HK1104031B

HK1104031B - Benzimidazolone carboxylic acid derivatives

Info

Publication number: HK1104031B
Application number: HK07108217.3A
Authority: HK
Inventors: 安藤幸司; 井口聪; 德晃村濑; 村田好德; 沼田丰治; 曾根大纪; 内田力; 上木达生
Original assignee: 辉瑞大药厂
Priority date: 2004-06-15
Filing date: 2005-06-01
Publication date: 2012-10-12

Description

Benzimidazolone carboxylic acid derivatives

Technical Field

The present invention relates to benzimidazolone carboxylic acid derivatives. These compounds have selective 5-HT₄Receptor agonistic activity. The invention also relates to a pharmaceutical composition containing the derivative and application of the derivative in treating 5-HT₄Receptor activity, especially 5-HT₄Methods of treatment and uses for diseases mediated by receptor agonist activity.

Background

In general, 5-HT has been found₄Receptor agonists are useful in the treatment of a wide variety of diseases, such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, Irritable Bowel Syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disorders, Alzheimer's disease, cognitive disorders, emesis, migraine, neurological disorders, pain, cardiovascular disease, heart failure, cardiac arrhythmias, diabetes, and apnea syndrome (see TiPs, 1992, 13, 141; Ford A.P.D.W. et al, Med.Res.Rev., 1993, 13, 633; Gullikson G.W. et al, DrugDev. res., 1992, 26, 405; richard m. eglen et al, TiPS, 1995, 16, 391; bockaert j, et al, CNS Drugs, 1, 6; romanelli m.n. et al, arzheimforsch/Drug res, 1993, 43, 913; kaumann a. et al, nauyn-Schmiedeberg's 1991, 344, 150; and Romanelli m.n. et al, Arzheim forsch./Drug res., 1993, 43, 913).

WO 94/00449 discloses as 5-HT₄Agonists or antagonists and/or 5-HT₃An antagonist benzimidazolone compound. In particular, a compound represented by the following formula is disclosed as example 10:

compound A

There is a need to provide novel 5-HT as good drug candidates₄An agonist. In particular, preferred compounds should react with 5-HT₄The receptors bind strongly while showing little affinity for other receptors and show functional activity as agonists. They should be well absorbed from the gastrointestinal tract, be metabolically stable and have favourable pharmacokinetic properties. When receptors in the central nervous system are targeted then they should be free to cross the blood brain barrier, and when receptors in the peripheral nervous system are selectively targeted then they should not cross the blood brain barrier. They should be non-toxic and demonstrate few side effects. Furthermore, the ideal drug candidate should exist in a physical form that is stable, non-hygroscopic and easy to formulate.

Disclosure of Invention

In the present invention, it has been found that (1) replacement of the quinuclidine with a piperidine/pyrrolidine ring increases p-5-HT₄Receptor affinity, and/or (2) introduction of a carboxyl moiety reduces affinity for dofetilide, such that QT prolongation is prevented.

Thus, it has now surprisingly been found that the inventionThe compounds have a greater selectivity for 5-HT than the prior art₄Agonistic activity and/or increased affinity for dofetilide and are therefore useful in the treatment of inflammation caused by 5-HT₄Activity-mediated disease conditions such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, Irritable Bowel Syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disease, heart failure, arrhythmia, diabetes and apnea syndrome (particularly due to opioid administration).

The present invention provides compounds of the following formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein

A is alkylene having 1 to 4 carbon atoms which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen atoms, alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents may together with the carbon atom to which they are attached form a 3-, 4-, 5-or 6-membered ring optionally containing at least one heteroatom selected from N, O and S;

R¹is isopropyl or cyclopentyl;

R²is a hydrogen atom, a halogen atom or a hydroxyl group;

R³is carboxy, tetrazolyl, 5-oxo-1, 2, 4-Oxadiazol-3-yl or 5-oxo-1, 2, 4-thiadiazol-3-yl; and is

m is an integer of 1 or 2.

An embodiment of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as described above, wherein:

a is an alkylene group having 1 to 4 carbon atoms, which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms, hydroxy-alkyl groups having 1 to 4 carbon atoms and alkoxy-alkyl groups having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents may together with the carbon atom to which they are attached form a 6-membered ring optionally containing at least one heteroatom selected from N, O and S;

R¹is isopropyl or cyclopentyl;

R²is a hydrogen atom, a halogen atom or a hydroxyl group;

m is an integer of 1 or 2.

a is an alkylene group having 1 to 4 carbon atoms substituted with 1 to 4 substituents independently selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms, hydroxy-alkyl groups having 1 to 4 carbon atoms, and alkoxy-alkyl groups having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents may together with the carbon atom to which they are attached form a 5-membered ring optionally containing at least one heteroatom selected from N, O and S;

R¹is isopropyl or cyclopentyl;

R²is a hydrogen atom, a halogen atom or a hydroxyl group;

m is an integer of 1 or 2.

In one embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as described above, wherein:

a is an alkylene group having 1 to 4 carbon atoms substituted with 1 to 4 substituents independently selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms, hydroxy-alkyl groups having 1 to 4 carbon atoms, and alkoxy-alkyl groups having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents may together with the carbon atom to which they are attached form a3 to 4-membered ring optionally containing at least one heteroatom selected from N, O and S;

R¹is isopropyl or cyclopentyl;

R²is a hydrogen atom, a halogen atom or a hydroxyl group;

m is an integer of 1 or 2.

Furthermore, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, each as described herein, for use in the manufacture of a medicament for the treatment of inflammation caused by 5-HT₄Receptor activity, especially 5-HT₄Use in the manufacture of a medicament for treating a disease condition mediated by agonistic activity.

Preferably, the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, each as described herein, in the manufacture of a medicament for the treatment of a disease selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, Irritable Bowel Syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, alzheimer's disease, cognitive disorders, emesis, migraine, neurological disease, pain, cardiovascular disease, heart failure, arrhythmia, diabetes and apnea syndrome.

Furthermore, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, each as described herein, and a pharmaceutically acceptable carrier for the compound.

Furthermore, the present invention provides a method of treating a mammal suffering from 5-HT₄A method of treating a disease condition mediated by receptor activity, which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, each as described herein.

From 5-HT₄Examples of disease conditions mediated by receptor activity include, but are not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, Irritable Bowel Syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, alzheimer's disease, cognitive disorders, emesis, migraine, neurological disease, pain, cardiovascular disease, heart failure, cardiac arrhythmia, diabetes, and apnea syndrome.

Furthermore, the present invention provides a compound of formula (XI):

or a salt thereof, wherein:

R²is a hydrogen atom, a hydroxyl group or a halogen atom;

R⁶is a hydrogen atom or an amino-protecting group;

y is an alkoxy group having 1 to 4 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an imidazolyl group, a phthalimido group, a succinimidyl group or a sulfonyl group; and m is 1 or 2.

Furthermore, the present invention provides compounds of formula (IXa):

or a salt thereof, wherein:

a is alkylene having 1 to 4 carbon atoms which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen atoms, alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents may together with the carbon atom to which they are attached form a3 to 6-membered ring optionally containing at least one heteroatom selected from N, O and S;

R²is a hydrogen atom, a hydroxyl group or a halogen atom;

R³is a hydroxy or carboxy-protecting group;

R⁶is a hydrogen atom or an amino-protecting group; and is

m is 1 or 2.

The compounds of the invention may exhibit lower toxicity, good absorption, distribution, good solubility, lower protein binding affinity, lower drug-drug interactions and good metabolic stability.

Detailed Description

In the compounds of the invention:

when a is an alkylene group having 1 to 4 carbon atoms, it may be a straight chain group, and examples include, but are not limited to, methylene, ethylene, trimethylene and tetramethylene groups. Of these, methylene and ethylene are preferred, and ethylene is most preferred.

When the substituent of a is an alkyl group having 1 to 4 carbon atoms, it may be a straight or branched chain group, and examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Preferred of these are alkyl groups having 1 to 3 carbon atoms; more preferred are methyl, ethyl, propyl and isopropyl; and most preferred are methyl and ethyl.

When the substituent of Y is an alkoxy group having 1 to 4 carbon atoms, this represents an oxygen atom substituted with the alkyl group, and examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. Among these, preferred are alkyl groups having 1 to 2 carbon atoms; and more preferably methoxy.

When the substituent of Y is a dialkylamino group having 2 to 8 carbon atoms, this represents an amino group substituted with two of the alkyl groups, and examples include, but are not limited to, dimethylamino, N-methyl-N-ethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, and N, N-bis (1-methylpropyl) amino. Among these, preferred is a dialkylamino group having 2 to 4 carbon atoms; more preferred are dimethylamino, N-methyl-N-ethylamino and diethylamino.

When the substituent of a is hydroxy-alkyl having 1 to 4 carbon atoms, it may be straight-chain or branched, and examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-methylethyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 3-hydroxy-2-methylpropyl and 3-hydroxy-1-methylpropyl. Of these, preferred are hydroxy-alkyl groups having 1 to 3 carbon atoms; more preferred are hydroxymethyl, 2-hydroxyethyl and 2-hydroxypropyl, and most preferred are hydroxymethyl and 2-hydroxyethyl.

When the substituent of a is alkoxy-alkyl having 2 to 6 carbon atoms, it may be a straight or branched chain group, and examples include, but are not limited to, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-methoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2-methoxypropyl, 2-methoxy-1-methylethyl, 4-methoxybutyl, 4-ethoxybutyl, 3-methoxybutyl, 2-methoxybutyl, 3-methoxy-2-methylpropyl and 3-methoxy-1-methylpropyl. Of these, preferred are alkyloxy-alkyl groups having 2 to 4 carbon atoms; more preferred are methoxymethyl, 2-methoxyethyl and 3-methoxypropyl; and most preferred are 2-methoxyethyl and 3-methoxypropyl.

When any 2 non-halogen substituents may form together with the carbon atom to which they are attached a3, 4, 5 or 6-membered ring optionally containing at least one heteroatom selected from N, O and S, the ring may be cycloalkyl or heterocyclyl and examples include cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclohexyl, hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl, methoxycyclopropyl, methoxycyclopentyl, methoxycyclohexyl, tetrahydrofuranyl and tetrahydropyranyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxycyclohexyl and tetrahydropyranyl, and most preferably cyclobutyl, cyclopentyl, cyclohexyl and tetrahydropyranyl.

When R is⁶When an amino-protecting group, it represents a protecting group that can be cleaved by chemical means such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and is described by t.w. greene et al (John Wiley)&Sons, 1999) and examples include, but are not limited to, benzyl, C₂H₅O(C＝O)-、CH₃(C ═ O) -, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyloxycarbonyl, and tert-butoxycarbonyl. Among these groups, preferred is tert-butoxycarbonyl.

When R is⁴In the case of the carboxyl-protecting group, it represents a protecting group that can be cleaved by chemical means such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and is described by t.w. greene et al (John Wiley)&Sons, 1999) and examples include, but are not limited to, methoxy, ethoxy, t-butoxy, methoxymethoxy, 2, 2, 2-trichloroethoxy, benzyloxy, diphenylmethoxy, trimethylsilyloxy, t-butyldimethylsilyloxy, and allyloxy, of which preferred is t-butoxy, methoxy, or ethoxy.

When R is¹And when the substituent of A represents a halogen atom, these may be a fluorine, chlorine, bromine or iodine atom, and among these, a fluorine or chlorine atom is preferred.

The term "treatment" as used herein refers to curative, palliative and prophylactic treatment, including reversing, palliating, preventing or inhibiting the progression of the disorder or disease condition to which the term applies, or one or more symptoms of the disorder or disease condition.

The articles "a" and "an" as used herein refer to both the singular and the plural of the referenced item, unless otherwise specified.

A preferred class of compounds of the invention are those of formula (I) or a pharmaceutically acceptable salt or solvate thereof, each as described herein, wherein:

(A)R¹is isopropyl;

(B)R²is a hydrogen atom, a fluorine atomA proton or a hydroxyl group;

(C)R²is a hydrogen atom;

(D)R³is carboxy or tetrazolyl;

(E)R³is a carboxyl group;

(F) a is an alkylene group having 1 to 2 carbon atoms, which is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms, hydroxy-alkyl groups having 1 to 4 carbon atoms and alkoxy-alkyl groups having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents may together with the carbon atom to which they are attached form a 6-membered ring optionally containing at least one heteroatom selected from N, O and S;

(G) a is alkylene having 1 to 2 carbon atoms, which alkylene group is substituted with 2 geminal substituents independently selected from the group consisting of halogen atom, alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms (i.e. substituents on the same carbon atom), wherein non-halogen geminal substituents may form together with the carbon atom to which they are attached a 6-membered ring optionally containing at least one heteroatom selected from N, O and S;

(H) a is alkylene having 1 to 2 carbon atoms substituted with 2 substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein any 2 of the substituents may form together with the carbon atom to which they are attached a 5-membered ring optionally containing at least one heteroatom selected from N, O and S;

(I) a is alkylene having 1 to 2 carbon atoms, which alkylene is substituted with 2 geminal substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein the geminal substituents may form together with the carbon atom to which they are attached a 5-membered ring optionally containing at least one heteroatom selected from N, O and S;

(J) a is alkylene having 1 to 2 carbon atoms substituted with 2 substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein the substituents may form together with the carbon atom to which they are attached a3 to 4-membered ring optionally containing at least one heteroatom selected from N, O and S;

(K) a is alkylene having 1 to 2 carbon atoms, which alkylene is substituted with 2 geminal substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein the geminal substituents may form together with the carbon atom to which they are attached a 3-to 4-membered ring optionally containing at least one heteroatom selected from N, O and S;

(L) A is

(M) A is

(N) A is

(O) A is

(P) A is

(Q) m is an integer of 2.

Particularly preferred compounds of the invention are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein

(R)R¹Is isopropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is carboxy or tetrazolyl; a is an alkylene group having 1 to 2 carbon atoms, which is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms, hydroxy-alkyl groups having 1 to 4 carbon atoms and alkoxy-alkyl groups having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents may together with the carbon atom to which they are attached form a 6-membered ring optionally containing at least one heteroatom selected from N, O and S; and m is an integer 2;

(S)R¹is isopropyl; r²Is a hydrogen atom; r³Is carboxy or tetrazolyl; a is alkylene having 1 to 2 carbon atoms, which alkylene is substituted with 2 geminal substituents independently selected from the group consisting of halogen atom, alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein the geminal substituents may form together with the carbon atom to which they are attached a 6-membered ring optionally containing at least one heteroatom selected from N, O and S; and m is an integer 2;

(T)R¹is isopropyl; r²Is a hydrogen atom; r³Is carboxy or tetrazolyl; a isAnd m is an integer 2;

(U)R¹is different fromPropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is a carboxyl group; a is alkylene having 1 to 2 carbon atoms, which is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of halogen atom, alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein any 2 non-halogen geminal substituents may together with the carbon atom to which they are attached form a 6-membered ring optionally containing at least one heteroatom selected from N, O and S; and m is an integer 2;

(V)R¹is isopropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is a carboxyl group; a isAnd m is an integer 2;

(W)R¹is isopropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is carboxy or tetrazolyl; a is alkylene having 1 to 2 carbon atoms substituted with 2 substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein any 2 of the substituents may form together with the carbon atom to which they are attached a 5-membered ring optionally containing at least one heteroatom selected from N, O and S; and m is an integer 2;

(X)R¹is isopropyl; r²Is a hydrogen atom; r³Is carboxy or tetrazolyl; a is alkylene having 1 to 2 carbon atoms, which alkylene is substituted with 2 geminal substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein said geminal substituents may form together with the carbon atom to which they are attached a 5-membered ring optionally containing at least one heteroatom selected from N, O and S; and m is an integer 2;

(Y)R¹is isopropyl; r³Is a hydrogen atom; r³Is carboxy or tetrazolyl; a isAnd m is an integer 2;

(Z)R¹is isopropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is a carboxyl group; a is alkylene having 1 to 2 carbon atoms substituted with 2 substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein any 2 of the substituents may form together with the carbon atom to which they are attached a 5-membered ring optionally containing at least one heteroatom selected from N, O and S; and m is an integer 2;

(AA)R¹is isopropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is a carboxyl group; a isAnd m is an integer 2;

(AB)R¹is isopropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is carboxy or tetrazolyl; a is alkylene having 1 to 2 carbon atoms substituted with 2 substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein the substituents may form together with the carbon atom to which they are attached a3 to 4-membered ring optionally containing at least one heteroatom selected from N, O and S; and m is an integer 2;

(AC)R¹is isopropyl; r²Is a hydrogen atom; r³Is carboxy or tetrazolyl; a is an alkylene group having 1 to 2 carbon atoms, which is substituted with 2 geminal substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxy-alkyl having 1 to 4 carbon atoms and alkoxy-alkyl having 2 to 6 carbon atoms, wherein the geminal substituents may form together with the carbon atom to which they are attachedA3 to 4-membered ring optionally containing at least one heteroatom selected from N, O and S; and m is an integer 2;

(AD)R¹is isopropyl; r²Is a hydrogen atom; r³Is carboxy or tetrazolyl; a isAnd m is an integer 2;

(AE)R¹is isopropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is a carboxyl group; a is an alkylene group having 1 to 2 carbon atoms substituted with 2 substituents independently selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms, hydroxy-alkyl groups having 1 to 4 carbon atoms, and alkoxy-alkyl groups having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents may together with the carbon atom to which they are attached form a3 to 4-membered ring optionally containing at least one heteroatom selected from N, O and S; and m is an integer 2;

(AF)R¹is isopropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is a carboxyl group; a isAnd m is an integer 2;

(AG)R¹is isopropyl; r²Is a hydrogen atom, a fluorine atom or a hydroxyl group; r³Is a carboxyl group; a is(ii) a And m is an integer 2;

(AH)R¹is isopropyl; r²Is a hydrogen atom; r³Is carboxy or tetrazolyl; a is(ii) a And m is an integer 2.

One embodiment of the present invention provides a compound selected from the group consisting of:

4- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } tetrahydro-2H-pyran-4-carboxylic acid;

1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclohexanecarboxylic acid;

1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopentanecarboxylic acid;

1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopropanecarboxylic acid;

1- { [ 4-hydroxy-4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclohexanecarboxylic acid;

1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclobutanecarboxylic acid; and

a pharmaceutically acceptable salt or solvate thereof.

and pharmaceutically acceptable salts and solvates thereof.

1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclobutanecarboxylic acid;

and pharmaceutically acceptable salts and solvates thereof.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and base salts (including disalts) thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptanoate, gluconate, glucuronate, hexafluorophosphate, salicylate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogenphosphate, glucarate, stearate, succinate, citrate, dihydrogenphosphate, glucarate, stearate, succinate, salicylate, and salicylate, Tartrate and trifluoroacetate.

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, dibenzylethylenediamine salts, calcium salts, choline salts, diethylamine salts, dialcohol salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

For reviews on suitable salts, see Stahl and Wermuth, the handbook for pharmaceutical salts: properties, Selection and uses (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) "(Wiley-VCH, Weinheim, Germany, 2002). Pharmaceutically acceptable salts of the compounds of formula (I) can be readily prepared by mixing the compounds of formula (I) together as desired with solutions of the desired suitable acids or bases. The salt may precipitate from solution and be collected by filtration, or may be recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to nearly unionized.

The compounds of the invention may exist in both non-solvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

Pharmaceutically acceptable solvates of the invention include hydrates and crystalline solvents therein which are isotopically substituted, e.g. D₂O、d₆-acetone, d₆-solvates of DMSO.

Included within the scope of the present invention are complexes such as clathrates, drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the solvates described above. Also included are complexes of drugs comprising two or more organic and/or inorganic components present in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For a review of such complexes, seeJ Pharm Sci64(8), 1269-.

All references to compounds of formula (I) and pharmaceutically acceptable derivatives thereof hereinafter include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

The term "compounds of the invention" means, unless otherwise indicated, the compounds of formula (I) as defined hereinbefore, the polymorphs, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined hereinafter, and the isotopically labeled compounds of formula (I).

So-called "prodrugs" of the compounds of formula (I) are also within the scope of the present invention. Thus, certain derivatives of compounds of formula (I) which themselves have little or no pharmacological activity may be converted, e.g. by hydrolytic cleavage, into compounds of formula (I) having the desired activity when administered into or onto the body. This derivative is referred to as a "prodrug". Further information on prodrug use can be found in "Pro-drugs as Novel Delivery Systems, volume 14, ACS symposium series (T. Higuchi and W Stella) and" Bioreversible Carriers in drug design ", Pergamon Press, 1987(E B Roche editors, American pharmaceutical Association).

Prodrugs according to the invention may be produced, for example, by substituting the appropriate functionality present in a compound of formula (I) with certain moieties known to those skilled in the art, known as "prodrug moieties", as described, for example, in H Bundgaard, in "Design of Prodrugs" (Elsevier, 1985).

Some examples of prodrugs according to the invention include:

(i) in the case where the compound of formula (I) contains a carboxylic acid functionality (-COOH), the ester thereof, for example, with C₁-C₈Alkyl replacing hydrogen;

(ii) in the case where the compound of formula (I) contains an alcohol functionality (-OH), the ether thereof, for example, is as C₁-C₆Replacement of hydrogen by alkanoyloxymethyl; and

(iii) the compounds of formula (I) contain a primary or secondary amino functionality (-NH)₂or-NHR, where R.noteq.H), acyl thereofAmines, e.g. with C₁-C₁₀Alkanoyl displaces one or two hydrogens.

Further examples of substituent groups according to the foregoing examples and examples of other prodrug types can be found in the above references.

Finally, certain compounds of formula (I) may themselves be useful as prodrugs of other compounds of formula (I).

The compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. In case the compound of formula (I) comprises an alkenyl or alkenylene group, geometrical cis/trans (or Z/E) isomers are possible. In the case of compounds comprising, for example, a ketone or oxime group or an aromatic moiety, tautomerism ('tautomerism') may occur. Thus a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism and mixtures of one or more thereof. Also included are acid addition or base salts in which the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., DL-tartrate or DL-arginine.

The cis/trans isomers may be separated by conventional techniques known to those skilled in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Performance Liquid Chromatography (HPLC).

Alternatively, the racemate (or racemic precursor) may be reacted with an appropriate optically active compound (e.g. an alcohol) or, in the case of compounds of formula (I) containing an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixtures can be separated by chromatography and/or fractional crystallization and one or both of the diastereomers can be converted to the corresponding pure enantiomers by methods well known to those skilled in the art.

The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon (typically heptane or hexane) comprising from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentrating the eluate provides an enriched mixture.

Stereoisomeric aggregates can be isolated by conventional techniques known to those skilled in the art-see, e.g., E L Eliel, "Stereochemistry of organic Compounds" (Wis, New York, 1994).

The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, for example²H and³h; isotopes of carbon, e.g.¹¹C、¹³C and¹⁴c; isotopes of chlorine, e.g.³⁶Cl; isotopes of fluorine, e.g.¹⁸F; isotopes of iodine, e.g.¹²³I and¹²⁵i; isotopes of nitrogen, e.g.¹³N and¹⁵n; isotopes of oxygen, e.g.¹⁵O，¹⁷O and¹⁸o; isotopes of phosphorus, e.g.³²P; and isotopes of sulfur, e.g.³⁵S。

Certain isotopically-labeled compounds of formula (I), for example those into which a radioisotope is incorporated, are useful in drug and/or substrate tissue distribution studies. The radioactive isotope tritium, that is,³h, and carbon-14, alsoThat is to say that the first and second electrodes,¹⁴c, are particularly suitable for this purpose in view of their ready availability for easy binding and detection.

The heavy chain is replaced with a heavier isotope such as deuterium, that is,²h substitution may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life or reduced dosage requirements in vivo and, therefore, may be preferred in certain circumstances.

Using positron-emitting isotopes, e.g.¹¹C、¹⁸F、¹⁵O and¹³n substitution, can be suitable for examining Positron Emission Tomography (PET) research with a high substrate receptor occupancy.

Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, using a suitable isotopically-labelled reagent in place of the non-isotopically-labelled reagent employed above.

All compounds of formula (I) can be prepared by the procedures described in the general methods shown below or by the specific methods described in the examples section and the preparation section, or by routine modifications thereof. In addition to any novel intermediate used therein, the present invention also encompasses any one or more of these methods for preparing compounds of formula (I).

General Synthesis

The compounds of the present invention can be prepared by various methods well known for the preparation of such compounds, for example, according to the methods shown in the following methods A to G.

The following methods A and B illustrate the preparation of compounds of formula (I). Methods C to G illustrate the preparation of various intermediates.

Unless otherwise stated, R in the following methods¹、R²、R³M and A are as defined above. The term "protecting group" as used hereinafter means a hydroxyl, carboxyl or amino-protecting group selected from the group consisting ofProtecting groups in organic synthesis as edited by T.W.Greene et al ((R))ProtectiveGroups in Organic Synthesis)(John Wiley &Sons, 1999) under the name of a typical hydroxy, carboxy or amino-protecting group. All starting materials in the following general syntheses are commercially available or are obtained by customary methods known to the person skilled in the art, e.g.European Journal ofMedicinal Chemistry12, (1), 87-91; 1977, and the disclosure of which is incorporated herein by reference.

Method A

This process illustrates the preparation of compounds of formula (I).

In reaction scheme A, R^3aIs R as defined above³Or formula-C (═ O) -R⁴Wherein R is⁴Is a carboxyl protecting group.

The term "carboxy-protecting group" as used herein means a protecting group that can be cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and the carboxy-protecting group method is described in t.w. greene et al (John Wiley)&Protecting groups in organic Synthesis as published by Sons, 1999: (Protective Groups in Organic Synthesis) In (1). Conventional carboxy-protecting groups include, but are not limited to, methoxy, ethoxy, t-butoxy, methoxymethoxy, 2, 2, 2-trichloroethoxy, benzyloxy, diphenylmethoxy, trimethylsilyloxy, t-butyldimethylsilyloxy, and allyloxy. Of these groups, t-butoxy, methoxy or ethoxy is preferable.

Step A1

In this step, the desired compound of formula (I) of the present invention is prepared by carbonylating a compound of formula (II) with a compound of formula (III). The compounds of formula (II) are commercially available. The compounds of formula (III) can be prepared according to procedure C, as set forth below.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include, but are not limited to, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and nitrobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and diisopropyl etherAn alkane; and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. Among these solvents, dichloromethane is preferred.

There is also no particular limitation on the nature of the carbonylation agent used, and any carbonylation agent commonly used in such reactions may be equally used herein. Examples of such carbonylating agents include, but are not limited to, imidazole derivatives such as N, N' -Carbonyldiimidazole (CDI); chloroformates such as trichloromethyl potassium chloride and 4-nitrophenyl chloroformate; urea and triphosgene. Preferred of these is 4-nitrophenyl chloroformate.

The reaction can be carried out over a wide temperature range and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. However, it is convenient to carry out the reaction at a temperature of from about-78 ℃ to about 120 ℃. The time required for the reaction also varies widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours will generally be sufficient.

If R is^3aIs of the formula-C (═ O) -R⁴And performing deprotection reaction to obtain carboxyl. This reaction is described in detail in T.W. Greene et al, Protective Groups in organic Synthesis, 369-453, (1999), the disclosure of which is incorporated herein by reference. The following list relates to a general reaction for protecting a tert-butyl group.

The deprotection reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include, but are not limited to, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane, and aromatic hydrocarbons such as benzene, toluene and nitrobenzene. Preferred of these solvents are halogenated hydrocarbons.

The deprotection reaction is carried out in the presence of an acid. There is also no particular limitation on the nature of the acid used, and any acid commonly used in such reactions may be equally used herein. Examples of such acids include (but are not limited to): acids such as hydrochloric acid, acetic acid, p-toluenesulfonic acid or trifluoroacetic acid. Preferred of these is trifluoroacetic acid.

The deprotection reaction may be carried out in the presence of a radical remover, again there is no particular limitation on the nature of the radical remover used, and radical removers conventionally used in such reactions may be used equally herein. Examples of such radical scavengers include (but are not limited to): HBr, dimethyl sulfoxide or (CH)₃CH₂)₃SiH. Preferred of these is (CH)₃CH₂)₃SiH。

The deprotection reaction can be carried out over a wide temperature range and the precise reaction temperature is not critical to the present invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃, more preferably from about 0 ℃ to about 50 ℃. The time required for the reaction also varies widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours, more preferably from about 1 hour to about 24 hours, will generally be sufficient.

Process R

This process illustrates an alternative process for the preparation of the desired compound of formula (I).

Reaction scheme R

In reaction scheme B, R^3aAs defined above, R⁵Is an amino-protecting group, A^aA as defined above or an alkylene group having 1 to 3 carbon atoms, which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms, hydroxy-alkyl groups having 1 to 4 carbon atoms and alkoxy-alkyl groups having 2 to 6 carbon atoms, wherein 2 of the substituents may optionally form a 3-to 6-membered ring together with carbon atoms, and X is a halogen atom such as an iodine atom, a chlorine atom or a bromine atom.

The term "amino-protecting group" as used herein means a protecting group that can be cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and is described in t.w. greene et al (John Wiley)&Sons, 1999) Protective Groups in Organic Synthesis. Conventional amino-protecting groups include, but are not limited to, benzyl, C₂H₅O(C＝O)-、CH₃(C ═ O) -, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyloxycarbonyl, and tert-butoxycarbonyl. Preferred of these groups is tert-butoxycarbonyl.

Step B1

In this step, the compound of formula (V) is prepared by deprotecting a compound of formula (IV), which can be prepared, for example, by a method analogous to the preparation of the compound of formula (I) from the compound of formula (II) described in method a. This deprotection method is described in T.W. Greene et al [ Protective Groups in Organic Synthesis, 494-653, (1999) ] the disclosure of which is incorporated herein by reference. Typical methods involving the protection of tert-butoxycarbonyl are listed below.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include, but are not limited to, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane, and alcohols such as methanol, ethanol, propanol, 2-propanol and butanol. Preferred of these solvents is an alcohol.

The reaction is carried out in the presence of an excess of acid. There is also no particular limitation on the nature of the acid used, and any acid conventionally used in such reactions may be equally used herein. Examples of such acids include (but are not limited to): acids such as hydrochloric acid or trifluoroacetic acid. Preferred of these is hydrochloric acid.

The reaction can be carried out over a wide temperature range and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction also varies widely depending on many factors, especially the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours will generally be sufficient.

Step B2

In this step, the desired compound of formula (I) is prepared by coupling the compound of formula (V) prepared as described in step B1 with the compound of formula (VI) (B2-a), or by reductively aminating the compound of formula (V) with the compound of formula (VII) (B2-B).

(B2-a) coupling with a compound of formula (V):

the reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Suitable for dissolvingExamples of agents include, but are not limited to, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and diisopropyl etherAn alkane; amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, N-methylpyrrolidine, pyridine, 4-pyrrolidinylpyridine, N-dimethylaniline and N, N-diethylaniline; and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. Preferred of these are N, N-dimethylformamide or N-methylpyrrolidine.

The reaction is carried out in the presence of a base. There is again no particular limitation on the nature of the base used, and any base conventionally used in such reactions may be used equally herein. Examples of such bases include (but are not limited to): amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinylpyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2, 6-di (tert-butyl) -4-methylpyridine, quinoline, N-dimethylaniline, N-diethylaniline, 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, 4-diazabicyclo [2.2.2] octane (DABCO) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU); alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide. Preferred of these is diisopropylethylamine.

The reaction can be carried out over a wide temperature range and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 120 ℃. The time required for the reaction also varies widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 48 hours will generally be sufficient.

(B2-B) reductive amination:

the reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include, but are not limited to, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran and diisopropyl etherAn alkane; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; acetic acid and water. Preferred of these solvents are halogenated hydrocarbons.

The reaction is carried out in the presence of a reducing agent. There is also no particular limitation on the nature of the reducing agent used, and any reducing agent conventionally used in such reactions may be equally used herein. Examples of such reducing agents include (but are not limited to): sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. Preferred of these is sodium triacetoxyborohydride. The amount of reducing agent required for the reaction may also vary widely depending on a number of factors, particularly the reaction temperature and the nature of the starting materials and solvents used. However, a stoichiometric ratio of 1 to 3 of reducing agent to starting material will generally be sufficient, as long as the reaction is carried out under the preferred conditions.

The reaction can be carried out over a wide temperature range and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about-20 ℃ to about 60 ℃. The time required for the reaction also varies widely depending on a number of factors, especially the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours will generally be sufficient.

If R is^3aIs of the formula-C (═ O) -R⁴Based on that, proceedThe deprotection reaction will yield a carboxyl group. The reaction may be carried out under the same conditions as described in step a1 of method a.

Method C

This process illustrates the preparation of the compound of formula (III).

Reaction scheme C

In reaction scheme C, X, A, A^a、R^3aAnd R⁶Are as defined above. Therefore, when R is^3ais-C (═ O) -R⁴When the compound of the formula (IX) is used, the following compounds can be used.

Step C1

In this step, the compound of formula (IX) is prepared by coupling the compound of formula (VIII) with the compound of formula (VI) or by reductively aminating the compound of formula (VIII) with the compound of formula (VII). The compounds of formula (VIII) can be prepared or are commercially available according to the methods F and G listed below.

Step C2

In this step, the compound of formula (III) is prepared by deprotecting the compound of formula (IX) prepared as described in step C1. The reaction may be carried out under the same conditions as described in step B1 of method B.

Method D

This process illustrates the preparation of the compound of formula (IIIa).

Reaction scheme D

In reaction scheme D, R^3a、R⁴、R⁶And Y are each as defined above, and R⁷Is a silane group such as a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a triethylsilyl group or a trimethylsilyl group, preferably a trimethylsilyl group; r⁸And R⁹Independently represent a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein R⁸And R⁹Optionally together with the carbon atom to which they are attached form a3 to 6-membered ring; a. the^bA is as defined above, provided that methylene and substituted methylene are excluded.

Step D1

In this step, the compound of formula (XI) is prepared by condensing the compound of formula (VIII) with the compound of formula (X) in the presence of paraformaldehyde. The compounds of formula (VIII) can be prepared according to methods F and G or are commercially available.

If Y is not an alkoxy group, the reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; and alcohols such as methanol, ethanol, propanol, 2-propanol and butanol. Preferred of these is dichloromethane or ethanol.

The reaction can be carried out over a wide temperature range, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 120 ℃. The time required for the reaction also varies widely depending on many factors, especially the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 48 hours will generally be sufficient.

Step D2

In this step, the compound of formula (IIIa) is prepared by subjecting the compound of formula (XI) and the compound of formula (XII) to a mannich reaction.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and diisopropyl etherAn alkane; nitriles such as acetonitrile and benzonitrile; and amides such as N, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide. Among these solvents, dichloromethane is preferred.

The reaction is carried out in the presence of a lewis acid. There is also no particular limitation on the nature of the lewis acid used, and any lewis acid commonly used in this type of reaction may be equally used herein. Examples of such lewis acids include (but are not limited to): BF (BF) generator₃、AlCl₃、FeCl₃、MgCl₂、AgCl、Fe(NO₃)₃、CF₃SO₃Si(CH₃)₃、Yb(CF₃SO₃)₃And SnCl₄. Of these, Yb (CF) is preferred₃SO₃)₃、MgCl₂Or CF₃SO₃Si(CH₃)₃。

The reaction can be carried out over a wide temperature range, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction also varies widely depending on a number of factors, especially the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours will generally be sufficient.

Method E

This process illustrates compounds of formula (III) (wherein R²Is a hydrogen atom and A is A^b) And (4) preparing.

Reaction scheme E

In reaction scheme E, A^a、A^bAnd R^3aEach as defined above, each R and R' is an alkyl group having 1 to 4 carbon atoms, preferably methyl, or an aralkyl group such as benzyl or phenethyl, preferably benzyl.

Step E1

In this step, the compound of formula (XIV) is prepared by reducing the cyano group of the compound of formula (XIII) (commercially available).

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and diisopropyl etherAn alkane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; and alcohols such as methanol, ethanol, propanol, 2-propanol and butanol. Preferred of these is methanol.

The reaction is carried out in the presence of a reducing agent. There is also no particular limitation on the nature of the reducing agent used, and any reducing agent conventionally used in such reactions may be equally used herein. Examples of such reducing agents include (but are not limited to): metal borohydrides such as sodium borohydride and sodium cyanoborohydride; hydrogen in combination with catalysts such as palladium-carbon, platinum and raney nickel; and hydride compounds such as lithium aluminum hydride and diisobutylaluminum hydride. Of these, Raney nickel is preferred.

The reaction can be carried out over a wide temperature range and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction also varies widely depending on a number of factors, especially the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours will generally be sufficient.

Step E2

In this step, the compound of formula (XVI) is prepared by reacting a commercially available compound of formula (XV) with a compound of formula (XIV).

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): water and alcohols such as methanol, ethanol, propanol, 2-propanol and butanol. Preferred among these is a mixture of water and ethanol.

The reaction is carried out in the presence of a base. There is again no particular limitation on the nature of the base used, and any base conventionally used in such reactions may be used equally herein. Examples of such bases include (but are not limited to): alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate. Preferred of these is potassium carbonate.

The reaction can be carried out over a wide temperature range, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 120 ℃. The time required for the reaction also varies widely depending on a number of factors, especially the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours will generally be sufficient.

Step E3

In this step, the compound of formula (XVII) is prepared by converting the carbonyl group of the compound of formula (XVI) into a cyano group in the presence of p-toluenesulfonylmethyl isocyanide.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and diisopropyl etherAn alkane; and alcohols such as methanol, ethanol, propanol, 2-propanol and butanol. Preferred of these is a mixture of ethylene glycol dimethyl ether and ethanol.

The reaction is carried out in the presence of a base. Again, there is no particular limitation on the nature of the base used, and any base conventionally used in such reactions may be used equally herein. Examples of such bases include (but are not limited to): alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. Preferred among these is potassium tert-butoxide.

Step E4

In this step, the compound of formula (IIIb) is prepared by reducing the cyano group of the compound of formula (XVII). The reaction can be carried out under the same conditions as described in step E1 of method E.

Method F

This process illustrates compounds of formula (VIII) (wherein R²Is a halogen atom).

Reaction scheme F

In reaction scheme F, R^2aIs a halogen atom; r⁶As defined above, and R¹⁰As the amino protecting group, a benzoyl group is preferred.

Step F1

In this step, the compound of formula (XIX) is prepared by converting the carbonyl group of the compound of formula (XVIII) into an epoxy group.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfolane. Preferred of these solvents is dimethyl sulfoxide.

The reaction is carried out in the presence of a base. There is again no particular limitation on the nature of the base used, and any base conventionally used in such reactions may be used equally herein. Examples of such bases include (but are not limited to): alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; and alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Preferred among these is potassium tert-butoxide.

The reaction can be carried out over a wide temperature range, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃, more preferably from about 10 ℃ to about 50 ℃. The time required for the reaction also varies widely depending on a number of factors, especially the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours, more preferably from about 60 minutes to about 12 hours, will generally be sufficient.

Step F2

In this step, the compound of formula (XX) is prepared by reacting a hydrogen halide with the compound of formula (XIX).

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and diisopropyl etherAn alkane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide. Preferred of these solvents is tetrahydrofuran.

Step F3

In this step, formula (XXI) is prepared by reacting a compound of formula (XX) with sodium azide (F3-a), followed by reduction of the azide group (F3-b).

(F3-a) reaction with sodium azide

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and diisopropyl etherAn alkane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; and sulfoxides such as dimethyl sulfoxide and sulfolane. Preferred of these solvents is N, N-dimethylformamide.

Prior to the addition of sodium azide, the hydroxyl group is converted to leaving groups such as methylsulfonyl, trifluoromethylsulfonyl and 4-methylphenylsulfonyl by the addition of reagents such as trifluoromethane sulfonyl chloride, methane sulfonyl chloride and toluene sulfonyl chloride. Among these reagents, methanesulfonyl chloride is preferred.

The reaction can be carried out over a wide temperature range, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 120 ℃. The time required for the reaction also varies widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours will generally be sufficient.

(F3-h) reduction:

the reaction may be carried out under the same conditions as described in step E1 of method E.

Step F4

In this step, the compound of formula (VIIIa) is prepared by reacting an amino protecting group R⁶Introduction into a primary amino group (F4-a), and reaction of the amino-protecting group R of the secondary amino group¹⁰Selective deprotection (F4-b).

(F4-a) introduction of amino protecting group:

this reaction is described in detail by T.W. Greene et al, [ protective groups in Organic Synthesis, 494-653, (1999) ], the disclosure of which is incorporated herein by reference. Typical reactions involving the protecting group tert-butoxycarbonyl are listed below.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): water, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and diisopropyl etherAn alkane; and sulfoxides such as dimethyl sulfoxide and sulfolane. Preferred of these solvents is tetrahydrofuran.

The reaction is generally carried out in the presence of a reagent. There is also no particular limitation on the nature of the reagents used, and any reagents conventionally used in such reactions may be equally used herein. Examples of such agents include (but are not limited to): di-tert-butyl carbonate and 1- (tert-butoxycarbonyl) benzotriazole. Of these, di-tert-butyl carbonate is preferred.

The reaction can be carried out over a wide temperature range and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 120 ℃, more preferably from about 20 ℃ to about 80 ℃. The time required for the reaction also varies widely depending on a number of factors, especially the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours, more preferably from about 60 minutes to about 12 hours, will generally be sufficient.

(F4-b) deprotection

This process is detailed by T.W. Greene et al, protective groups in Organic Synthesis, 494-653, (1999) which disclosure is incorporated herein by reference.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagent (at least to some extent). Examples of suitable solvents include (but are not limited to): halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and diisopropyl etherAn alkane. The preferred one of these solvents is methanol.

The reaction can be carried out over a wide temperature range and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 120 ℃. The time required for the reaction also varies widely depending on a number of factors, especially the reaction temperature and the nature of the starting materials and solvents used. However, as long as the reaction is carried out under the preferred conditions listed above, a time period of from about 5 minutes to about 24 hours will generally be sufficient.

Method G

Description of the process wherein R²Preparation of a compound of formula (VIII) which is hydroxy.

Reaction scheme G

In reaction scheme G, R⁶And R¹⁰Each as defined above.

Step G1

In this step, a compound of formula (XXII) is prepared by reacting the carbonyl group of a compound of formula (XVIII) (commercially available) with trimethylsilylcyanide.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used, as long as there is no negative effect on the reaction or reagents involved and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include (but are not limited to): aromatic hydrocarbons such as benzene, toluene and nitrobenzene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and diisopropyl etherAn alkane; nitriles such as acetonitrile and benzonitrile; and alcohols such as methanol, ethanol, propanol, 2-propanol and butanol. Preferred of these is toluene.

The reaction is carried out in the presence of a reagent. There are also no particular restrictions on the nature of the reagents used, and any reagents customary in such reactions can be used equally wellHerein, reference is made to the appended claims. Examples of such agents include (but are not limited to): lewis acids such as BF₃、AlCl₃、FeCl₃、AgCl、ZnI₂、Fe(NO₃)₃、CF₃SO₃Si(CH₃)₃、Yb(CF₃SO₃)₃And SnCl₄(ii) a Bases such as CaO; ethers such as 18-crown-6; acids such as Amberlite XAD-4 resin. Preferred of these is ZnI₂。

Step G2

In this step, a compound of formula (XXIII) is prepared by converting the cyano group of a compound of formula (XXII) to an amino group, followed by the amino-protecting group R¹⁰Deprotection. The reaction can be carried out under the same conditions as described in method E, step E1 and method F, step F4.

Step G3

In this step, the compound of formula (VIIIb) is prepared by protection and deprotection of the amino group of the compound of formula (XXIII). The reaction may be carried out under the same conditions as described in method F, step F4.

The compounds of formula (I) and intermediates in the above preparation processes may be isolated and purified by conventional procedures, such as distillation, recrystallization or chromatographic purification.

The compounds of the invention intended for pharmaceutical use may be administered in crystalline or amorphous products. They can be obtained by this method, for example, by precipitation, crystallization, freeze drying, spray drying or evaporation drying, for example, in the form of, for example, solid plugs, powders or films. Microwave or radiation frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or any combination thereof). Typically, they will be administered in the form of a formulation in association with one or more pharmaceutically acceptable carriers or excipients. The term "carrier" or "excipient" is used herein to describe any ingredient other than a compound of the invention. The choice of excipient will depend in large part on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and their methods of preparation may be found, for example, in Remington's Pharmaceutical Sciences, version 19 (Mack publishing company, 1995).

Oral administration

The compounds of the invention may be administered orally. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, by which route the compound may pass directly from the mouth into the bloodstream.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids, or powders, lozenges (including liquid-filled), chewable lozenges, poly-and nano-particles, gels, solid solutions, liposomes, films (including mucoadhesive), ovules (ovule), sprays and liquid formulations.

Liquid preparations include, for example, suspensions, solutions, syrups and elixirs. The formulations may be employed as fillers in soft or hard gelatin capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil and one or more emulsifying agents and/or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid (e.g., from a small pack).

The compounds of the invention may also be in the form of rapidly dissolving, rapidly disintegrating dosage forms as described, for example, by Liang and ChenExpert Opinion in Therapeutic Patents，11(6) Those of 981-.

For tablet dosage forms, depending on the dosage, the drug may comprise from about 1% to about 80% by weight of the dosage form, more typically from about 5% to about 60% by weight of the dosage form. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant will comprise from about 1% to about 25% by weight of the dosage form, preferably from about 5% to about 20% by weight.

Binders are commonly used to impart cohesive qualities to the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydrous, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant may comprise about 0.2% to about 5% by weight of the tablet and the glidant may comprise about 0.2% to about 1% by weight of the tablet.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant generally comprises from about 0.25% to about 10%, preferably from about 0.5% to about 3% by weight of the tablet.

Other possible ingredients include antioxidants, coloring agents, flavoring agents, preservatives, and taste-masking agents.

A typical tablet contains up to about 80% drug, about 10% to about 90% binder by weight, about 0% to about 85% diluent by weight, about 2% to about 10% disintegrant by weight, and about 0.25% to about 10% lubricant by weight.

The tablet blend may be compressed directly or by roller compression to form tablets. The tablet blend or portion of the blend can alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

Formulation of tablets is discussed by h.lieberman and l.lachman in "Pharmaceutical Dosage Forms: tablets, volume 1 ", Marcel Dekker, New York, 1980(SIBN 0-8247-

Solid formulations for oral administration may be formulated for immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

A suitable modified release formulation for the purposes of the present invention is described in U.S. patent No. 6,106,864. Details of other suitable delivery techniques such as high energy dispersions and penetrating and coating particles are found in Verma et alPharmaceutical Technology On-line,25(2),1-14(2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

Parenteral administration

The compounds of the invention may also be administered directly into the bloodstream, into muscle, or into internal organs. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably a pH of about 3 to about 9), but for some applications they may be more suitably formulated as sterile non-aqueous solutions or in dry form for use in combination with a suitable vehicle such as sterile pyrogen-free water.

Preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of formula (I) used in the formulation of parenteral solutions can be increased by using appropriate formulation techniques, e.g., incorporating solubility-enhancing agents.

Formulations for parenteral administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the present invention may therefore be formulated as solids, semi-solids, or thixotropic liquids for administration in an implanted depot form that provides for modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

Topical administration of drugs

The compounds of the present invention may also be administered topically to the skin or mucosa, i.e., through the skin or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated-see, e.g., jnmann's JPharm Sci,88(10) 955- "958 (10 months 1999).

Other partsDevices for administration include by electroporation, iontophoresis, sonophoresis, and microneedles or needles-free devices (e.g., Powderject)^TM、Bioject^TMEtc.) injection delivery.

Formulations for topical administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Inhalation/intranasal administration

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, in a mixture, e.g., as a dry blend with lactose, or as mixed component particles, e.g., mixed with a phospholipid, e.g., phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, nebulizer, atomizer (preferably an atomizer that produces a fine mist using electrohydrodynamic (electro-hydrodynamic)), or nebulizer, with or without the use of a suitable propellant, e.g., 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive, for example, chitosan or cyclodextrin.

A pressurized container, pump, nebulizer, atomizer, or nebulizer contains a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol, or a substitute suitable for dispersion, dissolution, or extended release of the active ingredient, a propellant as a solvent, and optionally a surfactant, such as sorbitan trioleate, oleic acid, or oligomeric lactic acid.

Prior to use in dry powder or suspension formulations, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethyl cellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base such as lactose or starch and a potency-modifying agent such as l-leucine, mannitol or magnesium stearate. Lactose can be in anhydrous or monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers that generate fine mist using electrohydrodynamic devices may contain from about 1 microgram to about 20 milligrams of a compound of the present invention per actuation and the actuation volume may vary from about 1 microliter to about 100 microliters. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavouring agents, for example menthol and levomenthol, or sweetening agents, for example saccharin or saccharin sodium, may be added to the formulations of the invention intended for inhalation/intranasal administration. Formulations for inhalation/intranasal administration may be formulated for immediate and/or modified release using, for example, (DL-lactic-co-glycolic acid) (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the unit of metering is determined by the valve delivering the metered amount. The units of the invention are generally arranged to administer a metered dose or "puff' containing from about 1 to about 100 micrograms of a compound of formula (I). The total daily dose is typically between about 50 micrograms and about 20 milligrams, which may be administered as a single dose or as multiple (often) divided doses throughout the day.

Rectal/intravaginal administration

The compounds of the invention may be administered rectally or vaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated for immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Eye/ear administration

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particle or vesicle systems, such as vesicular agents (niosomes) or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, fibrous polymers, e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose, or heteropolysaccharide polymers, e.g., gelan gum, may be blended with preservatives, such as benzalkonium chloride. The formulation may also be delivered by iontophoresis.

Formulations for ocular/otic administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Other techniques

The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol containing polymers in order to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability when used in any of the above modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrins may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. The most commonly used for these purposes are alpha-, beta-and gamma-cyclodextrins, examples of which may be found in international patent applications nos. WO 91/11172, WO 94/02518 and WO 98/55148.

Medicine box of parts (kit)

Insofar as it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which comprises a compound according to the invention, may conveniently be combined in a form suitable for co-administration of the compositions in a kit.

The kit of the invention thus comprises two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I) according to the invention, and means for separately retaining the compositions, such as a container, a separate bottle, or a separate foil pouch. Examples of such kits are the familiar blister packs used for packaging tablets, capsules and the like.

The kit of the invention is particularly suitable for administration in different dosage forms, e.g. oral and parenteral, for administration of the separate compositions at different dosage intervals, or for stepwise increasing (titrating) of the separate compositions from each other. To aid compliance, kits typically contain instructions for administration and may be provided with so-called memory aids.

Dosage form

For administration to a human patient, the total daily dose of a compound of the present invention is generally between about 0.05 mg to about 100 mg, depending on the mode of administration, preferably between about 0.1 mg to about 50 mg, and more preferably between about 0.5 mg to about 20 mg. For example, a total daily dose of between about 1 mg and about 20 mg may be required for oral administration, but an intravenous dose of only about 0.5 mg to about 10 mg may be required. The total daily dose may be administered as a single dose or as divided doses.

These doses are based on an average human being weighing from about 65 kg to about 70 kg. A physician can readily determine dosages for subjects with weights outside of this range, such as infants and elderly.

Combination therapy

As mentioned above, the compounds of the invention exhibit 5-HT₄Agonist activity. 5-HT of the invention₄The agonist may be used in combination with at least one other pharmacologically active agent or compound, especially in the treatment of gastroesophageal reflux disease. For example, 5-HT₄Agonists, especially a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, may be administered simultaneously, sequentially or separately in combination with one or more pharmacologically active agents selected from:

(i) histamine H₂Receptor antagonists such as ranitidine, lafutidine, nizatidine, cimetidine, famotidine and roxatidine;

(ii) proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole;

(iii) acid pump antagonists such as loratadine (soraprazan), revaprazan (revaprazan) (YH-1885), AZD-0865, CS-526, AU-2064 and YJA-20379-8;

(iv) antacid mixtures for oral administration, e.g. Mallox、AludroxAnd Gaviscon；

(v) Mucosal protecting groups such as polaprezinc, sodium ecafibrate, rebamipide, teprenone, cetrimide, sucralfate, chloropillin (chloropallaline) -copper, and plaunotol;

(vi)GABA_Bagonists such as baclofen and AZD-3355;

(vii) alpha 2 agonists such as clonidine, metomidine, lofexidine, moxonidine, tizanidine, guanfacine, guanabenz, talipexole and dexmedetomidine;

(viii) anthoxanthin derivatives such as theophylline, aminophylline and doxofylline;

(ix) calcium channel blockers, e.g. aranidipine, lacidipine, farodipine (falodipine), azelnidipine, clinodipine, lomerizine, diltiazemGallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine, and fasudil;

(x) BenzodiazepineAgonists such as diazepam, zaleplon, zolpidem, halosalazolam, clonazepam, pramazepam, quazepam, flutazolam, triazolam, chlordiazepam, midazolam, tofisopam, clobazam, flunitrazepam and flutolazepam;

(xi) Prostaglandin analogs such as prostaglandin, misoprostol, treprostinil (treprostinil), epoprostenol (esoprostenol), latanoprost, eloprost, beraprost, enprost, ibudilast and ozagrel;

(xii) Histamine H₃Agonists such as R- α -methylhistamine and BP-294;

(xiii) Anti-gastric agents such as anti-gastrin vaccine, itramine and Z-360;

(xiv)5-HT₃antagonists such as dolasetron, palonosetron, alosetron, azasetronSetron, ramosetron, mirtazapine, granisetron, tropisetron, E-3620, ondansetron, and indisetron;

(xv) Tricyclic antidepressants such as imipramine, amitriptyline, clomipramine, amoxapine and lofepramine;

(xvi) GABA agonists such as gabapentin, topiramate, cilostazol, clonazepam, pregabalin, brotizolam, zopiclone, pregabalin and epizopiclone;

(xvii) Opioid analgesics such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levonororphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, dextropropoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;

(xviii) Somatostatin analogs such as octreotide, AN-238 and PTR-3173;

(xix) Cl channel activators such as lubiprostone (lubiprostone);

(xx) Selective 5-hydroxytryptamine reuptake inhibitors such as sertraline, escitalopram, fluoxetine, nefazodone, fluvoxamine, citalopram, milnacipran, paroxetine, venlafaxine, tramadol, sibutramine, duloxetine, desvenlafaxine, and dapoxetine;

(xxi) Anticholinergics such as dicyclomine and hyoscyamine;

(xxii) Laxatives such as Trifyba、Fybogel、Konsyl、Isogel、Regulan、CelevacAnd Normacol；

(xxiii) Fibrous products such as Metallul；

(xxiv) Spasmolytics such as mebeverine;

(xxv) Dopamine antagonists such as metoclopramide, domperidone and levosulpiride;

(xxvi) Cholinergics such as neostigmine;

(xxvii) AChE inhibitors such as galantamine, metrazine, rivastigmine, etoposide and donepezil;

(xxviii) Tachykinin (NK) antagonists, in particular NK-3, NK-2 and NK-1 antagonists, such as nepadutant, saredutant, talnetutant;

(α R, 9R) -7- [3, 5-bis (trifluoromethyl) benzyl ] -8, 9, 10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1, 4] diazocino [2, 1-g ] [1, 7] naphthyridine-6-13-dione (TAK-637), 5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] methyl ] -1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), ropinirotan, naproxen, Dapiprant and

3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] methylamino ] -2-phenyl-piperidine (2S, 3S).

Methods for evaluating biological activity:

5-HT of Compounds of the invention by the following procedure₄Receptor binding affinity.

Human 5-HT₄Combination (1)

Preparation of human 5-HT_4(d)Transfected HEK293 cells and allowed to grow internally (in-house). The collected cells were suspended in 50mM HEPES (pH 7.4, 4 ℃) supplemented with protease inhibitor cocktail (Boehringer, 1: 1000 dilution) and homogenized on ice for 30 seconds using a hand-held Polytron PT 1200 disruptor set at full power. The homogenate was centrifuged at 40,000Xg for 30 minutes at 4 ℃. The pellet was then resuspended in 50mM HEPES (pH 7.4, 4 ℃) and centrifuged once more in the same manner. The final pellet was resuspended in the appropriate volume of 50mM HEPES (pH 7.4 at 25 ℃), homogenized, aliquoted and stored at-80 ℃ until use. Aliquots of the membrane fractions were subjected to protein concentration determination using the BCA protein assay kit (PIERCE) and the ARVOsx plate reader (Wallac).

For the binding experiment, at room temperature, 25. mu.l of [ alpha ], [ 2]³H]GR113808(Amersham), final 0.2nM) and 150. mu.l of membrane homogenate and WGA-SPA bead (Amersham) suspension solution (10. mu.g protein and 1 mg SPA beads/well) 25. mu.l of test compound were incubated for 60 min. Nonspecific binding was determined by 1 μ M GR113808(Tocris) at the final concentration. The culture was terminated by centrifugation at 1000 rpm.

Receptor-bound radioactivity was quantified by counting in a MicroBeta plate counter (Wallac).

All compounds of the examples showed 5HT₄Receptor affinity.

Human 5-HT₄Combination (2)

Preparation of human 5-HT_4(d)Transfected HEK293 cells and allowed to grow inside. The collected cells were suspended in 50mM Tris buffer (pH 7.4, 4 ℃) supplemented with protease inhibitor cocktail (Boehringer, 1: 1000 dilution) and used in a setting at full-motionThe hand-held Polytron PT 1200 disruptor under force was homogenized on ice for 30 seconds. The homogenate was centrifuged at 40,000Xg for 10 minutes at 4 ℃. The pellet was then resuspended in 50mM Tris buffer (pH 7.4, 4 ℃) and centrifuged once more in the same manner. The final pellet was resuspended in 10mM MgCl₂In an appropriate volume of 50mM Tris buffer (pH 7.4, 25 ℃), homogenized, aliquoted and stored at-80 ℃ until use. Protein concentration determinations were performed on the aliquoted membrane fractions using the BCA protein assay kit (PIERCE) and the ARVOsx plate reader (Wallac).

For the binding experiment, at room temperature, 50. mu.l of [ alpha ], [ 2]³H]5-HT (Amersham, Final 8.0nM) and 400. mu.l membrane homogenate (300. mu.l protein/tube) 50. mu.l of test compound were incubated for 60 min. Nonspecific binding was determined by 50 μ M GR113808(Tocris) at the final concentration. All cultures were terminated by rapid vacuum filtration on glass fiber filter paper soaked with 0.2% PEI using a BRANDEL harvester followed by three washes with 50mM Tris buffer (pH 7.4, 25 ℃). Receptor-bound radioactivity was quantified by liquid scintillation counting using a Packard LS counter.

All compounds of the examples showed 5HT₄Receptor affinity.

Human 5-HT_4(d) Agonist-induced cAMP elevation in transfected HEK293 cells

Internally establishing human 5-HT_4(d)Transfected HEK293 cells. The cells were incubated at 37 ℃ and 5% CO₂Growth was performed in DMEM supplemented with 10% FCS, 20mM HEPES (pH 7.4), 200. mu.g/ml hygromycin B (Gibco), 100 units/ml penicillin and 100. mu.g/ml streptomycin. Cells were grown to 60-80% confluence. One day before treatment with compound, dialyzed fcs (gibco) was replaced normally and cells were allowed to grow overnight. Compounds were prepared in 96-well plates (12.5. mu.l/well). Cells were harvested with PBS/1mM EDTA, centrifuged and washed with PBS. At the beginning of the analysis, the cell pellet was pelleted at 1.6X 10⁵Cell/ml concentration, resuspended in 10. mu.L supplemented with 20mM HEPESM pargyline (Sigma) and 1mM 3-isobutyl-1-methylxanthine (Sigma) in DMEM and allowed to stand at room temperature for 15 minutes. The reaction was initiated by adding cells to the plate (12.5 μ l/well). After incubation for 15 minutes at room temperature, the reaction was stopped by addition of 1% Triton X-100 (25. mu.l/well) and the plates were allowed to stand for 30 minutes at room temperature. Homogeneous time resolved fluorescence-based cAMP (Schering) assays were performed according to the manufacturer's instructions. Using ARVO_SXA multiplex identification counter (Wallac) measures HTRF (excitation 320nm, emission 665nm/620nm, delay time 50 μ s, window time 400 μ s). Data were analyzed based on the ratio of fluorescence intensity at 620nm and 665nm for each well, followed by cAMP quantification using a cAMP standard curve. The enhancement of cAMP production elicited by each compound was normalized to the amount of cAMP produced by 1000nM 5-hydroxytryptamine (Sigma).

All compounds of the examples showed 5HT₄Receptor agonistic activity.

Human dofetilide binding

Human HERG-transfected HEK293S cells were prepared and grown in-house. The collected cells were suspended in 50mM Tris-HCl (pH 7.4, 4 ℃) and homogenized on ice for 20 seconds using a hand-held Polytron PT 1200 disruptor set up at full power. The homogenate was centrifuged at 48,000 Xg for 20 minutes at 4 ℃. The pellet is then resuspended, homogenized and centrifuged once more in the same manner. The final pellet was resuspended in the appropriate volume of 50mM Tris-HCl, 10mM KCl, 1mM MgCl₂(pH 7.4, 4 ℃), homogenized, aliquoted and stored at-80 ℃ until use. Aliquots of the membrane fractions were subjected to protein concentration determination using the BCA protein assay kit (PIERCE) and the ARVOsx plate reader (Wallac).

Binding assays were performed in 96-well plates in a total volume of 200. mu.l. At room temperature, 20. mu.l of³H]Doffilide (Amersham, 5nM final) and 160. mu.l of membrane homogenate (25. mu.g protein) 20. mu.l of test compound were incubated for 60 min. Nonspecific binding was determined at the final concentration with 10 μ M dofetilide. Using Skatron cell harvester at 50mM Trs-HCl、10mM KCl、1mM MgCl₂(pH 7.4 at 4 ℃) the culture was terminated by rapid vacuum filtration on GF/B Betaplate filters pre-soaked with 0.5%. The filter was dried, placed in a sample bag and filled with scintillation fluid Betaplate Scint. Radioactivity bound to the filters was counted in a wallac betaplate counter.

Permeability of Caco-2

Caco-2 permeability was measured according to the method described in Shiyin Yee, Pharmaceutical Research, 763 (1997).

Caco-2 cells were grown on a filter holder (Falcon HTS porous insert system) for 14 days. The medium was removed from both apical and basolateral compartments and the monolayer was pre-incubated with pre-warmed 0.3 ml of apical buffer and 1.0 ml of basolateral buffer in a shaker water bath at 37 ℃ at 50 cycles/min. The apical buffer was composed of Hanks Balanced Salt Solution (Hanks Balanced Salt Solution), 25mM D-glucose monohydrate, 20mM MES Biobuffer, 1.25mM CaCl₂And 0.5mM MgCl₂(pH 6.5). The buffer solution on the outer side of the substrate is composed of a hank's balanced salt solution, 25mM D-glucose monohydrate, 20mM HEPES biological buffer solution, 1.25mM CaCl₂And 0.5mM MgCl₂(pH 7.4). At the end of the pre-incubation, the medium was removed and a buffer containing test compound solution (10 μ M) was added to the apical compartment. Inserts were moved to wells containing fresh buffer outside the substrate at 1 hour. The drug concentration in the buffer was measured by LC/MS analysis.

The flow rate (F, mass/time) is calculated from the slope of the cumulative appearance of the matrix on the receiver side, and the apparent permeability coefficient (P)_app) Is calculated by the following equation.

P_app(cm/sec)＝(F*VD)/(SA*MD)

Where SA is the surface area transferred (0.3 cm)²) VD is the donor volume (0.3 ml) and MD is the total amount of drug on the donor side at t ═ 0. All data represent 2 insertions of flatsAnd (4) average value. Monolayer integration was determined by Lucifer Yellow transfer.

Half-life of Human Liver Microsomes (HLM)

On 96-deep well plates at 37 ℃ to contain 3.3mM MgCl₂And 0.78 mg/ml of HLM (HL101) in 100mM potassium phosphate buffer (Ph 7.4) to culture the test compound (1. mu.M). The reaction mixture was divided into two groups, non-P450 and P450. NADPH was added only to the reaction mixtures of group P450. Aliquots of the P450 group samples were collected at time points of 0, 10, 30 and 60 minutes, where the 0 minute time point refers to the time that NADPH was added to the P450 group reaction mixture. Aliquots of the non-P450 groups were collected at-10 and 65 minute time points. Collected aliquots were extracted with acetonitrile solution containing an internal standard. The precipitated proteins were spun down by centrifugation (2000rpm, 15 minutes). The concentration of the compound in the supernatant was measured with an LC/MS system.

Half-life values were obtained by plotting the natural logarithm of the peak area ratio of compound/internal standard versus time. The rate of metabolism (k) is generated by the slope of the best fit line of points. This can be converted to a half-life value using the following equation.

Half-life ═ ln 2/k

Examples

The invention is illustrated in the following non-limiting examples, in which all reagents are commercially available unless otherwise stated, all operations being carried out at room or ambient temperature, that is to say, between about 18 and 25 ℃, the evaporation of the solvent being carried out using a rotary evaporator under reduced pressure and at a bath temperature of up to about 60 ℃; the reaction was monitored by thin layer chromatography (tlc), and reaction times are given for illustration only; the melting point (m.p.) provided is uncorrected (polymorphism may result in different melting points); the structure and purity of all isolated compounds was confirmed by at least one of the following techniques: tlc (Merck silica gel 60F)₂₅₄Precoated TLC plates or Merck NH₂F_254SPre-coated HPTLC plate), mass spectrometry, Nuclear Magnetic Resonance (NMR), infrared absorption spectroscopy (IR)) Or microanalysis. The yields are given for illustrative purposes only. Flash column chromatography using Merck silica gel 60(230-DU3050 (amino form, 30-50 μm). Low-resolution mass spectral data (EI) were obtained with either an integrity (waters) mass spectrometer or an autorass 120(JEOL) mass spectrometer. Low resolution mass spectral data (ESI) were obtained with either a ZMD2(Waters) mass spectrometer or a Quattro II (Micromass) mass spectrometer. NMR data were measured in parts per million (ppm) relative to Tetramethylsilane (TMS) as an internal standard at 270MHz (JEOL JNM-LA 270 photometer) or 300MHz (JEOL JNM-LA300) using deuterated chloroform (99.8% D) and dimethylsulfoxide (99.9% D) as solvents (unless otherwise indicated); the conventional abbreviations used are: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br. is broad, etc. The IR spectrum was measured with a Shimazu infrared spectrometer (IR-470). Optical rotation was measured using a JASCO DIP-370 digital polarimeter (Japan Spectroscopic co., Ltd.). Chemical symbols have their usual meanings; b.p. (boiling point); m.p. (melting point); l (l), ml (ml), g (g), mg (mg), mol (mol), mmol (mmol), eq (eq). Powder X-ray diffraction (PXRD) patterns were measured using a Rigaku RINT-TTR powder X-ray diffractometer equipped with an autosampler exchanger, a 2 theta-theta goniometer, beam divergence slits, a secondary monochromator, and a scintillation counter. Samples were prepared for analysis by filling the powder on an aluminum sample carrier. The sample was rotated by 60.00rpm and scanned at room temperature with Cu-ka radiation at 4 °/min.

Example 1:

4- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } tetrahydro-2H-pyran-4-carboxylic acid

Step 1.4-Cyanotetrahydro-2H-pyran-4-carboxylic acid tert-butyl ester

At 0 ℃ and N₂To a stirred suspension of NaH (17.7 g, 0.443 mol) in DMF (200 ml) was added dropwise tert-butyl cyanoacetate (25.0 g, 0.177 mol) in DMF (100 ml). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. Bis (2-bromoethyl) ether (49.3 g, 0.177 mol) was then added to the mixture, and the resulting mixture was stirred at 90 ℃ for 24 h. After cooling to 0 ℃, the mixture was quenched with water (100 ml). The volatile components were removed by evaporation and the residue was precipitated with a mixture of EtOAc-toluene (1:2, 500 mL) and water (500 mL). The organic phase was washed three times with water (500 ml) and Na₂SO₄Dried, filtered and evaporated. The solid was washed with hexane and dried under vacuum to yield 19.0 g (57%) of the title compound as white crystals.

¹H-NMR(CDCl₃)δ：3.96(2H，dt，J＝3.9Hz，12.3Hz)，3.73(2H，dt，J＝2.6Hz，12.3Hz)，2.20-1.94(4H，m)，1.52(9H，s)。

Step 2.4- (aminomethyl) tetrahydro-2H-pyran-4-carboxylic acid tert-butyl ester

A mixture of tert-butyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (18.95 g, 0.0897 mol, step 1) and Raney nickel (1.00 g) in methanol (200 ml) was hydrogenated at room temperature (3atm) for 12H. The mixture was then filtered through a pad of celite and the filtrate was concentrated in vacuo to give 16.01 g (83%) of the title compound as a yellow syrup.

¹H-NMR(CDCl₃) δ: 3.86(2H, dt, J ═ 4.1Hz, 11.4Hz), 3.48(2H, dt, J ═ 2.5Hz, 11.5Hz), 2.75(2H, s), 2.03(2H, br d, J ═ 10.7Hz), 1.55 to 1.35(13H, m, including 9H, s, 1.49 ppm).

Step 3.4- [ (4-Oxopiperidin-1-yl) methyl ] tetrahydro-2H-pyran-4-carboxylic acid tert-butyl ester

To a solution containing tert-butyl 4- (aminomethyl) tetrahydro-2H-pyran-4-carboxylate (8.00 g, 0.0372 mol)Step 2) and K₂CO₃(0.51 g, 0.0372 mol) of EtOH-H₂O (2: 1, 240 ml) refluxing mixture is added dropwise with 1-ethyl-1-methyl-4-oxopiperidineIodide (12.0 g, 0.0445 mol, journal of organic chemistry (j. org. chem. 1995),604324-4330) in EtOH-H₂O (2: 1, 150 ml) and the resulting mixture was stirred at the same temperature (reflux) for 1 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was poured into saturated NaHCO₃In aqueous solution (200 ml) and with CH₂Cl₂The mixture was extracted (three 200 ml times). Extracting the extractive solution with Na₂SO₄Dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with hexane/ethyl acetate (3: 1 to 2: 1), to give 10.77 g (98%) of the title compound as a colorless syrup.

MS(ESI)m/z：298(M+H)⁺。

¹H NMR(CDCl₃) δ 3.84(2H, br d, J ═ 11.4Hz), 3.50(2H, dt, J ═ 2.0Hz, 11.7Hz), 2.85(4H, t, J ═ 5.9Hz), 2.61(2H, s), 2.39(4H, t, J ═ 6.1Hz), 2.05(2H, d, J ═ 11.5Hz), 1.75-1.45(11H, m, including 9H, s, 1.49 ppm).

Step 4.4- [ (4-Cyanopiperidin-1-yl) methyl ] tetrahydro-2H-pyran-4-carboxylic acid tert-butyl ester

At 0 ℃ in the presence of 4- [ (4-oxopiperidin-1-yl) methyl]To a stirred solution of tert-butyl tetrahydro-2H-pyran-4-carboxylate (8.77 g, 0.0295 mol, step 3) in 1, 2-dimethoxyethane (250 ml) were added p-toluenesulfonylmethylisocyanide (11.51 g, 0.0590 mol), EtOH (3.96 ml, 0.0678 mol) and t-BuOK (11.58 g, 0.1032 mol). The resulting mixture was stirred at 50 ℃ for 16 h. After cooling, the reaction mixture was poured into saturated NaHCO₃Aqueous solution (200 ml) and the mixture was taken up with CH₂Cl₂(200 ml. times.3 times) extraction. Extracting the extractive solution with Na₂SO₄Dried and concentrated. Residue in siliconChromatography on a gel column eluting with hexane/ethyl acetate (2: 1) gave 5.76 g (63%) of the title compound as a yellow syrup.

MS(ESI)m/z：309(M+H⁺)。

¹H-NMR(CDCl₃) δ: 3.81(2H, dt, J ═ 3.1Hz, 11.0Hz), 3.48(2H, dt, J ═ 2.1Hz, 11.7Hz), 2.76 to 2.64(2H, m), 2.64 to 2.52(1H, m), 2.50 to 2.35(4H, m, inclusive of 2H, s, 2.46ppm), 1.98(2H, br d, J ═ 11.9Hz), 1.92 to 1.70(4H, m), 1.65 to 1.40(11H, m, inclusive of 9H, s, 1.47 ppm).

Step 5.4- { [4- (aminomethyl) piperidin-1-yl ] methyl } tetrahydro-2H-pyran-4-carboxylic acid tert-butyl ester

A mixture of tert-butyl 4- [ (4-cyanopiperidin-1-yl) methyl ] tetrahydro-2H-pyran-4-carboxylate (5.76 g, 0.0187 mol, step 4) and Raney nickel (3.00 g) in methanol (100 ml) was hydrogenated at room temperature (3atm) for 12H. The mixture was then filtered through a pad of celite and the filtrate was concentrated in vacuo to give 5.72 g (98%) of the title compound as a yellow syrup.

MS(ESI)m/z：313(M+H⁺)。

¹H-NMR(CDCl₃) δ: 3.80(2H, dt, J ═ 3.1Hz, 11.5Hz), 3.49(2H, dt, J ═ 2.1Hz, 12.2Hz), 2.80(2H, br d, J ═ 11.5Hz), 2.58-2.40(4H, m, including 2H, s, 2.43ppm), 2.15(2H, br t, J ═ 7.3Hz), 1.98(2H, br d, J ═ 13.7Hz), 1.70-1.40(16H, m, including 9H, s, 1.47ppm), 1.30-1.10(2H, m).

Step 6.4- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } tetrahydro-2H-pyran-4-carboxylic acid tert-butyl ester

P-nitrophenyl chloroformate (4.14 g, 0.0205 mol), 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one (3.62 g, 0.0205 mol, J.Med.chem.)1999, 42, 2870-one 2880) and Et₃N (7.81 ml)0.0560 moles) of CH₂Cl₂(100 ml) the mixture was stirred at room temperature for 4 h. Subsequently, 4- { [4- (aminomethyl) piperidin-1-yl group is added]Methyl } tetrahydro-2H-pyran-4-carboxylic acid tert-butyl ester (5.72 g, 0.0187 mol, step 5), and the resulting mixture was stirred at room temperature for 24H. The reaction mixture was saturated with NaHCO₃Diluted with aqueous solution (300 ml) and CH₂Cl₂Extracted three times (300 ml). The combined extracts are washed with Na₂SO₄Dried and concentrated. The residue was chromatographed on a NH-silica column eluting with hexane/ethyl acetate (1: 1) to give 9.83 g (100%) of the title compound as a yellow syrup.

MS(ESI)m/z：515(M+H)⁺。

¹H NMR(CDCl₃) δ 8.90(1H, t, J ═ 4.9Hz), 8.31-8.21(1H, m), 7.25-7.10(3H, m), 4.80-4.60(1H, m), 3.80(2H, dt, J ═ 3.1Hz, 11.5Hz), 3.49(2H, dt, J ═ 1.7Hz, 11.4Hz), 3.28(2H, t, J ═ 6.4Hz), 2.81(2H, brd, J ═ 10.4Hz), 2.44(2H, s), 2.16(2H, t, J ═ 10.4Hz), 1.98(2H, d, J ═ 12.4Hz), 1.81-1.20(22H, m, including 6H, d, J ═ 7.1, 1, 1.56, 9ppm, s, and 1.47 ppm).

Step 7.4- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } tetrahydro-2H-pyran-4-carboxylic acid

At 0 ℃ in a solution containing 4- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl]Amino } methyl) piperidin-1-yl]Methyl } tetrahydro-2H-pyran-4-carboxylic acid tert-butyl ester (3.67 g, 7.13 mmol, step 6) in THF (80 ml) stirred solution concentrated HCl (40 ml) was added and the resulting mixture was stirred at room temperature for 20H. The mixture was concentrated to remove the solvent and the residue was poured into saturated NaHCO₃In aqueous solution. The mixture is mixed with CH₂Cl₂Extracting three times, and mixing the organic layer with Na₂SO₄And (5) drying. The solvent was removed to give a residue which was applied to a silica gel column with MeOH/CH₂Cl₂(1: 10) chromatography on elution gave 3.01 g (92%) of the standardThe title compound. The product was recrystallized from THF to yield the title compound as white crystals (0.893 g).

MS(ESI)m/z：459(M+H)⁺。

¹H NMR(CDCl₃) δ 8.99(1H, t, J ═ 5.6Hz), 8.30-8.15(1H, m), 7.25-7.105(3H, m), 4.80-4.60(1H, m), 3.95-3.70(4H, m), 3.34(2H, t, J ═ 6.3Hz), 3.14(2H, br d, J ═ 12.0Hz), 2.65-2.45(4H, m, inclusive of 2H, s, 2.59ppm), 1.92(4H, t, J ═ 13.8Hz), 1.85-1.40(11H, m, inclusive of 6H, d, J ═ 6.9Hz, 1.57 ppm).

m.p.：176℃。

IR(KBr)v：3281，2947，1720，1688，1611，1595，1547，1481，1447，1375，1200，1159，1136，1105，760cm^-1。

C₂₄H₃₄N₄O₅The calculated value of (a): c, 62.86; h, 7.47; n, 12.22. Measured value: c, 62.77; h, 7.42; and N, 12.16.

Another route for the synthesis of 4- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } tetrahydro-2H-pyran-4-carboxylic acid is described below.

Step 8 { [1- (ethoxymethyl) piperidin-4-yl ] methyl } carbamic acid tert-butyl ester

To a stirred solution of tert-butyl (piperidin-4-ylmethyl) carbamate (7.0 g, 33 mmol) in ethanol (19 ml) was added paraformaldehyde (1.2 g, 39 mmol) and potassium carbonate (5.4 g, 39 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 4 h. The mixture was filtered and the filter cake was washed with ethanol (50 ml). The volatile components were removed by evaporation to give 8.9 g (quantitative) of the title compound as a white powder.

¹H-NMR(CDCl₃)δ：4.60(1H，brs)，4.07(2H，s)，3.49(2H，q，J＝7.1Hz)，3.08-2.83(4H，m)，2.50-2.36(2H，m)，1.75-1.60(2H，m)， 1.44(9H，s)，1.52-1.35(1H，m)，1.19(3H，t，J＝7.1Hz)，1.31-1.12(2H，m)。

Step 9 [ methoxy (tetrahydro-4H-pyran-4-ylidene) methoxy ] (trimethyl) silane

To a stirred solution of diisopropylamine (1.6 g, 0.016 mol) in tetrahydrofuran (4 ml) was added n-butyllithium (1.59M in hexane, 9.2 ml, 0.014 mol) dropwise at 0 ℃ under nitrogen and stirred for 20 min. Subsequently, the reaction mixture was cooled to-40 ℃, tetrahydrofuran (1 ml) containing methyl tetrahydro-2H-pyran-4-carboxylate (1.9 g, 0.013 mol) and trimethylsilyl chloride (2.0 ml, 0.015 mol) was added, and the resulting mixture was gradually warmed to room temperature over 3H. The volatile components were removed by evaporation and the residue was filtered through a pad of celite washed with hexane. The filtrate was dried in vacuo to yield 2.9 g (quantitative) of the title compound as a clear yellow oil.

¹H-NMR(CDCl₃)δ：3.64-3.59(4H，m)，3.52(3H，s)，2.24(2H，t，J＝5.2Hz)，2.15(2H，t，J＝5.3Hz)，0.22(9H，s)。

Step 10.4- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] tetrahydro-2H-pyran-4-carboxylate

Trimethylsilyl trifluoromethanesulfonate (0.24 ml, 1.3 mmol) was added dropwise to a stirred solution of tert-butyl { [1- (ethoxymethyl) piperidin-4-yl ] methyl } carbamate (4 g, 14 mmol, step 8) and [ methoxy (tetrahydro-4H-pyran-4-ylidene) methoxy ] (trimethyl) silane (2.9 g, 13 mmol, step 9) in dichloromethane (30 ml) at 0 ℃ and the resulting mixture was stirred at room temperature for 12H. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (150 ml), extracted with dichloromethane (30 ml × 2), and the combined organic layers were dried over sodium sulfate. The solvent was removed to give a residue, which was subjected to chromatography on a silica gel column eluting with ethyl acetate/hexane (1: 1) to give 6.3 g (64%) of the title compound as a clear colorless oil.

MS(ESI)m/z：371(M+H)⁺。

¹H-NMR(CDCl₃)δ：4.57(1H，br s)，3.84-3.78(2H，m)，3.70(3H，s)，3.49-3.41(2H，m)，2.99-2.95(2H，m)，2.73-2.68(2H，m)，2.47(2H，s)，2.19-2.11(2H，m)，2.06-2.01(2H，m)，1.61-1.51(5H，m)，1.44(9H，s)，1.24-1.11(2H，m)。

Step 11.4- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] tetrahydro-2H-pyran-4-carboxylic acid

At room temperature in the presence of 4- [ (4- { [ (tert-butoxycarbonyl) amino group]Methyl } piperidin-1-yl) methyl]To a solution of tetrahydro-2H-pyran-4-carboxylic acid methyl ester (6.47 g, 17.5 mmol, step 10) in MeOH (32 ml) was added 5N aqueous NaOH (10 ml) (exothermic). The resulting solution was stirred at 60 ℃ for 7h, then cooled to 5-10 ℃ in an ice cooling bath. To this solution was added 5N HCl (10 ml), and the resulting solution was concentrated (pH about 6). To the residue was added 2-propanol (80 ml). The solution was concentrated. To the residue was added 2-propanol (80 ml) and concentrated again. The residue was diluted with EtOH (80 ml) and the mixture was stirred at room temperature for 2 h. The solution was filtered through a celite pad (5.0 g) to remove NaCl. The celite pad was washed with EtOH (20 ml) and the combined filtrates were concentrated. Adding CH to the residue₃CN (40 ml) and concentrated. During this procedure a white precipitate was found to form. Addition of CH to the residue₃CN (40 ml) and the resulting suspension was stirred at room temperature for 2 h. The mixture was filtered and the resulting solid was taken up in CH₃CN (10 ml) washing followed by drying under reduced pressure gave 4.1 g (65%) of the title compound as a white powder.

¹H NMR(300MHz，CDCl₃)δ4.66(1H，m)，3.93-3.82(3H，m)，3.15-2.99(4H，m)，2.58(2H，s)，2.58-2.45(2H，m)，1.98-1.76(4H，m)，1.55-1.35(6H，m)，1.44(9H，s)。

mp 129℃。

Step 12.4- { [4- (aminomethyl) piperidin-1-yl ] methyl } tetrahydro-2H-pyran-4-carboxylic acid 4-methylbenzenesulfonate

In N₂Next, 4- [ (4- { [ (tert-butoxycarbonyl) amino group was charged in a300 ml 3-neck round-bottom flask]Methyl } piperidin-1-yl) methyl]tetrahydro-2H-pyran-4-carboxylic acid (10 g, 28 mmol, step 11) and poured at room temperature into a flask containing p-TsOH H₂A solution of O (16 g, 84 mmol) in IPA (150 ml). The resulting mixture was at 60 ℃ and N₂Stirring for 7h, and slowly dropping Et while seeding in 2h₃N (8.6 ml, 62 mmol). Addition of Et₃A white precipitate formed during N. The resulting white suspension was stirred at 60 ℃ for 3h, at 50 ℃ for 5h and at room temperature for 10 h. The suspension was filtered and the resulting solid was washed with IPA (100 ml) and dried at 50 ℃ for 5h to yield 10.5 g (87%) of the title compound as a white powder.

¹H-NMR(D₂O)δ7.54(2H，d，J＝7.4Hz)，7.22(2H，J＝7.4Hz)，3.80-3.65(2H，m)，3.55-3.40(4H，m)，3.20-2.75(6H，m)，2.24(3H，s)， 1.90-1.80(6H，m)，1.55-1.35(4H，m)。

mp 247℃。

Step 13.4- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } tetrahydro-2H-pyran-4-carboxylic acid

CH containing 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one (1.0 g, 5.7 mmol) and 4-nitrophenyl chloroformate (1.14 g, 5.7 mmol)₂Cl₂(20 ml) the mixture was at room temperature and N₂And stirred for 5 minutes. To this mixture Et was added slowly₃N (1.7 ml, 12.5 mmol) and the resulting mixture was added to a solution containing 4- { [4- (aminomethyl) piperidin-1-yl]Methyl } tetrahydro-2H-pyran-4-carboxylic acid 4-methylbenzenesulfonate (2.4 g, 5.7 mmol, step 12) in CH₂Cl₂(15 ml) in the mixture. The resulting mixture was stirred at room temperature for 2 h. The mixture was washed with 0.5N aqueous HCl (100 mL)) Washed and the organic layer was saturated with NaHCO₃The aqueous solution (75 ml) was washed, followed by concentration of the organic layer. The residue was diluted with EtOAc (75 ml) and concentrated to about 15 ml. After seeding of the product, the mixture was allowed to stir at room temperature for 30 minutes. During this procedure, a solid was formed and the mixture was filtered. The resulting solid was washed with EtOAc (10 ml) and dried under vacuum at 50 ℃ to yield 1.9 g (73%) of the title compound as a white solid.

Step 14.4- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } tetrahydro-2H-pyran-4-carboxylic acid benzenesulfonate

At room temperature in the presence of 4- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl]Amino } methyl) piperidin-1-yl]CH of methyl } tetrahydro-2H-pyran-4-carboxylic acid (750 mg, step 13)₃CN (5 mL) suspension was added with CH containing benzenesulfonic acid monohydrate (288 mg)₃CN (5 ml) solution. The resulting mixture was stirred at room temperature for 2 days and concentrated. The residue was dried to obtain 909 mg (90%) of the title compound as a solid.

¹H-NMR(CD₃OD) δ 9.10(1H, t, J =5.7Hz),8.11(1H, dt, J =8.0,0.8Hz), 7.88-7.76(2H, m), 7.46-7.36(3H, m), 7.32(1H, dt, J ═ 8.0,0.8Hz), 7.22(1H, td, J ═ 7.8, 1.4Hz), 7.13(1H, td, J ═ 7.8, 1.4Hz), 4.70(1H, hexamer, J ═ 6.9Hz), 3.85-3.55(5H, m), 3.50-3.38(4H, m), 3.23-3.05(2H, m), 2.15-1.90(5H, m), 1.78-1.58(5H, m), 1.6H, 6 d ═ 6H, m).

mp 223℃。

C₃₀H₄₀N₄O₈Calculated value of S: c, 58.42; h, 6.54; and N, 9.08. Measured value: c, 58.50; h, 6.51; and N, 9.11.

PXRD(2θ(+/-0.1)：5.3，12.6，21.4，21.9)。

Example 2:

1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclohexanecarboxylic acid

Step 1.4-Cyanocyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure shown in example 1, step 1, using 1, 5-dibromopentane.

¹H-NMR(CDCl₃)δ：2.07(2H，d，J＝13.0Hz)，1.85-1.57(7H，m)，1.50(9H，s)，1.35-1.15(1H，m)。

Step 2.1- (aminomethyl) cyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure shown in example 1, step 2.

MS(ESI)m/z：214(M+H)⁺。

¹H-NMR(CDCl₃) δ: 2.69(2H, s), 2.02(2H, d, J ═ 13.2Hz), 1.65-1.05(19H, m, including 9H, s, 1.47 ppm).

Step 3.1- [ (4-Oxopiperidin-1-yl) methyl ] cyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure shown in example 1, step 3.

MS(ESI)m/z：296(M+H)+。

¹H-NMR(CDCl₃) δ: 2.84(4H, t, J ═ 6.1Hz)2.57(2H, s), 2.38(4H, t, J ═ 6.1Hz), 2.04(2H, d, J ═ 12.2Hz), 1.65-1.15(17H, m, including 9H, s, 1.47 ppm).

Step 4.1- [ (4-Cyanopiperidin-1-yl) methyl ] cyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure shown in example 1, step 4.

MS(ESI)m/z：307(M+H)⁺。

¹H-NMR(CDCl₃) δ: 2.53-2.66(2H, m), 2.53-2.48(1H, m), 2.48-2.30(4H, m, including 2H, s, 2.41ppm), 1.97(2H, d, J ═ 12.5Hz), 1.92-1.70(4H, m), 1.65-1.10(19H, m, including 9H, s, 1.45 ppm).

Step 5.1- { [4- (aminomethyl) piperidin-1-yl ] methyl } cyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure shown in example 1, step 5.

MS(ESI)m/z：311(M+H)⁺。

¹H-NMR(CDCl₃) δ: 2.81(2H, d, J ═ 11.37Hz), 2.55(2H, d, J ═ 5.8Hz), 2.39(2H, s), 2.11(2H, t, J ═ 11.0Hz), 2.03-1.85(5H, m), 1.65-1.10(21H, m, including 9H, s, 1.45 ppm).

Step 6.1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure shown in example 1, step 6.

MS(ESI)m/z：513(M+H)⁺。

¹H NMR(CDCl₃) δ 8.89(1H, t, J ═ 5.3Hz), 8.33-8.20(1H, m), 7.23-7.10(3H, m), 4.80-4.60(1H, m), 3.27(2H, t, J ═ 6.3Hz), 2.82(2H, d, J ═ 11.5Hz), 2.39(2H, s), 2.12(2H, t, J ═ 11.4Hz), 1.97(2H, d, J ═ 13.2Hz), 1.73-1.10(28H, m, including 6H, d, J ═ 6.9Hz, 1.56ppm and 9H, s, 1.45 ppm).

Step 7.1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclohexanecarboxylic acid

The title compound was prepared in analogy to the procedure shown in example 1, step 7.

MS(ESI)m/z：457(M+H)⁺。

¹H NMR(CDCl₃) δ 8.98(1H, t, J ═ 5.8Hz), 8.28-8.18(1H, m), 7.25-7.10(3H, m), 4.80-4.60(1H, m), 3.34(2H, t, J ═ 6.3Hz), 3.11(2H, d, J ═ 11.9Hz), 2.61(2H, s), 2.48(2H, t, J ═ 12.2Hz), 2.05-1.20(21H, m, including 6H, d, J ═ 6.9Hz, 1.57 ppm).

m.p.：151℃。

IR(KBr)v：3291，2930，1732，1690，1545，1481，1373，1298，1202，1134，762cm^-1。

C₂₅H₃₆N₄O₄The calculated value of (a): c, 65.76; h, 7.95; and N, 12.27. Measured value: c, 65.41; h, 8.18; and N, 12.18.

Example 3

1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopentanecarboxylic acid

Step 1.1- (iodomethyl) cyclopentanecarboxylic acid methyl ester

In N₂Neutralizing at-10 deg.C in a medium containing HN (iPr)₂To a stirred solution of (1.31 ml, 9.36 mmol) in THF (5 ml) was added n-BuLi (1.58M in hexane, 5.43 ml, 8.58 mmol) and the mixture was stirred at-10 ℃ for 1 h. Subsequently, methyl cyclopentanecarboxylate (1) was added dropwise to the mixture at 0 ℃.00 g, 7.80 mmol) in THF (3 ml) and the mixture was stirred at 0 ℃ for 2 h. Finally, CH is added to the mixture at 0 DEG C₂I₂(0.628 ml, 7.80 mmol) and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was saturated with NH₄Aqueous Cl (50 mL) quenched with Et₂O (75 ml) was extracted twice and the combined organic layers were washed with brine (75 ml). The organic layer is coated with Na₂SO₄Dried, filtered and concentrated. The solvent was removed to give a residue which was chromatographed on a silica gel column eluting with EtOAc/hexanes (1: 20-1: 10) to give 1.085 g (52%) of the title compound as a colorless oil.

¹H-NMR(CDCl₃)δ3.73(3H，s)，3.42(2H，s)，2.30-2.15(2H，m)，1.80-1.55(6H，m)。

Step 2.1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] cyclopentanecarboxylic acid methyl ester

Containing methyl 1- (iodomethyl) cyclopentanecarboxylate (5.52 g, 0.0206 mol, step 1), tert-butyl piperidin-4-ylmethyl) carbamate (8.83 g, 0.0412 mol) and iPr₂A mixture of NEt (10.76 ml, 0.0618 mol) in N-methylpyrrolidone (70 ml) was stirred at 120 ℃ for 24 h. After cooling, the reaction mixture was saturated with NaHCO₃The aqueous solution (200 ml) was diluted, extracted three times with AcOEt (200 ml) and the combined organic layers were washed with water (200 ml) and brine (200 ml). The organic layer is coated with Na₂SO₄Dried, filtered and concentrated. The solvent was removed to give a residue which was chromatographed on silica gel eluting with EtOAc/hexanes (1: 1) to give 4.91 g (67%) of the title compound as a yellow syrup.

MS(ESI)m/z：355(M+H)⁺。

¹H-NMR(CDCl₃)δ4.58(1H，br s)，3.66(3H，s)，2.97(2H，t，J＝6.3Hz)，2.77(2H，br d，J＝11.5Hz)，2.55(2H，s)，1.70-1.50(9H，m)，1.44(9H，s)，1.25-1.08(2H，m)。

Step 3.1- { [4- (aminomethyl) piperidin-1-yl ] methyl } cyclopentanecarboxylic acid methyl ester

By reacting a compound containing 1- [ (4- { [ (tert-butoxycarbonyl) amino group]Methyl } piperidin-1-yl) methyl]CH of methyl cyclopentanecarboxylate (1.16 g, 3.27 mmol, step 2)₂Cl₂(25 ml) and trifluoroacetic acid (5 ml) solution were stirred at room temperature for 1.5 h. The reaction mixture was again concentrated and saturated NaHCO₃Basified with aqueous solution (100 ml) and CHCl₃Five extractions (100 ml) were performed. The combined extracts were dried and concentrated to yield 0.831 g (100%) of the title compound as a yellow syrup.

MS(ESI)m/z：255(M+H)+。

¹H-NMR(CDCl₃)δ3.66(3H，s)，2.78(2H，d，J＝11.5Hz)，2.62-2.50(4H，m)，2.15-1.98(4H，m)，1.80-1.40(9H，m)，1.30-1.05(2H，m)。

Step 4.1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopentanecarboxylic acid methyl ester

MS(ESI)m/z：457(M+H)⁺。

¹H NMR(CDCl₃) δ 8.94(1H, t, J ═ 5.7Hz), 8.28-8.20(7.25-7.10(3H, m), 4.80-4.60(1H, m), 3.66(3H, s), 3.27(2H, t, J ═ 6.4Hz), 2.84(2H, d, J ═ 11.6Hz), 2.62(2H, s), 2.20-2.00(4H, m), 1.75-1.50(15H, m, including 6H, d, J ═ 7.0Hz, 1.56ppm), 1.40-1.20(2H, m).

Step 5- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopentanecarboxylic acid

With 1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl group]Amino } methyl) piperidin-1-yl]A mixture of methyl cyclopentanecarboxylate (1.33 g, 2.90 mmol, step 4) in 4N-HCl (6 ml) and acetic acid (6 ml) was stirred at reflux for 18 h. After cooling, the reaction mixture was concentrated and purified with NaHCO₃Basified with aqueous solution (100 ml) and CH₂Cl₂Extracted three times (150 ml). The combined extracts are washed with Na₂SO₄Dried, filtered and concentrated. The residue was loaded onto a silica gel column with MeOH/CH₂Cl₂(1: 10) chromatography was carried out, yielding 1.12 g (85%) of the title compound as a white solid. The crude compound was recrystallized from EtOAc × 2 and dried under vacuum at 50 ℃ for 2 days to yield 610 mg of the title compound as white crystals.

MS(ESI)m/z：443(M+H)⁺。

m.p.：165℃。

IR(KBr)v：3271，2934，1736，1684，1607，1558，1483，1454，1379，1358，1298，1209，1167，1097，758cm^-1。

¹H NMR(CDCl₃) δ 9.00(1H, t, J ═ 5.5Hz), 8.30-8.18(1H, m), 7.25-7.10(3H, m), 4.80-4.60(1H, m), 3.34(2H, t, J ═ 11.0Hz), 2.32-2.17(2H, m), 2.00-1.30(17H, m, including 6H, d, 7.0Hz, 1.57 ppm).

C₂₄H₃₄N₄O₄·0.2H₂Calculated value of O: c, 64.61; h, 7.77; n, 12.56. Measured value: c, 64.34; h, 7.79; and N, 12.48.

Another route for the synthesis of 1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopentanecarboxylic acid is described below.

Step 6.1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] cyclopentanecarboxylic acid methyl ester

The title compound was prepared according to the procedure described in example 1, step 10, using [ cyclopentylidene (methoxy) methoxy ] (trimethyl) silane (Synthesis, 1982, 1, 58-60) instead of [ methoxy (tetrahydro-4H-pyran-4-ylidene) methoxy ] (trimethyl) silane.

MS(ESI)m/z：355(M+H)⁺。

¹H-NMR(CDCl₃)δ4.58(1H，br s)，3.66(3H，s)，2.97(2H，t， J＝6.3Hz)，2.77(2H，br d，J＝11.5Hz)，2.55(2H，s)，2.18-1.95(4H，m)，1.70-1.50(9H，m)，1.44(9H，s)，1.25-1.08(2H，m)。

Step 7.1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] cyclopentanecarboxylic acid

At room temperature in the presence of 1- [ (4- { [ (tert-butoxycarbonyl) amino group]Methyl } piperidin-1-yl) methyl]To a solution of methyl cyclopentanecarboxylate (2.8 g, 8.0 mmol, step 6) in MeOH (11 ml) was added aqueous 2N NaOH (6 ml) (exothermic). The resulting solution was stirred at 70 ℃ for 4h and then cooled to 5-10 ℃ in an ice cooling bath. To this solution was added dropwise 5N aqueous HCl (6 ml). The resulting solution was concentrated (pH about 6) and 2-propanol (40 ml) was added to the residue. The solution was concentrated and CH was added to the residue₃CN (40 ml). The resulting mixture was stirred at room temperature for 2h, and filtered through a pad of celite (5.0 g) to remove NaCl. The filtrate was concentrated to obtain 2.4 g (quantitative) of the title compound as a white solid.

¹H NMR(300MHz，DMSO-d6)δ6.90-6.75(1H，m)，2.95-2.80(2H，m)，2.79(2H，t，J＝6.4Hz)，2.58(2H，s)，2.25-2.05(2H，m)，2.05-1.85(2H，m)，1.65-1.50(6H，m)，1.50-1.25(3H，m)，1.37(9H，s)，1.20-0.95(2H，m)。

mp 150℃。

Step 8.1- { [4- (aminomethyl) piperidin-1-yl ] methyl } cyclopentanecarboxylic acid 4-methylbenzenesulfonate

In a 100 ml 2-necked round-bottomed flask at room temperature containing 1- [ (4- { [ (tert-butoxycarbonyl) amino group]Methyl } piperidin-1-yl) methyl]Cyclopentanecarboxylic acidsTo a mixture of THF (25 mL) (5 g, 14.7 mmol, step 7) was added p-TsOH H₂O (8.4 g, 44 mmol) in THF (25 ml). The resulting mixture was at 70 ℃ and N₂Stirred for 3h and cooled to room temperature. Et was slowly added dropwise to the solution₃N (6 ml, 44 mmol). Addition of Et₃A white precipitate formed during N and the resulting mixture was stirred at room temperature for 14 h. The suspension was filtered and the resulting solid was washed with THF (10 ml) and dried at 50 ℃ for 5h to yield 5.9 g (97%) of the title compound as a white solid.

¹H-NMR(D₂O)δ7.51(2H，J＝8.2Hz)，7.19(2H，J＝8.2Hz)，3.38(2H，d，J＝11.0Hz)，3.09(2H，d，J＝2.6Hz)，2.88(2H，t，J＝12.1Hz)， 2.79(2H，t，J＝6.6Hz)，2.21(3H，s)，1.94-1.75(5H，m)，1.61-1.27(9H，m)。

Step 9- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopentanecarboxylic acid

1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one (10 g, 56.8 mmol) and 4-nitrophenyl chloroformate (11.4 g, 56.8 mmol) in CH₂Cl₂(150 ml) the mixture was stirred at room temperature for 5 minutes. To this mixture Et was added slowly₃N (17.4 mL, 125 mmol) and the resulting mixture was added to a solution containing 1- { [4- (aminomethyl) piperidin-1-yl]Methyl } cyclopentanecarboxylic acid 4-methylbenzenesulfonate (23.4 g, 56.8 mmol, step 8) CH₂Cl₂(75 ml) in the mixture. After stirring for 10 min, Et was added₃N (7.9 ml, 56.8 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was washed with 1N aqueous HCl (100 ml). The organic layer was concentrated at 50 ℃ until about 5vol and replaced with acetone (50 ml × 3) at 80 ℃ until about 5 vol. Adding H to the mixture at 80 deg.C₂O (100 ml) and the resulting mixture was concentrated at 100 ℃. After cooling to 50 ℃, 20% aqueous N, N-dimethylaminoethanol (100 ml) was addedIn this mixture, solids were found. The resulting mixture was cooled in an ice-cold bath and allowed to stir at that temperature for 18 h. The mixture is filtered and the resulting solid is washed with H₂O (100 ml) and dried at 50 ℃ under vacuum to yield 17.9 g (71%) of the title compound as a white solid.

mp.166℃

PXRD(2θ(+/-0.1)：4.4，8.8，13.2，17.6)。

Example 4

1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopropanecarboxylate

Step 1.1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] cyclopropanecarboxylic acid tert-butyl ester

Following the procedure described in example 3, step 1, tert-butyl cyclopropanecarboxylate (j. organomet. chem., 1983,252267-274) instead of methyl cyclopentanecarboxylate, tert-butyl 1- (iodomethyl) cyclopropanecarboxylate (comprising the starting material, 3: 2 mixture) was prepared. Used in the next step without further purification.

The title compound was prepared in analogy to the procedure shown in example 3, step 2.

MS(ESI)m/z：369(M+H)⁺。

¹H NMR(CDCl₃)δ4.59(1H，br s)，2.99(2H，d，J＝5.9Hz)，2.89(2H，br d，J＝11.5Hz)，2.57(2H，s)，2.00(2H，t，J＝11.7Hz)，1.62(2H，d，J＝12.9Hz)，1.55-1.35(1H，m)，1.44(9H，s)，1.42(9H，s)，1.30-1.15(2H，m)，1.13(2H，dd，J＝3.8Hz，6.6Hz)，0.74(2H，dd，J＝3.5Hz，6.3Hz)。

Step 2.1- { [4- (aminomethyl) piperidin-1-yl ] methyl } cyclopropanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure described in example 3, step 3.

MS(ESI)m/z：269(M+H)⁺。

¹H NMR(CDCl₃) δ 2.96(2H, br d, J ═ 11.5Hz), 2.60-2.50(4H, m), 2.00(2H, t, J ═ 11.4Hz), 1.75-1.35(14H, m, including 2H, br d, J ═ 9.6Hz, 1.66ppm and 9H, s, 1.43ppm), 1.33-1.16(2H, m), 1.13(2H, dd, J ═ 4.0Hz, 6.9Hz), 0.74(2H, dd, J ═ 3.8Hz, 6.6 Hz).

Step 3.1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopropanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure described in example 3, step 4.

MS(ESI)m/z：471(M+H)⁺。

¹H NMR(CDCl₃) δ 8.91(1H, br t, J ═ 5.5Hz), 8.32-8.20(1H, m), 7.25-7.10(3H, m), 4.80-4.60(1H, m), 3.30(2H, t, J ═ 6.4Hz), 2.91(2H, br d, J ═ 11.6Hz), 2.57(2H, s), 2.01(2H, br t, J ═ 9.5Hz), 1.73(2H, brd, J ═ 12.1Hz), 1.67-1.50(10H, m, including 6H, d, J ═ 7.0Hz, 1.56ppm), 1.43(9H, s), 1.34-1.20(2H, m), 1.12(2H, dd, J ═ 4.0Hz, 7.0Hz, 3.73 Hz), 3.7H, 3.73 (ddh, 3 Hz).

Step 4.1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclopropanecarboxylate

The title compound was prepared in analogy to the procedure described in example 1, step 7.

MS(ESI)m/z：415(M+H)⁺。

m.p.：206℃。

IR(KBr)v：2936，2700，1732，1688，1556，1485，1383，1359，1182，1164，758cm^-1。

¹H NMR(DMSO-d₆) δ 8.86(1H, t, J ═ 6.3Hz), 8.07(1H, dd, J ═ 1.0Hz, 7.8Hz), 7.45(1H, d, J ═ 7.1Hz), 7.22(1H, dt, J ═ 1.3Hz, 7.6Hz), 7.15(1H, dt, J ═ 1.2Hz, 7.7Hz), 4.95-4.60(1H, m), 3.70-3.10(6H, m), 3.10-2.90(2H, m), 1.86(3H, m, including 2H, d, J ═ 11.2Hz, 1.86ppm), 1.70-1.53(2H, m), 1.49(6H, d, J ═ 6.9Hz), 1.35-1.15(4H, m).

C₂₂H₃₀N₄O₄·HCl·0.2H₂Calculated value of O: c, 58.13; h, 6.96; n,12.33. found: c, 57.93; h, 6.97; and N, 12.18.

Example 5

3- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] propanoic acid hydrochloride

Step 1.4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one (J.Med.chem.1999, 42, 2870-2880) (3.00 g, 17.02 mmol) and triethylamine (7.12 ml, 51.06 mmol) in 70 ml of tetrahydrofuran was added at room temperature 14 ml of tetrahydrofuran containing triphosgene (5.15 g, 17.02 mmol). The reaction mixture was refluxed for 19 h. The mixture was cooled to room temperature and added with 4- (aminomethyl) piperidine-1-carboxylic acid tert-butyl ester (j.prugh, l.a.birchenough and m.s.egbertson, synth.commun., 1992, 222357-60) (3.28 g, 15.32 mmol) of 10 ml of tetrahydrofuran. The reaction mixture was refluxed for a further 24 h. Cooled again and saturated NaHCO at 50 ml₃The aqueous solution was basified and extracted three times with 100 ml of ethyl acetate. The combined extracts were washed with brine, MgSO₄Dried and concentrated. The residue was flash chromatographed (eluent: hexane/ethyl acetate 5/1 to 1/2) to yield 3.99 g (62%) of the title compound as a colorless oil.

¹H-NMR(CDCl₃)δ：9.04-8.88(1H，m)，8.83-8.20(¹H，m)，7.26-7.10(3H，m)，4.80-4.60(¹H，m)，4.28-4.02(2H，m)，3.32(2H，t，J＝6.1Hz)，2.82-2.60(2H，m)，1.94-1.10(5H，m)，1.57(6H，d，J＝7.1Hz)，1.45(9H，s)。

Step 2.3-isopropyl-2-oxo-N- (piperidin-4-ylmethyl) -2, 3-dihydro-1H-benzimidazole-1-carboxamide

By reacting a compound containing 4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl]Amino } methyl) piperidine-1-carboxylic acid tert-butyl ester (3.992 g, 9.58 mmol) was stirred at room temperature for 18h in 50 ml methanol with 10% hydrochloric acid and 10 ml concentrated hydrochloric acid. The mixture was then concentrated and washed with Na₂CO₃Basified with aqueous solution of CHCl₃Extracted three times (100 ml). The combined extracts were dried and concentrated. The residue is subjected to flash chromatography (NH-silica gel, eluent: CH)₂Cl₂Methanol 100/1) to yield 2.272 g (75%) of the title compound as a colorless oil.

MS(ESI)m/z：317(M+H)⁺。

¹H-NMR(CDCl₃)δ：8.93(¹H，br)，8.32-8.22(¹H，m)，7.24-7.02(3H，m)，4.80-4.61(¹H，m)，3.31(2H，t，J＝6.0Hz)，3.20-3.05(2H，m)，2.79-2.54(2H，m)，1.84-1.52(3H，m)，1.57(6H，d，J＝6.9Hz)，1.36-1.13(2H，m)。

Step 3.3- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] propanoic acid tert-butyl ester

A mixture of 3-isopropyl-2-oxo-N- (piperidin-4-ylmethyl) -2, 3-dihydro-1H-benzimidazole-1-carboxamide (0.50 g, 1.58 mmol, step 2), tert-butyl acrylate (0.340 ml, 2.37 mmol), and iPrNEt (0.275 ml, 2.37 mmol) in THF (20 ml) was refluxed for 18H. After cooling, the reaction mixture was saturated with NaHCO₃Diluted with aqueous solution (100 ml) and CH₂Cl₂Extracted three times (100 ml). The combined extracts are washed with Na₂SO₄Dry, filter and concentrate. The residue was loaded onto a silica gel column with MeOH/CH₂Cl₂(1:20 → 1:10) followed by chromatography on NH-silica gel eluting with EtOAc/hexanes (1:5 → 1:2) afforded 0.111 g (16%) of the title compound as a colorless syrup.

MS(ESI)m/z：445(M+H)⁺。

¹H NMR(CDCl₃) δ 8.94(1H, br s), 8.30-8.20(1H, m), 7.25-7.11(3H, m), 7.11-7.00(1H, m), 4.80-4.62(1H, m), 3.31(2H, t, J ═ 6.2Hz), 2.95(2H, br t, J ═ 11.6Hz), 2.68(2H, t, J ═ 7.2Hz), 2.43(2H, t, J ═ 7.7Hz), 2.03(2H, br t, J ═ 11.4Hz), 1.98-1.82(1H, m), 1.79(2H, d, J ═ 12.1Hz), 1.56(6H, d, J ═ 7.2), 1.50-1.30(11H, m, 11.44H, 44 ppm).

Step 4.3- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl]Amino } methyl) piperidin-1-yl]Propionic acid hydrochloride

MS(ESI)m/z：389(M+H)⁺。

IR(KBr)v：2939，2637，1724，1682，1542，1466，1373，1217，1194，953，762cm^-1。

¹H NMR(DMSO-d₆) δ 8.86(1H, t, J ═ 5.9Hz), 8.07(1H, dd, J ═ 0.8Hz, 7.7Hz), 7.49(1H, d, J ═ 7.6Hz), 7.22(1H, dt, J ═ 1.3Hz, 7.6Hz), 7.15(1H, dt, J ═ 1.0Hz, 7.6Hz), 4.75-4.60(1H, m), 3.70-3.10(6H, m), 2.93(2H, br t, J ═ 11.2Hz), 2.85-2.70(2H, m), 1.95-1.75(3H, m, including 2H, d, J ═ 11.5Hz, 1.87ppm), 1.65-1.40(8H, m, including 6H, d, J ═ 1.49 ppm).

C₂₀H₂₈N₄O₄·HCl·0.8H₂Calculated value of O: c, 54.68; h, 7.02; n, 12.75. Measured value: c, 54.67; h, 6.88; and N, 12.70.

Example 6

1- { [ 4-hydroxy-4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl]Amino } methyl) piperidin-1-yl]Methyl cyclohexanecarboxylic acid

Step 1.1- (iodomethyl) cyclohexanecarboxylic acid methyl ester

The title compound was prepared in analogy to the procedure shown in example 3, step 1.

¹H NMR(CDCl₃)δ3.73(3H，s)，3.32(2H，s)，2.20-2.05(2H，m)，1.70-1.20(8H，m)。

Step 2.1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } -4-hydroxypiperidin-1-yl) methyl ] cyclohexanecarboxylic acid methyl ester

Using a method similar to that shown in example 3, step 2, [ (4-hydroxypiperidin-4-yl) methyl ] was used]Tert-butyl carbamate (chem. pharm. bull., 2002,50(9)1187-1194) and methyl 1- (iodomethyl) cyclohexanecarboxylate (step 1 of example 6).

MS(ESI)m/z：385(M+H)⁺。

¹H NMR(CDCl₃) δ 4.86(1H, br s), 3.66(3H, s), 3.11(2H, d, J ═ 6.3Hz), 2.55-2.45(6H, m), 2.03(2H, br d, J ═ 10.4Hz), 1.70-1.15(18H, m, including 9H, s, 1.44 ppm).

Step 3.1- { [4- (aminomethyl) -4-hydroxypiperidin-1-yl ] methyl } cyclohexanecarboxylic acid methyl ester

The title compound was prepared in analogy to the procedure shown in example 3, step 3.

MS(ESI)m/z：285(M+H)⁺。

¹H NMR(CDCl₃)δ3.66(3H，s)，2.61(1H，br s)，2.57-2.45(5H，m)，2.35-2.11(3H，m)，2.04(2H，br d，J＝11.5Hz)，1.65-1.45(6H，m)，1.45-1.20(4H，m)。

Step 4.1- { [ 4-hydroxy-4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclohexanecarboxylic acid methyl ester

The title compound was prepared in analogy to the procedure shown in example 3, step 4.

MS(ESI)m/z：487(M+H)⁺。

¹H NMR(CDCl₃)δ9.12(1H，t，J＝5.6Hz)，8.30-8.20(1H，m)，7.25-7.10(3H，m)，4.80-4.65(1H，m)，3.66(3H，s)，3.54(2H，d，J＝5.9Hz)，2.60-2.45(6H，m)，2.03(2H，br d，J＝9.1Hz)，1.75-1.47(12H，m)，1.47-1.15(6H，m)。

Step 5- { [ 4-hydroxy-4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclohexanecarboxylic acid

The title compound was prepared in analogy to the procedure shown in example 3, step 5.

MS(ESI)m/z：473(M+H)⁺。

m.p.：184℃。

IR(KBr)v：3437，3273，2943，1732，1688，1601，1533，1479，1452，1371，1134，978，762cm^-1。

¹H NMR(DMSO-d₆) δ 8.94(1H, t, J ═ 5.6Hz), 8.09(1H, d, J ═ 7.7Hz), 7.43(1H, d, J ═ 7.7Hz), 7.22(1H, t, J ═ 7.8Hz), 7.14(1H, t, J ═ 7.4Hz), 4.75-4.58(1H, m), 4.59(1H, s), 2.47(2H, s), 4.00-3.00(6H, m), 1.86(2H, d, J ═ 11.4Hz), 1.60-1.10(18H, m, including 6H, d, J ═ 6.9Hz, 1.49 ppm).

C₂₅H₃₆N₄O₅·0.5H₂Calculated value of O: c, 62.35; h, 7.74; n, 11.63. Measured value: c, 62.52; h, 7.70; n, 11.66.

Example 7

1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclobutanecarboxylic acid

Step 1.1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] cyclobutanecarboxylic acid methyl ester

Acetic acid (8.6 ml, 150 mmol) was added to a stirred mixture of (piperidin-4-ylmethyl) carbamic acid tert-butyl ester (12.8 g, 60 mmol), i.e. methyl 1-formylcyclobutanecarboxylate (2.13 g, 15 mmol, Davis, charles r.; Swenson, Dale c.; Burton, Donald j., j.org.chem., 1993, 58, 6843) in tetrahydrofuran at ambient temperature. After 30 minutes, sodium triacetoxyborohydride (12.7 g, 60 mmol) was added to the mixture. The mixture was then heated to 60 ℃ for 2 h.

After cooling, the reaction mixture was poured into saturated NaHCO₃In aqueous solution. The aqueous layer was extracted three times with dichloromethane. The combined organic phases were washed with brine, MgSO₄Dried and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (1: 1) to give 4.25 g (83%) of the title compound as a white solid.

MS(ESI)m/z：341(M+H⁺)。

¹H-NMR(CDCl₃)δ：3.69(3H，s)，2.96(2H，t，J＝6.2Hz)，2.75(2H，d，J＝11.4Hz)，2.67(2H，s)，2.37-2.46(2H，m)，1.78-2.05(6H，m)，1.45-1.65(2H，m)，1.43(9H，s)，1.09-1.21(2H，m)。

Step 2.1- { [4- (aminomethyl) piperidin-1-yl ] methyl } cyclobutanecarboxylic acid methyl ester

The title compound was prepared according to the procedure described in example 3, step 3, from methyl 1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] cyclobutanecarboxylate (step 1 of example 7).

MS(ESI)m/z：241(M+H⁺)。

¹H-NMR(CDCl₃)δ：3.67(3H，s)，2.72-2.78(2H，m)，2.66(2H，s)，2.54(2H，d，J＝6.2Hz)，2.34-2.47(2H，m)，1.79-2.04(8H，m)，1.54-1.64(2H，m)，1.05-1.35(3H，m)。

Step 3.1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclobutanecarboxylic acid methyl ester

The title compound was prepared according to the procedure described in example 1, step 6 from 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one and methyl 1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] cyclobutanecarboxylate (step 2 of example 7).

¹H-NMR(CDCl₃)δ：8.92-8.86(1H，m)，8.28-8.24(1H，m)，7.20-7.12(3H，m)，4.75-4.62(1H，m)，3.70(3H，s)，3.27(2H，t，J＝6.4Hz)，2.85-2.72(2H，m)，2.68(2H，s)，2.47-2.35(2H，m)，2.05-1.92(4H， m)，1.92-1.76(2H，m)，1.71-1.61(2H，m)，1.56(6H，d，J＝7.0Hz)，1.32-1.17(2H，m)。

MS(ESI)m/z：443(M+H⁺)。

Step 4.1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclobutanecarboxylic acid

The title compound was prepared according to the procedure described in example 3, step 5 from methyl 1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclobutanecarboxylate (step 3 of example 7).

IR(KBr)v：3293，2979，2937，2875，1732，1687，1610，1548，1479，1375，1298，1203，1099，761，704cm^-1。

¹H-NMR(CDCl₃)δ：9.02-8.95(1H，m)，8.26-8.22(1H，m)，7.22-7.12(3H，m)，4.76-4.62(1H，m)，3.33(2H，t，J＝6.2Hz)，3.10-3.00(2H，m)，2.77(2H，s)，2.58-2.48(2H，m)，2.44-2.24(2H，m)，1.92-1.79(2H，s)，1.99-1.80(5H，m)，1.56(6H，d，J＝7.0Hz)，1.50-1.33(3H，m)。

MS(ESI)m/z：429(M+H⁺)。

C₂₃H₃₂N₄O₄The calculated value of (a): c, 64.46; h, 7.53; and N, 13.07. Measured value: c, 64.47; h, 7.43; and N, 12.93.

Another route for the synthesis of 1- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclobutanecarboxylic acid is described below.

Step 5.1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] cyclobutanecarboxylic acid ethyl ester

The title compound was prepared according to the procedure described in example 1, step 10, substituting [ methoxy (tetrahydro-4H-pyran-4-ylidene) methoxy ] (trimethyl) silane with [ cyclobutyl (ethoxy) methoxy ] (trimethyl) silane (chem. commun., 1971, 136-137).

MS(ESI)m/z：355(M+H)⁺。

¹H-NMR(CDCl₃)δ：4.55(1H，br)，4.17(2H，q，J＝7.1Hz)，2.96(2H，t，J＝6.3Hz)，2.76(2H，d，J＝11.4Hz)，2.48-2.33(2H，m)，2.05-1.80(6H，m)，1.43(9H，s)，1.25(3H，q，J＝7.1Hz)，1.40-1.05(7H，m)。

Step 6.1- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] cyclobutanecarboxylic acid

Containing 1- [ (4- { [ (tert-butoxycarbonyl) amino group]Methyl } piperidin-1-yl) methyl]A mixture of ethyl cyclobutanecarboxylate (4.2 g, 11.9 mmol, step 5), 2N NaOH (18 ml) and EtOH (12 ml) was heated at 50 ℃ for 4 h. The resulting solution was cooled in an ice bath and 2N HCl (about 19 ml) was added until the pH of the mixture was about 5-6. All with CH₂Cl₂iPrOH (3: 1, 30 ml. times.3) extraction. The combined organic layers were dried (Na)₂SO₄) And filtered. The filtrate was concentrated to yield 3.8 g (98%) of the title compound as a yellow solid.

¹H NMR(300MHz，CDCl₃)δ4.08(1H，m)，3.20-3.10(2H，m)，3.08-2.99(2H，m)，2.91(2H，s)，2.60-2.38(4H，m)，2.35-2.16(2H，m)，2.05-1.76(6H，m)，1.65(1H，m)，1.44(9H，s)。

mp 160℃。

Step 7.1- { [4- (aminomethyl) piperidin-1-yl ] methyl } cyclobutanecarboxylic acid 4-methylbenzenesulfonate

In N₂In a 500 ml 3-neck round-bottom flask,by reacting a compound containing 1- [ (4- { [ (tert-butoxycarbonyl) amino group]Methyl } piperidin-1-yl) methyl]A mixture of cyclobutanecarboxylic acid (30 g, 92 mmol, step 6) in THF (150 ml) was stirred at room temperature for 10 min. To this suspension was added p-TsOH H at room temperature₂O (52.4 g, 276 mmol) in THF (150 ml). After stirring at this temperature for 10 minutes, the resulting solution was heated under reflux for 3 h. After cooling to room temperature Et was added very slowly while seeding within 1h₃N (28.1 ml, 202 mmol). Addition of Et₃During N a white precipitate formed. The resulting white suspension was stirred at room temperature for 6h, filtered and the resulting solid washed with THF (100 ml × 2) and dried at 50 ℃ for 5h to yield 35 g (96%) of the title compound as a white powder.

¹H-NMR(D₂O)δ7.40(2H，d，J＝7.2Hz)，7.07(2H，d，J＝7.2Hz)，3.28-3.00(4H，m)，2.80-2.57(4H，m)，2.09(3H，s)，2.18-1.97(2H，m)，1.85-1.58(8H，m)，1.36-1.12(2H，m)。

mp：210℃。

Step 8- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } cyclobutanecarboxylic acid

CH containing 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one (486 mg, 2.8 mmol) and 4-nitrophenyl chloroformate (556 mg, 2.8 mmol)₂Cl₂(10 ml) the mixture was stirred at room temperature for 5 minutes. To this mixture Et was added slowly₃N (0.84 ml, 6.1 mmol) and the mixture became a solution. The solution was added to a solution containing 1- { [4- (aminomethyl) piperidin-1-yl group at room temperature]Methyl } cyclobutanecarboxylic acid 4-methylbenzenesulfonate (1.1 g, 2.8 mmol, step 7) for CH₂Cl₂(5 ml) in the mixture. After stirring for 10 min, Et was added₃N (0.38 ml, 2.8 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was washed with 0.5N aqueous HCl (10 mL) and saturated NaHCO₃Aqueous (10 ml) washes, followed by concentration of the organic phaseAnd (3) a layer. Saturated NaHCO was added to the residue at room temperature₃Aqueous solution (15 ml) and heptane (15 ml) and allowed to stir at this temperature for 6 h. A solid was found and the mixture was filtered. The obtained solid is treated with H₂O and heptane washes. Crude material was obtained as a white solid after drying (1.0 g, 82%). The crude material (4.0 g) was purified by recrystallization from toluene (36 ml) to yield 2.6 g of the title compound (66%) as a white solid.

mp.173℃。

PXRD(2θ(+/-0.1)：10.8，16.9，18.9，26.5)。

Example 8:

n- ({1- (2-oxycarbonyl-2-methylpropyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

Step 1.[ {1- (2-benzyloxycarbonyl-2-methylpropyl) piperidin-4-yl } methyl ] carbamic acid tert-butyl ester

To a stirred solution of tert-butyl (piperidin-4-ylmethyl) carbamate (38.8 g, 181 mmol) in N, N-dimethylformamide (100 ml) was added benzyl 3-chloropivalate (14.2 g, 124 mmol, prepared from 3-chloropivaloyl chloride (25.6 g, 165 mmol) and benzyl alcohol (19.6 g, 181 mmol), ethyldiisopropylamine (64.0 g, 495 mmol) and sodium iodide (27.1 g, 181 mmol) at ambient temperature. The resulting mixture was stirred at 120 ℃ for 14 h. The volatile constituents are removed by evaporation and the residue is chromatographed on a column of silica gel, eluting with hexane/ethyl acetate (1: 1), to give 640 mg (1%) of the title compound as a pale yellow oil.

MS(ESI)m/z：405(M+H⁺)。

¹H NMR(CDCl₃)δ7.43-7.23(5H，m)，5.10(2H，s)，4.58(1H，brt)，2.95(2H，m)，2.71(2H，m)，2.46(2H，br s)，2.06(2H，m)，1.57-1.36(3H，m)，1.44(9H，s)，1.12(2H，m)，1.17(6H，s)。

Step 2.N- ({1- (2-benzyloxycarbonyl-2-methylpropyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

4-Nitrophenyl chloroformate (470 mg, 2.33 mmol) was added to a stirred mixture at room temperature in dichloromethane (20.0 mL) containing 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one (J.Med.chem.1999, 42, 2870-2880) (411 mg, 2.33 mmol) and triethylamine (1.00 mL, 7.17 mmol). The resulting mixture was stirred at room temperature for 2 h. To the mixture was added a solution containing 1- (2-benzyloxycarbonyl-2-methylpropyl) -4-aminomethylpiperidine hydrochloride { by concentration [ {1- (2-benzyloxycarbonyl-2-methylpropyl) piperidin-4-yl } methyl group]A mixture of tert-butyl carbamate (step 1 of example 1) (640 mg, 1.49 mmol) and MeOH with 10% HCl (20.0 ml) was prepared } and a suspension of triethylamine (1.00 ml, 7.17 mmol) in dichloromethane (5.00 ml). The resulting mixture was stirred at room temperature for 13h and 0.5M aqueous NaOH solution was added to the mixture. The mixture was extracted with dichloromethane. The extract was washed with 0.5M aqueous NaOH and brine, and MgSO₄Dried and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, eluting with dichloromethane/methanol (10: 1)) to give 508 mg (63%) of the title compound as a pale yellow oil.

MS(ESI)m/z：507(M+H⁺)。

¹H NMR(CDCl₃) δ 8.89(1H, br t, J ═ 5.7Hz), 8.26(1H, m), 7.43-7.05(8H, m), 5.10(2H, s), 4.70(1H, heptad, J ═ 7.0Hz), 3.26(2H, m), 2.75(2H, m), 2.48(2H, br s), 2.11(2H, m), 1.61(2H, m), 1.56(6H, d, J ═ 7.0Hz), 1.52(1H, m), 1.26(2H, m), 1.18(6H, s).

Step 3.N- ({1- (2-oxycarbonyl-2-methylpropyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

N- ({1- (2-benzyloxycarbonyl-2-methylpropyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide (step 2 of example 8) (418 mg, 0.825 mmol) and 20% Pd (OH) were reacted at room temperature in hydrogen₂A mixture of/C (58.0 mg) in methanol (80 ml) was stirred for 12 h. The catalyst was filtered over a pad of celite and the filtrate was evaporated under reduced pressure. The obtained solid is extracted with hexane-CH₂Cl₂Recrystallization afforded 285 mg (84%) of the title compound as a colorless solid.

MS(ESI)m/z：417(M+H)⁺。

¹H NMR(DMSO-d₆) δ 8.80(1H, br t, J ═ 5.8Hz), 8.05(1H, m), 7.42(1H, m), 7.20(1H, m), 7.12(1H, m), 4.65(1H, heptad, J ═ 7.0Hz), 3.20(2H, m), 2.85(2H, m), 2.44(2H, br s), 2.18(2H, m), 1.61(2H, m), 1.50(1H, m), 1.47(6H, d, J ═ 7.0Hz), 1.20(2H, m), 1.04(6H, s). No signal corresponding to carboxylic acid was observed.

C₂₂H₃₂N₄O₄·0.1H₂Calculated value of O: c, 63.17; h, 7.76; n, 13.39. Measured value: c, 62.78; h, 7.74; n, 13.11.

Example 9:

n- ({1- (2-tetrazol-2-methylpropyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

Step 1.2-benzyl-alpha, alpha-dimethyl-2H-tetrazole-5-acetic acid, ethyl ester

The reaction was carried out at ambient temperature under a pressure of a gas containing α, α -dimethyltetrazole-5-acetic acid, ethyl ester (j.med. chem.1996,39, 2354-₂CO₃To a stirred mixture of (12.3 g, 89.0 mmol) in acetone (200 ml) was added benzyl bromide (4.45 ml, 37.4 mmol). The resulting mixture was stirred at 50 ℃ for 18h and concentrated under reduced pressure. The residue is chromatographed on a column of silica gel, eluting with hexane/ethyl acetate (10: 1), to give 6.14 g (60%) of the title compound as a colorless oil.

MS(ESI)m/z：275(M+H⁺)。

¹H NMR(CDCl₃)δ7.45-7.23(5H，m)，5.73(2H，s)，4.11(2H，q，J＝7.2Hz)，1.70(6H，s)，1.13(3H，t，J＝7.2Hz)。

Step 2.2-benzyl-alpha, alpha-dimethyl-2H-tetrazole-5-acetaldehyde

DIBAL (1.0M in toluene, 50.0 ml, 50.0 mmol) was added to a stirred mixture of 2-benzyl- α, α -dimethyl-2H-tetrazole-5-acetic acid ethyl ester acetaldehyde (step 1 of example 9) (6.14 g, 22.4 mmol) in dichloromethane (100 ml) at-78 ℃. The resulting mixture was stirred at-78 ℃ for 4 h. DIBAL (1.0M in toluene, 25.0 ml, 25.0 mmol) was added to the reaction mixture and the resulting mixture was stirred at-78 ℃ for 8 h. To the mixture was added 2M aqueous HCl (100 mL) and saturated NH₄Aqueous Cl (20 ml). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, eluting with hexane/ethyl acetate (10: 1), to give 3.45 g (67%) of the title compound as a colorless oil.

MS(ESI)m/z：231(M+H⁺)。

¹H NMR(CDCl₃)δ9.68(1H，s)，7.45-7.23(5H，m)，5.74(2H，s)，1.56(6H，s)。

Step 3.[ {1- (2- (2-benzyltetrazol) -2-methylpropyl) piperidin-4-yl } methyl ] carbamic acid tert-butyl ester

In a reaction mixture containing 2-benzyl-alpha, alpha-dimethyl-2H-tetrazole-5-acetaldehyde (example)Step 2) of example 9 (1.28 g, 5.56 mmol) and tert-butyl (piperidin-4-ylmethyl) carbamate (2.40 g, 11.2 mmol) in tetrahydrofuran (300 ml) was stirred and NaBH (OAc) was added₃(5.90 g, 27.8 mmol) and AcOH (1.67 g, 27.8 mmol). The resulting mixture was stirred at 60 ℃ for 9 hours and concentrated under reduced pressure. Adding saturated NaHCO to the stirred residual oil and solid₃Aqueous solution and dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, eluting with hexane/ethyl acetate (1: 1), to give 830 mg (35%) of the title compound as a colorless oil.

MS(ESI)m/z：429(M+H)⁺。

¹H NMR(CDCl₃)δ7.43-7.23(5H，m)，5.72(2H，s)，4.50(1H，brt)，2.91(2H，m)，2.58(2H，br s)，2.49(2H，m)，2.05(2H，m)，1.68-1.14(3H，m)，1.44(9H，s)，1.38(6H，s)，1.00(2H，m)。

Step 4.N- ({1- (2- (2-benzyltetrazol-2-methylpropyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described in example 8, step 2, from 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one and tert-butyl [ {1- (2- (2-benzyltetrazol) -2-methylpropyl) piperidin-4-yl } methyl ] carbamate (step 3 of example 9).

MS(ESI)m/z：531(M+H⁺)。

¹H NMR(CDCl₃) δ 8.86(1H, br t, J ═ 5.7Hz), 8.26(1H, m), 7.43 to 7.08(8H, m), 5.72(2H, s), 4.70(1H, heptad, J ═ 7.0Hz), 3.21(2H, m), 2.59(2H, br s), 2.51(2H, m), 2.07(2H, m), 1.65 to 1.32(3H, m), 1.56(6H, d, J ═ 7.0Hz), 1.38(6H, s), 1.10(2H, m).

Step 5.N- ({1- (2-methyl-2-tetrazolopropyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described in example 8, step 3, from N- ({1- (2- (2-benzyltetrazole) -2-methylpropyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide (step 4 of example 9).

MS(ESI)m/z：441(M+H)⁺。

¹H NMR(DMSO-d₆) δ 8.77(1H, br t, J ═ 5.9Hz), 8.04(1H, m), 7.40(1H, m), 7.18(1H, m), 7.11(1H, m), 4.63(1H, heptad, J ═ 7.0Hz), 3.15(2H, m), 2.54(2H, br s), 2.43(2H, m), 2.10(2H, m), 1.60-1.25(3H, m), 1.45(6H, d, J ═ 7.0Hz), 1.32(6H, s), 1.14(2H, m). No signal corresponding to tetrazole was found.

C₂₂H₃₂N₈O₄·0.95H₂Calculated value of O: c, 57.74; h, 7.47; and N, 24.48. Measured value: c, 58.03; h, 7.43; and N, 24.10.

Example 10:

n- ({1- (2-cyclopentyl-2-tetrazoloethyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

Step 1. alpha-cyclopentyltetrazole-5-acetic acid, ethyl ester

1, 4-bis (1-cyano-1-cyclopentanecarboxylic acid ethyl ester) (bioorg. Med. chem. Lett.1999, 9, 369-Alkane (100 ml) was added to the stirred solutionⁿBu₃SnN₃(12.3 g, 37.0 mmol). The resulting mixture was refluxed for 15h and concentrated under reduced pressure. In thatTo the residue was added 4M HCl in 1, 4-bisAlkane (50 ml) and concentrated under reduced pressure. The resulting oil was washed twice with hexane to give the crude product as the title compound as a yellow oil which was used in the next step without further purification.

Step 2.2-benzyl- α -cyclopentyl-2H-tetrazole-5-acetic acid, ethyl ester

The title compound was prepared according to the procedure described in step 1 of example 9 from α -cyclopentyltetrazole-5-acetic acid, ethyl ester (step 1 of example 10).

MS(ESI)m/z：301(M+H⁺)。

¹H NMR(CDCl₃)δ7.45-7.23(5H，m)，5.73(2H，s)，4.11(2H，q，J＝7.1Hz)，2.55-2.35(4H，m)，1.88-1.56(4H，m)，1.12(3H，t，J＝7.1Hz)。

Step 3.2-benzyl-alpha-cyclopentyl-2H-tetrazole-5-acetaldehyde

The title compound was prepared according to the procedure described in step 2 of example 9 from 2-benzyl- α -cyclopentyl-2H-tetrazole-5-acetic acid, ethyl ester (step 2 of example 10).

MS(ESI)m/z：257(M+H⁺)。

¹H NMR(CDCl₃)δ9.71(1H，s)，7.50-7.30(5H，m)，5.74(2H，s)，2.45-2.18(4H，m)，1.85-1.66(4H，m)。

Step 4.[ {1- (2- (2-benzyltetrazol) -2-cyclopentylethyl) piperidin-4-yl } methyl ] carbamic acid tert-butyl ester

The title compound was prepared according to the procedure described in step 3 of example 9 from 2-benzyl- α -cyclopentyl-2H-tetrazole-5-acetaldehyde (step 3 of example 10).

MS(ESI)m/z：455(M+H)⁺。

¹H NMR(CDCl₃)δ7.43-7.23(5H，m)，5.72(2H，s)，4.67(1H，brt)，2.88(2H，m)，2.66(2H，br s)，2.48(2H，m)，2.24(2H，m)，1.93(2H，m)，1.83(2H，m)，1.78-1.48(4H，m)，1.43(9H，s)，1.37(2H，m)，1.23(1H，m)，0.94(2H，m)。

Step 5.N- ({1- (2-benzyltetrazol) -2-cyclopentylethyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described in step 2 of example 8 from 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one and tert-butyl [ {1- (2- (2-benzyltetrazol) -2-cyclopentylethyl) piperidin-4-yl } methyl ] carbamate (step 4 of example 10).

MS(ESI)m/z：557(M+H⁺)。

¹H NMR(CDCl₃) δ 8.85(1H, br t, J ═ 5.5Hz), 8.26(1H, m), 7.43 to 7.08(8H, m), 5.73(2H, s), 4.70(1H, heptad, J ═ 7.0Hz), 3.19(2H, m), 2.70(2H, br s), 2.53(2H, m), 2.25(2H, m), 2.15 to 1.35(11H, m), 1.56(6H, d, J ═ 7.0Hz), 1.07(2H, m).

Step 6.N- ({1- (2-cyclopentyl-2-tetrazoloethyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described in step 3 of example 8 from N- ({1- (2-benzyltetrazole) -2-cyclopentylethyl } piperidin-4-yl) methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide (step 5 of example 10).

MS(ESI)m/z：467(M+H)⁺。

¹H NMR(DMSO-d₆) δ 8.76(1H, br t, J ═ 5.9Hz), 8.04(1H, m), 7.40(1H, m), 7.18(1H, m), 7.11(1H, m), 4.64(1H, heptad, J ═ 7.0Hz), 3.14(2H, m), 2.63(2H, br s), 2.54(2H, m),2.08(2H, m), 2.00(2H, m), 1.76(2H, m), 1.68-0.96(9H, m), 1.46(6H, d, J ═ 7.0 Hz). No signal corresponding to tetrazole was found.

C₂₄H₃₄N₈O₄·1.0H₂O·0.5CH₂Cl₂The calculated value of (a): c, 55.83; h, 7.08; and N, 21.26. Measured value: c, 55.71; h, 7.48; and N, 20.86.

Example 11:

n- ({1- (2-cyclohexyl-2-tetrazoloethyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

Step 1. alpha-Cyclohexyltetrazole-5-acetic acid, ethyl ester

The title compound was prepared from 1-cyano-1-cyclohexanecarboxylic acid, ethyl ester (bioorg. med. chem. left.1999, 9, 369-374) according to the procedure described in step 1 of example 10.

Step 2.2-benzyl-alpha-cyclohexyl-2H-tetrazole-5-acetic acid, ethyl ester

The title compound was prepared according to the procedure described in step 1 of example 9 from α -cyclohexyltetrazole-5-acetic acid, ethyl ester (step 1 of example 11).

MS(ESI)m/z：315(M+H⁺)。

¹H NMR(CDCl₃)δ7.45-7.23(5H，m)，5.75(2H，s)，4.11(2H，q，J＝7.1Hz)，2.36-2.16(4H，m)，1.70-1.44(6H，m)，1.12(3H，t，J＝7.1Hz)。

Step 3.2-benzyl-alpha-cyclohexyl-2H-tetrazole-5-acetaldehyde

The title compound was prepared according to the procedure described in step 2 of example 9 from 2-benzyl- α -cyclohexyl-2H-tetrazole-5-acetic acid, ethyl ester (step 2 of example 11).

MS(ESI)m/z：271(M+H⁺)。

¹H NMR(CDCl₃)δ9.55(1H，s)，7.45-7.25(5H，m)，5.75(2H，s)，2.34-2.16(2H，m)，2.14-1.94(2H，m)，1.70-1.32(6H，m)。

Step 4.[ {1- (2- (2-benzyltetrazol) -2-cyclohexylethyl) piperidin-4-yl } methyl ] carbamic acid tert-butyl ester

The title compound was prepared according to the procedure described in step 3 of example 9 from 2-benzyl- α -cyclohexyl-2H-tetrazole-5-acetaldehyde (step 3 of example 11).

MS(ESI)m/z：469(M+H)⁺。

¹H NMR(CDCl₃)δ7.43-7.23(5H，m)，5.74(2H，s)，4.55(1H，brt)，2.87(2H，m)，2.62-1.05(17H，m)，2.49(2H，br s)，1.43(9H，s)，0.93 (2H，m)。

Step 5.N- ({1- (2- (2-benzyltetrazol-2-cyclohexylethyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described in step 2 of example 8 from 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one and tert-butyl [ {1- (2- (2-benzyltetrazol) -2-cyclohexylethyl) piperidin-4-yl } methyl ] carbamate (step 4 of example 11).

MS(ESI)m/z：571(M+H⁺)。

¹H NMR(CDCl₃) δ 8.86(1H, br t, J ═ 5.7Hz), 8.26(1H, m), 7.43-7.08(8H, m), 5.73(2H, s), 4.70(1H, heptad, J ═ 7.0Hz), 3.18(2H, m), 2.51(2H, br s), 2.45-1.15(17H, m), 1.56(6H, d, J ═ 7.0Hz), 1.04(2H, m).

Step 6.N- ({1- (2-cyclohexyl-2-tetrazoloethyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described in step 3 of example 8 from N- ({1- (2- (2-benzyltetrazole) -2-cyclohexylethyl) piperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide (step 5 of example 11).

MS(ESI)m/z：481(M+H)⁺。

¹H NMR(DMSO-d₆) δ 8.76(1H, br t, J ═ 5.9Hz), 8.04(1H, m), 7.41(1H, m), 7.18(1H, m), 7.12(1H, m), 4.64(1H, heptad, J ═ 7.0Hz), 3.14(2H, m), 2.38(2H, br s), 2.33-2.10(4H, m), 1.98(2H, m), 1.65-0.96(13H, m), 1.46(6H, d, J ═ 7.0 Hz). No signal corresponding to tetrazole was found.

Example 12:

1- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] cyclohexanecarboxylic acid hydrochloride

Step 1.1- (4-Oxopiperidin-1-yl) cyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure shown in example 1, step 3, using tert-butyl 1-aminocyclohexanecarboxylate (Kenner et al, j.chem.soc.,. 1965, 6239, 6243).

MS(ESI)m/z：282(M+H⁺)。

¹H-NMR(CDCl₃)δ：2.92(4H，t，J＝5.9Hz)，2.41(4H，t，J＝6.0Hz)，2.01-1.89(2H，m)，1.76-1.62(4H，m)，1.45(9H，s)，1.53-1.33(4H，m)。

Step 2.1- (4-Cyanopiperidin-1-yl) cyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure described in example 1, step 4, using tert-butyl 1- (4-oxopiperidin-1-yl) cyclohexanecarboxylate.

MS(ESI)m/z：293(M+H⁺)。

¹H-NMR(CDCl₃)δ：2.94-2.85(2H，m)，2.67-2.56(1H，m)，2.55-2.42(2H，m)，1.96-1.72(6H，m)，1.70-1.23(8H，m)，1.48(9H，s)。

Step 3.1- [4- (aminomethyl) piperidin-1-yl ] cyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure described in example 1, step 5, using tert-butyl 1- (4-cyanopiperidin-1-yl) cyclohexanecarboxylate.

¹H-NMR(CDCl₃)δ：3.07-3.18(2H，m)，2.55(2H，d，J＝6.4Hz)，2.15-1.94(4H，m)，1.47(9H，s)，1.76-1.19(13H，m)，1.19-1.03(2H，m)。

MS(ESI)m/z：297(M+H⁺)。

Step 4.1- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] cyclohexanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure described in example 1, step 6, using 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one and tert-butyl 1- (4-cyanopiperidin-1-yl) cyclohexanecarboxylate.

¹H-NMR(CDCl3)δ：8.97-8.86(1H，m)，8.29-8.24(1H，m)，7.21-7.11(3H，m)，4.78-4.64(1H，m)，3.29(2H，t，J＝6.2Hz)，3.19-3.09(2H，m)，2.16-2.05(2H，m)，2.04-1.93(2H，m)，1.83-1.73(2H，m)，1.56(6H，d，J＝7.0Hz)，1.46(9H，s)，1.70-1.39(2H，m)，1.38-1.16(7H，m)。

MS(ESI)m/z：499(M+H⁺)。

Step 5.1- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] cyclohexanecarboxylic acid hydrochloride

At room temperature in the presence of 1- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl]Amino } methyl) piperidin-1-yl]To a stirred solution of tert-butyl cyclohexanecarboxylate (400 mg, 0.802 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml, 65.2 mmol). After 12h, the volatile constituents were removed under reduced pressure. The residue was added with a di-4N HClAlkane (5.0 ml) and stirred for 10 minutes. Subsequently, the volatiles were removed under reduced pressure. The residue was precipitated in diethyl ether/ethanol to yield 370 mg of the title compound as a colorless powder.

¹H-NMR(DMSO-d₆)δ：8.94-8.82(1H，m)，7.45(1H，d，J＝7.9Hz)，7.27-7.10(2H，m)，4.73-4.61(1H，m)，3.71-3.19(7H，m)，2.98-2.81(2H，m)，2.38-2.26(2H，m)，1.98-1.53(10H，m)，1.49(6H，d，J＝7.0Hz)，1.38-1.03(2H，m)。

MS(ESI)m/z：443(M+H⁺)。

C₂₄H₃₅N₄O₄·2H₂Calculated value of O: c, 55.97; h, 7.63; n, 10.88. Found C, 55.61; h, 7.51; n, 10.48.

Example 13:

2-Ethyl-2- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } butanoic acid

Step 1.2- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] -2-ethylbutanoic acid methyl ester

The title compound was prepared in analogy to the procedure described in example 7, step 1, using methyl 2-ethyl-2-formylbutyrate (Okano, k.; Morimoto, t.; Sekiya, m.journal of the Chemical Society, Chemical Communications, 1985, 3, 119).

¹H-NMR(CDCl₃)δ：4.62-4.48(1H，br)，3.65(3H，s)，3.01-2.93(2H，m)，2.73-2.65(2H，m)，2.46(2H，s)，2.13-2.02(2H，m)，1.73-1.50(6H，m)，1.44(9H，s)，1.28-1.10(3H，m)，0.76(6H，t，J＝7.5Hz)。

MS(ESI)m/z：357(M+H⁺)。

Step 2.2 methyl ethyl-2- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } butanoate

The title compound was prepared according to the procedure described in step 2 of example 8 from 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one and methyl 2- [ (4- { [ (tert-butoxycarbonyl) amino ] methyl } piperidin-1-yl) methyl ] -2-ethylbutanoate (step 1 of example 13).

¹H-NMR(CDCl₃)δ：8.92-8.86(1H，m)，8.28-8.23(1H，m)，7.20-7.12(3H，m)，4.77-4.61(1H，m)，3.65(3H，s)，3.27(2H，t，J＝6.4Hz)，2.75-2.66(2H，m)，2.47(2H，s)，2.16-2.05(2H，m)，1.72-1.49(10H，m)，1.38-1.21(5H，m)，0.76(6H，d，J＝7.5Hz)。

MS(ESI)m/z：459(M+H⁺)。

Step 3.2-Ethyl-2- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } butanoic acid

The title compound was prepared from methyl 2-ethyl-2- { [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] methyl } butanoate (step 3 of example 13) following the procedure described in step 5 of example 3.

¹H-NMR(CDCl₃)δ：8.03-8.94(1H，m)，8.27-8.21(1H，m)，7.20-7.12(3H，m)，4.76-4.63(1H，m)，3.34(2H，t，J＝6.2Hz)，3.16-3.05(2H，m)，2.60(2H，s)，2.55-2.38(2H，m)，1.94-1.38(2H，m)，1.80-1.38 (15H，m)，0.88(6H，d，J＝7.5Hz)。

MS(ESI)m/z：445(M+H⁺)。

C₂₄H₃₇N₄O₄Cl·0.2H₂Calculated value of O: 59.48; h, 7.78; n, 11.56. Measured value: c, 59.38; h, 7.74; n, 11.29.

Example 14:

1- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] cyclopentane carboxylate hydrochloride

Step 1.1- (4-Oxopiperidin-1-yl) cyclopentanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure described in example 1, step 3, using tert-butyl 1-aminocyclopentanecarboxylate (WO 9105796).

MS(ESI)m/z：268(M+H⁺)。

¹H-NMR(CDCl₃)δ：2.93(4H，t，J＝5.9Hz)，2.41(4H，t，J＝6.0Hz)，2.39-2.26(2H，m)，1.85-1.54(8H，m)，1.46(9H，s)。

Step 2.1- (4-Cyanopiperidin-1-yl) cyclopentanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure described in example 1, step 4, using tert-butyl 1- (4-oxopiperidin-1-yl) cyclopentanecarboxylate.

MS(ESI)m/z：279(M+H⁺)。

¹H-NMR(CDCl₃)δ：2.94-2.82(2H，m)，2.67-2.49(3H，m)，2.33-2.21(2H，m)，1.96-1.72(5H，m)，1.70-1.40(6H，m)，1.48(9H，s)。

Step 3.1- [4- (aminomethyl) piperidin-1-yl ] cyclopentanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure described in example 1, step 5, using tert-butyl 1- (4-cyanopiperidin-1-yl) cyclopentanecarboxylate.

¹H-NMR(CDCl₃)δ：3.07-2.95(2H，m)，2.60-2.52(2H，m)，2.41-1.19(4H，m)，1.76-1.62(4H，m)，1.61-1.40(12H，m)，1.19-1.03(2 H，m)。

MS(ESI)m/z：283(M+H⁺)。

Step 4.1- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] cyclopentanecarboxylic acid tert-butyl ester

The title compound was prepared in analogy to the procedure described for example 1 step 6, using 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one and tert-butyl 1- [4- (aminomethyl) piperidin-1-yl ] cyclopentanecarboxylate.

¹H-NMR(CDCl₃)δ：8.96-8.84(1H，m)，8.29-8.22(1H，m)，7.21-7.11(3H，m)，4.77-4.56(1H，m)，3.29(2H，t，J＝6.2Hz)，3.07-2.94(2H，m)，2.37-2.17(4H，m)，1.82-1.63(6H，m)，1.56(6H，d，J＝7.1Hz)，1.46(9H，s)，1.61-1.49(2H，m)，1.38-1.16(3H，m)。

MS(ESI)m/z：485(M+H⁺)。

Step 5.1- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] cyclopentane carboxylate hydrochloride

The title compound was prepared in analogy to the procedure described for example 12, step 5, using tert-butyl 1- [4- ({ [ (3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl) carbonyl ] amino } methyl) piperidin-1-yl ] cyclopentanecarboxylate.

¹H-NMR(DMSO-d₆)δ：8.91-8.82(1H，m)，8.07(1H，d，J＝7.5Hz)，7.45(1H，d，J＝7.7Hz)，7.26-7.09(2H，m)，4.74-4.56(1H，m)，3.60-3.00(6H，m)，2.26-2.10(4H，m)，1.96-1.57(9H，m)，1.49(6H，d，J＝7.0Hz)。

MS(ESI)m/z：429(M+H⁺)。

C₂₃H₃₃N₄O₄Calculated Cl: c, 59.41; h, 7.15; n, 12.05. Measured value: c, 59.14; h, 7.22; n, 11.82.

Example 15:

n- ({1- [ (4-Oxycarbonyltetrahydro-2H-pyran-4-yl) methyl ] -4-fluoropiperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

Step 1 tetrahydropyran-4-yl-carboxylic acid benzyl ester

Reaction of a solution containing tetrahydropyran-4-yl-carboxylic acid (910 mg, 6.99 mmol) and SOCl₂The mixture (5.0 ml) was stirred at 60 ℃ for 1h and concentrated in vacuo. To the residue were added benzyl alcohol (1.52 g, 14.1 mmol) and tetrahydrofuran (5.0 ml) at ambient temperature. The resulting mixture was stirred at ambient temperature for 13h and concentrated in vacuo. The residue is subjected to preparative thin layer chromatography (Silica gel, eluting with hexane/ethyl acetate (2: 1) to yield 1.08 g (70%) of the title compound as a pale yellow oil.

¹H NMR(CDCl₃)δ7.45-7.25(5H，m)，5.13(2H，s)，3.95(2H，m)，3.42(2H，m)，2.59(1H，m)，1.94-1.68(4H，m)。

Step 2.4-iodomethyl-tetrahydropyran-4-yl-carboxylic acid benzyl ester

The title compound was prepared according to the procedure described in step 1 of example 3 from tetrahydropyran-4-yl-carboxylic acid benzyl ester (step 1 of example 15).

¹H NMR(CDCl₃)δ7.45-7.25(5H，m)，5.19(2H，s)，3.80(2H，m)，3.47(2H，m)，3.31(2H，s)，2.18(2H，m)，1.56(2H，m)。

Step 3. N-benzoyl-4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine

A mixture of N-benzoyl-4-aminomethyl-4-fluoropiperidine (J.Med.chem.1999, 42, 1648-1660) (3.54 g, 15.0 mmol) and di-tert-butyl dicarbonate (4.91 g, 22.5 mmol) in methanol (80 ml) was stirred at room temperature for 15h and concentrated in vacuo. The residue is chromatographed on a column of silica gel, eluting with hexane/ethyl acetate (1: 1), to give 4.52 g (89%) of the title compound as a colorless oil.

MS(ESI)m/z：337(M+H)⁺。

¹H NMR(CDCl₃)δ7.55-7.25(5H，m)，5.16(1H，br t，J＝6.3Hz)，4.51(1H，m)，3.62(1H，m)，3.55-3.00(4H，m)，2.10-1.25(4H，m)，1.43(9H，s)。

Step 4.4-tert-Butoxycarbonylaminomethyl-4-fluoropiperidine

The resulting mixture was purified by reacting N-benzoyl-4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (step 3 of example 15) (4.42 g, 13.1 mmol), NaOH (2.62 g, 65.5 mmol), and H₂O (9.00 mm)L) and ethanol (90.0 ml) were refluxed for 15h and concentrated in vacuo. To the resulting residue were added water and chloroform. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The obtained solid is extracted with hexane-CH₂Cl₂Recrystallization gave 1.77 g (58%) of the title compound as a colorless solid.

MS(ESI)m/z：233(M+H)⁺。

¹H NMR(CDCl₃) δ 4.93(1H, m), 3.30(2H, dd, J ═ 21.5, 6.3Hz), 2.91(4H, m), 1.88-1.34(4H, m), 1.45(9H, s), no signal corresponding to an amino group was found.

Step 5.({1- [ (4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl) methyl ] -4-fluoropiperidin-4-yl } methyl) carbamic acid tert-butyl ester

The title compound was prepared according to the procedure described in step 2 of example 3 from 4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (step 4 of example 15) and benzyl 4-iodomethyltetrahydropyran-4-yl-carboxylate (step 2 of example 15).

MS(ESI)m/z：465(M+H)⁺。

¹H NMR(CDCl₃)δ7.45-7.25(5H，m)，5.16(2H，s)，4.78(1H，brt)，3.80(2H，m)，3.46(2H，m)，3.23(2H，dd，J＝21.9，6.3Hz)，2.64-2.32(4H，m)，2.52(2H，s)，2.08(2H，m)，1.90-1.35(6H，m)，1.45(9H，s)。

Step 6.N- ({1- [ (4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl) methyl ] -4-fluoropiperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described in step 6 of example 1 from 1-isopropyl-1, 3-dihydro-2H-benzimidazol-2-one and tert-butyl ({1- [ (4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl) methyl ] -4-fluoropiperidin-4-yl } methyl) carbamate (step 5 of example 15).

MS(ESI)m/z：567(M+H⁺)。

¹H NMR(CDCl₃) δ 9.08(1H, br t, J ═ 6.0Hz), 8.25(1H, m), 7.46-7.06(8H, m), 5.16(2H, s), 4.71(1H, heptad, J ═ 7.0Hz), 3.80(2H, m), 3.54(2H, dd, J ═ 20.9, 6.0Hz), 3.46(2H, m), 2.65-2.36(4H, m), 2.53(2H, br s), 2.08(2H, m), 1.88-1.44(6H, m), 1.56(6H, d, J ═ 7.0 Hz).

Step 7.N- ({1- [ (4-Oxycarbonyltetrahydro-2H-pyran-4-yl) methyl ] -4-fluoropiperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described in step 3 of example 1 from N- ({1- [ (4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl) methyl ] -4-fluoropiperidin-4-yl } methyl) -3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazole-1-carboxamide (step 6 of example 15).

MS(ESI)m/z：477(M+H)⁺。

¹H NMR(CD₃OD) δ 7.93(1H, m), 7.12(1H, m), 7.02(1H, m), 6.93(1H, m), 4.49(1H, heptad, J ═ 7.0Hz), 3.65-3.36(6H, m), 3.15-2.82(4H, m), 2.80(2H, br s), 1.98-1.70(6H, m), 1.35(6H, d, J ═ 7.0Hz), 1.34(2H, m). No signals corresponding to amide and carboxylic acid were found.

All publications, including but not limited to issued patents, patent applications, and journal articles cited in this application, are each incorporated by reference herein in their entirety.

Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It will be understood that various modifications may be made without departing from the spirit of the invention. Accordingly, the invention is not to be restricted except in light of the following claims.

Claims

1. A compound of the formula,

or a pharmaceutically acceptable salt thereof, wherein:

a is an alkylene group having 1 to 2 carbon atoms, which is substituted with 2 substituents selected from alkyl groups having 1 to 3 carbon atoms, wherein the 2 substituents may form together with the carbon atom to which they are attached a 3-to 6-membered ring optionally containing one O atom;

R¹is isopropyl;

R²is a hydrogen atom or a hydroxyl group;

R³is carboxy or tetrazolyl; and is

m is an integer 2.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

R²Is a hydrogen atom; and is

The 2 substituents are geminal substituents.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

R¹Is isopropyl;

R²is a hydrogen atom;

R³is carboxy or tetrazolyl;

a is

(ii) a And is

m is an integer 2.

4. A compound according to claim 1, selected from:

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.