirred at 115 ℃ for 16 h. After cooling to room temperature, the precipitate was collected by filtration, washed with water, and dried in vacuo to provide the title compound (2.38g, 89%) as a white solid. MS-ESI: [ M + H ]]⁺266.0

6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidine-4-carbonitrile. A mixture of 4-chloro-6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidine (0.53g, 2.0mmol) and tetraethylammonium cyanide (1.34g, 5.0mmol) in dimethylformamide (15mL) was stirred at 120 ℃ for 16 hours. To this mixture was added water and EA. The organic phase was separated, washed with water, dried and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.20g, 40%) as a pale yellow solid. MS-ESI: [ M + H ]]⁺256.9

(6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-4-yl) methylamine. A50-mL single-neck round-bottom flask was purged with nitrogen and loaded with 6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidine-4-carbonitrile (0.20g, 0.78mmol), 10% palladium on carbon (50% wet, 50mg), 12N HCl (0.10mL) and MeOH (6 mL). The mixture was evacuated, charged with hydrogen and stirred at room temperature for 4 h. The hydrogen was then evacuated and nitrogen charged to the flask. The catalyst was removed by filtration through a pad of celite and the filtrate was concentrated under reduced pressure to provide the title compound (0.20g, 99%). MS-ESI: [ M + H ]]⁺261.0

2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-4-yl) methyl) acetamide. A mixture of (6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-4-yl) methylamine (130mg, 0.50mmol), 2- (4-fluoro-N-isopropylbenzenesulfonylamino) acetic acid (138mg, 0.50mmol), HATU (380mg, 1.0mmol) and DIPEA (129mg, 1.0mmol) in DCM (8mL) was stirred at 25 ℃ for 2 h. The mixture was evaporated under reduced pressure and the residue was purified by reverse phase prep-HPLC to give the title compound (72mg, 27%) as a white solid. MS-ESI: [ M + H ]]⁺517.2。

1H NMR(500MHz，CDCl₃)1H NMR(500MHz，CDCl₃)8.55(s，1H)，7.94-7.91(m，2H)，7.29-7.24(m，3H)，6.71(s，1H)，4.62-4.60(m，2H)，4.51(d，J＝6.0Hz，2H)，4.25-4.21(m，1H)，3.79(s，2H)，2.91-2.86(m，2H)，2.34-2.31(m，1H)，1.98-1.95(m，2H)，1.58-1.54(m，2H)，1.03(d，J＝7.0Hz，6H)。

Example 81

N- ((6- (4, 4-difluoropiperidin-1-yl) pyrimidin-4-yl) methyl) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) acetamide

4-chloro-6- (4, 4-difluoropiperidin-1-yl) pyrimidine. A mixture of 4, 6-dichloropyrimidine (0.89g, 6.0mmol, DIPEA (1.55g, 12mmol) and 4, 4-difluoropiperidine hydrochloride (942mg, 6.0mmol) in water (10mL) was stirred at 115 ℃ for 16H]⁺233.8

6- (4, 4-Difluoropiperidin-1-yl) pyrimidine-4-carbonitrile. 4-chloro-6- (4, 4-difluoropiperidin-1-yl) pyrimidine (0.47g, 2.0mmol) and cyanogenA mixture of tetraethylammonium chloride (1.34g, 5.0mmol) in dimethylformamide (15mL) was stirred at 120 ℃ for 16 h. To this mixture was added water and EA. The organic phase was separated, washed with water, dried and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography over 10: 1PE/EA to afford the title compound (0.35g, 71%) as a pale yellow solid. MS-ESI: [ M + H ]]⁺225.1

(6- (4, 4-difluoropiperidin-1-yl) pyrimidin-4-yl) methylamine. A50-mL single-neck round bottom flask was purged with nitrogen and loaded with 6- (4, 4-difluoropiperidin-1-yl) pyrimidine-4-carbonitrile (0.35g, 1.56mmol), 10% palladium on carbon (50% wet, 100mg), 12N HCl (0.25mL), and MeOH (10 mL). The mixture was evacuated, charged with hydrogen and stirred at room temperature for 4 h. The hydrogen was then evacuated and nitrogen charged to the flask. The catalyst was removed by filtration through a pad of celite and the filtrate was concentrated under reduced pressure to provide the title compound (0.35g, 99%). MS-ESI: [ M + H ]]⁺229.1。

N- ((6- (4, 4-difluoropiperidin-1-yl) pyrimidin-4-yl) methyl) -2- (4-fluoro-N-isopropylbenzenesulfonylamino) acetamide. A mixture of (6- (4, 4-difluoropiperidin-1-yl) pyrimidin-4-yl) methylamine (114mg, 0.50mmol), 2- (4-fluoro-N-isopropylbenzenesulfonylamino) -acetic acid (138mg, 0.50mmol), HATU (380mg, 1.0mmol) and DIPEA (129mg, 1.0mmol) in DCM (8mL) was stirred at 25 ℃ for 2 h. The mixture was evaporated under reduced pressure and the residue was purified by reverse phase prep-HPLC to give the title compound (71mg, 30%) as a white solid. MS-ESI: [ M + H ]]⁺486.1。1HNMR(500MHz，CDCl₃)8.56(s，1H)，7.93-7.90(m，2H)，7.29-7.24(m，3H)，6.78(s，1H)，4.52(d，J＝6.0Hz，2H)，4.25-4.23(m，1H)，3.86-3.84(m，4H)，3.78(s，2H)，2.03-1.98(m，4H)，1.03(d，J＝7.0Hz，6H)。

Example 82

2- (N-isopropyl-1-methyl-1H-pyrazole-3-sulfonylamino) -N- ((4' - (trifluoromethyl) biphenyl-3-yl) methyl) acetamide

(4' - (trifluoromethyl) biphenyl-3-yl) methylamine. A100-mL single-necked round bottom flask equipped with a magnetic stir bar and reflux condenser was charged with (3-bromophenyl) methylamine (570mg, 3.0mmol), 4- (trifluoromethyl) phenylboronic acid (558mg, 3.0mmol), Pd (PPh)₃)₄(173mg，0.15mmol)，K₃PO₄(1.91g, 9.0mmol), DME (30mL) and H₂O (6 mL). The system was subjected to 3 cycles of vacuum/argon rinse and heated at reflux overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 1: 20MeOH/CH₂Cl₂Elution provided the title compound (640mg, 85%) as a brown solid. MS-ESI: [ M + H ]]⁺252.1。

2- (N-isopropyl-1-methyl-1H-pyrazole-3-sulfonamide) acetic acid methyl ester. A25-mL single-necked round bottom flask equipped with a magnetic stirrer was charged with 1-methyl-1H-pyrazole-3-sulfonyl chloride (220mg, 1.2mmol), 2- (isopropylamino) -acetic acid methyl ester (157mg, 1.2mmol), DIPEA (310mg, 2.4mmol), DMAP (12mg, 0.10mmol), and CH₂Cl₂(10 mL). The mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC to provide the title compound (202mg, 61%) as a white solid. MS-ESI: [ M + H ]]⁺276.1。¹H NMR(500MHz，CDCl₃)7.43(d，J＝2.5Hz，1H)，6.74(d，J＝2.0Hz，1H)，4.27-4.24(m，1H)，4.02(s，2H)，3.99(s，3H)，3.77(s，3H)，1.09(d，J＝6.5Hz，6H)。

2- (N-isopropyl-1-methyl-1H-pyrazole-3-sulfonamide) acetic acid. A25-mL single-necked round bottom flask equipped with a magnetic stir bar was charged with methyl 2- (N-isopropyl-1-methyl-1H-pyrazole-3-sulfonamide) acetate (150mg, 0.55mmol), LiOH (65mg, 2.73mmol), THF (10mL), and H₂O (2 mL). The mixture was stirred at room temperature for 1h and the resulting mixture was adjusted to pH 4 with 1N HCl. It is subsequently concentrated under reduced pressure and taken up with ethyl acetateAnd (4) ester extraction. The combined organic layers were concentrated under reduced pressure to give the crude title compound (120mg, 84%), which was used directly in the next step without any further purification. MS-ESI: [ M + H ]]⁺262.1。

2- (N-isopropyl-1-methyl-1H-pyrazole-3-sulfonamide) -N- ((4' - (trifluoromethyl) -biphenyl-3-yl) methyl) acetamide. A25-mL single-necked round bottom flask equipped with a magnetic stir bar was charged with (4' - (trifluoromethyl) biphenyl-3-yl) methylamine (50mg, 0.20mmol), 2- (N-isopropyl-1-methyl-1H-pyrazole-3-sulfonamide) acetic acid (52mg, 0.20mmol), HATU (152mg, 0.40mmol), DIPEA (52mg, 0.40mmol), and CH₂Cl₂(10 mL). The mixture was stirred at room temperature for 1 h. To the resulting mixture was added 2% KHSO₄The solution was extracted with DCM. The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC to provide the title compound as a white solid (45mg, 46%). MS-ESI: [ M + H ]]⁺495.1。¹H NMR(500MHz，CDCl₃)7.85-7.83(m，1H)，7.71-7.68(m，4H)，7.58(s，1H)，7.52(d，J＝8.5Hz，1H)，7.47-7.44(m，1H)，7.40(d，J＝2.0Hz，1H)，7.36(d，J＝7.5Hz，1H)，6.74(d，J＝2.5Hz，1H)，4.63(d，J＝6.0Hz，2H)，4.17-4.14(m，1H)，4.01(s，2H)，3.78(s，3H)，1.11(d，J＝6.0Hz，6H)。

Example 83

2, 2-dideuterio-2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) acetamide

2-oxo-2- ((6- (6- (trifluoromethyl) pyridine)Pyridin-3-yl) pyrimidin-4-yl) methylamino) ethylcarbamic acid 2, 2-dideuterio-tert-butyl ester. Reacting [6- [6- (trifluoromethyl) pyridin-3-yl group]Pyrimidin-4-yl]A mixture of methylamine (574mg, 2.26mmol, 1.00 equiv.), 2, 2-dideuteroglycine (400mg, 2.26mmol, 1.00 equiv.), DIPEA (875mg, 6.77mmol, 3.00 equiv.), HATU (1.03g, 2.71mmol, 1.20 equiv.) in DMF (50mL) was stirred at 25 ℃ for 2h under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100mL) and washed with brine (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10: 1) to provide the title compound (1.4g) as a brown slurry. MS-ESI: [ M + H ]]⁺414.2。

2, 2-dideuterio-2-amino-N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) acetamide hydrochloride. 2-oxo-2- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methylamino) ethylcarbamic acid 2, 2-dideutero-tert-butyl ester (1.4g, 3.39mmol, 1.00 eq), 4N HCl (10mL) in twoThe mixture in alkane (60mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to provide the crude title compound (1.5g, HCl salt form) as a light brown solid, which was used without further purification. MS-ESI: [ M + H ]]⁺314.2。

2, 2-dideuterio-2- (isopropylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) acetamide. Reacting NaBH (OAc)₃(909mg, 4.29mmol, 3.00 equiv.) A solution of 2, 2-didedeuterium-2-amino-N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) -acetamide hydrochloride (500mg, 1.43mmol, 1.00 equiv.), propan-2-one (83mg, 1.43mmol, 1.00 equiv.) in DMF (20mL) was added. The reaction mixture was stirred at room temperature overnight and then quenched by the addition of water (10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with methylene chloride/methanol (10: 1) to provide the title compound (220mg, 43%)As a brown solid. MS-ESI: [ M + H ]]⁺356

2, 2-dideuterio-2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) acetamide. To a solution of 2, 2-dideuterio-2- (isopropylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) acetamide (220mg, 0.62mmol, 1.00 eq) and triethylamine (182mg, 1.80mmol, 2.90 eq) in dichloromethane (10mL) was added 4-fluorobenzene-1-sulfonyl chloride (180mg, 0.92mmol, 1.50 eq) at room temperature. The resulting solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1: 10) to provide the title compound (38.1mg, 12%) as a white solid. MS-ESI: [ M + H ]]⁺514。¹H NMR(300MHz，DMSO-d₆)9.45(s，1H)，9.29(s，1H)，8.76-8.72(m，2H)，8.16(s，1H)，8.08-8.02(m，3H)，7.45-7.39(m，2H)，4.52(d，J＝6.0Hz，2H)，3.95-3.86(m，1H)，0.97(d，J＝6.5Hz，6H)。

Example 84

1- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) cyclopropanecarboxamide

1-Aminocyclopropanecarboxylic acid methyl ester hydrochloride. Reacting 1- [ [ (tert-butoxy) carbonyl group]Amino group]Cyclopropane-1-carboxylic acid methyl ester (2.15g, 9.99mmol, 1.00 equiv.) and 4N HCl in bisThe mixture in alkane (20mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give the crude title compound (1.52g, HCl salt) as a white solid. MS-ESI: [ M + H ]]⁺116

1- (4-fluorophenylsulphonamido) cyclopropanecarboxylic acid methyl ester. A mixture of 1-aminocyclopropane-1-carboxylic acid methyl ester hydrochloride (1.51g, 9.96mmol, 1.00 equiv.), triethylamine (2.52g, 24.90mmol, 2.50 equiv.), dichloromethane (20mL), 4-fluorobenzene-1-sulfonyl chloride (1.95g, 10.02mmol, 1.00 equiv.) was stirred at room temperature for 4 h. Water (50mL) was added. The mixture was extracted with dichloromethane (3 × 50 mL). The combined extracts were washed successively with water (50mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (2.5g) as a yellow oil. MS-ESI: [ M + H ]]⁺274。

1- (4-fluoro-N-isopropylphenylsulfonamido) cyclopropanecarboxylic acid methyl ester. Reacting 1- [ (4-fluorobenzene) sulfonamide]Cyclopropane-1-carboxylic acid methyl ester (1.5g, 5.49mmol, 1.00 equiv.), 2-iodopropane (5.6g, 32.94mmol, 6.00 equiv.), and K₂CO₃(3.04g, 22.03mmol, 4.00 equiv.) in CH₃The mixture in CN (30mL) was stirred in an oil bath overnight at 65 ℃. The reaction mixture was then concentrated under reduced pressure. Water (30mL) and ethyl acetate (50mL) were added and the phases separated. The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined extracts were washed with water (2 × 50mL) and brine (50mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1: 5) to provide the title compound (360mg) as a yellow oil. MS-ESI: [ M + H ]]⁺316

1- (4-fluoro-N-isopropylphenylsulfonamido) cyclopropanecarboxylic acid. Reacting 1- [ N- (propyl-2-yl) (4-fluorobenzene) sulfonamide]A mixture of methyl cyclopropane-1-carboxylate (250mg, 0.79mmol, 1.00 equiv.) and potassium hydroxide (265mg, 4.74 mmol, 6.00 equiv.) in methanol/water (24mL, 5: 1) was stirred at room temperature for 1 h. Methanol was removed by distillation under reduced pressure. Water (30mL) was added. The remaining solution was extracted with dichloromethane (3 × 20 mL). The aqueous phase was acidified to pH-2 by addition of concentrated HCl solution. The acidic solution was extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed successively with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (40mg, 17%) as a white solid. MS-ESI：[M-H]^-300。

1- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) cyclopropanecarboxamide. Reacting 1- [ N- (propyl-2-yl) (4-fluorobenzene) sulfonamide]Cyclopropane-1-carboxylic acid (40mg, 0.13mmol, 1.00 eq.), 6- [6- (trifluoromethyl) pyridin-3-yl]A mixture of pyrimidin-4-ylmethylamine (36mg, 0.14mmol, 1.07 equiv.), HATU (57mg, 0.15mmol, 1.13 equiv.), DIPEA (40mg, 0.31mmol, 2.33 equiv.) in DMF (5mL) was stirred at room temperature for 2 h. Water (20mL) was added to the reaction mixture. The reaction mixture was then extracted with ethyl acetate (3 × 30 mL). The extract was washed successively with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (2: 1) to provide the title compound (25mg, 35%) as a white solid. MS-ESI: [ M + H ]]538。¹H NMR(400MHz，DMSO-d₆)9.46(s，1H)，9.29(s，1H)，8.77(d，J＝8Hz，1H)，8.16-8.12(m，3H)，7.99(dd，J＝8.4，5.2Hz，2H)，7.41(t，J＝8.4Hz，2H)，4.47(s，2H)，4.19-4.16(m，1H)，1.49-1.13(m，10H)。

Example 85

2- [ N- (prop-2-yl) (4-fluorophenyl) sulfonylamino ] -N- ([6- [4- (trifluoromethyl) cyclohex-1-en-1-yl ] pyrimidin-4-yl ] methyl) acetamide

4- (trifluoromethyl) cyclohex-1-enyl trifluoromethanesulfonate. To a solution of 4- (trifluoromethyl) cyclohex-1-one (1.00g, 6.02mmol, 1.00 equiv.) in THF (12mL) at-78 deg.C under nitrogen was added dropwise a solution of 1M LiHMDS (6mL, 1.00 equiv.) in THF with stirring. The reaction mixture was stirred at-78 ℃ for 1 h. To this mixture was added 1, 1, 1-trifluoro-N-phenyl-N- (trifluoromethane) sulfonylmethanesulfonamide (2.152g, 6.02mmol, 1.00 equiv.) in THF at-78 deg.C over 30min dropwise(2 mL). The mixture was stirred at-78 ℃ for an additional 2h and at room temperature for 6 h. The mixture is subsequently reacted in H₂Partition between O (50mL) and ethyl acetate (50 mL). The phases were separated and the aqueous phase was extracted twice with ethyl acetate (50 ml). The combined organic phases are washed with H₂O (2 × 50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1: 20) to give the title compound (705mg) as a pale yellow solid. GCMS: 298

4, 4, 5, 5-tetramethyl-2- (4- (trifluoromethyl) cyclohex-1-ene) -1, 3, 2-dioxaborolane. 4- (trifluoromethyl) cyclohex-1-en-1-yl trifluoromethanesulfonate (3.636g, 12.19mmol, 1.00 equiv.), 4, 4, 5, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolan (3.626g, 14.28mmol, 1.17 equiv.), KOAc (3.892g, 39.66mmol, 3.25 equiv.), Pd (dppf) Cl₂(398mg, 0.54mmol, 0.03 equiv.), dppf (203mg, 0.37mmol, 0.03 equiv.) in 1, 4-bisThe mixture in alkane (60mL) was stirred at 80 ℃ under nitrogen overnight. The reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50mL) and water (50mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined extracts were washed with water (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate petroleum ether (1: 10) to give the title compound (2.6g) as a white solid. GCMS: 276.

6- (4- (trifluoromethyl) cyclohex-1-ene) pyrimidine-4-carboxylic acid methyl ester. 4, 4, 5, 5-tetramethyl-2- [4- (trifluoromethyl) cyclohex-1-en-1-yl]-1, 3, 2-dioxaborolane (2.00g, 7.24mmol, 1.00 eq.), methyl 6-chloropyrimidine-4-carboxylate (1.25g, 7.27mmol, 1.00 eq.), Pd (dppf) Cl₂.CH₂Cl₂(560mg, 0.10 eq), K₂CO₃(3.1g, 3.00 equiv),water (4mL) in 1, 4-bisThe mixture in alkane (20mL) was stirred at 100 ℃ under nitrogen for 2h and then allowed to cool to room temperature. Subjecting the mixture to hydrogenation with H₂O (120mL) was diluted and extracted with ethyl acetate (3 × 50 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1: 3) to provide the title compound (520mg) as a yellow solid. MS-ESI: [ M + H ]]⁺287。

(6- (4- (trifluoromethyl) cyclohex-1-enyl) pyrimidin-4-yl) methanol. Reacting 6- [4- (trifluoromethyl) cyclohex-1-en-1-yl]Pyrimidine-4-carboxylic acid methyl ester (500mg, 1.75mmol, 1.00 equiv.), NaBH₄A mixture of (127mg, 3.36mmol, 2.00 equiv.) in methanol (10mL) was stirred at reflux for 1h and then cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1: 1) to provide the title compound (230mg) as an off-white solid. MS-ESI: [ M + H ]]⁺259。

2- ((6- (4- (trifluoromethyl) cyclohex-1-enyl) pyrimidin-4-yl) methyl) isoindoline-1, 3-dione. Reacting [6- [4- (trifluoromethyl) cyclohex-1-en-1-yl]Pyrimidin-4-yl]Methanol (220mg, 0.85mmol, 1.00 equiv.), 2, 3-dihydro-1H-isoindole-1, 3-dione (138mg, 0.94mmol, 1.10 equiv.), DIAD (345mg, 1.71mmol, 2.00 equiv.), PPh₃A mixture of (447mg, 1.70mmol, 2.00 equiv.) in THF (10mL) was stirred at 25 deg.C for 2h and then quenched by addition of brine (20 mL). The mixture was extracted with dichloromethane (3 × 20 mL). The combined extracts were washed with brine (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1: 1) to provide the title compound (425mg) as a white solid. MS-ESI: [ M + H ]]⁺388。

(6- (4- (trifluoromethyl) cyclohex-1-enyl) pyrimidin-4-yl) methylamine. 2- ([6- [4- (trifluoromethyl) cyclohex-1-en-1-yl)]Pyrimidines-4-yl]A mixture of methyl) -2, 3-dihydro-1H-isoindole-1, 3-dione (425mg, 1.10mmol, 1.00 equiv.), hydrazine hydrate (80%) (687mg, 13.72mmol, 10.00 equiv.) in methanol (10mL) was stirred at 40 ℃ for 3H and then concentrated under reduced pressure. The mixture was washed with ethyl acetate (2 × 20mL) and concentrated under reduced pressure to give the title compound 211mg as a white solid. MS-ESI: [ M + H ]]⁺258。

2- (4-fluoro-N-isopropylbenzenesulfonylamino) -N- ((6- (4- (trifluoromethyl) cyclohex-1-enyl) pyrimidin-4-yl) methyl) acetamide. Reacting 2- [ N- (propyl-2-yl) (4-fluorobenzene) sulfamide]Acetic acid (346mg, 1.26mmol, 1.20 equiv.), HATU (600mg, 1.58mmol, 1.50 equiv.), DIPEA (407mg, 3.15mmol, 3.00 equiv.) [6- [4- (trifluoromethyl) cyclohex-1-en-1-yl ]]Pyrimidin-4-yl]A mixture of methylamine (270mg, 1.05mmol, 1.00 equiv.) in N, N-dimethylformamide (20mL) was stirred overnight at 25 ℃ under nitrogen and then quenched with water (10 mL). The mixture was extracted with dichloromethane (3x100mL) and the organic layer was washed with brine (2x200mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (180mg) was purified by prep-HPLC at high pH to provide the title compound (71.1mg, 13%) as a white solid. LCMS (5cm _ ESI _ Formic _ MeCN): [ MH⁺]515 min at 2.377 min.¹H NMR(300MHz，CD₃OD)8.96(d，J＝1.2Hz，1H)，8.07-8.02(m，2H)，7.80(s，1H)，7.37-7.31(m，2H)，7.05(s，1H)，4.53(s，2H)，4.13-4.09(m，1H)，3.92(s，2H)，2.91-2.43(m，7H)，1.72-1.45(m，1H)，1.05(d，J＝6.6Hz，6H)。

Example 86

2- (4-fluoro-N- (4-fluorophenyl) phenylsulphonylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) acetamide

Step 1: 4-fluoro-N- (4-fluorophenyl) benzenesulfonamides

Pyridine (6.11g, 76.29mmol) was added dropwise to a stirred solution of 4-fluorobenzene-1-sulfonyl chloride (5.0g, 25.69mmol) in dichloromethane (50mL) at 0 ℃. 4-fluoroaniline (5.67g, 51.03mmol) was then slowly added to the reaction solution. The reaction was stirred at room temperature overnight, diluted with water (200mL) and extracted with dichloromethane (3 × 100 mL). The organic layers were combined and washed with brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (0-30%) to provide the title compound (6.13g) as a pale yellow solid. MS-EI: [ M + H ]]⁺269。

Step 2: 2- (4-fluoro-N- (4-fluorophenyl) phenylsulfonamido) acetic acid methyl ester

A mixture of sodium hydride (360mg, 15.00mmol) in N, N-dimethylformamide (20mL) was added dropwise to a stirred solution of 4-fluoro-N- (4-fluorophenyl) benzene-1-sulfonamide (2g, 7.43mmol) in DMF (3mL) at 0 ℃. The mixture was warmed to room temperature and stirred at room temperature for 1 h. The reaction was then cooled back to 0 ℃ and methyl 2-bromoacetate (1.7g, 11.11mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight, quenched with ice/water (200mL), and extracted with dichloromethane (2 × 200 mL). The organic layers were combined and washed with brine (3 × 200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (0-30% in 30 min) to afford the title compound (1.6g) as a white solid.

MS-ESI：[M+H]⁺342。

And step 3: 2- (4-fluoro-N- (4-fluorophenyl) phenylsulphonylamino) acetic acid

LiOH (560mg, 23.38mmol) in water (23.3mL) was added dropwise to a stirred mixture of methyl 2- [ N- (4-fluorophenyl) sulfonamido ] acetate (1.6g, 4.69mmol) in tetrahydrofuran (20mL) at room temperature. The reaction mixture was stirred overnight and the organic solvent was subsequently removed under reduced pressure. The pH of the aqueous layer was adjusted to 2-3 with 2M HCl. The solid was collected by filtration to give the title compound (650mg) as a white solid.

MS-ESI：[M-H]^-326。

And 4, step 4: 2- (4-fluoro-N- (4-fluorophenyl) phenylsulphonylamino) -N- ((6- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) methyl) acetamide

Reacting 2- [ N- (4-fluorophenyl) (4-fluorobenzene) sulfamide]Acetic acid (150mg, 0.46mmol), HATU (261.5mg, 0.69mmol), DIEA (236.7mg, 1.83mmol), and [6- [6- (trifluoromethyl) pyridin-3-yl ]]Pyrimidin-4-yl]A mixture of methylamine hydrochloride (133mg, 0.46mmol) in N, N-dimethylformamide (4mL, 64.61mmol) was stirred at room temperature overnight. The crude product (4mL) was purified by flash-prep-HPLC using the following conditions: (Intel flash-1): column, C18 silica gel; mobile phase, CH₃CN：H₂O(NH₄HCO₃) From 36% to 86% in 30 min; detector, UV254 nm. This gave 31.2mg of the title compound as a white solid.

LCMS[M+H]⁺564。¹H-NMR(400MHz，CD₃OD)9.45(s，1H)，9.23(d，J＝0.8Hz，1H)，8.76-8.74(m，1H)，8.02(s，1H)，7.97(d，J＝8.4Hz，1H)，7.74-7.70(m，2H)，7.33-7.29(m，4H)，7.08-7.03(m，2H)，4.63(s，2H)，4.43(s，2H)。

Example 87

IC of exemplified Compounds₅₀Determining

Dose response assay: chan Test hTRPA1-CHO stably transfected cell line

Cell culture and assay reagents:

CHO-K1 Tet-On _ HOMSA _ TRPA1_ clone _20

Chinese hamster ovary cells, inducible expression

Clone #20, received at passage #26

Channel expression in this cell line has been shown to be stable for at least 80 passages

Mycoplasma-free proof by MycoAlert kit

Expansion of cell lines and storage

Growth conditions are as follows:

growth Medium for CHO-K1 Tet-On _ HOMSA _ TRPA1_ clone _20

Ham's F-12 containing 10% tetracycline-free FBS

-1X penicillin-streptomycin

-1X glutamax

-0.01mg/ml blasticidin

-0.40mg/ml Zeocin

The cell line doubling rate was-15 hours. The plates were not more than 80% confluent.

To induce expression, tetracycline was added to the blasticidin-free/zeocin-free medium at a final concentration of 1 ug/ml. Experiments were performed 24 hours after induction.

Plating conditions CHOK1/TRPA1 cells:

cells were harvested with 0.025% trypsin/EDTA.

Resuspend cells in growth medium without selection antibiotics.

Cell density was measured and diluted to 2.4x10 in medium containing 1ug/ml doxycycline⁵Cells/ml, plated at 25 ul/well into 384 well black/clear tissue culture treated plates.

Incubate overnight at 37 ℃.

Calcium flow determination:

and (3) measuring the days:

reagent:

-substitution buffer: hank's Balanced salt solution, 20mM HEPES and 0.005% BSA and 2 Xprobenecid

Dye loading buffer: cal-3NW calcium dye was prepared by dissolving one vial of the contents in 500ml of Hank's balanced salt solution containing 20mM HEPES

Control compounds of CHOK1/TRPA1 cells:

AP-18, stock 10mM, 3.5 compound dilutions were made in compound buffer (HBSS/20mM HEPES/0.005% BSA) -10 uM final concentration.

Preparation of cinnamaldehyde (agonist addition): FW (132.16)

Specific gravity of 1.046gm/cc

Stock solution of-1.32 gm/1.046gm/cc 1.26ml

-addition of 1.74ml DMSO ═ 3.3M stock solutions

Working solution 4.5X (final 100uM in compound buffer: HBSS/20mM HEPES/0.005% BSA)

-compound dilutions were prepared from 5 or 10mM stock solutions (100% DMSO):

● the volume and concentration are adjusted during titration to reflect the desired final assay concentration.

● test compounds were diluted 20 μ M three times for 11 steps or 30 μ M two times for 11 steps.

● mu.l of the diluted compound were transferred in duplicate in a Weidmann 384-well plate.

● the compound plate was resuspended in 100ul of HBSS/20mM HEPES/0.005% BSA buffer (compound buffer):

columns 1A-H: buffer/DMSO (bk)

Columns 2A-H: AP-18 (control antagonist for CHOK1 TRPA1 cells)

Column 1I-P: ATP (control for CHOK1 teton cells)

Column 2I-P: 2APB (control antagonist of CHOK1/TRPM8 cells).

Growth medium (20ul) was removed from the cell plate and 20ul of replacement buffer was added, followed by 25ul of dilution dye. All three steps were performed using Plate Washer BioTek 407. The plates were then incubated at RT for 30'.

After incubation, cells and compound plates were brought to the FLIPR and 20ul of diluted compound/antagonist/bk was transferred to the cell plates by the FLIPR. The plates were then incubated at room temperature for 30'. After 30' incubation, the plates were returned to the FLIPR and 20ul of 4.5X cinnamaldehyde was added to the cell plates. During compound addition as well as agonist addition, fluorescence readings were taken from all 384 wells of the cell plate simultaneously every 1.5 seconds. Five readings were taken to establish a stable baseline, and then 20ul samples were added to each well of the cell plate rapidly (30ul/sec) and simultaneously. Fluorescence was continuously monitored before, during and after sample/agonist addition for a total elapsed time of 100 seconds (compound addition) and 120 seconds (agonist addition). The response (increase in peak fluorescence) in each well after agonist addition was determined. The initial fluorescence reading for each well prior to ligand stimulation was used as the zero baseline value for the data from that well. The response was expressed as% inhibition of inhibitor control, as shown in table 1 below:

TABLE 1

Example 88

IC of exemplified Compounds₅₀Determining

IC of compounds on human TRPA1 channel₅₀(effective concentration) was determined using Hamamatsu FDSS fluorescence plate reader. CHO cells expressing human TRPA1 were plated in 384-well plates, incubated overnight at 37 ℃, and loaded with BD calcium indicator dye for 1hr at 37 ℃, followed by 15 minutes at room temperature. The assay buffer was Hank's Balanced Salt Solution (HBSS) containing 20mM HEPES (pH readjusted to 7.4) and 0.02% BSA.

After dye loading and plate cooling, compounds were added to the cells using FDSS while monitoring fluorescence to determine if any of the test compounds had TRPA1 agonist activity. The plates were then incubated with compound for 20 minutes at room temperature before addition of agonist. After this incubation, 100mM cinnamaldehyde was added to all wells of the plate and the blockade of cinnamaldehyde-induced calcium influx was measured.

Will IC₅₀Fit with a standard Hill function, keeping the Hill coefficient (n) fixed at 1.5. A fixed Hill constant will generally lower the IC₅₀Variability of the assay. Eye detection of IC₅₀To ensure that the minimum and maximum points are set correctly, after which the results are confirmed. Data for representative compounds of formula (I) are provided in table 2 below.

TABLE 2

It is to be understood that the invention is not limited to the particular embodiments of the invention described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. All documents cited or relied upon herein are expressly incorporated by reference.

Claims

1. A compound of formula (I):

wherein:

R¹is unsubstituted phenyl, phenyl mono-or disubstituted independently by halogen or-CN, an unsubstituted five-or six-membered heteroaryl ring or by C_1-7Alkyl, halogen or halogeno C_1-10An alkyl-substituted five-or six-membered heteroaryl ring;

R²selected from the group consisting of methyl, -CH₂CF₃Ethyl, hydroxy-ethyl, propyl, hydroxy-propyl, cyclopropyl, isopropyl, methoxy-ethyl, tert-butyl, oxetan-3-ylmethyl or oxetanyl;

R³and R^3′Each independently selected from hydrogen; deuterium; halogen substituted C_1-10An alkyl group; c_3-10Cycloalkyl and C_1-7Alkyl, wherein said halo C_1-10Alkyl radical, C_3-10Cycloalkyl and C_1-7Alkyl being optionally deuterium, F, Cl, Br, hydroxy or C_1-10Alkoxy substitution; or R³And R^3′Together with the carbon to which they are attached form optionally substituted deuterium, F, Cl, Br, hydroxy or C_1-10Alkoxy-substituted 3, 4,5 or 6-membered cycloalkyl;

R⁴is hydrogen or C_1-7An alkyl group; and is

Selected from:

wherein "heteroaryl" denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms comprising 1, 2,3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R¹Is unsubstituted phenyl, pyrazinyl, pyridyl or thienyl.

3. The compound of claim 1, wherein R¹Is phenyl optionally substituted by cyano, F or Cl, pyrazinyl optionally substituted by F or Cl, pyridinyl optionally substituted by F or Cl, pyrazole optionally substituted by F or Cl, or thienyl optionally substituted by F or Cl.

4. The compound of claim 1, wherein R¹Is phenyl substituted by F or Cl, pyrazinyl substituted by F or Cl, pyridinyl substituted by F or Cl, or thienyl substituted by F or Cl.

5. The compound according to any one of claims 1-4, wherein R²Is methyl, -CH₂CF₃Ethyl, hydroxy-ethyl, 2-hydroxypropyl, cyclopropyl, isopropyl, 2-methoxyethyl, tert-butyl, oxetan-3-ylmethyl, or 3-oxetanyl.

6. The compound according to any one of claims 1-4, wherein R³And R^3′Are all hydrogen.

7. The compound according to any one of claims 1-4, wherein R³Or R^3′One of which is hydrogen and the other is methyl, tert-butyl, cyclopropyl, -CH₂OH or-CH₂OCH₃。

8. The compound according to any one of claims 1-4, wherein R³Or R^3′One is hydrogen, deuterium or methyl and the other is hydrogen, methyl, isopropyl, cyclopropyl, hydroxymethyl, methoxymethyl or deuterium; or R³And R^3′Together with the carbon to which they are attached form a 3-membered cycloalkyl group.

9. The compound according to any one of claims 1-4, wherein R⁴Is hydrogen.

10. The compound according to any one of claims 1-4, wherein R⁴Is methyl.

11. A compound, said compound being:

12. A compound, said compound being:

n- (3-cyclopropylbenzyl) -2- (4-fluoro-N-isopropylphenylsulfonamido) acetamide;

or a salt thereof.

13. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

14. Use of a compound of formula (I) as claimed in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of a respiratory disease.

15. Use of a compound of formula (I) as described in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by TRPA1 activity.

16. The use of claim 15, wherein the disease or condition is pain, itch, an inflammatory disease, an inner ear disease, fever or another thermoregulatory disease, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disease, chronic obstructive pulmonary disease, incontinence, or a disease associated with reduced blood flow to the CNS or CNS hypoxia.

17. The use of claim 15, wherein the disease or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disease.