EA012834B1 - Novel carboxamide compounds having an mch-antagonistic effect, medicaments containing said compounds, and methods for the production thereof - Google Patents

Abstract

The invention relates to carboxamide compounds of general formula (I),in which the groups and radicals A, B, W, X, Y, Z, U, U, R, R, R, R, [R], [R], n, m and k have the meanings indicated in claim 1. The invention also relates to methods for producing said carboxamide compounds and medicaments containing at least one inventive carboxamide. The inventive medicaments are suitable for treating metabolic disorders and/or eating disorders, especially obesity, bulimia, anorexia, hyperphagia, and diabetes due to the MCH receptor-antagonistic activity thereof.

Description

The present invention relates to new carboxamide compounds, to a method for their preparation and preparation of their physiologically compatible salts, as well as their use as MCH antagonists and their use for the manufacture of a medicament suitable for the prophylaxis and / or treatment of conditions and / or diseases, caused by SIT or consisting in a different causal relationship with SIT. The present invention further relates to the use of at least one compound according to the invention for influencing the nutritional behavior of a mammal, as well as for reducing body weight and / or for preventing an increase in body weight of a mammal. In addition, the present invention relates to compositions and drugs containing at least one compound proposed in it, as well as to a method for producing such compositions and drugs.

BACKGROUND OF THE INVENTION

Nutrition, i.e. food intake and its digestion, absorption and assimilation in the body, is vital for all living organisms throughout their lives. Therefore, any deviations from the norm during food intake and its digestion, absorption and assimilation in the body usually lead to the appearance of various kinds of disorders, as well as various diseases. Changes in people's lifestyles and their eating habits, mainly in industrialized countries, have contributed in recent decades to an increase in the number of obese people. Obesity in people suffering from it directly leads to a limitation of their mobility and a decrease in the quality of life. These problems are further exacerbated by the fact that obesity is often the cause of other diseases, such as diabetes, dyslipidemia, arterial hypertension, arteriosclerosis, and coronary heart disease. In addition, due to excess body weight alone, the load on the musculoskeletal system increases, which can lead to the development of chronic pathological processes and diseases, such as arthritis or osteoarthritis. Thus, obesity is a serious public health problem.

The term obesity refers to an excess of adipose tissue in the body. In this regard, obesity should in principle be considered as any increased degree of fat deposition in the body associated with a risk to a person’s health. It is ultimately not possible to draw a clear line between normal and obese individuals, but it is reasonable to assume that the obesity-related risk to a person’s health increases in proportion to an increase in the amount of excess fat stored in his body. For the sake of simplicity, in the context of the present invention, obesity is mainly considered to be individuals whose body mass index (or indicator), which is calculated as the ratio of body weight measured in kilograms to squared height (in meters), exceeds 25, above all, value 30.

With the exception of physical activity and the transition to a balanced, rational diet, there is currently no other way to achieve a 100% result of the possibility of effective weight loss by medical means. Since, however, obesity is an increased risk factor for serious and even life-threatening diseases, the importance attached to the search for pharmaceutical active substances for the prevention and / or treatment of obesity increases significantly. The recently proposed approach to solving this problem is based on the therapeutic use of MCH antagonists (see, in particular, XVO 01/21577, νθ 01/82925).

Melanin-concentrating hormone (abbreviated as MCH from the English te1apsh-sseps1g1td yogtoe) is a cyclic neuropeptide consisting of 19 amino acids. In mammals, this hormone is synthesized mainly in the hypothalamus, from where it reaches other areas of the brain through projections of hypothalamic neurons. In the human body, the biological activity of this hormone is mediated by two different glycoprotein-related receptors (ORSKs) from the family of rhodsin-related ORSK receptors, i.e. MCH receptors 1 and 2 (MCH-1K, MCH-2K).

The results of studies of the function of SIT in animal models make it possible to obtain quite reliable data on the role that this peptide plays in the regulation of energy balance, i.e. in a change in metabolic activity in animals and their feed intake [1, 2]. So, for example, rats after intraventricular administration of MCH to them began to consume a greater amount of food compared to control animals. Along with this, transgenic rats, the body of which produces SIT in large quantities in comparison with the amount of SIT produced in the body of control animals, gained much faster weight gain when compared with animals with an unchanged experimental level of SIT. In addition, it was found that a positive correlation exists between the phases of increased need for food and the number of MCH mRNA in the rat hypothalamus. However, the data of experiments on knockout mice on the MCH hormone have special informativeness regarding the function of SIT. As a result of the loss of this neuropeptide, animals, consuming significantly less food compared to control animals, begin to lose weight, and their fat mass decreases.

The anorectic effect of MCH in rodents is mediated by the C ,,, MCH-1K receptor associated with C [36]. Unlike primates, albino ferrets and dogs, rodents have so far failed

- 1 012834 detect the second receptor. After the loss of the MCH-1K receptor in knockout mice of this trait, fat mass decreases compared to control animals, the degree of energy conversion in their body increases, and they do not gain weight when consumed in a diet rich in fat. The influence of the MCH / MCH-1K system on the regulation of energy balance is also confirmed by experiments with an antagonist of the above receptor (8ΝΛΡ-7941) [3]. In the course of lengthy experiments, animals that were injected with this antagonist significantly lost weight.

Along with its anorectic action, 8ΝΆΡ-7941, which is an antagonist of MCH-1 receptor, also exhibits anxiolytic and antidepressant effects in experiments on rats to study their behavioral reactions [3]. The results of these experiments, thus, convincingly indicate that the MCH / MCH-1K system is involved not only in the regulation of energy balance, but also in emotional regulation.

Literature

1. He Ώ. et al., Gole Gog Shelap1n-ssepsepigaypog yogtope ίη 1st segPga! Geghiayop OG Geebshts Lejuyug, No. Shge, 380 (6571), 1996, ss. 243-247.

2. 670-674.

3. To the homosexual of V. et al., Apydergeszap !, upyuyuys apy apogeis eGGesR oG and te1atp-sseps! Gaypg yogtope-1 geser! May., 8 (8), 2002, ss. 825-830.

4. Syep Υ. et al., Taggéed eGruyop oG 1ye te1apsh-sosep1gaypg yogtope geser! og-1 gesiyz sh yuregrya1a apy ge ^ Yapse 1o d1eRdised oezyu, Epdospo1ou, 143 (143). 2469-2477.

5. Magz Ώ.Ι. et al., Mélatp-consepgaypog yogtope 1 geser1og-eG1s1ep1 pishe age 1eap, yuregasyue, apy yuregryady apy yaue ayegey te1aBoyzt, Prgos. No. 11. Assad. 8st I. 8.A., 99 (5), 2002, ss. 3240-3245.

6. Takekama 8. et al., T-226296: a pooe1, aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa I. Ryagtaso. 1, 438 (3), 2002, ss. 129-135.

The patent literature describes certain amine compounds that have been proposed for use as MCH antagonists. So, in particular, in the application AO 01/21577 (in the name Takeya) describes compounds of the formula p ¹

Ar ¹ - Χ-Αγ-Υ-Ν ^, in ² in which Ar ¹ is a cyclic group, X is a spacer, Υ is a bond or spacer, Ar is an aromatic ring that can be condensed with a non-aromatic ring, K? and K ² independently of one another denote H or a hydrocarbon group, while K? and K ² together with the neighboring Ν-atom can form a Ν-containing heterocycle, and K ² together with Ar can also form a spirocyclic ring and K ² together with the neighboring Ν-atom and Υ can also form a Ν-containing heterocycle, as MCH antagonists suitable, inter alia, for the treatment of obesity.

In addition, the application AO 01/82925 (in the name Takeia) also describes compounds of the formula

Ar ¹ —Χ-Αγ-Υ-Ν ^χ , in which Ar ¹ is a cyclic group, X and Υ are spacer groups, Ar is an optionally substituted fused polycyclic aromatic ring system, K ¹ and K ^{2 are} independently H or hydrocarbon a group, while K ¹ and K ² together with their adjacent Ν-atom can form a Ν-containing heterocyclic ring, and K ² together with its neighboring Ν-atom and Υ can form a Ν-containing heterocycle, as antagonists of MCH, suitable inter alia for the treatment of Irene.

Other amine compounds possessing MSH antagonistic activity are proposed in AO application 02/057233 (in the name of 8pp. § Co.). The compounds described in this application correspond to the general formula

in which Ag ¹ , Ag ² , Ag ³ are, inter alia, aryl or heteroaryl, X is O, 8 or ΝCH Υ is a single bond or C ₁ -C ₄ alkylene, and K ¹ and K ² are as defined in this application.

Similarly, the presence of an antagonistic effect on MSN possess and is described

- 2 012834 in piperidine derivatives of the formula AO 02/051809 (in the name of 8egg§ Comp.)

in which A represents an aminocarbonyl group or a carbonylamino group with the meanings described in more detail in the indicated application, X represents —CNA ⁸ , —CO—, —C (= LOC ⁹ ) - or —CC ⁸ =, Υ represents CH, C ( OH), C (C 1 -C 4 alkoxy) or in the case of a double bond represents C, K ² represents a substituted aryl or heteroaryl group, K ¹⁰ represents H, C 1 -C ₆ alkyl or aryl, and the remaining residues are as indicated in This application values.

In the application AO 02/10146 (in the name 8pn1111 <1te VeesIat) carboxylic acid amides are proposed as antagonists of the human 11CBu receptor. These compounds are representatives of the family of compounds of general structural formula

BUT

in which A is H, alkyl, alkoxy, alkenyl, acyl, halogen, OH, CH or CP ₃ , K ³ is H, methyl or ethyl, K ⁴ is an optionally substituted aromatic carbocyclic or heterocyclic ring, Ζ is O, 8, ON , CH ₂ or a single bond, K ⁵ denotes an optionally substituted aromatic saturated or unsaturated carbocyclic or heterocyclic ring and O denotes a group -Χ-Υ-ΝΒ / ζΒ ² ), in which, according to various special cases, X denotes O, 8 or Ν, Υ denotes alkylene or cycloalkylene uppu, which can also be substituted, and K ¹ and K ² are alkyl or phenylalkyl, with K ¹ and K ² , K ¹ and Υ or K ¹ and X can also, as indicated, be interconnected to form a ring system .

Other compounds with MSH antagonistic properties are proposed in AO 03/035055, AO 03/033480, AO 02/06245, AO 02/04433, AO 01/87834, AO 01/21169 and GR 2001-226269.

Application AO 01/23365 (in the name of Megsk) describes quinazolinone compounds of the general formula

in which Ζ denotes a bond or phenylene, and in the application AO 01/23364 (in the name Megsk) describes quinazolinone compounds of the same general formula in which Ζ denotes cyclohexylene. In both cases, Υ is a bond or C2-C4 alkenyl, and K ⁴ is an aryl, cycloalkyl, phenylalkyl or heterocyclic system. These compounds are OP1X inhibitors, primarily inhibitors of this receptor, the ligand of which is von Willebrand factor (uAR).

In addition, aromatic compounds are known from the literature that may contain an amide bridge and an amino group and which have been proposed for use in other indications. So, in particular, in the application AO 99/01127 (in the name of 8pn1111 <1te WeightIat Comp.) Describes compounds of the general formula Ag-A-E, in which Ag represents an optionally substituted aromatic one- or bicyclic group, A denotes an amide or amine bridge and E, inter alia, denotes a phenyl group which is substituted at the para position through the spacer group B with a substituted aminoalkylene group.

These compounds as CCK5 receptor ligands are proposed for the treatment of, in particular, asthma, atopic diseases and rheumatoid arthritis.

In the application AO 01/72712 (in the name of Sog TIegareijs 1ps.) Isoquinoline compounds of the following formula are described:

in which A is an optionally substituted amino or amidino group, Ζ is a bond or an alkyl, cycloalkyl, alkenyl, alkynyl or aryl spacer group, t and η are 0-3, Ό is a bond or said bridge, X is LK ¹² or SNK ¹² , p stands for

- 3 012834

0-3, E along with the indicated ether, amine, amide and carboxyl groups also denotes a bond, I denotes a bond, cycloalkylene, phenylene, naphthylene or heteroaryl group, O represents amide, imino or amidino groups with the meanings specified in more detail in this application , and the remaining residues have the meanings indicated in this application. These compounds are proposed for use as inhibitors of isolated factor Xa, as well as blood coagulation inhibitors, and thus as antithrombotic and thrombolytic active substances.

In the application EE 19718181 A1 (in the name of Voyegtdeg 1pdeShe1t), disubstituted bicyclic heterocycles of the formula K _a -A-He! -Ag-E are described, in which K _a represents one of the amino groups with the meanings specified in more detail in this application or under certain conditions may also be a Κ4-8Ο2-ΝΒ5 or K ₄ -8O ₂ group with the meanings indicated for K ₄ and K ₅ in this application, A represents a phenylene-C ₁ -C ₃ alkylene group, n-C ₂ -C ₆ alkylene group or a C ₅ -C ₇ tsikloalkilenS ₁ -C ₃ alkylene group which may be substituted indicated in this application way, no! represents an optionally substituted benzimidazole, indole, tetrahydroquinolinone or quinazolinone group, Ar represents an optionally substituted phenylene, naphthylene, thienylene, thiazolylene, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinylene group,) K _b denotes H, OH, C ₁ -C ₃ alkyl or a leaving ίη νινο residue. These compounds are proposed for use as inhibiting thrombin and extending thrombin time active substances.

Object of the invention

The present invention was based on the task of proposing new carboxamide compounds, especially carboxamide compounds, which have activity as MCH antagonists. An object of the present invention was also to provide novel carboxamide compounds which would influence the nutritional behavior of mammals and, in particular, would provide a reduction in the body weight of mammals and / or would prevent the increase in body weight of mammals. An object of the present invention was further to propose new drugs suitable for the prophylaxis and / or treatment of conditions and / or diseases caused by MCH or in any other causal relationship with MCH. In this regard, the object of the present invention was, first and foremost, to provide drugs for the treatment of metabolic disorders, such as obesity and / or diabetes, as well as diseases and / or disorders caused by obesity and diabetes. Another objective of the present invention was to offer preferred uses for the compounds provided therein. Likewise, the object of the present invention was to provide a process for the preparation of the carboxamide compounds according to the invention. Other, obvious to a person skilled in the art tasks of the present invention directly follow from the previous and subsequent description of the present invention and its options for implementation.

Object of invention

The first object of the present invention are carboxamide compounds of General formula I

in which both ¹ and ² denote CH, where one of both ¹ and ² can denote Ν; and V ¹ , V ² , V ³ are CH, where one or two of V ¹ , V ² and V ³ may be Ν; and K ¹ , K ^{2 are} independently H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkyl, w-hydroxy-C ₂ -C ₃ alkyl, w- (C ₁ -C ₃ alkoxy) -C ₂ -C ₃ alkyl, C ₁ -C ₄ alkoxycarbonyl-C ₁ -C ₃ alkyl, amino-C ₂ -C ₄ alkyl, C ₁ -C ₃ alkylamino C ₂ -C ₄ alkyl or di (C ₁ -C ₃ alkyl) amino-C ₂ -C ₄ alkyl, phenyl or phenyl (C ₁ -C ₃ alkyl), with one or more C atoms in these groups and residues can be mono- or multisubstituted by an E atom and / or one or two Satoms independently of each other can be monosubstituted by a C1 atom or a Br atom, and the phenyl group can be mono- or multisubstituted with a K ¹² residue and / or may be monosubstituted with a nitro group, or

K ¹ and K ² form a C ₂ -C ₈ alkylene bridge in such a way that Κ ¹ Κ ² Ν - denotes a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1H-pyrrole, 1,2, 3,6-tetrahydropyridine, 2,3,4,7-1H-tetrahydro-1H-azepinyl, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free imine function may be substituted by K ¹³ , morpholine and thiomorpholine, while in the indicated alkylene bridge one or more hydrogen atoms can be replaced by a K ¹⁴ residue, and this alkylene bridge can be replaced by one or two identical mi or various carbo- or heterocyclic Oy groups in such a way that the alkylene bridge and the Cy group are connected by a single or double bond through a joint C-atom to form a spiro cycle

- 4 012834 ring system, through two joint adjacent C - and / or Ν-atoms with the formation of a condensed bicyclic ring system or through three or more C - and / or атомов-atoms with the formation of a system of bridge-connected rings,

K ³ is H or C1-C ₆ alkyl,

X denotes an alkylene bridge selected from methylene, 1,2-ethylene, 1,3-propylene and 1,4 butylene, with one or two carbon atoms independently of one another being substituted by hydroxyl, n-hydroxy-C ₁ -C ₃ alkyl, u- (C ₁ -C ₃ alkoxy) -C ₁ -C ₃ alkyl and / or C ₁ -C ₃ alkoxy group, one or two carbon atoms in each case may be substituted with one or two identical or different C ₁ -C ₄ alkyl groups in each case one or more carbon atoms may be mono- or polysubstituted by F atoms, in each case one or two atoms uglero and independently of one another may be monosubstituted by C1 atom or a Br atom, and / or the alkylene bridge may be connected with R ¹ including coupled with R ¹ and X Ν-atom to form a heterocyclic group,

Ζ is selected from the group consisting of -CH2-, -CH2-CH2-, -CH2-SCHCH3) -, -CH2-C (SCH2-, -CH (CH ₃ ) -CH2-, -C (CH3) 2-CH2- ,

Υ is selected from divalent cyclic groups, which include phenylene and pyridinyl, where the above cyclic groups can be mono- or multisubstituted at one or more C-atoms with a K ²⁰ residue, and in the case of a phenyl ring, can also be additionally monosubstituted with a nitro group,

And selected from divalent cyclic groups, which include 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinyl, 1,2,3,6-tetrahydropyridin-1,4-ylene, 2,5-pyridinyl and 1,4-piperazinyl, where the above cyclic groups can be mono- or multisubstituted at one or more C-atoms with a K ²⁰ residue, and in the case of a phenyl ring, can also be additionally monosubstituted with a nitro group, and / or can be single or multisubstituted at one or more Ν-atoms with a K ²¹ residue, or

A and K ³ can be interconnected so that the fragment

in formula I is a fragment of subformula II I ³

and

O denotes a group selected from groups of subformulas Sha-Sh§

-Rm ⁶ K ⁷ - Sha -sk ⁶ = ck ⁷ - SH, -Ν = € Κ ⁸ - Cc -Ν = Ν- PM -CO-ΝΚ ⁹ - Sha -οκ ⁸ = ν- W £, -so- W £, and

E ¹ , b ² , b ³ independently of one another have one of the following values: H, G, C1, Br, CH ₃ , CIS ₂ , SG ₃ , C ₂ H ₅ , C ₃ H ₇ , CH (CH ₃ ) ₂ , OSN ₃ , OSNG ₂ , OSG ₃ , OS ₂ N ₅ , OS ₃ N ₇ and OSN (CH ₃ ) ₂ ,

B is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkyl, C ₃ -C ₇ cyclo alkenyl-C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkenyl or C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkynyl, wherein one or more C-atoms can be mono- or multisubstituted with halogen and / or hydroxy monosubstituted - either a cyano group and / or cyclic groups can be mono- or multisubstituted with a K ²⁰ residue, denotes a single bond, an imino group or ^ (Cr ^ alkyl ^ mino group, k is 1, or

B is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrroinyl, pyrrolyl, piperidinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinylpyridinyl triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl,

- 5 012834 isoindolyl, quinolinyl, benzoimidazolyl, isoquinolinyl, furanyl or thienyl, while bonding to the group or, under certain conditions, directly to group A is via the C atom of the carbocyclic moiety or optionally fused phenyl or pyridine ring or via the Ν or C atom heterocyclic fragment, or

In conjunction with the double bond attached, the group is selected from the group consisting of cyclopentylidenemethyl, cyclohexylidenemethyl and cyclohexanone-4-ylidenemethyl, wherein the above cyclic groups can be mono- or multisubstituted at one or more C-atoms with a K ²⁰ residue, and in the case of a phenyl group in addition, they can also be monosubstituted with a nitro group, and / or can be single- or multisubstituted at one or more Ν-atoms with the remainder K ²¹ , denotes a single bond, -CH ₂ - or -CH = and k denotes 1,

Cy denotes one of the following carbo - or heterocyclic groups:

a saturated 3-7-membered carbocyclic group, an unsaturated 5-7-membered carbocyclic group, a phenyl group, a saturated 4-7-membered or unsaturated 5-7-membered heterocyclic group with a ,-, O- or 8-atom as a heteroatom, a saturated or unsaturated 57-membered heterocyclic group with two or more Ν-atoms or one or two Ν-atoms and one O- or 8-atom as heteroatoms or an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected and Ν, O and / or 8, wherein the aforementioned cyclic groups may be mono- or polysubstituted by one or more C-atoms of residues to ^20, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and / or mono- or polysubstituted by one or more atoms with the remainder K ²¹ ,

K ⁶ , K ⁷ , K ⁸ , K ^{9 are} independently H, methyl, trifluoromethyl, ethyl, isopropyl or npropyl, and K ⁶ and K ⁷ may also be P,

K ¹² has one of the values indicated for K ²⁰ ,

K ¹³ is H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkyl, C ₄ -C ₇ cycloalkenyl, C ₄ -C ₇ cycloalkenyl-C ₁ - C ₃ alkyl-, w-hydroxy-C ₂ -C ₃ alkyl, w- (C ₁ -C ₃ alkoxy) -C ₂ -C ₃ alkyl, amino-C ₁ C ₆ alkyl, C ₁ -C ₃ alkylamino-C ₁ -C ₆ alkyl or di (C ₁ -C ₃ alkyl) amino-C ₁ -C ₆ alkyl, phenyl, phenyl (C ₁ -C ₃ alkyl) -, pyridinyl, dioxolan-2-yl, C ₁ -C ₃ alkylcarbonyl, hydroxycarbonyl-C ₁ -C ₃ alkyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₃ alkylcarbonylamino-C ₂ -C ₃ alkyl, C ₁ -C ₃ alkylsulfonyl or C ₁ -C ₃ alkylsulfonylamino-C ₂ C3 alkyl,

K ¹⁴ is halogen, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C3 alkyl, C1-4 alkoxycarbonylamino, C1-C4 alkoxycarbonylamino-C1-C3 alkyl, amino, (C1-C4-alkyl)

K ²⁰ means halogen, hydroxy group, cyano group, C1-C4 alkyl, C3-C7 cycloalkyl, hydroxy-C1C3 alkyl, K ²² -C1-C ₃ alkyl or has one of the meanings indicated for K ²² , a carboxy group, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₃ alkylsulfonyl, phenylcarbonyl or phenyl-C ₁ C3 alkylcarbonyl,

K ²² is pyridinyl, phenyl, phenyl-C ₁ -C ₃ alkoxy group, C ₁ -C ₃ alkoxy group, C ₁ -C ₃ alkylthio group, H-CO-, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, aminocarbonyl C ₁ -C ₃ alkylaminocarbonyl, di (C1 -C3 alkyl) aminocarbonyl, C1-S3alkilsulfonil, C1-S3alkilsulfinil, C1-S3alkilsulfonilaminogruppu, amino, C1-S3alkilaminogruppu, di (C1 -C3 alkyl) amino, phenyl-C1C ₃ alkylamino, № ( C / -CAalkyl) phenyl-C # C ₃ alkylamino group. acetylamino group, propionylamino group, phenylcarbonyl, phenylcarbonylamino group, phenylcarbonylmethylamino group, (4-morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl-1-4 , methylenedioxy group or aminocarbonylamino group,

K ²⁶ , K ²⁷ independently of one another have one of the meanings indicated for K ²⁰ or, in the case of a phenyl group, can also denote a nitro group, while the repeatedly present residues K ²⁶ , K ²⁷ can have identical or different values, and m, η independently from each other are 0, 1 or 2, while in each of the groups and each of the residues Ζ, K, K, K, K, K, K, K one or more C-atoms can be mono- or multisubstituted by fluorine and / or one or two C-atoms independently of one another can be monosubstituted with chlorine or bromine and / or one or more phenyl rings, independently from each other, additionally contain one, two or three substituents selected from the group consisting of P, C1, Br, I, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, difluoromethyl, trifluoromethyl, hydroxy group, amino group, C ₁ -C ₃ alkylamino group, di (C ₁ -C ₃ alkyl) amino group, acetylamino group, aminocarbonyl, C ^ difluoromethoxy group, trifluoromethoxy group, amino-C ₁ -C ₃ alkyl, C ₁ -C ₃ alkylamino-C ₁ -C ₃ alkyl and di (C1-C3 alkyl) amino-C1-C3 alkyl, and / or may be monosubstituted with a nitro group, as well as their tautomers, their diastereomers, their enantiomers and mixtures thereof and x physiologically sovmes

- 06 012834 thymal salts.

The invention also relates to the corresponding compounds according to the invention, in the form of individual optical isomers, mixtures of individual enantiomers or racemates, in the form of tautomers, as well as in the form of free compounds or corresponding acid addition salts with pharmacologically acceptable acids. Likewise, the compounds of the invention, including their salts, in which one or more hydrogen atoms are substituted with deuterium, are also included in the scope of the present invention in accordance with this subject.

The next object of the present invention is a method for producing carboxamide compounds of the formula I

in which A, B, ^, X, Υ, Ζ, and ¹ , and ² , V ¹ , V ² , V ³ , B ¹ , B ² , B ³ , B ²⁶ , B ²⁷ , k, η and t have the meanings indicated above for them, namely that for case A, when the residue B ^{3 is} not connected to group A,

a) in case A represents a nitrogen-containing heterocyclic group connected through a nitrogen atom to a carboxamide group, which along with the nitrogen atom may also contain one or other heteroatoms selected from Ν, O and 8, at least one amine of the formula 1- 1, Ζ ^Ζ \

K — Ν Υ Ν-Η 1-1,

K ² K ³ in which B ¹ , B ² , B ³ , X, Υ and Ζ have the above meanings, are subjected to interaction with CDT (1,1'carbonyldi (1, 2,4-triazole)) and at least one secondary amine of the formula 1-2 ^A + ^t Chg ^{in μ2} 'in which A, B, and k have the above meanings, and group A contains a secondary amine as a functional group, and

b) in other cases, at least one carboxylic acid of the formula 1-3

in which A, B, and k have the above meanings, are subjected to interaction with TBTU (tetrafluoroboron 2- (1H-benzotriazol-1-yl) -1,1,3 in a solvent or mixture of solvents in the presence of at least one base, 3-tetramethyluronium) and at least one amine of formula 1-1 in which B ¹ , B ² , B ³ , X, Υ and Ζ have the above meanings, and for case B, when the residue B ^{3 is} connected to group A,

a) in the case where group 9 is —CB ⁶ B ⁷ - (111a), wherein B ⁶ and B ⁷ are as defined above, an amine of formula 1a. one

in which B ¹ , B ² , X, Υ and Ζ have the above meanings, are reacted with an o-bromomethylbenzoic acid ester derivative of the formula 1a.2

- 7 012834

in which K ⁶ , K ⁷ , A, B and k have the above meanings,

b) in case the group P denotes —SK ⁶ = CK ⁷ - (SH), where K ⁶ and K ⁷ have the above meanings, the isoquinolinone derivative of the formula 1.2

K ⁷

O in which K ⁶ , K ⁷ , A, B and k have the above meanings, are reacted with an electrophilic compound of the formula lb. 3.

in which Υ and Ζ have the above meanings, and OM3 represents an acceptable leaving group, preferably a mesylate, to give an isoquinoline derivative of the formula lb. 4

in which K ⁶ , K ⁷ , A, B, Υ, Ζ and k have the above meanings, and then this isoquinoline derivative of the formula I.4 is derivatized by known methods to a compound of the formula I,

c) in case the group O denotes -Y = CK ⁸ - (111c), where K ⁸ has the above meanings, the phthalazinone derivative of the formula 1c.4

N

IN n 'in which K ⁸ , A, B and K have the above meanings, are reacted with an electrophilic compound of the formula 1c.5

in which Υ and Ζ have the above meanings, and OM3 represents an acceptable leaving group, preferably mesylate, to obtain a phthalazinone derivative of the formula 1c. 6 to ⁸

in which K ⁸ , A, B, Υ, Ζ and k have the above meanings, and then the phthalazinone derivative of formula 1c.6 obtained in this way is derivatized by known methods to a compound of formula I in which O is —Y = SK ⁸ - ( 111c)

d) if the group O denotes -Ν = Ν- (ΙΙΙά), the o-aminobenzamide derivative of the formula Ιά. one

O in which K ¹ , K ² , A, B, X, Υ, Ζ and k have the above meanings, are converted in the presence of an acceptable nitrite and acid into a compound of formula I in which P is —Ν = Ν-,

d) in case the group P denotes —CO — YK ⁹ - (111e), where K ⁹ has the above meanings, o — 8 012834

1, an aminobenzamide derivative of the formula 1e. one

in which K ¹ , K ² , K ⁹ , ^, B, X, Υ, Ζ and k have the above meanings, are converted in the presence of CDI (carbonyldiimidazole) to a compound of formula I, in which O is —CO-ΝΚ ⁹ -,

f) if group 9 means-обозначает ⁸ = Ν- (III!), where K ⁸ has the above meanings, the oaminobenzamide derivative of the formula H.1

ΙΓ.1, in which K ¹ , K ² , ^, B, X, Υ, Ζ and k have the above meanings, are reacted with the carboxylic acid K ⁸ COOH, where K ⁸ has the above meanings, and / or with the corresponding activated carboxylic acid derivative to obtain a quinazolinone derivative of the formula I, in which O denotes -SC ⁸ = No.,

g) in the case when group 9 is —CO— (III), the isobenzofurandion derivative of the formula! & 2

in which ^, B and k have the indicated mules 1d.1 above, are subjected to interaction with the amine form

in which K ¹ , K ² , X, Υ and Ζ are as defined above, to give a compound of formula I in which O is —CO—.

The object of the present invention are further physiologically compatible salts of the carboxamide compounds of the invention described above and below.

The present invention also provides compositions containing at least one carboxamide compound of the invention and / or one salt of the invention and optionally one or more physiologically compatible excipients.

The next object of the present invention are medicines containing at least one proposed in the invention carboxamide compound and / or one proposed in the invention salt and optionally one or more inert carriers and / or diluents.

Likewise, an object of the present invention is the use of at least one carboxamide compound according to the invention and / or one salt according to the invention for influencing the nutritional behavior of a mammal.

The object of the present invention is, in addition, the use of at least one carboxamide compound according to the invention and / or one salt thereof, for reducing body weight and / or for preventing an increase in the body weight of a mammal.

The object of the present invention is the use of at least one carboxamide compound according to the invention and / or one salt according to the invention for the manufacture of a medicament with MCH receptor antagonistic activity.

In addition, another object of the present invention is the use of at least one carboxamide compound and / or one salt thereof, for the manufacture of a medicament suitable for the prophylaxis and / or treatment of conditions and / or diseases caused by MCH or consisting in another causal relationship with SIT.

A further object of the present invention is the use of at least one carboxamide compound and / or one salt thereof, for the manufacture of a medicament suitable for the prophylaxis and / or treatment of metabolic disorders and / or eating disorders, in particular obesity, bulimia nervosa, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia.

The object of the present invention is the use of at least one carboxamide compound and / or one salt thereof, for the manufacture of a medicament suitable for the prophylaxis and / or treatment of obesity-related diseases and / or disorders, especially diabetes mainly type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, rovoizliyaniya in brain, heart failure, cardiovascular disease, especially arteriosclerosis and hypertension, arthritis and drives.

The next object of the present invention is the use of at least one carboxamide compound and / or one salt thereof, for the manufacture of a medicament suitable for the prophylaxis and / or treatment of hyperlipidemia, panniculitis, fat deposition, malignant mastocytosis, systemic mastocytosis, emotional disorders , affective disorders, depressions, fears, sleep disorders, reproductive function disorders, sexual disorders, memory disorders, epilepsy, decomp. other forms of dementia and hormonal disorders.

Another object of the present invention is the use of at least one carboxamide compound and / or one salt thereof, for the manufacture of a medicament suitable for the prophylaxis and / or treatment of urination disorders, for example, urinary incontinence, bladder hyperactivity, and urgent urge to urination, nocturia and enuresis.

The object of the present invention is, moreover, a method for producing a drug according to the invention, characterized in that at least one carboxamide compound according to the invention and / or at least one salt according to the invention are chemically combined with one or more inert carriers and / or diluents.

Another object of the present invention is a medicament containing a first active substance selected from the carboxamide compounds and / or corresponding salts of the invention, as well as a second active substance selected from the group consisting of active ingredients for treating diabetes, active ingredients for treating diabetic complications, active ingredients for the treatment of obesity, preferably other than MCH antagonists, active ingredients for the treatment of arterial hypertension, active ingredients e agents for treating hyperlipidemia, including arteriosclerosis, active ingredients for treating arthritis, active ingredients for treating anxiety conditions and active ingredients for treating depression, and optionally one or more inert carriers and / or diluents.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, all groups, residues, substituents and indices mentioned in the following, in particular A, B, V, X, Υ, Ζ, K ¹ -K ³ , K ⁶ -K ⁹ , K ¹² -K ¹⁴ , K ²⁰ , K ²¹ , K ²² , K ²⁶ , K ²⁷ , b ¹ , b ² , b ³ , n, t and k, have one of the values indicated above and / or below for them.

In one preferred embodiment of the present invention, there are provided compounds of formula I in which

K ³ is H, _C1-C6 alkyl,

B represents a _C1-C6 alkyl, _C1-C6 alkenyl, C1-C ₆ alkynyl, C ₃ -C ₇ cycloalkyl-C 1 C ₃ alkyl, C _{3 to} C ₇ cycloalkenyl-C1-C ₃ alkyl, C ₃ -C ₇ cycloalkyl-C1-C ₃ alkenyl or C ₃ -C ₇ cycloalkyl-C 1-C ₃ alkynyl,

Cy denotes one of the following carbo - or heterocyclic groups:

a saturated 3-7-membered carbocyclic group, an unsaturated 5-7-membered carbocyclic group, a phenyl group, a saturated 4-7-membered or unsaturated 5-7-membered heterocyclic group with a ,-, O- or 8-atom as a heteroatom, a saturated or unsaturated 57-membered heterocyclic group with two or more Ν-atoms or one or two Ν-atoms and one O- or 8-atom as heteroatoms or an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected and Ν, O and / or 8, wherein the aforementioned cyclic groups may be mono- or polysubstituted by one or more C-atoms of residues to ^20, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and / or mono- or polysubstituted by one or more atoms with the remainder K ²¹ ,

K ²² is phenyl, phenyl-C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, carboxy, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl, aminocarbonyl, C ₁ -C ₃ alkylaminocarbonyl, di (C1-C3alkyl) aminocarbonyl, C1-C3alkylsulfonyl, C1-C3alkylsulfonyl, C1-C3alkylsulfonylamino, amino, C1-C3alkylamino, di (C1-C3alkyl) amino, C1-C3-phenyl, C1-C3-phenyl alkyl) phenyl-C | -C ₃ alkylamino group. acetylamino group, propionylamino group, phenylcarbonyl, phenylcarbonylamino group, phenylcarbonylmethylamino group, hydroxyalkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl, (1-piperidinyl-carbonyl, (hexaginyl-1-p-methyl-1-p-azyl-1-p-azyl-1-p-azyl-1-p-azyl-1-p-azyl-1-p-azyl-l-p-azyl-1-azyl-1-azyl-1-azyl-1-azyl-1-azyl-1-azyl-1-az)) ) carbonyl, methylenedioxy group, aminocarbonylamino group or alkylaminocarbonylamino group,

12 14 20 21 22 while in each of the groups and residues Ζ, K, K-K, K, K, K one or more C-atoms can

- 10 012834 can be mono- or multisubstituted with fluorine and / or one or two C-atoms independently of one another can be monosubstituted with chlorine or bromine, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

In the first group of compounds proposed in the preferred embodiment of the invention, group A and the remainder of K ³ are interconnected so that the fragment

in formula I is a fragment of subformula II

P, where 9 denotes a group selected from groups of subformulas Sha-Shd

-sk ⁶ to ⁷ - Sha -sk ⁶ = ck ⁷ - SH, -s = sk. ⁸ - Cc -Ν = Ν- sha -CO-ΝΚ ⁹ - Sha -ϋΚ ⁸ = Ν- pi -CO- §§

Among the above values of group 9, the preferred ones are selected from the subformulas Ш1, Шб, Ше, ПИ and Шд, first of all Шб, Ше, ПИ and Шд.

The substituents K ⁶ , K ⁷ , K ^8, and K ⁹ are preferably independently H or C1-C4 alkyl, especially H, methyl or ethyl.

The substituents L ¹ , L ² , L ³ in a preferred embodiment, independently of one another, have one of the following meanings: H, E, C1, Br, CH ₃ , CHE ₂ , CE ₃ , C ₂ H ₅ , C ₃ H ₇ , CH (CH ₃ ) ₂ , OCH ₃ , OSHE ₂ , OSE ₃ , OS ₂ N ₅ , OS3N7 and OCH (CH3) 2.

Preferably, a value other than H, primarily one of the above as preferred values, has only one of the substituents L ¹ , L ² , L ³ . In the most preferred embodiment, all three substituents b ¹ , b ² , b ³ represent N.

In a preferred embodiment, the residues K ¹ and K ^{2 are} independently H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkyl, w-hydroxy-C ₂ -C ₃ alkyl, w- (C ₁ -C ₃ alkoxy) -C ₂ -C ₃ alkyl, C ₁ -C ₄ alkoxycarbonyl-C ₁ -C ₃ alkyl, amino-C ₂ -C ₄ alkyl, C ₁ -C ₃ alkylamino-C ₂ -C ₄ alkyl, di (C ₁ -C ₃ alkyl) amino-C2-C4 alkyl, phenyl or phenyl-C1-C3 alkyl, while in the above groups and residues one or more C atoms can be one - or multisubstituted by fluorine and / or one or two C-atoms independently of one another can be monosubstituted by chlorine or bromine and the phenyl moiety may be mono- or multisubstituted with K ¹² and / or monosubstituted with a nitro group.

In a particularly preferred embodiment, the residues K ¹ and K ^{2 are} independently C ₁ C ₄ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkyl, w-hydroxy-C ₂ -C ₃ alkyl, w- (C ₁ -C ₃ alkoxy) -C ₂ C3 alkyl or C1-C4 alkoxycarbonyl-C1-C3 alkyl, wherein one of the residues K ¹ and K ² may also denote N.

In another preferred embodiment, K ¹ and K ² form a C2-C8 alkylene bridge so that K'K ^ forms a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro1H-pyrrole, 1,2,3, 6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepinyl, 2,3,6,7-tetrahydro-1H-azepine, piperazine, where the free imine function can be replaced by the remainder of K ¹³ , morpholine and thiomorpholine, with However, according to the general definition residues K ¹ and K ^2, one or more H atoms may be substituted on R ¹⁴ and / or said alkylene bridge may be substituted by decree nnym residues according to the general definition of K ¹ and K ² one way or two identical or different carbo- or heterocyclic groups Cy.

In a particularly preferred embodiment, the fragment

K ² represents a group of one of the following subformulas:

- 11 012834

- 12 012834

where one or more H atoms of the formed KPC group of the ^ -heterocycle can be replaced by K ¹⁴ and the ring connected to the formed group of the CPC ^ -heterocycle can be one or more substituted on one or more C-atoms with a K ²⁰ residue, and in the case of phenyl the rings may additionally also be monosubstituted with a nitro group.

Most preferred are the above-described groups Κ ¹ Κ ² Ν-, in which K ¹ and K ² together with the Ν-atom of the group Κ ¹ Κ ² Ν- form a pyrrolidine, piperidine or 2,5-dihydro-1H-pyrrole ring, which may be replaced by the above.

Preferred values for the K ¹⁴ group include C ₁ -C ₄ alkyl, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy-C ₁ -C ₃ alkyl, hydroxy-C ₁ -C ₃ alkyl, C ₁ -C ₄ alkylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ C ₄ alkoxycarbonyl-C ₁ -C ₃ alkyl, C ₁ -C ₄ alkoxycarbonylamino, C ₁ -C ₄ alkoxycarbonylamino-C ₁ C ₃ alkyl, amino group, (C ₁ -C ₄ alkyl) amino group, di (C ₁ -C ₄ alkyl) amino group.

Preferred among the above, a substituted group of Cypiperidine group has the structure

where Cy is preferably phenyl, which may be substituted as described above. Preferably X denotes an unbranched bridge selected from methylene, 1,2-ethylene, 1,3propylene, while the alkylene bridge can be connected to K ^{1 in the} above manner.

Most preferably, X denotes an alkylene bridge selected from methylene, 1,2 ethylene, where one or two C-atoms can be independently replaced by a hydroxy group, ω-hydroxy-C ₁ -C ₃ alkyl, ω- (C ₁ -C ₃ alkoxy) -C ₁ -C ₃ alkyl and / or C ₁ -C ₃ alkoxy group and / or each of them may be substituted by one or two identical or different C ₁ -C ₄ alkyl groups, in which case one or more C-atoms can be mono- or multisubstituted with fluorine and / or in each case one or two C-atoms independently of each other can be one substituted by chlorine or bromine.

If in group X one or two C-atoms are substituted with a hydroxy and / or C ₁ -C ₃ alkoxy group, then the substituted C-atom is preferably not in the position directly adjacent to the amino group, especially the group -№ ^ K ² or -№ K ⁴ -.

In a preferred embodiment, the value of Ζ is selected from the group consisting of —CH ₂ -, —CH ₂ —CH ₂ -, —CH ₂ CH (CH3) -, —CH2-C (CH3) 2-, —CH (CH3) —CH2- , -C (CH3) 2-CH2-, especially -CH2-CH2- and -CH (CH3) -CH2-.

The K ³ residue is preferably selected from the group consisting of methyl, ethyl, n-propyl, isopropyl. In a most preferred embodiment, the K ³ residue is H, methyl or ethyl, especially H or methyl.

Preferred values for the K ²⁰ group are halogen, hydroxy group, cyano group, C ₁ C ₄ alkyl, C ₃ -C ₇ cycloalkyl and hydroxy-C ₁ -C ₃ alkyl. Most preferably, K ²⁰ is E, C1, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or isopropoxy.

- 13 012834

The group Υ is preferably selected from the group of divalent cyclic groups, which include phenylene and pyridinyl, while the above cyclic groups can be joined at one or more C-atoms by the residue K ²⁰ , and in the case of a phenyl group can also be additionally monosubstituted by a nitro group.

Preferred group A values are selected from the group of divalent cyclic groups, which include 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinyl, 1,2,3,6tetrahydropyridine-1,4- ylene, 2,5-pyridinyl and 1,4-piperazinyl, where the above cyclic groups can be mono- or multisubstituted at one or more C-atoms with a K ²⁰ residue, and in the case of a phenyl ring, can also be monosubstituted with a nitro group, and / or can be mono- or multisubstituted at one or more Ν-atoms with a K ²¹ residue.

The divalent cyclic groups indicated above as values for Υ and / or A in each case also include their mirror-symmetric forms, namely, the forms in which the bonds with neighboring groups, i.e. in the case of group Υ its relations with X and Ζ, as well as in the case of group A, its relations with CO and ^ change places. So, for example, 1,4-cyclohexenylene means both a group and a group

By the values indicated above for Υ and A divalent cyclic groups are also meant all their possible isomers. The following are indicated in the previous description as preferred values in more detail.

In a preferred embodiment, the group A and / or B are unsubstituted or mono- or disubstituted by residues to ^20, most preferably unsubstituted or monosubstituted residue K ^20.

In a preferred embodiment, the value of the group B according to a first embodiment of the invention is selected from the group consisting of C1-C ₆ alkyl, C ₇ -C ₆ alkenyl, C 1 C ₆ alkynyl, C ₃ -C ₇ tsikloalkilS1-C ₃ alkyl, C ₃ -C ₇ cycloalkenyl-C1-C ₃ alkyl, C ₃ -C ₇ cycloalkyl-C ₇ -C ₃ alkenyl and C ₃ -C ₇ cycloalkyl-C ₇ C3 alkynyl, wherein one or more C-atoms can be mono- or poly-substituted with halogen and / or monosubstituted with a hydroxy or cyano group and / or cyclic groups may be mono- or multisubstituted with a K ²⁰ residue, denotes a single bond, an imino group, No. (C ₇ -C ₃ al kil) an imino group, k is 1, and K ²⁰ has one of the meanings indicated above.

With the above preferred values of group B, the index k preferably denotes 1, and preferably denotes a single bond, an imino group, especially a single bond.

Moreover, in the most preferred embodiment, group B is C3-C6 alkynyl, especially C ₃ -C ₆ alk-1-ynyl, and / or the group is a single bond, and k is 1.

In another preferred embodiment, the value of group B according to the second embodiment of the invention is selected among cyclic groups, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolinyl , piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, azepanyl, piperazinyl, 1H-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl, isoindolyl, quinol nyl, benzoimidazolyl, isoquinolinyl, furanyl and thienyl, and the bond with the group or under certain conditions directly with group A is via the C-atom of the carbocyclic fragment or optionally condensed phenyl or pyridine ring or through the Ν- or C-atom of the heterocyclic fragment, or B together with the double bond attached, the group is selected from the group consisting of cyclopentylidenemethyl, cyclohexylidenemethyl and cyclohexanone-4-ylidenemethyl, with the above cyclic groups being single or are multisubstituted at one or more Satoms with a K ²⁰ residue, and in the case of a phenyl group, they can additionally also be monosubstituted with a nitro group, and / or can be single or multisubstituted at one or more Ν-atoms with a K ²¹ residue.

In a particularly preferred embodiment, group B is phenyl, which is one-, two- or trisubstituted, preferably mono- or disubstituted, with a K ²⁰ moiety.

By the above values of group B are also meant all possible isomers of each of the groups. So, in particular, this refers primarily to the following isomers: cyclopenten-1-, -3- and -4-yl, cyclohexanon-4-yl, cyclohexen-1-, -3- and -4-yl, cycloheptene -1-, -3-, -4- and -5-yl, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, piperidin-1 - and -4-yl, pyridin-2-, -3- and -4-yl, azepan-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, thiomorpholin4-yl , quinolin-2-, -3-, -4-, -5-, -6-, -7- and -8-yl, isoquinolin-1-, -3-, -4-, -5-, -6 -, -7- and -8-yl, as well as 1Nbenzoimidazol-1-, -2-, -4-, -5-, -6- and -7-yl.

By pyrazole is meant isomers 1H-, 3H- and 4H-pyrazole. Under pyrazolyl

- 14 012834 preferably implies 1H-pyrazol-1-yl.

By imidazole is meant isomers 1H-, 2H- and 4H-imidazole. By imidazolyl is preferably meant 1H-imidazol-1-yl.

By tetrahydropyridine is meant isomers 1,2,3,4-, 1,2,3,6- and 2,3,4,5tetrahydropyridine. By tetrahydropyridinyl is preferably meant 1,2,3,4- and 1,2,3,6tetrahydropyridin-1-yl.

By dihydropyridine is meant isomers of 1,2-, 1,4-, 2,3-, 2,5- and 4,5-dihydropyridine. By dihydropyridinyl is preferably meant 1,2- and 1,4-dihydropyridin-1-yl.

By triazole is meant isomers of 1H-, 3H- and 4H- [1,2,4] triazole, as well as 1H-, 2Hi and 4H- [1,2,3] triazole. With this in mind, triazolyl means 1H- [1,2,4] triazol-1-, -3- and -5-yl, 3H- [1,2,4] triazol-3- and -5-yl, 4H- [1,2,4] triazol-3-, -4- and -5-yl, 1H- [1,2,3] triazol-1-, -4- and -5-yl, 2H [1,2, 3] triazol-2-, -4- and -5-yl, as well as 4H- [1,2,3] triazol-4- and -5-yl.

By the term tetrazole is meant isomers of 1H-, 2H- and 5H-tetrazole. With this in mind, tetrazolyl means 1H-tetrazol-1- and -5-yl, 2H-tetrazol-2- and -5-yl, as well as 5H-tetrazol-5-yl.

By indole is meant 1H- and 3H-indole isomers. By indolyl is preferably meant 1H-indol-1-yl.

The value isoindole refers to the isomers of 1H- and 2H-isoindole. By isoindolyl is preferably meant 2H-isoindol-2-yl.

In general, a bond with one of the aforementioned heterocyclic groups, primarily with a pyrazolyl, imidazolyl, tetrahydropyridinyl, dihydropyridinyl, triazolyl, tetrazolyl, indolyl or isoindolyl group, can be via the C-atom or, under certain conditions, through the Ν-atom of the imine function.

Group B is preferably unsubstituted or one-, two- or three-substituted with residue B ²⁰ . In a most preferred embodiment, group B is mono- or disubstituted with residue B ²⁰ . In the case where B is a substituted six-membered ring, the substituent is preferably in the para position relative to the bond with the group

The index k takes the value 0. In a preferred embodiment, in which k is 1, the bridge has the above values, preferably denotes a single bond or -CH =. Preferred values of the subformula group —L — ^ —B are selected from the structures below, in which V represents a C- or атом-atom, preferably a C-atom, and the cyclic groups shown below can be mono- or multisubstituted one or more C- atoms with the residue B ²⁰ , and in the case of phenyl or phenylene groups, they can additionally also be monosubstituted with a nitro group:

- 15 012834

Particularly preferred are those compounds of formula I in which k is 1 and A is a single bond.

Among the compounds proposed in the invention, those are preferred in which one or more groups, one or more residues, one or more substituents and / or one or more indices have one of the above as preferred values.

Preferred K ²⁰ values are selected from the group consisting of fluoro, chloro, bromo, C1-C4 alkyl, and C1-C3 alkoxy.

According to the invention, especially those compounds according to it are preferred in which Υ and A are independently selected from the group of divalent cyclic groups, which include 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1, 4-piperidinyl, 1,2,3,6-tetrahydropyridin-1,4-ylene, 2,5-pyridinyl and 1,4-piperazinyl, while A can also be connected to K ³ according to claim 2, and above cyclic groups may be mono- or polysubstituted by one or more C-atoms of residues to ^20, and in the case of the phenyl GRU nN may additionally also be monosubstituted by nitro, and / or may be mono- or polysubstituted by one or more atoms ^Ν-21 K residue, B represents a phenyl or cyclohexyl group, said groups may be mono- or polysubstituted residue K ^20, and / or the phenyl ring can additionally be monosubstituted with a nitro group, where K ²⁰ has the meanings indicated in claim 1, k is 1, A is a single bond, Ζ is —CH ₂ —CH ₂ -, —CH ₂ —CH (CH ₃ ) - , -CH ₂ -C (CH ₃ ) ₂ -, -CH (CH3) -CH2-, -C (CH3) 2-CH2-.

A group of particularly preferred compounds of the invention are formed by compounds of the following formulas k1-k14:

- 17 012834

where and, V independently represent C or Ν,

K ²³ , K ^{24 are} independently H, P, methyl, trifluoromethyl, ethyl, isopropyl or npropyl; in compounds of the formulas Y-G6, K ²⁴ can be connected to K ³ so that a fragment of the subformula

represents one of the groups selected from 1,3-pyrrolidinylene and 1,3-piperidinyl,

K ²⁵ , K ²⁶ , K ²⁷ independently of one another have one of the meanings indicated for K ²⁰ or, in the case of a phenyl group, can also denote a nitro group, while the residues repeatedly present

- 18 012834

K ²⁵ , K ²⁶ , K ²⁷ may have identical or different meanings, ΐ denotes 0, 1, 2, 3, or 4, and t, n independently of one another, denote 0, 1, or 2.

Compounds of the above formulas 1.1, 1.2, 1.8, 1.10 and 1.12 are particularly preferred. The structure of such particularly preferred compounds can be represented, in particular, by the following formulas:

- 19 012834 where the residues and substituents are as defined above and in the following description. According to the invention, further preferred compounds of the following subformula

in which B is selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkenyl- C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkenyl and C ₃ -C ₇ cycloalkyl C ₁ -C ₃ alkynyl, where one or more C-atoms may be mono- or multisubstituted with halogen and / or monosubstituted with a hydroxy or cyano group and / or cyclic groups can be mono- or multisubstituted with a K ²⁰ residue, denotes a single bond, an imino group, a (C1-C ₃ alkyl) imino group, and k is 1.

According to this embodiment of the invention, those compounds are further preferred in which group B is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkynyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl- C ₁ -C ₃ alkynyl, where one or more C atoms can be mono- or multisubstituted with halogen and / or monosubstituted with a hydroxy or cyano group and / or cyclic groups can be mono- or multisubstituted with a K ²⁰ residue, and / or is a single bond , or No. (C _g C ₃ alkyl) imino group and k equals 1.

Among the preferred compounds of the invention described above, in particular subformulas X.1-X.15, those in which K ¹ , K ² , K ³ , L ¹ , L ² , L ³ and / or group X have one of the above for their preferred values.

Particularly preferred are those compounds of the invention in which X is —CH2—, —CH (CHe) - or —C (CHe) 2-.

Particularly preferred are further those compounds of subformulas X.1-X.15 in which

a) the group and represents a Ν-atom, and the group V represents a C-atom, or

b) the group and represents a C-atom, and the group V represents a Ν-atom, or

c) each of the groups and AND V represents a C-atom.

In the particularly preferred compounds of the invention, the substituents K ²⁵ , K ²⁶ , K ²⁷ independently represent P, C1, Bg, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, methoxy, difluoromethoxy, trifluoromethoxy group, ethoxy group, n-propoxy group or isopropoxy group, and in case of substitution of the phenyl group, they can also denote a nitro group, while the repeatedly present residues K ²⁵ , K ²⁶ , K ²⁷ may have identical or different values), denotes 0, 1 or 2, and t and η independent they are 0 or 1 from each other.

The preferred values of the residues K ⁶ , K ⁷ , K ⁸ and / or K ⁹ in the above, as preferred compounds of the invention, are independently H, methyl, trifluoromethyl, ethyl, isopropyl or n-propyl, and K ⁶ and K ⁷ may also denote R.

Most preferred individual compounds are selected from the group consisting of (1) 7- (4-chlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (2) 3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -7-p-tolyl-3H-quinazolin-4-one, (3) 3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -7 - (4-trifluoromethylphenyl) -3H-quinazolin-4-one, (4) 7- (4-methoxyphenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one , (5) 7- (3,4-dichlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (6) 7- (4-fluorophenyl) - 3- [2- (4-pyrrolidin-1-methylmethylphenyl) ethyl] -3H-quinazolin-4-one, (7) 7- (4-ethylphenyl) -3- [2- (4-pyrrolidin-1-ilm tilphenyl) ethyl] -3H-quinazolin-4-one, (8) 2-methyl-3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -7- (4-trifluoromethylphenyl) -3H-quinazolin-4one , (9) 2-methyl-3 - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -7-p-tolyl-3H-quinazolin-4-one, (10) 7- (4-chlorophenyl) - 2-methyl-3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (11) 7- (4-chlorophenyl) -3- [2- (4-pyrrolidin- 1-ylmethylphenyl) ethyl] -1H-quinazolin-2,4-dione, (12) 7- (4-chlorophenyl) -3- {2- [4 - ((8) -2-methoxymethylpyrrolidin-1-methylmethyl) phenyl ] ethyl} -3Hquinazolin-4-one, (13) 7- (4-chlorophenyl) -3- [2- (4-dimethylaminomethylphenyl) ethyl] -3H-quinazolin-4-one, (14) 7- (4- chlorophenyl) -3- [2- (4-piperidin-1-ylmethylphenyl) ethyl] -3H- quinazolin-4-one, (15) 7- (4-chlorophenyl) -3- [2- (4-morpholin-4-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (16) 7- (4- chlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-benzo [4] [1,2,3] triazin-4-one, (17) 5- (4-fluorophenyl) - 2- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] isoindol-1,3-dione, (18) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acids, (19) [2- (4-diethylaminomethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid,

- 20 012834 (20) [2- (4-piperidin-1-ylmethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid, (21) [2- (4-diethylaminomethylphenyl) ethyl] amide 4'-methoxybiphenyl- 4-carboxylic acid, (22) [2- (4-diethylaminomethylphenyl) ethyl] methylamide 4'-chlorobiphenyl-4-carboxylic acid, (23) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- ( 4-chlorophenyl) cyclohexanecarboxylic acid, (24) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4-methylphenylpiperidin-1-carboxylic acid amide, (25) [2- (4-pyrrolidin-1-methylmethylphenyl) ethyl ] 4- (4-chlorophenyl) -3,6-dihydro-2H-pyridin-1 carboxylic acid amide, (26) [2- (4-pyrrolidin-1-ylmethylphenyl) e 4- (4-chlorophenyl) piperidine-1-carboxylic acid yl] amide, (27) [2- (4-pyrrolidin-1-ylmethylphenyl) propyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (28) (4) 4'-chlorobiphenyl-4-carboxylic acid-pyrrolidin-1-ylmethylbenzyloxy) amide, (29) 4-cyclohexyl-I- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (30) [2- ( 3-methoxy-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, (31) 7- (4-chlorophenyl) -3- {2- [6- (4-methylpiperazin-1 -yl) pyridin-3-yl] ethyl} 3H-quinazolin-4-one, (32) {2- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] ethyl} amide 4'-chlorobiphenyl -4-carboxylic acid, (33) 7- (3-methoxyphenyl) -3- [2- (4-pi rrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (34) 4- (4-oxocyclohexyl) -I- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (35) [ 4- Cyclohexyl-1-cyclohexylcarboxylic acid 2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide, (36) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4-benzylpiperidin-1-carboxylic acid amide, (37) [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4-cyclohexylpiperidin-1-carboxylic acid, (38) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4- chlorophenyl) piperazine-1-carboxylic acid, (39) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4- (4-fluorophenyl) piperidine-1-carboxylic acid amide, (40) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-methoxyphenyl) piperazine-1-carboxylic acid, (41) [2- (4-pyrrolidin-1-methylmethylphenyl) ethyl] amide 4-phenylpiperidin-1-carboxylic acid, (42) (4'-chlorobiphenyl-4-yl) - [3- (4-pyrrolidin-1-ylmethylphenyl) piperidin-1-yl] methanone, (43) [2-methyl 2- (4-pyrrolidin-1-ylmethylphenyl) propyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (44) [2- (4-pyrrolidin-1-ylmethylcyclohexyl) ethyl] 4'-chlorobiphenyl-4- amide carboxylic acid, (45) 4-benzyl-Ν - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (46) 4- (4-oxocyclohexylidenemethyl) -Y- [2- (4-pyrrolidin-1 -ylmethylphenyl) ethyl] be nzamide, (47) [2- (2-fluoro-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, (48) 5- (4-chlorophenyl) -2- [2- (4-pyrrolidin-1-methylmethyl) ethyl] -2,3-dihydroisoindol-1-one, (49) 4-piperidin-1-yl-Y- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide , (50) 7- (4-chlorophenyl) -3- {2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} -3H-benzo [b] [1,2,3 ] triazin-4-one, (51) 7- (4-chlorophenyl) -3- {2- [4- (3-azaspiro [5.5] undec-3-ylmethyl) phenyl] ethyl} -3H-quinazolin-4- he, (52) 7- (4-chlorophenyl) -3- {2- [4- (3-azaspiro [5.5] undec-3-ylmethyl) phenyl] ethyl} -3Nbenzo [b] [1,2,3] triazin-4-one, (53) 7- (4-chlorophenyl) -3- {2- [4- (4-hydroxy-4-phenylpiperidin-1-ylm thyl) phenyl] ethyl} -3Hquinazolin-4-one, (54) 7- (4-chlorophenyl) -3- (2- {4- [4- (pyridin-2-yloxy) piperidin-1-ylmethyl] phenyl} ethyl) -3Hquinazolin-4-one, (55) 6- (4-chlorophenyl) -2- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -2H-isoquinolin-1-one, (56) [2 - (3-Bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (57) [2- (3-methyl-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4 '-chlorobiphenyl-4-carboxylic acid, (58) {2- [4- (1-ethylpiperidin-2-yl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (59) {2- [4 - (4-acetylpiperazin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (60) {2- [4- (2-azabicyclo [2.2.1] hep 4-chlorobiphenyl-4-carboxylic acid t-5-en-2-ylmethyl) phenyl] ethyl} amide, (61) {2- [4- (1,3-dihydroisoindol-2-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (62) (2- {4 - [(diisopropylamino) methyl] phenyl} ethyl) 4'-chlorobiphenyl-4-carboxylic acid amide, (63) {2- [3-bromo -4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} 4'-chlorobiphenyl-4-carboxylic acid amide, (64) {2- [4- (2-dimethylaminomethylpyrrolidin-1-ylmethyl) phenyl] ethyl } 4'-chlorobiphenyl-4-carboxylic acid amide,

- 21 012834 (65) {2- [4- (3-dimethylaminopyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (66) [2- (2-bromo-4-pyrrolidine -1-methylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, (67) 4-pent-1-vinyl-L- [2- (4-pyrrolidin-1-methylphenyl) ethyl] benzamide, (68) [2- (6-Pyrrolidin-1-ylmethylpyridin-3-yl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (69) [2- (1-pyrrolidin-1-ylindan-5-yl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (70) [2- (2-nitro-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (71) [2- ( 4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 2 ', 4'-dichlorobife nyl-4-carboxylic acid, (72) {2- [4- (3-aminopyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (73) {2- [4- ( 2-aminomethylpyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (74) {2- [4- (2-methyl-2,6-diazaspiro [3.4] oct-6-ylmethyl ) phenyl] ethyl} 4'-chlorobiphenyl-4-carboxylic acid amide, (75) [2- (5-pyrrolidin-1-ylmethylpyridin-2-yl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (76 ) [2- (3-ethyl-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (77) {2- [4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} 4'-bromobiphenyl-4-carboxylic acid amide , (78) 4- (5-chlorothiophen-2-yl) -Y- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (79) [2- (2-methyl-4-pyrrolidin-1 4'-chlorobiphenyl-4-carboxylic acid-methylmethylphenyl) ethyl amide, (80) {2- [3-bromo-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide 4'-bromo- 3-fluorobiphenyl-4-carboxylic acid, (81) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chloro-2-fluorobiphenyl-4-carboxylic acid amide, (82) [2- (4- pyrrolidin-1-ylmethylphenyl) ethyl] 4'-ethylbiphenyl-4-carboxylic acid amide, (83) [1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} tert-butyl ester} benzyl) pyrrolidin-2ylmethyl] carbamic acid, (84) {2- [4- (2-methylpiperide 4'-chlorobiphenyl-4-carboxylic acid n-1-ylmethyl) phenyl] ethyl} amide, (85) {2- [4- (2-methylpyrrolidin-1-ylmethyl) phenyl] ethyl} 4'-chlorobiphenyl-4 amide -carboxylic acid, (86) (2- {4 - [(cyclopropylmethylamino) methyl] phenyl} ethyl) amide 4'-chlorobiphenyl-4-carboxylic acid, (87) {2- [4- (3,4-dihydro- 4H-chloro-biphenyl-4-carboxylic acid 1H-isoquinolin-2-ylmethyl) phenyl] amide, (88) [2- (4- {[((2-hydroxyethyl) methylamino] methyl} phenyl) ethyl] amide 4 ' -chlorobiphenyl-4-carboxylic acid, (89) tert-butyl ether [1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrolidin-3yl] carbamic acid, (90 ) {2- [4- (2,6-dimethylp peridin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (91) [2- (4-azetidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, ( 92) [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 3,4'-dichlorobiphenyl-4-carboxylic acid amide, (93) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'- fluorobiphenyl-4-carboxylic acid, (94) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-fluorobiphenyl-4-carboxylic acid, (95) [2- (4-pyrrolidin- 1'-ylmethylphenyl) ethyl] amide 2'-fluoro-4'-chlorobiphenyl-4-carboxylic acid, (96) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 5- (4-chlorophenyl) pyridin-2 carbon acids, (97) {2- [4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide of 4'-chlorobiphenyl-4-carboxylic acid, (98) [2- (4-pyrrolidin-1- 4'-bromobiphenyl-4-carboxylic acid ylmethylphenyl) ethyl] amide and 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (1-pyrrolidin-1-yl-ethyl) phenyl] ethyl} amide.

Among the above individual compounds, compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11) are particularly preferred ), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (47), and (50) - (99).

The following part of the description provides a more detailed interpretation of the terms and concepts that are used above and below to describe the compounds of the invention.

The term halogen refers to an atom selected from the group consisting of P, C1, Br and I.

The term C ₁ -C _p alkyl, where η has a value from 3 to 8, denotes a saturated hydrocarbon group with a branched or unbranched chain containing from 1 to η C-atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and others.

The term C ₁ -C _p alkylene, where η may have a value from 1 to 8, denotes a saturated hydrocarbon bridge with a branched or unbranched chain containing from 1 to η C-atoms. Examples of such groups include methylene (-CH ₂ -), ethylene (-CH ₂ -CH ₂ -), 1-methylethylene (-CH (CH ₃ ) -CH ₂ -), 1,1-dimethylethylene (-C (CH ₃ ) ₂ -CH ₂ -), n-prop-1,3-ylene (-CH ₂ -CH ₂ -CH ₂ -), 1-methylprop-1,3ylene (-CH (CH ₃ ) -CH ₂ -CH ₂ -), 2-methylprop-1,3-ylene (-CH ₂ -CH (CH ₃ ) -CH ₂ -) and others, as well as their corresponding mirror-symmetric forms.

- 22 012834

The term C ₂ -C _p alkenyl, where η has a value from 3 to 6, denotes a hydrocarbon group with a branched or unbranched chain containing from 2 to η C atoms and having at least one carbon-carbon double bond (C = C) . Examples of such groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1propenyl, 1-pentenyl, 2-pentenyl , 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and others.

The term C ₁ -C _p alkoxy group refers to an —O — C ₁ -C _p alkyl group, where C ₁ -C _p alkyl corresponds to the above definition. Examples of such groups include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group, isopentoxy group, neopentoxy group, tert pentoxy hexoxy.

The term C ₁ -C _p alkylthio group denotes a -8-C ₁ -C _p alkyl group, where C ₁ -C _p alkyl corresponds to the above definition. Examples of such groups include methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group, iso-hentiuentiuenti-group, other .

The term C ₁ -C _p alkylcarbonyl means -CO = O) -C ₁ -C _p alkyl group, where C ₁ -C _p alkyl corresponds to the above definition. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, tert-p-pentylcarbonyl, other .

The term C3-Cn cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group containing from 3 to p C-atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1] octyl, spiro [4.5] decyl, norpinyl, norbornyl, norkaryl, adamantyl and others.

The term C ₃ -C _p cycloalkylcarbonyl means —C (═O) —C ₃ -C _p cycloalkyl group, where C ₃ C _p cycloalkyl is as defined above.

The term aryl refers to a carbocyclic aromatic ring system, such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and others.

As used herein, the term heteroaryl refers to a heterocyclic aromatic ring system, which along with at least one C atom contains one or more heteroatoms selected from из, O and / or 8. Examples of such groups are furanyl, thiophenyl (thienyl), pyrrolyl , oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4 oc sadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl , benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinosilinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, others. The term heteroaryl also means partially hydrogenated heterocyclic aromatic ring systems, especially those listed above. Examples of such partially hydrogenated ring systems include 2,3-dihydrobenzofuranyl, pyrolyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and others.

In terms of the type aryl-C ₁ -C _p alkyl, heteroaryl-C ₁ -C _p alkyl, and the like. denoted C ₁ -C _p alkyl, which corresponds to the above definition and which is substituted by an aryl or heteroaryl group.

Some of the above terms may occur several times in the definition of a particular formula or group and in each such case, independently of one another, have one of the meanings indicated for them.

By the term unsaturated carbocyclic group or an unsaturated heterocyclic group, used primarily in the definition of the Cy group, along with completely unsaturated groups are also meant corresponding, only partially unsaturated groups, mainly single and double unsaturated groups.

The term optionally substituted as used herein means that the group provided with this definition is either unsubstituted or mono- or multisubstituted with the substituents indicated in each case. If the corresponding group is polysubstituted, then its substituents may be identical or different.

The radicals and substituents described above can be mono- or multisubstituted with fluorine as described above. Preferred fluorinated alkyl residues include fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy residues include fluorine

- 23 012834 methoxy group, difluoromethoxy group and trifluoromethoxy group. Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups include trifluoromethylsulfinyl and trifluoromethylsulfonyl.

The compounds of the general formula I according to the invention may contain acidic groups, mainly carboxyl groups, and / or basic groups, such as, for example, amino functional groups. In view of this, the compounds of general formula I can be represented as internal salts, as salts with pharmaceutically acceptable acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (e.g. maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid), or in the form of salts with pharmaceutically acceptable bases, such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines, for example diethylamine, triethylamine, triethanolamine and others.

The compounds of the invention can be prepared using synthesis methods that are known in principle as such. The compounds of the invention are preferably prepared by the methods described above and described in more detail below.

The inventive method for producing compounds forming the first group of compounds according to preferred embodiments of the invention, i.e. those compounds in which group A and residue B are not directly connected to each other are subdivided into two variants that are fundamentally different from each other.

The first option relates to the preparation of those compounds of formula I in which group A is a nitrogen-containing heterocyclic group joined through a nitrogen atom to a carboxamide group, which along with the nitrogen atom may also contain one or other heteroatoms selected from Ν, O and 8. The interaction of an amine of formula Γ1 with a secondary amine of formula G2 is illustrated in the following general reaction scheme 1.

Reaction Scheme 1

1-1

1-2 cdt about

K — Ν ^{Ζ Χ} Ν ^Ζ ^ Α4-ννφ _Γ Β I k ² K ³

According to the above scheme, first an amine of formula Γ1 is preferably reacted with CDT (1,1'-carbonyldi (1,2,4-triazole)) in a solvent or mixture of solvents, and then the reaction mixture is further reacted with an amine of formula G2, wherein at least one base is added to the reaction mixture before and / or after the interaction of the amine with KDT. In this case, the amine of the formula Γ1 is preferably reacted with KDT in the temperature range from -20 to 20 ° C, and the subsequent reaction of this reaction mixture with the amine of the formula G2 is preferably carried out in the temperature range from 40 to 100 ° C with a molar ratio between the amine of the formula Γ1, an amine of the formula G2, KDT and a base of 1 ± 0.25: 1 ± 0.25: 1 ± 0.25: 3 ± 1.5. As bases, it is preferable to use nitrogen-containing bases, in particular tertiary amines, for example triethylamine.

An amine of formula G2 may be a saturated Ν-heterocyclic compound, for example, the piperazine derivative shown in Reaction Scheme 2 below.

- 24 012834

A second embodiment of the method of the invention relates to the preparation of the remaining compounds that are not within the first embodiment of the compounds of formula I, in which group A is not directly connected to the K ³ residue. The interaction of a carboxylic acid of formula L3 with TBTU (2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate) and an amine of the formula B, carried out in a solvent or mixture of solvents in the presence of at least one base, illustrated in reaction scheme 3.

Reaction Scheme 3 to ¹ -Ν ^Ζ \ ~ H 1-1

According to this scheme, a carboxylic acid of formula b3 is preferably reacted with TBTU in a solvent or solvent mixture, and then the reaction mixture is further reacted with an amine of formula Σ-ί, at least at least one is added to the reaction mixture of the carboxylic acid with TBTU at least one basis. Instead of a carboxylic acid, its corresponding activated derivatives can also be used, such as for example esters, ortho esters, acid chlorides or anhydrides. As the base, it is preferable to use a nitrogen-containing base, in particular a tertiary amine, for example triethylamine. The interaction of the carboxylic acid of formula L3 with TBTU, as well as the subsequent interaction of this reaction mixture with an amine of formula L, is preferably carried out in the temperature range from 0 to 60 ° C with a molar ratio between carboxylic acid of formula L3, amine of formula Ζ-1, TBTU and the base 1 ± 0.25: 1 ± 0.25: 1 ± 0.25: 1-4.

The starting compound of formula b3 is prepared according to a method known to those skilled in the art. Thus, in particular, diaryl compounds are prepared by a combination according to the Suzuki reaction (8i / ir1), starting, for example, from derivatives of p-bromarylcarboxylic acids and derivatives of arylboronic acids in the presence of Pd-based catalysts [0].

The inventive method for producing compounds forming the second group of compounds corresponding to preferred embodiments of the invention, i.e. those compounds in which group A and the remainder of K ^{3 are} connected to each other, is divided into seven options according to the number of values of group P, which can be one of the groups of formulas Sha-Shd.

According to a first embodiment, which relates to the preparation of compounds in which O represents a group —SK ⁶ K ⁷ - (Sha), an amine of formula Sh.1 is reacted with an ester derivative of obromomethylbenzoic acid of formula Y.2, as illustrated in the reaction scheme below 4, which, for simplicity, does not show the substituents b ¹ , b ² , b ³ in the phenyl ring.

Reaction Scheme 4

! / ^X \ / Ρ ¹ —Ν Υ Ν-H I ^{1 +} p ^{2 n} 1a. one th to ⁷ to _? from ₃ CH ₃ 1a.2 G ? ⁶ \ P ⁷ ± "± ⁱⁿ x l N ί / \ 7 Ρ — Ν Υ I 1a P ² ABOUT

According to this scheme, the o-bromomethylbenzoic acid ester derivative of formula B.2 is preferably reacted with an amine of formula B.1 in a solvent or mixture of solvents with at least one base added. Instead of the derivative of the o-bromomethylbenzoic acid ester of the formula N.2, other corresponding derivatives of the benzene benzoic acid esters (with iodine or mesylate instead of bromine) can be used. As the base, it is preferable to use potassium carbonate or cesium carbonate, however, tertiary amines can also be used,

- 25 012834 for example triethylamine. The o-bromomethylbenzoic acid ester derivative of formula 1a.2 is preferably reacted in acetonitrile with an amine of formula 1a. 1 and potassium carbonate as a base in the temperature range from 40 to 80 ° C with a molar ratio between the derivative of o-bromomethylbenzoic acid ester 1a.2, an amine of formula 1a.1 and potassium carbonate, comprising 1 ± 0.25: 1 ± 0, 25: 3 ± 0.50.

According to a second embodiment, which relates to the preparation of compounds in which b represents a group —CK ⁶ = K ⁷ - (Bb), the isoquinolinone derivative of formula l.3 is reacted with an electrophilic compound of formula l.4 to obtain an isoquinoline derivative of formula l.5. , which is then derivatized by known methods to a compound of formula I. The isoquinolinone derivative of the formula ^ .3 is obtained from cinnamic acid derivatives of the formula ^ .1 by their interaction with (ΕΐΟ) ₂ Ρ (Ο) Ν ₃ . A method for synthesizing the skeleton of a molecule is described by M. Weskeg et al. In Vyuguds & MeLs1na1 Sjet1§ £ gu LéDegz, 9, 1999, ss. 2753-2758. The sequence of chemical transformations in accordance with the second embodiment of the method of the invention is illustrated in reaction scheme 5 below, which, for simplicity, does not show the substituents b ¹ , b ² , b ³ in the phenyl ring.

Reaction Scheme 5

ABOUT

A compound of formula ^ .2 is preferably prepared in accordance with the reaction sequence described below. The acrylic acid derivative of the formula ^ .1 is first converted by chlorination agents such as thionyl chloride, phosphorus pentachloride or oxalyl chloride to the acid chloride of this acid by reaction without solvent or, if necessary, in an inert solvent such as dichloromethane, at a temperature in the range from 0 to 80 ° C. This acid chloride is then converted under the action of sodium azide in a solvent or mixture of solvents into the azide derivative of acrylic acid. The solvent can be, for example, dioxane, tetrahydrofuran or water. The isocyanate derivative of the formula ^ .2 is preferably synthesized directly by exposing the acrylic acid derivative of the formula ^ .1 in the presence of a base to diphenyl azide

26 012834 phosphoric acid ester in a solvent at a temperature in the range from 0 to 150 ° C. As a solvent, for example, toluene or dioxane can be used. As bases, tertiary amines, such as, for example, triethylamine, can be used. The duration of the above reactions is from 1 to 12 hours. The reaction of the acrylic acid derivative of formula 1.1 with azide of phosphoric acid diphenyl ester and triethylamine is preferably carried out at a molar ratio between them of 1 + 0.25: 1 + 0.25: 1+ 0.25 in toluene as solvent.

When the isocyanate derivative of formula 1.2 is heated in a solvent, optionally in the presence of a base, such as tributylamine, an isoquinolone derivative of formula 1.3 is formed. The reaction is preferably carried out in diphenyl ether at a temperature in the range of the boiling point of the reaction mixture. As heat sources for heating the reaction mixture, oil baths, metal melt baths or microwave ovens can be used.

The interaction of the isoquinolone derivative of formula I.3 with the mesylate derivative of formula I.4 to obtain the isoquinolone derivative of formula I.5 is carried out in a solvent in the presence of a base at a temperature in the range from 0 to 150 ° C. The reaction of the isoquinolone derivative of formula I.3 with a mesylate derivative of formula I.4 and sodium hydride is preferably carried out at a molar ratio between them of 1 + 0.25: 1 + 0.25: 1 + 0.25 in DMF as a solvent.

The isoquinolone derivative of formula I.5 for the conversion of acetal to the corresponding aldehyde is first subjected to chemical conversion in a solvent in the presence of an acid. This aldehyde is then converted in a solvent in the presence of a proton transfer agent, as well as in the presence of an amine and an acid, into a compound of formula 1b. Examples of proton transfer agents include sodium triacetoxyborohydride, sodium borohydride and sodium cyanoborohydride. The reaction of the aldehyde released from the isoquinolone derivative of formula I.5 with an amine and sodium cyanoborohydride is preferably carried out at a molar ratio between them of 1 + 0.25: 1 + 0.25: 0.8 + 0.25 in methanol and acetic acid at a temperature of about 20 ° C.

The synthesis of isoquinolines of formula 1b, including the starting compounds, as well as their subsequent derivatization to an amine, are illustrated in the reaction scheme below using a specific compound as an example, and for the synthesis of educt 1 indicated in reaction scheme 6 below, we can refer to the description of the process for producing phthalazinones ( reaction scheme 8).

Reaction Scheme 6

According to a third embodiment, which relates to the preparation of compounds in which C) represents an ASA ⁸ - (111c) group, the phthalazinone derivative of formula 1c.4 is reacted with an electrophilic compound of formula 1c.5 to obtain a phthalazinone derivative of formula 1c.6, which then by known methods, they are derivatized to a compound of formula 1c. The phthalazinone derivative of formula 1c.4 for the case where K ⁸ is hydrogen is prepared from the phenyloxazole derivative of formula 1c. 1, which is acylated to o-oxazolylbenzaldehyde

- 27 012834 a derivative of the formula K.2, which in turn is then cyclized to a 3-hydroxy-3H-isobenzofuran-1-one derivative of the formula K.3. A method for synthesizing the skeleton of a molecule is described by M. Noroe! Apo et al. In Vyuguds & Messta, Siepst, Lebedegs, 12, 2002, ss. 5-8. The chemical conversion to compounds of general formula k is illustrated in reaction scheme 7 below, which, for simplicity, does not show the substituents b ¹ , 1?, B ³ in the phenyl ring.

Reaction Scheme 7

1. Wii

2. DMF at n ⁸ = n

H ₂ 8O ₄

o hydrazine

ABOUT

νν- ^ Β

about

The reaction sequence presented in the above diagram is described in more detail below. First, the oxazoline derivative of the formula E.1 is subjected to metallization by its interaction with an acceptable organometallic reagent, and then it is subjected, at a temperature in the range from -70 to 20 ° C, preferably from -20 to 0 ° C, with an equivalent of formaldehyde, such as, for example dimethylformamide, or with formic acid orthoester to give a compound of formula K.2. As a solvent, for example, dioxane, tetrahydrofuran or diethyl ether can be used. Further, from this compound, under the action of aqueous sulfuric acid in a solvent, such as, for example, ethanol, at a temperature near the boiling point of the solvent or mixture of solvents for a period of time ranging from 1 to 24 hours, a compound of the general formula K.3 is obtained. The phthalazinone derivative of formula K.4 can be prepared by reacting a compound of formula K.3 with hydrazine in acetic acid and, if necessary, in a solvent at a temperature in the range of 20 and 120 ° C. For the synthesis of the phthalazinone derivative of the formula k, a similar sequence of chemical transformations is used, which is discussed above in the description of the synthesis process of the compound of general formula k.

- 28 012834

The procedure for the synthesis of phthalazinone derivatives of formula 1c, primarily the synthesis of the starting compounds and their subsequent derivatization, is illustrated by the example of a specific compound in the following reaction scheme 8, the abbreviations used in them have the following meanings: AHL stands for lithium aluminum hydride, ΒιιΕί stands for n-butyllithium, DMF stands for dimethylformamide, MeOH is methanol and Mg-C1 is methanesulfonic acid chloride.

According to a fourth embodiment, which relates to the preparation of compounds in which () is a group —Ν = Ν- (Sh), the o-aminobenzamide derivative of the formula 1y. 1 is converted in the presence of an acceptable nitrite and acid via an intermediate diazonium compound into a benzotriazinone derivative of the formula 1y . This chemical transformation is illustrated in reaction scheme 9 below, which, for simplicity, does not show the substituents b ¹ , b ² , b ³ in the phenyl ring.

The reaction scheme 9

The compound of the general formula 1y.1 is preferably chemically converted in a solvent, such as, for example, methanol, in the presence of a mineral acid, for example hydrochloric acid, and a salt containing a nitrite ion at a temperature in the range of from -10 to 30 ° C. Amine compound

- 29 012834 mules 1st. 1, it is preferable to react with sodium nitrite at a molar ratio between them of 1 ± 0.25: 1.5 ± 0.25, carrying out the reaction in methanol as a solvent and in the presence of hydrochloric acid.

According to a fifth embodiment, which relates to the preparation of compounds in which C) represents a group —CO — ΝΗ ⁹ - (111e), an o-aminobenzamide derivative of the formula 1e. 1 is chemically converted in the presence of CDI to a quinazolinedione derivative of formula 1e. CDI is used in a molar ratio to the benzamide derivative of formula 1e.1 greater than or equal to 1, and the reaction is at least partially carried out in the temperature range from 35 to 100 ° C., preferably at a temperature in the boiling range of the reaction mixture. A similar chemical conversion is illustrated in reaction scheme 10 below, which, for simplicity, does not show the substituents L ¹ , L ² , L ³ in the phenyl ring.

The reaction scheme 10

ABOUT

According to a sixth embodiment, which relates to the preparation of compounds in which C) represents a group -ίΊ < ⁸ = Ν- (ΙΙΙΓ), the o-aminobenzamide derivative of the formula ΙΓ.1 is reacted with K ⁸ COOH carboxylic acid and / or its corresponding activated derivative to obtain a quinazolinone derivative of the formula ΙΓ. Examples of suitable activated carboxylic acid derivatives include esters, ortho esters, acid chlorides or anhydrides. Carboxylic acid, under certain conditions in the form of its activated derivative, is used in a molar ratio to the carboxamide compound of the formula ΙΓ.1 greater than or equal to 1, and the reaction is at least partially carried out in the temperature range from 35 to 100 ° C, preferably at a temperature of boiling range of the reaction mixture. A similar chemical conversion is illustrated in reaction scheme 11 below, which, for simplicity, does not show the substituents L ¹ , L ² , L ³ in the phenyl ring.

The reaction scheme 11

ABOUT

R ⁸ COOH

The synthesis of quinazolinone derivatives of the formula ΙΓ, primarily the starting compounds, is illustrated by the example of a specific compound in the following reaction scheme 12, the abbreviations used in which have the following meanings: CDI stands for carbonyldiimidazole, TBTU stands for 2- (1H-benzotriazol-1-yl) - tetrafluoroborate 1,1,3,3-tetramethyluronium, and ΝΕ1 ₃ is triethylamine. The reaction scheme first illustrates the synthesis processes of both starting compounds 1 and 2.

- 30 012834

The reaction scheme 12

Starting compounds 1 and 2 are subjected to combination with each other by amide coupling using TBTU. The nitro group in the ortho position with respect to the obtained amide bond is reduced in the presence of P1O ₂ to an amine. Cyclization to quinazolinone is carried out using carboxylic acid, in which case formic acid is used.

According to a seventh embodiment, which relates to the preparation of compounds in which C represents a —CO— (111d) group, the isobenzofurandion derivative of formula 1d.2 is reacted with an amine of formula 1d.1 to give an isoindolinedione derivative of formula 1d. This chemical transformation is illustrated in the following reaction scheme 13, which, for simplicity, does not show the substituents L ¹ , L ² , L ³ in the phenyl ring.

The reaction scheme 13

Ι & 1 1 _yo .2

- 31 012834

According to the above scheme, the isobenzofurandion derivative 1d.2 is reacted with an amine of the general formula 1d.1 at a molar ratio between them of 1 + 0.25: 1.5 + 0.25 in a solvent such as, for example, acetic acid. This reaction is preferably carried out at the boiling point of the solvent.

At the same time, the isoindol-dione derivative of the formula 1e can also be obtained in accordance with the following reaction scheme 14. The method of synthesis of one individual compound illustrated in this scheme can, as is obvious to a person skilled in the art, be used without any problems, if necessary, with some modifications , and for the synthesis of other compounds of formula 1d. First, the isoindol-dione function is obtained from the isobenzofurandion derivative by the addition of an amine, and then the following aryl group is added by the combination of the Suzuki reaction in the presence of Ρά [0].

The possible approaches to the synthesis of the compounds proposed in the invention discussed above can be applied using methods known to the person skilled in the art, at least in principle, as described, for example, in Noyep-Sheu1 - Meshoyep run dogashzsep Sbesh1e, without any problems to modify and / or supplement in relation to individual synthesized compounds.

When carrying out the reactions described above, the reactive groups present under certain conditions, such as hydroxy, carboxy, amino, or imino groups, can be protected according to methods known from the literature for the duration of the reaction by conventional protective groups, which can be used primarily as commonly used in chemistry of peptides are protective groups, and cleave them again at the end of the reaction. More detailed information regarding such protective groups and their use can be found, for example, in application SHO 98/11128.

The stereoisomeric compounds of formula (I) can, in principle, be separated into individual stereoisomers by conventional methods. The separation of the obtained compounds into individual diastereomers is based on differences in their physicochemical properties and is possible, for example, by fractional crystallization from suitable solvents, by high pressure liquid chromatography (HPLC) or column chromatography using chiral or preferably achiral stationary phases.

The compounds of formula (I) can, as mentioned above, be converted into their salts, especially for pharmaceutical use, into their physiologically compatible and pharmacologically acceptable salts. Such salts, on the one hand, can be physiologically compatible and pharmacologically acceptable acid addition salts of the compounds of formula (I) formed with inorganic or organic acids. On the other hand, the compound of formula (I), if it has a carboxylic hydrogen atom, can also be converted, with inorganic bases, into physiologically compatible and pharmacologically acceptable salts containing alkali or alkaline earth metal cations as counterions. For the formation of acid addition salts, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid can be used. These acids can, in addition, be used in the form of mixtures thereof. For the formation of salts of a compound of formula (I) containing a carboxylic hydrogen atom with alkali and alkaline earth metals, it is preferable to use alkali and alkaline earth metal hydroxides and hydrides, among which alkali metal hydroxides and hydrides, especially sodium and potassium, are more preferred, and most preferred are sodium and potassium hydroxide.

The compounds of the invention, including their physiologically compatible salts, possess the action of antagonists of the MCH receptor, especially the MCH 1 receptor, and in experiments on binding to the MCH receptor show a rather high degree of affinity (affinity) for it.

- 32 012834

Pharmacological study systems of the MSA-antagonistic properties of the compounds of the invention are discussed in the subsequent experimental part of the present description.

The compounds of the invention, given their properties of MCH receptor antagonists, are preferably used as pharmaceutical active substances for the prevention and / or treatment of conditions and / or diseases caused by MCH or in any other causal relationship with MCH. In general, the compounds according to the invention have low toxicity, as well as good oral absorption and intracerebral permeability, primarily the ability to penetrate the brain.

Therefore, MCH antagonists that contain at least one compound of the invention can be used for the treatment and / or prophylaxis of MCH caused by or otherwise associated with MCH conditions and / or diseases, especially in mammals, for example rats, mice, guinea pigs , hares, dogs, cats, sheep, horses, pigs, cattle, monkeys, as well as humans.

Diseases caused by MCH or otherwise causally associated with MCH include mainly metabolic disorders, such as obesity, and eating disorders, such as bulimia, including bulimia nervosa. The use of the compounds of the invention is indicated mainly for such forms of obesity as exogenous obesity, hyperinsulinemic obesity, obesity with hyperplasia, pituitary obesity, obesity with hypoplasia, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, obesity and upper obesity hypogonadal obesity and central obesity. Indications of a similar type include, in addition, cachexia, anorexia and hyperphagia. The compounds of the invention make it possible, first of all, to effectively reduce the feeling of hunger, to reduce, appropriately suppress appetite, control eating behavior and / or cause a feeling of fullness.

In addition to diseases caused by SIT or consisting in a different causal relationship with SIT, hyperlipidemia, panniculitis, fat deposition, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, fear, reproductive function, memory impairment, various forms of dementia and hormonal disorders.

The compounds of the invention can also be used as active substances for the prophylaxis and / or treatment of other diseases and / or disorders, and especially those caused by obesity and which can be mentioned as diabetes, diabetes mellitus, mainly type II diabetes, hyperglycemia mainly chronic hyperglycemia, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological tolerance glucose, cardiovascular disease, primarily arteriosclerosis and arterial hypertension, and drives.

The MCH antagonists and compositions of the invention can be used to achieve appropriate advantages in combination with nutritional therapy, such as diabetes nutritional therapy, and exercise.

Other indications for which the compounds of the invention are preferably used include the prevention and / or treatment of urination disorders, such as urinary incontinence, urinary bladder hyperactivity, peremptory urination, nocturia and enuresis, while bladder hyperactivity and peremptory urination may be associated or not associated with benign prostatic hyperplasia.

In order to achieve the corresponding effect, the compounds of the invention are advantageously administered from 1 to 3 times a day in a dose which, when administered intravenously or subcutaneously, is from 0.001 to 30 mg / kg body weight, preferably from 0.01 to 5 mg / kg body weight body, and when administered orally, nasally or by inhalation is from 0.01 to 50 mg / kg body weight, preferably from 0.1 to 30 mg / kg body weight.

To this end, the compounds of the general formula I proposed in the invention, optionally in combination with other active substances, which are discussed in more detail below, are processed together with one or more physiologically compatible excipients, usual inert carriers and / or diluents, for example, corn starch, lactose , cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycer other, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fat-containing substances, such as hardened fat, or their acceptable mixtures, in ordinary galenic forms, such as tablets, dragees, capsules, cachets, powders, granules , emulsions, syrups, formulations for aerosol inhalation, ointments or suppositories.

In addition to drugs, the present invention also provides compositions comprising at least one carboxamide compound of the invention and / or one pre

- 33 012834 the salt of the invention and optionally one or more physiologically compatible excipients. Similar compositions may also be presented in the form of food products in solid or liquid form, the composition of which includes the compound of the invention.

Among the other active substances that are suitable for the above use in combination with the compounds of the invention are, first of all, those which, for example, can increase the therapeutic efficacy of the MCH antagonist according to the invention when used in one of the above indications and / or reduce the dosage of the inventive MCH antagonist. One or more of these other active ingredients is preferably selected from the group consisting of active ingredients for treating diabetes, active ingredients for treating diabetic complications, active ingredients for treating obesity, preferably other than MCH antagonists, active ingredients for treating hypertension, active ingredients for treating hyperlipidemia including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of fear and active substances Twa to treat depression.

The above classes of active substances are discussed in more detail below on their specific examples.

As an example of the active ingredients for treating diabetes, insulin sensitizers can be mentioned, accelerating the secretion of insulin substances, biguanides, insulins, α-glucosidase inhibitors, and adrenergic receptor agonists.

The insulin sensitizer group includes pioglitazone and its salts (preferably hydrochloride), troglitazone, rosiglitazone and its salts (preferably maleate), IT-501, 6L262570, MCC-555, M-440, M-2593, BM-13-1258, KKR-297, K-119702 and 6T-1929.

Substances that accelerate insulin secretion include sulfonylureas, such as, for example, tolbutamide, chlorpropamide, trazamide, acetohexamide, glycopyramide and its ammonium salts, glibenclamide, glyclazide and glimepiride. Other examples of insulin secretion-accelerating substances include repaglinide, nateglinide, mitiglinide (ΚΑΌ-1229) and PT-608.

Biguanides include metformin, buformin, and phenformin.

The group of insulins includes insulin of animal origin, primarily secreted from the body of cattle or pigs, semi-synthetic human insulins synthesized enzymatically from animal insulin, and human insulin obtained by genetic engineering, for example, from Exxeps Co11 or yeast. In addition, insulin also means insulin-zinc (with a zinc content of 0.45 to 0.9 wt.%) And protamine-insulinzinc obtained from zinc chloride, protamine sulfate and insulin. In addition, insulin can also be obtained from insulin fragments or derivatives (e.g. ΣΝ8-1, etc.). Insulin can also cover its various types, classified, for example, by the time of onset and duration of action (ultrafast action, fast action, two-stage type, intermediate type, prolonged action, etc.) and selected depending on the pathological condition of the patient.

The group of α-glucosidase inhibitors includes acarbose, voglibose, miglitol and emiglitate.

Agonists in ₃ -adrenoreceptors include L1-9677, BM8-196085, 8B-226552 and ΑΖ40140.

Ergoset, pramlintide, leptin, BΑΥ-27-9955, as well as glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors (L-iditol dehydrogenase), protein tyrosine phosphatase inhibitors 1B, are different from the active ingredients listed above for treating diabetes dipeptidyl proteases, glipazide and glyburide.

Active ingredients for treating diabetic complications include, for example, aldose reductase inhibitors (aldehyde reductases), glycate ion inhibitors and protein kinase C inhibitors.

Inhibitors of aldose reductase (aldehyde reductase) are, for example, tolrestat, epalrestat, imirestat, zenarestat, 8ΝΚ-860, zopolrestat, ΑΠ! -50ί and Α8-3201.

An example of a glycate ion inhibitor is pimagedin.

As an example of protein kinase C inhibitors, ΝΟΕ and ΕΥ-333531 can be mentioned.

Other than the active ingredients listed above for the treatment of diabetic complications include alprostadil, tiapride hydrochloride, cilostazole, mexiletine hydrochloride, ethyl eicosapentate, memantine, and pimagedin (ABT-711).

Active ingredients for treating obesity, preferably other than MCH antagonists, include lipase inhibitors and appetite suppressants.

A preferred example of a lipase inhibitor is orlistat.

Phentermine, Mazindole, Dexfenfluramine, Fluoxetine, Sibutramine, Baiamine, (8) Sibutramine, 8K-141716 and Ν6Ω-951 can be mentioned as examples of preferred appetite suppressing agents.

Another, different from the above active substance for the treatment of obesity is

- 34 012834 lipstatin.

In the context of the present invention, appetite suppressing agents are also included in the group of active substances that help fight obesity, among which it is especially worth highlighting as ₃ -agonists, thyreomimetics and antagonists ΝΡΥ. As an example of substances which in this case are preferred anti-obesity / appetite-suppressing agents, the following active substances can be mentioned: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A agonist (hereinafter abbreviated as CCK-A), a reverse inhibitor monoamine uptake (in particular sibutramine), sympathomimetic, serotonergic active substance (in particular dexfenfluramine or fenfluramine), dopamine antagonist (in particular bromocriptine), il agonist receptor mimetic of melanocytostimulating hormone, analog of melanocytostimulating hormone, cannabinoid receptor antagonist, MCH antagonist, OB protein (hereinafter referred to as leptin), leptin analog, leptin receptor agonist, galanin antagonist, gastrointestinal lipase inhibitor or, in particular, its lowering agent ) Other appetite-suppressing agents include bombesin agonists, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin-binding protein antagonists, glucagon-like peptide-1 receptor agonists, in particular, neurotrophic neurotrophins, and exendinase factors.

Active ingredients for treating arterial hypertension include dipeptidyl carboxypeptidase I (angiotensin converting enzyme) inhibitors, calcium antagonists, potassium channel opening agents, and angiotensin II antagonists.

Dipeptidyl carboxypeptidase I inhibitors include captopril, enalapril, alacetril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril and manidipine (hydrochloride).

Examples of calcium antagonists include nifedipine, amlodipine, efonidipine and nicardipine.

Levkromakalim, L-27152, AB0671 and ΝΣΡ-121 include potassium channel opening agents.

Antagonists of angiotensin II include telmisartan, losartan, candesartan, cilexetil, valsartan, irbesartan, C8-866 and E4177.

Active ingredients for the treatment of hyperlipidemia, including arteriosclerosis, include NMS-CoA reductase inhibitors and fibrate compounds.

NMS-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ΖΌ-4522 and their salts.

Compounds of the fibrate series include bezafibrate, clinofibrate, clofibrate, and simfibrate.

The active substances for the treatment of arthritis include ibuprofen.

Active ingredients for treating fear include chlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam and fludiazepam.

Active ingredients for treating depression include fluoxetine, fluvoxamine, imipramine, paroxetine and sertraline.

It is advisable to use the above active substances in this case in a dose of 1/5 of the usually recommended minimum dose to 1/1 of the usually recommended dose.

The present invention according to another variant of its implementation also relates to the use of at least one carboxamide compound proposed therein and / or one salt proposed therein to influence the nutritional behavior of a mammal. The use of the compounds of the invention for such purposes is primarily based on the fact that they can effectively reduce hunger, reduce appetite, respectively, control eating behavior and / or induce a feeling of fullness. The effect on eating behavior is primarily to reduce the amount of food consumed by a mammal. With this in mind, the compounds of the invention can preferably be used to reduce body weight. The compounds of the invention can also be used to prevent an increase in body weight, for example, in people who have previously taken measures to reduce their weight and are interested in maintaining subsequently achieved results in reducing their body weight. According to this variant embodiment of the invention, it is preferably a question of using the compounds provided therein for non-therapeutic purposes. In this regard, the non-therapeutic use of the compounds of the invention may consist of their use for cosmetic purposes, for example, for a person to change his appearance, or for his use by a person to improve his general condition. For non-therapeutic purposes, the compounds of the invention are preferably administered to mammals, especially humans, who have not been diagnosed with any eating disorder and have not been diagnosed with obesity, bulimia, diabetes and / or urination disorders, especially urinary incontinence.

The compounds of the invention are preferably administered for non-therapeutic purposes into the body of those people whose body mass index (or indicator), which is calculated as the ratio of body weight measured in kilograms to squared height (in meters), does not exceed 30,

- 35 012834 primarily does not exceed the value 25.

Below the invention is illustrated in more detail with examples.

Preliminary Explanations

For the compounds obtained in the examples below, there is usually data on their melting point, ¹ H-NMR spectrum and / or mass spectrum. Unless otherwise specified, to determine the values of Kg (retention time) used ready-made plates for thin layer chromatography (TLC) type Silica gel 60 E ₂₅₄ (firm E. Megsk, Darmstadt, article No. 1.05714) without saturation in the chamber. The values of K, which were determined using the material designated as alox, were obtained using ready-made plates for TLC type Alumina 60 E ₂₅₄ (E. Megsk company, Darmstadt, article No. 1.05713) without saturation in the chamber.

The HPLC analysis data indicated in the examples was obtained under the following conditions and parameters: column ΖοιΓαχ (Adyep! Tesipo1o§1e8), 8B (81ae Vopb) - C18; 3.5 microns; 4.6x75 mm; column temperature 30 ° C; flow rate 0.8 ml / min; injection volume of 5 μl; detection at a wavelength of 254 nm.

Method A. For elution, a mixture of water / acetonitrile / formic acid was used in a ratio varying from 9: 1: 0.01 to 1: 9: 0.01 for 9 minutes.

Method B. For elution, a mixture of water / acetonitrile / formic acid was used in a ratio varying from 9: 1: 0.01 to 1: 9: 0.01 for 4 minutes, and then for 6 minutes this ratio was 1: 9 : 0.01.

In the absence of more detailed data on the configuration of a particular compound, the question remains open whether these are pure enantiomers or whether partial or complete racemization has occurred.

The abbreviations and abbreviations used for the compounds used above and in the following description have the following meanings:

BOC anhydride tert-butyloxycarbonyl anhydride

qdi KDT DMF ethyl acetate / EJAc carbonyldiimidazole 1,1'-carbonyldi (1,2,4-triazole) dimethylformamide ethyl acetate ether GBT diethyl ether 1-hydroxybenzotriazole hydrate foundation Hyunig Ν, Ν-diisopropylethylamine

END concentrated Me methyl Meon methanol CT room temperature (about 20 ° C) Tbtu tetrafluoroborate 2- (1 H-benzotriazole-1-yl) -1,1,3,3- tetramethyluronium THF tetrahydrofuran eq. equivalent calculation discovered. calculated detected

General method I (combination using TBTU).

To a solution of a carboxylic acid (1.0 equiv.) In THF or DMF, triethylamine (1.5 equiv.) And TBTU (1.0 equiv.) Are successively added. The mixture is then stirred for a period of time, depending on the particular carboxylic acid, from 10 minutes to 12 hours, at a temperature in the range from room temperature to 40 ° C., after which an amine (1.0 eq.) Is added. Next, the reaction mixture is stirred for a period of time ranging from 30 minutes to 2 hours, at a temperature in the range from room temperature to 40 ° C, and then a semi-saturated solution of a11CO _{3 is} added. After extraction of the aqueous phase with an appropriate solvent (e.g. ethyl acetate), the organic phase is dried over magnesium sulfate. After that, the solvent was removed on a rotary evaporator, and the product was further purified by column chromatography or HPLC. The reaction can also be carried out in a Sieshzreeb automatic synthesizer.

General Method II (combination using CDT).

To a solution of primary amine (1.0 equiv.) In DMF (1 mmol / ml) at 0 ° C, add KDT (1 equiv.) And ne

- 36 012834 stirred at 0 ° C for the next 30 minutes Then the reaction mixture was heated to 25 ° C. and triethylamine (3 equiv.) Was added. Next, a secondary amine (1.0 equiv.) In DMF (0.25 mmol / ml) is added, after which the reaction solution is heated to a temperature in the range from 60 to 80 ° C and maintained at this temperature for a time period of 30 min up to 3 hours. Then DMF is removed in vacuo and the residue is dissolved in dichloromethane and a 5% solution of Na ₂ CO ₃ or with water and tert-butyl methyl ether. The organic phase is extracted with water and, if necessary, after drying over magnesium sulfate, the solvent is removed on a rotary evaporator, and the product is further purified by column chromatography or crystallization. The reaction can also be carried out in an automated synthesizer

Example 1.1. 7- (4-Chlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one.

C1

1.1. but. 4-bromo-2-nitrobenzoic acid.

To the reaction mixture of 82 g (0.379 mol) of 4-bromo-2-nitrotoluene in 700 ml of pyridine and 500 ml of water, 174.5 g (1.104 mol) of potassium permanganate are added portionwise over 8 hours. After that, the reaction mixture was stirred for 12 hours at 60 ° C. Then, an additional 20 g (0.092 mol) of 4-bromo-2-nitrotoluene, 50 ml of pyridine and 30 g (0.189 mol) of potassium permanganate are subsequently added. Next, the reaction mixture was stirred for 12 hours at 60 ° C, mixed with 200 ml of ethanol, and refluxed for 30 minutes. After that, the reaction mixture is filtered while hot and the filtrate is concentrated on a rotary evaporator. The resulting residue was alkalinized with 10% sodium hydroxide solution and extracted with diethyl ether. The aqueous phase is separated and acidified with dilute hydrochloric acid. The resulting crystals are filtered off, washed with water, dehydrated by azeotropic distillation with tetrahydrofuran and stirred with diisopropyl ether.

Yield: 37 g (32.8% of theory). C ₇ H ₄ Br _{4 4} (M = 246.018). Calcd .: molecular peak (M + Na) ⁺ : 268/270; detection: molecular peak (M + Na) ⁺ : 268/270. The value of K _g : 0.46 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 8: 2: 0.1).

1.1.b. 4'-Chloro-3-nitrobiphenyl-4-carboxylic acid.

To a solution of 1.92 g (7.81 mmol) of 4-bromo-2-nitrobenzoic acid in 30 ml of dioxane is successively added 0.288 g (0.25 mmol) of tetrakis (triphenylphosphine) palladium, 1.25 g (7.99 mmol) 4chlorophenylboronic acid in 30 ml of methanol and 2.31 g (21.7 mmol) of sodium carbonate in 14 ml of water. Next, the reaction mixture is kept in the microwave for an hour at a radiation power of 300 W and at a temperature of 110 ° C. After this, the reaction mixture is concentrated on a rotary evaporator, the residue is dissolved in water and using 1 molar hydrochloric acid, the pH value is set to

3. The aqueous solution is then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is distilled off on a rotary evaporator and the residue is stirred with diisopropyl ether.

Yield: 2.04 g (93.9% of theory). C ₁₃ H ₈ ClO ₄ (M = 277.666). Calcd .: molecular peak (M-H) ^- : 276; detection: molecular peak (M-H) ^- : 276. The value of K _g : 0.5 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 9: 1: 0.1).

1.1. in. 4-cyanomethylbenzoic acid ethyl ester.

To a solution of 147.5 g (2.263 mol) of potassium cyanide in 250 ml of hot water, a solution of 500 g (2.057 mol) of 4-bromomethylbenzoic acid ethyl ester in 1000 ml of ethanol is added dropwise. Next, the reaction mixture was refluxed for one hour, and then stirred for 12 hours at room temperature. After this, an additional 73.7 g (0.5 mol) of potassium cyanide is added and refluxed for two hours. The solid present in the reaction mixture is filtered off and the filtrate is filtered through a mixture of silica gel and activated carbon. The resulting filtrate was concentrated and the residue was poured into 1000 ml of water. The aqueous solution was extracted with tert-butyl methyl ether and the organic phase was extracted three times with water. After that, the organic phase is dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 8: 2).

Yield: 164.46 g (42.2% of theory). C ₁₁ H ₁₁ NO ₂ (M = 189.216). Calculation: molecular peak (M + H) ⁺ : 190; detection: molecular peak (M + H) ⁺ : 190. The value of K _g : 0.3 (silica gel, petroleum ether / acetic acid in the ratio of ethyl ether 8: 2).

1.1. 4-cyanomethylbenzoic acid.

A solution of 10 g (53 mmol) of ethyl 4-cyanomethylbenzoic acid and 2.02 ml of a 1 molar solution of sodium hydroxide in 100 ml of ethanol is refluxed for one hour. After this, the reaction solution was concentrated and the residue was mixed with a mixture of water and ice. Then, concentrated hydrochloric acid was added dropwise to the reaction solution until precipitation had ceased. This precipitate is filtered off, washed twice with water and dried.

- 37 012834

Yield: 4.7 g (55% of theory). C9H7NO ₂ (M = 161.162). Calcd .: molecular peak (M-H) ^- : 160; found: molecular peak (M-H) ^- : 160.

1.1. D. (4-Hydroxymethylphenyl) acetonitrile.

To a solution of 4.7 g (29 mmol) of 4-cyanomethylbenzoic acid in 250 ml of tetrahydrofuran, 5.17 g (32 mmol) of CDI are added and stirred until gas evolution ceases. This reaction mixture is then added dropwise to a solution of 3.29 g (87 mmol) of sodium borohydride in 200 ml of water so that the temperature does not rise above 30 ° C. After that, the reaction mixture is stirred for two hours and then its pH value is set to 3-4 with a solution of potassium hydrosulfate. It is then extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and the solvent is separated on a rotary evaporator.

Yield: 2.6 g (60.9% of theory). C9H9NO (M = 147.178). Calcd .: molecular peak (M-H) ^- : 146; detection: molecular peak (M-H) ^- : 146.

1.1. e. (4-Bromomethylphenyl) acetonitrile.

To a solution of 2.6 g (17.66 mmol) of (4-hydroxymethylphenyl) acetonitrile in 25 ml of tert-butyl methyl ether at 0 ° C. was added dropwise 0.86 ml (9 mmol) of phosphorus tribromide. Upon completion of the reaction, the reaction mixture at room temperature is mixed with water, the organic phase is separated and subsequently extracted with a solution of sodium bicarbonate and water. The organic phase is dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator.

Yield: 2.9 g (78.1% of theory). C ₉ H ₈ VGO (M = 210.075). Calcd .: molecular peak (M + H) ⁺ : 209/211; detection: molecular peak (M + H) ⁺ : 209/211.

1.1. g. (4-Pyrrolidin-1-ylmethylphenyl) acetonitrile.

0.446 ml (5.44 mmol) of pyrrolidine and 1.366 g (9.882 mmol) of potassium carbonate are added to 20 ml of dimethylformamide. Then, 1.038 g (4.941 mmol) of (4-bromomethylphenyl) acetonitrile was added with stirring and stirred for 12 hours at room temperature. After that, the reaction mixture was concentrated on a rotary evaporator and the residue was extracted with ethyl acetate and water. The organic phase is dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator.

Yield: 0.732 g (74% of theory).

C ₁₃ H _{1 &} S ₂ (M = 200.286).

Calcd .: molecular peak (M + H) ⁺ : 201; detection: molecular peak (M + H) ⁺ : 201.

The value of K _£ : 0.5 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.1.3 2- (4-Pyrrolidin-1-ylmethylphenyl) ethylamine.

A reaction mixture of 0.73 g (3.66 mmol) of (4-pyrrolidin-1-ylmethylphenyl) acetonitrile and 0.1 g of Raney nickel in 25 ml of a methanolic ammonia solution is hydrogenated for 9 hours at 50 ° C and a hydrogen pressure of 3 bar .

Yield: 0.72 g (96.4% of theory). C1 ₃ H ₂₀ ^ (M = 204.31). Calculation: molecular peak (M + H) ⁺ : 205; detection: molecular peak (M + H) ⁺ : 205. K _£ value: 0.23 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.1. and. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

A solution of 0.4 (1.44 mmol) of 4'-chloro-3-nitrobiphenyl-4-carboxylic acid, 0.29 g (1.44 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine, 0.46 g ( 1.44 mmol) TBTU, 0.19 g (1.44 mmol) of HOBT and 0.42 ml (3 mmol) of triethylamine in 30 ml of tetrahydrofuran are stirred at room temperature for 14

h. Then the reaction mixture was concentrated on a rotary evaporator, extracted with water and ethyl acetate and dried over magnesium sulfate. The product was purified by silica gel column chromatography (eluent: dichloromethane / methanol / ammonia mixture in a ratio of 90: 10: 1).

Yield: 0.47 g (70.3% of theory).

С26Н26СШ ₃ О ₃ (M = 463.96).

Calcd .: molecular peak (M + H) ⁺ : 464/466; detection: molecular peak (M + H) ⁺ : 464/466.

The value of K _£ : 0.36 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.1. K. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

A reaction mixture of 0.47 g (1.01 mmol) of [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3 nitrobiphenyl-4-carboxylic acid and 0.1 g of Raney nickel in 50 ml of methanol the ammonia solution is hydrogenated for 24 hours at 20 ° C and a hydrogen pressure of 3 bar. The crude product without purification is used in the subsequent reaction.

Yield: 0.46 g of crude product.

С26Н28СШ ₃ О (M = 433.98).

Calcd .: molecular peak (M + H) ⁺ : 434/436; detection: molecular peak (M + H) ⁺ : 434/436.

The value of K _£ : 0.34 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.1. l 7- (4-Chlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one.

0.46 g (1.06 mmol) of [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-aminobiphenyl-4

- 38 012834 carboxylic acid and 5 ml of formic acid are stirred for 3 hours at room temperature and for 2 hours at 100 ° C. Then the reaction mixture is mixed with water, alkalinized 6N. sodium hydroxide solution and the precipitate was separated by vacuum filtration. This precipitate is then dissolved in dichloromethane and dried over magnesium sulfate. The solvent was distilled off on a rotary evaporator and the residue was triturated with diisopropyl ether.

Yield: 0.3 g (64.6% of theory). Melting point: 178-179 ° C. С ₂₇ Н ₂₆ СШ ₃ О (M = 443.98). Calcd .: molecular peak (M + H) ⁺ : 444; found: molecular peak (M + H) ⁺ : 444. K value 0.35 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

Example 1.2 3- [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] -7-p-tolyl-3H-quinazolin-4-one.

1.2. but. 4'-methyl-3-nitrobiphenyl-4-carboxylic acid.

The specified connection receive analogously to example 1.1. b from 4-bromo-2-nitrobenzoic acid and 4-methylphenylboronic acid.

Yield: 1.48 g (70.8% of theory). C ₁₄ H _{1b #} O ₄ (M = 257.24). Calcd .: molecular peak (M-H) ^- : 256; detection: molecular peak (M-H) ^- : 256. The value of Kc is 0.54 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 9: 1: 0.1).

1.2.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-methyl-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 4'-methyl-3-nitrobiphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine.

Yield: 0.51 g (78.3% of theory). C ₂₇ H ₂ cX ₃ O ₃ (M = 443.55). Calcd .: molecular peak (M + H) ⁺ : 444; found: molecular peak (M + H) ⁺ : 444. K value 0.35 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.2. in. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-methyl-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1.k from [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-methyl-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.2 g (69.2% of theory). C ₂₈ H ₃ ^ ₃ O (M = 413.56). Calcd .: molecular peak (M + H) ⁺ : 414; detection: molecular peak (M + H) ⁺ : 414. 1%: 0.36 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

Example 1.3 3- [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] -7- (4-trifluoromethylphenyl) -3H-quinazolin-4one.

1.3. but. 4'-Trifluoromethyl-3-nitrobiphenyl-4-carboxylic acid.

The specified connection receive analogously to example 1.1. b from 4-bromo-2-nitrobenzoic acid and 4-trifluoromethylphenylboronic acid.

Yield: 1.24 g (49% of theory). C ₁₄ H ₈ P ^ O ₄ (M = 311.21). Calculation: molecular peak (M-H) ^- : 310; detection: molecular peak (M-H) ^- : 310. The value of Kc 0.3 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 9: 1: 0.1).

1.3.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4'-trifluoromethyl-3-nitrobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 1.1. And from 4'-trifluoromethyl-3-nitrobiphenyl-4 carboxylic acid and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine.

Yield: 0.36 g (49.3% of theory). C ₂₇ H ₂₆ P ₃ ^ O ₃ (M = 497.52). Calcd .: molecular peak (M + H) ⁺ : 498; detection: molecular peak (M + H) ⁺ : 498. Value 1%: 0.3 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.3. in. [2- (4-Pyrrolidin-1-methylmethyl) ethyl] 4'-trifluoromethyl-3-aminobiphenyl-4-carboxylic acid amide.

A reaction mixture of 0.1 g (0.2 mmol) of [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'trifluoromethyl-3-nitrobiphenyl-4-carboxylic acid and 0.08 g of platinum oxide in 50 ml ethyl acetate guide

- 39 012834 are filtered off at 20 ° C for 2.5 hours. After this, the catalyst is filtered off. The product was purified by silica gel column chromatography (eluent: dichloromethane / methanol / ammonia mixture in a ratio of 90: 10: 1).

Yield: 0.06 g (63.8% of theory). C ₂₇ H ₂ ^ ₃ ^ O (M = 467.53). Calculation: molecular peak (M + H) ⁺ : 468 detection: molecular peak (M + H) ⁺ : 468. The value of K _G : 0.46 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0, one).

Example 1.4 7- (4-Methoxyphenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one.

1.4. but. 4'-methoxy-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1.b from 4-bromo-2-nitrobenzoic acid and 4-methoxyphenylboronic acid.

Yield: 0.38 g (48.9% of theory). C _M 1 Ι _Η Ν () ₅ (M = 273.24). Calcd .: molecular peak (M-H) ^- : 272; detection: molecular peak (M-H) ^- : 272. The value of CG: 0.39 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 9: 1: 0.1).

1.4.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-methoxy-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1.k from 4'-methoxy-3-nitrobiphenyl-4 carboxylic acid and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine.

Yield: 0.23 g (57% of theory). C ₂₇ H ₂ ^ ₃ O ₄ (M = 459.55). Calcd .: molecular peak (M + H) ⁺ : 460; detection: molecular peak (M + H) ⁺ : 460. The value of K _G : 0.48 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.4. in. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4'-methoxy-3-aminobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 1.3. In from [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-methoxy-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.09 g (42% of theory). C ₂₇ H ₃ ^ ₃ O ₂ (M = 429.56). Calcd .: molecular peak (M + H) ⁺ : 430; detection: molecular peak (M + H) ⁺ : 430. The value of K _G : 0.44 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

Example 1.5 7- (3,4-Dichlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one.

1.5. but. 3 ', 4'-Dichloro-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1.b from 4-bromo-2-nitrobenzoic acid and 3,4-dichlorophenylboronic acid.

Yield: 0.72 g (28.4% of theory). C ₁₃ H ₇ C1 ^ O ₄ (M = 312.11). Calcd .: molecular peak (M-H) ^- : 310/312/314; detection: molecular peak (M-H) ^- : 310/312/314. The value of K _G : 0.39 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 9: 1: 0.1).

1.5.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 3 ', 4'-dichloro-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 3 ', 4'-dichloro-3-nitrobiphenyl-4 carboxylic acid and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine.

Yield: 0.47 g (64.2% of theory). C ₂₆ H ₂₅ Cl ₂ ^ O ₃ (M-498.41). Calcd .: molecular peak (M + H) ⁺ : 498/500/502; detection: molecular peak (M + H) ⁺ : 498/500/502. The value of K _G : 0.24 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.5. in. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 3 ', 4'-dichloro-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. From [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 3 ', 4'-dichloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.11 g (25% of theory). С ₂₆ Н ₂₇ С1 ₂ ^ О (М = 468.43). Calcd .: molecular peak (M + H) ⁺ : 468/470/472; detection: molecular peak (M + H) ⁺ : 468/470/472. The value of K _G : 0.46 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

Example 1.6 7- (3-Methoxyphenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one.

- 40 012834

1.6. but. 3'-Methoxy-3-nitrobiphenyl-4-carboxylic acid.

The specified connection receive analogously to example 1.1. b from 4-bromo-2-nitrobenzoic acid and 3-methoxyphenylboronic acid.

Yield: 0.39 g (73.6% of theory). C ₁₄ H ^ O ₅ (M = 273.24). Calcd .: molecular peak (M + H) ⁺ : 274; detection: molecular peak (M + H) ⁺ : 274. Value K _£ : 0.35 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 9: 1: 0.1).

1.6.6. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 3'-methoxy-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 3'-methoxy-3-nitrobiphenyl-4 carboxylic acid and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine.

Yield: 0.39 g (57% of theory). C ₂₇ H ₂ ^ ₃ O ₄ (M = 459.55). Calcd .: molecular peak (M + H) ⁺ : 460; detection: molecular peak (M + H) ⁺ : 460. K _£ value: 0.23 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.6. in. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 3'-methoxy-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1.k from [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 3'-methoxy-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.11 g (30.6% of theory). C ₂₇ H ₃ ^ ₃ O ₂ (M = 429.56). Calcd .: molecular peak (M + H) ⁺ : 430; detection: molecular peak (M + H) ⁺ : 430. K _£ value: 0.36 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

Example 1.7 7- (4-Fluorophenyl) -3- [2- (4-pyrrolidin-1-methylphenyl) ethyl] -3H-quinazolin-4-one.

1.7. but. 4'-Fluoro-3-nitrobiphenyl-4-carboxylic acid.

The specified connection receive analogously to example 1.1. b from 4-bromo-2-nitrobenzoic acid and 4-fluorophenylboronic acid.

Yield: 1.3 g (61.2% of theory). C ₁₃ H ₈ No. O ₄ (M = 261.21). Calculation: molecular peak (M-H) ^- : 260; detection: molecular peak (M-H) ^- : 260. K _£ value: 0.34 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 9: 1: 0.1).

1.7.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4'-fluoro-3-nitrobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 1.1. And from 4'-fluoro-3-nitrobiphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine.

Yield: 0.38 g (57.8% of theory). C ₂₆ H ₂₆ No. ₃ O ₃ (M = 447.51). Calcd .: molecular peak (M + H) ⁺ : 448; found: molecular peak (M + H) ⁺ : 448. K _£ value: 0.24 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.7. in. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4'-fluoro-3-aminobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 1.3. From [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-fluoro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.06 g (32% of theory). C ₂₆ H ₂₈ No. ₃ O (M = 417.53). Calcd .: molecular peak (M + H) ⁺ : 418; detection: molecular peak (M + H) ⁺ : 418. The value of K _£ : 0.63 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

Example 1.8 7- (4-Ethylphenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one.

1.8.a. 4'-vinyl-3-nitrobiphenyl-4-carboxylic acid.

The specified connection receive analogously to example 1.1. b from 4-bromo-2-nitrobenzoic acid and 4-vinylphenylboronic acid.

Yield: 0.58 g (53% of theory). C ₁₅ 11 _And G) ₄ (M = 269.25). Calcd .: molecular peak (M-H) ^- : 268; detection: molecular peak (M-H) ^- : 268. The value of K _£ : 0.39 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 9: 1: 0.1).

1.8.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-vinyl-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 4'-vinyl-3-nitrobiphenyl-4

- 41 012834 carboxylic acids and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine.

Yield: 0.38 g (56.8% of theory). C ₂₈ H ₂₉ No. ₃ O ₃ (M = 455.56). Calcd .: molecular peak (M + H) ⁺ : 456; Detection .: molecular peak (M + H) ^+: 456. The value K _I: 0.21 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1).

1.8.v. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4'-ethyl-3-aminobiphenyl-4-carboxylic acid.

The specified connection receive analogously to example 1.3. to from 4'-vinyl-3-nitrobiphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide.

Yield: 0.15 g (63.9% of theory). C ₂₈ H _{3; 3} H ₃ O (M = 427.59). Calcd .: molecular peak (M + H) ⁺ : 428; Detection .: molecular peak (M + H) ^+: 428. The value K _I: 0.47 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1).

Similarly to example 1.1. l receive the following compounds:

Example to ²⁰ Educt Total formula Mass spectrum 1pl G ° C1 Value Kg 1.1 4-chlorophenyl 1.1.L S ₂₇ Н2бСШзО 444 [M + H] ⁺ 178- 179 0.35 (A) 1.2 4-methylphenyl 1.2.c Crz ^ MzO 424 [M + H] ⁺ 157- 158 0.36 (A) 1.3 4-trifluoromethylphenyl 1.3.c С28Н2бГз ^ зО 478 [M + H] ⁺ 179- 181 0.4 (A) 1.4 4-methoxyphenyl 1.4.c ^ 281129 ^ 02 440 [M + H] ⁺ .143- 144 0.37 (A) 1.5 3,4-dichlorophenyl 1.5.-B С2 ₇ Н ₂₅ С1 ₂ МЗО 478/80/82 [M + H] ⁺ 148- 149 0.36 (A) 1.6 3-methoxyphenyl 1.6.c C ₂ 8Н ₂ 9НзО ₂ 440 [M + H] ⁺ wax 0.14 (A) 1.7 4-fluorophenyl 1.7.c SZUZBRIZO 428 [M + H] ⁺ 160- 161 0.45 (A) 1.8 4-ethylphenyl 1.8.c C ₂ 9 yz ^ zO 438 [M + H] ⁺ 165- 166 0.37 (A)

Note: the value of K _And : A = (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1). Example 1.9

1.9. but. 7- (4-Trifluoromethylphenyl) -2-methyl-3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin4-one.

A solution of 0.07 g (0.15 mmol) of [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4'-trifluoromethyl-3aminobiphenyl-4-carboxylic acid (see example 1.3.c) in 4 ml of acetic acid and 0.028 ml (0.3 mmol) of acetic anhydride was heated under reflux for 12 hours. Then the reaction solution was diluted with water, the pH was adjusted to 8 with a dilute sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over magnesium sulfate. The product was purified by silica gel column chromatography (eluent: dichloromethane / methanol / ammonia mixture in a ratio of 90: 10: 1).

Yield: 0.008 g (11% of theory). C ^ H ^ E ^ O (M = 491.56). Calcd .: molecular peak (M + H) ⁺ : 492; Detection .: molecular peak (M + H) ^+: 492. The value K _I: 0.36 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1).

Analogously to example 1.9.a receive the following compounds:

- 42 012834

Example about & Educt Total formula Mass spectrum G ° s] Value 1.9 4-trifluoromethylphenyl 1.3.c 029 ^ 3 ^ 0 492 [M + H] ⁺ wax 0.36 (A) 1.10 4-methylphenyl 1.2.c C ₂ 9H ₃ 1K ₃ O 437 [M + H] ⁺ wax 0.66 (A) 1.11 4-chlorophenyl 1.1.k S28N ₂ 8SShzO 458/60 [M + H] ⁺ 160- 163 0.40 (A)

Note: the value of K _£ : A = (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

Example 1.10. 2-Methyl-3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -7-p-tolyl-3H-quinazolin-4-one.

Example 1.11. 7- (4-Chlorophenyl) -2-methyl-3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4one.

Example 1.12.

1.12. but. 7- (4-Chlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -1H-quinazolin-2,4-dione.

A reaction mixture of 0.3 g (0.69 mmol) of [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3aminobiphenyl-4-carboxylic acid (see example 1.1.k) and 0, 1 g (0.65 mmol) of CDI in 50 ml of tetrahydrofuran is refluxed for 24 hours. After that, 0.1 g of CDI was additionally added, and the reaction mixture was refluxed for the next 24 hours. Then, the reaction mixture was concentrated on a rotary evaporator. The product was purified by silica gel column chromatography (eluent: dichloromethane / methanol / ammonia mixture in a ratio of 60: 1: 0.1).

Yield: 0.2 g (62.9% of theory). Melting point: 274-276 ° C. C ₂₇ H ₂₆ Cl ₃ O ₂ (M = 459.98).

Calcd .: molecular peak (M + H) ⁺ : 460/462; detection: molecular peak (M + H) ⁺ : 460/462. The value of K _£ : 0.1 (silica gel, dichloromethane / methanol / ammonia in a ratio of 50: 1: 0.1).

Example 1.13. 7- (4-Chlorophenyl) -3- {2- [4 - ((8) -2-methoxymethylpyrrolidin-1-ylmethyl) phenyl] ethyl} -3Hquinazolin-4-one.

1.13. but. [4- (2- (8) -Metoxymethylpyrrolidin-1-ylmethyl) phenyl] acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from 2- (8) -methoxymethylpyrrolidine and (4-bromomethylphenyl) acetonitrile.

Yield: 0.9 g (51.6% of theory). C ₁₅ H ₂₀ N ₂ O (M = 244.33). Calcd .: molecular peak (M + H) ⁺ : 245; found: molecular peak (M + H) ⁺ : 245. K _£ value: 0.3 (silica gel, cyclohexane / ethyl acetate in a 1: 1 ratio).

1.13. b. 2- [4- (2- (8) -Metoxymethylpyrrolidin-1-ylmethyl) phenyl] ethylamine.

The specified compound is obtained analogously to example 1.1.z from [4- (2- (8) -methoxymethylpyrrolidin-1 methylmethyl) phenyl] acetonitrile.

Yield: 0.5 g (54.7% of theory). C ₁₅ H ₂₄ N ₂ O (M = 248.37). Calcd .: molecular peak (M + H) ⁺ : 249; detection: molecular peak (M + H) ⁺ : 249. The value of K _£ : 0.3 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 20: 1: 0.1).

1.13. in. {2- [4- (2- (8) -Metoxymethylpyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4-carboxylic acid and 2- [4- (2- (8) -methoxymethylpyrrolidin-1-ylmethyl) phenyl] ethylamine.

Yield: 0.5 g (54.7% of theory). C ₂₈ H ₃₀ Cl ₃ O ₄ (M = 508.02). Calcd .: molecular peak (M + H) ⁺ : 508/510; detection: molecular peak (M + H) ⁺ : 508/510. The value of K _£ .: 0.6 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 20: 1: 0.1).

1.13. d. {2- [4- (2- (8) -methoxymethylpyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. From {2- [4- (2- (8) -methoxymethylpyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.24 g (51% of theory). C ₂₈ H ₃₂ Cl ₃ O ₂ (M = 478.03). Calcd .: molecular peak (M + H) ⁺ : 478/480; detection: molecular peak (M + H) ⁺ : 478/480. The value of K _£ : 0.2 (silica gel, dichloromethane / methanol / ammonia in a ratio of 10: 1: 0.1).

- 43 012834

Example 1.14. 7- (4-Chlorophenyl) -3- [2 - [(4-dimethylaminomethylphenyl) ethyl] -3H-quinazolin-4-one.

1.14. but. (4-Dimethylaminomethylphenyl) acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from dimethylamine and (4-bromomethylphenyl) acetonitrile.

Yield: 1.0 g (30% of theory). C _P H ₁₄ ^ (M = 174.24). Calcd .: molecular peak (M + H) ⁺ : 175; detection: molecular peak (M + H) ⁺ : 175. K _g value: 0.2 (silica gel, cyclohexane / ethyl acetate in a 1: 1 ratio).

1.14.b. 2- (4-Dimethylaminomethylphenyl) ethylamine.

The specified compound is obtained analogously to example 1.1.z from (4-dimethylaminomethylphenyl) acetonitrile.

Yield: 1.0 g of crude product. C _P H ₁₈ ^ (M = 178.28). Calcd .: molecular peak (M + H) ⁺ : 179; detection: molecular peak (M + H) ⁺ : 179. The value of K _g : 0.2 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 20: 1: 0.1).

1.14. in. [2- (4-Dimethylaminomethylphenyl) ethyl] 4'-chloro-3-nitrobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4-carboxylic acid and 2- (4-dimethylaminomethylphenyl) ethylamine.

Yield: 0.5 g (63.4% of theory). С ₂₄ Н ₂₄ СШ ₃ О ₃ (M = 437.93). Calcd .: molecular peak (M + H) ⁺ : 438/440; detection: molecular peak (M + H) ⁺ : 438/440. The value of Kg: 0.35 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 20: 1: 0.1).

1.14. g. [2- (4-Dimethylaminomethylphenyl) ethyl] amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. From [2- (4-dimethylaminomethylphenyl) ethyl] amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.2 g (43% of theory). С ₂₄ Н ₂₆ СШ ₃ О (M = 407.94). Calcd .: molecular peak (M + H) ⁺ : 408/410; detection: molecular peak (M + H) ⁺ : 408/410. The value of K _g : 0.2 (silica gel, dichloromethane / methanol / ammonia in a ratio of 20: 1: 0.1).

Example 1.15. 7- (4-Chlorophenyl) -3- [2- (4-piperidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one.

1.15. but. (4-piperidin-1-ylmethylphenyl) acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from piperidine and (4-bromomethylphenyl) acetonitrile.

Yield: 1.6 g (39% of theory). C ₁₄ H ₁₈ ^ (M = 214.31). Calcd .: molecular peak (M + H) ⁺ : 215; found: molecular peak (M + H) ⁺ : 215. The value is 1% 0.4 (silica gel, cyclohexane / ethyl acetate in a 1: 1 ratio).

1.15. b. 2- (4-piperidin-1-ylmethylphenyl) ethylamine.

The specified compound is obtained analogously to example 1.1.z from (4-piperidin-1 methylmethyl) acetonitrile.

Yield: 1.4 g (85.9% of theory). C ₁₄ H ₂ ^ ₂ (M = 218.34). Calcd .: molecular peak (M + H) ⁺ : 219; detection: molecular peak (M + H) ⁺ : 219. K _£ value: 0.2 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 20: 1: 0.1).

1.15. in. [2- (4-Piperidin-1-ylmethylphenyl) ethyl] 4'-chloro-3-nitrobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4 carboxylic acid and 2- (4-piperidin-1-ylmethylphenyl) ethylamine.

Yield: 0.07 g (40.7% of theory). С ₂₇ Н ₂₈ СШ ₃ О ₃ (М = 477.99). Calcd .: molecular peak (M + H) ⁺ : 478/480; detection: molecular peak (M + H) ⁺ : 478/480. The value of K _£ : 0.5 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 20: 1: 0.1).

1.15. d. [2- (4-Piperidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. In [2- (4-piperidin-1-ylmethylphenyl) ethyl] amide from 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.05 g (76.4% of theory). С ^ ШСМО (М = 448.01).

- 44 012834

Example 1.16. 7- (4-Chlorophenyl) -3- [2- (4-morpholin-4-ylmethylphenyl) ethyl] -3H-quinazolin-4-one.

1.16. but. (4-Morpholin-4-ylmethylphenyl) acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from morpholine and (4-bromomethylphenyl) acetonitrile.

Yield: 1.63 g (98.9% of theory). C _P H ₁₆ ^ O (M = 216.28). Calcd .: molecular peak (M + H) ⁺ : 217; found: molecular peak (M + H) ⁺ : 217. B _£ value: 0.33 (silica gel, cyclohexane / ethyl acetate in a 1: 1 ratio).

1.16. b. 2- (4-Morpholin-1-methylmethyl) ethylamine.

The specified compound is obtained analogously to example 1.1.3 from (4-morpholin-1-ylmethylphenyl) acetonitrile.

Yield: 1.65 g (99.4% of theory). C ₁₃ H ₂ ^ ₂ O (M = 220.31). Calcd .: molecular peak (M + H) ⁺ : 221; detection: molecular peak (M + H) ⁺ : 221. B _£ value: 0.54 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 9: 1: 0.1).

1.16. in. [2- (4-Morpholin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4 carboxylic acid and 2- (4-morpholin-1-ylmethylphenyl) ethylamine.

Yield: 0.53 g (76.6% of theory). С ₂₆ Н ₂₆ СШ ₃ О ₄ (М = 479.97). Calculation: molecular peak (M + H) ⁺ : 480/482; detection: molecular peak (M + H) ⁺ : 480/482. The value of B _£ : 0.5 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 90: 1: 0.1).

1.16. d. [2- (4-Morpholin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. In from [2- (4-morpholin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.45 g (90.6% of theory). С ₂₆ Н ₂₈ СШ ₃ О ₂ (М = 449.98). Calcd .: molecular peak (M + H) ⁺ : 450/452; detection: molecular peak (M + H) ⁺ : 450/452. Value B _£ : 0.67 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 90: 1: 0.1).

Similarly to example 1.1. l receive the following compounds:

Example κ ^ ν-χ- Educt Total formula Mass spectrum 1pl [° C] The value of K _g 1.13 L 1.13.G C ₂ 9NzoSShz0 ₂ 488/490 [M + H] ⁺ 133- 135 0.3 (V) 1.14 1.14.G С25Н ₂₄ С1ЗзО 418/420 [M + H] ⁺ 183 0.66 (V) 1.15 (L 1.15.G S ₂₈ N ₂₈ S ₃ O 458 [M + H] ⁺ 169- 170 0.4 (g) 1.16 Ss 1.16.G S ₂₇ H ₂₆ NW ₂ 460/462 [M + H] ⁺ 169- 170 0.77 (A)

Note: B £ value:

A = (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1),

B = (silica gel, dichloromethane / methanol / ammonia in a ratio of 10: 1: 0.1),

G = (silica gel, dichloromethane / ethanol / ammonia in a ratio of 20: 1: 0.1).

Example 1.17. 7- (4-Chlorophenyl) -3- {2- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] ethyl} -3H-quinazolin4-one.

1.17. but. (6-Chloropyridin-3-yl) acetonitrile.

- 45 012834

To a solution of 6.91 g (41.66 mmol) of potassium iodide and 2.24 g (49.01 mmol) of sodium cyanide in 400 ml of an ethanol / water mixture (9: 1 ratio), a solution of 7.5 g ( 41.66 mmol) of 2-chloro-5-chloromethylpyridine in 100 ml of ethanol. Then the reaction mixture is heated to 85 ° C and maintained at this temperature for five hours. After this, the solvent was almost completely distilled off in vacuo and the residue was extracted with water and ethyl acetate. The organic phase is washed three times with water and dried over sodium sulfate. The product was purified by silica gel column chromatography (eluent: dichloromethane / ethanol mixture).

Yield: 2.9 g (45.6% of theory). C ₇ H ₅ SC ₂ (M = 152.58). Calcd .: molecular peak (M + H) ⁺ : 151/153; detection: molecular peak (M + H) ⁺ : 151/153.

1.17. b. [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] acetonitrile.

A solution of 2.9 g (19 mmol) of (6-chloropyridin-3-yl) acetonitrile, 5.27 ml (38 mmol) of triethylamine and 2.1 ml (19 mmol) of Ν-methylpiperazine in 50 ml of n-butanol is heated to 180 ° C in a microwave oven and kept at this temperature for 2 hours. Then, the solvent was distilled off in vacuo, the residue was suspended in water and then extracted with ethyl acetate. The combined organic phases are extracted three times with water and dried over sodium sulfate. The product is purified by column chromatography on alox (eluent: 1: 1 petroleum ether / ethyl acetate mixture).

Yield: 1 g (24.6% of theory). Melting point: 58-59 ° C. C ₁₂ H ₁₆ ^ (M = 216.28). Calcd .: molecular peak (M + H) ⁺ : 217; detection: molecular peak (M + H) ⁺ : 217.

The value of K _£ : 0.35 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.17. in. 2- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] ethylamine.

The specified compound is obtained analogously to example 1.1. And from [6- (4-methylpiperazin-1-yl) pyridin3-yl] acetonitrile. Yield: 0.94 g (96% of theory). C ₁₂ H ₂ ^ ₄ (M = 220.32).

Calcd .: molecular peak (M + H) ⁺ : 221; detection: molecular peak (M + H) ⁺ : 221.

1.17. d. {2- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] ethyl} amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1.k from 4'-chloro-3-nitrobiphenyl-4-carboxylic acid and 2- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] ethylamine.

Yield: 0.48 g (36.7% of theory). Melting point: 158-159 ° C. С ₂₅ Н ₂₆ СШ ₅ О ₃ (М = 479.97).

Calculation: molecular peak (M + H) ⁺ : 480/482; detection: molecular peak (M + H) ⁺ : 480/482.

1.17. d. {2- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from {2- [6- (4-methylpiperazin-1yl) pyridin-3-yl] ethyl} amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.12 g (64% of theory). Melting point: 198-199 ° C. С ₂₅ Н ₂₈ СШ ₅ О (M = 449.98). Calcd .: molecular peak (M + H) ⁺ : 450/452; detection: molecular peak (M + H) ⁺ : 450/452.

1.17. e. 7- (4-Chlorophenyl) -3 - {(2- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] ethyl} -3H-quinazolin-4-one.

The specified compound is obtained analogously to example 1.1.1 from {2- [6- (4-methylpiperazin-1yl) pyridin-3-yl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid and formic acid.

Yield: 0.06 g (53.5% of theory). Melting point: 263-264 ° C. C ₂₆ H ₂₆ Cg ₅ O (M = 459.98).

Calcd .: molecular peak (M + H) ⁺ : 460/462; found: molecular peak (M + H) ⁺ : 4460/462.

Example 1.18. 7- (4-Chlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-benzo [0] [1,2,3] triazin-4-one.

1.18.a. 7- (4-Chlorophenyl) -3- (2- [4- (1-pyrrolidin-1-yl-ethyl) phenyl] ethyl} -3H-benzo [0] [1,2,3] triazin-4 one.

To a solution of 0.27 g (0.62 mmol) of [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3aminobiphenyl-4-carboxylic acid (see example 1.1.k) in 10 ml of methanol and the same amount of 1n. hydrochloric acid at a temperature of 0-5 ° C, a solution of 0.09 g (0.93 mmol) of sodium nitrite in 2 ml of water is slowly added dropwise. Then the reaction mixture was stirred for three hours at room temperature, after which it was diluted with 30 ml of water and made basic with an ammonia solution. The aqueous solution was extracted with ethyl acetate. The combined organic phases are washed three times with water, dried over sodium sulfate and filtered through activated carbon. Then, the solvent was removed and the residue was washed with diisopropyl ether.

Yield: 0.09 g (32.5% of theory). Melting point: 151-152 ° C. C ₂₆ H ₂₅ SS ₄ O (M = 444.96).

Calcd .: molecular peak (M + H) ⁺ : 445/447; detection: molecular peak (M + H) ⁺ : 445/447. The value of K _£ : 0.35 (silica gel, dichloromethane / ethanol in a ratio of 10: 1).

Example 1.19. 7- (4-Chlorophenyl) -3- (4-pyrrolidin-1-ylmethylbenzyl) -3H-benzo [0] [1,2,3] triazin-4-one.

- 46 012834

about

1.19. but. 4- (1-Pyrrolidin-1-yl-ethyl) benzonitrile.

The specified compound is obtained analogously to example 1.1.zh from piperidine and 4-bromomethylbenzonitrile.

Yield: 2.4 g (85.9% of theory). C ₁₂ H ₁₄ ^ (M = 186.25). Calcd .: molecular peak (M + H) ⁺ : 187; detection: molecular peak (M + H) ⁺ : 187. K _£ value: 0.63 (silica gel, dichloromethane / methanol / ammonia in a ratio of 8: 2: 1).

1.19.b. 4- (1-Pyrrolidin-1-ethyl) benzylamine.

The specified compound is obtained analogously to example 1.1.z from 4- (1-pyrrolidin-1-yl-ethyl) benzonitrile.

Yield: 2.42 g (98.7% of theory). C ₁₂ H ₁₈ ^ (M = 190.29). Calcd .: molecular peak (M + H) ⁺ : 191; detection: molecular peak (M + H) ⁺ : 191. The value of K _£ : 0.26 (silica gel, dichloromethane / methanol / ammonia in a ratio of 90: 10: 1).

1.19. in. 4- (1-Pyrrolidin-1-yl-ethyl) benzylamide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4 carboxylic acid and 2- (4- (1-pyrrolidin-1-yl-ethyl)) benzylamine.

Yield: 0.28 g (28.8% of theory). С ₂₅ Н ₂₄ СШ ₃ О ₃ (М = 449.94). Calcd .: molecular peak (M + H) ⁺ : 450/452; detection: molecular peak (M + H) ⁺ : 450/452.

1.19. d. 4- (1-Pyrrolidin-1-yl-ethyl) -benzylamide 3-amino-4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. In from 4- (1-pyrrolidin-1-yl-ethyl) benzylamide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.19 g (72.7% of theory). С ₂₅ Н ₂₆ СШ ₃ О (M = 419.95). Calcd .: molecular peak (M + H) ⁺ : 420/422; detection: molecular peak (M + H) ⁺ : 420/422.

1.19. d. 7- (4-Chlorophenyl) -3- [4- (1-pyrrolidin-1-yl-ethyl) benzyl] -3H-benzo [b] [1,2,3] triazin-4-one.

The specified compound is obtained analogously to example 1.18.a from 4- (1-pyrrolidin-1-yl-ethyl) benzylamide 3-amino-4'-chlorobiphenyl-4-carboxylic acid.

Yield: 0.045 g (31.4% of theory).

Melting point: 147-148 ° C. С ₂₅ Н ₂₃ СШ ₄ О (М = 430.94). Calcd .: molecular peak (M + H) ⁺ : 431/433; detection: molecular peak (M + H) ⁺ : 431/433. The value of K _£ : 0.3 (silica gel, dichloromethane / ethanol in a ratio of 10: 1).

Example 1.20. 5- (4-Fluorophenyl) -2- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] isoindol-1,3-dione.

1.20.a. 5-bromo-2- {2- [4- (1-pyrrolidin-1-yl-ethyl) phenyl] ethyl} isoindol-1,3-dione.

A solution of 0.8 g (3.52 mmol) of 5-bromisobenzofuran-1,3-dione and 0.72 g (3.52 mmol) of 2- (4-pyrrolidin-1 methylmethyl) phenylamine (see Example 1.1.h) in 10 ml of acetic acid is heated to 110 ° C and maintained at this temperature for 4 hours. After this, the reaction mixture is poured into water, made alkaline with 2N. sodium hydroxide solution and the precipitate is filtered off. This precipitate is then washed several times with water and dried.

Yield: 0.5 g (34.3% of theory). C ₂₁ H ₂₁ B ^ ₂ O ₂ (M = 413.31). Calcd .: molecular peak (M + H) ⁺ : 413/415; detection: molecular peak (M + H) ⁺ : 413/415.

1.20.b. 5- (4-Fluorophenyl) -2- {2- [4- (1-pyrrolidin-1-yl-ethyl) phenyl] ethyl} isoindol-1,3-dione.

The specified compound is obtained analogously to example 1.1.b from 5-bromo-2- {2- [4- (1-pyrrolidin-1ylethyl) phenyl] ethyl} isoindole-1,3-dione and 4-fluorophenylboronic acid.

Yield: 0.01 g (4.8% of theory). C ₂₇ H ₂₅ P ^ O ₂ (M = 428.51). Calcd .: molecular peak (M + H) ⁺ : 429; detection: molecular peak (M + H) ⁺ : 429.

Example 1.21. 7- (4-Chlorophenyl) -3- (2- [4- (4-phenylpiperidin-1-ylmethyl) phenyl] ethyl) -3H-quinazolin-4one.

- 47 012834

1.21 .a. [4- (4-Phenylpiperidin-1-ylmethyl) phenyl] acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from 4-phenylpiperidine and (4bromomethylphenyl) acetonitrile.

Yield: 3.8 g (98% of theory). C ₂₀ H ₂ ^ ₂ (M = 290.41). Calcd .: molecular peak (M + H) ⁺ : 291; detection: molecular peak (M + H) ⁺ : 291. The value of K _p : 0.5 (silica gel, cyclohexane / ethyl acetate in a ratio of 1: 1).

1.21.b. 2- [4- (4-Phenylpiperidin-1-ylmethyl) phenyl] ethylamine.

The specified compound is obtained analogously to example 1.1.z from [4- (4-phenylpiperidin-1 methylmethyl) phenyl] acetonitrile.

Yield: 3.6 g of crude product. C ₂₀ H ₂ ^ ₂ (M = 294.44). Calcd .: molecular peak (M + H) ⁺ : 295; detect molecular peak (M + H) ⁺ : 295.

The value of K _p : 0.49 (silica gel, dichloromethane / ethanol in a ratio of 20: 1).

1.21. in. 4'-chloro-3-nitrobiphenyl-4-carboxylic acid {2- [4- (4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} amide.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4 carboxylic acid and 2- [4- (4-phenylpiperidin-1-ylmethyl) phenyl] ethylamine.

Yield: 1.33 g (70.7% of theory). C ₃₃ H ₃₂ SS ₃ O ₃ (M = 554.09). Calcd .: molecular peak (M + H) ⁺ : 554/556; detection: molecular peak (M + H) ⁺ : 554/556. The value of K _p : 0.58 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 10: 1: 0.1).

1.21. d. {2- [4- (4-Phenylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. In from {2- [4- (4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.82 g (65.2% of theory). C ₃₃ H ₃₄ SS ₃ O (M = 524.11). Calcd .: molecular peak (M + H) ⁺ : 524/526/528; detection: molecular peak (M + H) ⁺ : 524/526/528. The value of K _p : 0.65 (silica gel, dichloromethane / methanol 10: 1).

Example 1.22. 7- (4-Chlorophenyl) -3- {2- [4- (4-phenylpiperazin-1-ylmethyl) phenyl] ethyl} -3H-quinazolin-4-one.

1.22. but. [4- (4-Phenylpiperazin-1-ylmethyl) phenyl] acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from 4-phenylpiperazine and (4-bromomethylphenyl) acetonitrile.

Yield: 3.7 g (97% of theory). C ₁₉ H ₂ ^ ₃ (M = 291.39). Calcd .: molecular peak (M + H) ⁺ : 292; found: molecular peak (M + H) ⁺ : 292. K _p value: 0.6 (silica gel, cyclohexane / ethyl acetate in a 1: 1 ratio).

1.22.b. 2- [4- (4-Phenylpiperazin-1-ylmethyl) phenyl] ethylamine.

The specified compound is obtained analogously to example 1.1.3 from [4- (4-phenylpiperazin-1-ylmethyl) phenyl] acetonitrile.

Yield: 1.1 g (28.6% of theory). C ₁₉ H ₂₅ ^ (M = 295.43). Calcd .: molecular peak (M + H) ⁺ : 296; detection: molecular peak (M + H) ⁺ : 296.

1.22. in. 4'-chloro-3-nitrobiphenyl-4-carboxylic acid {2- [4- (4-phenylpiperazin-1-methylmethyl) phenyl] ethyl} amide.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4-carboxylic acid and 2- [4- (4-phenylpiperazin-1-ylmethyl) phenyl] ethylamine.

Yield: 0.32 g (18.2% of theory). С ₃₂ Н ₃₃ СШ ₄ О ₃ (M = 555.08). Calcd .: molecular peak (M + H) ⁺ : 555/557; detection: molecular peak (M + H) ⁺ : 555/557.

1.22. d. {2- [4- (4-Phenylpiperazin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. B from {2- [4- (4-phenylpiperazin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.11 g (38.8% of theory). C ₃₂ H ₃₃ SS ₄ O (M = 525.09). Calcd .: molecular peak (M + H) ⁺ : 525/527; detection: molecular peak (M + H) ⁺ : 525/527.

Example 1.23. 7- (4-Chlorophenyl) -3- {2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} -3Hquinazolin-4-one.

- 48 012834

1.23. but. [4- (4-G idroxy-4-phenylpiperidin-1-ylmethyl) phenyl] acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from 4-hydroxy-4-phenylpiperidine and (4bromomethylphenyl) acetonitrile.

Yield: 3.8 g (98% of theory). C ₂₀ H ₂ ^ ₂ O (M = 306.41). Calcd .: molecular peak (M + H) ⁺ : 307; detection: molecular peak (M + H) ⁺ : 307. K _£ value: 0.1 (silica gel, cyclohexane / ethyl acetate in a 1: 1 ratio).

1.23. b. 2- [4- (4-Hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethylamine.

The specified compound is obtained analogously to example 1.1.z from [4- (4-hydroxy-4-phenylpiperidin-1 methylmethyl) phenyl] acetonitrile.

Yield: 3.36 g (92.1% of theory). C ₂₀ H ₂ ^ ₂ O (M = 310.44). Calcd .: molecular peak (M + H) ⁺ : 311; detection: molecular peak (M + H) ⁺ : 311. K _£ value: 0.1 (silica gel, dichloromethane / methanol / acetic acid in a ratio of 9: 1: 0.1).

1.23. in. (2- [4- (4-Hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-nitrobiphenyl4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4 carboxylic acid and 2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethylamine.

Yield: 1.2 g (65.3% of theory). С ₃₃ Н ₃₂ СШ ₃ О ₄ (М = 570.09). Calcd .: molecular peak (M + H) ⁺ : 570/572; detection: molecular peak (M + H) ⁺ : 570/572. The value of K _£ : 0.35 (silica gel, dichloromethane / methanol / ammonia in a ratio of 10: 1: 0.1).

1.23. d. {2- [4- (4-Hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. In from {2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 1.04 g (91.5% of theory). C ₃₃ H ₃₄ SS ₃ O ₂ (M = 540.11). Melting point: 175-180 ° C. Calcd .: molecular peak (M + H) ⁺ : 540/542/544; detection: molecular peak (M + H) ⁺ : 540/542/544. The value of K _£ : 0.34 (silica gel, dichloromethane / methanol / ammonia in a ratio of 10: 1: 0.1).

1.23. d. 7- (4-Chlorophenyl) -3- (2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl) -3H-quinazolin-4-one.

The specified compound is obtained analogously to example 1.1. L from {2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

Yield: 0.025 g (8.2% of theory). Melting point: 204-205 ° C. С ₃₄ Н ₃₂ СШ ₃ О ₂ (М = 550.10). Calcd .: molecular peak (M + H) ⁺ : 550/552; detection: molecular peak (M + H) ⁺ : 550/552. The value of K _£ : 0.46 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 10: 1: 0.1).

Example 1.24. 7- (4-Chlorophenyl) -3- {2- [4- (4-phenyl-3,6-dihydro-2H-piperidin-1-ylmethyl) phenyl] ethyl} -3H-quinazolin-4-one.

1.24.a. 7- (4-Chlorophenyl) -3- (2- [4- (4-phenyl-3,6-dihydro-2H-piperidin-1-ylmethyl) phenyl] ethyl) -3H-quinazolin-4-one.

The specified connection receive analogously to example 1.1. l of {2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid, obtained as a by-product in Example 1.23. d.

Yield: 0.08 g (27.1% of theory). Melting point: 166-167 ° C. C ₃₄ H ₃₀ SS ₃ O (M = 532.09). Calcd .: molecular peak (M + H) ⁺ : 532/534; detection: molecular peak (M + H) ⁺ : 532/534. The value of K _£ : 0.57 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 10: 1).

Example 1.25. 7- (4-Chlorophenyl) -3- {2- [4- (3-azaspiro [5.5] undec-3-ylmethyl) phenyl] ethyl} -3H-quinazolin-4-one

1.25.a. [4- (3-Azaspiro [5.5] undec-3-ylmethyl) phenyl] acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from 3-azaspiro [5.5] undecane and (4bromomethylphenyl) acetonitrile.

Yield: 3.38 g (98% of theory). C ₁₉ H ₂₆ ^ (M = 282.43). Calcd .: molecular peak (M + H) ⁺ : 283; found: molecular peak (M + H) ⁺ : 283. K _£ value: 0.56 (silica gel, cyclohexane / ethyl acetate in a 1: 1 ratio).

- 49 012834

1.25. b. 2- [4- (3-Azaspiro [5.5] undec-3-ylmethyl) phenyl] ethylamine.

The specified compound is obtained analogously to example 1.1.3 from [4- (3-azaspiro [5.5] undec-3ylmethyl) phenyl] acetonitrile.

Yield: 3.33 g (96.6% of theory). C ₁₉ H ₃ ^ ₂ (M = 286.46). Calcd .: molecular peak (M + H) ⁺ : 287; detection: molecular peak (M + H) ⁺ : 287. K _£ value: 0.18 (silica gel, dichloromethane / ethanol in a 20: 1 ratio).

1.25. in. {2- [4- (3-Azaspiro [5.5] undec-3-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4 carboxylic acid and 2- [4- (3-azaspiro [5.5] undec-3-ylmethyl) phenyl] ethylamine.

Yield: 1 g (52.5% of theory). C ₃₂ H ₃₆ S ₃ O ₃ (M = 546.11). Calcd .: molecular peak (M + H) ⁺ : 546/548; detection: molecular peak (M + H) ⁺ : 546/548. The value of K _£ : 0.3 (silica gel, dichloromethane / ethanol in a ratio of 20: 1).

1.25. d. {2- [4- (3-Azaspiro [5.5] undec-3-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.3. In from {2- [4- (3-azaspiro [5.5] undec-3ylmethyl) phenyl] ethyl} amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.8 g (84.7% of theory). С ₃₂ Н ₃₈ СШ ₃ О (M = 516.13). Calcd .: molecular peak (M + H) ⁺ : 516/518; detection: molecular peak (M + H) ⁺ : 516/518. The value of K _£ : 0.38 (silica gel, dichloromethane / methanol in a ratio of 10: 1).

Example 1.26. 7- (4-Chlorophenyl) -3- (2- {4- [4- (pyridin-2-yloxy) piperidin-1-ylmethyl] phenyl} ethyl) 3H-quinazolin-4-one.

1.26. but. {4- [4- (Pyridin-2-yloxy) piperidin-1-ylmethyl] phenyl} acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from 2- (piperidin-4-yloxy) pyridine and (4-bromomethylphenyl) acetonitrile.

Yield: 0.91 g (49.8% of theory). C1 ₉ H ₂ ^ ₃ O (M = 307.39). Calcd .: molecular peak (M + H) ⁺ : 308; detection: molecular peak (M + H) ⁺ : 308. K _£ value: 0.49 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.26.b. 2- {4- [4- (Pyridin-2-yloxy) piperidin-1-ylmethyl] phenyl} ethylamine.

The specified compound is obtained analogously to example 1.1.z from {4- [4- (pyridin-2-yloxy) piperidin1-ylmethyl] phenyl} acetonitrile.

Yield: 0.92 g (99.8% of theory). C [ ₉ H ₂₅ ^ O (M = 311.43). Calcd .: molecular peak (M + H) ⁺ : 312; detection: molecular peak (M + H) ⁺ : 312. The value of K _£ : 0.16 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.26. in. (2'{4- [4- (Pyridin-2-yloxy) piperidin-1-ylmethyl] phenyl} ethyl) amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4-carboxylic acid and 2- {4- [4- (pyridin-2-yloxy) piperidin-1-ylmethyl] phenyl} ethylamine.

Yield: 0.8 g (97.2% of theory). C ₃₂ N _M SSH ₄ O ₄ (M = 571.08). Calcd .: molecular peak (M + H) ⁺ : 571/573; detection: molecular peak (M + H) ⁺ : 571/573. The value of K _£ : 0.52 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.26. d. (2- {4- [4- (Pyridin-2-yloxy) piperidin-1-ylmethyl] phenyl} ethyl) 4'-chloro-3-aminobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 1.3. In from (2- {4- [4- (pyridin-2-yloxy) piperidin-1-ylmethyl] phenyl} ethyl) amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.38 g (50% of theory). C ₃₂ H ₃₃ SS ₄ O ₂ (M = 541.09). Calcd .: molecular peak (M + H) ⁺ : 541/543; detection: molecular peak (M + H) ⁺ : 541/543. The value of K _£ : 0.5 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

Example 1.27. 7- (4-Chlorophenyl) -3- (2- {4- [4- (pyridin-2-ylamino) piperidin-1-ylmethyl] phenyl} ethyl) 3H-quinazolin-4-one.

1.27.a. {4- [4- (Pyridin-2-ylamino) piperidin-1-ylmethyl] phenyl} acetonitrile.

- 50 012834

The specified compound is obtained analogously to example 1.1.zh from 2- (piperidin-4-ylamino) pyridine and (4-bromomethylphenyl) acetonitrile.

Yield: 1.57 g (86.1% of theory). C ₁₉ H ₂₂ ^ (M = 306.41). Calcd .: molecular peak (M + H) ⁺ : 307; detection: molecular peak (M + H) ⁺ : 307. The value of K _G : 0.43 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.27.b. 2- {4- [4- (Pyridin-2-ylamino) piperidin-1-ylmethyl] phenyl} ethylamine.

The specified compound is obtained analogously to example 1.1.z from {4- [4- (pyridin-2-ylamino) piperidin-1-ylmethyl] phenyl} acetonitrile.

Yield: 1.62 g (99.8% of theory). C ₁₉ H ₂₆ ^ (M = 310.44). Calcd .: molecular peak (M + H) ⁺ : 311; detection: molecular peak (M + H) ⁺ : 311. The value of K _G : 0.1 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.27. in. (2- (4- [4- (pyridin-2-ylamino) piperidin-1-ylmethyl] phenyl} ethyl) 4'-chloro-3-nitrobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 1.1. And from 4'-chloro-3-nitrobiphenyl-4-carboxylic acid and 2- {4- [4- (pyridin-2-ylamino) piperidin-1-ylmethyl] phenyl} ethylamine.

Yield: 0.36 g (43.8% of theory). С ₃₂ Н ₃₂ СШ ₅ О ₃ (М = 570.09). Calcd .: molecular peak (M + H) ⁺ : 570/572; detection: molecular peak (M + H) ⁺ : 570/572. The value of K _G : 0.28 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

1.27. d (2- {4- [4- (pyridin-2-ylamino) piperidin-1-ylmethyl] phenyl} ethyl) amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.3.b from (2- {4- [4- (pyridin-2ylamino) piperidin-1-methylmethyl] phenyl} ethyl) amide 4'-chloro-3-nitrobiphenyl-4-carboxylic acid.

Yield: 0.29 g (85.7% of theory). C ₃₂ H ₃₄ SS ₅ O (M = 540.11). Calcd .: molecular peak (M + H) ⁺ : 540/542; detection: molecular peak (M + H) ⁺ : 540/542. The value of K _G : 0.27 (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1).

Similarly to example 1.1. l receive the following compounds:

Example Κ ^ -Ν-Χ- Educt Total formula Mass spectrum 1pl GY Value K _G 1.21 ABOUT ~ ss 1.21.G СзЛгСШзО 534/536 [M + H] ⁺ 178- 179 0.72 (D) 1.22 'Smiling 1.22.g С ₃₃ Нз1ССШ ₄ О 535/537 [M + H] ⁺ 199- 200 1.23 about b 1.23.G Sz ₄ Nz2SShzO2 550/552 [M + H] ⁺ 204- 205 0.46 (E) Example -Ν-Χ- Educt Total formula Mass spectrum % l G ° s] Value 1.24 about 1.23.G SzdnzoSZhzO 532/534 [M + H] ⁺ 166- 167 0.57 (D) 1.25 1.25.G SZZNzeSShzO 526/528 [M + H] ⁺ 184- 185 0.62 (D) 1.26 about to / to / 1.26.G Szznztsshdog 551/553 [M + H] ⁺ 154- 158 0.46 (A) 1.27 about 1.27.G СззНзгСЙ ^ О 550/552 [M + H] ⁺ 164- 166 0.45 (A)

Note: _KG value:

A = (silica gel, dichloromethane / methanol / ammonia in a ratio of 9: 1: 0.1),

D = (silica gel, dichloromethane / ethanol in a ratio of 10: 1),

Ε = (silica gel, dichloromethane / ethanol / ammonia in a ratio of 10: 1: 0.1).

- 51 012834

Example 1.28. 7- (4-Chlorophenyl) -3- {2- [4- (4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} -3H-benzo [4] [1,2,3] triazin-4-one.

1.28.a. 7- (4-Chlorophenyl) -3- {2- [4- (4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} -3H-benzo [4] [1,2,3] triazin-4-one.

The specified compound is obtained analogously to example 1.18.a from {2- [4- (4-phenylpiperidin-1 methylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

Yield: 0.13 g (50.9% of theory). Melting point: 183-184 ° C. C ₃₃ H ₃₁ SS ₄ O (M = 535.09). Calcd .: molecular peak (M + H) ⁺ : 535/537; detection: molecular peak (M + H) ⁺ : 535/537. The value of K _£ : 0.66 (silica gel, dichloromethane / ethanol in a ratio of 10: 1).

Example 1.29. 7- (4-Chlorophenyl) -3- {2- [4 - ([4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} -3benzo [4] [1,2,3] triazin-4- it.

1.29. but. 7- (4-Chlorophenyl) -3 - {2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} -3H-benzo [ά] [1,2,3] triazin-4 -it.

The specified compound is obtained analogously to example 1.18.a from {2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

Yield: 0.21 g (68.7% of theory). Melting point: 265-266 ° C. C ₃₃ H ₃₁ SC ₄ O ₂ (M = 551.09). Calcd .: molecular peak (M + H) ⁺ : 551/553; detection: molecular peak (M + H) ⁺ : 551/553. The value of K _£ : 0.53 (silica gel, dichloromethane / ethanol in a ratio of 10: 1).

Example 1.30. 7- (4-Chlorophenyl) -3- {2- [4- (3-azaspiro [5.5] undec-3-ylmethyl) phenyl] ethyl} -3H-benzo [4] [1,2,3] triazin-4 -it.

1.30.a. 7- (4-Chlorophenyl) -3- {2- [4- (3-azaspiro [5.5] undec-3-ylmethyl) phenyl] ethyl} -3H-benzo [4] [1,2,3] triazin-4 -it.

The specified compound is obtained analogously to example 1.18.a from {2- [4- (3-azaspiro [5.5] undec-3ylmethyl) phenyl] ethyl} amide 4'-chloro-3-aminobiphenyl-4-carboxylic acid.

Yield: 0.14 g (54.9% of theory). Melting point: 165-166 ° C. C ₃₂ H ₃₅ SS ₄ O (M = 527.11). Calcd .: molecular peak (M + H) ⁺ : 527; detection: molecular peak (M + H) ⁺ : 527. K £ value: 0.56 (silica gel, dichloromethane / ethanol in a 10: 1 ratio).

1.31.a. 2- [2- (4-Bromophenyl) ethoxy] tetrahydropyran.

To a solution of 4.83 g (24.02 mmol) of 2- (4-bromophenyl) ethanol in 12 ml of dichloromethane at 0 ° C, 0.025 g of p-toluenesulfonic acid and 2.575 ml (28.22 mmol) of dihydropyran are successively added. After that, the reaction mixture was stirred for three hours at room temperature. Then the reaction mixture was extracted with sodium bicarbonate solution and the organic phase was dried over sodium sulfate. The product was purified by column chromatography on alox (eluent: 8: 2 cyclohexane / ethyl acetate).

Yield: 37 g (32.8% of theory). C ₁₃ H ₁₇ BrO ₂ (M = 285.18). Calcd .: molecular peak (M) ⁺ : 284/286; found: molecular peak (M) ⁺ : 284/286.

1.31.b. 4- [2- (Tetrahydropyran-2-yloxy) ethyl] benzaldehyde.

To a solution of 5 g (17.53 mmol) of 2- [2- (4-bromophenyl) ethoxy] tetrahydropyran in 80 ml of tetrahydrofuran at -70 ° C, 11.5 ml (18.41 mmol) of 1.6 molar are added dropwise. a solution of n-butyllithium and stirred for one hour at this temperature. After this, 2.8 ml (36.46 mmol) of dime are added dropwise.

- 52 012834 tilformamide and the reaction mixture is stirred for another 2 hours at -70 ° C. Then the reaction mixture is mixed with a solution of ammonium chloride and extracted with ethyl acetate. The combined organic phases are extracted three times with saturated sodium chloride and dried over sodium sulfate. The product was purified by silica gel column chromatography (eluent: 6: 4 cyclohexane / ethyl acetate).

Yield: 2.8 g (68.2% of theory). C ₁₄ H ₁₈ O ₃ (M = 234.29). Calcd .: molecular peak (M + H) ⁺ : 235; found: molecular peak (M + H) ⁺ : 235. Kg value: 0.57 (silica gel, petroleum ether / ethyl acetate in a 3: 1 ratio).

1.31. in. 4- (2-Hydroxyethyl) benzaldehyde.

A solution of 2.8 g (11.95 mmol) of 4- [2- (tetrahydropyran-2-yloxy) ethyl] benzaldehyde in a mixture of 48 ml of 1 molar hydrochloric acid and 60 ml of acetone is stirred for 5 hours at 5 ° C. Then the reaction mixture is mixed with 140 ml of a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic phases are extracted three times with water and dried over sodium sulfate. The product was purified by silica gel column chromatography (eluent: 1: 1 cyclohexane / ethyl acetate).

Yield: 1.3 g (72.4% of theory). CdH ₁₀ O ₂ (M = 150.17). Calcd .: molecular peak (M + H) ⁺ : 151; found: molecular peak (M + H) ⁺ : 151. Value K _g : 0.52 (silica gel, petroleum ether / ethyl acetate in a 1: 1 ratio).

1.31. g. 2- (4- [1,3] dioxan-2-ylphenyl) ethanol.

A suspension of 9.4 g (62.59 mmol) of 4- (2-hydroxyethyl) benzaldehyde, 15.83 ml (219.07 mmol) of 1,3-propanediol, 0.3 g of p-toluenesulfonic acid and 150 ml of toluene for three hours heated under reflux. Then the reaction mixture was extracted three times with saturated sodium bicarbonate solution and the organic phase was dried over sodium sulfate.

Yield: 8 g (61.4% of theory). C1 ₂ H1 ₆ O ₃ (M = 208.26). Calcd .: molecular peak (M + H) ⁺ : 209; detection: molecular peak (M + H) ⁺ : 209.

1.31. d. 2- (4- [1,3] dioxan-2-ylphenyl) methanesulfonic acid ethyl ester.

g (38.41 mmol) of 2- (4- [1,3] dioxan-2-ylphenyl) ethanol and 10.65 ml (42.25 mmol) of triethylamine are dissolved in 300 ml of dichloromethane and mixed with 3 at 0 ° C. 27 ml of methanesulfonic acid chloride dissolved in 50 ml of dichloromethane. Then the reaction mixture was stirred for one hour at room temperature, after which it was extracted three times with water and the organic phase was dried over sodium sulfate. The product was purified by silica gel column chromatography (eluent: 1: 1 petroleum ether / ethyl acetate mixture).

Yield: 7.7 g (70% of theory). ScN1 ₈ O ₅ 8 (M = 286.34). Calcd .: molecular peak (M + H) ⁺ : 287; found: molecular peak (M + H) ⁺ : 287. Value K _g : 0.49 (silica gel, petroleum ether / ethyl acetate in a 1: 1 ratio).

1.31. e. (E) -3- (3-Bromophenyl) acryloylazide.

To a solution of 25 g (111.1 mmol) of (E) -3- (3-bromophenyl) acrylic acid and 15.26 ml (110.10 mmol) of triethylamine in 800 ml of acetone at 0 ° C., 11.5 ml are added dropwise. (121.11 mmol) of chloroformic acid ethyl ester. After an hour, also at 0 ° C., 11.45 g (176.16 mmol) of sodium azide dissolved in 88 ml of distilled water are added dropwise. After this, the reaction mixture was allowed to warm to room temperature and then it was poured into 1.3 L of a mixture of water and ice. The precipitate formed is filtered off, washed with water and dried in a drying chamber with air circulation at 30 ° C.

Yield: 21.1 g (76.1% of theory). C ₉ H ₆ Br ^ O (M = 252.07). Calcd .: molecular peak (M + H) ⁺ : 256/258; detection: molecular peak (M + H) ⁺ : 256/258. The value of K _g : 0.85 (silica gel, petroleum ether / ethyl acetate in a ratio of 1: 1).

1.31. g. 6-Bromo-2H-isoquinolin-1-one.

150 g of biphenyl ether and 7.08 ml (29.75 mmol) of tributylamine are heated to 100 ° C. At this temperature, 5 g (19.83 mmol) of (E) -3- (3-bromophenyl) acryloyl azide are added, after which it is heated to 195-205 ° C and maintained at this temperature for 2 hours. Then the reaction mixture is allowed to cool and it is then poured into chilled p-hexane. The precipitate was filtered off and washed with a mixture of chilled n-hexane and diethyl ether. After that, the solid is dried in a drying chamber with air circulation at 50 ° C. This solid is then stirred with a mixture of diisopropyl ether and ethyl acetate and the drying process is repeated.

Yield: 0.6 g (13.5% of theory). C ₉ H ₆ Br ^ O (M = 224.05). Calcd .: molecular peak (M + H) ⁺ : 224/226; detection: molecular peak (M + H) ⁺ : 224/226.

1.31. 6- (4-Chlorophenyl) -2H-isoquinolin-1-one.

A reaction mixture of 0.57 g (2.54 mmol) of 6-bromo-2H-isoquinolin-1-one, 0.398 g (2.54 mmol) of 4-chlorophenylboronic acid, 2.6 ml of a 2 molar solution of sodium carbonate in 20 ml of dioxane and 5 ml of methanol is heated in a microwave oven to 110 ° C and maintained at this temperature for two hours. After that, the reaction mixture is poured into water, the precipitate is filtered off and dried in a drying chamber with air circulation at 40 ° C.

- 53 012834

Yield: 0.42 g (64.6% of theory). C1 ₅ H1 ₀ C1O (M = 255.70). Calcd .: molecular peak (M + H) ⁺ : 256/258; detection: molecular peak (M + H) ⁺ : 256/258. The value of K _£ : 0.6 (silica gel, dichloromethane / ethanol in a ratio of 10: 1).

1.31 .i. 2- [2- (4-Formylphenyl) ethyl] -6- (4-chlorophenyl) -2H-isoquinolin-1-one.

A solution of 0.41 g (1.6 mmol) of 6- (4-chlorophenyl) -2H-isoquinolin-1-one in 10 ml of dimethylformamide is mixed with 0.18 g (1.6 mmol) of potassium tert-butylate and stirred for 30 min at 50 ° C. Then, 0.46 g (1.6 mmol) of 2- (4- [1,3] dioxan-2-ylphenyl) ethyl methanesulfonic acid ester is added. Then the reaction mixture is heated in a microwave oven to 180 ° C and maintained at this temperature for five hours, after which it is poured into a 10% citric acid solution. Then extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate mixture in a ratio ranging from 3: 1 to 1: 1).

Yield: 0.15 g (24.1% of theory). С ₂₄ Н1 ₈ С1ЫО ₂ (М = 387.87). Calcd .: molecular peak (M + H) ⁺ : 388/390; detection: molecular peak (M + H) ⁺ : 388/390. The value of K _£ : 0.7 (silica gel, petroleum ether / ethyl acetate in a ratio of 1: 1).

1.31.k. 6- (4-Chlorophenyl) -2- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -2H-isoquinolin-1-one.

0.14 g (0.36 mmol) of 2- [2- (4-formylphenyl) ethyl] -6- (4-chlorophenyl) -2H-isoquinolin-1-one and 0.03 ml (0.36 mmol) of pyrrolidine dissolved in 40 ml of dichloromethane. After that, the pH of the mixture is set to three with glacial acetic acid. Then, 0.076 g (0.36 mmol) of sodium triacetoxyborohydride was added and stirred for 48 hours at room temperature. Then the reaction mixture was extracted with a 2 molar solution of sodium carbonate and dried over sodium sulfate. The product is purified by silica gel column chromatography (eluent: dichloromethane / ethanol mixture in a ratio ranging from 10: 1 to 1: 1).

Yield: 0.04 g (25% of theory). Melting point: 136-137 ° C. C ₂₈ H ₂₇ Cl ₂ O (M = 442.99). Calcd .: molecular peak (M + H) ⁺ : 443; detection: molecular peak (M + H) ⁺ : 443. K _£ value: 0.5 (silica gel, dichloromethane / methanol 10: 1).

Similarly to examples 1.1-1.31 receive the following compounds:

- 54 012834

Example β / ιΡν-χ- to ²⁰ 1.43 ss 1.44 Aa 1.45 Ss d ^ A 1.46 Ss well 1.47 4X 1.48 ABOUT · 7 OMe 1.49 0 <4 7 ^ 1.50 one . 7 ^ 1.51 ss X7 1.52 Ss 7 ’ 1.53 ss 7 ' 1.54 Ss 4X

Example κ'κ ² ν-χ- to ²⁰ 1.55 0 mx ° 1.56 7 ’ 1.57 ABOUT / ° o \ 1.58 about ⁷ 1.59 <A > 0 1.60 Ον >> 7 1.61 Me? H 1.62 > 0

- 55 012834

5.83 g (29.0 mmol) of 4-bromobenzoic acid are dissolved in 50 ml of dioxane and 29 ml of a 2 molar solution of sodium carbonate. Then, 4.5 g (29.0 mmol) of 4-chlorophenylboronic acid and 1.68 g (1.45 mmol) of tetrakis (triphenylphosphine) palladium are successively added and the reaction mixture is refluxed for 6 hours. The hot reaction solution is vacuum filtered through a glass fiber filter. The filtrate was extracted with ethyl acetate. The aqueous phase is acidified with citric acid and stirred for one hour at 0 ° C. The precipitate formed is filtered off, washed with water and dried in vacuo.

Yield: 5.1 g (75.6% of theory). C1 ₃ H ₉ C1O ₂ (M = 232.668). Calcd .: molecular peak (M-H) ^- : 231/233; found: molecular peak (M-H) ^- : 231/233.

2.1.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid.

To a suspension of 251 mg (1.08 mmol) of 4'-chlorobiphenyl-4-carboxylic acid in 5 ml of THF, 471 mg (1.47 mmol) of TBTU and 0.26 ml (1.47 mmol) of Hunig base are added at room temperature. The reaction mixture was stirred for 10 minutes, and then 200 mg (0.98 mmol) of 2- (4-pyrrolidin-1-methylphenyl) ethylamine was added (see Example 1.1.h). After this, the mixture is left to mix overnight. Then the reaction solution is mixed with a saturated solution of ΙαΙ 1CO ₃ , the aqueous phase is extracted with ethyl acetate, and the organic phase is dried over magnesium sulfate. After that, the solvent was distilled off on a rotary evaporator and the residue was stirred with tert-butyl methyl ether upon heating. The solid formed is filtered off, washed with a small amount of tert-butyl methyl ether and dried in air.

Yield: 210 mg (51.2% of theory). C ₂₆ H ₂₇ SC ₂ O (M = 418.971). Calcd .: molecular peak (M + H) ⁺ : 419/421; detection: molecular peak (M + H) ⁺ : 419/421. Value B _£ : 0.57 (silica gel, dichlorome-

0.88 ml (8.38 mmol) of diethylamine is dissolved in 30 ml of acetone and 2.1 g (15.2 mmol) of potassium carbonate and 1.6 g (7.62 mmol) of (4-bromomethylphenyl) are successively added to the resulting solution. acetonitrile (see example 1.1.e). The reaction mixture was stirred for 2 hours at room temperature, after which it was filtered through a glass frit and then washed with ethyl acetate. The filtrate was concentrated on a rotary evaporator and extracted with water and ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. Subsequently, the product was purified by silica gel column chromatography (eluent: dichloromethane / methanol 9: 1).

Yield: 900 mg (58.4% of theory). C ₁₃ H ₁₈ ^ (M = 202.30). Calcd .: molecular peak (M + H) ⁺ : 203; found: molecular peak (M + H) ⁺ : 203. B _£ value: 0.65 (silica gel, dichloromethane / methanol in a 9: 1 ratio).

2.2. b. 2- (4-Diethylaminomethylphenyl) ethylamine.

A solution of 900 mg (4.45 mmol) of (4-diethylaminomethylphenyl) acetonitrile in 20 ml of methanolic ammonia solution is mixed with 100 mg of Raney nickel and shaken in an autoclave at 50 ° C and a pressure of 5 bar. After separation of the catalyst by vacuum filtration, the solvent was removed on a rotary evaporator.

Yield: 900 mg (98.0% of theory). C ₁₃ H ₂₂ Ng (M = 206.334). Calcd .: molecular peak (M + H) ⁺ : 207; detection: molecular peak (M + H) ⁺ : 207. Value B _£ : 0.12 (silica gel, dichloromethane / methanol ^ H ₃ in a ratio of 9: 1: 0.1).

- 56 012834

2.2.c. [2- (4-Diethylaminomethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 2.1.b from 4'-chlorobiphenyl-4-carboxylic acid (248 mg, 1.07 mmol) and 2- (4-diethylaminomethylphenyl) ethylamine (200 mg, 0.97 mmol).

Yield: 280 mg (68.6% of theory). C ₂₆ H ₂₉ SC ₂ O (M = 420.987). Calcd .: molecular peak (M + H) ⁺ : 421/423; detection: molecular peak (M + H) ⁺ : 421/423. The value of K _£ : 0.49 (silica gel, dichloromethane / methanoa / ΝΙ 1 ₃ in a ratio of 9: 1: 0.1).

Example 2.3 [2- (4-Piperidin-1-ylmethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

2.3.a. [2- (4-Piperidin-1-ylmethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.1.b from 4'-chlorobiphenyl-4-carboxylic acid (234 mg, 1.01 mmol) and 2- (4-piperidin-1-ylmethylphenyl) ethylamine (see example 1.15.6, 200 mg , 0.92 mmol).

Yield: 260 mg (65.6% of theory). С ₂₇ Н ₂₉ СШ ₂ О (М = 432,998). Calcd .: molecular peak (M + H) ⁺ : 433/435; detection: molecular peak (M + H) ⁺ : 433/435. The value of K _£ : 0.57 (silica gel, dichloromethane / methanoa / ΝΙ 1 ₃ in a ratio of 9: 1: 0.1).

Example 2.4 [2- (4-Diethylaminomethylphenyl) ethyl] 4'-methoxybiphenyl-4-carboxylic acid amide.

2.4.a. 1- (4'-methoxybiphenyl-4-yl) ethanone.

To a solution of 11.3 g (85.0 mmol) of aluminum chloride in 100 ml of carbon disulfide, 4-methoxy biphenyl is added. The mixture is heated to 40 ° C. and then mixed very slowly with 6.07 ml (81.4 mmol) of acetyl chloride. After that, the reaction mixture was refluxed for one hour. After cooling, the reaction solution was poured into 100 g of ice and 25 ml of conc. of hydrochloric acid. After extraction with dichloromethane, the organic phase is dried over magnesium sulfate. Next, the solvent was removed on a rotary evaporator and the residue was recrystallized from isopropanol.

Yield: 8.8 g (48.0% of theory). C ₁₅ H ₁₄ O ₂ (M = 226.278). Calcd .: molecular peak (M + H) ⁺ : 227; detection: molecular peak (M + H) ⁺ : 227.

2.4. b. 4'-methoxybiphenyl-4-carboxylic acid.

To a solution of 15.6 g (390.9 mmol) Ν α (.) Ι I in 70 ml of water at 0 ° C, 6.0 ml (117 mmol) of bromine is slowly added dropwise. Then, 8.8 g (39.1 mmol) of 1- (4'-methoxybiphenyl-4-yl) ethanone in 50 ml of dioxane are slowly added. After three hours, the resulting solid is filtered off, dissolved in dichloromethane and re-filtered. A solvent is added from the filtrate on a rotary evaporator.

Yield: 9.0 g (100.0% of theory). C ₁₅ H ₁₄ O ₂ (M = 228.250). Calcd .: molecular peak (M-H) ^- : 227; found: molecular peak (M-H) ^- : 227.

2.4.v. 4'-methoxybiphenyl-4-carboxylic acid chloride.

A solution of 3.0 g (0.013 mol) of 4'-methoxybiphenyl-4-carboxylic acid in 47.4 ml (0.65 mol) of thionyl chloride is stirred for three hours at 50 ° C. After removal of thionyl chloride on a rotary evaporator, the product is obtained in the form of a yellowish solid, which is stored in a refrigerator.

Yield: 3.2 g (99.8% of theory). C ₁₅ H ₁₄ O ₂ (M = 246.696). Calcd .: molecular peak (M + H) ⁺ : 246/248; detection: molecular peak (M + H) ⁺ : 246/248.

2.4.y. [2- (4-Diethylaminomethylphenyl) ethyl] 4'-methoxybiphenyl-4-carboxylic acid amide.

To a solution of 200 mg (0.97 mmol) of 2- (4-diethylaminomethylphenyl) ethylamine and 0.25 ml (1.45 mmol) of Hunig base in 5 ml of dichloromethane at 0 ° C, 287 mg (1.16 mmol) obtained on previous acid chloride stage. The reaction mixture was allowed to stir overnight, and then mixed with a semi-saturated solution of Inso ₃ . The aqueous phase is washed with dichloromethane and the combined organic phase is dried over magnesium sulfate. After removing the solvent on a rotary

- 57 012834 on the evaporator, the residue was triturated with tert-butyl methyl ether and the resulting solid was suction filtered.

Yield: 90 mg (22.3% of theory). C ₂₇ H ₃₂ H ₂ O ₂ (M = 416.568). Calcd .: molecular peak (M + H) ⁺ : 417; detection: molecular peak (M + H) ⁺ : 417. K _£ value: 0.46 (silica gel, ethyl acetate / methanol ЖН ₃ in the ratio 9: 1: 0.1).

Example 2.5 [2- (4-Diethylaminomethylphenyl) ethyl] methylamide 4'-chlorobiphenyl-4-carboxylic acid.

2.5. but. [2- (4-Diethylaminomethylphenyl) ethyl] carbamic acid tert-butyl ester.

To a solution of 700 mg (3.93 mmol) of 2- (4-diethylaminomethylphenyl) ethylamine in 5.0 ml of dichloromethane and 0.52 ml (3.73 mmol) of triethylamine, 815 mg (3.73 mmol) of BOC anhydride are added and left mix overnight at room temperature. Then the mixture is mixed with saturated NaHCO3 solution. The aqueous phase is washed with dichloromethane and the organic phase is dried over magnesium sulfate. After removing the solvent on a rotary evaporator, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol / NO ₃ in a ratio of 9: 1: 0.1).

Yield: 600 mg (57.7% of theory). C ₁₈ H ₃₀ H ₂ O ₂ (M = 306.452). Calcd .: molecular peak (M + H) ⁺ : 307 detected: molecular peak (M + H) ⁺ : 307.

2.5.b. [2- (4-Diethylaminomethylphenyl) ethyl] methylamine.

To a suspension of 250 mg (6.59 mmol) of lithium aluminum hydride in 10 ml of tetrahydrofuran, 600 mg (1.96 mmol) of [2- (4-diethylaminomethylphenyl) ethyl] carbamic acid tert-butyl ester in THF are slowly added dropwise. The reaction mixture was allowed to stir overnight, after which it was heated to 50 ° C and held at this temperature for the next hour. For processing, 0.25 ml of water, 0.25 ml of a 15% NaOH solution and 0.75 ml of water are successively added. After filtration, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator.

Yield: 350 mg (81.1% of theory). C ₁₄ H ₂₄ H ₂ (M = 220.361). Calcd .: molecular peak (M + H) ⁺ : 221; detection: molecular peak (M + H) ⁺ : 221.

2.5. in. [2- (4-Diethylaminomethylphenyl) ethyl] methylamide 4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.1.b from 4'-chlorobiphenyl-4-carboxylic acid (222 mg, 0.95 mmol) and [2- (4-diethylaminomethylphenyl) ethyl] methylamine (175 mg, 0.79 mmol).

Yield: 60 mg (17.4% of theory). C ₂₇ H ₃₁ SC ₂ O (M = 435.014). Calcd .: molecular peak (M + H) ⁺ : 435/437; detection: molecular peak (M + H) ⁺ : 435/437. The value of K _£ : 0.39 (silica gel, ethyl acetate / methanol / NH ₃ in a ratio of 9: 1: 0.1).

Example 2.6.

2.6.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-chlorophenyl) cyclohexanecarboxylic acid.

The title compound was prepared according to General Procedure I from 4- (4-chlorophenyl) cyclohexanecarboxylic acid (239 mg, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (204 mg, 1.0 mmol) .

Yield: 65 mg (15.3% of theory). C ₂₆ H ₃₃ SS ₂ O (M = 425.019). Calcd .: molecular peak (M + H) ⁺ : 425/427; detection: molecular peak (M + H) ⁺ : 425/427. The value of K _£ : 0.3 (silica gel, ethyl acetate / methanol / NH ₃ in a ratio of 9: 1: 0.1).

Example 2.7 4-piperidin-1-yl-H- [2- (4-pyrrolidin-1-methylphenyl) ethyl] benzamide.

- 58 012834

2.7. but. 4-piperidin-1-yl-benzoic acid ethyl ester.

To a suspension of 0.5 ml (4.13 mmol) of ethyl 4-fluorobenzoic acid and 571 mg (4.13 mmol) of potassium carbonate in 20 ml of DMSO was added 0.41 ml of piperidine. The reaction mixture was allowed to stir overnight at 70 ° C, after which an additional 1 ml (2.44 mmol) of piperidine was added and stirred for another 6 hours at 70 ° C. After filtration, it was mixed with water, extracted with ethyl acetate, the organic phase was separated and the solvent removed on a rotary evaporator. The product without purification is used in the subsequent reaction.

Yield: 706 mg (73.2% of theory). C ₁₄ 11 ₁₉ G) ₂ (M = 233.313). Calcd .: molecular peak (M + H) ⁺ : 234; detection: molecular peak (M + H) ⁺ : 234. Retention time by HPLC: 6.2 min (method A).

2.7.b. 4-piperidin-1-ylbenzoic acid.

To a solution of 350 mg (1.50 mmol) of 4-piperidin-1-yl-benzoic acid ethyl ester in 10 ml of ethanol was added 0.78 ml (0.74 mmol) of 2N. No. OH. Then the reaction solution was stirred for 2 hours at 60 ° C, after which the pH was adjusted to 6-7 with 1N. HC1. After filtration, the precipitate formed is dried under high vacuum overnight.

Yield: 158 mg (51.3% of theory). C ₁₂ 11 ₁₅ G) ₂ (M = 205.259). Calcd .: molecular peak (M + H) ⁺ : 206; detection: molecular peak (M + H) ⁺ : 206. Retention time with HPLC: 6.2 min (method A).

2.7. in. 4-piperidin-1-yl-no. [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1 methylmethyl) ethylamine (157 mg, 0.77 mmol) and 4-piperidin-1-yl-benzoic acid (158 mg, 0.77 mmol).

Yield: 102 mg (33.8% of theory). C ₂₅ H ₃₃ ^ O (M = 391.561). Calcd .: molecular peak (M + H) ⁺ : 392; detection: molecular peak (M + H) ⁺ : 392. Retention time by HPLC: 4.4 min (method A).

Example 2.8.

2.8.a. 4-benzyl-no. [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to the general procedure described above from diphenylmethane-4-carboxylic acid (104 mg, 0.49 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (100 mg, 0.49 mmol).

Yield: 66 mg (33.9% of theory). C ₂₇ H ₃₀ ^ O (M = 398.553). Calculation: molecular peak (M + H) ⁺ : 399; found: molecular peak (M + H) ⁺ : 399. K _£ value: 0.46 (silica gel, ethyl acetate / methanol / MH ₃ in a ratio of 9: 1: 0.1).

Example 2.9. 4- (4-Oxocyclohexylidenemethyl) -№ [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

2.9.a. 4- (1,4-dioxaspiro [4.5] dec-8-ylidenomethyl) benzoic acid ethyl ester.

To a solution of 90.0 ml (0.63 mol) of diisopropylamine in 100 ml of THF at −20 ° C., 350 ml (0.56 mol) of a solution of n-Cu (1.6 molar in hexane) are added dropwise and the reaction solution is stirred for 30 min at -20 ° C. Then, 112 g (0.37 mol) of 4 (diethoxyphosphorylmethyl) benzoic acid ethyl ester in 100 ml of THF are slowly added dropwise. The reaction solution was stirred for 1 h at −20 ° C. and then 58 g (0.37 mol) of 1,4-dioxaspiro [4.5] decan-8-one in 200 ml of THF were added dropwise. After this, the reaction solution was stirred for 30 minutes at -12 ° C, and then heated to room temperature for 2 hours. It is then mixed with water and the aqueous phase is extracted with ether, ethyl acetate and dichloromethane. The organic phase is filtered through silica gel. After removing the solvent on a rotary evaporator, the residue was purified by chromatography (silica gel, petroleum ether / ethyl acetate 9: 1).

Yield: 80 g (72.0% of theory).

2.9.b. 4- (1,4-dioxaspiro [4.5] dec-8-ylidenomethyl) benzoic acid.

To a solution of 35 g (0.12 mol) of 4- (1,4-dioxaspiro [4.5] dec-8-ylidenomethyl) benzoic acid ethyl ester in 150 ml of ethanol was added 20 g of NO in 130 ml of water and the mixture for 2 hours refluxed. Then the reaction solution is poured into 400 g of ice and 60 ml of conc. hydrochloric acid, the aqueous phase is extracted with ethyl acetate and the solvent is removed on a rotary evaporator.

Yield: 32 g (91.4% of theory). Melting point: 164-165 ° C.

- 59 012834

2.9.v. 4- (4-Oxocyclohexylidenemethyl) -№- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I from 4- (1,4-dioxaspiro [4.5] dec-8-ylidenomethyl) benzoic acid (134 mg, 0.49 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (100 mg, 0.49 mmol).

Yield: 57 mg (28.0% of theory). C ₂₇ H ₃ ^ ₂ O ₂ (M = 416.568). Calcd .: molecular peak (M + H) ⁺ : 417; detection: molecular peak (M + H) ⁺ : 417. The value of K _£ : 0.36 (silica gel, ethyl acetate / methanol / No. H ₃ in a ratio of 9: 1: 0.1).

Example 2.10.

2.10.a. 4- (4-oxocyclohexyl) -№- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I from 4- (4-oxocyclohexyl) benzoic acid (128 mg, 0.49 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (100 mg, 0.49 mmol) .

Yield: 26 mg (13.1% of theory). C ₂₆ H ₃ ^ ₂ O ₂ (M = 404.557). Calcd .: molecular peak (M + H) ⁺ : 405; found: molecular peak (M + H) ⁺ : 405. K _£ value: 0.31 (silica gel, ethyl acetate / methanol / NН ₃ in the ratio 9: 1: 0.1).

Example 2.11. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4-cyclohexyl-1-cyclohexylcarboxylic acid amide.

2.11.a. 4-cyclohexyl-1-cyclohexylcarboxylic acid.

To a solution of 500 mg (2.10 mmol) of 4- (4-chlorophenyl) cyclohexanecarboxylic acid in 10 ml of methanol was added 0.44 ml of conc. hydrochloric acid and 100 mg of platinum oxide. Then the reaction mixture was stirred for 3 hours at 50 ° C and a hydrogen pressure of 5 bar. After separation of the catalyst, the solvent is removed on a rotary evaporator.

Yield: 440 mg (99.9% of theory). C1 ₃ H ₂₂ O ₂ (M = 210.319). Calcd .: molecular peak (M-H) ^- : 209; detection: molecular peak (M-H) ^- : 209.

2.11.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4-cyclohexyl-1-cyclohexylcarboxylic acid amide.

The title compound was prepared according to General Procedure I from bicyclohexyl-4-carboxylic acid (103 mg, 0.49 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (100 mg, 0.49 mmol).

Yield: 2.0 mg (1.0% of theory). C ₂₆ H ₄₀ H ₂ O (M = 396.622). Calcd .: molecular peak (M + H) ⁺ : 397; found: molecular peak (M + H) ⁺ : 397. K _£ value: 0.46 (silica gel, ethyl acetate / methanol / HH ₃ in a ratio of 9: 1: 0.1).

Example 2.12

2.12.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4-methylphenylpiperidin-1-carboxylic acid.

The title compound was prepared according to General Procedure II above from 4 methylphenylpiperidine (175 mg, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (204 mg, 1.0 mmol).

Yield: 90.0 mg (22.2% of theory). C ₂₆ H ₃₅ ^ O (M = 405.558). Calcd .: molecular peak (M + H) ⁺ : 406; detection: molecular peak (M + H) ⁺ : 406. K _£ value: 0.30 (silica gel, ethyl acetate / methanol / HH ₃ in a ratio of 9: 1: 0.1).

- 60 012834

Example 2.13. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-chlorophenyl) -3,6-dihydro-2N-pyridine-1-carboxylic acid.

about

2.13.a. 4- (4-Chlorophenyl) -1,2,3,6-tetrahydropyridine.

To 100 ml (1.2 mol) of a formalin solution (37% in water) and 32.1 g (0.6 mol) of ammonium chloride at 60 ° C. 4-chloromethylstyrene was added dropwise. Then the reaction mixture was stirred at 60 ° C for 3 hours, after which it was cooled to room temperature. Next, 100 ml of methanol was added and the mixture was allowed to stir overnight. After evaporation of the solvent on a rotary evaporator, the residue was mixed with 150 ml conc. hydrochloric acid and stirred for 4 hours at 100 ° C. After cooling to room temperature, the mixture was poured onto ice and alkalized with OH (in the form of flakes). After repeated extraction with ether, the organic phase is dried over sodium sulfate. After removing the solvent on a rotary evaporator, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol / YN ₃ mixture in the ratio 9: 1: 0.1).

Yield: 17.0 g (29.3% of theory). ScN _{12 of the} secondary school (M = 193.678). Calcd .: molecular peak (M + H) ⁺ : 194; found: molecular peak (M + H) ⁺ : 194. The value of K _£ : 0.26 (silica gel, ethyl acetate / methanol / NH ₃ in a ratio of 6: 4: 0.4).

2.13.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4- (4-chlorophenyl) -3,6-dihydro-2H-pyridine-1 carboxylic acid amide.

The title compound was prepared according to General Procedure II from 4- (4-chlorophenyl) -1,2,3,6tetrahydropyridine (193 mg, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (204 mg 1.0 mmol).

Yield: 40.0 mg (9.4% of theory). С ₂₅ Н ₃₀ СШ ₃ О (M = 423,990). Calculation: molecular peak (M + H) ⁺ : K _£ value: 0.30 (silica gel, ethyl acetate 424/426; detected: molecular peak tat / methanol / NH ₃ in a ratio of 9: 1: 0.1).

Example 2.14.

(M + H) ⁺ : 424/426.

3,4,5,6-tetrahydro-2H- [4,4 '] bipyridinyl-12.14. but. [2- (4-Pyrrolidin-1-methylmethyl) ethyl] carboxylic acid amide.

The specified compound is obtained in accordance with General method II of 1,2,3,4,5,6-hexahydro [4,4 '] bipyridinyl (81 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl ) ethylamine (102 mg, 0.50 mmol).

Yield: 43.8 mg (22.3% of theory). C ₂₄ H ₃₂ P ₄ O (M = 392.549). Calcd .: molecular peak (M + H) ⁺ : 393; detection: molecular peak (M + H) ⁺ : 393. K _£ value: 0.14 (silica gel, ethyl acetate / methanol / NН ₃ in the ratio 9: 1: 0.1).

Example 2.15.

2.15.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4-benzylpiperidin-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4-benzylpiperidine (87.7 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 33.5 mg (16.5% of theory). C ₂₆ H ₃₅ P ₃ O (M = 405.6). Calcd .: molecular peak (M + H) ⁺ : 406; detection: molecular peak (M + H) ⁺ : 406. K _£ value: 0.36 (silica gel, ethyl acetate / methane / NН ₃ in the ratio 9: 1: 0.1).

Example 2.16.

2.16.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (1H-indol-3-yl) piperidine-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 3-piperidin-4-yl-1indole (100 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol) .

Yield: 56.5 mg (26.2% of theory). C ₂₇ H ₃₄ P ₄ O (M = 430.6). Calcd .: molecular peak (M + H) ⁺ : 431;

- 61 012834 found .: molecular peak (M + H) ⁺ : 431.

The value of K _£ : 0.36 (silica gel, ethyl acetate / methanol / ₃ in a ratio of 9: 1: 0.1). Example 2.17.

2.17.a. 1 '- [2- (4-pyrrolidin-1-ylmethylphenyl) ethylcarbamoyl] 1- [4,4'] bipiperidinyl-1-carboxylic acid tert-butyl ester.

The specified compound is obtained in accordance with General procedure II from tert-butyl ether [4,4 '] bipiperidinyl-1-carboxylic acid (134 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 51.0 mg (20.5% of theory). C ₂₉ H ₄₆ ^ O ₃ (M = 498.7). Calcd .: molecular peak (M + H) ⁺ : 499; found: molecular peak (M + H) ⁺ : 499. K _£ value: 0.40 (silica gel, ethyl acetate / methanol / NН ₃ in the ratio 9: 1: 0.1).

Example 2.18. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4-cyclohexylpiperidin-1-carboxylic acid amide.

2.18.a. 4-Cyclohexylpiperidine.

To a solution of 1.0 g (6.4 mmol) of 4-phenylpyridine in 20 ml of methanol, 1.35 ml of conc. hydrochloric acid and 200 mg of platinum oxide. Then the reaction mixture is stirred for 2.5 hours at 50 ° C and a hydrogen pressure of 3 bar. After separation of the catalyst, the solvent was removed on a rotary evaporator, during which time the product precipitated as hydrochloride.

Yield: 1.2 g (91.4% of theory). C _P H ₂ ^ * HC1 (M = 203.758). Calcd .: molecular peak (M + H) ⁺ : 168; detection: molecular peak (M + H) ⁺ : 168.

2.18.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4-cyclohexylpiperidin-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4-cyclohexylpiperidine (83.7 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 38.0 mg (19.1% of theory). C ₂₅ H ₃ ^ ₃ O (M = 397.6). Calcd .: molecular peak (M + H) ⁺ : 398; found: molecular peak (M + H) ⁺ : 398. Value K _£ : 0.54 (silica gel, ethyl acetate / methanol / NН ₃ in the ratio 9: 1: 0.1).

Example 2.19. carboxylic acid.

2.19.a. 4- (4-chlorophenyl) piperidine.

To a solution of 5.0 g (21.7 mmol) of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine (see Example 2.13.a) in 20 ml of methanol was added 500 mg Ρά / C. Then the reaction mixture was stirred for 7 hours at room temperature and a hydrogen pressure of 10 psi. After separation of the catalyst, the solvent is removed on a rotary evaporator. Subsequently, the product was purified by silica gel column chromatography (eluent: dichloromethane / methanol / ammonia in a ratio of 5: 4.9: 0.1).

Yield: 3.2 g (75.3% of theory). С _П Н ₁₄ СШ (М = 195.694). Calcd .: molecular peak (M + H) ⁺ : 196/198; detection: molecular peak (M + H) ⁺ : 196/198. The value of K _£ : 0.37 (silica gel, dichloromethane / methanol / KH ₃ in a ratio of 5: 4.9: 0.1).

2.19.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4- (4-chlorophenyl) piperidin-1-carboxylic acid.

The specified compound is obtained in accordance with General procedure II from 4- (4-chlorophenyl) piperidine (97.9 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol )

Yield: 9.0 mg (4.2% of theory). С ₂₅ Н ₃₂ СШ ₃ О (M = 426.0). Calcd .: molecular peak (M + H) ⁺ : 426/428; detection: molecular peak (M + H) ⁺ : 426/428. The value of K _£ : 0.49 (silica gel, ethyl acetate / methaneJH ₃ in a ratio of 9: 1: 0.1).

Example 2.20.

2.20.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4-hydroxy-4- (4-trifluoromethylphenyl) piperine din-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4-hydroxy-4- (4 trifluoromethylphenyl) piperidine (123 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol )

Yield: 35.0 mg (14.7% of theory). С ₂₆ Н ₃₂ ЕЖ ₃ О ₂ (M = 475.6). Calcd .: molecular peak (M + H) ⁺ : 476; found: molecular peak (M + H) ⁺ : 476. K _p value: 0.45 (silica gel, ethyl acetate / methanol ЖН ₃ in the ratio 9: 1: 0.1).

Example 2.21.

2.21a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 3-phenyl-8-azabicyclo [3.2.] Octane-8-carboxylic acid.

The title compound was prepared according to General Procedure II from 3-phenyl-8-azabicyclo [3.2.1] octane (93.7 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg 0.50 mmol).

Yield: 26.0 mg (12.5% of theory). C ₂₇ H ₃₅ ^ O (M = 417.6). Calcd .: molecular peak (M + H) ⁺ : 418; found: molecular peak (M + H) ⁺ : 418. The value of K _p : 0.51 (silica gel, ethyl acetate / methane ₃ in a ratio of 9: 1: 0.1).

Example 2.22.

2.22.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-chlorophen) piperazine-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4- (4-chlorophenyl) piperazine (117 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 13.0 mg (6.1% of theory). C ₂₄ H ₃₁ SS ₄ O (M = 427.0). Calcd .: molecular peak (M + H) ⁺ : 427/429; found: molecular peak (M + H) ⁺ : 427/429. The value of K _p : 0.42 (silica gel, ethyl acetate / methanol / ₃ in a ratio of 9: 1: 0.1).

Example 2.23.

2.23.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4-cyano-4-phenylpiperidin-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4-cyano-4-phenylpiperidine (111 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 27.0 mg (13.0% of theory). C ₂₆ H ₃ W ₄ O (M = 416.6). Calcd .: molecular peak (M + H) ⁺ : 417; detection: molecular peak (M + H) ⁺ : 417. K _p value: 0.46 (silica gel, ethyl acetate / methanol ЖН ₃ in the ratio 9: 1: 0.1).

Example 2.24.

2.24.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 3-azaspiro [5.5] undecan-3-carboxylic acid.

The specified compound is obtained in accordance with General procedure II from 3-azaspiro [5.5] undecane (76.7 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol) .

Yield: 24.0 mg (12.5% of theory). C ₂₄ H ₃ W ₃ O (M = 383.6). Calcd .: molecular peak (M + H) ⁺ : 384; found: molecular peak (M + H) ⁺ : 384. The value of K _p : 0.49 (silica gel, ethyl acetate / methanol / ₃ in a ratio of 9: 1: 0.1).

Example 2.25.

2.25.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-fluorophenyl) piperidine-1-carboxylic

- 63 012834 slots.

The title compound was prepared according to General Procedure II from 4- (4-fluorophenyl) piperidine (108 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 32.0 mg (15.6% of theory). C ₂₅ H ₃₂ W ₃ O (M = 409.6). Calcd .: molecular peak (M + H) ⁺ : 410; detection: molecular peak (M + H) ⁺ : 410. The value of K _g : 0.50 (silica gel, ethyl acetate / methanol / ₃ in a ratio of 9: 1: 0.1).

Example 2.26.

2.26.a. [2- (4-Pyrrolidin-1-methylmethyl) ethyl] 1,2-dihydro-1 - (methylsulfonyl) spiro [3H-indole-3,4'-piperidine] -1-carboxylic acid amide.

The specified compound is obtained in accordance with General method II of 1,2-dihydro-1- (methylsulfonyl) spiro [3H-indole-3,4'-piperidine] (133.2 mg, 0.50 mmol) and 2- (4 -pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 28.0 mg (11.3% of theory). C ₂₇ H ₃₆ ^ O ₃ 8 (M = 496.7). Calcd .: molecular peak (M + H) ⁺ : 497; found: molecular peak (M + H) ⁺ : 497. Value K _g : 0.42 (silica gel, ethyl acetate / methanol ЖН ₃ in the ratio 9: 1: 0.1).

Example 2.27.

2.27.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-chlorophenyl) -4-hydroxypiperidin-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4- (4-chlorophenyl) -4 hydroxypiperidine (106 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol) .

Yield: 32.0 mg (14.5% of theory). С ₂₅ Н ₃₂ СШ ₃ О ₂ (М = 442.0). Calcd .: molecular peak (M + H) ⁺ : 442/444; detection: molecular peak (M + H) ⁺ : 442/444. The value of K _g : 0.44 (silica gel, ethyl acetate / methanol / ₃ in a ratio of 9: 1: 0.1).

Example 2.28.

2.28.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-methoxyphenyl) piperazine-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4- (4-methoxyphenyl) piperazine (133 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 35.0 mg (16.6% of theory). C ₂₅ H ₃ W ₄ O ₂ (M = 422.6). Calcd .: molecular peak (M + H) ⁺ : 423; found: molecular peak (M + H) ⁺ : 423. Value K _g : 0.47 (silica gel, ethyl acetate / methanol ЖН ₃ in the ratio 9: 1: 0.1).

Example 2.29.

2.29.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (2-methoxyphenyl) piperidine-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4- (2-methoxyphenyl) piperidine (114 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 20.0 mg (9.5% of theory). C ₂₆ H ₃₅ ^ O ₂ (M = 421.6). Calcd .: molecular peak (M + H) ⁺ : 422; found: molecular peak (M + H) ⁺ : 422. Value K _g : 0.55 (silica gel, ethyl acetate / methanol ЖН ₃ in the ratio 9: 1: 0.1).

Example 2.30.

- 64 012834

2.30.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 1,3-dihydroisoindole-2-carboxylic acid.

The title compound was prepared according to General Procedure II from 1,3-dihydroisoindole (77.8 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 13.0 mg (7.4% of theory). C ₂₂ H ₂ ^ ₃ O (M = 349.48). Calcd .: molecular peak (M + H) ⁺ : 350; detection: molecular peak (M + H) ⁺ : 350. B _£ value: 0.30 (silica gel, dichloromethane / methanol MH ₃ in a ratio of 9: 1: 0.1).

Example 2.31.

2.31.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 1,2,4,5-tetrahydrobenzo [4] azepine-3-carboxylic acid.

The specified compound is obtained in accordance with General procedure II from 1,2,4,5-tetrahydrobenzo [4] azepine (73.6 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg 0.50 mmol).

Yield: 12.0 mg (6.4% of theory). C ₂₄ H ₃ ^ ₃ O (M = 377.534). Calcd .: molecular peak (M + H) ⁺ : 378; detection: molecular peak (M + H) ⁺ : 378. Value B _£ : 0.33 (silica gel, dichloromethane / methanolMN ₃ in the ratio 9: 1: 0.1).

Example 2.32.

2.32.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4-phenylpiperidin-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4-phenylpiperidine (80.6 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 24.0 mg (12.3% of theory). C ₂₅ H ₃₃ ^ O (M = 391.561). Calcd .: molecular peak (M + H) ⁺ : 392; detection: molecular peak (M + H) ⁺ : 392. B _£ value: 0.35 (silica gel, dichloromethane / methanol MN ₃ in a ratio of 9: 1: 0.1).

Example 2.33. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-dimethylaminomethylphenyl) piperidine-1-carboxylic acid.

2.33. but. 4- (4-Dimethylaminomethylphenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester.

To a solution of 81 g (0.38 mol) of 4-bromodimethylbenzylamine in 450 ml of THF at −65 ° C., 236 ml (0.38 mol) of n-TiO (1.6 molar in hexane) was added dropwise over 35 minutes. Then, 75 g (0.38 mol) of 4-oxopiperidin-1-carboxylic acid tert-butyl ester in 150 ml of THF are added dropwise over 60 minutes so that the temperature does not exceed -60 ° C. The reaction solution was stirred for 2 hours at −65 ° C. and then for a further 17 hours at room temperature. Then the reaction mixture is mixed with 300 ml of ether, cooled to 5 ° C and the precipitate formed is suction filtered. This precipitate is then mixed with 200 ml of water and 700 ml of ether and stirred for 10 minutes. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The resulting product was dried in vacuo.

Yield: 45 g (35.7% of theory).

2.33.b. Dimethyl- [4- (1,2,3,6-tetrahydropyridin-4-yl) benzyl] amine.

To a solution of 45 g (0.14 mol) of 4- (4-dimethylaminomethylphenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester in 140 ml of dichloromethane at -10 ° C, 70 ml of trifluoroacetic acid are added dropwise. Then the solution was stirred for 1.5 hours at room temperature, after which it was cooled to -10 ° C and 30 ml of conc. sulfuric acid. After half an hour, add another 10 ml of sulfuric acid. After 1 h, the solvent was removed on a rotary evaporator and the residue was poured into 300 g of ice. After that, the pH value is set at 14 with 6n. solution Να () Ι I. The aqueous phase is saturated with potassium carbonate and extracted twice with ether. The combined organic phases are evaporated to dryness on a rotary evaporator.

Yield: 25.2 g (86.9%).

2.33. in. Dimethyl (4-piperidin-4-ylbenzyl) amine.

To a solution of 16 g (74 mmol) of dimethyl [4- (1,2,3,6-tetrahydropyridin-4-yl) benzyl] amine in 200 ml of methanol was added 6 g of P0 / Ba8O ₄ . The solution was stirred for 1 h in a hydrogen atmosphere at room temperature, after which the catalyst was filtered off and the solvent was removed on a rotary evaporator. The residue is dissolved in methanol, methanol hydrochloric acid is added and then until turbid

65 012834 is mixed with ether. After exposure at -20 ° C, the resulting hydrochloride is separated by vacuum filtration.

Yield: 16 g (84.9%).

2.33.g. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-dimethylaminomethylphenyl) piperidine-1 carboxylic acid.

The title compound was prepared according to General Procedure II from 4- (4-dimethylaminomethylphenyl) piperidine (127 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 37.0 mg (16.5% of theory). C ₂₈ H ₄₀ ^ O (M = 448.657). Calcd .: molecular peak (M + H) ⁺ : 449; detection: molecular peak (M + H) ⁺ : 449. The p-value is 0.37 (silica gel, dichloromethane / methanol / YN ₃ in a ratio of 9: 1: 0.1).

Example 2.34. 4 '- (Chlorobiphenyl-4-yl) - [3- (4-pyrrolidin-1-ylmethylphenyl) piperidin-1-yl] methanone.

2.34. but. 1- (4-Bromobenzyl) pyrrolidine.

To a solution of 13.1 ml (0.16 mmol) of pyrrolidine and 200 ml of tetrahydrofuran 20.0 g (0.080 mol) of 4-bromobenzyl bromide in THF are slowly added dropwise so that the temperature does not exceed 20 ° C. After this, the reaction solution was allowed to stir overnight, and then, after mixing with ice, it was acidified with concentrated hydrochloric acid. After extraction with ether, the aqueous phase is made alkaline with sodium hydroxide solution and saturated with potassium carbonate. After extraction with ether, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator.

Yield: 18.1 g (94.2% of theory). Scn1 ₄ VrH (M = 240.145). Calculation: molecular peak (M + H) ⁺ : 240/242; detection: molecular peak (M + H) ⁺ : 240/242.

The value of Ke is 0.19 (silica gel, petroleum ether / ethyl acetate in a ratio of 8: 2).

2.34. b. 3- (4-Pyrrolidin-1-methylmethyl) pyridine.

1.11 g (4.64 mmol) of 1- (4-bromobenzyl) pyrrolidine is dissolved in 10 ml of dioxane and 5 ml of a 2 molar solution of sodium carbonate. Then 570 mg (4.64 mmol) of pyridin-3-boronic acid and 270 mg (0.23 mmol) of tetrakis (triphenylphosphine) palladium are added successively and the reaction mixture is refluxed for 6 hours. Next, the reaction solution is subjected to vacuum filtration through a glass fiber filter. The filtrate was extracted several times with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. Subsequently, the product was purified by silica gel column chromatography (eluent: ethyl acetate / methanol / NH ₃ in a ratio of 8: 2: 0.1).

Yield: 500 mg (45.2% of theory). C1 ₆ H1 ₈ X ₂ (M = 238.335). Calcd .: molecular peak (M + H) ⁺ : 239; detection: molecular peak (M + H) ⁺ : 239.

2.34. in. 3- (4-Pyrrolidin-1-methylmethyl) piperidine.

To a solution of 500 mg (2.10 mmol) of 3- (4-pyrrolidin-1-ylmethylphenyl) pyridine in 10 ml of ethanol, 4 ml of 1 molar hydrochloric acid and 200 mg of platinum oxide are added. The reaction mixture is then stirred for 4.5 hours at room temperature and a hydrogen pressure of 3 bar. After separation of the catalyst, the solvent was removed on a rotary evaporator, during which time the product precipitated as hydrochloride.

Yield: 600 mg (100% of theory). C1 ₆ H ₂₄ X ₂ —HC1 (M = 280.844). Calcd .: molecular peak (M + H) ⁺ : 245; detection: molecular peak (M + H) ⁺ : 245.

2.34. g. (4'-Chlorobiphenyl-4-yl) - [3- (4-pyrrolidin-1-ylmethylphenyl) piperidin-1-yl] methanone.

Said compound was prepared according to General Procedure I from 4′-chlorobiphenyl-4 carboxylic acid (183 mg, 0.78 mmol) and 3- (4-pyrrolidin-1-ylmethylphenyl) piperidine (200 mg, 0.71 mmol).

Yield: 20.0 mg (6.1% of theory). C ₂₉ N _M SSH ₂ O (M = 459.036). Calcd .: molecular peak (M + H) ⁺ : 459/461; detection: molecular peak (M + H) ⁺ : 459/461. The value of K ₍ ·: 0.58 (silica gel, ethyl acetate / methanol / NH ₃ in a ratio of 9: 1: 0.1).

Example 2.35. [2-Methyl-2- (4-pyrrolidin-1-ylmethylphenyl) propyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

- 66 012834

2.35. but. 2-Methyl-2- (4-pyrrolidin-1-ylmethylphenyl) propionitrile.

To a solution of 2.0 g (10.0 mmol) of (4-pyrrolidin-1-ylmethylphenyl) acetonitrile (see Example 1.1.g) in 50 ml of tetrahydrofuran, 3.4 g (30 mmol) of potassium tert-butoxide are added at room temperature . Then the reaction solution was briefly stirred, mixed with 1.9 ml (30 mmol) of methyl iodide, stirred for another 2 hours at room temperature and then evaporated to dryness on a rotary evaporator. The residue was partitioned between water and ethyl acetate, the organic phase was washed with water and dried over magnesium sulfate. After that, the solvent is distilled off on a rotary evaporator and the crude product is used without purification in the subsequent reaction.

Yield: 1.4 g (61.3% of theory). C ₁₅ H ₂₀ No. ₂ (M = 228.340). Calcd .: molecular peak (M + H) ⁺ : 229; found: molecular peak (M + H) ⁺ : 229. K _£ value: 0.40 (silica gel, ethyl acetate / methanol / NН ₃ in the ratio 9: 1: 0.1).

2.35. b. 2-Methyl-2- (4-pyrrolidin-1-ylmethylphenyl) propylamine.

To a solution of 1.4 g (6.13 mmol) of 2-methyl-2- (4-pyrrolidin-1-ylmethylphenyl) propionitrile in 20 ml of a methanolic ammonia solution, 150 mg of Raney nickel is added. After that, the reaction mixture was stirred overnight at 50 ° C in a hydrogen atmosphere at a pressure of 5 bar. After filtering off the catalyst, the solvent is removed on a rotary evaporator.

Yield: 1.4 g (98.3% of theory). C ₁₅ H ₂₄ ^ (M = 232.372). Calcd .: molecular peak (M + H) ⁺ : 233; found: molecular peak (M + H) ⁺ : 233. K _£ value: 0.30 (silica gel, ethyl acetate / methanol / NН ₃ in the ratio 9: 1: 0.1).

2.35. in. [2-Methyl-2- (4-pyrrolidin-1-ylmethylphenyl) propyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I from 4'-chlorobiphenyl-4carboxylic acid (233 mg, 1.0 mmol) and 2-methyl-2- (4-pyrrolidin-1-ylmethylphenyl) propylamine (232 mg, 1.0 mmol).

Yield: 400 mg (89.5% of theory). C ₂₈ H ₃ 1SSH ₂ O (M = 447.025). Calcd .: molecular peak (M + H) ⁺ : 447/449; detection: molecular peak (M + H) ⁺ : 447/449. The value of K _£ : 0.35 (silica gel, ethyl acetate / methanol ^ H3 in a ratio of 9: 1: 0.1).

Example 2.36. [2- (4-Pyrrolidin-1-ylmethylphenyl) propyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.36. but. 2- (4-Pyrrolidin-1-ylmethylphenyl) propionitrile.

To a solution of 2.0 g (10.0 mmol) of (4-pyrrolidin-1-ylmethylphenyl) acetonitrile (see Example 1.1.g) in 50 ml of tetrahydrofuran, 1.12 g (10 mmol) of potassium tert-butylate was added at room temperature . The reaction solution was then stirred for 30 minutes, after which it was mixed with 0.63 ml (10 mmol) of methyl iodide. Next, the reaction mixture was stirred for 1 h at 50 ° C and then evaporated to dryness on a rotary evaporator. The residue was partitioned between water and ethyl acetate, the organic phase was washed twice with water and dried over magnesium sulfate. The solvent is distilled off on a rotary evaporator and the crude product, which contains about 20% dimethylated compound, is used in the subsequent reaction without purification.

Yield: 0.5 g (23.3% of theory). C ₁₄ H ₁₈ Ng (M = 214.313). Calcd .: molecular peak (M + H) ⁺ : 215; found: molecular peak (M + H) ⁺ : 215. K _£ value: 0.40 (silica gel, ethyl acetate / methanol / NН ₃ in the ratio 9: 1: 0.1).

2.36. b. 2- (4-Pyrrolidin-1-methylmethyl) propylamine.

To a solution of 400 mg (1.87 mmol) of 2- (4-pyrrolidin-1-ylmethylphenyl) propionitrile in 20 ml of a methanol solution of ammonia, 100 mg of Raney nickel is added. Then the reaction mixture was stirred overnight at 50 ° C. under a hydrogen atmosphere at a pressure of 5 bar. After filtering off the catalyst, the solvent is removed on a rotary evaporator. An amine that contains about 20% dimethylated compound is used in the subsequent reaction without further purification.

Yield: 0.4 g (98.6% of theory). C ₁₅ H _{2; 2} No. ₂ (M = 218.345). Calcd .: molecular peak (M + H) ⁺ : 219; found: molecular peak (M + H) ⁺ : 219. K _£ value: 0.30 (silica gel, ethyl acetate / methanol / NН ₃ in the ratio 9: 1: 0.1).

2.36. in. [2- (4-Pyrrolidin-1-ylmethylphenyl) propyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I from 4'-chlorobiphenyl-4carboxylic acid (233 mg, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) propylamine (218 mg, 1.0

- 67 012834 mmol).

Yield: 10 mg (2.3% of theory). C ₂₈ H ₃₁ Cl ₂ O (M = 447.025). Calcd .: molecular peak (M + H) ⁺ : 447/449; detection: molecular peak (M + H) ⁺ : 447/449. The value of K _£ : 0.35 (silica gel, ethyl acetate / methanol / LNZ in a ratio of 9: 1: 0.1).

Example 2.37. 4'-chlorobiphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethylbenzyloxy) amide.

2.37. but. 2- (4-Pyrrolidin-1-ylmethylbenzyloxy) isoindol-1,3-dione.

To a solution of 13.2 g (50 mmol) of α, α'-dibromo-p-xylene in 125 ml of acetonitrile, a mixture of 8.2 g (50 mmol) of Ν-hydroxyphthalimide and 8.7 ml (50 mmol) is added at room temperature Hyunig bases in 125 ml of acetonitrile. The reaction solution was stirred for 10 minutes, after which 4.1 ml (50 mmol) of pyrrolidine was added and stirred for the next hour. After filtration, the mother liquor is concentrated to dryness on a rotary evaporator. The residue was purified by silica gel chromatography (eluent: ethyl acetate / methanol / ammonia). After purification, the obtained substance is immediately used in the subsequent reaction.

Yield: 1.0 g (5.9% of theory). The value of K _£ : 0.60 (alox, ethyl acetate / petroleum ether in a ratio of 1: 1).

2.37. b. O- (4-Pyrrolidin-1-methylmethylbenzyl) hydroxyamine.

To a solution of 1.0 g (2.97 mmol) of 2- (4-pyrrolidin-1-ylmethylbenzyloxy) isoindole-1,3-dione in 50 ml of toluene was added 50 ml of a 40% solution of methylamine in water and the mixture was stirred for 2.5 days at room temperature. After separation of the organic phase, the aqueous phase is extracted twice with tert-butyl methyl ether. The combined organic phases are washed with water and dried over magnesium sulfate. After that, the solvent is removed on a rotary evaporator and the resulting product is used without purification in the subsequent reaction.

Yield: 260 mg (42.4% of theory). C1 ₂ H ₁₈ N ₂ O (M = 206.290). Calcd .: molecular peak (M + H) ⁺ : 207; detection: molecular peak (M + H) ⁺ : 207.

2.37. in. 4'-chlorobiphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethylbenzyloxy) amide.

Said compound was prepared according to General Procedure I from 4′-chlorobiphenyl-4-carboxylic acid (116 mg, 0.5 mmol) and O- (4-pyrrolidin-1-ylmethylbenzyl) hydroxyamine (103 mg, 0.5 mmol).

Yield: 10.0 mg (4.8% of theory). C ₂₀ H ₂₅ Cl ₂ O ₂ (M = 420.943). Calcd .: molecular peak (M + H) ⁺ : 421/423; detection: molecular peak (M + H) ⁺ : 421/423. The value of K _£ : 0.38 (silica gel, ethyl acetate / methanol / NH ₃ in a ratio of 9: 1: 0.1).

Example 2.38. [1,1-Dimethyl-2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.38.a. (4-Pyrrolidin-1-ylmethyl-phenyl) -acetic acid ethyl ester.

3.0 g (15 mmol) of (4-pyrrolidin-1-ylmethylphenyl) acetonitrile (see Example 1.1.g) was dissolved in an ethanolic hydrochloric acid solution (saturated) and heated under reflux for 4 hours. After that, the solvent was removed on a rotary evaporator and the residue was dissolved in a dilute NaHCO ₃ solution and tert-butyl methyl ether. The organic phase is dried over sodium sulfate, suction filtered through activated carbon and then the solvent is removed on a rotary evaporator.

Yield: 3.4 g (91.6% of theory). C1 ₅ H ₂₁ NO ₂ (M = 247.340). Calcd .: molecular peak (M + H) ⁺ : 248; detection: molecular peak (M + H) ⁺ : 248. The value of K _£ : 0.25 (silica gel, ethyl acetate / methanol / HE ₃ in a ratio of 9: 1: 0.1).

2.38.b. 2-Methyl-1- (4-pyrrolidin-1-ylmethylphenyl) propan-2-ol.

- 68 012834

To a 13.3 ml (40 mmol) of a 3.0 molar solution of methylmagnesium chloride in tetrahydrofuran, 3.4 g (13.8 mmol) of ethyl ester (4-pyrrolidin-1 methylmethylphenyl) acetic acid in 20 ml of tetrahydrofuran is added dropwise at room temperature. In this case, the temperature rises to 40 ° C. The reaction mixture was stirred for one hour, after which it was poured into 100 ml of a solution of ammonium chloride. The aqueous phase is extracted several times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the residue was purified by alox column chromatography (activity 2-3) (eluent: 4: 1 cyclohexane / ethyl acetate mixture).

Yield: 800 mg (24.9% of theory). C1 ₅ H ₂₃ No. O (M = 233.357). Calcd .: molecular peak (M + H) ⁺ : 234; detection: molecular peak (M + H) ⁺ : 234. Value K _£ : 0.50 (alox, petroleum ether / ethyl acetate in a ratio of 6: 4).

2.38. in. Ν- [1,1-Dimethyl-2- (4-pyrrolidin-1-methylmethyl) ethyl] formamide.

To a solution of 250 mg (5.0 mmol) of sodium cyanide in 2 ml of glacial acetic acid, a mixture of 2 ml of sulfuric acid and 1 ml of glacial acetic acid is added dropwise so that the temperature of the reaction mixture does not exceed 20 ° C. After this, 800 mg (3,43 mmol) of 2-methyl1- (4-pyrrolidin-1-ylmethylphenyl) propan-2-ol in 2 ml of glacial acetic acid are added dropwise. The temperature is maintained below 20 ° C. After this, the reaction solution was stirred for one hour at room temperature, and then poured onto ice and neutralized with sodium carbonate solution. The aqueous phase is extracted with ether and the organic phase is dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the product was used without purification in the subsequent reaction.

Yield: 520 mg (58.2% of theory). WGWF ^ O (M = 260.382). Calcd .: molecular peak (M + H) ⁺ : 261; detection: molecular peak (M + H) ⁺ : 261.

2.38. g. 1,1-Dimethyl-2- (4-pyrrolidin-1-methylmethyl) ethylamine.

To a solution of 520 mg (2 mmol) No. [1,1-dimethyl-2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] formamide in 10 ml of ethanol was added 25 ml of conc. hydrochloric acid and heated overnight under reflux. After cooling, the reaction solution was made basic with a 25% aqueous solution of sodium hydroxide and the aqueous phase was extracted several times with tert-butyl methyl ether. The combined organic phases are washed with water, dried over magnesium sulfate and filtered through activated carbon. Finally, the solvent is removed on a rotary evaporator.

Yield: 380 mg (81.8% of theory). ^ ₅ Π ₂₄ Ν ₂ (M = 232.372). Calcd .: molecular peak (M + H) ⁺ : 233; found: molecular peak (M + H) ⁺ : 233. K _£ value: 0.10 (silica gel, ethyl acetate / methanol ЖН ₃ in the ratio 9: 1: 0.1).

2.38. D. [1,1 - Dimethyl-2- (4-pyrrolidin-1-methylmethyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I from 4'-chlorobiphenyl-4-carboxylic acid (116 mg, 0.5 mmol) and 1,1-dimethyl-2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (116 mg, 0 5 mmol).

Yield: 73.0 mg (32.7% of theory). C ₂₈ Π ₃ 1C1N ₂ O ₂ (M = 447.025). Calcd .: molecular peak (M + H) ⁺ : 447/449; detection: molecular peak (M + H) ⁺ : 447/449. The value of K _£ : 0.48 (silica gel, ethyl acetate methanol ΝΙ1 ₃ in a ratio of 9: 1: 0.1).

Example 2.39. 4- (2-Pyrrolidin-1-yl-ethyl) benzylamide 4'-chlorobiphenyl-4-carboxylic acid.

C1

2.39.a. 4- (2-Pyrrolidin-1-yl-ethyl) benzonitrile.

To a solution of 500 mg (2.74 mmol) of 4- (2-aminoethyl) benzonitrile in 50 ml of acetonitrile, 91 mg (0.56 mmol) of potassium iodide, 453 mg (3.28 mmol) of potassium carbonate and 0.33 ml are successively added. (2.74 mmol) of 1,4-dibromobutane.

The reaction mixture was stirred for 6 hours at 78 ° C. After that, 0.08 ml (0.66 mmol) of 1,4-dibromobutane was further added and the reaction mixture was allowed to stir overnight at 78 ° C. After filtration, the filtrate was evaporated to dryness. Subsequently, the product was purified by silica gel column chromatography (dichloromethane / methanol in a ratio of 8: 2).

Yield: 183.0 mg (33.4% of theory). C ₁₃ H ₁₆ K ₂ (M = 200.286). Calcd .: molecular peak (M + H) ⁺ : 201; detection: molecular peak (M + H) ⁺ : 201.

2.39.b. 4- (2-Pyrrolidin-1-yl-ethyl) benzylamine.

To a solution of 183 mg (0.91 mmol) of 4- (2-pyrrolidin-1-yl-ethyl) benzonitrile in 20 ml of an ethanolic ammonia solution was added 75 mg of Raney nickel. After this, the reaction solution was allowed to stir overnight at 50 ° C and a hydrogen pressure of 3 bar. Then, 75 mg of Raney nickel is further added and the mixture is stirred for a further 6 hours at 50 ° C. and a hydrogen pressure of 3 bar. Further

69 012834, the catalyst is filtered off and the solvent is removed on a rotary evaporator. The crude product can be used without further purification in the subsequent reaction.

Yield: 114.0 mg (61.0% of theory). C ₁₃ H ₂ ^ ₂ (M = 204.318). Calculation: molecular peak (M + H) ⁺ : 205; detection: molecular peak (M + H) ⁺ : 205.

2.39.in. 4- (2-Pyrrolidin-1-yl-ethyl) benzylamide 4'-chlorobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I from 4'-chlorobiphenyl-4-carboxylic acid (130 mg, 0.56 mmol) and 4- (2-pyrrolidin-1-yl-ethyl) benzylamine (114 mg, 0.56 mmol).

Yield: 75.0 mg (32.1% of theory). C ₂₆ H ₂₇ SC ₂ O (M = 418.971). Calcd .: molecular peak (M + H) ⁺ : 419/421; detection: molecular peak (M + H) ⁺ : 419/421. The value of K _£ : 0.38 (silica gel, ethyl acetate / methanote / ΝΙ 1 ₃ in a ratio of 9: 1: 0.1).

Example 2.40.

2.40.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide [1,4] bipiperidinyl-1'-carboxylic acid.

The title compound was prepared according to General Procedure II from 4-piperidinopiperidine (84.1 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (102 mg, 0.50 mmol).

Yield: 3.0 mg (1.5% of theory). C ₂₄ H ₃₈ P ₄ O (M = 398.597). Calculation: molecular peak (0.5M + H) ⁺ : 200; detection: molecular peak (0.5M + H) ⁺ : 200. Retention time by HPLC: 1.59 min (method A).

Example 2.41.

2.41.a. 4-Cyclohexyl-L- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I from 4-cyclohexylbenzoic acid (102 mg, 0.50 mmol) and 4- (2-pyrrolidin-1-yl-ethyl) benzylamine (102 mg, 0.50 mmol).

Yield: 2.0 mg (1.0% of theory). C ₂₆ H ₃₄ P ₂ O (M = 390.574). Calcd .: molecular peak (M + H) ⁺ : 391; detection: molecular peak (M + H) ⁺ : 391. The value of K _£ : 0.38 (silica gel, ethyl acetate / methanol / LN ₃ in a ratio of 9: 1: 0.1).

Example 2.42. [2- (4-Pyrrolidin-1-ylmethylcyclohexyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.42. but. 2- (4-Pyrrolidin-1-ylmethylcyclohexyl) ethylamine.

To a solution of 500 mg (2.45 mmol) of 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (see Example 1.1.z) in 10 ml of methanol was added 1.52 ml of conc. hydrochloric acid and 300 mg of platinum oxide. The reaction mixture is then stirred for 50 hours at 50 ° C and a hydrogen pressure of 5 bar. After separation of the catalyst, the solvent is removed on a rotary evaporator. Subsequently, the product was purified by silica gel column chromatography (dichloromethane / methanol / ammonia in a ratio of 8: 2: 0.2).

Yield: 130 mg (25.3% of theory). C ₁₃ H ₂₆ P ₂ (M = 210.366). Calcd .: molecular peak (M + H) ⁺ : 211; detection: molecular peak (M + H) ⁺ : 211. K _£ value: 0.14 (silica gel, dichloromethane / methanol ^ H ₃ in a ratio of 8: 2: 0.2).

2.42.b. [2- (4-Pyrrolidin-1-ylmethylcyclohexyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I from 4'-chlorobiphenyl-4-carboxylic acid (116 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethylcyclohexyl) ethylamine (105 mg, 0.50 mmol).

Yield: 53.0 mg (24.9% of theory). C ₂₆ H ₃₃ SS ₂ O (M = 425.019). Calcd .: molecular peak (M + H) ⁺ : 425/427; detection: molecular peak (M + H) ⁺ : 425/427. The value of K _£ : 0.16 (silica gel, ethyl acetate / methanote / ΝΙ 1 ₃ in a ratio of 9: 1: 0.1).

Example 2.43. [2- (3-Methoxy-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

- 70 012834

2.43. but. 4-cyanomethyl-2-methoxybenzoic acid.

The specified connection receive analogously to example 1.1. g from 4-cyanomethyl-2methoxybenzoic acid methyl ester.

Yield: 6.5 g (69.8% of theory). С ₁₀ Нс№О ₃ (M = 191.18). Calcd .: molecular peak (M + H) ⁺ : 192; Detection .: molecular peak (M + H) ^+: 192. The value K _I: 0.64 (silica gel, dichloromethane / ethanol = 10: 1).

2.43.b. (4-Hydroxymethyl-3-methoxyphenyl) acetonitrile.

The specified connection receive analogously to example 1.1. d of 4-cyanomethyl-2-methoxybenzoic acid.

Yield: 4.81 g (81% of theory). C ₁₀ H ₁₁ LO ₂ (M = 177.20). Calcd .: molecular peak (M): 177; detection: molecular peak (M) ⁺ : 177.

2.43. in. (4-Bromomethyl-3-methoxyphenyl) acetonitrile.

The specified compound is obtained analogously to example 1.1.e from (4-hydroxymethyl-3-methoxyphenyl) acetonitrile.

Yield: 4.2 g (64.6% of theory). C ₁₀ H ₁₀ B1NO (M = 240.10). Calcd .: molecular peak (M) ⁺ : 239/241; found: molecular peak (M) ⁺ : 239/241. The value of K _And : 0.84 (silica gel, dichloromethane / ethanol in a ratio of 50: 1).

2.43. g. (3-Methoxy-4-pyrrolidin-1-methylmethyl) acetonitrile.

The specified compound is obtained analogously to example 1.1.zh from (4-bromomethyl-3-methoxyphenyl) acetonitrile and piperidine.

Yield: 0.95 g (24.2% of theory). C ₁₄ H ₁₈ L ₂ O (M = 230.31). Calcd .: molecular peak (M + H) ⁺ : 231; detection: molecular peak (M + H) ⁺ : 231.

2.43. d. (3-Methoxy-4-pyrrolidin-1-ylmethylphenyl) ethylamine.

The specified compound is obtained analogously to example 1.1.3 from (3-methoxy-4-pyrrolidin-1 methylmethyl) acetonitrile. The crude product without purification is immediately used in the subsequent reaction.

2.43. e. [2- (3-Methoxy-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

Said compound was prepared according to General Procedure I from 2- (3-methoxy-4pyrrolidin-1-methylmethyl) ethylamine and 4'-chlorobiphenyl-4-carboxylic acid.

Yield: 0.5 g (86.2% of theory). Melting point: 162-163 ° C. С ₂₇ Н ₂₉ СШ ₂ О ₂ (M = 448.99). Calcd .: molecular peak (M + H) ⁺ : 449/451; detection: molecular peak (M + H) ⁺ : 449/451. The value of K _And : 0.85 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 5: 1: 0.1).

Example 2.44. [2- (2-Fluoro-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.44.a. (E) -3- (4-Cyano-2-fluorophenyl) acrylic acid.

To a solution of 20.0 g (100 mmol) of 4-bromo-3-fluorobenzonitrile in 200 ml of DMF was added 2.75 g (10 mmol) of palladium acetate and 7.0 g (25 mmol) of tri-o-tolylphosphane. Then add 50 ml of triethylamine and 30 ml (30 mmol) of ethyl ester of acrylic acid. Next, the reaction mixture was stirred for 3 hours at 100 ° C, and then, after cooling, it was diluted with 400 ml of dichloromethane and washed twice with water. After that, the solvent is removed on a rotary evaporator and the residue is dissolved in 250 ml of methanol by heating. Insoluble components are removed by vacuum filtration through diatomaceous earth and the filtrate is concentrated on a rotary evaporator to half the volume. After repeated filtration, they are mixed with 150 ml of THF, 100 ml of MeOH and 43 ml of 2N. No. OH and stirred for 2 hours at room temperature. Then the solvent is removed on a rotary evaporator and the residue is mixed with 100 ml of water. After extraction with ether, the aqueous phase is acidified with conc. hydrochloric acid. The precipitated crystals are dissolved in 300 ml of warm ethyl acetate and the aqueous phase is separated. Ethyl acetate was then distilled off and the resulting crystals were agitated in ether and separated by suction filtration.

Yield: 11.5 g (60.2% of theory). Melting point: 214-218 ° C.

2.44.b 3- (4-Cyano-2-fluorophenyl) propionic acid.

- 71 012834

A solution of 11.5 g (60 mmol) of (E) -3- (4-cyano-2-fluorophenyl) acrylic acid in 200 ml of water is mixed with 4.0 g of 5% N / C and 24.4 g of potassium carbonate . The mixture is then shaken for 6 hours in an autoclave at room temperature and normal pressure of hydrogen. After separation of the catalyst by vacuum filtration, the mother liquor is acidified with conc. hydrochloric acid. The precipitated crystals are dissolved in 250 ml of warm ethyl acetate, dried and ethyl acetate is distilled off. The resulting crystals were stirred with ether / hexane and suction filtered.

Yield: 900 mg (98.0% of theory). Melting point: 102-106 ° C.

2.44. in. [2- (4-Cyano-2-fluorophenyl) ethyl] carbamic acid tert-butyl ester.

To a solution of 500 mg (2.6 mmol) of 3- (4-cyano-2-fluorophenyl) propionic acid in 5 ml of tert-butanol, 1.25 ml of triethylamine and 0.61 ml (2.8 mmol) of diphenylphosphorylazide are added. Next, the reaction mixture is refluxed overnight, after which the solvent is removed on a rotary evaporator. The product was purified by silica gel column chromatography (dichloromethane / methanol 9: 1).

Yield: 138 mg (20.2% of theory). C ₁₄ H ₁₇ E ^ O ₂ (M = 264.302). Calcd .: molecular peak (M + H) ⁺ : 265; detection: molecular peak (M + H) ⁺ : 265.

2.44. g. [2- (4-Aminomethyl-2-fluorophenyl) ethyl] carbamic acid tert-butyl ester.

A solution of 138 mg (0.52 mmol) of [2- (4-cyano-2-fluorophenyl) ethyl] carbamic acid tert-butyl ester in 15 ml of an ethanolic ammonia solution is mixed with 75 mg of Raney nickel and the mixture is shaken overnight in an autoclave at 50 ° C and a hydrogen pressure of 3 bar. After separation of the catalyst by vacuum filtration, the solvent was removed on a rotary evaporator.

Yield: 137 mg (97.8% of theory). C ₁₄ H ₂₁ E ^ O ₂ (M = 268.334). Calcd .: molecular peak (M + H) ⁺ : 269; detection: molecular peak (M + H) ⁺ : 269.

2.44. e. [2- (2-Fluoro-4-pyrrolidin-1-ylmethylphenyl) ethyl] carbamic acid tert-butyl ester.

To a solution of 300 mg (1.12 mmol) of [2- (4-aminomethyl-2-fluorophenyl) ethyl] carbamic acid tert-butyl ester in 15 ml of acetonitrile, successively add 42 mg (0.25 mmol) of potassium iodide, 180 mg ( 1.30 mmol) of potassium carbonate and 0.13 ml (1.11 mmol) of 1,4-dibromobutane. Next, the reaction mixture was stirred for 6 hours at 78 ° C. Thereafter, 0.08 ml (0.66 mmol) of 1,4-dibromobutane was further added and the reaction mixture was allowed to stir overnight at 78 ° C. After that, the solvent is removed on a rotary evaporator and the product is used without further purification in the subsequent reaction.

Yield: 320 mg (88.8% of theory). C ₁₈ H ₂₇ E ^ O ₂ (M = 322.426). Calcd .: molecular peak (M + H) ⁺ : 323; detection: molecular peak (M + H) ⁺ : 323.

2.44. e. 2- (2-Fluoro-4-pyrrolidin-1-ylmethylphenyl) ethylamine.

To a solution of 232 mg (0.72 mmol) of [2- (2-fluoro-4-pyrrolidin-1-ylmethylphenyl) ethyl] carbamic acid tert-butyl ester in 5 ml of dichloromethane was added 1.5 ml of trifluoroacetic acid. Next, the reaction mixture was stirred for 2 hours at room temperature. After that, the solvent is removed on a rotary evaporator and the crude product is used without purification in the subsequent reaction.

Yield: 160 mg (100% of theory). C ₁₃ H ₁₉ E ^ (M = 222.308). Calcd .: molecular peak (M + H) ⁺ : 223; detection: molecular peak (M + H) ⁺ : 223.

2.44. g. [2- (2-Fluoro-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

Said compound was prepared according to General Procedure I from 2- (2-fluoro-4-pyrrolidin-1 methylmethylphenyl) ethylamine (160 mg, 0.72 mmol) and 4'-chlorobiphenyl-4-carboxylic acid (168 mg, 0.72 mmol).

Yield: 49 mg (15.6% of theory). С ₂₆ Н ₂₆ С1Е ^ О (М = 436.961). Calcd .: molecular peak (M + H) ⁺ : 437/439; detection: molecular peak (M + H) ⁺ : 437/439. Retention time with HPLC: 6.6 min (method A).

Example 2.45. 4-Pyridin-4-yl-no. [2- (4-pyrrolidin-1-methylphenyl) ethyl] benzamide

2.45.a. 4-Pyridin-4-yl-benzoic acid methyl ester.

3.0 g (15 mmol) of 4-bromopyridine is dissolved in 50 ml of dioxane and 15 ml of a 2 molar solution of sodium carbonate. Next, 2.7 g (15 mmol) of 4-methoxycarbonylphenylboronic acid and 1.73 g (2 mmol) of tetrakis (triphenylphosphine) palladium are added successively and the reaction mixture is refluxed for 6 hours. The hot reaction solution is then suction filtered through a glass fiber filter. After that, the solvent was removed on a rotary evaporator and the product was purified by silica gel column chromatography (dichloromethane / methanol in a 9: 1 ratio).

- 72 012834

Yield: 845 mg (26.4% of theory). C1 ₃ H1 ^ O ₂ (M = 213.238). Calcd .: molecular peak (M + H) ⁺ : 214; detection: molecular peak (M + H) ⁺ : 214. Retention time with HPLC: 4.1 min (method A).

2.45.b. 4-pyridin-4-ylbenzoic acid.

To a solution of 150 mg (0.70 mmol) of 4-pyridin-4-ylbenzoic acid methyl ester in 10 ml of ethanol was added 0.37 ml (0.74 mmol) of 2N. \ aO11. Then the reaction solution was stirred for 2 hours at 60 ° C, after which the pH was adjusted to 6-7 with 1N. HC1. After filtration, the precipitate formed is dried overnight in high vacuum.

Yield: 84 mg (60.0% of theory). C1 ₂ H ^ O ₂ (M = 199.211). Calculation: molecular peak (M + H) ⁺ : 200; detection: molecular peak (M + H) ⁺ : 200. Retention time with HPLC: 2.5 min (method A).

2.45.in. 4-Pyridin-4-yl-No. [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

Said compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1-methylphenyl) ethylamine (86 mg, 0.42 mmol) and 4-pyridin-4-ylbenzoic acid (84 mg, 0.42 mmol).

Yield: 65 mg (40.0% of theory). C ₂₅ H ₂₇ ^ O (M = 385.513). Calcd .: molecular peak (M + H) ⁺ : 386; detection: molecular peak (M + H) ⁺ : 386. Retention time with HPLC: 4.7 min (81aBe eBopb C18, 3.5 μm, water / acetonitrile / formic acid in a ratio of 91: 9: 0.01).

Example 2.46. 5- (4-Chlorophenyl) -2- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -2,3-dihydroisoindol-1one.

.C1

2.46. but. 4-bromo-2-methylbenzoic acid ethyl ester.

A solution of 5.0 g (23.3 mmol) of 4-bromo-2-methylbenzoic acid in 50 ml of ethanol hydrochloric acid was stirred for 8 hours at 45 ° C. Then the reaction solution was cooled overnight to room temperature, after which the solvent was removed on a rotary evaporator. The residue was dissolved in ether, filtered and the solvent was removed on a rotary evaporator. The residue without purification is used in the subsequent reaction.

The value of K _p : 0.88 (silica gel, dichloromethane / ethanol in a ratio of 95: 5).

2.46.b. 4'-chloro-3-methylbiphenyl-4-carboxylic acid ethyl ester.

1.66 g (6.83 mmol) of 4-bromo-2-methylbenzoic acid ethyl ester are dissolved in 70 ml of dioxane and 7 ml of a 2 molar solution of sodium carbonate. Then, 1.07 g (6.83 mmol) of 4-chlorophenylboronic acid and 0.40 g (0.34 mmol) of tetrakis (triphenylphosphine) palladium are added successively, after which the reaction mixture is refluxed for 6 hours and then stirred over the next 60 hours at room temperature. After that, the hot reaction solution is subjected to vacuum filtration through a glass fiber filter. The solvent is removed on a rotary evaporator.

The residue was mixed with water and the aqueous phase was extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 8: 2).

Yield: 1.3 g (69.3% of theory). C1 ₆ H1 ₅ C1O ₂ (M = 274.750). Calcd .: molecular peak (M + H) ⁺ : 275/277; detection: molecular peak (M + H) ⁺ : 275/277. The value of K _p : 0.67 (silica gel, petroleum ether / ethyl acetate in a ratio of 8: 2).

2.46. in. 3-Bromomethyl-4'-chlorobiphenyl-4-carboxylic acid ethyl ester.

To a solution of 1.3 g (4.73 mmol) of 4'-chloro-3-methylbiphenyl-4-carboxylic acid ethyl ester and 0.84 g (4.73 mmol) of Ν-bromosuccinimide in 10 ml of carbon tetrachloride, 78 mg ( 0.47 mmol) 2,2'-azobis (isobutyronitrile). Then the reaction mixture was refluxed overnight. After filtration, the solvent was concentrated on a rotary evaporator. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 8: 2).

Yield: 1.6 g (62.1% of theory). C1 ₆ H1 ₄ BrC1O ₂ (M = 353.646). Calcd .: molecular peak (M + H) ⁺ : 353/355/357; detection: molecular peak (M + H) ⁺ : 353/355/357. The value of K _p : 0.57 (silica gel, petroleum ether / ethyl acetate in a ratio of 8: 2).

2.46. 5- (4-Chlorophenyl) -2- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -2,3-dihydroisoindol-1-one.

To a suspension of 800 mg (1.47 mmol) of 3-bromomethyl-4'-chlorobiphenyl-4-carboxylic acid ethyl ester and 508 mg (3.68 mmol) of potassium carbonate in 7.5 ml of acetonitrile, 375 were slowly added dropwise at room temperature. mg (1.47 mmol) of 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine. Next, the reaction mixture is refluxed for 5 hours. After removing the solvent on a rotary evaporator, the residue was dissolved in water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over magnesium sulfate. After removing the solvent on a rotary evaporator, the residue was dissolved in DMF and purified using HPLC (81a1e1Bopb C18, 3.5 μm, water / acetonitrile / formic acid in a ratio varying from 9: 1: 0.01 to 1: 9: 0, 01 for 9 minutes).

- 73 012834

Yield: 82 mg (12.9% of theory). ^ SZHST (M = 430,982). Calculation: molecular peak (M + H) ⁺ :

431/433; detection: molecular peak (MV + H) ⁺ : 431/433. Retention time with HPLC: 6.13 min (Method A).

Example 2.47. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4-piperidin-1-ylmethylpiperidin-1 carboxylic acid.

2.47. but. 4-piperidin-1-methylmethyridine.

To a solution of 100 g (0.61 mol) of 4-chloromethylpyridine in 600 ml of dry methanol was added dropwise 242 ml of piperidine (2.44 mol) and the reaction mixture was stirred at 50 ° C. for one hour. After that, the solvent is removed on a rotary evaporator. The residue was made basic with a 40% sodium hydroxide solution and the aqueous phase was extracted with ether. The organic phase is dried over sodium sulfate and, after filtration through activated carbon, the solvent is removed on a rotary evaporator. The crude product without purification is used in the subsequent reaction.

Yield: 106 g (98% of theory).

2.47. b. 4-piperidin-1-methylpiperidine.

A solution of 106 g (0.6 mol) of 4-piperidin-1-ylmethylpyridine in 1.0 L of glacial acetic acid was mixed with 7 g of platinum dioxide and shaken in an autoclave at room temperature and a hydrogen pressure of 3 bar. After separation of the catalyst by vacuum filtration, the solvent was removed on a rotary evaporator. The crude product without purification is used in the subsequent reaction.

Yield: 48 g (43.9% of theory).

2.47. in. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4-piperidin-1-ylmethylpiperidin-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 4-piperidin-1 methylmethylpiperidine (182 mg, 1.00 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (204 mg, 1.00 mmol).

Yield: 160.0 mg (38.8% of theory). C ₂₅ Ndo ^ O (M = 412.624). Calcd .: molecular peak (M + H) ⁺ : 413; detection: molecular peak (M + H) ⁺ : 413. Retention time by HPLC: 1.75 min (81aE Vopb C18, 3.5 μm, water / acetonitrile / formic acid in a ratio varying from 9: 1: 0, 01 to 4: 6: 0.01 for 8 minutes).

Example 2.48.

2.48.a. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (1H-benzoimidazol-2-yl) piperidine-1-carboxylic acid.

The title compound was prepared according to General Procedure II from 2-piperidin-4-yl-1Nbenzoimidazole (164 mg, 1.00 mmol) and 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine (204 mg, 1.00 mmol) .

Yield: 80.0 mg (18.5% of theory). C ₂₆ H ₃₃ ^ O (M = 431.586). Calcd .: molecular peak (M + H) ⁺ : 432; detection: molecular peak (M + H) ⁺ : 432.

Retention time with HPLC: 2.80 min (81aE Vopb C18, 3.5 μm, water / acetonitrile / formic acid in a ratio varying from 9: 1: 0.01 to 4: 6: 0.01 for 8 min) .

Example 2.49. 4- (1-Methylpiperidin-4-yl) -№- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

2.49.a. 4-piperidin-4-yl-benzoic acid methyl ester.

To a solution of 695 mg (3.26 mmol) of 4-pyridin-4-yl-benzoic acid methyl ester (see Example 2.45.a) in 10 ml of ethanol, 4.0 ml of 1 molar hydrochloric acid and 200 mg of platinum oxide are added. The reaction mixture is then stirred for 2 hours at room temperature and a hydrogen pressure of 3 bar. After adding 300 mg of platinum oxide and 6.0 ml of 1 molar hydrochloric acid again, the mixture was stirred for another 16 hours at room temperature and a hydrogen pressure of 3 bar. After separation of the catalyst, the solvent is removed on a rotary evaporator. Raw product without

- 74 012834 purification is used in the subsequent reaction.

Yield: 589 mg (82.4% of theory). C ₁₃ H ₁₇ KO ₂ (M = 219.286). Calculation: molecular peak (M + H) ⁺ : 220; detection: molecular peak (M + H) ⁺ : 220. Retention time with HPLC: 3.5 min (method A).

2.49.b. 4- (1-Methylpiperidin-4-yl) benzoic acid methyl ester.

To a solution of 429 mg (1.96 mmol) of 4-piperidin-4-ylbenzoic acid methyl ester in 10 ml of DMF in a nitrogen atmosphere at 0 ° C., 48 mg (2.00 mmol) of sodium hydride are added in portions. Then the reaction mixture was stirred for 1 h at room temperature. Thereafter, 0.13 ml (2.10 mmol) of methyl iodide was added dropwise and the solution was stirred at room temperature for two hours. The reaction solution is then mixed with water, the aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product was purified by column chromatography (silica gel; dichloromethane / methanol in a ratio of 8: 2).

Yield: 70 mg (15.3% of theory). C ₁₄ H ₁₉ KO ₂ (M = 233.313). Calcd .: molecular peak (M + H) ⁺ : 234; detection: molecular peak (M + H) ⁺ : 234. Retention time by HPLC: 2.7 min (method A).

2.49. in. 4- (1-Methylpiperidin-4-yl) benzoic acid.

To a solution of 70 mg (0.30 mmol) of 4- (1-methylpiperidin-4-yl) benzoic acid methyl ester in 10 ml of ethanol was added 0.37 ml (0.74 mmol) of 2N. No. O11. Next, the reaction solution was stirred for 2 hours at 60 ° C, after which the pH was adjusted to 6-7 with 1N. HC1. After filtration, the precipitate formed is dried under high vacuum overnight.

Yield: 50 mg (76.0% of theory). C ₁₃ H ₁₇ KO ₂ (M = 219.286). Calculation: molecular peak (M + H) ⁺ : 220; detection: molecular peak (M + H) ⁺ : 220. Retention time with HPLC: 1.5 min (method A).

2.49. 4- (1-Methylpiperidin-4-yl) -M- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1-methylphenyl) ethylamine (47 mg, 0.23 mmol) and 4- (1-methylpiperidin-4-yl) benzoic acid (50 mg, 0.23 mmole).

Yield: 22 mg (23.8% of theory). C ₂₆ H ₃₅ K ₃ O (M = 405.588). Calcd .: molecular peak (M + H) ⁺ : 406; detection: molecular peak (M + H) ⁺ : 406. Retention time with HPLC: 2.4 min (method A).

Example 2.50.

2.50.a. {2- [6- (4-Methylpiperazin-1-id) pyridin-3-yl] ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 1.1. And from 2- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] ethylamine and 4'-chlorobiphenyl-4-carboxylic acid.

Yield: 0.94 g (96% of theory). Melting point: 211-213 ° C. С ₂₅ Н ₂₇ СШ ₄ О (М = 434.97). Calcd .: molecular peak (M + H) ⁺ : 435/437; detection: molecular peak (M + H) ⁺ : 435/437.

Example 2.51. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (4-methylpiperazine-1-carbonyl) phenyl] ethyl} amide.

about

2.51.a. [4- (4-Methylpiperazine-1-carbonyl) phenyl] acetonitrile.

A solution of 2 g (12.41 mmol) of 4-cyanomethylbenzoic acid, 1.25 g (12.5 mmol) of Ν-methylpiperazine, 4.01 g (12.5 mmol) of TBTU and 3.48 ml (25 mmol) of triethylamine 40 ml of DMF was stirred for 12 hours at room temperature. After this, the reaction mixture was slightly concentrated and mixed with water. This mixture was extracted with ethyl acetate and the solvent was distilled off on a rotary evaporator. The aqueous phase is also concentrated and combined with the residue obtained by concentrating the organic phase.

The product is purified by silica gel column chromatography (eluent: dichloromethane / ethanol / ammonia mixture in a ratio of 30: 1: 0.1).

Yield: 2.6 g (86% of theory). C ₁₄ H ₁₇ K ₃ O (M = 243.31). Calcd .: molecular peak (M + H) ⁺ : 244; found: molecular peak (M + H) ⁺ : 244. K _£ value: 0.35 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 20: 1: 0.1).

- 75 012834

2.51.b. [4- (2-aminoethyl) phenyl] - (4-methylpiperazin-1-yl) methanone.

The specified compound is obtained analogously to example 1.1. And from [4- (4-methylpiperazin-1carbonyl) phenyl] acetonitrile.

Yield: 2.9 g (90% of theory). C1 ₄ H ₂₁ H5O-HC1 (M = 283.80). The value of K _G : 0.25 (silica gel, dichloromethane / ethanol / ammonia in a ratio of 10: 1: 0.1).

2.51.c. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (4-methylpiperazine-1-carbonyl) phenyl] ethyl} amide.

The specified compound is obtained in accordance with the General method Ι of [4- (2-aminoethyl) phenyl] - (4methylpiperazin-1-yl) methanone and 4'-chlorobiphenyl-4-carboxylic acid.

Yield: 0.18 g (48.4% of theory). Melting point: 217-218 ° C. С ₂₇ Н ₂₈ СШ ₃ О ₂ (M = 461.99). Calcd .: molecular peak (M + H) ⁺ : 462/464; detection: molecular peak (M + H) ⁺ : 462/464. The value of K _G : 0.25 (silica gel, dichloromethane / methanol / ammonia in a ratio of 10: 1: 0.1).

Example 2.52. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4'-bromobiphenyl-4-carboxylic acid amide.

2.52. but. 4'-bromobiphenyl-4-carboxylic acid methyl ester /

0.54 g (2.5 mmol) of 4-bromobenzoic acid methyl ester is dissolved in 10 ml of dioxane and 2.5 ml of a 2 molar solution of sodium carbonate. Then, 0.6 g (3 mmol) of 4-bromophenylboronic acid and 0.12 g (0.1 mmol) of tetrakis (triphenylphosphine) palladium are successively added and the reaction mixture is refluxed for 5 hours. Then the reaction mixture is mixed with water and E1OAc, filtered and the phases are separated. The aqueous phase was extracted E1OAs and the combined organic phases were dried over Md8O _4. After removal of the desiccant and solvent, the residue was triturated with acetonitrile, suction filtered and air dried.

Yield: 100 mg (13.7% of theory). C1 ₄ NcBrO ₂ (M = 291.15). Calcd .: molecular peak (M + H) ⁺ : 291/293; detection: molecular peak (M + H) ⁺ : 291/293. The value of K _G : 0.68 (silica gel, petroleum ether / E1OAc in a ratio of 8: 2).

2.52.b. 4'-Bromobiphenyl-4-carboxylic acid.

A solution of 100 mg (0.34 mmol) of 4'-bromobiphenyl-4-carboxylic acid methyl ester in 3 ml of THF was mixed with 3 ml of a 1 molar solution of No. O11 in water and heated under reflux for 3 hours. Then the reaction mixture was concentrated in vacuo, the aqueous residue was acidified with 1 molar HC1, the precipitated product was filtered off and dried in air.

Yield: 60 mg (63.1% of theory). C1 ₃ H ₉ BrO ₂ (M = 277.19). Calcd .: molecular peak (M-H) ^- : 275/277; found: molecular peak (M-H) ^- : 275/277. HPLC Retention Time: 8.48 min (Method A).

2.52. in. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4'-bromobiphenyl-4-carboxylic acid amide.

This compound is prepared according to the general procedure метод from 45 mg (0.22 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 60 mg (0.22 mmol) of 4'-bromobiphenyl-4-carboxylic acid.

Yield: 28 mg (27.5% of theory). C ₂₆ H ₂₇ B ^ ₂ O (M = 463.42). Calcd .: molecular peak (M + H) ⁺ : 463/465; detection: molecular peak (M + H) ⁺ : 463/465. Retention time with HPLC: 6.46 min (method A).

Example 2.53. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4'-ethylbiphenyl-4-carboxylic acid amide.

The specified compound is obtained in accordance with the General method Ι of 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 113 mg (0.5 mmol) of 4'-ethylbiphenyl-4-carboxylic acid (Lapsa §1eg )

Yield: 65 mg (31.5% of theory). C ₂₈ H ₃ ^ ₂ O (M = 412.58). Calcd .: molecular peak (M + H) ⁺ : 463; detection: molecular peak (M + H) ⁺ : 463. Retention time by HPLC: 6.64 min (method A).

Example 2.54. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] biphenyl-4-carboxylic acid amide.

The specified compound is obtained in accordance with the General method Ι of 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 99 mg (0.5 mmol) of biphenyl-4-carboxylic acid.

- 76 012834

Yield: 46 mg (23.9% of theory). C ₂₆ H ₂₈ N ₂ O (M = 384.53). Calcd .: molecular peak (M + H) ⁺ : 385; detection: molecular peak (M + H) ⁺ : 385. Retention time by HPLC: 5.70 min (method A).

Example 2.55. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4'-fluorobiphenyl-4-carboxylic acid amide.

2.55.a. 4'-Fluorobiphenyl-4-carboxylic acid.

14.27 g (71 mmol) of 4-bromobenzoic acid is dissolved in 120 ml of dioxane and 70 ml of a 2 molar solution of Na ₂ CO ₃ . Then 10 g (71 mmol) of 4-fluorophenylboronic acid and 4.1 g (4 mmol) of tetrakis (triphenylphosphine) palladium are added successively and the reaction mixture is refluxed for 6 hours. Then the catalyst is suction filtered and then washed with hot water. The reaction mixture was then mixed with ESAc, the phases were separated and the aqueous phase was acidified with citric acid. The precipitate formed is suction filtered, washed with water and dried in vacuo at 45 ° C.

Yield: 4.9 g (31.9% of theory). C ₁₃ H ₉ PO ₂ (M = 216.21). Calcd .: molecular peak (M-H) ^- : 215; detection: molecular peak (M-H) ^- : 215.

2.55.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 4'-fluorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 108 mg (0.5 mmol) of 4'-fluorobiphenyl-4-carboxylic acid.

Yield: 12 mg (6.0% of theory). С ₂₆ Н ₂₇ РЫ ₂ О (М = 402.52). Calcd .: molecular peak (M + H) ⁺ : 403; detection: molecular peak (M + H) ⁺ : 403. Retention time by HPLC: 5.83 min (method A).

Example 2.56. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4'-hydroxy-3'-nitrobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I, from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 130 mg (0.5 mmol) of 4'-fluoro-3'-nitrobiphenyl-4-carbon acids.

Yield: 9 mg (4.0% of theory). C ₂₆ H ₂₇ L ₃ O ₄ (M = 445.52). Calcd .: molecular peak (M + H) ⁺ : 446; detection: molecular peak (M + H) ⁺ : 446. Retention time by HPLC: 5.83 min (method A).

Example 2.57. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 3'-chlorobiphenyl-4-carboxylic acid amide.

2.57. but. 3'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.55.a from 9.64 g (47.96 mmol) of 4-bromobenzoic acid and 7.5 g (47.96 mmol) of 3-chlorophenylboronic acid.

Yield: 6.2 g (55.6% of theory). C ₁₃ H ₉ s _{1 2} (M = 232.67). Calcd .: molecular peak (M-H) ^- : 231/233; found: molecular peak (M-H) ^- : 231/233.

2.57.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 3'-chlorobiphenyl-4-carboxylic acid amide.

The specified compound is obtained in accordance with General procedure I from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 116 mg (0.5 mmol) of 3'-chlorobiphenyl-4-carboxylic acid.

Yield: 63 mg (30.1% of theory). C ₂₆ H ₂₇ Cl ₂ O (M = 418.97). Calcd .: molecular peak (M + H) ⁺ : 419/421; detection: molecular peak (M + H) ⁺ : 419/421. Retention time with HPLC: 6.20 min (Method A).

Example 2.58. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 3 ', 4'-dichlorobiphenyl-4-carboxylic acid.

2.58.a. 3 ', 4'-dichlorobiphenyl-4-carboxylic acid.

- 77 012834

The specified connection receive analogously to example 2.55. and from 5.27 g (26.20 mmol) of 4-bromobenzoic acid and 5.0 g (26.20 mmol) of 3 ', 4'-dichlorophenylboronic acid.

Yield: 4.05 g (57.9% of theory). C ₁₃ H ₈ Cl ₂ O ₂ (M = 267.11). Calcd .: molecular peak (M-H) ^- : 265/267/269; detection: molecular peak (M-H) ^- : 265/267/269.

2.58.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 3 ', 4'-dichlorobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I, from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 134 mg (0.5 mmol) of 3 ', 4'-dichlorobiphenyl-4-carboxylic acid.

Yield: 45 mg (19.8% of theory). С ₂₆ Н ₂₆ С1 ₂ Н ₂ О (М = 453.42). Calcd .: molecular peak (M + H) ⁺ : 453/455/457; detection: molecular peak (M + H) ⁺ : 453/455/457. Retention time with HPLC: 6.45 min (method A).

Example 2.59. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 2 ', 4'-dichlorobiphenyl-4-carboxylic acid.

2.59.a. 2 ', 4'-dichlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.55.a from 5.23 g (26.0 mmol) of 4-bromobenzoic acid and 10.0 g (52.0 mmol) of 2,4-dichlorophenylboronic acid by refluxing the reaction mixture for 48 hours

Yield: 1.5 g (21.6% of theory). C ₁₃ H ₈ Cl ₂ O ₂ (M = 267.11). Calcd .: molecular peak (M-H) ^- : 265/267/269; detection: molecular peak (M-H) ^- : 265/267/269.

2.59.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 2 ', 4'-dichlorobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I, from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 134 mg (0.5 mmol) of 2 ', 4'-dichlorobiphenyl-4-carboxylic acid.

Yield: 72 mg (31.8% of theory). С ₂₆ Н ₂₆ С1 ₂ Н ₂ О (М = 453.42). Calcd .: molecular peak (M + H) ⁺ : 453/455/457; detection: molecular peak (M + H) ⁺ : 453/455/457. Retention time with HPLC: 6.84 min (Method A).

Example 2.60. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 2'-fluoro-4'-chlorobiphenyl-4-carboxylic acid

2.60. but. 2'-Fluoro-4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.55.a from 0.52 g (2.5 mmol) of 1-bromo-4-chloro-2-fluorobenzene and 0.5 g (3.0 mmol) of 4-carboxyphenylboronic acid.

Yield: 0.5 g (79.8% of theory). C ₁₃ H ₈ ClO ₂ (M = 250.66). Calcd .: molecular peak (M-H) ^- : 249/251; detection: molecular peak (M-H) ^- : 249/251. Retention time with HPLC: 8.39 min (method A).

2.60.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 2'-fluoro-4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained in accordance with General procedure I from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 125 mg (0.5 mmol) of 2'-fluoro-4'-chlorobiphenyl-4-carbon acids.

Yield: 36 mg (16.5% of theory). C ₂₆ H ₂₆ C1PY ₂ O (M = 436.96). Calcd .: molecular peak (M + H) ⁺ : 437/439; detection: molecular peak (M + H) ⁺ : 437/439. Retention time with HPLC: 6.32 min (Method A).

Example 2.61. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 3,4'-dichlorobiphenyl-4-carboxylic acid amide.

2.61.a. 3,4'-Dichlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.55.a from 0.59 g (2.5 mmole) 4-bromo-2

78 012834 of chlorobenzoic acid and 0.47 g (3.0 mmol) of 4-chlorophenylboronic acid.

Yield: 0.55 g (82.4% of theory). C ₁₃ H ₈ Cl ₂ O ₂ (M = 267.11). Calcd .: molecular peak (M-H) ^- : 265/267/269; detection: molecular peak (M-H) ^- : 265/267/269. Retention time with HPLC: 8.83 min (method A).

2.61.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] 3,4'-dichlorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I, from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 134 mg (0.5 mmol) of 3,4'-dichlorobiphenyl-4-carboxylic acid.

Yield: 24 mg (10.6% of theory). С ₂₆ Н ₂₆ С1 ^ ₂ О (M = 453.42). Calcd .: molecular peak (M + H) ⁺ : 453/455/457; detection: molecular peak (M + H) ⁺ : 453/455/457. Retention time with HPLC: 6.41 min (method A).

Example 2.62. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-fluorobiphenyl-4-carboxylic acid.

2.62.a. 4'-Chloro-3-fluorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.55.a from 0.55 g (2.5 mmol) of 4-bromo-2-fluorobenzoic acid and 0.47 g (3.0 mmol) of 4-chlorophenylboronic acid.

Yield: 0.60 g (95.7% of theory). С ₁₃ Н ₈ С1ГО ₂ (M = 250.66). Calcd .: molecular peak (M-H) ^- : 249/251; detection: molecular peak (M-H) ^- : 249/251. Retention time with HPLC: 8.22 min (Method A).

2.62.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-3-fluorobiphenyl-4-carboxylic acid.

The specified compound is obtained in accordance with General method I of 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 125 mg (0.5 mmol) of 4'-chloro-3-fluorobiphenyl-4-carboxylic acid .

Yield: 37 mg (16.9% of theory). С ₂₆ Н ₂₆ С1Ш ₂ О (M = 436.96). Calcd .: molecular peak (M + H) ⁺ : 437/439; detection: molecular peak (M + H) ⁺ : 437/439.

Retention time with HPLC: 6.45 min (method A).

Example 2.63. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-2-fluorobiphenyl-4-carboxylic acid.

2.63.a. 4'-Chloro-2-fluorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.55.a from 0.66 g (3.0 mmol) of 4-bromo-3-fluorobenzoic acid and 0.47 g (3.0 mmol) of 4-chlorophenylboronic acid.

Yield: 0.60 g (79.8% of theory). С ₁₃ Н ₈ С1ГО ₂ (M = 250.66). Calcd .: molecular peak (M-H) ^- : 249/251; detection: molecular peak (M-H) ^- : 249/251. Retention time with HPLC: 8.50 min (Method A).

2.63.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chloro-2-fluorobiphenyl-4-carboxylic acid.

The specified compound is obtained in accordance with General procedure I from 163 mg (0.8 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 201 mg (0.8 mmol) of 4'-chloro-2-fluorobiphenyl-4-carboxylic acid .

Yield: 74 mg (21.2% of theory). С ₂₆ Н ₂₆ С1Ш ₂ О (M = 436.96). Calcd .: molecular peak (M + H) ⁺ : 437/439; detection: molecular peak (M + H) ⁺ : 437/439. Retention time with HPLC: 6.61 min (Method ^A) .

Example 2.64. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide of 3-nitrobiphenyl-4-carboxylic acid.

2.64. but. 3-nitrobiphenyl-4-carboxylic acid.

- 79 012834

To a solution of 1.0 g (4.07 mmol) of 4-bromo-2-nitrobenzoic acid in 20 ml of toluene, 150 mg (0.13 mmol) of tetrakis (triphenylphosphine) palladium are added and stirred for 10 minutes at RT. After this, a solution of 0.5 g (4.10 mmol) of phenylboronic acid in 10 ml of MeOH and a solution of 1.0 g of No. ₂ CO ₃ in 10 ml of water are added. The reaction mixture is then heated under reflux for 5 hours and then left to mix over the weekend at RT. Then the solvent is removed in vacuo, the residue is mixed with water, acidified with conc. HCl, extracted with EAAc, the organic phase is dried over No. ₂ 8O ₂ and the solvent is finally removed.

Yield: 0.87 g (87.5% of theory). The value of K _And : 0.40 (silica gel, dichloromethane / ethanol in a ratio of 3: 1).

2.64.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 3-nitrobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I, from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 122 mg (0.5 mmol) of 3-nitrobiphenyl-4-carboxylic acid.

Yield: 100 mg (46.6% of theory). C ₂₆ H ₂ ^ ₃ O ₃ (M = 429.52). Calcd .: molecular peak (M + H) ⁺ : 430; detection: molecular peak (M + H) ⁺ : 430. Retention time by HPLC: 5.83 min (method A).

Example 2.65. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 5- (4-chlorophenyl) pyridine-2-carboxylic acid.

2.65.a. 5- (4-Chlorophenyl) pyridine-2-carboxylic acid.

The specified compound is obtained analogously to example 2.55.a from 0.51 g (2.5 mmol) of 5-bromopyridin-2 carboxylic acid and 0.47 g (3.0 mmol) of 4-chlorophenylboronic acid.

Yield: 0.23 g (39.4% of theory). С ₁₂ Н ₈ ССО ₂ (М = 233.66). Calcd .: molecular peak (M-H) ^- : 232/234; found: molecular peak (M-H) ^- : 232/234. Retention time with HPLC: 5.89 min (method A).

2.65.b. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 5- (4-chlorophenyl) pyridine-2-carboxylic acid.

The specified compound is obtained in accordance with General procedure I from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 116 mg (0.5 mmol) of 5- (4-chlorophenyl) pyridin-2-carboxylic acid .

Yield: 7 mg (3.3% of theory). С ₂₅ Н ₂₆ СШ ₃ О (M = 419.96). Calcd .: molecular peak (M + H) ⁺ : 420/422; detection: molecular peak (M + H) ⁺ : 420/422. Retention time with HPLC: 6.40 min (method A).

Example 2.66. No. [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -4-thiophen-3-ylbenzamide.

2.66. but. 4-Thiophen-3-ylbenzoic acid ethyl ester.

The specified compound is obtained analogously to example 2.46.b from 414 mg (1.5 mmol) of ethyl ester of 4-iodobenzoic acid and 230 mg (1.8 mmol) of thiophene-3-boronic acid.

Yield: 348 mg (100% of theory). C ₁₃ H ₁₂ O ₂ 8 (M = 232.30). Calcd .: molecular peak (M + H) ⁺ : 233; detection: molecular peak (M + H) ⁺ : 233. Retention time by HPLC: 6.20 min (method B).

2.66. b. 4-thiophen-3-ylbenzoic acid.

The specified compound is obtained analogously to example 2.7.b from 280 mg (1.5 mmol) of ethyl 4-thiophen-3-ylbenzoic acid.

Yield: 146 mg (59.3% of theory). C ₁₁ H ₈ O ₂ 8 (M = 204.25). Calcd .: molecular peak (M-H) ^- : 203; found: molecular peak (M-H) ^- : 203. Retention time with HPLC: 7.60 min (method A).

2.66. in. No. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] -4-thiophen-3-ylbenzamide.

The title compound was prepared according to General Procedure I, from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 102 mg (0.5 mmol) of 4-thiophen-3-ylbenzoic acid.

Yield: 103 mg (53.0% of theory). C ₂₂ 1 1 ₂₆ Ν ₂ () 8 (M = 390.55). Calcd .: molecular peak (M + H) ⁺ : 391; detection: molecular peak (M + H) ⁺ : 391. Retention time by HPLC: 6.10 min (method A).

Example 2.67. No. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] -4-thiophen-2-ylbenzamide.

- 80 012834

2.67. but. 4-Thiophen-2-yl-benzoic acid ethyl ester.

The specified compound is obtained analogously to example 2.46.b from ethyl ether 414 mg (1.5 mmol) of 4-iodobenzoic acid and 230 mg (1.8 mmol) of thiophene-2-boronic acid.

Yield: 348 mg (100% of theory). C ₁₃ H ₁₂ O ₂ 8 (M = 232.30). Calcd .: molecular peak (M + H) ⁺ : 233; detection: molecular peak (M + H) ⁺ : 233. Retention time by HPLC: 6.29 min (method B).

2.67.b. 4-thiophen-2-ylbenzoic acid.

The specified compound is obtained analogously to example 2.7.b from 280 mg (1.5 mmol) of ethyl 4-thiophen-2-yl-benzoic acid.

Yield: 126 mg (51.2% of theory). C ₁₁ H ₈ O ₂ 8 (M = 204.25). Calcd .: molecular peak (M-H) ^- : 203; found: molecular peak (M-H) ^- : 203. Retention time with HPLC: 7.60 min (method A).

2.67. in. \ - [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] -4-thiophen-2-ylbenzamide.

The title compound was prepared according to General Procedure I, from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 102 mg (0.5 mmol) of 4-thiophen-2-ylbenzoic acid.

Yield: 112 mg (57.5% of theory). C ₂₄ H ₂₆ \ ₂ O8 (M = 390.55). Calcd .: molecular peak (M + H) ⁺ : 391; detection: molecular peak (M + H) ⁺ : 391. Retention time with HPLC: 6.05 min (method A).

Example 2.68. 4- (5-Chlorothiophen-2-yl) - \ - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

C1

2.68. but. 4- (5-Chlorothiophen-2-yl) benzoic acid.

The specified compound is obtained analogously to example 2.55.a from 300 mg (1.52 mmol) of 2-bromo-5-chlorothiophene and 277 mg (1.67 mmol) of 4-carboxyphenylboronic acid using a KH8O ₄ solution to acidify the reaction mixture after processing it.

Yield: 76 mg (21.0% of theory). C ₁₁ H ₇ C1O ₂ 8 (M = 238.69). Calcd .: molecular peak (M-H) ^- : 237/239; found: molecular peak (M-H) ^- : 237/239. Retention time with HPLC: 8.75 min (Method A).

2.68.b. 4- (5-Chlorothiophen-2-yl) - \ - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The specified compound is obtained in accordance with General method I of 61 mg (0.3 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 71 mg (0.3 mmol) of 4- (5-chlorothiophen-2-yl) benzoic acid .

Yield: 29 mg (22.9% of theory). С ₂₄ Н ₂₅ С1 \ ₂ О8 (M = 425.0). Calcd .: molecular peak (M + H) ⁺ : 425/427; detection: molecular peak (M + H) ⁺ : 425/427. Retention time with HPLC: 6.65 min (Method A).

Example 2.69. 4-Furan-2-yl - \ - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

2.69.a. 4-furan-2-ylbenzoic acid.

The specified compound is obtained analogously to example 2.68.a from 302 mg (1.5 mmol) of 4-bromobenzoic acid and 201 mg (1.8 mmol) of furan-2-boronic acid.

Yield: 166 mg (58.8% of theory). C ₁₁ H ₈ O ₃ (M = 188.19). Calcd .: molecular peak (M-H) ^- : 187; detection: molecular peak (M-H) ^- : 187. Retention time by HPLC: 6.82 min (method A).

2.69.b. 4-Furan-2-yl - \ - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I, from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 94 mg (0.5 mmol) of 4-furan-2-ylbenzoic acid.

Yield: 91 mg (48.4% of theory). C ₂₄ H _{26 2} O ₂ (M = 374.49). Calcd .: molecular peak (M + H) ⁺ : 375; detection: molecular peak (M + H) ⁺ : 375. Retention time by HPLC: 6.48 min (method A).

Example 2.70. 4- (5-Methylpyridin-2-yl) - \ - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

2.70. but. 4- (5-Methylpyridin-2-yl) benzoic acid.

The specified compound is obtained analogously to example 2.55.a from 430 mg (2.50 mmol) of 2-bromo-5 methylpyridine and 498 mg (3.00 mmol) of 4-carboxyphenylboronic acid.

Yield: 300 mg (56.3% of theory). C _H 11c \ O) ₂ (M = 213.24). Calcd .: molecular peak (M + H) ⁺ : 214;

- 81 012834 found .: molecular peak (M + H) ⁺ : 214. Retention time with HPLC: 4.55 min (method A).

2.70.b. 4- (5-Methylpyridin-2-yl) -N- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The specified compound is obtained in accordance with General procedure I from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 107 mg (0.5 mmol) of 4- (5-methylpyridin-2-yl) benzoic acid .

Yield: 53 mg (26.5% of theory). C ^ A ^ ^ O (M = 399.54). Calcd .: molecular peak (M + H) ⁺ : 400; detection: molecular peak (M + H) ⁺ : 400. Retention time by HPLC: 3.98 min (method A).

Example 2.71. 4- (6-Methylpyridin-3-yl) -N- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

2.71.a. 4- (6-Methylpyridin-3-yl) benzoic acid.

The specified compound is obtained analogously to example 2.55.a from 430 mg (2.50 mmol) of 5-bromo-2-methylpyridine and 498 mg (3.00 mmol) of 4-carboxyphenylboronic acid.

Yield: 300 mg (56.3% of theory). SvNpKOG (M = 213.24). Calcd .: molecular peak (M + H) ⁺ : 214; detection: molecular peak (M + H) ⁺ : 214. Retention time with HPLC: 2.66 min (Method A).

2.71.b. 4- (6-Methylpyridin-3-yl) -N- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I, from 102 mg (0.5 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 107 mg (0.5 mmol) of 4- (6-methylpyridin-3-yl) benzoic acid .

Yield: 48 mg (24.0% of theory). C ^ A ^ ^ O (M = 399.54). Calcd .: molecular peak (M + H) ⁺ : 400; detection: molecular peak (M + H) ⁺ : 400. Retention time by HPLC: 3.06 min (method A).

Example 2.72. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-chlorophenyl) thiophene-2-carboxylic acid.

2.72. but. 4- (4-Chlorophenyl) thiophene-2-carboxylic acid methyl ester.

420 mg (1.25 mmol) of 4-bromothiophen-2-carboxylic acid methyl ester is dissolved in 10 ml of dioxane and 5 ml of a 2 molar solution of Na ₂ CO ₃ . Next, 196 mg (0.06 mmol) of 4-chlorophenylboronic acid and 72 mg (0.06 mmol) of tetrakis (triphenylphosphine) palladium are added successively, after which the reaction mixture is refluxed for 6 hours and then stirred for a further 60 hours at CT After reheating, the hot reaction solution is subjected to vacuum filtration through a glass fiber filter, then it is washed with dioxane, mixed with a half-saturated NaΠCO ₃ solution and extracted with HU Ac. The combined organic phases are dried over MD8O ₄ . After removal of the desiccant and solvent, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 9: 1).

Yield: 150 mg (47.3% of theory). C ₁₂ H ₉ SC ₂ 8 (M = 252.72). Calcd .: molecular peak (M + H) ⁺ : 253/255; detection: molecular peak (M + H) ⁺ : 253/255. Retention time with HPLC: 6.21 min (method B).

2.72.b. 4- (4-Chlorophenyl) thiophene-2-carboxylic acid.

To a solution of 150 mg of 4- (4-chlorophenyl) thiophene-2-carboxylic acid methyl ester in 10 ml of EUN, 2 ml of a 1 molar solution of aO11 was added and the reaction solution was allowed to stir overnight at RT. After that, the solvent is evaporated in vacuo, the residue is mixed with 2 ml of 1 N. hydrochloric acid and cooled to 0 ° C. The precipitated product is suction filtered, washed with water and dried at 50 ° C.

Yield: 140 mg (98.7% of theory). С11Н7СЮ28 (M = 238.69). Calcd .: molecular peak (M + H) ⁺ : 239/241; detection: molecular peak (M + H) ⁺ : 239/241. Retention time with HPLC: 8.31 min (method A).

2.72. in. [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-chlorophenyl) thiophene-2-carboxylic acid.

The title compound was prepared according to General Procedure I from 144 mg (0.70 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 140 mg (0.59 mmol) of 4- (4-chlorophenyl) thiophene-2-carboxylic acid .

Yield: 78 mg (31.3% of theory). C ^ A ^ NU (M = 425.00). Calcd .: molecular peak (M + H) ⁺ : 425/427; detection: molecular peak (M + H) ⁺ : 425/427. Retention time with HPLC: 3.90 min (method A).

Example 2.73. 4- (5-Acetylthiophen-2-yl) -M- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

- 82 012834

2.73.a. 4-Iodo-N- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

Said compound was prepared according to General Procedure I from 2.04 g (10.0 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 2.48 g (10.0 mmol) of 4-iodobenzoic acid.

Yield: 1.91 g (44.0% of theory). C ₂₀ H ₂₃ W ₂ O (M = 434.32). Calcd .: molecular peak (M + H) ⁺ : 435; detection: molecular peak (M + H) ⁺ : 435. Retention time by HPLC: 5.40 min (method A).

2.73.b. 4- (5-Acetylthiophen-2-yl) -№-2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The specified compound is obtained analogously to example 2.46.b from 250 mg (0.58 mmol) of 4-iodo-N- [2- (4pyrrolidin-1-ylmethylphenyl) ethyl] benzamide and 118 mg (0.69 mmol) of 5-acetyl-2 -thiophenboronic acid by heating the reaction mixture under reflux for 15 hours

Yield: 50 mg (20.2% of theory). C ₂₆ H ₂ ^ ₂ O ₂ 8 (M = 432.59). Calcd .: molecular peak (M + H) ⁺ : 433; detection: molecular peak (M + H) ⁺ : 433. Retention time by HPLC: 3.91 min (method B).

Example 2.74. 4- (5-Formylthiophen-2-yl) -№- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The specified compound is obtained analogously to example 2.46.b from 250 mg (0.58 mmol) of 4-iodine-N- [2- (4pyrrolidin-1-ylmethylphenyl) ethyl] benzamide and 107 mg (0.69 mmol) of 5-formyl-2 -thiophenboronic acid by heating the reaction mixture under reflux for 15 hours

Yield: 22 mg (9.1% of theory). C ₂₅ H ₂₆ ^ O ₂ 8 (M = 418.56). Calcd .: molecular peak (M + H) ⁺ : 419; detection: molecular peak (M + H) ⁺ : 419. Retention time by HPLC: 3.82 min (method B).

Example 2.75. [2- (4-Aminomethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.75. but. 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid ethyl ester.

To 9.31 g (40 mmol) of 4'-chlorobiphenyl-4-carboxylic acid, 20 ml of thionyl chloride and 1 ml of DMF are added dropwise. Then the reaction mixture is heated to 60 ° C and maintained at this temperature for 2 hours. Then, the excess thionyl chloride is distilled off in vacuo at 50 ° C and the residue is dissolved in 200 ml of CH2C12. This solution was added dropwise to 9.19 g (40 mmol) of 4- (2 aminoethyl) benzoic acid ethyl ester used as the hydrochloride in 100 ml of a 10% aqueous solution of No. ₂ CO ₃ and the reaction mixture was stirred for the next hour with CT. After adding water and CH ₂ Cl _{2, the} organic phase is separated off, the aqueous phase is extracted with CH ₂ Cl ₂ , the combined organic phases are washed with a semi-saturated solution of 11CO ₃ and water and dried over MD8O ₄ . After removal of the desiccant, the solution was filtered through activated carbon, concentrated in vacuo, and the residue was recrystallized from tert-butyl methyl ether.

Yield: 11.93 g (73.1% of theory). С ₂₄ Н ₂₂ ССО ₃ (М = 407.90). Calcd .: molecular peak (M + H) ⁺ : 408; detection: molecular peak (M + H) ⁺ : 408. Retention time by HPLC: 9.8 min (method A).

2.75.b. 4- {2 - [(4'-Chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid.

To a solution of 11.93 g (29.25 mmol) of 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid ethyl ester in 150 ml of UNN, 50 ml of a 2 molar solution # O11 are added and stirred for 2 hours at RT. Then the pH of the reaction solution is set to 6-7 using 1N. HC1 solution, after which the precipitated product is filtered off and dried in a vacuum oven.

Yield: 10.74 g (96.7% of theory). С ₂₂ Н ₁₈ ССО ₃ (М = 379.85). Calculation: molecular peak (M + H) ⁺ : 380/382; detection: molecular peak (M + H) ⁺ : 380/382. HPLC Retention Time: 8.0 min (Method A).

2.75. in. [2- (4-Hydroxymethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

To a solution of 10.74 g (28.28 mmol) of 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid in 150 ml of dry THF, 4.82 g (29.69 mmol) are added CDI, after which the reaction mixture is heated to 50 ° C and maintained at this temperature for 2 hours. This solution is then added to a suspension of 2.14 g (56.56 mmol) No. B11. | in 5 ml of water and intensively stirred for the next hour at RT. Next, the pH of the solution is set to 6 with 1N. HC1, after which the solution is mixed with EJAc and filtered. The filtrate is washed with a semi-saturated solution No. 11CO ₃ and water and dried over

- 83 012834

Mg8O ₄ . Since, after removal of the desiccant and solvent, the residue still contains unreacted 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid, the reaction step described above is repeated. The resulting product is dried at 40 ° C.

Yield: 9.3 g (89.9% of theory). C ₂₂ H ₂₀ SCO ₂ (M = 365.86). Calcd .: molecular peak (M + H) ⁺ : 366/368; detection: molecular peak (M + H) ⁺ : 366/368. Retention time with HPLC: 8.11 min (method A).

2.75. g. [2- (4-Bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

To a solution of 7.9 g (21.59 mmol) of [2- (4-hydroxymethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid in 300 ml of CH ₂ Cl ₂ , 1.22 ml of Rvg _{3 was} added dropwise. Then the reaction mixture was allowed to stir at RT overnight. After this, the precipitate formed is suction filtered and the filtrate is concentrated. The residue is triturated with a small amount of acetonitrile and CH ₂ Cl ₂ , separated by vacuum filtration, combined with the previously obtained precipitate and dried in air.

Yield: 8.6 g (92.9% of theory). C ₂₂ H ₁₉ VgSSO (M = 428.76). Calcd .: molecular peak (M + H) ⁺ : 428/430/432; detection: molecular peak (M + H) ⁺ : 428/430/432. The value of K _g : 0.40 (silica gel, CH ₂ Cl ₂ ).

2.75. D. [2- (4-Aminomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

To a solution of 150 mg (0.35 mmol) of [2- (4-bromomethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide in 10 ml of acetonitrile was added 3 ml of a 0.5 molar solution of ΝΉ ₃ in dioxane and stirred in within 3 days at CT. Then the reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ in a ratio of 9: 1: 0.1).

Yield: 8 mg (6.3% of theory). C ₂₂ H ₂ 1SSH ₂ O (M = 364.88). Calcd .: molecular peak (M + H) ⁺ : 365/367; detection: molecular peak (M + H) ⁺ : 365/367. HPLC Retention Time: 5.97 min (method

BUT).

Example 2.76. (2- {4 - [(Diisopropylamino) methyl] phenyl} ethyl) 4'-chlorobiphenyl-4-carboxylic acid amide.

To a suspension of 129 mg (0.3 mmol) of [2- (4-bromomethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid and 55 mg (0.4 mmol) To ₂ CO ₃ in 20 ml of acetonitrile add 47 μl (0.33 mmol) of diisopropylamine and the reaction mixture are allowed to stir at RT overnight. After that, CH2C12 was diluted, insoluble inorganic salts were filtered off, and the filtrate was concentrated. The residue was triturated with acetonitrile, suction filtered and dried in air.

Yield: 75 mg (55.7% of theory). C ₂₈ H ₃₃ SS ₂ O (M = 449.04). Calcd .: molecular peak (M + H) ⁺ : 449/451; detection: molecular peak (M + H) ⁺ : 449/451. The value of K _g : 0.35 (silica gel, CH ₂ Cl ₂ / Meon / NH ₃ in a ratio of 95: 5: 0.5).

Example 2.77. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (3-oxopiperazin-1-ylmethyl) phenyl] ethyl} amide.

The specified compound is obtained analogously to example 2.76 from 129 mg (0.3 mmol) of [2- (4 bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid and 33 mg (0.33 mmol) of piperazin-2one.

Yield: 23 mg (17.1% of theory). С ₂₆ Н ₂₆ СШ ₃ О ₂ (М = 447.97). Calcd .: molecular peak (M + H) ⁺ : 448/450; detection: molecular peak (M + H) ⁺ : 448/450. Value K _g : 0.10 (silica gel,

CH2C12 / MeOH / NH3 in a ratio of 95: 5: 0.5).

Example 2.78. [(4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) methylamino] acetic acid ethyl ester

The specified compound is obtained analogously to example 2.76 from 257 mg (2- (4 bromomethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, 193 mg K ₂ CO ₃ and 101 mg (0.66 mmol) ethyl methylaminoacetic acid ester (used as hydrochloride).

Yield: 152 mg (54.5% of theory). С ₂₇ Н ₂₉ СШ ₂ О ₃ (M = 465.0). Calcd .: molecular peak (M + H) ⁺ : 465/467; detection: molecular peak (M + H) ⁺ : 465/467. Value K _g : 0.40 (silica gel,

- 84 012834

С ^ С ^ / МеОНЖН in the ratio 95: 5: 0.5).

Example 2.79. [(4- {2 - [(4'-Chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) methylamino] acetic acid.

To a solution of 80 mg (0.17 mmol) of ethyl [(4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) methylamino] acetic acid ethyl acetate in 3 ml of CJS, 0.3 ml of 1 -molar solution ШО11 and heated for 1 h under reflux. Then the solvent was evaporated in vacuo and the residue was mixed with water and 0.3 ml of 1 molar HCl. The precipitate was suction filtered and dried at 40 ° C.

Yield: 76 mg (100% of theory). С ₂₅ Н ₂₅ СШ ₂ О ₃ (М = 436.94). Calcd .: molecular peak (M + H) ⁺ : 437/439; detection: molecular peak (M + H) ⁺ : 437/439. Retention time with HPLC: 6.35 min (Method A).

Example 2.80. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (4-Acetylpiperazin-1-ylmethyl) phenyl] ethyl} amide.

The specified compound is obtained analogously to example 2.76 of 129 mg (0.3 mmol) of [2- (4 bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid and 42 mg (0.33 mmol) of 1-piperazine-1-ethanone.

Yield: 60 mg (42.0% of theory). С ₂₈ Н ₃₀ СШ ₃ О ₂ (M = 476.02). Calcd .: molecular peak (M + H) ⁺ : 476/478; detection: molecular peak (M + H) ⁺ : 476/478. The value of K _p : 0.15 (silica gel, CH ₂ Cl ₂ / Meon / ΝΙ P in a ratio of 95: 5: 0.5).

Example 2.81. {(2- [4- (2-Azabicyclo [2.2.1] hept-5-en-2-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4carboxylic acid.

The specified compound is obtained analogously to example 2.76 from 129 mg (0.3 mmol) of [2- (4-bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid and 31 mg (0.33 mmol) of 2-azabicyclo [2.2. 1] hept-5ena.

Yield: 100 mg (75.2% of theory). С ₂₈ Н ₂₇ СШ ₂ О (М = 442,99). Calcd .: molecular peak (M + H) ⁺ : 443/445; detection: molecular peak (M + H) ⁺ : 443/445. The value of K _p : 0,08 (silica gel,

CH ₂ Cl ₂ / MeONMN ₃ in a ratio of 95: 5: 0.5).

Example 2.82. 4'-chlorobiphenyl-4-carboxylic acid {(2- [4- (1,3-dihydroisoindol-2-ylmethyl) phenyl] ethyl} amide.

The specified compound is obtained analogously to example 2.76 from 129 mg (0.3 mmol) of [2- (4 bromomethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, 97 mg K ₂ CO ₃ and 51 mg (0.33 mmol) 2 , 3-dihydro-1H-isoindole (used as hydrochloride).

Yield: 80 mg (57.1% of theory). C ₃₀ H ₂₇ SC ₂ O (M = 467.02). Calcd .: molecular peak (M + H) ⁺ : 467/469; detection: molecular peak (M + H) ⁺ : 467/469. The value of K _p : 0,40 (silica gel,

CH2C12 / MeONZHN ₃ in a ratio of 95: 5: 0.5).

Example 2.83. {(2- [4- (7-Methyl-2,7-diazaspiro [4.4] non-2-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl 4-carboxylic acid.

- 85 012834

The specified compound is obtained analogously to example 2.76 from 129 mg (0.3 mmol) of [2- (4 bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid and 46 mg (0.33 mmol) of 2-methyl-2,7 diazaspiro [ 4.4] nonana.

Yield: 42 mg (28.7% of theory). C ₃₀ H ₃₄ SS ₃ O (M = 488.08). Calculation: molecular peak (M + H) ⁺ : 488-490; detection: molecular peak (M + H) ⁺ : 488/490. K _£ value: 0.05 (silica gel,

CH ₂ Cl ₂ / MeOH / LN ₃ in a ratio of 95: 5: 0.5).

Example 2.84. {(2- [4- (3-Diethylaminoazetidin-1-ylmethyl) phenyl] ethyl) amide of 4'-chlorobiphenyl-4carboxylic acid.

The specified compound is obtained analogously to example 2.76 from 129 mg (0.3 mmol) of [2- (4 bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid, 138 mg of K2CO3 and 66 mg (0.33 mmol) of azetidine-3- yldiethylamine (used as dihydrochloride), and the product is purified by column chromatography.

Yield: 15 mg (10.5% of theory). C ₂₉ H ₃₄ SS ₃ O (M = 476.07). Calcd .: molecular peak (M + H) ⁺ : 476/478; detection: molecular peak (M + H) ⁺ : 476/478. K _£ value: 0.10 (silica gel,

CH ₂ Cl ₂ / MeOH / LN ₃ in a ratio of 95: 5: 0.1).

Example 2.85. (8) -1- (4 - {(2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrolidine-2-carboxylic acid ethyl ester.

The specified compound is prepared analogously to example 2.76 from 257 mg (0.6- mmol) of 2- (4-bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid, 193 mg of K2CO3 and 119 mg (0.66 mmol) of ethyl ester (8 ) -pyrrolidine-2-carboxylic acid (used as hydrochloride), the product being purified by column chromatography.

Yield: 160 mg (54.3% of theory). C ₂₉ H ₃₁ SC ₂ O ₃ (M = 491.04). Calcd .: molecular peak (M + H) ⁺ : 491/493; detection: molecular peak (M + H) ⁺ : 491/493. K _£ value: 0.60 (silica gel,

CH ₂ Cl ₂ / MeOH / LN ₃ in a ratio of 95: 5: 0.5).

Example 2.86. (8) -1- (4- {2 - [(4'-Chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrolidine-2-carboxylic acid.

The specified compound is obtained analogously to example 2.79 from 130 mg (0.27 mmol) of ethyl ether (8) -1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrolidin-2- carboxylic acid.

Yield: 120 mg (97.8% of theory). С ₂₇ Н ₂₇ СШ ₂ О ₃ (M = 462.98). Calcd .: molecular peak (M + H) ⁺ : 463/465; detection: molecular peak (M + H) ⁺ : 463/465. Retention time with HPLC: 6.20 min (Method A).

Example 2.87. [1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyr- tert-butyl ether

The specified compound is obtained analogously to example 2.76 of 429 mg (1.0 mmol) of [2- (4 bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid and 205 mg (1.10 mmol) of pyrrolidin-3-yl-carbamic acid tert-butyl ester .

Yield: 500 mg (93.6% of theory). C ₃₁ H ₃₆ S ₃ O ₃ (M = 534.10). Calcd .: molecular peak (M + H) ⁺ : 534/536; detection: molecular peak (M + H) ⁺ : 534/536. The value of K _£ : 0.33 (silica gel, CH ₂ Cl ₂ / Meon / ΝΙ1 ₃ in a ratio of 95: 5: 0.5).

- 86 012834

Example 2.88. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (3-aminopyrrolidin-1-ylmethyl) phenyl] ethyl} amide.

To a solution of 500 mg (0.94 mmol) of tert-butyl ether [1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrolidin-3-yl] carbamic acid in 15 ml of CH ₂ Cl ₂ add 1 ml of trifluoroacetic acid and the reaction mixture is allowed to stir overnight. Then the reaction mixture is concentrated, the residue is dissolved in a small amount of CH ₂ Cl ₂ and mixed with a semi-saturated solution of KHCO ₃ . The precipitated product was suction filtered, triturated with acetonitrile and dried at 40 ° C.

Yield: 240 mg (59.1% of theory). С ₂₆ Н ₂₈ СШ ₃ О (M = 433.99). Calcd .: molecular peak (M + H) ⁺ : 434/436; detection: molecular peak (M + H) ⁺ : 434/436. The value of K _£ : 0.22 (silica gel, CH ₂ Cl ₂ / MeOH / ΝΙΙ ₃ in a ratio of 9: 1: 0.1).

Example 2.89. 4'-Chlorobiphenyl-4-carboxylic acid {2- [4- (3-Dimethylaminopyrrolidin-1-ylmethyl) phenyl] ethyl} amide.

To a solution of 60 mg (0.14 mmol) of {2- [4- (3-aminopyrrolidin-1-ylmethyl) phenyl] ethyl} amide of 4'-chlorobiphenyl-4-carboxylic acid in 5 ml of acetonitrile was added 0.12 ml of 37% aqueous formaldehyde solution, 28 mg (0.45 mmol) KaVN ₃ SC and one drop of glacial acetic acid. After this, the reaction mixture was allowed to stir at RT overnight, and then mixed with a diluted solution of No. O11 and EJAc. Phases were then separated, the organic phase was dried over Md8O ₄ and thereafter the desiccant was removed and the solvent. The residue was purified by column chromatography.

Yield: 10 mg (15.7% of theory). С ₂₈ Н ₃₂ СШ ₃ О (M = 462.04). Calcd .: molecular peak (M + H) ⁺ : 462/464; detection: molecular peak (M + H) ⁺ : 462/464. Retention time with HPLC: 5.16 min (Method A).

Example 2.90. [1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrolidin-2-ylmethyl] carbamic acid tert-butyl ester.

The specified compound is obtained, analogously to example 2.76, from 230 mg (0.54 mmol) of [2- (4-bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid and 116 mg (1.10 mmol) of pyrrolidine- tert-butyl ester 2-ylmethylcarbamic acid.

Yield: 230 mg (78.3% of theory). C ₃₂ H ₃₈ C1C ₃ O ₃ (M = 548.13). Calcd .: molecular peak (M + H) ⁺ : 548/550; detection: molecular peak (M + H) ⁺ : 548/550. K _£ value: 0.35 (silica gel,

CH ₂ Cl ₂ / Meon / KH ₃ in a ratio of 95: 5: 0.5).

Example 2.91. {(2- [4- (2-Aminomethylpyrrolidin-1-ylmethyl) phenyl] ethyl} amide of 4'-chlorobiphenyl-4carboxylic acid.

The specified compound is obtained analogously to example 2.88 from 230 mg (0.42 mmol) of tert-butyl ether [1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrolidin-2-ylmethyl ] carbamic acid.

Yield: 188 mg (100% of theory). С ₂₇ Н ₃₀ СШ ₃ О (M = 448.01). Calculation: molecular peak (M + H) ⁺ :

- 87 012834

448/450; detection: molecular peak (M + H) ⁺ : 448/450. The value of K _G : 0.35 (silica gel, CH ₂ Cl ₂ / Meon / ΝΙ1 ₃ in a ratio of 9: 1: 0.1).

Example 2.92. {(2- [4- (2-Dimethylaminomethylpyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.89 from 40 mg (0.09 mmol) {2- [4- (2aminomethylpyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, 0.08 ml 37% - aqueous solution of formaldehyde and 19 mg (0.30 mmol) No.VN ₃ SK

Yield: 10 mg (23.6% of theory). C ₂₉ H ₃₄ SS ₃ O (M = 476.07). Calcd .: molecular peak (M + H) ⁺ : 476/478; detection: molecular peak (M + H) ⁺ : 476/478. Value K _G : 0.12 (silica gel,

CH ₂ Cl ₂ / MeONMN ₃ in a ratio of 9: 1: 0.1).

Example 2.93. {(2- [4- (2-Methyl-2,6-diazaspiro [3.4] oct-6-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl 4-carboxylic acid.

The specified compound is obtained analogously to example 2.76 from 250 mg (2- (4 bromomethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, 97 mg K ₂ CO ₃ and 81 mg (0.64 mmol) 2 methyl -2,6-diazaspiro [3.4] octane, with the product being purified by HPLC.

Yield: 20 mg (7.2% of theory). C ₂₉ H ₃₂ C1 ^ O (M - 474.05). Calcd .: molecular peak (M + H) ⁺ : 474/476; detection: molecular peak (M + H) ⁺ : 474/476. Value K _G : 0.20 (silica gel,

CH ₂ Cl ₂ / MeONMN ₃ in a ratio of 9: 1: 0.1).

Example 2.94. 3 - [(4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) ethylamino] propionic acid.

Suspension of 257 mg (0.6 mmol) of [2- (4-bromomethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid, 166 mg (1.2 mmol) of K2CO3 and 138 mg of 3-ethylaminopropionic acid (0.9 mmol used as hydrochloride) in 20 ml of acetonitrile was stirred for 3 days at RT. Next, 5 ml of DMF was added, heated to 50 ° C and maintained at this temperature for 3 hours. After that, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by HPLC.

Yield: 50 mg (17.9% of theory). С ₂₇ Н ₂₉ СШ ₂ О ₃ (M = 465.0). Calcd .: molecular peak (M + H) ⁺ : 465/467; detection: molecular peak (M + H) ⁺ : 465/467. Retention time with HPLC: 5.85 min (Method A).

Example 2.95. (8) -1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrole methyl ester

2.95.a. 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid ethyl ester.

The specified compound is obtained in accordance with the General method Ι of 10.0 g (42.98 mmol) of 4'-chlorobiphenyl-4-carboxylic acid and 9.87 g (42.98 mmol) of ethyl 4- (2-aminoethyl) benzoic acid .

Yield: 10.64 g (60.7% of theory). С ₂₄ Н ₂₂ ССО ₃ (М = 407.90). Calcd .: molecular peak (M + H) ⁺ : 408/410; detection: molecular peak (M + H) ⁺ : 408/410.

- 88 012834

The value of K® is 0.87 (silica gel, CH ₂ Cl ₂ / MeOH 95: 5).

2.95. b. 4- {2 - [(4'-Chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid.

To a solution of 10.64 g (26.08 mmol) of 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid ethyl ester in 100 ml of E1OH, 14 ml of a 2 molar solution of HaOH are added, after whereby the reaction mixture is heated to 60 ° C and left overnight at this temperature. Then 30 ml of HaON solution are added again and kept at this temperature for a further 3 hours. Next, the pH of the reaction mixture is adjusted to 6-7 with a 1 molar solution of HC1, the precipitated product is filtered off and dried in vacuo.

Yield: 7.65 g (77.2% of theory). С ₂₂ Н ₁₈ ССО ₃ (М = 379.85). Calculation: molecular peak (M + H) ⁺ : 380/382; detection: molecular peak (M + H) ⁺ : 380/382. Retention time with HPLC: 8.1 min (method A).

2.95. in. [2- (4-Hydroxymethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

To a solution of 7.2 g (18.97 mmol) of 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid in 150 ml of dry THF, 3.24 g (20 mmol) of CDI are added, then the reaction mixture is heated to 50 ° C and maintained at this temperature for 2 hours. This solution is then added to a suspension of 1.44 g (38 mmol) of HaBH ₃ in 5 ml of water and stirred for the next hour. Then the pH of the reaction mixture is set to 6-7 using a 1 molar solution of HC1 and carefully extracted with E1OAc. The organic phase is washed with a solution of Xa11CO ₃ and water and dried over Md ₈ O ₄ . After removal of the desiccant and solvent, the residue was purified by chromatography (silica gel, CH ₂ Cl ₂ / MeOH in a ratio of 9: 1). Since educt is still present in the product, the above procedure is repeated using reagents in amounts reduced by 50% of the above.

Yield: 2.85 g (41.0% of theory). C ₂₂ H ₂₀ CAO ₂ (M = 365.86). Calcd .: molecular peak (M + H) ⁺ : 366/368; detection: molecular peak (M + H) ⁺ : 366/368. HPLC Retention Time: 8.0 min (Method A).

2.95. d. 4- {2 - [(4'-Chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid

To a solution of 1.0 g (2.73 mmol) of [2- (4-hydroxymethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid in 100 ml of dry THF, 1.25 ml (9 mmol) of triethylamine are added and cooled to -20 ° C. Then, 0.64 ml (8.2 mmol) of methanesulfonic acid chloride is added dropwise and stirred for the next 2 hours at this temperature. Then add a 5% solution of HaNSO ₃ and carefully extracted with EAAc. The organic phase is dried over Xa ₂ 8O ₃ , the desiccant and solvent are removed, and the residue is dried in vacuo at 30 ° C.

Yield: 1.21 g (99.7% of theory). C ₂₃ 1 1 ₂₂ CAO ₃ 8 (M = 443.95). Calcd .: molecular peak (M + H) ⁺ : 444/446; detection: molecular peak (M + H) ⁺ : 444/446. Retention time with HPLC: 8.8 min (method A).

2.95. e. (8) -1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrolidine 2-carboxylic acid methyl ester.

A solution of 50 mg (0.3 mmol) of (28) -pyrrolidine-2-carboxylic acid methyl ester (used as hydrochloride) and 0.7 ml (0.5 mmol) of triethylamine in 4 ml of DMF is stirred in the atmosphere for 20 minutes Ν ₂ at CT. Then 111 mg (0.25 mmol) of 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid are added, after which it is heated to 60 ° C and kept at this temperature for 2 h. Then the reaction mixture was concentrated in vacuo and the residue was purified by HPLC.

Yield: 4 mg (3.4% of theory). C ₂₈ H ₂₉ C1X ₂ O ₃ (M = 477.01). Calcd .: molecular peak (M + H) ⁺ : 477/479; detection: molecular peak (M + H) ⁺ : 477/479. Retention time with HPLC: 6.51 min (method A).

Example 2.96. 4'-Chlorobiphenyl-4-carboxylic acid {2- [4- (2-Methylpiperidin-1-ylmethyl) phenyl] ethyl} amide.

The specified compound is obtained analogously to example 2.95.d from 111 mg (0.42 mmol) of 4- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid and 35 μl (0.3 mmol) 2 -methylpiperidine without triethylamine.

Yield: 7 mg (6.3% of theory). C ₂₈ H ₃₁ SC ₂ O (M = 447.03). Calcd .: molecular peak (M + H) ⁺ : 447/449; detection: molecular peak (M + H) ⁺ : 447/449. HPLC Retention Time: 6.4 min (Method A).

Example 2.97. 4'-Chlorobiphenyl-4-carboxylic acid {2- [4- (2-Methylpyrrolidin-1-ylmethyl) phenyl] ethyl} amide.

- 89 012834

The specified compound is obtained analogously to example 2.95.d from 111 mg (0.42 mmol) of 4- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid and 32 μl (0.3 mmol) 2 -methylpyrrolidine without the use of triethylamine.

Yield: 2 mg (1.8% of theory). С ₂₇ Н ₂₉ СШ ₂ О (М = 433.0). Calcd .: molecular peak (M + H) ⁺ : 433/435; detection: molecular peak (M + H) ⁺ : 433/435. Retention time with HPLC: 6.3 min (method A).

Example 2.98. (2- {4 - [(Cyclopropylmethylamino) methyl] phenyl} ethyl) 4'-chlorobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 2.95.d from 111 mg (0.42 mmol) of 4- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid and 26 μl (0.3 mmol) of cyclopropylmethylamine without triethylamine.

Yield: 4 mg (3.8% of theory). C ₂₆ H ₂₇ SC ₂ O (M = 418.97). Calcd .: molecular peak (M + H) ⁺ : 418/420; detection: molecular peak (M + H) ⁺ : 418/420. HPLC Retention Time: 6.4 min (Method A).

Example 2.99. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (3,4-dihydro-1H-isoquinolin-2-ylmethyl) phenyl] ethyl} amide.

The specified compound is obtained analogously to example 2.95.d from 111 mg (0.42 mmol) of 4- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid and 40 mg (0.3 mmol) 1 , 2,3,4-tetrahydroisoquinoline without triethylamine.

Yield: 21 mg (17.5% of theory). C ₂₆ H ₂₇ SC ₂ O (M = 481.04). Calcd .: molecular peak (M + H) ⁺ : 481/483; detection: molecular peak (M + H) ⁺ : 481/483. Retention time with HPLC: 6.8 min (method A).

Example 2.100. [2- (4 - {[(2-Hydroxyethyl) methylamino] methyl} phenyl) ethyl] amide 4'-chlorobiphenyl-4carboxylic acid.

The specified compound is obtained analogously to example 2.95.d from 111 mg (0.42 mmol) of 4- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid and 24 μl (0.3 mmol) 2 -methylaminoethanol without the use of triethylamine.

Yield: 13 mg (12.3% of theory). C ₂₅ H ₂₇ SC ₂ O ₂ (M = 422.96). Calcd .: molecular peak (M + H) ⁺ : 423/425; detection: molecular peak (M + H) ⁺ : 423/425. Retention time with HPLC: 5.8 min (method A).

Example 2.101. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (2,6-dimethylpiperidin-1-ylmethyl) phenyl] ethyl} amide.

The specified compound is obtained analogously to example 2.95. D from 111 mg (0.42 mmol) of 4- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid and 41 μl (0.3 mmol) 2 , 6-dimethylpiperidine without the use of triethylamine.

Yield: 8 mg (6.9% of theory). C ₂₉ H ₃₃ SS ₂ O (M = 461.05). Calcd .: molecular peak (M + H) ⁺ : 461/463; detection: molecular peak (M + H) ⁺ : 461/463. HPLC Retention Time: 6.6 min (method

- 90 012834

BUT).

Example 2.102. [2- (4-Azetidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.95.d from 111 mg (0.42 mmol) of 4- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid and 20 μl (0.3 mmol) of azetidine without triethylamine.

Yield: 3 mg (3.0% of theory). С ₂₅ Н ₂₅ С1Ы ₂ О (M = 404.94). Calcd .: molecular peak (M + H) ⁺ : 405/407; detection: molecular peak (M + H) ⁺ : 405/407. Retention time with HPLC: 5.9 min (method A).

Example 2.103. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide.

The specified compound is obtained analogously to example 2.95.d from 50 mg (0.11 mmol) of 4- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl ester of methanesulfonic acid and 11 μl (0.14 mmol) 2 , 5-dihydro-1H-pyrrole without triethylamine.

Yield: 18 mg (38.2% of theory). C ₂₆ H ₂₅ Cl ₂ O (M = 416.95). Calcd .: molecular peak (M + H) ⁺ : 417/419; detection: molecular peak (M + H) ⁺ : 417/419. Retention time with HPLC: 6.2 min (method A).

Example 2.104. 4'-bromobiphenyl-4-carboxylic acid {2- [4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide

2.104. but. 4'-bromobiphenyl-4-carboxylic acid ethyl ester.

The specified compound is obtained analogously to example 2.46.b from 1.22 ml (7.47 mmol) of ethyl ester of 4-bromobenzoic acid and 1.8 g (8.96 mmol) of 4-bromophenylboronic acid by heating under reflux for 72 hours The product is crystallized from acetonitrile.

Yield: 293 mg (12.8% of theory). C ₁₅ H ₁₃ BrO ₂ (M = 305.17). Calcd .: molecular peak (M + H) ⁺ : 304/306; detection: molecular peak (M + H) ⁺ : 304/306. The value of K _£ : 0.9 (silica gel, petroleum ether / EJAc in a ratio of 6: 4).

2.104.b. 4'-Bromobiphenyl-4-carboxylic acid.

To a solution of 270 mg (0.89 mmol) of 4'-bromobiphenyl-4-carboxylic acid ethyl ester in 10 ml of ENJ, 1.24 ml of a 2 molar NaOH solution was added and the reaction mixture was stirred for 2 hours at RT. Next, the pH value is set at 6-7 using 1 molar HCl and the precipitated product is filtered off and dried.

Yield: 205 mg (83.6% of theory). C ₁₁ H ₉ BrO ₂ (M = 277.12). Calcd .: molecular peak (M-H) ^- : 275/277; found: molecular peak (M-H) ^- : 275/277. Retention time with HPLC: 8.5 min (method A).

2.104. in. [4- (2-aminoethyl) phenyl] methanol.

To 5.8 g (39.41 mmol) of (4-hydroxymethylphenyl) acetonitrile (see Example 1.1. E) in 116 ml of a methanol solution of OH ₃ , 580 mg of Raney nickel is added and the reaction mixture is hydrogenated at a pressure of H ₂ 50 psi. inch. Upon completion of the reaction, the catalyst was filtered off, the solvent was removed, and the residue was purified by chromatography (silica gel, EyAc / MeOH / UN ₃ in a ratio of 7: 3: 0.3).

Yield: 3.9 g (65.4% of theory). С ₉ Н ₁₃ НО (М = 151.21). Calcd .: molecular peak (M + H) ⁺ : 152; detection: molecular peak (M + H) ⁺ : 152. The value of K _£ : 0.18 (silica gel, EYuAc / Meon / Un ₃ in a ratio of 8: 2: 0.2).

2.104. g. [2- (4-Hydroxymethylphenyl) ethyl] carbamic acid tert-butyl ester.

To a solution of 2.5 g (16.53 mmol) of [4- (2-aminoethyl) phenyl] methanol in 50 ml of CH2C12 at RT, 17.36 ml of a 1 molar solution of BOC anhydride in CH ₂ Cl _{2 is} added and the reaction mixture is left mix overnight at CT. Then add 100 ml of KH8O ₄ solution, the organic phase is separated, washed

- 91 012834 with a diluted solution of CaHCO ₃ and water and dried over Md ₈ O ₄ . After removal of the desiccant and solvent, the expected product is obtained.

Yield: 4.06 g (97.7% of theory). C1 ₄ Π ₂ 1NO ₃ (M = 251.33). Calcd .: molecular peak (M + H) ⁺ : 252; detection: molecular peak (M + H) ⁺ : 252. Retention time with HPLC: 6.4 min (method A).

2.104. e. [2- (4-Chloromethylphenyl) ethyl] carbamic acid tert-butyl ester.

To a solution of 2.6 g (10.35 mmol) of [2- (4-hydroxymethylphenyl) ethyl] carbamic acid tert-butyl ester in 50 ml of CH ₂ Cl ₂ add 1 ml of pyridine, cool to 0 ° C and add 1.03 ml (12.41 mmol) of thionyl chloride. Then the mixture was kept for 1 h at 0 ° C, after which it was allowed to warm to CT. Next, the reaction mixture was washed with water, a diluted KH8O ₄ solution, and again with water, dried over MD8O ₄ and filtered through activated carbon. After removing the solvent, the product is obtained in the form of an oil, which is used without additional in the next reaction.

Yield: 1.8 g (64.5% of theory). C1 ₄ H ₂₀ C1CO ₂ (M = 269.77). Calcd .: molecular peak (M-H) ^- : 268/270; found: molecular peak (M-H) ^- : 268/270. The value of K _£ : 0.62 (silica gel, petroleum ether / EJAc in a ratio of 7: 3).

2.104. e. {2- [4- (2,5-Dihydropyrrol-1-ylmethyl) phenyl] ethyl} carbamic acid tert-butyl ester.

To a solution of 1.4 g (5.19 mmol) of [2- (4-chloromethylphenyl) ethyl] carbamic acid tert-butyl ester in 50 ml of acetonitrile, 2.37 g (17.13 mmol) of K2CO3 and 0.8 ml ( 10.38 mmol) of 2,5-dihydro1H-pyrrole and allowed to stir overnight at RT. The reaction mixture was diluted SN2S12, washed with water and dried over Md8O _4. After removal of the desiccant and solvent, the expected product is obtained.

Yield: 1.46 g (93.0% of theory). C1 ₈ H ₂₆ K ₂ O ₂ (M = 302.42). Calcd .: molecular peak (M + H) ⁺ : 303; detection: molecular peak (M + H) ⁺ : 303. K _£ value: 0.15 (silica gel, petroleum ether / ЕУАс in the ratio 7: 3).

2.104. g. 2- [4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethylamine.

To a solution of 1.21 g (4 mmol) of {2- [4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} carbamic acid tert-butyl ester in 50 ml of CH2C12, 5 ml of trifluoroacetic acid was added and stirred for 2 hours at CT. Then the reaction mixture was concentrated in vacuo, the residue was mixed with water and CH ₂ Cl ₂ and made basic with a solution of K ₂ CO ₃ . The organic phase is separated, washed with water and dried over MgO ₄ . After removal of the desiccant and solvent, the expected product is obtained.

Yield: 0.35 g (43.3% of theory). C1 ₃ H1 ₈ K ₂ (M = 202.30). Calcd .: molecular peak (M + H) ⁺ : 203; detection: molecular peak (M + H) ⁺ : 203. The value of K _£ : 0.05 (silica gel, EuAc / MeOH / HH ₃ in a ratio of 9: 1: 0.1).

2.104.z. 4'-bromobiphenyl-4-carboxylic acid {2- [4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide.

The specified compound is obtained in accordance with the General method I of 139 mg (0.50 mmol) of 4'-bromobiphenyl-4-carboxylic acid and 101 mg (0.50 mmol) of 2- [4- (2,5-dihydropyrrol-1-ylmethyl ) phenyl] ethylamine.

Yield: 21 mg (9.1% of theory). C ₂₆ H ₂₅ BrK ₂ O (M = 461.41). Calcd .: molecular peak (M + H) ⁺ : 461/463; detection: molecular peak (M + H) ⁺ : 461/463. Retention time with HPLC: 6.46 min (method A).

Example 2.105. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (1-Ethylpiperidin-2-yl) phenyl] ethyl} amide.

• C1

2.105.a. (4-Pyridin-2-ylphenyl) acetonitrile.

The specified compound is obtained analogously to example 2.46.b from 0.52 ml (5.40 mmol) of 2-bromopyridine and 1.0 g (5.96 mmol) of 4-cyanomethylphenylboronic acid. After removal of the desiccant and solvent, the residue was triturated with diisopropyl ether and dried in air.

Yield: 0.76 g (72.5% of theory). C1 ₃ H1 ₀ K ₂ (M = 194.24). Calculation: molecular peak (M + H) ⁺ : 195; detection: molecular peak (M + H) ⁺ : 195. Retention time with HPLC: 3.56 min (method B).

2.105.b. 2- (4-Cyanomethylphenyl) -1-ethylpyridinium iodide.

To a solution of 760 mg (3.91 mmol) of (4-pyridin-2-ylphenyl) acetonitrile in 5 ml of DMF was added 0.38 ml (4.7 mmol) of ethyl iodide and allowed to stir at RT overnight. To complete the reaction, the solution is kept in a microwave oven at 120 ° C for 20 minutes. After that, the solvent was evaporated in vacuo, the residue was mixed with water and extracted with ЕУАс. The aqueous phase is concentrated, the residue is triturated with THF and the suspension is cooled to 0 ° C. The product is suction filtered and

- 92 012834 dried at 50 ° C.

Yield: 800 mg (58.4% of theory). C ₁₅ H ₁₅ W ₂ (M = 350.21). Calcd .: molecular peak (M) ⁺ : 223; detection: molecular peak (M) ⁺ : 223. Retention time by HPLC: 1.76 min (method A).

2.105. in. 2- [4- (1-Ethylpiperidin-2-yl) phenyl] ethylamine.

To a solution of 800 mg (2.28 mmol) of 2- (4-cyanomethylphenyl) -1-ethylpyridinium iodide in 10 ml of a methanol solution of MH ₃ , 100 mg of Raney nickel was added and the reaction mixture was hydrogenated in an autoclave for 24 hours at a pressure of 20 psi. inch and CT. Then the catalyst is suction filtered, the reaction solution was mixed with 100 mg of ₂ P1o and again hydrogenated for 30 hours at RT and a pressure of 20 pounds / square inch. After removal of the catalyst, a product is obtained (in the form of a hydroiodide), which is used in the subsequent reaction without purification.

Yield: 700 mg (85.1% of theory). C ₁₅ H ₂₄ W ₂ (M = 360.28). Calcd .: molecular peak (M) ⁺ : 233; detection: molecular peak (M) ⁺ : 233.

Retention time with HPLC: 0.93 min (elution with a mixture of water / acetonitrile / formic acid in a ratio of 95: 5: 0.01 in isocratic mode for 8 min).

2.105. d. {2- [4- (1-Ethylpiperidin-2-yl) phenyl] ethyl} amide of 4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained in accordance with General procedure I from 480 mg (1.33 mmol) of 2- [4 (1-ethylpiperidin-2-yl) phenyl] ethylamine (used as hydroiodide) and 310 mg (1.33 mmol) 4 'chlorobiphenyl-4-carboxylic acid.

Yield: 20 mg (3.4% of theory). C ₂₈ H ₃₁ SC ₂ O (M = 447.03). Calcd .: molecular peak (M + H) ⁺ : 447/449; detection: molecular peak (M + H) ⁺ : 447/449. HPLC Retention Time: 6.68 min (method

BUT).

Example 2.106. [2- (1-Pyrrolidin-1-ylindan-5-yl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.106. but. (E) -3- (1-oxoindan-5-yl) acrylic acid ethyl ester.

To a solution of 4.64 g (21.99 mmol) of 5-bromindan-1-one in 110 ml of triethylamine in an atmosphere of Ν ₂ , 5.96 ml (55 mmol) of ethyl ester of acrylic acid, 275 mg (1.21 mmol) of P0 are added (OLc) ₂ and 704 mg (2.31 mmol) of tri-o-tolylphosphine, after which the reaction mixture is heated to 100 ° C and maintained at this temperature for 4 hours. Then, the solvent is distilled off, the residue is mixed with 150 ml of Е1Олс and 100 ml of a mixture of water with ice, acidify conc. HCl, the organic phase is washed with 100 ml of water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue was purified by chromatography (silica gel, hexane / EuAc in a ratio varying from 9: 1 to 8: 2).

Yield: 4.0 g (79.0% of theory). Melting point: 100-102 ° C.

2.106.b. (E) -3- (1-oxoindan-5-yl) acrylic acid.

To a solution of 4.0 g (17.0 mmol) of (E) -3- (1-oxoindan-5-yl) acrylic acid ethyl ester in 50 ml of MeOH was added 10 ml of 2N. NaOΉ and the reaction mixture were heated under reflux for 30 minutes. Then mixed with 11 ml of 2n. HCl solution, MeOH is distilled off, the crystals are separated by vacuum filtration and dried.

Yield: 3.0 g (87.3% of theory). Melting point: 240-244 ° C.

2.106. in. 3- (1-Oxoindan-5-yl) propionic acid.

To a solution of 1.6 g (7.91 mmol) of (E) -3- (1-oxoindan-5-yl) acrylic acid in 50 ml of MeOH, 150 mg of 10% Pb / C are added and the reaction mixture is shaken in a Parr autoclave at CT and a pressure of H ₂ 3 bar to theoretical absorption of H ₂ . Then mixed with 10 ml of 1N. NaOΉ and remove the solvent. The residue was acidified with dilute HC1, extracted well EYuAs and the organic phase was dried over M§8O _4. After removal of the desiccant and solvent, the residue was triturated with tert-butyl methyl ether, the precipitate was suction filtered and dried.

Yield: 500 mg (31.0% of theory). C ₁₂ H ₁₂ O ₃ (M = 204.23). Calcd .: molecular peak (MH) ': 203; found: molecular peak (M-H) ^- : 203. The value of K _g : 0.45 (silica gel, CH ₂ Cl ₂ / MeOH in a ratio of 9: 1).

2.106. g. [2- (1-Oxoindan-5-yl) ethyl] carbamic acid tert-butyl ester.

1.6 g (7.83 mmol) of 3- (1-oxoindan-5-yl) propionic acid are added under argon to 25 ml of tert-butanol and 2.5 ml of triethylamine. Azidophosphoric acid diphenyl ester 2.22 ml (10.0 mmol) was added to this solution, then it was heated to 80 ° C and held at this temperature for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography.

Yield: 750 mg (34.8% of theory). C ₁₆ H ₂ ^ O ₃ (M = 275.35). Calcd .: molecular peak (M) ⁺ : 275; about

- 93 012834 outdoor temp .: molecular peak (M) ^+: 275. The value of K _and 0.65 (silica gel, CH ₂ C1 ₂ / MeOH 95: 5).

2.106. d. [2- (1-Hydroxyindan-5-yl) ethyl] carbamic acid tert-butyl ester.

To a solution of 700 mg (2.54 mmol) of [2- (1-oxoindan-5-yl) ethyl] carbamic acid tert-butyl ester in 70 ml of MeOH 700 mg (18.5 mmol) \ aB11 ₄ are added in portions and left on stir nightly at CT. Then the reaction solution was carefully mixed with 10% KH8O ₄ solution, diluted with water and extracted thoroughly with tert-butyl methyl ether. The organic phase is washed with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue was purified by silica gel chromatography.

Yield: 350 mg (49.7% of theory). C | ₆ H ₂₃ \ O ₃ (M = 277.37). Calcd .: molecular peak (M) ⁺ : 277; Detection .: molecular peak (M) ^+: 277. The value K _I: 0.30 (silica gel, petroleum ether / EYuAs in the ratio 6: 4).

2.106. e. [2- (1-Pyrrolidin-1-ylindan-5-yl) ethyl] carbamic acid tert-butyl ester.

To a solution of 350 mg (1.26 mmol) of [2- (1-hydroxyindan5-yl) ethyl] carbamic acid tert-butyl ester in 7.5 ml of CH2C12 cooled to 0 ° C, 109 μl (1.5 mmol) are slowly added dropwise. ) thionyl chloride (dissolved in a small amount of CH2C12). Then it is stirred for a further 30 min at 10 ° C, after which the reaction solution is mixed with an ice-cold solution of HaNSO ₃ , the organic phase is separated, washed with cold water and dried over Md ₈ O ₄ . After removal of the desiccant, the filtrate was cooled to 0 ° C, 417 μl (5.0 mmol) of pyrrolidine was added dropwise, and the reaction mixture was allowed to stir at RT overnight. Then the reaction mixture was concentrated and the residue was purified by silica gel chromatography.

Yield: 120 mg (28.8% of theory). C ₂₀ H ₃₀ X ₂ O ₂ (M = 330.47). Calcd .: molecular peak (M + H) ⁺ : 331; found: molecular peak (M + H) ⁺ : 331. Retention time by HPLC: 5.6 min (Method A).

2.106. g. 2- (1-Pyrrolidin-1-ylindan-5-yl) ethylamine.

To a solution of 100 mg (0.3 mmol) of [2- (1-pyrrolidin-1-ylindan-5-yl) ethyl] carbamic acid tert-butyl ester in 10 ml of CH2C12, 100 μl of trifluoroacetic acid was added with gentle cooling and stirred for 1 hour at CT. To complete the reaction completely, it is additionally mixed with 500 μl of trifluoroacetic acid under cooling and stirred for 2 hours at RT. After that, the reaction mixture was concentrated in vacuo and the product (in the form of bistrifluoroacetate) was used without purification in the subsequent reaction.

Yield: 100 mg (72.7% of theory). C | ₉ H ₂₂ E ₆ \ ₂ O. | (M = 458.51). Calcd .: molecular peak (M + H) ⁺ : 231; Detection .: molecular peak (M + H) ^+: 231. The value K _I: 0.3 (silica gel, CH ₂ C1 ₂ / MeONMN ₃ in a ratio of 9: 1: 0.1).

2.106.z. [2- (1-Pyrrolidin-1-ylindan-5-yl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I from 100 mg (0.29 mmol) of 2- (1pyrrolidin-1-ylindan-5-yl) ethylamine (used as bistrifluoroacetate) and 70 mg (0.3 mmol) 4'- chlorobiphenyl-4-carboxylic acid.

Yield: 40 mg (30.0% of theory). С ₂₈ Н ₂₉ СШ ₂ О (М = 445.01). Calcd .: molecular peak (M + H) ⁺ : 445/447; detection: molecular peak (M + H) ⁺ : 445/447. HPLC Retention Time: 6.65 min (method

BUT).

Example 2.107. [2- (3-Bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

C1

2.107.a. 2-Bromo-4-cyanomethylbenzoic acid methyl ester.

To a solution of 24.51 g (0.5 mol) \ aC \ in 40 ml of water is added a solution of 98.55 g (0.32 mol) of 2-bromo-4-bromomethylbenzoic acid methyl ester in 60 ml of UNN and the reaction mixture for Heat for 5 hours under reflux.

Then it is mixed with 1 l of tert-butyl methyl ether and 500 ml of water, the organic phase is separated, washed with water several times and dried over MgO ₄ . After removal of the desiccant and solvent, the residue was purified by silica gel chromatography (petroleum ether / EyAc 8: 2).

Yield: 15.0 g (16.6% of theory). C ₁₀ H ₈ B1XO ₂ (M = 254.09). Calcd .: molecular peak (M-H) ^- : 252/254; found: molecular peak (M-H) ^- : 252/254.

2.107.b. 2-bromo-4-cyanomethylbenzoic acid.

To a solution of 7.9 g (31.0 mmol) of 2-bromo-4-cyanomethylbenzoic acid methyl ester in 100 ml of EUN, 35 ml of a 1 molar solution of aO11 was added, after which the reaction mixture was heated under reflux for 1 h and then allowed to stir at RT overnight. Next, it is mixed with a mixture of water and ice and acidified with a dilute KH8O ₄ solution. The precipitate was suction filtered, washed with water and dried at 50 ° C.

- 94 012834

Yield: 6.2 g (83.3% of theory). C ₉ H ₆ BrCO ₂ (M = 240.06). Calcd .: molecular peak (M-H) ^- : 238/240; found: molecular peak (M-H) ^- : 238/240. Retention time with HPLC: 3.99 min (method B).

2.107. in. (3-Bromo-4-hydroxymethylphenyl) acetonitrile.

To a solution of 2.4 g (10 mmol) of 2-bromo-4-cyanomethylbenzoic acid in 50 ml of THF, 1.78 g (11 mmol) of CDI are added and heated in a water bath until gas evolution ceases. Then this solution is added to a solution of 0.76 g (20 mmol) of CaBH ₄ in 50 ml of water, while the temperature should not exceed 30 ° C. The mixture is stirred for a further 2 h at RT, the reaction mixture is carefully acidified with dilute KN8O4 thoroughly extracted with tert-butyl methyl ether, the organic phase was washed with water and dried over Md8O _4. Finally, it is filtered through activated carbon and the solvent is removed in vacuo.

Yield: 2.2 g (97.3% of theory). C ₉ H ₈ BrCO (M = 226.07). Calcd .: molecular peak (M-H) ^- : 224/226; detection: molecular peak (M-H) ^- : 224/226. The value of K _£ : 0.6 (silica gel, CH ₂ Cl ₂ / MeOH in a ratio of 9: 1).

2.107. g. (3-Bromo-4-pyrrolidin-1-ylmethylphenyl) acetonitrile.

To a solution of 1.9 g (8.4 mmol) of (3-bromo-4-hydroxymethylphenyl) acetonitrile in 50 ml of CH ₂ Cl _2, add 1.25 ml (9 mmol) of triethylamine, cool to 0 ° C and add the solution dropwise 0.66 ml (8.5 mmol) of methanesulfonic acid chloride in 10 ml of CH2C12. Then it is stirred for 1 h at 0 ° C, after which, under ice cooling, a solution of 1.4 ml (17 mmol) of pyrrolidine in 10 ml of CH2C12 is added dropwise. The reaction mixture was allowed to warm to RT overnight, then mixed with water, the organic phase was separated, washed twice with water, filtered through activated carbon and concentrated in vacuo. The residue was evaporated twice with toluene twice and the obtained product was used without further purification in the subsequent reaction.

Yield: 2.25 g (95.9% of theory). C ₁₃ H ₁₅ BrK ₂ (M = 279.18). Calcd .: molecular peak (M + H) ⁺ : 279/281; detection: molecular peak (M + H) ⁺ : 279/281. The value of K _£ : 0.5 (silica gel, CH ₂ Cl ₂ / MeOHMH ₃ in a ratio of 9: 1: 0.1).

2.107. D. 2- (3-Bromo-4-pyrrolidin-1-ylmethylphenyl) ethylamine.

To a solution of 225 mg (0.81 mmol) of (3-bromo-4-pyrrolidin-1-ylmethylphenyl) acetonitrile in 5 ml of methanolic solution N11 ₃ and 5 ml of EuAc, 20 mg of Raney nickel is added and shaken for 1 h in a Parr autoclave at CT and pressure N ₂ 5 psi. After that, the catalyst was filtered off, the solvent was evaporated in vacuo, and the product was used without purification in the subsequent reaction.

Yield: 225 mg (98.1% of theory). C ₁₃ H ₁₉ BrK ₂ (M = 283.21). Calcd .: molecular peak (M + H) ⁺ : 283/285; detection: molecular peak (M + H) ⁺ : 283/285. The value of K _£ : 0.08 (silica gel, CH ₂ Cl ₂ / MeOHMN ₃ in a ratio of 9: 1: 0.1).

2.107. e. Hydrochloride of [2- (3-bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4carboxylic acid.

The specified compound is obtained in accordance with General procedure I from 220 mg (0.78 mmol) of 2- (3bromo-4-pyrrolidin-1-ylmethylphenyl) ethylamine and 186 mg (0.8 mmol) of 4'-chlorobiphenyl-4-carboxylic acid . After removal of the desiccant and solvent, the residue was dissolved in isopropanol / tert-butyl methyl ether, mixed with a solution of HCl in ether and concentrated in vacuo. The residue was redissolved in 20 ml of isopropanol, triturated, suction filtered, washed with a small amount of isopropanol and dried at 50 ° C.

Yield: 165 mg (39.6% of theory). С ₂₆ Н ₂₇ ВГС1 ₂ К ₂ О (М = 534.33).

Calcd .: molecular peak (M + H) ⁺ : 497/499/501; detection: molecular peak (M + H) ⁺ : 497/499/501. The value of K _£ : 0.35 (silica gel, CH ₂ Cl ₂ / MeOHMN ₃ in a ratio of 9: 1: 0.1).

Example 2.108. [2- (3-Methyl-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

To a suspension of 150 mg (0.28 mmol) of [2- (3-bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid hydrochloride in 5 ml of dioxane was added 17.3 mg (0 , 28 mmol) of methylboronic acid, 2.5 ml of a 2 molar solution of Ka ₂ CO ₃ and 32 mg (0.03 mmol) of tetrakis (triphenylphosphine) palladium and the reaction mixture was heated under reflux for 5 hours. Then the hot suspension is subjected to vacuum filtration through a fiberglass filter, the filtrate is mixed with a semi-saturated solution of No. 1YO ₃ , carefully extracted with EAAc and dried over MdO ₄ . After removal of the desiccant and solvent, the residue was purified by silica gel chromatography (CH2C12 / MeOH in a ratio of 8: 2).

Yield: 20 mg (16.4% of theory). C ₂₇ H ₂₉ C1K ₂ O (M = 433.0). Calcd .: molecular peak (M + H) ⁺ : 433/435 found: molecular peak (M + H) ⁺ : 433/435. HPLC Retention Time: 6.47 min (Method

- 95 012834

BUT).

Example 2.109. [2- (2-Bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.109. but. 4- (2-aminoethyl) -3-nitrobenzoic acid ethyl ester.

To a solution of 12.0 g (52 mmol) of ethyl 4- (2-aminoethyl) benzoic acid in 80 ml conc. 5.78 g (57 mmol) of ΚNΟ ₃ are added in portions of H ₂ O _{4 in} portions and then stirred for 1 h at this temperature. Next, the reaction solution is slowly poured dropwise into a mixture of ice water (temperature should not exceed 0 ° C) and then stirred for 1 h. The precipitate is suction filtered, washed with water and dried at 50 ° C.

Yield: 8.2 g (66.2% of theory). ScN ₁₄ X ₂ O ₄ (M = 238.25). Calculation: molecular peak (M + H) ⁺ : 239 detection: molecular peak (M + H) ⁺ : 239. Retention time on HPLC: 3.64 min (method A).

2.109.b. 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -3-nitrobenzoic acid ethyl ester.

The title compound was prepared according to General Procedure I from 8.2 g (34 mmol) of 4- (2-aminoethyl) -3-nitrobenzoic acid ethyl ester and 7.91 g (34 mmol) of 4'-chlorobiphenyl-4-carboxylic acid .

Yield: 7.7 g (50.0% of theory). С ₂₄ Н ₂₁ СШ ₂ О ₅ (М = 452.90). Calcd .: molecular peak (M + H) ⁺ : 452/454; detection: molecular peak (M + H) ⁺ : 452/454. Retention time with HPLC: 6.14 min (method B).

2.109. in. 3-amino-4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid ethyl ester.

To a solution of 7.7 g (17 mmol) of 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -3-nitrobenzoic acid ethyl ester in 200 ml of EuAc was added 0.5 g of Raney nickel and the reaction mixture shake overnight in an autoclave at RT and a pressure of H ₂ 10 psi. To complete the reaction, add 50 ml of THF and shake for another 2 hours. After this, the catalyst is separated by filtration, thoroughly washed with THF, the solvent is evaporated off in vacuo, the residue is triturated with EuAc, again subjected to vacuum filtration and dried in air.

Yield: 5.0 g (69.5% of theory). С ₂₄ Н ₂₃ СШ ₂ О ₃ (М = 422.92). Calcd .: molecular peak (M + H) ⁺ : 423/425; detection: molecular peak (M + H) ⁺ : 423/425. Retention time with HPLC: 5.71 min (method B).

2.109. d. 3-Bromo-4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid ethyl ester.

To a solution of 5.0 g (7.69 mmol) of 3-amino-4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid ethyl ester in 20 ml of water is added 20 ml of 48% - No NVg and cooled to 0 ° C. Then, a solution of 0.9 g (13 mmol) of NaNΟ ₂ in 5.2 ml of water is added dropwise so that the temperature does not exceed 5 ° C, and then it is stirred for 10 min at 0 ° C. Then, at this temperature, a solution of 1.87 g (13 mmol) of CuBr in 6.65 ml of 48% HBr is slowly added dropwise. After that, the reaction mixture was heated to 60 ° C and maintained at this temperature for 1 h. Then water was added and the extract was carefully extracted with ЕУАс. The organic phase is washed with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue was purified by silica gel chromatography (petroleum ether / EuAc 6: 4).

Yield: 1.3 g (34.7% of theory). С ₂₄ Н ₂ 1ВрСШО ₃ (М = 486.80). Calcd .: molecular peak (M + H) ⁺ : 486/488/490; detection: molecular peak (M + H) ⁺ : 486/488/490. The value of K _£ : 0.55 (silica gel, petroleum ether / EJAc in a ratio of 6: 4).

2.109. d. 3-Bromo-4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid.

To a suspension of 1.3 g (2.67 mmol) of 3-bromo-4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid ethyl ester in 20 ml of UNN and 5 ml of THF are added 6 ml 1N a solution of aO11 and the reaction mixture are allowed to stir at RT overnight. It was then concentrated in vacuo, the residue was mixed with water and neutralized with 1N. HC1, which is accompanied by the precipitation of the product. Then it is stirred for the next hour under ice-cooling, subjected to vacuum filtration, washed with water and the product is dried at 50 ° C.

Yield: 1.2 g (97.9% of theory). С ₂₂ Н1 ₇ ВрССО ₃ (М = 458.74). Calcd .: molecular peak (M + H) ⁺ : 456/458/460; detection: molecular peak (M + H) ⁺ : 456/458/460. Retention time with HPLC: 5.51 min (method B).

2.109. e. [2- (2-Bromo-4-hydroxymethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

To a solution of 1.2 g (2.62 mmol) of 3-bromo-4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid in 10 ml of DMF was added 0.64 g (3, 92 mmol) CDI, heated to 50 ° C and maintained at this temperature until gas evolution ceases. Then the reaction mixture was added to a solution of 0.3 g (7.85

- 96 012834 mmol) No. B11. | in 10 ml of water, stirred for 1 h at RT, acidified with a diluted KH8O ₄ solution and carefully extracted with ЕУАс. The organic phase is washed with a semi-saturated solution of ΝαΙ 1CO ₃ and dried over MD8O ₄ . After removal of the desiccant and solvent, the residue without purification is used in the subsequent reaction.

Yield: 0.87 g (74.8% of theory). C ₂₂ H ₁₉ VgSSO ₂ (M = 444.76). Calcd .: molecular peak (M + H) ⁺ : 444/446/448; detection: molecular peak (M + H) ⁺ : 444/446/448. Retention time with HPLC: 8.07 min (method A).

2.109.zh. [2- (2-Bromo-4-chloromethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

To a solution of 0.87 g (1.96 mmol) of [2- (2-bromo-4-hydroxymethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid in 20 ml of CH ₂ Cl ₂ add 0.24 ml (2.93 mmol) of pyridine and cooled to 0 ° C. Then, 0.21 ml (2.93 mmol) of thionyl chloride was added, stirred for 1 h at this temperature and then allowed to warm to RT overnight. After that, water is added, filtered through celite, the aqueous phase is extracted with CH ₂ Cl _2, and the combined organic phases are dried over Md ₈ O ₄ . After removal of the desiccant and solvent, the residue without purification is used in the subsequent reaction.

Yield: 0.66 g (72.8% of theory). C ^ H ^ BrC ^ O (M = 463.21).

Calcd .: molecular peak (M + H) ⁺ : 462/464/466; detection: molecular peak (M + H) ⁺ : 462/464/466.

Retention time with HPLC: 6.37 min (method B).

2.109.z. [2- (2-Bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

To a solution of 0.66 g (1.43 mmol) of [2- (2-bromo-4-chloromethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4 carboxylic acid in 20 ml of acetonitrile and 6 ml of DMF was added 0.59 g (4, 28 mmol) K ₂ CO ₃ and 0.24 ml (2.85 mmol) of pyrrolidine and stirred for 5 hours at RT. After this was mixed with water, exhaustively extracted EYuAs, the organic phase was washed several times with water and dried over Md8O _4. After removal of the desiccant and solvent, the residue was purified by silica gel chromatography (CH2C12 / MeOH in a ratio of 9: 1).

Yield: 0.2 g (28.2% of theory). С ₂₆ Н ₂₆ ВгСШ ₂ О (М = 497.87). Calcd .: molecular peak (M + H) ⁺ : 497/499/501; detection: molecular peak (M + H) ⁺ : 497/499/501. Retention time with HPLC: 4.39 min (method B).

Example 2.110. [2- (2-Methyl-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 2.108 from 200 mg (0.40 mmol) of [2- (2-bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid and 27.3 mg (0.44 mmol) of methylboronic acid, while the reaction mixture was heated under reflux for only 2 hours, and the product was purified using HPLC.

Yield: 62 mg (35.6% of theory). С ₂₇ Н ₂₉ СШ ₂ О (М = 433.0). Calcd .: molecular peak (M + H) ⁺ : 433/435; detection: molecular peak (M + H) ⁺ : 433/435. Retention time with HPLC: 6.15 min (method A).

Example 2.111. [2- (2-Nitro-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.111. but. 4- {2 - [(4'-Chlorobiphenyl-4-carbonyl) amino] ethyl} -3-nitrobenzoic acid.

To a solution of 200 mg (0.44 mmol) of 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -3 nitrobenzoic acid ethyl ester (see Example 2.109.b) in 10 ml of UNN, add 2 ml 1n solution No. OH and the reaction mixture was stirred for 1 h at RT. It was then concentrated in vacuo, the residue was mixed with water and 2 ml of 1N. HC1 solution and the suspension are stirred for 30 minutes in an ice bath. The product is suction filtered, washed with water and dried at 50 ° C.

Yield: 180 mg (95.9% of theory). С ₂₂ Н _П СШ ₂ О ₅ (М = 424.84). Calcd .: molecular peak (M + H) ⁺ : 425/427; detection: molecular peak (m + H) ⁺ : 425/427. The value of B _£ : 0.07 (silica gel, 1TOCA / MeO11 / L in a ratio of 9: 1: 0.1).

2.111.b. [2- (4-Hydroxymethyl-2-nitrophenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 2.109.e from 180 mg (0.42 mmol) of 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -3-nitrobenzoic acid.

Yield: 110 mg (63.1% of theory). C ₂₂ H1 ₉ S ₂ O ₄ (M = 410.86). Calculation: molecular peak (M + H) ⁺ :

- 97 012834

411/413; detection: molecular peak (M + H) ⁺ : 411/413. Retention time with HPLC: 8.27 min (Method A).

2.111.v. [2- (2-Nitro-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

To a solution of 110 mg (0.27 mmol) [2- (4-hydroxymethyl-2-nitrophenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid and 48 μl of triethylamine in 5 ml of CH2C12, gradually dropwise, cooled to 5 ° C add 23 μl of methanesulfonic acid chloride. Then the solution is heated to 40 ° C and maintained at this temperature for 1 h, after which 5 ml of DMF and 115 μl (1.34 mmol) of pyrrolidine are added, heated to 80 ° C and maintained at this temperature for another hour, which accompanied by evaporation of CH ₂ Cl ₂ . The reaction mixture was concentrated in vacuo, the residue is combined with water, exhaustively extracted EYuAs and the organic phase was dried over Md8O _4. After removal of the desiccant and solvent, the residue is purified by HPLC.

Yield: 11 mg (8.8% of theory). С ₂₆ Н ₂₆ СШ ₃ О ₃ (М = 463.97). Calcd .: molecular peak (M + H) ⁺ : 464/466; detection: molecular peak (M + H) ⁺ : 464/466. Retention time with HPLC: 6.44 min (method A).

Example 2.112. [2- (2-Methanesulfonylamino-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

2.112. but. 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -3-methanesulfonylaminobenzoic acid ethyl ester.

To a solution of 200 mg (0.47 mmol) of ethyl ester of 3-amino-4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} benzoic acid cooled to 0 ° C (see example 2.109.c ) in 5 ml of pyridine, 44 μl (0.57 mmol) of methanesulfonic acid chloride is slowly added dropwise and the reaction mixture is stirred for 1 h at RT. Next, blended with water with ice, extracted well EYuAs, the organic phase was washed several times with water and dried over Md8O _4. After removal of the desiccant and solvent, the residue without purification is used in the subsequent reaction.

Yield: 230 mg (97.1% of theory). С ₂₅ Н ₂₅ СШ ₂ О ₅ 8 (М = 501.01). Calcd .: molecular peak (M + H) ⁺ : 501/503; detection: molecular peak (M + H) ⁺ : 501/503. Retention time with HPLC: 5.66 min (method B).

2.112.b. 4- {2 - [(4'-Chlorobiphenyl-4-carbonyl) amino] ethyl} -3-methanesulfonylaminobenzoic acid.

The specified compound is obtained analogously to example 2.111.a from 230 mg (0.46 mmol) of ethyl 4- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -3-methanesulfonylaminobenzoic acid ethyl ester.

Yield: 180 mg (82.9% of theory). С ₂₃ Н ₂₁ СШ ₂ О ₅ 8 (М = 472.95). Calculation: molecular peak (M-H) ^- : 471/473: detection: molecular peak (M-H) ^- : 471/473. Retention time with HPLC: 7.67 min (Method A).

2.112. in. [2- (4-Hydroxymethyl-2-methanesulfonylaminophenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The specified compound is obtained analogously to example 2.109.e from 180 mg (0.38 mmol) of 4- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} -3-methanesulfonylaminobenzoic acid.

Yield: 150 mg (85.8% of theory). С ₂₃ Н ₂₃ СШ ₂ О ₄ 8 (М = 458.97). Calcd .: molecular peak (M + H) ⁺ : 459/461; detection: molecular peak (M + H) ⁺ : 459/461. Retention time with HPLC: 7.53 min (Method A).

2.112. g. [2- (2-Methanesulfonylamino-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4carboxylic acid.

The specified compound is obtained analogously to example 2.111. From 150 mg (0.33 mmol) of [2- (4-hydroxymethyl-2-methanesulfonylaminophenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid and 140 μl (1.64 mmol) of pyrrolidine. After purification by HPLC, the product is formed as a formate salt.

Yield: 18 mg (9.9% of theory). С ₂₇ Н ₃₀ СШ ₃ О ₃ 8-СН ₂ О ₂ (M = 558.10). Calcd .: molecular peak (M + H) ⁺ : 512/514; detection: molecular peak (M + H) ⁺ : 512/514. Retention time with HPLC: 6.13 min (Method A).

Example 2.113. [2- (3-Pyridin-4-yl-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

- 98 012834

The specified compound is obtained analogously to example 2.108 from 200 mg (0.40 mmol) of [2- (3-bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid and 74 mg (0.60 mmol) pyridine-4-boronic acid, wherein the product is purified by HPLC.

Yield: 13 mg (6.5% of theory). С ₃ 1Н ₃₀ С1 \ ₃ О (М = 496.06). Calcd .: molecular peak (M + H) ⁺ : 496/498; detection: molecular peak (M + H) ⁺ : 496/498. Retention time with HPLC: 6.37 min (method A).

Example 2.114. 5- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -2-pyrrolidin-1-methylmethylbenzoic acid methyl ester.

2.114. but. 5-Cyanomethyl-2-pyrrolidin-1-ylmethylbenzoic acid methyl ester.

To a solution of 500 mg (1.79 mmol) of (3-bromo-4-pyrrolidin-1-ylmethylphenyl) acetonitrile (see example

2.107.d) in 10 ml of MeOH and 10 ml of DMF add 0.5 ml of triethylamine (3.58 mmol), 40 mg (0.18 mmol) of RT (OAc) ₂ and 99 mg (0.18 mmol) of 1.1 'diphenylphosphinoferrocene. The reaction mixture at 50 ° C is stirred for 15 hours in an autoclave at a pressure of CO 2 bar. To complete the reaction, 0.5 ml of triethylamine, 40 mg of Ryo (OLS) ₂ and 99 mg of 1,1'-diphenylphosphinoferrocene are again added and stirred for a further 10 hours at 50 ° C and a pressure of CO 2 bar, and then overnight at a pressure of CO 4 bar and a temperature of 70 ° C. After that, the solvent was evaporated in vacuo, the residue was mixed with EluAc and extracted twice with water. The aqueous phase is saturated with K ₂ CO ₃ , carefully extracted with EAAc and dried over Mg ₈ O ₄ . After removal of the desiccant and the solvent, a product remains in the form of black oil, which is used in the subsequent reaction without purification.

Yield: 380 mg (82.1% of theory). C1 ₅ H1 ₈ \ ₂ O ₂ (M = 258.32). Calcd .: molecular peak (M + H) ⁺ : 259; detection: molecular peak (M + H) ⁺ : 259. Retention time by HPLC: 2.49 min (method B).

2.114.b. 5- (2-aminoethyl) -2-pyrrolidin-1-ylmethylbenzoic acid methyl ester.

To a solution of 380 mg (1.47 mmol) of 5-cyanomethyl-2-pyrrolidin-1-ylmethylbenzoic acid methyl ester in 20 ml of methanol solution \ N _{3 was} added 100 mg of Raney nickel and the reaction mixture was hydrogenated for 27 hours at a pressure of Н ₂ 20 psi and at CT. After that, the catalyst was suction filtered, the solvent was distilled off, and the residue was used without further purification in the subsequent reaction.

Yield: 330 mg (85.5% of theory). C1 ₅ H ₂₂ \ ₂ O ₂ (M = 262.36). Calcd .: molecular peak (M + H) ⁺ : 263; detection: molecular peak (M + H) ⁺ : 263. Retention time by HPLC: 1.40 min (method A).

2.114. in. 5- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -2-pyrrolidin-1-ylmethylbenzoic acid methyl ester.

The title compound was prepared according to General Procedure I from 330 mg (1.26 mmol) of 5- (2-aminoethyl) -2-pyrrolidin-1-ylmethylbenzoic acid methyl ester and 293 mg (1.26 mmol) of 4'-chlorobiphenyl-4 -carboxylic acid.

Yield: 315 mg (52.5% of theory). С ₂₈ Н ₂₉ С1 \ ₂ О ₃ (M = 477.01). Calcd .: molecular peak (M + H) ⁺ : 477/479; detection: molecular peak (M + H) ⁺ : 477/479. Retention time with HPLC: 6.82 min (Method A).

Example 2.115. 5- {2 - [(4'-Chlorobiphenyl-4-carbonyl) amino] ethyl} -2-pyrrolidin-1-ylmethylbenzoic acid.

The title compound was prepared analogously to Example 2.111.a from 310 mg (0.65 mmol) of 5- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -2-pyrrolidin-1-ylmethylbenzoic acid methyl ester.

Yield: 85 mg (28.2% of theory). С ₂₇ Н ₂₇ С1 \ ₂ О ₃ (М = 462.98). Calcd .: molecular peak (M + H) ⁺ : 463/465; detection: molecular peak (M + H) ⁺ : 463/465. Retention time with HPLC: 6.30 min (Method A).

Example 2.116. (5- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -2-pyrrolidin-1-ylmethylphenyl) carbamic acid tert-butyl ester.

- 99 012834

To a solution of 740 mg (1.6 mmol) of 5- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -2-pyrrolidin-1 methylmethylbenzoic acid in 10 ml of tert-butanol is added 0.27 ml (1 , 92 mmol) of triethylamine and 0.41 ml (1.92 mmol) of diphenyl ether of azidophosphoric acid, and the reaction mixture is heated under reflux for 5 hours. It is then concentrated in vacuo, the residue is mixed with CH ₂ Cl ₂ , extracted with 1N. solution No. HE and the organic phase is dried over MD8O ₄ . After removal of the desiccant and solvent, the residue was purified by silica gel chromatography.

Yield: 85 mg (28.2% of theory). C ₃₁ H ₃₆ S ₃ O ₃ (M = 534.10). Calcd .: molecular peak (M + H) ⁺ : 534/536; detection: molecular peak (M + H) ⁺ : 534/536. Retention time with HPLC: 4.82 min (Method B).

Example 2.117. [2- (3-Ethyl-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.117. but. (4-Pyrrolidin-1-ylmethyl-3-trimethylsilanylethynylphenyl) acetonitrile.

A suspension of 0.36 g (1.29 mmol) of (3-bromo-4-pyrrolidin-1-ylmethylphenyl) acetonitrile (see example

2.107.d), 0.36 ml (2.58 mmol) of trimethylsilylacetylene, 0.36 ml (2.58 mmol) of triethylamine, 25 mg (0.13 mmol) of CO and 0.15 g (0.13 mmol) of tetrakis (triphenylphosphine) palladium in 3 ml of DMF is stirred for 15 minutes in a microwave oven (CEM) at 100 ° C and a radiation power of 200 watts. After cooling the reaction mixture, it was mixed with a saturated solution HaS1, EYuAs carefully extracted and the organic phase was dried over Md8O _4. After removal of the desiccant and solvent, the residue was purified by silica gel chromatography (EyAc).

Yield: 50 mg (13.1% of theory). C ₁₈ H ₂₄ X ₂ 81 (M = 296.49). Calcd .: molecular peak (M + H) ⁺ : 297; detection: molecular peak (M + H) ⁺ : 297. Retention time by HPLC: 6.39 min (method A).

2.117.b. 2- (3-Ethyl-4-pyrrolidin-1-ylmethylphenyl) ethylamine.

To a solution of 50 mg (0.17 mmol) of (4-pyrrolidin-1-ylmethyl-3-trimethylsilanylethynylphenyl) acetonitrile in 5 ml of a methanolic solution of XH3 was added 20 mg of Raney nickel and the reaction mixture was shaken for 22 hours at RT and H ₂ 3 bar. After that, the catalyst was separated by vacuum filtration and the solvent was distilled off in vacuo. The crude product without purification is used in the subsequent reaction.

Yield: 39 mg (100% of theory). C ₁₅ H ₂₄ X ₂ (M = 232.37). Calcd .: molecular peak (M + H) ⁺ : 233; detection: molecular peak (M + H) ⁺ : 233.

2.117. in. [2- (3-Ethyl-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I from 40 mg (0.17 mmol) of 2- (3 ethyl-4-pyrrolidin-1-ylmethylphenyl) ethylamine and 48 mg (0.21 mmol) of 4'-chlorobiphenyl-4-carboxylic acid .

Yield: 2 mg (2.6% of theory). C ₂₈ H ₃₁ SC ₂ O (M = 447.03). Calcd .: molecular peak (M + H) ⁺ : 447/449; detection: molecular peak (M + H) ⁺ : 447/449. Retention time with HPLC: 6.87 min (Method A).

Example 2.118. [2- (6-Pyrrolidin-1-ylmethylpyridin-3-yl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.118.a. 6-Dibromomethyl nicotinic acid methyl ester.

To a solution of 38.96 g (0.25 mol) of 6-methylnicotinic acid methyl ester in 1 L of CC14, 53.4 g (0.3 mol) of X-bromosuccinimide and 2 g of dibenzoyl peroxide were added and the reaction mixture was heated under reflux overnight . Then, 26.7 g (0.15 mol) of Ν bromosuccinimide and 1 g of dibenzoyl peroxide are further added and the reaction mixture is heated for another 24 hours

- 100 012834 by a fridge. After cooling the reaction mixture, the precipitate was suction filtered, the solvent was distilled off, and the residue was purified by chromatography.

Yield: 15.0 g (19.4% of theory). C ₈ H ₇ Br ^ O ₂ (M = 308.96). Calcd .: molecular peak (M + H) ⁺ : 308/310/312; detection: molecular peak (M + H) ⁺ : 308/310/312. The value of B _£ : 0.6 (silica gel, petroleum ether / EJAc in a ratio of 8: 2).

2.118.b. 6-Dimethoxymethylnicotinic acid methyl ester.

13.9 ml of No. 1OMc in MeOH (30%, 75 mmol) in 100 ml of MeOH are heated to boiling. Then, a solution of 11.0 g (34.1 mmol) of 6-dibromomethylnicotinic acid methyl ester in 10 ml of MeOH was added dropwise to the boiling solution and heated under reflux overnight. To complete the reaction, an additional 1.5 ml (8.1 mmol) of the No. OMe solution is added and continued to reflux for another 24 hours. Then the reaction mixture is concentrated in vacuo, the residue is mixed with a diluted KH8O ₄ solution, neutralized with a diluted NaHCO solution ₃ , thoroughly extracted with EuAc, the organic phase is washed with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue without purification is used in the subsequent reaction.

Yield: 5.0 g (69.5% of theory). C ₁₀ H ₁ ^ O ₄ (M = 211.22). Calcd .: molecular peak (M + H) ⁺ : 212; detection: molecular peak (M + H) ⁺ : 212. B _£ value: 0.44 (silica gel, petroleum ether / EuAc in a ratio of 6: 4).

2.118. in. 6-Dimethoxymethylnicotinic acid.

To a solution of 2.8 g (13.26 mmol) of 6-dimethoxymethylnicotinic acid methyl ester in 50 ml of MeOH was added 15 ml of 1N. solution No. 1OH and stirred for 24 hours at RT. Then the reaction mixture is neutralized with 15 ml of 1N. HCl was concentrated in vacuo, the residue was triturated with MeOH / THF, the precipitate was suction filtered and the filtrate was concentrated. The resulting product without purification is used in the subsequent reaction.

Yield: 2.6 g (99.4% of theory). С ₉ Н ₁ ЩО ₄ (M = 197.19). Calcd .: molecular peak (M + H) ⁺ : 198; detection: molecular peak (M + H) ⁺ : 198. Retention time by HPLC: 3.65 min (method A).

2.118. g. (6-Dimethoxymethylpyridin-3-yl) methanol.

The specified compound is obtained analogously to example 2.109.e from 2.7 g (13.7 mmol) of 6-dimethoxymethylnicotinic acid using THF as a solvent and tert-butyl methyl ether for extraction.

Yield: 2.1 g (83.7% of theory). C ₉ H ₁₃ CH ₃ (M = 183.21). Calcd .: molecular peak (M + H) ⁺ : 184; detection: molecular peak (M + H) ⁺ : 184. Retention time by HPLC: 2.85 min (method A).

2.118. 5-Hormethyl-2-dimethoxymethylpyridine.

To a solution of 500 mg (2.73 mmol) (6-dimethoxymethylpyridin-3-yl) methanol in 10 ml of CH2C12 cooled to 0 ° C, 0.3 ml (4.14 mmol) of thionyl chloride dissolved in a small amount of CH are slowly added dropwise. ₂ C1 ₂ , and stirred for the next 30 minutes at this temperature. Then the reaction mixture was diluted with CH ₂ Cl ₂ , washed with a cold NaHCO ₃ solution and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue without purification is used in the subsequent reaction.

Yield: 500 mg (90.8% of theory). С ₉ Н ₁₂ ССО ₂ (М = 201.65). Calcd .: molecular peak (M + H) ⁺ : 202/204; detection: molecular peak (M + H) ⁺ : 202/204. The value of B _£ : 0.3 (silica gel, petroleum ether / EJAc in a ratio of 6: 4).

2.118. e. (6-Dimethoxymethylpyridin-3-yl) acetonitrile.

To 5.21 g (80 mmol) of KSN in 5.2 ml of water was added 20 ml of DMSO, after which a solution of 500 mg (2.48 mmol) of 5-chloromethyl-2-dimethoxymethylpyridine in 10 ml of DMSO was added dropwise at 80 ° C. and the reaction mixture is kept for the next hour at 80 ° C. Then the mixture is poured into 200 ml of water, saturated with C1, carefully extracted with EuAc, the organic phase is dried over MgSO ₄ and filtered through activated carbon. The filtrate was concentrated and the residue was purified by silica gel chromatography (CH2C12 / MeOH in a 9: 1 ratio).

Yield: 330 mg (69.2% of theory). C ₁₀ H ₁₂ ^ O ₂ (M = 192.22). Calcd .: molecular peak (M + H) ⁺ : 193; detection: molecular peak (M + H) ⁺ : 193. B _£ value: 0.48 (silica gel, CH ₂ Cl ₂ / MeOH in a 9: 1 ratio).

2.118. g. 2- (6-Dimethoxymethylpyridin-3-yl) ethylamine.

To a solution of 330 mg (1.72 mmol) of (6-dimethoxymethylpyridin-3-yl) acetonitrile in 10 ml of methanol solution No. ₃ , 50 mg of Raney nickel was added and the reaction mixture was hydrogenated for 15 hours in a Parr autoclave at 30 ° C and pressure Н ₂ 3 bars. After that, the catalyst was filtered off, the solvent was evaporated in vacuo, and the residue was used without further purification in the subsequent reaction.

Yield: 340 mg (100% of theory). C ₁₀ H ₁₆ No. O ₂ (M = 196.25). Calculation: molecular peak (M + H) ⁺ : 197; detection: molecular peak (M + H) ⁺ : 197. Retention time by HPLC: 1.3 min (method A).

2.118.z. [2- (6-Dimethoxymethylpyridin-3-yl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained in accordance with General method I of 340 mg (1.73 mmol) 2- (6

101 012834 dimethoxymethylpyridin-3-yl) ethylamine and 419 mg (1.80 mmol) of 4'-chlorobiphenyl-4-carboxylic acid.

Yield: 210 mg (28.4% of theory). C ₂₃ H ₂₃ SS ₂ O ₃ (M = 410.90). Calcd .: molecular peak (M + H) ⁺ : 411/413; detection: molecular peak (M + H) ⁺ : 411/413. The value of K is 0.4 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ in a ratio of 9: 1: 0.1).

2.118. and. [2- (6-Formylpyridin-3-yl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

To a solution of 205 mg (0.5 mmol) of [2- (6-dimethoxymethylpyridin-3-yl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid in 10 ml of MeOH, 5 ml of 12% HCl are added and the reaction mixture for 4 h. stirred at RT, after which it is heated to 80 ° C and left overnight at this temperature. Then again add 2.5 ml of 12% HC1, kept at 80 ° C for another 8 hours, then heated to 100 ° C and left overnight at this temperature. Then the reaction mixture is mixed with 50 ml of water, the pH value is set to 8 using a solution of No. ₂ CX) ₃ , carefully extracted with CH ₂ Cl ₂ and the organic phase is dried over Md ₈ O ₄ . After removal of the desiccant and solvent, the residue without purification is used in the subsequent reaction.

Yield: 180 mg (98.7% of theory). С ₂₁ Н ₁₇ СШ ₂ О ₂ (M = 364.84). Calcd .: molecular peak (M + H) ⁺ : 365/367; detection: molecular peak (M + H) ⁺ : 365/367. Retention time with HPLC: 5.25 min (Method A).

2.118. K. [4- Chlorobiphenyl-4-carboxylic acid [2- (6-Pyrrolidin-1-ylmethylpyridin-3-yl) ethyl] amide.

To a solution of 180 mg (0.49 mmol) of [2- (6-formylpyridin-3-yl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid in 5 ml of acetonitrile was added 50 μl (0.6 mmol) of pyrrolidine, 37 7 mg (0.6 mmol) of NaH ₃ CN and 2 ml of MeOH, after which the pH is adjusted to 5-6 with glacial acetic acid and stirred for 5 hours at RT. Then the reaction mixture was acidified with a 1 molar solution of KH8O ₄ , alkalized with a 2 molar solution of No. ₂ CX) ₃ , extracted carefully with CH ₂ Cl ₂ and the organic phase was dried over Md ₈ O ₄ . After removal of the desiccant and solvent, the residue was purified by silica gel chromatography (CH ₂ Cl ₂ / MeOHMH ₃ in a ratio of 9: 1: 0.1).

Yield: 25 mg (12.1% of theory). С ₂₅ Н ₂₆ СШ ₃ О (M = 419.96). Calcd .: molecular peak (M + H) ⁺ : 420/422; detection: molecular peak (M + H) ⁺ : 420/422. The value of K _g : 0.2 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ in a ratio of 9: 1: 0.1).

Example 2.119. [2- (5-Pyrrolidin-1-ylmethylpyridin-2-yl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.119. but. 6-hydroxymethylnicotinic acid methyl ester.

The specified compound is obtained analogously to example 2.109.e from 5.0 g (27.6 mmol) of pyridine-2,5-dicarboxylic acid 5-methyl ester using THF as a solvent and using tert-butyl methyl ether for extraction.

Yield: 2.0 g (43.3% of theory). C ₈ Hc # O ₃ (M = 167.17). Calcd .: molecular peak (M + H) ⁺ : 168; detection: molecular peak (M + H) ⁺ : 168. The value of Cu is 0.2 (silica gel, CH ₂ Cl ₂ / MeOH in a ratio of 95: 5).

2.119.b. 6-chloromethylnicotinic acid methyl ester.

To a solution of 2.0 g (11.96 mmol) of 6-hydroxymethylnicotinic acid methyl ester in 100 ml of CH2C12 cooled to 0 ° C, 1.06 ml (13 mmol) of pyridine was added, and then 1.08 ml (13) were slowly added dropwise. mmole) thionyl chloride. Then it is stirred for the next hour at 0 ° C, after which the mixture is allowed to slowly warm to RT. To complete the reaction, 1 ml (12 mmol) of thionyl chloride was added again and then stirred for 1 h at RT. Thereafter, the reaction mixture was mixed with water, the organic phase was separated, washed with dilute NaHCO ₃ solution and water and dried over Md8O _4. It is then filtered through activated carbon and the solvent is evaporated off under vacuum. The resulting product without purification is used in the subsequent reaction.

Yield: 1.7 g (65.1% of theory). С ₈ Н ₈ ССО ₂ (М = 185.61). Calcd .: molecular peak (M + H) ⁺ : 186/188; detection: molecular peak (M + H) ⁺ : 186/188. Retention time with HPLC: 6.7 min (Method A).

2.119. in. 6-Cyanomethyl nicotinic acid methyl ester.

The specified compound is obtained analogously to example 2.118.e from methyl ester of 1.5 g (8.08 mmol) of 6-chloromethylnicotinic acid and 5.2 g (80 mmol) of CSI. In this case, cyclohexane / ELS mixture is used as an eluent for purification by chromatography on silica gel. in a ratio of 8: 2.

Yield: 220 mg (15.5% of theory). C91 ₈ Ν ₂ (') ₂ (M = 176.18). Calcd .: molecular peak (M + H) ⁺ : 177; detection: molecular peak (M + H) ⁺ : 177. The value of Ku is 0.6 (silica gel, petroleum ether / EULS in the ratio 1: 1).

2.119. d. 6- (2-Aminoethyl) nicotinic acid methyl ester.

To a solution of 75 mg (0.43 mmol) of 6-cyanomethyl nicotinic acid methyl ester in 5 ml of meta

- 102 012834 of an NN ₃ -nol solution, 20 mg of Raney nickel are added and the reaction mixture is hydrogenated for 6 hours in a Parr autoclave at 30 ° С and a pressure of Н ₂ 3 bar. After that, the catalyst was filtered off, the solvent was evaporated in vacuo, and the residue was used without further purification in the subsequent reaction.

Yield: 70 mg (90.3% of theory). C ₉ H1 ₂ N ₂ O ₂ (M = 180.21). Calcd .: molecular peak (M + H) ⁺ : 181; found: molecular peak (M + H) ⁺ : 181. Retention time by HPLC: 2.5 min (Method A).

2.119. e. 6- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} nicotinic acid methyl ester.

The title compound was prepared according to General Procedure I from 70 mg (0.39 mmol) of 6- (2-aminoethyl) nicotinic acid methyl ester and 100 mg (0.43 mmol) of 4'-chlorobiphenyl-4-carboxylic acid.

Yield: 150 mg (88.3% of theory). С ₂₂ Н1 ₉ С1Ы ₂ О ₃ (М = 394.86). Calcd .: molecular peak (M + H) ⁺ : 395/397; detection: molecular peak (M + H) ⁺ : 395/397. Retention time with HPLC: 8.6 min (method A).

2.119. e. 6- {2 - [(4'-Chlorobiphenyl-4-carbonyl) amino] ethyl} nicotinic acid.

To a solution of 150 mg (0.38 mmol) of 6- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} nicotinic acid methyl ester in 25 ml of MeOH, 0.8 ml of a 1 molar NaOH solution are added and the reaction the mixture is heated under reflux for 1 h. Then neutralize 0.8 ml of 1N. HC1 was concentrated in vacuo, the residue was stirred with water and the precipitate was suction filtered. This residue was then dissolved in THF, the solution was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue without purification is used in the subsequent reaction.

Yield: 90 mg (62.2% of theory). С ₂ 1НЦС1Ы ₂ О ₃ (М = 380.83). Calcd .: molecular peak (M + H) ⁺ : 381/383; detection: molecular peak (M + H) ⁺ : 381/383. Retention time with HPLC: 6.9 min (method A).

2.119. g. [2- (5-Hydroxymethylpyridin-2-yl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid.

The specified compound is obtained analogously to example 2.109.e from 90 mg (0.24 mmol) of 6- {2 - [(4'chlorobiphenyl-4-carbonyl) amino] ethyl} nicotinic acid using THF as a solvent and using tert-butyl methyl ether for extraction.

Yield: 50 mg (56.8% of theory). С ₂ 1Н1 ₉ С1Ы ₂ О ₂ (M = 366.85). Calcd .: molecular peak (M + H) ⁺ : 367/369; detection: molecular peak (M + H) ⁺ : 367/369. The value of K _£ : 0.5 (silica gel, CH ₂ Cl ₂ / MeOH in a ratio of 9: 1).

2.119.z. [2- (5-Pyrrolidin-1-ylmethylpyridin-2-yl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

To a solution of 50 mg (0.14 mmol) [2- (5-hydroxymethylpyridin-2-yl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid in 5 ml of CH ₂ Cl ₂ cooled to 0 ° C, 22 are added dropwise 22 μl of thionyl chloride and the reaction mixture were allowed to slowly warm to RT. After exposure for 1 h at RT to complete the reaction, 22 μl of thionyl chloride are additionally added dropwise and stirred for 1 h. Then, the reaction mixture is diluted with 30 ml of CH2C12, mixed with ice-water, alkalized with NaHCO ₃ solution, the organic phase is separated, washed with water and dried over MgSO ₄ . After removal of the desiccant, 50 μl (0.6 mmol) of pyrrolidine was added to this solution, and the reaction mixture was allowed to stir at RT overnight. It was then concentrated in vacuo and the residue was purified by HPLC.

Yield: 2.4 mg (4.1% of theory). C ₂₅ H ₂₆ Cl ₃ O (M = 419.96). Calcd .: molecular peak (M + H) ⁺ : 420/422; detection: molecular peak (M + H) ⁺ : 420/422. The value of K _£ : 0.3 (silica gel, CH ₂ Cl ₂ / MeOH in a ratio of 9: 1). HPLC Retention Time: 6.0 min (Method A).

Example 2.120. 4'-chlorobiphenyl-4-carboxylic acid {2- [4- (1-Pyrrolidin-1-yl-ethyl) phenyl] ethyl} amide.

2.120.a. [2- (4-Acetylphenyl) ethyl] carbamic acid tert-butyl ester.

To a solution of 4.99 g (25 mmol) of 1- [4- (2-aminoethyl) phenyl] ethanone (used as hydrochloride) in 100 ml of CH ₂ Cl ₂ , 5.46 g (25 mmol) of BOC anhydride are added, then with CT, 25 ml of 1N is slowly added dropwise. NaOH solution and, upon completion of this operation, the additions are stirred for 2 hours at RT. Next, the reaction mixture was filtered through celite, washed twice with water and dried over MgO ₄ . It is then filtered through activated carbon, concentrated in vacuo and the product used without purification in the subsequent reaction.

Yield: 6.4 g (97.2% of theory). C1 ₅ H _{2 £} L0 ₃ (M = 263.34). Calcd .: molecular peak (M + H) ⁺ : 262; detection: molecular peak (M + H) ⁺ : 262. The value of K _£ : 0.88 (silica gel, CH ₂ Cl ₂ / Meon / N ₃ in the ratio of 9: 1: 0.1).

2.120.b. {2- [4- (1-hydroxyethyl) phenyl] ethyl} carbamic acid tert-butyl ester.

- 103 012834

To a solution of 6.58 g (25 mmol) of [2- (4-acetylphenyl) ethyl] carbamic acid tert-butyl ester in 250 ml of MeOH at RT, 4.72 g (125 mmol) No. B11 are added in portions. and the reaction mixture was allowed to stir for the weekend. Then it is carefully acidified with a solution of KH8O ₄ , thoroughly extracted with tert-butyl methyl ether, the organic phase is washed with a saturated solution of No. C1 and dried over MD8O ₄ . After removal of the desiccant and solvent, the product remains in the form of a yellowish oil, which crystallizes upon standing.

Yield: 5.4 g (81.4% of theory). C ₁₅ H ₂₃ KO ₃ (M = 265.36). Calcd .: molecular peak (M + H) ⁺ : 266; detection: molecular peak (M + H) ⁺ : 266. K _£ value: 0.4 (silica gel, petroleum ether / ЕУАс in the ratio 6: 4).

2.120. in. {2- [4- (1-Pyrrolidin-1-yl-ethyl) phenyl] ethyl} carbamic acid tert-butyl ester.

To a solution of 2.89 g (10.89 mmol) of {2- [4- (1-hydroxyethyl) phenyl] ethyl} carbamic acid tert-butyl ester in 50 ml of CH ₂ Cl ₂ and 1.25 ml, cooled to 0 ° C triethylamine is added dropwise 0.66 ml (8.5 mmol) of methanesulfonic acid chloride dissolved in 10 ml of CH ₂ Cl ₂ . It is further stirred for 1 h at this temperature, after which a solution of 1.4 ml (17 mmol) of pyrrolidine in 10 ml of CH ₂ Cl _{2 is} slowly added dropwise. The reaction mixture was stirred overnight at RT and then mixed with dilute sodium KN8O4, the organic phase was separated, washed twice with dilute it KN8O _4, the combined aqueous phases were basified with a solution of K ₂ CO ₃ and extracted well with tert-butyl methyl ether. The combined organic phases are washed several times with a small amount of water and dried over MgO ₄ . After removal of the desiccant and solvent, the product without purification is used in the subsequent reaction.

Yield: 0.3 g (8.7% of theory). C ₁₉ H ₃₀ K ₂ O ₂ (M = 318.46). Calcd .: molecular peak (M + H) ⁺ : 319; detection: molecular peak (M + H) ⁺ : 319. K _£ value: 0.22 (silica gel, CHCH / MeOHMN in the ratio 9: 1: 0.1).

2.120. g. 2- [4- (1-Pyrrolidin-1-yl-ethyl) phenyl] ethylamine.

To a solution of 300 mg (0.94 mmol) of {2- [4- (1-pyrrolidin-1-yl-ethyl) phenyl] ethyl} carbamic acid tert-butyl ester in 20 ml of CH2C12, 0.72 ml of trifluoroacetic acid was added and stirred for 1 hour at CT. To complete the reaction, 0.72 ml of trifluoroacetic acid was added again and the reaction mixture was kept at RT for 1 h. After that, the solvent was evaporated in vacuo, the residue was dissolved in water, alkalized with 2N. No. O11, carefully extracted with EAUc and the organic phase is dried over MgO ₄ . After removal of the desiccant and solvent, the product without purification is used in the subsequent reaction.

Yield: 150 mg (72.9% of theory). C ₁₄ H ₂₂ H ₂ (M = 218.35). Calcd .: molecular peak (M + H) ⁺ : 219; detection: molecular peak (M + H) ⁺ : 219. K _£ value: 0.15 (silica gel, CH ^^ / MeOH / NL in a ratio of 8: 2: 0.2).

2.120. D. {2- [4- (1-Pyrrolidin-1-yl-ethyl) phenyl] ethyl} -amide of 4'-chlorobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I from 150 mg (0.69 mmol) of 2- [4 (1-pyrrolidin-1-yl-ethyl) phenyl] ethylamine and 176 mg (0.76 mmol) of 4'-chlorobiphenyl-4- carboxylic acid.

Yield: 150 mg (88.3% of theory). С ₂₇ Н ₂₉ СШ ₂ О (М = 433.0). Calcd .: molecular peak (M + H) ⁺ : 433/435; detection: molecular peak (M + H) ⁺ : 433/435. Retention time with HPLC: 6.33 min (method A).

Example 2.121. {2- [3-Bromo-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4carboxylic acid.

2.121.a. [4- (2-aminoethyl) -2-bromophenyl] methanol.

To a solution of 4 g (17.68 mmol) (3-bromo-4-hydroxymethylphenyl) acetonitrile (see Example 2.107.c) in 100 ml of THF and 50 ml of a methanolic solution of HH, 100 mg of Raney nickel and the reaction mixture were added over 5 hours shake in a Parr autoclave at RT and a pressure of H ₂ 5 psi. After this, the catalyst is filtered off, the solvent is distilled off, and the product is used without purification in the subsequent reaction.

Yield: 3.8 g (93.4% of theory). C ₉ H ₁₂ VgMO (M = 230.11). Calcd .: molecular peak (M + H) ⁺ : 230/232; detection: molecular peak (M + H) ⁺ : 230/232. Retention time with HPLC: 1.85 min (Method A).

2.121.b [2- (3-bromo-4-hydroxymethylphenyl) ethyl] carbamic acid tert-butyl ester.

To a solution of 3.8 g (16.51 mmol) of [4- (2-aminoethyl) -2-bromophenyl] methanol in 50 ml of CH2C12, 17 ml of a 1 molar solution of BOC anhydride in CH ₂ Cl _{2 was} added and the reaction mixture was left on stir nightly at CT. It is then diluted with 100 ml of a diluted KH8O ₄ solution, the organic phase is separated off, washed with a diluted MAHCO ₃ solution and water, and dried over MD8O ₄ . After wasp removal

- 104 012834 solvent and solvent, the residue was purified by silica gel chromatography.

Yield: 2.3 g (42.2% of theory). C1 ₄ H ₂₀ B ^ O ₃ (M = 330.22). The value of K _g : 0.44 (silica gel, petroleum ether / EJAc in a ratio of 6: 4).

2.121. in. [2- (3-Bromo-4-chloromethylphenyl) ethyl] carbamic acid tert-butyl ester.

To a solution of 1.98 g (6.0 mmol) of tert-butyl ester of [2- (3-bromo-4-hydroxymethylphenyl) ethyl] carbamic acid in 50 ml of CH ₂ Cl ₂ and 0.53 ml of pyridine cooled slowly to 0 ° C 0.54 ml (6.5 mmol) of thionyl chloride are added dropwise, stirred for the next hour at 0 ° C and then heated to RT. After this, the reaction mixture was mixed with water, the organic phase was washed with a diluted KH8O ₄ solution and water and dried over MgSO ₄ . The product obtained after filtration through activated carbon and removal of solvent without purification is used in the subsequent reaction.

Yield: 2.0 g (95.6% of theory). C1 ₄ H1 ₉ VgSShO ₂ (M = 348.67). Calcd .: molecular peak (M + H) ⁺ : 348/350/352; detection: molecular peak (M + H) ⁺ : 348/350/352. The value of K _g : 0.6 (silica gel, petroleum ether / EJAc in a ratio of 6: 4).

2.121. g. tert-Butyl ester {2- [3-bromo-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} carbamic acid.

To a suspension of 1.9 g (5.45 mmol) of [2- (3-bromo-4-chloromethylphenyl) ethyl] carbamic acid tert-butyl ester and 2.5 g (18.1 mmol) of K2CO3 in 50 ml of acetonitrile was added 0 , 84 ml (11 mmol) of 2,5-dihydro-1H-pyrrole and the reaction mixture was stirred overnight at RT. After that, the suspension was filtered, the filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography.

Yield: 0.5 g (24.1% of theory). C, ₈ 11 ₂₅ Br \ ' ₂ O ₂ (M = 381.32). Calcd .: molecular peak (M + H) ⁺ : 381/383; detection: molecular peak (M + H) ⁺ : 381/383. Value K _g : 0.58 (silica gel, CH ₂ Cl ₂ / MeOH in a ratio of 8: 2).

2.121.d 2- [3-Bromo-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethylamine.

To a solution of 500 mg (1.31 mmol) of {2- [3-bromo-4- (2,5-dihydropyrrol-1 methylmethyl) phenyl] ethyl} carbamic acid tert-butyl ester in 50 ml of CH ₂ Cl ₂ add 5 ml of trifluoroacetic acid acids and the reaction mixture is stirred at RT for 2 hours. It is then concentrated in vacuo, mixed with water and CH2C12, the pH is adjusted to alkaline with a K2CO3 solution, the organic phase is separated and it is again washed with water. It was then concentrated in vacuo and the product was purified by silica gel chromatography.

Yield: 350 mg (95.0% of theory). C ^ H ^ Br ^ (M = 281.20). Calcd .: molecular peak (M + H) ⁺ : 281/283; detection: molecular peak (M + H) ⁺ : 281/283. The value of K _g : 0.08 (silica gel, CH ₂ Cl ₂ / MeOH / Ν ^ in a ratio of 95: 5: 0.5).

2.121 .е. {2- [3-Bromo-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I, from 141 mg (0.5 mmol) of 2- [3brom-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethylamine and 116 mg (0.5 mmol) 4 ' -chlorobiphenyl-4carboxylic acid.

Yield: 140 mg (56.5% of theory). С ₂₆ Н ₂₄ ВгСШ ₂ О (М = 495.85). Calcd .: molecular peak (M + H) ⁺ : 495/497/499; detection: molecular peak (M + H) ⁺ : 495/497/499. Retention time with HPLC: 6.6 min (method A).

Example 2.122. 4'-bromo-3-fluorobiphenyl-4-carboxylic acid {2- [3-Bromo-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide.

2.122.a. 4'-bromo-3-fluorobiphenyl-4-carboxylic acid.

To a solution of 1.1 g (5 mmol) of 4-bromo-2-fluorobenzoic acid in 5 ml of DMF and 5 ml of dioxane, 1.04 g (5 mmol) of 4-bromophenylboronic acid, 115 mg (0.1 mmol) of tetrakis are successively added. (triphenylphosphine) palladium and 2 ml of a 2 molar solution of a ₂ CO ₃ and the reaction mixture is heated under reflux for 2 hours. To complete the reaction, it is again mixed with 250 mg (1.25 mmol) of 4-bromophenylboronic acid and heated under reflux for another 2 hours. Then, the reaction mixture is filtered while hot through a fiberglass filter, washed with water, acidified with diluted KH8O ₄ solution. the precipitate formed is suction filtered and washed with water. The residue was triturated with acetonitrile and a small amount of MeOH, the insoluble matter was filtered off, the filtrate was concentrated, the residue was triturated with MeOH and the product was suction filtered.

Yield: 140 mg (9.5% of theory). C1 ₃ H ₈ BrH ₂ (M = 295.11). Calculation: molecular peak (M + H) ⁺ :

- 105 012834

293/295; detection: molecular peak (M + H) ⁺ : 293/295. The value of K <0.5 (silica gel, CH ₂ Cl ₂ / MeOH in a ratio of 9: 1).

2.122.b. 4'-bromo-3-fluorobiphenyl-4-carboxylic acid {2- [3-Bromo-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide.

The title compound was prepared according to General Procedure I, from 141 mg (0.5 mmol) of 2- [3 bromo-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethylamine and 140 mg (0.47 mmol) 4 ' β-bromo-3-fluorobiphenyl 4-carboxylic acid.

Yield: 10 mg (3.8% of theory). C ₂₆ H ₂₃ Br ₂ PX ₂ O (M = 558.29). Calcd .: molecular peak (M + H) ⁺ : 557/559/561; detection: molecular peak (M + H) ⁺ : 557/559/561. Retention time with HPLC: 7.0 min (method A).

Example 2.123. [2- (3-amino-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

To a solution of 40 mg (0.08 mmol) of (5- {2 - [(4'-chlorobiphenyl-4-carbonyl) amino] ethyl} -2-pyrrolidin-1-ylmethylphenyl) carbamic acid tert-butyl ester (see example 2.116) in 3 ml of CH ₂ Cl _2, add 0.12 ml of trifluoroacetic acid and the reaction mixture is allowed to stir overnight at RT. Next, concentrated in vacuo, combined with semisaturated sodium Hansen ₃ EYuAs extracted and the organic phase was dried over Md8O _4. After removal of the desiccant and solvent, the residue is purified by HPLC.

Yield: 3 mg (7.3% of theory). С ₂₆ Н ₂₈ СШ ₃ О-С ₂ НР ₃ О ₂ (M = 548.01). Calcd .: molecular peak (M + H) ⁺ : 434/436; detection: molecular peak (M + H) ⁺ : 434/436. Retention time during HPLC: 5.35 min (81aE Vopb C18, 3.5 μm, water / acetonitrile / formic acid in a ratio of 6: 4: 0.015).

Example 2.124. Ethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid.

2.124.a. Ethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine.

To a solution of 204 mg (1.0 mmol) of 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine and 0.17 ml of triethylamine in 5 ml of THF was added dropwise a solution of 89 μl (1.1 mmol) of ethyl iodide in 1 ml of THF and the reaction mixture was stirred for 24 hours at RT. Next, mixed with saturated sodium Hansen ₃ EYuAs extracted and the organic phase was dried over Md8O _4. After removal of the desiccant and solvent, the residue without purification is used in the subsequent reaction.

Yield: 70 mg (30.1% of theory).

2.124.b. Ethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I from 70 mg (0.3 mmol) ethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine and 81 mg (0.35 mmol) 4'-chlorobiphenyl-4- carboxylic acid.

Yield: 20 mg (14.9% of theory). C ₂₈ H ₃₁ SC ₂ O (M = 447.03). Calcd .: molecular peak (M + H) ⁺ : 447/449; detection: molecular peak (M + H) ⁺ : 447/449. Retention time with HPLC: 6.92 min (Method A).

Example 2.125. Isobutyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.125. but. Isobutyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine.

A solution of 204 mg (1.0 mmol) of 2- (4-pyrrolidin-1-ylmethylphenyl) ethylamine and 91 μl (1.0 mmol) of isobutyric aldehyde in 20 ml of THF is slightly acidified with glacial acetic acid, mixed with 253 mg (1.2 mmol) HaVN (OAc) ₃ and left to mix overnight at RT. Then the reaction mixture is mixed with a half-saturated solution of HaNCO ₃ , carefully extracted with EAUc, the aqueous phase is saturated with K ₂ CO ₃ and extracted with EAUc. The combined organic phases are dried over MD8O ₄ . After removal of the desiccant and solvent, the residue without purification is used in the subsequent reaction.

- 106 012834

Yield: 250 mg (96.0% of theory). C ₁₇ H ₂₈ S ₂ (M = 260.43). Calcd .: molecular peak (M + H) ⁺ : 261; found: molecular peak (M + H) ⁺ : 261. The value of Ku is 0.4 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ in a ratio of 8: 2: 0.2).

2.125.b. Isobutyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I from 250 mg (0.96 mmol) of isobutyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine and 244 mg (1.05 mmol) of 4'-chlorobiphenyl-4- carboxylic acid.

Yield: 67 mg (14.7% of theory). C ₃₀ H ₃₅ Cl ₂ O (M = 475.08). Calcd .: molecular peak (M + H) ⁺ : 475/477; detection: molecular peak (M + H) ⁺ : 475/477. Retention time with HPLC: 7.67 min (Method A).

Example 2.126. Cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid.

2.126. but. Cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-methylphenyl) ethyl] amine.

The specified compound is obtained analogously to example 2.125.a from 204 mg (1.0 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 114 μl (1.0 mmol) of 1,2,3,6-tetrahydrobenzaldehyde.

Yield: 100 mg (33.5% of theory). C ₂₀ H ₃₀ N ₂ (M = 298.48). The value of K _g : 0.2 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ in a ratio of 8: 2: 0.2).

2.126.b. Cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4carboxylic acid.

The title compound was prepared according to General Procedure I from 100 mg (0.34 mmol) of cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine and 86 mg (0.37 mmol) 4 ′ -chlorobiphenyl-4carboxylic acid.

Yield: 46 mg (26.8% of theory). C ₃₃ H ₃₇ Cl ₂ O (M = 513.13). Calcd .: molecular peak (M + H) ⁺ : 513/515; detection: molecular peak (M + H) ⁺ : 513/515. Retention time with HPLC: 8.20 min (method A).

Example 2.127. Benzyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.127.a. Benzyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine.

The specified compound is obtained analogously to example 2.125.a from 204 mg (1.0 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 102 μl (1.0 mmol) of benzaldehyde.

Yield: 160 mg (54.3% of theory). C ₂₀ H ₂₆ L ₂ (M = 294.44). The value of Ku is 0.28 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ in a ratio of 8: 2: 0.2).

2.127.b. Benzyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I from 160 mg (0.54 mmol) of benzyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine and 140 mg (0.60 mmol) of 4'-chlorobiphenyl-4- carboxylic acid.

Yield: 16 mg (5.8% of theory). С ₃₃ Н ₃₃ С1Ы ₂ О (M = 509.10). Calcd .: molecular peak (M + H) ⁺ : 509/511; detection: molecular peak (M + H) ⁺ : 509/511. Retention time with HPLC: 7.51 min (method A).

Example 2.128. Cyclohexylmethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.128. but. Cyclohexylmethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine.

The specified compound is obtained analogously to example 2.125.a from 204 mg (1.0 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 121 μl (1.0 mmol) of cyclohexanecarbaldehyde.

- 107 012834

Yield: 100 mg (33.3% of theory). C ₂₀ H ₃₂ \ ₂ (M = 300.49). The value of K _£ : 0.18 (silica gel, CH ₂ Cl ₂ / MeOH / \ H ₃ in a ratio of 8: 2: 0.2).

2.128.b. Cyclohexylmethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid.

The title compound was prepared according to General Procedure I, from 100 mg (0.33 mmol) of cyclohexylmethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine and 86 mg (0.37 mmol) of 4'-chlorobiphenyl-4-carboxylic acid .

Yield: 70 mg (40.8% of theory). С ₃₃ Н ₃₃ С1 \ ₂ О (М = 515.15). Calcd .: molecular peak (M + H) ⁺ : 515/517; detection: molecular peak (M + H) ⁺ : 515/517. Retention time with HPLC: 8.63 min (method A).

Example 2.129. Cyclopropylmethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

2.129. but. Cyclopropylmethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine.

The specified compound is obtained analogously to example 2.125.a from 204 mg (1.0 mmol) of 2- (4pyrrolidin-1-ylmethylphenyl) ethylamine and 75 μl (1.0 mmol) of cyclopropanecarbaldehyde.

Yield: 100 mg (38.7% of theory). C1 ₇ H ₂₆ \ ₂ (M = 258.41). The value of K _£ : 0.30 (silica gel, CH ₂ Cl ₂ / MeOH / \ H ₃ in a ratio of 8: 2: 0.2).

2.129.b. Cyclopropylmethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide.

The title compound was prepared according to General Procedure I, from 100 mg (0.39 mmol) of cyclopropylmethyl [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amine and 100 mg (0.43 mmol) of 4'-chlorobiphenyl-4-carboxylic acid .

Yield: 23 mg (12.6% of theory). C ₃₀ H ₃₃ C1 \ ₂ O (M = 473.06). Calcd .: molecular peak (M + H) ⁺ : 473/475; detection: molecular peak (M + H) ⁺ : 473/475. Retention time with HPLC: 7.45 min (Method A).

Example 2.130. 4-Pentyl - \ - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1-methylphenyl) ethylamine (102 mg, 0.50 mmol) and 4-pentylbenzoic acid (96 mg, 0.50 mmol).

Yield: 75 mg (39.6% of theory). C ₂₅ H ₃₄ \ ₂ O (M = 378.56). Calcd .: molecular peak (M + H) ⁺ : 379; detection: molecular peak (M + H) ⁺ : 379. Retention time by HPLC: 6.5 min (method A).

Example 2.131. 4-Butyl - \ - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

Said compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1 methylmethyl) ethylamine (102 mg, 0.50 mmol) and 4-butylbenzoic acid (89 mg, 0.50 mmol).

Yield: 60 mg (32.9% of theory). C ₂₄ H _{32 2} O (M = 364.54). Calculation: molecular peak (M + H) ⁺ : 365; detection: molecular peak (M + H) ⁺ : 365. Retention time with HPLC: 6.0 min (method A).

Example 2.132. 4-Butylamino - \ - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

n

I

The title compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1 methylmethyl) ethylamine (204 mg, 1.0 mmol) and 4-butylaminobenzoic acid (155 mg, 0.80 mmol).

Yield: 30 mg (9.9% of theory). C ₂₄ H _{33 3} O (M = 379.55). Calculation: molecular peak (M + H) ⁺ : 380; detection: molecular peak (M + H) ⁺ : 380. Retention time with HPLC: 6.0 min (method A).

Example 2.133. 4- (1-Methylbutyl) - \ - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

- 108 012834

The title compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1 methylmethyl) ethylamine (82 mg, 0.40 mmol) and 4- (1-methylbutyl) benzoic acid (75 mg, 0.39 mmol).

Yield: 40 mg (27.1% of theory). C ₂₄ H ₃₂ K ₂ O (M = 378.56). Calcd .: molecular peak (M + H) ⁺ : 379; detection: molecular peak (M + H) ⁺ : 379. Retention time with HPLC: 4.3 min (method B).

Example 2.134. K- [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] -4- (4,4,4-trifluorobutoxy) benzamide.

R

2.134. but. 4- (4,4,4-trifluorobutoxy) benzoic acid methyl ester.

To a solution of 304 mg (2.0 mmol) of 4-hydroxybenzoic acid methyl ester in 10 ml of DMF was added 608 mg (4.4 mmol) of ₂ CO ₃ and then 382 mg (2.0 mmol) of 1-bromo-4, 4,4-trifluorobutane. The mixture was allowed to stir at RT overnight, then mixed again with 1-bromo-4,4,4-trifluorobutane and stirred for another 24 hours at RT. Then the reaction solution was diluted with water and twice extracted with EAUc. The combined organic extracts were dried over MgSO ₄ and concentrated in vacuo. The crude product without further purification is used in the reaction in the next step.

Yield: 500 mg (95.3% of theory). C ₁₂ H ₁₃ P ₃ O ₃ (M = 262.23). Calcd .: molecular peak (M + H) ⁺ : 263; detection: molecular peak (M + H) ⁺ : 263. The value of K _£ : 0.9 (silica gel, petroleum ether / EyAc in a ratio of 6: 4).

2.134.b. 4- (4,4,4-trifluorobutoxy) benzoic acid.

To a solution of 500 mg (1.9 mmol) of 4- (4,4,4-trifluorobutoxy) benzoic acid methyl ester in 7 ml of THF was added 10.0 ml (10.0 mmol) of a 1 molar sodium hydroxide solution. The mixture was stirred for 8 hours while heating under reflux. After this, THF is removed in vacuo and the residue acidified with hydrochloric acid. The precipitate formed after filtration is dried in air.

Yield: 350 mg (73.9% of theory). C ₁₁ H ₁₁ P ₃ O ₃ (M = 248.20). Calcd .: molecular peak (M-H) ^- : 247; detection: molecular peak (M-H) ^- : 247. Retention time by HPLC: 7.5 min (method A).

2.134. in. K- [2- (4-Pyrrolidin-1-ylmethylphenyl) ethyl] -4- (4,4,4-trifluorobutoxy) benzamide.

The title compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1 methylmethyl) ethylamine (102 mg, 0.50 mmol) and 4- (4,4,4-trifluorobutoxy) benzoic acid (124 mg, 0.50 mmole).

Yield: 37 mg (17.0% of theory). C ₂₄ H ₂₉ P ₃ K ₂ O ₂ (M = 434.51). Calcd .: molecular peak (M + H) ⁺ : 435; detection: molecular peak (M + H) ⁺ : 435. Retention time with HPLC: 5.8 min (method A).

Example 2.135. 3-Methyl-4-pent-1-ynyl-K- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

2.135.a. 3-Methyl-4-pent-1-ynylbenzoic acid methyl ester 0.39 ml (4.0) are added successively to a solution of 458 mg (2.0 mmol) of 4-bromo-3-methylbenzoic acid methyl ester in 3.0 ml of DMF mmol) of pentin, 0.56 ml (4.0 mmol) of triethylamine, 70 mg (0.1 mmol) of bis (triphenylphosphine) palladium (P) chloride and 19 mg (0.1 mmol) of iodide medif. Then the reaction solution is stirred for 10 minutes in a microwave oven with a radiation power of 200 W and a temperature of 65 ° C. Then, 0.20 ml (2.0 mmol) of pentin is additionally added and the reaction solution is stirred for another 20 minutes in a microwave at a radiation power of 200 W and a temperature of 70 ° C. After this, the mixture was diluted with 30 ml of EluAc, filtered through celite and the filtrate washed three times with 50 ml of water. The combined organic extracts were dried over MgSO ₄ , filtered through activated carbon, and the solvent was removed in vacuo. The product was purified by silica gel column chromatography (cyclohexane and then 9: 1 cyclohexane / ethyl acetate).

Yield: 200 mg (46.2% of theory). C ₁₄ H ₁₆ O ₂ (M = 216.28). Calcd .: molecular peak (M + H) ⁺ : 217; detection: molecular peak (M + H) ⁺ : 217. Retention time by HPLC: 6.8 min (method B).

2.135.b. 3-Methyl-4-pent-1-ynylbenzoic acid.

To a solution of 200 mg (0.93 mmol) of 3-methyl-4-pent-1-ynylbenzoic acid methyl ester in 3 ml of methanol was added 3.0 ml (3.0 mmol) of a 1 molar sodium hydroxide solution. Next, the mixture for 3 hours

- 109 012834 stirred under reflux. After this, the reaction solution was diluted with water and once extracted with 40 ml of EYuac. The aqueous phase is acidified with a 1 molar solution of KH8O ₄ and extracted twice with 40 ml of EuAc. The combined organic phases are dried over MD8O ₄ . After removal of the desiccant and solvent, the crude product is used in the reaction in the next step without further purification.

Yield: 50 mg (26.7% of theory). C1 ₃ H1 ₄ O ₂ (M = 202.26). Calcd .: molecular peak (M-H) ^- : 201; detection: molecular peak (M-H) ^- : 201. Retention time with HPLC: 5.6 min (method B).

2.135.in. 3-Methyl-4-pent-1-ynyl-N- [2- (4-pyrrolidin-1-methylmethyl-phenyl) ethyl] benzamide.

The specified compound is obtained in accordance with General procedure I from 2- (4-pyrrolidin-1 methylmethyl) ethylamine (51 mg, 0.25 mmol) and 3-methyl-4-pent-1-ynylbenzoic acid (50 mg, 0.25 mmol )

Yield: 22 mg (22.9% of theory). C ₂₆ H ₃₂ ^ O (M = 388.558). Calcd .: molecular peak (M + H) ⁺ : 389; detection: molecular peak (M + H) ⁺ : 389. Retention time by HPLC: 6.9 min (method A).

Example 2.136. 4-Pent-1-ynyl-No. [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

2.136. but. 4-pent-1-ynylbenzoic acid ethyl ester.

To a solution of 552 mg (2.0 mmol) of 4-iodobenzoic acid ethyl ester in 3 ml of DMF, 0.39 ml (4 mmol) of 1-pentin, 0.56 ml of triethylamine, 70 mg (0.1 mmol) of bis chloride are successively added (triphenylphosphine) palladium (P) and 19 mg (0.1 mmol) Cu! Then the reaction solution is stirred for 4 hours at 80 ° C. The mixture was diluted with 30 ml EYuAs, filtered through celite and the filtrate was washed three times with 50 ml of water in portions and dried over Md8O _4. After filtration through activated carbon, the solvent was removed in vacuo. The product was purified by silica gel column chromatography (cyclohexane and then 9: 1 cyclohexane / ethyl acetate).

Yield: 150 mg (34.7% of theory). C1 ₄ H ₁₆ O ₂ (M = 216.282). Calcd .: molecular peak (M + H) ⁺ : 217; detection: molecular peak (M + H) ⁺ : 217. Retention time by HPLC: 6.8 min (method B).

2.136.b. 4-Pent-1-ynylbenzoic acid.

To a solution of 150 mg (0.69 mmol) of 4-pent-1-ynylbenzoic acid ethyl ester in 3 ml of methanol was added 5.0 ml (5.0 mmol) of a 1 molar sodium hydroxide solution. The mixture was then stirred for 3 hours under reflux. After this, the reaction solution was diluted with water and once extracted with 40 ml of EYuac. The aqueous phase is acidified with a 1 molar solution of KH8O ₄ and extracted twice with 40 ml of EuAc. The combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product without further purification is used in the reaction in the next step.

Yield: 150 mg (115% of theory). C1 ₂ H1 ₂ O ₂ (M = 188.23). Calcd .: molecular peak (M-H) ^- : 187; detection: molecular peak (M-H) ^- : 187. The value of K _p : 0.2 (silica gel, petroleum ether / EJAc in a ratio of 8: 2).

2.136. in. 4-Pent-1-vinyl-N- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

Said compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1 methylmethyl) ethylamine (163 mg, 0.80 mmol) and 4-pent-1-ynylbenzoic acid (150 mg, 0.80 mmol).

Yield: 122 mg (40.9% of theory). C ₂₅ H _3C No. ₂ O (M = 374.53). Calcd .: molecular peak (M + H) ⁺ : 375; detection: molecular peak (M + H) ⁺ : 375. K _p value: 0.35 (silica gel, EJAc / methanol / LN ₃ in a ratio of 9: 1: 0.1).

Example 2.137. (4-Pent-1-enyl) -№ [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

2.137.a. 4-pent-1-enylbenzoic acid methyl ester.

To a solution of 1.08 g (2.2 mmol) of (4-methoxycarbonylbenzyl) triphenylphosphonium bromide in 20 ml of THF under argon at 0 ° C. was added 246 mg (2.2 mmol) of potassium tert-butylate. The orange solution was stirred for another 15 minutes at 0 ° C, after which it was mixed with 0.18 ml (2.0 mmol) of butyraldehyde. Then, the reaction solution was refluxed for 3 hours, after which it was diluted with ЕУАс. The organic phase is washed twice with water, dried over magnesium sulfate and the solvent is removed in vacuo. The residue was triturated with diisopropyl ether, filtered and the filtrate was concentrated. Subsequently, the product was purified by silica gel column chromatography (petroleum ether / EYAc in a ratio of 6: 4). In this way, 4-pent-1enylbenzoic acid methyl ester is obtained as a mixture of E ^ isomers in a ratio of 2: 1.

Yield: 350 mg (56.5% of theory). C1 ₃ H1 ₆ O ₂ (M = 204.27). Calcd .: molecular peak (M + H) ⁺ : 204;

- 110 012834 detection: molecular peak (M + H) ⁺ : 204. K _£ value: 0.90 (silica gel, petroleum ether / EYAc in a ratio of 6: 4).

2.137. b. 4-Pent-1-enylbenzoic acid.

To a solution of 350 mg (1.71 mmol) of 4-pent-1-enylbenzoic acid ethyl ester in 4 ml of methanol was added 5.0 ml (5.0 mmol) of a 1 molar sodium hydroxide solution. The mixture was then stirred for 2 hours under reflux. Then, the solvent was removed in vacuo and the residue was mixed with a 6 molar hydrochloric acid solution. The precipitate formed is suction filtered and dried at 35 ° C. in a drying chamber with air circulation. Subsequently, the product was purified by filtration through a silica gel column (petroleum ether / EuAc in a ratio of 6: 4).

Yield: 300 mg (92.1% of theory). C1 ₂ N _M O ₂ (M = 190.24). Calcd .: molecular peak (M-H) ^- : 189; detection: molecular peak (M-H) ^- : 189. The value of K _£ : 0.4 (silica gel, petroleum ether / EyAc in a ratio of 6: 4).

2.137. in. (4-Pent-1-enyl) -X- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1 methylmethyl) ethylamine (306 mg, 1.50 mmol) and 4-pent-1-enylbenzoic acid (300 mg, 1.56 mmol) as a mixture E / 2 isomers in a ratio of 2: 1.

Yield: 130 mg (23.0% of theory). C ₂₅ H ₃₂ JO (M = 376.547). Calcd .: molecular peak (M + H) ⁺ : 377; detection: molecular peak (M + H) ⁺ : 377. Retention time by HPLC: 6.9 min (method A).

Example 2.138. 3-Chloro-4-cyclohexyl-X- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide.

The title compound was prepared according to General Procedure I from 2- (4-pyrrolidin-1 methylmethyl) ethylamine (102 mg, 0.50 mmol) and 3-chloro-4-cyclohexylbenzoic acid (119 mg, 0.50 mmol).

Yield: 46 mg (21.6% of theory). C ₂₆ H ₃₃ SS ₂ O (M = 425.019). Calcd .: molecular peak (M + H) ⁺ : 425/427; detection: molecular peak (M + H) ⁺ : 425/427. Retention time with HPLC: 4.7 min (method B).

Experimental methods for determining the MCH receptor antagonistic activity of the compounds of the invention are described below. In addition to these methods, for the same purposes, other experimental methods known to the person skilled in the art can be used to determine the activity of substances antagonistic with respect to the MCH receptor, based, for example, on determining the degree of inhibition of the MCH receptor-mediated suppression of cAMP production in accordance with the procedure described at M. Noodbyup et al. in Me1ap1n-ssepsläg11n§ Nogtop apb From geser! oge ehrgezeb apb ips! 1opt t Nitapkt, Wusnet. Wurnuz. Kez. Sottip., 296, 2002, ss. 698701, as well as on the biosensor determination of the degree of binding of MCH to its receptor in the presence of antagonistic substances based on plasmon resonance in accordance with the method described by O. and CoGaS 8. in 'T'1o \\ - Meb1a1eb Op-8ig £ ae KesopzSiuop, Oo-Prgoet Soir1eb KeserUzs og ArrNsiopz m 8ig £ ase P1aztop Kesopaps Wuzepzogz, Apa1. WussNo. 300, 2002, ss. 132-138. Other experimental methods for the determination of the activity of substances antagonistic with respect to the MCH receptor are presented in the literature and patent documents indicated in the introductory part of this description, the description of which experimental methods is hereby incorporated by reference into this description.

Experience in determining the binding to the MCH-1 receptor

Method: binding of MCH to transfected NMHC-1 receptor cells

Type: people

Experimental cells: stably transfected with IMSH-1K receptor CHO / Oa1pIa16 cells

Results: as values Yu50

Membranes from CHO / Oa1pHa16 cells stably transfected with the human NMCH-1K receptor are resuspended using a syringe (with a 0.6x25 mm needle) and diluted in assay buffer (containing HEPE8 (No. 2-hydroxyethylpiperazine-X'-2-ethanesulfonic acid) at a concentration of 50 mM, MdC1 ₂ at a concentration of 10 mM, EHTC (ethylene glycol tetraacetic acid) at a concentration of 2 mM with a pH of 7.00, bovine serum albumin (without proteases) in an amount of 0.1%, bacitracin in an amount of 0.021%, aprotinin in a concentration 1 μg / ml, leipeptin at a concentration of 1 μg / ml and phosphoramidone ontsentratsii 1 uM) to a concentration ranging from 5 to 15 micrograms / ml. 200 μl of this membrane fraction

- 111 012834 (contains from 1 to 3 μg of protein) for 60 min, incubated at room temperature in the presence of ^ Etirozylmelanin-concentrating hormone (^ EMCH, a commercially available hormone supplied by ΝΓΝ) at a concentration of 100 pM and in the presence of a test compound in an increasing concentration in a final volume of 250 μl. After incubation, the reaction mixture is filtered using a harvester through a glass fiber filter treated with 0.5% polyethyleneimine solution (OE / B, IshIeg Raskagd). The radioactivity retained on the membranes retained on the filter is then determined after adding a scintillator (Raskagd Myugozst! 20) in an appropriate measuring device (TorSoip! Of Raskagd company).

The degree of non-specific binding is determined based on the associated radioactivity in the presence of 1-micromolar MCH during the incubation period.

A curve of the degree of binding of the test compound to its concentration is analyzed, assuming a single receptor binding site.

results

Non-radiolabelled MCH competes with ^125- labeled NMSN for binding to the receptor at a CE value ranging from 0.06 to 0.15 nM. The ΚΌ value of the radioligand is 0.156 nM.

Experience in mobilizing Ca ²⁺ using the MCH-1 receptor Method: experience in mobilizing calcium with human MCH (EYRK ³⁸⁴ tablet reader)

Type: people

Experimental cells: stably transfected with 11MSH-1K.-receptor CHO / Oa1p11a16 cells

Results: 1st analysis: stimulation in% relative to control (SIT at a concentration of 10 ^b M)

2nd analysis: as pKV values

Reagents: HB88 (Hanks balanced salt solution) (10 times) (company О1ВСО)

HEPE8-buffer (H-2-hydroxyethylpiperazine-M'-2ethanesulfonic acid) (1 molar) (С1ВСО company) pluronic Р-127 (company Mo1eci1ag Prgoev)

Myo-4 (fluorochrome) (Mo1eci1ag PrgoBez) probenecid (81gta firm) MSH hormone (Vasieth company) bovine serum albumin (BSA, without proteases) (firm

8egua)

DMSO (dimethyl sulfoxide) (8egua firm) Ham R12 medium (VuMUYMakeg firm)

FCS (fetal calf serum) (VyuAuShakeg company)

B-glutamine (company О1ВСО) hygromycin B (company О1ВСО) ΡΕΝδίΓβρ (streptomycin) (company ВюАДДпПакег) zeocin (company ΙηνΐίΓ0§εη)

The cloned CHO / Oa1rBa16 cells stably transfected with the LMSH-1K receptor were cultured in a Ham culture medium E12 (with L-glutamine, Vu ^ LVakeg, Cat. No. BE12615E). This medium contains 500 ml of 10% FCS, 1% PEK81ger, 5 ml of L-glutamine (as a 200 millimolar stock solution), 3 ml of hygromycin B (50 mg / ml in phosphate buffered saline (PBS)) and 1.25 ml zeocin (in the form of a mother liquor at a concentration of 100 μg / ml). The day before the experiment, the cells were plated on a 384-well microtiter plate (with black walls and a transparent bottom, manufacturer: Co §1ag) with a density of 2500 cells per well and cultured overnight in the medium of the above composition at 37 ° C, 5% the content of CO2 and 95% relative humidity. On the day of the experiment, the cells, together with their culture medium, to which E1io-4 was added at a concentration of 2 mM and probenecid at a concentration of 4.6 mM, were cultured for 45 min at 37 ° C. After adding the fluorescent dye, the cells are washed four times with Hanks buffer solution (1-fold HB88, HEPE8 at a concentration of 20 mM), to which

- 112 012834 probenecid in an amount of 0.07%. Test substances are diluted in Hanks buffer solution mixed with 2.5% DMSO. The background fluorescence of unstimulated cells was measured in an EORK ³⁸⁴ plate reader (Mo1eci1ag Oeu1ce8, excitation wavelength: 488 nm, emission wavelength: in the passband width from 510 to 570 nm) in the presence of the test substance in a 384-well microtiter plate five minutes after last flushing operation. To stimulate the cells, MCH was diluted in Hanks' buffer solution supplemented with 0.1% BSA, 35 minutes after the last washing operation, they were pipetted into the wells of a 384-well culture plate and then the hormone-stimulated MCH hormone stimulated fluorescence was measured in the EORK ³⁸⁴ plate reader. .

Data analysis

1st analysis: the mobilization of cellular Ca ²⁺ is determined as the maximum relative fluorescence minus background fluorescence and expressed as a percentage of the maximum signal intensity coming from control cells (MCH at a concentration of 10 ^-6 M). This analysis is used to identify possible agonistic effects of the test substance.

2nd analysis: mobilization of cellular Ca ²⁺ is determined as the maximum relative fluorescence minus background fluorescence and is expressed as a percentage of the maximum signal intensity coming from control cells (MCH at a concentration of 10 ^-6 M, the signal intensity is normalized to 100%). EC ₅₀ values are determined graphically based on the curves of the dependence of the effect on the dose of SIT in the presence and absence of the test substance (at a certain concentration), using the program for constructing and analyzing SgaryRab Pg1§t 2.01 curves. In the graph constructed in this way, the curve reflecting the dependence of cell stimulation by the MCH hormone in the presence of MCH antagonists shifts to the right.

Degree of inhibition is expressed as PKB values, calculated by the following formula: ^BWR = ^{1od (EC} 50 (the test in into- + MCH) / EC50 (SIT) - 1) - ^with 1od (test in ^quantity).

In both of the above experiments, the compounds of the invention, including their salts, exhibit an MH receptor antagonistic effect. In the above experience in binding to the MCH-1 receptor, the compounds of the invention exhibit antagonistic activity against it in the concentration range from about 10 ^-10 to 10 ^-5 M, especially from 10 ^-9 to 10 ^-6 M.

In the above experiment on binding to the MCH-1 receptor, the following Κ '\ ₀ values were obtained:

The compound of example No. Value 1C ₅₀

The compound of example No. Value 1C ₅₀

Below are examples of dosage forms in which under the active substance is meant one or more of the compounds of the invention, including their salts. When using the compounds of the invention in combination with one or more other active substances from the above, the term active substance includes, inter alia, similar other active substances.

Example 3. Capsules with powder for inhalation containing 1 mg of active substance

Composition based on 1 capsule:

active ingredient lactose hard gelatin capsules

1.0 mg

20.0 mg

50.0 mg

71.0 mg

Obtaining: the active substance is crushed to particles of the size required for inhalation. The crushed active substance is mixed until homogeneous with lactose. This mixture is packaged in hard gelatin capsules.

Example 4. Inhalation solution containing 1 mg of active substance for an Kezr1ta1® inhaler.

The composition per one serving, issued in the form of a spray jet: the active substance benzalkonium chloride disodium edetate

1.0 mg

0.002 mg

0.0075 mg purified water up to 15.0 μl

- 113 012834

Obtaining: the active substance and benzalkonium chloride are dissolved in water and packaged in replaceable cartridges intended for an inhaler of the type Be ^ rnpa! ®.

Example 5. Inhalation solution containing 1 mg of active substance for an inhaler with a nebulizer.

Composition based on the contents of 1 bottle:

active substance 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g purified water up to 20.0 ml

Obtaining: the active substance, sodium chloride and benzalkonium chloride are dissolved in water. Example 6. Dosed aerosol with a propellant containing 1 mg of active substance. The composition based on one portion, issued in the form of a spray jet:

active substance 1.0 mg lecithin 0.1% propellant up to 50.0 μl

Preparation: The micronized active substance is suspended until homogeneous in a mixture of lecithin and propellant. The resulting suspension is packaged in a pressurized aerosol can with a metering valve.

Example 7. Nasal spray containing 1 mg of active substance.

Composition: active substance 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg purified water up to 0.1 ml

Getting: the active substance and excipients are dissolved in water and packaged in an appropriate container.

Example 8. Injection solution containing 5 mg of active substance per 5 ml.

Composition:

active substance 5 mg glucose 250 mg human serum albumin 10 mg glycofurol 250 mg water for injections up to 5 ml

Preparation: glycofurol and glucose are dissolved in water for injection (VdI), then human serum albumin is added, then the active substance is dissolved in this solution with heating, the volume of the mixture is adjusted to the above by adding VdI, and then it is packaged in an atmosphere of nitrogen into ampoules.

Example 9. An injection solution containing 100 mg of active substance per 20 ml.

Composition:

active substance 100 mg monopotassium dihydrogen phosphate (KH2RO4) 12 mg disodium hydrophosphate (KagNRSTs ^ NgO) 2 mg sodium chloride 180 mg human serum albumin 50 mg polysorbate 80 20 mg water for injections up to 20 ml

Preparation: Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injection (VdI), then human serum albumin is added, then the active substance is dissolved in this solution by heating with vdI, the volume of the mixture is brought to the above and then packaged in ampoules.

Example 10. Lyophilisate containing 10 mg of active substance.

- 114 012834

Composition:

active substance 10 mg mannitol 300 mg

human serum albumin 20 mg

Obtaining: mannitol is dissolved in water for injection (VdI), after which human serum albumin is added, then the active substance is dissolved in this solution with heating, the volume of the mixture is adjusted to the above by adding VdI, packaged in bottles and finally freeze-dried.

Solvent for lyophilisate:

polysorbate 80 (twin 80) 20 mg mannitol 200 mg water for injections up to 10 ml

Receiving:

Polysorbate 80 and mannitol are dissolved in water for injection (VdI) and packaged in ampoules. Example 11. Tablets containing 20 mg of active ingredient.

Composition:

active substance 20 mg lactose 120 mg corn starch 40 mg magnesium stearate povidone K25 2 mg 18 mg

Obtaining: the active substance is homogenously mixed with lactose and corn starch, then the resulting mixture is granulated using an aqueous solution of povidone, mixed with magnesium stearate and finally pressed on a tablet press. The weight of one tablet is 200 mg.

Example 12. Capsules containing 20 g of active ingredient.

Composition:

active ingredient corn starch 20 mg 80 mg finely divided silicic acid 5 mg magnesium stearate 2.5 mg

Obtaining: the active substance is mixed homogeneously with corn starch and silicic acid, then mixed with magnesium stearate and finally the mixture in a capsule filling machine is packaged in size 3 hard gelatin capsules.

Example 13. Suppositories containing 50 mg of active ingredient.

Composition:

active substance 50 mg

hardened fat (AAerz zoiaiz} d.8, up to 1700 mg

Preparation: The cured fat is melted at a temperature of approximately 38 ° C, then the crushed active ingredient is dispersed in this molten cured fat until homogeneous and the dispersion is poured into pre-cooled forms after cooling to about 35 ° C.

Example 14. Injection solution containing 10 mg of active substance per 1 ml

Composition:

active substance 10 mg mannitol 50 mg human serum albumin water for injection 10 mg to 1 ml

Obtaining: mannitol is dissolved in water for injection (VdI), after which human serum albumin is added, then the active substance is dissolved in this solution with heating, the volume of the mixture is adjusted to the above by adding VdI, and then it is packaged in a nitrogen atmosphere in ampoules.

Claims (24)

CLAIM 1. Carboxamide compounds of the general formula I in which ¹ and ² are CH, where one of both ¹ and ² can be обознач; and V ¹ , V ² , V ³ denote CH, where one or two of V ¹ , V ² and V ³ can denote Ν; and 12 K, K are independently H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl-C ₁ C ₃ alkyl, w-hydroxy-C ₂ -C ₃ alkyl, w- ( C ₁ -C ₃ alkoxy) -C ₂ -C ₃ alkyl, C1-C ₄ alkoxycarbonyl-C1-C ₃ alkyl, amino-C ₂ -C ₄ alkyl, C1-C ₃ alkylamino-C ₂ -C ₄ alkyl or di _(C1-C3 alkyl) amino-C ₂ -C ₄ alkyl, phenyl or phenyl _(C1-C3 alkyl), wherein in these groups and residues one or more C atoms may be mono- or polysubstituted by F atom and / or one or two C-atoms, independently of one another, can be monosubstituted by a C1 atom or a Br atom, and the phenyl group can be mono- or polysubstituted by a K ¹² moiety and / or may be monosubstituted with a nitro group, or K ¹ and K ² form a C ₂ -C ₈ alkylene bridge such that K ¹ K ² X- represents a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1H-pyrrole, 1,2, 3,6-tetrahydropyridine, 2,3,4,7-1H-tetrahydro-1H-azepinyl, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free imine function may be substituted by K ¹³ , morpholine and thiomorpholine, wherein in said alkylene bridge one or more H atoms may be replaced by a K residue ^14, and the alkylene bridge that may be substituted by one or two identical and or with various carbon or heterocyclic Cy groups such that the alkylene bridge and Cy group are connected by a simple or double bond through a joint C atom to form a spirocyclic ring system, through two joint adjacent C and / or Ν atoms to form a condensed bicyclic ring system or through three or more C and / or атом atoms to form a system of bridged rings; K ³ is H or C _g C ₆ alkyl; X denotes an alkylene bridge selected from methylene, 1,2-ethylene, 1,3-propylene and 1,4 butylene, with one or two carbon atoms being independently substituted by hydroxyl, w-hydroxy-C ₁ -C ₃ alkyl, w- (C ₁ -C ₃ alkoxy) -C ₁ -C ₃ alkyl and / or C ₁ -C ₃ alkoxy group, one or two carbon atoms in each case may be substituted by one or two identical or different C ₁ -C ₄ alkyl groups in each case one or more carbon atoms may be mono- or polysubstituted by F atoms, in each case one or two atoms uglero and independently of one another may be monosubstituted by C1 atom or a Br atom, and / or the alkylene bridge may be connected with R ¹ including coupled with R ¹ and X Ν-atom to form a heterocyclic group; Ζ is selected from the group consisting of -CH2-, -CH2-CH2-, -CH2-CH (CH3) -, -CH2-C (CH3) 2-, -CH (CH3) -CH2-, -C (CH3) 2 -CH2-; Υ is selected from divalent cyclic groups, which include phenylene and pyridinyl, where the above cyclic groups can be mono- or multisubstituted at one or more C-atoms with a K ²⁰ residue, and in the case of a phenyl ring, can also be additionally monosubstituted with a nitro group; And selected from divalent cyclic groups, which include 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinyl, 1,2,3,6-tetrahydropyridin-1,4-ylene, 2,5-pyridinyl and 1,4-piperazinyl; where the above cyclic groups can be mono- or multisubstituted at one or more C-atoms with a K ²⁰ residue, and in the case of a phenyl ring, can be additionally monosubstituted with a nitro group, and / or can be mono- or multisubstituted at one or more C atoms with a K moiety ²¹ , or A AND K ³ can be interconnected so that the fragment in formula I is a fragment of subformula II - 116 012834 ζ) denotes a group selected from groups of subformulas Sha-Sh§ -SK ⁶ K ⁷ -, Sha • SK ⁶ = SK ⁷ -, GPb, Shs ΑΆ-, PI -CO-ΝΚ ⁹ -, She -skMe, ShG -so-, pi I ?, I ?, I? independently of one another, they have one of the following meanings: Η, B, C1, Br, CH ₃ , CHP ₂ , СРз, С ₂ Н ₅ , С ₃ Н ₇ , СН (СН ₃ ) ₂ , ОСНз, ОСР ₂ , ОСРз, ОС ₂ Н ₅ , ОС3Н7, and ОСН (СН ₃ ) ₂ ; B represents a _C1-C6 alkyl, _C1-C6 alkenyl, C1-C ₆ alkynyl, C ₃ -C ₇ cycloalkyl-C 1 C ₃ alkyl, C ₃ -C _{7 cycloalkenyl-C1-C3-alkyl,} Cs-C _{7 cycloalkyl-C1-C3} alkenyl or Cs-C ₇ cycloalkyl-C 1-C ₃ alkynyl, wherein one or more C atoms may be mono- or polysubstituted by halogen and / or monosubstituted by hydroxy or cyano and / or cyclic groups may be single or multisubstituted with K ²⁰ ; XV is a single bond, an imino group or a 1 \ [- (C1-Szalkyl) imino group; k is 1; or B is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrroinyl, pyrrolyl, piperidinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinylpyridinyl triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl, isoindolyl, quinolinyl, benzoimidazolyl, isoquinolinyl, furanyl or thienyl, the bond with group XV or under certain conditions directly with group A arises through the C atom of a carbocyclic fragment or an optionally condensed phenyl or pyridine ring, or through the Ν or C atom of a heterocyclic fragment, or In conjunction with the double bond attached, group XV is selected from the group consisting of cyclopentylidenemethyl, cyclohexylidenemethyl and cyclohexanone-4-ylidenemethyl, wherein the above cyclic groups can be mono- or multisubstituted at one or more C-atoms with a K ²⁰ residue, and in the case of phenyl the groups may additionally also be monosubstituted with a nitro group, and / or may be mono- or multisubstituted at one or more Ν-atoms with a K ²¹ residue; XV is a single bond, —CH ₂ - or —CH═; k is 1; Cy denotes one of the following carbo - or heterocyclic groups: a saturated 3-7-membered carbocyclic group, an unsaturated 5-7-membered carbocyclic group, a phenyl group, a saturated 4-7-membered or unsaturated 5-7-membered heterocyclic group with a ,-, O- or 8-atom as a heteroatom, a saturated or unsaturated 57-membered heterocyclic group with two or more Ν-atoms or one or two Ν-atoms and one O- or 8-atom as heteroatoms or an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected and Ν, O and / or 8, wherein the aforementioned cyclic groups may be mono- or polysubstituted by one or more C-atoms of residues to ^20, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and / or mono- or polysubstituted by one or more Atoms with the remainder of K ²¹ ; K ⁶ , K ⁷ , K ⁸ , K ^{9 are} independently H, methyl, trifluoromethyl, ethyl, isopropyl or npropyl, and K ⁶ and K ⁷ may also be B; K ¹² has one of the values indicated for K ²⁰ ; By ¹³ is H, C1-C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl-C 1 C ₃ alkyl, C ₄ -C ₇ cycloalkenyl, C ₄ -C _{7 cycloalkenyl-C1-C3} alkyl - co-hydroxy-C ₂ -C ₃ alkyl, co- (C1-C ₃ alkoxy) -C ₂ -C ₃ alkyl, _amino-C1-C6 alkyl, _C1-C3 alkylamino, _C1-C6 alkyl or di (C1-C ₃ alkyl) _amino-C1-C6 alkyl, phenyl, phenyl _(C1-C3 alkyl) -, pyridinyl, dioxolan-2-yl, _C1-C3 alkylcarbonyl, hydroxycarbonyl-C1-C ₃ alkyl, _C1-C4 alkoxycarbonyl, C1-Szalkilkarbonilamino-C ₂ -C ₃ alkyl, C 1 C ₃ alkylsulfonyl or C1-Szalkilsulfonilamino-C ₂ -C ₃ alkyl; By ¹⁴ is halogen, _C1-C4 alkyl, hydroxyl, _C1-C4 alkoxy, _{C1-C4 alkoxy-C1-C3} alkyl, hydroxy _C1-C3 alkyl, _C1-C4 alkylcarbonyl, _C1-C4 alkoxycarbonyl , _{C1-C4 alkoxycarbonyl-C1-C3} alkyl, C1-C4 - 117012834 alkoxycarbonylamino group, a _{C1-C4-alkoxycarbonylamino-C1-Szalkil,} amino, _(C1-C4 alkyl) amino or di _(C1-C4 alkyl) amino; K ²⁰ is halogen, hydroxy, cyano, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, hydroxy-C 1 C 3 alkyl, K ²² -C 1 -C 3 alkyl or has one of the meanings specified for K ²² ; By ²¹ is _C1-C3 alkyl, co-hydroxy-C ₂ -C ₃ alkyl, phenyl, _phenyl-C1-C3 alkyl, _C1-C3 alkylcarbonyl, carboxy, C 1 C ₄ alkoxycarbonyl-C 1 C ₃ alkylsulfonyl , phenylcarbonyl or _phenyl-C1-C3 alkylcarbonyl; By ²² denotes pyridinyl, phenyl, _phenyl-C1-C3 alkoxy, _C1-C3 alkoxy, _C1-C3 alkylthio group, Η-CO-, _C1-C3 alkylcarbonyl, _C1-C4 alkoxycarbonyl, aminocarbonyl, _C1-C3 alkylaminocarbonyl, di _(C1-C3 alkyl) aminocarbonyl, C 1 C ₃ alkyl sulfonyl, C 1 C ₃ alkyl sulfinyl, C 1 C ₃ alkyl sulfonylamino, amino, _C1-C3 alkylamino, di _(C1-C3 alkyl) amino, _phenyl-C1-C3 alkylamino group, a 1 \ [- (C1-Szalkil) phenyl-C1-Szalkilaminogruppu, acetylamino, propionylamino, phenylcarbonyl, fenilkarbonilaminogruppu, fenilkarbonilmetilaminogru ny, (4-morpholinyl) carbonyl, (1 -pyrrolidinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-azepine 1) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy or aminocarbonylamino; K ²⁶ , K ²⁷ independently of one another have one of the meanings indicated for K ²⁰ or, in the case of a phenyl group, can also denote a nitro group, while the repeatedly present residues K ²⁶ , K ²⁷ can have identical or different values; and w, η independently from each other are 0, 1 or 2; 3 12 13 14 20 21 22 while in each of the groups and in each of the residues Ζ, K, K, K, K, K, K, K, one or more C-atoms can be mono- or multisubstituted by fluorine, and / or one or two C-atoms independently of one another can be monosubstituted with chlorine or bromine and / or one or more phenyl rings independently of each other additionally contain one, two or three substituents selected from the group consisting of G, C1, Br, I, _C1-C4 alkyl, _C1-C4 alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, _C1-C3 alkylamino, di _(C1-C3 alkyl) amino group, and etilaminogruppu, aminocarbonyl, FT4, difluoromethoxy, trifluoromethoxy, _amino-C1-C3 alkyl, C1-Szalkilamino _C1-C3 alkyl and di (C1-Szalkil) _amino-C1-C3 alkyl, and / or may be monosubstituted by nitro, as well as their tautomers, their diastereomers, their enantiomers and their mixtures and their physiologically compatible salts. 2. Carboxamide compounds according to claim 1, characterized in that A and K ³ are interconnected so that the fragment O in formula I is a fragment of subformula II where <2 is a group selected from groups of subformulas Sha-Sh§ -sk ⁶ to ⁷ -, 1Pa -sk ^b = ck ⁷ -, 1ПЬ -Ν = ΟΚ ⁵ -, Cc -Ν = Ν-, PI -CO-ΝΚ ⁹ -, Sha -σκ ⁸ = Ν-, LEE -CO-, ΙΙΙβ I ?, I ?, I ?, K ⁶ , K ⁷ , K ⁸ and K ⁹ are indicated in π. 1 values. 3. Carboxamide compounds according to claim 1, characterized in that the fragment K ² represents a group of one of the following subformulas: - 118012834 where one or more H atoms of the Q'QJ heterocycle formed by the group can be replaced by K ¹⁴ and the ring connected to the formed Ι <'ΐ < ² Ν heterocycle group can be mono- or multisubstituted at one or more C atoms the remainder K ²⁰ , and in the case of a phenyl ring can additionally also be monosubstituted by a nitro group, and K ¹³ , K ¹⁴ , K ²⁰ , K ²¹ and X have the meanings indicated in paragraph 1. 4. Carboxamide compounds according to one of the preceding paragraphs, selected from the group of compounds of formulas 04.14: - 119 012834 - 120 012834 where and ¹ , and ² , V ² independently from each other represent C or Ν; K ²³ , K ²⁴ independently represent Η, P, methyl or trifluoromethyl; K, K, K independently of one another have one of the meanings indicated for K in clause 1 or, in the case of a phenyl group, can also denote a nitro group, while the repeatedly present residues K ²⁵ , K ²⁶ , K ²⁷ can have identical or different values; ΐ is 0, 1, 2, 3, or 4; t, η are independently 0, 1 or 2 and L ¹ , L ² , L ³ , K ¹ , K ² , K ³ , K ⁶ , K ⁷ , K ⁸ , K ⁹ , K ²⁰ and X have the meanings indicated in paragraph 1. 5. Carboxamide compounds according to one of the preceding paragraphs, characterized in that they are in which B is selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkenyl-C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₃ alkenyl and C ₃ -C ₇ cycloalkyl C ₁ -C ₃ alkynyl, where one or more C-atoms can be mono- or multisubstituted with halogen and / or monosubstituted with a hydroxy or cyano group and / or cyclic groups can be mono- or multisubstituted with a K ²⁰ residue, and k, \, and ² , V ² , K ²³ , K ²⁴ , K ²⁶ , K ²⁷ , t, η, b ¹ , b ² , b ³ , K ¹ , K ² , K ³ , K ⁶ , K ⁷ , K ⁸ , K ⁹ , K ²⁰ and X have the meanings indicated in clause 4. 6. Carboxamide compounds according to claim 4 or 5, characterized in that each of and and V denotes a C-atom. 7. Carboxamide compounds according to one of claims 4 to 6, characterized in that X is —CH ₂ -, —CH (CHe) - or —C (CHe) 2-. 8. Carboxamide compounds according to one of claims 4 to 6, characterized in that K ²⁵ , K ²⁶ , K ²⁷ independently represent P, C1, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, npropyl, isopropyl, methoxy group, difluoromethoxy group, trifluoromethoxy group, ethoxy group, npropoxy group or isopropoxy group, and in case of substitution of the phenyl group, may also denote a nitro group, while the repeatedly present residues K ²⁵ , K ²⁶ , K ²⁷ may have identical or different values; ] denotes 0, 1 or 2 and m, η independently from each other represent 0 or 1. 9. Carboxamide compounds according to one of the preceding paragraphs, characterized in that K ⁶ , K ⁷ , K ⁸ and / or K ^{9 are} independently H, methyl, trifluoromethyl, ethyl, isopropyl or npropyl, and K ⁶ and K ⁷ may also denote R. 10. Carboxamide compounds according to claim 1, selected from the group of compounds including: (1) 7- (4-chlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (2) 3- [2- (4-pyrrolidin-1 -ylmethylphenyl) ethyl] -7-p-tolyl-3H-quinazolin-4-one, - 121 012834 (3) 3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -7- (4-trifluoromethylphenyl) -3H-quinazolin-4-one, (4) 7- (4-methoxyphenyl) - 3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (5) 7- (3,4-dichlorophenyl) -3- [2- (4-pyrrolidin-1- ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (6) 7- (4-fluorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, ( 7) 7- (4-ethylphenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (8) 2-methyl-3- [2- (4- pyrrolidin-1-ylmethylphenyl) ethyl] -7- (4-trifluoromethylphenyl) -3H-quinazolin-4-one, (9) 2-methyl-3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -7 -p-tolyl-3H-quinazolin-4-one, (10) 7- (4-chlorophenyl) -2-methyl- 3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (11) 7- (4-chlorophenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -1H-quinazolin-2,4-dione, (12) 7- (4-chlorophenyl) -3- {2- [4 - ((8) -2-methoxymethylpyrrolidin-1-ylmethyl) phenyl] ethyl} - 3H-quinazolin-4-one, (13) 7- (4-chlorophenyl) -3- [2- (4-dimethylaminomethylphenyl) ethyl] -3H-quinazolin-4-one, (14) 7- (4-chlorophenyl) -3- [2- (4-piperidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (15) 7- (4-chlorophenyl) -3- [2- (4-morpholin-4-ylmethylphenyl ) ethyl] -3H-quinazolin-4-one, (16) 7- (4-chlorophenyl) -3- [2- (4-pyrrolidin-1-methylmethyl) ethyl] -3H-benzo [b] [1,2 , 3] triazin-4-one, (17) 5- (4-fluorophenyl) -2- [2- (4-pyrrolidin-1-ylmethylphenyl) these ] isoindol-1,3-dione, (18) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, (19) [2- (4-diethylaminomethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (20) [2- (4-piperidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (21) [2- (4-diethylaminomethylphenyl) 4'-methoxybiphenyl-4-carboxylic acid ethyl] amide, (22) [2- (4-diethylaminomethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid methylamide, (23) [2- (4-pyrrolidin-1- 4- (4-chlorophenyl) cyclohexanecarboxylic acid ylmethylphenyl) ethyl] amide, (24) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4-methylpheni amide piperidine-1-carboxylic acid, (25) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-chlorophenyl) -3,6-dihydro-2H-pyridine-1 carboxylic acid, (26) [ 4- (4-Chlorophenyl) piperidin-1-carboxylic acid 2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide, (27) [2- (4-pyrrolidin-1-ylmethylphenyl) propyl] 4'-chlorobiphenyl amide -4-carboxylic acid, (28) 4'-chlorobiphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethylbenzyloxy) amide, (29) 4-cyclohexyl-K- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (30) [2- (3-methoxy-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, (31) 7- (4-chlorophenyl) -3- { 2- [6- (4-me tylpiperazin-1-yl) pyridin-3-yl] ethyl} -3H-quinazolin-4-one, (32) {2- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (33) 7- (3-methoxyphenyl) -3- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -3H-quinazolin-4-one, (34) 4 - (4-oxocyclohexyl) -K- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (35) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4-cyclohexyl-1-cyclohexylcarboxylic acids, (36) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4-benzylpiperidin-1-carboxylic acid, (37) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4-cyclohexylpiperidine -1-carboxylic acid, (38) [2- (4-pyrrrh) 4- (4-chlorophenyl) piperazine-1-carboxylic acid olidin-1-ylmethylphenyl) ethyl] amide, (39) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4- (4-fluorophenyl) piperidine- amide 1-carboxylic acid, (40) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4- (4-methoxyphenyl) piperazine-1-carboxylic acid, (41) [2- (4-pyrrolidin-1- 4-phenylpiperidin-1-carboxylic acid ylmethylphenyl) ethyl] amide, (42) (4'-chlorobiphenyl-4-yl) - [3- (4-pyrrolidin-1-ylmethylphenyl) piperidin-1-yl] methanone, (43 ) [2-methyl-2- (4-pyrrolidin-1-ylmethylphenyl) propyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (44) [2- (4-pyrrolidin-1-ylmethylcyclohexyl) ethyl] amide 4 ' x lorbiphenyl-4-carboxylic acid, (45) 4-benzyl-Ν - [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (46) 4- (4-oxocyclohexylidenemethyl) -K- [2- (4 -pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (47) [2- (2-fluoro-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, (48) 5- (4 -chlorophenyl) -2- [2- (4-pyrrolidin-1-methylmethyl) ethyl] -2,3-dihydroisoindol-1-one, (49) 4-piperidin-1-yl-K- [2- (4- pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (50) 7- (4-chlorophenyl) -3- {2- [4- (4-hydroxy-4-phenylpiperidin-1-ylmethyl) phenyl] ethyl} -3H-benzo [b] [1,2,3] triazin-4-one, (51) 7- (4-chlorophenyl) -3- {2- [4- (3-azaspiro [5.5] undec-3-ylmethyl) phenyl] ethyl} -3H-quinazolin-4-one, (52) 7- (4-chlorophenyl) -3- {2- [4- (3-azaspiro [5.5] undec-3-ylmethyl) phenyl] ethyl} -3H- benzo [b] [1,2,3] tri- 122 012834 zin-4-one, (53) 7- (4-chlorophenyl) -3- {2- [4- (4-hydroxy-4-phenylpiperidin-1 -ylmethyl) phenyl] ethyl} -3H-quinazolin-4-one, (54) 7- (4-chlorophenyl) -3- (2- {4- [4- (pyridin-2-yloxy) piperidin-1-ylmethyl ] phenyl} ethyl) -3H-quinazolin-4-one, (55) 6- (4-chlorophenyl) -2- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] -2H-isoquinolin-1-one, (56) [2- (3-bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid, (57) [2- (3-methyl-4-pyrrolidin-1-ylmethylphenyl ) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (58) {2- [4- (1-ethylpiper idin-2-yl) phenyl] ethyl} 4'-chlorobiphenyl-4-carboxylic acid amide, (59) {2- [4- (4-acetylpiperazin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4 -carboxylic acid, (60) {2- [4- (2-azabicyclo [2.2.1] hept-5-en-2-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (61) {2- [4- (1,3-Dihydroisoindol-2-ylmethyl) phenyl] ethyl} amide of 4'-chlorobiphenyl-4-carboxylic acid, (62) (2- {4 - [(diisopropylamino) methyl] phenyl} ethyl ) 4'-chlorobiphenyl-4-carboxylic acid amide, (63) {2- [3-bromo-4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} 4'-chlorobiphenyl-4-carboxylic acid amide , (64) {2- [4- (2-dimethylaminomethylpyrrolidin-1-ylmethyl) phen yl] ethyl} 4'-chlorobiphenyl-4-carboxylic acid amide, (65) {2- [4- (3-dimethylaminopyrrolidin-1-ylmethyl) phenyl] ethyl} 4'-chlorobiphenyl-4-carboxylic acid amide, (66 ) [2- (2-bromo-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, (67) 4-pent-1-vinyl-Y- [2- (4-pyrrolidine -1-methylmethylphenyl) ethyl] benzamide, (68) [2- (6-pyrrolidin-1-ylmethylpyridin-3-yl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid, (69) [2- (1- pyrrolidin-1-ylindan-5-yl) ethyl] amide of 4'-chlorobiphenyl-4-carboxylic acid, (70) [2- (2-nitro-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl- 4-carboxylic acid, (71) [2- (4-pyrrolide n-1-ylmethylphenyl) ethyl] amide 2 ', 4'-dichlorobiphenyl-4-carboxylic acid, (72) {2- [4- (3-aminopyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl- 4-carboxylic acid, (73) {2- [4- (2-aminomethylpyrrolidin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (74) {2- [4- (2- methyl 2,6-diazaspiro [3.4] oct-6-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (75) [2- (5-pyrrolidin-1-ylmethylpyridin-2-yl) 4'-chlorobiphenyl-4-carboxylic acid ethyl] amide, (76) [4- (3-ethyl-4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chlorobiphenyl-4-carboxylic acid amide, (77) {2 - [4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl } 4'-bromobiphenyl-4-carboxylic acid amide, (78) 4- (5-chlorothiophen-2-yl) -Y- [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] benzamide, (79) [2 - (2-methyl-4-pyrrolidin-1-ylmethylphenyl) ethyl] amide 4'-chlorobiphenyl-4-carboxylic acid, (80) {2- [3-bromo-4- (2,5-dihydropyrrol-1-ylmethyl ) phenyl] ethyl} 4'-bromo-3-fluorobiphenyl-4-carboxylic acid amide, (81) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chloro-2-fluorobiphenyl-4-carboxylic amide acids, (82) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-ethylbiphenyl-4-carboxylic acid amide, (83) tert-butyl ether [1- (4- {2 - [(4 ' -chlorobiphenyl-4-carbonyl) amino] ethyl} benzyl) pyrrolidin-2ylmethyl] car amino acid, (84) {2- [4- (2-methylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (85) {2- [4- (2-methylpyrrolidine- 4'-chlorobiphenyl-4-carboxylic acid 1-ylmethyl) phenyl] ethyl} amide, (86) (2- {4 - [(cyclopropylmethylamino) methyl] phenyl} ethyl) 4'-chlorobiphenyl-4-carboxylic acid amide, ( 87) {2- [4- (3,4-dihydro-1H-isoquinolin-2-ylmethyl) phenyl] ethyl} amide of 4'-chlorobiphenyl-4-carboxylic acid, (88) [2- (4- {[( 4'-chlorobiphenyl-4-carboxylic acid 2-hydroxyethyl) methylamino] methyl} phenyl) ethyl] amide, (89) [1- (4- {2 - [(4'-chlorobiphenyl-4-carbonyl) tert-butyl ester amino] ethyl} benzyl) pyrrolidin-3yl] arbamic acid, (90) {2- [4- (2,6-dimethylpiperidin-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (91) [2- (4-azetidin-1 4'-chlorobiphenyl-4-carboxylic acid-methylmethyl] amide, (92) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 3,4'-dichlorobiphenyl-4-carboxylic acid amide, (93) [ 4'-fluorobiphenyl-4-carboxylic acid 2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide, (94) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] 4'-chloro-3-fluorobiphenyl amide -4-carboxylic acid, (95) [2- (4-pyrrolidin-1-ylmethylphenyl) ethyl] amide of 2'-fluoro-4'-chlorobiphenyl-4-carboxylic acid, (96) [2- (4-pyrrolidin- 1-ylmethylphenyl) these l] 5- (4-chlorophenyl) pyridine-2-carboxylic acid amide, - 123 012834 (97) {2- [4- (2,5-dihydropyrrol-1-ylmethyl) phenyl] ethyl} amide 4'-chlorobiphenyl-4-carboxylic acid, (98) [2- (4-pyrrolidin-1 4'-bromobiphenyl-4-carboxylic acid-methylmethylphenyl) -amide and (99) {2- [4- (1-pyrrolidin-1-yl-ethyl) phenyl] ethyl} -amide of 4'-chlorobiphenyl-4-carboxylic acid. 11. Carboxamide compounds of claim 10, selected from the group of compounds (1) to (30), (47) and (50) to (99). 12. A method of producing carboxamide compounds of the formula I in which A, B, ^, X, Υ, Ζ, K ¹ , K ² , K ³ and k have one of the meanings indicated for them in paragraph 1, which consists in the fact that for case A, when the remainder of K ^{3 is} not connected to group A: a) in the case where A represents a nitrogen-containing heterocyclic group connected through a nitrogen atom to a carboxamide group, which along with the nitrogen atom may also contain one or other heteroatoms selected from Ν, O and 8, at least one amine of the formula H1, ζ ^χ \ ζ ^ζ \ k — Ν Υ Ν-n 1-1, in which K ¹ , K ² , K ³ , X, Υ and Ζ have the above meanings, are exposed in a solvent or mixture of solvents in the presence of at least one bases for reaction with CDT (1,1'-carbonyldi (1,2,4-triazole)) and at least one secondary amine of the formula H2 dA - ^ - to ^{6 1_2} 'in which A, B and k have the abovementioned meanings and the group A contains as the functional group secondary amine, and b) in other cases, at least one carboxylic acid of the formula H3 About d NS) A-D / -Dv 1-3, in which A, B, and k have the above meanings, are subjected to interaction with TBTU (2- (1H-benzotriazole- tetrafluoroborate) in a solvent or mixture of solvents in the presence of at least one base 1-yl) -1,1,3,3-tetramethyluronium) and at least one amine of the formula H1 X / ^ζ \ K ¹ —Ν Υ Ν-Η 1-1, K ² to ³ in which K ¹ , K ² , K ³ , X, Υ and Ζ have the above meanings; for case B, when the remainder K ^{3 is} connected to group A: a) in case the group O is —SK ⁶ K ⁷ - (Sha), where K ⁶ and K ⁷ have the above meanings, an amine of the formula Ы. 1 in which K ¹ , K ² , X, Υ and Ζ have the above meanings, are reacted with an o-bromomethylbenzoic acid ester derivative of the formula Y.2 in which K ⁶ , K ⁷ , ^, B and k have the above meanings, b) if the group O denotes -SK ⁶ = CK ⁷ - (SH), where K ⁶ and K ⁷ have the above meanings, the isoquinolinone derivative of the formula - 124 012834 ρ ⁷ in which K ⁶ , K ⁷ , Ψ, B and k have the above meanings, are reacted with an electrophilic compound of the formula TB.3 in which Υ and Ζ have the above meanings, and OM3 represents an acceptable leaving group , preferably mesylate, to give an isoquinoline derivative of formula TB. 4 1 b. 4, in which K ⁶ , K ⁷ , Ψ, B, Υ, Ζ and k have the above meanings, and then this isoquinoline derivative of the formula TB.4 is derivatized by known methods to a compound of the formula I, c) in case the group P denotes G = CK ⁸ - (Cc), where K ⁸ has the above meanings, the phthalazinone derivative of formula 04 O in which K ⁸ , Ψ, B, and k have the above meanings, are reacted with an electrophilic compound of formula 05 in which Υ And Ζ have the above meanings, and OM3 represents an acceptable leaving group, preferably mesylate, to obtain a phthalazinone derivative of formula 0.6 to ⁸ in which K ⁸ , Ψ, B, Υ, Ζ and k have the above meanings, and then the phthalazinone derivative of formula 06 obtained in this way is derivatized by known methods to a compound of formula I in which P is G = CK ⁸ - (C ), d) if the group P denotes -Ν = Ν- (PO), the o-aminobenzamide derivative of the formula 0.1 in which K ¹ , K ² , Ψ, B, X, Υ, Ζ and k have the above meanings, turn into the presence of an acceptable nitrite and acid in a compound of formula I in which P is —Ν = Ν-, d) in the case where the group P is —SOF ⁹ - (Sch), where K ⁹ has the above meanings, the oaminobenzamide derivative of the formula 01 O in which K ¹ , K ² , K ⁹ , Ψ, B, X, Υ, Ζ and k have the above meanings, - 125 012834 is converted in the presence of CDI (carbonyldiimidazole) to a compound of formula I in which C) is —ίΌ-ΝΧ ⁹ -, f) if the group O denotes —CB ⁸ = № ((Ш), where B ⁸ has the above meanings, the oaminobenzamide derivative of the formula £ O in which B ¹ , B ² , ^, B, X, Υ, Ζ and k have the above meanings, are reacted with carboxylic acid B ⁸ COOH, where B ⁸ has the above meanings, and / or with the corresponding activated carbon derivative acid to obtain a quinazolinone derivative of the formula I, in which C) is —CB ⁸ = N, g) in case the group O is -CO- (III), the isobenzofurandion derivative of the formula ^ .2 in which ^, B and k have the above meanings, are reacted with an amine of the formula ^ .1 K ¹ ζ \ Ζ ^ΝΗ * 18.1, X ^χ ζ in which B ¹ , B ² , X, Υ and Ζ have the above meanings, to give a compound of formula I in which C) is —CO—. 13. Physiologically compatible salts of carboxamide compounds according to one of claims 1 to 11. 14. A composition comprising at least one carboxamide compound according to one of claims 1 to 11 and / or a salt according to claim 13 and optionally one or more physiologically compatible excipients. 15. A medicament containing at least one carboxamide compound according to one of claims 1 to 11 and / or a salt according to claim 13 and optionally one or more inert carriers and / or diluents. 16. The use of at least one carboxamide compound according to one of claims 1 to 11 and / or a salt according to claim 13 for influencing the nutritional behavior of a mammal. 17. The use of at least one carboxamide compound according to one of claims 1 to 11 and / or the salt of claim 13 to reduce body weight and / or to prevent an increase in body weight of a mammal. 18. The use of at least one carboxamide compound according to one of claims 1 to 11 and / or a salt according to claim 13 for the preparation of a medicament with antagonistic activity with respect to the MCH receptor. 19. The use of at least one carboxamide compound according to one of claims 1 to 11 and / or a salt according to claim 13 for the manufacture of a medicament suitable for the prophylaxis and / or treatment of conditions and / or diseases caused by MCH or consisting of another causal Relations with SIT. 20. The use of at least one carboxamide compound according to one of claims 1 to 11 and / or the salt of claim 13 for the manufacture of a medicament suitable for the prevention and / or treatment of metabolic disorders and / or eating disorders, primarily obesity, bulimia nervosa, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia. 21. The use of at least one carboxamide compound according to one of claims 1 to 11 and / or the salt of claim 13 for the manufacture of a medicament suitable for the prophylaxis and / or treatment of obesity-related diseases and / or disorders, especially diabetes, mainly type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, brain hemorrhage, heart failure, cardiovascular disease timetotal, particularly arteriosclerosis and high blood pressure, arthritis and drives. 22. The use of at least one carboxamide compound according to one of claims 1 to 11 and / or the salt of claim 13 for the manufacture of a medicament suitable for the prophylaxis and / or treatment of hyperlipidemia, panniculitis, fat deposition, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, fears, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, various - 126 012834 forms of dementia and hormonal disorders. 23. The use of at least one carboxamide compound according to one of claims 1 to 11 and / or the salt of claim 13 for the manufacture of a medicament suitable for the prophylaxis and / or treatment of urination disorders, for example, urinary incontinence, bladder hyperactivity, peremptory urges for urination, nocturia and / or enuresis. 24. A pharmaceutical composition comprising a first active substance selected from carboxamide compounds according to one of claims 1 to 11 and / or salts according to item 13, as well as a second active substance selected from the group comprising active substances for treating diabetes, active substances for the treatment of diabetic complications, active ingredients for the treatment of obesity, preferably different from MCH antagonists, active ingredients for the treatment of hypertension, active ingredients for the treatment of hyperlipidemia, including arteriosclerosis , active substances for the treatment of arthritis, active substances for the treatment of fear and active substances for the treatment of depression, and optionally one or more inert carriers and / or diluents.