HK1018956B

HK1018956B - Novel substituted n-methyl-n-(4-(piperidin-1-yl)-2-(aryl)butyl benzamides useful for the treatment of allergic diseases

Info

Publication number: HK1018956B
Application number: HK99104010.0A
Authority: HK
Inventors: G‧D‧梅纳德; J‧M‧坎恩; L‧D‧布拉顿; E‧M‧库德拉兹
Original assignee: 阿温蒂斯药物公司
Priority date: 1996-02-21
Filing date: 1997-01-27
Publication date: 2003-08-29

Description

Novel substituted N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamides for the treatment of allergic diseases

The present invention relates to novel substituted N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamide derivatives, referred to herein as compounds of formula (1), and their use as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of asthma; bronchitis; enteritis, including crohn's disease and ulcerative colitis; allergic rhinitis, including seasonal rhinitis and sinusitis; (ii) an allergic reaction; and vomiting.

Tachykinin receptor antagonists are known in the art, e.g. EP0630887 discloses certain 4-aryl or heteroaryl-piperidines, EP0625509 discloses 4-alkylpiperidines, EP0515240 discloses certain 4-alkylamino and 4-alkylamidopiperidines, EP0474561 discloses certain substituted piperidines.

The compounds of the present invention are valuable for their pharmacological activity, such as histamine receptor antagonism and tachykinin receptor antagonism. Antagonism of the histamine response may be manifested by blockade of histamine receptors. Antagonism of the tachykinin response can be shown by blocking tachykinin receptors. It is an object of the present invention to provide novel and useful histamine antagonists. It is another object of the present invention to provide novel and useful tachykinin antagonists. It is a particular object of the invention to simultaneously exhibit H₁And NK₁Those compounds which antagonize the receptor.

Summary of The Invention

The present invention provides novel substituted N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamide derivatives of the formula

An object:wherein

R' is 1 to3 substituents, each independently selected from hydrogen, halogen, C₁-C₆Alkyl and C₁-C₆An alkoxy group; r "is hydrogen or a group selected from:wherein R is₂₀Selected from hydrogen, C₁-C₄Alkyl and-CF₃；Ar₁Is a group selected from:

wherein

R₁Is 1 to3 substituents, each independently selected from hydrogen, halogen, hydroxy, -CF₃、C₁-C₆Alkyl and C₁-C₆An alkoxy group;

R₂is 1 to 2 substituents, each independently selected from hydrogen, halogen, C₁-C₆Alkyl and C₁-C₆An alkoxy group;

X₁and X₂As defined in one of parts A), B) or C):

A)X₁is hydrogen; x₂Is a group selected from:

wherein

p is 1 or 2;

R₃is 1 to3 substituents, each independently selected from hydrogen, halogen, -CF₃、C₁-C₆Alkyl and C₁-C₆An alkoxy group;

R₄is 1 to3 substituents, each independently selected from hydrogen, halogen, -CF₃、C₁-C₆Alkyl and C₁-C₆An alkoxy group;

R₅is hydrogen or hydroxy; ar (Ar)₂Is a group selected from:

wherein

R₆Is 1 to3 substituents, each independently selected from hydrogen, halogen, -CF₃、C₁-C₆Alkyl radical, C₁-C₆Alkoxy and-CO₂R₉Wherein R is₉Selected from hydrogen and C₁-C₄An alkyl group;

R₇is 1 to 2 substituents, each independently selected from hydrogen, halogen, C₁-C₆Alkyl and C₁-C₆An alkoxy group;

R₈selected from hydrogen, -CH₃and-CH₂OH；

R₁₀Selected from hydrogen, C₁-C₄Alkyl and benzyl;

z is selected from hydrogen and C₁-C₆Alkyl, - (CH)₂)_w-O-(CH₂)_t-Y、-(CH₂)_fA、-(CH₂)_uCO₂R₁₁、-(CH₂)_uC(O)NR₁₂R₁₃、-(CH₂)_qC(O)(CH₂)_hCH₃、-(CH₂)_w’-O-Ar₃、-CH₂CH₂OCF₃、-CH₂CF₃、-CH₂CH₂CH₂CF₃、-(CH₂)₂CH＝CH₂、-CH₂CH＝CH₂、-CH₂CH＝CHCH₃、-CH₂CH＝CHCH₂CH₃、-CH₂CH＝C(CH₃)₂and-CH₂OCH₂CH₂Si(CH₃)₃

Wherein

w is an integer from 2 to 5;

t is an integer from 1 to 3;

f is 2 or 3;

u is an integer from 1 to 4;

g is an integer from 1 to 3;

h is an integer from 0 to 3;

w' is an integer from 2 to 4;

y is selected from hydrogen, -CF₃、-CH＝CH₂、-CH＝C(CH₃)₂and-CO₂R₁₄Wherein R is₁₄Selected from hydrogen and C₁-C₄An alkyl group;

a is selected from-NR₁₅R₁₆Acetamido and morpholino wherein R₁₅Selected from hydrogen and C₁-C₄Alkyl and R₁₆Is C₁-C₄An alkyl group;

R₁₁selected from hydrogen and C₁-C₄An alkyl group;

R₁₂selected from hydrogen, C₁-C₄Alkyl and benzyl;

R₁₃selected from hydrogen and C₁-C₄An alkyl group;

Ar₃is a group selected from:wherein v is an integer from 1 to 3; r₁₇Selected from hydrogen and-CO₂R₁₈Wherein R is₁₈Selected from hydrogen and C₁-C₄An alkyl group; B) x₁Is a hydroxyl group; x₂Is a group selected from:wherein p and R₃Z and Ar₃The definition is as before; C) x₂Is a group of the formula:

wherein R is₃And R₄The definition is as before; and is

X₁And Z₁Together with X₁And Z₁Another bond is formed between the carbon atoms of the group;

and stereoisomers and pharmaceutically acceptable salts thereof.

It is well known to those of ordinary skill in the art that the compounds of formula (1) may exist as stereoisomers of N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamide. In particular, it will be appreciated that the N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamides of the present invention may exist as stereoisomers of the butyl group at the 2-position (i.e., the attachment position of the aryl substituent). Any description herein of compounds of formula (1) includes stereoisomeric forms or mixtures of stereoisomers.

Oriented stereoisomers may be prepared by stereospecific synthesis using enantiomerically pure or enriched enantiomerically pure starting materials. The stereoisomeric starting material or product may be resolved or recovered by techniques well known in the art, such as chiral solid phase chromatography, enzymatic resolution or fractional recrystallization of an addition salt formed using an agent suitable for the purpose. Useful methods for resolving and recovering oriented stereoisomers are well known in the art and are described inStereochemistry of organic compoundsEliel and S.H.Wilen, Wiley (1994) andenantiomers, racemates and resolutionJacques, a.colet and s.h.wilen, Wiley (1981).

As used herein:

a) the term "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom;

b) the term "C₁-C₆Alkyl "means a branched or straight chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, etc.;

c) the term "C₁-C₆Alkoxy "means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopentyloxy, cyclohexyloxy, etc.;

d) the symbols-C (O) -or- (O) C-refer to a carbonyl group of the formula:

e) symbolRefers to a stereochemically undefined bond;

f) the term "kg" used in examples and preparations means kg, "g" means g, "mg" milligram, "μ g" means microgram, "mol" means mol, "mmol" means millimole, "nmole" means nanomole, "L" means liter, "mL" or "mL" means milliliter, "μ L" means microliter, "° C" means centigrade, "R" means microliter_f"means retention time," mp "means melting point," dec "means decomposition," bp "means boiling point," mmHg "means millimeter mercury pressure," cm "means centimeter," nm "means nanometer," [ alpha ] "]_D ²⁰"means the D-line optical rotation of sodium obtained in a 1 dm cup at 20 ℃," c "means the g/mL concentration," THF "means tetrahydrofuran," DMF "means dimethylformamide," brine "means a saturated aqueous sodium chloride solution," M "means moles," mM "means millimoles," μ M "means micromoles," nM "means nanomoles," pounds per square inch (psi) "means pounds per square inch," TLC "means thin layer chromatography," HPLC "means high pressure liquid chromatography," HRMS "means high resolution mass spectrometry," μ Ci "means microcurie," i.p. "means intraperitoneal," i.v. "means intravenous and" DPM "means the rate of disintegration per minute.

g) Symbol

Refers to phenyl or substituted phenyl, understood as a group attached in the 1 position, and one or more substituents represented by R may be attached in any position in the 2, 3, 4, 5 or 6 position;

h) symbol

Refers to pyridine, substituted pyridine, pyridyl or substituted pyridyl, and is understood to be a group that can be attached at the 2, 3 or 4 position, and is also understood to mean that when the group is attached at the 2 position, one or more substituents represented by R can be attached at any of the 3, 4, 5 or 6 positions; and when the group is attached at the 3-position, one or more substituents represented by R may be attached at any of the 2-, 4-, 5-or 6-positions; that is, when the group is attached at the 4-position, one or more substituents represented by R may be attached at any of the 2-, 3-, 5-, or 6-positions;

i) symbolRefers to thienyl or thiophene, it being understood that the group is attached in the 2 or 3 position;

j) symbol

Refers to naphthyl or substituted naphthyl, it being understood that the group may be attached in position 1 or 2, and it being understood that when the group may be attached in position 1, one or more substituents represented by R may be attached in any of positions 2, 3, 4, 5, 6, 7 or 8; when the group is attached in the 2-position, one or more substituents represented by R may be attached in any of the 1, 3, 4, 5, 6, 7 or 8-positions;

k) the term "enantiomeric excess" or "ee" means that one enantiomer, E1, is in excess in a mixture of the two enantiomers, E1 plus E2, such that

{(E1-E2)÷(E1+E2)}×100％＝ee，

The symbol "(+) -" refers to the positive enantiomer and "(-) -" refers to the negative enantiomer.

l) the term "C₁-C₄Alkyl "means a saturated straight or branched chain alkyl group containing 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert-butyl;

m) sign-CO₂R and-C (O) OR refer to a group of the formula:

n) the symbol-C (O) NRR refers to a group of the formula:

o) symbolRefers to furyl or furan and is understood to be a group attached at the 2 or 3 position;

p) the term "pharmaceutically acceptable salts thereof" refers to acid addition salts or base addition salts.

"pharmaceutically acceptable acid addition salt" means any nontoxic organic or inorganic acid addition salt using the basic compound represented by the formula (1) or an intermediate thereof. Examples of inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; metal salts of acids such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Examples of organic acids that form suitable salts include mono-, di-, or tricarboxylic acids. Examples of such acids are, for example, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and sulfonic acids, such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Such salts may exist in hydrated or substantially anhydrous form. Acid addition salts of such compounds are generally soluble in water and various hydrophilic organic solvents, and they generally have higher melting points than their free base compounds.

"pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt using the acidic compound represented by formula (1) or an intermediate thereof. Examples of bases which form suitable salts include alkali or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia and aliphatic, alicyclic or aromatic organic amines such as methylamine, dimethylamine, trimethylamine and picoline.

Preferred embodiments of the compound of formula (1) are given below:

1) wherein X₁Compounds that are hydrogen are preferred;

2) wherein X₂Is a group of the formula:the compounds of (1) are preferred; 3) wherein X₂Is a group of the formula:

wherein p is 1 and Ar₂Compounds which are 4-fluorophenyl, pyridin-2-yl, furan-2-yl or furan-3-yl are more preferred;

4) wherein X₂Is a group of the formula:the compounds of (1) are preferred; 5) wherein X₂Is a group of the formula:

wherein Z is- (CH)₂)_w-O-(CH₂)_t-Y, compounds wherein w is 2 are preferred; compounds wherein Z is 2-ethoxyethyl are more preferred.

The present invention includes the following compound examples. It is understood that these examples include both the (+) -isomer and the (-) -isomer of the compound and mixtures thereof. The following list is merely representative of the compounds and is not intended to limit the scope of the invention in any way:

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzoimidazol-2-yl) -4-hydroxypiperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzoimidazol-2-yl) -4-hydroxypiperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzoimidazol-2-yl) -4-hydroxypiperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzoimidazol-2-yl) -4-hydroxypiperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) -trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (3- (4-fluorophenoxy) propyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (3- (4-fluorophenoxy) propyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (3- (4-fluorophenoxy) propyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1-furan-3-ylmethyl) -1H-benzisoimidazole-2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-oxobutyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (2-oxobutyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-oxobutyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-oxobutyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1-methyl-1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1-methyl-1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1-methyl-1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (3- (4-carboxyphenyl) propyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (3- (4-carboxyphenyl) propyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (3- (4-carboxyphenyl) propyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-oxopropyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (2-oxopropyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-oxopropyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-oxopropyl) -1H-benzimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (5-methylfuran-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (5-methylfuran-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (5-methylfuran-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (5-methylfuran-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (4-carboxybenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (4-carboxybenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (4-carboxybenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (4-carboxybenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (4-carboxybenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (4-carboxybenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (4-methoxycarbonylbenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (4-methoxycarbonylbenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (4-methoxycarbonylbenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (4-methoxycarbonylbenzyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (3-ethoxycarbonylpropyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (3-ethoxycarbonylpropyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (3-ethoxycarbonylpropyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (morpholin-4-yl) ethyl) -1H-benzoimidazole-2-carbonyl) -piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4-benzhydrylidenepiperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4-benzhydrylidenepiperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (furan-3-ylmethyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1-ethyl-1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1-propyl-1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1-butyl-1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-carboxyethyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (thiophen-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (dimethylamino) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2-phenoxyethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (imidazol-2-ylmethyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (3, 3-dimethylallyloxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2-allyloxyethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (2-allyloxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dimethoxyphenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-difluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (4, 4, 4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (allyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (allyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (allyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (allyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (allyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (allyl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (but-2-en-1-yl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (but-2-en-1-yl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (but-2-en-1-yl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (but-2-en-1-yl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (but-2-en-1-yl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (but-2-en-1-yl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

N-methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;

N-methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide;

N-methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;

N-methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;

a common synthetic method for preparing these compounds of formula (1) is shown in scheme A. Reagents and starting materials are readily available to those of ordinary skill in the art. In reaction scheme a, all substituents are as defined above, unless otherwise indicated. Reaction scheme A

In step 1 in reaction scheme A, the hydroxy group of a suitable alcohol of formula 2 may be converted to a suitable leaving group to provide a compound of formula 2 a. A suitable alcohol of formula 2 is one in which the stereochemistry is as required in the final product of formula (1), and R', R "and Ar are also as required in the final product of formula (1). Alternatively, a suitable alcohol of formula 2 may be a compound whose stereochemistry is resolved to give the stereochemistry as required in the final product of formula (1), and R ', R' and Ar are also as required in the final product of formula (1). Suitable alcohols of formula 2 may also be compounds in which stereochemistry, R 'and R' are as required in the final product of formula (1) and Ar₁Deprotection to give the desired Ar in the compound of formula (1)₁. Alternatively, suitable alcohols of formula 2 may also be compounds wherein the stereochemistry after resolution gives the stereochemistry required in the final product of formula (1), R 'and R' are as required in the final product of formula (1), and Ar is₁Deprotection to give Ar as required in the final product of formula (1)₁。

Suitable alcohols of formula 2 may be prepared using the methods described herein and methods well known in the art, for example, U.S. Pat. Nos. 5317020 and 5236921, which are incorporated herein by reference; european patent applications 0428434 (published 5/22/1991), 0630887 (published 12/28/1994), 0559538 (published 9/8/1993); PCT applications WO9417045 (published 8/4 1994) and WO95415961 (published 6/15 1995); andbiological organic&Pharmaceutical chemistry Communication， 3，925-930(1993)。

Suitably away fromRemoving the group L₁Can be replaced by piperidine of formula 3 to give compounds of formula (1). Suitable leaving groups L₁Including, but not limited to, chlorine, bromine, iodine, mesylate, tosylate, besylate, and the like. Conversion of hydroxyl groups to leaving groups such as chloro, bromo, iodo, mesylate, tosylate and besylate are well known in the art.

For example wherein L₁The compound that is bromine can be formed by contacting the appropriate alcohol of formula 2 with 1.0 to 1.5 molar equivalents of carbon tetrabromide and 1.75 molar equivalents of triphenylphosphine. (P.J.Kocienski et al,organic compounds Chemical journal， 42,353-355(1977)). The reaction is carried out by mixing the alcohol of formula 2 with carbon tetrabromide in a suitable solvent, such as dichloromethane or chloroform, and then adding a solution of triphenylphosphine in a suitable solvent, such as dichloromethane or chloroform. Typically, the reaction is carried out at a temperature of-10 ℃ to room temperature. Generally, the reaction takes from 5 minutes to 24 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Wherein L is₁Compounds that are bromine can also be formed by contacting the appropriate alcohol of formula 2 with a slight molar excess of triphenylphosphine dibromide. (R.F. Borch et al,american society of chemistry， 99,1612-1619(1977)). This reaction can be carried out by contacting the appropriate alcohol of formula 2 with the preformed triphenylphosphine dibromide. The reaction is carried out in a suitable solvent, such as tetrahydrofuran and diethyl ether. The reaction is carried out in the presence of a suitable base, such as pyridine. Typically, the reaction is carried out at a temperature of from 0 ℃ to 50 ℃. Generally, the reaction takes from 5 minutes to 24 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Or, for example, wherein L₁The compound that is a mesylate may be formed by contacting the appropriate alcohol of formula 2 with a slight molar excess of methanesulfonyl chloride. The reaction is carried out in a suitable solvent such as dichloromethane, chloroform, toluene, benzene or pyridine. The reaction is carried out in a suitable base, e.g. triethylIn the presence of an amine, diisopropylethylamine or pyridine. The reaction is generally carried out at room temperature from-20 ℃ to 50 ℃. Generally, the reaction takes from 1 hour to 24 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Wherein L is₁The compound of formula 2a which is iodine may be prepared from wherein L₁The compound of formula 2a, which is a mesylate, chloride or bromide, is prepared by a metathesis reaction, such as the Finkelstein reaction.

For example, will wherein L₁The compound of formula 2a, which is a mesylate, chlorine or bromine, is contacted with 1.0 to 10.0 molar equivalents of an iodide salt, such as sodium iodide or potassium iodide. The reaction is carried out in a suitable solvent, such as acetone, butanone, tetrahydrofuran/water mixtures, toluene and acetonitrile. The reaction is generally carried out at room temperature to the reflux temperature of the solvent. Generally, the reaction takes from 1 to 24 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In step 2 of scheme A, a compound of formula 2a is reacted with an appropriate piperidine compound of formula 3 or a salt thereof to provide a protected compound of formula (1) or a compound of formula (1).

A suitable piperidine or salt thereof of formula 3 is wherein X₁And X₂As required in the final product of formula (1) or X₁And X₂Modified or deprotected to give the compound as claimed in the final product of formula (1). Suitable piperidines of formula 3 are well known in the art and are described in International patent application (PCT) WO92/06086, U.S. Pat. No. 4908372(1990 month 3, day 13), U.S. Pat. No. 4254129(1981 year 3, day 3), U.S. Pat. No. 4254130(1981 year 3, day 3), U.S. Pat. No. 4285958(1981 year 4, month 25), U.S. Pat. No. 4550116(1985 year 10, month 29), and European patent application 0533344(1993 year 3, month 24; analogous to these procedures, are prepared by suitable deprotection, protection and alkylation as is well known in the art, in the order and number required to form the appropriate piperidine of formula 3. Wherein X₁And Z₁Together with X₁And Z₁The piperidine of formula 3 having another bond formed between carbon atoms thereof may be prepared by reacting a compound of formula (I) wherein X₁The corresponding compound, which is a hydroxyl group, is prepared by dehydration using methods conventional in the art, such as refluxing in a strong acid solution. Suitable piperidines of formula 3 can also be prepared by adding a readily available organometallic compound reagent to a suitably protected 4-piperidone or a suitably protected isonipecotic acid derivative, using methods known in the art, such as g.d. maynard et al,biological organisms Organic and pharmaceutical chemical communication， 3753-756 (1993). Suitable piperidines of formula 3 can also be prepared from readily available starting materials or by analogous methods known in the art, such as c.g.wahlgren and a.w.addison,journal of heterocyclic chemistry， 26541 (1989); r.iemura and h.ohtka, proceedings of medicinal chemistry, 37, 967-; and K.Ito and G.Tsukamoto,journal of heterocyclic chemistry， 2431(1987), by suitable deprotection, protection and alkylation as is well known in the art, in the order and number required to form the appropriate piperidine of formula 3.

For example, contacting a compound of formula 2a with an appropriate piperidine compound of formula 3 or a salt thereof, provides a protected compound of formula (1) or a compound of formula (1). The reaction is carried out in a suitable solvent, such as dioxane, tetrahydrofuran/water mixtures, acetone/water mixtures, ethyl acetate/water mixtures, pyridine, acetonitrile, toluene/water mixtures, chlorobenzene or dimethylformamide. The reaction is carried out in the presence of 1.0 to 6.0 molar equivalents of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, pyridine or diisopropylethylamine. When a salt of a suitable piperidine of formula 3 is employed, an additional molar excess of a suitable base is employed. The reaction is facilitated by the addition of a catalytic amount of 0.1-0.5 molar equivalents of an iodide salt, such as sodium iodide, potassium iodide or tetrabutylammonium iodide. The reaction is generally carried out at room temperature to the reflux temperature of the solvent. Generally, the reaction takes from 1 to 72 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In optional step 3 of reaction scheme A, a compound of formula (1) or a protected compound of formula (1) wherein Z is hydrogen is modified to provide a compound of formula (1) or a protected compound of formula (1) wherein Z is not hydrogen. Optional step 3, deprotection of the protected compound of formula (1) to give the compound of formula (1) is also included in reaction scheme a.

The modification reaction includes the formation of an amide and the nitrogen alkylation of the benzimidazole. The formation of amides from esters and acids is well known in the art. Alkylation of benzimidazole nitrogen using suitable alkylating agents is also well known in the art. The reaction is carried out in a suitable solvent, such as dioxane, tetrahydrofuran/water mixtures, acetone or acetonitrile. Suitable alkylating agents are those which can react the end product, the group Z or (CH) as claimed in formula (1)₂)_pAr₂Or protected Z or (CH)₂)_pAr₂(deprotection provides the desired Z or (CH) in the final compound of formula (1)₂)_pAr₂) Alkylating agent to carry out the conversion. The reaction is carried out in the presence of 1.0 to 6.0 molar equivalents of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, 1, 8-diazabicyclo [5.4.0]Undec-7-ene, 1, 5-diazabicyclo [4.3.0]Non-5-ene, potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, or diisopropylethylamine. The reaction is generally carried out at room temperature to the reflux temperature of the solvent. Generally, the reaction takes from 1 to 72 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Alternatively, a compound of formula (1) or a protected compound of formula (1) wherein Z is hydrogen and bears a benzimidazole-2-carbonyl group may be alkylated by a Mitsunobu reaction using a suitable alcohol. Suitable alcohols are the radicals Z or (CH) required in the end product formula (1)₂)_pAr₂Or protected Z or (CH)₂)_pAr₂(deprotection provides the desired Z or (CH) in the final compound of formula (1)₂)_pAr₂) The alcohol undergoing conversion.

Using suitable protecting groups, e.g. T.Greene inProtecting groups in organic synthesisSubjecting those groups described in (1) to deprotection reactions, such as removal of a hydroxyl protecting group or hydrolysis of an ester, is well known in the art.

A common synthetic method for preparing the alcohol of formula 2 is shown in reaction scheme B. The reagents and raw materials are all easily available to one of ordinary skill in the art. In scheme B, all substituents are as previously defined unless otherwise indicated. Reaction scheme B

In step 1 of reaction scheme B, an appropriate nitrile of formula 5 is alkylated with an appropriate protected alcohol of formula 4 to provide a 4- (protected hydroxy) butanenitrile of formula 6.

Suitable nitriles of formula 5 are those wherein Ar₁Is as claimed in the final product formula (1) or after deprotection to give Ar as claimed in the final product formula (1)₁A nitrile of (a). A suitable protected alcohol of formula 4 is one wherein the leaving group L₂Alcohols that can be displaced by anions derived from suitable nitriles of formula 5. Suitable leaving groups include, but are not limited to, chloro, bromo, iodo and mesylate, with bromo and iodo being preferred. For the appropriate hydroxyl protecting group Pg₁(e.g., in T.GreeneProtecting groups in organic synthesisThose described in (1) are well known in the art. In general, tetrahydropyran-2-yl and tert-butyldisilylhydroxy protecting groups are preferably used.

For example, a suitable nitrile of formula 5 is contacted with 0.8 to 1.2 molar equivalents of a suitable protected alcohol of formula 4 under phase transfer catalysis conditions. The reaction is carried out in the presence of a 1-to 10-fold molar excess of a suitable base, such as sodium hydroxide or potassium hydroxide. The reaction is carried out in a solvent such as water, an ethyl acetate/water mixture, a dichloromethane/water mixture or a tetrahydrofuran/water mixture. The reaction is carried out in the presence of a suitable phase transfer catalyst, such as benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltrimethylammonium chloride, benzyltributylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, and the like. The reaction is generally carried out at a temperature of-20 ℃ to 60 ℃. The reaction usually takes from 1 to 72 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Alternatively, for example, the suitable nitrile of formula 5 is contacted with 1.0 to 1.2 molar equivalents of the suitable protected alcohol of formula 4. The reaction is carried out in the presence of equimolar amounts of a suitable base such as sodium hydride, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, potassium tert-butoxide, sec-butyllithium and lithium diisopropylamide. The reaction is carried out in a solvent such as dimethylformamide or tetrahydrofuran. The reaction is generally carried out at-78 ℃ to 0 ℃. The reaction usually takes from 1 to 72 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In step 2 of reaction scheme B, the 4- (protected hydroxy) butanenitrile of formula 6 is reduced to provide the amino compound of formula 7.

For example, contacting the 4- (protected hydroxy) butyronitrile of formula 6 with an excess of a suitable reducing agent, such as sodium borohydride in the presence of cobalt (II) chloride; or with hydrogen in the presence of a suitable catalyst, such as raney nickel or platinum oxide. For Ar in the₁For compounds of formula 6 that are thienyl or pyridyl, sodium borohydride in the presence of cobalt (II) chloride hexahydrate is preferably employed.

When sodium borohydride is used in the presence of cobalt chloride, the reaction is carried out in a suitable solvent, such as methanol or ethanol. The reaction is generally carried out at a temperature of from 0 ℃ to 50 ℃. Generally, the reaction takes from 1 to 72 hours. The product may be isolated and purified by techniques well known in the art, such as aqueous acid extraction, evaporation, trituration, chromatography and recrystallization.

When Raney nickel is used, the reaction is carried out in a suitable solvent containing ammonia, such as ethanol/aqueous ammonium hydroxide or methanol/aqueous ammonium hydroxide. The reaction is generally carried out at a temperature of from room temperature to 70 ℃. The reaction is carried out under a hydrogen pressure of 15 psig to 120 psig in a pressure-resistant vessel such as a Parr hydrogenation apparatus. The product was isolated by carefully removing the catalyst by filtration and evaporation. The product can be purified by extraction, evaporation, trituration, chromatography and recrystallization.

When platinum oxide is employed, the reaction is carried out in a suitable solvent, such as ethanol, methanol, chloroform, an ethanol/chloroform mixture or a methanol/chloroform mixture. The reaction is generally carried out at a temperature of from room temperature to 50 ℃. The reaction is carried out under a hydrogen pressure of 15 psig to 120 psig in a pressure-resistant vessel such as a Parr hydrogenation apparatus. The reaction usually takes 8 to 48 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.

In step 3 of reaction scheme B, the amino compound of formula 7 is benzoylated with a suitable benzoylating reagent to provide the benzamide of formula 8. Suitable benzoylating reagents are capable of transferring a benzoyl or substituted benzoyl group to give a compound of formula 8 benzamide, such as benzoyl halide, substituted benzoyl halide, benzoic anhydride, substituted benzoic anhydride, mixed anhydrides of benzoic acid or mixed anhydrides of substituted benzoic acid. Suitable benzoylation reagents give benzamides of formula 8 wherein R' and R "are as claimed in the final product formula (1).

For example, the amino compound of formula 7 is contacted with 1 to 1.5 molar equivalents of a suitable benzoylating reagent. The reaction is carried out in a suitable solvent, such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide or pyridine. The reaction is carried out in the presence of a base, such as sodium carbonate, sodium bicarbonate, triethylamine, N-methylmorpholine, diisopropylethylamine or pyridine. The reaction is generally carried out at a temperature of-20 ℃ to 50 ℃. Generally, the reaction takes 1 to 6 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Alternatively, for example, the amino compound of formula 7 can be reacted with 1-1.5 molar equivalents of a suitable benzoylating agent under Schotten-Baumann conditions. The reaction is carried out in a suitable solvent, such as an ethyl acetate/water mixture, an acetone/water mixture, a tetrahydrofuran/water mixture or a dichloromethane/water mixture. The reaction is carried out in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or sodium hydroxide. The reaction is generally carried out at a temperature of from 0 ℃ to the reflux temperature of the solvent. Generally, the reaction takes 1 to 6 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In step 4 of reaction scheme B, the benzamide of formula 8 is methylated with a suitable methylating agent to provide the N-methylbenzamide of formula 9. Suitable methylating agents are compounds which transfer a methyl group to the benzamide of formula 8 and include methyl iodide, methyl bromide, dimethyl sulfonate, trimethyloxonium tetrafluoroborate, and the like.

For example, the benzamide of formula 8 is contacted with 1 to 4 molar equivalents of a suitable methylating agent. The reaction is carried out in the presence of 1 to 4 molar equivalents of a suitable base, such as n-butyllithium, sec-butyllithium, sodium hydride, sodium bis (trimethylsilyl) amide, potassium tert-butoxide, and lithium diisopropylamide, but sodium hydride, sodium bis (trimethylsilyl) amide, and sec-butyllithium are preferred. The reaction is carried out in a solvent such as dimethylformamide or tetrahydrofuran. The reaction is generally carried out at-20 ℃ to 60 ℃. Generally, the reaction takes from 1 to 72 hours. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In step 5 of reaction scheme B, the N-methylbenzamide of formula 9 is deprotected to provide the alcohol of formula 2. Deprotection reactions, e.g. removal of hydroxy protecting groups using suitable protecting groups, e.g. T.Greene inProtecting groups in organic synthesisThose reactions described in (a) are well known in the art.

The following examples and preparations represent typical syntheses of compounds of formula (1). These examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Preparation example 1

Synthesis of 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide

Piperidine-4-carboxylic acid (500g), water (4.2L), tert-butanol (4L) were mixed with 50% aqueous sodium hydroxide (386 g). Di-tert-butyl dicarbonate (di-t-butyldicarbonate) (930g) was added in portions. After 20 hours, the reaction mixture was concentrated in vacuo to about half volume. A 10% hydrochloric acid solution was slowly added to a pH of about 4. Extract with diethyl ether (3X 4L). The organic layer was dried over magnesium sulfate, filtered and evaporated on a steam bath to about 4L. Ethyl acetate (4L) was added and evaporated on a steam bath to about 4L. Filtered and evaporated again on a steam bath to about 2L. Cooled and filtered to give 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid.

1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (813.7g) was combined with dichloromethane (6L). Carbonyldiimidazole (633.1g) was added in portions. After 1 hour, N-methyl-O-methylhydroxylamine hydrochloride (380.5g) was added. After 56 hours, the reaction mixture was extracted with 5% aqueous hydrochloric acid and 5% aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give 1- (tert-butoxycarbonyl) piperidine-4- (N-methyl-O-methyl) hydroxamic acid.

Benzimidazole (57.8g, 490mmol) was mixed with dimethylformamide (570 ml). Cooled to about 20 ℃ with an ice bath. Sodium hydride (20.2g, 60% oil dispersion, 500mmol) was added in portions at a rate to maintain the temperature of the reaction mixture at about 20 ℃. After the addition of sodium hydride was complete, it was allowed to stir for 1 hour. A solution of 2- (trimethylsilyl) ethoxymethyl chloride (60g, 360mmol) in dimethylformamide (60ml) was added at a rate to maintain the reaction temperature below about 20 ℃. After 18 hours, water (50ml) was added dropwise. After the addition was complete, the reaction mixture was poured into water (2L). The extraction was repeated with diethyl ether. The organic layers were combined and extracted with water. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to yield 1- ((2-trimethylsilyl) ethoxymethyl) -1H-benzimidazole.

1- ((2-trimethylsilyl) ethoxymethyl) -1H-benzimidazole (91.2g, 367mmol) was combined with tetrahydrofuran (500 ml). Cooled to-78 ℃ with a dry ice/acetone bath. A solution of n-butyllithium (146ml, 2.5M in hexane, 367mmol) was added at a rate to maintain the reaction temperature below about-70 ℃. After the addition of n-butyllithium was complete, it was stirred at-78 ℃ for 30 minutes. A solution of 1- (tert-butoxycarbonyl) piperidine-4- (N-methyl-O-methyl) hydroxamic acid (99.9g, 367mmol) in tetrahydrofuran (100ml) was added dropwise. Warm to room temperature. After 18 hours, saturated aqueous ammonium chloride (100ml) was added dropwise. Water (300ml) was added and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 10% ethyl acetate/hexanes provided a residue. The residue was recrystallized from methanol/water to give 1- (tert-butoxycarbonyl) -4- (1- ((2-trimethylsilyl) ethoxymethyl) -1H-benzimidazole-2-carbonyl) piperidine.

(1- (tert-Butoxycarbonyl) -4- (1- ((2-trimethylsilyl) ethoxymethyl) -1H-benzimidazole-2-carbonyl) piperidine (20.0g, 43.5mmol) was added portionwise to an aqueous solution of hydroiodic acid (48%, 140ml), after the addition was complete, heated to 50 ℃ for 1.5 hours, cooled to room temperature after 2.5 hours, extracted twice with diethyl ether, diethyl ether (300ml) and isopropanol (60ml) were added to the aqueous layer to give a solid, which was collected by filtration and rinsed with diethyl ether to give the title compound₁₃H₁₅N₃Theoretical value of elemental analysis of o.2hi: c32.19; h3.53; n8.66; measured value: c32.24; h3.37; and N8.48.

Preparation example 2

Synthesis of 1- (tert-butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine

4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide (9.17g, 18.9mmol) was combined with tert-butanol (100 ml). Aqueous sodium bicarbonate (40ml, 1M, 40mmol) was added. Di-tert-butyl dicarbonate (5.2g, 23.9mmol) was added. After 72 hours, concentrate in vacuo to give a residueA compound (I) is provided. The residue was mixed with ethyl acetate. Extraction was performed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, 0.5M aqueous sodium thiosulfate and brine. The separated organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give a solid. The solid was triturated with ether, the solid collected by filtration, recrystallized from ethyl acetate, collected and dried to give the title compound: melting point 226-. R_f0.30 (silica gel, 20% ethyl acetate/hexane).

Preparation example 3

Synthesis of 4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodide

1- (tert-Butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine (2.0g, 6.1mmol), 2- (chloromethyl) pyridine (2.32g, 18.2mmol) (obtained by mixing and stirring 2- (chloromethyl) pyridine hydrochloride, sodium carbonate and dichloromethane, then filtering and evaporating) and potassium carbonate (4.2g, 30.4mmol) were mixed in acetone (40ml) and water (10 ml). Heated to reflux. After 24 hours, cool to room temperature and dilute with ethyl acetate. Extracting with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 50% ethyl acetate/hexanes to give 1- (tert-butoxycarbonyl) -4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine: the melting point is 45-50 ℃. R_f0.24 (silica gel, 40% ethyl acetate/hexane). C₂₄H₂₈N₄O₃Theoretical value of elemental analysis of (1): c68.08; h6.74; n13.23; measured value: c67.88; h6.68; and N13.00.

1- (tert-Butoxycarbonyl) -4- (1- (piperidin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine (1.96g, 4.7mmol) was combined with dichloromethane (150 ml). Cooled to 0 ℃ with an ice bath. Hydroiodic acid (gas) was added until the solution was saturated and stirred. After 30 minutes, hydroiodic acid (gas) was added again until the solution was saturated. After 2 hours, evaporation in vacuo and drying gave the title compound: melting point 165-.

Preparation example 4

Synthesis of 1- (tert-butyldisilyloxy) -2-bromoethane

Imidazole (59.5g, 880mmol), tert-butyldimethylsilyl chloride (60.3g, 400mmol) and dimethylformamide (300ml) were combined. Cooled to 0 ℃ in an ice salt bath. 2-Bromoethanol (50.0g, 400mmol) was added dropwise at such a rate that the temperature of the reaction mixture did not exceed 0 ℃. After 2 hours, warm to room temperature. After 18 hours, the reaction mixture was extracted three times with hexane. The hexane layers were combined and extracted three times with saturated aqueous ammonium chloride solution, three times with saturated aqueous sodium bicarbonate solution, and then with brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Preparation example 5

Synthesis of 1- (tert-butyldisilyloxy) -2-iodoethane

Prepared by the method of preparation 4 using 2-iodoethanol to give the title compound.

Example 1

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide

1.1.12 Synthesis of- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyronitrile

By usingOrganic synthesis assembly, Volume VI (org. Syn. Collection Volume VI)897-900(1988), 4-fluorophenylacetonitrile (56.5g, 418mmol), 50% aqueous sodium hydroxide (106.3g, 1330mmol) and benzyltriethylammonium chloride (0.95g) were mixed in water (100 ml). Warmed to about 30 ℃ and stirred vigorously. 1- (tert-butyl) was added dropwise over about 30 minutesDimethylsiloxy) -2-bromoethane (50g, 209 mmol). After the addition was complete, the mixture was warmed to about 40 ℃ and stirred vigorously. After 18 hours, the reaction mixture was diluted with ethyl acetate and stirred. After 30 minutes, the organic layer was separated and extracted three times with saturated aqueous ammonium chloride solution, twice with saturated aqueous sodium bicarbonate solution and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was distilled to give the title compound: boiling point 100 and 115 deg.C (0.2 mmHg). R_f0.35 (silica gel, 1/1 dichloromethane/hexane).

1.1.1 Synthesis of 22- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyronitrile

4-Fluorophenylacetonitrile (5.0g, 37.0mmol) was mixed with tetrahydrofuran (45 ml). Cooled to-65 ℃ with a dry ice/acetone bath. A solution of potassium bis (trimethylsilyl) amide (89ml, 0.5M in toluene, 44.5mmol) was added. After 1 hour, a solution of 1- (tert-butyldisilyloxy) -2-iodoethane (12.7g, 44.4mmol) in tetrahydrofuran (10ml) was added. After the addition of 1- (tert-butyldisilyloxy) -2-iodoethane, the mixture was warmed to room temperature. After 18 hours, the reaction mixture was diluted with tetrahydrofuran, extracted 3 times with saturated aqueous ammonium chloride solution and 2 times with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel with 1/1 dichloromethane/hexane to give the title compound.

1.1.32 Synthesis of- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyronitrile

4-Chlorophenylacetonitrile (1.0g, 7.4mmol) and tetrahydrofuran (9ml) were mixed. Cooled to-70 ℃ with a dry ice/acetone bath. A solution of potassium bis (trimethylsilyl) amide (14.8ml, 0.5M in toluene, 7.4mmol) was added. After 2 hours, the solution prepared above was added by cannula to a cooled (-25 ℃ C.) solution of 1- (tert-butyldisilyloxy) -2-iodoethane (2.1g, 7.4mmol) in tetrahydrofuran (4 ml). After the addition of 1- (tert-butyldisilyloxy) -2-iodoethane was completed, the mixture was warmed to room temperature. After 18 hours, the reaction mixture was diluted with tetrahydrofuran and extracted three times with saturated aqueous ammonium chloride solution, then twice with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 1/1 dichloromethane/hexanes afforded the title compound.

1.1.42 Synthesis of- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyronitrile4-Fluorophenylacetonitrile (1.0g, 7.4mmol) and tetrahydrofuran (20ml) were mixed. Cooled to-70 ℃ with a dry ice/acetone bath. Sec-butyllithium solution (6.3ml, 1.3M cyclohexane solution, 8.1mmol) was added. After 1 hour, a solution of 1- (tert-butyldisilyloxy) -2-iodoethane (2.1g, 7.4mmol) in tetrahydrofuran (4ml) was added. After 2 hours, warm to room temperature. After 18 hours, the reaction mixture was mixed with ethyl acetate and extracted twice with saturated aqueous ammonium chloride solution and then twice with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 1/1 dichloromethane/hexanes afforded the title compound.

1.22 Synthesis of- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butylamine

2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butanenitrile (43.0g, 146.5mmol) was mixed with ethanol (200ml) in a Pal flask. Raney nickel (129g) was added to the reaction mixture. Concentrated ammonium hydroxide solution (40ml) was added. Hydrogenation was carried out in a Parr shaker at 50 psig. After 24 hours, filter through a pad of celite and rinse the solids with ethanol. The filtrate was concentrated in vacuo to give the title compound.

1.3N- (2- (4-fluorophenyl) -4- (tert-butyldimethylsiloxy) butyl) -3, 4, 5-trimethoxybenzyl Synthesis of amides

2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butylamine (7.33g, 24.6mmol) and sodium carbonate (2.61g, 24.6mmol) were combined in 4/1 ethyl acetate/water (400 ml). The reaction mixture was cooled to 0 ℃ with an ice salt bath. Slowly adding 3, 4, 5-trimethyl in such a rate that the temperature of the reaction mixture does not exceed about 5 deg.CA solution of oxybenzoyl chloride (5.96, 25.9mmol) in ethyl acetate (50 ml). After 2 hours, warm to room temperature. After 18 hours, the layers were separated and the organic layer was extracted twice with saturated aqueous ammonium chloride, twice with saturated aqueous sodium bicarbonate and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 50% ethyl acetate/hexane to give, after drying, the title compound: melting point 113-. R_f=0.30 (silica gel, 50% ethyl acetate/hexane). C₂₆H₃₈FNO₃Elemental analysis theoretical value of Si: c63.51; h7.79; n2.85; measured value: c63.43; h7.51; and (6) N2.66.

1.4N-methyl-N- (2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl-3, 4, 5-trimethoxy-N-methyl Synthesis of phenylbenzamides

Hexane-washed sodium hydride (0.48g, 50% in oil, 10.0mmol) was mixed with dimethylformamide (5 ml). The reaction mixture was cooled to 0 ℃ with an ice salt bath. A solution of N- (2- (4-fluorophenyl) -4- (t-butyldimethylsilyloxy) butyl-3, 4, 5-trimethoxybenzamide (4.0g, 8.1mmol) in dimethylformamide (10ml) was added slowly, stirring was continued until no more air bubbles appeared, iodomethane (0.62ml, 10.0mmol) was added after 16 h, the reaction mixture was diluted with ethyl acetate and extracted three times with water, then extracted with brine, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue which was chromatographed on silica gel, eluted with 1/1 ethyl acetate/hexane and dried to give the title compound R_f=0.15 (silica gel, 1/1 ethyl acetate/hexane). C₂₇H₄₀FNO₃Elemental analysis theoretical value of Si: c64.13; H7.97N2.77, respectively; measured value: c63.73; h7.90; and (6) N2.88.

1.5 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide

Reacting N-methyl-N- (2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl-3, 4, 5-trimethoxy-benzylThe amide (3.9g, 7.65mmol) was combined with methanol (40 ml). Ammonium fluoride (1.71g, 46.0mmol) was added. Heated to reflux. After 20 hours, concentrate in vacuo to give a residue. The residue was mixed with water and dichloromethane. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound: the melting point is 30-35 ℃. R_f=0.30 (silica gel, 10/1 ethyl acetate/methanol).

1.6N-methyl-N- (2- (4-fluorophenyl) -4-methylsulfonylbutyl) -3, 4, 5-trimethoxybenzamide Synthesis of (2)

N-methyl-N- (2- (4-fluorophenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide (2.5g, 6.36mmol), diisopropylethylamine (2.4ml, 14.0mmol) and anhydrous dichloromethane (25ml) were combined. The reaction mixture was cooled to 0 ℃ with an ice bath. Methanesulfonyl chloride (0.69ml, 8.9mmol) was added slowly. After 1 hour, the reaction mixture was diluted with dichloromethane and extracted three times with 1M aqueous hydrochloric acid, twice with saturated sodium bicarbonate solution and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound: r_f=0.43 (silica gel, 10/1 ethyl acetate/methanol).

1.7N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid Synthesis of yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide

N-methyl-N- (2- (4-fluorophenyl) -4-methylsulfonylbutyl) -3, 4, 5-trimethoxybenzamide (0.37g, 0.79mmol), diisopropylethylamine (1.23ml, 7.1mmol) and 4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodide (0.83g, 1.2mmol) were combined in acetonitrile (15 ml). Heated to reflux. After 18 hours, the reaction mixture was cooled, diluted with ethyl acetate and extracted with saturated sodium bicarbonate solution, then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue is chromatographed on silica gel, eluting with 10/0.3/89.7 methanol/concentrated aqueous ammonia/dichloromethane, and dried to give the title compound.

Preparation example 6

Synthesis of 1- (tetrahydropyran-2-yloxy) -2-bromoethane

2-Bromoethanol (14.2ml, 200mmol) and dihydropyran (18.25ml, 200mmol) were mixed in dichloromethane (20 ml). Pyridinium p-toluenesulfonate (5g, 20mmol) was added. After 2.5 hours, the reaction mixture was diluted with ether and extracted with water, 1/1 water/brine, water, then brine. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue. Distillation of the residue gave the title compound: boiling point 80-90 deg.C (15-20 mmHg).

Example 2

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4- Dichlorophenyl) butyl) benzamide

2.12 Synthesis of (3, 4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butanenitrile

Sodium hydride (1.2g, 50mmol) and tetrahydrofuran (20ml) were combined. A solution of 3, 4-dichlorophenylacetonitrile (8.9g, 47.8mmol) in tetrahydrofuran (50ml) was added dropwise at about 0 ℃. After the addition was complete, it was allowed to warm to room temperature and stirred. After 2.5 h, cool to 0 ℃ and add 1- (tetrahydropyran-2-yloxy) -2-bromoethane (10.0g, 47.9 mmol). Warm to room temperature. After 16 hours, the reaction mixture was poured into saturated ammonium chloride and extracted with ether. The organic layer was separated and extracted with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting sequentially with 5% ethyl acetate/hexane, 10% ethyl acetate/hexane and 20% ethyl acetate/hexane afforded the title compound.

2.2 Synthesis of 22- (3, 4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butylamine

2- (3, 4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butanenitrile (7g) and ethanol (20ml) were mixed in a Pal bottle. Raney nickel (1g) was added to the reaction mixture. Concentrated ammonium hydroxide solution (3.5ml) was added. Hydrogenation was carried out at 50psi in a Parr shaker. After 24 hours, filter through a pad of celite and rinse the solids with ethanol. The filtrate was concentrated in vacuo to give a residue. The residue was chromatographed on silica gel sequentially eluting with 50% ethyl acetate/hexane and 10% methanol/dichloromethane to give the title compound.

2.3 Synthesis of N- (2- (3, 4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butyl) benzamide

2- (3, 4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butylamine (3.05g, 9.6mmol) and N-methylmorpholine (2.2ml, 20mmol) were combined in dry dichloromethane (25 ml). The reaction mixture was cooled to 0 ℃ with an ice salt bath. Benzoyl chloride (1.2ml, 10.3mmol) was added slowly. After 1 hour, the reaction mixture was extracted with saturated sodium bicarbonate and then with water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting sequentially with 35% ethyl acetate/hexane and 50% ethyl acetate/hexane afforded the title compound.

Process for preparing 4N-methyl-N- (2- (3, 4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butyl) benzamide Synthesis of

N- (2- (3, 4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butyl) benzamide (3.84g) was mixed with tetrahydrofuran (20 ml). Sodium hydride (0.28g, 11.5mmol) was added and stirred until no more air bubbles were bubbled. Methyl iodide (1.5ml, 24.1mmol) was added. After 6 hours, the reaction mixture was diluted with ether and extracted with saturated ammonium chloride solution. The organic layer was separated and extracted with sodium bisulfite solution, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound.

2.5 Synthesis of N-methyl-N- (2- (3, 4-dichlorophenyl) -4-hydroxybutyl) benzamide

N-methyl-N- (2- (3, 4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butyl) benzamide (3.7g) was mixed with methanol (30 ml). Hydrated p-toluenesulfonic acid (0.73g) was added and stirred. After 18 hours, concentrate in vacuo to give a residue. The residue was mixed with dichloromethane and extracted with saturated sodium bicarbonate solution, then with water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel sequentially with 50% ethyl acetate/hexane and then hexane afforded the title compound.

Synthesis of N-methyl-N- (2- (3, 4-dichlorophenyl) -4- (methylsulfonylbutyl) benzamide

N-methyl-N- (2- (3, 4-dichlorophenyl) -4-hydroxybutyl) benzamide (0.5g), diisopropylethylamine (0.3ml, 1.7mmol) and anhydrous dichloromethane (8ml) were mixed. The reaction mixture was cooled to 0 ℃ with an ice bath. Methanesulfonyl chloride (0.13ml, 1.7mmol) was added slowly. Warm to room temperature. After 18 hours, ice was added to quench the reaction. The organic layer was separated, extracted three times with 1M hydrochloric acid solution and twice with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound.

2.7N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Synthesis of (3, 4-dichlorophenyl) butyl) benzamide

N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) benzamide (0.6g, 1.4mmol), sodium bicarbonate (0.23g, 2.8mmol) and 4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piridine trifluoroacetate (0.63g, 1.4mmol) were combined in tetrahydrofuran (15ml) and water (5 ml). Heated to reflux. After 3 days, the reaction mixture was cooled, diluted with ethyl acetate and extracted with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel sequentially eluting with 10% toluene/ethyl acetate, then 10% ethanol/10% toluene/ethyl acetate to give, after drying, the title compound: the melting point is 65-70 ℃.

2.8N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Synthesis of (3, 4-dichlorophenyl) butyl) benzamide hydrochloride

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide (0.71g, 1.4mmol) was mixed with methanol (10 ml). A saturated solution of hydrochloric acid in diethyl ether (3ml) was added. Evaporation in vacuo gave a residue. The residue was mixed with butanone (5ml) and diethyl ether was added slowly to give a solid. The solid was collected and dried to give the title compound.

Example 3

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazol-2-yl) -4-hydroxypiperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide

3.12 Synthesis of- (4-methoxyphenyl) -4- (tert-butyldisilyloxy) butanenitrile

Prepared by the method of example 1.1.1 using 4-methoxyphenylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

3.4 Synthesis of 4- (4-methoxyphenyl) -4- (tert-butyldisilyloxy) butylamine

Prepared by the method of example 1.2 using 2- (4-methoxyphenyl) -4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

3.3 N-(2Synthesis of (4-methoxyphenyl) -4- (tert-butyldisilyloxy) butyl) benzamide Become into

Prepared by the method of example 1.3 using 2- (4-methoxyphenyl) -4- (tert-butyldisilyloxy) butylamine and benzoyl chloride to give the title compound.

3.4N-methyl-N- (2- (4-methoxyphenyl) -4- (tert-butyldisilyloxy) butyl) benzoyl Synthesis of amines

Prepared by the method of example 1.4 using N-2- (4-methoxyphenyl) -4- (tert-butyldisilyloxy) butyl) benzamide to give the title compound.

3.5 Synthesis of N-methyl-N- (2- (4-methoxyphenyl) -4-hydroxybutyl) benzamide

Prepared by the method of example 1.5 using N-methyl-N-2- (4-methoxyphenyl) -4- (tert-butyldisilyloxy) butyl) benzamide to give the title compound.

3.6 Synthesis of N-methyl-N- (2- (4-methoxyphenyl) -4-methylsulfonylbutyl) benzamide

Prepared by the method of example 1.6 using N-methyl-N-2- (4-methoxyphenyl) -4-hydroxybutyl) benzamide and methanesulfonyl chloride to give the title compound.

3.7N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazol-2-yl) -4-hydroxypiperidine-1-) Synthesis of phenyl) -2- (4-methoxyphenyl) butyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (4-methoxyphenyl) -4-methanesulfonylbutyl) benzamide and 4- (1- (4-fluorobenzyl) -1H-benzimidazol-2-yl) -4-hydroxypiperidine to give the title compound.

Preparation example 7

Synthesis of 4- (1- (2- (5-hydroxymethylfuran-2-ylmethyl) -4- (1H-benzimidazole-2-carbonyl) piperidine

Hexane-washed sodium hydride (20mmol) and tetrahydrofuran (40ml) were mixed according to the method of P.G. McDougal et al, J.org.Chem.51, 3388-3390 (1986). 2, 5-Furandimethanol (20mmol) was added slowly. After the bubbling did not escape, tert-butyldimethylsilyl chloride (20mmol) was added and stirred vigorously. After about 1 hour, the reaction mixture was poured into ether, extracted with saturated aqueous sodium carbonate solution, water, and then brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give 5- (tert-butyldisilyloxy) methyl-2-hydroxymethylfuran.

1- (tert-Butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine (10mmol), 5- (tert-butyldisilyloxy) methyl-2-hydroxymethylfuran (10mmol) and triphenylphosphine (10mmol) were combined in tetrahydrofuran (100 ml). Diethyl azodicarboxylate (10mmol) was added. After 18 hours, the reaction mixture was evaporated in vacuo to give a residue. The residue was partitioned between ethyl acetate and water. The organic layer was separated and extracted with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give a residue. Chromatography of the residue on silica gel gave 1- (tert-butoxycarbonyl) -4- (1- (5- (tert-butyldisilyloxy) methylfuran-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine.

1- (tert-Butoxycarbonyl) -4- (1- (5- (tert-butyldisilyloxy) methylfuran-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine (7mmol) and methanol (40ml) were mixed. Ammonium fluoride (42mmol) was added. Heated to reflux. After 20 h, concentrate in vacuo to give a residue. The residue was combined with water and dichloromethane. The layers were separated and the aqueous layer was extracted twice with dichloromethane, the organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo to give 1- (tert-butoxycarbonyl) -4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine.

1- (tert-Butoxycarbonyl) -4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine (5mmol) and dioxane (25ml) were combined. A solution of hydrochloric acid in dioxane (1.25ml, 4M, 5mmol) was added slowly. After 45 min, ether was added and evaporated in vacuo to give a residue. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated and extracted with brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Example 4

N-methyl-N- (4- (4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzimidazole) -4-hydroxypiperidine -1-yl) -2-phenylbutyl) benzamide

4.1N-methyl-N- (4- (4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzimidazole) -4-hydroxy Synthesis of piperidin-1-yl) -2-phenylbutyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzamide and 4- (1- (5-hydroxymethylfuran-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Example 5

N-methyl-N- (4- (4- (benzothiazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzene Carboxamides

5.1N-methyl-N- (4- (4- (benzothiazol-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) Synthesis of benzamide

Prepared by the method of example 2.7 using N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) benzamide and 4- (benzothiazole-2-carbonyl) piperidine to give the title compound.

Example 6

N-methyl-N- (4- (4- (hydroxydiphenylmethyl) piperidin-1-yl) -2-phenylbutyl) benzamide

6.12 Synthesis of phenyl-4- (tert-butyldisilyloxy) butanenitrile

Prepared by the method of example 1.1.1 using phenylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

6.22 Synthesis of phenyl-4- (tert-butyldisilyloxy) butylamine

Prepared by the method of example 1.2 using 2-phenyl-4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

6.3 Synthesis of N- (2-phenyl-4- (tert-butyldisilyloxy) butyl) benzamide

Prepared by the method of example 1.3 using 2-phenyl-4- (tert-butyldisiloxy) butylamine and benzoyl chloride to give the title compound.

6.4 Synthesis of N-methyl-N- (2-phenyl-4- (tert-butyldisilyloxy) butyl) benzamide

Prepared by the method of example 1.4 using N-2-phenyl-4- (tert-butyldisilyloxy) butyl) benzamide to give the title compound.

6.5 Synthesis of N-methyl-N- (2-phenyl-4-hydroxybutyl) benzamide

Prepared by the method of example 1.5 using N-methyl-N-2-phenyl-4- (tert-butyldisilyloxy) butyl) benzamide to give the title compound.

6.6 Synthesis of N-methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide

Prepared by the method of example 1.6 using N-methyl-N-2-phenyl-4-hydroxybutyl) benzamide and methanesulfonyl chloride to give the title compound.

6.7 preparation of N-methyl-N- (4- (4-hydroxydiphenylmethyl) piperidin-1-yl) -2-phenylbutyl) benzamide Synthesis of

Prepared by the method of example 1.7 using N-methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (hydroxydiphenylmethyl) piperidine to give the title compound.

Example 7

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4- Dimethoxyphenyl) butyl) benzamide

7.12 Synthesis of (3, 4-dimethoxyphenyl) -4- (tert-butyldisilyloxy) butyronitrile

Prepared by the method of example 1.1.1 using 3, 4-dimethoxyphenylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

7.22 Synthesis of (3, 4-dimethoxyphenyl) -4- (tert-butyldisilyloxy) butylamine

Prepared by the method of example 1.2 using 2- (3, 4-dimethoxyphenyl) -4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

7.3N- (2- (3, 4-dimethyl)Process for preparing oxyphenyl) -4- (tert-butyldisilyloxy) butyl) benzamide Synthesis of

Prepared by the method of example 1.3 using 2- (3, 4-dimethoxyphenyl) -4- (tert-butyldisilyloxy) butylamine and benzoyl chloride to give the title compound.

7.4N-methyl-N- (2- (3, 4-dimethoxyphenyl) -4- (tert-butyldimethylsiloxy) butyl) benzene Synthesis of formamide

Prepared by the method of example 1.4 using N-2- (3, 4-dimethoxyphenyl) -4- (tert-butyldisilyloxy) butyl) benzamide to give the title compound.

7.5 Synthesis of N-methyl-N- (2- (3, 4-dimethoxyphenyl) -4-hydroxybutyl) benzamide

Prepared by the method of example 1.5 using N-methyl-N-2- (3, 4-dimethoxyphenyl) -4- (tert-butyldisilyloxy) butyl) benzamide to give the title compound.

7.6 Synthesis of N-methyl-N- (2- (3, 4-dimethoxyphenyl) -4-methanesulfonylbutyl) benzamide

Prepared by the method of example 1.6 using N-methyl-N-2- (3, 4-dimethoxyphenyl) -4-hydroxybutyl) benzamide and methanesulfonyl chloride to give the title compound.

7.7N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Synthesis of (3, 4-dimethoxyphenyl) butyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3, 4-dimethoxyphenyl) -4-methanesulfonylbutyl) benzamide and 4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Example 8

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (benzo [1，3]Dioxolen-5-yl) butyl) benzamide

8.12- (benzo [1, 3]]Synthesis of m-oxolane-5-yl) -4- (tert-butyldisiloxyl) butyronitrile

Prepared by the method of example 1.1.1 using benzo [1, 3] metaoxolan-5-ylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

8.22- (benzo [1, 3]]Synthesis of m-oxolan-5-yl) -4- (tert-butyldisiloxy) butylamine

Prepared by the method of example 1.2 using 2- (benzo [1, 3] metaxolan-5-yl) -4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

8.3N- (2- (benzo [1, 3 ]) N]M-Oxolan-5-yl) -4- (tert-butyldisilyloxy) butyl) benzyl Synthesis of amides

Prepared by the method of example 1.3 using 2- (benzo [1, 3] metaxolan-5-yl) -4- (tert-butyldisiloxy) butylamine and benzoyl chloride to give the title compound.

8.4N-methyl-N- (2- (benzo [1, 3]]M-Oxolan-5-yl) -4- (tert-butyldisilyloxy) butanes Yl) Synthesis of benzamide

Prepared by the method of example 1.4 using N-2- (benzo [1, 3] metaxolan-5-yl) -4- (tert-butyldisiloxy) butyl) benzamide to give the title compound.

8.5N-methyl-N- (2- (benzo [1, 3]]Synthesis of m-oxolane-5-yl) -4-hydroxybutyl) benzamide

Prepared by the method of example 1.5 using N-methyl-N-2- (benzo [1, 3] metaxolan-5-yl) -4- (tert-butyldisilyloxy) butyl) benzamide to give the title compound.

8.6N-methyl-N- (2- (benzo [1, 3]]M-Oxolan-5-yl) -4-methanesulfonylbutyl) benzamide Synthesis of (2)

Prepared by the method of example 1.6 using N-methyl-N-2- (benzo [1, 3] metaxolan-5-yl) -4-hydroxybutyl) benzamide and methanesulfonyl chloride to give the title compound.

8.7N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (benzo [1, 3]]Synthesis of m-oxolane-5-yl) butyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (benzo [1, 3] oxolan-5-yl) -4-methanesulfonylbutyl) benzamide and 4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Example 9

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (naphthalene-2-) Yl) butyl) benzamide

9.12 Synthesis of 4- (tert-butyldisilyloxy) butyronitrile

Prepared by the method of example 1.1.1 using naphthalen-2-ylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

9.22- (Naphthalen-2-yl) -4- (tert-butyldimethyl ether)Synthesis of siloxy) butylamine

Prepared by the method of example 1.2 using 2- (naphthalen-2-yl) -4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

9.3 Synthesis of N- (2- (naphthalen-2-yl) -4- (tert-butyldisilyloxy) butyl) benzamide

Prepared by the method of example 1.3 using 2- (naphthalen-2-yl) -4- (tert-butyldisilyloxy) butylamine and benzoyl chloride to give the title compound.

9.4 Synthesis of N-methyl-N- (2- (naphthalen-2-yl) -4- (tert-butyldisilyloxy) butyl) benzamide Become into

Prepared by the method of example 1.4 using N-2- (naphthalen-2-yl) -4- (tert-butyldisilyloxy) butyl) benzamide to give the title compound.

9.5 Synthesis of N-methyl-N- (2- (naphthalen-2-yl) -4-hydroxybutyl) benzamide

Prepared by the method of example 1.5 using N-methyl-N-2- (naphthalen-2-yl) -4- (tert-butyldisilyloxy) butyl) benzamide to give the title compound.

9.6 Synthesis of N-methyl-N- (2- (naphthalen-2-yl) -4-methanesulfonylbutyl) benzamide

Prepared by the method of example 1.6 using N-methyl-N-2- (naphthalen-2-yl) -4-hydroxybutyl) benzamide and methanesulfonyl chloride to give the title compound.

9.7N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Synthesis of (naphthalen-2-yl) butyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (naphthalen-2-yl) -4-methanesulfonylbutyl) benzamide and 4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Example 10

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4- Dichlorophenyl) butyl) -3, 5-bis (trifluoromethyl) benzamide

10.1N- (2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 5-bis (trifluoromethyl) Yl) Synthesis of benzamide

Prepared by the method of example 1.3 using 2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butylamine and 3, 5-bis (trifluoromethyl) benzoyl chloride to give the title compound.

10.2N-methyl-N- (2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 5-bis Synthesis of (trifluoromethyl) benzamide

Prepared by the method of example 1.4 using N-2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 5-bis (trifluoromethyl) benzamide to give the title compound.

10.3N-methyl-N- (2- (3, 4-dichlorophenyl) -4-hydroxybutyl) -3, 5-bis (trifluoromethyl) benzamide Synthesis of (2)

Prepared by the method of example 1.5 using N-methyl-N-2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 5-bis (trifluoromethyl) benzamide to give the title compound.

10.4N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -3, 5-bis (trifluoromethyl) benzene Synthesis of formamide

Prepared by the method of example 1.6 using N-methyl-N-2- (3, 4-dichlorophenyl) -4-hydroxybutyl) -3, 5-bis (trifluoromethyl) benzamide and methanesulfonyl chloride to give the title compound.

10.5N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Synthesis of (3, 4-dichlorophenyl) butyl) -3, 5-bis (trifluoromethyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -3, 5-bis (trifluoromethyl) benzamide and 4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Example 11

N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-trifluoromethylphenyl) butyl) -3, 4, 5-trimethoxybenzamide

11.12 Synthesis of (3-trifluoromethylphenyl) -4- (tert-butyldisilyloxy) butyronitrile

Prepared by the method of example 1.1.1 using 3-trifluoromethylphenylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

11.22 Synthesis of (3-trifluoromethylphenyl) -4- (tert-butyldimethylsiloxy) butylamine

Prepared by the method of example 1.2 using 2- (3-trifluoromethylphenyl) -4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

11.3N- (2- (3-trifluoromethylphenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trisFirst of all Synthesis of oxybenzamides

Prepared by the method of example 1.3 using 2- (3-trifluoromethylphenyl) -4- (tert-butyldisilyloxy) butylamine and 3, 4, 5-trimethoxybenzoyl chloride to give the title compound.

11.4N-methyl-N- (2- (3-trifluoromethylphenyl) -4- (tert-butyldisilyloxy) butyl) - Synthesis of 3, 4, 5-trimethoxy benzamide

Prepared by the method of example 1.4 using N-2- (3-trifluoromethylphenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

11.5N-methyl-N- (2- (3-trifluoromethylphenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzoyl Synthesis of amines

Prepared by the method of example 1.5 using N-methyl-N-2- (3-trifluoromethylphenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

11.6N-methyl-N- (2- (3-trifluoromethylphenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxy Synthesis of benzamide

The title compound was obtained by the method of example 1.6 using N-methyl-N-2- (3-trifluoromethylphenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide.

11.7N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid Synthesis of phenyl) -2- (3-trifluoromethylphenyl) butyl) -3, 4, 5-trimethoxybenzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3-trifluoromethylphenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzamide and 4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Example 12

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (thiophene) -2-yl) butyl) -3, 4, 5-trimethoxybenzamide

12.12 Synthesis of (thien-2-yl) -4- (tert-butyldisilyloxy) butanenitrile

Prepared by the method of example 1.1.1 using thiophen-2-ylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

12.2 Synthesis of 22- (thien-2-yl) -4- (tert-butyldisilyloxy) butylamine

2- (Thien-2-yl) -4- (tert-butyldisilyloxy) butanenitrile (3.24mmol) and cobalt (II) chloride hexahydrate (1.54g, 6.48mmol) were combined in methanol (50 ml). While the reaction temperature was kept to not more than 20 ℃ using an ice bath, sodium borohydride (2.17g, 57mmol) was added in portions. After the addition was complete, the reaction mixture was allowed to stand at room temperature for 18 hours. The reaction mixture was evaporated in vacuo to give a residue. The residue was partitioned between dichloromethane and saturated aqueous ammonium chloride. The aqueous layer was adjusted to pH about 8 using 1M aqueous hydrochloric acid. The layers were separated and the aqueous layer was extracted several times with dichloromethane and the organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound.

12.3N- (2- (thien-2-yl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzene Synthesis of formamide

Prepared by the method of example 1.3 using 2- (thiophen-2-yl) -4- (tert-butyldisilyloxy) butylamine and 3, 4, 5-trimethoxybenzoyl chloride to give the title compound.

12.4N-methyl-N- (2- (thien-2-yl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-tris Synthesis of methoxybenzamide

Prepared by the method of example 1.4 using N-2- (thiophen-2-yl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

Synthesis of 5N-methyl-N- (2- (thien-2-yl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide Become into

Prepared by the method of example 1.5 using N-methyl-N-2- (thiophen-2-yl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

12.6N-methyl-N- (2- (thien-2-yl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzoyl Synthesis of amines

Prepared by the method of example 1.6 using N-methyl-N-2- (thiophen-2-yl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide and methanesulfonyl chloride to give the title compound.

12.7N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Synthesis of (thien-2-yl) butyl) -3, 4, 5-trimethoxybenzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (thiophen-2-yl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzamide and 4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Example 13

N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid methyl ester-yl) -2- (pyridine -3-yl) butyl) -3, 4, 5-trimethoxybenzamide

13.12 Synthesis of (pyridin-3-yl) -4- (tert-butyldisilyloxy) butyronitrile

Prepared by the method of example 1.1.2 using pyridin-3-ylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

13.22 Synthesis of- (pyridin-3-yl) -4- (tert-butyldisilyloxy) butylamine

Prepared by the method of example 12.2 using 2- (pyridin-3-yl) -4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

3N- (2- (pyridin-3-yl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzeneSynthesis of formamide

Prepared by the method of example 1.3 using 2- (pyridin-3-yl) -4- (tert-butyldisilyloxy) butylamine and 3, 4, 5-trimethoxybenzoyl chloride to give the title compound.

4.4N-methyl-N- (2- (pyridin-3-yl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-tris Synthesis of methoxybenzamide

Prepared by the method of example 1.4 using N-2- (pyridin-3-yl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

13.5 Synthesis of N-methyl-N- (2- (pyridin-3-yl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide Become into

Prepared by the method of example 1.5 using N-methyl-N-2- (pyridin-3-yl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

13.6N-methyl-N- (2- (pyridin-3-yl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzoyl Synthesis of amines

Prepared by the method of example 1.6 using N-methyl-N-2- (pyridin-3-yl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide and methanesulfonyl chloride, isolated by extraction with saturated sodium bicarbonate solution to give the title compound.

13.7N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Synthesis of (pyridin-3-yl) butyl) -3, 4, 5-trimethoxybenzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (pyridin-3-yl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzamide and 4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Example 14

N-methyl-N- (4- (4- (4-diphenylmethylenepiperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzyl Amides of carboxylic acids

14.1N-methyl-N- (4- (4- (4-diphenylmethylenepiperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) Benzamide derivatives

Prepared by the method of example 2.7 using N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) benzamide and 4-benzhydrylidenepiperidine to give the title compound.

Example 15

N-methyl-N- (4-)(1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butan 3, 4, 5-Trimethoxybenzamide

15.1N- (2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxy benzene Synthesis of phenylbenzamides

Prepared by the method of example 1.3 using 2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butylamine and 3, 4, 5-trimethoxybenzoyl chloride to give the title compound.

15.2N-methyl-N- (2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5- Synthesis of trimethoxybenzamide

Prepared by the method of example 1.4 using N-2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

Process for preparing 3-methyl-N- (2- (3, 4-dichlorophenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide Synthesis of

Prepared by the method of example 1.5 using N-methyl-N-2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

15.4N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxy-benzyl Synthesis of amides

Prepared by the method of example 1.6 using N-methyl-N-2- (3, 4-dichlorophenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide and methanesulfonyl chloride to give the title compound.

15.5N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl)Synthesis of butyl) -3, 4, 5-trimethoxybenzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzamide and 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Example 16

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butane Yl) benzamide

16.1N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) Butyl) benzamide synthesis

Prepared by the method of example 1.7 using N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) benzamide and 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Example 17

N-methyl-N- (4- (4- (1- (2- (morpholin-4-yl) ethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid 2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide

17.1N-methyl-N- (4- (4- (1- (2- (morpholin-4-yl) ethyl) -1H-benzimidazole-2-carbonyl) piperidine- Synthesis of 1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide (0.70mmol) was mixed with 4- (2-chloroethyl) morpholine hydrochloride (0.84mmol) and potassium carbonate (3.36mmol) in acetone (10ml), water (4ml) and dichloromethane (5 ml). Heated to reflux. After 20 h, cool to room temperature and concentrate the reaction mixture in vacuo and dilute with ethyl acetate. Extraction was performed with saturated aqueous ammonium chloride solution, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

Example 18

N-methyl-N- (4- (4- (1- (3-ethoxycarbonylpropyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) - 2- (3, 4-dichlorophenyl) butyl) benzamide

18.1N-methyl-N- (4- (4- (1- (3-ethoxycarbonylpropyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid Synthesis of phenyl) -2- (3, 4-dichlorophenyl) butyl) benzamide

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide (1.35mmol), ethyl 4-bromobutyrate (5.4mmol) and potassium carbonate (2.24g, 16.2mmol) were combined in 13/1 acetone/water (25 ml). Heated to reflux. After 38 hours, cool to room temperature and dilute with ethyl acetate. Extraction was performed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

Example 19

N-methyl-N- (4- (4- (1- (4-methoxycarbonylbenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) - 2- (3, 4-dichlorophenyl) butyl) benzamide

19.1N-methyl-N- (4- (4- (1- (4-methoxycarbonylbenzyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid) Synthesis of phenyl) -2- (3, 4-dichlorophenyl) butyl) benzamide

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide (1.69mmol), methyl (4-bromomethyl) benzoate (1.55g, 6.76mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (2.06g, 13.52mmol) were combined in acetonitrile (20 ml). Heated to reflux. After 72 hours, the reaction mixture was diluted with ethyl acetate and extracted with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

Example 20

N-methyl-N- (4- (4- (1- (4-carboxybenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide

20.1N-methyl-N- (4- (4- (1- (4-carboxybenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) - Synthesis of 2- (3, 4-dichlorophenyl) butyl) benzamide

N-methyl-N- (4- (4- (1- (4-methoxycarbonylbenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichloropropyl) butyl) benzamide (0.92mmol) and lithium hydroxide hydrate (0.12g, 2.75mmol) were combined in 4/1 tetrahydrofuran/water (45 ml). After 72 hours, the reaction mixture was diluted with water and evaporated in vacuo to remove most of the tetrahydrofuran. Acidified to pH2 with 1M hydrochloric acid solution. Extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound.

Example 21

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide

21.1N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid) Synthesis of phenyl) -2- (3, 4-dichlorophenyl) butyl) benzamide

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichloropropyl) butyl) benzamide (1.36mmol), 2-chloroethylethyl ether (0.59g, 5.44mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.66g, 10.9mmol) were combined in acetonitrile (16 ml). Heated to reflux. After 18 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. Extraction was performed with saturated aqueous ammonium chloride solution, 5% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

Preparation example 8

Synthesis of 4- (1- (furan-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine

1- (tert-Butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine (1.16mmol), furfuryl alcohol (0.10ml, 1.16mmol) and triphenylphosphine (0.33g, 1.28mmol) were combined in tetrahydrofuran (5 ml). Diethyl azodicarboxylate (0.20ml, 1.28mmol) was added. After 18 hours, the reaction mixture was evaporated in vacuo to give a residue. The residue was partitioned between ethyl acetate and water. The organic layer was separated and extracted with water and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound. The residue was chromatographed on silica gel eluting with 5% acetone/dichloromethane to give 1- (tert-butoxycarbonyl) -4- (1- (furan-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine.

1- (tert-Butoxycarbonyl) -4- (1- (furan-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine (1.0mmol) and dichloromethane (5ml) were cooled. A cooled solution of trifluoroacetic acid (1mmol) in dichloromethane (2ml) was added slowly. After 15 minutes, the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated and extracted with brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Example 22

N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperazin-1-yl) -2- Phenylbutyl) benzamide

22.1N-methyl-N- (4- (4- (1- (furan-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid) Synthesis of 2-phenylbutyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (furan-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Preparation example 9

Synthesis of 4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine

Furfuryl alcohol (1ml, 11.6mmol) and tetrahydrofuran (20ml) were combined. Sodium hydride (0.57g, 60% in oil, 14mmol) was added in portions. When no more gas was bubbled out, ethyl bromoacetate (1.33ml, 11.7mmol) was added. Heated to reflux. After 2.5 hours, cool to room temperature. After 18 hours, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. Is combined withThe organic layer was extracted with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 1% ethyl acetate/dichloromethane, to give furan-2-ylmethoxyacetic acid ethyl ester: r_f=0.62 (silica gel, 5% ethyl acetate/dichloromethane).

Ethyl 2-furan-2-ylmethoxyacetate (1.2g, 6.5mmol) was mixed with tetrahydrofuran (10 ml). Cooled in an ice bath. A lithium aluminum hydride solution (8.0ml, 1.0M in THF, 8.0mmol) was added dropwise. After 2 hours, water (0.3ml) was added, 15% sodium hydroxide solution (0.3ml) was added and water (0.9ml) was added. Stirring vigorously. After 15 min, the reaction mixture was filtered, the filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 2% ethyl acetate/dichloromethane, to give furan-2-ylmethyl 2-hydroxyethyl ether: r_f0.22 (silica gel, 5% acetone/dichloromethane).

1- (tert-Butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine (1.71g, 5.2mmol), furan-2-ylmethyl 2-hydroxyethyl ether (0.74g, 5.2mmol) and triphenylphosphine (1.67g, 6.4mmol) were combined in tetrahydrofuran (20 ml). Diethyl azodicarboxylate (1.0ml, 6.35mmol) was added. After 21 hours, the reaction mixture was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel eluting with 5% acetone/dichloromethane to give 1- (tert-butoxycarbonyl) -4- (1- (2-furan-2-ylmethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidine: r_f0.30 (silica gel, 5% acetone/dichloromethane).

1- (tert-Butoxycarbonyl) -4- (1- (2-furan-2-ylmethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidine (1.0mmol) was mixed with dioxane (10 ml). Cooled in an ice bath. A solution of hydrogen chloride in dioxane (0.25ml, 4M, 1.0mmol) was added slowly. After 45 minutes, the reaction mixture was diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate. The organic layer was separated and extracted with brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Example 23

N-methyl-N- (4- (4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperazines Pyridin-1-yl) -2-phenylbutyl) benzamide

23.1N-methyl-N- (4- (4- (1- (furan-2-ylmethoxy) -1H-benzimidazole-2-carbonyl) piperidine- Synthesis of 1-yl) -2-phenylbutyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (2- (furan-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Preparation example 10

Synthesis of 4- (1- (2-allyloxyethyl) -1H-benzimidazole-2-carbonyl) piperidine

Allyl hydroxyethyl ether (1.02g, 10mmol), diisopropylethylamine (4.0ml, 23mmol) and dichloromethane (20ml) were combined. Cooled in an ice bath. Methanesulfonyl chloride (1.0ml, 13mmol) was added dropwise. After 1.5 hours, the reaction mixture was extracted with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to afford allyl methylsulfonylether: r_f=0.80 (silica gel, 20% ethyl acetate/dichloromethane).

1- (tert-Butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine (1.87g, 5.68mmol), allyl methylsulfonylether (1.83g, 10.1mmol) and potassium carbonate (1.60g, 11.5mmol) were combined in acetone (21ml) and water (7 ml). Heated to reflux. After 18 hours, the reaction mixture was concentrated in vacuo to remove most of the acetone. The concentrated reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were extracted with saturated aqueous sodium chloride solution. Organic layer warpDried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 15% ethyl acetate/dichloromethane, to give 1- (tert-butoxycarbonyl) -4- (1- (2-allyloxyethyl) -1H-benzimidazole-2-carbonyl) piperidine: r_f=0.48 (silica gel, 20% ethyl acetate/dichloromethane).

1- (tert-Butoxycarbonyl) -4- (1- (2-allyloxyethyl) -1H-benzimidazole-2-carbonyl) piperidine (1.0mmol) and dioxane (3ml) were combined. A solution of hydrochloric acid in dioxane (4ml, 4M, 16mmol) was added. After 30 minutes, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated and extracted with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Example 24

N-methyl-N- (4- (4- (1- (2-allyloxyethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) - 2-phenylbutyl) benzamide

24.1N-methyl-N- (4- (4- (1- (2-allyloxyethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid) Synthesis of 2-phenylbutyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (2- (2-allyloxyethyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Preparation example 11

Synthesis of 4- (1- (2- (3, 3-dimethylallyloxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine

Prepared by the method of preparation 10, using 3-methyl-2-butene hydroxyethyl ether.

Example 25

N-methyl-N- (4- (4- (1- (2- (3, 3-dimethylallyloxy) ethyl) -1H-benzimidazole-2-carbonyl) Piperidin-1-yl) -2-phenylbutyl) benzamide

25.1N-methyl-N- (4- (4- (1- (2- (3, 3-dimethylallyloxy) ethyl) -1H-benzimidazole-2-) Synthesis of carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (2- (3, 3-dimethylallyloxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Example 26

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) - 3, 4, 5-trimethoxybenzamide

26.12 Synthesis of (3-chlorophenyl) -4- (tert-butyldisilyloxy) butyronitrile

Prepared by the method of example 1.1.1 using 3-chlorophenylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

26.22 Synthesis of- (3-chlorophenyl) -4- (tert-butyldisilyloxy) butylamine

Prepared by the method of example 1.2 using 2- (3-chlorophenyl) -4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

26.3N- (2- (3-chloro)Phenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzene Synthesis of formamide

Prepared by the method of example 1.3 using 2- (3-chlorophenyl) -4- (tert-butyldisilyloxy) butylamine and 3, 4, 5-trimethoxybenzoyl chloride to give the title compound.

26.4N-methyl-N- (2- (3-chlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethyl Synthesis of oxybenzamides

Prepared by the method of example 1.4 using N-2- (3-chlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

26.5 Synthesis of N-methyl-N- (2- (3-chlorophenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide Become into

Prepared by the method of example 1.5 using N-methyl-N-2- (3-chlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

26.6N-methyl-N- (2- (3-chlorophenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzoyl Synthesis of amines

The title compound was obtained by the method of example 1.6 using N-methyl-N-2- (3-chlorophenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide.

26.7N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butan Synthesis of 3, 4, 5-trimethoxy benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3-chlorophenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzamide and 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Example 27

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide

27.1N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid) Synthesis of phenyl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide

Prepared by the method of example 21.1 using N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide and 2-chloroethylethyl ether to give the title compound.

Example 28

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) - 3, 4, 5-trimethoxybenzamide

28.12 Synthesis of (4-chlorophenyl) -4- (tert-butyldisilyloxy) butyronitrile

Prepared by the method of example 1.1.1 using 4-chlorophenylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

28.22 Synthesis of- (4-chlorophenyl) -4- (tert-butyldisilyloxy) butylamine

Prepared by the method of example 1.2 using 2- (4-chlorophenyl) -4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

28.3N- (2- (4-chlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzene Synthesis of formamide

Prepared by the method of example 1.3 using 2- (4-chlorophenyl) -4- (tert-butyldisilyloxy) butylamine and 3, 4, 5-trimethoxybenzoyl chloride to give the title compound.

28.4N-methyl-N- (2- (4-chlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethyl Synthesis of oxybenzamides

Prepared by the method of example 1.4 using N-2- (4-chlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

28.5 Synthesis of N-methyl-N- (2- (4-chlorophenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide Become into

Prepared by the method of example 1.5 using N-methyl-N-2- (4-chlorophenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

28.6N-methyl-N- (2- (4-chlorophenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzoyl Synthesis of amines

The title compound was obtained by the method of example 1.6 using N-methyl-N-2- (4-chlorophenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide.

28.7N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butan Synthesis of 3, 4, 5-trimethoxy benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (4-chlorophenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzamide and 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Example 29

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide

29.1N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid) Synthesis of phenyl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide

Prepared by the method of example 21.1 using N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3, 4, 5-trimethoxybenzamide and 2-chloroethylethyl ether to give the title compound.

Example 30

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dimethylphenyl) Butyl) -3, 4, 5-trimethoxybenzamide

30.12 Synthesis of (3, 4-dimethylphenyl) -4- (tert-butyldisilyloxy) butanenitrile

Prepared by the method of example 1.1.1 using 3, 4-dimethylphenylacetonitrile and 1- (tert-butyldisilyloxy) -2-bromoethane to give the title compound.

30.2 Synthesis of 22- (3, 4-dimethylphenyl) -4- (tert-butyldisilyloxy) butylamine

Prepared by the method of example 1.2 using 2- (3, 4-dimethylphenyl) -4- (tert-butyldisilyloxy) butanenitrile to give the title compound.

3N- (2- (3, 4-dimethylphenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethyl Synthesis of oxybenzamides

Prepared by the method of example 1.3 using 2- (3, 4-dimethylphenyl) -4- (tert-butyldisilyloxy) butylamine and 3, 4, 5-trimethoxybenzoyl chloride to give the title compound.

30.4N-methyl-N- (2- (3, 4-dimethylphenyl) -4- (tert-butyldisilyloxy) butyl) - Synthesis of 3, 4, 5-trimethoxy benzamide

Prepared by the method of example 1.4 using N-2- (3, 4-dimethylphenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

30.5N-methyl-N- (2- (3, 4-dimethylphenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide Synthesis of (2)

Prepared by the method of example 1.5 using N-methyl-N-2- (3, 4-dimethylphenyl) -4- (tert-butyldisilyloxy) butyl) -3, 4, 5-trimethoxybenzamide to give the title compound.

30.6N-methyl-N- (2- (3, 4-dimethylphenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxy-benzene Synthesis of formamide

The title compound was obtained by the method of example 1.6 using N-methyl-N-2- (3, 4-dimethylphenyl) -4-hydroxybutyl) -3, 4, 5-trimethoxybenzamide.

30.7N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid)-yl) -2- (3, 4-dimethylbenzene Synthesis of (yl) butyl) -3, 4, 5-trimethoxybenzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3, 4-dimethylphenyl) -4-methanesulfonylbutyl) -3, 4, 5-trimethoxybenzamide and 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Example 31

N-methyl-N- (4- (4- (1- (imidazol-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Phenylbutyl) benzamide

31.1N-methyl-N- (4- (4- (1- (1-benzylimidazol-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperazines Synthesis of pyridin-1-yl) -2-phenylbutyl) benzamide

Prepared by the method of example 21.1 using N-methyl-N- (4- (4- (1H-benzoimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide and 1-benzyl-imidazol-2-ylmethyl chloride hydrochloride to give the title compound.

31.2N-methyl-N- (4- (4- (1- (imidazol-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid 2-phenylbutyl) benzamide

N-methyl-N- (4- (4- (1- (1-benzylimidazol-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide (5mmol) and 10% palladium on charcoal (1.5g) were combined in methanol (50 ml). Anhydrous ammonium formate (25mmol) was added. Heated to reflux. After 18 h, filtration and rinsing with dichloromethane and evaporation in vacuo gave the title compound.

Preparation example 12

4- (1- (2-ethoxyethyl) -1H-benzimidazole) -4-hydroxySynthesis of piperidines

1- (2-ethoxyethyl) -1H-benzimidazole (2.0g, 10.51mmol) and tetrahydrofuran (20ml) were mixed. Cooled to-78 ℃ in a dry ice/acetone bath. Lithium diisopropylamide solution (4.62ml, 2.5M in hexane, 11.56mmol) was added dropwise. After 1 hour, a solution of 1- (tert-butoxycarbonyl) piperidin-4-one (2.09g, 10.51mmol) in tetrahydrofuran (10ml) was added dropwise. Warm to room temperature over 3 hours. Water was added and the layers separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 1/1 ethyl acetate/hexanes to give 1- (tert-butoxycarbonyl) -4- (1- (2-ethoxyethyl) -1H-benzimidazole) -4-hydroxypiperidine: r_f0.25 (silica gel, 1/1 ethyl acetate/hexane).

1- (tert-Butoxycarbonyl) -4- (1- (2-ethoxyethyl) -1H-benzimidazole) -4-hydroxypiperidine (2.05g) was cooled in an ice bath. Trifluoroacetic acid (25ml) was added dropwise. After 1h, diethyl ether (100ml) was added and evaporated in vacuo to give a residue. Dichloromethane and 5% potassium carbonate solution were added. Stirring vigorously. After 3 hours, the layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over potassium carbonate, filtered and evaporated in vacuo to give the title compound: r_f0.18 (silica gel, 2% triethylamine/ethyl acetate).

Example 32

N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole) -4-hydroxypiperidin-1-yl) -2- Phenylbutyl) benzamide

32.1N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole) -4-hydroxypiperidine-1-) Synthesis of 2-phenylbutyl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (2-ethoxyethyl) -1H-benzimidazole) -4-hydroxypiperidine to give the title compound.

Preparation example 13

Synthesis of 2-methoxy-5- (1H-tetrazol-1-yl) benzoyl chloride

2-hydroxy-5-nitrobenzoic acid (21.5g, 117mmol), potassium carbonate (162.3g, 1.174mol) and iodomethane (136.8g, 96.4mmol) were combined in acetone (500 ml). Heated to reflux. After 18 h, the reaction mixture was cooled to room temperature and iodomethane (136.8g, 96.4mmol) was added. Again heated to reflux. After 56 hours, the reaction mixture was cooled to room temperature and filtered, rinsed with acetone, and the filtrate was evaporated in vacuo to give a residue. The residue was recrystallized from ethanol to give a second residue. The second residue was combined with chloroform (ca. 100ml), filtered and the filtrate evaporated in vacuo to give methyl 2-methoxy-5-nitrobenzoate. R_f0.38 (silica gel, ethyl acetate/hexane 1/1).

Methyl 2-methoxy-5-nitrobenzoate (13.3g, 63mmol) was mixed with methanol. 5% Palladium on carbon (0.66g) was added. Hydrogenation was carried out in a pressure vessel at 50 psi. After 17 hours, the catalyst was removed by filtration through a pad of celite and the filtrate was evaporated in vacuo to give a residue. The residue and dichloromethane were combined and extracted with water. The organic layer was coated with Na₂SO₄Dried, filtered and evaporated in vacuo to give methyl 2-methoxy-5-aminobenzoate. R_f0.18 (silica gel, ethyl acetate/methanol 1/1). C₉H₁₁NO₃Theoretical value of elemental analysis of (1): c, 59.66; h, 6.12; n, 7.73; measured value: c, 59.44; h, 6.04; and N, 7.62.

Methyl 2-methoxy-5-aminobenzoate (3.94g, 21.7mmol) and triethyl orthoformate (12.8g, 86.7mmol) were combined in glacial acetic acid (20 ml). After 20 hours, the reaction mixture was concentrated in vacuo to remove ethanol. Glacial acetic acid (20ml) and sodium azide (5.64g, 86.7mmol) were added. Heating to 70 ℃. After 1 hour, glacial acetic acid (10ml) was added and heating continued to 70 ℃. After 1 hour, the reaction mixture was cooled to room temperature and diluted with water (500 ml). The solid was collected by filtration, rinsed with water and dried to give methyl 2-methoxy-5- (1H-tetrazol-1-yl) benzoate.

Methyl 2-methoxy-5- (1H-tetrazol-1-yl) benzoate (2.86g, 12.2mmol) and 1M aqueous sodium hydroxide (13.43ml, 14.43mmol) were combined in methanol/water (100ml, 5: 1 v/v). Heated to reflux. After 4 hours, concentrate in vacuo to remove most of the methanol, add water (50ml) and adjust the pH to about 4 with 1M aqueous hydrochloric acid. Evaporation in vacuo gave a solid. Water was added to slurry the solid, filtered and dried to give 2-methoxy-5- (1H-tetrazol-1-yl) benzoic acid.

Alternatively, methyl 2-methoxy-5- (1H-tetrazol-1-yl) benzoate (13.3g, 56.8mmol) was mixed with methanol (150 ml). 1M aqueous sodium hydroxide (62.5ml, 62.5mmol) was added. Heated to reflux. After 30 minutes, methanol (50ml) and water (50ml) were added and heating continued to reflux. After 1 hour, the product was concentrated in vacuo to remove most of the solvent. The pH was adjusted to about 1 to 2 using 1M aqueous hydrochloric acid to give a solid. The solid was collected by filtration, washed with water and dried to give 2-methoxy-5- (1H-tetrazole-1-benzoic acid).

2-methoxy-5- (1H-tetrazol-1-yl) benzoic acid (1.2g, 5.5mmol) and dichloromethane (40ml) were added. Oxalyl chloride (0.72ml, 8.25mmol) was added dropwise followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.

Example 33

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) -2- Methoxy-5- (1H-tetrazol-1-yl) benzamides

33.1N- (2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- (1H- Synthesis of tetrazol-1-yl) benzamides

2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butylamine (5.0g, 16.8mmol) and sodium bicarbonate (7.0g, 83mmol) were combined in acetone (50ml) and water (50 ml). 2-methoxy-5- (1H-tetrazol-1-yl) benzoyl chloride (3.3g, 14.55mmol) was added. After 18 hours, the reaction mixture was diluted with ethyl acetate, the layers were separated, and the organic layer was extracted with saturated aqueous sodium bicarbonate, water, and then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel sequentially eluting with 50% ethyl acetate/hexane and 75% ethyl acetate/hexane to give, after drying, the title compound: r_f=0.58 (silica gel, ethyl acetate).

33.2 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide

N- (2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide (3.75g, 7.13mmol) was mixed in tetrahydrofuran (20 ml). Cooled in a dry ice/acetone bath. Sec-butyllithium (7.2ml, 1.3M in cyclohexane, 9.5mmol) was added. After 30 min, iodomethane (2.0ml, 32.1mmol) was added. The reaction mixture was warmed to room temperature and then heated to reflux. After 18 hours, cool, dilute the reaction mixture with ethyl acetate, extract with saturated aqueous sodium bicarbonate solution, then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 3/7 ethyl acetate/hexane, to give, after drying, the title compound: r_f=0.63 (silica gel, ethyl acetate).

33.3N-methyl-N- (2- (4-fluorophenyl) -4-hydroxybutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzene Synthesis of formamide

Prepared by the method of example 1.5 using N-methyl-N-2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide to give the title compound: r_f=0.18 (silica gel,ethyl acetate).

33.4N-methyl-N- (2- (4-fluorophenyl) -4-methylsulfonylbutyl) -2-methoxy-5- (1H-tetrazole-1-) Yl) Synthesis of benzamide

The title compound was obtained by the method of example 1.6 using N-methyl-N-2- (4-fluorophenyl) -4-hydroxybutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide.

33.5N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butan-e Synthesis of yl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (4-fluorophenyl) -4-methylsulfonylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide and 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Example 34

N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butane 2-methoxy-5- (1H-tetrazol-1-yl) benzamide

34.1N- (2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- Synthesis of (1H-tetrazol-1-yl) benzamides

Prepared by the method of example 33.1 using 2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butylamine (5.0g, 16.8mmol) to give the title compound.

34.2N-methyl-N- (2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methyl Synthesis of oxy-5- (1H-tetrazol-1-yl) benzamide

Prepared by the method of example 1.4 using N- (2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide to give the title compound.

34.3N-methyl-N- (2- (3, 4-dichlorophenyl) -4-hydroxybutyl) -2-methoxy-5- (1H-tetrazol-1-yl) Synthesis of benzamide

Prepared by the method of example 1.5 using N-methyl-N-2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide to give the title compound.

34.4N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5- (1H-tet-etrakis Synthesis of oxazol-1-yl) benzamides

The title compound was obtained by the method of example 1.6 using N-methyl-N-2- (3, 4-dichlorophenyl) -4-hydroxybutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide.

34.5N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) Synthesis of butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide and 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Preparation example 14

Synthesis of 2, 2, 2-trifluoroethyl trifluoromethanesulfonate

2, 2, 2-trifluoroethanol (12.4ml, 170mmol), pyridine (13.6ml, 170mmol) and dichloromethane (40ml) were combined. Cooled in an ice bath. Trifluoromethanesulfonic anhydride (50g, 196mmol) was added over about 45 minutes. After 15 minutes, water was added, the two layers were separated and the organic layer was extracted with water. The organic layer was dried over magnesium sulfate, filtered and concentrated by short path distillation to give the title compound: the boiling point is 89-91 ℃.

Example 35

N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide

35.1N-methyl-N- (4- (4- (1- (2, 2, 2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid Synthesis of yl) -2- (4-fluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide

Prepared by the method of example 21.1 using 2, 2, 2-trifluoroethyl triflate to give the title compound.

Preparation example 15

Synthesis of 4- (1-allyl-1H-benzimidazole-2-carbonyl) piperidine

Prepared by the method of preparation 8 using allyl alcohol to give the title compound.

Example 36

N-methyl-N- (4- (4- (1-allyl-1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichloro Phenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide

36.1N-methyl-N- (4- (4- (1-allyl-1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4- Synthesis of dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide and 4- (1-allyl-1H-benzimidazole-2-carbonyl) piperidine to give the title compound.

Preparation example 16

Synthesis of 2-methoxy-5- (4H-triazol-4-yl) benzoyl chloride

According toChemistry society (J.chem.Soc.)(C) 1664(1967) methyl 2-methoxy-5-aminobenzoate (2.0g, 11mmol), N-dimethylformamide azine (1.56g, 11mmol), p-toluenesulfonic acid (190mg) were mixed in toluene (25 ml). The reaction vessel was equipped with a vent inlet to purge the headspace of the vessel with argon and the off-gas was scrubbed with dilute aqueous hydrochloric acid. Heated to reflux. After 20 hours, the reaction mixture was concentrated in vacuo to give a residue. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel eluting with 70% ethyl acetate/dichloromethane then 5% methanol/dichloromethane to give a residue. The residue was recrystallized from ethyl acetate/hexane to give methyl 2-methoxy-5- (4H-triazol-4-yl) benzoate: melting point 191-195.5 ℃.

Or, according toJournal of pharmaceutical chemistry (j.med.chem.), 211100(1978) by mixing methyl 2-methoxy-5-aminobenzoate (1.8g, 10mmol), diformylhydrazine (0.97g, 11mmol) and phosphorus pentoxide (1.84g, 13 mmol). Heating to 160 ℃. After 1.5 hours, the reaction mixture was cooled and saturated aqueous sodium bicarbonate solution was added. Extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel using 40% acetic acidEthyl ester/dichloromethane then eluted with 5% methanol/dichloromethane to give methyl 2-methoxy-5- (4H-triazol-4-yl) benzoate: melting point 179-182 ℃.

Methyl 2-methoxy-5- (4H-triazol-4-yl) benzoate (56mmol) was mixed with methanol (200ml) and water (50 ml). 1M aqueous sodium hydroxide (62.5ml, 62.5mmol) was added. Heated to reflux. After 8 hours, concentrate in vacuo to remove most of the solvent. The pH was adjusted to about 1-2 with 1M aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give 2-methoxy-5- (4H-triazol-4-yl) benzoic acid.

2-methoxy-5- (4H-triazol-4-yl) benzoic acid (5mmol) and dichloromethane (40ml) were combined. Oxalyl chloride (0.72ml, 8.25mmol) was added dropwise followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.

Example 37 N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluoro Phenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide

37.1N- (2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- (4H-triazolyl-) Synthesis of 4-yl) benzamides

Prepared by the method of example 33.1 using 2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butylamine and 2-methoxy-5- (4H-triazol-4-yl) benzoyl chloride to give the title compound.

37.2N-methyl-N- (2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- Synthesis of (4H-triazol-4-yl) benzamide

Prepared by the method of example 1.4 using N-2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide to give the title compound.

37.3N-methyl-N- (2- (4-fluorophenyl) -4-hydroxybutyl) -2-methoxy-5- (4H-triazol-4-yl) benzoyl Synthesis of amines

Prepared by the method of example 1.5 using N-methyl-N-2- (4-fluorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide to give the title compound.

37.4N-methyl-N- (2- (4-fluorophenyl) -4-methylsulfonylbutyl) -2-methoxy-5- (4H-triazol-4-yl) Synthesis of benzamide

The title compound was obtained by the method of example 1.6 using N-methyl-N-2- (4-fluorophenyl) -4-hydroxybutyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide.

37.5N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Synthesis of (4-fluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (4-fluorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide and 4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Preparation example 18 Synthesis of 2-methoxy-5-trifluoromethoxy benzoyl chloride

2-methoxy-5-trifluoromethoxybenzene (1.0g, 5.2mmol) and trifluoroacetic acid (200ml) were combined. Hexamethylene tetramine (26g, 185.7mmol) was added slowly in portions. Heating at 60 deg.C. After 24 hours, cool to room temperature and pour the reaction mixture into 2M aqueous sulfuric acid (500 ml). Cooled and extracted 10 times with ether. The combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 1/4 ethyl acetate/hexane afforded 2-methoxy-5-trifluoromethoxybenzaldehyde.

According toHeterocycles (heterocycles), 162091(1981) method in which 2-methoxy-5-trifluoromethoxybenzaldehyde (0.58g, 2.65mmol) and 2-methylbut-2-ene (37ml) were mixed in t-butanol (16 ml). A solution of hydrated sodium dihydrogen phosphate (0.92g) and sodium chloride (0.42g, 4.7mmol) in water (10ml) was added dropwise. After 4 hours the pH of the reaction mixture was adjusted to 8-9 with 1M aqueous sodium hydroxide solution. The reaction mixture was evaporated at near room temperature to remove most of the n-butanol. Water (40ml) was added and extracted three times with hexane (10 ml). The aqueous layer was adjusted to about 1 pH with 1M aqueous hydrochloric acid and extracted five times with ether. The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 1/1 ethyl acetate/hexanes with 0.5% acetic acid to give 2-methoxy-5-trifluoromethoxybenzoic acid: r_f=0.34 (silica gel, 1/1 ethyl acetate/hexane with 0.5% acetic acid).

2-methoxy-5-trifluoromethoxybenzoic acid (0.6g, 2.53mmol) and dichloromethane (10ml) were combined. Cooled in an ice bath. Oxalyl chloride (0.64ml, 5.0mmol) was added dropwise followed by dimethylformamide (1 drop). Warm to room temperature. After 3 hours, evaporate in vacuo and dry to give the title compound.

Example 38 N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2- Methoxy-5-trifluoromethoxybenzamide

38.1N- (2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5-trifluoromethyl Synthesis of oxybenzamides

Prepared by the method of example 33.1 using 2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butylamine (5.0g, 16.8mmol) and 2-methoxy-5-trifluoromethoxybenzoyl chloride to give the title compound.

38.2N-methyl-N- (2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy- Synthesis of 5-trifluoromethoxy benzamide

Prepared by the method of example 1.4 using N-2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5-trifluoromethoxybenzamide to give the title compound.

38.3N-methyl-N- (2- (3, 4-dichlorophenyl) -4-hydroxybutyl) -2-methoxy-5-trifluoromethoxybenzoyl Synthesis of amines

Prepared by the method of example 1.5 using N-methyl-N-2- (3, 4-dichlorophenyl) -4- (tert-butyldisilyloxy) butyl) -2-methoxy-5-trifluoromethoxybenzamide to give the title compound.

38.4N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5-trifluoromethoxy Synthesis of benzamide

The title compound was obtained by the method of example 1.6 using N-methyl-N-2- (3, 4-dichlorophenyl) -4-hydroxybutyl) -2-methoxy-5-trifluoromethoxybenzamide.

38.5N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butan Synthesis of 2-methoxy-5-trifluoromethoxy benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (3, 4-dichlorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5-trifluoromethoxybenzamide and 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Example 39 N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4- Dichlorophenyl) butyl) -2-methoxy-5-trifluoromethoxy benzamide

39.1N-methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Synthesis of (3, 4-dichlorophenyl) butyl) -2-methoxy-5-trifluoromethoxy benzamide

Prepared by the method of example 21.1 using N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) -2-methoxy-5-trifluoromethoxybenzamide and 2-chloroethylethyl ether to give the title compound.

Preparation example 17 Synthesis of 4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodide

According toTet.Let.，353997-Journal of chemical communication of the chemical society (J.chem, Soc, Chem, Commun.)1766(1990) (5.0mmol), diethyl 1, 1-azodicarboxylate (10mmol), 2, 2, 2-trifluoroethanol (100mmol) and tributylphosphine (10mmol) were mixed in benzene (100 ml). After 6 hours, concentrate in vacuo to give a residue. Chromatography of the residue on silica gel gave 2-tetrahydropyran-2-yloxyethyl 2, 2, 2-trifluoroethyl ether.

2-tetrahydropyran-2-yloxyethylbut-2-en-1-yl ether (2mmol) and magnesium bromide (6mmol) were combined in diethyl ether (10 ml). After 24 hours, it was extracted with water and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 2-hydroxyethyl 2, 2, 2-trifluoroethyl ether.

Prepared using 2-hydroxyethyl 2, 2, 2-trifluoroethyl ether and 1- (tert-butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine (2.0g, 6.1mmol) by the method of preparation 9 to give 1- (tert-butoxycarbonyl) -4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine.

1- (tert-Butoxycarbonyl) -4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine (5.0mmol) and dichloromethane (150ml) were combined. Mix with ice bath and cool to 0 ℃. Hydroiodic acid (gas) was added until the solution was saturated and stirred. After 30 minutes, hydroiodic acid (gas) was added again until the solution was saturated. After 2 hours, evaporation in vacuo and drying gave the title compound.

Example 40 N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine-1-carboxylic acid 2- (4-fluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-) benzamide

40.1N-methyl-N- (4- (4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperazines Synthesis of pyridin-1-yl) -2- (4-fluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide

Prepared by the method of example 1.7 using N-methyl-N- (2- (4-fluorophenyl) -4-methylsulfonylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide and 4- (1- (2- (2, 2, 2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodide to give the title compound.

Tachykinin is a class of neuropeptides having a common C-terminal sequence, Phe-Xaa-Gly-Leu-Met-NH₂. Tachykinins are widely distributed in the peripheral and central nervous systems and bind to at least three types of receptors. Among the tachykinin receptors, NK is defined by preferential binding affinity to substance P, neurokinin A (NKA) and neurokinin B (NKB), respectively₁、NK₂And NK₃A receptor.

Tachykinin antagonists have been shown to be useful in the treatment of various tachykinin-mediated diseases and indications, including: allergic reactions; an adverse immune response; asthma; bronchitis; allergic rhinitis, including seasonal rhinitis and sinusitis; (ii) an allergic reaction; contact dermatitis; allergic dermatitis; inflammatory bowel diseases including crohn's disease and ulcerative colitis; and vomiting.

Tachykinin-mediated diseases and indications are understood to be those diseases in which tachykinins are involved, in whole or in part, in one or more of their clinical manifestations. Also, tachykinin-related factors are not necessarily the cause of particular tachykinin-mediated diseases and indications. Tachykinin antagonists are useful in the control or amelioration of those tachykinin-mediated diseases and indications.

The present invention provides novel useful tachykinin antagonists of formula (1) or stereoisomers or pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides a method of treating tachykinin-mediated diseases and conditions comprising administering to said patient in need thereof a therapeutically effective amount of a compound of formula (1), said diseases and conditions comprising: allergic reactions; an adverse immune response; asthma; bronchitis; allergic rhinitis, including seasonal rhinitis and sinusitis; (ii) an allergic reaction; contact dermatitis; allergic dermatitis; inflammatory bowel diseases including crohn's disease and ulcerative colitis; and vomiting.

Immediate hypersensitivity reactions can occur when IgE antibodies react directly to non-toxic antigens such as pollen. During this reaction, it turns out that often pharmacological mediators such as histamine are released by IgE-sensitized mast cells in an acute inflammatory response. The response is characterized by the occurrence of a reaction and the tissues that cause allergic diseases, including: allergic rhinitis, including seasonal rhinitis and sinusitis; pulmonary diseases, such as asthma; allergic dermatitis, such as urticaria, angioedema, eczema, allergic dermatitis, and contact dermatitis; gastrointestinal allergies, such as those caused by food and drugs; spasm; nausea; vomiting; diarrhea and ocular allergy.

By activating H₁Histamine, which acts at receptors, is an important transmitter of the above-mentioned reactions associated with immediate hypersensitivity reactions. In the acute stage of allergic rhinitis, histamine H has been shown₁Receptor antagonists are effective in inhibiting rhinocnesmus, rhinorrhea and sneezing associated with this indication. However, histamine H₁Receptor antagonists are not effective in relieving nasal congestion. Acute reactions to allergens in rhinitis are often followed by chronic inflammatory reactions during which the inflamed nasal mucosa becomes allergic to antigens and non-specific stimuli. Histamine H₁Receptor antagonists are also ineffective in alleviating the symptoms of this chronic phase response.

The present invention provides novel useful histamine antagonists of formula (1) or stereoisomers or pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides a method of treating allergic diseases, including allergic rhinitis, including seasonal rhinitis and sinusitis; pulmonary diseases, such as asthma; allergic dermatitis, such as urticaria, angioedema, eczema, allergic dermatitis, and contact dermatitis; gastrointestinal allergies, such as those caused by food and drugs; spasm; nausea; vomiting; diarrhea and ocular allergy.

In addition to histamine, tachykinins, especially substance P, also play an important role in allergic reactions and produce certain symptoms different from the histamine reaction. These symptoms occur as a result of the release of tachykinins stimulated by stimuli or inflammatory mediators, such as histamine, from sensory nerves located in the trigeminal nerve region around blood vessels and in the lining of the nasal mucosa.

Patients with allergic rhinitis have been shown to have higher nasal substance P levels when they have rhinitis symptoms (Mosimann et al,journal of allergy and clinical immunology (J.allergy Clin.Immunol.92)95 (1993); the Takeyama et al,journal of pharmacology of drugs (J.P)harm.Pharmacol.)，4641 (1994); and a Wattanable or the like,Ann.Otol.Rhinol.and Laryngol.，102,16(1993). In human patients with allergic rhinitis, local or intravenous administration of tachykinins induces nasal obstruction, inflammatory cell recruitment, glandular secretion and microvascular leakage. It was found that nasal obstruction produced by substance P is NK₁Is receptor-mediated. The branstein et al (r) compounds,Am.Rev.Respir.Dis.，144630 (1991); a Devilleier et al, in general,Eur.Respir.J.，1,356(1988). In addition, sensory nerve-mediated effects such as nasal irritation and hypersensitivity which occur later in the allergic reaction are also a result of the release of tachykinins. The number of the trigger signals of the Anggard,Acta Otolarynglo.113,394(1993). Depletion of tachykinins in the nasal sensory nerves after chronic capsaicin administration ameliorates rhinitis symptoms in patients. A salt of an acid such as lacriox and the like,Clin.and Exper.Allergy，21，595(1991)。

histamine pair H₁Antagonism of the receptor is useful in the treatment of allergic diseases such as rhinitis. Similarly, antagonism of tachykinins, particularly substance P, at their preferential receptors is useful in treating conditions which occur concurrently with allergic disease. Thus, simultaneously have H₁And NK₁A potential advantage of antagonists of receptor affinity is that clinical manifestations of allergic disease mediated by both receptors will be attenuated or prevented.

More particularly, the present invention provides novel and useful compounds of formula (1) or stereoisomers or pharmaceutically acceptable salts thereof, which are both tachykinin antagonists and histamine antagonists.

In another embodiment, the present invention provides a method of treating an allergic disorder with a compound which is both a tachykinin antagonist and a histamine antagonist, comprising administering to said patient in need of such treatment a therapeutically effective amount of a compound of formula (1), said allergic disorder comprising: allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including crohn's disease and ulcerative colitis.

The various diseases and indications treated herein are well known to those of ordinary skill in the art. It will also be appreciated that one of ordinary skill in the art may affect the disease by treating a patient suffering from the disease or prophylactically treating a patient suffering from the disease with a therapeutically effective amount of a compound of formula (1).

The term "patient" as used herein refers to a warm-blooded animal, such as a mammal, suffering from a particular allergic disease. Guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals within the meaning of the term.

The term "therapeutically effective amount" of a compound of formula (1) as used herein refers to an amount effective to control the diseases described herein. The term "controlling" means slowing, intervening, inhibiting or arresting the overall process of disease progression as described herein, and also includes prophylactic treatment of the disease when not necessarily meaning complete elimination of all disease symptoms.

A therapeutically effective amount is readily determined by the attending physician, as a person skilled in the art, by the application of routine techniques and by observing results obtained under analogous circumstances. In determining a therapeutically effective amount, the diagnosing physician will consider a number of factors including, but not limited to: the species of mammal; its size, age and health; the specific diseases involved; the extent of the disease and the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; bioavailability characteristics of the administered formulation; a selected dosing regimen; drugs for simultaneous use; and other related circumstances.

A therapeutically effective amount of a compound of formula (1) is expected to be from 0.1 milligrams per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are determined by one skilled in the art.

In the effective treatment of patients suffering from the above-mentioned diseases, the compounds of formula (1) may be administered in any form or manner that renders an effective amount of the compound bioavailable, including orally, by inhalation, and by parenteral routes. For example, the compounds of formula (1) may be administered orally, by inhalation of an aerosol or dry powder, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, and topically. Oral or inhalation administration is generally preferred for the treatment of allergic diseases. One of ordinary skill in the art of preparing pharmaceutical agents can readily select the appropriate form and mode of administration depending on the identity of the compound selected, the disease or indication being treated, the stage of the disease or indication, and other relevant circumstances. (Remington's pharmaceutical sciences, 18th Edition, Mack Publishing Co. (1990)).

The compounds of the present invention may be administered alone or in pharmaceutical compositions in combination with pharmaceutically acceptable carriers or excipients, the ratio and nature of which will depend upon the solubility and chemical nature of the compound selected, the chosen route of administration and standard pharmaceutical practice. The compounds of the invention, which are effective per se, are also formulated or administered in the form of their pharmaceutically acceptable salts, including acid addition salts or base addition salts, for reasons of stability, ease of crystallization and improved solubility, for example.

In another embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (1) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions may be prepared in a conventional manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material which acts as a carrier or medium for the active ingredient. Suitable carriers or excipients are known in the art. The pharmaceutical compositions are suitable for oral, inhalation, parenteral or topical use and may be administered to a patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions or suspensions and the like.

The compounds of the invention may be administered orally, for example, with an inert diluent or a comestible carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic purposes, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, sachets, chewing gums and the like. These preparations should contain at least 4% of the compound of the present invention as an active ingredient by unit weight, but may vary depending on the particular dosage form, and generally contain from 4% to about 70%. The amount of compound present in the composition is that amount which will provide a suitable dosage. Preferred compositions and formulations of the present invention may be determined by one skilled in the art.

Tablets, pills, capsules, lozenges and the like may also contain one or more of the following adjuvants: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose; disintegrating agents such as alginic acid, Primogel, and corn starch, etc.; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose and saccharin or flavoring agents such as peppermint, methyl salicylate or tangeretin. When the dosage unit form is a capsule, it may contain, in addition to the above materials, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the morphology of the dosage unit, such as coatings. Thus, tablets or pills may be coated with sugar, shellac or other enteric coating material. In addition to the compounds of the present invention, the syrups may contain sucrose as a sweetening agent and certain preservatives, colors and colorings and flavors. The materials used in preparing the various compositions should be pharmaceutically pure and non-toxic in the amounts applied.

For parenteral therapeutic administration, the compounds of the invention may be incorporated into solutions or suspensions. These preparations should contain at least 0.1% of the compound of the invention, but they may also be present in amounts of from 0.1% to 50% by weight. The amount of the compound of formula (1) in such compositions should be that which will provide a suitable dosage. Preferred compositions and formulations may be determined by one skilled in the art.

The compounds of the invention may also be administered by inhalation, e.g. in the form of an aerosol or a dry powder. The compounds of the invention or formulations thereof may be administered by liquefied or compressed gas or by release from a suitable pump system. Formulations for administration of the compounds of formula (1) for inhalation may be delivered in the form of monophasic, biphasic or triphasic systems. Different systems may be used for the aerosol administration of the compounds of formula (1) according to the invention. Dry powder formulations may be prepared by granulating or grinding a compound of formula (1) to a suitable particle size or by mixing the granulated or ground compound of formula (1) with a suitable carrier material such as lactose or the like. Inhalation delivery includes the necessary containers, activators, valves, internal containers, etc. Preferred aerosols and dry powders for administration by inhalation may be determined by one skilled in the art.

The compounds of the invention may also be administered topically, and when administered topically, the carrier may suitably comprise a solution, ointment or gel base. For example, the matrix may contain one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and ethanol, and emulsifiers and stability. The topical formulations contain a compound of formula (1) or a pharmaceutically acceptable salt thereof in a concentration of about 0.1 to about 10% w/v (weight per unit volume).

The solution or suspension may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and substances for adjusting the osmotic pressure such as sodium chloride or glucose. Parenteral formulations may be enclosed in ampoules, disposable syringes, or multiple dose vials of glass or plastic.

Example A Antagonist pairs to be used with histamine H ₁ Receptor-bound [ H ³ ]Antagonism of mepyramine

The person skilled in the art can use human histamine H₁Evaluation in rat brain or Chinese hamster ovary cells (CHOpcDNA3H1R cells) transfected with receptor genes determination of H intended for histamine antagonists₁Receptor affinity.

For studies in rat brains, young male rats were decapitated and brains were removed immediately. The cortex was isolated and used immediately or stored at-20 ℃. For studies in chinese hamster ovary cells, the fused cells were freshly scraped from the culture flask. The tissue or cells were homogenized with Polytron (set at 6 stops for 15 seconds) in 20ml of 50mM sodium potassium phosphate (pH7.4 at 4 ℃ C.)). The homogenate was centrifuged at 48000Xg for 12 minutes at 4 ℃. The pellet was resuspended in culture buffer (50mM sodium potassium phosphate, pH7.4, at room temperature, containing 0.1% bovine serum albumin) to a concentration of 40mg/ml using a Polytron (set at 6 th, 15 seconds) and immediately added to the tube to begin analysis. The protein content of the crude membrane suspension can be determined by o.h.lowery et al,journal of biochemistry, 193265 (1951).

Binding assays were performed in duplicate in 12X 75mM polypropylene tubes with 50mM sodium potassium phosphate (pH7.4, at room temperature) containing 0.1% bovine serum albumin. A radioligand, [ H ]³]Mepiramide was diluted to a concentration of 2nM in culture buffer and added to each tube (50. mu.l). Test Compounds are diluted in culture buffer (10)^-10M to 10^-5M) and added to a suitable tube (50. mu.l). Analysis was started by adding 250. mu.l of well mixed tissue suspension. The final culture volume was 0.5 ml. The analysis was performed at room temperature for 30 minutes. The culture was stopped by adding 3.5ml of 0.9% sodium chloride solution (4 ℃) and filtered through a GF/B funnel, previously soaked overnight in 0.1% polyethyleneimine, using a Brandel cell trap. The filters were quickly washed twice with two 3.5ml aliquots of culture buffer and transferred to scintillation vials. Ecolume (9ml) was added to the vial. The vial was shaken and allowed to stand for 4 hours before being counted by liquid scintillation photometry. Specific binding was determined by the difference between test tubes containing no test compound and test tubes containing 10 μ M promethazine. The total membrane bound radioactivity was typically about 5% of that added to the tube. According to M.D.Debacker et al,biochemical and biophysical research communications 197(3)Specific binding, as determined by the method of 1601(1991), is typically 75% to 90% of total binding.

The molar filter of the compound producing 50% inhibition of ligand binding at the screening dose is IC₅₀Values, expressed as the cumulative mean (± s.e.m.) of n independent experiments.

Example B Proposed antagonist pairs with NK ₁ Antagonism of receptor-bound iodotachykinins

One skilled in the art can determine the NK intended for tachykinin antagonists by evaluation in guinea pig lungs (Keystone Biologicals, Cleveland, OH)₁Receptor affinity. The tissue was homogenized in 15 volumes of 50mM Tris-HCl buffer (pH7.4, 4 ℃) with Polytron and centrifuged. Resuspending the pellet in Tris-HCl buffer and centrifuging; the precipitate was washed twice by resuspension. The final pellet was resuspended in culture buffer at a concentration of 40mg/ml and kept at room temperature for at least 15 minutes prior to use.

250 μ l of membrane preparation was added in duplicate to 0.1nM¹²⁵Substance I-Bolton Hunter Lys-3 labeled substance P elicits receptor binding in a solution of a final volume of 500. mu.l of buffer containing 50mM Tris-HCl (pH7.4 at room temperature), 0.1% bovine serum albumin, 2mM manganese dichloride, 40. mu.g/ml bacitracin, 4. mu.g/ml each of leupeptin and chymostatin, 1. mu.M thiorphan, and various doses of tachykinin antagonist. Incubation at room temperature for 90 minutes; the incubation was terminated by adding 50mM Tris-HCl buffer (pH7.4, 4 ℃) and vacuum filtered through GF/B filters previously soaked in 0.1% polyethyleneimine. The filter bound radioactivity was quantified using a gamma counter. Non-specific binding is defined as binding in the presence of 1 μ MP material.

Specific binding was calculated by subtracting non-specific binding from total binding. The competition for binding of the iodo-P substance to the test compound or standard is expressed as a percentage of the maximum competition. IC of various test Compounds₅₀Values (concentration required to inhibit 50% receptor binding) were generated by non-linear regression using an iterative curve fitting method (GraphPAD Inplot, San Diego, CA).

Example C Histamine in Guinea pig ileum (H) ₁ ) Antagonism

One skilled in the art can confirm that the compounds of the present invention are H in vivo by evaluating the ability of the compounds to inhibit histamine-mediated smooth muscle contraction₁A receptor antagonist. Will weigh 200-450 grams of male Hartlev guinea pigs were sacrificed by carbon dioxide inhalation. An approximately 20 cm long section of ileum was removed and cut into 2 cm sections. Each ileum was placed in a 37 ℃ organ bath containing Tyrode's solution with continuous passage of 95% O₂/5％CO₂. Tyrode's solution composition was as follows: 136.9mM of sodium chloride, 2.68nM of potassium chloride, 1.8mM of calcium chloride, 0.42mM of sodium dihydrogen phosphate, 11.9mM of sodium bicarbonate and 5.55mM of glucose. The concentration was measured with an equivalent transducer (Grass FTO3C) and recorded on a multi-track recorder and/or computer. The experiment was started after loading 1.0 gram of tension on the ileal strip and allowing it to equilibrate for at least 30 minutes. The tissue is pre-incubated with vehicle or test compound at various concentrations, followed by histamine stimulation.

Competitive H₁The receptor antagonist parallels the dose-response curve of histamine to the right with no drop-back in the maximal response.

The potency of antagonism was determined by the magnitude of the shift and expressed as pA₂Values are expressed as the negative logarithm of the molar concentration of antagonist that shifts the dose-response curve two-fold to the right. The pA is₂Values can be calculated using Schild analysis. Arunlakshana and h.o.schild, br.j.pharmacolchemither, 14, 48-58 (1958). When the slope of the line obtained by Schild analysis is not significantly different from (1), the compound acts like a competitive antagonist.

Example D Antagonism of tachykinin-induced phosphatidylinositol turnover in vivo by antagonists contemplated

One skilled in the art can determine the presence or absence of NK by₁NK confirmation by substance P-induced phosphatidylinositol (PI, phosphoinositide) accumulation in UCll cells in the presence of receptor antagonists₁Receptor antagonism. Two or three days prior to analysis, cells were seeded in 24-well culture plates at 125000 cells/well. 20-24 hours before analysis, cells were plated with 0.5ml of 0.2. mu.M myo- [2-H (N)]Inositol (American Radiolabed Chemicals Inc., specific Activity; 20. mu. Ci/mmol) was loaded. Will be provided withThe cultured cells were maintained at 37 ℃ and 5% CO₂In the environment.

On the day of analysis, the medium was aspirated and the cells were cultured in RPMI-1640 medium containing 40. mu.g/ml of bacitracin, 4. mu.g/ml each of leupeptin and chymostatin, 0.1% bovine serum albumin, 10. mu.M thiorphan and 10mM lithium chloride. After 15 minutes, 0.1ml of test compound was added to the cells. After another 15 minutes, various concentrations of substance P were added to UCll cells to initiate the reaction, followed by 5% CO at 37 deg.C₂Incubate for 60 minutes in ambient conditions to a final volume of 1 ml. To terminate the reaction, the medium was aspirated and methanol (0.1ml) was added to each well. Two equal portions of methanol (0.5ml) were added to the culture wells and the cells were collected in chloroform-resistant tubes. Chloroform (1ml) was added to each tube, followed by double distilled water (0.5 ml). The sample was vortexed for 15 seconds and centrifuged at 1700Xg for 10 minutes. An aliquot (0.9ml) of the aqueous phase (top layer) was removed and double distilled water (2ml) was added. The mixture was vortexed and loaded onto a 50% Bio-Rad AG1-X8 (formate-type, 100-200 mesh) exchange column (Bio-Rad Laboratories, Hercules, Calif.). The column was eluted sequentially with the following eluents: 1)10ml of double distilled water, 2)5ml of 5mM disodium tetraborate/60 mM sodium formate, and 3)2ml of 1M ammonium formate/0.1M formic acid. The third eluate was collected and counted in 9ml scintillation fluid. A50. mu.l aliquot of the organic phase (bottom layer) was removed, dried in scintillation vials and counted in 7ml of scintillation fluid.

DPM (Total inositol phosphate) in each aqueous phase and DPM in each organic phase (Total binding [ 50 ] l) were calculated for each sample³H]Inositol). Data are expressed as agonist-induced³H]-cumulative percentage of inositol phosphates at basal level. This ratio in the presence of test compound and/or standard is compared to the ratio of a control sample (i.e., without stimulatory agonist).

Dose response plots were generated and the ability of the test compounds to inhibit tachykinin-induced phosphatidylinositol conversion was determined by means of a computer program. The data represent the percent stimulation of basal levels of total inositol phosphate accumulation corrected for the maximal response to substance P production. The dose response curve was used for Schild analysis,the resulting value represents the strength of the competitive antagonist as pA₂Is represented by the formula pA₂Is the negative logarithm of the molar concentration of antagonist that reduces the effect of a dose of agonist to half the expected effect. The slope of the line obtained by Schild analysis was not significantly different from (1), and the compound acted as a competitive antagonist.

Example E Evaluation H ₁ (or NK) ₁ ) In vivo antagonism

One skilled in the art can confirm that the compounds of the present invention mediate an immediate allergic response in vivo by evaluating the ability of the compounds to inhibit histamine (or substance P) induced wheal formation in guinea pigs. Animals were anesthetized with pentobarbital (intraperitoneally). The dorsal skin was shaved and the shaved surface was injected subcutaneously with histamine (or substance P) at the appropriate time after application of the test compound. The dosage, route and timing of administration can vary according to the experimental design. The design of such experiments is well known in the art. Immediately after subcutaneous stimulation, the animals were injected intravenously with 1% Evan's blue dye to visualize the wheal. By CO at appropriate times after stimulation of the animals₂Animals were sacrificed by inhalation. The skin was removed and the diameter of each wheal was measured in two perpendicular directions.

The wheal response was used as an index for the edema response. The percent inhibition of the wheal response was calculated by comparing the drug treated group to the vehicle treated group. Dose response inhibition curves were subjected to linear regression to determine ED₅₀Values, expressed in mg/kg, ED₅₀Is a dose of the compound that inhibits histamine-induced cutaneous wheal by 50%.

Example F In vivo NK ₁ Evaluation of antagonism

One skilled in the art can determine that the compounds of the invention are NK cells in vivo by evaluating the ability of the compounds to inhibit substance P-induced plasma protein extravasation in guinea pig trachea₁A receptor antagonist. Substance P induced protein passageLeakage of the posterior capillary venules can be estimated by measuring the accumulation of Evans blue dye in the guinea pig trachea.

When the antagonist is administered intravenously, the animals are anesthetized with pentobarbital and then injected with Evans blue dye (20mg/kg, intravenously, prepared in 0.9% sodium chloride solution). One minute after dye injection, antagonist was administered intravenously, followed by substance P (0.3nmol/kg, intravenously), and 5 minutes later, excess dye was removed from the circulation by transapical infusion with 50ml of 0.9% sodium chloride solution. The trachea and major bronchi were removed, blotted dry and weighed.

When the preparation is administered orally, the animals are anesthetized 1 hour after administration with pentobarbital and injected with Evans blue dye (20mg/kg, intravenously, prepared in 0.9% sodium chloride solution). Substance P (0.3nmol/kg, i.v.) was administered intravenously one minute after dye injection, and 5 minutes later, excess dye was removed from circulation by transcardial infusion with 50ml of 0.9% sodium chloride solution. The trachea and major bronchi were removed, blotted dry and weighed.

The tissue was extracted in formamide at 50 ℃ for 24 hours and the dye (620nm) was quantified spectrophotometrically. This value was subtracted from the blank (dye only, no agonist). Calculation of ED from Linear regression analysis₅₀(dose of compound that inhibits substance P-induced plasma protein extravasation by 50%).

Claims

1. A compound of the formulaWherein R' is 1 to3 substituents, each independently selected from hydrogen, CF₃、-OCF₃And C₁-C₆An alkoxy group; r "is hydrogen or a group selected from:

wherein R is₂₀Selected from hydrogen, C₁-C₄Alkyl and-CF₃；Ar₁Is a group selected from:

wherein

R₁Is 1 to3 substituents, each independently selected from hydrogen, halogen, -CF₃、C₁-C₆Alkyl and C₁-C₆An alkoxy group;

R₂is 1 to 2 substituents, each independently selected from hydrogen, halogen, C₁-C₆Alkyl and C₁-C₆An alkoxy group; x₁And X₂As defined in one of parts A), B) or C): A) x₁Is hydrogen;

X₂is a group selected from:

wherein

p is 1 or 2;

R₅is hydrogen or hydroxy;

Ar₂is a group selected from:

wherein

R₆Is 1 to3 substituents, each independently selected from hydrogen, halogen, -CF₃、C₁-C₆

Alkyl radical, C₁-C₆Alkoxy and-CO₂R₉Wherein R is₉Selected from hydrogen and C₁-C₄An alkyl group;

R₇is 1 to 2 substituents, each independently selected from hydrogen, halogen, C₁-C₆Alkyl radical

And C₁-C₆An alkoxy group;

R₈selected from hydrogen, -CH₃and-CH₂OH；

R₁₀Selected from hydrogen, C₁-C₄Alkyl and benzyl; z is selected from hydrogen and C₁-C₆Alkyl, - (CH)₂)_w-O-(CH₂)_t-Y、-(CH₂)_fA、-(CH₂)_uCO₂R₁₁、-(CH₂)_uC(O)NR₁₂R₁₃、-(CH₂)_qC(O)(CH₂)_hCH₃、-(CH₂)_w′-O-Ar₃、-CH₂CH₂OCF₃、-CH₂CF₃、-CH₂CH₂CH₂CF₃、-(CH₂)₂CH＝CH₂、-CH₂CH＝CH₂、-CH₂CH＝CHCH₃、-CH₂CH＝CHCH₂CH₃、-CH₂CH＝C(CH₃)₂and-CH₂OCH₂CH₂Si(CH₃)₃

Wherein

w is an integer from 2 to 5;

t is an integer from 1 to 3;

f is 2 or 3;

u is an integer from 1 to 4;

g is an integer from 1 to 3;

h is an integer from 0 to 3; w' is an integer from 2 to 4; y is selected from hydrogen, -CF₃、-CH＝CH₂、-CH＝C(CH₃)₂and-CO₂R₁₄Wherein R is₁₄Selected from hydrogen and C₁-C₄An alkyl group; a is selected from-NR₁₅R₁₆Acetamido and morpholino wherein R₁₅Selected from hydrogen and C₁-C₄Alkyl and R₁₆Is C₁-C₄An alkyl group; r₁₁Selected from hydrogen and C₁-C₄An alkyl group; r₁₂Selected from hydrogen, C₁-C₄Alkyl and benzyl; r₁₃Selected from hydrogen and C₁-C₄An alkyl group; ar (Ar)₃Is a group selected from:

wherein

v is an integer from 1 to 3;

R₁₇selected from hydrogen and-CO₂R₁₈Wherein R is₁₈Selected from hydrogen and C₁-C₄An alkyl group; B) x₁Is a hydroxyl group;

X₂is a group selected from:wherein p and R₃Z and Ar₃The definition is as before; C) x₂Is a group of the formula:

wherein R is₃And R₄The definition is as before; and is

X₁And Z₁Together with X₁And Z₁Another bond is formed between the carbon atoms of the group; and stereoisomers and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein X₁Is hydrogen.

3. The compound of claim 2, wherein X₂Is a group of the formula:wherein R is₃、Ar₂And p is as defined in claim 1.

4. The compound of claim 3, wherein R₃Is hydrogen, p is 1 and Ar₂Is 4-fluorophenyl.

5. The compound of claim 3, wherein R₃Is hydrogen, p is 1 and Ar₂Is pyridin-2-yl.

6. The compound of claim 3, wherein R₃Is hydrogen, p is 1 and Ar₂Is furan-2-yl.

7. The compound of claim 3, wherein R₃Is hydrogen, p is 1 and Ar₂Is furan-3-yl.

8. The compound of claim 2, wherein X₂Is a group of the formula:wherein R is₃And Z is as defined in claim 1.

9. The compound of claim 8, wherein Z is- (CH)₂)_w-O-(CH₂)_t-Y, wherein w, t and Y are as defined in claim 1.

10. The compound of claim 9, wherein w is 2.

11. The compound of claim 10, wherein Z is 2-ethoxyethyl.

12. The compound of claim 1, wherein X₁Is a hydroxyl group.

13. The compound of claim 12, wherein X₂Is a group of the formula:wherein R is₃、Ar₂And p is as defined in claim 1.

14. The compound of claim 13, wherein R₃Is hydrogen, p is 1 and Ar₂Is 4-fluorophenyl.

15. The compound of claim 1, wherein the compound is (+) -or (-) -N-methyl-N- (4- (4- (1- (pyridin-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3, 4, 5-trimethoxybenzamide or a mixture thereof.

16. The compound of claim 1, wherein the compound is (+) -or (-) -N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3, 4-dichlorophenyl) butyl) benzamide or a mixture thereof.

17. A pharmaceutical composition comprising a compound of claim 1.

18. A pharmaceutical composition comprising a compound of claim 1 in admixture with one or more inert carriers.

19. Use of a compound according to claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis.

20. Use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the treatment of asthma.

21. Use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the treatment of emesis.

22. Use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the treatment of inflammatory bowel disease.