UA82297C2 - Benzimidazolone carboxylic acid derivatives - Google Patents

Abstract

This invention relates to compounds of the formula (I): wherein R, R, R, A and m are each as described herein or a pharmaceutically acceptable salt or solvate thereof, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HTreceptor activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.

Description

Description of the invention

The present invention relates to benzimidazolone carboxylic acid derivatives. These compounds have the activity of 2 selective agonists of the 5-HT receptor. In addition, the present invention relates to a pharmaceutical composition, a method of treatment and application, including the above derivatives, for the treatment of painful conditions mediated by the activity of the 5-HT receptor; in particular, the activity of the 5-HT receptor agonist.

5-HT 4 receptor agonists have been found to be mainly applicable in the treatment of various diseases such as gastroesophageal reflux disease, gastrointestinal diseases, gastric motility disorders, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IB5), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, pain, cardiovascular disorder, heart failure, cardiac arrhythmia, diabetes, and respiratory arrest syndrome.

IDiv. TiRv, 1992, 13, 141; Roga A. R. O. MU. Hey, May. Kev. Keu., 1993, 13, 633; OSshckKvop LLC. MU. hey ay.,

Abomination Oem. Kev., 1992, 26, 405; Kispaga M. Ediep eyi ai, TiR5, 1995, 16, 391; VosKaeti U. EE ai., CM5 Ogydv, 1, b; Kotapeyi M. M. ei a), Agapyeit Rohesp./Ogyd Kev., 1993, 43, 913; Katapp A. ei ai.,

Mashypup-Zsptiederehod v. 1991. 344, 150; apa Kotapeii M. M. ei ai., Aggpeiit ERogassp./Ogyd Kez., 1993, 43, 913).

In MO 94/00449| disclosed benzimidazolone compounds as agonists or antagonists of 5-HT in and/or antagonists of 5-HT3. Specifically, the compounds represented by the following structural formula are disclosed in Example 10: o; 7 M s ho d--MN (8)

M

(o : "M (2) ra ; sia

Compound А сч 3о There is a need for the development of new 5-HT agonists, which are good candidates for the role of medicinal products. co

In particular, preferred compounds should bind strongly to the 5-HT/ receptor, while showing little affinity for other receptors, and also exhibit functional agonist activity. They should be well absorbed from the gastrointestinal tract, be resistant to metabolism and have favorable "pharmacokinetic properties." If the target of these compounds is the receptors of the central nervous system, they should freely penetrate the blood-brain barrier, and if the selective target is the receptors of the peripheral nervous system, they should not penetrate the blood-brain barrier. They should be non-toxic and show little side effects. In addition, an ideal drug candidate must exist in a physical form that is stable, non-hygroscopic, and can be easily incorporated into a drug formulation.

In the present invention, it was found that (1) replacement of the quinuclidine ring with a piperidine/pyrrolidine ring improves the affinity for the 5-HT receptor, and/or (2) the introduction of a carboxyl fragment reduces the affinity of CO for dofetilide, which leads to the prevention of an increase in the duration of the OT interval. c Therefore, in the process of working on the present invention, it was unexpectedly discovered that the compounds of the present invention have stronger and more selective activity as 5-HT 4 agonists and/or improved affinity for codofetilide compared to the compounds of the prior art and, thus, they are applicable for the treatment of "with 20 disease states mediated by the activity of 5-HT; such as gastroesophageal reflux disease, gastrointestinal diseases, gastric motility disorders, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IB5), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, pain, cardiovascular disorder, heart failure, cardiac arrhythmia, diabetes, and respiratory arrest syndrome (especially opioid-induced ). o This invention relates to the compound of the following formula (1): ko 60 b5 r

M IV fii "o; tA -i - U . and or a pharmaceutically acceptable salt or solvate thereof, where

A is an alkylene group containing from 1 to 4 carbon atoms, and the indicated alkylene group is unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group containing from 1 up to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms and an alkoxyalkyl group containing from 2 to 6 carbon atoms, and any two or more non-halogen substituents together with the carbon atoms to which they are attached attached, can form 3-,4-,. (In a 5- or 6-ene ring, which optionally contains at least one heteroatom selected from M, O and 5;

B" is an isopropyl group or a cyclopentyl group;

IN? represents a hydrogen atom, a halogen atom or a hydroxy group; Cha

BZ is a carboxyl group, a tetrazolyl group, a 5-oxo-1,2,4-oxadiazol-Z-yl group or a 5-oxo-1,2,4-thiadiazol-Z-yl group; and Me, t means an integer equal to 1 or 2. Ha

One of the variants of implementation of this invention relates to the compound of the above formula (I) or its pharmaceutically acceptable salts or solvates, in which: c

A is an alkylene group containing from 1 to 4 carbon atoms, and the specified alkylene group is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group comprising 1 to 4 carbon atoms and an alkoxyalkyl group comprising 2 to 6 carbon atoms, and any two non-halogen substituents together with the carbon atoms to which they are attached attached, may form a 70 b-membered ring, which optionally contains at least one heteroatom selected from M, O and 5; with c B" represents an isopropyl group or a cyclopentyl group; "with B? represents a hydrogen atom, a halogen atom or a hydroxyl group; " BZ represents a carboxyl group, a tetrazolyl group, a 5-oxo-1,2,4-oxadiazol-3-yl group, or a 5-oxo-1,2,4-thiadiazol-3-yl group; and t is an integer, which is equal to 1 or 2. One of the variants of implementation of this invention relates to the compound of the above formula (I) or its t pharmaceutically acceptable salts and solvates, in which:

A is an alkylene group containing from 1 to 4 carbon atoms, and the indicated alkylene group is substituted by 1 to 4 substituents, independently selected from the group consisting of a halogen atom, from 20 alkyl groups containing from 1 up to 4 carbon atoms, a hydroxyalkyl group comprising from 1 to 4 carbon atoms and an alkoxyalkyl group comprising from 2 to 6 carbon atoms, any two non-halogen substituents together with the carbon atoms to which they are attached , can form a 5-ene ring, which optionally contains at least one heteroatom selected from M, O and 5;

B" is an isopropyl group or a cyclopentyl group; 59 B" is a hydrogen atom, a halogen atom or a hydroxy group;

HF) BZ is a carboxyl group, tetrazolyl group, 5-oxo-1,2,4-oxadiazol-Z-yl group or 5-oxo-1,2,4-thiadiazol-Z-yl group; and о t means an integer equal to 1 or 2. о One embodiment of the present invention relates to a compound of the above formula (I) or its pharmaceutically acceptable salts and solvates, in which:

A is an alkylene group containing from 1 to 4 carbon atoms, and the indicated alkylene group is substituted by 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group containing from 1 to 4 carbon atoms , a hydroxyalkyl group containing from 1 to 4 carbon atoms and an alkoxyalkyl group containing from 2 to 6 carbon atoms, wherein any two non-halogen substituents, together with the carbon atoms to which they are attached, may form 3-4-ene ring, which optionally contains at least one heteroatom selected from M, O and 5;

B" is an isopropyl group or a cyclopentyl group;

IN? represents a hydrogen atom, a halogen atom or a hydroxy group;

BZ is a carboxyl group, a tetrazolyl group, a 5-oxo-1,2,4-oxadiazol-Z-yl group or a 5-oxo-1,2,4-thiadiazol-Z-yl group; and t means an integer equal to 1 or 2.

In addition, the present invention relates to the use of compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, each as described in this application, for the manufacture of a medicament for the treatment of a condition mediated by 5-HT receptor activity; in particular, by the activity of the 5-HT receptor agonist.

Preferably, the present invention also relates to the use of compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, each as described herein, for the manufacture of a medicament for the treatment of diseases selected from gastroesophageal reflux disease, gastrointestinal diseases, gastric motility disorders, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IV5), constipation, dyspepsia, esophagitis, gastroesophageal diseases, nausea, diseases of the central nervous system, Alzheimer's disease, cognitive disorders, vomiting, migraine, neurological diseases, pain, cardiovascular disorders, heart failure, cardiac arrhythmia, diabetes and respiratory arrest syndrome.

In addition, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, each as described herein, together with a pharmaceutically acceptable carrier for said compound.

Further, the present invention provides a method of treating a condition mediated by 5-HT receptor activity in a mammal, comprising 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 in this application. at

Examples of conditions mediated by 5-HT receptor activity include, but are not limited to, gastroesophageal reflux disease, gastrointestinal disorders, gastric motility disorders, nonulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, b pain, cardiovascular disorders, heart failure, cardiac arrhythmia, diabetes and respiratory arrest syndrome.

In addition, the present invention relates to compounds of the formula (XI) se 2 c o y (he) t (Xi)

Tv and - c or their salts, where: "with B" means a hydrogen atom, a hydroxy group or a halogen atom; 25 means a hydrogen atom or an amino protecting group;

Y means an alkoxy group containing from 1 to 4 carbon atoms, a dialkylamino group containing from 2 to 8 carbon atoms, an imidazolyl group, a phthalimidyl group, a succinimidyl group or a sulfonyl group; and t represents 1 or 2. io) This invention also relates to compounds of the formula (IXa) ko 2 8 o KU.

M) o; m N t (IXa)

M. p. 4

A Kk o or their salts, where: ko A represents an alkylene group including from 1 to 4 carbon atoms, and the indicated alkylene group is unsubstituted or substituted by 1 to 4 substituents, independently selected from the group consisting of 60 a halogen atom, an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms and an alkoxyalkyl group containing from 2 to 6 carbon atoms, and any two substituents that are not halogen , together with the carbon atoms to which they are attached, can form a 3-6-ene ring, which optionally contains at least one heteroatom selected from M, O and 5;

IN? means a hydrogen atom, a hydroxy group or a halogen atom; 55 B" means a hydroxy group or a carboxy protecting group;

VZ means a hydrogen atom or an amino protecting group; and t is 1 or 2.

Compounds of the present invention may exhibit lower toxicity, good absorption, distribution, good solubility, lower protein binding affinity, less interaction with other drugs, and good metabolic resistance.

In the compounds according to the present invention:

If A is an alkylene group containing from 1 to 4 carbon atoms, it may be an unbranched chain group, and examples include, but are not limited to, methylene, ethylene, trimethylene, and tetramethylene. Of these groups, methylene and ethylene are predominant; and ethylene is the most preferred.

When A is an alkyl group containing from 1 to 4 carbon atoms, it may be a straight or branched chain group, examples of which include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Alkyl groups containing from 1 to 3 carbon atoms are preferred among the 75 substituents listed; methyl, ethyl, propyl and isopropyl are more preferred; both methyl and ethyl are most preferred.

When the substituent M is an alkoxy group containing from 1 to 4 carbon atoms, it is an oxygen atom substituted by the indicated alkyl group, and examples include, but are not limited to, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy. Of the above, alkyl groups containing from 1 to 2 carbon atoms are preferred; the methoxy group is more preferred.

When substituent Y is a dialkylamino group containing from 2 to 8 carbon atoms, it is an amino group substituted with two of the specified alkyl groups and examples include, but are not limited to, dimethylamino, M-methyl-M-ethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino and M,M-di(1-methylpropyl)amino. Of these groups, dialkylamino groups containing from? up to 4 carbon atoms; more preferred are dimethylamino, M-methyl-M-ethylamino and diethylamino.

When substituent A is a hydroxyalkyl group containing from 1 to 4 carbon atoms, it may be a linear or branched chain group, and examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2 -hydroxypropyl, 2-hydroxy-1-methyl ethyl, 4-hydroxybutyl,

3-hydroxybutyl, 2-hydroxybutyl, 3-hydroxy-2-methylpropyl and 3-hydroxy-1-methylpropyl. Of the indicated groups, hydroxyalkyl groups containing from 1 to 3 carbon atoms are preferred; more preferred are hydroxymethyl, 2-hydroxyethyl and 2-hydroxypropyl; and most preferred are hydroxymethyl and 2-hydroxyethyl. Me,

If the substituent A is an alkoxyalkyl group containing from 2 to b carbon atoms, it can be a group with. straight or branched chain, examples of which 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, so

C-methoxy-2-methylpropyl and C-methoxy-1-methylpropyl. Of the listed substituents, the preferred ones are alkoxyalkyl groups, which include from 2 to 4 carbon atoms; more preferred are methoxymethyl, 2-methoxyethyl and

C-methoxypropyl; and 2-methoxyethyl and 3-methoxypropyl are most preferred.

If two substituents A, which are not halogens, can, together with the carbon atoms to which they are attached, « 70 form 3, 4, 5 or b-membered rings, which optionally contain at least one heteroatom selected from M, O or with C 3. Such a ring may be cycloalkyl or heterocyclic, and examples include cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclohexyl, hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl, methoxycyclopropyl, methoxycyclobutyl, methoxycyclopentyl, methoxycyclohexyl, tetrahydrofuryl and tetrahydropyranyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, o cyclohexyl, methoxycyclohexyl and tetrahydropyranyl, and most preferably cyclobutyl, cyclopentyl, cyclohexyl and tetrahydropyranyl. o If KE? is an amino protecting group, it is a protecting group, capable of splitting under the action of chemicals

Go) means such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and such amino-protecting groups are described in (Rgoyesiime Sgourv ip Ogdapis Zupipeviz under the editorship of T.M/. Sgeepe ei ai. (oip UMpPeu 5 Bopv, 1999)) and examples of include, but are not limited to, benzyl, СонХО(С-0)-, СНУ(С-О), t-butyldimethylsilyl, "I t-butyldiphenylsilyl, benzyloxycarbonyl and t-butoxycarbonyl. Of these groups, t-butoxycarbonyl is predominant.

If KK" is a carboxy-protecting group, it is a protecting group capable of removal under the action of chemical agents, such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and such carboxy-protecting groups 2o are described in (Rgoigesiime OSgoshrz ip Ogdapis Zupipevziv edited by T.M and examples include methoxy, ethoxy, t-butyloxy, methoxymethoxy, 2,2,2-trichloroethoxy, benzyloxy, diphenylmethoxy, and) trimethylsilyloxy, t-butyldimethylsilyloxy and allyloxy Of these groups, t-butyloxy, methoxy or co-ethoxy are preferred.

If in! and substituent A are halogen atoms, they can be fluorine, chlorine, bromine or iodine atoms. Of these 60 atoms, fluorine and chlorine atoms are predominant.

The term "treatment" as used herein refers to curative, palliative, or prophylactic treatment, including stopping, alleviating, slowing, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.

Preferred classes of compounds of the present invention are those compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, each as described herein, in which:

(A) B! is an isopropyl group; (B) 2? represents a hydrogen atom, a fluorine atom or a hydroxy group; (C) In? is a hydrogen atom; 9 (p) VZ is a carboxy group or a tetrazolyl group; (E) VZ is a carboxy group; (P) A represents an alkylene group comprising from 1 to 2 carbon atoms, and said alkylene group is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a halogen atom, an alkyl group comprising from 1 to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms and an alkoxyalkyl group containing from 2 to b carbon atoms, and any two substituents that are not halogens together with carbon atoms to which they are attached, may form a b-membered ring, which optionally contains at least one heteroatom selected from M, O and 5; (b) A is an alkylene group of 1 to 2 carbon atoms, said alkylene group being substituted by two geminal substituents independently selected from the group consisting of 19 halogen atoms, an alkyl group of 1 to 4 carbon atoms , a hydroxyalkyl group containing from 1 to 4 carbon atoms, and an alkoxyalkyl group containing from 2 to b carbon atoms, and the geminal substituents, which are not halogens, together with the carbon atoms to which they are attached, can form b-- ring ring, which optionally contains at least one heteroatom selected from M, O and 5; (H) A is an alkylene group containing from 1 to 2 carbon atoms, and said alkylene group is substituted by two substituents independently selected from the group consisting of an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group, which includes from 1 to 4 carbon atoms, and an alkoxyalkyl group, including from 2 to 6 carbon atoms, and any two of these substituents, together with the carbon atoms to which they are attached, may form a 5-membered ring, which is not necessarily contains at least one heteroatom selected from M, O and 5; c (I) A is an alkylene group containing from 1 to 2 carbon atoms, and the indicated alkylene (He) group is substituted by two geminal substituents independently selected from the group consisting of an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group, including from 1 to 4 carbon atoms, and an alkoxyalkyl group, including from 2 to b carbon atoms, and the specified geminal substituents together with the carbon atoms to which they are attached can form a 5-membered ring, which is necessarily contains Che at least one heteroatom selected from M, O and 5; Those! (Y) A represents an alkylene group containing from 1 to 2 carbon atoms, and the indicated alkylene group is substituted by two substituents independently selected from the group consisting of an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group, which includes from 1 to 4 carbon atoms, and the sth alkoxyalkyl group, which includes from 2 to b carbon atoms, and the specified substituents together with the atoms

From the carbon to which they are attached, they can form 3-4-membered rings, which do not necessarily contain at least one heteroatom selected from M, O and 5; (Y) A is an alkylene group containing from 1 to 2 carbon atoms, and the indicated alkylene group is substituted by two geminal substituents independently selected from the group consisting of an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group , which includes from 1 to 4 carbon atoms, and 70 of the alkoxyalkyl group, which includes from 2 to b carbon atoms, and the indicated geminal substituents together with the o, c carbon atoms to which they are attached can form 3-4-membered rings that optionally contain at least one heteroatom selected from M, O and 5;

DU A represents

Fo B kl Aa o nn x bort xx Z U ko o ser z zmrya la le z ona Homon a , o Osn» Osn» z (M) A represents 60 ; Kya t, i, b5 ha)

(M) A represents r И - - or ! (0) A is a science

B. with (P) A is ) ; with k. (8) or (0) t is an integer equal to 2. m zo Particularly preferred compounds according to the present invention are such compounds of formula (I) or their pharmaceutically acceptable salts or solvates, in which: b (B) B is an isopropyl group ; 2 is a hydrogen atom, a fluorine atom or a hydroxy group; VZ is a carboxyl group or a tetrazolyl group; A represents an alkylene group including from 1 to 2 carbon atoms, and the specified alkylene group is unsubstituted or substituted by substituents in the amount of 1 to 2, independently selected from "M c5 C of the group consisting of a halogen atom, an alkyl group including from 1 to 4 carbon atoms, with a hydroxyalkyl group containing from 1 to 4 carbon atoms and an alkoxyalkyl group containing from 2 to 6 carbon atoms, and any two non-halogen substituents together with the carbon atoms, to which they are attached, can form a b-h-len ring, which optionally contains at least one heteroatom selected from M, O and 5; and t means the integer 2; " (5) In! is an isopropyl group; VE? is a hydrogen atom; EZ is a carboxy group or a tetrazolyl group; A is an alkylene group containing from 1 to 2 carbon atoms, and the indicated alkylene group is substituted by two geminal substituents independently selected from the group consisting of a halogen atom, an alkyl group, and a group containing from 1 to 4 carbon atoms, a hydroxyalkyl group, including from 1 to 4 carbon atoms, and an alkoxyalkyl group, including from 2 to b carbon atoms, and the specified geminal substituents together with the carbon atoms to which they are attached can form a b-membered ring, which is not necessarily contains at least one heteroatom selected from M, O and 5; and t means the integer 2; (T) V! is an isopropyl group; IN? is a hydrogen atom; KZ is a carboxy group or a tetrazolyl group; A represents 50. And (Se) hear "A them 5 oh, oh"

Y t means the integer 2; where (3) B is an isopropyl group; K2 is a hydrogen atom, a fluorine atom or a hydroxy group; KZ is a carboxy group; in A is an alkylene group containing from 1 to 2 carbon atoms, and the specified alkylene group is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of a halogen atom, an alkyl group containing from 1 of up to 4 carbon atoms, a hydroxyalkyl group of 1 to 4 carbon atoms, and an alkoxyalkyl group of 2 to 6 carbon atoms, and any two geminal substituents that are not halogens together with carbon atoms to which they are attached, they can form a b--len ring, which optionally contains at least one heteroatom selected from M, CO and 5; and t means the integer 2;

(M) B is an isopropyl group; 2 is a hydrogen atom, a fluorine atom or a hydroxy group; B? is a carboxy group;

A represents itself

All Adm member of Io or

b 8). in

Y t means the integer 2; (MU) B" is an isopropyl group; K2 is a hydrogen atom, a fluorine atom or a hydroxy group; KZ is a carboxyl group 72 or a tetrazolyl group; A is an alkylene group containing from 1 to 2 carbon atoms, and the specified alkylene group is substituted by two substituents, independently selected from the group consisting of an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms, and an alkoxyalkyl group containing from 2 to b carbon atoms, wherein any two said substituents, together with the carbon atoms to which they are attached, may form a 5-membered ring, which optionally contains at least one heteroatom selected from M, O, and 5; and t is an integer of 2; (X) B! is is an isopropyl group; BE is a hydrogen atom; EZ is a carboxy group or a tetrazolyl group; A is an alkylene group containing from 1 to 2 carbon atoms, and the indicated alkylene group is substituted by two geminal substituents independently selected from the group consisting of from an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms, and an alkoxyalkyl group containing from 2 to 6 carbon atoms, and the indicated geminal substituents together with carbon atoms, to (3 to which they are attached may form a 5-ene ring, which optionally contains at least one heteroatom selected from M, O, and 5; and t means the integer 2; (U) B" is an isopropyl group; K2 is a hydrogen atom; KZ is a carboxy group or a tetrazolyl group; A is a compound (2)

Y t means the integer 2; (2) in! is an isopropyl group; IN? is a hydrogen atom, a fluorine atom or a hydroxy group; C is a carboxy group; " 70 A is an alkylene group containing from 1 to 2 carbon atoms, and this alkylene group is substituted with two substituents independently selected from the group consisting of an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group , which includes from 1 to 4 carbon atoms, and the alkoxyalkyl group, "" which includes from 2 to 6 carbon atoms, and any two specified substituents together with the carbon atoms to which they are attached can form a 5--lene ring, which optionally contains at least one heteroatom, 5 selected from M, O and 5; and t means the integer 2; (о е| (AA) B is an isopropyl group; BK? is a hydrogen atom, a fluorine atom or a hydroxy group; BZ is a carboxy group; A is a co to m chu (Ce) ye po - 99 and t means an integer 2;

GF! (AB) B" is an isopropyl group; B? is a hydrogen atom, a fluorine atom or a hydroxy group; BZ is a carboxy group or a tetrazolyl group; A is an alkylene group including from 1 to 2 carbon atoms, and the indicated alkylene group is substituted by two substituents , independently selected from the group consisting of an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms, and an alkoxyalkyl group containing from 2 to 6 carbon atoms, and the specified substituents together with the carbon atoms to which they are attached, may form 3-4 membered rings, which optionally contain at least one heteroatom selected from M, O, and 5; and t is an integer of 2; (AC) K is an isopropyl group; K is a hydrogen atom; K is a carboxy group or a tetrazolyl group; A is an alkylene group containing from 1 to 2 carbon atoms, and the specified alkylene group is substituted by two geminal substituents independently selected from the group consisting of a an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms, and an alkoxyalkyl group containing from 2 to 6 carbon atoms, and the geminal substituents are indicated together with the carbon atoms to which they are attached , can form 3-4-membered rings, which optionally contain at least one heteroatom selected from M, O and 5; and t means the integer 2; (AC) B is an isopropyl group; B? is a hydrogen atom; KZ is a carboxy group or a tetrazolyl group; A represents m and I and G z

Y t means the integer 2; (AB) B' is an isopropyl group; BC? is a hydrogen atom, a fluorine atom or a hydroxy group; VZ is a carboxy group; A is an alkylene group containing from 1 to 2 carbon atoms, and this alkylene group is substituted by two substituents independently selected from the group consisting of a halogen atom, an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group, which includes from 1 to 4 carbon atoms, and an alkoxyalkyl group including from 2 to 6 carbon atoms, and any two non-halogen substituents, together with the carbon atoms to which they are attached, may form a 3-4-h -leny cycles, which optionally contain at least one heteroatom selected from M, O and 5; and t means the integer 2; (AR) B' is an isopropyl group; K?2 is a hydrogen atom, a fluorine atom or a hydroxy group; KZ is a carboxy group; A is the sum of 30. 4 (22)

Her t means the integer 2; (AC) vk is an isopropyl group; BC? is a hydrogen atom, a fluorine atom or a hydroxy group; KZ is a C carboxy group; A is so 7 | - with or etc

И» о и т means an integer 2; or o (AN) B is an isopropyl group; BC? is a hydrogen atom; KZ is a carboxy group or a tetrazolyl group; A is a cot t z, KYA ; h

F. . current "A . c; (F) Y t means an integer 2. with One of the variants of implementation of this invention relates to compounds selected from the group consisting of: 4-C4-(((3-isopropyl-2-oxo-2 ,3-dihydro-1H-benzimidazol-1-yl)carbonyl|Iamino)methyl)piperidin-1-yl|methyl)tebo trahydro-2H-pyran-4-carboxylic acid; 1-44-((3-isopropyl- 2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-ylmethyl)cyclohexanecarboxylic acid; 1-44-((3-isopropyl-2-oxo-2, 3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-ylmethyl)cyclopentanecarboxylic acid; 65 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H) -benzimidazol-1-yl)carbonyl|amino)methyl)piperidin-1-ylmethyl)cyclopropanecarboxylic acid;

1-C4-hydroxy-4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-yl|methyl)cyclohexanecarboxylic acid; 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|amino)methyl)piperidin-1-ylmethyl)cyclobutanecarboxylic acid; as well as their pharmaceutically acceptable salts or solvates.

One of the variants of implementation of this invention concerns a compound from the group consisting of: 4-C4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|Iamino)methyl) piperidin-1-yl|methyl)te trahydro-2H-pyran-4-carboxylic acid; 70 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|amino)methyl)piperidin-1-ylmethyl)cyclohexanecarboxylic acid; as well as their pharmaceutically acceptable salts and solvates.

One of the variants of implementation of this invention concerns a compound from the group consisting of: 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidine -1-ylmethyl)cyclopentanecarboxylic acid; as well as its pharmaceutically acceptable salts and solvates.

One of the variants of implementation of this invention concerns a compound from the group consisting of: 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidine -1-ylmethyl)cyclopropanecarboxylic acid; 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|amino)methyl)piperidin-1-ylmethyl)cyclobutanecarboxylic acid; as well as their pharmaceutically acceptable salts and solvates.

Pharmaceutically acceptable salts of compounds of formula (I) include their acid addition salts and salts with bases (including double salts). high school

Suitable acid addition salts are formed with acids that give non-toxic salts. Examples include salts such as acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, (8)edisylate, hesylate, formate, fumarate, glucoceptate, gluconate, glucuronate, hexafluorophosphate, gibenzate, hydrochloride /chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate. maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, r.zo phosphate/hydrophosphate/dihydrophosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate.

Suitable salts with bases are those formed with bases that give non-toxic salts. Examples include aluminum, (o)arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc.

For an overview of suitable salts, see |"NapadbrsokK oi Rpagtaseciisa! Zaiyev: Rgoregieev, Zeiesiop s apa Ove" Bai and Muegtyi (Ulieu-MSN, U/eippeit, Septapu, 2002)). Pharmaceutically acceptable salts of the compounds of formula (I) can be readily obtained by mixing solutions of the compound of formula (I) and the desired acid or base, respectively. The salt can be precipitated from the solution and collected by filtration or obtained by evaporation of the solvent. The degree of salt ionization can vary from fully ionized to almost non-ionized.

The compounds of the present invention can exist in both unsolvated and solvated forms. The term 470 "solvate" within the scope of this application is used to describe a molecular complex that includes a compound of the present invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.

If the specified solvent is water, the term "hydrate" is used. Pharmaceutically acceptable solvates of the present invention include hydrates and solvates in which the solvent included in the crystal structure may be isotopically substituted, for example, 020, deo-acetone, 46-DMSO.

The scope of this invention includes complexes such as clathrates, complexes of the inclusion of a medicinal substance in a co-carrier, in which, in contrast to the above-mentioned solvates, the drug and the carrier are present in stoichiometric or non-stoichiometric amounts. In addition, the scope of the invention includes drug complexes containing two or more organic and/or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized, or non-ionized. For an overview of similar complexes, see INapebiiap, U.RNagt.zsi, 64(8), (Se) 1269-1288 (Atsdivy 1975). "m Further in the text of the application, all references to compounds of formula (I) include references to their salts, solvates and complexes, as well as to solvates and complexes of their salts.

The term "compound of the present invention" or "compounds of the present invention", unless otherwise indicated, refers to the compounds of formula (I) defined in this description above, their polymorphic modifications, prodrugs and isomers (including optical and geometric isomers, and tautomers) as defined hereinafter, as well as

HF) of isotopically labeled compounds of formula (1).

F In addition, the scope of this invention includes so-called "prodrugs" of compounds of formula (I). Thus, some derivatives of compounds of formula (I), which by themselves may have little or no pharmacological activity, when introduced into the body or applied to the body, can be transformed into compounds of formula (I) that have the desired activity, for example, due to hydrolytic splitting. Such derivatives are called "prodrugs".

Additional information on the use of prodrugs can be found in "Rgodgydz az Mome! Oeiiimegu Zuvietv",

MoI.14, AS5 Butrovzisht Zegiev (T. Nidispi and MU. e(eya) and "Viohemegvirie Sagiegz ip YuOgid Oevzidp", Regdatop

Rgezz, 1987 (ed. E.V. Kospe, Ategisap Ripagtaseciisa| Azzosiai(op)|. 65 Prodrugs according to this invention can, for example, be obtained by replacing suitable functional groups present in the compounds of formula (I) with defined fragments, known to specialists in this field of technology as "pro-fragments"7, which is described, for example, in (Oevidp oyi Rgodgydv" N. Vypaddaag (Eivzemieg, 1985)). Some examples of prodrugs according to the present invention include: () if the compound of formula (I) contains a carboxylic acid functional group (-СООН), its ester, for example, replacement of hydrogen by (C.-Cd)alkyl; (if the compound of formula (I) contains an alcohol functional group (-OH), its ether, for example, replacement hydrogen by (C.4-C)alkanoyloxymethyl; and (iii) if the compound of formula (I) contains a primary or secondary amine functional group (-"МНх or МНК, where КАН), its amide, for example, substitution of one or both hydrogens (С .4-C.o)alkanoyl. 70 Other examples of substitution groups according to the examples mentioned above, as well as examples of prodrugs and other types can be found in the previously indicated links.

Finally, some compounds of formula (I) can themselves serve as prodrugs of other compounds of formula (1).

Compounds of formula (I) containing one or more asymmetric carbon atoms can exist in the form of two or more stereoisomers. If the compound of formula (I) contains an alkenyl or alkenylene group, 7/5 geometric cis/trans (or 2/E) isomers are possible. If the compound contains, for example, a ketone or oxime group, or an aromatic moiety, tautomeric isomerism ("tautomerism") may occur. It follows that one compound can exhibit more than one type of isomerism.

The scope of this invention includes all stereoisomers, geometric isomers and tautomeric forms of compounds of formula (I), incl. compounds that exhibit more than one type of isomerism, and a mixture of one or more such compounds. In addition, the scope of the invention includes acid-addition salts or salts with bases in which the counterion is optically active, for example, UO-lactate or I-lysine, or a racemic mixture, for example, Oi-tartrate or r-arginine.

Cis/trans isomers can be separated using standard techniques well known to those skilled in the art, such as chromatography and fractional crystallization. with

Standard techniques for the preparation/isolation of individual enantiomers include chiral synthesis from suitable optically pure starting materials or resolution of the racemate (or racemate salt or derivative) with i) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or racemic starting material) may be reacted with a suitable optically active compound, for example an alcohol or, in the case where the compound of formula (I) contains an acidic group or a basic moiety, an acid or base such such as tartaric acid or 1-phenylethylamine. The resulting mixture of diastereomers can be separated by chromatography and/or fractional crystallization, and one Me or both diastereomers converted to the corresponding pure enantiomer(s) by methods well known to those skilled in the art.

Chiral compounds according to the present invention (and chiral starting substances for their preparation) can be obtained in an enantiomerically enriched form using chromatography, usually HPLC, on an asymmetric resin using a mobile phase consisting of hydrocarbons, usually heptane or hexane containing 0 to 5090 isopropanol, typically 2 to 20905 and 0 to 595 alkylamine, typically 0.190 diethylamine.

Concentration of the eluate allows obtaining an enriched mixture.

Conglomerates of stereoisomers can be separated using standard techniques known to those skilled in the art, see (for example, "Z(iegeospetiv(u oi Ogdapis Sotrotspav)" E.S.Epe! (UMypeu, Mem -o s mok, 1994) The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula (I) in which 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 available in nature.

Examples of isotopes suitable for incorporation into the compounds of the present invention include hydrogen isotopes such as 2H | ZN, carbon, such as "C, Cs and 14C, chlorine, such as ZbSI, fluorine, such as "ZE, iodine, such as 729| 125), from nitrogen, such as ЗМ and ЗМ, oxygen, such as 750, 170 and 180, phosphorus, such as ЗР, and sulfur, such as 358,

Certain isotopically labeled compounds of formula (I), for example, those that include radioactive isotopes, io) are useful in drug and/or substrate tissue distribution studies. Such radioactive isotopes as tritium, "c 20 i.e. ZN, and carbon-14, i.e. 14C, are particularly applicable for this purpose due to the ease of their inclusion in compounds and the available means of detection. "and Substitution with heavier isotopes such as deuterium, i.e., hH, may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life or reduced dosage requirements, and may therefore be preferable in some circumstances.

Substitution with positron-emitting isotopes such as C, ZE, 750 and ZM may be applicable in

F! positron emission tomography (PET) study to study the location of the receptor substrate.

Isotopically labeled compounds of formula (I) can, as a rule, be prepared by standard techniques known to those skilled in the art or by methods similar to those described in the accompanying

Examples and Syntheses, using suitable isotope-labeled reagents instead of the previously used 60 unlabeled reagents.

All compounds of formula (I) can be obtained by the methods described in the general methods section below, or by specific methods described in the Examples section and the Syntheses section, or by standard modifications of the indicated methods. The present invention also encompasses any or most of these processes for the preparation of compounds of formula (I), in addition to any new intermediates used in these processes.

General description of synthesis methods

The compounds of the present invention can be prepared by a variety of methods well known for the preparation of compounds of this type, for example, as shown in methods A-O described below.

The following methods A and B relate to the preparation of compounds of formula (I). C-C methods allow to obtain

Carriage intermediates.

Unless otherwise noted, the vv and A in the following methods are as defined above. The term "protecting group" as used hereinafter in this specification means hydroxy, carboxy and amino protecting groups which are selected from the typical hydroxy, carboxy and amino protecting groups described in

Sgotsre ip Ogdapis Zupipevziz under the editorship. T.MU.Sgeepe ei ai. (Oipp UMpeu b Bopv, 1999)). All starting substances in the 70 general synthesis methods described below can be commercially available or obtained by standard methods known to specialists in this field of technology, such as in (Eiygoreap Tsdoshgpa! oi Medisipa! Spetivigu, 12 (1), 87-91; 1977), and the disclosure of which is incorporated into this application by reference.

Method A

This description illustrates the preparation of compounds of formula (1).

Reaction scheme A

M "Fgadiya A1 of this; I (Where Peony sat in the rice fields

In the scheme of the reaction A, Ba represents LC C, according to the definition given above, or a cm group of the formula C(-O)-K7, where B" is a carboxyl protecting group. (o)

The term "carboxy-protecting group" within the scope of this description means a protecting group capable of removal by chemical means such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and such carboxy-protecting groups are described in .Ogeepe ei ai. (oipp UMieu 5 5opv, 1999))|. Cha

Typical carboxy protecting groups include, but are not limited to: methoxy, ethoxy, t-butyloxy, methoxymethoxy, 2,2,2-trichloroethoxy, benzyloxy, diphenylmethoxy, trimethylsilyloxy, FU t-butyldimethylsilyloxy and allyloxy. Among these groups, t-butyloxy, methoxy or ethoxy are preferred. high school

Stage A1

At this stage, the desired compound of the formula (I) according to the present invention is obtained by carbonylation of the compound of the formula "I (I) in the presence of the compound of the formula (I). The compound of formula (II) is commercially available. The compound of formula (PP) CO can be prepared by method C, outlined below.

The reaction is usually and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent used, provided that it does not adversely affect the course of the reaction and the reagents involved in it, and that it is able to dissolve the reagents, at least to a certain extent. Examples of suitable solvents include, but are not limited to, halogenated hydrocarbons such as C dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, c toluene and nitrobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as N,M-dimethylformamide and N,M-dimethylacetamide. Of these solvents, dichloromethane is preferable. 415 There is also no particular limitation on the nature of the carbonylating reagents used, and any co carbonylating reagent commonly used in reactions of this type can also be used in this reaction. Examples of such carbonylating reagents include, but are not limited to: derivatives of io) imidazole, such as M,M-carbonyldiimidazole (SOI); chloroformates such as trichloromethyl chloroformate and t 4-nitrophenyl chloroformate; urea and triphosgene. Of the listed reagents, 4-nitrophenyl chloroformate is preferred. (se) The described reaction can take place in a wide range of temperatures, and the exact temperature of the reaction is not critical to the present invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, it is generally convenient to carry out the reaction at a temperature of from about -782C to about 1202C. The time required for the reaction can also vary widely depending on many factors, especially the reaction temperature, as well as the nature of the starting substances and the solvent used. However, provided that the reaction is carried out under the preferred conditions described

GF) above, usually a sufficient period of time from about 5 minutes to about 24 hours. t In the case when Ba is a group of the formula C(-0)-K"7, the deprotection reaction will lead to the production of a carboxy group. This reaction is described in detail by T.MU. -453, (1999)), which description is incorporated herein by reference.Next, a typical reaction using a t-butyl protecting group is described as an example.

The deprotection reaction is usually and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent used, provided that it does not have a harmful effect on the course of the reaction and the reagents involved in it, and that it is able to dissolve the reagents, at least to a certain 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. Halogenated hydrocarbons are preferred among these solvents.

The deprotection reaction is performed in the presence of an acid. There are also no particular restrictions on the nature of the acids used, and any of the acids commonly used in reactions of this type can also be used in this case. Examples of such acids include, but are not limited to, such acids as: hydrochloric acid, acetic acid, p-toluenesulfonic acid or trifluoroacetic acid. Of these acids, trifluoroacetic acid is predominant.

The deprotection reaction can be carried out in the presence of a radical scavenger. As in the previous cases, there are no particular restrictions on the nature of the radical scavenger used, and any of the radical scavengers commonly used in reactions of this type may also be used in this case.

Examples of such radical scavengers include, but are not limited to: HBr, dimethylsulfoxide or (CH3CH»)zZiH. Of these substances, the predominant one is (СНЗзСН»)»з5in.

The deprotection reaction can take place over a wide range of temperatures, and the exact 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 starting substances. However, it is generally convenient to carry out this reaction at temperatures from about 09C to about 1002, more preferably from about 02C to about 509C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature, as well as the nature of the starting substances and the solvent used.

However, provided that the reaction is carried out under the preferred conditions described above, a time period of from about 5 minutes to about 24 hours, more preferably from about 1 hour to about 24 hours, will usually be sufficient.

Method B

This description illustrates an alternative preparation of the desired compound of formula (1).

Scheme of reaction V s o oogoh Stage VI n t o oO- sh- zh i! i s s cha (m M (2) p

Stadin in Sn village

None on Sun Sat same 1

Tl C is

In the reaction diagram, Ka corresponds to the above definition, KE? is an amino protecting group, A 2 is "

Corpse A as defined above or an alkylene group containing from 1 to 3 carbon atoms, and the specified alkylene group is unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms and an alkoxyalkyl group containing from 2 to b carbon atoms, and two of the specified substituents may optionally together with the carbon atom(s) to form a 3-beneal cycle; and X represents 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 capable of being removed by chemical means such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and such amino protecting groups are described in Irgoyesiime Sgourv ip Ogdapis bZupipeziz ed. T.MU. OSgeepe her aI. (Oypp MUpeu 5 Bopv, 1999)). Typical 5p amino-protecting groups include, but are not limited to: benzyl, CoHnO(C-O)-, SNUuC-O), t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyloxycarbonyl, and t-butoxycarbonyl. Of the specified groups, t-butoxycarbonyl is preferred.

Stage B1

At this stage, a compound of formula (M) is obtained by deprotection of a compound of formula (IM), which can be obtained, for example, by a method similar to that described in method A for obtaining a compound of formula (I) from a compound of formula (II). The method of removing protection is described in detail by T.Mu.«zgeepe ei ai. |Rgogesiime (gotsmrz ip Ogdapis (F) Zupipeziv, 494-635, (1999)), and this description is included in this application by reference. Next, as an example, a typical method with the participation of a t-butoxycarbonyl protective group is described.

The reaction is usually and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent used, provided that it does not have a detrimental effect on the progress of the reaction and the reagents involved in it, and that it is able to 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. Of these solvents, alcohols are preferred. 65 The reaction is carried out in the presence of excess acid. As in the previous case, there are no particular restrictions on the nature of the acids used, and any of the acids commonly used in reactions of this type can also be used in this case. Examples of such acids include, but are not limited to, such acids as: hydrochloric acid or trifluoroacetic acid. Of these acids, trifluoroacetic acid is predominant.

The reaction can take place over a wide range of temperatures, and the exact 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 substances. However, it is generally convenient to carry out this reaction at temperatures from about 02 to about 10022. The time required for the reaction to proceed can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting 7/0 substances and the used solvent. However, provided that the reaction is carried out under the preferred conditions described above, a period of time from about 5 minutes to about 24 hours will usually be sufficient.

Stage B2

At this stage, the desired compound of formula (I) is obtained by reacting (82-a) the compound of formula (M), obtained in stage B1, as described above, with the compound of formula (MI) or by means of reductive amination 75. (B2-5) compounds of formula (M) using compounds of formula (MI). (82-a) interaction with the compound of formula (M):

The interaction is usually and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent used, provided that it does not have an undesirable effect on the course of the reaction and the reagents involved in it, and that it is able to 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 dioxane; amines such as M-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, M-methylpiperidine, M-methylpyrrolidine, pyridine, 4-pyrrolidinepyridine, M,M-dimethylaniline and M,M-diethylaniline; as well as amides such as M,M-dimethylformamide and

M,M-dimethylacetamide. Of these solvents, M,M-dimethylformamide or M-methylpyrrolidine are preferred.

The reaction is carried out in the presence of a base. As in the previous case, there are no particular restrictions on i) the nature of the base used, and any base commonly used in reactions of this type can also be used in this case. Examples of such bases include, but are not limited to: amines such as M-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, m.

M-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(M,M-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, M,M-dimethylaniline, M,M- diethylaniline, 1,5-diazabicyclo|4.3.0|non-5-ene (22) (OVM), 1,4-diazabicyclo(2.2.2)octane (ОАВСО) and 1,8-diazabicyclo|5.4.0undec-7 -en (OB); hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; as well as alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide. Of the listed bases, diisopropylethylamine is preferred. with

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical from the point of view of this invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, it is generally convenient to carry out this reaction at temperatures from about 02 to about 1202C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature, as well as the nature of the starting substances and the solvent used. However, provided that the reaction is carried out under the preferred conditions described above (under c conditions, a period of time from about 5 minutes to about 48 hours will usually be sufficient. and (82-5) reductive amination: "" This reaction is usually and preferably carried out in the presence of solvent There is no particular restriction on the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved, and that it is capable of dissolving the reagents at least to some

Go! measures 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 dioxane; alcohols such as methanol, ethanol, co-propanol, 2-propanol and butanol; acetic acid; as well as water. Halogenated hydrocarbons are preferred among these solvents. The reaction is carried out in the presence of a reducing reagent. As in the previous case, there is no particular limitation on the nature of the reducing reagent used, and any reducing reagent commonly used in reactions of this type may also be used in this case. Examples of such reducing reagents include, but are not limited to indicated: sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. Of the listed reagents, sodium triacetoxyborohydride is preferred. The amount of reducing reagent required for the reaction can also vary widely depending on many (F. factors, especially the reaction temperature, as well as the nature of the starting materials and the solvent used. c However, provided that the reaction is carried out under favorable conditions, a ratio of chemical equivalents of the reducing reagent to the starting material of 1 to 3 will usually be satisfactory. 60 The reaction can proceed over a wide range of temperatures, and the exact temperature reaction is not critical to this invention the actual reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, it is generally convenient to carry out this reaction at temperatures from about -202C to about 602C. The time required for the reaction to proceed can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting materials and the solvent used. . However, provided that the reaction is carried out under the preferred conditions described above, a period of time from about 5 minutes to about 24 hours will usually be sufficient.

In the case when B is a group of the formula -C(-0)-B 7, the deprotection reaction will lead to the formation of a carboxy group. This reaction can be carried out under the same conditions as described for stage A1 of method A.

Method C

This description illustrates the preparation of a compound of formula (IP).

Scheme of the reaction C 2 y 2 ge B Stage C1 in, y

M )p -----k SNM )t Stage C2

N Za nn nen r

Mn MD

HE makes the moves. dec or

SIV (Mu (MI) (x) to "Obe

M. ..K

Shi. (1

On the reaction diagram, each of the symbols C, X, A, A? and Za 5 corresponds to the definition given above. Therefore, if KZa is -C(-0)-K7, the above compound of formula (IX) has the following structure. o 2 v v z Ya t (Kha) F "d te s sch

From Stage C1 so

At this stage, a compound of the formula (IX) is obtained by the interaction of a compound (MI) with a compound of the formula (MI) or by reductive amination of a compound of the formula (MI!) with a compound of the formula (MI). The compound of formula (MI!) can be prepared according to methods E and C below, or it is commercially available. "

Stage C2 10 At this stage, the compound of formula (II) is obtained by deprotection of the compound of formula (IX) obtained in step c) according to the description of stage ST. The reaction can be carried out under the same conditions as described for stage B1 "» of method B. p

Method O

This description illustrates the preparation of the compound of formula (Ia). 15 Scheme of the O so tyu reaction. ve ve to v2 yu M )t Stage 01, m )" Stage 02 uyu nzh Zla n MN N M. hi M. this ise, N-U and 7 7A ko two "and TI and (MIV (Khi) in (a) ( Hi)

GF) In the reaction scheme, each of the symbols О, ваз вл, 5 и У corresponds to the definitions given above, and K t is with a silicon-containing group, such as t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or trimethylsilyl, preferably trimethylsilyl; KZ and KE? independently represent a halogen atom, an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms, and an alkoxyalkyl group containing from 2 to 6 carbon atoms, and KZ and BE? together with the carbon atoms to which they are attached may optionally form a 3-6 membered cycle; A is A as defined above, except for methylene group and substituted methylene group.

Stage 01 65 At this stage, the compound of formula (IX) is obtained by condensation of the compound of formula (MI!) with the compound of formula (X) in the presence of paraformaldehyde. The compound of formula (MI) can be obtained according to method E and b, or it is commercially available.

In the event that Y is not an alkoxy group, the reaction is usually and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved, and that it is able to 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. Of these solvents, dichloromethane or ethanol are preferred. 70 The reaction can take place over a wide range of temperatures, and the exact 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 substances. However, it is generally convenient to carry out this reaction at temperatures between about 09°C and about 120°C. The time required for the reaction to proceed can also vary widely, depending on many factors, particularly the temperature of the reaction, as well as the nature of the starting materials used. and solvent. However, provided that the reaction is carried out under the preferred conditions described above, a period of time from about 5 minutes to about 48 hours will usually be sufficient.

Stage 02

At this stage, the compound of the formula (Ia) is obtained by means of the Mannich reaction between the compound of the formula (XI) and the compound of the formula (XII).

The reaction is usually and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved, and that it is able to 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; simple ethers, such as

Diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile and benzonitrile; and amides such as formamide, M,M-dimethylformamide, M,M-dimethylacetamide, and phosphoric acid hexamethyltriamide. Of these solvents, dichloromethane is preferable.

The reaction is carried out in the presence of a Lewis acid. As in the previous case, there is no particular restriction on the nature of the Lewis acid used, and any Lewis acid commonly used in reactions of this type can also be used in this case. Examples of such Lewis acids include, but are not limited to: VEz, AlICyz, ReCyz, MaSi”, AaSiI, Re(MOz)z, CEz5OzZi(SNaz)z, UB(CE550O5)3, and ZpSiH. Of the listed reagents, UB(СЕ55053)z, MaSi» or SEzZ5OZZI(CH 3) are preferable. with

The reaction can take place over a wide range of temperatures, and the exact 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. However, it is generally convenient to carry out this reaction at temperatures between about 09 and about 1002 C. The time required for the reaction to proceed can also vary widely, depending on many factors, especially the temperature of the reaction, as well as the nature of the starting materials used and solvent. However, provided that the reaction is carried out under the preferred conditions described above, a period of time from about 5 minutes to about 24 hours will usually be sufficient. "

Method E shsh c This description illustrates the preparation of the compound of formula (III), where K2 is a hydrogen atom, and A is Ag. h Reaction scheme E and? at

Ba and Y 1. « where 0 Stage 1! o moodeo00/ Stage E2 )t t (HIN) de i yu M PYTUM-VU. yu oi" (HM) "se : t m)

ЕЗз M , o Stage 29 bu) 0 Stage 4, nab urdt ke M заАА | M "see 60 (im (sh)

On the reaction diagram, each of the symbols E, A?, A? and Be corresponds to the definitions given above; each of the substituents 65 Ki Kk represents an alkyl group including from 1 to 4 carbon atoms, preferably a metal group or an aralkyl group such as benzyl or phenylethyl, preferably a benzyl group.

Stage E1

At this stage, compounds of the formula (KHIM) are obtained by reducing the cyano group of the compound of the formula (XIII), which is

Commercially available.

The reaction is usually and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved, and that it is able to dissolve the reagents at least to some extent. Examples of suitable solvents include, but are not limited to: ethers such as 70 diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; and alcohols such as methanol, ethanol, propanol, 2-propanol, and butanol. Of these solvents, methanol is preferable.

The reaction is carried out in the presence of a reducing reagent. As in the previous case, there are no particular restrictions on the nature of the reducing reagent used, and any reducing reagent commonly used in reactions of this type can also be used in this case. Examples of such reducing agents include, but are not limited to: metal borohydrides such as sodium borohydride and sodium cyanoborohydride; combinations of hydrogen gas and a catalyst such as palladium on carbon, platinum and Raney nickel, and hydride compounds such as lithium aluminum hydride and diisobutylaluminum hydride. Of the listed reducing agents, Raney nickel is preferred.

The reaction can take place over a wide range of temperatures, and the exact 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 substances. However, it is generally convenient to carry out this reaction at temperatures from about 09C to about 1002. The time required for the reaction to proceed can also vary widely, depending on many factors, especially the temperature of the reaction, as well as the nature of the starting materials used. and solvent. However, provided that the reaction is carried out under the preferred conditions described above, a period of time from about 5 minutes to about 24 hours will usually be sufficient. at

Stage E2

At this stage, compounds of the formula (XMI) are obtained by the interaction of compounds of the formula (XM), which are commercially available, with compounds of the formula (XIM). what

The reaction is usually and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved in it, and that it is able to 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. Of the specified solvents, a mixture of water and ethanol is preferable. with

The reaction is carried out in the presence of a base. As in the previous case, there are no particular restrictions on the nature of the base used and any base commonly used in reactions of this type can also be used in this case. 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 t-butoxide; as well as alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Of the listed bases, potassium carbonate is predominant. 2 s The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, it is generally convenient to carry out this reaction at temperatures from about 09C to about 120C. The time required for the reaction to proceed can also vary widely, depending on many factors, especially the temperature of the reaction, and the nature of the starting (ee) substances and solvent used, However, provided the reaction is carried out under the preferred conditions described above, a time period of from about 5 minutes to about 24 hours will usually be sufficient .di Stage EZ ko At this stage, compounds of the formula (XMII) are obtained by converting the carbonyl group of the compound of the formula (XM) into a cyano group in the presence of p-toluenesulfonylmethylisocyanide. sho The reaction is usually and preferably carried out in the presence of a solvent. There are no special restrictions on "I nature of the solvent , which must be used, provided that it does not have an undesirable effect on the course of the reaction or reagents that participate in it, and also that it is able to dissolve reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: ethers such as diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane; and alcohols such as methanol, ethanol, propanol, 2-propanol, and butanol. Of the specified solvents, a mixture of iF) dimethyl ether of ethylene glycol and ethanol is preferred.

Kz The reaction is carried out in the presence of a base. As in the previous case, there are no particular restrictions on the nature of the base used, and any base commonly used in reactions of this type can also be used in this case. Examples of such bases include, but are not limited to: alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. Of the listed bases, potassium t-butoxide is preferred.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the 65 starting materials. However, it is generally convenient to carry out this reaction at temperatures from about 09 to about 1002. The time required for the reaction to proceed can also vary widely, depending on many factors, particularly the temperature of the reaction, as well as the nature of the starting materials used and solvent However, provided that the reaction is carried out under the preferred conditions described above, a period of time from about 5 minutes to about 24 hours will usually be sufficient.

Stage E4

At this stage, compounds of the formula (PV) are obtained by reduction of the cyano group of the compound of the formula (CHMI).

The reaction can be carried out under the same conditions as described for stage E1 of method E.

There is a method

This description illustrates the preparation of compounds of formula (MI) in which K2 is a halogen atom. 70 Reaction scheme E o -0 to )t Stage P1 )t Stage 2 НО )t y o ----- MA ------ me (CH3)ze(OX (XM) (XIX) 000 da nt

Stage EZ Stage 4 You ion x MT MU )t shi M )t

MA | n MN sch

Still at (XXI) (Ma)

In the reaction diagram, E ha is a halogen atom; 25 corresponds to the above definition; and B" represents an amino protecting group, preferably a benzoyl group.

Stage E1 (22

At this stage, the compound of the formula (XIX) is obtained by converting the carbonyl group of the compound of the formula (KHMIII) into an epoxide group.

The reaction is usually and preferably carried out in the presence of a solvent. There are no special restrictions on se

35 of the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved in it, and that it is able to dissolve the reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: amides such as formamide, M,M-dimethylformamide, M,M-dimethylacetamide and phosphoric acid hexamethyltriamide; sulfoxides such as dimethyl sulfoxide or sulfolane. Of these solvents, dimethyl sulfoxide is preferred. "

The reaction is carried out in the presence of a base. As in the previous case, there are no particular restrictions on the nature of the base used, and any base commonly used in reactions of this type can also be used in this case. Examples of such bases include, but are not limited to: "" alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium t-butoxide; and alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Of the listed bases, potassium t-butoxide is preferred. o The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, it is generally convenient to carry out this reaction at temperatures from about 09C to about 1002C, more preferably from about 1023 to about 502C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction, as well as the nature of the starting materials and solvent used. However, provided that the I reaction is carried out under the preferred conditions described above, a time period of from about 5 minutes to about 24 hours, more preferably from about 60 minutes to about 12 hours, will usually be sufficient.

Stage E2

At this stage, the compound of formula (XX) is obtained by the interaction of hydrogen halide with the compound of formula (XIX).

The reaction is usually and preferably carried out in the presence of a solvent. There are no special restrictions on

F) the nature of the solvent to be used, provided that it does not have an undesirable effect on the process

Ho) the reaction or reagents involved in it, and also that it is able to dissolve the reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: ethers such as 60 diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as formamide,

M,M-dimethylformamide, M,M-dimethylacetamide and phosphoric acid hexamethyltriamide. Of these solvents, tetrahydrofuran is preferred.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the 65 starting materials. However, it is generally convenient to carry out this reaction at temperatures from about 09C to about 1002C, more preferably from about 1023 to about 502C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature, as well as the nature of the starting materials and solvent used. However, provided that the reaction is carried out under the preferred conditions described above, a period of time from about 5

Minutes to about 24 hours, more preferably from about 60 minutes to about 12 hours.

Stage EZ

At this stage, the compound of the formula (XXI) is obtained by the interaction of the compound of the formula (XX) with sodium azide (EZ-a) with subsequent reduction of the azido group (EZ-B). (EZ-a) reaction with sodium azide: 70 The reaction is usually and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved, and that it is able to 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, isopropyl ether, tetrahydrofuran and dioxane; amides such as formamide,

M,M-dimethylformamide, M,M-dimethylacetamide and phosphoric acid hexamethyltriamide; and sulfoxides such as dimethyl sulfoxide and sulfolane. Of these solvents, M,M-dimethylformamide is preferable.

Before adding sodium azide, the hydroxy group is converted to a leaving group such as methylsulfonyl, trifluoromethylsulfonyl, and 4-methylphenylsulfonyl by adding reagents such as trifluoromethanesulfonyl chloride, mesyl chloride, and tosyl chloride. Of these reagents, mesyl chloride is preferred.

The reaction can take place over a wide range of temperatures, and the exact 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 substances. However, it is generally convenient to carry out this reaction at temperatures from about 09°C to about 120°C. The time required for the reaction to proceed can also vary widely, depending on many factors, especially the temperature of the reaction, as well as the nature of the starting materials used and solvent. However, provided that the reaction is carried out under the preferred conditions described above, a period of time from about 5 minutes to about 24 hours will usually be sufficient. (E3-B5) recovery:

The reaction can be carried out under the same conditions as described for stage E1 of the E. che method

Stage 4

At this stage, the compound of the formula (MPa) is obtained by introducing the amino-protecting group KZ to the primary amino group b (E4-a) and selectively removing the amino-protecting group B 79 of the secondary amino group (E4-B). c (g4-a) introduction of an amino protecting group: ch

This reaction is described in detail by T.M. Sgeepe. |Rgoyesiime Sgotsrz ip Ogdapis Zupipevziz, 494-653, (1999)), and this description is incorporated into this application by reference. Next, as an example, a typical reaction with the use of a t-butoxycarbonyl protecting group is described.

The reaction is usually and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved, and that it is able to 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 dioxane; as well as sulfoxides such as m dimethyl sulfoxide and sulfolane. Of these solvents, tetrahydrofuran is preferred. i The reaction is carried out using a reagent. As in the previous case, there are no particular restrictions on the nature of the reagent used, and any reagent commonly used in reactions of this type can also be used in this case. Examples of such reagents include, but are not limited to: di-t-butylcarbonate and 1-(t-butoxycarbonyl)benztriazole. Of these reagents, di-tert-butyl carbonate is preferred.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, it is generally convenient to carry out this reaction at temperatures from about 09C to about 120C, more preferably from about 202C to about 802C. The time required for the reaction to proceed can also vary widely, depending on many factors, especially the temperature of the reaction, as well as the nature of the starting materials and solvent used. However, provided that the reaction is carried out under the preferred conditions described above, of course a period of time from about 5 29 minutes to about 24 hours, more preferably from about 60 minutes to about 12 hours, will be sufficient.o (E4-B) deprotection:

This method is described in detail |T.MU. Stgeepe ey aiYi. Rgoyesime Sgotsrz ip Ogdapis Bupipeziz, 494-653, ko (1999)), and this description is incorporated in this application by reference. Next, as an example, a typical method is described using a benzoyl protecting group in the presence of hydrogen gas and a catalyst such as 60 palladium on carbon or platinum.

The reaction is usually and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved, and that it is able to 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; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane. Of these solvents, methanol is preferable.

The reaction can take place over a wide range of temperatures, and the exact 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 substances. However, it is generally convenient to carry out this reaction at temperatures from about 09°C to about 120°C. The time required for the reaction to proceed can also vary widely, depending on many factors, particularly the temperature of the reaction, as well as the nature of the starting materials used and solvent However, provided that the reaction is carried out under the preferred conditions described above, usually 70 will be sufficient for a period of time from about 5 minutes to about 24 hours.

Method b

This description illustrates the preparation of compounds of formula (MI) in which K is a hydroxy group.

Scheme of the reaction o o) me on de ka Te v

Me?"

MA MN

. - zo (XX) (MIN) : (2)

On the scheme of reaction C, each of the symbols B and B "9 corresponds to the definition given above. Ha

Stage 01

At this stage, the compound of the formula (XXII) is obtained by the interaction of the carbonyl group of the compound of the formula (XIII), which is commercially available, with trimethylsilyl cyanide. co

The reaction is usually and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent to be used, provided that it does not adversely affect the course of the reaction or the reagents involved, and that it is able to 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, and ethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; nitriles such as acetonitrile and benzonitrile; and "» also alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, toluene is preferable.

The reaction is carried out using a reagent. As in the previous case, there are no particular restrictions on the nature of the reagent used, and any reagent commonly used in reactions of this type can also be used in this case. Examples of such reagents include, but are not limited to: Lewis acids, such as BE»z, AlCiz, ReCiz, AocSi, 2pio, Re(MOz)z, Cez5O»zZi(CHnaz)z, UB(CEz5Oz3)z and Zp; co bases, such as CaO; ethers such as 18-crown-b; acids such as Atrebegier High-4 resin. Of these reagents, 2pi5 is preferred. d) The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and starting materials. However, it is generally convenient to carry out this reaction at temperatures from about 09C to about 1002. The time required for the reaction to proceed can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the starting materials and solvent used.However, provided that the reaction is carried out in under the prevailing conditions described above, of course (F, a period of time from about 5 minutes to about 24 hours will be sufficient. ke Stage 52

At this stage, the compound of the formula (XXI) is obtained by converting the cyano group of the compound of the formula (XXII) into the 60 amino group with subsequent deprotection formed by the amino-protecting group K "9. The reaction can be carried out under the same conditions as described for stage E1 of method E and stage 4 method of R.

OZ stage

At this stage, the compound of the formula (UNIB) is obtained by protecting and deprotecting the amino groups of the compound of the formula (XXIII). This reaction can be carried out under the same conditions as described for stage G4 of method P. b5. Compounds of formula (I) and intermediates in the above-described production methods can be isolated and purified using well-known techniques, such as distillation, recrystallization or chromatographic purification.

Compounds according to the present invention, intended for pharmaceutical use, can be introduced into the body in the form of crystalline and amorphous products. They can be obtained, for example, in the form of solid compressed dosage forms, powders or films, by methods such as precipitation, crystallization, lyophilization, spray drying or evaporation drying. Drying with microwave or radio frequency waves can be used for this purpose.

The compounds of the present invention may be administered alone or in combination with one or more other substances of the present invention, or in combination with one or more other drugs (or any combination thereof). They will generally be administered as a pharmaceutical formulation or 7/0 formulation in combination with one or more pharmaceutically acceptable carriers or excipients. The term "carrier" or "excipient" is used herein to describe any ingredient other than the compound(s) of the present invention. The choice of carrier or excipient will largely depend on factors such as the particular route of administration, the effect of the excipient on solubility and stability, and the type of dosage form.

Pharmaceutical compositions suitable for delivery of the compounds of the present invention and methods of their preparation are readily understood by those skilled in the art. Such compositions and methods of their preparation can be found, for example, in "Retipdiopye Rnagtaseciisa! Zsiepsev", 1917 Edyop (Mask Rybiizpipd Sotrapu, 1995).

Oral administration

The compounds of the present invention may be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, whereby the compound enters the bloodstream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as, for example, tablets, capsules containing small particles, liquids or powders, lozenges (including liquid-filled), chewing gums, multi- and nano-particles, gels, solid solutions, liposomes, films (including those attached to the mucous membrane of the urinary membranes), oval capsules, sprays and liquid compositions.

Liquid compositions include, for example, suspensions, solutions, syrups and elixirs. Such formulations may i) be used as fillers in soft or hard capsules and typically include a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents . Liquid compositions can also be obtained by dissolving solids, for example, from sachet packages.

The compounds of the present invention can also be used in rapidly soluble or rapidly disintegrating dosage forms, such as, for example, in the dosage forms described (iapd and Spep in Echreg Ha

Oriope ip Tpegaretsiis Rayepiv, 11 (6), 981-986 (2001)|.

For tablet dosage forms, depending on the dose, the drug may be from about 1 wt.bo to about 8Omas.bo by weight of the dosage form, more typically from about 5wt.9o to about 50 bOmas.bo by weight of the dosage form. In addition to the medicinal product, tablets usually contain a disintegrating agent. Examples of disintegrants include starch glycolate sodium, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. As a rule, the agent for disintegration - c will be included in the composition in an amount from approximately Tmas.9o to approximately 25mas.9o, preferably from approximately 5mas.95 to approximately 2Omas.9o of the total weight of the dosage form. "» Binders are mainly used to give the composition of the tablet the ability to combine into a single unit. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch,

Go! hydroxypropyl cellulose and hydroxypropyl methyl cellulose. In addition, tablets may contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate. In addition, tablets may optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silicon dioxide and talc. If surfactants are present, their content can be from about 0.2 wt.95 to about 5 wt.95 of the total weight of the tablet, and the glidants can be from about 0.2 wt.95 to about T wt.95 of the total tablet mass.

Tablets usually contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants are mainly contained in an amount of from about 0.25wt.oo to about 1Owt.9o, preferably from about

O,bmas.bo to, approximately, Zmas.9o from the total weight of the tablet. (F) Other possible ingredients include antioxidants, colors, flavors, preservatives, and flavor maskers.

Typical tablets contain up to 8095% of drug, from about 1% by weight to about 9% by weight of binder, from about 9% by weight to about 85% by weight of diluent, from about 2% by weight to about 1% by weight of disintegrant. and from about 0.25wt to about 1wt.9o of lubricant.

Mixtures for obtaining tablets can be pressed directly or with the help of a shaft. On the other hand, tableting mixtures or portions of these mixtures can be wet, dry or melt granulated, melt solidified or extruded prior to tableting. The final composition may include one or more layers and may be coated or not coated; in addition, it can be encapsulated.

The composition of the tablets is discussed in |"РНагтасециисай Юозаде Богте: Tariyeeiv, Moi" ru N. Shereptap apa

Y. Sasptap, Mags! Oekkeg, M.U., 1980 (IZVM 0-8247-6918-X)).

Solid compositions for oral administration can be designed for immediate and/or modified release of the drug. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

Modified release formulations suitable for the purposes of this invention are described in |(US patent Mob 106,864). Details of other suitable release technologies such as high energy dispersions and 7/0 osmotic and coated particles should be consulted in Thespoiodu Op-Iipe, 25(2), 1-14 (2001)). The use of chewing gum to achieve controlled release is described in (M/O 00/352981I.

Parenteral administration

The compounds of this invention can also be administered directly into the bloodstream, muscles and internal organs.

Suitable routes of parenteral administration include intravenous, intraarterial, 7/5 intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include injection devices with needles (including microneedles), injection devices without needles, and infusion devices.

Parenteral formulations are generally aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to maintain a pH in the range of about 3 to about 9), but for some applications it is more convenient to formulate the formulations as sterile non-aqueous solutions or as dry forms used in combination with a suitable carrier such as sterile pyrogen-free water.

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

The solubility of compounds of formula (I) used in parenteral solution preparations can be increased by suitable formulation techniques, such as the inclusion of solubility-enhancing agents.

Formulations for parenteral administration can be designed for immediate and/or modified release.

Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted, and programmed-release formulations. Thus, the compounds according to the present invention can be included in the composition of solid and semi-solid preparations, as well as thixotropic liquids for administration as a depot, which 9) is implanted, which provides a modified release of the active compound. Examples of such formulations include drug-coated vascular endoprostheses and ROGA microspheres.

Topical introduction se

The compounds of the present invention can also be administered topically, to the skin or mucosa, i.e. dermally or transdermally. Typical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, bandages, foams, films, skin patches, plates, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petroleum jelly, white petroleum jelly, glycerin, polyethylene glycol, and propylene glycol. The composition may include "means to improve penetration - see, for example, |Rippip apa Moghdap, U RNagt Zsi, 88 (10), 955-958 with p (October 1999)|.

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and injections with or without microneedles (eg, Rom/dehysi tm, Vio|esitm, etc.).

Compositions for topical administration can be designed for immediate and/or modified release

Go! medicinal product. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. ko Inhalation/intranasal administration t The compounds of the present invention may also be administered intranasally or by inhalation, typically

In dry powder form (or by themselves as a mixture, e.g. dry mixture with lactose, or (se) as mixed component particles, e.g. mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler, or in the form of an aerosol spray from a pressurized container, pump, atomizer, atomizer (predominantly an atomizer using electrohydrodynamic forces to produce a fine mist) or aerosol apparatus with or without the use of a suitable propellant such as 1,1,1,2 -tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or (F; cyclodextrin). A pressurized container, pump, nebulizer, nebulizer, or aerosol device contains a solution or suspension of the compound(s) of the present invention, including, for example, ethanol, aqueous ethanol or other suitable means for dispersing, dissolving or increasing the release time of the active substance, propellant(s) as a solvent and, optionally, a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

Before use in a dry powder or suspension formulation, the medicinal product is finely ground to a size suitable for inhalation (usually less than 5 microns). This result can be achieved by any suitable milling method, such as spiral milling, fluidized bed milling, nanoparticle supercritical fluid treatment, high pressure homogenization, or spray drying.

Formulations of capsules (made, for example, of gelatin or HPMC), blister packs and cartridges for use in inhalers and insufflators can be formulated to contain a mixture of a powdered compound of the present invention, a suitable powdered base such as lactose or starch, and

A performance modifier such as 1-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in monohydrate form, with the latter form being more preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable composition of the solution for use in a nebulizer using electrohydrodynamic forces to produce a fine mist may contain from about 1 mcg to about 20 mcg of a compound of the present invention per actuation, and the volume released upon actuation may vary from about 1 µml to about 100 μl A typical composition may include a compound of formula (I), propylene glycol, sterile water, ethanol, and sodium chloride. Other solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

Suitable flavors such as menthol and levomenthol or sweeteners such as saccharin or saccharin sodium can be added to these compositions of the present invention intended for inhalation/intranasal administration. Formulations for inhalation/intranasal administration can be designed for immediate or modified release of the drug, for example, poly(OI)-lactic-glycolic acid (PO A).

Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

In the case of dry powder inhalers and aerosols, the dosage unit is defined by a valve that releases a measured amount of content. These devices according to the present invention are generally adapted to administer a metered dose or a single "shot" containing from about 1 to about 100 µg of a compound of formula (I). The total daily dose will generally be in the range of about 5Omg to about 2Omg, and this amount may be administered as a single dose or, more commonly, in separate doses over the course of several hours.

of the day

Rectal/intravaginal injection (o)

The compounds of the present invention can be administered rectally or vaginally, for example, in the form of suppositories, pessaries or enemas. Cocoa butter is the traditional suppository base, but various suitable alternatives can be used. Compositions for rectal/vaginal administration can be designed for immediate and/or modified release of the drug. Modified release formulations include delayed, (o)sustained, pulsed, controlled, targeted and programmed release formulations. with

Ocular/aural administration

The compounds of the present invention can also be administered directly into the eyes or ears, as a rule, in the form of drops of a finely dispersed suspension or a solution in an isotonic sterile saline solution with a suitable pH value. Other formulations suitable for ocular or auricular administration include ointments, biodegradable (eg, absorbable, gel sponges, collagen) and non-biodegradable (eg, silicone) implants, plates, lenses, and microparticle or vesicle systems such as niosomes or liposomes. . The composition may include a polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose-based polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or c-methylcellulose, or heteropolysaccharide-based polymers such as gelatin gum, together with a preservative such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis. z Formulations for eye/ear administration can be designed for immediate and/or modified release of the drug. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. Co. Other technologies

The compounds of the present invention can be combined with soluble macromolecular entities, such as co-cyclodextrin and its suitable derivatives or polymers containing polyethylene glycol, to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the above methods of introduction. (Se) For example, drug-diclodextrin complexes have been found to be generally applicable for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to the direct formation of a complex with the drug, cyclodextrin can be used as an auxiliary admixture, that is, as a carrier, diluent or solubilizer. dv More common for these purposes is the use of alpha-, beta- and gamma-cyclodextrins, examples of which can be found (in international patent applications MoMoUuUO 91/11172, UMO 94/02518 and MO 98/551481.

GF) Component part of the kits

Due to the fact that it may be desirable to introduce a combination of active compounds, for example, for the purpose of treating a specific disease or condition, the scope of this invention includes such a method of application, in which two or more pharmaceutical compositions, at least one of which contains a compound according to the present invention, can be easily combined in the form of a kit suitable for joint administration of these compositions.

Thus, a kit according to the present invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the present invention and means for separate storage of said compositions, such as a container, compartmentalized bottle or compartmentalized bag from foil 65 An example of such a kit is the well-known blister pack used for packing tablets, capsules, etc.

The kit according to the present invention is particularly suitable for the administration of different dosage forms, for example, oral or parenteral, for the administration of individual compositions in different dosage intervals or for titration of individual compositions in relation to each other. To promote compliance with legal regulations

The kit, as a rule, includes instructions for use and may be provided with a so-called manual.

Dosage

When administered to humans, the total daily dose of the compounds of the present invention, which of course depends on the route of administration, is generally in the range of about 0.05 mg to about 100 ug, preferably in the range of about 0.1 mg to about 5 ug, and more preferably in range from about 0.5 mg to 70 about 20 mg. For example, oral administration may require a total daily dose of from about 1mg to about 2Omg, while intravenous administration may only require a dosage of from about 0.5mg to about 1Omg. The total daily dose can be administered in one dose or in separate doses.

These dosages apply to an average person weighing from about 65 kg to about 7Okg. The physician will easily be able to determine the dosage for subjects whose weight is outside this range, as well as for younger children and the elderly.

Combinations

As discussed above, the compounds of the present invention exhibit 5-HT agonist activity. 5-HT agonists according to the present invention can be successfully combined at least 6 with one of the other pharmacologically active agents or compounds, in particular, in the treatment of gastroesophageal reflux disease. For example, the agonist 5-HT,, 2o in particular, the compound of formula (1) or its pharmaceutically acceptable salt or solvate, defined above, can be administered simultaneously, sequentially or separately, in combination with . one or more pharmacologically active agents selected from: () antagonists of the histamine receptor No, for example, ranitidine, lafutidine, nizatidine, cimetidine, famotidine and roxatidine; with (her) proton pump inhibitors, for example, omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole; o (ii) acid pump antagonists, for example, soraprazan, revaprazan (UN-1885), A2O-0865, C5-526,

АЦИ-2064 and MA-20379-8; (im) oral antacid mixtures, for example Maaiokh7, AIagohU and Samivsop?; cha (M) means to protect mucous membranes, for example, polaprezinc, ecabet sodium, rebamipide, teprenone, cetraxate, sucralfate, chlorpilin-midi and plaunotol; io (mi) agonists of ZAVAv, for example, baclofen and A2O-3355; A2 agonists, such as clonidine, medetomidine, lofexidine, moxonidine, tizanidine, guanfacine, guanabenz, talipexole, and dexmedetomidine; c (my) xanthine derivatives, for example, theophylline, aminophylline and doxofylline; with (their) calcium channel blockers, for example, arandipine, lacidipine, phalodipine, azelnidipine, clinidipine, lomerizine, diltiazem, halopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine and fasudil; (9) benzodiazepine agonists, such as diazepam, zaleplon, zolpidem, haloxazolam, clonazepam, - with prazepam, quazepam, flutazolam, triazolam, lormetazepam, midazolam, tofizopam, clobazam, and flunitrazepam and flutoprazepam; "" (xii) prostaglandin analogues, for example, prostaglandin, misoprostol, treprostinil, esoprostenol, latanoprost, iloprost, beraprost, enprostyl, ibudilast and ozagrel; (xii) histamine H3 agonists, for example K-alphamethylhistamine and BP-294;

Go! (chii) antigastric agents, for example, anti-gastrin vaccine, itriglumide and 727-360; (chem) 5-HT3 antagonists, such as dolasetron, palonosetron, alosetron, azasetron, ramosetron, mitrazapine, granisetron, tropisetron, E-3620, ondansetron and indicetron; co (hu) tricyclic antidepressants, for example, imipramine, amitriptyline, clomipramine, amoxapine and lofepramine; d) (chemicals) SABA agonists, for example, gabapentin, topiramate, cinolazepam, clonazepam, progabid, "M brotizolam, zopiclone, pregabalin and eszopiclone; (chemicals) opioid analgesics, for example, morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone , meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, and pentazocine; (F) (chemicals) somatostatin analogs, such as octreotide, AM-238, and RTAK -3173; with (xix) SI channel activators, for example, lubiprostone; (09 selective serotonin reuptake inhibitors, for example, sertraline, escitalopram, bo fluoxetine, nefazodone, fluvoxamine, citalopram, milnacipran, paroxetine, venlafaxine, tramadol, sibutramine, duloxetine, desvenlafaxine and dapoxetine; (xxi) anticholinergic agents, for example, dicyclomine and hyoscyamine; (xxii) laxatives, for example Tgiuva?, Rurode!", Kopzui-, Ivodei" , KedshapU, Seiemas? and Mogtasso!?; (xhiii) fibrous products, for example, Megatisia U; 65 (хим) antispasmodics, for example mebeverin; (xu) dopamine antagonists, for example metoclopramide, domperidone and levosulpiride;

(khmi) cholinergic agents, for example neostigmine; (chemicals) ASNE inhibitors, for example, galantamine, metrifonate, rivastigmine, itopride and donepecil; (Skhmiiii) tachykinin (MK) antagonists, in particular MK-Z3, MK-2 and MK-1 antagonists, for example nepadutant, saredutant, talnetant, (AK,OK)-7-IZ,5-bis(trifluoromethyl)benzyl-8, 9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-/1,4)diazocinoin2,1-9)

P.Ya of naphthridine-6-13-dione (TAK-637), 5-(2K,35)-2-(1K)-1-IZ,5-bis(trifluoromethyl)phenyl|ethoxy-3-(4-fluorophenyl) )-4-morpholinyl|methyl/i-1,2-dihydro-ZH-1,2"A4-triazol-3-one (MK-869), lanepitant, dapitant and 70. C-Ce-methoxy-5-( trifluoromethoxy)phenyl|methylamino)|-2-phenylpiperidine (25,35).

Methods of assessing biological activity:

The affinity of the compounds of the present invention for binding to the 5-HT 4 receptor was determined using the following methods.

Binding to human 5-HT, (1)

Human 5-NTA(4) transfected HEK293 cells were obtained and grown independently. The collected cells were suspended in HOMM NEREZ (pH? 4 at 42С) with the addition of a protease inhibitor cocktail (Voephipdeg, dilution 1:1000) and homogenized for 30 seconds. on ice using a Royiop RT 1200 hand grinder set to full power. Homogenates were centrifuged at 40,000 x 9 at 42C for 30 minutes. Then the sediment particles were resuspended in 5HOMM STAINLESS STEEL (pH74 at 42C) and centrifuged again in the same way. The resulting sediment particles were resuspended in a suitable volume of 5X0MM NEREB5 (pH 7.4 at 252С), homogenized, divided into aliquots and stored at -809С until use. An aliquot of the membrane fractions was used to determine the protein concentration, using a kit for the determination of BSA protein (RIEKSE) and an AKMOzh tablet reader (UMaiIas).

For binding experiments, 25 μl of the studied compounds were incubated with 25 μl |IZNI-OV113808 (Atehepat, si final content 0.2 nM), as well as with solutions of suspensions of 150 μl of membrane homogenate and M/CA-5RA granules) (Atehepat) (1Omkg protein and img granules 5RA/well) for 60 minutes at room temperature. Non-specific binding was determined using iMm OK113808 (Tostgiv) at the final concentration. Incubation was interrupted by centrifugation at 1000°6/min.

Receptor-bound radioactivity was quantified by counting pulses using a counter - Mysgoveya tablets (/maiIas). b

All the compounds described in the examples showed affinity for the 5HT receptor.

Binding to human 5-HT, (2) with.

Human 5-NTA(4) transfected HEK293 cells were obtained and grown independently. Collected cells were suspended in 50 mM Tris buffer (pH7.4 at 422) with the addition of a protease inhibitor cocktail (Voenpngipdeg, 30 dilution 1:1000) and homogenized for 30 seconds. on ice using a Royup RT so 1200 hand grinder set to full power. The homogenates were centrifuged at 40,000 x 9 at 42C for 1 hour. Then the sediment particles were re-suspended in 50 MM Tgiz buffer (pH7.4 at 42C) and centrifuged again in the same way. The resulting sediment particles were re-suspended in a suitable volume of 5 MM Ttgiz buffer (pH7 4 at "2522) containing 10 MM Mass", homogenized, divided into aliquots and stored at -809С until use. An aliquot of the membrane fractions was used to determine the protein concentration, using a kit for the determination of BSA protein (RIEKSE) and an AKMO plate reader (UmaiIas). with For binding experiments, 5 µm of the tested compounds were incubated with 5 µm of | ZNIZ-NT (Ategzpat, final content of 8.0 NM) and 400 μl of membrane homogenate (ZOO μg of protein/tube) for 60 minutes at room temperature. Nonspecific binding was determined using 5 μM sK113808 (Tosgiv) at the final c concentration. All incubations were terminated by rapid vacuum filtration through glass fiber paper impregnated with 0.295 REI using a VCAMOEIG collector, followed by three washes with 500 mM Ttiv buffer (pH7.4 at 2522). Receptor-bound radioactivity was quantified by liquid scintillation counting using a Raskag I 5 counter.

All the compounds described in the examples showed affinity for the 5HT receptor. (Ce) Agonist-induced increase in CAMP production in human 5-HT (non-transfected HEK293 cells) Human 5-HTa (transfected HEK293 cells were obtained independently. Cells were grown at 372C in an atmosphere with a CO content of 595 in OMEM with impurities of 10956 EC5, 20 MM NEREZ (pH7.4), 200 μg/ml of hygromycin B (Sirso), 100 units/ml of penicillin and 10 μg/ml of streptomycin.

Cells were grown to 60-8095 confluency. One day before treatment with the studied compounds, the dialyzed EC (Birso) was replaced with normal, and the cells were incubated overnight. Compounds were placed in (F) 96-well tablets (12.5 μl/well). Cells were harvested with PB5/MM EDTA, centrifuged and washed with PB5. At the beginning of the analysis, the cell pellet was re-suspended in OMEM with impurities of 20 mM NEREZ, 10 mM pargyline (Zidta) and mM 3-isobutyl-1-methylxanthine (Zidta) at a concentration of 1.6x10 cells/ml and left for 15 minutes at 60°C at room temperature. The reaction was initiated by adding cells to the tablets (12.5 μl/well). After incubation for 15 minutes at room temperature, 195 Top X-100 was added to stop the reaction (25μl/well), and the plates were left at room temperature for 30 minutes. A homogeneous determination of cAMP was performed based on time-resolved fluorescence (Zpegipo) according to the manufacturer's instructions. To measure NTKE (excitation 32 Ohms, emission 665 nm/620 nm, delay 5 Ohms, time window 40 Ohms) a multilabel 65 counter AKMOzh (UMaiIas) was used. Data were analyzed based on the ratio of the fluorescence intensity of each well at 62Ohm and 6b5nm, followed by CAMP quantification by using a standard curve with

AMR. The increase in AMP production caused by each compound was normalized to the amount

CAMP produced under the action of 1000NM of serotonin (Zidta).

All the compounds described in the examples demonstrated 5HT receptor agonist activity.

Binding of human dofetilide

Human NEKOS transfected NEK2935 cells were obtained and grown independently. Collected cells were suspended in 50 mM Ttivz-HCII (pH7.4 at 42) and homogenized for 20 seconds. on ice using a Royuigop RT 1200 hand grinder set to full power. The homogenates were centrifuged at 48,000 x 9 at 49°C for 20 minutes. Then parts of the sediment were re-suspended, homogenized and centrifuged again 70 in a similar way. The resulting parts of the sediment were re-suspended in a suitable volume of 50 OMM

Ttiv-NSI, 10 mM KSI, 1 mM Masi" (pH 7.4 at 42С), homogenized, divided into aliquots and stored at -809С until use. An aliquot of the membrane fractions was used to determine the protein concentration, using a kit for the determination of BSA protein (RIEKSE) and an AKMOzh tablet reader (UmaiIas).

Binding assays were performed in a total volume of 200 μl in 9b-well tablets. Twenty microliters of 75 studied compounds were incubated with 2O0 microliters of NI-dofetilide (Ategepat, final content 5 nM) and 1 μm of membrane homogenate (25 mg of protein) for 60 minutes at room temperature. Non-specific binding was determined using 1µM dofetilide at the final concentration. Incubations were terminated by rapid vacuum filtration through a pre-impregnated 0.595 SR/V Veyriave filter using a Zkapop cell collector with 50 mM Ttiv-HCl, 10 mM KS, 1 mM Masi', pH7.4 at 420. Filters were dried, placed in sample bags, and filled Veiariage Zsipi. The radioactivity bound on the filter was counted with a U/aIMas counter

Vegariaie.

Penetration of Saso-2

Permeability of Saso-2 was measured according to the method described in Zpiwip, Hee, RNagtaseciisa! Kezeagsy, 763 (1997). with

Saso-2 cells were grown on filter substrates (Baysop NT tiyumeyi ipzegi zuviet) for 14 days. The culture medium was removed from both the apical and basolateral compartments, and the monolayers were pre-incubated with pre-warmed 0.3 ml of apical buffer and 1.0 ml of basolateral buffer for 0.5 h at 372C in a vibrating water bath at 50 cycles/min. The apical buffer consisted of Napkz VaYapsea zaiYe Boishiop, 25 mM O-glucose monohydrate, 20 mM ME5 Viiodis! Viybeg, 1.25 mm Sasio and 0.5 mm Masi" (rnb, 5). -

The basolateral buffer consisted of Napkz Vaiapsea Zaiiy Zoishtsiop, 25 mM O-glucose monohydrate, 20 mM NEREZ b

Vioiodisa! Vybeg, 1.25 mM Sasi" and 0.5 mM Mosi" (pH7.4). At the end of pre-incubation, the medium was removed and a solution of the tested compound (10 mM) in buffer was added to the apical compartment. Inserts per hour moved M cells containing fresh basolateral buffer. The concentration of the medicinal product in the buffer was measured using the LC/MS method.

The flow rate (P, mass/time) was calculated based on the slope of the curve of the integral flow of the substrate to the receiver side, and the apparent permeability coefficient (Rarr) was calculated from the following equation.

Rarr (cm/sec.)-(E"MO)(ZA"MO), where ZA means the surface area for substance transfer (0.3cm g), MO means the volume from which the substance enters (0.3ml) , MO means the total amount of medicinal substance on the output side at the time of i-0.

All data represent average values for 2 measured inserts. The integrity of the monolayer was determined by the transfer of the I isiteg WayPom. "z Half-life time in human liver microsomes (NI M) " The studied compounds (1 μM) were incubated with 3.3 mM MoSi» and 0.78 mg/ml NIM (NI1O01) in 100 mM potassium phosphate buffer (pH7.4) at 372C for 96- pitted tablet with deep pits. The reaction mixtures were divided into two groups: the non-P450 group and the P450 group. MAORN was added only to the reaction mixtures of the P450 group. Aliquots of samples from the P450O group were taken at time points 0, 10, 30 and bOkhv., where the time point of Okhv. corresponded to the time when MAORN km was added to the reaction mixtures of the P450 group. Aliquots of non-P450 group samples were taken at time points of -10 and 65 minutes. Collected aliquots were extracted with an acetonitrile solution containing an internal standard. The precipitated protein was concentrated by rotation in a centrifuge (2000 rpm, 15 min.). The concentration of the compound in the supernatant liquid "se 20" was measured in the LC/MS/MS system.

The value of the half-life was obtained by plotting the dependence of the natural logarithm and the ratio of the peak areas of the compounds to the internal standard against time. The slope of the line that best fits the obtained points gave the rate of metabolism (k). The obtained value was converted into the value of the half-life using the following equation: 99 half-life time - Ip2/kC

Ge) Examples

The present invention is illustrated by the following non-limiting examples, in which, unless otherwise indicated: all reagents are commercially available, all operations were performed at room temperature or ambient temperature, that is, in the range of approximately 18-252C; evaporation of the solvent was carried out using a rotary evaporator under reduced pressure at a bath temperature of approximately 602C; the progress of the reactions was monitored using thin-layer chromatography (TLC) and the reaction times are given as an illustration only; the specified melting points are uncorrected (polymorphism can lead to different melting points); the structure and purity of all isolated compounds were confirmed by at least one of the following methods: TLC (Megek ziiisa de! 60 254 pre-coated plates for TLC or Megsk МНо Е2545 pre-coated plates for ВТХХ), mass spectrometry, nuclear magnetic resonance (NMR), infrared absorption spectra (14) or microanalysis. Outputs are shown for illustrative purposes only. Column flash chromatography was performed using MegsK ziiis de! 60 (230-400 mesh AZTM) or Zyuvia

Spgotayeh? DI 3050 (Atipo Toure, 30-5Ωm). Low-resolution mass spectrometry data (LMS) were recorded on an Ipieogig mass spectrometer (UUa(egg)) or an Ashiotavs 120 mass spectrometer (ZEOI). or mass spectrometers of Otsakgo I! (Misgotazv).

NMR data were recorded on a 27 Ω spectrometer (ШЕОИ OMM-ГА270) or a 30 Ω spectrometer (ЕОИ ОММ-Й AZOO) using deuterated chloroform (99.895 U) or dimethyl sulfoxide (99.995 U) as a solvent, unless otherwise indicated, against tetramethylsilane (TMS) as internal standard in parts per million (ppm); 70 standard abbreviations are: c-singlet, a-doublet, Y-triplet, d-quartet, t-multiplet, Bg-expanded, etc.

IR spectra were recorded on an infrared spectrometer Zpita?y (IK-470). Optical rotation was measured using a CHABSO OIR-370 digital polarimeter (Charap Zresigozsoris So., TO). Chemical abbreviations have their usual meaning: t.kip. (boiling temperature), b.p. (melting point), l (liter (liters)), ml (milliliter (milliliters)), g (gram (grams)), mg (milligram (milligrams)), mol (moles), mmol |(millimoles), eq. 75 (equivalent(s)). The X-ray diffraction pattern on crystalline powder (XPR) was recorded using a Kidaka KIMT-TTK X-ray powder diffractometer equipped with a device for automatic sample replacement, 2 theta-theta goniometers, beam divergence slits, a secondary monochromator, and a scintillation counter. Samples were prepared for analysis by packing the powder in an aluminum sample tank. The sample was rotated at a speed of 60.00 rpm. and scanned at a speed of 42/min. at room temperature with Si-KA radiation.

Example 1: 4-ShCh4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|methylated trahydro-2H-pyran-4 -carbonic acid p

N o o o (in k on sh -om F

M schi sch p

A- co

Stage 1. tert-butyl 4-cyanotetrahydro-2H-pyran-4-carboxylate

Tert-butyl cyanoacetate (25.0 g, 0.177 mol) in DMF (100 ml) was added dropwise to a stirred suspension of Man (17.77, 044 mol) in DMF (200 ml) at 02С in an atmosphere of Mo. The mixtures were allowed to warm to room temperature and stirred for 1 hour. Then bis(2-bromomethyl) ether - c (49.3 g, 0.177 mol) was added to the mixture, and the resulting mixture was stirred at 902C for 24 hours. After cooling to 0°C, the mixture was quenched with water (1O0Oml). Volatile components were removed by evaporation and the residue was precipitated with a mixture of E(Ac-toluene) (1:22, 50Oml) and water (500ml). The organic phase was washed three times with water (500ml), dried over NaCl, filtered and evaporated. The solid residue was washed with hexane and dried in vacuo to give 19.0 g (5790) of the title compound as white crystals. (2H, dt, U-3.9Hz, 12.3Hz), 3.73 (2H, dt, U-2.6Hz, 12.3Hz), 2.20-1.94 (4H, m), 1, 52 (9H, p). ke Stage 2. tert-butyl 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate Mixture of tert-butyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (18.95g, 0 .0897mol, stage 1) and Me Raney (1.00g) in methanol (200mL) was treated with hydrogen gas (Z atm) at room temperature for 12 hours. (The mixture was then filtered through a pad of celite and the filtrate was concentrated in vacuo to give 16 .01 g (8390) of the compound indicated in the title in the form of a yellow syrup.

In TN NMR (SOSIv) 5: 3.86 (2H, dt, 9U-41Hz, 11.4Hz), 3.48 (2H, dt, 9-2.5Hz, 11.5Hz), 2.75 (2H, s), 2.03 (2H, width d, U-10.7Hz), 1.55-1.35 (1ZH, m, including 9H.s, 1.49 m.h.).

Stage 3. tert-butyl 4-((4-oxopiperidin-1-yl)umethyltetrahydro-2H-pyran-4-carboxylate

To a boiling mixture of tert-butyl 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate (8.00g, 0.0372mol, stage

GF) 2) iodide was added dropwise to its CoCOz (051g, 0.0372mol) in EUN-NYO (2:11, 240ml)

F 1-ethyl-1-methyl-4-oxopiperidinium (12.0g, 0.0445mol, |(U.Ogud.Spet. 1995, 60, 4324-4330) in EYN-NoO (2:11, 15Oml) and the obtained the mixture was stirred at the same temperature (reflux) for about 1 hour. After cooling to room temperature, the solvent was removed in vacuo. The residue was poured into a saturated aqueous solution of MnNsSO3 (200 mL), and the mixture was extracted with SiOCl (200 mL three times) The extracts were dried over NaClO) and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane/ethyl acetate (3:11 to 2:1), to give 10.77 g (9895) of the title compound as a colorless syrup. 65 MS (EI) t/2: 298 (MEN). 0Hz, 11.7Hz), 2.85 (4H, t, 9-5.9Hz),

2.61 (2H, s), 2.39 (4H, t, 9-6.1Gu), 2.05 (2H, d, 9U-11.5Hz), 1.75-1.45 (11H, m , including ON, p, 1.49 m.h.).

Stage 4. tert-butyl 4-(4-cyanopiperidin-1-yl)umethyl/|hetrahydro-2H-pyran-4-carboxylate

To a stirred solution of tert-butyl 4-|((4-oxopiperidin-1-yl)umethylyltetrahydro-2H-pyran-4-carboxylate (8.77g, 0.0295mol, stage 3) in 1,2-dimethoxyethane (2500ml) was added p-toluenesulfonylmethylisocyanide (11.51g, 0.059Omol), EUN (3.9bml, 0.0678mol) and t-VOK (11.58g, 0.1032mol) at 00. The resulting mixture was stirred at 502 for 16 hours. After cooling, the reaction the mixture was poured into a saturated aqueous solution

MnSO 3 (200 mL), and the mixture was extracted with CHCl 3 (200 mL 3 times). The extracts were dried over Mazo and concentrated. The residue was chromatographed on a silica gel column, eluting with a mixture of hexane/ethyl acetate 70. (2.1), and 5.76 g (63905) of the title compound was obtained as a yellow syrup.

MS (E5I) t/2: 309 (MAN).

TN NMR (SOSIv) 5: 3.81 (2H, dt, 9U-31Hz, 11.0Hz), 3.48 (2H, dt, 9-2.1Hz, 11.7Hz), 2.76-2.64 (2H, m), 2.64-2.52 (1H, m), 2.50-2.35 (4H, m, including 2H, s, 2.46 m.h.), 1.98 (2H, width, 9U-11.9Hz), 1.92-1.70 (4H, m), 1.65-1.40 (11H, m, including 9H, s, 1.47 m.h.).

Stage 5. tert-butyl 4-Ch4-(aminomethyl)piperidin-1-yl)methyl|tetrahydro-2H-pyran-4-carboxylate

A mixture of tert-butyl 4-(4-cyanopiperidin-1-yl)umethyltetrahydro-2H-pyran-4-carboxylate (5.76 g, 0.0187 mol, stage 4) and Me Raney (3.00 g) in methanol (100 ml) was treated with hydrogen (Zatm.) at room temperature for 12 hours. The mixture was then filtered through a pad of celite and the filtrate was concentrated in vacuo to give 5.72 g (9890) of the title compound as a yellow syrup.

MS (EI) t/2: 313 (MEN).

TN NMR (SOSIv) 5: 3.80 (2H, dt, 9-31Hz, 11.5Hz), 3.49 (2H, dt, 9U-21Hz, 12.2Hz), 2.80 (2H, width , u11.5Hz), 2.58-2.40 (4H, m, including 2H, s, 2.43m.h4.), 2.15 (2H, width.t, 9U-7.3Hz), 1, 98 (2H, width d, u13.7Gu), 1.70-1.40 (16H, m, including 9H, s, 1.47 m.h.), 1.30-1.10 (2H, m) . with

Stage 6. tert-butyl 4-C4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|methyl)tetrag (o ) hydro-2H-pyran-4-carboxylate

A mixture of p-nitrophenyl chloroformate (4.14 g, 0.0205 mol), 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (3.62 g, 0.0205 mol, U.Mea.Spet. 1999, 42 . Then tert-butyl 4-(C4-(aminomethyl)piperidin-1-yl)ylmethyl utetrahydro-2H-pyran-4-carboxylate (5.72 g, 0.0187 mol, stage 5) was added and the resulting mixture was stirred at room temperature within 24 hours The reaction mixture was diluted with a saturated aqueous Manso solution (300 ml), extracted three times with SNCI (300 ml). The combined extracts were dried over NaClSO and concentrated. The residue was chromatographed on a column with MH-silica gel, eluting with a mixture of hexane/ethyl acetate (1:1), and 9.83 g.ШШЩС (10095) of the title compound was obtained in the form of a yellow syrup. co

MS (E5I) t/2: B15(MN) 7.

TN NMR (SOSIv) 85: 8.90 (1H, t, 9-4.9Hz), 8.31-8.21 (1H, m), 7.25-7.10 (ZH, m), 4, 80-4.60 (1H, m), 3.80 (2H, dt, 9-31Hz, 11.5Hz), 3.49 (2H, dt, 9-1.7Hz, 114Gu), 3.28 (2H , t, 9U-64HZ), 2.81 (2H, width,

U-10.4Hz), 2.44 (2H, s), 2.16 (2H, t, 1-10.4Hz), 1.98 (2H, d, 9U-12.4Hz), 1.81- 1.20 (22H, m, including 6H, d, « 40. ch9e7 HC, 1.56 m.h. and 9H, s, 1.47 m.h.). in c Stage 7. ц 4-Ц4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|methyl)tetrag "» hydro-2H-pyran-4-carboxylic acid

To the stirred solution tert-butyl

A-Ch4A-(((33-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|methyl utetrag o hydro-2H-pyran-4-carboxylate (3.67g, 7.1Zmmol, stage 6) in THF (8Oml) at 02C was added concentrated NCI (40ml), and the resulting mixture was stirred for 20h. at room temperature. The mixture was concentrated to remove the solvent, and the obtained residue was poured into a saturated aqueous solution of ManCO3. The mixture was extracted three times

Kz СНоСИ", and the organic layer was dried over Ma»5O). Removal of the solvent resulted in a residue, which was chromatographed on a silica gel column, eluting with a mixture of Meon/cSnH si" (1:10), and 3.01 g of (9290) of the title compound was obtained. The product was recrystallized from THF to give the title compound (0.893) as white crystals.

MS (E5I) t/:: 459 (MEN).

TN nMR (SOSIZ) 85: 8.99 (IN, t, U-5.6Hz), 8.30-8.15 (IN, m), 7.25-7.105 (ZN, m), 4.80- 4.60 (1H, m), 52 3.95-3.70 (4H, m), 3.34 (2H, t, 9U-6.3HZ), 3.14 (2H, w.d., 1- 12.0 Hz), 2.65-2.45 (4H, m, including 2H, s, about 2.59 ml.), 1.92 (AN, t, 9U-13.8Gu), 1.85-1, 40 (11H, m, including B6H, d, U-6.9Hz, 1.57m.h.). t.pl.: 17696. IR days (KVh) M: 3281, 2947, 1720, 1688, 1611, 1595, 1547, 1481, 1447, 1375, 1200, 1159, 1136, 1105, 760 cm". in Data of elemental analysis. :

Calculated for C24NzaMaO; in: C, 62.86; N, 7.47; M, 12.22; Found: C, 62.77; N, 7.42; M, 12,16.

An alternative method of synthesis of 4-C4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|methyl)tetrahydro-2H is described below -pyran-4-carboxylic acid.

Stage 8.tert-butyl//1-(«ethoxymethyl)piperidin-4-yl|Imethyl)carbamate b5 y y y

To a stirred solution of tert-butyl(piperidin-4-ylmethyl)carbamate (7.0g, 33mmol) in ethanol (19ml) at room temperature was added paraformaldehyde (1.2g, 30mmol) and potassium carbonate (5.4g, 3mmol). The mixture was stirred at room temperature for 4 hours. The mixture was filtered and the cake of the filtered sediment was washed with ethanol (500 ml). Volatile components were removed by evaporation, yielding 8.9 g (quantitative yield) of the title compound as a white powder. "IN NMR (SOSIv) 5: 4.60 (1H, width s), 4.07 (2H, s), 3.49 (2H, sq., uU-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 (ZH, t, 9U-7.1 Hz), 1.31-1.12 (2H, m).

Stage 9. |Methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy|(trimethyl)silane

To a stirred solution of diisopropylamine (1.6g, 0.01bmol) in tetrahydrofuran (4ml) 70 n-butyllithium (1.59M in hexane, 9.2ml, 0.014mol) was added dropwise at 02C in a nitrogen atmosphere and stirred for 20 minutes.

Then the reaction mixture was cooled to -4092C, methyltetrahydro-2H-pyran-4-carboxylate (1.9g, 0.01mol) and trimethylsilyl chloride (2.0ml, 0.015mol) in tetrahydrofuran (1ml) were added, and the resulting mixture was gradually heated to room temperature. temperature for 3 hours. Volatile components were removed by evaporation and the residue was filtered through a pad of celite, washing with hexane. The filtrate was dried in vacuo to give 2.9 g 75 (quantitative yield) of the title compound as a clear yellow oil. "H NMR (SOSI»B) 5: 3.64-3.59 (AN, m), 3.52 (ZH, s), 2.24 (2H, t, 9U-5.2Hz), 2.15 (2H, t, 9-5.3 Hz), 0.22 (9H, s).

Stage 10. 4-K4-(tert-butoxycarbonyl)amino|methyl)piperidin-1-yl)methyl-tetrahydro-2H-pyran-4-carboxylate

To a stirred solution of tert-butyl //1-(«ethoxymethyl)piperidin-4-yl|methyl)carbamate (4g, 14mmol, stage 8) and |methoxy(tetrahydro-4H-pyran-4-ylidene)umethoxy)trimethyl)silane (2.9g, 1Zmmol, stage 9) in dichloromethane (30ml) at 09C was added dropwise trimethylsilyltrifluoromethanesulfonate (0.24ml, 1.3mmol), and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (150ml), extracted with dichloromethane (30mlx 2), and the combined organic layers were dried over sodium sulfate. Removal of the solvent afforded a residue, which was chromatographed on a silica gel column, eluting with a mixture of ethyl acetate/hexane (1:1), to give 6.3 g (64965) with 729 g of the title compound as a clear, colorless oil. Gee)

MS (EI) t/2: 371 (MAN). ЗН, с), 3.49-3.41 (2Н, m), 2.99-2.95 (2Н, m), 2.73-2.68 (2Н, m), 2.47 (2Н, c), 2.19-2.11 (2Н, m), 2.06-2.01 (2Н, m), 1.61-1.51 (5Н, m), 1.44 (9Н, с) , chn zo 1.24-1.11 (2H, m).

Stage 11. 4-K4-C-tert-butoxycarbonyl)amino)methyl)piperidin-1-ylmethylyltetrahydro-2H-pyran-4-carboxylic (22) acid with

To a solution of methyl-4-K4-((tert-butoxycarbonyl)amino|methyl)ipiperidin-1-yl)umethyltetrahydro-2H-pyran-4-carboxylate with.

Zv (6.47g, 17.5mmol, stage 10) in MeonH (32ml) at room temperature was added 5N aqueous solution of Mmason (10ml) with (the reaction is exothermic). The resulting solution was stirred at 602C for 7 hours, then cooled to 5-102C in an ice bath. A 5N aqueous solution of NOSI (1Oml) was added to this solution and the resulting solution (pH value approximately 6) was concentrated. 2-Propanol (8 Oml) was added to the residue. The solution was concentrated. 2-propanol (80 ml) was added to the residue and concentrated again. The residue was diluted with EN (8 Oml) and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through a pad of Celite (5.0 g) to remove Mass. The celite layer was washed with EUN (20 ml) and the combined filtrates were concentrated. SNUSM (40 ml) was added to the residue and the resulting mixture was concentrated. In the process, the formation of a white precipitate was observed. "» SNHSM (40ml) was added to the precipitate and the resulting suspension was stirred at room temperature for 2 hours. This mixture was filtered and a solid was obtained, which was washed with SNHSM (10ml), then dried under reduced pressure to give 4.1g (6595) of the title compound compound in the form of a white powder. m), 2.58 (2Н, с), 2.58-2.45 (2Н, m), 1.98-1.76 (4Н, m), 1.55-1.35 (6Н, m) , 1.44 (9H, s). with m.p. 12996, io) Stage 12. 4-Methylbenzenesulfonate 4-(4-(aminomethyl)piperidin-1-yl|methyl|tetrahydro-2H-pyran-4-carboxylic acid 20 acids

4-K4-(tert-butoxycarbonyl)amino|methyl)piperidin-1-yl)umethyl-tetrahydro-2H-pyran-4-carboxylic acid (10 Hg, 28 mmol, stage 11) was placed in a ZOOml 3-neck round-bottom flask under a nitrogen atmosphere and at room temperature, a solution of p-TZON-H 20 (16 g, in 4 mmol) in IRA (isopropyl alcohol) (150 ml) was added. The resulting mixture was stirred at 602 for 7 hours. in an atmosphere of Me" and 29 was slowly added dropwise E35M (8.bml, b2mmol) for 2 hours, introducing seeds for crystallization. During the addition of Е(ІзМ) a white precipitate was formed. The obtained white suspension was stirred at 602С for 1 hour, at 502 for 5 hours and at room temperature for 1 hour. The suspension was filtered, and the resulting solid was washed with IRA (100 Oml), dried at 502 for 5 hours, obtaining 10.5 g (8790) of the title compound in the form of a white powder. bo TN NMR (050) 5: 7.54 (2Н, d, 9-74Hz), 7.22 (2Н, 9-7 ,4Hz), 3.80-3.65 (2H, m), 3.55-3.40 (4H, m), 3.20-2.75 (6H, m), 2.24 (ZH, s ), 1.90-1.80 (6H, m), 1.55-1.35 (4H, m). mp 24796.

Stage 13. 65 4-Ch4-((3-isopropyl-2-oxo-2,3-dihydro-IN-benzimidazol-1-yl)carbonyl|amino)methyl)piperidin-1-yl|methyl)utetrag hydro-2H -pyran-4-carboxylic acid

A mixture of // 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (1.0 g, 5.7 mmol) and 4-nitrophenyl ether of chloroformic acid (1.14 g, 5.7 mmol) in CHClCl (20 ml ) were stirred at room temperature for 5 minutes in an atmosphere of M". EBM (1.7 mL, 12.5 mmol) was slowly added to this mixture and the resulting mixture was added to a mixture of 4-(4-(aminomethyl)piperidin-1-ylmethyl)tetrahydro-2H-pyran-4-carboxylic acid 4-methylbenzenesulfonate (2.4 g, 5.7 mmol, stage 12) from

СНоСИЙ (15 ml) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with a 0.5 N aqueous solution of NOSI and the organic layer was washed with a saturated aqueous solution

Manso" (75 ml), after which the organic layer was concentrated. The residue was diluted with EAs (75 ml) and concentrated with 7/0 to a volume of approximately 15 ml. After inoculation, this mixture was stirred at room temperature for a while

REFERENCE A solid formed during this procedure and the resulting mixture was filtered. The obtained solid was washed with EtOAc (1 Oml), dried at 502C in a vacuum, obtaining 1.9 g (73905) of the title compound as a white solid.

Stage 14. benzene sulfonate 75... A-1I4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl)amino)methyl)piperidin-1-yl|methylutetrag hydro-2H-pyran-4-carboxylic acid

To the suspension of 4-C4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|methyl)tetrahydro-2H-pyran- of 4-carboxylic acid (75mg, stage 13) in CHZSM (5ml) at room temperature, a solution of benzenesulfonic acid monohydrate (288mg) in CHZSM (5ml) was added. The resulting mixture was stirred at room temperature for 2 days and concentrated. The residue was dried to give 909 mg (9090) of the title compound as a solid. "YAN NMR (СО5О0) 5: 9.10 (1H, t, 9U-5.7Hz), 8.11 (1H, dt, U-8.0, 0.8Hz), 7.88-7.76 ( 2H, m), 7.46-7.36 (ZN, m), 7.32 (IN, dt, uU-8.0, 0.8HZ), 7.22 (1H, td, 9U-7.8 , 1.4Hz), 7.13 (1IN, td, 9U-7.8, 1.4Hz), 4.70 (IN, sextet,,) SI d6.9Hz), 3.85-3.55 (5 , m), 3.50-3.38 (4Н, m), 3.23-3.05 (2Н, m), 2.15-1.90 (5Н, m), 1.78-1.58 (5H, m), 1.55 o (EN, d, -6.9Hz), melting point: 22396.

Elemental analysis data:

Calculated for SzoNaloMaOve: C, 58.42; H, 6.54; M, 9.08; Found: C, 58.50; H, 6.51; M, 9.11. -

RKKO (206(7/-0.1): 5.3, 12.6, 21.4, 21.9). (2)

Example 2: 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ucarbonylamino)methyl)piperidin-1-yl|methyl)cyclohexanecarboxylic acid ee) about N she

M M

- On h | More | - 2» M so ko ! !

Stage 1. tert-butyl 4-cyanocyclohexanecarboxylate (io) The title compound was prepared by a method similar to that shown for stage 1 of example 1, so 50 using 1,5-dibromopentane. "IN NMR (SOSI»V) 5: 2.07 (2Н, d, U-13.0Hz), 1.85-1.57 (7Н, m), 1.50 (9Н, s), 1.35 -1.15 (1H,m). "and Stage 2. tert-butyl 1-(aminomethyl)cyclohexanecarboxylate

The title compound was obtained by a method similar to that shown for stage 2 of example 1.

MS (EI) t/2: 214 (MEN)".

T"H NMR (SOSI") 5: 2.69 (2H, s), 2.02 (2H, d, U-13.2Hz), 1.65-1.05 (19H, m, including OH, s , 1.47 m.h.).

GF) Stage 3. tert-butyl 1-(4-oxopiperidin-1-yl)umethyl|cyclohexanecarboxylate from The title compound was obtained by a method similar to that shown for stage C of example 1.

MS (E5I) t/:: 296 (MN). for IN NMR (SOSIv) 5: 2.84 (4H, t, 9U-6.1Hz) 2.57 (2H, s), 2.38 (4H, t, U-6.1Hz), 2.04 ( 2H, d, 9-12.2Gu), 1.65-1.15 (17H, m, including 9H, s, 1.47 m.h.).

Stage 4. tert-butyl 1-((4-cyanopiperidin-1-yl)umethyl|cyclohexanecarboxylate

The title compound was obtained by a method similar to that shown for stage 4 of example 1.

MS (EI) t/2: 307 (MEAN)". because "YAN YMR (SOSIV) 5: 2.53-2.66 (2H, m), 2.53-2.48 (1H, m), 2 ,48-2.30 (4H, m, including 2H, s, 2.41 m.h.),

1.97 (2H, d, 9-12.5Hz), 1.92-1.70 (4H, m), 1.65-1.10 (19H, m, including OH, s, 1.45 m.h .).

Stage 5. tert-butyl 1-14-(aminomethyl)piperidin-1-yl|methyl)cyclohexane-carboxylate

The title compound was obtained by a method similar to that shown for stage 5 of example 1.

MS (E5I) t/2: З11(МН) 7. 18 NMR (SOSIv) 5: 2.81 (2Н, d, 9У-11.37Hz), 2.55 (2Н, d, 9У-5.8ГцС) , 2.39 (2H, s), 2.11 (2H, t, 9U-11.0Gu, 2.03-1.85 (5H, m), 1.65-1.10 (21H, m, including 9H, p, 1.45 m.h.).

Stage 6. tert-butyl 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-ylmethyl)cyclolog 70 hexane- carboxylate

The title compound was obtained by a method similar to that shown for stage 6 of example 1.

MS (E5I) t/2: 513(MN) 7.

TN NMR (SOSIv) 5: 8.89 (1H, t, 9-5.3 Hz), 8.33-8.20 (1H, m), 7.23-7.10 (ZH, m), 4, 80-4.60 (1H, m), 3.27 (2H, t, 9U-6.3Hz), 2.82 (2H, d, 9U-11.5Hz), 2.39 (2H, s), 2.12 (2Н, т, 9U-11.4ГЦ), 1.97 (2Н, d, 9-13.2Гу), 79 41.73-1.10 (28Н, m, including 56Н, d, У- 6.9 Hz, 1.56 bm.h and 9H, s, 1.45 m.h.).

Stage 7. 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-ylmethyl)cyclohexanecarboxylic acid

The title compound was obtained by a method similar to that shown for stage 7 of example 1.

MS (E5I) t/h: 457 (Main).

TN NMR (SOSIv) 5: 8.98 (1H, t, 9-5.8Hz), 8.28-8.18 (1H, m), 7.25-7.10 (ZH, m), 4, 80-4.60 (1H, m), 3.34 (2H, t, 9-6.3Hz), 3.11 (2H, d, 9U-11.9Hz), 2.61 (2H, s), 2.48 (2H, t, 9U-12.2 Hz), 2.05-1.20 (21H, m, including

EbN, d, -6, ahz, 1.57 m.h.). sch t.pl.: 15196,

IR (KVh) M: 3291, 2930, 1732, 1690, 1545, 1481, 1373, 1298, 1202, 1134, 762cm7. and)

Elemental analysis data:

Calculated for SoBNzeMAaOu: C, 65.76; H, 7.95; M, 12.27; Found: C, 65.41; H, 8.18; M, 12,18.

Example 3: part 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-ylmethyl)cyclopentanecarboxylic acid Me, c o s o N ce (ge) of; and

ON

M "-o - - M ;" and A- so

Stage 1. Methyl 1--iodomethyl)cyclopentanecarboxylate. To a stirred solution of NiCiRg)" (1.3 ml, 9U, 10 mmol) in THF (bml) was added H-VIII and (1.58 M in hexane, t 5.4 ml, 8, 58 mmol), maintaining a temperature of -102C in an atmosphere of M", and the mixture was stirred at -102C for 1 hour. Then, a solution of methylcyclopentanecarboxylate (1.00 g, ike, 7.8 mmol) in THF (3ml) was added dropwise at 09 to this mixture, and the mixture was stirred at 02 for 2 hours. Finally, to the mixture at 09 was added 1SNO10 (0.62 in 8 ml, 7.800 mmol), and the resulting mixture was stirred at room temperature for 16 h.

The reaction mixture was quenched with a saturated aqueous solution of MNACI (50 ml), extracted twice with EBO (75 ml), and the combined organic layers were washed with a saturated salt solution (75 ml). The organic layer was dried over NaCl5O, filtered and concentrated. Removal of the solvent provided a residue, which was chromatographed on a silica gel column, eluting with a mixture of EAs/hexane (1:2021:10), and 1.085 g (52905) of the title compound specified in IF) was obtained as a colorless oil. co TN NMR (SOSI") 5: 3.73 (ZN, s), 3.42 (2Н, s), 2.30-2.15 (2Н, m), 1.80-1.55 (6Н, m).

Stage 2. methyl 1-K4-((tert-butoxycarbonyl)amino|methyl)piperidin-1-ylmethyl|cyclopentanecarboxylate 60 A mixture of methyl 1--iodomethyl)cyclopentanecarboxylate (5.52g, 0.020bmol, stage 1), tert-butyl( piperidin-4-ylmethyl)carbamate (8.83 g, 0.0412 mol) and iRCOMEI (10.7 bml, 0.0618 mol) in

M-methylpyrrolidone (/Oml) was stirred at 1202C for 24 hours. After cooling, the reaction mixture was diluted with saturated aqueous Manso solution (200ml), extracted three times with AcSOE (200ml), and the combined organic layers were washed with water (200ml) and saturated salt solution (200ml). The organic layer was dried over NaCl, filtered and concentrated. Removal of the solvent gave a residue, which was chromatographed on a silica gel column, eluting with a mixture of E(AdAc/hexane (1:1), to give 4.91 g (67905) of the title compound as a yellow syrup.

MS (EI) t/2: 355 (MEN). 9-6.3Hz), 2.77 (2H, width, 9-11.5Hz), 2.55 (2H, s), 1.70-1.50 (9H, m), 1.44 ( 9H, c), 1.25-1.08 (2H, m).

Stage 3. methyl 1-(4-(aminomethyl)piperidin-1-ylmethyl)cyclopentane carboxylate

A solution of methyl 1-K4-"tert-butoxycarbonyl)amino|methyl)piperidin-1-ylmethyl)cyclopentanecarboxylate (1.16g, 3.27mmol, stage 2) in CHCl" (25ml) and trifluoroacetic acid (bml) was stirred at room temperature 70 temperature for 1.5 hours. Then the reaction mixture was concentrated and alkalized with a saturated aqueous solution

Manso» with (10 Oml), extracted five times with SNSY with (100 ml). The combined extracts were dried and concentrated to give 0.831 g (10095) of the title compound as a yellow syrup.

MS (E5I) t/2x: 255 (MEN).

TN NMR (SOSIv) 5: 3.66 (ZN, s), 2.78 (2H, d, 9U-I 1.5Hz), 2.62-2.50 (4H, m), 2.15-1 .98 (4H, m), 1.80-1.40 75 (OH, m), 1.30-1.05 (2H, m).

Stage 4. methyl 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-ylmethyl)cyclopentanecarboxylate

The title compound was obtained by a method similar to that shown for stage 6 of example 1.

MS (EVI) t/y: 457 (MANU

TN NMR (SOSIv) 85: 8.94 (1H, t, 9U-5.7Hz), 8.28-8.20 (7.25-7.10 (ZN, m), 4.80-4.60 (1H, m), 3.66 (ZN, boss), 3.27 (2H, t, 9U-64 Hz), 2.84 (2H, d, 9U-11.6 Hz), 2.62 (2H, s ), 2.20-2.00 (4N, m), 1.75-1.50 (15N, m, including

ОН, d, 9-7, О0ГЦ, 1.56 m.h.), 1.40-1.20 (2Н, m). high school

Stage 5. 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-ylmethylicyclo (o) ethanecarboxylic acid

A mixture of methyl 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-ylmethyl)cyclopentanecarboxylate (1.33g, 2, 90 mmol, stage 4), 4N HCl (bml) and acetic acid (bml) were mixed under reflux for 18 hours. After cooling, the reaction mixture was concentrated and He» was alkalized with a saturated aqueous solution of Manso» (100 ml), extracted three times with СНоSiO» (150 ml). The combined extracts were dried over NaCl5O), filtered and concentrated. The residue was chromatographed on a silica gel column eluting with Meon/Snesi (1:10) to give 1.12 g (8595) of the title compound C as a white solid. The crude compound was recrystallized twice from E(OAc) and dried in a vacuum at 502C for 2 days, obtaining 610 mg of the title compound in the form of white crystals.

MS (E5I) t/2: 443 (MEN)". t.pl.: 165960,

IR (KVh) M: 3271, 2934, 1736, 1684, 1607, 1558, 1483, 1454, 1379, 1358, 1298, 1209, 1167, 1097,758 cm". "

TN NMR (SOSIV) 5: 9.00 (1H, t, U-5.5Hz), 8.30-8.18 (IN, m), 7.25-7.10 (ZN, m), 4, 80-4.60 (IN, m), 3.34 SHCHO s (2H, t, 9-11.0Hz), 2.32-2.17 (2H, m), 2.00-1.30 (17H , m, including 56Н, d, 7.0 Hz, 1.57 m.h.). "» Data of elemental analysis: " Calculated for Со4НзаМаОд.0.2Н20: C, 64.61; H, 7.77; M, 12.56. Found: C, 64.34; N, 7.79; M, 12.48.

An alternative pathway for the synthesis of 1-CH4-(F(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-ylmethyl)ucyclopentanecarboxylic acid is described below. Stage 6. methyl 1-K4-((tert-butoxycarbonyl)amino|methyl)piperidin-1-ylmethyl|cyclopentanecarboxylate

The title compound was obtained according to the method described for stage 10 of example 1, using cyclopentylidene(methoxy)methoxy|(tri-methyl)silane (Zupipeziv, 1982, 1, 58-60) instead of "with 20|methoxy(tetrahydro-4H -pyran-4-ylidene)methoxy)(trimethyl)silane.

MS (EI) t/2: 355 (MEN)".

More. "YAN yaMR (SOSIV) 5: 4.58 (IN, width s), 3.66 (ZN, s), 2.97 (2H, t, 9-6.3Hz), 2.77 (2H, width .d, 9-11.5Hz), 2.55 (2H, s), 2.18-1.95 (4H, t), 1.70-1.50 (9H, m), 1.44 (9H , c), 1.25-1.08 (2Н, m).

Stage 7. 1-C4-4C-tert-butoxycarbonyl)amino|methyl)piperidin-1-yl)umethyl|cyclopentanecarboxylic acid

To a solution of methyl 1-(4-((tert-butoxycarbonyl)amino|methyl)piperidin-1-yl)umethyl|cyclopentanecarboxylate

HF) (2.8g, 8.00mmol, stage 6) in MeonH (11ml), at room temperature 2N aqueous solution of Maon (bml) was added (the reaction is exothermic). The resulting solution was stirred at 702C for 4 hours, then cooled to 5-10 o'clock; in a bath with ice water. A 5N aqueous solution of NS was added dropwise to this solution. The resulting solution (pH value about 6) was concentrated and 2-propanol (40 ml) was added to the residue. This solution was concentrated and SNZSM (40 Oml) was added to the residue. The resulting mixture was stirred at room temperature for 2 hours. and filtered through a pad of Celite (5.0 g) to remove Mass. The filtrate was concentrated to give 2.4 g (quantitative yield) of the title compound as a white solid.

TN nMR (300MHz, DMSO-iv) 5: 6.90-6.75 (IN, m), 2.95-2.80 (2H, m), 2.79 (2H, t, 9U-6.4Hz ), 2.58 (2H, os), 65 2.25-2.05 (2H, m), 2.05-1.85 (2H, m), 1.65-1.50 (6H, m) , 1.50-1.25 (ЗН, m), 1.37 (9Н, с), 1.20-0.95 (2Н, m). t.pl. 15096,

Stage 8. 1-14-(aminomethyl)piperidin-1-ylmethyl)cyclopentanecarboxylic acid 4-methylbesol sulfonate

In a 10O0ml 2-necked round-bottom flask, a solution of 1-K4-Ct-butoxycarbonyl)amino|methyl)piperidin-1-ylylmethyl|cyclopentanecarboxylic acid (5g, 14.7mmol, stage 7) and THF (25ml) was added at room temperature -TeOH.NoO (8.4 g, 44 mmol) in THF (25 ml).

The resulting mixture was stirred at 709C for 10 minutes. in an M o atmosphere and cooled to room temperature. EE5zM (bml, 44 mmol) was slowly added dropwise to this solution. During the addition of EizM, a white precipitate was formed, and the resulting mixture was stirred at room temperature for 14 hours. The suspension was filtered and the resulting solid was washed with THF (1 Oml), dried at 502C for 5 hours. and 70 gave 5.9 g (9790) of the title compound as a white solid. "YAN nMR (050) 5: 7.51 (2H, U-8.2Hz), 7.19 (2H, 9U-8.2Hz), 3.38 (2H, d, U-11.0Hz), 3 .09 (2H, d, 9U-2.6Hz), 2.88 (2H, t, 9-12.1Hz), 2.79 (2H, t, U-6.6Hz), 2.21 (ЗН, c), 1.94-1.75 (5Н, m), 1.61-1.27 (OH, m).

Stage 9. 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-ylmethyl)cyclop 72 ethanecarboxylic acid

A mixture of // 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (10g, 56b, mmol) and 4-nitrophenyl ether of chloroformic acid (11.4g, 56.8mmol) in СНоСи" (150 ml) was stirred at room temperature for 5 minutes. EM (17.4 mL, 125 mmol) was slowly added to the mixture, and the resulting mixture was added to a mixture of 1-14-(aminomethyl)piperidin-1-ylmethyl)ucyclopentanecarboxylic acid 4-methylbezole sulfonate (23.4 g, 56.mmol, step 8) and CH 2SiI" (7Bml) at room temperature. After stirring for 10 minutes, EBM (7.9 mL, 56.8 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours.

This mixture was washed with a 1N aqueous solution of NSII (100 ml). The organic layer was concentrated at 502C to about 1/5 volume and the removed solvent was replaced with acetone (5Omlx 3) at 802C until the volume increased by about 5 times. NiO (10O0ml) was added to this mixture at 8092 and the resulting mixture was concentrated at 10020. After cooling to 50 9C, 2095 of an aqueous solution of M,M-dimethylaminoethanol (10Oml) and Ge) was observed to precipitate a solid substance. The resulting mixture was cooled in an ice bath and stirred at this temperature for 18 hours. After that, the mixture was filtered, and the resulting solid was washed with HO (100 ml), dried at 502C in a vacuum, obtaining 17.9 g (7195) of the title compound as a white solid. t t.pl.: 16690. b)

RKKO (20(1-/-0.1): 4.4, 8.8, 13.2, 17.6). with

Example 4:

1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-ylmethyl)cyclosporanecarboxylic acid hydrochloride "I'm with; that 7 s. . because I so M not with /A- de Stage 1. tert-butyl 1-(4-((tert-butoxycarbonyl)amino|methyl)piperidin-1-ylmethylipyclopropanecarboxylate «se 20 Tert-butyl. 1--iodomethyl)cyclopropanecarboxylate ( including a mixture of starting substances 3:2) was obtained according to the method described for stage 1 of example C, using tert-butylcyclopropanecarboxylate "and M. Ogdapotei. Spet., 1983, 252, 267-274| instead of methyl cyclopentanecarboxylate. The resulting compound was used in the next stage without further purification.

The title compound was obtained by a method similar to that shown for stage 2 of example 3.

MS (EBI) tuh: 369 (Maine).

HF) TN nNMR (SOSIv) 5: 4.59 (IN, width c), 2.99 (2H, d, 9-5.9Hz), 2.89 (2H, width, U-11.5Hz), 2.57 (2H, os), with 2.00 (2H, t, 9-11.7Hz), 1.62 (2H, d, 9U-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, U-3.8Hz, 6.6Hz), 0.74 (2H, dd, U-3.5Hz, 6.3Hz). in Stage 2. tert-butyl 1-C4-(aminomethyl)piperidin-1-yl)methyl)ucyclopropane carboxylate

The title compound was obtained by a method similar to that shown for stage C of example 3.

MS (EI) t/2: 269 (MEN)".

TN nMR (SOSIv) 85: 2.96 (2H, wide, 4U-11.5Hz), 2.60-2.50 (4H, m), 2.00 (2H, t, 9-11.4Hz), 1.75-1.35 (14H, m, including 2H, width, 9-9.6Gu, 1.6bm.h. and 9H, s, 1.43m.h.), 1.33-1, 16 (2H, m), 1.13 (2H, dd, 65 4-4.oHz, 6.9Gu), 0.74 (2H, dd, 9U-3.8Hz, 6.6Hz).

Stage C. tert-butyl 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzymi dazol-1-yl)/ucarbonylamino)methyl)piperidin-1-yl)methyl)ucyclopropane- carboxylate

The title compound was obtained by a method similar to that shown for stage 4 of example 3.

MS (E5I) t/2: 471(MN) 7. "YAN yaNMR (SOSIV) 5: 8.91 (IN, width t, U-5.5Hz), 8.32-8.20 (IN, m ), 7.25-7.10 (ZH, m), 4.80-4.60 (1H, m), 3.30 (2H, t, 9U-64Hz), 2.91 (2H, width, 9U -11.6HzC), 2.57 (2H, s), 2.01 (2H, width.t, 9U-9.5Hz), 1.73 (2H, width.d, 9U-12.1Hz), 1 ,67-1.50 (ION, m, including bH, d, 9U-7.0 Hz, 1.56 m.h.), 1.43 (9H, s), 1.34-1.20 (2H, m ), 1.12 (2H, dd, U-4.0Hz, 7.0Hz), 0.73 (2H, dd, 9U-3.9Hz, 6.8Hz).

Stage 4. Hydrochloride 70...1-44-4((3Z-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|methyl)cyclop propane carboxylic acid

The title compound was obtained by a method similar to that shown for stage 7 of example 1.

MS (E5I) t/:: 415 (MEN). t.pl.: 20696.

IR (KVe) in: 2936, 2700, 1732, 1688, 1556, 1485, 1383, 1359, 1182, 1164,758cm7.

TN NMR (DMSO-yv) 5: 8.86 (IN, t, 9U-6.3Hz), 8.07 (1Н, dd, 9У-1.0Hz, 7.8Hz), 7.45 (1Н, d , 9U-7.1Hz), 7.22 (IN, dt, 9U-1.3Hz, 7.6Hz), 7.15 (1H, dt, 9U-1.2Hz, 7.7Hz), 4.95- 4.60 (1Н, m), 3.70-3.10 (6Н, m), 3.10-2.90 (2Н, m), 1.86 (ЗН, m, including 2Н, d, 9У- 11.2Hz, 1.86bm.h.), 1.70-1.53 (2H, m), 1.49 (6H, d, 9U-6.9Hz), 1.35-1.15 (4H, m).

Elemental analysis data:

Calculated for Со2НазоМааОу-НСИ.О,2Н2О: С, 58.13; Н, 6.96; M, 12.33. Found: C, 57.93; H, 6.97; M, 12,18.

Example 5:

3-I4-«((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|Ipropanoic acid hydrochloride

Ku ket du

M , (2) y-o p

A- "NOI co

Stage 1. tert-butyl « 20 4-(((3-isopropyl-2-oxo-2,3-dihydro-IN-benzimidazol-1-yl)/ucarbonylamino)methyl)piperidine-1-carboxylate -o s To stirred solution of 1-isopropyl 1,3-dihydro-2H-benzimidazol-2-one. Med.Spet. 1999, 42, 2870-2880) (3.00, 17.02 mmol) and triethylamine (7.12 ml, 51.0 mmol) in 7 Oml of tetrahydrofuran at room temperature: triphosgene (5.15 g, 17.02 mmol) in 14 ml was added tetrahydrofuran. The reaction mixture was refluxed for 19 hours. Then the mixture was cooled to room temperature and tert-butyl 4-(aminomethyl)piperidine-i-carboxylate was added. 60) (3.28 g, 15.32 mmol) in 1 mL of tetrahydrofuran. The reaction mixture was refluxed for another 24 hours. Then the reaction mixture was cooled, basified with a saturated aqueous solution of Mansozo (50 ml) and extracted three times with ethyl acetate (100 ml). The combined extracts were washed with saturated salt solution, dried over Mo5O, and concentrated. Flash chromatography of the residue (eluent: hexane/ethyl acetate/1 to 1/2) afforded 3.99 g (6295) of the title compound as a colorless oil. with TN NMR (SOSIz) 5: 9.04-8.88 (IN, m), 8.83-8.20 (IN, m), 7.26-7.10 (ZN, m), 4.80 -4.60 (1H, m), 4.28-4.02 "M (2H, m), 3.32 (2H, t, 9-6.1Gu), 2.82-2.60 (2H, m), 1.94-1.10 (5H, m), 1.57 (6H, d, U-7.1 Hz), 1.45 (OH, s).

Stage 2. C-isopropyl-2-oxo-K-(piperidin-4-ylmethyl)-2,3-dihydro-THN-benzimidazole-1-carboxamide

A solution of tert-butyl 4-Ci(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|amino)methyl)piperidine-1-carboxylate (3.992g, 9.58mmol) in 5Oml of 1095 hydrochloric acid in methanol and 1Oml of concentrated hydrochloric (F) acid were mixed at room temperature for 18 hours. Then the mixture was concentrated, basified with an aqueous solution of NaClCO3 and extracted three times with CHCl3 (100 ml). The combined extracts were dried and concentrated. Flash chromatography of the residue (MH-silica gel, eluent: CH SiO/methanol--100/1) resulted in obtaining 2.272 g (7595) of the title compound as a colorless oil.

MS (E5I) t/2: 317(MN) 7. "YAN yaNMR (SOSIV) 5: 8.93 (IN, lat.), 8.32-8.22 (1H, m), 7.24-7 .02 (ZH, m), 4.80-4.61 (1H, m), 3.31 (2H, t, y-6.0Hz), 3.20-3.05 (2H, m), 2 ,79-2.54 (2H, m), 1.84-1.52 (ZH, m), 1.57 (6H, d, U-6.9Gu), 1.36-1.13 (2H, m).

Stage 3. tert-butyl bo 3-ID-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|amino)methyl)piperidine-1-ylpropanoate

A mixture of 3-isopropyl-2-oxo-N-(piperidin-4-ylmethyl)-2,3-dihydro-IN-benzimidazole-1-carboxamide (0.5Og,

1.58mmol, stage 2), tert-butyl acrylate (0.34Oml, 2.37mmol) and IRGMEI (0.275ml, 2.37mmol) in THF (20ml) were refluxed for 18h. After cooling, the reaction mixture was diluted with a saturated aqueous solution of MnSOCl (100 ml) and extracted three times with СНоClі (10 ml). The combined extracts were dried over NaCl, filtered and concentrated. The residue was chromatographed on a column with silica gel, eluting with a mixture of Meon/CHNcSt" (1:20»51:10) and then with MH-silica gel, eluting with a mixture of E((dArs/hexane (1:521:2), and obtained 0.111 g ( 1695) of the compound indicated in the title in the form of a colorless syrup.

MS (E5I) those: 445 (MAN) "7. "YAN yaYMR (SOSIV) 5: 8.94 (IN, width s), 8.30-8.20 (1H, m), 7.25-7 ... .95 (2H, width t, 9U-11.6Hz), 2.68 (2H, t, 9U-7.2Hz), 2.43 (2H, t, 9U-7.7Gu), 2.03 ( 2H, width t, 9U-11.4Hz), 1.98-1.82 (1H, m), 1.79 (2H, d, 9-12.1Hz), 1.56 (6H, d, 9U -7.2Hz), 1.50-1.30 (11N, m, including 9N, s, 1.44 m.h.).

Stage 4. Hydrochloride 3-I4-«((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylIiamino)methyl)piperidin-1-yl|Ipropanoic acid 75

The title compound was obtained by a method similar to that shown for stage 7 of example 1.

MS (EI) t/2: 389 (M'ANU.

IR (KVh) M: 2939, 2637, 1724, 1682, 1542, 1466, 1373, 1217, 1194, 953, 762 cm"!

TN NMR (DMSO-yv) 5: 8.86 (IN, t, 9U-5.9Hz), 8.07 (IN, dd, U-0.8Hz, 7.7Hz), 7.49 (1Н, d , 9U-7.6Hz), 7.22 (1H, dt, 9-1.3Hz, 7.6Hz), 7.15 (IN, dt, 9-1.0Hz, 7.6Hz), 4.75- 4.60 (1H, m), 3.70-3.10 (6H, m), 2.93 (2H, width, 9U-11.2Hz), 2.85-2.70 (2H, m ), 1.95-1.75 (ZH, m, including 2H, d, 9U-11.5Hz, 1.87 m.h.), 1.65-1.40 (8H, m, including BN, d, 9U-7.1 Hz, 1.49 m.h.).

Elemental analysis data:

Calculated for SooNovMAaOu-NSI.O,8 NEW: C, 54.68; H, 7.02; M, 12.75. Found: C, 54.67; H, 6.88; M, 12.70. si 29 Example 6: ge) 1-I(4-hydroxy-4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidine-1- yl|methyl)cyclohexanecarboxylic acid o - 7 Y o nn F u Me ton sc

M s bno on y

M

! "-c Stage 1. Methyl 1-(iodomethyl)cyclohexanecarboxylate:c" The title compound was prepared by a method similar to that shown for stage 1 of example 3, using methylcyclohexanecarboxylate.

TN NMR (SOS) 5: 3.73 (ZN, s), 3.32 (2Н, s), 2.20-2.05 (2Н, m), 1.70-1.20 (ВН, m) . oo Stage 2. Methyl 1-C4-4C tert-Butoxycarboxyl(Amiso|Methyl)-4-Hydroxypiperidin-1-yl)uMethyl|Cyclohexanecarboxylate Co (4-Hydroxypiperidin-4-yl)umethylcarbamate |Spet. RIagt. Viy., 2002, 50(9), 5ro001187-1194) and methyl 1-(iodomethyl)cyclohexanecarboxylate (stage 1 of example 6). so MS (EI) t/2: 385 (MEN)". "I "YAN YMR (SOSIz) 5: 4.86 (1H, width s), 3.66 (ZH, s), 3.11 (2H , d, U-6.3Hz), 2.55-2.45 (6N, m), 2.03 (2N, width d, 9U-10.4Gu), 1.70-1.15 (18N, m, including ОН, с, 1.44 m.h.).

Stage 3. Methyl 1-CH4-(aminomethyl)-4-hydroxypiperidin-1-yl)methyl)cyclohexanecarboxylate 22 The title compound was obtained by a method similar to that shown for stage C of example 3. o MS (EI) t/2: 285 (MEN)".

TN nMR (SOSIi) 5: 3.66 (ZN, s), 2.61 (IN, width s), 2.57-2.45 (BN, m), 2.35-2.11 (ZN, m), 2.04 (2H, and width, 9U-11.5HZ), 1.65-1.45 (6H, m), 1.45-1.20 (4H, m).

Stage 4. Methyl 60 1-C4-hydroxy-4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|m ethyl) cyclohexane carboxylate

The title compound was obtained by a method similar to that shown for stage 4 of example 3.

MS (E5I) t/2: 487 (MNN) 7. v5 "YAN YMR (SOSIV) 5: 9.12 (1H, t, U-5.6Hz), 8.30-8.20 (IN, m) , 7.25-7.10 (ZH, m), 4.80-4.65 (1H, m), 3.66 (ZH, s), 3.54 (2H, d, 9U-5.9Hz) , 2.60-2.45 (6H, m), 2.03 (2H, width, 9U-9.1Hz), 1.75-1.47 (12H, m), 1.47-1, 15 (6H, m).

Stage 5. 1-C4-hydroxy-4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|methyl)cyclohexane- carboxylic acid

The title compound was obtained by a method similar to that shown for stage 5 of example 3.

MS (E5I) t/2: 473 (MAN)". t.pl.: 18496.

IR (KVh) in: 3437, 3273, 2943, 1732, 1688, 1601, 1533, 1479, 1452, 1371, 1134, 978, 762cm7.

TN NMR (DMSO-yv) 5: 8.94 (IN, t, 9-5.6Hz), 8.09 (IN, d, 9-7.7Hz), 7.43 (1Н, d, 9-7 ,7Hz), 7.22 (1H, t, 70 det7.8hC), 7.14 (1H, t, 9UM7.4Hz), 4.75-4.58 (1H, m), 4.59 (1H, s), 2.47 (2H, s), 4.00-3.00 (6H, m), 1.86 (2H, d, 9-11.4Hz), 1.60-1.10 (18H, m, including BN, d, U-6.9 Hz, 1.49 m.h.).

Elemental analysis data:

Calculated for SoBNazieMAaO».0.5H.O: C, 62.35; N, 7.74; M, 11.63; Found: C, 62.52; N, 7.70; M, 11.66.

Example 7: 12 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ucarbonylamino)methyl)piperidin-1-yl|methyl)cyclobutanecarboxylic acid 2 U--Mn o

N

S, o sch ra 7

Stage 1. Methyl 1-((4-(tert-butoxycarbonyl)amino|methyl)piperidin-1-yl)umethyl|cyclobutanecarboxylate -

To a stirred mixture of tert-butyl(piperidin-4-ylmethyl)carbamate (12.8g, bOmmol) and methylyl du1-formylcyclobutanecarboxylate (2.13g, 15mmol, Oamiz, Spapez K.; Zuepzop, Yuae S; Vygop, Ropaid) 3.,

U.Oga.Spet., 1993, 58, 68341) in tetrahydrofuran at room temperature, acetic acid (8.bml, se 15O0mmol) was added. Through ЗОхв. sodium triacetoxyborohydride (12.77, bOmmol) was added to this mixture. Then the mixture was heated to 602 for 2 hours.

After cooling, the reaction mixture was poured into a saturated aqueous Manso solution. The aqueous layer was extracted three times with dichloromethane. The combined organic phases were washed with saturated salt solution, dried over

Ma95O, and concentrated. The residue was chromatographed on a silica gel column, eluting with a mixture of hexane/ethyl acetate (1:1), to give 4.25 g (83905) of the title compound as a white solid. « du MO (E5I) t/2: ZAL (M'-N). With c TN NMR (SOSIv) 5: 3.69 (ZN, c), 2.96 (2Н, t, U-6.2Hz), 2.75 (2Н, d, 9У-114Hz), 2.67 ( 2H, c), 2.37-2.46 (2H, m), 1.78-2.05 (6H, m), 1.45-1.65 (2H, m), 1.43 (OH, c), 1.09-1.21 (2H, m). :z» Stage 2. Methyl 1-C4-(aminomethyl)piperidin-1-ylmethyl)ucyclobutane carboxylate

The title compound was prepared according to the procedure described for stage C of example C from methyl 1-K4-(tert-butoxycarbonyl)amino|methyl)piperidin-1-yl)umethyl|cyclobutanecarboxylate (stage 1 of example 7). for MS (E5I) t/2: 241 (MAN)7.

TN NMR (SOSIV) 5: 3.67 (ZN, s), 2.72-2.78 (2H, m), 2.66 (2H, s), 2.54 (2H, d, 9-6, 2Hz), 2.34-2.47 (2H, o m), 1.79-2.04 (8H, m), 1.54-1.64 (2H, m), 1.05-1.35 (ZN, m).

Ho) Stage 3. Methyl 1-Ch4-4((33-isopropyl-2-oxo-2,3-dihydro-IN-benzimidazol-1-yl)/carbonylamino)methyl)piperidin-1-ylmethyl)ucyclobutanecarboxylate I The title compound was prepared according to the method described for stage b of Example 1 from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and methyl 1-K4-(C-tert-butoxycarbonyl)amino|methyl)piperidine -1-ylmethyl|cyclobutane carboxylate (stage 2 of example 7).

TN NMR (SOSIv) 5: 8.92-8.86 (1Н, m), 8.28-8.24 (1Н, m), 7.20-7.12 (ЗН, m), 4.75- 4.62 (1H, m), 3.70 (ZH, s), 3.27 (2H, t, 9U-64Hz), 2.85-2.72 (2H, m), 2.68 (2H, c), 2.47-2.35 (2H, m), 2.05-1.92 (4H, m), 1.92-1.76 o (2H, m), 1.71-1.61 (2H, m), 1.56 (6H, d, I-7.0 Hz), 1.32-1.17 (2H, m). co MS (E5I) t/:: 443 (MAN).

Stage 4. bo 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-yl|Imethylcyclobutanecarboxylic acid

The title compound was prepared according to the procedure described for step 5 of Example 3 from methyl 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino) methyl)piperidin-1-yl|Imethylcyclobutan-carboxylate (stage C of example 7). because IR (KV) x: 3293, 2979, 2937, 2875, 1732, 1687, 1610, 1548, 1479, 1375, 1298, 1203, 1099, 761, 704 cm".

TN NMR (SOSIv) 5: 9.02-8.95 (1Н, m), 8.26-8.22 (1Н, m), 7.22-7.12 (ЗН, m), 4.76- 4.62 (1H, m), 3.33 (2H, t, 9-6.2Hz), 3.10-3.00 (2H, m), 2.77 (2H, s), 2.58- 248 (2H, m), 2.44-2.24 (2H, m), 1.92-1.79 (2H, s), 1.99-1.80 (5H, m), 1.56 ( E6H, d, 9U-7.0 Hz), 1.50-1.33 (ZN, m).

MS (E5I) t/x: 429 (MEN).

Elemental analysis data:

Calculated for SozNz»MAaOu: C, 64.46; N, 7.53; M, 13.07; Found: C, 64.47; N, 7.43; M, 12,93.

An alternative synthesis route of 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-yl|Imethylicyclob 70 utancarboxylic acid is described below

Stage 5. Ethyl 1-K4-((tert-butoxycarbonyl)amino|methyl)piperidin-1-ylmethyl|cyclobutanecarboxylate

The title compound was prepared according to the procedure described for step 10 of Example 1 using |cyclobutylidene(ethoxy)methoxy| (trimethyl)silane (Set. Sottip., 1971, 136-137) instead of

Imethoxy(tetrahydro-4H-pyran-4-ylidene)methoxy|(trimethyl)silane.

MS (EI) t/2: 355 (MEN)".

TN NMR (SOSIi) 5: 4.55 (1H, wide), 4.17 (2H, sq., 9U-7.1GHz), 2.96 (2H, t, 9-6.3Hz), 2, 76 (2H, d, y-11.4Hz), 2.48-2.33 (2H, m), 2.05-1.80 (6H, m), 1.43 (9H, s), 1, 25 (ZN, sq., 9U-7.1 Hz), 1.40-1.05 (7H, m).

Stage 6. 1-K4-(tert-butoxycarbonyl)amino|methyl)piperidin-1-yl)umethyl|cyclobutanecarboxylic acid

A mixture of ethyl 1-C4-tert-butoxycarbonyl)amino)methyl)piperidin-1-ylmethyl|cyclobutanecarboxylate (4.2g, 11.9mmol, stage 5), 2n Mahon (18ml) and EUN (12ml) was heated at 502C for 4 hours . The resulting solution was cooled in an ice bath and 2N HCl (approximately 19 ml) was added until the pH of the mixture was approximately 5-6.

The whole obtained mixture was extracted with SNSO/RHOH (3:11, ZOmlch 3). The combined organic layers were dried (Ma»5O) and filtered. The filtrate was concentrated to give 33.8 g (98905) of the title compound as a yellow solid. sia

TN nMR (300 MHz, SOSIA) 5: 4.08 (1H, m), 3.20-3.10 (2H, m), 3.08-2.99 (2H, m), 2.91 (2H, s), 2.60-2.38 (o) (AN, m), 2.35-2.16 (2Н, m), 2.05-1.76 (6Н, m), 1.65 (1Н , m), 1.44 (9H, s).

T.pl. 160960

Stage 7. 4-methylbenzenesulfonate of 1-(4-(aminomethyl)piperidin-1-ylmethyl)cyclobutanecarboxylic acid m.

In a B5bOml three-neck round-bottom flask in an atmosphere of Mo at room temperature for 10 min. a mixture of /1-K4-«(tert-butoxycarbonyl)amino|methyl)piperidin-1-yl)umethyl|cyclobutanecarboxylic acid/(ZOg, Me, 92 mmol, stage 6) and THF (150 ml) was stirred. A solution of si p-TgOH-NoO (52.4 g, 27 mmol) in THF (150 ml) was added to the resulting suspension at room temperature. After stirring at this temperature for 10 minutes, the resulting solution was heated to reflux for 3 hours. After cooling to -:SEM room temperature, EizM (28.1 ml, 202 mmol) was added very slowly over the course of one hour, introducing seeds for crystallization. In the process of adding Eya 5M, a white precipitate was formed. The resulting white suspension was stirred at room temperature for 2h, filtered, and the resulting solid was washed with THF (100mlx2), dried at 502 for 5h. and obtained 35g (9695) of the title compound in the form of a white powder. "

IN NMR (050) 5: 7.40 (2H, d, 9-7.2Hz), 7.07 (2H, d, 9-7.2Hz), 3.28-3.00 (4H, m), 2.80-2.57 (4H, m), 2.09. XX s (ZN, s), 2.18-1.97 (2Н, m), 1.85-1.58 (8Н, m), 1.36-1.12 (2Н, m). h T.pl. 21096 -» Stage 8. 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-yl|Imethylicyclobutancarboxylic acid so A mixture of /1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (48bmg, 2.8mmol) and 4-nitrophenyl ether and chloroformic acid (556bmg, 2.8mmol) in SiOCl (100ml) was stirred at room temperature. temperature for 5 minutes. E15M (0.84 mL, b.immol) was slowly added to this mixture and the mixture turned into a solution. This io) solution was added to a mixture of 4-methylbenzenesulfonate "so 20 1-C4-(aminomethyl)piperidin-1-yl|Imethylcyclobutanecarboxylic acid (1.1g, 2.8mmol, stage 7) and CHCl" (bml) at room temperature . After stirring for 10 minutes, Ei zm (0.38 ml, 2.8 mmol) was added, and the resulting mixture was stirred at room temperature for 2 h. This mixture was washed with 0.5 N aqueous solution of HCl (10 ml) and saturated aqueous solution of MansSO»z ( 10ml), then the organic layer was concentrated. To the obtained precipitate at room temperature was added a saturated aqueous solution of MnSO2O3 (15ml) and heptane (15ml), and it was stirred for 6 hours at the same temperature. The formation of a solid precipitate was observed, and the mixture was filtered. the solid was washed with HO and heptane. After drying, the crude compound (1.0g, 8290) was obtained as a white solid. The crude compound (4.0g) was purified by recrystallization from io)toluene (Zbml) to give 2.6g of the title compound (6695) as a white solid.

T.pl. 17396 60 RKKO (206(7/-0.1): 10.8, 16.9, 18.9, 26.5).

Example 8:

IM-(411-(2-oxycarbonyl-2-methylpropyl)piperidin-4-ylylmethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide b5 on?

In him

M

So yo re

Stage 1. tert-butyl (1-(2-benzyloxycarbonyl-2-methylpropyl)piperidin-4-yl)methyl I|carbamate

To a stirred solution of tert-butyl(piperidin-4-ylmethyl)carbamate (38.8 g, 181 mmol) in

Benzyl Z-chloropivalate (14.2g, 124mmol), prepared from Z-chloropivaloyl chloride (25.6g, 16bmmol) and benzyl alcohol (19.6bg, 181mmol), ethyldiisopropylamine (64, 0g, 495mmol) and sodium iodide (27.1g, 181mmol)). The resulting mixture was stirred at 1202 for 14 hours. Volatiles were removed by evaporation and the resulting residue was chromatographed on a silica gel column, eluting with hexane/ethyl acetate (1:1), to give 64 mg (195) of the title compound as a pale yellow oil.

MS (E5I) t/2: 405 (MAN).

IN NMR (SOSI) 5: 7.43-7.23 (BN, m), 5.10 (2H, s), 4.58 (1H, lat.t), 2.95 (2H, m), 2 ... , 1.12 (2Н, m), 1.17 (6Н, с).

Stage 2. Fr

IM-(411-2-benzyloxycarbonyl-2-methylpropyl)piperidin-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-IN-benzimidazol-1-carboxamide

To a stirred mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (U.Mea.Spet. 1999, 42, 2870-2880) chazo (411 mg, 2.33 mmol) and triethylamine (1.00 ml , 7.17 mmol) in dichloromethane (20.0 ml) at room temperature was added 4-nitrophenyl chloroformate (47 Ω, 2.33 mmol). The resulting mixture was stirred for 2 hours. at room /F" temperature. To this mixture was added a suspension of 1-(2-benzyloxycarbonyl-2-methylpropyl)-4-aminomethylpiperidine hydrochloride (obtained by concentrating a mixture of tert-butyl/1-(2-benzyloxycarbonyl-2-methylpropyl)piperidine-4-ylmethylcarbamate (stage 1 of example 1) se (640mg, 1409mmol) and 1095 solution of HCl in Meon (20ml) | and triethylamine (1.00ml, 7.17mmol) in dichloromethane so (5.00ml). The resulting mixture was stirred for 1h at room temperature, and 0.5M aqueous Mason solution was added to the mixture. The mixture was extracted with dichloromethane. The extracts were washed with 0.5M aqueous Mason solution and saturated salt solution, dried over MoSO4, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (on silica gel, eluting with a mixture of dichloromethane/ methanol (10:1)) and obtained "20 508 mg (6390) of the title compound in the form of a pale yellow oil. 7 s MS (E5I) t/2: 507 (MAN). and "YAN NMR (SOSIV) 5: 8.89 (IN, width.t, 9U-5.7Hz), 8.26 (1IN, m), 7.43-7.05 (8Н, m), 5.10 (2Н, s), 4.70 ( 1H, ,» septet, U -7.0Hz), 3.26 (2H, m), 2.75 (2H, m), 2.48 (2H, width s), 2.11 (2H, m), 1.61 (2H, m), 1.56 (6H, d,

U-7.0Hz), 1.52 (1H, m), 1.26 (2H, m), 1.18 (6H, s).)

Stage 3. (se) IM-(411-(2-oxycarbonyl-2-methylpropyl)piperidin-4-ylylmethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-car boxamide o A mixture of IM-(411-2-benzyloxycarbonyl-2-methylpropyl)piperidin-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-IN-benzimidazol-1-carboxamide (stage 2 of example 8) (418 mg, 0.825 mmol) and 2095 RY(OH) 25/C (58.0 mg) in methanol (8 Oml) were stirred in an atmosphere of hydrogen gas at room temperature for 12 hours. Catalyst "I was filtered on a celite pad and the filtrate was evaporated under reduced pressure. Recrystallization of the obtained solid from a mixture of hexane-CH2CI2 made it possible to obtain the title compound in the form of a colorless solid 285 mg (8495).

MS (E5I) t/2: 417(MH) 7. o "IN NMR (DMSO-div) 5: 8.80 (1H, width t, U-5.8Hz), 8.05 (IN, m) , 7.42 (1H, m), 7.20 (1H, m), 7.12 (1H, m), 4.65 (1H, septet, U-7.0Hz), 3.20 (2H, m ), 2.85 (2H, m), 2.44 (2H, width s), 2.18 (2H, m), 1.61 (2H, m), 1.50 ko (IN, m), 1.47 (B6H, d, 9-7.0Hz), 1.20 (2H, m), 1.04 (6H, s).

No signal corresponding to carboxylic acid was observed. 60 Elemental analysis data:

Calculated for Co2Naz»2MAOu.0.1H20: C, 63.17; H, 7.76; M, 13.39; Found: C, 62.78; N, 7.74; M, 13,11.

Example 9:

IM-(411-(2-tetrazole-2-methylpropyl)piperidin-4-ylylmethyl)-3-isopropyl-2-oxo-2,3-dihydro-THN-benzimidazole-1-car boxamide b5

; in-m | ra.

M

Pho: 70 | rya

Stage 1. Ethyl ether of 2-benzyl-a,.a-dimethyl-2H-tetrazole-5-acetic acid To the stirred mixture 72 of ethyl ether of a.a-dimethyltetrazole-5-acetic acid (U.Meid.Spet. 1996, 39 , 2354-2366) (6.87 g, 37.3 mmol) and KSO" (12.3 g, 89.00 mmol) in acetone (200 ml) at room temperature was added benzyl bromide (4.45 ml, 37.4 mmol). The resulting mixture was stirred at 5092 for 18 hours. and concentrated under reduced pressure.

The resulting residue was chromatographed on a silica gel column, eluting with a mixture of hexane/ethyl acetate (10.1), and 6.14 g (6095) of the title compound was obtained as a colorless oil. 20 MS (E5I) t/2: 275 (MAN). "IN NMR (SOSIV) 5: 7.45-7.23 (BN, m), 5.73 (2H, s), 4.11 (2H, sq., 9U-7.2Hz), 1.70 ( 6H, c), 1.13 (ZH, t, 9U-7.2 Hz).

Stage 2. 2-benzyl-a a-dimethyl-2H-tetrazole-5-acetaldehyde

To a stirred solution of 2-benzyl-A,A-dimethyl-2H-tetrazole-5-acetic acid ethyl ether (stage 1 of Example 9) (6.14g, 22.4mmol) in dichloromethane (10Oml) at -782C was added OIVAY (diisobutylaluminum hydride) (1.0M in toluene, 50.00ml, 50.0mmol). The resulting mixture was stirred at -782C for 4 hours. OIVAI (1.0M in toluene, 25.0ml, 25.0mmol) was added to the reaction mixture, and the resulting mixture was stirred at -782C for 8 hours. A 2M aqueous solution of NOSI (100 ml) and a saturated aqueous solution of MH, SI (20 ml) were added to the mixture. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue p 30 was chromatographed on a column with silica gel, eluting with a mixture of hexane/ethyl acetate (10:1), and 3.45 g (6795) of the title compound was obtained as a colorless oil. io

MS (E5I) t/x: 231 (MN). everything

T"H NMR (SOSI") 5: 9.68 (1H, s), 7.45-7.23 (BN, m), 5.74 (2H, s), 1.56 (ВН, s). high school

Stage 3. tert-butyl|(1-(2-(2-benzyltetrazole)-2-methylpropyl)piperidin-4-yl)umethylcarbamate

Zo To a stirred solution of 2-benzyl-A,A-dimethyl-2H-tetrazole-5-acetaldehyde (stage 2 of example 9) (1.28 g, «0 5.5 mmol) and tert-butyl (piperidin-4-ylmethyl)carbamate (2.40 g, 11.2 mmol) in tetrahydrofuran (300 ml) was added

Mavn(oAc) with (5.90g, 27.8mmol) and AsOnH (1.67g, 27.8mmol). The resulting mixture was stirred at 602 during

agreement and concentrated under reduced pressure. To the remaining mixture of oil and solid matter, while stirring, a saturated aqueous solution of ManHsSO» and dichloromethane were added. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue - c was chromatographed on a column with silica gel, eluting with a mixture of hexane/ethyl acetate (1:1), and 830 mg "» (35905) of the title compound was obtained as a colorless oil. MS (EI) t/2: 429 (MEN ). .58 (2H, width s), 2.49 (2H, m), 2.05 (2H, m), 1.68-1.14 (ZH, m), 1.44 (9H, s), 1.38 (6H, s), 1.00 (2H, m). co Stage 4. co IM-(11-(2-(2-benzyltetrazole)-2-methylpropyl)piperidin-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-THN-benzimidazole - 1-carboxamide 50 The title compound was prepared according to the procedure described for stage 2 of example 8 from (Te) 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl 11--2- (2-benzyltetrazole)-2-methylpropyl)piperidin-4-yl)methylcarbamate (stage C of example 9).

Also MS (E5I) t/2: 531 (MAN). "YAN yaYMR (SOSIV) 5: 8.86 (IN, width.t, 9U-5.7Hz), 8.26 (1IN, m), 7.43-7.08 (8Н, m), 5.72 (2H, s), 4.70 (IN, septet, 9-7.0Hz), 3.21 (2H, m), 2.59 (2H, widths), 2.51 (2H, m), 2.07 (2H, m), 1.65-1.92 (ZH, m), 1.56 (BN, d, U-7.0GuC), 1.38 (6H, s), 1.10 ( 2H, m). (F) Stage 5. M-(41-(2-methyl-2-tetrazolpropyl)piperidin-4-ylylmethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H- benzimidazole-1-carboxamide

The title compound was obtained by the method described for step C of example 8 with 0 M-(1-(2-(2-benzyltetrazole)-2-methylpropyl)piperidin-4-yl)methyl)-3-isopropyl-2- oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (stage 4 of example 9).

MS (EZ5I) t/2: 441 (MAN)". "YAN NMR (DMSO-yv) 5: 8.77 (1H, width t, 9U-5.9Hz), 8.04 (IN, m), 7.40 (IN, m), 7.18 (1H, m), 7.11 (1H, m), 4.63 (1H, septet, U-7.0Hz), 3.15 (2H, m) , 2.54 (2H, width s), 2.43 (2H, m), 2.10 (2H, m), 1.60-1.25 (ZH, m), because 1.45 (6H, d, 9-7.0 Hz), 1.32 (6H, s), 1.14 (2H, m).

A signal corresponding to tetrazole was not observed.

Elemental analysis data:

Calculated for Co2NazoMaO4.0.95H20: C, 57.74; N, 7.47; M, 24.48; Found: C, 58.03; N, 7.43; M, 24,10.

Example 10:

M-(41-(2-cyclopentyl-2-tetrazolethyl)piperidin-4-ylylmethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide 706 U. and Z in iMN

Pho:

Mrich

Stage 1. Ethyl ether of a-cyclopentyltetrazole-5-acetic acid

To a stirred solution of ethyl ether of 1-cyano-1-cyclopentane-carboxylic acid IVisogd. Honey. Spent

I ekf., 1999, 9, 369-374) (6.19g, 37.Omol) in 1,4-dioxane (10Oml) at room temperature was added H-VisZpMa3 (12.3g, 37.0mmol). The resulting mixture was refluxed for 15 hours. and concentrated under reduced pressure. 4M HCl in 1,4-dioxane (5 Oml) was added to the obtained residue and concentrated under reduced pressure. The resulting oil was washed twice with hexane to afford the crude title compound,

The appearance of yellow oil, which was used in the next stage without further purification.

Stage 2. Ethyl ether of 2-benzyl-A-cyclopentyl-2H-tetrazole-5-acetic acid i)

The title compound was obtained by the method described for stage 1 of example 9 from ethyl ether of a-cyclopentyltetrazole-5-acetic acid (stage 1 of example 10).

MS (E5I) t/2: 301 (MAN). Cha

TN NMR (SOSI) 5: 7.45-7.23 (BN, m), 5.73 (2H, s), 4.11 (2H, sq., 9U-7.1Hz), 2.55-2 .35 (4H, m), 1.88-1.56 o" (AN, m), 1.12 (ZH, t, 9-7 1Hz).

Stage 3. 2-benzyl-A-cyclopentyl-2H-tetrazole-5-acetaldehyde se

The title compound was obtained according to the method described for stage 2 of example 9 from the ethyl ether of 2-benzyl-A-cyclopentyl-2H-tetrazole-5-acetic acid (stage 2 of example 10).

MS (E5I) t/2: 257 (MEN). (ge) "H NMR (SOSIV) 5: 9.71 (1H, s), 7.50-7.30 (BN, m), 5.74 (2H, s), 2.45-2.18 ( DN, m), 1.85-1.66 (AN, m).

Stage 4. tert-butyl |(1-(2-(2-benzyltetrazole)-2-cyclopentylethyl)piperidin-4-yl)iummethylcarbamate

The title compound was prepared by the method described for step C of example 9 from 2-benzyl-A-cyclopentyl-2H-tetrazole-5-acetaldehyde (step C of example 10). s 70 MS (EZ5I) t/2: 455 (MAN). not "YAN yaYMR (SOSIV) 5: 743-723 (BN, m), 5.72 (2H, s), 4.67 (IN, width.t), 2.88 (2H, m), 2.66 (2H, width s), ;" 2.48 (2Н, m), 2.24 (2Н, m), 1.93 (2Н, m), 1.83 (2Н, m), 1.78-1.48 (4Н, m), 1 .43 (9H, s), 1.37 (2H, m), 1.23 (IN, m), 0.94 (2H, m).

Stage 5. oo IM-(411-(2-(2-benzyltetrazole)-2-cyclopentylethyl)piperidin-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-IN-benzimide azole- 1-carboxamide The title compound was prepared according to the method described for stage 2 of Example 8, from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl 500 H1-(2-(2 -benzyltetrazole)-2-cyclopentylethyl)piperidin-4-yl)methyl)|carbamate (stage 4 of example 10). so MS (E5I) t/2: 557 (MEN). "I TN NMR (SOSIz) 5: 8.85 (IN, width.t, 9U-5.5Hz), 8.26 (1Н, m), 7.43-7.08 (8Н, m), 5, 73 (2H, s), 4.70 (1H, septet, U-7.0HZ), 3.19 (2H, m), 2.70 (2H, width.s), 2.53 (2H, m) , 2.25 (2H, m), 2.15-1.35 (PN, m), 1.56 (6H, d, U-7.0GuC), 1.07 (2H, m). 25 Stage b.

M-(411-2-cyclopentyl-2-tetrazolethyl)piperidin-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-car

F, boxamide

Kkz The compound specified in the title was obtained by the method described for stage C of example 8, with

IM-(411-(2-(2-benzyltetrazole)-2-cyclopentylethyl)piperidin-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-IN-benzimide 60 azole-1-carboxamide (stage 5 of example 10).

MS (E5I) t/2: 467 (MEN)". "NN NMR (DMSO-yv) 5: 8.76 (1H, width t, 9U-5.9Hz), 8.04 (IN, m), 7.40 (IN, m), 7.18 (1H, m), 7.11 (1H, m), 4.64 (1H, septet, U-7.0Hz), 3.14 (2H, m) , 2.63 (2H, width s), 2.54 (2H, m), 2.08 (2H, m), 2.00 (2H, m), 1.76 (2H, m), 1, 68-0.96 (ОН, m), 1.46 (6Н, d, У-7.0ХЦ). because the signal corresponding to tetrazole was not observed.

Elemental analysis data:

Calculated for C 24NzaMaO.1.0 NhO.0.5 SnOSiI: C, 55.83; N, 7.08; M, 21.26; Found: C, 55.71; H, 7.48;

M, 20.86.

Example 11:

M-(41-(2-cyclohexyl-2-tetrazolethyl)piperidin-4-ylylmethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamid ik H m-m 70 M M |! Univ

M

- about "M

Stage 1. Ethyl ether of a-cyclohexyltetrazole-5-acetic acid

The compound indicated in the title was obtained according to the method described for stage 1 of example 10 from the ethyl ether of 1-cyano-1-cyclohexanecarboxylic acid |Viosogd.Med.Spet.! ek, 1999, 9, 369-374).

Stage 2. Ethyl ether of 2-benzyl-A-cyclohexyl-2H-tetrazole-5-acetic acid with

The title compound was obtained by the method described for stage 1 of example 9 from ethyl ether of a-cyclohexyltetrazole-5-acetic acid (stage 1 of example 11). and)

MS (E5I) t/2: З15(МН) 7. "YAN yNMR (SOSIV) 5: 7.45-7.23 (BN, m), 5.75 (2Н, с), 4.11 (2Н, sq., U-7.1Hz), 2.36-2.16 (4H, m), 1.70-1.44 (EN, m), 1.12 (ZH, t, 9-7 1Hz). -

Stage 3. 2-benzyl-A-cyclohexyl-2H-tetrazole-5-acetaldehyde b

The title compound was obtained by the method described for stage 2 of example 9 from 2-benzyl-A-cyclohexyl-2H-tetrazole-5-acetic acid ethyl ether (stage 2 of example 11). with

MS (E5I) t/2: 271 (MEN). with

TN NMR (SOSIv) 5: 9.55 (IN, s), 7.45-7.25 (BN, m), 5.75 (2Н, s), 2.34-2.16 (2Н, m) , 2.14-1.94 (2Н, m), 4.70-1.32 (ВН, m). co

Stage 4. tert-butyl|(1-(2-(2-benzyltetrazole)-2-cyclohexylethyl)piperidin-4-yl)umethyl I|carbamate

The title compound was prepared by the method described for step C of example 9 from 2-benzyl-A-cyclohexyl-2H-tetrazole-5-acetaldehyde (step C of example 11). « 20 MS (EZ5I) t/:: 469 (MAN). - s "YAN NMR (SOSIv) 5: 7.43-7.23 (BN, m), 5.74 (2H, s), 4.55 (1H, width t), 2.87 (2H, m ), 2.62-1.05 (17N, m),

І 2.49 (2Н, width с), 1.43 (ОН, с), 0.93 (2Н, m). etc. Stage 5.

M-((1-(2-(2-benzyltetrazole)-2-cyclohexylethyl)piperidin-4-ylmethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimide azole-1-carboxamide o Indicated the title compound was prepared by the method described for stage 2 of example 8 from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl/1-(2-(2-benzyltetrazole)-2 -cyclohexylethyl)piperidin-4-yl)methylcarbamate (stage 4 of example 11). ka MS (E5I) t/2: 571(MN). "YAN yaYMR (SOSIV) 5: 8.86 (IN, width.t, 9U-5.7Hz), 8.26 (1IN, m), 7.43-7.08 (8Н, m), 5.73 (2H, s), 4.70 (1H, i-o septet, U-7.0Hz), 3.18 (2H, m), 2.51 (2H, wis.s), 2.45-1, 15 (17H, m), 1.56 (6H, d, 9U-7.0Hz), 1.04 (2H, m). "A Stage b.

IM-(411--2-cyclohexyl-2-tetrazolethyl)piperidin-4-ylylmethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide 22 The title compound was obtained by by the method described for stage C of example 8, with

IM-(41-(2-(2-benzyltetrazole)-2-cyclohexylethyl)piperidin-4-ylmethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimide o azole-1-carboxamide (stage 5 of example 11). co MS (EZ5I) t/2: 481 (MEAN)". "IN NMR (DMSO-div) 5: 8.76 (1H, width t, U-5.9Hz), 8.04 (IN, m) , 7.41 (1H, m), 7.18 (IN, m), 7.12 (1H, m), because 4.64 (1H, septet, U-7.0Hz), 3.14 (2H, m), 2.38 (2H, width c), 2.33-2.10 (4H, m), 1.98 (2H, m), 1.65-0.96 (1Ш, m), 1 ,46 (6H, d, U-7.0Hz).

A signal corresponding to tetrazole was not observed.

Example 12:

Hydrochloride bo 1-I4-44((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylIamino)methyl)piperidin-1-yl|cyclohexane boronic acid o i X-Mm i IF о и о : y iv No

Stage 1. tert-butyl 1-(4-oxopiperidin-1-yl)ucyclohexanecarboxylate

The title compound was obtained by a method similar to that shown for stage C of Example 1, using tert-butyl 1-aminocyclohexane carboxylate IKeppeg et al., U.Spet.bos, 1965, 6239, 62431.

MS (E5I) t/2: 282 (MAN). 20 TN NMR (SOSIv) 6: 2.92 (4H, t, 9U-5.9Hz), 2.41 (4H, t, 9U-6.0Hz), 2.01-1.89 (2H, m) , 1.76-1.62 (4H, m), 1.45 (9H, s), 1.53-1.33 (4H, m).

Stage 2. tert-butyl 1-(4-cyanopiperidin-1-yl)ucyclohexanecarboxylate

The title compound was prepared by a method similar to that shown for stage 4 of example 1, using tert-butyl 1-(4-oxopiperidin-1-yl)ucyclohexanecarboxylate. s » MS (E5I) t/2: 293 (MAN). at

TN NMR (SOCI3) 5: 2.94-2.85 (2Н, m), 2.67-2.56 (1Н, m), 2.55-2.42 (2Н, m), 1.96- 1.72 (6H, m), 1.70-1.23 (8H, m), 1.48 (9H, s).

Stage 3. tert-butyl 1-I4-(aminomethyl)piperidin-1-yl|cyclohexane-carboxylate m. 30 The title compound was prepared by a method similar to that shown for stage 5 of example 1, using tert-butyl 1-(4-cyanopiperidine -1-yl)ucyclohexanecarboxylate. Me

IN NMR (SOSIv) 5: 3.07-3.18 (2H, m), 2.55 (2H, d, U-6.4Hz), 2.15-1.94 (4H, m), 1, 47 (9Н, s), 1.76-119 s (1ЗН, m), 1.19-1.03 (2Н, m).

MS (E5I) t/2: 297 (MEN). c 35 Stage 4. tert-butyl c 1-I4-44((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|cyclohexane carboxylate

The title compound was prepared by a method similar to that shown for step b of Example 1, using 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl 40 1-(4-cyanopiperidin-1-yl) ucyclohexanecarboxylate. - with TN NMR (SOSIv) 5: 8.97-8.86 (1Н, m), 8.29-8.24 (1Н, m), 7.21-7.11 (ЗН, m), 4, 78-4.64 (1H, m), 3.29 (2H, "with t, 9-6.2Hz), 3.19-3.09 (2H, m), 2.16-2.05 (2H , m), 2.04-1.93 (2Н, m), 1.83-1.73 (2Н, m), 1.56 (6Н, d, " -7.0Gu), 1.46 (9Н , c), 1.70-1.39 (2Н, m), 1.38-1.16 (7Н, m).

MS (EZ5I) t/:: 499 (MAN).

Stage 5. Co 1-I4-«(«(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino|methyl)piperidin-1-yl)cyclohexane hydrochloride

Ho) of carboxylic acid

To a stirred solution of tert-butyl 1-I4-44(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl Trifluoroacetic acid (5 ml, 65.2 mmol) was added to 50 carboxylate (400 mg, 0.802 mmol) in dichloromethane (bml) at room temperature. After 12 hours volatile components were removed under reduced pressure. Added to the remainder

Another 4n NOI in dioxane (5.0ml) and stirred for 10 minutes. Then the volatiles were removed under reduced pressure. The residue was precipitated in a mixture of diethyl ether/ethanol and 37 mg of the title compound was obtained as a colorless powder. "YAN NMR (DMSO-yv) 5: 8.94-8.82 (1H, m), 7.45 (1H, d, 9-7.9Hz), 7.27-7.10 (2H, m) , 4.73-4.61 (1H, m),

HF) 3.71-3.19 (7Н, m), 2.98-2.81 (2Н, m), 2.38-2.26 (2Н, m), 1.98-1.53 (TON , m), 1.49 (6H, d, U-7.0 Hz), 1.38-1.03 (2H, m). from MS (E5I) t/2: 443 (MAN).

Elemental analysis data: calculated for С24Нз5МАОу-2Н»О: С, 55.97; N, 7.63; M, 10.88; Found: C, 55.61; H, 7.51; M, 10.48.

Example 13: 2-ethyl-2-C4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-yl|m ethyl )butanoic acid b5 o. ; U-kn o - rya ON o

And yes

Stage 1. Methyl 2-K4-"(tert-butoxycarbonyl)amino|methyl)piperidin-1-yl)umethyl/|-2-ethylbutanoate

The title compound was prepared by a method similar to that shown for step 1 of Example 7 using methyl 2-ethyl-2-formylbutanoate (OKapo, K.; Mogitoio, T.; Zekiua, M., Uoigpa! oi Shte SPetisai! zZosieu, Spetisai! Sottipisaiopv, 1985, Z, 119). "YAN yaYMR (SOSIV) 5: 4.62-4.48 (IN, width), 3.65 (ZH, 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) .

Stage 2. Methyl 2-ethyl-2-C4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-yl|Imethyl) |butanoate sc re The title compound was prepared in accordance with the procedure described for stage 2 of example 8, from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and methyl H0) 2-K4-ShKtert-butoxycarbonyl) amino)methyl)piperidin-1-ylylmethyl|-2-ethylbutanoate (stage 1 of example 13). "YAN yaYMR (SOSIV) 5: 8.92-8.86 (IN, m), 8.28-8.23 (IN, m), 7.20-7.12 (ZN, m), 4.77 -4.61 (IN, m), 3.65 (ZN, s), 327 (2H, t, U-6.4Hz), 2.75-2.66 (2H, m), 247 (2H, s ), 2.16-2.05 (2H, m), 1.72-149 (ION, m), 1.38-121 m zo (ZH, m), 0.76 (6H, d, U-7 .5 Hz).

MS (EZ5I) t/:: 459 (MAN). b"

Stage 3. c 2-ethyl-2-C4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-yl|Imethyl) |butanoic acid p

The title compound was obtained by the method described for step 5 of example C from methyl c 2-ethyl-2-C4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl) |iamino)methyl)piperidin-1-yl|Imethyl)|butanoate (stage C of example 13). "YAN yaYMR (SOSIV) 5: 8.03-8.94 (IN, m), 8.27-8.21 (IN, m), 7.20-7.12 (ZN, m), 4.76 -4.63 (IN, m), 3.34 (2H, « t, 9-6.2Hz), 3.16-3.05 (2H, m), 2.60 (2H, s), 2, 55-2.38 (2Н, m), 1.94-1.38 (2Н, m), 1.80-1.38 (15Н, m), 0.88 2 (6Н, d, 9-7, 5HC). - with MS (E5I) t/2: 445 (MAN). "» Data of elemental analysis: " Calculated for С24Наз7МАО,СИ.0.2Н2»0: C, 59.48; H, 7.78; M , 11.56; Found: C, 59.38; H, 7.74; M, 11.29.

Example 14:

Co 1-I4-44((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylamino)methyl)piperidin-1-yl|cyclopentane tricarboxylic acid hydrochloride

Te Um "m M i o, o shk tm ra her 60

Stage 1. tert-butyl 1-(4-oxopiperidin-1-yl cyclopentanecarboxylate)

The compound indicated in the title was obtained by a method similar to that shown for stage C of example 1, using tert-butyl 1-aminocyclopentane carboxylate (MO 91057961.

MS (E5I) t/2: 268 (MAN). for "H NMR (SOSI") 5: 2.93 (4H, t, U-5.9Hz), 2.41 (AN, t, 9U-6.0Hz), 2.39-2.26 (2H, m), 1.85-1.54 (8H, m), 1.46 (9H, s).

Stage 2. tert-butyl 1-(4-cyanopiperidin-1-yl)ucyclopentanecarboxylate

The title compound was prepared by a method similar to that shown for stage 4 of Example 1, using tert-butyl 1-(4-oxopiperidin-1-yl)ucyclopentanecarboxylate.

MS (E5I) t/2: 279 (MAN).

TN NMR (SOCI3) 5: 2.94-2.82 (2H, m), 2.67-2.49 (ZH, m), 2.33-2.21 (2H, m), 1.96- 1.72 (BN, m), 1.70-1.40 (EN, m), 1.48 (9Н, s).

Stage 3. tert-butyl 1-(4-(aminomethyl)piperidin-1-yl|cyclopentane carboxylate

The title compound was prepared by a method similar to that shown for stage 5 of Example 1, 70 using tert-butyl 1-(4-cyanopiperidin-1-yl)ucyclopentanecarboxylate. "YAN iNMR (SOSIV) 5: 3.07-2.95 (2H, m), 2.60-2.52 (2H, m), 2.41-1.19 (4H, m), 1.76 -1.62 (4Н, m), 1.61-1.40 (12Н, m), 1.19-1.03 (2Н, m).

MS (E5I) t/7: 283 (MAN).

Stage 4. tert-butyl 1-I4-44((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonylIamino)methyl)piperidin-1-yl|cyclopentane carboxylate

The title compound was prepared by a method similar to that shown for step b of Example 1, using 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl 1-(4-(aminomethyl)piperidin-1-yl |cyclohexanecarboxylate. 720 TN NMR (SOCI3) 5: 8.96-8.84 (1Н, m), 8.29-8.22 (1Н, m), 7.21-7.11 (ЗН, m), 4.77-4.56 (1H, m), 3.29 (2H, t, 9-6.2Hz), 3.07-2.94 (2H, m), 2.37-2.17 (4H , m), 1.82-1.63 (6H, m), 1.56 (6H, d, 9U-7.1Hz), 1.46 (9H, s), 1.61-1.49 (2H , m), 1.38-1.16 (ZN, m).

MS (EZ5I) t/:: 485 (MAN). with

Stage 5. Hydrochloride 1-4-H((3-isopropyl-2-oxo-2,3-dihydro-IN-benzimidazol-1-yl)carbonyl|Iamino)methyl)piperidin-1-yl|cyclopentane (8) rbonova acid

The title compound was prepared by a method similar to that shown for step 5 of Example 12, using tert-butyl iso 1-14-4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl )carbonyl|amino)methyl)piperidin-1-yl)cyclopentane rboxylate. (22)

TN NMR (DMSO-yv) 6: 8.91-8.82 (IN, m), 8.07 (IN, d, 9U-7.5Hz), 7.45 (1Н, d, 9-7.7Hz ), 7.26-7.09 (2Н, si m), 4.74-4.56 (1Н, m), 3.60-3.00 (6Н, m), 2.26-2.10 ( 4H, m), 1.96-1.57 (9H, m), 1.49 (6H, d, U-7.0Hz).

MS (EZ5I) t/:x: 429 (MAN). high school

Elemental analysis data: co

Calculated for SozNazazMaO, SI: C, 59.41; H, 7.15; M, 12.05; Found: C, 59.14; H, 7.22; M, 11.82.

Example 15:

M-(41-K4-oxycarbonyltetrahydro-2H-pyran-4-yl)umethyl/|-4-fluoropiperidin-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-T1H-benzimidazole -1-carboxamide « и о - с дн M

And" in Son

M E o so -- o o t -M yu K- (Se) "I Stage 1. Benzyl tetrahydropyran-4-yl-carboxylate

A mixture of tetrahydropyran-4-ylcarboxylic acid (91Omg, 6b,99mmol) and OSI" (5.0ml) was stirred for 1 hour at 602C and concentrated in vacuo. Benzyl alcohol (1.52 g, 14.1 mmol) and tetrahydrofuran (5.0 ml) were added to the residue at room temperature. The resulting mixture was stirred for 1 hour. at room temperature and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (silica gel, eluted with a mixture of hexane/ethyl acetate (2:1)) and 1.08 g (70905) of the title compound was obtained as a pale yellow oil.

T"N NMR (SOSIV) 5: 7.45-7.25 (BN, m), 5.13 (2Н, s), 3.95 (2Н, m), 3.42 (2Н, m), 2 .59 (1H, m), 1.94-1.68 (4H, m). 60 Stage 2. Benzyl 4-iodomethyltetrahydropyran-4-yl-carboxylate

The title compound was obtained by the method described for step 17 of example C from benzyl tetrahydropyran-4-ylcarboxylate (step 1 of example 15). "YAN yaYMR (SOSIV) 6: 7.45-7.25 (BN, 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). bo Stage 3. M-benzoyl-4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine

A mixture of M-benzoyl-4-aminomethyl-4-fluoropiperidine |). Honey. Spet., 1999, 42, 1648-1660) (3.54 g, 15.0 mmol) and di-tert-butyl dicarbonate (4.91 g, 22.5 mmol) in methanol (800 ml) were stirred at room temperature for 15 hours. and concentrated in vacuo. The resulting residue was chromatographed on a silica gel column, eluting with a mixture of hexane/ethyl acetate (1:1), and 4.52 g (8995) of the title compound was obtained as a colorless oil.

MS (E5I) t/:x: 337 (MN). "YAN yaNMR (SOSIV) 5: 7.55-7.25 (BN, m), 5.16 (IN, width.t, U-6.3Hz), 4.51 (IN, m), 3.62 (1N, m), 3.55-3.00 (AN, m), 2.10-1.25 (AN, m), 1.43 (9N, s).

Stage 4. 4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine

A mixture of M-benzoyl-4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (stage C of example 15) (4.42g, 13.1mmol), Masson (2.62g, 65.5mmol), H 20 (9.00ml) and ethanol (90, Oml) was boiled under reflux for 15 hours. and concentrated in vacuo. Water and chloroform were added to the obtained residue. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization of the resulting solid from a mixture of hexane-CHCl gave the title compound as a colorless solid 1.77g (58965).

MS (E5I) t/:x: 233 (MN).

T"H NMR (SOSI") 5: 4.93 (1H, m), 3.30 (2H, dd, U-21.5, 6.3Hz), 2.91 (AN, m), 1.88 -1.34 (4H, m), 1.45 (OH, s).

A signal corresponding to the amino group was not observed.

Stage 5. tert-butyl (1-K4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl)umethyl|-4-fluoropiperidin-4-yl)umethyl)carbamate

The title compound was prepared by the method described for step 2 of example 3 from 4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (step 4 of example 15) and benzyl 4-iodomethyltetrahydropyran-4-ylcarboxylate (step 2 of example 15). s 725 MS (EVI) tukh: 465 (Men. o "YAN yaYMR (SOSIV) 5: 7.45-7.25 (BN, m), 5.16 (2H, s), 4.78 (IN, width .t), 3.80 (2Н, m), 3.46 (2Н, m), 3.23 (2Н, dd, 9-21.9, 6.3Hz), 2.64-2.32 (4Н , m), 2.52 (2H, s), 2.08 (2H, m), 1.90-1.35 (6H, m), 1.45 (9H, s).

Stage b. M-(41-K4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl)umethyl|-4-fluoropiperidin-4-yl)umethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole -1-carboxamide (22)

The title compound was obtained according to the method described for stage b of Example 1, from c 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl(11-(4-benzyloxycarbonyltetrahydro-2H-pyran- 4-yl)umethyl I|-4-fluoropiperidin-4-yl)umethyl)carbamate c (stage 5 of example 15). co

MS (E5I) t/2: 567 (MAN).

TN NMR (SOSIz) 5: 9.08 (IN, wide.t, U-6.0Hz), 8.25 (1Н, m), 7.46-7.06 (8Н, m), 5.16 ( 2H, c), 4.71 (1H, septet, 9U-7.0Hz), 3.80 (2H, m), 3.54 (2H, dd, 9U-20.9, 6.0Hz), 3, 46 (2H, m), 2.65-2.36 (4H, m), 2.53 (2H, width s), 2.08 (2H, m), 1.88-1.44 (6H, m), 1.56 (6H, d, 9U-7.0Hz). "

Stage 7. shsh with M-(41-K4-oxycarbonyltetrahydro-2H-pyran-4-yl)umethyl/|-4-fluoropiperidin-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihyde a ro-1H-benzimidazole-1-carboxamide "» The compound specified in the title was obtained according to the method described for stage C of example 1, with

M-(41-K4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl)umethyl|-4-fluoropiperidin-4-yl)umethyl)-3-isopropyl-2-oxo-2,3-dihydro-THN-benzimidazole-1 -carboxamide (stage 6 of example 15). so MS (EI) t/2: 477 (MEN)". TN NMR (СО50О0) 5: 7.93 (IN, m), 7.12 (IN, m), 7.02 (IN, m), 6.93 (IN, m), 4.49 (1H, septet, U-7.0Hz), 3.65-3.36 (6H, m), 3.15-2.82 (AN, m), 2.80 (2H, width s), 1.98-1.70 (6H, m), 1.935 (6H, d, 9U-7.0Hz), 1.34 (2H, m). ko Signals that corresponding to an amide and a carboxylic acid were not observed. "se 20 All publications, including, but not limited to, issued patents, patent applications, and journal articles, cited in this application are incorporated into the application in their entirety by reference." and Although the present invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments described in detail are merely illustrative of the present invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

F) co

Claims (5)

The formula of the invention 60 1. A compound of the formula: b5 a ne () 0-7 yin y i M y y ped z УЖ dm ІЙ Ф or its pharmaceutically acceptable salt or solvate, where: A is an alkylene group that includes from 1 to 4 carbon atoms , and the specified alkylene group is unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group containing from 1 to 4 carbon atoms, and an alkoxyalkyl group comprising from 2 to 6 carbon atoms, and any two non-halogen substituents, together with the carbon atoms to which they are attached, may form a 3-6-ene ring which optionally contains at least one heteroatom selected from M, O and 5; B" represents an isopropyl group or a cyclopentyl group; B? represents a hydrogen atom, a halogen atom or a hydroxy group; 20 BZ represents a carboxy group, a tetrazolyl group, a 5-oxo-1,2,4-oxadiazol-3-yl group or a 5- an oxo-1,2,4-thiadiazol-3-yl group; and t is an integer equal to 1 or 2. 2. The compound or its pharmaceutically acceptable salt or solvate according to claim 1, where B is an isopropyl group; urine 25 V? represents a hydrogen atom, a fluorine atom or a hydroxy group; o VZ is a carboxy group or a tetrazolyl group; A is an alkylene group containing from 1 to 2 carbon atoms, and the indicated alkylene group is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of a halogen atom, an alkyl group containing from 1 up to 4 carbon atoms, a hydroxyalkyl group of 1 to 4 carbon atoms, and an hydroxyalkyl group of 2 to 6 carbon atoms, with any two non-halogen substituents together with the carbon atoms , to which they are attached, can form a 3-6-ene ring, which optionally contains at least one heteroatom selected from M, C and 5; and se t means the integer 2. 3. The compound or its pharmaceutically acceptable salt or solvate according to claim 1, where 3o B" represents an isopropyl group; (he) B? represents a hydrogen atom; BZ represents a carboxy group or a tetrazolyl group; A represents an alkylene group, including from 1 to 2 carbon atoms, and the indicated alkylene group is substituted by two geminal substituents independently selected from the group consisting of a halogen atom, 70 alkyl group, including from 1 to 4 carbon atoms, hydroxyalkyl group, including from 1 to 4 atoms in c carbon, and an alkoxyalkyl group including from 2 to 6 carbon atoms, and the specified geminal substituents "z together with the carbon atoms to which they are attached can form a 3-6-ene ring, which optionally contains at least one heteroatom selected from M, O and 5; and t means the integer 2. 4. The compound or its pharmaceutically acceptable salt or solvate according to claim 1, where B" represents an isopropyl group; where B? represents a hydrogen atom; c BZ represents a carboxy group or a tetrazolyl group; A represents and Pe t-' in the sachet no There are 5 sa CO what a o what - another change 7 60 xx Z or o b5 Ий З З or » ШХВ) in Кк К- or о т means the whole number 2. 5. The compound or its pharmaceutically acceptable salt or solvate according to claim 4, where "B" represents an isopropyl group; B? represents a hydrogen atom, a fluorine atom or a hydroxy group; BZ represents a carboxy group; A represents - and Pe c -, 5 ув : or З о: сч - ю я бтяс- Ши 'о х 23 З or З - И 9 Ф ОО и й кашко ii si or so ШХВ) t- Ka i «k blt- " « yu K Z s or about ;" " t means the integer 2. 6. The compound according to claim 1, which is selected from: 4-C4-(((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|Iamino)methyl)piperidine-1- il|methyl)te o trahydro-2H-pyran-4-carboxylic acid; with 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|amino)methyl)piperidin-1-ylmethyl)cyclohexanecarboxylic acid; kz 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-ylmethyl)cyso 50 clopentanecarboxylic acid; 1-44-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-ylmethyl)cy"I clopropanecarboxylic acid; 1-C4- hydroxy-4-(4(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-yl|methyl)cyclohexanecarboxylic acid; 22 1-44 -((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl|iamino)methyl)piperidin-1-ylmethyl)cyclobutanecarboxylic acid or their pharmaceutically acceptable salts or solvates. 7. Pharmaceutical composition containing a compound or its pharmaceutically acceptable salt or solvate according to any one of claims 1-6, as well as a pharmaceutically acceptable carrier. 60 8. Pharmaceutical composition according to claim 7, which additionally contains another pharmacologically active agent. 9. A method of treating a condition mediated by 5-HT receptor activity in a mammal, including a human, comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compounds or their pharmaceutically acceptable salts or solvates according to any of claims 1-6 . 10. The method according to claim 9, in which the specified condition is gastroesophageal reflux disease, because gastrointestinal diseases, gastric motility disorders, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IB5), constipation, dyspepsia, esophagitis, gastroesophageal diseases, nausea , central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, pain, cardiovascular disorders, heart failure, cardiac arrhythmia, diabetes, and respiratory arrest syndrome. 5. Kk K-4. . . by Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 06, 25.03.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s 7 o'clock (22) s s Zo so - with . and? so ko ko (Se) that ko 60 b5 -BO0-