EA008060B1 - Chemokine receptor antagonists and methods of use thereof - Google Patents

Abstract

Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by: formula (1)

Description

Chemically attracting (chemoattractants) cytokines or chemokines are a family of mediators that precede inflammation, which contribute to the restoration and activation of complex gene sequences of leukocytes and lymphocytes. They can be secreted in many types of tissue cells after activation. The continuous release of chemokines at the sites of inflammation is an intermediate link in the developing migration of effector cells in chronic inflammation. The chemokines described so far are linked into a primary structure. They distribute four stored cysteines that form disulfide bonds. Based on this stored cysteine motif, this family is divided into two main lines, designated as C-XC chemokines (alpha chemokines) and C-C chemokines (beta chemokines), in which the first two stored cysteines are separated by an intermediate or adjacent residue, respectively (Vaddyunsh M., EaYpbep S.A., 1thodiood Tobau, νοί. 15, pp. 127-133 (1994)).

C-X-C-chemokines contain a number of potent chemo-attractants and neutrophil activators, such as interleukin 8 (1L-8), β-4 and neutrophil-activating peptide-2 (β-2). C-C chemokines include ΚΑΝΤΕ8 (Regulated upon Activation, Normally T-Expressed and Secreted), macrophage inflammatory proteins 1α and 1β (ΜΙΡ-1α and ΜΙΡ-1β), eotaxin and monocytic chemotactic proteins (MCP) of human 1-3 (MCP) -1, MCP-2, MCP-3), which were characterized as chemo-attractants and activators of monocytes or lymphocytes, but, apparently, they are not chemo-attractants for neutrophils. Chemokines, such as ΡΑΝΤΕ8 and ΜΙΡ-1α, are involved in a wide range of acute and chronic inflammatory diseases in humans, including respiratory diseases such as asthma and allergic disorders.

Chemokine receptors are members of the superfamily of receptors with a paired C-protein (SRS), in which structural signs are distributed that reflect the general mechanism of action of signal transduction (Segagb S., Segagb лии., Aliya Ret. 1ptipo1., 12, pp. 775-808 ( 1994); Segagb S, Segagb Ν., Sigg. Ορίη. 1tipo1., 6, pp 140-145 (1994)). Preserved traits include seven hydrophobic regions spanning plasma membranes that are joined by hydrophilic extracellular and intracellular loops. Most of the primary homologous sequence occurs in hydrophobic intermembrane regions, with hydrophilic regions being more diverse. The first receptor for C-Schemokines, which was subjected to cloning and expression, binds ΜΙΡ-1α and ΡΑΝΤΕ8. Accordingly, this ΜΙΡ-1α / ΡΑΝΤΕ8 receptor was designated as the C-C chemokine receptor 1 (also called CCP-1; Noo! E e! A1., Ce11, 72, pp. 415-425 (1993); Nogik and al., \\ 'O 94/11504, 05.26.94; Cao 1. e! a1., 1. Exp. Meb., 177, pp. 1421-1427 (1993)). Three receptors have been characterized that give a connection and / or an impulse in response to ΚΑΝΤΕ8: CCP3 mediates the binding or transmission of a chemokine impulse, including eotaxin, ΚΑΝΤΕ8 and MCP-3! A1., 1. Exp. Meb., 183, p. 2437 (1996)), SSR4 binds chemokines, including ΚΑΝΤΕδ, ΜΙΡ-1α and MCP-3 photo e! A1., 1. Vu1. Siet., 270, pp. 194-95, 1995)) and CCK5 binds chemokines including ΡΑΝΤΕδ, ΜΙΡ-1α and ΜΙΡ-1β (Zatzop e! A1., Vuyet. 35, pp. 3362-3367 (1996)). ΚΑΝΤΕ8 is a chemotactic chemokine for a variety of cell types, including monocytes, eosinophils, and a subset of T cells. The response of these different cells cannot always be transmitted by the same receptor, and it is possible that for the CK1, CCP4 and CK5 receptors, a certain selectivity will be detected in the distribution and functioning of the receptor between the types of leukocytes, as has already been demonstrated for CCP3, etc.). In particular, the ability of ΚΑΝΤΕ8 to induce directed migration of monocytes and a memory population of circulating T cells (§111 T. e! A1. No. 11ige. 347, 66971 (1990)) suggests that this chemokine and its receptor (receptors) can play crucial role in chronic inflammatory diseases, as these diseases are characterized by destructive T-cell and monocyte infiltrates.

Many existing drugs have been developed as receptor antagonists for biogenic amines, such as dopamine and histamine receptor antagonists. However, effective receptor antagonists have not been developed for larger proteins such as chemokines and C5a. Small molecules of antagonists of the interaction between C-C chemokine receptors and their ligands, including ΡΑΝΤΕ8 and ΜΙΡ-1α, could provide compounds suitable for inhibiting the harmful inflammatory processes triggered by the interaction of receptor ligands, as well as a valuable “tool” (probe) for studies of receptor-ligand interactions.

SUMMARY OF THE INVENTION

It has been found that a class of small organic molecules that are antagonists of the action of the chemokine receptor and can inhibit the activation and / or restoration of leukocytes. The chemokine receptor antagonist is a molecule that can inhibit the binding and / or activation of one or more chemokines, including C-C chemokines, such as ΚΆΝΤΕ8, ΜΙΡ-1α, MCP-2, MCP-3, and MCP- 4, with one or more chemokine receptors on white blood cells and / or other types of cells. As a result, these small organic molecules can inhibit the processes and cellular responses transmitted by chemokine receptors. Based on this finding, a method is described for treating a disease associated with impaired recovery and / or activation of white blood cells, as well as a method for treating a disease transmitted through the action of a chemokine receptor. This method involves administering to a needy subject an effective amount of a compound or small organic molecules that are antagonists of the chemokine receptor. Compounds or small organic molecules for which it has been found that they are antagonists of the chemokine receptor are discussed in detail below, and they can be used to manufacture drugs for the treatment or prevention of a disease associated with impaired recovery and / or activation of leukocytes. In one embodiment of the invention, a compound having the formula

or its physiologically acceptable salt, in which Ζ, η, Μ, K ⁷⁰ , K ⁷¹ , K ⁷² and K ⁷³ are as described in the application.

This invention also relates to the described compounds or small organic molecules used in the treatment or prevention of a disease associated with impaired recovery and / or activation of white blood cells. The invention also includes pharmaceutical compositions containing one or more compounds or small organic molecules for which it has been found to be antagonists of the chemokine receptor, and a suitable pharmaceutical carrier. The invention additionally relates to new compounds that can be used to treat a patient with a disease associated with impaired recovery and / or activation of leukocytes, and methods for their preparation.

Brief Description of the Drawings

FIG. 1 is a diagram for preparing compounds represented by structural formula (I).

FIG. 2 is a diagram for the preparation of compounds represented by compound (Y1-b).

FIG. 3 is a diagram for preparing compounds represented by structural formula (I).

FIG. 4 is a diagram of the preparation of compounds represented by structural formula (I), in which the group Ζ is represented by the structural formula (III) and in which ring A and / or ring B in Ζ is substituted with m> 40 by radical K.

FIG. 5 is a diagram of the preparation of compounds represented by structural formula (I), in which group Ζ is represented by structural formula (III) and in which ring A and / or ring B in Ζ is substituted by groups - (O) _and - (CH2) ₁ -COOC ²⁰ , - (O) u - (СН2) 1-ОС (О) К ²⁰ , - (О) and - (СН2) gС (ОЖ ²¹ К ²² or - (О) _and - (СН2) ^ НС (О) О -K ²⁰ .

FIG. bA-όΖ illustrate examples of structures of the compounds of the present invention.

FIG. 7 illustrates the preparation of compounds represented by structural formula (I) in which group Ζ is represented by structural formula (III) and in which ring A or ring B in Ζ is substituted with K ⁴⁰ .

FIG. 8A is a diagram for the preparation of 4- (4-chlorophenyl) -4-fluoropiperidine.

FIG. 8B is a diagram for preparing 4-4-azido-4- (4-chlorophenyl) piperidine.

FIG. 8C is a diagram for the preparation of 4- (4-chlorophenyl) -4-methylpiperidine.

FIG. 9A is a diagram for preparing compounds represented by structural formulas (I), (VIII) and (VIII), in which K ¹ represents an amine.

FIG. 9B is a diagram for preparing compounds represented by structural formulas (I), (VIII) and (VIII) in which K ¹ is an alkylamine.

FIG. 9C — Scheme for the preparation of 2- (4-chlorophenyl) -1- (No. methyl) ethylamine.

FIG. 9Ό is a scheme for the preparation of 3- (4-chlorophenyl) -3-chloro-1-hydroxypropane.

FIG. 9E is a diagram for the preparation of 3- (4-chlorophenyl) -1- (No. methyl) aminopropane.

FIG. 10A is a diagram for the preparation of 3- (4-chlorophenyl) -3-hydroxyl-3-methyl-1-no. Methylaminopropane.

FIG. 10B is a schematic for the preparation of 1- (4-chlorobenzoyl) -1,3-propylene diamine.

FIG. 10C is a diagram of the preparation of compounds represented by structural formulas (I), (VII), (VIII), (IX) and (XI), in which group Ζ is represented by structural formula (III) and in which ring A and / or ring B in Ζ substituted by the radical K ⁴⁰ . For FIG. 10C, the radical K ⁴⁰ represents a group - (O) _and (CH ₂ ) _g C (O ^ K ²¹ K ²² , and is equal to unity, and ΐ is equal to zero.

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FIG. 10Ό is a scheme for the preparation of 4- (4-chlorophenyl) -4-pyridine.

FIG. 11A-11T illustrate examples of structures of compounds of the present invention.

FIG. 12 is a diagram for preparing compounds of formula (νΐ-c).

FIG. 13 is a diagram for preparing compounds of the formula (νΐ-e).

FIG. 14 is a schematic of the preparation of compounds in Examples 434 and 435.

FIG. 15 is a schematic of the preparation of compounds in Examples 436-438.

FIG. 16 is a diagram for preparing compounds of formula (формулы-ί).

FIG. 17 is a schematic of the preparation of compounds in Examples 441 and 442.

FIG. 18 is a schematic of the preparation of the compound in Example 443.

FIG. 19 is a schematic of the preparation of compounds in Examples 315, 455, 338, and 446.

FIG. 20-28 illustrate examples of structures of compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds - small molecules that are modulators of the action of the chemokine receptor. In a preferred embodiment of the compound, the small molecules are antagonists of the chemokine receptor. Accordingly, the processes or cellular responses transmitted by binding of the chemokine to the receptor can be inhibited (weakened or prevented, in whole or in part), including leukocyte migration, integrin activation, a transition process of an increase in the concentration of intracellular free calcium [Ca ⁺⁺ ] ₁ , and / or granular release of mediators preceding inflammation.

The invention also relates to a method of treatment, including prophylactic and therapeutic treatment, diseases associated with impaired recovery and / or activation of leukocytes, or transmitted by chemokines, or by the action of a chemokine receptor, including chronic inflammatory disorders, which are characterized by the presence of ΚΑΝΤΕ8, ΜΙΡ-1α, MCP- 2, MCP-3 and / or MCP-4 sensitive T cells, monocytes and / or eosinophils, including but not limited to diseases such as arthritis (e.g., rheumatoid arthritis), atherosclerosis, arteriosclerosis, p estenosis, ischemic / reperfusion injury, diabetic mellitus (e.g. type 1 diabetic mellitus), psoriasis, multiple sclerosis, inflammatory diseases of the intestinal tract, such as ulcerative colitis or granulomatous disease, rejection of transplanted organs and tissues (e.g., acute allogeneic transplant rejection, chronic allogeneic transplant rejection), transplant versus host reaction, as well as allergic diseases and asthma. Other diseases associated with impaired recovery and / or activation of white blood cells that can be treated (including prophylactic treatment) by the methods described in this invention are inflammatory diseases associated with infection of the human immunodeficiency virus (HIV), for example, encephalitis associated with acquired immune deficiency (AIDS) AIDS-related macropapular skin rash, AIDS-related interstitial pneumonia, AIDS-related bowel disease, AIDS-related imported liver inflammation and AIDS-related glomerular nephritis. This method comprises administering to a subject in need of treatment an effective amount of a compound (i.e., one or more compounds) that are inhibitors of the chemokine receptor, inhibit chemokine binding to leukocytes and / or other types of cells, and / or which inhibit leukocyte migration and / or their activation in the area of inflammation.

The present invention also relates to methods for antagonizing a chemokine receptor, such as CCK1, in a mammal, which comprise administering to the mammal a compound as described in this invention.

In accordance with this method, it is possible to inhibit chemokine-transmitted chemotaxis and / or activation of inflammatory cells preceding inflammation carrying chemokine receptors. The expression used here prior to inflammation of the cells includes, but is not limited to leukocytes, since chemokine receptors can be expressed on other types of cells, such as neurons and epithelial cells.

Despite the reluctance to associate itself with any particular theory or mechanism of action, it is assumed that the compounds of the invention are antagonists of the CCK1 chemokine receptor and that the therapeutic benefits obtained from the method of the invention are the result of antagonism of the action of the CCK.1 receptor. Thus, the method and compounds of this invention can be used to conservatively treat a condition that includes cells on the surface of which CCK1 is expressed and that respond to signals transferred through CCK1, as well as the specific conditions listed above.

In one embodiment, the chemokine receptor antagonist is represented by the structural formula (ΐ)

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(I) and its physiologically acceptable salts, where Ζ is a cycloalkyl or non-aromatic group of a heterocyclic ring fused with one, two or more aromatic rings, each ring in Ζ is independently substituted or unsubstituted, η is an integer from 1 to 4. Preferably , η is 1, 2 or 3. More preferably, η is 2. In alternative embodiments, instead of the group (CH ₂ ) _P , other aliphatic or aromatic space groups (b) - spacers can be used.

Group M represents> ΝΚ ² or> SK ¹ K ² . Preferably M is a group> C (OH) K ² .

The radical K ¹ is a hydrogen atom, a —OH, —Ν ₃ group, a halogen atom, an aliphatic group substituted with an aliphatic group, an aminoalkyl group, —O— (an aliphatic group), —O (substituted an aliphatic group), -811, -8- (aliphatic group), -8- (substituted by an aliphatic group), -ОС (О) - (by an aliphatic group), -ОС (О) - (substituted by an aliphatic group), -С (О) О (by an aliphatic group), -С (O) O- (substituted by an aliphatic group), -COOH, -CH -№ΝΚ ³ Κ ⁴ , -ΝΚ ³ Κ ⁴ ; or K ¹ may be a covalent bond between a ring atom in group M and an adjacent carbon atom in a ring that contains M. Preferably K ¹ is a hydrogen atom or an —OH group.

The radical K ² is a hydrogen atom, a —OH group, a halogen, an acyl group substituted by an acyl group, —ΝΚ ⁵ Κ ⁶ , an aliphatic group substituted by an aliphatic group, an aromatic group substituted by an aromatic group, a benzyl group substituted by a benzyl group, a nonaromatic heterocyclic group substituted by a non-aromatic heterocyclic group, —O— (substituted or unsubstituted aromatic group), or —O— (substituted or unsubstituted aliphatic group), or —C (O) - (substituted or unsubstituted aromatics group), or C (O) - (substituted or unsubstituted aliphatic group). Preferably, K ² represents an aromatic group or a substituted aromatic group.

The substituents K ³ , K ⁴ , K ⁵ and K ⁶ are independently a hydrogen atom, an acyl group substituted by an acyl group, an aliphatic group substituted by an aliphatic group, an aromatic group substituted by an aromatic group, a benzyl group substituted by a benzyl group, a non-aromatic heterocyclic group or substituted non-aromatic heterocyclic group.

The substituents K ¹ and K ² , K ³ and K ^4, or K ⁵ and K ⁶ , taken together with the atom to which they are attached, can alternatively form a substituted or unsubstituted, non-aromatic carbocyclic or heterocyclic ring.

In embodiments in which M is a group> SK ¹ K ² and K ¹ is a covalent bond between a carbon atom in group M and an adjacent carbon atom in a ring that contains M, a chemokine antagonist can be represented by structural formula (1a)

(1a) where Ζ, η, and K are as described in structural formula (I).

In one preferred embodiment, Ζ is a tricyclic ring system containing two carbocyclic aromatic groups fused to a 6-, 7- or 8-membered cycloalkyl group or to a non-aromatic heterocyclic ring. In one example, Ζ pre-

The phenyl rings in structural formula (II) labeled A and B are referred to in this invention as ring A and ring B, respectively. A central ring labeled C is called a C ring, and may be, for example, a 6-, 7- or 8-membered non-aromatic carbocyclic ring (e.g., a cycloheptane or cyclooctane ring) or a non-aromatic heterocyclic ring. When ring C is a non-aromatic heterocyclic ring, it may contain one or

- 4 008060 two heteroatoms, such as nitrogen, sulfur or oxygen. When Ζ is represented by structural formula (II), the tricyclic ring system can be connected to the rest of the molecule by a covalent double bond between the carbon atom in ring C and the carbon atom that is bonded to Ζ, as shown in structural formula (I).

Ring A and / or ring B in structural formula (II) may be unsubstituted. Alternatively, ring A and / or ring B may have one or more substituents. Suitable substituents are described below. In one example, ring A or ring B is substituted by the group - (O) _and - (CH ₂ ) _G C (O) OK ²⁰ , - (O) and (CH2) 1-OC (O) K ²⁰ , - (O), -1С117-С (О) - \ | + to ²² or - (О) и- (СН2) 1-ННС (О) ОК ²⁰ , and is equal to zero or one, I is an integer from zero to about 3, and the methylene group - (CH2) _G may be substituted or unsubstituted as described herein for aliphatic groups.

The substituents K ²⁰ , K ^21, or K ^{22 are} independently a hydrogen atom, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group. Alternatively, K ²¹ and K ²² taken together with the nitrogen atom to which they are bonded can form a non-aromatic heterocyclic ring.

Ring C optionally contains one or more substituents, which are described below.

Examples of suitable tricyclic ring systems, Ζ, are represented by structural formula (III)

Ring A and ring B in structural formula (III) are as described for structural formula (II).

The group X ₁ is a bond, -O-, -8-, -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -8, -8-CH ₂ -, -O-CH ₂ -, - CH ₂ -O-, - \ Vs-CH2-, -CH2- \ Vs-, -8O-CH2-, -CH2-8O-, -8 (O) 2-CH2-, -CH ₂ -8 (O) 2, -CH = CH-, - \ K _with -CO or -CO- \ Kc-. Preferably, X ₁ is —CH ₂ —O—, —CH ₂ —CH ₂ -, —CH ₂ —8—, - | K _with —CO, or —CO— | K _with -.

The radical K _c is a hydrogen atom, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.

In one example, K represents a group - (SND-COOK ³⁰ , - (CH2) 8-C (O) - \ K ³¹ K ³² or - (CH2) § \ HC (O) -O-K ³⁰ , in which § is a goal number from 1 to about 3.

o / \ o 1 -ep

The substituents K, K and K are independently a hydrogen atom, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group. Alternatively, K ³¹ and K ³² taken together with the nitrogen atom to which they are bonded form a non-aromatic heterocyclic ring.

Other examples of suitable tricyclic ring systems for Ζ include benzodiazepines, benzooxazepines, benzooxazines, phenothiazines and groups represented by the following structural formulas

In other preferred embodiments, Ζ is a tricyclic ring system containing two aromatic groups fused to a 7- or 8-membered cycloalkyl group or to a non-aromatic heterocyclic ring in which at least one aromatic group is a heteroaryl group. In one example, Ζ is represented by structural formula (IV)

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Ring A in structural formula (IV) may be a substituted or unsubstituted heteroaryl group. Ring B in structural formula (IV) may be a substituted or unsubstituted aromatic group, for example a heteroaryl group or a carbocyclic aryl group. Suitable substituents are described below. In one example, ring A and / or ring B is substituted by the group - (O) _and - (CH ₂ ) _G C (O) OK ²⁰ , - (O) and - (CH2) GOS (O) K ²⁰ , (O) and - (CH ₂ ) _G C (O) -YK ²¹ K ²² or - (O) C- (CH2) GYNS (O) O-K ²⁰ , as described above. The numbers and, ί and the substituents K ²⁰ , K ²¹ and K ²² are as described above. X1 and may be as described above for structural formula (III).

In another embodiment, настоящего is represented by structural formula (IV) wherein ring A is a pyridyl group and ring B is an aromatic or heteroaromatic group. In one example, Ζ is represented by the structural formula (GUa)

(1Ua).

In this embodiment, ring A and ring B are independently substituted or unsubstituted and preferably ring B is a phenyl group. Groups X ₁ and Kc may be as described above in structural formula (III).

In another embodiment, both ring A and ring B are pyridyl groups, and Ζ is represented by the structural formula (TUY)

(1YB)

Ring A and ring B may be independently substituted or unsubstituted, as described above, in structural formula (II), and group X ₁ may be as described above, in structural formula (III).

In other embodiments, Ζ is represented by structural formula (V)

Ring A and ring B may be independently substituted or unsubstituted, as described above, in structural formula (II), and group X ₁ may be as described above, in structural formula (III).

In particularly preferred embodiments, ring B in structural formula (V) is substituted in a para position relative to the carbon atom of ring B, which is bonded to group X ₁ in ring C,

Group X ₁ may be as described above in structural formula (II). Preferably, X ₁ is a —CH ₂ —O—, —CH ₂ —CH ₂ - or —CH ₂ -3— group.

Substituent K ⁴⁰ is as described below for aromatic groups. In one embodiment, K ⁴⁰ is an —OH, —COOH, —O ₂ group, a halogen atom, an aliphatic group substituted by an aliphatic group, an aromatic group substituted by an aromatic group, —YK. ²⁴ to ²⁵ ,

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-SOYK ²⁴ K ²⁵ , -Ο (= ΝΚ ⁶⁰ ) ΝΚ ²¹ Κ ²² , ^ - (aliphatic group), ^ - (substituted by an aliphatic group), -O- (aliphatic group), -O- (substituted by an aliphatic group), -O- (aromatic group), -O (substituted aromatic group), electron-withdrawing group or - (О) and- (СН2) ГС (О) О-К ²⁰ , - (О) and- (СН2) _Г ОС (О ) -K ²⁰ , K ²² , - (O) and- (CH2), - C (O) -F ²¹ K ²² or - (O) and- (CH2> ^ C (O) O-K ^{20 of} Group ς, K ²⁰ , K ²¹ , K ²² , K ²⁴ , K ²⁵ , K ⁶⁰ , and ΐ have the above meanings.

Preferably, K ⁴⁰ is an aliphatic group substituted with an aliphatic group, —O (aliphatic group) or —O— (substituted aliphatic group). In some embodiments, K ⁴⁰ is —O-alkyl, such as —O — CH ₃ , —O — C ₂ H ₅ , —O — C ₃ H ₇ , or —O — C ₄ H ₉ .

In another embodiment of the invention, K can be represented by the group - (O) _and - (CH ₂ ) _G C (O) ^ K K, in which and equal to 1, ΐ is zero, and K ²¹ and K ²² have the above values. In this embodiment, each K ²¹ and K ²² radical may independently be a hydrogen atom, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, or K ²¹ and K ²² taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted aromatic non-aromatic heterocyclic ring (e.g., pyrrolidine, piperidine, morpholine).

21 22

In another embodiment of the invention, K can be represented by the group - (O) _and - (CH ₂ ) _G C (O) -LK K, in which is equal to zero, ΐ is from 1 to 3, and K ²¹ and K ²² have the above values.

In another embodiment of the invention, the radical K ⁴⁰ may be represented by the group - (O) _and - (CH ₂ ) _G C (O) 0100 0100

ΝΓ K, in which and and ΐ are equal to zero, while K and K have the above meanings.

In another embodiment of the invention, K ⁴⁰ is an aliphatic group, for example methyl, ethyl, propyl, which is substituted with a group —XK ²⁴ K ²⁵ , or —SOKK ²⁴ K ²⁵ , in which K ²⁴ and K ²⁵ are as previously described. For example, K ⁴⁰ can be represented by γ

In another embodiment of the invention, K ⁴⁰ is a —O — C (O) —PK ²¹ K ²⁶ group, in which K ²¹ is as previously described, K ²⁶ may be a hydrogen atom, an aliphatic group substituted with an aliphatic group, an aromatic group substituted aromatic group, non-aromatic heterocyclic group, -C (O) -O- (substituted or unsubstituted aliphatic group), -C (O) -O (substituted or unsubstituted aromatic group), -8 (O) ₂ - (substituted or unsubstituted aliphatic group), -8 (O) ₂ - (substituted or unsubstituted aromatic group), or K ²¹ and K ²⁶ taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring.

In further embodiments, K ⁴⁰ may be a group -8 (O) ₂ ^ K ²¹ K ²² or -№C (O) 21 22 21 22

NK K, in which K and K are as previously described.

In a preferred embodiment, the chemokine receptor antagonist is represented by structural formula (I) in which η is three, M is —C (OH) K ² , K ² is a phenyl group or halo phenyl group (eg 4-chlorophenyl), and Ζ is structural formula (VI) in which X ₁ is a group —CH ₂ —O—. In one example of this embodiment, K ⁴⁰ may be —O— (substituted aliphatic), such as

In particularly preferred embodiments of the invention, K ⁴⁰ is

In other preferred embodiments, K ⁴⁰ is a substituted aliphatic group, a substituted aromatic group, an-O-substituted aliphatic group, or an-O-substituted aromatic group. Preferably, an aliphatic or aromatic fragment of a substituted aliphatic group, a substituted aromatic group, an —O-substituted aliphatic group, or

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The —O-substituted aromatic group has a substituent selected from the group consisting of —OH, —COOC, —P-aliphatic or a substituted P-aromatic group, wherein O is as described in the application. Preferably, O is a group —C (O) O—. For example, K ⁴⁰ may be a linear, branched or cyclic aliphatic group that contains from 1 to 6 carbon atoms, such as a C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, which is substituted with a —OH, —COOH, —C (O) O— (C1-C6 aliphatic) or —C (O) O— (aromatic) group.

In another embodiment of the invention, a chemokine activity antagonist may be represented by a compound of structural formula (VII)

and its physiologically acceptable salts, η — as described in structural formula (I), Ζ — as previously described, preferably as described in structural formula (V) or (VI), group M is> ΝΚ ² ,> SK ¹ K ² , —O — CK ¹ K ² —O— or —CH ₂ —CK ¹ K ² —O—, the radicals K ¹ and K ² are as described in structural formula (I), q ¹ is an integer from zero to about 3, and q ² is an integer from zero to unity. A ring containing M may be substituted or unsubstituted.

Thus, an antagonist of the action of the chemokine receptor can be represented, for example, by the structural formulas ^ Pa) - (UPC)

and their physiologically acceptable salts, in which Ζ, η and M are as described in structural formula (VII), and the ring containing M is substituted or unsubstituted. A ring containing a group M may have one or more suitable substituents that are the same or different. Suitable substituents for a ring that contains a group M and others

- 8 008060 non-aromatic heterocyclic rings are as described above. For example, a ring containing a group M may be substituted with methyl, ethyl, propyl, butyl or an oxo group.

When a ring containing a group M is substituted, the compound may be represented by structural formula (VIII)

or its physiologically acceptable salt.

The substituents K ⁷⁰ , K ⁷¹ , K ⁷² , K ⁷³ , K ⁷⁴ , K ⁷⁵ , K ⁷⁶ and K ⁷⁷ independently represent a hydrogen atom, —OH, —Ν ₃ , a halogen atom, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -O- (aliphatic group), -O- (substituted aliphatic group), -8H, -8- (aliphatic group), -8- (substituted aliphatic group), -OS (O) - (aliphatic group), -OS (O) (substituted aliphatic group), -C (O) O- (aliphatic group), -C (O) O- (substituted aliphatic group), -COOH, -CH, -CO-ChK ³ K ⁴ , -CHK ³ K ^4, an acyl group, a substituted acyl group, a benzyl group, a substituted benzyl group, a nonaromatic heterocyclic group, a substituted non-aromatic heterocyclic group, - (O) - (substituted or unsubstituted aromatic group), or any two substituents of R ^70, K ^71, K ^72, K ^73, K ^74, K ⁷⁵ , K ⁷⁶ and K ⁷⁷ , taken together with the atoms to which they are bonded, form a 3-8 membered ring.

The number η is as described in structural formula (I). Group Ζ is as described in the invention, preferably as described in structural formula (V) or (VI). Group M is as described in structural formula (VII), preferably M is> ChK ² or> SK ¹ K ² .

In some embodiments, the K ⁷⁴ , K ⁷⁵ , K ^76, and K ⁷⁷ radicals represent a hydrogen atom. In other embodiments, K ⁷⁴ , K ⁷⁵ , K ⁷⁶ and K ⁷⁷ represent a hydrogen atom and at least one of K ⁷⁰ , K ⁷¹ , K ⁷² and K ⁷³ is an aliphatic group or a substituted aliphatic group. Preferred aliphatic groups at K ⁷⁰ , K ⁷¹ , K ⁷² , K ⁷³ , K ⁷⁴ , K ⁷⁵ , K ⁷⁶ and K ⁷⁷ are C1-C6 alkyls, preferred substituted aliphatic groups are C1-C6 alkyl substituted with —OH, - ( O) u (CH 2) HS (O) OK ²⁰ or -O- (aliphatic group) in which I - integer from 0 to 3, and a is zero or one and R ²⁰ is C 1 C ₆ -alkyl. In more specific embodiments, the compound has the formula of structural formula (VIII) in which the radicals K ⁷⁰ , K ⁷¹ , K ⁷² , K ⁷³ , K ⁷⁴ , K ⁷⁵ , K ⁷⁶ and K ⁷⁷ are hydrogen atoms and at least one of K ⁷¹ and K ⁷² is methyl (—CH ₃ ).

In a preferred embodiment, the chemokine receptor antagonist is represented by structural formula (VIII) in which η is two; group M is> C (OH) K ² ; K ² is a halo phenyl group (e.g. 4-chlorophenyl); the radicals K ⁷² , K ⁷³ , K ⁷⁴ , K ⁷⁵ , K ⁷⁶ and K ⁷⁷ are hydrogen atoms, and K ⁷⁰ and K ⁷¹ independently are C1-C6 alkyl or substituted C1-C6 alkyl; or the radicals K ^72, K ^73, K ^74, K ^75, K ⁷⁶ and K ⁷⁷ are hydrogen atoms and R ⁷² and R ⁷³ are independently C 1 C ₆ alkyl or substituted C ₁ -C ₆ -alkyl; and group Ζ is represented by structural formula (VI) in which X ₁ represents —CH 2 O—.

When K ⁷² and K ^{73 are} each methyl, the compounds of this preferred embodiment may have the formula

P ²

or physiologically acceptable salts thereof are used in which K ² is 4-halo phenyl.

Preferably, K ^{2 is} selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4 fluorophenyl. Preferred groups at K ^{40 are} described in this invention. Particularly preferred groups at K ⁴⁰ are aliphatic groups (e.g., C ₁ -C ₆ alkyl) and substituted aliphatic groups.

In a particularly preferred embodiment, the compound is (8) an enantiomer of the compound of formula (XII) and has the structure

- 9 008060

(Xl) or a physiologically acceptable salt thereof, in which K ² is 4-halo phenyl. Particularly preferred compounds of the invention have the structure of formula (XIII) in which K ² is 4 chlorophenyl and K ^{40 is} selected from the group consisting of

In another embodiment, the compound represented by the structural formula (CS) (CH ₂ ) _H --- N or a physiologically acceptable salt thereof, in which p, K ¹ and K ² are as described in structural formula (I), and a group Ζ such as described in structural formula (V) or (VI).

In some embodiments, group Ζ is represented by structural formula (VI) in which X ₁ is —CH ₂ —O—; n is two, K ¹ is a hydrogen atom and K ² is -№K ⁵ K ⁶ . Preferably, in these embodiments, the compounds have a structure or physiologically acceptable salts thereof, in which K ⁵ and K ⁶ are as described in structural formula (I), and preferred K ⁴⁰ groups are as described in the invention.

In specific embodiments, K ⁵ is an aliphatic group (eg, C1-C6 alkyl) or a substituted aliphatic group, and K ⁶ is benzyl or substituted benzyl; or K ⁵ and K ⁶ taken together with the atoms to which they are attached form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring. In more specific embodiments, K ⁵ is C1-C ₆ -alkyl and R ⁶ is a halo benzyl. In a preferred embodiment, K ⁵ is ethyl and K ⁶ is chlorosubstituted benzyl (e.g. 4 chlorobenzyl).

The nitrogen atom in the ring that contains the M group may be a tertiary nitrogen atom as depicted in structural formula (IV), or the nitrogen atom may be quaternized with a suitable substituent, such as a substituted or unsubstituted aliphatic group having from about 1 to 6 carbon atoms or from about 1 to 3 carbon atoms. Compounds that contain a nitrogen atom may also contain a counter anion, such as chloride, bromide, iodide, acetate, perchlorate and

etc.

The chemokine receptor antagonist can be represented by structural formula (VII), in which a heterocyclic ring containing a group M is replaced by a suitable divalent group that is linked to two atoms in the ring, resulting in the formation of a bicyclic functional group. Suitable divalent groups include, for example, substituted or unsubstituted divalent aliphatic groups, such as C ₁ -C ₆ alkylene groups.

A chemokine receptor antagonist may contain a variety of bicyclic functional groups. In one embodiment, this chemokine receptor antagonist may be represented by structural formula (VIII)

- 10 008060

(VIII) and its physiologically acceptable salts.

Group M is> ΝΗ ² ,> SK ³ K ² , —O — SK ³ K ² O— or —CH ₂ —SK ³ K ² —O—. Preferably M is a group> ΝΗ ² or> SK ³ K ² . The substituents K ¹ and K ² are as described in structural formula (I), and η and Ζ are as described in structural formula (VII).

In another embodiment, the chemokine receptor antagonist is represented by structural formula (IX)

(Ix) and its physiologically acceptable salts.

Group Ζ is as described above, preferably as described in structural formula (V) or (VI).

η is an integer from 1 to about 4. Preferably, η is 1, 2 or 3. More preferably, η is 2. In other embodiments, other aliphatic or aromatic space groups (b) may be used instead of (CH ₂ ) _n .

Each of the substituents K ⁵⁰ and K ⁵¹ independently represents —H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —MK ³ K ⁴ , an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic a heterocyclic group or a covalent bond between a nitrogen atom and an adjacent carbon atom.

The substituents K ³ and K ⁴ independently represent —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.

The substituents K ³ and K ⁴ , taken together with the atom to which they are attached, can alternatively form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

In a preferred embodiment, K ⁵⁰ is a substituted aliphatic group, such as a substituted C1 to C12 alkyl group, and K ⁵¹ is —H or a substituted or unsubstituted aliphatic group. More preferably, K ⁵⁰ represents a substituted linear or branched aliphatic group from C2 to about C ₇ , in which one or more carbon atoms can be replaced by a heteroatom such as nitrogen, oxygen or sulfur, and K ⁵¹ represents —H or linear or a branched aliphatic group from C1 to about C6 or an aliphatic group having from about 1 to 3 carbon atoms, in which one or more carbon atoms can be replaced by a heteroatom. The radicals K ⁵⁰ and K ⁵¹ can be substituted by one or more suitable substituents, which are described in the description. An aromatic group is preferred (e.g., phenyl, 4-halo phenyl). For example, K ⁵⁰ may be selected from the group consisting of

On the activity of chemokine receptor antagonists represented by the structural formula

- 11 008060 (IX), the nature of the nitrogen atom to which the K ⁵⁰ and K ⁵¹ radicals are attached can affect. It is believed that compounds in which the specified nitrogen atom is basic may have potent chemokine receptor antagonist activity. It is known that the basicity of a nitrogen atom can be weakened when this nitrogen atom is bonded to a carbonyl group, a sulfonyl group or a sulfinyl group. Therefore, it is preferable that neither K ⁵⁰ nor K ⁵¹ contain a carbonyl group, a sulfonyl group or a sulfinyl group, which is directly bonded to a nitrogen atom.

On the other hand, the chemokine receptor antagonist appears to be structural formula (X) _

X

(X) and its physiologically acceptable salts.

The group Ζ is a cycloalkyl or a group of a non-aromatic heterocyclic ring fused with one, two or more aromatic rings in which each ring in Ζ is independently substituted or unsubstituted. Preferably, Ζ is as described in structural formula (VI).

η is an integer from 1 to about 4. Preferably, η is 1, 2 or 3. More preferably, η is 2. In other embodiments, other aliphatic or aromatic space groups (b) may be used instead of (CH ₂ ) _P.

Group M represents> ΝΚ ² or> SK ² .

The substituent K ² is —H, —OH, an acyl group substituted by an acyl group, —NoK? K ⁶ , an aliphatic group substituted by an aliphatic group, an aromatic group substituted by an aromatic group, a benzyl group substituted by a benzyl group, a non-aromatic heterocyclic group, substituted a non-aromatic heterocyclic group, —O— (substituted or unsubstituted aromatic group) or —O— (substituted or unsubstituted aliphatic group). Preferably, K ² is an aromatic group or a substituted aromatic group.

The substituents K ⁵ and K ⁶ independently are —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.

The substituents K ⁵ and K ⁶ , taken together with the atom to which they are attached, can alternatively form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

Group X ^- is a physiologically acceptable anion. Preferably, X ^- is C1 ^- or Br.

The chemokine receptor antagonist described herein can be prepared and administered to a patient as active compounds or as prodrugs. Typically, prodrugs are analogues of pharmaceutical agents that can undergo chemical transformation as a result of metabolic processes in order to acquire full activity. For example, a prodrug can be obtained from the corresponding groups for K ⁴⁰ . In one embodiment, the prodrug may be represented by structural formula (XI)

in which K ⁴⁰ represents a P-substituted aliphatic group, and the aliphatic group is substituted by the group - (O) _and - (CH ₂ ) _G C (O) OK ²⁰ , in which O represents -C (O) O-, and is equal to unit, ΐ is zero and K ²⁰ is a cyclic aliphatic group. For example, when a substituted aliphatic group is a substituted ethyl group, K ⁴⁰ may be represented by the formula

- 12 008060

Such a prodrug can be converted into an active chemokine receptor antagonist represented by structural formula (XI) in which K ⁴⁰ is a —COOH group.

Another embodiment of the present invention includes novel compounds that are used in these methods.

The compounds described in this invention can be obtained in the form of isomers with the E and Ζ configuration. It should be noted that this invention includes compounds with an E-configuration and a Ζ-configuration around a double bond connecting a ring C of group Ζ to the rest of the molecule, and a method for treating a subject with compounds with an E-configuration, Ζ-configuration and mixtures thereof. Accordingly, the structural formulas used in this invention use the% symbol to represent both the E-configuration and the Ζ-configuration. Preferably, ring A and the alkylene chain bonded to ring C are in a cis configuration. For example, connections can be configured

It is understood that compounds in one configuration may have greater activity than in another configuration. The desired configuration can be determined by screening the compounds for activity using the methods described here.

In addition, certain compounds of the invention may be prepared as various stereoisomers (e.g., diastereoisomers and enantiomers). The compounds of this invention can be prepared as racemates or as substantially pure stereoisomers. The stereoisomers of the invention (e.g., (8) and (K) enantiomers) can be obtained using any suitable method. For example, enantiomers can be cleaved from the racemic mixture using chiral chromatography or recrystallization. Preferably, stereoisomers (e.g., (8) and / or (K) enantiomers) are prepared using the stereospecific synthesis described in the invention.

The optical configuration of the stereoisomers of the invention is established by the (K), (8) method CaEp1pdo1b-Prge1od (see book I. Magse, Abuaiseb Ogdashs Chesh181gu, 4 ^1E Eb., ^ 11еу 1п1eg§сepseps, P. 109., 1992)).

The present invention includes all isomeric forms and racemic mixtures of the disclosed compounds and a method for treating a subject with both pure isomers and mixtures thereof, including racemic mixtures. The stereoisomers can be resolved and isolated using any suitable method, such as chromatography. And in this case, it is understood that one stereoisomer may be more active than another. The target isomer may be established by screening.

Physiologically acceptable salts of the compounds represented by structural formulas (I) to (XI) are also included in the present invention. Salts of compounds containing an amine or other basic group can be obtained, for example, by reaction with appropriate organic or inorganic acids, such as hydrogen chloride, hydrogen bromide, acetic acid, citric acid, perchloric acid and the like. Compounds with a quaternary ammonium group also contain a counter anion such as chloride, bromide, iodide, acetate, perchlorate and the like. Salts of compounds containing a carboxylic acid group or other acidic functional group can be prepared by reaction with an appropriate base, for example a hydroxide base. Salts of acidic functional groups contain an anti-cation such as sodium, potassium, ammonium, calcium, and the like. (see, for example, the article by Vegde 8.M. e1 a1., Reaghasei11ca1 8a118, I. Reagsha. 8c1., 66: 1 (1977)).

Aliphatic groups used herein include straight or branched chain hydrocarbons or C1-C20 cyclic hydrocarbons that are fully saturated or that contain one or more unsaturated bonds. Preferred aliphatic groups are hydrocarbon groups of about C ₁ to C ₁₀ . More preferred are hydrocarbon groups of from about C1 to C6 or from C1 to C3. One or more carbon atoms in the aliphatic group may be replaced by a heteroatom, such as nitrogen, oxygen or sulfur. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl or alkynyl groups.

- 13 008060

An aminoalkyl group is an alkyl group substituted with a group of ΝΚ ²⁴ Κ ²⁵ , where K ²⁴ and K ²⁵ are as described above. Preferably, the alkyl fragment contains from one to about twelve, more preferably from 1 to about 6 carbon atoms. The alkyl moiety of the aminoalkyl group may be unsubstituted or substituted as described above for aliphatic groups. Examples of suitable aminoalkyl groups include aminomethyl, 2aminoethyl, 3-aminopropyl, 4-aminobutyl, dimethylaminoethyl, diethylaminomethyl, methylaminohexyl, aminoethylenyl and the like.

Aromatic groups include carbocyclic aromatic groups such as phenyl, 1naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, and heterocyclic aromatic or heteroaryl groups such as Ν-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl 2-thienyl, 3-thienyl, 2furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4- pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl. In those cases when these rings are condensed, for example, with ring C, the specified point of attachment can be either of the two condensed bonds.

Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other rings. Examples include tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3quinolinyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-quinoline quinolinyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl and the like. The scope of the term aromatic group, which is used in this invention, also includes a group in which one or more carbocyclic aromatic rings and / or heteroaryl rings are fused to a cycloalkyl or non-aromatic heterocyclic ring, for example benzocyclopentane, benzocyclohexane.

Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings that include one or more heteroatoms, such as nitrogen, oxygen, or sulfur in the ring. This ring may be 5-, 6-, 7- or 8-membered and / or fused to another ring, such as a cycloalkyl or aromatic ring. Examples include 1,3-dioxolan-2-yl, 3-1Nbenzimidazol-2-one, 3-1-alkylbenzimidazol-2-one, 3-1-methylbenzimidazol-2-one, 2-tetrahydrofuranyl, 3tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1 2-piperidinyl, 3-piperidinyl, 4 piperidinyl, 4-thiazolidinyl, diazolonyl, Ν-substituted diazolonyl, 1-phthalimidyl, 1-3-alkylphthalimidyl, benzoxane, benzopyrolidine, benzopiperidine, benzoxolane, b Benzothiolan, benzothian, tetrahydrofuran-2-one-3-yl, 2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl, 2-oxo-3H-1,2,3, 5-oxathiadiazole-4yl,

Suitable substituents on the aliphatic group, aromatic group (carbocyclic and heteroaryl), non-aromatic heterocyclic ring or benzyl group include, for example, an electron withdrawing group, halogen (chloride, bromide, fluoride, iodide), azido groups, -ΟΝ, -COOH, -OH , -ΟΟΝΚ ²⁴ Κ ²⁵ , ΝΚ ²⁴ Κ ²⁵ , Ο8 (Ο) 2ΝΚ ²⁴ Κ ²⁵ , 8 (Ο) 2ΝΚ ²⁴ Κ ²⁵ , -8Ο3Η, -8 (Ο) 2ΝΗ2, guanidino, - (О) and (SI2 ) 1-С (О) OK ²⁰ , - (Ο) „- (ΟΗ2) ιΟΟ (Ο) Κ ²⁰ , - (Ο)„ - (ΟΗ2) ι-Ο (Ο) ΝΚ ²¹ Κ ²² , - (Ο) π- (ΟΗ2) ₁ -ΝΗΟ (Ο) ΟΚ ²⁰ , ϋ-Η, -ϋ (aliphatic group), -0- (substituted aliphatic group), -O- (aryl), -O- (aromatic group), - 0- (deputy schennaya aromatic group), -0- (Cu2) p- (substituted or unsubstituted aromatic group) (p - an integer from 1 to 5) -P- (non-aromatic heterocyclic group) or -ϋ- (ΟΗ ₂₎ ρ (nonaromatic heterocyclic group).

The substituents K ²⁰ , K ²¹ or K ²² independently represent a hydrogen atom, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -NIS (Ο) -Ο- (aliphatic group), -ΝΗί '( Ό) -Ο

- 14 008060 (aromatic group), —NHC (O) —O- (non-aromatic heterocyclic group), with K ²¹ and K ²² taken together with the nitrogen atom to which they are attached can form a non-aromatic heterocyclic ring.

The radical K ⁶⁰ is a hydrogen atom, a —OH, —ΝΗ ₂ group, an aromatic group or a substituted aromatic group.

ΐ is an integer from zero to about three, and the methylene group - (CH ₂ ) ₁ may be substituted, as described here for aliphatic groups, or unsubstituted.

The number and is equal to zero or one.

The group O represents —O—, -8-, -8 (O) -, -8 (O) ₂ -, -O8 (O) ₂ -, -C (O) -, -OC (O) -, - С (О) О-, -С (О) С (О) -О-, -О-С (О) С (О) -, -ϋ (Θ) ΝΗ-, -МНС (О) -, - OS (O) 1MN-, -ΝΗϋ (Θ) Θ-, -ΝΗ- € (Θ) -ΝΗ-, -8 (Θ) 2ΝΗ-, -ΝΗ8 (Θ) ₂ -, -Ν (Κ ²³ ) -, - ^ ΝΚ ^ ΝΗΝΗ-, -ΝΗΝΗ ^ ΝΚ ²³ ) -, -ΝΗ ^; Γ (Θ) - or -ΝΚ ²⁴ 8 (Θ) ₂ -.

The radical K ²³ represents a hydrogen atom, an aliphatic group, a benzyl group, an aryl group or a non-aromatic heterocyclic group.

The radicals K ²⁴ and K ²⁵ independently are a hydrogen atom, an —OH group, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, a non-aromatic heterocyclic group, or K ²⁴ and K ²⁵ taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring.

A substituted non-aromatic heterocyclic ring, benzyl group or aromatic group may also have an aromatic group, an aliphatic or substituted aliphatic group as a substituent. When a non-aromatic ring (carbocyclic or heterocyclic) or an aromatic ring (carbocyclic aromatic or heteroaryl) is substituted with another ring, these two rings may be fused. A substituted aliphatic group may also have, as a substituent, an oxo group, an eloxy group, a non-aromatic heterocyclic ring, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group. In addition, a substituted non-aromatic heterocyclic ring may have, as a substituent, the group = O, = 8, = ΝΗ or = Maliphatic. aromatic or substituted aromatic group). A substituted aliphatic group, a substituted aromatic, substituted non-aromatic heterocyclic ring or a substituted benzyl group may have more than one substituent, which may be the same or different.

Acyl groups include substituted and unsubstituted aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl and aromatic sulfonyl.

Suitable electron withdrawing groups include, for example, alkylimines, alkylsulfonyl, carboxamido, carboxylic alkyl esters, -ΟΗ = ΝΗ, -ΟΝ, -ΝΘ ₂ groups and halogen atoms.

In the structural formulas of this invention, a single or double bond by which a chemical group or functional group is attached to the rest of the molecule or compound is indicated by the following symbol: ⁷

For example, the corresponding symbol in structural formulas (II), (III) and (IV) denotes a double bond through which the central ring of the tricyclic ring system is connected to the rest of the molecule represented by structural formula (I).

Preferably, the subject is a bird or mammal, such as a human, but it can also be an animal in need of veterinary treatment, for example, domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, domestic poultry, pigs, horses, etc.) and laboratory animals (e.g. rats, mice, guinea pigs, etc.).

An effective amount of a compound is that amount that inhibits one or more of the processes that are transmitted by binding the chemokine to a receptor in the body of a subject affected by a disorder associated with impaired recovery and / or activation of white blood cells. Examples of such processes include leukocyte migration, integrin activation, transient increase in the concentration of intracellular free calcium [Ca ^2+] _s and granular selection of mediators preceding inflammation. Alternatively, an effective amount of a compound is an amount that is sufficient to achieve the desired therapeutic and / or prophylactic effect, i.e. such an amount that leads to the prevention or amelioration of symptoms associated with the disease associated with impaired recovery and / or activation of leukocytes.

The amount of compound to be administered to a patient will depend on the type and severity of the disease, and on the patient’s characteristics such as general health, age, gender, body weight, and drug tolerance. In addition, it will depend on the severity and type of disease. A qualified specialist in this field will be able to determine the appropriate dosage, depending on the above and other factors. Typically, for an adult patient, an effective amount of a compound can vary from about 0.1 mg per day to about 100 mg per day. Preferably, the dosage varies from about 1 mg per day to about 100 mg per day. In addition, an antagonist of the action of the chemokine receptor can be prescribed in the kidney.

- 15 008060 tania with one or more additional therapeutic agents, for example theophylline, beta-adrenergic bronchodilators, corticosteroids, antihistamines, anti-allergic drugs, immune suppressants (e.g. cyclosporin A, EK-506, prednisone, methylprednisolone), hormones (e.g. , adrenocorticotropic hormone (ACTH)), cytakines (for example, interferons (for example, [ΡΝβ-1; · ι.! ΡΝβ-1ό)), etc.

Any suitable route of administration of the compound may be prescribed, including, for example, oral administration in capsules, suspensions or tablets, or parenteral administration. Parenteral administration may include, for example, systemic administration, such as intramuscular, intravenous, subcutaneous or intraperitoneal injection. In addition, the compound can be administered orally (e.g., with food), through the skin, locally, via inhalation (e.g., inside the bronchi, inside the nose, into the oral cavity or drops in the nose) or rectally, depending on the type of disease or condition to be treatment. Oral or parenteral administration are preferred routes of administration.

The compound may be administered to a patient in combination with a pharmaceutically or physiologically acceptable carrier, as part of a pharmaceutical composition for treating HIV infection, inflammatory disease, or other diseases discussed above. The form of use of the intended compound may vary in accordance with the chosen method of administration (e.g., solution, emulsion, capsule). Suitable carriers may contain inert components that do not interact with the compound. Conventional drug-preparation technologies can be used, such as described in the reference book Ket ^ pdΐοp'8 Riattasei11ca1 80 101 1005, Mask Ryu1511td Sotra ^, Easton, pc. Pennsylvania. Carriers suitable for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic physiological saline (physiological saline containing approximately 0.9% benzyl alcohol), physiological saline with phosphate buffer, Hank's solution, Ringer's lactate, and the like. In the prior art (see the book of Wakeg et al. Controlled Release of Biologically Active Agents - SopkgoPeb Ke1ease οί Vy1odyu1 AsRoe Adeiy, ί. \ UPeu & 8οη5, 1986), methods for encapsulating compositions (such as hard gelatin or cyclodextran coating) are known.

The amount of active ingredient (one or more compounds of the invention) in the composition may vary from about 0.1 to 99.9 wt.%. Preferably, the amount of active ingredient is from about 10 to 90%, or from about 20 to 80% by weight. A standard preparation package may contain from 1 mg to about 1000 mg of the active ingredient, preferably from about 10 to 100 mg of the active ingredient. In addition, if desired, the composition may contain other compatible therapeutic agents, such as theophylline, beta-adrenergic bronchodilators, corticosteroids, antihistamines, antiallergic drugs, immune suppressants (e.g., cyclosporin A, PK-506, prednisone, methylprednisolone), hormones ( for example, adrenocorticotropic hormone (ACTH)), cytokines (for example, interferons (for example, ShIV-k, ΣΕΝβ-1Ε)), etc.

In one embodiment, the pharmaceutical composition comprises the (8) enantiomer of a compound of the invention (for example, a compound of structural formula (XIII)) and a physiologically acceptable carrier or drug medium. For example, in one embodiment, the composition comprises (8) -4- (4chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cyclopenten-5-ylidene] propyl} -3,3-dimethylpiperidin-4-ol and a physiologically acceptable carrier or drug medium. In some embodiments, the pharmaceutical composition contains an (8) enantiomer of a compound of the invention (for example, a compound of structural formula (XI)) and substantially does not contain the corresponding (K) enantiomer (the content of the (8) enantiomer is at least about 98% or at least about 99% or more). In another embodiment, the composition comprises a (8) enantiomer of a compound of the invention (for example, a compound of structural formula (XII)), a corresponding (K) enantiomer, and a physiologically acceptable carrier or drug medium. In a more specific embodiment, the composition comprises a racemic compound of structural formula (XII), for example, racemic 4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-aza -dibenzo [a, b] cyclopenten-5-ylidene] propyl} -3,3-dimethylpiperidin-4-ol. In other embodiments, the ratio of the (8) enantiomer to the (K) enantiomer (by weight) in the composition is at least about 2: 1, or about 5: 1, or about 10: 1, or about 20: 1 , or approximately 50: 1.

The activity of the compounds of the present invention can be assessed using suitable assays, such as receptor binding assays and chemotaxis assays. For example, as described in the Examples section, small KLUGES and MHR-1a binding antagonist molecules were identified using THP-1 cells that bind KLNΤE8 and chemotax in response to KLNΤE8 and MHR-1a, as a model of white blood cell chemotaxis. Specifically, a high-throughput receptor binding assay was used in which the binding of iodine-125, ¹²⁵ I-KLNΤE8 and 'E-MSChA labeled with the THP-1 cell membranes was tracked to identify small antagonist molecules that block the binding of KLNΤE8 and MGR- 1a. In addition, with

The compounds of the present invention can be identified due to their ability to inhibit activation steps that are triggered by binding of a chemokine to its receptor, such as chemotaxis, integrin activation, and granular excretion of a mediator. They can also be identified due to their ability to block Hb-60 transmitted by ΒΛΝΤΕ8 and MF-1a, T cells, peripheral blood mononuclear cells and the chemotactic eosinophil response.

The compounds disclosed in this invention can be prepared according to the schemes of FIG. 1-5 and 7. These schemes are described in more detail below.

In FIG. 1 shows a scheme for producing compounds represented by structural formula (I). The group L ¹ represents a C 1 -C ₃ PP1, PP1 ₃ Br RR11D (RRy ₃ - triphenylphosphine) or dietoksifosfinoksogruppu (ITS) ₂ P (O), L ² is a suitable leaving group such as a halide group, p-toluenesulfonate, mesylate, alkoxy and phenoxy group; Rd is a suitable protecting group such as tetrahydropyranyl; and other characters are as defined above.

In step 1 of FIG. 1, the Wittig reaction is carried out in a solvent such as ether or tetrahydrofuran (THF), in the presence of a base such as sodium hydride, n-butyl lithium or lithium diisopropylamide (LOL), at a temperature of from 0 ° C to the boiling point of the solvent used, in from 5 minutes to 72 hours. The compounds represented by formula (II) in FIG. 1 can be obtained by the methods disclosed in Japanese Patent Publication No. 61/152673, US Pat. No. 5,089,496, AO 89/10369, AO 92/20681 and AO 93/02081, all of which are incorporated herein by reference.

In step 2 of FIG. 1, the protecting group is removed by the action of an acid in a solvent, such as methanol, at room temperature to the boiling point of the solvent used, for 5 minutes to 72 hours. Alternatively, the compound represented by formula (V) in FIG. 1 can be obtained directly in step 1, without isolation of the intermediate. The reaction mixture obtained after completion of the reaction described in stage 1 can be dissolved in a solvent and treated with an acid.

In step 3 of FIG. 1 hydroxyl group can be converted to a leaving group by known methods. The compounds represented by formula (VI) in FIG. 1 can be obtained by the methods described in journal 1. Meb. Siet., 1992 (35), 2074-2084 and Japanese Patent 1P 61/152673.

In step 4 of FIG. 1, the alkylation reaction is carried out in a solvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF), in the presence of a base such as potassium carbonate or sodium hydride, and a catalyst such as alkali metal iodide, at a temperature from room temperature to the boiling point of the solvent used, for 5 minutes to 72 hours

In FIG. 2 shows a scheme for producing compounds represented by the formula (UTM). In step 1 of FIG. 2, the Grignard reaction can be carried out in a solvent, such as ether or tetrahydrofuran (THF), at a temperature of from 0 ° C to the boiling point of the solvent used, for 5 minutes to 72 hours. Compound (VII) is commercially available.

In step 2 of FIG. 2, the bromination can be carried out with brominating agents such as hydrobromic acid, bromotrimethylsilane or the borate methylsulfide tribromide complex in a solvent such as acetic acid, dichloromethane or dichloroethane, at a temperature from room temperature to the boiling point of the solvent used, for 5 minutes to 72 hours.

In FIG. 3 shows a scheme for producing compounds represented by structural formula (I). As can be seen from FIG. 3, reductive amination can be carried out with reducing agents such as sodium cyanoborohydride, sodium acetoxyborohydride or sodium borohydride in a solvent such as methanol, ethanol, tetrahydrofuran (THF), dichloromethane or dichloroethane at room temperature to the boiling point of the solvent used, for 5 minutes to 72 hours

In FIG. Figure 4 shows the preparation of compounds represented by structural formula (I), in which the group Ζ is represented by the structural formula (III) and in which ring A and / or ring B in Ζ is substituted by the radical K ⁴⁰ . As can be seen from FIG. 4, the alkylation reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF), in the presence of a base such as potassium carbonate or sodium hydride, and a catalyst such as alkali metal iodide , at a temperature from room temperature to the boiling point of the solvent used, for 5 minutes to 72 hours

In FIG. 5 shows a scheme for producing compounds represented by structural formula (I), in which group Ζ is represented by structural formula (III) and in which ring A and / or ring B in Ζ is substituted by the group - (O) _and - (CH2) _G COOC ²⁰ , - (O) and- (CH2) GOS (O) K ²⁰ , - (O), - (C113) .- C (OA + 1A or - (O) _and - (CH2) g MHC (O) O-K ^20. According to Fig. 5, the hydrolysis reaction can be carried out in a mixture of an aqueous solution of an alkali metal hydroxide and a solvent, such as methanol, ethanol, tetrahydrofuran (THF) or dioxane, at a temperature from room temperature to the boiling point of the solvent used, from 5 minutes to 72 hours. The acylation reaction can be carried out using dicyclohexylcarbodiimide (ESA) or (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (OEC), in a solvent such as tetrahydrofuran (THF), dimethylformamide (DMF) or methylene chloride, in the presence of a base such as pyridine or triethylamine (if necessary) at a temperature of from 0 to 100 ° C, for 5 minutes

- 17 008060 to 72 hours

In FIG. 7 shows a scheme for producing compounds represented by structural formula (I), in which group Ζ is represented by structural formula (III) and in which ring A and / or ring B in Ζ is substituted by radical K ⁴⁰ . The b ⁴ group is a suitable leaving group, such as a halogen or trifluoromethyl sulfonate.

According to FIG. 7 a mating reaction by palladium, such as Stille mating, Suzuki mating, Heck's reaction, or carboxylation using carbon monoxide, can be carried out using a palladium catalyst such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride and palladium acetate in a solvent such as tetrahydrofuran (THF), 1,4-dioxane, toluene, dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), in the presence of an additive (if necessary) such as triphenylphosphine, 1,1'-bis (diphenylphosphino ) ferrocene, triethylamine, sodium bicarbonate, tetraethylammonium chloride or lithium chloride, at a temperature from room temperature to the boiling point of the solvent used, for 5 minutes to 72 hours

In FIG. 10C shows three methods for the preparation of compounds represented by structural formulas (I), (VII), (VIII) and (IX) in which group Ζ is represented by structural formula (III) and in which ring A or ring B in Ζ is replaced by radical K ⁴⁰ . In FIG. 10C, the K ⁴⁰ radical is represented by the group - (O) _and (CH ₂ ) ₁ -C (O) - \ K ²¹ K ²² , and is equal to unity, ΐ is zero.

In accordance with FIG. A 10C phenol-containing compound may be reacted with a carbonate equivalent such as carbamoyl chloride (method A), isocyanate (method B) or acylimidazole (method C), in the presence of a base such as sodium hydroxide, potassium carbonate or sodium carbonate, in a solvent, such as dimethylformamide or tetrahydrofuran, at a temperature of from 0 ° C to the boiling point of the solvent used, for about 5 minutes to 72 hours

Compounds represented by structural formula (I) in which the group Ζ is represented by structural formulas (III) or (IV), X represents a group —CO— | K _c - and K _c is a group - (CH ₂ ) §СООК ³⁰ , - (CH2) §-C (O) \ K ³¹ K ³² or - (CH2) §- \ HC (O) O-K ³⁰ can be obtained by a suitable modification of the circuit shown in FIG. 1-5 and 7. In one modification, the starting material shown in FIG. 1, in which X is —CO— | H—. The amide is then alkylated with an L ³ - (CH ₂ ) §-COOC ³⁰ reagent, in which L ³ is a suitable leaving group using the alkylation techniques described above. The rest of the synthesis is carried out as described in FIG. 1-5 and 7.

In FIG. 12 shows the preparation of compounds of formula (B-c). The Friedel Crafts acylation reaction can be carried out using an acid chloride, in the presence of a Lewis acid such as aluminum trichloride or titanium tetrachloride, in a solvent such as dichloromethane, dichloroethane, nitrobenzene or carbon disulfide. The acylation reaction can be carried out at a temperature of from about room temperature to the boiling point of the selected solvent, for a period of from about 5 minutes to 72 hours

In FIG. 13 shows the preparation of compounds of formula (Sche). In step 1 of FIG. 13, a chlorosulfonylation reaction can be carried out using chlorosulfonic acid in a solvent, such as dichloromethane, or in the absence of a solvent, at a temperature of from about 0 to 60 ° C, for a period of about 5 minutes to 72 hours. In step 2 of FIG. 12, a mating reaction can be carried out using an amine in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, acetone, ethanol, THF or DMF. The reaction can be carried out at a temperature of from about room temperature to the boiling point of the selected solvent, for a period of from about 5 minutes to 72 hours

Although in FIG. 1-5, 7 and 13 show a scheme for producing compounds in which rings A and B are phenyl rings, similar compounds with heteroaryl groups for rings A and B can be obtained using starting materials with heteroaryl groups in the corresponding positions. These starting materials can be prepared according to the methods disclosed in Japanese Patent 1P 61/152673, US Pat. No. 5,089,496, XVO 89/10369, XVO 92/20681 and HUO 93/02081.

The invention is illustrated by the following examples, which are in no way intended to limit it.

Examples

Example 1. 4- (4-Chlorophenyl) -1- [3- (10,11-dihydro-5H-dibenzo [a, b] cyclohepten-5-ylidene) propyl] piperidin-4-ol.

To a solution of 200 mg of 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene (described in Japanese Patent 1P 48-030064) in 10 ml of DMF was added 230 mg of 4- (4-chlorophenyl ) -4-hydroxypiperidine, 360 mg potassium carbonate and 50 mg potassium iodide. The mixture was stirred for 24 hours at 70 ° C. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with a 1: 1 ethyl acetate / hexane mixture to give 250 mg of the title compound. Nuclear Magnetic Resonance Spectrum 'H (SEST,) δ: 1.65-2.11 (5H, m),

- 18 008060

2.32-3.10 (8H, m), 3.22-3.67 (4H, m), 5.87 (1H, t), 7.03-7.44 (12H, m). Mass spectrum (MS) t / ζ: 444 (M + 1). m multiplet, t - triplet, M - molecular weight.

Example 2. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4ol.

The title compound was prepared following the procedure for Example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, th] cycloheptene with 11- (3-bromopropylidene) -6,11-dihydrodibenz [b , e] oxepine. Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ ) δ: 1.61-2.16 (5Н, m), 2.37-2.80 (8Н, m), 5.22 (2Н, br.s), 5.70 (0.6x1H, t), 6.03 (0.4x1H, t), 6.73-6.90 (2H, m), 7.09-7.45 (10H, m). MS t / ζ: 446 (M + 1). b.s. - wide singlet.

Example 3. Chemokine binding membrane preparations and binding assays.

Membranes are prepared from THP-1 cells (Collection of American-type cultures ATCC No. ΊΊΒ202). Cells are harvested by centrifugation, washed twice with physiological saline with phosphate buffer (ΡΒ8), and the cell pellet is frozen at a temperature of -70 to -85 ° C. A frozen pellet is thawed in an ice-cooled lysis buffer that contains 5 mmol / L (Ν2-hydroxy-ethylpiperazine-L′-2-ethanesulfonic acid (HEPE8), pH 7.5, 2 mmol / L ethylenediaminetetraacetic acid (EDTA) and 5 micrograms (μg) / ml of each of the protease inhibitors aprotinin, leipeptin and chymostatin, and 100 μg / ml of phenylmethanesulfonyl fluoride (PM8E, also a protease inhibitor) at a concentration of 10 to 50 million cells / ml. This treatment leads to cell lysis The suspension is mixed well to resuspend all frozen cell pellet. Nuclei and cell debris are removed by centrifugation at 400 d for 10 min at 4 ° C. Liquid above the pellet is transferred to a clean tube and membrane fragments are collected by centrifugation at 25 000 d for 30 min at 4 ° C. the precipitate is suctioned off and the precipitate is resuspended in a cooled buffer solution containing 10 mmol / L HEPE8 with a pH of 7.5, 300 mmol / L sucrose, 1 μg / ml each of aprotinin, leipeptin and chymostatin and 10 μg / ml PM8E (approximately 0 , 1 ml for every 100 million cells). All cell aggregates were peptized using a mini-homogenizer, and the total protein concentration was determined using a protein assay kit (Xo-Kai, Negse1e8, Calif., Catalog No. 500-0002). Aliquots of the membrane solution are then taken and frozen at a temperature of from -70 to -85 ° C until they are needed. In the analysis of binding using the above membranes. The protein of the membrane (from 2 to 20 μg of the total protein of the membrane) is maintained with the addition of 0.1 to 0.2 nmol / L KLHGEZ or M [P-1a. labeled with the iodine-125 isotope, in the presence (or absence) of an unlabeled competitor (KLHGEZ or M! P-1a), or at different concentrations of the compounds. The binding reaction is carried out in a volume of from 60 to 100 μl (microliter) of a binding buffer solution containing 10 mmol / L HEPE8 with a pH of 7.2, 1 mmol / L CaCl ₂ , 5 mmol / L MDC1 ₂ and 0.5% bovine serum albumin (Β8Ά) for 60 minutes at room temperature. The binding reaction is terminated by collecting the membranes by rapid filtration through glass fiber filters (CE / Β or CE / C, Raskagi company), which are pre-impregnated with 0.3% polyethyleneimine. The filters are washed with approximately 600 μl of binding buffer containing 0.5 mol / L sodium chloride, dried, and the amount of bound radioactivity is determined by scintillation counting in a Torsoip beta plate counter !.

The table below shows the activity values of the tested compounds in the form of IC ₅₀ values or the inhibitor concentration that is required for 50% inhibition of specific binding in the receptor binding test using ^I25 I-KΑNTE§ or D-MSL and THP cell membranes as ligands -one. The amount of specific binding is determined by the difference: total binding minus non-specific binding; the nonspecific binding value is the number of pulses per minute, which is still determined in the presence of an excess of unlabeled KLHTEZ or EMSL.

- 19 008060

Biological Test Data

Example IR ₅₀ , micromol / l Example IR ₅ about, micromol / l Example IR ₅₀ , micromol / l Example IR ₅₀ , micromol / l one <1 38 <1 63 <10 114 <1 2 <1 39 <10 64 <1 117 <1 8 <1 40 <1 65 <1 118 <1 12 <1 41 <1 66 <1000 120 <1 17 <10 42 <1 67 <1 122 <1 eighteen <1 43 <10 68 <10 123 <1 nineteen <1 44 <1 69 <1 128 <1 21 <1 45 <1 71 <1 130 <1 22 <1 46 <1 72 <10 131 <1 23 <1 47 <1 73 <10 132 <1 24 <10 48 <1 74 <1000 133 <1 25 <1 49 <1 75 <10 134 <1 26 <1 51 <1 76 <10 135 <1 27 <1 52 <1 77 <1 138 <1 28 <1. 53 <1 78 <1 139 <1 29th <1 54 <1 79 <1 140 > 10 thirty <1 55 <1 83 <1000 141 <1 31 <1 56 <1 85 <1 142 <10 32 <1 57 <10 86 > 10 143 <1 33 <1 59 <1 89 > 10 144 <1 34 <1 60 <1 90 <1 145 10 35 <1 61 <10 91 <1 146 > 10 36 <1 62 <10 111 <1

- 20 008060

Example IR ₅₀ , micromol / l Example IR ₅₀ , micromol / l Example IR ₅₀ , micromol / l Example IR ₅₀ , micromol / l 147 <10 180 <1 212 <1 282 <1 148 <10 181 <1 215 <1 283 <1 149 <1000 182 <1 216 <1 284 <1 150 <10 183 <1 218 <1 285 <1 151 <1 184 <10 242 <1 286 <1 152 <1 185 <1000 248 10 287 <1 153 <1 186 <1 249 <1 288 <1 154 <1 187 <1 262 <1 289 <1 155 <1 188 > 10 263 <1 290 <1 158 <1 190 > 10 264 <1 291 <1 159 <1 191 > 10 265 <1 292 <1 160 <1 192 > 10 266 <1 306 <1 161 <10 193 <1 267 <1 422 <1 162 <1 194 <1 268 <1 423 <1 163 <1 195 <10 269 <1 424 <1 166 <10 197 <1 270 <1 425 <1 167 > 1 198 <1 271 <1 426 <1 168 ^one 199 <1 272 <1 427 <1 172 <1 200 <1 273 <1 428 <1 173 <1 201 <1 277 <1 429 <1 174 <1 203 <1 278 <1 430 <1 175 <1 204 <1 279 <1 431 <1 176 <1 205 <1 280 <1 432 <1 178 <1 1 211 <1 281 <1

- 21 008060

Example IR ₅₀ , micromol / l Example IR ₅ about, micromol / l 456 <1 479 <1 457 <1 480 <1 458 <10 481 <1 459 <10 482 <1 460 <1 483-1 <1 483-2 <10 461 <10 484 <1 462 <10 485 <1 463 <10 486 <1 464 <1 487 <1 465 <1 488 <1 466 <50 489 <10 467 <1 490 <1 468 <1 491 <1 469 <1 492 <10 470 <1 493 <10 471 <1 494 <1 472 <1 495 <1 473 <1 496 <10 474 <1 497 <10 475 <1 498 <10 476 <1 499 <10 477 <10 500 <10 478 <10 501 <10 Example IR ₅₀ , micromol / l Example IR ₅₀ , micromol / l 548 <10 554 <1 549 <1 555 <1 550 <1 556 <1 551 <1 557 <1 552 <1 558 <10 553 <1 559 <1

Example IR ₅₀ , micromol / l Example IR ₅₀ , micromol / l 502 <1 525 <20 503 <1 526 <1 504 <1 527 <1 505 <1 528 <10 506 <1 529 <20 507 <1 530 <20 508 <1 531 <1 509 <1 532 <2 510 <1 533 <10 511 <1 534 <1 512 <1 535 <10 513 <1 536 <1 514 <1 537 <1 515 <1 538 <10 516 <1 539 <10 517 <1 540 <10 518 <1 541 <10 519 <1 542 <10 520 <1 543 <10 521 <1 544 <10 522 <1 545 <10 523 <1 546 <1 524 <1 547 <1 Example IR ₅₀ , micromol / l Example IR ₅₀ , micromol / l 560 <10 566 <20 561 <10 567 <1 562 <10 568 <1 563 <10 569 <1 564 <10 570 <10 565 <10 571 <10

Example 8. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydrodibenz [b, e] thiepin-11-ylidene) propyl] piperidin-4-ol.

Stage 1

11- (3-Bromopropylidene) -6,11-dihydrodibenz [b, e] thiepine is prepared following the procedure of Example 45, steps 1 and 2, but replacing 5,11-dihydro-7-methoxypyrido [2,3-c] [ 1] benzoxepin-5-one on 6,11 dihydrodibenz [b, e] thiepin-11-one.

- 22 008060

'11 (С0С1 ₃ ) NMR spectrum δ: 2.50-2.64 (2Н, m), 3.36-3.47 (3Н, m), 4.99 (1Н, d), 5.94 (1Н) , t), 6.98-7.31 (8H, m). d - doublet.

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with the product of step 1.

'11 NMR spectrum (SPS1 ₃ ) δ: 1.65-1.80 (3H, m), 1.95-2.70 (10H, m), 3.35 (1H, d) 4.98 (1H, d) 5.96 (1H, t); 7.09-7.43 (12H, m). MS t / ζ: 462 (M + 1).

Example 12. 1- [3- (5-Benzyl) - (6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] -4- (4chlorophenyl) piperidin-4 -ol.

To a solution of 300 mg of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin11-ylidene) propyl] piperidin-4-ol hydrochloride (example 39) 200 ml of sodium hydride (60%, in oil), 0.15 ml of benzyl bromide are added to 5 ml of DMF and the mixture is stirred for 1 h at room temperature. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate to give 180 mg of the title compound.

'11 NMR spectrum (SPS1 ₃ ) δ: 1.62-1.67 (2H, m), 1.99-2.20 (3H, m), 2.33-2.65 (8H, m), 5 10 (1H, d), 5.75 (1H, d), 5.94 (1H, t), 7.11-7.42 (16H, m), 7.91 (1H, dd). MS t / ζ: 549 (Μ + 1).

Example 17. 1- [3- (5-Carboxymethyl-6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] 4- (4-chlorophenyl) piperidin-4- ol.

1.0 g of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-5-ethoxycarbonylmethyl-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidine is dissolved -4-ol (Example 18) in a one-molar solution of hydrogen chloride in diethyl ether and the mixture was stirred for 24 hours at room temperature. An aqueous solution of sodium hydroxide and ethyl acetate were added to the reaction mixture, the aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitate was filtered off to obtain 250 mg of the title compound.

'11 NMR spectrum (DMSO-b ₆ ) δ: 1.44-1.61 (2H, m), 2.07-2.17 (1H, m), 2.35-3.01 (9H, m) 4.28 (1H, d), 4.59 (1H, d), 5.83 (1H, t), 7.18-7.71 (12H, m). MS t / ζ: 517 (M + 1).

Example 18. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-5-ethoxycarbonylmethyl-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidin-4 -ol.

The title compound was prepared following the procedure of Example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with 11- (3-bromopropylidene) -5-ethoxycarbonylmethyl-6-oxo -5H-dibenz [b, e] azepine.

'11 NMR spectrum (СОС1 ₃ ) δ: 1.30 (3Н, m), 1.64-1.69 (2Н, m), 1.97-2.10 (3Н, m), 2.38-2 71 (8H, m), 4.27 (2H, q), 4.32 (1H, d), 4.84 (1H, d), 5.88 (1H, t), 7.16-7, 45 (11H, m), 7.88 (1H, dd). MS t / ζ: 545 (M + 1), quartet.

Example 19. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-5-methyl-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidin-4 -ol.

The title compound was prepared following the procedure for Example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with 11- (3-bromopropylidene) -5-methyl-6-oxo5H -dibenz [b, e] azepine.

NMR spectrum 11 (SPS1 ₃ ) δ: 1.58-2.06 (5H, m), 2.39-2.75 (8H, m), 3.53 (3H, s), 5.84 (1H, t), 7.10-7.44 (11H, m), 7.85-7.89 (1H, m). MS t / ζ: 473 (M + 1).

Example 21. 4- (4-Chlorophenyl) -1- [3- (5H-dibenz [a, b] cyclohepten-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with 5- (3-bromopropylidene) -5H-dibenzo [a, b ] cycloheptane.

'11 NMR spectrum (SPS1 ₃ ) δ: 1.58-1.63 (2H, m), 2.00-2.05 (2H, m), 2.26-2.46 (6H, m), 2 62-2.66 (2H, m), 5.55 (1H, t), 6.85 (2H, s), 7.24-7.40 (12H, m). MS t / ζ: 442 (M + 1).

Example 22. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-methoxycarbonyldibenz [b, e] -oxepin-11-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure for Example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with 11- (3-bromopropylidene) -6,11-dihydro -2-methoxycarbonyl dibenz [b, e] oxepine.

'11 NMR spectrum (SPS1 ₃ ) δ: 1.65-1.70 (2H, m), 2.01-2.13 (3H, m), 2.41-2.80 (7H, m), 3 85 (3H, s), 5.40 (2H, br.s), 5.73 (0.6x1H, t), 6.09 (0.4x1H, t), 6.76 (0.6x1H, d), 6.82 (0.4x1H, d), 7.21-7.43 (8H, m), 7.73 (1H, dd), 7.87 (0.6x1H, d), 7.97 (0.4x1H, d). MS t / ζ: 504 (M + 1).

Example 23. 1- [3- (2-Butoxycarbonyl-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure for Example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with 11- (3-bromopropylidene) -2-butoxy-6,11

23 008060 Dihydrodibenz [b, e] oxepine.

'11 (С0С1 ₃ ) NMR spectrum δ: 0.96 (3Н, t), 1.53 (2Н, к), 1.70-1.77 (3Н, m), 2.02-2.14 (3Н) , m), 2.39-2.78 (5H, m), 4.27 (2H, t), 5.27 (2H, b.s.), 5.75 (0.8x1H, t), 6 10 (0.2x1H, t), 6.78 (1H, d), 7.27-7.43 (8H, m), 7.76 (1H, dd), 7.89 (0.8x1H, d ), 7.98 (0.2x1H, d). MS t / ζ: 546 (M + 1).

Example 24. 1- [3- (2-Carboxyl-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

To a solution of 100 mg of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-methoxycarbonyldibenz [b, e] oxepin-11ilidene) propyl] piperidin-4-ol (Example 22) in 3 ml of ethanol add 0.6 ml of a 15% aqueous solution of sodium hydroxide and the mixture is heated to boiling for 12 hours. The solvent is distilled off under reduced pressure. Water and ethyl acetate were added to the reaction mixture, the aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitate was filtered off to obtain 80 mg of the title compound.

'11 (C1UO1) NMR spectrum) δ: 1.73-1.79 (2H, m), 2.14-2.19 (2H, m), 2.80-2.93 (3H, m), 3 02-3.11 (3H, m), 3.24-3.29 (2H, m), 5.25 (2H, br.s.), 5.61 (0.7x1H, t), 6, 05 (0.3x1H, t), 6.72 (1H, d), 7.22-7.40 (8H, m), 7.52-7.65 (1H, m), 7.75 (0, 7x1H, d), 7.80 (0.3x1H, d). MS t / ζ: 490 (M + 1).

Example 25. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-dimethylaminocarbonyl dibenz [b, e] -oxepin-11ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure for Example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with 11- (3-bromopropylidene) -2-dimethylaminocarbonyl-6.11 -dihydrodibenz [b, e] oxepine.

'11 NMR spectrum (SPS1 ₃ ) δ: 1.62-1.67 (2H, m), 2.00-2.12 (2H, m), 2.37-2.47 (8H, m), 2 89 (6H, s), 5.25 (2H, br.s), 5.68 (0.7x1H, t), 6.03 (0.3x1H, t), 6.71 (0.3x1H, d) 6.78 (0.7x1H, d), 7.13-7.40 (10H, m). MS t / ζ: 517 (M + 1).

Example 26. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-hydroxymethyldibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol.

To a solution of 110 mg of (4-chlorophenyl) -1- [3- (6,11-dihydromethoxycarbonyl-dibenz [b, e] -oxepin-11ylidene) propyl] piperidin-4-ol in 8 ml of THF was added dropwise 0.42 ml of a 1 molar solution of lithium aluminum hydride at 0 ° C and the reaction mixture was stirred for 1 h at room temperature. A 1 molar aqueous solution of sodium hydroxide was added to the reaction mixture, stirred for 30 minutes, then ethyl acetate and brine were added to the mixture. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with a 10: 1 dichloromethane: methanol mixture to give 90 mg of the title compound.

'11 NMR spectrum (SPS1 ₃ ) δ: 1.61-1.66 (2H, m), 1.98-2.03 (2H, m), 2.39-2.48 (3H, m), 2 , 57-2.79 (6H, m), 4.52 (2H, s), 5.20 (2H, b.s.), 5.66 (0.8x1H, t), 6.01 (0, 2x1H, t), 6.67 (0.2x1H, d), 6.79 (0.8x1H, d), 7.06 (1H, dd), 7.15-7.37 (9H, m). MS t / ζ: 476 (M + 1).

Example 27. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2- (1-hydroxy-1-methyl) ethyldibenz [b, e] -oxepin-11ilidene) propyl] piperidin-4 -ol.

To a solution of 60 mg of (4-chlorophenyl) -1- [3- (6,11-dihydro-2-methoxycarbonyldibenz- [b, e] -oxepin-11-ylidene) propyl] piperidin-4-ol in 6 ml of THF according to 0.16 ml of a 3 molar solution of methylmagnesium chloride was added dropwise at 0 ° C and the mixture was stirred for 2 hours at room temperature, the reaction in the mixture was quenched by the addition of a saturated aqueous solution of ammonia, then ethyl acetate and water were added to the mixture. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluting with a 95: 5 ethyl acetate / methanol mixture to give 20 mg of the title compound.

'11 NMR spectrum (SPS1 ₃ ) δ: 1.54 (0.7x6H, s), 1.62 (0.3x6H, s), 1.63-1.70 (2H, m), 2.03-2 , 10 (3H, m), 2,382.49 (3H, m), 2.62-2.82 (4H, m), 5.17 (2H, br.s), 5.68 (0.7x1H, t), 6.05 (0.3x1H, t), 6.75 (0.3x1H, d), 6; 83 (0.7x1H, d), 7.18-7.43 (10H, m). MS t / ζ: 504 (M + 1).

Example 28. 4- (4-Chlorophenyl) -1- [3- (2-cyano-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with 11- (3-bromopropylidene) -2-cyano-6,11 dihydrodibenz [B, e] oxepine.

¹ H NMR spectrum (SPS1 ₃ ) δ: 1.67-1.72 (2H, m), 2.02-2.13 (2H, m), 2.37-2.77 (8H, m), 5 , 35 (2H, br.s), 5.75 (0.7x1H, t), 6.07 (0.3x1H, t), 6.78 (0.3x1H, d), 6.82 (0, 7x1H, d), 7.25-7.51 (10H, m). MS t / ζ: 471 (M + 1).

Example 29. 1- [3- (2-Aminomethyl-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

To a solution of 380 mg of 4- (4-chlorophenyl) -1- [3- (2-cyano-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol in 20 ml of ethanol is added 60 mg of Raney nickel (50% suspension in water) and the mixture was hydrogenated at 100 kPa (15 psi) for 2 hours. The mixture was filtered.

- 24 008060 through a layer of celite and distilled under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture (95: 5: 1) dichloromethane: methanol: aqueous ammonia to give 130 mg of the title compound.

¹ H NMR spectrum (СОС1 ₃ ) δ: 1.76-1.94 (3Н, m), 2.18-2.34 (2Н, m), 2.85-3.10 (8Н, m), 3 88 (2H, s), 5.30 (2H, br.s), 5.59 (1H, t), 6.78 (1H, d), 7.13-7.40 (10H, m) . MS t / ζ: 475 (M + 1).

Example 30. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-nitrodibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 1, but replacing 5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with 11- (3-bromopropylidene) -6,11-dihydro-2 nitrodibenz [B, e] oxepine.

Nuclear Magnetic Resonance Spectrum Ή (SBS1 ₃ ) δ: 1.62-1.67 (2H, m), 1.80-2.12 (3H, m), 2.28-2.78 (8H, m), 5, 05 (0.3x2H, bhp), 5.40 (0.7x2H, bhp), 5.90 (0.7x1H, t), 6.17 (0.3x1H, t), 6, 82 (0.3x1H, d), 6.92 (0.7x1H), 7.28-7.41 (8H, m), 8.15 (0.7x1H, d), 8.22 (0.3x1H, e). MS t / ζ: 491 (M + 1).

Example 31. 1- [3- (2-Amino-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

To a solution of 120 mg of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-nitrodibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol in 15 ml of ethanol is added 190 mg of tin (II) chloride and the mixture was heated to boiling for 1 hour. The solvent was distilled off under reduced pressure. Ethyl acetate and an aqueous solution of sodium hydroxide are added to the residue to neutralize. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluting with a 95: 5 dichloromethane: methanol mixture to obtain 70 mg of the title compound.

Я NMR spectrum (DMSO-b ₆ ) δ: 1.54-1.60 (2H, m), 1.85-2.00 (2H, m), 2.30-2.80 (8H, m), 3.88 (2H, s), 5.07 (2H, br.s), 5.66 (1H, t), 6.41-6.46 (2H, m), 6.59 (1H, d ), 7.24-7.49 (8H, m). MS t / ζ: 461 (M + 1).

Example 32. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-hydroxydibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol.

Stage 1

11- (3-Bromopropylidene) -6,11-dihydro-2-hydroxydibenz [b, e] oxepine is obtained following the procedure of Example 45, steps 1 and 2, but replacing 5,11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin-5-one on 6,11 dihydro-2-hydroxydibenz [b, f] oxepin-11-one.

'11 NMR spectrum (COS1 ₃ ) δ: 2.69 (2H, t), 3.39 (2H, t), 5.20 (2H, br.s), 5.92 (1H, t), 6 50-6.81 (4H, m); 7.17-7.37 (4H, m).

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with the product of step 1.

'11 NMR spectrum (СОС1 ₃ ) δ: 1.60-1.75 (3Н, m), 1.95-2.10 (2Н, m), 2.35-2.80 (8Н, m), 5 10 (2H, br.s.), 5.93 (1H, br.s), 6.56 (2H, br.s), 6.71 (1H, br.s), 7.11-7, 35 (8H, m). MS t / ζ: 462 (M + 1).

Example 33. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] -oxepin-11-ylidene) propyl] piperidin-4-ol.

Stage 1

11- (3-Bromopropylidene) -6,11-dihydro-2-methoxydibenz [b, e] oxepine is obtained following the procedure of Example 45, stages 1 and 2, but replacing 5,11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin-5-one on 6,11 dihydro-2-methoxydibenz [b, f] oxepin-11-one.

Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ ) δ: 2.74 (2Н, q), 3.43 (2Н, t), 3.77 (3Н, s), 5.10 (2Н, br.s.), 6, 02 (1H, t), 6,706.83 (3H, m), 7.21-7.38 (4H, m).

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with the product of step 1.

NMR spectrum р (СОС1 ₃ ) δ: 1.59-1.65 (2Н, m), 1.95-2.66 (11Н, m), 3.75 (3Н, s), 5.10 (2Н, b.s.), 6.03 (1H, b.s.), 6.82 (1H, b.s.), 7.20-7.40 (8H, m ) MS t / ζ: 476 (M + 1).

Example 34. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-2-ethoxydibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol.

To a solution of 200 mg of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-hydroxydibenz [b, e] -oxepin-11ylidene) propyl] piperidin-4-ol (Example 32) in 5 ml of DMF add 25 mg of sodium hydride (60%, in oil), 0.052 ml of ethyl iodide and the mixture is stirred for 1 h at room temperature. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with a 1: 1 ethyl acetate: hexane mixture to give 170 mg of the title compound.

Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ ) δ: 1.37 (3Н, t), 1.60-1.65 (2Н, m), 1.95-2.08 (3Н, m), 2.28-2, 75 (8H, m), 3.96 (2H, q), 5.15 (2H, bhp), 6.02 (1H, t), 6.68 (2H, bhp), 6 82 (1H, br.s.), 7.19-7.42 (8H, m). MS t / ζ: 490 (M + 1).

- 25 008060

Example 35. 1- [3- (3-Bromo-6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol.

Stage 1

3-Bromo-11- (3-bromopropylidene) -6,11-dihydrodibenz [b, e] oxepine is prepared following the procedure of Example 45, steps 1 and 2, but replacing 5,11-dihydro-7-methoxypyrido [2,3 -c] [1] benzoxepin-5-one on 3-bromo-6,11-dihydrodibenz [b, f] oxepin-11-one.

¹ Η NMR spectrum (SPS1 ₃ ) δ: 2.74 (2Н, t), 3.43 (2Η, t), 3.77 (3Η, s), 5.10 (2Η, br.s), 6 02 (1Η, t), 6,706.83 (3Η, m), 7.21-7.38 (4Η, m).

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with the product of step 1.

'11 NMR spectrum (ΟΌΟ1 ₃ ) δ: 1.63-1.70 (3Η, m), 1.96-2.10 (2Η, m), 2.32-2.69 (8Η, m), 5 , 20 (2H, br.s.), 6.00 (1Η, t), 6.92-7.00 (2Η, m), 7.11-7.14 (1Η, m), 7.24- 7.42 (8Η, m). MS t / ζ: 524, 526 (M + 1).

Example 36. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] -4-methoxypiperidin-4-ol.

To a solution of 400 mg of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] -oxepin-11-ylidene) propyl] piperidin-4-ol (example 2) in 5 ml of DMF add 50 mg of sodium hydride (60%, in oil), 0.07 ml of methyl iodide and the mixture is stirred for 1 h at room temperature. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluting with a 1: 1 ethyl acetate: hexane mixture to give 100 mg of the title compound.

'11 NMR spectrum (SPS1 ₃ ) δ: 1.90-2.04 (4Η, m), 2.34-2.62 (8Η, m), 2.93 (3Η, s), 5.25 (2Η , b.h.), 6.04 (1Η, t), 6.75-6.91 (3Η, m), 7.09-7.37 (9Η, m). MS t / ζ: 460 (M + 1).

Example 37. 4-Acetoxy-4- (4-chlorophenyl) -1- [3- (6,11-dihydrodibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4-ol.

To a solution of 200 mg of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] -oxepin-11-ylidene) propyl] piperidin-4-ol (example 2) 0.06 ml of acetyl chloride and 0.19 ml of triethylamine are added to 5 ml of dichloromethane and the mixture is stirred for 1 h at room temperature. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluting with a 1: 4 ethyl acetate: hexane mixture to give 190 mg of the title compound.

'11 NMR spectrum (СОС1 ₃ ) δ: 1.98-2.85 (12Η, m), 2.02 (3Η, s), 2.93 (3Η, s), 5.23 (2Η, br.s .), 6.01 (1Η, t), 6.73-6.90 (3Η, m), 7.11-7.40 (9Η, m). MS t / ζ: 488 (M + 1).

Example 38. 1- [3- (8-Bromo-4,10-dihydrothieno [3,2-c] [1] benzoxepin-10-ylidene) propyl] piperidin-4 (4-chlorophenyl) -4-ol.

Stage 1

8-Bromo-10- (3-bromopropylidene) -4,10-dihydrothieno [3,2-c] [1] benzoxepine is obtained following the procedure of example 45, stages 1 and 2, but replacing 5,11-dihydro-7- methoxypyrido [2,3-s] [1] benzoxepin-5-one on 4,10 dihydrothieno [3,2-s] [1] benzoxepin-10-one.

'11 NMR spectrum (CBC1 ₃ ) δ: 2.84 (2H, q), 3.45 (2Η, t), 5.10 (2H, s), 6.11 (1Η, t), 6.11 ( 1Η, t), 7.03-7.08 (2Η, m), 7.38-7.43 (2Η, m).

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with the product of step 1.

'11 NMR spectrum (CBC1 ₃ ) δ: 1.66-1.75 (3Η, m), 2.03-2.16 (2Η, m), 2.40-2.86 (8Η, m), 5 , 09 (0.7x2H, s), 5.14 (0.3x2H, s), 5.90 (0.3xW, t), 6.10 (0.7xW, t), 6.64 (0.7x1H d) 6.75 (0.3x1H, d), 6.90 (0.3x1H, d), 7.037.09 (2Η, m), 7.21-7.45 (6Η, m). MS t / ζ: 532 (M + 1).

Example 39. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidin-4-ol.

Stage 1

11- (3-Bromopropylidene) -6,11-dihydro-6-oxo-5H-dibenz [b, e] azepine is prepared following the procedure of Example 45, steps 1 and 2, but replacing 5,11-dihydro-7-methoxypyrido - [2,3-c] [1] -benzoxepin-5-one on 6,11 dihydro-6-5H-dibenz [b, e] azepin-6,11-dione.

'11 NMR spectrum (СОС1 ₃ ) δ: 2.70-2.92 (2Н, m), 3.45 (2Η, t), 5.92 (1Η, t), 7.08-7.58 (7Η , m), 8.05 (1H, dd), 9.00 (1Η, br.s.).

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with the product of step 1.

'11 NMR spectrum (ΟΌΟ1 ₃ ) δ: 1.61-1.66 (2Η, m), 1.97-2.20 (3Η, m), 2.35-2.68 (8Η, m), 5 80 (1Η, t), 7.037.53 (11Η, m), 8.02 (1Н, dd), 9.27 (1Η, br.s.). MS t / ζ: 459 (M + 1).

- 26 008060

Example 40. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-5-ethyl-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidin-4 -ol.

The title compound was prepared following the procedure of Example 12, but replacing benzyl bromide with ethyl iodide.

¹ H NMR spectrum (SPS1 ₃ ) δ: 1.19-1.28 (3H, m), 1.63-1.69 (2H, m), 1.99-2.16 (3H, m), 2 , 37-2.7 (8H, m), 3.77-3.85 (1H, m), 4.40-4.48 (1H, m), 5.85 (1H, t), 7.12 -7.45 (11H, m) 7.85 (1H, dd). Mass spectrum (MS) t / ζ: 487 (M + 1).

Example 41. 1- [3- (5-n-Butyl-6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidine -4-ol

The title compound was prepared following the procedure of Example 12, but replacing benzyl bromide with n-butyl iodide.

NMR spectrum р (SBS1 ₃ ) δ: 0.90-0.98 (3H, m), 1.25-2.20 (9H, m), 2.40-2.87 (8H, m), 3, 62-3.72 (1H, m), 4.52-4.64 (1H, m), 5.85 (1H, t), 7.16-7.45 (11H, m) 7.88 (1H , dd). MS t / ζ: 515 (M + 1).

Example 42. 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-5- (3-hydroxypropyl) -6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl ] piperidin-4-ol.

To a solution of 500 mg of hydrochloric 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] piperidin-4 -ol (Example 39) in 8 ml of DMF add 200 mg of sodium hydride (60%, in oil), 0.5 ml of 2- (3-bromopropoxy) tetrahydro-2H-pyran and the mixture is stirred for 6 hours at room temperature. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in a 1 molar solution of hydrogen chloride in diethyl ether and stirred for 1 h at room temperature. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate to give 250 mg of the title compound.

Nuclear Magnetic Resonance Spectrum Ή (SHS1 ₃ ) δ: 1.25-2.87 (15Н, m), 3.51-3.56 (2Н, m), 3.76-3.82 (1Н, m), 4, 81-4.87 (1H, m), 5.86 (1H, t), 7.16-7.45 (11H, m), 7.82 (1H, dd). MS t / ζ: 517 (M + 1).

Example 43. 1 - [3 - (5-tert-Butoxycarbonylmethyl-6,11-dihydro-6-oxo-5H-dibenz [b, e] azepin-11-ylidene) propyl] -4- (4-chlorophenyl) piperidine -4-ol

The title compound was prepared following the procedure of Example 12, but replacing benzyl bromide with tert-butyl bromoacetate.

'11 NMR spectrum (SPS1 ₃ ) δ: 1.50 (9H, s), 1.65-1.70 (2H, m), 1.95-2.10 (3H, m), 2.42-2 75 (8H, m), 4.24 (1H, d), 4.75 (1H, d), 5.88 (1H, t), 7.16-7.46 (11H, m) 7.90 (1H, dd). (MS) t / ζ: 573 (M + 1).

Example 44. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

Stage 1

To a solution of 4.3 g of the product of Example 45, step 1, in 100 ml of dichloroethane was added 19.3 g of a boron-methyl sulfide tribromide complex and the mixture was heated to boiling for 3 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with a dilute hydroxide solution sodium. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with (1: 2) ethyl acetate: hexane to give 3.2 g of 5- (3-bromopropylidene) -5,11-dihydro-7hydroxy [1] benzoxepino- [2,3-b] pyridine .

'11 NMR spectrum (SPS1 ₃ ) δ: 2.72 (2H, t), 3.45 (2H, t), 5.28 (2H, br.s), 6.03 (1H, t), 6 66-6.80 (3H, m),

7.26 (1H, dd), 7.58 (1H, dd), 8.51 (1H, dd).

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridine with the product of step 1.

'11 NMR spectrum (DMSO-b ₆ ) δ: 1.46-1.51 (2H, m), 1.74-1.85 (2H, m), 2.29-2.51 (8H, m) 5.15 (2H, br.s.), 6.07 (1H, t), 6.61-6.70 (3H, m), 7.33-7.48 (5H, m), 7, 73 (1H, dd), 8.47 (1H, dd), 9.06 (1H, s). MS t / ζ: 463 (M + 1).

Example 45. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

Stage 1

To a solution of 5.09 g of 5.11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one in 50 ml of tetrahydrofuran (THF), 25 ml of a 1.1 molar solution are added at 0 ° C. solution of cyclopropyl magnesium bromide in THF. The reaction mixture was warmed to room temperature and stirred for 30 minutes. An aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue is filtered and washed with a mixture (1: 2) ethyl acetate: hexane,

- 27 008060, yielding 5.0 g of 5-cyclopropyl-5,11-dihydro-7-methoxy [1] benzoxepino- [2,3-b] pyridin-5-ol.

Stage 2

To a solution of 4.3 g of the product of stage 1 in acetic acid (30 ml) was added 25 ml of aqueous hydrogen bromide (48% HBg) at 10 ° C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture, and neutralized with a diluted solution of #UN. The organic layer was isolated and washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate: hexane (1: 4) to obtain 5 (3-bromopropylidene) -5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridine (5, 6 g).

'H-NMR (SBS _{1 3} ) δ: 2.74 (2H, t), 3.46 (2H, t), 3.78 (3H, s), 5.25 (2H, br.s.), 6 07 (1H, t), 6.72-6.82 (3H, m), 7.21-7.42 (5H, m), 7.56 (1H, dd), 8.45 (1H, dd )

Stage 3.

To a solution of 1.1 g of the product of stage 2 in DMF (15 ml), 4- (4-chlorophenyl) -4-hydroxypiperidine (0.81 g) and potassium carbonate (0.53 g) were added and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with a mixture of methylene chloride: methanol (10: 1) to obtain the title compound as the main regioisomer (0.86 g) and 0.05 g of the secondary regioisomer.

The main isomer.

'H-NMR (SPS1 ₃ ) δ: 1.64-1.69 (2H, m), 1.91-2.08 (3H, m), 2.34-2.69 (8H, m), 3 77 (3H, s), 5.25 (2H, br.s), 6.07 (1H, t), 6.72-6.82 (3H, t), 7.21-7.42 ( 5H, m), 7.56 (1H, dd), 8.45 (1H, dd). MS t / ζ: 477 (M + 1).

Minor isomer.

'H-NMR (SPS1 ₃ ) δ: 1.65-1.79 (3H, m), 2.01-2.13 (2H, m), 2.35-2.76 (8H, m), 3 76 (3H, s), 5.22 (2H, br.s), 5.95 (1H, t), 6.72-6.80 (2H, m), 7.06 (1H, d) 7.16 (1H, dd), 7.28 (2H, d), 7.42 (2H, d), 7.66 (1H, dd), 8.39 (1H, dd). MS t / ζ: 477 (M + 1).

Example 46. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure for Example 34, but replacing 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-2-hydroxydibenz [b, e] oxepin-11-ylidene) propyl] piperidine -4-ol on 4- (4chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidin-4ol (Example 44) .

'H-NMR (СОС1 ₃ ) δ: 1.38 (3Н, m), 1.67-1.72 (3Н, m), 2.05-2.16 (2Н, m), 2.40-2 , 80 (8H, m), 3.99 (2H, q),

5.26 (2H, br.s.), 6.05 (1H, t), 6.71-6.82 (3H, m), 7.23-7.43 (5H, m), 7.57 (1H, dd), 8.47 (1H, dd). MS t / ζ: 491 (M + 1).

Example 47. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-isopropoxy [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with isopropyl bromide.

'H-NMR (СОС1 ₃ ) δ: 1.30 (6Н, d), 1.60-1.70 (3Н, m), 1.99-2.09 (2Н, m), 2.33-2 69 (8H, m), 4.37-4.48 (1H, m), 5.26 (2H, br.s), 6.06 (1H, t), 6.73-6.82 ( 3H, m), 7.21-7.43 (5H, m), 7.55 (1H, dd), 8.47 (1H, dd). MS t / ζ: 505 (M + 1).

Example 48. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxycarbonylmethyloxy [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl bromoacetate.

'H-NMR (СОС1 ₃ ) δ: 1.28 (3Н, m), 1.63-1.68 (2Н, m), 1.97-2.02 (3Н, m), 2.33-2 68 (8H, m), 4.24 (2H, q), 4.55 (2H, s), 5.26 (2H, br.s), 6.06 (1H, t), 6.73 -6.88 (3H, m), 7.21-7.42 (5H, m), 7.55 (1H, dd), 8.44 (1H, dd). MS t / ζ: 549 (M + 1).

Example 49. 4- (4-Chlorophenyl) -1- [3- (7-cyanomethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with bromoacetonitrile.

'H-NMR (ΟΌΟ1 ₃ ) δ: 1.62-1.67 (2H, m), 1.94-2.06 (2H, m), 2.21 (1H, br.s.), 2, 34-2.66 (8H, m), 4.70 (2H, 8),

5.26 (2H, br.s.), 6.10 (1H, br.s), 6.80 (2H, br.s), 6.92 (1H, br.s), 7.22-7 41 (5H, m), 7.56 (1H, dd), 8.44 (1H, dd). MS t / ζ: 502 (M + 1).

Example 50. 1- [3- (7- (2-Acetoxyethyl) oxy-5,11-dihydro [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidine 4-ol

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with 2-bromoethyl acetate.

'H-NMR (ΟΌΟ1 ₃ ) δ: 1.65-1.72 (3H, m), 1.97-2.09 (5H, m), 2.37-2.70 (8H, m), 4 11-4.14 (2H, m), 4.37-4.41

- 28 008060 (2H, m), 5.25 (2H, br.s), 6.07 (1H, t), 6.75-6.84 (3H, m), 7.23-7.43 (5H, m), 7.56 (1H, dd), 8.47 (1H, dd). MS t / ζ: 549 (M + 1).

Example 51. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-hydroxyethyl) oxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

To a solution of 140 mg of 1- [3- (7- (2-acetoxyethyl) oxy-5,11 [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4chlorophenyl) piperidin-4 -ol (example 50) in ethanol (5 ml) add 2 ml of a 15% aqueous sodium hydroxide solution and the mixture is refluxed for 1 hour. Water and ethyl acetate are added to the reaction mixture, the organic layer is isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with a mixture of methylene chloride: methanol (10: 1) to obtain the title compound (120 mg).

¹ H-NMR (SBS _{1 3} ) δ: 1.64-1.69 (2H, m), 1.98-2.10 (3H, m), 2.36-2.79 (8H, m), 3 89-3.94 (2H, m), 3.99-4.04 (2H, m), 5.24 (2H, br.s), 6.04 (1H, t), 6.71- 6.84 (3H, m), 7.23-7.41 (5H, m), 7.54 (1H, dd), 8.43 (1H, dd). MS t / ζ: 507 (M + 1).

Example 52. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-morpholinoethyl) oxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with 4- (2-chloroethyl) morpholine hydrochloride.

¹ H-NMR (CBC1 ₃ ) δ: 1.62-1.67 (2H, m), 1.95-2.08 (2H, m), 2.20-2.67 (13H, m), 2 74 (2H, t), 3.67-3.71 (4H, m), 4.04 (2H, t), 5.23 (2H, br.s), 6.05 (1H, t) 6.73-3.82 (3H, m), 7.20-7.41 (5H, m), 7.53 (1H, dd), 8.42 (1H, dd). MS t / ζ: 576 (M + 1).

Example 53. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

Stage 1

5- (3-Bromopropylidene) -5,11-dihydro [1] benzoxepino [2,3-b] pyridine is prepared following the procedure of Example 45, steps 1 and 2, but replacing 5,11-dihydro-7-methoxy [1 ] benzoxepino [2,3-b] pyridin-5-one on 5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-one.

¹ H-NMR (CBC1 ₃ ) δ: 2.71 (2H, t), 3.46 (2H, t), 5.33 (2H, br.s), 6.04 (1H, t), 7 01-7.17 (3H, m), 7.29 (1H, dd), 7.56 (1H, dd), 8.53 (1H, dd).

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridine with the product of step 1.

¹ H-NMR (СОС1 ₃ ) δ: 1.66-1.71 (2Н, m), 2.00-2.20 (3Н, m), 2.36-2.69 (8Н, m), 5 34 (2H, br.s), 6.10 (1H, t), 6.83-6.96 (3H, m), 7.17-7.44 (6H, m), 7.60 ( 1H, dd), 8.46 (1H, dd). MS t / ζ: 447 (M + 1).

Example 54. 1- [3- (8-Bromo-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol .

Stage 1

8-Bromo-5- (3-bromopropylidene) -5,11-dihydro [1] benzoxepino [2,3-b] pyridine is obtained following the procedure of Example 45, steps 1 and 2, but replacing 5,11-dihydro-7 -methoxy [1] benzoxepino [2,3-b] pyridin-5-one on 8-bromo-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-one.

¹ H-NMR (CBC1 ₃ ) δ: 2.75 (2H, t), 3.50 (2H, t), 5.38 (2H, br.s), 6.08 (1H, t), 6 85-6.98 (2H, m), 7.18-7.35 (3H, m), 7.59 (1H, dd), 8.54 (1H, dd).

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -5,11 dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridine with the product of step 1.

¹ H-NMR (СОС1 ₃ ) δ: 1.64-1.69 (2Н, m), 1.90-2.07 (3Н, m), 2.30-2.67 (8Н, m), 5 30 (2H, br.s), 6.08 (1H, t), 7.00-7.07 (2H, m), 7.13 (1H, d), 7.25-7.42 ( 5H, m), 7.56 (1H, dd), 8.47 (1H, dd). MS t / ζ: 525, 527 (M + 1).

Example 55. 4- (4-Chlorophenyl) -1- [3- (10,11-dihydro-10-oxo-5H-pyrido [2,3c] [2] benzazepin-5-ylidene) propyl] piperidin-4- ol.

Stage 1

5- (3-Bromopropylidene) -10,11-dihydro-10-oxo-5H-pyrido [2,3-c] [2] benzazepine is obtained following the procedure of Example 45, steps 1 and 2, but replacing 5.11- dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one on 10,11-dihydro-5H-pyrido [2,3-c] [2] benzazepine-5,10-dione.

¹ H-NMR (SBS _{1 3} ) δ: 2.75-2.90 (2H, m), 3.45 (2H, t), 5.92 (1H, t), 7.04-7.70 (5H , m), 8.10 (1H, dd), 8.48 (1H, dd), 10.00 (1H, br.s.).

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 5 (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [a, b] cycloheptene with the product of step 1.

¹ H-NMR (COS1 ₃ ) δ: 1.64-1.69 (3H, m), 2.00-2.12 (2H, m), 2.35-2.70 (8H, m), 5 82 (1H, d), 7.08 (1H, dd), 7.23-7.62 (8H, m), 8.04 (1H, dd), 8.32 (1H, dd), 8, 76 (1H, br.s.). MS t / ζ: 460 (M + 1).

Example 56. 4- (4-Chlorophenyl) -1- [3- (10,11-dihydro-11-methyl-10-oxo-5H-pyrido [2,3-s] [2] benzase

- 29 008060 pin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 36, but replacing 4- (4chlorophenyl) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4 -ol on 5- (3-bromopropylidene) -10,11-dihydro-10-oxo-5H-pyrido [2,3-s] [2] benzazepine.

Ή-NMR (SBS1 ₃ ) δ: 1.64-1.70 (3Η, m), 2.00-2.10 (2Η, m), 2.41-2.69 (8Η, m), 3, 62 (3Η, s), 5.82 (1Η, t), 7.07 (1H, dd), 7.25-7.54 (8Η, m), 7.91 (1H, dd), 8.34 (1H, dd). MS t / ζ: 474 (M + 1).

Example 57. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) ethyl] piperidin-4-ol .

Stage 1

In a solution of methyltriphenylphosphonium bromide (2.2 g) in 20 ml of THF, a 1.6 molar solution of n-butyllithium in hexane (2.9 ml) is added at a temperature of 0 ° C over 30 minutes. 5.11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one (1.0 g) was added dropwise to the reaction mixture, cooled to 0 ° C., as a solution in THF (5 ml) and the mixture was warmed to room temperature and stirred for 3 hours. An aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate: hexane (1: 4) to give 5.11-dihydro-7-methoxy-5-methylenepyrido [2,3-c] [1] benzoxepine (0.14 g).

Stage 2

Phosphorus oxychloride (0.41 ml) was added to a DMF solution (0.54 ml) over 10 minutes at 0 ° C. The product of stage 1 (210 mg) in carbon tetrachloride (5 ml) was added to this reaction mixture, and the mixture was refluxed for 5 hours. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixture, the organic layer was isolated, washed with saturated aqueous sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate: hexane (1: 4) to give 3- (5.11 dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) acetaldehyde (130 mg )

Я-NMR (SBS1 ₃ ) δ: 3.77 (0.7x3S s), 3.79 (0.3x3S s), 5.31 (2H, s), 6.46 (0.7x1H, d), 6 52 (0.3x1H, d), 6.78-7.40 (4Η, m), 7.68 (0.3x1H, dd), 7.78 (0.7x1H, dd), 8.55 (0 , 7x1H, dd), 8.64 (0.3xW, dd), 9.62 (0.3x1H, d), 9.79 (0.7x1H, d).

Stage 3.

The title compound was prepared following the procedure of Example 58, step 2, but replacing 3 (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propanaldehyde with the product of step 2.

Ή-NMR (SPS1 ₃ ) δ: 1.64-1.82 (2Η, m), 1.92-2.22 (3Η, m), 2.43-2.58 (2Η, m), 2, 79-3.45 (6Η, m), 3.68 (0.3х3 Щ s), 3.70 (0.7х3 Щ с), 5.24 (2Η, Ш.С), 6.18 (0.7хШ , t), 6.21 (0.3xW, t), 6.72-7.42 (8Η, m), 7.78 (0.3x1H, dd), 7.85 (0.7x1H, dd), 8.42 (0.7x1H, dd), 8.46 (0.3x1H, dd). MS t / ζ: 463 (M + 1).

Example 58. 4- (4-Chlorophenyl) -1- [4- (5,11-dihydro-7methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) butyl] piperidin-4-ol.

Stage 1

3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propenaldehyde is prepared following the procedure of Example 57, step 2, but replacing 5,11-dihydro-7- methoxy-5-methylene [1] benzoxepino [2,3-b] pyridine on 5,11-dihydro-7-methoxy-5- (propyl-1-ene) [1] benzoxepino [2,3-b] pyridine ( a by-product of example 45, step 3).

Ή-NMR (SBS1 ₃ ) δ: 3.78 (Θ ^ Η, s), 3.80 (0.7х3 Щ s), 5.32 (2Η, b.s.), 6.34-6.39 ( 1Η, m), 6.72-7.38 (6Η, m), 7.58 (0.7x1H, dd), 7.77 (0.3x1H, dd), 8.49 (0.3x1H, dd) 8.60 (0.7x1H, dd), 9.51 (0.7x1H, d), 9.54 (0.3x1H, d).

Stage 2

Sodium triacetoxyborohydride borohydride (170 mg), 4- (4chlorophenyl) -4-hydroxypiperidine (70 mg) and acetic acid (0.02 ml) are added to a solution of the product of stage 1 (90 mg) in dichloromethane (6 ml) and the mixture is stirred at room temperature 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was isolated and washed with saturated aqueous sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with dichloromethane / methanol (95: 5) to give 4- (4-chlorophenyl) 1- [4- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3- B] pyridin-5-ylidene) buten-2-yl] piperidin-4-ol (110 mg).

Ή-NMR (SBS1 ₃ ) δ: 1.68-1.73 (2Η, m), 2.04-2.16 (2Η, m), 2.43-2.72 (3Η, m), 2, 77-2.81 (2Η, m), 3.08-3.13 (2Η, m), 3.73 (0.3х3 Щ s), 3.77 (0.7х3 Щ s), 5.20 (2Η, b.s.), 5.98-6.05 (1Η, m), 6.23-7.43 (10Η, m), 7.58 (0.7x1H, dd), 7.65 (0.3x1H dd), 8.37 (0.3xW, dd), 8.45 (0.7xW, dd). MS t / ζ: 489 (M + 1).

Stage 3.

A catalyst of 10% Pb / C (2 mg) was added to a solution of the product of stage 2 (8 mg) in ethanol (2 ml), stirred in a hydrogen atmosphere (from a balloon) at room temperature for 1 h. The mixture was filtered through celite and distilled under reduced pressure to obtain the title compound

- 30 008060 unit (6 mg).

¹ H-NMR (SBS _{1 3} ) δ: 1.68-3.00 (15H, m), 3.77 (3H, s), 5.18-5.35 (2H, m), 5.94 (0 , 4H, t, E isomer), 6.06 (0.6H, t, Ζ isomer), 6.65-6.88 (3H, m), 7.05-7.73 (6H, m), 8 30-8.56 (1H, m). MS t / ζ: 491 (M + 1).

Example 59. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-phenyl-4-ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4-phenyl-4-hydroxypiperidine.

¹ H-NMR (СОС1 ₃ ) δ: 1.68-1.73 (2Н, m), 2.02-2.15 (3Н, m), 2.38-2.72 (8Н, m), 3 77 (3H, s), 5.26 (2H, br.s), 6.08 (1H, t), 6.72-6.83 (3H, m), 7.21-7.36 ( 4H, m), 7.46-7.49 (2H, m), 7.58 (1H, dd), 8.46 (1H, dd). MS t / ζ: 443 (M + 1).

Example 60. 4- (4-Bromophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-bromophenyl) -4-hydroxypiperidine.

¹ H-NMR (СОС1 ₃ ) δ: 1.65-1.69 (2Н, m), 2.00-2.10 (3Н, m), 2.37-2.71 (8Н, m), 3 76 (3H, s), 5.24 (2H, br.s), 6.05 (1H, t), 6.70-6.82 (3H, m), 7.24 (1H, dd) 7.38 (2H, d), 7.44 (2H, s), 7.52 (1H, dd), 8.44 (1H, dd). MS t / ζ: 521, 523 (M + 1).

Example 61. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4-hydroxypiperidine.

¹ H-NMR (CBC1 ₃ ) δ: 1.43-1.60 (2H, m), 1.80-1.98 (2H, m), 2.00-2.18 (3H, m), 2 34-2.48 (4H, m), 2.63-2.76 (2H, m), 3.64-3.73 (1H, m), 3.70 (3H, 8), 5.35 (2H, br.s), 6.06 (1H, t), 6.74-6.84 (3H, m), 7.25 (1H, dd), 7.60 (1H, dd), 8 50 (1H, dd). MS t / ζ: 367 (M + 1).

Example 62. 4-Benzyl-1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4-benzyl-4-hydroxypiperidine.

¹ H-NMR (SBS _{1 3} ) δ: 1.42-1.57 (3H, m), 1.62-1.75 (2H, m), 2.22-2.70 (8H, m), 2 79 (2H, s), 3.80 (3H, s),

5.25 (2H, br.s), 6.08 (1H, t), 6.73-6.84 (3H, m), 7.18-7.24 (6H, m), 7.57 (1H, dd), 8.50 (1H, dd). MS t / ζ: 457 (M + 1).

Example 63. 4-Cyano-1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4-phenylpiperidine.

The title compound was prepared following the procedure for Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4-cyano-4-phenylpiperidine.

'H-NMR (СОС1 ₃ ) δ: 1.97-2.06 (4Н, m), 2.37-2.60 (6Н, m), 2.85-2.90 (2Н, m), 3 79 (3H, s), 5.27 (2H, br.s), 6.08 (1H, t), 6.72-6.84 (3H, m), 7.24-7.58 ( 7H, m), 8.49 (1H, dd). MS t / ζ: 452 (M + 1).

Example 64. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4-phenylpiperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4-phenylpiperidine.

'H-NMR (SBS _{1 3} ) δ: 1.73-1.79 (4H, m), 1.96-2.03 (2H, m), 2.37-2.52 (5H, m), 2 86-2.94 (2H, m), 3.77 (3H, s), 5.26 (2H, br.s.). 6.08 (1H, t), 6.72-6.83 (3H, m), 7.17-7.31 (6H, m), 7.56 (1H, dd), 8.49 (1H, dd). MS t / ζ: 426 (M + 1).

Example 65. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine.

The title compound was prepared following the procedure for Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) piperidine.

Я-NMR (SBS1 ₃ ) δ: 1.68-1.74 (4H, m), 1.96-2.03 (2H, m), 2.36-2.48 (5H, m), 2, 89-2.94 (2H, m), 3.77 (3H, s), 5.27 (2H, br.s), 6.07 (1H, t), 6.73-6.83 (3H , m), 7.10-7.27 (5H, m), 7.57 (1H, dd), 8.48 (1H, dd). MS t / ζ: 461 (M + 1).

Example 66. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4-piperidinopiperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4-piperidinopiperidine.

Я-NMR (SBS1 ₃ ) δ: 1.40-2.00 (12Н, m), 2.15-2.60 (9Н, m), 2.80-2.92 (2Н, m), 3, 80 (3H, s), 5.28 (2H, br.s), 6.05 (1H, t), 6.75-6.86 (3H, m), 7.30 (1H, dd), 7.55 (1H, dd), 8.46 (1H, dd). MS t / ζ: 434 (M + 1).

Example 67. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (2keto-1-benzimidazolinyl) piperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (2-keto-1-benzimidazolinyl) piperidine.

- 31 008060 ¹ H-NMR (SBS _{1 3} ) δ: 1.75-1.79 (2H, m), 2.03-2.15 (2H, m), 2.38-2.52 (6H, m ), 2.93-2.98 (2H, m), 3.78 (3H, s), 4.30-4.38 (1H, m), 5.30 (2H, br.s.), 6 10 (1H, t), 6.73-6.84 (3H, m), 7.01-7.03 (3H, m), 7.21-7.28 (2H, m), 7.59 (1H, dd), 8.48 (1H, dd). MS t / ζ: 483 (M + 1).

Example 68. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (2keto-3-methyl-1-benzimidazolinyl ) piperidine.

The title compound was prepared following the procedure of Example 36, but replacing 4- (4chlorophenyl) -1- [3- (6,11-dihydro-2-methoxydibenz [b, e] oxepin-11-ylidene) propyl] piperidin-4 -ol on 1- [3 (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (2-keto -1-benzimidazolinyl) piperidine.

^! H-NMR (CBC1 ₃ ) δ: 1.72-1.76 (2H, m), 2.09-2.14 (2H, m), 2.23-2.54 (6H, m), 2, 91-2.96 (2H, m), 3.38 (3H, s), 3.77 (3H, s), 4.30-4.37 (1H, m), 5.27 (2H, br. s.), 6.08 (1H, t), 6.71-6.83 (3H, m), 6.93-7.06 (3H, m), 7.23-7.60 (2H, m ), 8.08 (1H, dd), 8.48 (1H, dd). MS t / ζ: 497 (M + 1).

Example 69. 8- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -1-phenyl-1,3,8-triazaspiro [ 4,5] decan-4-one.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one.

^! H-NMR (CBC1 ₃ ) δ: 1.65-1.70 (2H, m), 2.36-2.41 (2H, m), 2.53-2.79 (8H, m), 3, 76 (3H, s), 4.70 (2H, s),

5.25 (2H, br.s), 6.10 (1H, t), 6.71-6.88 (6H, m), 7.21-7.27 (3H, m), 7.58 -7.61 (2H, m), 8.48 (1H, dd). MS t / ζ: 497 (M + 1).

Example 70. 4-Anilino-4-carbamyl-1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4-anilino-4-carbamylpiperidine.

^! H-NMR (CBC1 ₃ ) δ: 1.85-1.90 (2H, m), 2.03-2.08 (2H, m), 2.19-2.46 (6H, m), 2, 62-2.67 (2H, m), 3.75 (3H, s), 3.97 (1H, b.s.), 5.27 (2H, b.s.), 5.53 (1H, b.s.), 6.03 (1H, t), 6.60 (2H, d), 6.70-6.85 (4H, m), 7.12-7.25 (4H, m), 7.53 (1H, dd), 8.46 (1H, dd). MS t / ζ 485 (M + 1).

Example 71. 1- (4-Chlorophenyl) -4- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperazine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1- (4-chlorophenyl) piperazine.

^! H-NMR (CBC1 ₃ ) δ: 2.36-2.53 (8H, m), 3.07-3.09 (4H, m), 3.76 (3H, s), 5.26 (2H, b.s.), 6.08 (1H, t), 6.726.81 (5H, m), 7.16-7.28 (3H, m), 7.56 (1H, dd), 8.49 ( 1H, dd). MS t / ζ: 462 (M + 1).

Example 72. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (2pyrimidyl) piperazine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1- (2-pyrimidyl) piperazine.

^! H-NMR (SPS1 ₃ ) δ: 2.37-2.53 (8H, m), 3.74-3.83 (7H, m), 5.27 (2H, br.s.), 6.08 (1H, t), 6.45 (1H, t), 6.726.83 (3H, m), 7.25 (1H, dd), 7.56 (1H, dd), 8.27 (2H, d) 8.49 (1H, dd). MS t / ζ: 430 (M + 1).

Example 73. 1-Cyclohexyl-4- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperazine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1-cyclohexylpiperazine.

^! H-NMR (CBC1 ₃ ) δ: 1.12-1.27 (6H, m), 1.74-1.86 (6H, m), 2.18-2.52 (11H, m), 3, 76 (3H, s), 5.26 (2H, br.s), 6.04 (1H, t), 6.74-6.81 (3H, m), 7.23 (1H, dd), 7.55 (1H, dd), 8.48 (1H, dd). MS t / ζ: 434 (M + 1).

Example 74. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (2furoyl) piperazine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1- (2-furoyl) piperazine.

^! H-NMR (SPS1 ₃ ) δ: 2.34-2.48 (8H, m), 3.71-3.74 (7H, s), 5.24 (2H, br.s.), 6.05 (1H, t), 6.42 (1H, dd), 6.70-6.80 (3H, m), 6.93 (1H, d), 7.23 (1H, dd), 7.42 ( 1H, d), 7.53 (1H, dd), 8.46 (1H, dd). MS t / ζ: 446 (M + 1).

Example 75. 4- (3-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure for Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (3-chlorophenyl) -4-hydroxypiperidine.

^! H-NMR (СОС1 ₃ ) δ: 1.61-1.75 (2Н, m), 1.98 (1Н, b.s.), 1.99 (2Н, dt), 2.25 (3Н, s ), 2.30-2.76 (8H, m), 3.73 (3H, s), 5.22 (2H, br.s), 5.95 (0.1H, t, E isomer), 6.04 (0.9H, t, Ζ isomer), 6.71-6.89 (3H, m), 6.95 (1H, dd), 7.15-7.20 (0.3H, m, E isomer), 7.21-7.35 (2.7H, m, Ζ isomer), 7.53 (0.9H, dd, Ζ isomer), 7.65 (0.1H, dd, E isomer), 8.35 (0.1H, dd, E isomer), 8.45 (0.9H, dd, Ζ isomer). MS t / ζ: 477 (M + 1).

Example 76. 4- (2-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, step 3, but substituting 4

- 32 008060 (4-chlorophenyl) -4-hydroxypiperidine to 4- (2-chlorophenyl) -4-hydroxypiperidine.

^! H-NMR (C0C1 ₃ ) δ: 1.98-2.08 m), 7.33 (1H, dd), 7.49 (1H, dd), 7.58 (1H, dd), 8.40 ( 0.1H, dd, Ζ isomer),

8.47 (0.9H, dd, E isomer). MS t / ζ: 477 (M + 1).

Example 77. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4 fluorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-fluorophenyl) -4-hydroxypiperidine.

^! H-NMR (SPS1 ₃ ) δ: 1.58-1.72 (2H, m), 2.04 (2H, dt), 2.22-2.78 (9H, m), 3.75 (3H, s), 5.26 (2H, br.s), 6.09 (1H, t), 6.70-6.88 (3H, m), 7.00 (2H, dd), 7.23 ( 1H, dd), 7.42 (2H, dd), 7.56 (1H, dd), 8.41 (1H, dd). MS t / ζ: 461 (Μ + 1).

Example 78. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (p-tolyl) piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (p-tolyl) -4-hydroxypiperidine.

'H-NMR (SBSl) δ: 1.65-1.78 (2H, m), 2.02 (2H, dt), 2.31 (3H, s), 2.24-2.75 (9H, m), 3.75 (3H, s), 5.25 (2H, br.s), 6.07 (1H, t), 6.72-6.84 (3H, m), 7.13 ( 2H, d), 7.23 (1H, dd), 7.34 (1H, d), 7.56 (1H, dd), 8.43 (1H, dd). MS t / ζ: 457 (M + 1).

Example 79. 4- (3,4-Dichlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (3,4-dichlorophenyl) -4-hydroxypiperidine.

'H-NMR (SPS1 ₃ ) δ: 1.58-1.72 (2H, m), 1.84 (1H, br.s.), 2.02 (2H, td, 2.32-2.72 (8H, m), 3.76 (3H, s), 5.27 (2H, br.s), 5.95 (0.1H, t, E isomer), 6.07 (0.9H, t , Ζ isomer), 6.72-6.85 (3H, m), 7.12-7.20 (0.2H, m, E isomer), 7.21-7.32 (0.18H, m, Ζ isomer), 7.32-7.45 (1H, m), 7.52-7.56 (2H, m), 8.37 (0.9H, dd, E isomer), 8.45 (0, 1H, dd, Ζ isomer). MS t / ζ: 512 (M + 1).

Example 83. 4- (5-Chloropyridin-2-yl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidin-4 -ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (5-chloropyridin-2-yl) -4-hydroxypiperidine.

'H-NMR (SPS1 ₃ ) δ: 1.77-1.82 (2H, m), 2.36-2.94 (11H, m), 3.77 (3H, br.s.), 5, 26 (2H, br.s), 6.07 (1H, t), 6.76-6.84 (3H, m), 7.26 (1H, dd), 7.57 (1H, dd), 8.49-7.48 (1H, d); 8.42-8.53 (3H, m). MS t / ζ: 478 (M + 1).

Example 85. 4- (5-Chloro-2-keto-1-benzimidazolinyl) 1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (5-chloro-2-keto-1-benzimidazolinyl) piperidine.

'H-NMR (SPS1 ₃ ) δ: 1.68-1.72 (2H, m), 2.03-2.60 (8H, m), 2.90-3.02 (2H, m), 3 78 (3H, s), 4.32-4.21 (1H, m), 5.29 (2H, br.s), 5.95 (0.1H, t, E isomer), 6.08 (0.9H, t, Ζ isomer), 6.70-6.92 (3H, m), 7.02 (1H, dd), 7.087.20 (1H, m), 7.26 (1H, dd) 7.58 (0.9H, dd, Ζ isomer), 7.70 (0.1H, dd, E isomer), 8.42 (0.1H, dd, E isomer),

8.48 (0.9H, dd, Ζ isomer), 10.5 (1H, s), (group ΝΉ is not observed in the spectrum). MS t / ζ: 517 (M + 1).

Example 86. 4- (p-Chloralino) -1- [3- (5,11-dihydro-7methoxy [1] benzoxepino [2,3-b] pyridin-5ilidene) propyl] piperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (chloranilino) piperidine.

'H-NMR (SBSl) δ: 1.20-1.54 (2H, m), 1.85-2.20 (4H, m), 2.24-2.60 (4H, m), 2, 73 (2H, m), 3.18 (1H, m), 3.77 (3H, s), 5.27 (2H, br.s.), 6.06 (1H, t), 6.47 ( 2H, m), 6.68-6.90 (3H, m), 7.07 (2H, m), 7.24 (1H, dd), 7.57 (1H, m), 8.48 (1H , dd). ΝΉ no signal is observed. MS t / ζ: 476 (M + 1).

Example 89. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (ptosyl) piperazine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1- (p-tosyl) piperazine.

'H-NMR (SPS1 ₃ ) δ: 2.20-2.54 (1H, m), 2.82-3.10 (4H, m), 3.73 (3H, s), 5.16 (2H) bp), 6.00 (1H, t), 6.666.85 (3H, m), 7.21 (1H, dd), 7.31 (2H, m), 7.51 (1H, dd ), 7.61 (2H, m), 8.45 (1H, dd). MS t / ζ: 506 (M + 1).

Example 90. 1 '- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] spiro [isobenzofuran-1 (3H), 4'- piperidine].

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with spiro [isobenzofuran-1 (3H), 4'-piperidine].

'H-NMR (SBSl) δ: 1.62-1.82 (2H, m), 1.92 (2H, dt), 2.25-2.85 (8H, m), 3.76 (3H, s), 5.03 (2H, s), 5.30 (2H, br.s), 6.11 (1H, t), 6.68-6.90 (3H, m), 7.02- 7.34 (5H, m), 7.58 (1H, dd), 8.48 (1H, dd). MS t / ζ: 455 (M + 1).

Example 91. 5-Chloro-1 '- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] spiro [isobenzofuran-1 (3H) , 4'-piperidine].

- 33 008060

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 5-chlorospiro [isobenzofuran-1 (3H), 4'-piperidine].

^! H-NMR (SES1 ₃ ) δ: 1.69-1.74 (2H, m), 1.81-1.93 (2H, m), 2.30-2.44 (4H, m), 2, 52-2.63 (2H, m), 2.71-2.75 (2H, m), 3.79 (3H, s), 5.00 (2H, s), 5.28 (2H, br. s.), 6.09 (1H, t), 6.73-6.84 (3H, m), 7.03 (1H, d), 7.17-7.28 (3H, m), 7, 58 (1H, dd), 8.49 (1H, dd). MS t / ζ: 489 (M + 1).

Example 111. 4- (4-Chlorophenyl) -1 - [3- (5,11-dihydro [1] benzothiepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 5,11-dihydro [1] benzothiepino [2,3 -B] pyridine 5-one.

^! H-NMR (SES1 ₃ ) δ: 1.66-1.78 (3H, m), 2.04-2.65 (10H, m), 3.66 (1H, bd), 5.05 ( 1H, broad d), 6.03 (1H, t), 7.04-7.46 (10H, m), 8.44 (1H, dd). MS t / ζ: 463 (M + 1).

Example 114. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-8-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 5,11-dihydro-8-methoxy [1] benzoxepino [2,3b] pyridin-5-one.

^! H-NMR (SES1 ₃ ) δ: 1.66-1.70 (3H, m), 1.98-2.09 (2H, m), 2.342.70 (8H, m), 3.75 (3H, s), 5.32 (2H, br.s.), 6.02 (1H, t), 6.39 (1H, d), 6.51 (1H, dd), 7.19-7.44 ( 6H, m), 7.57 (1H, dd), 8.49 (1H, dd). MS t / ζ: 477 (M + 1).

Example 115. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 5,11-dihydro-7-methyl [1] benzoxepino [2,3-b] pyridin-5-one.

^! H-NMR (SES1 ₃ ) δ: 1.50 (1H, br.s.), 1.66-1.70 (2H, m), 1.98-2.10 (2H, m), 2.28 (3H, s), 2.34-2.42 (4H, m), 2.52-2.57 (2H, m), 2.66-2.70 (2H, m), 5.30 (2H bp), 6.08 (1H, d), 6.76 (1H, d), 6.97 (1H, dd), 7.09 (1H, d), 7.24-7.44 (5H, m), 7.57 (1H, dd), 8.49 (1H, dd). MS t / ζ: 461 (M + 1).

Example 117. 1- [3- (7-Chloro-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3b] pyridin-5-one with 7-chloro-5,11-dihydro [1] benzoxepino [2,3b] pyridine 5-one.

'H-NMR (SBSl) δ: 1.66-1.71 (3H, m), 2.00-2.10 (2H, m), 2.36-2.44 (4H, m), 2, 52-2.57 (2H, m), 2.66-2.70 (2H, m), 5.32 (2H, br.s), 6.13 (1H, t), 6.78 (1H d) 7.11 (1H, dd), 7.26-7.44 (5H, m), 7.58 (1H, dd), 8.51 (1H, dd). MS t / ζ: 481 (M + 1).

Example 118. 1- [3- (7-Carboxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4chlorophenyl) piperidin-4-ol.

A mixture of the product of example 169 (500 mg), potassium acetate (330 mg), palladium (II) diacetate (10 mg), 1,1'bis (diphenylphosphino) ferrocene (93 mg), in dimethyl sulfoxide (10 ml) is purged with carbon monoxide 5 min and stirred in an atmosphere of carbon monoxide (from a cylinder) at 60 ° C for 3 hours. Water was added to the reaction mixture and the precipitate was filtered off. This precipitate is dissolved in a solution of ethyl acetate and dilute sodium hydroxide. The aqueous layer is isolated and neutralized with dilute hydrochloric acid. The precipitate was filtered off to obtain the title compound (250 mg).

'H-NMR (EM8O-b ₆ ) δ: 1.45-1.55 (2H, m), 1.75-1.85 (2H, m), 2.36-2.62 (8H, m) 5.42 (2H, br.s), 6.21 (1H, t), 6.90 (1H, d), 7.40-7.52 (5H, m), 7.75 (1H, dd), 7.83 (1H, dd), 7.95 (1H, d), 8.56 (1H, dd). MS t / ζ: 491 (M + 1).

Example 120. 4- (4-Chlorophenyl) -1- [3- (7-carboxymethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin5-ylidene) propyl] piperidin-4-ol.

To a solution of the product of Example 290 (3.7 g) in methanol (74 ml), acetic acid (6 ml) and water (37 ml) was added sodium periodate (1.7 g) in water (15 ml) at 0 ° C and the mixture was stirred at room temperature for 1 hour. Amidosulfuric acid (1.2 g) and sodium chlorite (0.89 g) in water (10 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was evaporated under reduced pressure to half the volume. The residue was neutralized with a 1N sodium hydroxide solution. The precipitate was filtered off and washed with water to obtain the title compound (2.6 g).

'H-NMR (EM8O-b ₆ ) δ: 1.45-1.50 (2H, m), 1.73-1.82 (2H, m), 2.24-2.50 (8H, m) 3.50 (2H, s), 4.84 (1H, br.s), 5.24 (2H, br.s), 6.13 (1H, t), 6.74 (1H, d ), 7.06 (1H, dd), 7.21 (1H, d), 7.33-7.48 (5H, m), 7.74 (1H, dd), 8.50 (1H, dd) .

Example 122. 4- (4-Chlorophenyl) -1- [3- (7-dimethylaminocarbonylmethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 134, but replacing the product.

- 34 008060 of example 133 per product of example 120.

^! H-NMR (SBSl) δ: 1.65-1.70 (2H, m), 1.95-2.06 (2H, m), 2.31-2.66 (9H, m), 2.93 (3H, s), 3.00 (3H, s), 3.61 (2H, s), 5.29 (2H, br.s), 6.09 (1H, t), 6.78 (1H d) 7.00 (1H, dd), 7.20-7.43 (6H, m), 7.56 (1H, dd), 8.42 (1H, dd). MS t / ζ: 532 (M + 1).

Example 123. 1- [3- (7- (2-Carboxy) ethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 288.

^! H-NMR (ΌΜ8Ο-6 ₆ ) δ: 1.44-1.49 (2H, m), 1.70-1.82 (2H, m), 2.22-2.48 (10H, m), 2.75 (2H, t.s.), 4.82 (1H, t.s.), 5.23 (2H, t.s.), 6.14 (1H, t), 6.71 (1H, d) 7.04 (1H, dd), 7.17 (1H, d), 7.33-7.48 (5H, m), 7.72 (1H, dd),

8.49 (1H, dd). MS t / ζ: 519 (Μ + 1).

Example 128. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-propoxy [1] benzoxepino [2,3-b] pyridin-5ilidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with propyl iodide.

^! H-NMR (СОС1 ₃ ) δ: 1.03 (3Н, t), 1.65-1.70 (2Н, m), 1.78 (2Н, q), 1.98-2.09 (3Н, m), 2.37-2.45 (4H, m), 2.51-2.56 (2H, m), 2.66-2.70 (2H, m), 3.88 (2H, t) 5.26 (2H, br.s.), 6.08 (1H, t), 6.72-6.84 (3H, m), 7.23-7.43 (5H, m), 7, 58 (1H, dd), 8.43 (1H, dd). MS t / ζ: 505 (Μ + 1).

Example 130. 4- (4-Chlorophenyl) -1- [3- (7-cyclopropylmethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with cyclopropylmethyl bromide.

^! H-NMR (SPS1 ₃ ) δ: 0.31-0.37 (2H, m), 0.60-0.67 (2H, m), 1.21-1.28 (1H, m), 1, 66-1.72 (3H, m), 2.01-2.11 (2H, m), 2.37-2.71 (8H, m), 3.77 (2H, d), 5.27 ( 2H, br.s), 6.08 (1H, t), 6.73-6.86 (3H, m), 7.23-7.44 (5H, m), 7.58 (1H, dd ), 8.47 (1H, dd). MS t / ζ: 517 (Μ + 1).

Example 131. 4- (4-Chlorophenyl) -1 - [3- (5,11-dihydro-7- (2-dimethylaminoethyl) oxy) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl ] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with 2- (dimethylamino) ethyl chloride hydrochloride.

^! H-NMR (SBSl) δ: 1.71-1.76 (2H, m), 2.12-2.21 (2H, m), 2.38 (6H, s), 2.40-2.79 (11H, m), 4.07 (2H, t),

5.28 (2H, br.s), 6.07 (1H, t), 6.74-6.86 (3H, m), 7.27-7.46 (5H, m), 7.59 (1H, dd), 8.49 (1H, dd). MS t / ζ: 534 (Μ + 1).

Example 132. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (tetrazol-5-yl) methyloxy) [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl ] piperidin-4-ol.

Stage 1

4- (4-Chlorophenyl) -1 - [3- (5,11-dihydro-7- (2-triphenylmethyltetrazol-5-yl) methyloxy) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol was prepared following the procedure of Example 46, but replacing ethyl iodide with (2-triphenylmethyltetrazol-5-yl) methyl chloride.

^! H-NMR (SBSl) δ: 1.64-1.70 (3H, m), 2.02-2.15 (2H, m), 2.35-2.71 (8H, m), 5.29 (2H, br.s), 5.33 (2H, s), 6.03 (1H, t), 6.77 (1H, d), 6.83 (1H, dd), 6.96 (1H d) 7.04-7.08 (6H, m), 7.23-7.45 (14H, m), 7.54 (1H, dd),

8.50 (1H, dd).

Stage 2

A solution of the product of stage 1 (530 mg) in acetone (2.5 ml), acetic acid (2.5 ml) and water (2.5 ml) was stirred at 55 ° C for 30 minutes. The reaction mixture was distilled under reduced pressure. The residue was washed with methanol to give the title compound (280 mg).

^! H-NMR (ΌΜ8Ο-6 ₆ ) δ: 1.69-1.74 (2H, m), 1.99-2.09 (2H, m), 2.95-3.14 (8H, m), 5.18 (2H, br.s), 5.20 (2H, s), 6.14 (1H, t), 6.76 (1H, d), 6.93 (1H, dd), 7, 04 (1H, d), 7.39-7.48 (5H, m), 7.78 (1H, dd), 8.52 (1H, dd). MS t / ζ: 545 (Μ + 1).

Example 133. 1- [3- (7-Carboxymethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

To a solution of the product of Example 48 (3.0 g) in methanol (50 ml) was added a 1N sodium hydroxide solution (8 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was distilled under reduced pressure. The residue was dissolved in water and neutralized with 1N hydrochloric acid. The precipitate was filtered off and washed with water to obtain the title compound (2.6 g).

^! H-NMR (ΌΜ8Ο-6 ₆ ) δ: 1.48-1.53 (2H, m), 1.76-1.88 (2H, m), 2.32-2.60 (8H, m), 4.60 (2H, s), 5.18 (2H, br.s), 6.16 (1H, t), 6.72-6.84 (3H, m), 7.34-7.48 (5H, m), 7.73 (1H, dd), 8.50 (1H, dd). ΜC t / ζ: 521 (Μ + 1).

Example 134. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-dimethylaminocarbonylmethyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

To a solution of the product of example 133 (420 mg) in dimethylformamide (17 ml) was added 1hydroxybenzotriazole hydrate (250 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (310 mg), dimethylamine hydrochloride (270 mg) and triethylamine (0 , 45 ml) and the mixture is stirred at room temperature

- 35 008060 temperature for 12 hours. Water and chloroform are added to the reaction mixture, the organic layer is isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (380 mg).

^! H-NMR (SBSl) δ: 1.67-1.71 (2H, m), 1.95-2.11 (3H, m), 2.37-2.71 (8H, m), 2.97 (3H, s), 3.08 (3H, s), 4.64 (2H, s), 5.27 (2H, br.s.), 6.09 (1H, t), 6.74-6 82 (2H, m), 6.93 (1H, d), 7.24-7.44 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd). MS t / ζ: 548 (M + 1).

Example 135. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-morpholinocarbopylmethyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 134, but replacing dimethylamine hydrochloride with morpholine.

^! H-NMR (SBSl) δ: 1.67-1.71 (2H, m), 1.87 (1H, br.s), 2.00-2.11 (2H, m), 2.38- 2.71 (8H, m), 3.61-3.68 (8H, m), 4.65 (2H, s), 5.27 (2H, br.s), 6.09 (1H, t ), 6.74-6.83 (2H, m), 6.90 (1H, d), 7.25-7.44 (5H, m), 7.58 (1H, dd), 8.48 ( 1H, dd). MS t / ζ: 590 (M + 1).

Example 138. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-methoxycarbonyl-1-methylethyl) hydroxy [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl 2-bromobisobutylate.

^! H-NMR (SIS1 ₃ ) δ: 1.27 (3H, s), 1.56 (6H, s), 1.63-1.71 (3H, m), 2.01-2.10 (2H, m), 2.35-2.70 (8H, m), 4.24 (2H, br), 5.28 (2H, br.s), 6.05 (1H, t), 6.67- 6.75 (2H, m), 6.87 (1H, d), 7.24-7.44 (5H, m), 7.56 (1H, dd),

8.49 (1H, dd). MS t / ζ: 577 (M + 1).

Example 139. 1- [3- (7- (1-Carboxy-1-methylethyl) oxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] -4- (4- chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 138.

^! H-NMR (OM8O _6th ) δ: 1.45-1.52 (8H, m), 1.79-1.85 (2H, m), 2.28-2.53 (8H, m), 5.19 (2H, br.s.), 6.07 (1H, t), 6.69-6.73 (2H, m), 6.85 (1H, d), 7.33-7.47 (5H, m), 7.71 (1H, dd), 8.48 (1H, dd). MS t / ζ: 549 (M + 1).

Example 140. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4 methoxyphenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-methoxyphenyl) -4-hydroxypiperidine.

^! H-NMR (SIS1 ₃ ) δ: 1.62-1.75 (2H, m), 2.08 (2H, dt), 2.41-2.76 (9H, m), 3.77 (3H, s), 3.78 (3H, s), 5.26 (2H, br.s), 6.06 (1H, t), 6.75-6.871 (5H, m), 7.23 (1H, dd), 7.38 (2H, d), 7.57 (1H, dd), 8.45 (1H, dd). MS t / ζ: 473 (M + 1).

Example 141. 4- (4-Cyanophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure for Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-cyanophenyl) -4-hydroxypiperidine.

1 H-NMR (COCO ₃ ) δ: 1.58-1.70 (2H, m), 2.03 (2H, t), 2.31-2.64 (7H, m), 2.65-2, 78 (2H, m), 3.75 (3H, s),

5.26 (2H, br.s.), 5.95 (0.1H, t, E isomer), 6.05 (0.9H, t, Ζ isomer), 6.70-6.80 (3H, m), 7.22 (1H, dd), 7.547.68 (5H, m), 8.31 (0.1H, dd, E isomer), 8.39 (0.9H, dd, Ζ isomer). MS m ^: 468 (M + 1).

Example 142. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4hydroxyphenyl) piperidin-4-ol.

The title compound was prepared following the procedure for Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-hydroxyphenyl) -4-hydroxypiperidine.

^! H-NMR (СОС1 ₃ ) δ: 1.76-1.88 (2Н, m), 2.08-2.22 (2Н, m), 2.45-2.95 (9Н, m), 3, 76 (3H, s), 5.28 (2H, br.s), 5.95 (0.3H, t, E isomer), 6.04 (0.7H, t, Ζ isomer), 6.69 -6.72 (3H, m), 6.90 (2H, d), 7.20-7.30 (3H, m), 7.56 (0.7H, dd, Ζ isomer), 7.67 ( 0.3H, dd, E isomer), 8.46 (0.7H, dd, Ζ isomer), 8.47 (0.3H, dd, E isomer). OH signal is not observed. MS t / ζ: 473 (M + 1).

Example 143. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4 fluoro-3-methylphenyl) piperidin-4 -ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-fluoro-3-methylphenyl) -4-hydroxypiperidine.

^! H-NMR (SIS1 ₃ ) δ: 1.62-1.75 (2H, m), 2.05 (1H, br.s.), 2.09 (2H, dt), 2.25 (3H, s ), 2.30-2.76 (8H, m), 3.76 (3H, s), 5.26 (2H, br.s), 5.96 (0.1H, t, E isomer), 6.07 (0.9H, t, Ζ isomer), 6.75-6.89 (3H, m), 6.93 (1H, t), 7.11-7.20 (0.3H, m, E isomer), 7.21-7.35 (0.24H, m, Ζ isomer), 7.56 (0.9H, dd, E isomer), 7.67 (0.1H, dd, E isomer), 8.38 (0.1H, dd, E isomer), 8.45 (0.9H, dd, Ζ isomer). MS t / ζ: 475 (M + 1).

Example 144. 4- (3,4-Difluorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (3,4-difluorophenyl) -4-hydroxypiperidine.

^! H-NMR (SIS1 ₃ ) δ: 1.58-1.72 (2H, m), 1.96 (2H, dt), 2.33-2.71 (8H, m), 3.73 (3H, s), 5.23 (2H, br.s.), 5.94

- 36 008060 (0.1H, t, E isomer), 6.04 (0.9H, t, Ζ isomer), 8.38-8.36 (0.9H, m, Ζ isomer), 6.68- 6.79 (3H, m), 6.98-7.38 (4H, m), 7.50-7.62 (0.9H, m, Ζ isomer), 7.63-7.68 (0, 1H, m, E isomer), 8.29-8.32 (0.1H, m, E isomer), 8.32-8.44 (0.9H, m, Ζ isomer). OH signal is not observed. MS t / ζ: 479 (M + 1).

Example 145. 4- (4-Chloro-3-trifluoromethylphenyl) -1 [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidin-4- ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chloro-3-trifluoromethylphenyl) -4-hydroxypiperidine.

Я-NMR (SBS1 ₃ ) δ: 1.62-1.74 (2H, m), 2.10 (2H, dt), 2.35-2.80 (8H, m), 2.42 (1H, b.s.), 3.76 (3H, s), 5.26 (2H, b.s.), 6.07 (0.9H, t, Ζ isomer), 6.03 (0.1H, t , E isomer), 6.82-6.71 (3H, m), 7.24 (1H, dd), 7.43 (1H, d),

7.56 (1.8H, dd, Ζ isomer), 7.65 (0.2H, dd, E isomer), 7.83 (1H, d), 8.36 (0.1H, dd, E isomer) 8.44 (0.9H, dd, Ζ isomer), MS t / ζ: 545 (M + 1).

Example 146. 4- (3,5-Dichlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5ilidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (3,5-dichlorophenyl) -4-hydroxypiperidine.

Я-NMR (SBS1 ₃ ) δ: 1.58-2.22 (5H, m), 2.38-2.77 (8H, m), 3.76 (3H, s), 5.26 (2H, b.s.), 5.92 (0.1H, t, E isomer), 6.07 (0.9H, t, Ζ isomer), 6.83-6.71 (3H, m), 7.19 -7.42 (4H, m), 7.56 (0.9H, dd, Ζ isomer), 7.68 (0.1H, dd, E isomer), 8.38 (0.1H, dd, E isomer ), 8.45 (0.9H, dd, Ζ isomer). MS t / ζ: 512 (M + 1).

Example 147. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (2pyridyl) piperidin-4-ol.

The title compound was prepared following the procedure for Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (2-pyridyl) -4-hydroxypiperidine.

Я-NMR (SBS1 ₃ ) δ: 1.54-1.65 (2H, m), 2.06 (2H, dt), 2.07 (1H, br.s.), 2.35-2.62 (7H, m), 2.73-2.87 (2H, m), 3.78 (3H, s), 5.28 (2H, br.s), 6.08 (1H, t), 6 72-6.85 (3H, m), 7.14-7.29 (2H, m), 7.57 (1H, d), 7.70 (1H, dd), 8.48 (2H, dd ) MS t / ζ: 444 (M + 1).

Example 148. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (3pyridyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (3-pyridyl) -4-hydroxypiperidine.

Я-NMR (SBS1 ₃ ) δ: 1.65-1.78 (2H, m), 2.08 (2H, dt), 2.37-2.88 (7H, m), 2.63-2, 79 (2H, m), 3.78 (3H, s),

5.28 (2H, br.s.), 6.02 (0.1H, t, E isomer), 6.07 (0.9H, t, Ζ isomer), 6.70-6.84 (3H, m), 7.22-7.32 (3H, m), 7.56 (1H, dd), 7.77 (1H, dd), 8.46 (0.9H, d), 8.57 (0 , 1H, dd, E isomer), 8.73 (1H, dd). MS t / ζ: 444 (M + 1).

Example 149. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4pyridyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-pyridyl) -4-hydroxypiperidine.

Я-NMR (SBS1 ₃ ) δ: 1.58-1.72 (2Н, m), 2.03 (2Н, dt), 2.34-2.89 (8Н, m), 2.96 (1Н, b.s.), 3.76 (3H, s), 5.25 (2H, b.s.), 6.06 (1H, t), 6.72-6.83 (3H, m), 7 24 (1H, dd), 7.37 (2H, dd), 7.56 (1H, dd), 8.45 (1H, dd), 8.48 (2H, dd). MS t / ζ: 444 (M + 1).

Example 150. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4trifluoromethylphenyl) piperidin-4-ol.

The title compound was prepared following the procedure for Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-trifluoromethylphenyl) -4-hydroxypiperidine.

Я-NMR (SBS1 ₃ ) δ: 1.64-1.75 (2H, m), 2.01 (1H, br.s), 2.16 (2H, dt), 2.38-2.86 (8H, m), 3.76 (3H, s), 5.26 (2H, br.s), 6.04 (1H, t), 6.72-6.84 (3H, m), 7 23 (1H, dd), 7.56 (5H, m), 8.42 (1H, dd). MS t / ζ: 511 (M + 1).

Example 151. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine.

The title compound was prepared following the procedure of Example 44, step 2, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) piperidine.

Я-NMR (SPS1 ₃ ) δ: 1.62-1.92 (4H, m), 1.94-2.18 (2H, m), 2.28-2.64 (5H, m), 2, 99 (2H, m), 5.25 (2H, br.s ..), 6.00 (1H, t), 6.60-6.82 (3H, m), 7.02-7.36 ( 5H, m), 7.50 (1H, dd), 8.47 (1H, dd). OH signal is not observed. MS t / ζ: 447 (M + 1).

Example 152. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine.

The title compound was prepared following the procedure of Example 46, but replacing the product of Example 44 with the product of Example 151.

Я-NMR (СОС1 ₃ ) δ: 1.40 (3Н, t), 1.52-2.14 (6Н, m), 2.30-2.57 (5Н, m), 2.94 (2Н, m), 4.00 (2H, br), 5.28 (2H, br.s), 6.07 (1H, t), 6.68-6.86 (3H, m), 7.05- 7.36 (5H, m), 7.58 (1H, m), 8.49 (1H, m). MS t / ζ: 475 (M + 1).

Example 153. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxycarbonylmethyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine.

The title compound was prepared following the procedure of Example 48, but replacing the product.

- 37 008060 of example 44 per product of example 151.

Я-NMR (СОС1 ₃ ) δ: 1.29 (3Н, t), 1.56-1.85 (4Н, m), 1.99 (2Н, dt), 2.28-2.55 (5Н, m), 2.91 (2H, m), 4.27 (2H, s), 4.58 (2H, s), 5.28 (2H, br.s), 6.09 (1H, t) 6.68-6.95 (3H, m), 7.07-7.32 (5H, m), 7.58 (1H, dd), 8.49 (1H, dd). MS t / ζ: 533 (M + 1).

Example 154. 1- [3- (7- (Carboxymethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidine.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 153.

Ή-NMR (ί.Ό ₃ ΟΌ) δ: 1.82-2.17 (4H, m), 2.69 (2H, m), 2.86 (1H, m), 3.07 (2H, m ), 3.30 (2H, m), 3.57 (2H, m), 4.57 (2H, s), 5.21 (2H, br.s), 6.10 (1H, t), 6.70-7.04 (3H, m), 7.16-7.38 (4H, m), 7.44 (1H, m), 7.77 (1H, m), 8.47 (1H, m). COOH signal is not observed. MS t / ζ: 505 (M + 1).

Example 155. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-dimethylaminocarbonylmethyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine.

The title compound was prepared following the procedure for Example 134, but replacing the product of Example 133 with the product of Example 154.

Ή-NMR (СОС1 ₃ ) δ: 1.58-1.92 (4Н, m), 2.04 (2Н, m), 2.30-2.68 (5Н, m), 2.93 (2Н, m), 2.98 (3H, s), 3.08 (3H, s), 4.65 (2H, s), 5.28 (2H, br.s), 6.07 (1H, t) 6.70-6.98 (3H, m), 7.08-7.36 (5H, m), 7.60 (1H, m), 8.50 (1H, t). MS t / ζ: 532 (M + 1).

Example 156. 1- [3- (7- (2-Acetoxyethyl) hydroxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine.

The title compound was prepared following the procedure of Example 50, but replacing the product of Example 44 with the product of Example 151.

Ή-NMR (СОС1 ₃ ) δ: 1.55-1.88 (4Н, m), 1.90-2.32 (2Н, m), 2.10 (3Н, s), 2.28-2, 60 (5H, m), 2.82-3.02 (2H, m), 4.14 (2H, dd), 4.41 (2H, dd), 5.29 (2H, br.s.), 6.08 (1H, t), 6.72-6.90 (3H, m), 7.18-7.34 (5H, m), 7.57 (1H, m), 8.50 (1H, t). MS t / ζ: 533 (M + 1).

Example 157. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-hydroxyethyl) oxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine.

The title compound was prepared following the procedure for Example 51, but replacing the product of Example 50 with the product of Example 156.

Я-NMR (SB _; OB) δ: 1.66-1.98 (4H, m), 2.40-2.73 (5H, m), 2.82-2.94 (2H, m), 3 22 (2H, m), 3.84 (2H, dd), 4.01 (2H, dd), 5.23 (2H, br.s), 6.13 (1H, t), 6.64 -6.98 (3H, m), 7.13-7.34 (4H, m), 7.45 (1H, m), 7.77 (1H, m), 8.47 (1H, t). OH signal is not observed. MS t / ζ: 491 (M + 1).

Example 158. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-methoxycarbonyl-1-methylethyl) hydroxy [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidine.

The title compound was prepared following the procedure of Example 138, but replacing the product of Example 44 with the product of Example 151.

Ή-NMR (СОС1 ₃ ) δ: 1.28 (3Н, s), 1.56 (6Н, s), 1.56-1.85 (4Н, m), 1.97 (2Н, dt), 2 , 28-2.55 (5H, m), 2.93 (2H, m), 4.24 (2H, q), 5.28 (2H, b.s.), 6.04 (1H, t) 6.62-6.95 (3H, m), 7.07-7.32 (5H, m), 7.57 (1H, dd), 8.50 (1H, dd). MS t / ζ: 561 (M + 1).

Example 159. 1- [3- (7- (1-Carboxy-1-methylethyl) oxy-5,11-dihydro [1] benzoxepino- [2,3-b] pyridin-5ylidene) propyl] -4- (4 -chlorophenyl) piperidine.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 158.

Я-NMR (SB _; OB) δ: 1.50 (6H, s), 1.82-2.18 (4H, m), 2.70 (2H, m), 2.87 (1H, m), 3.12 (2H, m), 3.30 (2H, m), 3.60 (2H, m), 5.25 (2H, br.s), 6.07 (1H, t), 6, 67-7.04 (3H, m), 7.16-7.38 (4H, m), 7.58 (1H, m), 7.96 (1H, m), 8.52 (1H, t) . COOH signal is not observed. MS t / ζ: 533 (M + 1).

Example 160. 1- [3- (8-Bromo-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidine.

The title compound was prepared following the procedure for Example 65, but replacing the product of Example 45, Step 2 with the product of Example 54, Step 1.

Я-NMR (СОС1 ₃ ) δ: 1.50-1.86 (4Н, m), 1.98 (2Н, m), 2.26-2.60 (5Н, m), 2.88 (2Н, m), 5.30 (2H, br.s), 6.09 (1H, t), 6.96-7.36 (8H, m), 7.57 (1H, dd), 8.51 ( 1H, dd). MS t / ζ: 509, 511 (M + 1).

Example 161. 1- [3- (8-Carboxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4chlorophenyl) piperidine.

To a solution of 130 mg of 1- [3- (8-bromo-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4chlorophenyl) piperidine (Example 161) THF (1.0 ml) add 0.17 ml of a 1.6 molar solution of nbutyl lithium in hexane at a temperature of -78 ° C. After stirring for 10 minutes at the same temperature, carbon dioxide (dry ice) is added to the mixture. After warming to room temperature, the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated in vacuo. The resulting oil was purified by chromatography on silica gel eluted with dichloromethane: methanol (5: 1) to give the title compound (50 mg).

- 38 008060

Ή-NMR (C1 + O1)) δ: 1.55-1.95 (4H, m), 2.17 (2H, dt), 2.32-2.78 (5H, m), 3.00 ( 2H, m), 5.30 (2H, br.s), 6.19 (1H, t), 7.08-7.54 (8H, m), 7.76 (1H, dd), 8, 45 (1H, dd). COOH signal not observed (50 mg). MS t / ζ: 475 (M + 1).

Example 162. 1- [3- (7-Bromo-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 8-bromo-5,11-dihydro [1] benzoxepino [2,3b] pyridin-5-one.

Ή-NMR (СОС1 ₃ ) δ: 1.60-1.71 (3Н, m), 1.98-2.09 (2Н, m), 2.34-2.69 (8Н, m), 5, 32 (2H, br.s), 6.13 (1H, t), 6.73 (1H, d), 7.22-7.44 (7H, m), 7.57 (1H, dd), 8.52 (1H, dd). MS t / ζ: 525, 527 (M + 1).

Example 163. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-ethyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 5,11-dihydro-7-ethyl [1] benzoxepino [2,3b] pyridin-5-one.

Я-NMR (CBC1 ₃ ) δ: 1.23 (3H, t), 1.52 (1H, br.s.), 1.66-1.71 (2H, m), 1.98-2.06 (2H, m), 2.35-2.70 (11H, m), 5.31 (2H, b.s.), 6.09 (1H, t), 6.79 (1H, d), 7 01 (1H, dd), 7.11 (1H, d), 7.25-7.44 (5H, m), 7.58 (1H, dd),

8.49 (1H, dd). MS t / ζ: 475 (M + 1).

Example 164. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-8-vinyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 5,11-dihydro-8-vinyl [1] benzoxepino [2,3-b] pyridin-5-one.

Ή-NMR (CBC1 ₃ ) δ: 1.66-1.71 (3H, m), 2.00-2.10 (2H, m), 2.36-2.70 (8H, m), 5, 22 (2H, d), 5.34 (2H, br.s), 5.70 (1H, d), 6.11 (1H, t), 6.61 (1H, dd), 6.89 ( 1H, d), 6.99 (1H, dd), 7.24-7.44 (6H, m), 7.58 (1H, dd), 8.49 (1H, dd). MS t / ζ: 473 (M + 1).

Example 165. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-8-ethyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol

A mixture of the product of Example 164 (100 mg) with 20 mg of an Rb / C catalyst in ethanol (2 ml) was stirred under a hydrogen atmosphere (balloon) at room temperature for 1 hour. The mixture was filtered through celite and distilled under reduced pressure. The residue was purified by preparative thin layer chromatography, eluting with a mixture of chloroform: methanol (15: 1) to obtain the title compound (50 mg).

Ή-NMR (CBC1 ₃ ) δ: 1.22 (3H, t), 1.55-1.77 (3H, m), 2.00-2.13 (2H, m), 2.33-2, 74 (10H, m), 5.32 (2H, br.s), 6.07 (1H, t), 6.70 (1H, d), 6.78 (1H, dd), 7.19- 7.44 (6H, m), 7.57 (1H, dd), 8.49 (1H, dd). MS t / ζ: 475 (M + 1).

Example 166. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-9-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 5,11-dihydro-9-methoxy [1] benzoxepino [2,3b] pyridin-5-one.

Я-NMR (СОС1 ₃ ) δ: 1.65-1.70 (2Н, m), 1.95-2.06 (2Н, m), 2.15 (1Н, br.s.), 2.37 -2.67 (8H, m), 3.83 (3H, s), 5.43 (2H, br.s), 6.09 (1H, t), 6.79-6.91 (3H, m), 7.22-7.43 (5H, m), 7.57 (1H, dd), 8.44 (1H, dd). MS t / ζ: 477 (M + 1).

Example 167. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro [1] benzoxepino [4,3-c] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 5,11-dihydro [1] benzoxepino [4,3 -c] pyridine 5-one.

Я-NMR (CBC1 ₃ ) δ: 1.67-1.71 (2H, m), 1.97-2.08 (2H, m), 2.16 (1H, s), 2.40-2, 69 (8H, m), 5.16 (2H, br.s.),

6.14 (1H, m), 6.80 (1H, dd), 6.91-6.97 (1H, m), 7.13-7.19 (1H, m), 7.26-7, 44 (6H, m), 7.50-8.54 (2H, br). MS t / ζ: 447 (M + 1).

Example 168. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro [1] benzoxepino [4,3-b] pyrimidin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 5,11-dihydro [1] benzoxepino [4,3 b] pyrimidin-5-one.

Я-NMR (СОС1 ₃ ) δ: 1.68-1.72 (2Н, m), 1.90 (1Н, br.s), 2.06-2.19 (2Н, m), 2.41 -2.78 (8H, m), 5.20 (2H, s), 6.12 (1H, t), 7.14-7.45 (8H, m), 8.72 (1H, s), 8.97 (1H, s). MS t / ζ: 448 (M + 1).

Example 169. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-trifluoromethanesulfonyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

- 39 008060

To a solution of the product of Example 44 (1.0 g) in pyridine (10 ml) was added trifluoromethanesulfonic anhydride (0.55 ml) at 0 ° C and the mixture was stirred at room temperature for 1 h. Water and diethyl ether, organic, were added to the reaction mixture. the layer is isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by chromatography on silica gel eluting with ethyl acetate: methanol (10: 1) to obtain the title compound (1.1 g).

Я-NMR (SPS1 ₃ ) δ: 1.56 (1Н, br.s), 1.66-1.71 (2Н, m), 1.97-2.09 (2Н, m), 2.35 -2.69 (8H, m), 5.35 (2H, br.s.) 6.15 (1H, t), 6.88 (1H, d), 7.05 (1H, dd), 7, 21-7.44 (6H, m), 7.60 (1H, dd), 8.54 (1H, dd). MS t / ζ: 595 (M + 1).

Example 170. 1- [3- (7-Allyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4chlorophenyl) piperidin-4-ol.

To the mixture of the product of example 169 (240 mg), allyl tributyltin (0.19 ml), 30 mg of dichlorobis (triphenylphosphine) palladium (II) and 76 mg of lithium chloride in dimethylformamide (3 ml) were added, heated under argon at 120 ° C for 2 hours. An aqueous solution of ammonium fluoride and ethyl acetate are added to the reaction mixture, the organic layer is isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by chromatography on silica gel eluting with a mixture of chloroform: methanol (10: 1) to obtain the title compound (180 mg).

Ή-NMR (СОС1 ₃ ) δ: 1.62-1.72 (3Н, m), 2.03-2.11 (2Н, m), 2.39-2.73 (8Н, m), 3, 31 (2H, d), 5.04-5.11 (2H, m), 5.29 (2H, br.s), 5.87-6.02 (1H, m), 6.06 (1H , t), 6.77 (1H, d), 6.99 (1H, dd), 7.10 (1H, d), 7.23-7.43 (5H, m),

7.57 (1H, dd), 8.40 (1H, dd).

Example 171. 1 - [3 - (7- (2-tert-Butoxycarboxy) ethenyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

A mixture of the product of example 169 (1.7 g), tert-butyl acrylate (0.85 ml), triethylamine (2.5 ml), 1,1'bis (diphenylphosphino) ferrocene (250 mg) and 33 mg of palladium (II) diacetate in dimethylformamide (3 ml) under argon atmosphere was stirred at 90 ° C for 24 hours. Aqueous ethyl acetate was added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by chromatography on silica gel eluting with ethyl acetate: methanol (30: 1) to obtain the title compound (780 mg).

Я-NMR (СОС1 ₃ ) δ: 1.45 (9Н, s), 1.63-1.71 (3Н, m), 1.98-2.10 (2Н, m), 2.35-2, 72 (8H, m), 5.35 (2H, br.s.),

6.15 (1H, t), 6.26 (1H, d), 6.83 (1H, d), 7.22-7.44 (7H, m), 7.53 (1H, d), 7 58 (1H, dd), 8.52 (1H, dd).

Example 172. 1- [3- (7- (2-Carboxy) ethenyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4 (4-chlorophenyl) piperidine -4-ol

The product of example 171 (330 mg) was dissolved in 4n. a solution of hydrochloric acid in 1,4 dioxane (4 ml) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Water was added to the residue and neutralized with sodium hydroxide solution. The precipitate was filtered off to obtain the title compound (190 mg).

Я-NMR (OM8O-b ₆ ) δ: 1.45-1.52 (2H, m), 1.72-1.84 (2H, m), 2.25-2.58 (8H, m), 5.25 (2H, br.s.), 6.28 (1H, t), 6.43 (1H, d), 6.82 (1H, d), 7.34-7.60 (8H, m ), 7.75 (1H, dd), 8.52 (1H, dd).

Example 173. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-propargyloxy [1] benzoxepino [2,3-b] pyridin5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with propargyl chloride.

Я-NMR (CBC1 ₃ ) δ: 1.66-1.71 (2H, m), 1.79 (1H, bp), 1.99-2.10 (2H, m), 2.35 -2.71 (9H, m), 4.66 (2H, d),

5.28 (2H, br.s.), 6.10 (1H, t), 6.80-6.93 (3H, m), 7.24-7.46 (5H, m), 7.59 (1H, dd), 8.48 (1H, dd). MS t / ζ: 501 (M + 1).

Example 174. 4- (4-Chlorophenyl) -1- [3- (7-cyclopentoxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridine 5ilidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with cyclopentyl bromide.

Ή-NMR (СОС1 ₃ ) δ: 1.54-2.18 (13Н, m), 2.41-2.72 (8Н, m), 4.66-4.73 (1Н, m), 5, 27 (2H, br.s), 6.08 (1H, t), 6.70-6.87 (3H, m), 7.23-7.44 (5H, m), 7.58 (1H dd), 8.49 (1H, dd). MS t / ζ: 531 (M + 1).

Example 175, 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-methoxyethyl) oxy) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl ] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with 2-methoxyethyl chloride.

Я-NMR (SBS1 ₃ ) δ: 1.66-1.75 (3H, m), 2.00-2.11 (2H, m), 2.36-2.71 (8H, m), 3, 45 (3H, s), 3.71-3.75 (2H, m), 4.07-4.11 (2H, m), 5.27 (2H, br.s), 6.09 (1H , t), 6.75-6.91 (3H, m), 7.23-7.44 (5H, m), 7.57 (1H, dd), 8.48 (1H, dd). MS t / ζ: 521 (M + 1).

Example 176. 4- (4-Chlorophenyl) -1- [3- (7- (1-dimethylaminocarbonyl-1-methyl) ethyloxy-5,11-dihydro [1]

- 40 008060 benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 134, but replacing the product of Example 133 with the product of Example 139.

^! H-NMR (CBC1 ₃ ) δ: 1.59 (6H, s), 1.67-1.72 (2H, m), 1.99-2.09 (2H, m), 2.36-2, 70 (9H, m), 2.96 (3H, s), 3.21 (3H, s), 5.25 (2H, br.s), 6.02 (1H, t), 6.60- 6.77 (3H, m), 7.24-7.44 (5H, m), 7.58 (1H, dd), 8.44 (1H, dd). MS t / ζ: 576 (M + 1).

Example 177. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-methoxycarbonylethyl) hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl 2-bromopropionate.

^! H-NMR (SPS1 ₃ ) δ: 1.25 (3H, t), 1.59 (3H, d), 1.65-1.70 (2H, m), 1.98-2.08 (2H, m), 2.35-2.68 (8H, m), 2.80 (1H, br.s), 4.21 (2H, q), 4.68 (1H, q), 5.24 ( 2H, br.s), 6.07 (1H, t), 6.68-6.79 (2H, m), 6.88 (1H, d), 7.227.44 (5H, m), 7, 56 (1H, dd), 8.40 (1H, dd).

Example 178. 1- [3- (7- (1-Carboxyethyl) hydroxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 177.

^! H-NMR (EM8O-b ₆ ) δ: 1.46 (3H, d), 1.58-1.63 (2H, m), 1.98-2.06 (2H, m), 2.41- 2.45 (2H, m), 2.72-2.86 (6H, m), 4.7 4 (1H, q), 5.18 (2H, br.s), 6.11 (1H, t), 6.73 (2H, s), 6.84 (1H, s), 7.36-7.47 (5H, m), 7.73 (1H, dd),

8.50 (1H, dd). MS t / ζ: 535 (M + 1).

Example 179. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-methoxycarbonyl) cyclobutoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl 2-bromocyclobutanecarboxylate.

^! H-NMR (COC1 ₃ ) δ: 1.19 (3H, t), 1.67-1.71 (2H, m), 1.92-2.11 (5H, m), 2.33-2, 77 (12H, m), 4.21 (2H, q),

5.25 (2H, br.s.), 6.05 (1H, d), 6.47 (1H, dd), 6.70 (1H, d), 6.73 (1H, d), 7, 23-7.44 (5H, m), 7.55 (1H, dd), 8.44 (1H, dd).

Example 180. 1- [3- (7- (1-Carboxy) cyclobutoxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 179.

^! H-NMR (EM8O-b ₆ ) δ: 1.60-1.65 (2H, m), 1.86-2.08 (4H, m), 2.24-2.90 (12H, m), 5.17 (2H, br.s.), 6.05 (1H, d), 6.50 (1H, dd), 6.66 (1H, d), 6.73 (1H, d), 7, 37-7.48 (5H, m), 7.74 (1H, dd), 8.5 1 (1H, dd). MS t / ζ: 561 (M + 1).

Example 181. 1- [3- (7-Carbamoylmethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol .

The title compound was prepared following the procedure of Example 134, but replacing dimethylamine hydrochloride with ammonium hydroxide.

^! H-NMR (COS1 ₃ ) δ: 1.66-1.71 (2H, m), 1.98-2.09 (2H, m), 2.21 (1H, br.s.), 2.38 -2.70 (8H, m), 4.45 (2H, s),

5.28 (2H, br.s.), 6.09 (1H, br.s), 6.11 (1H, br.s), 6.58 (1H, br.s), 6.74-6 85 (3H, m), 7.24-7.44 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd). MS t / ζ: 520 (M + 1).

Example 182. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methylaminocarbonylmethyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 134, but replacing dimethylamine hydrochloride with methylamine.

^! H-NMR (СОС1 ₃ ) δ: 1.67-1.72 (2Н, m), 1.99-2.10 (2Н, m), 2.36-2.70 (9Н, m), 2, 89 (3H, d), 4.45 (2H, s),

5.28 (2H, br.s.), 6.08 (1H, br.s), 6.66 (1H, br.s.), 6.73-6.84 (3H, m), 7.25- 7.45 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd). MS t / ζ: 534 (M + 1).

Example 183. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4hydroxyphenyl) piperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-hydroxyphenyl) piperidine.

^! H-NMR (CBC1 ₃ ) δ: 1.52-1.88 (4H, m), 2.01 (2H, dt), 2.28-2.60 (5H, m), 2.93 (2H, m), 3.79 (3H, s), 5.28 (2H, br.s), 6.08 (1H, t), 6.68-6.88 (3H, m), 7.05- 7.36 (5H, m), 7.58 (1H, dd), 8.50 (1H, dd). MS t / ζ: 461 (M + 1).

Example 184. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (2hydroxyphenyl) piperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (2-hydroxyphenyl) piperidine.

^! H-NMR (SBS _{1 3} ) δ: 1.78-1.92 (4H, m), 2.12-2.25 (2H, m), 2.32-2.70 (4H, m), 2, 80-2.97 (1H, m), 3.01-3.15 (2H, m), 3.77 (3H, s), 3.78 (1H, br.s.), 5.28 (2H (bs), 6.03 (1H, t), 6.74-6.86 (4H, m), 7.05 (1H, dd), 7.11 (1H, dd), 7.23 -7.28 (2H, m), 7.56 (1H, dd), 8.48 (1H, dd), OH signal is not observed. MS t / ζ: 443 (M + 1).

- 41 008060

Example 185. 4- (7-Chloro-1,2-benzisoxazol-3-yl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3b] pyridin-5-ylidene ) propyl] piperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (7-chloro-1,2-benzisoxazol-3-yl) piperidine. This piperidine was obtained in the same manner as described in journal 1. Meb. Sket. 28: 761-769 (1985).

^! H-NMR (СОС1 ₃ ) δ: 1.94-2.20 (6Н, m), 2.30-2.60 (4Н, m), 2.86-3.14 (3Н, m), 3, 79 (3H, s), 5.29 (2H, br.s), 6.10 (1H, t), 6.70-6.88 (3H, m), 7.22 (1H, t), 7.27 (1H, dd), 7.50 (1H, dd), 7.57-7.68 (2H, m), 8.49 (1H, dd).

Example 186. 4- (7-Chloroindol-3-yl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (7-chloroindol-3-yl) piperidine. This piperidine was obtained in the same manner as described in journal 1. Meb. Sket. 36: 4006-4014 (1993), followed by hydrogenation as described in Example 58, step 3.

^! H-NMR (SES1 ₃ ) δ: 1.66-1.88 (2H, m), 1.92-2.22 (4H, m), 2.32-2.63 (4H, m), 2, 78 (1H, m), 2.97 (2H, m), 3.79 (3H, s), 5.29 (2H, br.s), 6.09 (1H, t), 6.70- 6.87 (3H, m), 6.97-7.07 (2H, m), 7.12-7.30 (2H, m), 7.52 (1H, m), 7.59 (1H, dd), 8.45 (1H, br.s.), 8.50 (1H, dd).

Example 187. 4-Azido-4- (4-chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidine.

Stage 1

4-Azido-4- (4-chlorophenyl) piperidine (15) in FIG. 8b. In a cold (0 ° С) solution of compound 1 (3.0 g, 14 mmol) in anhydrous dioxane (15 ml) in an inert atmosphere, sodium azide Ν; · ιΝ ₃ 1.0 g, 15.4 mmol) is added followed by a slow по ₃ ΌΕΐ (4.4 ml, 35 mmol) dropwise added with boron trifluoride etherate. The reaction mixture was stirred at 0 ° C for 3 hours and the reaction was stopped at 0 ° C by carefully and slowly adding a saturated aqueous NaHCO ₃ solution until the main reaction. The organic layer was isolated and dried over sodium sulfate. The reaction mixture was purified by flash chromatography on silica gel eluting with 2% methanol in dichloromethane to give 2 g of a 1: 3 mixture of azidopiperidine (2) and olefin (3). This mixture is used directly in the next reaction.

Stage 2

The title compound is then obtained according to the following procedure for Example 45, step 3, with the above reaction mixture (whereby 4- (4-chlorophenyl) -4-hydroxypiperidine is replaced by 4-azido-4- (4-chlorophenyl) piperidine) ), but the amount of bromide is limited to 0.25 eq.

^! H-NMR (SES1 ₃ ) δ: 1.88 (2H, m), 2.55-2.85 (4H, m), 3.00-3.30 (6H, m). 3.75 (3H, s), 5.19 (2H, br.s), 5.97 (1H, t), 6.68-6.65 (3H, m), 7.20-7.46 (5H, m), 7.6 3 (1H, dd), 8.35 (1H, dd). MS m / z: 477 (M + 1 - + + H ₂ ).

Example 188. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] -4-phenylpiperidin-4-carboxylic acid methyl ester.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with methyl 4-phenylpiperidin-4-carboxylate.

'H-NMR (SES1 ₃ ) δ: 1.82-2.15 (4H, m), 2.28-2.60 (6H, m), 2.78-2.82 (2H, m), 3 62 (3H, s), 3.68 (3H, s),

5.26 (2H, br.s.), 5.95 (0.1H, t, E isomer), 6.05 (0.9H, t, Ζ isomer), 6.82-6.70 (3H, m), 7.33-7.22 (6H, m), 7.65 (0.1H, dd, Ζ isomer), 7.55 (0.9H, dd, Ζ isomer), 8.39 (0, 1H, E isomer), 8.48 (0.9H, dd, Ζ isomer). MS t / ζ: 485 (M + 1).

Example 189. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4-phenylpiperidin-4-carboxylic acid.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 188.

'H-NMR (SE ₃ OE) δ: 2.16-2.23 (2H, m), 2.69-2.91 (4H, m), 3.00-3.16 (2H, m), 3.37-3.25 (2H, m), 3,683.73 (2H, m), 3.76 (3H, 8), 5.34 (2H, br.s.), 6.24 (1H, t ), 6.70-7.04 (3H, m), 7.26-7.55 (5H, m), 7.79-7.89 (1H, m), 8.21-8.34 (1H , m), 8.56-8.62 (0.1H, m), 8.63-8.77 (0.9H, m). MS t / ζ: 471 (M + 1).

Example 190. 1- (2-Chlorophenylsulfonyl) -4- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperazine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1- (2-chlorophenylsulfonyl) piperazine.

'H-NMR (SES1 ₃ ) δ: 2.20-2.58 (8H, m), 3.12-3.38 (4H, m), 3.76 (3H, s), 5.22 (2H bp), 6.03 (1H, t), 6.646.90 (3H, m), 7.23 (1H, dd), 7.32-7.60 (4H, m), 8.01 (1H, dd), 8.48 (1H, dd). MS t / ζ: 526 (M + 1).

Example 191. 1- (3-Chlorophenylsulfonyl) -4- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperazine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1- (3-chlorophenylsulfonyl) piperazine.

'H-NMR (SES1 ₃ ) δ: 2.20-2.60 (8H, m), 2.82-3.12 (4H, m), 3.76 (3H, s), 5.18 (2H bp), 6.00 (1H, t), 6.646.90 (3H, m), 7.23 (1H, dd), 7.42-7.78 (5H, m), 8.48 (1H, dd). MS t / ζ: 526 (M + 1).

Example 192. 1- (4-Chlorophenylsulfonyl) -4- [3- (5,11-dihydro-7-methoxy [1] benzoxepino- [2,3-b] pi

42 008060 Ridin-5-ylidene) propyl] piperazine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1- (4-chlorophenylsulfonyl) piperazine.

¹ H-NMR (SIS1 ₃ ) δ: 2.20-2.56 (8H, m), 2.82-3.10 (4H, m), 3.76 (3H, s), 5.18 (2H bp), 5.99 (1H, t), 6.626.92 (3H, m), 7.23 (1H, dd), 7.42-7.78 (5H, m), 8.48 (1H, dd). MS t / ζ: 526 (M + 1).

Example 193. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -1,2, 3,6-tetrahydropyridine.

The title compound was prepared following the procedure for Example 44, step 2, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine.

¹ H-NMR (SPS1 ₃ ) δ: 2.37-2.72 (8H, m), 3.07 (2H, m), 5.25 (2H, br.s.), 6.00 (1H, m), 6.07 (1H, t), 6.60-6.78 (3H, m), 7.18-7.47 (5H, m), 7.56 (1H, dd), 8.50 (1H, dd). OH signal is not observed. MS t / ζ: 445 (M + 1).

Example 194. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -1,2, 3,6-tetrahydropyridine.

The title compound was prepared following the procedure for Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine.

¹ H-NMR (SPS1 ₃ ) δ: 2.37-2.72 (8H, m), 3.06 (2H, m), 3.78 (3H, s), 5.27 (2H, br s .), 5.99 (1H, m), 6.10 (1H, t), 6.72-6.90 (3H, m), 7.20-7.44 (5H, m), 7.60 (1H, dd), 8.50 (1H, dd). MS t / ζ: 459 (M + 1).

Example 195. 4- (7-Chloroindol-3-yl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] - 1, 2,3,6-tetrahydropyridine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (7-chloroindol-3-yl) -1,2,3,6-tetrahydropyridine. This piperidine was obtained in the same manner as described in the journal I. Meb. S11st. 36: 4006-4014 (1993).

¹ H-NMR (SPS1 ₃ ) δ: 2.37-2.76 (8H, m), 3.14 (2H, m), 3.78 (3H, s), 5.29 (2H, br s .), 6.02-6.23 (2H, m), 6.67-6.90 (3H, m), 7.05 (1H, dd), 7.12-7.33 (3H, m) 7.60 (1H, dd), 7.77 (1H, d), 8.50 (1H, dd), 9.06 (1H, br.s.).

Example 196. 5-Chloro-1 '- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] spiro [isobenzofuran-1 (3H) , 4'-piperidine].

The title compound was prepared following the procedure of Example 44, step 2, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 5-chlorospiro [isobenzofuran-1 (3H), 4'-piperidine].

¹ H-NMR (CBC1 ₃ ) δ: 1.66-1.71 (2H, m), 1.79-1.91 (2H, m), 2.26-2.73 (8H, m), 4 99 (2H, s), 5.22 (2H, br.s), 6.07 (1H, t), 6.63-6.70 (2H, m), 6.76 (1H, d) 7.06 (1H, d), 7.19-7.32 (3H, m), 7.60 (1H, dd), 8.47 (1H, dd), 8.63 (1H, 8). MS t / ζ: 475 (M + 1).

Example 197. 5-Chloro-1 '- [3- (5,11-dihydro-7- (2-methoxyethyl) oxy [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] spiro [isobenzofuran-1 (3H), 4'-piperidine].

The title compound was prepared following the procedure of Example 175, but replacing the product of Example 44 with the product of Example 196.

¹ H-NMR (SPS1 ₃ ) δ: 1.69-1.74 (2H, m), 1.83-1.94 (2H, m), 2.31-2.76 (8H, m), 3 45 (3H, s), 3.72-3.75 (2H, m), 4.08-4.11 (2H, m), 5.00 (2H, s), 5.28 (2H, w (s.), 6.09 (1H, t), 6.74-6.82 (2H, m), 6.89 (1H, d), 7.04 (1H, d), 7.17-7 28 (3H, m), 7.57 (1H, dd), 8.49 (1H, dd). MS t / ζ: (M + 1).

Example 198. 4- (4-Chlorophenyl) -1- [3- (7-dimethylaminocarbonyl-5,11-dihydro [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 134, but replacing the product of Example 133 with the product of Example 118.

¹ H-NMR (СОС1 ₃ ) δ: 1.65-1.70 (2Н, m), 1.99-2.09 (3Н, m), 2.32-2.69 (8Н, m), 2 , 17 (3H, s), 5.35 (2H, br.s.),

6.15 (1H, t), 6.82 (1H, d), 7.19 (1H, dd), 7.28-7.46 (6H, m), 7.58 (1H, dd), 8 49 (1H, dd).

Example 199. 4- (4-Chlorophenyl) -1- [3- (7- (2- (1-hydroxy-2-methyl) propyl) hydroxy-5,11-dihydro [1] benzoxepino [2,3L] pyridine -5-ylidene) propyl] piperidin-4-ol.

Sodium borohydride (330 mg) was added to a solution of the product of Example 138 (500 mg) in methanol (5 ml), and the mixture was refluxed for 1 hour. The mixture was distilled under reduced pressure. Water and ethyl acetate were added to the residue, the organic layer was isolated and washed with saturated aqueous sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by chromatography on silica gel eluting with a mixture of chloroform: methanol (10: 1) to obtain the title compound (440 mg).

¹ H-NMR (SPS1 ₃ ) δ: 1.26 (6H, s), 1.66-1.70 (2H, m), 1.79 (1H, br.s), 2.00-2, 08 (2H, m), 2.37-2.70 (9H, m),

3.58 (2H, s), 5.30 (2H, br.s), 6.05 (1H, t), 6.75-6.84 (2H, m), 6.91 (1H, d ), 7.26-7.44 (5H, m), 7.58 (1H, dd), 8.49 (1H, dd). MS t / ζ: 535 (M + 1).

Example 200. 4- (4-Chlorophenyl) -1- [3- (7- (1- (2-methyl-2-hydroxy) propyl) hydroxy-5,11-dihydro [1] benzoxepino [2,3L] pyridine -5-ylidene) propyl] piperidin-4-ol.

To a solution of the product of Example 48 (500 mg) in tetrahydrofuran (5 ml) was added a 0.95 molar solution of methylmagnesium bromide in tetrahydrofuran (3.8 ml) at 0 ° C and the mixture was stirred at room temperature for 20 minutes. An aqueous solution of ammonium chloride and ethyl acetate are added to the mixture, the organic layer is isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. Solvent Solvent

- 43 008060 was removed under reduced pressure and the residue was purified by chromatography on silica gel eluting with a mixture of chloroform: methanol (10: 1) to obtain the title compound (360 mg).

'Η-NMR (SBS _{1 3} ) δ: 1.34 (6H, s), 1.58 (1Η, br.s), 1.66-1.71 (2Η, m), 1.99-2, 10 (2Η, m), 2.25 (1Η, br.s), 2.36-2.71 (8Η, m), 3.77 (2Н, s), 5.28 (2Η, br.s .), 6.09 (1Η, m), 6.74-6.86 (3Η, m), 7.24-7.44 (5Η, m), 7.57 (1H, dd), 8.49 (1H, dd). MS t / ζ: 535 (M + 1).

Example 203. 4- (4-Chlorophenyl) -1- [3- (7- (2-methoxy) ethyloxy) -5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl ] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with 2-methoxyethyl bromide.

Ή-NMR (СОС1 ₃ ) δ: 1.24 (3Η, t), 1.66-1.75 (3Η, m), 2.00-2.11 (2Η, m), 2.36-2, 71 (8Η, m), 3.59 (2H, q), 3.71-3.75 (2Η, m), 4.07-4.11 (2Η, m), 5.27 (2Η, br. s.), 6.09 (1Η, t), 6.75-6.91 (3Η, m), 7.23-7.44 (5Η, m), 7.57 (1Н, dd), 8, 48 (1H, dd). MS t / ζ: 535 (M + 1).

Example 205. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1- (2,3-dihydroxy) propyloxy) [1] benzoxepino [2,3-b] pyridine- 5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with glycidol.

Ή-NMR (SBS1 ₃ ) δ: 1.66-1.75 (2Η, m), 2.00-2.11 (2Η, m), 2.36-2.71 (8Η, m), 3, 62-3.76 (2Η, m), 3.94-4.02 (4Η, m), 4.21 (2Η, b.s.), 5.27 (2Η, b.s.), 6, 09 (1Η, t), 6.76-6.86 (3Η, m), 7.23-7.44 (5Η, m), 7.57 (1Н, dd), 8.48 (1Н, dd) . MS t / ζ: 537 (M + 1).

Example 211. 1- [3- (7- (1-Carbamoyl-1-methyl) ethyloxy-5,11-dihydro [1] benzoxepino- [2,3-b] pyridin5-ylidene) propyl] -4- (4chlorophenyl ) piperidin-4-ol.

The title compound was prepared following the procedure of Example 176, but replacing dimethylamine hydrochloride with ammonium hydroxide.

Ή-NMR (СОС1 ₃ ) δ: 1.50 (6Н, s), 1.67-1.72 (2Η, m), 1.96-2.09 (3Η, m), 2.36-2, 70 (8Η, m), 5.30 (2Η, sh.), 5.70 (1Η, sh.), 6.05 (1Η, t), 6.75-6.90 (4Η, m), 7.25-7.44 (5Η, m), 7.58 (1H, dd), 8.49 (1H, dd). MS t / ζ: 548 (M + 1).

Example 212. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-methylaminocarbonyl-1-methyl) ethyloxy [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 176, but replacing dimethylamine hydrochloride with methylamine.

Я-NMR (SBS1 ₃ ) δ: 1.47 (6Н, s), 1.67-1.72 (2Η, m), 1.96-2.09 (2Η, m), 2.20 (1Η, b.w.), 2.36-2.70 (8Η, m), 2.87 (3Η, d), 5.29 (2Η, b.w.), 6.04 (1Η, t), 6 72-6.86 (4Η, m), 7.27-7.44 (5Η, m), 7.58 (1H, dd), 8.47 (1H, dd). MS t / ζ: 562 (M + 1).

Example 215. 4- (4-Chlorophenyl) -1- [3- (7- (2-dimethylaminocarboxy) ethenyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure for Example 134, but replacing the product of Example 133 with the product of Example 172.

Ή-NMR (SBS1 ₃ ) δ: 1.63-1.71 (3Η, m), 1.98-2.10 (2Η, m), 2.35-2.72 (8Η, m), 3, 07 (3Η, s), 3.17 (3Η, s),

5.36 (2Η, bs), 6.16 (1Η, t), 6.76 (1H, d), 6.84 (1H, d), 7.28-7.45 (7Η, m ), 7.59-7.65 (2Η, m), 8.52 (1H, dd). MS t / ζ: 544 (M + 1).

Example 218. 1- [3- (7- (2-Carbamoyl) ethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 181, but replacing the product of Example 133 with the product of Example 123.

Ή-NMR (SBS1 ₃ ) δ: 1.65-1.90 (3Η, m), 2.10-2.22 (2Η, m), 2.40-2.80 (10Η, m), 2, 91 (2Η, t), 5.31-5.46 (4Η, m), 6.11 (1Η, t), 6.78 (1H, d), 7.01 (1H, dd), 7.16 (1H, d), 7.28-7.46 (5Η, m), 7.57 (1H, dd), 8.49 (1H, dd). MS t / ζ: 518 (M + 1).

Example 234. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidine) propyl] -4 (indol-3-yl) piperidine.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (indol-3-yl) piperidine. This piperidine was obtained in the same manner as described in the journal I. Meb. Oh. 36: 4006-4014 (1993), followed by hydrogenation as described in Example 58, step 3.

Ή-NMR (SBS1 ₃ ) δ: 1.65-1.93 (2Η, m), 1.94-2.28 (4Η, m), 2.34-2.70 (4Η, m), 2, 81 (1Η, m), 2.96 (2Η, m), 3.78 (3Η, s), 5.28 (2Η, b.s.), 6.09 (1Η, t), 6.70- 7.42 (8Η, m), 7.53-7.72 (2Η, m), 8.28 (1Η, b.s.), 8.49 (1Η, m).

Example 235. 1- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidine) propyl] -4 (indol-3-yl) -1,2 , 3,6-tetrahydropyridine.

The title compound was prepared following the procedure for Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (indol-3-yl) -1,2,3,6-tetrahydropyridine. This piperidine was obtained in the same manner as described in the journal I. Meb. Oh. 36: 4006-4014 (1993).

Я-NMR (СОС1з) δ: 2.35-2.77 (8Η, m), 3.06-3.26 (2Η, m), 3.78 (3Η, s), 5.29 (2Η, w) .s.), 6.05-6.22 (2Η, m),

- 44 008060

6.70-6.88 (3H, m), 7.07-7.38 (5H, m), 7.60 (1H, dd), 7.87 (1H, m), 8.42 (1H, br.s.), 8.50 (1H, t).

Example 236. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (3-methoxycarbonyl) propyloxy [1] benzooxepino [2,3-b] pyridin-5-ylidine) propyl] piperidine.

The title compound was prepared following the procedure of Example 153, but replacing ethyl bromoacetate with ethyl 4-bromobutyrate.

^! H-NMR (SPS1 ₃ ) δ: 1.26 (3H, t), 1.56-1.85 (4H, m), 2.01 (2H, dt), 2.09 (2H, quintet), 2 30-2.60 (7H, m), 2.93 (2H, m), 3.98 (2H, t), 4.15 (2H, q), 5.28 (2H, b.s.) 6.07 (1H, t), 6.68-6.86 (3H, m), 7.07-7.33 (5H, m), 7.58 (1H, dd), 8.50 (1H , dd). MS t / ζ: 561 (M + 1).

Example 237. 1- [3- (7- (3-Carboxypropyl) oxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidine) propyl] -4- (4-chlorophenyl) piperidine.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 236.

^! H-NMR (C1 + O1)) δ: 1.92-2.20 (6H, m), 2.48 (2H, t), 2.70-3.02 (3H, m), 3.06- 3.45 (4H, m), 3.66 (2H, m), 4.01 (2H, t), 5.48 (2H, br.s.), 6.36 (1H, t), 6, 85 (2H, s), 7.00 (1H, s), 7.20-7.40 (4H, m), 8.11 (1H, dd), 8.64 (1H, d), 8.81 (1H, b). COOH signal is not observed. MS t / ζ: 533 (M + 1).

Example 242. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-hydroxy-1methyl) ethyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 200, but replacing the product of Example 48 with the product of Example 273.

^! H-NMR (CBC1 ₃ ) δ: 1.58 (6H, s), 1.65-1.70 (3H, m), 1.93-2.21 (2H, m), 2.28-2, 73 (8H, m), 5.32 (2H, br.s.),

6.13 (1H, t), 6.82 (1H, d), 7.20-7.50 (7H, m), 7.59 (1H, dd), 8.50 (1H, dd). MS t / ζ: 505 (M + 1).

Example 243. 1- [3- (7- (1-Carboxy-1-methyl) ethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4 (4 -chlorophenyl) piperidin-4-ol.

Stage 1

To a solution of the compound of Example 363, Step 2 (2.4 g) in toluene (30 ml), OSHL (1 molar solution in toluene, 9.2 ml) was added at -78 ° C and the mixture was stirred at 0 ° C for 1 h and at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture. 1N is added to the mixture. aqueous hydrochloric acid saturated with sodium chloride and ethyl acetate, the organic layer was isolated and washed with a saturated aqueous solution of sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate: hexane (1: 4) to give 5- (3bromopropylidene) -5,11-dihydro-7- (1-hydroxy-1-methyl) ethyl [1] benzoxepino- [2 3-b] pyridine (2.0 g).

^! H-NMR (CBC1 ₃ ) δ: 1.45 (H, s), 2.75 (2H, q), 3.47 (1H, t), 5.33 (2H, br.s.), 6, 04 (1H, t), 6.87 (1H, d), 7.09-7.14 (2H, m), 7.30 (1H, dd), 7.57 (1H, dd), 8.53 (1H, dd), 9.46 (1H, s).

Stage 2

5- (3-Bromopropylidene) -7- (1-carboxy-1-methyl) ethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridine is prepared according to the procedure for Example 382, step 2, but replacing the product of example 382, step 1, to the product obtained in step 1 above.

Stage 3.

The title compound was prepared following the procedure for Example 44, step 2, but replacing the product of Example 44, step 1, with the product of step 2.

^! H-NMR (EM8O-b ₆ ) δ: 1.46 (6H, 8), 1.63-1.84 (2H, m), 2.17-2.37 (4H, m), 2.37- 2.53 (4H, m), 3.20-3.43 (2H, m), 4.83 (1H, s), 5.23 (2H, br.s), 6.13 (1H, t ), 6.76 (1H, d), 7.16 (1H, dd), 7.25 (1H, d), 7.35 (2H, d), 7.427.48 (3H, m), 7.76 (1H, dd), 8.50 (1H, dd). MS t / ζ: 533 (M + 1).

Example 248. 1 '- [3- (5,11-Dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidine) propyl] -6-methylspiro [4H-3,1-benzoxazine -4,4'-piperidine] -2 (1H) -one.

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 6-methylspiro [4H-3,1-benzoxazine-4,4'-piperidine] -2 (1H )-it.

^! H-NMR (CBC1 ₃ ) δ: 1.99-2.06 (2H, m), 2.29 (3H, s), 2.32-2.69 (10H, m), 3.77 (3H, s), 5.27 (2H, br.s), 6.08 (1H, t), 6.69-6.83 (4H, m), 6.94 (1H, s), 7.02 ( 1H, d), 7.25 (1H, dd), 7.55 (1H, dd), 8.48 (1H, dd), 8.56 (1H, 8). MS t / ζ: 498 (M + 1).

Example 249. 5- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4,6- dioxazalan.

5- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] 4,6-diazacyclooctylamine.

Stage 1

5- (3- (H, Ch'-Bis (2-hydroxyethyl) amino) propylidene) -5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridine was prepared according to the procedure for Example 45, stage 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with diethanolamine.

^! H-NMR (C1) _; O1)) δ: 2.46 (2H, m), 2.84 (4H, t), 2.98 (2H, m), 3.67 (4H, t), 3.75 (3H, s), 5.20 (2H, br.s.),

6.16 (1H, t), 6.68-6.80 (2H, m), 6.87 (1H, d), 7.46 (1H, dd), 7.81 (1H, dd), 8 45 (1H, dd).

- 45 008060

Stage 2

To the mixture of the product of stage 1 (78 mg) and dimethyl acetal 4-chlorobenzaldehyde (0.1 ml) in 1.2 dichloroethane (60 ml) was added p-toluenesulfonic acid monohydrate (5 mg) at room temperature, and the mixture was stirred at the boil for 12 h Dichloromethane and a saturated aqueous solution of sodium bicarbonate are added to the cooled reaction mixture, the organic layer is isolated and washed with a saturated aqueous solution of sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by chromatography on silica gel eluting with dichloromethane methanol (20: 1) to give the title compound (40 mg).

Я-NMR (SIS1 ₃ ) δ: 2.35 (2Η, m), 2.64-2.94 (6H, m), 3.52-3.68 (2H, m), 3.78 (3Η, s), 3.72-3.90 (2Η, m),

5.27 (2Η, br.s), 5.66 (1 1, t), 6.08 (1Η, t), 6.68-6.88 (3Η, m), 7.18-7.46 (5Η, m), 7.58 (1H, dd), 8.50 (1Η, dd).

Example 252

Stage 1

In a cold (0 ° C) stirred solution of 4-oxo-homopiperidine hydrochloride (0.6 g, 4.05 mmol), potassium carbonate (0.615 g, 4.46 mmol) in anhydrous THF (10 ml), ethyl chloroformate (0, 44 ml, 4.05 mmol). The reaction mixture was warmed to room temperature for 2 hours, then the reaction was quenched by adding water, extracted with ethyl acetate and the organic layer was dried over sodium sulfate. Pure 1-ethylcarbonyl-4-oxo-homopiperidine was isolated by flash chromatography on silica gel.

Stage 2

To a cold (0 ° C) stirred solution of 1-ethylcarbonyl-4-oxo-homopiperidine (1.42 g, 6.07 mmol) in anhydrous THF (50 ml) in an argon atmosphere, 10 ml of a solution (1.0 mmol / L) is added dropwise. , 10 mmol) of 4-chlorophenylmagnesium bromide in diethyl ether. The reaction mixture was warmed to room temperature for 2 hours, then the reaction was quenched by the addition of a saturated aqueous solution of ΝΗ. · | Ί. 95 (95 ml). Then the reaction mixture can be extracted with ethyl acetate (2 times 50 ml), the organic layers are combined and dried over sodium sulfate. Pure 1-methoxycarbonyl-4- (4-chlorophenyl) -4-hydroxy-homopiperidine (2.1 g, 96%) can be isolated by flash chromatography on silica gel eluted with 50% ethyl acetate / hexane.

4- (4-Chlorophenyl) -4-hydroxyhomopiperidine can be prepared by reacting 1 methoxycarbonyl-4- (4-chlorophenyl) -4-hydroxyhomopiperidine with an equivalent nucleophilic hydroxide such as ΕίΘΗ in a solvent such as THF, methanol or ethanol. By removing the solvent, 4- (4-chlorophenyl) -4-hydroxyhomopiperidine can be obtained.

Stage 4.

This compound is prepared following the procedure of Example 44, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine 4- (4-chlorophenyl) -4-hydroxy-homopiperidine.

Examples 253 and 254.

Stage 1

To a stirred solution of 4-oxo-homopiperidine Ηί, Ί (1.2 g, 8.05 mmol), ΝαΘΗ (0.68 g, 16.9 mmol) in 10 ml of a mixture of tert-butanol / water (1: 1) is added dropwise tert-butyl dicarbonate (1.93 ml, 8.9 mmol). The reaction mixture was stirred at room temperature overnight, extracted with ethyl acetate (2x10 ml) and the organic layer was isolated. The organic layer was dried over sodium sulfate and concentrated in vacuo. Pure 1-tert-butoxycarbonyl-4-oxo-homopiperidine (1.42 g, 84%) was isolated by flash chromatography on silica gel eluted with 50% ethyl acetate / hexane.

Я-NMR (CBC1 ₃ ) δ: 1.44 (9H, 8), 1.72-1.84 (2H, m), 2.60-2.65 (4H, m), 3.55-3, 61 (4H, m).

Stage 2

In a cold (0 ° C) stirred solution of 1-tert-butoxycarbonyl-4-oxo-homopiperidine (1.42 g, 6.07 mmol) in anhydrous THF (50 ml) in an argon atmosphere, a 1.0 molar solution of 4- is added dropwise. chlorophenyl magnesium bromide in diethyl ether (10 ml, 10 mmol). The reaction mixture was warmed to room temperature for 2 hours, then the reaction was quenched by the addition of a saturated aqueous solution of ΝΗ + .Ί (5 ml). The reaction mixture was extracted with ethyl acetate (2x50 ml), the organic layers were combined and dried over sodium sulfate. Pure 1-tert-butoxycarbonyl-4- (4-chlorophenyl) -4-hydroxyhomopiperidine (2.1 g, 96%) was isolated by flash chromatography on silica gel eluting with 50% ethyl acetate / hexane.

Ή-NMR (CBC1 ₃ ) δ: 1.43 (9H, s), 1.61-2.22 (6H, m), 3.21-3.31 (2H, m), 3.48-3, 82 (2H, m).

Stage 3.

Trifluoroacetic acid (2.0 ml) was added to a stirred solution of 1-tert-butoxycarbonyl-4- (4-chlorophenyl) -4-hydroxy-homopiperidine (2.1 g) at room temperature in 48 ml of methylene chloride. The reaction mixture was stirred at room temperature for 2 hours. Excess solvent and trifluoroacetic acid were removed to give 2.0 g (92% yield) of a 1: 1 mixture of 3- (4-chlorophenyl) -2,3-dehydro-homopiperidine and 3- (4 -chlorophenyl) -3,4-dehydrohomopiperidine.

Ή-NMR (MeOI, isomer A) δ: 2.01-2.11 (2H, m, 4), 2.60-2.71 (2H, m, 5), 2.81-2.92 (2H , m, 4), 2.83-3.05 (2H, m, 5), 3.66-3.92 (4H, m, 5), 6.16-6.21 (1H, t, 5) .

- 46 008060 ^! H-NMR (MeOE, Isomer B) 3.44-3.56 (2H, m, 4), 3.88-3.97 (2H, m, 4), 6.01-6.12 (1H, t 4), 7.32-7.44 (1H, t, 4).

Stage 4.

Compounds can be prepared following the procedure of Example 44, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 3- (4-chlorophenyl) -3,4-dehydrohomopiperidine and 3- (4-chlorophenyl) -4,5-dehydrohomopiperidine.

Example 255. 1- (4-Chlorophenyl) -4- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperazinone.

The title compound was prepared following the procedure of Example 44, step 2, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1- (4-chlorophenyl) piperazinone.

'H-NMR (1) \ 18O-cP) δ: 2.30-2.34 (2H, m), 2.49-2.57 (2H, m), 2.68 (2H, t), 3 06 (2H, s), 3.58 (2H, t), 5.12 (2H, br.s), 6.06 (2H, t), 6.57-6.69 (3H, m) 7.35-7.71 (5H, m), 7.72 (1H, dd), 8.48 (1H, dd).

Example 256. 1- (4-Chlorophenyl) -4- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] homopiperazidine.

The title compound was prepared following the procedure of Example 44, step 2, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 1- (4-chlorophenyl) homopiperazidine.

'H-NMR (SBSl) δ: 1.89 (2H, br.s), 2.27-2.35 (2H, m), 2.51-2.70 (6H, m), 3.37 -3.53 (4H, m), 5.23 (2H, br.s), 5.98 (1H, t), 6.48-6.74 (6H, m), 7.05-7, 26 (2H, m), 7.52 (1H, dd), 8.45 (1H, dd). MS t / ζ: 462 (M + 1).

Example 260. 3- (4-Chlorophenyl) -8- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -8-azabicyclo [ 3.2.1] octane-3-ol.

The title compound was prepared following the procedure of Example 44, step 2, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 3- (4-chlorophenyl) -8-azabicyclo [3,2,1] octan-3-ol .

'H-NMR (COS1 ₃ ) δ: 1.65-2.10 (4H, m), 2.1-2.7 (8H, m), 3.32 (2H, br.s.), 3, 78 (3H, s), 5.24 (2H, br.s), 6.10 (1H, dd), 6.70-6.90 (3H, m), 7.15-7.31 (3H , m) 7.45 (broad d, 2H), 7.64 (dd, 1H), 8.46 (dd, 1H). MS t / ζ: 503 (M + 1).

Example 261. 1 '- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] spiro [5- chloro-1,3-benzodioxol-2,4'-piperidine].

The title compound was prepared following the procedure of Example 44, step 2, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with spiro [5-chloro-1,3-benzodioxol-2,4'-piperidine] (1OIT1 οί Meb1sta CPrepiNp . 1995, 38, 2009-2017).

'H-NMR (1) \ 18O-cP) δ: 1.78-2.02 (4H, m), 2.18-2.63 (8H, m), 4.97-5.27 (2H, b.s.), 6.06 (1H, t), 6.58-6.67 (3H, m), 6.79-6.87 (2H, m), 6.99 (1H, d), 7.42 (1H, dd), 7.72 (1H, dd), 8.49 (1H, M), 9.07 (1H, 8).

Example 262. 1- [3- (7- (1-Carbamoyl-1-methyl) ethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin5-ylidene) propyl] -4- (4chlorophenyl) -4-hydroxy-1-methylpiperidinium iodide.

To a solution of the product of example 211 (330 mg) in acetonitrile (1.2 ml) was added iodomethane (0.07 ml) and the reaction mixture was stirred at room temperature for 2 hours, the precipitate was filtered off and washed with acetonitrile to obtain the title compound ( 250 mg).

'H-NMR (1) \ 18O-cP) δ: 1.39 (6H, s), 1.65-1.85 (2H, m), 2.20-2.64 (4H, m), 3 09 (3H, s), 3.30-3.65 (6H, m), 5.20 (2H, m), 5.61 (1H, s), 6.01 (1H, t), 6, 75-6.92 (3H, m), 7.27 (1H, s), 7.38-7.64 (6H, m), 7.83 (1H, dd), 8.56 (1H, dd) . MS t / ζ: 562 [(M-G) +].

Example 263. 4- (4-Chlorophenyl) -1- [3- (7-diethylaminocarbonylmethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4- ol.

The title compound was prepared following the procedure of Example 134, but replacing dimethylamine hydrochloride with diethylamine.

'H-NMR (SBSl) δ: 1.67-1.72 (2H, m), 1.99-2.10 (2H, m), 2.36-2.70 (9H, m), 2, 89 (3H, d), 4.45 (2H, s),

5.28 (2H, br.s.), 6.08 (1H, br.s), 6.66 (1H, br.s.), 6.73-6.84 (3H, m), 7.25- 7.45 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd). MS t / ζ: 534 (M + 1).

Example 268. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methylaminocarbonyl [1] benzoxepino- [2,3b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 198, but replacing dimethylamine hydrochloride with methylamine.

'H-NMR (OM? O-b ₆ ) δ: 1.75-1.80 (2H, m), 2.38-2.50 (2H, m), 2.63-2.73 (2H, m), 2.78 (3H, d), 3.17-3.50 (6H, m), 5.38 (2H, br.s), 6.36 (1H, t), 6.87 ( 1H, d), 7.41-7.50 (4H, m), 7.55-7.99 (4H, m), 8.48-8.50 (1H, m), 8.61 (1H, dd). MS t / ζ: 504 (M + 1).

Example 269. 1- [3- (7-Carbamoyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4 (4-chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 198, but replacing dimethylamine hydrochloride with ammonium hydroxide.

'H-NMR (СОС1 ₃ ) δ: 1.67-1.79 (2Н, m), 2.01-2.10 (2Н, m), 2.17-2.71 (8Н, m), 5 38 (2H, br.s), 6.21 (1H, t), 6.85 (1H, d), 7.27-7.57 (9H, m), 7.90 (1H, dd) 8.50 (1H, dd). MS t / ζ: 490 (M + 1).

Example 270. 4- (4-Chlorophenyl) -1- [3- (7-diethylaminocarbonyl-5,11-dihydro [1] benzoxepino [2,3-b] pi

- 47 008060 Ridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 198, but replacing dimethylamine hydrochloride with diethylamine. MS t / ζ: 546 (M + 1).

Example 273. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (methoxycarbonyl [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] piperidin-4 -ol.

A mixture of the product of example 169 (15.0 g), palladium (II) diacetate (170 mg), 1,3-bis (diphenylphosphino) propane (310 mg) and triethylamine (7.0 ml) in methanol (100 ml) and dimethylformamide (150 ml) was purged with carbon monoxide for 5 minutes and stirred in an atmosphere of carbon monoxide (from a balloon) at 70 ° C for 8 hours. The reaction mixture was evaporated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was dried with magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (13.1 g).

^! H-NMR (SBSl) δ: 1.45-1.80 (3H, m), 1.90-2.15 (2H, m), 2.28-2.48 (4H, m), 2.50 -2.75 (4H, m), 3.89 (3H,

s), 5.25-5.50 (2H, m), 6.20 (1H, dd), 6.85 (1H, d), 7.20-7.37 (3H, m), 7.42 (2H, d), 7.58 (1H, d), 7.80 (1H, dd), 8.01 (1H, dd), 8.52 (1H, dd). MS t / ζ: 505 (M + 1).

Example 274. 4- (4-chlorophenyl) -1- [3- (5,11-dihydro-7-hydroxymethyl [1] benzoxepino [2,3-b] pyridin5-ylidene) propyl] piperidin-4-ol.

To an ice-cooled solution of the product of Example 273 (2.0 g) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (300 mg) and the reaction mixture was stirred at room temperature for 12 hours. After cooling the reaction mixture to 0 ° C, water was added (0, 3 ml), 15% aqueous sodium hydroxide solution (0.3 ml) and water (0.9 ml). The reaction mixture was filtered and the filtrate was dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol: 28% ammonia in water = 100: 5: 1) to obtain the title compound (1.6 g).

¹ H-NMR (СОС1 ₃ ) δ: 1.55-1.71 (3Н, m), 1.95-2.25 (2Н, m), 2.34-2.70 (8Н, m), 4 62 (2H, s), 5.20-5.45 (2H, br.s), 6.13 (1H, t), 6.84 (1H, d), 7.16 (1H, dd) 7.23-7.43 (6H, m), 7.58 (1H, dd), 8.51 (1H, dd). MS t / ζ: 477 (M + 1).

Example 275. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-propylamino) methyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

Acetic acid (0.36 ml) was added to a solution of the product of example 314 (300 mg) and 1-propylamine (0.26 ml) in tetrahydrofuran (6 ml) and the reaction mixture was stirred at 60 ° C for 30 minutes. Then sodium triacetoxyborohydride (670 mg) was added to the reaction mixture at 0 ° C and stirred for 1.5 hours at room temperature. Sodium bicarbonate, water and chloroform are added to the reaction mixture. The organic layer was extracted and dried over potassium carbonate and evaporated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (130 mg).

^! H-NMR (SBSl) δ: 0.92 (3H, t), 1.49-1.70 (6H, m), 1.98 (2H, m), 2.34-2.42 (4H, m ), 2.51-2.70 (6H, m), 3.71 (2H, s), 5.32 (2H, br.s), 6.12 (1H, t), 6.81 (1H d) 7.11 (1H, dd), 7.25-7.45 (6H, m), 7.57 (1H, dd), 8.49 (1H, dd). MS t / ζ: 518 (M + 1).

Example 276. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (3-hydroxy-1-propylamino) methyl [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 275, but replacing 1propylamine with 3-amino-1-propanol. MS t / ζ: 534 (M + 1).

Example 277. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-piperidino) methyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 275, but replacing 1propylamine with piperidine. MS t / ζ: 544 (M + 1).

Example 278. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (4-morpholino) methyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 275, but replacing 1-propylamine with morpholine. MS t / ζ: 546 (M + 1).

Example 279. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-pyrrolidino) methyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 275, but replacing 1-propylamine with 4-aminobutyric acid.

^! H-NMR (SPS1 ₃ ) δ: 1.70-1.75 (2H, m), 1.98 (2H, m), 2.12-2.23 (2H, m), 2.40-2, 86 (10H, m), 3.27 (2H, t),

4.36 (2H, 5), 5.29 (2H, br.s), 6.07 (1H, t), 6.80 (1H, d), 7.04 (1H, dd), 7, 19 (1H, d), 7.28-7.32 (3H, m), 7.50 (1H,

t), 7.61 (1H, dd), 8.51 (1H, dd). MS t / ζ: 544 (M + 1).

Example 280. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-hydroxy) ethyl [1] benzoxepino- [2,3-b] pyridin-5ilidene) propyl] piperidine -4-ol

The title compound was prepared following the procedure of Example 273, but replacing the product.

- 48 008060 of example 169 per product of example 274.

^! H-NMR (SBS _{1 3} ) δ: 1.60-1.70 (4H, m), 2.01-2.12 (2H, m), 2.37-2.70 (8H, m), 2, 81 (2H, t), 3.84 (2H, t), 5.31 (2H, br.s), 6.09 (1H, t), 6.81 (1H, d), 7.03 ( 1H, dd), 7.15 (1H, d), 7.26-7.43 (5H, m), 7.57 (1H, dd), 8.49 (1H, dd). ΜC t / ζ: 491 (M + 1).

Example 281. 1- [3- (7-Carbamoylmethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4- ol.

The title compound was prepared following the procedure of Example 122, but replacing dimethylamine hydrochloride with ammonium hydroxide.

^! H-NMR (SPS1 ₃ ) δ: 1.65-1.70 (2H, m), 1.98-2.06 (2H, m), 2.27-2.70 (9H, m), 3, 46 (2H, s), 5.30 (2H, br.s), 5.74 (1H, br.s), 6.04 (1H, br.s), 6.09 (1H, t ), 6.79 (1H, d), 7.02 (1H, dd), 7.18-7.41 (6H, m), 7.54 (1H, dd), 8.43 (1H, dd) . MS t / ζ: 504 (M + 1).

Example 288. 4- (4-Chlorophenyl) -1- [3- (7- (2-methoxycarboxy) ethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 165, but replacing the product of Example 164 with the product of Example 310.

^! H-NMR (SPS1 ₃ ) δ: 1.23 (3H, t), 1.63-1.71 (3H, m), 1.98-2.10 (2H, m), 2.35-2, 71 (10H, m), 2.89 (2H, t),

4.13 (2H, q), 5.31 (2H, br.s), 6.08 (1H, t), 6.78 (1H, d), 7.00 (1H, dd), 7, 12 (1H, d), 7.26-7.44 (5H, m), 7.57 (1H, dd), 8.49 (1H, dd). MS t / ζ: 548 (Μ + 1).

Example 289. 4- (4-Chlorophenyl) -1- [3- (7- (1- (3-hydroxy) propyl) -5,11-dihydro [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 288.

^! H-NMR (ΌΜ8Ο-6 ₆ ) δ: 1.45-1.50 (2H, m), 1.66-1.80 (4H, m), 2.26-2.57 (10H, m), 3.41 (2H, q), 4.46 (1H, t), 4.83 (1H, s), 5.23 (2H, br.s), 6.14 (1H, t), 6, 71 (1H, d), 7.01 (1H, dd), 7.13 (1H, d), 7.34-7.48 (5H, m), 7.72 (1H, dd), 8.49 (1H, dd). MS t / ζ: 505 (Μ + 1).

Example 290. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2,3-dihydroxy) propyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

To a solution of the product of Example 170 (6.9 g) in tetrahydrofuran (70 ml) and water (14 ml) was added methyl morpholine oxide (1.7 g) and osmium tetroxide at 0 ° C and the mixture was stirred at room temperature for 3 hours. ethyl acetate was added to the mixture, and the aqueous layer was isolated. A mixture of chloroform: isopropanol (4: 1) was added to the aqueous layer, the organic layer was extracted and dried with magnesium sulfate.

The solvent was distilled off under reduced pressure to obtain the title compound (7.0 g).

^! H-NMR (SPS1 ₃ ) δ: 1.65-1.73 (2H, m), 1.95-2.10 (2H, m), 2.30-2.75 (13H, m), 3, 45-3.50 (1H, m), 3.603.65 (1H, m), 3.83-3.90 (1H, m), 5.28 (2H, br.s.), 6.06 (1H , t), 6.84 (1H, d), 7.03 (1H, dd), 7.15 (1H, d), 7.267.43 (5H, m), 7.57 (1H, dd), 8 49 (1H, dd). MS t / ζ: 521 (Μ + 1).

Example 291. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-phenyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 170, but replacing allyl tributyl tin with phenyl tributyl tin.

^! H-NMR (SPS1 ₃ ) δ: 1.84-1.92 (2H, m), 2.85-3.40 (10H, m), 5.33 (2H, br.s.), 6.05 (1H, t), 6.95 (1H, d), 7.30-7.58 (12H, m), 7.63-7.66 (1H, m), 8.56-8.58 (1H , m). MS t / ζ: 523 (Μ + 1).

Example 292. 4- (4-Chlorophenyl) -1- [3- (7- (2-furyl) -5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine -4-ol

The title compound was prepared following the procedure of Example 170, but replacing allyl tributyltin with ethyl (2-furyl) tributyltin.

^! H-NMR (SPS1 ₃ ) δ: 1.70-1.80 (3H, m), 1.97-2.16 (2H, m), 2.3-2.8 (8H, m), 5, 36 (2H, m), 6.19 (1H, t), 6.45 (1H, dd), 6.55 (1H, d), 6.87 (1H, d), 7.20-7.50 (7H, m), 7.60-7.65 (2H, m), 8.52 (1H, dd). MS t / ζ: 513 (Μ + 1).

Example 293. 4- (4-Chlorophenyl) -1- [3- (7-methoxycarbonylamino-5,11-dihydro [1] benzoxepino [2,3b] pyridin-5-ylidine) propyl] piperidin-4-ol.

A mixture of the product of Example 118 (490 mg) and diphenylphosphonikazide (0.28 ml) was stirred at 110 ° C for 30 minutes. After cooling the mixture, triethylamine (0.14 ml) and ethanol (5 ml) were added and the mixture was refluxed for 8 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with saturated aqueous sodium bicarbonate and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (210 mg).

^! H-NMR (COC1 ₃ ) δ: 1.31 (3H, t), 1.65-1.70 (2H, m), 2.01-2.09 (2H, m), 2.36-2, 70 (8H, m), 4.21 (2H, q), 5.30 (2H, b.s.), 6.13 (1H, t), 6.46 (1H, b.s.), 6 80 (1H, d), 7.02 (1H, dd), 7.28-7.50 (6H, m), 7.57 (1H, dd), 8.50 (1H, dd). MS t / ζ: 534 (Μ + H).

Example 294. 1- [Bis (methoxycarbonylmethyl) methoxy-5,11-dihydro [1] benzoxepino- [2,3-b] pyridine

- 49 008060

5-ylidene) propyl] -4- (4chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with diethyl bromomalonate.

Я-NMR (С0С1 ₃ ) δ: 1.30 (3Н, t), 1.66-1.71 (2Н, m), 1.98-2.09 (2Н, m), 2.35-2, 69 (9H, m), 4.30 (2H, q),

5.14 (1H, s), 5.26 (2H, br.s), 6.10 (1H, t), 6.78 (2H, d), 7.00 (1H, t), 7, 26-7.45 (5H, m), 7.57 (1H, dd), 8.43 (1H, dd). MS t / ζ: 621 (M + 1).

Example 295. 1- [1,1-Bis (methoxycarbonylmethyl) ethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4chlorophenyl) piperidin-4- ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with diethyl-2-bromo-2-methylmalonate.

Я-NMR (СОС1 ₃ ) δ: 1.27 (6Н, m), 1.65-1.70 (5Н, m), 1.99-2.08 (3Н, m), 2.31-2, 69 (8H, m), 4.28 (4H, q), 5.27 (2H, br.s), 6.06 (1H, t), 6.72 (1H, d), 6.80 ( 1H, dd), 7.00 (1H, d), 7.27-7.45 (5H, m), 7.56 (1H, dd), 8.46 (1H, dd).

Example 296. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-hydroxy-1-hydroxymethyl) ethyloxy [1] benzoxepino [2,3-b] pyridin-5 - ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 199, but replacing the product of Example 138 with the product of Example 294.

Ή-NMR (SBS1 ₃ ) δ: 1.70-1.75 (2H, m), 2.10-2.80 (11H, m), 3.90 (4H, d), 4.36 (1H, quintet), 5.28 (2H, br.s), 6.13 (1H, t), 6.71-6.87 (2H, m), 7.00 (1H, d), 7.29- 7.45 (5H, m), 7.58 (1H, dd), 8.51 (1H, dd). MS t / ζ: 537 (M + 1).

Example 297. 1- [1,1-Bis (hydroxymethyl) ethyloxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] -4- (4-chlorophenyl) piperidin-4- ol.

The title compound was prepared following the procedure of Example 199, but replacing the product of Example 138 with the product of Example 295.

Я-NMR (SBS1 ₃ ) δ: 1.09 (3Н, s), 1.66-1.71 (2Н, m), 1.90-2.10 (3Н, m), 2.37-2, 75 (8H, m), 3.72-3.82 (4H, m), 5.29 (2H, br.s), 6.05 (1H, t), 6.77 (1H, d), 6.88 (1H, dd), 7.03 (1H, d), 7.26-7.43 (5H, m), 7.56 (1H, dd), 8.48 (1H, dd). MS t / ζ: 551 (M + 1).

Example 299. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (5-methoxycarbonylpropyl) hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl 4-bromobutyrate.

Я-NMR (SPS1 ₃ ) δ: 1.24 (3Н, t), 1.65-1.69 (2Н, m), 1.96-2.12 (4Н, m), 2.26-2, 67 (10H, m), 3.9 6 (2H, t), 4.12 (2H, q), 5.24 (2H, br.s), 6.08 (1H, t), 6.70 -6.83 (3H, m), 7.21-7.59 (6H, m), 8.39 (1H, dd).

Example 300. 1- [3- (7- (3-Carboxy-1-propyl) oxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 299.

Я-NMR (EM8O-b ₆ ) δ: 1.41-1.95 (2H, m), 1.41-1.95 (4H, m), 2.20-2.72 (10H, m), 3.95 (2H, t), MS t / ζ: 549 (M + 1).

Example 301. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (4-methoxycarbonylphenyl) methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with methyl 4-bromomethylbenzoate.

Я-NMR (SPS1 ₃ ) δ: 1.66-1.70 (2H, m), 1.93-2.09 (3H, m), 2.37-2.70 (8H, m), 3, 91 (3H, s), 5.09 (2H, q), 5.27 (2H, br.s), 6.06 (1H, t), 6.80-6.91 (3H, m), 7.24-7.60 (8H, m), 8.01-8.07 (2H, m), 8.47 (1H, dd).

Example 302. 1- [3- (7- (4-Carboxyphenyl) methoxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] -4- (4-chlorophenyl) piperidine 4-ol

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 301.

Я-NMR (EM8O-b ₆ ) δ: 1.44-1.49 (2H, m), 1.67-1.87 (2H, m), 2.26-2.56 (8H, m), 4.85 (1H, br.s.), 5.15-5.25 (4H, m), 6.17 (1H, t), 6.72-6.95 (3H, m), 7.30 -7.75 (8H, m), 7.92-7.99 (2H, m), 8.48 (1H, dd). MS t / ζ: 597 (M + 1).

Example 303. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7 - ((1-hydroxymethyl) cyclopropyl) methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene ) propyl] piperidin-4-ol.

Stage 1

1- [3- (7 - ((1-Benzoyloxymethyl) cyclopropyl) methoxy-5,11-dihydro [1] benzoxepino- [2,3-b] pyridin5-ylidene) propyl] -4- (4-chlorophenyl) piperidine -4-ol is obtained following the procedure of Example 46, but replacing ethyl iodide with (1-benzoyloxymethyl) cyclopropylmethylmethanesulfonate.

Я-NMR (SPS1 ₃ ) δ: 0.70-0.81 (4Н, m), 1.65-1.70 (3Н, m), 1.98-2.07 (2Н, m), 2, 35-2.70 (8H, m), 3.91 (2H, s), 4.39 (2H, s), 5.25 (2H, br.s), 6.06 (1H, t), 6.72-6.84 (3H, m), 7.23-7.59 (9H, m), 8.02-8.06 (2H, m), 8.48 (1H, dd).

- 50 008060

Stage 2

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

^! H-NMR (C0C1g) δ: 0.62 (4H, s), 1.67-1.72 (2H, m), 1.96-2.06 (2H, m), 2.34-2.69 (8H, m), 3.39 (1H, br.s.), 3.91 (2H, s), 3.91 (2H, s), 5.26 (2H, br.s.), 6, 09 (1H, t), 6.72-6.86 (3H, m), 7.27-7.60 (6H, m), 8.48 (1H, dd). MS t / ζ: 547 (M + 1).

Example 305. 1- [3- (5,11-Dihydro-7- (2-hydroxyethyl) aminocarbonyl [1] benzoxepino [2,3-b] pyridin5-ylidene) propyl] -4- (4-chlorophenyl) piperidine 4-ol

The title compound was prepared following the procedure of Example 198, but replacing dimethylamine hydrochloride with 2-hydroxyethylamine.

^! H-NMR (СОС1 ₃ ) δ: 1.65-1.70 (2Н, m), 2.03-2.06 (2Н, m), 2.21 (1Н, d), 2.32-2, 68 (8H, m), 3.63 (2H, dt), 3.83 (2H, t), 5.37 (2H, br.s), 6.18 (1H, t), 6.67 ( 1H, br.s.), 7.25-7.54 (7H, m), 7.86 (1H, dd), 8.50 (1H, dd). MS t / ζ: 534 (M + 1).

Example 306. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-cyclohexyloxycarbonyloxy) ethyloxycarbonyl [1] benzoxypino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol dihydrochloride.

To a solution of the product of Example 118 (1.1 g) in dimethylformamide (15 ml) was added sodium iodide (0.17 g), potassium carbonate (0.38 g) and 0.57 g cyclohexyl-1-chloroethyl carbonate (1 . Lpuyu1u8, 1987, 40, 81). The mixture was stirred at 70 ° C. for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100: 3). The resulting oil was dissolved in ethyl acetate and 4N was added. a solution of hydrochloric acid in ethyl acetate (0.8 ml). The precipitate was filtered off to obtain the title compound (0.96 g).

^! H-NMR (IM8O _6th ) δ: 1.22-1.47 (6H, m), 1.58 (3H, d), 1.63-1.81 (6H, m), 2.38- 3.30 (10H, m), 4.07-4.59 (1H, m), 5.80 (2H, b.s.), 6.28 (1H, t), 6.87 (1H, q ), 6.97 (1H, d), 7.40-7.49 (4H, m), 7.64 (1H, dd), 7.79 (1H, dd), 7.96 (1H, d) 8.03 (1H, dd), 8.65 (1H, dd), 11.07 (1H, br.s.). MS t / ζ: 661 [(M-2CH1) +1].

Example 307. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-methoxycarbonyloxy) ethyloxycarbonyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 307, but replacing cyclohexyl-1-chloroethyl carbonate with ethyl 1-chloroethyl carbonate. MS t / ζ: 607 (M + 1).

Example 308. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (5-hydroxyfuran-2-yl) [1] benzoxepino [2,3-b] pyridin-5-ylidene ) propyl] piperidin-4-ol.

Stage 1

4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (5-formylfuran-2-yl) [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidine- 4-ol is obtained following the procedure of Example 170, but replacing allyl tributyltin with (5-formylfuran-2-yl) tributyltin.

^! H-NMR (СОС1 ₃ ) δ: 1.40-1.80 (2Н, m), 1.89-2.12 (2Н, m), 2.20-2.75 (8Н, m), 5, 28 (2H, br.s), 6.16 (1H, t), 6.69 (1H, d), 6.84 (1H, d), 7.22-7.55 (8H, m), 7.76 (1H, d), 8.42 (1H, dd), 9.52 (1H, 8).

Stage 2

The title compound was prepared following the procedure of Example 199, but replacing the product of Example 138 with the product of Step 1. MS t / ζ: 543 (M + 1).

Example 309. 1- [3- (7- (5-Carboxyfuran-2-yl) -5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4 -chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 382, step 2, but replacing the product of Example 382, step 1 with the product of Example 307, step 1. MS t / ζ: 557 (M + 1).

Example 310. 4- (4-Chlorophenyl) -1- [3- (7- (2-methoxycarboxy) ethenyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 171, but replacing tert-butyl acrylate with ethyl acrylate.

^! H-NMR (СОС1 ₃ ) δ: 1.33 (3Н, m), 1.63-1.71 (3Н, m), 1.98-2.10 (2Н, m), 2.35-2, 72 (8H, m), 4.25 (2H, q),

5.36 (2H, br.s), 6.10 (1H, t), 6.33 (1H, d), 6.85 (1H, d), 7.22-7.44 (7H, m ), 7.58-7.65 (2H, m), 8.53 (1H, dd).

Example 311. 4- (4-Chlorophenyl) -1- [3- (7- (1- (2-ethyl-2-hydroxy) butyl) hydroxy-5,11-dihydro [1] benzoxepino [2,3-b ] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 200, but replacing ethyl magnesium bromide with methyl magnesium bromide.

^! H-NMR (SPS1 ₃ ) δ: 0.93 (6H, t), 1.60-1.70 (6H, m), 1.95-2.10 (3H, m), 2.36-2, 70 (8H, m), 3.79 (2H, s),

5.28 (2H, br.s.), 6.09 (1H, t), 6.77-6.86 (3H, m), 7.24-7.43 (5H, m), 7.57 (1H, dd), 8.47 (1H, dd). MS t / ζ: 563 (M + 1).

Example 312. 4- (4-Chlorophenyl) -1- [3- (7- (2- (2,3-dimethyl-3-hydroxy) butyl) hydroxy-5,11-dihydro [1] benzoxepino [2,3 -B] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 200, but replacing the product.

- 51 008060 of example 48 to the product of example 138.

Я-NMR (SPS1 ₃ ) δ: 1.22 (6Н, s), 1.32 (6Н, s), 1.66-1.71 (2Н, m), 1.99-2.10 (2Н, m), 2.35-2.85 (9H, m), 3.77 (2H, s), 5.28 (2H, br.s), 6.04 (1H, t), 6.74- 6.89 (3H, m), 7.26-7.43 (5H, m), 7.57 (1H, dd), 8.44 (1H, dd). MS t / ζ: 563 (M + 1).

Example 313. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-oxopropyl) oxy [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidine- 4-ol

The title compound was prepared following the procedure of Example 146, but replacing ethyl iodide with chloroacetone.

Я-NMR (SPS1 ₃ ) δ: 1.62-1.71 (3Н, m), 1.99-2.10 (2Н, m), 2.27 (3Н, s), 2.35-2, 70 (8H, m), 4.51 (2H, s),

5.28 (2H, br.s), 6.08 (1H, t), 6.70-6.84 (3H, m), 7.25-7.32 (3H, m), 7.41 -7.44 (2H, m), 7.58 (1H, dd), 8.50 (1H, dd). MS t / ζ: 519 (M + 1).

Example 314. 4- (4-Chlorophenyl) -1- [3- (7-formyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

To a solution of the product of Example 274 (1.0 g) in methylene chloride (200 ml) was added 3.0 g of manganese (IV) oxide and the suspension was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The solvent was evaporated under reduced pressure to obtain the title compound (930 mg).

Я-NMR (SPS1 ₃ ) δ: 1.71-1.80 (3H, m), 1.98-2.09 (2H, m), 2.35-2.43 (4H, m), 2, 53-2.69 (4H, m), 5.30 (2H, br.s), 6.24 (1H, t), 6.95 (1H, d), 7.27-7.44 (5H , m), 7.61 (1H, dd), 7.67 (1H, dd), 7.85 (1H, d), 8.54 (1H, dd), 9.88 (1H, s).

Example 315. 1- [3- (7-Acetyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4chlorophenyl) piperidin-4-ol.

Stage 1

To a solution of the compound of Example 53, step 1 (7.2 g) in dichloromethane (70 ml), aluminum chloride (9.1 g) and acetyl chloride (3.2 ml) were added and the mixture was stirred at 0 ° C for 10 minutes. The reaction mixture was poured onto ice. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate: hexane (1: 2) to give 7-acetyl-5- (3-bromopropylidene) -5,11-dihydro [1] benzoxepino [2,3-b] pyridine ( 7.9 g).

Я-NMR (SPS1 ₃ ) δ: 2.57 (3Н, ₈ ), 2.77 (2Н, m), 3.49 (2Н, t), 5.40 (2Н, br.s), 6, 16 (1H, t), 6.88 (1H, d), 8.33 (1H, dd), 7.58 (1H, dd), 7.77 (1H, dd), 7.96 (1H, d) ), 8.56 (1H, dd).

Stage 2

The title compound was prepared following the procedure for Example 44, step 2, but replacing the product of Example 44, step 1 with the product of step 1.

Я-NMR (SPS1 ₃ ) δ: 1.52-1.79 (2Н, m), 1.93-2.11 (2Н, m), 2.27-2.49 (4Н, m), 2, 49-2.60 (5H, m), 2.60-2.73 (2H, m), 5.40 (2H, b.s.), 6.22 (1H, t), 6.87 (1H d) 7.29-7.34 (3H, m), 7.42 (2H, d), 7.59 (1H, dd), 7.75 (1H, dd), 7.96 (1H, d) 8.53 (1H, dd). MS t / ζ: 489 (M + 1).

Example 316. In a stirred solution of phenol containing the product of example 44 (1.0 mmol) and potassium carbonate (1.5 mmol) in THF (10 ml), Ν, Ν dimethylcarbamoyl chloride (1.2 mmol) was added at room temperature. The reaction mixture was stirred at the boil for 24 hours. Excess solvent was removed and the pure compound was isolated by chromatography on silica gel eluting with 5% methanol / methylene chloride. MS t / ζ: (M + 535).

Example 317. To a stirred solution of phenol containing the product of example 44 (1.0 mmol) and potassium carbonate (1.5 mmol) in THF (10 ml), morpholinocarbamoyl chloride (1.2 mmol) was added at room temperature. The reaction mixture was stirred at the boil for 24 hours. The excess solvent was removed and the pure compound was isolated by chromatography on silica gel eluting with 5% methanol / methylene chloride. MS t / ζ: (M + 577).

Example 318. Sodium hydride (1.5 mmol) was added to a stirred solution of phenol containing the product of Example 44 (1.0 mmol) in DMF at room temperature, followed by Ν-isopropylisocyanate (1.5 mmol). The reaction mixture was heated to 60 ° C. for 6 hours. The reaction was quenched by adding 1.5 equiv. water, and excess DMF is removed under reduced pressure. The residue was loaded onto a silica gel column and eluted with 5% methanol / methylene chloride. MS t / ζ: (M + 548).

Example 319. In a stirred solution of phenol containing the product of example 44 (1.0 mmol) and potassium carbonate (1.5 mmol) in THF (10 ml), No. methyl-No. phenylcarbamoyl chloride (1.2 mmol) was added at room temperature. The reaction mixture was stirred at the boil for 24 hours. Excess solvent was removed and the pure compound was isolated by chromatography on silica gel eluting with 5% methanol / methylene chloride. MS t / ζ: (M + 597).

Example 320. In a stirred solution of phenol containing the product of example 44 (1.0 mmol) in DMF, sodium hydride (1.5 mmol) was added at room temperature, followed by the addition of Ν-phenylisocyanate (1.5 mmol). The reaction mixture is heated to 60 ° C. for 6 hours.

- 52 008060 are added by adding 1.5 equiv. water and excess DMF are removed under reduced pressure. The residue was loaded onto a silica gel column and eluted with 5% methanol / methylene chloride. MS t / ζ: (M + 583).

Example 321. In a stirred solution of phenol containing the product of Example 44 (1.0 mmol) in DMF, No. 1H (1.5 mmol) was added at room temperature, followed by the addition of N- (3pyridyl) isocyanate (1.5 mmol). The reaction mixture was heated to 60 ° C. for 6 hours. The reaction was quenched by adding 1.5 equiv. water, and excess DMF is removed under reduced pressure. The residue was loaded onto a silica gel column and eluted with 5% methanol / methylene chloride. MS t / ζ: (M + 584).

Example 322. In a stirred solution of phenol containing the product of example 44 (1.0 mmol) and potassium carbonate (1.5 mmol) in THF (10 ml), pyrrolidinylcarbamoyl chloride (1.2 mmol) was added at room temperature. The reaction mixture was stirred at the boil for 24 hours. Excess solvent was removed and the pure compound was isolated by chromatography on silica gel eluting with 5% methanol / methylene chloride. MS t / ζ: (M + 560).

Example 323. The compound was prepared following the procedure for Example 45, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) -4-cyanopiperidine. MS t / ζ: (M + 486).

Example 324. In a cold (0 ° C.) stirred solution of Example 323 (0.50 g, 0.104 mmol) in anhydrous THF (5 ml), lithium aluminum hydride (8 mg, 0.21 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was then interrupted by carefully adding water (0.21 ml), a 15% aqueous KOH solution (0.21 ml) and then water (0.21 ml). The organic layer was isolated and dried over sodium sulfate. The compound was purified by flash chromatography on silica gel eluted with 10% methanol / methylene chloride. MS t / ζ: (M + 490).

Example 325. The compound can be obtained by reducing the azide functional group in the compound of example 187 with a reducing agent, such as triphenylphosphine, lithium aluminum hydride, sodium borohydride, in a solvent such as tetrahydrofuran or diethyl ether, in the reaction temperature range from 0 ° C to the boiling point, moreover, the reaction time is between 5 minutes and 72 hours

Example 326. The compound is prepared following the procedure of Example 45, step 3, but replacing 4- (4chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) -4-methylpiperidine, which is provided in Example 329, steps 1-3. MS t / ζ: (M + 475).

Example 328

Step 1. No. Benzyl-4- (4-chlorophenyl) -4-hydroxypiperidine: FIG. 8a.

To a stirred solution of commercially available 4- (4-chlorophenyl) -4-hydroxypiperidine (10 g, 47 mmol, 1) in anhydrous DMF (10 ml), benzyl bromide (5.6 ml, 47 mmol) and potassium carbonate (7.4 g, 94 mmol) and stirred at room temperature overnight. Excess solvent is removed under reduced pressure, introduced into 100 ml of methylene chloride, washed with water (2 times 50 ml). The organic layer was isolated, dried over sodium sulfate and loaded onto a silica gel flash column. Elution with a mixture of 2% methanol gives 10 g of compound 2 (80% yield) as a viscous liquid. MS t / ζ: (M + 303).

Step 2. No. Benzyl-4- (4-chlorophenyl) -4-fluoropiperidine: FIG. 8a.

In a cold (-78 ° C) solution of compound 2 (10 g, 33 mmol) in 20 ml of methylene chloride, ΌΆ8Τ (diethylamino sulfur trifluoride, 5.3 ml, 39.8 mmol) is slowly added in an inert atmosphere. The reaction mixture was stirred at -78 ° C for another 45 minutes. The reaction was interrupted at -78 ° C by slowly adding a sufficient amount of a saturated aqueous solution of sodium bicarbonate, to a pH value> 8. As a result of this reaction, a quantitative conversion of the starting compound to a mixture (1: 1) of fluoropiperidine 3 and 4- (4chlorophenyl) tetrahydropyridine 4 is achieved. This mixture of 3 and 4 (3.5 g of the mixture, ~ 35% yield) is purified by flash chromatography silica gel eluted with 2% methanol / methylene chloride. It turned out that this mixture cannot be separated by flash chromatography on silica gel. To isolate the desired product, a mixture of 3 and 4 is subjected to oxidation with osmium tetroxide.

In a stirred solution of a mixture of 3 and 4 (1.8 g) in a mixture of acetone / water (5: 1, 10 ml), a catalytic amount of ОgО ₄ in isopropanol (2.5 mol%, 1 ml) and No.methylmorpholine No. Oxide (0.69 g, 6.56 mmol). The reaction mixture was stirred at room temperature overnight. Then the reaction mixture is evaporated to dryness, introduced into methylene chloride and washed with a solution of No. 1H5O ₃ . As a result of this reaction, the unwanted compound 4 in 5 is dihydroxylated and the desired fluoropiperidine 3 (1.0 g, 55% yield) is clearly separated from the by-product by flash chromatography on silica gel eluted with 2% methanol / methylene chloride. MS t / ζ: (M + 306).

Stage 3.4. 4- (4-chlorophenyl) -4-fluoropiperidine: FIG. 8a.

To a cold (0 ° C) solution of compound 3 (1.07 g, 3.5 mmol) in 1,2-dichloroethane was added 1.1 chloroethyl chloroformate (0.45 ml, 4.2 mmol). Then the reaction mixture was refluxed for 2 hours. The excess solvent was removed and the residue was taken up in 5 ml of methanol. This mixture was boiled for 2 hours and excess methanol was removed under reduced pressure. As a result of the precipitation of the hydrochloride salt of compound 6 by adding a methylene chloride / hexane mixture (1: 1), followed by filtration, the desired crystalline product 6 was quantitatively isolated (80%, 0.70 g). MS t / ζ: (M + 215).

- 53 008060

Stage 4.

The compound was prepared following the procedure of Example 44, but 4- (4-chlorophenyl) -4-hydroxypiperidine was replaced with 4- (4-chlorophenyl) -4-fluoropiperidine. MS t / ζ: (M + 466).

Example 329

Step 1. \ -benzyl-4-methylpiperidine: FIG. 8s

To a cold (-78 ° C) stirred solution of a 1.4 molar solution of methyl lithium in THF (39 ml, 54 mmol) in an inert atmosphere was added 5.1 g of β-benzyl-4-oxopiperidine (1.27 mmol). The reaction mixture was stirred at -78 ° C for 2 hours. The reaction was quenched by the slow addition of a saturated aqueous solution of \ H ₄ Cl, the organic layer was isolated and dried over sodium sulfate. Pure methylpiperidine (2) was isolated by flash chromatography on silica gel eluted with 5% methanol / methylene chloride. MS t / ζ: (M + 206).

Step 2. \ -benzyl-4- (4-chlorophenyl) -4-methylpiperidine: FIG. 8s

In a flask containing chlorobenzene (10 ml, excess) and methylpiperidine (0.42 g, 2.06 mmol, 2) aluminum trichloride (1.65 ml, 12.4 mmol) was added. The reaction mixture was refluxed for 24 hours. Excess chlorobenzene was removed under reduced pressure, and pure compound 3 was obtained by flash chromatography on silica gel eluting with ethyl acetate / hexane. MS t / ζ: (M + 300).

Step 3.4: 4- (4-chlorophenyl) -4-methylpiperidine: FIG. 8s

To a cold (0 ° C) solution of 0.41 g of 1-benzyl-4- (4-chlorophenyl) -4-methylpiperidine (3) (1.4 mmol) in methylene chloride, 1.1 equivalents of 1-chloroethyl chloroformate are added. Then the reaction mixture was refluxed for 2 hours. The excess solvent was removed and the residue was taken up in methanol. The mixture was boiled for 2 hours and excess methanol was removed under reduced pressure. The precipitation of the hydrochloride salt of compound 4 by adding methylene chloride, followed by filtration, leads to the quantitative isolation of the desired crystalline product 4 (100%, 0.34 g). MS t / ζ: (M + 210).

Stage 4.

The compound was prepared following the procedure of Example 44, step 2, but 4- (4-chlorophenyl) -4-hydroxypiperidine was replaced with 4- (4-chlorophenyl) -4-methylpiperidine. MS t / ζ: (M + 461).

Example 330

The compound was prepared following the procedure of Example 199, but the compound obtained in Example 44 was replaced with the compound obtained in Example 329. MS t / ζ: (M + 533).

Example 331

Stage 1

A mixture of epichlorohydrin (5.92 g, 64 mmol) and benzhydrylamine (11.7 g, 64 mmol) in methanol (120 ml) was stirred under argon at room temperature for 48 hours. The mixture was then stirred at 50 ° C for 72 hours. The reaction mixture was then stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (200 ml x 3), dried over MgSO ₄ and concentrated in vacuo. Chromatographic purification on silica gel (methylene chloride / methanol = 95/5) gives 10.0 g (65%) of 1 benzhydryl-3-hydroxyazetidine. MS t / ζ: 240 (M + 1).

Stage 2

A mixture of 1-benzhydryl-3-hydroxyazetidine (2.6 g, 11 mmol) and 0.26 g of palladium hydroxide on activated carbon (20 wt.%) In ethanol (40 ml) is shaken in a hydrogenation autoclave under a pressure of 60 psi. inch (420 kPa) for 24 hours. The reaction mixture was filtered through celite and concentrated in vacuo. Concentration in vacuo afforded 0.75 g (95%) of 3-hydroxyazetidine.

^! H-NMR (250 MHz, SI ₃ OI) 3.81-3.92 (2H, m), 4.14-4.25 (2H, m), 4.61-4.69 (1H, m).

Stage 3.

The compound 1- [3- (5,11-dihydro-7- (methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] azetidin-3-ol is obtained following the procedure of Example 45, step 3 but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 3-hydroxyazetidine. MS t / ζ 339 (M + 1).

Stage 4.

To a mixture of morpholine α-oxide (0.028 g, 0.244 mmol), ground molecular sieve (0.066 g) and Pr ₄ \ ⁺ KO ₄ (0.01 g, 0.024 mmol) in methylene chloride, 0.055 g of 1- [3- (5, 11-dihydro-7- (methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] azetidin-3-ol (0.16 mmol) under argon protection. The mixture was stirred overnight at room temperature. The reaction mixture is filtered through celite and concentrated in vacuo. Chromatography on silica gel (methylene chloride / methanol = 95/5 to 9/1) gives 0.033 g of the desired product 1- [3- (5.11-dihydro-7 ( methoxy [1] benzoxepino [2,3 B] pyridin-5-ylidene) propyl] azetidin3-one (60%). MS t / z 337 (M + 1).

Stage 5.

To a solution of 1- [3- (5,11-dihydro-7- (methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] azetidine-

3-one (0.06 g, 0.18 mmol) in THF (8 ml) was added dropwise a solution of 4-chlorophenylmagnesium bromide in diethyl ether (1.0 mol / l, 0.27 ml) in a protective atmosphere of argon at 0 ° FROM. The reaction mixture was stirred at room temperature for 1.5 hours and the reaction was quenched by the addition of saturated aqueous ammonia (4 ml). The aqueous layer was extracted with ethyl acetate (10 ml x 2), dried over MgSO ₄ and concentrated

- 54 008060 in a vacuum. Chromatographic purification on silica gel (methylene chloride / methanol = 95/5) gives 0.048 g of the desired product 3- (4-chlorophenyl) -1- [3- (5,11-dihydro-7- (methoxy- [1] benzoxepino [2] 3b] pyridin-5-ylidene) propyl] azetidine (51%). MS t / ζ 449 (M + 1).

Example 332

Step 1. 3- (4-Chlorobenzoyl) -1- (2-aminoethyl) carbamic acid tert-butyl ester: FIG. 10b.

N- (2-aminoethyl) carbamic acid tert-butyl ester 1 (0.50 g, 3.12 mmol) is added to a mixture of 4-chlorobenzoic acid chloride (0.547 g, 3.12 mmol) and triethylamine (1.74 ml, 12.5 mmol) in methylene chloride (20 ml) and in a protective atmosphere of argon. It was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (25 ml), extracted with methylene chloride (50 ml x 2), dried over MgSO4 and concentrated in vacuo. Chromatography on silica gel (methylene chloride / methanol = 95/5) gives 0.86 g of the desired product (2.93%) of 3- (4chlorobenzoyl) -1- (2-aminoethyl) carbamic acid tert-butyl ester. MS t / ζ: (M + 299).

Step 2: 1- (4-Chlorobenzoyl) -1,2-ethylenediamine: FIG. 10b.

Trifluoroacetic acid (7.5 ml) is added to a solution of 3- (4-chlorobenzoyl) 1- (2-aminoethyl) carbamic acid tert-butyl ester (2, 0.86 g, 2.89 mmol) in methylene chloride (35 ml) at 0 ° C. Stir at room temperature for 30 minutes. Concentration in vacuo provides 0.88 g (95%) of the desired product of 1- (4-chlorobenzoyl) -1,2-ethylenediamine (3). MS t / ζ: (M + 199).

Stage 3.

The compound was prepared following the procedure of Example 45, step 3, but replacing 4- (4-chlorophenyl) -4hydroxypiperidine with 1- (4-chlorobenzoyl) -1,3-propylene diamine. MS t / ζ: (M + 465).

Example 333

Step 1. 2- (4-Chlorophenyl) -1-bromoethylene: FIG. 9s

To a solution of A1C1 ₃ (1.96 g, 14.7 mmol) in anhydrous methylene chloride (50 ml), a borane complex with tert-butylamine (2.57 g, 29.6 mmol) is added at 0 ° C in an argon atmosphere, and stirred in 10 min until a clear solution forms. At 0 ° C., 1.11 g of 4chlorophenacyl bromide (1.491 mmol) in methylene chloride (5 ml) was added to the resulting mixture. The reaction mixture was stirred for 1.5 hours and then the reaction was quenched by adding 0.1N hydrochloric acid (25 ml). The mixture was extracted with ethyl acetate (80 ml × 3), dried over MgSO ₄ and concentrated in vacuo. Chromatographic purification on silica gel (hexane / ethyl acetate = 9: 1) gives 0.85 g (84%) of 2- (4-chlorophenyl) -1-bromethylene (2). MS t / ζ: (M + 219).

Step 2: 2- (4-chlorophenyl) -1- (No. methyl) ethylamine: FIG. 9s

A mixture of 1.02 g of 2- (4-chlorophenyl) -1-bromoethylene (2 g, 4.62 mmol), ethanol (3 ml) and methylamine in water (6 ml, 40 wt.%) Is heated to 135 ° C in overnight. The mixture was cooled to room temperature. The mixture was extracted with diethyl ether (5 ml x 2), dried over MD8O4 and concentrated in vacuo. Chromatographic purification on silica gel (methylene chloride / methanol / NH ₄ OH = 9/1 / 0.1) gives 0.61 g of 2- (4 chlorophenyl) -1- (methyl) ethylamine (3, 79%). MS t / ζ: (M + 170).

Stage 3.

The compound is prepared following the procedure of Example 45, step 3, but replacing 4- (4-chlorophenyl) -4hydroxypiperidine with 2- (4-chlorophenyl) -1- (No. methyl) ethylamine. MS w / x: (M + 451).

Example 334

Stage 1. 3- (4-chlorophenyl) -1-No. methylaminopropane: FIG. 9th.

A mixture of 0.70 g of 3- (4-chlorophenyl) -1-bromopropane (1 g, 3.73 mmol), ethanol (3 ml) and methylamine in water (6 ml, 40 wt.%) Is heated to 135 ° C in overnight. Then the mixture was cooled to room temperature. The mixture was extracted with diethyl ether (5 ml x 2), dried over MD8O4 and concentrated in vacuo. Chromatographic purification on silica gel (methylene chloride / methanol / NH ₄ OH = 9/1 / 0.1) gives 0.5 g (76%) of 3- (4chlorophenyl) -1-methylaminopropane (2). MS t / ζ: (M + 189).

Stage 2

The compound is prepared following the procedure of Example 45, step 3, but replacing 4- (4-chlorophenyl) -4hydroxypiperidine with 3- (4-chlorophenyl) -1-nomethylaminopropane. MS t / ζ: (M + 450).

Example 335. Step 1. 3- (4-chlorophenyl) -3-chloro-1-hydroxypropane: FIG. 9b.

To a solution of 3,4'-dichloropropylphenone (0.52 g, 2.53 mmol) in anhydrous methanol (10 ml) at 0 ° C in a protective atmosphere of argon was added sodium borohydride NaΒΚ ₄ (0.23 g, 3.03 in small portions) mmol). The reaction mixture was stirred under the same conditions for 15 minutes. The mixture was warmed to room temperature, further stirred for 30 minutes, then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate (30 ml × 2), dried over MgSO ₄ and concentrated in vacuo. Chromatographic purification on silica gel (hexane / ethyl acetate = (1/1) gives 0.52 g (99%) of 3- (4-chlorophenyl) -3-chloro-1-hydroxypropane. MS t / ζ: (M + 205).

Stage 2

The compound is prepared following the procedure of Example 45, step 3, but replace 4- (4-chlorophenyl) -4-hydroxypiperidine with 3- (4-chlorophenyl) -3-chloro-1-hydroxypropane. MS t / ζ: (M + 481).

- 55 008060

Example 336

Step 1. 3- (4-chlorophenyl) -3-hydroxy-3-methyl-1-chloropropane: FIG. 10a.

To a solution of 3,4'-dichloropropylphenone (1 g, 1.10 g, 5.40 mmol) in anhydrous THF at 0 ° C in a protective atmosphere of argon, methyl magnesium bromide (2.50 ml, 7.35 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for another 1 hour. The reaction was quenched by adding a saturated aqueous solution of ΝΉ ₄ Ο. The reaction mixture was then extracted with diethyl ether (60 ml x 2), dried over MgSO ₄ and concentrated in vacuo. Chromatographic purification on silica gel (hexane / ethyl acetate = 10/1) afforded 1.0 g (85%) of 3- (4-chlorophenyl) -3-hydroxy-3-methyl-1-bromopropane (2).

MS t / ζ: (M + 219).

Step 2. 3- (4-Chlorophenyl) -3-hydroxy1-3-methyl-1-no. Methylaminopropane: FIG. 10a.

A mixture of 1.04 g of 3,3,3- (4-chlorophenyl) hydroxymethyl-1-bromopropane (2, 4.74 mmol), ethanol (5 ml) and methylamine in water (10 ml, 40 wt.%) Is heated at 135 ° C. for 3 hours. The mixture was cooled to room temperature. The mixture was extracted with diethyl ether (5 ml × 2), dried over MgSO ₄ and concentrated in vacuo. Chromatographic purification on silica gel (methylene chloride / methanol / hydroxylamine = 9/1 / 0.1) gives 1.01 g of 3- (4-chlorophenyl) -3-hydroxy-3-methyl-1-no. Methylaminopropane (3.99%) . MS w / x: (M + 214).

Stage 3.

The compound is prepared following the procedure of Example 45, step 3, but replacing 4- (4-chlorophenyl) -4hydroxypiperidine with 3- (4-chlorophenyl) -3-hydroxy-3-methyl-1-No.methylaminopropane. MS t / ζ: (M + 480).

Example 345. Using the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 1-azaxantone, the desired compound is obtained.

Example 346. Using the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 1-4-azafluorene, the desired compound is obtained.

Example 347. Using the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 7-amino-1-azaxantone, the desired compound is obtained.

Example 348. Using the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 4,5-diazafluorene, the desired compound is obtained.

Example 349. Using the procedure of Example 45, but replacing 5,11-dihydro-7-methoxy [1] benzoxepino [2,3-b] pyridin-5-one with 1-aza-7-nitroxantone, the desired compound is obtained.

Example 350. 3- (4-chlorophenyl) -1- [3- (5,11-dihydro-7- (methoxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] pyrrolidine.

Stage 1

A mixture of 1-benzyl-3-pyrrolidinone (10.0 g, 57 mmol), di-tert-butyl dicarbonate (13.7 g, 63 mmol) and 2.5 g of the catalyst "palladium on activated carbon" (20 wt.%) in methanol was shaken in a Ragg autoclave for hydrogenation with hydrogen (50 psi, 350 kPa) for 48 hours. The reaction mixture was filtered through celite and concentrated in vacuo. Chromatographic purification on silica gel (hexane / ethyl acetate = 1/1) gives 6.21 g of 1-tert-butoxycarbonyl-3-pyrrolidinone (59%).

Ή-NMR (250 MHz, СОС1 ₃ ) δ: 1.46 (9Н, s), 2.57 (2Н, t, 1 = 7.8 Hz), 3.71-3.75 (4Н, m).

Stage 2

To a stirred solution of 1-tert-butoxycarbonyl-3-pyrrolidinone (0.57 g, 3.23 mmol) in THF (10 ml), 4-chlorophenylmagnesium bromide (1.0 mol / L, 5.2 ml) is added in a protective atmosphere of argon at 0 ° C. The reaction mixture was stirred at room temperature for 1 h and then the reaction was quenched by the addition of saturated aqueous ammonium hydroxide (8 ml). The aqueous layer was extracted with ethyl acetate (50 ml, 2 times), dried over MgSO ₄ and concentrated in vacuo. Chromatographic purification on silica gel (hexane / ethyl acetate = 3/1) gives 0.57 g of 1-tert-butoxycarbonyl-3- (4-chlorophenyl) -3-hydroxypyrrolidine (60%). MS t / ζ 298 (M + 1).

Stage 3.

Trifluoroacetic acid (2 ml) is slowly added to a stirred solution of 1-tert-butoxycarbonyl-3- (4-chlorophenyl) -3-hydroxypyrrolidine (0.335 g, 1.28 mmol) in methylene chloride (8 ml) at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The result is 0.355 g of the desired product - 3- (4-chlorophenyl) -3-hydroxypyrrolidine (100%). MS t / ζ 198 (M + 1).

Stage 4.

The title compound was prepared following the procedure for Example 44, but replacing 4- (4chlorophenyl) -4-hydroxypiperidine with 3- (4-chlorophenyl) -3-hydroxypyrrolidine. MS t / ζ 432 (M + 1).

Example 351

Step 1. 4- (4-chlorophenyl) -4-pyridine: FIG. 106.

To a solution of 1.94 g of 4-bromopyridine (1), 1.56 g of 4-chlorophenylboronic acid (2) and 2.76 g of potassium carbonate (2.0 eq.) In a mixture of ethanol / toluene (5 ml / 100 ml) add triphenylphosphine palladium Pb (PP ₃ ) ₃ . The reaction mixture was boiled for 1 h, cooled to room temperature and the reaction was quenched by adding water (15 ml). The reaction mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate. Pure 4- (4-chlorophenyl) -4-pyridine 2 (1.3 g, 68% yield) was isolated after purification on a flash column with a silica eluting with 50% ethyl acetate / hexane. MS t / ζ: (M + 191).

- 56 008060

Stage 2

The title compound was prepared following the procedure of Example 45, step 3, but replacing 4 (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) -4-pyridine. MS t / ζ: (M + 456).

Example 352. The compound was prepared following the procedure of Example 44, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-chlorophenyl) -4-pyridine. MS t / ζ: (M + 442).

Example 353. 5- (2-Sh- (4- (4-Chlorophenyl) -4-hydroxycyclohexyl) -methyl) ethylidene) -5,11-dihydro-7methoxy [1] benzoxepino [2,3-b] pyridine.

The compound was prepared according to the procedure for Example 57, step 3, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-Nomethyl- (4-chlorophenyl) -4-hydroxycyclohexylamine.The starting compound could be prepared according to the methods described in Chapter 1 of £ Mebuta1 Siet181gu, vol. 15, Mar. 12, pp. 1239-1243 (1972).

Example 354. 1- [3- (7- (4-Carboxyphenoxy) -5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidine -4-ol

Stage 1

4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (4-methoxycarbonylphenoxy) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4- ol is obtained following the procedure of Example 46, but replacing ethyl iodide with ethyl 4-fluorobenzoate.

Ή-NMR (CBC1 ₃ ) δ: 1.36 (3Η, t), 1.65-2.07 (4Η, m), 2.32-2.63 (8Η, m), 4.34 (2Н, j), 5.33 (2H, br.s.), 6.07 (1Η, t), 6.88-7.10 (5Η, m), 7.27-7.51 (5Η, m), 7.58 (1H, dd), 7.97-8.00 (2Η, m), 8.49 (1H, dd).

Stage 2

The title compound was prepared following the procedure for Example 133, but the product of Example 48 was replaced with the product of Step 1.

Ή-NMR (EM8O-b ₆ ) δ: 1.44-1.49 (2H, m), 1.67-1.87 (2Η, m), 2.26-2.56 (8Η, m), 4.85 (1Η, bhp), 5.29 (2Η, bhp), 6.17 (1Η, t), 6.88-7.09 (5Η, m), 7.33- 7.48 (5Η, m), 7.75 (1Η, dd), 7.89-7.93 (2Η, m), 8.52 (1H, dd). MS t / ζ: 582 (M).

Example 355. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-hydroxyimino) propyl) hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene ) propyl] piperidin-4-ol.

To a solution of the product of Example 313 (300 mg) in ethanol (3 ml) was added hydroxylamine chloride (80 mg) at room temperature and the mixture was stirred for 1 hour. The precipitate was filtered off and washed with ethanol to obtain the title compound (300 mg).

Ή-NMR (EM8O-b ₆ ) δ: 1.75-1.80 (2Η, m). 2.23-2.42 (2Η, m), 2.53 (3Η, s), 3.16-3.48 (8Η, m), 4.54 (2H, s), 5.19 (2Η, b.s.), 5.57 (1H, s), 6.14 (1Η, t), 6.76-6.98 (3Η, m), 7.41-7.48 (5Η, m), 7.79 (1Η, dd), 8.53 (1Η, dd),

10.93 (1Η, 8). MS t / ζ: 515 (M + 1).

Example 356. 1- [3- (7- (2-Carboxy-2-methyl-1-propyl) oxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

Stage 1

4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-methoxycarbonyl-2-methylpropyl) oxy) [1] benzoxepino [2,3-b] pyridin-5-ylidene ) propyl] piperidin-4-ol is obtained following the procedure of Example 46, but replacing ethyl iodide with ethyl 2-bromo-1,1-dimethylpropionate.

Ή-NMR (CBC1 ₃ ) δ: 1.31 (6H, s), 1.67-1.72 (2Η, m), 1.96-2.15 (2Η, m), 2.39-2, 78 (8Η, m), 3.69 (3Η, s),

3.93 (2H, s), 5.27 (2H, br.s), 6.09 (1Η, t), 6.70-6.83 (3Η, m), 7.23-7.59 (6Η , m) 8.46 (1H, dd).

Stage 2

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

Ή-NMR (EM8O-b ₆ ) δ: 1.46-1.50 (2Η, m), 1.74-1.85 (2Η, m), 2.22-2.38 (8Η, m), 3.92 (2H, s), 4.58 (1Η, br.s), 5.19 (2Η, br.s), 6.18 (1Η, t), 6.71-6.83 ( 3Η, m), 7.33-7.48 (5Η, m), 7.72 (1H, dd), 8.49 (1H, dd). MS t / ζ: 514 (M + 1).

Example 357. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2- (hydroxyimino) propyl) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 354, but replacing the product of Example 313 with the product of Example 315.

Ή-NMR (EM8O-b ₆ ) δ: 1.39-1.54 (2Η, m), 1.64-1.86 (2Η, m), 2.13 (3Η, s), 2.19- 2.36 (4Η, m), 2.36-2.52 (4Η, m), 4.83 (1H, s), 5.28 (2Η, br.s), 6.20 (1Η, t ), 6.80 (1H, d), 7.35 (2H, d), 7.43-7.49 (4Η, m), 7.58 (1H, d), 7.76 (1H, d) 8.51 (1H, dd), 11.04 (1Η, 8). MS t / ζ: 504 (M + 1).

Example 358. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-propionyl [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 315, but replacing acetyl chloride with propionyl chloride.

Ή-NMR (CBC1 ₃ ) δ: 1.22 (3Η, t), 1.63-1.77 (2Η, m), 1.97-2.13 (2Η, m), 2.25-2, 48 (4Η, m), 2.48-2.60 (2Η, m). 2.60-2.73 (2Η, m), 2.96 (2Н, br), 5.41 (2Η, br.s), 6.21 (1Η, t), 6.86 (1H, d) ), 7.30-7.34 (3Η, m), 7.43 (2H, d), 7.59 (1H, d), 7.75 (1H, dd), 7.97 (1H, d) 8.53 (1H, d). MS t / ζ: 503 (M + 1).

- 57 008060

Example 359. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-isobutyryl [1] benzoxanes [2,3-b] pyridin-5ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 315, but replacing acetyl chloride with isobutyryl chloride.

¹ H-NMR (SPS1 ₃ ) δ: 1.21-1.33 (2H, m), 1.76-2.00 (2H, m), 2.46-3.47 (8H, m), 3 53 (1H, m), 5.47 (2H, br.s), 6.09 (1H, t), 6.89 (1H, d), 7.32-7.45 (6H, m) 7.64 (1 H, d), 7.79 (1H, dd), 7.94 (1H, d), 8.57 (1H, d). MS t / ζ: 517 (M + 1).

Example 360. 4- (4-Chlorophenyl) -1- [3- (7-cyclopropylacetyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 315, but replacing acetyl chloride with cyclopropylacetyl chloride.

¹ H-NMR (SPS1 ₃ ) δ: 0.98-1.05 (2H, m), 1.20-1.24 (2H, m), 1.58-1.70 (2H, m), 1 99-2.09 (2H, m), 2.34-2.55 (4H, m), 2.58-2.68 (5H, m), 5.40 (2H, br.s.), 6.23 (1H, t), 6.89 (1H, d), 7.30-7.34 (3H, m), 7.43 (2H, d), 7.59 (1H, dd), 7 86 (1H, dd), 8.00 (1H, d), 8.53 (1H, dd). MS t / ζ: 515 (M + 1).

Example 361. 1- [3- (7- (3-Carboxypropionyl) -5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidine -4-ol

Stage 1

4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (3-methoxycarbonylpropionyl) [1] benzoxepino [2,3-b] pyridin-5-ylidene) piperidin-4-ol is obtained following the procedure of Example 315, but replacing acetyl chloride with methyl succinyl chloride.

¹ H-NMR (SPS1 ₃ ) δ: 1.57-1.77 (4H, m), 1.94-2.14 (4H, m), 2.27-2.61 (6H, t), 2 , 61-2.73 (2H, m), 3.67 (3H, s), 4.70 (1H, t), 5.30 (2H, br.s), 6.11 (1H, t) 6.83 (1H, d), 7.14 (1H, d), 7.29-7.32 (4H, m), 7.42 (2H, d), 7.58 (1H, d), 8.50 (1H, d).

Stage 2

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

¹ H-NMR (OM8O-b ₆ ) δ: 1.37-1.57 (2H, m), 1.63-1.86 (2H, m), 2.13-2.37 (4H, m) 2.45-2.63 (4H, m), 3.173.28 (4H, m), 4.85 (1H, b.s.), 5.36 (2H, b.s.), 6.30 (1H, t), 6.91 (1H, d), 7.35 (2H, d), 7.46-7.50 (3H, m), 7.787.83 (2H, m), 7.95 ( 1H, d), 8.53 (1H, dd). MS t / ζ: 547 (M + 1).

Example 362. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-ethyl-1-hydroxy) propyl [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 242, but replacing methyl magnesium bromide with ethyl magnesium bromide.

¹ H-NMR (SPS1 ₃ ) δ: 0.79 (6H, t), 1.65-2.04 (9H, m), 2.35-2.66 (8H, m), 5.37 (2H , br.s), 6.09 (1H, d), 6.81 (1H, d), 7.10 (1H, dd), 7.26-7.51 (6H, m), 7.59 (1H, dd), 8.49 (1H, dd). MS t / ζ: 533 (M + 1).

Example 363. 4- (4-Chlorophenyl) -1- [3- (7- (1-cyano-1-methyl) ethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

Stage 1

5- (3-Bromopropylidene) -7- (1-hydroxy-1-methyl) ethyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridine was obtained following the procedure of Example 200, but replacing the product of Example 48 for the product of example 315, stage 1.

¹ H-NMR (SPS1 ₃ ) δ: 1.58 (6H, s), 2.74 (2H, q), 3.47 (2H, t), 5.34 (2H, br.s.), 6 09 (1H, t), 6.82 (1H, d), 7.25-7.31 (2H, m), 7.45 (1H, d), 7.57 (1H, dd), 8, 52 (1H, dd).

Stage 2

To a solution of the product of stage 1 (3.8 g) in dichloromethane (40 ml) was added trimethylsilyl cyanide (4.1 ml) and boron trifluoride diethyl ether (2.5 ml) at 0 ° C and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvents are distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate / hexane (1: 3) to give 5- (3-bromopropylidene) -7- (1-cyano-1-methyl) ethyl-5,11-dihydro [1] benzoxepino [ 2,3-b] pyridine (3.4 g).

¹ H-NMR (SPS1 ₃ ) δ: 1.58 (6H, s), 2.76 (2H, m), 3.48 (2H, t), 5.34 (2H, br.s.), 6 09 (1H, d), 6.87 (1H, d), 7.22 (1H, dd), 7.32 (1H, dd), 7.42 (1H, d), 7.58 (1H, dd), 8.55 (1H, dd).

Stage 3.

The title compound was prepared following the procedure for Example 44, step 2, but replacing the product of Example 44, step 1 with the product of step 2.

¹ H-NMR (CBC1 ₃ ) δ: 1.58 (6H, s), 1.60-1.70 (2H, m), 1.93-2.12 (2H, m), 2.30-2 47 (4H, m), 2.50-2.74 (4H, m), 5.31 (2H, b.s.), 6.15 (1H, t), 6.86 (1H, d) 7.19 (1H, dd), 7.28-7.32 (3H, m), 7.41-7.43 (3H, m), 7.61 (1H, d), 8.53 (1H , dd). MS t / ζ: 514 (M + 1).

Example 364. 4- (4-Chlorophenyl) -1- [3- (7-cyano-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

- 58 008060

The title compound was prepared following the procedure for Example 44, step 2, but replacing the product of Example 44, step 1 with 5- (3-bromopropylidene) -7-cyano-5,11-dihydro [1] benzoxepino [2,3-b ] pyridine.

^! H-NMR (СОС1 ₃ ) δ: 1.62-1.75 (2Н, m), 1.98-2.09 (2Н, m), 2.36-2.69 (8Н, m), 5, 36 (2H, br.s), 6.19 (1H, t), 6.89 (1H, d), 7.29-7.62 (8H, m), 8.55 (1H, d). MS t / ζ: 472 (M + 1).

Example 365. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (tetrazol-5-yl) [1] benzoxepino [2,3-b] pyridin5-ylidene) propyl] piperidine -4-ol

Sodium azide (0.69 g) and ammonium chloride (0.56 g) were added to a solution of the product of example 364 (1.0 g) in DMF (10 ml), and the mixture was stirred at 100 ° C for 36 hours. water was added to the mixture, the precipitate was filtered and washed with ethanol to give the title compound (800 mg).

^! H-NMR (OMgO-b ₆ ) δ: 1.66-1.71 (2H, m), 1.91-2.01 (2H, m), 2.86-3.09 (8H, m ), 5.33 (2H, br.s), 6.22 (1H, t), 6.91 (1H, d), 7.39-7.51 (5H, m), 7.79-7 84 (2H, m), 8.03 (1H, d), 8.55 (1H, dd). MS t / ζ: 515 (M + 1).

Example 366. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (hydroxyiminomethyl) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4 -ol.

The title compound was prepared following the procedure of Example 357, but replacing the product of Example 315, Step 2 with the product of Example 314.

^! H-NMR (EM8O-b ₆ ) δ: 141-1.52 (2H, m), 1.70-1.82 (2H, m), 2.27-2.46 (8H, m), 4, 83 (1H, s), 5.37 (2H, br.s), 6.20 (1H, t), 6.83 (1H, d), 7.34-7.53 (7H, m), 7.76 (2H, dd). MS t / ζ: 490 (M + 1).

Example 367. 1- (4-Chlorophenyl) -4- [3- (5,11-dihydro-7- (1-hydroxy-1-methyl) ethyl [1] benzoxepino [2,3-b] pyridin-5 - ylidene) propyl] piperazine.

The title compound was prepared following the procedure for Example 71, but replacing the product of Example 45, step 2 with the product of Example 363, step 1.

^! H-NMR (CBC1 ₃ ) δ: 1.58 (6H, s), 2.31-2.63 (8H, m), 3.02-3.20 (4H, m), 5.32 (2H, b.s.), 6.12 (1H, t), 6.796.83 (3H, m), 7.17-7.31 (6H, m), 7.45 (1H, d), 7.58 ( 1H, dd), 8.51 (1H, dd). MS t / ζ: 490 (M + 1).

Example 368. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-sulfamoyl [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] piperidin-4-ol.

Stage 1

To the product of Example 53, stage 1 (5.4 g), chlorosulfonic acid (50 ml) was added and the mixture was stirred at 0 ° C for 1 h. The reaction mixture was poured on ice and ethyl acetate was added to the mixture, the organic layer was separated and washed with saturated aqueous sodium chloride solution and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. THF (250 ml) and ammonium hydroxide (30 ml) were added to the residue, and the mixture was stirred at room temperature for 10 minutes. Ethyl acetate and water were added to the mixture, the organic layer was isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate / hexane (1: 1) to give 5- (3-bromopropylidene) -5,11-dihydro-7-sulfamoyl [1] benzoxepino [2,3-b] pyridine (5 , 0 g).

^! H-NMR (CBC1 ₃ ) δ: 2.70-2.75 (2H, m), 3.48 (2H, t), 5.39-5.49 (4H, m), 6.16 (1H, t), 6.88 (1H, d), 7.257.34 (2H, m), 7.53 (1H, dd), 7.68 (1H, dd), 7.93 (1H, d), 8, 53 (1H, dd).

Stage 2

The title compound was prepared following the procedure for Example 44, step 2, but replacing the product of Example 44, step 1 with the product of step 1.

^! H-NMR (OMgO-b ₆ ) δ: 1.65-1.70 (3H, m), 1.98-2.07 (2H, m), 2.35-2.64 (8H, m ), 4.98 (2H, br.s.), 5.39 (2H, br.s.), 6.22 (1H, t), 6.92 (1H, d), 7.26-7, 43 (5H, m), 7.55-7.69 (2H, m), 7.91 (1H, d), 8.53 (1H, dd). MS t / ζ: 526 (M + 1).

Example 369. 1 - [- 3- (7- (2-Aminothiazol-4-yl) -5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- ( 4-chlorophenyl) piperidin-4-ol.

Stage 1

7-Bromoacetyl-5- (3-bromopropylidene) -5,11-dihydro [1] benzoxepino [2,3-b] pyridine was prepared following the procedure of Example 315, step 1, but replacing acetyl chloride with bromoacetyl chloride.

^! H-NMR (CBC1 ₃ ) δ: 2.77 (2H, m), 3.50 (2H, m), 4.40 (2H, s), 5.45 (2H, br.s.), 6, 17 (1H, t), 6.90 (1H, d), 7.35 (1H, dd), 7.60 (1H, dd), 7.79 (1H, dd), 8.01 (1H, d) ), 8.57 (1H, dd).

Stage 2

Thiourea (193 mg) was added to a solution of the product of stage 1 (1.1 g) in ethanol (11 ml) at room temperature, and the mixture was stirred at 70 ° C for 30 minutes. The reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate to give 7- (2-aminothiazol-4-yl) 5- (3-bromopropylidene) -5,11-dihydro [1] benzoxepino [2,3-b] pyridine (749 mg )

^! H-NMR (CBC1 ₃ ) δ: 2.74 (2H, t), 3.47 (2H, t), 5.02 (2H, br.s), 5.39 (2H, br.s) 6.16 (1H, d), 6.62 (1H, 8), 6.85 (1H, d), 7.30 (1H, dd), 7.54-7.57 (2H, m), 7.77 (1H, d), 8.53 (1H, dd).

- 59 008060

Stage 3.

The title compound was prepared following the procedure for Example 44, step 2, but replacing the product of Example 44, step 1, with the product of step 2.

Я-NMR (0Ό01 ₃ ) δ: 1.57-1.70 (2H, m), 1.83-2.13 (2H, m), 2.30-2.46 (4H, m), 2, 46-2.60 (2H, m), 2.60-2.73 (2H, M), 5.02 (2H, 8), 5.37 (2H, br.s.), 6.20 (1H , t), 6.61 (1H, 8), 6.85 (1Η, d), 7.27-7.32 (3Η, m), 7.42 (2H, d), 7.50-7, 58 (2H, m), 7.76 (1H, d), 8.50 (1H, dd). MS t / ζ: 545 (M + 1).

Example 370. 1- [3- (7- (3-Carboxy-1-hydroxy) propyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5 ylidene) propyl] -4- (4 -chlorophenyl) piperidin-4-ol.

Stage 1

4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (3-methoxycarbonyl-1-hydroxy) propyl [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidine -4-ol is obtained following the procedure of Example 199, but replacing the product of Example 138 with the product of Example 361, step 1.

Ή-NMR (ΟΌΟ1 ₃ ) δ: 1.57-1.77 (4Н, m), 1.94-2.14 (4Н, m), 2.27-2.61 (6Н, m), 2, 61-2.73 (2H, m), 3.67 (3Η, 8), 4.70 (1H, t), 5.30 (2H, br.s), 6.11 (1H, t), 6.83 (1Η, d), 7.14 (1H, d), 7.29-7.32 (4H, m), 7.42 (2H, d), 7.58 (1Η, d), 8 50 (1H, d).

Stage 2

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

Ή-NMR (Ι) \ 18Ο-6 ₆ ) δ: 1.44-1.63 (2H, m), 1.69-1.90 (2H, m), 2.17-2.29 (2H, m), 2.29-2.82 (6H, m), 3.243.53 (4H, m), 4.49 (1H, t), 5.03 (1H, br.s.), 5.20 ( 2H, br.s), 6.13 (1H, t), 6.76 (1H, d), 7.12 (1H, dd), 7.27 (1H, d), 7.37 (2H, d) 7.43-7.48 (3Η, m), 7.76 (1H, d), 8.32 (1H, s), 8.51 (1H, dd). MS t / ζ: 549 (M + 1).

Example 371. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-fluoroethylamino) carbonylmethyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 134, but replacing dimethylamine hydrochloride with 2-fluoroethylamine.

Ή-NMR (ΟΌΟ1 ₃ ) δ: 1.62-1.71 (3Η, m), 1.98-2.10 (2Н, m), 2.36-2.71 (8Н, m), 3, 63 (1H, q), 3.73 (1H, q), 4.46 (1H, t), 4.49 (2H, s), 4.63 (1Η, t), 5.29 (2H, w C.s.), 6.10 (1H, t), 6.75-6.96 (4H, m), 7.28-7.44 (5H, m), 7.60 (1H, dd), 8 51 (1H, dd). MS t / ζ: 566 (M + 1).

Example 372. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (No. methylsulfamoyl) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine- 4-ol

The title compound was prepared following the procedure of Example 368, but replacing ammonium hydroxide with methylamine.

Ή-NMR (ΟΌΟ1 ₃ ) δ: 1.57-1.70 (3Η, m), 1.93-2.08 (2H, m), 2.34-2.73 (11H, m), 4, 33 (1H, q), 5.36 (2H, br.s), 6.21 (1H, t), 6.91 (1H, d), 7.29-7.45 (6H, m), 7.58-7.65 (2H, m), 7.83 (1H, dd), 8.53 (1H, dd). MS t / ζ: 540 (M + 1).

Example 373. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (S, Ndimethylsulfamoyl) [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidine- 4-ol

The title compound was prepared following the procedure of Example 368, but replacing ammonium hydroxide with dimethylamine.

Ή-NMR (СОС1 ₃ ) δ: 1.55-1.75 (3Η, m), 1.96-2.07 (2Н, m), 2.35-2.67 (8Н, m), 2, 71 (6H, s), 5.51 (2H, br.s), 6.19 (1H, t), 6.92 (1H, d), 7.29-7.73 (8H, m), 8.55 (1H, dd). MS t / ζ: 554 (M + 1).

Example 374. 1- [3- (7- (1-Carboxy-2-hydroxyethyl) oxy-5,11-dihydro [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] -4- (4chlorophenyl) piperidin-4-ol.

Stage 1

4- (4-Chlorophenyl-1- [3- (5,11-dihydro-7- (1-methoxycarboxy-2-hydroxyethyl) oxy- [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol is obtained following the procedure of Example 199, but replacing the product of Example 138 with the product of Example 294.

Я-NMR (ΟΌΟ1 ₃ ) δ: 1.65-1.70 (2H, m), 2.01-2.11 (2H, m), 2.35-2.70 (8H, m), 3, 76 (3Η, s), 3.97-4.08 (2H, m), 4.71 (1H, t), 5.25 (1H, br.s) 6.02 (1H, t) 6, 70-6.91 (3Η, m), 7.23-7.56 (6H, m), 8.44 (1H, dd).

Stage 2

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

Ή-NMR (Ι) \ 18Ο-6 ₆ ) δ: 1.51-1.56 (2Н, m), 1.86-1.94 (2Н, m), 2.33-2.67 (8Н, m), 3.65-3.82 (2H, m), 4.58 (1H, t), 5.17 (2H, br.s), 6.10 (1H, t), 6.71- 6.89 (3Η, m), 7.34-7.47 (5H, m), 7.72 (1H, dd), 8.48 (1H, dd). MS t / ζ: 551 (M + 1).

Example 375. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-ureidomethyl [1] benzoxepino- [2,3-b] pyridin-5ylidene) propyl] piperidin-4-ol.

Urea (2 g) and trimethylsilyl chloride (0.24 ml) were added to a solution of the product of example 314 (800 mg) in acetic acid (20 ml) at room temperature, and the mixture was stirred for 2 hours. Sodium borohydride was added to the reaction mixture at room temperature and the mixture was stirred for 1 h. The solvent was distilled off under reduced pressure and chloroform, 2-propanol and

- 60 008060 do. The organic layer was extracted and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with chloroform / methanol / ammonium hydroxide (100: 10: 1) to give the title compound (250 mg).

^! H-NMR (ϋϋα ₃ ) δ: 1.62-2.04 (5H, m), 2.35-2.69 (8H, m), 4.26 (2H, d), 4.40 (2H, s), 4.48 (1H, t), 5.32 (2H, br.s), 6.12 (1H, t), 6.80 (1H, d), 7.07 (1H, dd) 7.23-7.58 (7H, m), 8.49 (1H, dd). MS t / ζ: 519 (M + 1).

Example 376. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methylthio [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure for Example 44, step 2, but replacing the product of Example 44, step 1 with 5- (3-bromopropylidene) -5,11-dihydro-7-methylthio [1] benzoxepino [2,3b] pyridine .

^! H-NMR (CBC1 ₃ ) δ: 1.53-1.70 (3H, m), 1.98-2.16 (2H, m), 2.17 (3H, 8), 2.34-2, 70 (8H, m), 5.32 (2H, br.s), 6.12 (1H, t), 6.81 (1H, d), 7.11-7.44 (7H, m), 7.57 (1H, dd), 8.50 (1H, dd). MS t / ζ: 493 (M + 1).

Example 377. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-furanon-3-yl) oxy [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 46, but replacing ethyl iodide with 3-bromotetrahydro-2-furanone.

^! H-NMR (CBC1 ₃ ) δ: 1.65-1.70 (2H, m), 1.97-2.13 (2H, m), 2.25-2.73 (10H, m), 4, 25-4.53 (2H, m), 4.82 (1H, t), 5.27 (2H, br.s), 6.09 (1H, t), 6.73-6.91 (2H , m), 7.03 (1H, d), 7.22-7.59 (6H, m), 8.43 (1H, dd). MS t / ζ: 547 (M + 1).

Example 378. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (C-methoxycarbonylmethylsulfamoyl) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine -4-ol

The title compound was prepared following the procedure of Example 368, but replacing ammonium hydroxide with methyl glycine ether hydrochloride.

^! H-NMR (CBC1 ₃ ) δ: 1.66-1.74 (3H, m), 1.97-2.15 (2H, m), 2.37-2.80 (8H, m), 3, 63 (3H, s), 3.78 (2H, s) 5.40 (2H, br.s), 6.22 (1H, t), 6.92 (1H, d), 7.28-7 45 (5H, m), 7.62 (2H, dd), 7.83 (1H, d), 8.53 (1H, dd). MS t / ζ: 598 (M + 1).

Example 379. 1- [3- (7- (H-Carboxymethylsulfamoyl) -5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] -4- (4-chlorophenyl) piperidin-4 -ol.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 378.

^! H-NMR (OM8O-b ₆ ) δ: 1.60-1.65 (2H, m), 2.16-2.25 (2H, m), 2.43-3.03 (8H, m), 3.45 (2H, s), 5.33 (2H, br.s), 6.39 (1H, t), 6.94 (1H, d), 7.41-7.57 (6H, m ), 7.83 (1H, dd), 8.00 (1H, d), 8.54 (1H, dd).

Example 380. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-furanon-5-yl) [1] benzoxepino [2,3-b] pyridin-5-ylidene ) propyl] piperidin-4-ol.

The title compound was prepared following the procedure for Example 249, Step 2, but replacing the product of Example 249, Step 1, with the product of Example 370, Step 1.

^! H-NMR (CBC1 ₃ ) δ: 1.45-1.78 (4H, m), 1.93-2.12 (2H, m), 2.30-2.50 (4H, m), 2, 50-2.78 (6H, m), 5.33 (2H, br.s), 5.46 (1H, t), 6.12 (1H, t), 6.86 (1H, d), 7.09 (1H, dd), 7.27-7.32 (4H, m), 7.42 (2H, d), 7.58 (1H, dd), 8.51 (1H, dd). MS t / ζ: 531 (M + 1).

Example 381. 1- [3- (7-amino-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] -4- (4chlorophenyl) piperidin-4-ol.

To a solution of the product of Example 293 (3.7 g) in ethanol (130 ml) was added a 5N sodium hydroxide solution (100 ml) and the mixture was stirred at 90 ° C. for 1 hour. The reaction mixture was distilled off under reduced pressure. The residue was dissolved in water and neutralized with 1N hydrochloric acid. Ethyl acetate was added to the mixture, the organic layer was isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate to obtain the title compound (3.0 g).

^! H-NMR (CBC1 ₃ ) δ: 1.62-1.72 (2H, m), 1.96-2.08 (2H, m), 2.27-2.72 (8H, m), 3, 48 (2H, br.s.), 5.23 (2H, br.s.), 6.01 (1H, t), 6.49-6.73 (3H, m), 7.18-7, 59 (6H, m), 8.49 (1H, dd). MS t / ζ: 462 (M + 1).

Example 382. 1- [3- (7- (2-Carboxyphenyl) -5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidine -4-ol

Stage 1

4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-formylphenyl) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4- Ol is obtained by following a procedure similar to that of Example 170, but replacing allyl tributyltin with 2-formyl phenylboronic acid.

^! H-NMR (CBC1 ₃ ) δ: 1.65-1.91 (3H, m), 1.99-2.04 (2H, m), 2.37-2.65 (8H, m), 5, 39 (2H, b.s.), 6.15 (1H, t), 6.95 (1H, d), 7.19-7.65 (10H, m), 7.97-8.05 (2H , m), 8.52 (1H, dd), 10.03 (1H, s).

Stage 2

To a solution of the product of stage 1 (270 mg) in acetic acid (2.2 ml) and water (0.5 ml), amidosulfuric acid (67 mg) and sodium chlorite (68 mg) in water (0.1 ml) are added and the mixture stirred at room temperature for 15 minutes The reaction mixture was evaporated under reduced pressure to half the volume. The residue is neutralized with 1N. sodium hydroxide solution. The precipitate is filtered off and washed with water,

- 61 008060 to obtain the title compound (80 mg).

^! H-NMR (EM8O-b ₆ ) δ: 1.41-1.57 (2H, m), 1.74-1.92 (2H, m), 2.21-2.58 (8H, m), 5.32 (2H, br.s.), 6.20 (1H, t), 6.82 (1H, d), 7.15 (1H, dd), 7.31-7.78 (11H, m ), 8.52 (1H, dd). MS t / ζ: 567 (M + 1).

Example 383. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (N- (2,2,2-trifluoroethyl) sulfamoyl) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 368, but replacing ammonium hydroxide with 2,2,2-trifluoroethylamine hydrochloride.

^! H-NMR (SPS1 ₃ ) δ: 1.64-1.77 (2H, m), 1.97-2.18 (2H, m), 2.35-2.80 (8H, m), 3, 63 (2H, q), 5.41 (2H, br.s), 6.21 (1H, t), 6.91 (1H, d), 7.22-7.65 (7H, m), 7.84 (1H, d), 8.57 (1H, dd). MS t / ζ: 608 (M + 1).

Example 384. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methylsulfonyl [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] piperidin-4- ol.

The title compound was prepared following the procedure of Example 44, step 2, but replacing the product of example 44, step 1 with 5- (3-bromopropylidene) -5,11-dihydro-7-methylsulfonyl [1] benzoxepino [2,3-b ] pyridine.

^! H-NMR (SBS1 ₃ ) δ: 1.54-1.71 (3H, m), 1.99-2.08 (2H, m), 2.34-2.68 (8H, m), 3, 04 (3H, s), 5.43 (2H, br.s), 6.24 (1H, t), 6.97 (1H, d), 7.22-7.70 (7H, m), 7.89 (1H, d), 8.55 (1H, dd). MS t / ζ: 525 (M + 1).

Example 385. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-ureido [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

Stage 1. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-phenoxycarbonylamino [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 293, but replacing ethanol with phenol.

^! H-NMR (SPS1 ₃ ) δ: 1.62-1.68 (2H, m), 1.96-2.08 (2H, m), 2.35-2.65 (8H, m), 5, 28 (2H, br.s), 6.10 (1H, t), 6.78 (1H, m), 7.08-7.40 (6H, m), 7.52 (1H, dd), 7.62 (1H, s), 8.44 (1H, dd). MS t / ζ: 582 (M + 1).

Stage 2

Ammonium hydroxide (1.5 ml) was added to a solution of the product of stage 1 (300 mg) in DMF (3 ml) and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the mixture, the organic layer was isolated and washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture (chloroform: methanol = 10: 1) to obtain the title compound (140 mg).

^! H-NMR (EM8O-b ₆ ) δ: 1.45-1.50 (2H, m), 1.72-1.88 (2H, m), 2.28-2.51 (8H, m), 4.82 (1H, 5s), 5.19 (1H, br.s.), 5.74 (2H, br.s.), 6.09 (1H, t), 6.69 (1H, d) 7.12 (1H, dd), 7.32-7.48 (6H, m), 7.74 (1H, dd), 8.37 (1H, s), 8.50 (1H, dd). MS t / ζ: 505 (M + 1).

Example 386. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-morpholinocarbonylamino [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine- 4-ol

The title compound was prepared following the procedure of Example 385, step 2, but replacing ammonium hydroxide with morpholine.

^! H-NMR (СОС1 ₃ ) δ: 1.62-1.67 (2Н, m), 1.95-2.16 (2Н, m), 2.28-2.64 (8Н, m), 3, 41 (4H, t), 3.69 (4H, t), 5.26 (2H, br.s), 6.08 (1H, t), 6.69-6.76 (2H, m), 6.98 (1H, dd), 7.21-7.51 (7H, m), 8.42 (1H, dd). MS t / ζ: 575 (M + 1).

Example 387. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (3- (2-methoxy) carbonylethyl) ureido [1] benzoxepino [2,3-b] pyridin-5 -ilidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 385, step 2, but replacing ammonium hydroxide with beta-alanine ethyl ester hydrochloride.

^! H-NMR (SBS _{1 3} ) δ: 1.18-1.39 (3H, t), 1.62-1.66 (2H, m), 1.92-2.01 (2H, m), 2, 21-2.62 (10H, m), 3.473.50 (2H, m), 4.08 (2H, q), 5.22 (2H, bs), 5.98-6.03 (2H , m) 6.68-6.92 (2H, m), 7.15-7.42 (7H, m), 7.62 (1H, s), 8.36 (1H, dd). MS t / ζ: 605 (M + 1).

Example 388. 1- [3- (7- (E) - (2-Carboxy-1-methyl) ethenyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] -4 - (4-chlorophenyl) piperidin-4-ol.

Stage 1

4- (4-Chlorophenyl) -1- [3- (7- (E) - (2-methoxycarboxy-1-methyl) ethenyl-5,11-dihydro [1] benzoxepino [2,3L] pyridin-5-ylidene ) propyl] piperidin-4-ol is obtained following the procedure of Example 411, but replacing ethyl cyanoformate with ethyl (trimethylsilyl) acetate.

'H-NMR (COS1 ₃ ) δ: 1.30 (3H, t), 1.67-1.72 (3H, m), 1.98-2.05 (2H, m), 2.42-2 67 (11H, m), 4.23 (2H, q), 5.36 (2H, b.s.), 6.14-6.19 (2H, m), 6.85 (1H, d) 7.20-7.61 (8H, m), 8.52 (1H, dd).

Stage 2

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

'H-NMR (EM8O-b ₆ ) δ: 1.50-1.55 (2H, m), 1.87-1.99 (2H, m), 2.34-2.61 (11H, m) 5.29 (2H, br.s.), 6.12 (1H, 5), 6.31 (1H, t), 6.83 (1H, d), 7.35-7.49 (7H, m), 7.76 (1H, dd), 8.52 (1H, dd). MS t / ζ: 530 (M + 1).

- 62 008060

Example 389. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-oxalo [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 361, but replacing methyl succinyl chloride with methyloxalyl chloride.

^! H-NMR (EM8O-b ₆ ) δ: 1.66-1.86 (2H, m), 2.08-2.34 (2H, m), 2.46-2.77 (2H, m), 3.00-3.68 (6H, m), 5.10 (2H, br.s), 5.53 (1H, s), 6.15 (1H, t), 6.89 (1H, d ), 7.34-7.49 (5H, m), 7.68 (1H, dd), 7.75 (1H, dd), 7.87 (1H, d), 8.53 (1H, dd) . MS t / ζ: 519 (M + 1).

Example 390. 1- [3- (7- (3- (2-Carboxy) ethyl) ureido-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Example 387.

^! H-NMR (EM8O-b ₆ ) δ: 1.45-1.55 (2H, m), 1.72-1.85 (2H, m), 2.32-2.49 (10H, m), 3.29 (2H, q), 4.88 (1H, s), 5.19 (2H, br.s), 6.06-6.14 (2H, m), 6.69 (1H, d ), 7.07 (1H, dd), 7.33-7.48 (6H, m), 7.73 (1H, dd), 8.43 (1H, s), 8.49 (1H, dd) . MS t / ζ: 577 (M + 1).

Example 391. 1 - [3 - (7- (3 - (2-Hydroxy) ethyl) ureido-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5 ylidene) propyl] -4- ( 4-chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 385, step 2, but replacing ammonium hydroxide with 2-aminoethanol.

^! H-NMR (EM8O-b ₆ ) δ: 1.45-1.51 (2H, m), 1.72-1.84 (2H, m), 2.24-2.51 (8H, m), 3.11-3.46 (4H, m), 4.71 (1H, t), 4.83 (1H, s), 5.19 (2H, br.s), 6.08 (1H, t) ), 6.69 (1H, d), 7.08 (1H, dd), 7.33-7.48 (6H, m), 7.73 (1H, dd), 8.41 (1H, s) 8.50 (1H, dd). MS t / ζ: 549 (M + 1).

Example 392. 1 - [3 - (5, 11-Dihydro-7- (1-hydroxy-1-methyl) ethyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- ( 2-keto-1-imidazolinyl) piperidine.

The title compound was prepared following the procedure for Example 67, but replacing the product of Example 45, step 2, with the product of Example 363, step 1.

^! H-NMR (CBC1 ₃ ) δ: 1.59 (6H, s), 1.71-1.87 (2H, m), 2.01-2.18 (2H, m), 2.28-2, 61 (6H, m), 2.86-3.00 (2H, m), 4.32 (1H, m), 5.36 (2H, br.s.), 6.15 (1H, t), 6.84 (1H, d), 7.02-7.07 (3H, m), 7.24-7.31 (3H, m), 7.47 (1H, d), 7.60 (1H, dd), 8.51 (1H, dd), 8.97 (1H, s). MS t / ζ: 511 (M + 1).

Example 393. 4- (4-Chlorophenyl) -1- [3- (7- (E) - (2-methoxycarboxy-2-methyl) ethenyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

To a solution of sodium hydride (60% in oil, 100 mg) in THF (6 ml) was added triethyl-2-phosphonopropionate (0.3 ml) and the product of example 314 (300 mg) at 0 ° C and the mixture was stirred at room temperature 30 min Water and ethyl acetate were added to the reaction mixture. The organic layer was extracted and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with chloroform / methanol (30: 1) to obtain the title compound (310 mg).

^! H-NMR (CBC1 ₃ ) δ: 1.34 (3H, t), 1.58-1.71 (3H, m), 1.98-2.15 (5H, m), 2.37-2, 70 (8H, m), 2.27 (2H, q), 5.37 (2H, br.s), 6.14 (1H, t), 6.86 (1H, d), 7.25- 7.44 (7H, m); 7.58-7.63 (2H, m); 8.52 (1H, dd). MS t / ζ: 559 (M + 1).

Example 394. 1- [3- (7- (E) - (2-Carboxy-2-methyl) ethenyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5ylidene) propyl] -4 - (4-chlorophenyl) piperidin-4-ol.

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

^! H-NMR (OM8O-b ₆ ) δ: 1.62-1.67 (2H, m), 1.91-2.05 (5H, m), 2.50-2.94 (8H, m), 5.28 (2H, br.s.), 6.23 (1H, t), 6.87 (1H, d), 7.34-7.55 (8H, m), 7.79 (1H, dd ), 8.54 (1H, dd). MS t / ζ: 531 (M + 1).

Example 395. 1- [3- (7- (5-Carboxy-1-pentyl) oxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- ( 4-chlorophenyl) piperidin-4-ol.

Stage 1

4- (4-Chlorophenyl) -1- [3- (7- (5-methoxycarbonyl-1-pentyl) hydroxy-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl ] piperidin-4-ol is prepared following the procedure of Example 46, but replacing ethyl iodide with ethyl 6-bromohexanoate.

^! H-NMR (СОС1 ₃ ) δ: 1.21 (3Н, t), 1.42-1.79 (8Н, m), 1.98-2.03 (2Н, m), 2.26-2, 67 (10H, m), 3.87 (2H, t), 4.16 (2H, q), 5.23 (2H, br.s), 6.09 (1H, t), 6.67- 6.81 (3H, m), 7.21-7.63 (6H, m), 8.16 (1H, dd).

Stage 2

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

^! H-NMR (EM8O-b ₆ ) δ: 1.41-1.95 (10H, m), 2.20-2.72 (10H, m), 3.92 (2H, t), 5.18 ( 2H, br.s), 6.17 (1H, t), 6.72-6.84 (3H, m), 7.36-7.48 (5H, m), 7.77 (1H, dd ), 8.50 (1H, dd). MS t / ζ: 577 (M + 1).

Example 396. 1- [3- (7- (1 - (2-Carboxy) ethyl) aminocarbonyl-1-methyl) ethyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

Stage 1

4- (4-Chlorophenyl) -1 - [3- (7- (1 - (2-methoxycarbonyl) ethyl) aminocarbonyl-1-methyl) ethyloxy [1] benzene

- 63 008060 sepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol was prepared following the procedure of Example 176, but replacing dimethylamine hydrochloride with beta-alanethyl ether hydrochloride.

Я-NMR (SPS1 ₃ ) δ: 1.42 (3Н, s), 1.62-1.67 (2Н, m), 1.95-2.10 (3Н, m), 2.35-2, 59 (10H, m), 3.51-3.53 (2H, m), 4.00 (2H, q), 5.23 (2H, br.s), 6.00 (1H, t), 6.68-6.81 (3H, m), 7.24-7.56 (6H, m), 8.39 (1H, dd).

Stage 2

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

Я-NMR (EM8O-b ₆ ) δ: 1.37 (6H, s), 1.41-1.52 (2H, m), 1.79-1.87 (2H, m), 2.28- 2.41 (10H, m), 3.33 (2H, q), 5.21 (2H, b.s.), 6.12 (1H, t), 6.70-6.87 (3H, m ), 7.34-7.48 (5H, m), 7.74 (1H, dd), 8.08 (1H, t), 8.50 (1H, dd). MS t / ζ: 620 (M + 1).

Example 397. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (thiazolin-2,4-dion-5-ylidene) methyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

To a solution of the product of Example 314 (590 mg) in ethanol (6 ml) was added 2,4-thiazolinedione (440 mg) and piperidine (0.36 ml), and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure and chloroform was added. , 2-propanol and water. The organic layer was extracted and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with chloroform / methanol (5: 1) to obtain the title compound (510 mg).

Ή-NMR (OM8O-b ₆ ) δ: 1.61-1.66 (2H, m), 1.97-2.12 (2H, m), 2.79-2.99 (8H, m), 5.21 (2H, br.s), 6.25 (1H, t), 6.90 (1H, d), 7.34-7.52 (7H, m), 7.81 (1H, dd ), 8.54 (1H, dd). MS t / ζ: 574 (M + 1).

Example 398. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methanesulfonamido [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 402, but replacing trifluoromethanesulfonic anhydride with methanesulfonyl chloride.

Я-NMR (SPS1 ₃ ) δ: 1.64-1.69 (2H, m), 1.89-2.05 (2H, m), 2.24-2.77 (8H, m), 2, 95 (3H, s), 5.29 (2H, br.s), 6.10 (1H, t), 6.84 (1H, d), 7.06 (1H, dd), 7.18- 7.40 (6H, m), 7.56 (1H, dd), 8.42 (1H, dd). MS t / ζ: 540 (M + 1).

Example 399. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (3-phenylureido) sulfonyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure for Example 320, but replacing the compound of Example 44, step 2 with the compound of Example 368, step 2.

Я-NMR (OM8O-b ₆ ) δ: 1.65-1.69 (2H, m), 1.95-2.05 (2H, m), 2.89-3.06 (8H, m), 5.31 (2H, br.s.), 6.14 (1H, t), 6.74-6.85 (2H, m), 7.08-7.12 (2H, m), 7.37 -7.64 (8H, m), 7.80-7.84 (2H, m), 8.44 (1H, s), 8.54 (1H, dd). MS t / ζ: 645 (M + 1).

Example 400. 4- (4-Chlorophenyl) -1- [3- (7- (3-cyclohexylureido) sulfonyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 399, but replacing phenyl isocyanate with cyclohexyl isocyanate.

Я-NMR (EM8O-b ₆ ) δ: 1.07-1.81 (14H, m), 2.23-2.58 (8H, m), 3.22-3.35 (1H, m), 4.91 (1H, s), 5.38 (2H, br.s), 6.17-6.29 (2H, m), 6.96 (1H, d), 7.34-7.51 (5H, m), 7.62-7.84 (3H, m), 8.53 (1H, dd). MS t / ζ: 651 (M + 1).

Example 401. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (3-propylureido) sulfonyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 399, but replacing phenyl isocyanate with propyl isocyanate.

Я-NMR (EM8O-b ₆ ) δ: 0.74 (3H, t), 1.25-1.53 (4H, m), 1.81-1.91 (2H, m), 2.33- 2.59 (10H, m), 2.89 (2H, q), 4.92 (1H, s), 5.35 (2H, br.s), 6.20 (1H, t), 6, 44 (1H, br.s), 6.96 (1H, d), 7.34-7.51 (5H, m), 7.64 (1H, dd), 7.787.85 (2H, m), 8.54 (1H, dd). MS t / ζ: 611 (M + 1).

Example 402. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-trifluoromethanesulfonamido [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure for Example 169, but replacing the product of Example 44, Step 2 with the product of Example 381.

Я-NMR (EM8O-b ₆ ) δ: 1.75-1.80 (2H, m), 2.02-2.07 (2H, m), 2.49-2.54 (2H, m), 3.10-3.40 (6H, m), 5.15 (2H, br.s), 5.52 (1H, s), 5.97 (1H, t), 6.58 (1H, d ), 6.80 (1H, dd), 6.96 (1H, d), 7.43-7.47 (5H, m), 7.78 (1H, dd), 8.51 (1H, dd) . MS t / ζ: 593 (M + 1).

Example 403. 1- [3- (7- (3-carboxy) propyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol.

Stage 1

To a solution of the product of example 361, step 1 (820 mg) in trifluoroacetic acid (8.0 ml), triethylsilane (0.92 ml) was added at 0 ° C and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure. The residue was poured into saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent is distilled off under reduced pressure.

- 64 008060 nii. The residue was purified by chromatography on silica gel eluted with ethyl acetate-hexane (1: 4) to give 4- (4-chlorophenyl) -1- [3- (5,11-dihydro-7- (3-methoxycarbonyl) propyl [1] benzoxepino [2,3-

b] pyridin-5-ylidene) propyl] piperidin-4-ol (636 mg).

Я-NMR (SBS1 ₃ ) δ: 1.93 (2H, m), 2.34 (2H, t), 2.59 (2H, t), 2.74 (2H, q), 3.47 (2H , t), 3.67 (3H, s), 5.33 (2H, br.s), 6.05 (1H, t), 6.78 (1H, d), 7.00 (1H, dd ), 7.09 (1H, dd), 7.29 (1H, dd), 7.57 (1H, dd), 8.52 (1H, dd).

Stage 2

The title compound was prepared following the procedure of Example 133, but replacing the product of Example 48 with the product of Step 1.

Я-NMR (EM5O-b ₆ ) δ: 1.37-1.57 (2H, m), 1.63-1.87 (4H, m), 2.10-2.36 (6H, m), 2.36-2.61 (6H, m), 4.83 (1H, bp), 5.24 (2H, bp), 6.14 (1H, t), 6.72 ( 1H, d), 7.00 (1H, dd), 7.12 (1H, d), 7.35 (2H, d), 7.41-7.48 (3H, m), 7.73 (1H dd), 8.49 (1H, dd). MS t / ζ: 533 (M + 1).

Example 404. 1- [3- (7-Benzoylsulfamoyl-5,11-dihydro [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] -4- (4-chlorophenyl) piperidin-4-ol .

The title compound was prepared following the procedure of Example 399, but replacing phenyl isocyanate with benzoyl chloride. MS t / ζ: 630 (M + 1).

Example 405. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) methyloxy [1] benzoxepino [2,3-b] pyridin-5-liden) propyl] piperidin-4-ol.

To a solution of the product of Example 407 (1.7 g) in DMF (20 ml) was added 2-ethylhexyl chloroformate (0.62 ml), and the mixture was stirred at 0 ° C. for 1 hour. Chloroform and water were added to the reaction mixture. The organic layer was extracted and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with chloroform / methanol (30: 1) and dissolved in xylene (50 ml). The solution was refluxed for 4 hours. The solvent was distilled off under reduced pressure. The residue was resuspended in ethanol to give the title compound (490 mg).

Я-NMR (EM5O-b ₆ ) δ: 1.60-1.65 (2H, m), 1.91-1.99 (2H, m), 2.41-2.52 (2H, m), 2.70-2.89 (6H, m), 4.90 (2H,

c), 5.19 (2H, br.s), 6.16 (1H, t), 6.75-7.05 (3H, m), 7.37-7.48 (5H, m), 7.75 (1H, dd), 8.52 (1H, dd). MS t / ζ: 561 (M + 1).

Example 406. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 405, but replacing the product of Example 407 with the product of Example 408.

Я-NMR (EM5O-b ₆ ) δ: 1.58-1.63 (2H, m), 1.87-1.96 (2H, m), 2.40-2.51 (2H, m), 2.63-2.85 (6H, m), 5.14 (2H, br.s), 6.23 (1H, t), 6.92 (1H, d), 7.36-7.62 (6H, m), 7.77-7.81 (2H, m), 8.54 (1H, dd). MS t / ζ: 531 (M + 1).

Example 407. 4- (4-Chlorophenyl) -1- [3- (7-hydroxyamidinomethoxy-5,11-dihydro [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 355, but replacing the product of Example 313 with the product of Example 49.

Я-NMR (EM5O-b ₆ ) δ: 1.45-1.50 (2H, m), 1.70-1.82 (2H, m), 2.27-2.51 (8H, m), 4.37 (2H, s), 4.83 (1H, s), 5.20 (1H, br.s), 5.57 (2H, br.s), 6.17 (1H, t) 6.72-6.94 (3H, m), 7.33-7.48 (5H, m), 7.72 (1H, dd), 8.49 (1H, dd), 9.26 (1H , from). MS t / ζ: 535 (M + 1).

Example 408. 4- (4-Chlorophenyl) -1- [3- (7-hydroxyamidino-5,11-dihydro [1] benzoxepino- [2,3-b] pyridin-5-ylidene) propyl] piperidin-4- ol.

The title compound was prepared following the procedure of Example 355, but replacing the product of Example 313 with the product of Example 364.

Я-NMR (OM8O-b ₆ ) δ: 1.45-1.50 (2H, m), 1.73-1.81 (2H, m), 2.28-2.51 (8H, m), 4.83 (1H, s), 5.79 (2H, br.s), 6.25 (1H, t), 6.81 (1H, d), 7.33-7.49 (6H, m ), 7.63-7.76 (2H, m), 8.51 (1H, dd), 9.48 (1H, s). MS t / ζ: 505 (M + 1).

Example 409. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl) methyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

Pyridine (0.21 ml) and thionyl chloride (0.1 ml) were added to a solution of the product of example 407 (700 mg) in THF (20 ml) at 0 ° C and the mixture was stirred at 0 ° C for 1 h, then the mixture was stirred at room temperature for 30 minutes Water, chloroform and 2-propanol are added to the reaction mixture. The organic layer was extracted and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with chloroform / methanol (5: 1) to obtain the title compound (170 mg). MS t / ζ: 581 (M + 1).

Example 410. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl) methyloxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

Thiocarbonyl-diimidazole (280 mg) was added to a solution of the product of Example 407 (700 mg) in THF (20 ml) and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. The organic layer was extracted and the solvent was distilled off under reduced pressure. THF (50 ml) and boron trifluoride diethyl ether (0.8 ml) were added to the residue, and the mixture was stirred at room temperature for 1 hour. Chloroform, 2-propanol and water were added to the reaction mixture.

- 65 008060

The organic layer was extracted and the solvent was distilled off under reduced pressure. The residue was resuspended in acetone to give the title compound (180 mg). MS t / ζ: 577 (M + 1).

Example 411. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxycarbonylacetyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

To a solution of the product of example 315 (250 mg) in THF (3.0 ml) was added 3.0 ml of a LOL solution (0.51 mol / L in a mixture of THF / hexane) at -78 ° C and the mixture was stirred at room temperature for 20 minutes . The reaction mixture was again cooled to −78 ° C., ethyl cyanoformate (76 μl) was added and stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride and an aqueous solution of sodium chloride were added to the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel eluted with chloroform / methanol (10: 1) to obtain the title compound (280 mg).

Я-NMR (SPS1 ₃ ) δ: 1.26 (3Н, t), 1.67-1.85 (2Н, m), 1.93-2.13 (2Н, m), 2.28-2, 47 (4H, m), 2.47-2.60 (2H, m), 2.60-2.76 (2H, m), 3.94 (2H, 8), 4.21 (2H, q) 5.60 (2H, br.s.), 6.22 (1H, t), 6.88 (1H, d), 7.29-7.34 (3H, m), 7.43 (2H, d) 7.59 (1H, d), 7.71 (1H, dd), 7.97 (1H, d), 8.53 (1H, d). MS t / ζ: 561 (M + 1).

Example 412. 4- (4-Fluorophenyl) -1- [3- (5,11-dihydro-7-hydroxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

To a solution of 5- (3-bromopropylidene) -5,11-dihydro-7-hydroxy- [1] benzoxepino [2,3-b] pyridine (2.59 g) in DMF (10 ml) was added 4- (4- fluorophenyl) -4-hydroxypiperidine (1.02 g) and triethylamine (835 μmol). The solution was stirred at room temperature for 23 hours. The reaction was quenched by adding water, the mixture was extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel chromatography (87: 10: 3 ethyl acetate: methanol: triethylamine) to give 0.9 g (39%) of the title compound.

Ή-NMR (OM§O-b ₆ ) δ: 1.64-1.69 (2H, m), 1.74-1.85 (2H, m), 2.27-2.52 (8H, m ), 4.81 (1H, s), 5.16 (2H, br.s), 6.08 (1H, t), 6.62-6.71 (3H, m), 7.12 (2H , t), 7.40-7.51 (3H, m), 7.72 (1H, dd), 8.48 (1H, dd), 9.09 (1H, s). MS (with ionization, stimulus. Electrons) t / ζ: 447 (M + 1).

Example 413. 4- (4-Fluorophenyl) -1- [3- (5,11-dihydro-7-carboxy [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure for Example 118, but replacing the compound of Example 169 with a triflate prepared from compound 412.

Ή-NMR (MeOE) δ: 1.78-1.85 (2H, m), 2.25-2.40 (2H, m), 2.57-2.70 (2H, m), 3.06 -3.35 (7H, m), 5.06-5.81 (2H, br.s), 6.23 (1H, t), 6.77 (1H, d), 7.00-7, 11 (2H, m), 7.37-7.56 (3H, m), 7.65-7.80 (2H, m), 8.01 (1H, d), 8.48 (1H, dd) . MS t / ζ: 475.

Example 414. 4- (4-Fluorophenyl) -1- [3- (5,11-dihydro-7- (1-hydroxy-1-methylethyl) [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl ] piperidin-4-ol.

The title compound was prepared following the procedure for Example 27, but starting from the methyl ester of the compound of Example 413.

Я-NMR (SPS1 ₃ ) δ: 1.57-2.14 (12Н, m), 2.34-2.45 (4Н, m), 2.50-2.61 (2Н, m), 2, 63-2.78 (2H, m), 5.225.43 (2H, br.s), 6.14 (1H, t), 6.95-7.10 (2H, m), 7.25-7 35 (2H, m), 7.40-7.60 (4H, m), 8.50 (1H, dd). MS t / ζ: 489.

Example 415. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-diethylcarbamoyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

The title compound was prepared following the procedure of Example 316, but replacing dimethylamine with diethylamine.

Я-NMR (SPS1 ₃ ) δ: 1.18-1.30 (6H, m), 1.65 (2H, d), 1.80 (1H, s), 2.05 (2H, dt), 2 30-2.45 (4H, m), 2.50 (2H, t), 2.60-2.70 (2H, m), 3.35-3.50 (4H, m), 5.30 (2H, br.s), 6.15 (1H, t), 6.83 (1H, d), 6.90 (1H, dd), 7.10 (1H, dd), 7.23-7 35 (3H, m), 7.40 (2H, d), 7.56 (1H, dd), 8.50 (1H, dd). MS t / ζ: 563.

Example 416. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-phenylsulfonylcarbamoyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

Sodium hydride (60% in mineral oil, 48 mg, 1.2 mmol) was added to a solution of the compound of Example 44 (0.511 g, 1.1 mmol) in dried THF (20 ml) and the suspension was heated at 40 ° C. under argon under stirring for 20 minutes Phenylsulfonylisocyanate (160 μl, 1.2 mmol) was added and the mixture was stirred for 14 hours. Then, the solvent was removed by evaporation (on a rotary evaporator) to obtain a crude product. The solid was washed 2 times with 20 ml methylene chloride and then with methanol / methylene chloride (1: 1.2 times 20 ml) to obtain the title compound (274 mg). MS t / ζ: 647.

Example 417. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxycarbonylcarbamoyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol .

Sodium hydride (60% in mineral oil, 28 mg, 0.7 mmol) was added to a solution of the compound of Example 44 (0.214 g, 0.46 mmol) in dried THF (5 ml) and the suspension was heated at 50 ° C. under argon under stirring for 20 minutes Methyl isocyanatoformate (56 μl, 0.7 mmol) is added and

- 66 008060 the mixture was stirred for 14 hours. Then, the solvent was removed on a rotary evaporator to obtain a crude product. The residue was purified by chromatography on silica gel eluted with a dichloromethane / 2.0 molar solution of ammonia in methanol (gradient from 0 to 4% methanol over 1 h) to obtain the title compound (102 mg).

^! H-NMR (SES1 ₃ ) δ: 1.60-1.65 (2H, m), 1.80 (1H, s), 2.05 (2H, dt), 2.30-2.45 (4H, m), 2.50 (2H, t), 2.602.70 (2H, m), 3.35 (3H, s), 5.30 (2H, b.s.), 6.15 (1H, t) 6.83 (1H, d), 6.90 (1H, dd), 7.10 (1H, dd), 7.23-7.35 (3H, m), 7.40 (2H, d), 7.56 (1H, dd), 8.50 (1H, dd). MS t / ζ: 565.

Example 418. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (11-3-methoxycarbonylpiperidin-1-yl) carbamoyl- [1] benzoxepino [2,3-b] pyridine -5-ylidene) propyl] piperidin-4-ol.

Stage 1

Nipecotate-t-tartaric acid p-ethyl ester (1.53 g) was transferred to the free base by treatment with an aqueous solution of sodium hydroxide and ethyl acetate. The organic layers were evaporated and the resulting amine was redissolved in THF (10 ml) and treated with carbonyldiimidazole (0.81 g). The resulting solution was stirred at room temperature for 23 hours, concentrated in vacuo, and redissolved in acetonitrile (5 ml). This solution was treated with methyl iodide (0.347 ml) and stirred for 18 hours at room temperature.

Stage 2

The compound of Example 44 (0.7 g) was suspended in THF (25 ml) and treated with sodium hydride (0.036 g) and stirred at room temperature for 1 h. The resulting anion was added to the imidazolinium salt obtained in stage 1, and the solution was boiled with refluxed for 18 hours. The crude material was then fed onto silica gel and purified by silica gel chromatography (87: 10: 3 ethyl acetate: methanol: triethylamine) to give the title compound in 0.278 g (64%) yield.

'H-NMR (ΌΜ8Ο-6 ₆ ) δ: 1.11-1.21 (3H, m), 1.45-2.0 (8H, m), 2.15-2.40 (6H, m) , 3.05-3.15 (2H, m), 3.31 (2H, m), 3.95-4.15 (3H, m), 5.31 (2H, br.s.), 6, 14 (1H, t), 6.78 (1H, d), 6.92 (1H, dd), 7.05 (1H, d), 7.33 (2H, d), 7.42-7.47 (3H, m), 7.72 (1H, dd), 8.50 (1H, dd). MS (with ionization, stimulus, electrons) t / ζ: 646 (Μ + 1).

Example 419. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (P-3-methoxycarbonylpiperidin-1-yl) carbamoyl [1] benzoxepino [2,3-b] pyridin- 5-ylidene) propyl] piperidin-4-ol.

The compound of example 418 (0.195 g) was dissolved in THF (1 ml) and treated with an aqueous solution of lithium hydroxide (0.0084 g) and stirred at room temperature for 18 hours. The resulting solution was concentrated in vacuo and the residue was purified by chromatography on an extraction column with a reversed solid phase eluted with water / acetonitrile, 0.1% formic acid to afford the title compound in 0.153 g (77%) yield.

'H-NMR (ΌΜ8Ο-6 ₆ ) δ: 1.55-2.25 (8H, m), 2.30-2.80 (10H, m), 3.22 (1H, m), 4.15 -4.35 (2H, m), 5.41 (2H, br.s), 6.35 (1H, t), 6.98 (1H, d), 7.13 (1H, dd), 7 , 25 (1H, d), 7.54 (2H, d), 7.64 (3H, m), 7.90 (1H, dd), 8.50 (1H, s), 8.70 (1H, dd). Μί .'- Ε8Ι (with ionization, stimul. Electrons) t / ζ: 618 (Μ + 1).

Example 420. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (4-methoxycarbonylsperidin-1-yl) carbamoyl [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 418, but replacing the nipecotate-t-tartaric acid P-ethyl ester with isonipecotic acid ethyl ester.

'H-NMR (SES1 ₃ ) δ: 1.25 (3H, t), 1.60-1.80 (4H, m), 1.90-2.05 (4H, m), 2.25-2 65 (10H, m), 2.90-3.15 (2H, m), 4.05-4.25 (4H, m), 5.30 (2H, br.s.), 6.15 ( 1H, t), 6.75-6.90 (2H, m), 7.05 (1H, d), 7.20-7.40 (3H, m), 7.40 (2H, d), 7 56 (1H, dd), 8.45 (1H, dd). MS t / ζ: 647.

Example 421. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (4-carboxypiperidin-1-yl) carbamoyl [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

A solution of the compound of Example 420 (91 mg, 0.14 mmol) in methanol (5 ml) was treated with a 0.4 molar solution of lithium hydroxide (5 ml, 2 mmol) and stirred for 3 hours. After adding 5 ml of 0.4N hydrochloric acid the acid solvent is removed under reduced pressure to obtain a crude product. The residue was purified by chromatography on silica gel eluted with a dichloromethane / methanol mixture (with a gradient of 0 to 50% methanol over 1 h) to obtain the title compound (48 mg).

'H-NMR (C1); C) 1)) δ: 1.60-1.65 (2H, m), 2.10-2.70 (10H, m), 5.30 (2H, br.s .), 6.15 (1H, t), 6.80-6.90 (2H, m), 7.20-7.50 (6H, m), 7.62 (1H, dd), 8.48 (1H, dd). MS t / ζ: 619.

Example 422. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (3-3-methoxycarbonylpiperidin-1-yl) carbamoyl [1] benzoxepino [2,3-b] pyridin- 5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 418, but replacing the n-pecotate-t-tartaric acid P-ethyl ester with (3) -isonipecotate-t-tartaric acid ethyl ester.

'H-NMR (SES1 ₃ ) δ: 1.25 (3H, t), 1.30-1.70 (5H, m), 1.94-2.05 (3H, m), 2.25-2 65 (11H, m), 3.05-3.15 (1H, m), 4.05-4.2 5 (4H, m), 5.30 (2H, br.s.), 6.15 (1H, t), 6.75-6.90 (2H, m), 7.05 (1H, d), 7.20-7.40 (3H, m), 7.40 (2H, d), 7.56 (1H, dd), 8.45 (1H, dd). MS t / ζ: 647.

Example 423. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxycarbonyl [1] benzoxepino [2,3-b] pi

67 008060 Ridin-5-ylidene) propyl] piperidin-4-ol.

The compound of Example 169 (0.166 g) was dissolved in DMF (1 ml) and treated with 7 mg of palladium (II) acetate, 1,3-bis-diphenylphosphinopropane (0.012 g), triethylamine (0.1 ml) and ethanol (1 ml) and stirred at 60 ° C for 18 hours in a CO atmosphere from a balloon. The resulting solution was quenched by adding water, the mixture was extracted with ethyl acetate, concentrated in vacuo and purified by silica gel chromatography (87: 10: 3 ethyl acetate: methanol: triethylamine). The residue was further purified by chromatography on a reversed solid phase extraction column eluted with water / acetonitrile, 0.1% formic acid, to give the title compound in 0.114 g (73%) yield.

^! H-NMR (OHM-b ₆ ) δ: 1.28 (3H, t), 1.40-1.55 (2H, m), 1.71-1.85 (2H, m), 2, 20-2.60 (6H, m), 3.22 (2H, m), 4.28 (2H, q), 5.00-5.60 (2H, b.s.), 6.21 (1H , t), 6.92 (1H, d), 7.40-7.80 (8H, m), 8.50 (1H, d). EZMS t / ζ: 519 (M + 1).

Example 424. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (methoxycarbonylmethyl) hydroxycarbonyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidine- 4-ol

By the procedure of Example 423, but replacing ethanol with ethyl glyoxylate, the title compound was obtained in 0.041 g (26%) yield.

^! H-NMR (OMNO-cP) δ: 1.10-1.30 (3H, m), 1.35-1.55 (2H, m), 1.60-1.85 (2H, m), 2 , 20-2.60 (6H, m), 3.32 (2H, m), 4.05-4.25 (2H, m), 4.87 (2H, s), 5.00-5.60 (2H, br.s.), 6.21 (1H, t), 6.92 (1H, d), 7.20-7.90 (8H, m), 8.50 (1H, d). EM-MS t / ζ: 577 (M + 1).

Example 425. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-cyclohexyloxycarbonyl [1] benzoxepino [2,3L] pyridin-5-ylidene) propyl] piperidin-4-ol.

According to the procedure for Example 423, but replacing ethanol with cyclohexanol, the title compound was obtained in 0.050 g (32%) yield.

^! H-NMR (MeOE) δ: 1.30-2.20 (14H, m), 2.53-2.60 (2H, m), 2.95-3.32 (6H, m), 5.00 (1H, m), 5.00-5.60 (2H, br.s), 6.28 (1H, t), 6.92 (1H, d), 7.40-7.55 (8H, m), 7.95 (2H, m), 8.05 (1H, s), 8.50 (2H, m). EZMS t / ζ: 573 (M + 1).

Example 426. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-propoxy) carbonyl- [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl ] piperidin-4-ol.

To a solution of the compound of Example 118 (109 mg, 0.22 mmol) in dried DMF (5 ml) was added potassium carbonate (91 mg) and then propyl iodide (24 μl, 0.66 mmol). The mixture was heated to 55 ° C. for 14 hours. The mixture was diluted with ethyl acetate (200 ml), washed 2 times with water (200 ml) and then with brine (100 ml), and dried with sodium sulfate. The organic solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using a dichloromethane / methanol mixture (with a gradient of 0 to 5% methanol for 1 h) to obtain the title compound (103 mg).

'H-NMR (SBS _{1 3} ) δ: 1.06 (3H, t), 1.50-2.10 (4H, m), 2.14-2.25 (2H, m), 2.31-2 75 (10H, m), 4.28 (2H, t), 6.15 (1H, t), 6.83 (1H, d), 7.24-7.38 (3H, m), 7, 42 (2H, d), 7.59 (1H, dd), 7.78 (1H, dd), 8.00 (1H, d), 8.50 (1H, dd). MS t / ζ: 533.

Example 427. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-butoxy) carbonyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

According to the procedure for Example 423, but replacing ethanol with n-butanol, the title compound was obtained in 0.065 g (45%) yield.

'H-NMR (MeOE) δ: 0.85-0.91 (3H, m), 1.25-1.45 (2H, m), 1.55-1.70 (2H, m), 1, 70-1.85 (2H, m), 2.10-2.28 (2H, m), 2.53-2.60 (2H, m), 3.15-3.38 (6H, m), 4.12-4.21 (2H, m), 5.00-5.60 (2H, br.s), 6.10 (1H, t), 6.76 (1H, d), 7.22 -7.40 (3H, m), 7.71 (1H, m), 7.95 (1H, m), 8.05 (1H, s), 8.30 (1H, s), 8.41 ( 1H, m). EM-MS t / ζ: 547 (M + 1).

Example 428. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-propoxy) carbonyl [1] benzoxepino [2,3-b] pyridin-5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 426, but replacing propyl iodide with 2-bromopropane.

'H-NMR (SBS _{1 3} ) 5: 1.30-2.10 (8H, m), 2.14-2.25 (2H, m), 2.31-2.75 (10H, m), 5 , 15-5.60 (2H, m), 6.15 (1H, t), 6.83 (1H, d), 7.24-7.38 (3H, m), 7.44 (2H, d) ), 7.59 (1H, dd), 7.80 (1H, dd), 8.02 (1H, d), 8.50 (1H, dd). MS t / ζ: 533.

Example 429. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-cyclopentyloxycarbonyl [1] benzoxepino [2,3b] pyridin-5-ylidene) propyl] piperidine-4-ol.

The title compound was prepared following the procedure of Example 426, but replacing propyl iodide with cyclopentyl bromide.

'H-NMR (CH _; OH) δ: 1.23-1.33 (1H, m), 1.50-2.04 (10H, m), 2.27-2.41 (2H, m), 2.70-2.90 (2H, m), 3.303.62 (5H, m), 5.21-5.85 (3H, m), 6.15 (1H, t), 6.85 (1H, d) 7.38 (2H, d), 7.42 (2H, d), 7.60-7.82 (2H, m), 8.04 (1H, d), 8.61 (1H, dd) ) MS t / ζ: 559.

Example 430. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-morpholinoethyl-1-yl) hydroxycarbonyl [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

- 68 008060

The title compound was prepared following the procedure of Example 426, but replacing propyl iodide with 2-morpholinoethyl chloride.

^! H-NMR (SPS1 ₃ ) δ: 1.62-1.70 (2H, m) 1.90-2.13 (2H, m), 2.30-2.80 (14 N, m), 3, 62-3.75 (4H, m), 4.41 (2H, t), 5.11-5.62 (2H, br.s), 6.19 (1H, t), 6.83 (1H d) 7.23-7.38 (3H, m), 7.42 (2H, d), 7.59 (1H, dd), 7.78 (1H, dd), 8.00 (1H, d) 8.50 (1H, dd). MS t / ζ: 604.

Example 431. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2,2-diethylaminoethyl-1-yl) hydroxycarbonyl [1] benzoxepino [2,3-b] pyridine- 5-ylidene) propyl] piperidin-4-ol.

The title compound was prepared following the procedure of Example 426, but replacing propyl iodide with 2 - (^ Ndiethylamino) ethyl chloride.

^! H-NMR (COC1 ₃ ) δ: 1.06 (6H, t), 1.62-1.71 (2H, m), 1.93-2.10 (2H, m), 2.30-2, 75 (12H, m), 2.85 (2H, t), 4.38 (2H, t), 5.20-5.58 (2H, br.s), 6.15 (1H, t), 6.83 (1H, d), 7.24-7.38 (3H, m), 7.42 (2H, d), 7.59 (1H, dd), 7.78 (1H, dd), 8 00 (1H, d), 8.50 (1H, dd). MS t / ζ: 590.

Example 432. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (1-2,2-dimethylshropionyloxymethyl) oxycarbonyl [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

Following the procedure of Example 426, but replacing propyl iodide with chloromethyl pivalate, the title compound was obtained in 0.36 g (77%) yield.

^! H-NMR (CBC1 ₃ ) δ: 1.18 (9H, s), 1.58-1.72 (2H, m), 1.85-2.85 (10H, m), 5.00-5, 60 (2H, br.s), 5.94 (2H, s), 6.17 (1H, t), 6.82 (1H, d), 7.22-7.42 (5H, m), 7.56 (1H, dd), 7.80 (1H, dd), 7.99 (1H, d), 8.05 (1H, d), 8.46 (1H, dd). EM-MS t / ζ: 605 (M + 1).

Example 433. 4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7- (2-hydroxyethyl-1-yl) hydroxycarbonyl [1] benzoxepino [2,3-b] pyridin-5- ylidene) propyl] piperidin-4-ol.

According to the procedure for Example 423, but replacing ethanol with ethylene glycol, the title compound was obtained in 0.076 g (42%) yield.

^! H-NMR (MeOI) δ: 1.80-2.00 (4H, m), 2.25-2.35 (2H, m), 2.55-2.65 (2H, m), 3.15 -3.45 (5H, m), 3.75 (2H, dd), 4.24 (2H, dd), 5.00-5.60 (2H, br.s), 6.10 (1H, t), 6.76 (1H, d), 7.18-7.42 (5H, m), 7.71 (2H, m), 7.99 (1H, m), 8.05 (1H, s ), 8.30 (1H, s), 8.41 (1H, m). EZPMS t / ζ: 535 (M + 1).

Example 434. 5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3-methylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, d] cyclohepten-7-ol.

Stage 1

3-Methylpiperidin-4-oxopiperidin-1-carboxylic acid tert-butyl ester.

In a reactor, Para (Ragg) with shaking is suspended in 75 ml of methanol 19 g (93 mmol) of 1-benzyl-

3-methyl-4-oxopiperidone, 27 g (121 mmol) of di-tert-butyl dicarbonate and 2.6 g of palladium hydroxide and then purged with argon. The reaction mixture was then purged with hydrogen and the reactor was placed in a shaker for approximately 16 hours under a hydrogen pressure of about 311 kPa (44 psi). The catalyst is filtered off on celite and washed with methanol.

The crude product is purified by chromatography on silica gel eluted with a 1: 5 ethyl acetate / hexane mixture to give a white crystalline solid.

'11 NMR spectrum (SPS1 ₃ ) δ: 0.97 (3H, d), 1.45 (9H, s), 2.37-2.53 (3H, m), 2.80 (1H, br s ), 3.16-3.26 (1H, m), 4.11-4.18 (2H, m).

Emission mass spectrometry (EMC) t / ζ: 158 (M - CH = C (CH ₃ ) ₂ +1).

Stage 2

4- (4-Chlorophenyl) -4-hydroxy-3-methylpiperidin-1-carboxylic acid, tert-butyl ether.

To 49 ml of a 1 molar solution of 4-chlorophenylmethylmagnesium bromide (49 mmol) in diethyl ether in an argon atmosphere at a temperature of about 0 ° C, 3-methyl-4oxopiperidin-1-carboxylic acid tert-butyl ether (7 g, 32.8 mmol) was added in 50 ml of tetrahydrofuran (THF) for approximately 1 hour. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, then with an aqueous solution of sodium chloride and dried with sodium sulfate. The solvent was evaporated and the crude residue was recrystallized in ethyl acetate to give a white solid.

'11 NMR spectrum (SPS1 ₃ ) δ: 0.58 (3Н, d), 1.45 (9Н, s), 1.50-1.69 (2Н, m), 1.76-2.13 (2Н) , m), 2.80 (1H, t), 3.10 (1H, t), 3.96 (2H, br s), 7.29 (4H, m). EMC t / ζ: 252 (M - CH = C (CH ₃ ) ₂ + 1-H ₂ O).

Stage 3.

4- (4-Chlorophenyl) -3-methylpiperidin-4-ol.

To a solution of 1.5 g (4.6 mmol) of 4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidin-1-carboxylic acid tert-butyl ester in 40 ml of dichloromethane at a temperature of about 0 ° C was added 10 ml of trifluoroacetic acid acids. The solution was stirred for approximately 2 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was neutralized with saturated sodium bicarbonate and washed with an aqueous solution of sodium chloride (brine) and dried with magnesium sulfate.

The solvent was removed to give a yellow solid. Substance cleaning is not required.

¹ H NMR (SOS1 ₃₎ δ: 0,65 (3H, d), 1.85 (1H, d), 2.52 (2H, m), 3.05 (1H, t), 3.27 ( 1H, dd), 3.34 (2H,

- 69 008060

d) 7.40 (4H, m). EMC t / ζ: 240 (M + 1).

Stage 4. 5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3-methylpiperidin-1-yl] propylidene} -5,11-dihydro10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-ol.

To a solution of 1.0 g (4.6 mmol) of 4- (4-chlorophenyl) -3-methylpiperidin-4-ol in 10 ml of dimethylformamide (DMF) with 1.75 ml (12.54 mmol) of triethylamine is added dropwise 1 , 38 g (4.18 mmol) of 5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-ol for about 1.5 hours at a temperature of about 0 ° C. The reaction mixture was stirred overnight at a temperature of about 50 ° C. The reaction was quenched by addition of water, extracted with ethyl acetate and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with a mixture (87: 10: 3 ethyl acetate: methanol: triethylamine) to obtain the title compound as a brown solid.

NMR spectrum ^! H (СОС1 ₃ ) δ: 0.53 (3Н, d), 1.60-1.69 (2Н, m), 2.07-2.30 (3Н, m), 2.34-2.51 ( 3H, m), 2,562.75 (3H, m), 2.76-2.87 (1H, m), 2.98-3.11 (1H, m), 5.25 (2H, br s) 6.12 (1H, t), 6.64-6.79 (3H, m), 7.20-7.40 (5H, m), 7.53 (1H, d), 8.50 (1H , d). EMC t / ζ: 477 (M + 1).

Example 435. Trifluoromethanesulfonic acid ester and 5- {3- [4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-ol.

The title compound was prepared according to the procedure for EXAMPLE 169 and was obtained as a brown solid.

NMR spectrum ^! H (SPS1 ₃ ) δ: 0.55 (3H, d), 1.55-1.68 (2H, m), 1.92-2.18 (2H, m), 2.24-2.69 ( 7H, m), 5.36 (2H, br s), 6.15 (1H, t), 6.88 (1H, d), 7.05 (1H, dd), 7.19-7.43 (6H, m), 7.60 (1H, d), 8.54 (1H, d). EMC t / ζ: 609 (M + 1).

Example 436. 5- {3- [4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo methyl ester [ a, b] cycloheptene-7-carboxylic acid.

The title compound was prepared according to the procedure for Example 423 and was obtained as a brown solid (formic acid salt).

NMR spectrum ^! H (SPS1 ₃ ) δ: 0.62 (3H, d), 1.75 (1H, d), 2.41-2.71 (5H, m), 2.90-3.14 (4H, m) , 3.27 (1H, d), 3.89 (3H, s), 5.00-5.70 (2H, br s), 6.08 (1H, t), 6.86 (1H, d) ), 7.26-7.39 (5H, m), 7.59 (1H, d), 7.83 (1H, d), 7.98 (1H, s), 8.34 (1H, s) 8.56 (1H, d). EMC t / ζ: 519 (M + 1).

Example 437. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} -3-methylpiperidin-4-ol.

The title compound was prepared according to the procedure for Example 27. The racemic substance was resolved using high-resolution preparative chiral liquid chromatography (HPLC) (Syga1 Cancer column, 20 mm * 250 mm, isocratic elution with 10% ethanol / 90% hexane, 15 ml / min. , experiment time 35 min). The more active enantiomer elutes first (at the 17th minute). The second less active enantiomer elutes (at the 23rd minute), a white solid (formic acid salt).

NMR spectrum ^! H (SPS1 ₃ ) δ: 0.61 (3H, d), 1.57 (6H, s), 1.76 (1H, d), 2.43-2.72 (5H, m), 2.91 -3.12 (4H, m), 3.25 (1H, d), 5.04-5.46 (2H, br s), 6.01 (1H, t), 6.82 (1H, d) ), 7.22-7.37 (5H, m), 7.46 (1H, s), 7.55 (1H, d), 8.30-8.40 (1H, br s), 8, 52 (1H, d). EMC t / ζ: 519 (M + 1).

Example 438. 5- {3- [4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene-7-carboxylic acid.

The title compound was prepared as described in Example 118 and was obtained as a brown solid (formic acid salt).

NMR spectrum ^! H (SPS1 ₃ ) δ: 0.49 (3H, d), 1.63 (1H, d), 2.29-2.43 (2H, m), 2.45-2.63 (3H, m) 2.78-3.18 (5H, m), 4.82-5.85 (2H, br s), 6.13 (1H, t), 6.67 (1H, d), 7.19 -7.31 (5H, m), 7.55 (1H, d), 7.67 (1H, d), 7.87 (1H, s), 8.19 (1H, s), 8.40 ( 1H, d). EMC t / ζ: 505 (M + 1).

Example 439. 5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] propylidene} -5,11 dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-ol.

Stage 1. 1-Benzyl-3,5-dimethylpiperidin-4-one.

To a solution of 1-benzyl-3-methyl-4-piperidone (2.0 g, 9.8 mmol) in THF at a temperature of about -78 ° C in an argon atmosphere add 7.35 ml of a solution (2 mol / l) of lithium diisopropylamide (14.7 mmol) in a mixture of heptane / THF / ethylbenzene. After stirring for approximately 1 hour at a temperature of about -78 ° C, 0.73 ml of methyl iodide (11.8 mmol) was added. The reaction mixture was stirred for about 1 hour at a temperature of about -78 ° C, then warmed to room temperature. Stirring at room temperature is continued overnight. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then with an aqueous solution of sodium chloride and dried with magnesium sulfate. The crude product is purified by chromatography on silica gel eluting with a mixture of (3:10) ethyl acetate / hexane to give a yellow oil of the title compound.

NMR spectrum ^! H (SPS1 ₃ ) δ: 0.96 (6H, d), 2.04 (2H, t), 2.62-2.78 (2H, m), 3.12-3.17 (2H, m) 3.59 (2H, s); 7.23-7.38 (5H, m). EMC t / ζ: 218 (M + 1).

- 70 008060

Stage 2

3,5-Dimethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester.

The title compound was prepared according to the procedure for Example 434, step 1, and was obtained as a white crystalline solid.

Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ ) δ: 1.02 (6Н, d), 1.5 (9Н, s), 2.47-2.75 (4Н, m), 4.25-4.54 (2Н, s). EMC t / ζ: 172 (M-CH = C (CH ₃ ) ₂ +1).

Stage 3.

4- (4-Chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-carboxylic acid.

The title compound was prepared according to the procedure for Example 434, step 2, and was obtained as a white solid.

NMR spectrum р (СОС1 ₃ ) δ: 0.57 (6Н, d), 1.49 (9Н, s), 1.98-2.08 (2Н, m), 2.71-2.98 (2Н, m), 3.79-4.10 (2H, m), 7.29-7.36 (4H, m). EMC t / ζ: 266 (M-CH = C (CH ₃ ) ₂ + 1-H ₂ O).

Stage 4. 4- (4-Chlorophenyl) -3,5-dimethylpiperidin-4-ol.

The title compound was prepared according to the procedure for Example 434, step 3, and was obtained as a pale yellow solid.

Nuclear Magnetic Resonance Spectrum Ή (SPS1 ₃ ) δ: 0.54 (6H, d), 1.97-2.11 (4H, m), 2.75 (2H, t), 2.88 (2H, d), 7 27-7.32 (4H, m). EMC t / ζ: 240 (M + 1).

5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene -7-ol

The title compound was prepared according to the procedure for Example 434 and was obtained as a yellow solid.

Nuclear Magnetic Resonance Spectrum Ή (SPS1 ₃ ) δ: 0.58 (6Н, d), 2.50-2.80 (6Н, m), 2.94-3.06 (2Н, m), 3.17 (2Н, d), 5.14-5.29 (2H, br s), 5.87 (1H, t), 6.75-6.90 (2H, m), 7.10-7.45 (6H, m), 8.44 (1Η, d), 8.52 (1H, s). EMC t / ζ: 491 (M + 1).

Example 440. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} -3,5-dimethylpiperidin-4-ol.

The title compound was prepared according to the procedure for Example 439, but using 2- (5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl) propan-2 -ol, and get in the form of a white solid (salt of formic acid).

Nuclear Magnetic Resonance Spectrum Ή (SPS1 ₃ ) δ: 0.59 (6Н, d), 1.58 (6Н, s), 2.49-2.74 (6Н, m), 2.97-3.10 (2Н, m), 3.16 (2H, d), 5.20-5.45 (2H, br s), 6.06 (1Η, t), 6.83 (1H, d), 7.12-7 43 (6H, m), 7.49 (1H, s), 7.60 (1H, d), 8.38 (1H, s), 8.54 (1H, m). EMC t / ζ: 533 (M + 1).

Examples 441 and 442. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5 -ilidene] propyl} -3-methylpiperidin-4-ol and 4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1methylethyl) -11H-10-oxa-1-aza-dibenzo [ a, b | cyclohepten-5-ylidene] propyl} -4-methylpiperidin-3-ol.

Stage 1

4- (4-Chlorophenyl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester.

To a solution of 3.27 g (15.0 mmol) of di-tert-butyl dicarbonate in 50 ml of dichloromethane is added 3.02-g (13.1 mmol) of 4- (4-chlorophenyl) -1,2,3,6- hydrochloride tetrahydro-piperidine and 3.6 ml (20 mmol) of triethylamine. The solution was stirred for approximately 15 hours at a temperature close to room temperature. Gas evolution is observed. The reaction was quenched by the addition of an aqueous solution of ammonium chloride, extracted with dichloromethane and the organic layers were evaporated in vacuo. The residue was purified by filtration through a plug of silica gel to give the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum Ή (SPS1 ₃ ) δ: 1.50 (9H, s), 2.46 (2H, br s), 3.62 (2H, br s), 4.05 (2H, br s) 6.01 (1H, br s); 7.25 (4H, s).

Stage 2

6- (4-Chlorophenyl) -7-oxa-3-aza-bicyclo [4.1.0] heptane-3-carboxylic acid tert-butyl ester.

To a solution of 3.8 g (13.0 mmol) of 4- (4-chlorophenyl) -3,6-dihydro-2H-pyridin-1 carboxylic acid tert-butyl ester in 50 ml of dichloromethane was added 3.8 g (17.0 mmol) ) 3-chlorobenzoic acid and 3.6 ml (20 mmol) of triethylamine. The solution was stirred for approximately 4 hours at room temperature. White precipitate is observed. The reaction was quenched by the addition of an aqueous sodium bicarbonate solution, extracted with dichloromethane and the organic layers were evaporated in vacuo. The residue was purified by flash chromatography on silica gel (35 g), gradient eluting from 100% hexane to 100% ethyl acetate, to give the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ ) δ: 1.50 (9Н, s), 2.15 (1Н, m), 3.15 (2Н, m), 3.6-4.2 (4Н, m), 7 31 (4H, s).

Stage 3.

4- (4-Chlorophenyl) -4-hydroxy-3-methylpiperidin-1-carboxylic acid tert-butyl ester; and 4- (4-chlorophenyl) -3-hydroxy-4-methylpiperidin-1-carboxylic acid tert-butyl ester.

A suspension of monovalent copper iodide (0.38 g, 2 mmol) in 20 ml of THF is cooled to a temperature of about 4 ° C and treated with methylmagnesium bromide (6 ml of a 3 molar solution in diethyl ether, 18 mmol). 6- (4-Chlorophenyl) -7-oxa-3aza-bicyclo [4.1.0] heptane-3-carboxylic acid tert-butyl ester (1.9 g, 6.1 mmol) in 5 is added to the cooled suspension of cuprate. ml THF. The solution is mixed and

- 71 008060 allowed it to warm to about room temperature in about 4 hours. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layers were evaporated in vacuo. The residue was purified by flash chromatography on silica gel (35 g), gradient eluting from 100% hexane to 50% ethyl acetate, to give a mixture of the title compounds as a white foam. This mixture is used in the next step.

Stage 4.

Synthesis of 4- (4-chlorophenyl) -3-methylpiperidin-4-ol and 4- (4-chlorophenyl) -4-methylpiperidin-3-ol.

A mixture of amino alcohols protected by butoxycarbonyl (0.8 g, 2.5 mmol) was dissolved in 5 ml of a 4 molar solution of HC1 in dioxane (20 mmol). The solution was stirred at room temperature for about 1 hour. The solvent was evaporated in vacuo. The residue was quenched with an aqueous solution of sodium hydroxide, extracted with ethyl acetate, and the organic layers were dried with sodium sulfate and evaporated in vacuo. The title compound was obtained as a brown solid. EMC t / ζ: 226 (M + 1), 208 (M + 1-H ₂ O). This mixture is used in the next step without further purification.

4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, 6] cycloheptene-5ylidene] propyl} -3 methylpiperidin-4-ol and 4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10oxa-1-aza-dibenzo [a, 6] cycloheptene-5 -ilidene] propyl} -4-methylpiperidin-3 -ol.

To a solution of a mixture of amino alcohols (0.53 g, 2.3 mmol) in 10 ml of isopropanol is added 0.23 ml (2.0 mmol) of 2,6-lutidine and the catalyst is potassium iodide. The reaction mixture is heated to approximately 80 ° C and treated with 0.37 g (1.0 mmol) of 5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, 6] cycloheptene-7- il) propan-2-ol, which is added in portions for approximately 2 hours. Then the solution is stirred for another 2 hours at a temperature of about 80 ° C. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (35 g), gradient eluting from 100% ethyl acetate to a mixture of 87% ethyl acetate: 10% methanol: 3% triethylamine to give the title compound. The rapidly eluting isomer 4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, 6] cycloheptene-5-ylidene] propyl } -3-methylpiperidin-4-ol, a brown semi-solid.

NMR spectrum Ή (SES1 ₃ ) δ: 0.70 (3Н, d, 1 = 7.2 Hz), 1.53 (6Н, s), 1.92 (3Н, m), 2.28-2.69 (8H, m), 5.30 (2H, br s), 6.15 (1H, t, 1 = 1.4 Hz), 6.79 (2H, d, 1 = 8.4 Hz), 7 18-7.45 (7H, m), 7.59 (1H, d, 1 = 8 Hz), 8.45 (1H, m). EMC t / ζ: 519 (M + 1).

Isomer eluting more slowly than 4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene] propyl} -4-methylpiperidin-3-ol, brown semi-solid.

Я NMR spectrum (SES1 ₃ ) δ: 1.16 (3Н, s), 1.55 (6Н, s), 2.28-2.69 (5Н, m), 3.86 (1Н, br s) 5.30 (2H, br s), 6.07 (1H, t, 1 = 1.4 Hz), 6.79 (2H, d, 1 = 8.4 Hz), 7.18-7, 45 (7H, m), 8.45 (1H, m). EMC t / ζ: 519 (M + 1).

Example 443. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, 6] cycloheptene-5-ylidene ] propyl} -3,3-dimethylpiperidin-4-ol.

Stage 1

1-Benzyl-3,3-dimethylpiperidin-4-one.

To a solution of 1-benzyl-3-methylpiperidin-4-one (2.03 g, 10 mmol) in 10 ml of THF was added 1.1 (10 mmol) of potassium tert-butoxide and 0.62 ml (10 mmol) of methyl iodide. The solution was then stirred at room temperature for approximately 72 hours. The reaction was quenched by the addition of sodium chloride and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, then purified by flash chromatography on silica gel (35 g), gradient eluting from 100% hexane to 100% ethyl acetate, to give the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum Ή (SES1 ₃ ) δ: 1.12 (6H, s), 2.41 (2H, s), 2.52 (2H, m), 2.73 (2H, m), 3.56 (2H c) 7.20-7.40 (5H, m). EMC t / ζ: 218 (M + 1).

Stage 2

3,3-Dimethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester.

To a solution of 2.48 g (11 mmol) of 1-benzyl-3,3-dimethylpiperidin-4-one in 100 ml of ethanol, 2.18 g (10 mmol) of di-tert-butyl dicarbonate and 0.10 g of palladium hydroxide are added. Then the reaction mixture was shaken in a hydrogen atmosphere of 283 kPa (40 psi) at room temperature for another approximately 12 hours

The reaction mixture was filtered on celite and evaporated in vacuo to give the title compound as a white solid.

Nuclear Magnetic Resonance Spectrum Ή (SES1 ₃ ) δ: 1.12 (6H, br s), 1.48 (9H, s), 2.45-2.80 (3H, m), 3.12 (1H, m) 3.42 (1H, br s); 3.70 (1H, m).

Stage 3.

4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-carboxylic acid tert-butyl ester.

To an ice-cooled solution of 3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 7.2 mmol) in 20 ml of THF is added chlorophenyl magnesium bromide (15 ml of a 1 molar solution in diethyl ether, 15 mmol). The solution is allowed to warm to a temperature close to room temperature, then

- 72 008060 was stirred at room temperature for approximately 22 hours. The reaction was quenched by the addition of an aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were evaporated in vacuo, then purified by flash chromatography on silica gel (35 g), gradient eluting from 100% hexane to 100% ethyl acetate, to give the title compound as a colorless oil.

¹ H NMR spectrum (SPS1 ₃ ) δ: 1.12 (6H, s), 1.50 (11H, m), 2.60 (1H, m), 3.20 (2H, m), 3.56 ( 1H, m), 4.20 (1H, m), 7.20-7.40 (4H, m). EMC t / ζ: 218 (M + 1).

Stage 4.

4- (4-Chlorophenyl) -3,3-dimethylpiperidin-4-ol.

4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-carboxylic acid tert-butyl ester (0.25 g, 0.73 mmol) is dissolved in 2 ml (8 mmol) of a 4 molar HC1 solution in dioxane. The solution was stirred at room temperature for approximately 4 hours. The solvent was evaporated in vacuo. The residue was quenched with an aqueous sodium hydroxide solution, extracted with ethyl acetate, and the organic layers were dried with sodium sulfate and evaporated in vacuo. The title compound was obtained as a yellow solid. This mixture is used in the next step without further purification.

4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5ylidene] propyl} -3 , 3-dimethylpiperidin-4-ol.

To a solution of a mixture of amino alcohols (0.17 g, 0.7 mmol) in 5 ml of isopropanol is added 0.23 ml (2.0 mmol) of 2,6-lutidine and the catalyst is potassium iodide. The reaction mixture is heated to approximately 80 ° C and treated with 0.19 g (0.5 mmol) of 2- (5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cycloheptene -7-yl) propan-2-ol, which is added in portions for approximately 2 hours. Then the solution is stirred for another 2 hours at a temperature of about 80 ° C. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (10 g) with gradient elution (from 100% ethyl acetate to a mixture of 87% ethyl acetate: 10% methanol: 3% triethylamine) to give the title compound as a brown semi-solid substances.

¹ H NMR (SOS1 ₃₎ δ: 0,7 8 (3H, s), 0.90 (3H, s), 1.45 (2H, m), 1.53 (6H, s), 2.28 -2.80 (9H, m), 5.30 (2H, br s), 6.15 (1H, t, 1 = 1.4 Hz), 6.79 (2H, d, I = 8.4 Hz), 7.18-7.45 (7H, m), 7.59 (1H, d, 1 = 8 Hz), 8.45 (1H, m). EMC t / ζ: 533 (M + 1).

Example 456. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} piperidin-4-carbonitrile.

Stage 1

Bis (2-chloroethyl) carbamic acid tert-butyl ester.

To a solution of 7.12 g (40 mmol) of bis- (2-chloroethyl) amine hydrochloride in 65 ml of dichloromethane, 34.8 ml (200 mmol) of Ν, Ν-diisopropylethylamine and a catalytic amount of 4-dimethylaminopyridine are added, followed by 8 portions. 72 g (40 mmol) of di-tert-butyl dicarbonate. The solution was stirred at room temperature for 72 hours. The reaction mixture was concentrated and the residue was triturated with 70 ml of ether. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with a 9: 1 hexane / ethyl acetate mixture to give the title compound (2.02 g, 21%).

¹ H NMR (SOS1 ₃₎ δ: 1,5 (9H, s), 3.5-3.6 (8H, m).

Stage 2

4- (4-Chlorophenyl) -4-cyanopiperidin-1-carboxylic acid tert-butyl ester.

2.02 g (8.37 mmol) of bis- (2-chloroethyl) carbamic acid tert-butyl ester in 25 ml of Ν, Ν-dimethylformamide are added to 1.26 g (8.37 mmol) of 4-chlorobenzyl cyanide. The resulting mixture was stirred and cooled in an ice bath, then 1.1 g (42 mmol) of sodium hydride (60%, suspension in mineral oil) were added portionwise. The reaction mixture was brought to room temperature and then heated in an oil bath at 60 ° C for 16 hours. The reaction mixture was quenched by adding ice water, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed 2 times with water, once with an aqueous solution of sodium chloride, dried with magnesium sulfate and concentrated in vacuo. The residue, a brown oil, was purified by chromatography on silica gel eluted with a 9: 1 hexane / ethyl acetate mixture to give the title compound (1.44 g, 54%).

¹ H NMR spectrum (SPS1 ₃ ) δ: 1.5 (9H, s), 1.8-2.0 (2H, m), 2.1 (2H, d), 3.2 (2H, t), 4.3 (2H, br s), 7.4 (4H, m). MS t / ζ: 221 (M + 1-100).

Stage 3.

4- (4-Chlorophenyl) piperidin-4-carbonitrile.

To a cooled solution of 315 mg (1 mmol) of 4- (4-chlorophenyl) -4-cyanopiperidin-1-carboxylic acid tert-butyl ester in 5 ml of dichloromethane was added 1 ml of trifluoroacetic acid. The reaction mixture was stirred at 0 ° C. for 3 hours, then concentrated in vacuo. The resulting oil was diluted with dichloromethane and washed 2 times with saturated aqueous sodium bicarbonate. Wash water is extracted 3 times with dichloromethane. United organic layers

- 73 008060 dried with magnesium sulfate and concentrated in vacuo to give 82% (180 mg) of the title compound.

'11 (С0С1 ₃ ) NMR spectrum δ: 1.9-2.1 (4Н, m), 3.0-3.2 (4Н, m), 7.3-7.5 (4Н, m). MS t / ζ: 221 (M + 1).

Stage 4.

To a suspension of 180 mg (0.8 mmol) of 4- (4-chlorophenyl) piperidin-4-carbonitrile in acetonitrile / water (4/1) was added 221 mg (1.6 mmol) of potassium carbonate and then 150 mg (0, 4 mmol) 2- (5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl) propan-2-ol. The reaction mixture was stirred for 48 hours at room temperature and then concentrated in vacuo. The resulting precipitate was treated with water and extracted with ethyl acetate. The solvent was evaporated from the combined organic layers dried with magnesium sulfate. The residue was purified by silica gel column chromatography, eluting with hexane: ethyl acetate (6: 4), to give the title compound.

'11 NMR spectrum (СОС1 ₃ ) δ: 1.5 (6Н, s), 1.8-2.0 (4Н, m), 2.4 (4Н, m), 2.55 (2Н, m), 2.8 (2H, d), 5.3 (2H, br s), 6.1 (1H, t), 6.8 (1H, d), 7.27-7.40 (7H, m) 7.5 (1H, d), 8.50 (1H, d). MS t / ζ: 514 (M + 1).

Example 457. 1- (4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene- 5-ylidene] propyl} piperidin-4-yl) ethanone.

Stage 1

1- (4- (4-Chlorophenyl) piperidin-4-yl) ethanone.

10 ml of a 1.4 molar solution of methylmagnesium bromide in toluene / tetrahydrofuran mixture (75/25) are added to a dry round-bottom flask from a syringe. The flask is cooled in an ice bath in a stream of nitrogen. A solution of 357 mg of 4- (4-chlorophenyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.11 mmol) in 4 ml of THF was added dropwise to the flask over 20 minutes, and the resulting mixture was stirred for 8 hours at 0 ° C. The reaction mixture was allowed to warm to room temperature and the mixture was stirred for 5 days. The reaction was interrupted by slowly adding 150 ml of a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. The yellow residue was purified by chromatography (reverse phase HPLC) to give 106 mg (40%) of the title compound as formic acid salt. MS t / ζ: 238 (M + 1).

Stage 2

To a suspension of 221 mg (1.6 mmol) of 1- (4- (4-chlorophenyl) piperidin-4-yl) ethanone in acetonitrile / water (4/1) was added 221 mg (1.6 mmol) of potassium carbonate and then 150 mg (0.4 mmol) 2- (5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl) propan-2-ol. The reaction mixture was stirred for 48 hours at room temperature and then concentrated in vacuo. The resulting precipitate was treated with water and extracted with ethyl acetate. The solvent was evaporated from the combined organic layers dried with magnesium sulfate. Chromatographic purification on silica gel eluted with a mixture of (9.5: 0.5) dichloromethane: methanol afforded the title compound.

'11 NMR spectrum (СОС1 ₃ ) δ: 1.3 (2Н, m), 1.5 (6Н, s), 1.9 (3Н, s), 2.1-2.5 (10Н, m), 5.3 (2H, br s), 5.9 (1H, t), 6.8 (1H, d), 7.3 (6H, m), 7.4 (1H, d), 7.6 (1H, d), 8.50 (1H, d). MS t / ζ: 531 (M + 1).

Example 458. Methyl 4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} piperidine-4-carboxylic acid.

Stage 1

4- (4-Chlorophenyl) -piperidin-1,4-dicarboxylic acid mono-tert-butyl ester.

To a solution of 1.1 g of 4- (4-chlorophenyl) -4-cyanopiperidin-1-carboxylic acid tert-butyl ester (3.44 mmol) in 40 ml of ethanol was added 10 ml of a 10-normal (10 N) aqueous hydroxide solution sodium. The resulting solution was heated and refluxed for 48 hours, cooled to room temperature, poured into a 1N hydrochloric acid solution and extracted with ethyl acetate. The organic extracts were washed with brine, dried with magnesium sulfate and concentrated in vacuo. The yellow oil recovered was purified by chromatography on silica gel eluting with a mixture of (9.5: 0.5) dichloromethane: methanol to give the title compound (1.0 g, 86%). MS t / ζ: 338 (M-1).

Stage 2

4- (4-Chlorophenyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl, 4-methyl ester.

To a stirred solution of 852 mg of 4- (4-chlorophenyl) piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.5 mmol) in a mixture of 5 ml of methanol and 17.5 ml of benzene add 15 ml of a 2 molar solution of (trimethylsilyl) diazomethane in hexane at room temperature. The mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The residual yellow oil was purified by chromatography on silica gel eluted with a mixture of (9: 1) hexane: ethyl acetate to give the corresponding ester (780 mg, 88%).

'11 NMR spectrum (СОС1 ₃ ) δ: 1.5 (9Н, s), 2.8-2.9 (2Н, m), 2.5 (2Н, d), 3.0 (2Н, t), 3.7 (3H, s), 4.0 (2H, d), 7.4 (4H, m). MS TX: 354 (M + 1).

Stage 3.

- 74 008060

4- (4-Chlorophenyl) piperidine-4-carboxylic acid methyl ester.

The title compound was prepared following the procedure of Example 456, step 3, but replacing 4- (4-chlorophenyl) -4-cyanopiperidin-1-carboxylic acid tert-butyl ester with 4- (4- methyl tert-butyl chlorophenyl) piperidine-1,4-dicarboxylic acid.

NMR spectrum Ή (0Ή01 ₃ ) δ: 1.9 (2Н, t), 2.55 (2Н, d), 2.9 (2Н, t), 3.25 (2Н, d), 3.8 (3Η c) 7.2 (4H, m). MS t / ζ: 254 (M + 1).

Stage 4.

Potassium carbonate (22 mg, 1.6 mmol) was added to a suspension of 4- (4-chlorophenyl) piperidine-4-carboxylic acid methyl ester in a mixture of acetonitrile / water (4/1) and then 2- [5- (3-bromopropylidene) ) -5.11 dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. The solvent is evaporated from the combined, dried with magnesium sulfate organic extracts. Chromatographic purification on silica gel eluted with dichloromethane: methanol (9.6: 0.4) gave the title compound.

Nuclear Magnetic Resonance Spectrum Ή (ΟΌΟ1 ₃ ) δ: 1.5 (6Н, s), 1.8-2.0 (4Н, m), 2.1 (2Н, m), 2.4-2.5 (7Н, m), 2.6 (2H, m), 5.3 (2H, br s), 6.1 (1Η, t), 6.8 (1H, d), 7.3 (6H, m), 7.4 (1Η, d), 7.6 (1H, d), 8.5 (1H, d). MS t / ζ: 547 (M + 1).

Example 459. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -1 Ш-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} piperidine-4-carboxylic acid.

To a solution of methyl ester 4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -1Sh-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene] propyl} piperidine-4-carboxylic acid (110 mg, 0.2 mmol) in methanol (5 ml) add 1 ml of aqueous 1N. sodium hydroxide solution. The resulting solution was heated to a temperature of 50 ° C for 16 hours, cooled to room temperature and concentrated in a stream of nitrogen. The residue was purified by chromatography (reverse phase HPLC) to give the formic acid salt of the title compound (96 mg, 90%).

Nuclear Magnetic Resonance Spectrum Ή (1,51 ₃ ) δ: 1.5 (6Н, s), 1.8-1.9 (2Н, m), 2.4 (4Н, m), 2.55 (2Н, m), 2 6-2.8 (4H, d), 5.3 (2H, br s), 5.9 (1Η, t), 6.8 (1Η, d), 7.27-7.4 (7H , m), 7.5 (1Η, m), 8.5 (1Η, d) MS t / ζ: 533 (M + 1).

Example 460. Amide 4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -1Sh-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5- ylidene] propyl} piperidine-4-carboxylic acid.

Stage 1

4-carbamoyl-4- (4-chlorophenyl) piperidine-1-carboxylic acid tert-butyl ester.

To a solution of 4- (4-chlorophenyl) -4-cyanopiperidin-1-carboxylic acid tert-butyl ester (500 mg, 1.56 mmol) in ethanol (15 ml) was added 2 ml of aqueous 10N. sodium hydroxide solution. The resulting solution is heated at boiling point for 2 hours, cooled to room temperature, poured into 1N. hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The yellow oil recovered was purified by chromatography on silica gel eluted with dichloromethane / methanol (9.6: 0.4) to obtain the title compound (306 mg, 58%). MS t / ζ: 339 (M + 1).

Stage 2

Amide 4- (4-chlorophenyl) piperidine-4-carboxylic acid.

The title compound was prepared following the procedure of Example 456, step 3, but replacing 4- (4-chlorophenyl) -4-cyanopiperidin-1-carboxylic acid tert-butyl ester with 4-carbamoyl-4- (4- tert-butyl ester chlorophenyl) piperidine-1-carboxylic acid. MS t / ζ: 239 (M + 1).

Stage 3.

The title compound was prepared following the procedure of Example 456, step 4, but replacing 4 (4-chlorophenyl) piperidin-4-carbonitrile with 4- (4-chlorophenyl) piperidin-4-carboxylic acid amide. Chromatographic purification on silica gel eluted with dichloromethane-methanol (9: 1) affords the title compound.

Nuclear Magnetic Resonance Spectrum Ή (ΟΌΟ1 ₃ ) δ: 1.5 (6Н, s), 1.8-2.0 (6Н, m), 2.3-2.6 (6Н, m), 5.3 (2Н, br s), 6.1 (1H, t), 6.8 (1H, d), 7.3 (6H, m), 7.4 (1Η, d), 7.5 (1H, d), 8.5 (1H, d).

Example 461. 2- (5- {3- [4- (4-Chlorophenyl) -4-hydroxymethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b ] cyclohepten-7-yl) propan-2-ol.

Stage 1

4- (4-Chlorophenyl) -4-hydroxymethylpiperidin-1-carboxylic acid tert-butyl ester.

To a cooled solution of 4- (4-chlorophenyl) piperidine-1,4-dicarboxylic acid, 1-tert-butyl, 4-methyl ether (700 mg, 1.98 mmol) in 6 ml of ether, 2 ml of a solution of lithium aluminum hydride (dropwise) are added 1 mol / L) in ether. The reaction mixture was stirred at 0 ° C. for 3 hours, then water (100 ml) was slowly added. The gel formed is filtered off and the aqueous filtrate is extracted three times with ether. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. The isolated oil was purified by chromatography on silica gel eluted with hexane-ethyl acetate (6: 4) to obtain the title compound (297 mg, 46%).

- 75 008060

NMR spectrum Ή (С0С1 ₃ ) δ: 1.5 (9Н, s), 1.7-1.8 (2Н, m), 2.1 (2Н, d), 3.0 (2Н, m), 3 5 (2H, s), 3.7 (2H, d), 7.4 (4H, m). MS t / ζ: 324 (M-1).

Stage 2

[4- (4-Chlorophenyl) piperidin-4-yl] methanol.

The title compound was prepared following the procedure of Example 456, step 3, but replacing 4- (4-chlorophenyl) -4-cyanopiperidin-1-carboxylic acid tert-butyl ester with 4- (4-chlorophenyl) -4 tert-butyl ester -hydroxymethylpiperidin-1-carboxylic acid. MS t / ζ: 224 (M-1).

Stage 3.

The title compound was prepared following the procedure of Example 456, step 4, but replacing 4 (4-chlorophenyl) piperidin-4-carbonitrile with [4- (4-chlorophenyl) piperidin-4-yl] methanol. Chromatographic purification on silica gel eluted with a dichloromethane-methanol mixture (9.5: 0.5) affords the title compound.

Я NMR spectrum (SPS1 ₃ ) δ: 1.5 (6Н, s), 2.0 (2Н, m), 2.2-2.3 (4Н, m), 2.4 (2Н, m), 2 55 (2H, m), 2.8 (2H, d), 3.5 (2H, s), 5.3 (2H, br s), 6.0 (1H, t), 6.8 ( 1H, d), 7.27-7.4 (7H, m), 7.5 (1H, d), 8.5 (1H, d). MS t / ζ: 517 (M-1).

Example 462. 2- (5- {3- [4- (4-Chlorophenyl) -4- (1-hydroxyethyl) piperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza dibenzo | a. b | cyclohepten-7-yl) propan-2-ol.

To a cooled solution of 1- (4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11Н-10-oxa-1-azadibenzo [a, b] cycloheptene-5- ylidene] propyl} piperidin-4-yl) ethanone (70 mg, 0.13 mmol), sodium borohydride (20 mg, 0.53 mmol) is added to 5 ml of methanol. The reaction mixture was stirred for 4 hours at 0 ° C. and then concentrated in a stream of nitrogen. The residue was purified by chromatography (reverse phase HPLC) to give the formic acid salt of the title compound (39 mg, 56%).

NMR spectrum р (SPS1 ₃ ) δ: 0.8 (4H, s), 1.5 (6H, s), 2.1-2.7 (10H, m), 3.1 (2H, m), 5 3 (2H, br s), 5.95 (1H, t), 6.8 (1H, d), 7.27-7.4 (7H, m), 7.5 (1H, d), 8.5 (N, d) MS t / ζ: 533 (M + 1).

Example 463. 2- (5- {3 - [4- (4-Chlorophenyl) -4- (1-hydroxy-1-methylethyl) piperidin-1-yl] propylidene} 5.11-dihydro-10-oxa-1 -aza-dibenzo [a, b] cyclohepten-7-yl) propan-2-ol.

Stage 1

4-Acetyl-4- (4-chlorophenyl) piperidine-1-carboxylic acid tert-butyl ester.

To a cooled solution of 1- [4- (4-chlorophenyl) piperidin-4-yl] ethanone (540 mg, 1.98 mmol) in dichloromethane (10 ml), triethylamine (0.6 ml, 3.82 mmol) was added, followed by adding in portions of ditret butyl dicarbonate (470 mg, 1.98 mmol).

The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated, quenched with 1N. hydrochloric acid and extracted with dichloromethane. The organic extracts were washed 2 times with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The isolated oil was purified by chromatography on silica gel eluted with hexane-ethyl acetate (8: 2) to give the title compound (445 mg, 67%).

NMR spectrum р (СОС1 ₃ ) δ: 1.5 (9Н, s), 1.9 (5Н, m), 2.3-2.4 (2Н, m), 3.1 (2Н, t), 3 7-3.8 (2H, m); 7.4 (4H, m). MS t / ζ: 338 (M + 1).

Stage 2

4- (4-Chlorophenyl) -4- (1-hydroxy-1-methylethyl) piperidine-1-carboxylic acid tert-butyl ester.

16 ml of a 1.4 molar solution of methylmagnesium bromide in toluene / tetrahydrofuran mixture (75:25) are added to a dry round-bottom flask from a syringe. The flask was cooled in an ice bath under a stream of nitrogen. A solution of 4-acetyl-4- (4-chlorophenyl) piperidine-1-carboxylic acid tert-butyl ester (337 mg, 1.02 mmol) in 5 ml of tetrahydrofuran was added dropwise to this flask over 20 minutes, and the resulting mixture was stirred at at 0 ° C for 8 hours. The reaction mixture was warmed to room temperature and stirred for 5 days. The reaction was interrupted by slowly adding 150 ml of a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The combined organic phases are washed with brine, dried over magnesium sulfate and concentrated in vacuo. The yellow residue was purified by chromatography on silica gel eluted with hexane-ethyl acetate (7.5: 2.5) to obtain the title compound (242 mg, 67%).

Nuclear Magnetic Resonance Spectrum Ή (SPS1 ₃ ) δ: 1.1 (6H, s), 1.4 (9H, s), 1.8-1.9 (2H, m), 2.3-2.4 (2H, d) 2.6 (2H, t), 3.9 (2H, d), 7.3 (4H, m). MS t / ζ: 354 (M + 1).

Stage 3. 2- [4- (4-Chlorophenyl) piperidin-4-yl] propan-2-ol.

The title compound was prepared following the procedure of Example 456, step 3, but replacing 4- (4-chlorophenyl) -4-cyanopiperidin-1-carboxylic acid tert-butyl ester with 4- (4-chlorophenyl) -4 tert-butyl ester - (1-hydroxy-1-methylethyl) piperidine-1-carboxylic acid. MS t / ζ: 254 (M + 1).

Stage 4.

The title compound was prepared following the procedure for Example 456, step 4, but replacing 4 (4-chlorophenyl) piperidin-4-carbonitrile with 2- [4- (4-chlorophenyl) piperidin-4-yl] propan-2-ol. Chromatographic purification on silica gel eluted with a dichloromethane-methanol mixture (9: 1) gives the compounds

- 76 008060 the title bar.

'11 (С0С1 ₃ ) NMR spectrum δ: 1.1 (6Н, s), 1.5 (6Н, s), 1.8 (2Н, m), 2.3-2.6 (10Н, m), 5.3 (2H, br s), 5.95 (1H, t), 6.8 (1H, d), 7.27-7.4 (7H, m), 7.5 (1H, d) 8.5 (1H, d) MS t / ζ: 547 (M + 1).

Example 464. 4- (4-Chlorophenylamino) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} piperidin-4-carbonitrile.

Stage 1

1-Benzyl-4- (4-chlorophenylamino) piperidin-4-carbonitrile.

To a solution of 1-benzylpiperidin-4-one (2.68 g, 14.20 mmol) in 13 ml of glacial acetic acid was added 4-chlorophenylamine (1.99 g, 15.6 mmol). The reaction mixture is cooled in a bath of cold water. Trimethylsilyl cyanide (1.89 ml, 14.20 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and the mixture was stirred overnight under nitrogen. The reaction mixture is cooled to 0 ° C. Concentrated ammonium hydroxide (15 ml) was slowly added. Then add cold water. The pH of the mixture is 10. The mixture is extracted three times with methylene chloride, and the organic layers are dried over magnesium sulfate, filtered and concentrated under reduced pressure. Ether was added to the residue and the white solid was filtered off and dried under high vacuum to give the title compound (3.73 g, 81%).

'11 NMR spectrum (СНС1 ₃ ) δ: 1.90-2.01 (2Н, t), 2.3-2.4 (2Н, m), 2.45-2.55 (2Н, t), 2 81-2.93 (2H, m), 3.61 (2H, s), 3.68 (1H, s), 6.87 (1H, s), 6.90 (1H, s), 7.2- 7.38 (7H, m). MS t / ζ: 326 (M + 1).

Stage 2. 4- (4-Chlorophenylamino) piperidine-4-carbonitrile.

65 l of 1-chloroethyl chloroformate (0.600 mmol) is added to 1-benzyl-4- (4-chlorophenylamino) piperidine-4-carbonitrile (163 mg, 0.5002 mmol) in dichloroethane (5 ml). The mixture is heated at boiling point and stirred in a nitrogen atmosphere. After 1 hour and 15 minutes, another 86 μl (0.800 mmol) of chloroformate was added to the reaction mixture and stirred for another 2 hours under reflux. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Methanol (5 ml) was added to this residue, and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was then allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water. The organic layer was removed and 1N was added to the aqueous layer. sodium hydroxide solution to pH 9. The aqueous layer was extracted 2 times with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (84 mg, 71%).

'11 NMR spectrum (SPS1 ₃ ) δ: 1.66-1.68 (1H, d), 1.70-1.75 (2H, d), 2.22-2.28 (2H, d), 2 87-3.12 (4H, m), 3.61 (1H, br s), 6.53-7.27 (4H, m). MS t / ζ: 236 (M + 1).

Stage 3.

The title compound was prepared by dissolving 2- [5- (3-bromopropylidene) -5,11 dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (106 7 mg, 0.285 mmol) in 4 ml of water and 1 ml of acetonitrile. Potassium carbonate (82.7 mg, 0.599 mmol) and 4- (4chlorophenylamino) piperidine-4-carbonitrile (84.0 mg, 0.356 mmol) are added to this solution. The reaction mixture was heated to 50 ° C and stirred overnight. The next day, the reaction mixture was allowed to cool to room temperature and the mixture was diluted with ethyl acetate and water. The organic layer was washed 2 times with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by chromatography (reverse phase HPLC) to give the title compound (11.5 mg, 8% yield, 88% purity according to liquid chromatography-mass spectrometry (LC / MS).

'11 NMR spectrum (СОС1 ₃ ) δ: 1.52 (6Н, br s), 2.2-2.8 (12Н, m), 3.4 (1Н, d), 5.16-5.36 (2H, d), 6.00-6.10 (1H, m), 6.75-6.80 (2H, m), 6.95-7.55 (7H, m), 8.45-8 76 (1H, m) MS t / ζ: 529 (M + 1).

Example 465. 4- (4-Chlorophenylamino) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylide methyl ester ] propyl} piperidine-4-carboxylic acid.

Stage 1

1-Benzyl-4- (4-chlorophenylamino) piperidine-4-carboxylic acid amide.

Concentrated sulfuric acid (50 ml) was added to 1-benzyl-4- (4-chlorophenylamino) piperidine-4-carbonitrile (1.97 g, 6.05 mmol). The reaction mixture was stirred at room temperature as an orange uniform solution. After 24 hours, the reaction mixture was cooled to 0 ° C and poured very slowly into a concentrated solution of ammonium hydroxide on ice. The precipitate was filtered off and washed with water to give a white solid (202 mg, 71%).

'11 NMR spectrum (SPS1 ₃ ) δ: 1.87-1.92 (2H, broad d), 2.06-2.14 (2H, t), 2.27-2.38 (2H, m) 2.70-2.78 (2H, broad d), 3.50 (2H, s), 3.05 (1H, s), 5.42-5.44 (1H, broad s), 6 55-6.57 (2H, d), 6.76-6.82 (1H, br s), 7.10-7.15 (2H, d), 7.24-7.31 (5H, m). MS t / ζ: 344 (M + 1).

Stage 2

1-benzyl-4- (4-chlorophenylamino) piperidine-4-carboxylic acid methyl ester.

To a solution of 1-benzyl-4- (4-chlorophenylamino) piperidin-4-carboxylic acid amide (1.19 g, 3.46 mmol) in methanol (10 ml) in a sealed tube, toluene sulfonic acid (2.33 g, 12, 11 mmol). The reaction mixture is heated to 120 ° C and stirred at this temperature for 5 days

- 77 008060 explosion-proof screen. The reaction mixture was then allowed to cool to room temperature and then it was treated by dilution with water, followed by the addition of a concentrated solution of ammonium hydroxide to a pH of about 8. The mixture was extracted three times with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. Yellow oil (744 mg, 60% yield) was used without purification.

'11 NMR spectrum (SIS1 ₃ ) δ: 1.93-2.03 (2H, broad d), 2.19-2.28 (2H, dt), 2.32-2.48 (2H, m) 2.55-2.64 (2H, m), 3.51 (2H, s), 3.68 (3H, s), 3.85 (1H, s), 6.47-6.51 (2H broad d), 7.07-7.10 (2H, broad d), 7.21-7.35 (5H, m). MS t / ζ: 359 (Μ + 1).

Stage 3.

4- (4-Chlorophenylamino) piperidine-4-carboxylic acid methyl ester.

The title compound was prepared following the procedure of Example 464, step 2, but replacing 1benzyl-4- (4-chlorophenylamino) piperidin-4-carbonitrile with 1-benzyl-4- (4-chlorophenylamino) piperidin-4-carboxylic acid methyl ester . In addition, this compound is purified by chromatography on a separation column (Ker-cancer) with silica gel eluting with a mixture of 2-10% methanol in dichloromethane.

'11 NMR spectrum (SIS1 ₃ ) δ: 1.92-1.99 (2H, br d), 2.11-2.22 (2H, m), 2.73-3.03 (4H, m) 3.69 (3H, s), 3.94 (1H, s), 6.50-6.53 (2H, broad d), 7.09-7.12 (2H, broad d). MS t / ζ: 269 (Μ + 1).

Stage 4.

The title compound was prepared following the procedure of Example 464, step 3, but replacing 4 (4-chlorophenylamino) piperidin-4-carbonitrile with 4- (4-chlorophenylamino) piperidin-4carboxylic acid methyl ester. The residue was purified by chromatography (reverse phase HPLC) to give the title compound (62 mg, 32%).

'11 NMR spectrum (SIS1 ₃ ) δ: 1.58 (6H, s) 2.09-2.20 (2H, m), 2.36-2.47 (2H, m), 2.51-2, 60 (2H, m), 2.853.02 (6H, m), 3.69 (3H, s), 5.19-5.41 (3H, br s), 6.01-6.06 (1H, t), 6.51-6.54 (2H, d), 6.82-6.84 (1H, d), 7.107.13 (2H, d), 7.24-7.34 (2H, m) 7.43-7.44 (1H, d), 7.55-7.58 (1H, d), 8.26 (1H, s), 8.53-8.55 (1H, dd). MS t / ζ: 562 (M).

Example 466. Amide 4- (4-chlorophenylamino) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene] propyl} piperidine-4-carboxylic acid.

Stage 1

Amide 4- (4-chlorophenylamino) piperidine-4-carboxylic acid.

The title compound was prepared following the procedure of Example 464, step 2, but replacing 1benzyl-4- (4-chlorophenylamino) piperidin-4-carbonitrile with 1-benzyl-4- (4-chlorophenylamino) piperidine-4-carboxylic acid amide.

'11 NMR spectrum (SIS1 ₃ ) δ: 1.82-1.92 (2H, br d), 2.10-2.37 (3H, m), 2.69-2.79 (2H, m) 2.89-3.03 (2H, m), 5.42-5.46 (1H, br s), 6.47-6.59 (2H, m), 6.76-6.82 ( 1H, broad s), 7.08-7.15 (2H, broad d). ΜC t / ζ: 254 (Μ + 1).

Stage 2

The title compound was prepared following the procedure of Example 464, step 3, but replacing 4 (4-chlorophenylamino) piperidin-4-carbonitrile with 4- (4-chlorophenylamino) piperidin-4-carboxylic acid amide. The sample was purified using chromatography (reverse phase HPLC) to give the title compound (25 mg, 25%).

'11 NMR spectrum (SIS1 ₃ ) δ: 1.53-1.55 (7H, s), 1.97-2.07 (2H, m), 2.40-2.61 (3H, m), 2 67-2.76 (3H, m), 2.86-2.96 (2H, m), 5.20-5.38 (2H, br s), 6.04-6.09 (1H, t), 6.51-6.54 (2H, broad d), 6.77-6.80 (1H, broad d), 7.08-7.11 (2H, broad d), 7, 19-7.29 (2H, m), 7.42-7.43 (1H, br d), 7.51-7.55 (1H, dd), 8.18 (1H, br s), 8,488.50 (1H, dd). MS t / ζ: 547 (M).

Example 467. 2- (5- {3- [4- (4-Chlorophenyl) -4-fluoropiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene -7-yl) propan-2-ol.

Stage 1

To a solution of hydrogen fluoride (65-70%) in pyridine (4 ml) cooled to 0 ° C was added 4- (4chlorophenyl) piperidin-4-ol (500 mg, 2.36 mmol). The resulting solution was stirred at 0 ° C for 15 minutes and then warmed to room temperature and stirred again for 1 hour. The mixture was slowly poured into saturated aqueous sodium bicarbonate (30 ml) and extracted with methylene chloride (100 ml; the solvent and extract were delivered slowly and carefully. ) Excess hydrogen fluoride is neutralized with solid sodium carbonate. The organic phases are washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel eluting with a gradient (from dichloromethane to dichloromethane / methanol / ammonium hydroxide = 8.5 / 1 / 0.5) to obtain 4- (4-chlorophenyl) -4-fluoropiperidine (260 mg, 52%).

'11 NMR spectrum (SIS1 ₃ , 300 MHz) δ: 2.98-3.14 (m, 4H), 1.87-2.10 (m, 4H), 7.33-7.36 (m, 4H )

¹⁹ P-NMR (SIS1 ₃ , 282 MHz) δ: -160.40-160.20 (m). MS t / ζ: 214 (M + 1).

Stage 2

2.6 lutidine (197 mg, 214 μl, 1.84 mmol) and potassium iodide (several mg) are added to a solution of the product of stage 1 (252 mg, 1.18 mmol) in isopropyl alcohol (5 ml). The resulting suspension of heat

- 78 008060 to a temperature of 80 ° C. Solid 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (221 mg, 0.591 mmol) was added, in approximately equal portions for 2 hours. Stirring is continued for another 20 hours at 80 ° C. The mixture was concentrated and the resulting residue was purified by chromatography on silica gel eluting with a gradient from dichloromethane to dichloromethane / methanol (95: 5) to obtain the title compound (160 mg, 54%).

NMR spectrum ^! N (СОС1 ₃ , 300 MHz) δ: 1.57-1.66 (m, 8Н), 1.88-1.97 (m, 3Н), 2.31-2.46 (m, 4Н), 2 52-2.62 (m, 2H), 2.67-2.76 (m, 2H), 5.20-5.45 (br s, 2H), 6.14 (t, 1H), 6 83 (d, 1H), 7.22-7.37 (m, 6H), 7.45 (d, 1H), 7.59 (dd, 1H), 10-8.51 (dd, 1H).

¹⁹ P-NMR (COC1 ₃ , 282 MHz) δ: -160.30-160.50 (m). MS t / ζ: 507 (M + 1).

Example 468. 4- (4-Chlorophenyl) -4-fluoro 1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene- 5-ylidene] propyl} piperidin-3-ol.

Stage 1

To a solution of 4- (4-chlorophenyl) -3,4-dihydroxypiperidin-1-carboxylic acid tert-butyl ester (1.213 g, 3.34 mmol) in methylene chloride (30 ml) at -78 ° С sulfur diethylamino trifluoride (ΌΑ8Τ . 3 ml). The resulting solution was stirred for 4 hours at -78 ° C. Methanol (20 ml) was added in order to destroy excess ΌΑ8Τ, and the mixture was kept at -78 ° C for 5 minutes, then warmed to room temperature. The mixture was concentrated and purified chromatographically on silica gel eluting with a gradient mixture (80% hexane / 20% ethyl acetate) to give 4- (4-chlorophenyl) -4 fluorosheridin-3-ol (262 mg, 24%).

NMR spectrum ^! H (SPS1 ₃ , 300 MHz) δ: 1.48 (s, 9H), 1.84 (broad dd, 1H), 2.50 (dddd, 1H), 3.15 (broad dd, 1H), 3.38 (d, 1H), 3.76 (s, 1H), 4.04-4.36 (m, 2H), 7.33-7.44 (m, 4H).

¹⁹ P-NMR (COC1 ₃ , 282 MHz) δ: -159.90 (d).

Stage 2

4- (4-Chlorophenyl) -4-fluoropiperidin-3-ol is obtained as in step 3 of Example 502, replacing 4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-carboxylic acid tert-butyl ester with tert-butyl 4- (4-chlorophenyl) -4-fluoro-3-hydroxypiperidin-1-carboxylic acid ester. After isolation from the crude mixture, the free amine is used immediately, without further purification.

In the NMR 'H (ССО1 ₃ , 300 MHz) spectrum: 4- (4-chlorophenyl) -4-fluoropiperidin-3-ol appears as the main component of the mixture of compounds. MS t / ζ: 230 (M + 1; main peak in the chromatogram).

Stage 3.

The title compound was prepared as in Step 5 of Example 502, replacing 8-4- (4chlorophenyl) -3,3-dimethylpiperidin-4-ol with 4- (4-chlorophenyl) -4-fluoropiperidin-3-ol.

Я NMR spectrum (СОС1 ₃ , 300 MHz) δ: 1.58 (s, 6Н), 1.74-1.96 (m, 2Н), 2.31-2.75 (m, 8Н), 2.80 (broad d, 1H), 3.06 (d, 1H), 3.67 (broad d, 1H), 5.20-5.45 (broad s, 2H), 6.11 (t, 1H) ), 6.84 (d, 1H), 7.22-7.36 (m, 4H), 7.397.47 (m, 3H), 7.57 (d, 1H), 8.56 (dd, 1H) .

¹⁹ P-NMR (COC1 ₃ , 282 MHz) δ: -158.30 (d). MS t / ζ: 523 (M + 1).

Example 469. 2- (5- {3- [4- (4-Chlorophenyl) -4-fluoro-3-methylpiperidin-1-yl] propylidene} -5,11-dihydro10-oxa-1-aza-dibenzo [a , b] cyclohepten-7-yl) propan-2-ol.

Stage 1

4- (4-Chlorophenyl) -4-fluoro-3-methylpiperidine is prepared by following the procedure for Step 1 in Example 467, replacing 4- (4-chlorophenyl) piperidin-4-ol with 4- (4-chlorophenyl) -3-methylpiperidine -4-ol

NMR spectrum ^! H (COC1 ₃ , 300 MHz) δ: 0.67 (d, 3H), 1.91-2.26 (m, 2H), 2.84 (t, 1H), 3.02 (dd, 1H), 3.063.21 (m, 2H), 3.33 (br s, 2H), 7.27 (d, 2H), 7.34 (d, 2H).

¹⁹ P-NMR (COC1 ₃ , 282 MHz) δ: -180.60 (ddd). MS m / ζ: 228 (M + 1).

Stage 2

The title compound was prepared following the procedure for Step 2 in Example 467, replacing 4 (4-chlorophenyl) -4-fluoropiperidine with 4- (4-chlorophenyl) -4-fluoro-3-methylpiperidine.

NMR spectrum ^! N (СОС1 ₃ , 300 MHz) δ: 0.63 (d, 3Н), 1.58 (s, 6Н), 1.76-1.96 (m, 2Н), 2.09-2.52 (m 6H), 2.55-2.88 (m, 4H), 5.18-5.50 (br s, 2H), 6.12 (t, 1H), 6.83 (d, 1H), 7.22-7.36 (m, 6H), 7.46 (dd, 1H), 7.59 (d, 1H), 8.51 (d, 1H). MS t / ζ: 521 (M + 1).

Example 470. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} piperidin-3,4-diol.

Stage 1

To a suspension of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (2 g, 8.73 mmol) in methylene chloride (50 ml), triethylamine (1.42 g, 1.95 ml, 14, 0 mmol). The resulting mixture was cooled to 0 ° C. and di-tert-butyl dicarbonate (2.19 g, 10.0 mmol) was added in one portion. After 10 minutes at 0 ° C, the mixture was warmed to room temperature and stirred for 90 minutes. The contents of the flask are poured into 250 ml of methylene chloride and washed with a mixture of 1-normal hydrochloric acid and brine (3: 1), saturated aqueous sodium bicarbonate and brine. The organic phases are dried over magnesium sulphate, filtered, concentrated and the resulting oil filtered

- 79 008060 through a silica layer washed with methylene chloride to obtain 2.88 g (> 100%) of 4- (4-chlorophenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester.

'11 NMR spectrum (СОС1 ₃ , 300 MHz) δ: 1.49 (s, 9H), 2.45-2.52 (m, 2H), 3.63 (t, 2H), 4.07 (q, 2H), 6.02 (br s, 1H), 7.29 (s, 4H).

Stage 2

The product of stage 1 (2.88 g, approximately 8.7 mmol) was dissolved in 15 ml of a mixture of (5: 1) acetone: water. Osmium tetraoxide (2.5% in tert-butyl alcohol, 1 ml) was added, followed by 4-methylmorpholine Ν-oxide (1.13 g, 9.65 mmol). The mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bisulfite (5 ml) was added and the acetone was removed under reduced pressure. The resulting aqueous phase was extracted with methylene chloride and the extracts washed with an aliquot of a saturated aqueous solution of sodium bisulfite, 1-normal hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The extracts are then dried over magnesium sulfate, filtered and concentrated to give an oil which is purified chromatographically on silica gel eluting with a gradient (100% dichloromethane to 90:10 dichloromethane / methanol mixture). 4- (4chlorophenyl) -3,4-dihydroxypiperidin-1-carboxylic acid tert-butyl ester was obtained as an oil (2.64 g, 83%, 2 steps).

'11 NMR spectrum (СОС1 ₃ , 300 MHz) δ: 1.44 (s, 9H), 1.62 (broad d, 1H), 1.82 (broad s, 2H), 2.69 (broad. s, 1H), 2.99 (br t, 1H), 3.12 (br s, 1H), 3.90-4.30 (m, 3H), 7.33 (d, 2H), 7 41 (d, 2H).

Stage 3.

The product of stage 2 (500 mg, 1.37 mmol) is dissolved in methylene chloride (10 ml) and the resulting solution is cooled to 0 ° C. 3 ml of trifluoroacetic acid are slowly added and the reaction mixture is stirred at 0 ° C. for 2 hours and then concentrated under reduced pressure. The trifluoroacetic acid salt is dissolved in tetrahydrofuran and an excess of triethylamine is added. The solid formed is removed by suction filtration and the solution over the precipitate is concentrated to obtain 4- (4-chlorophenyl) piperidin-3,4-diol.

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.91 (ddd, 1H), 2.13 (ddd, 1H), 3.12-3.28 (m, 4H), 4.08 (dd, 1H), 7.37 (ddd, 2H), 7.51 (ddd, 2H).

Stage 4.

The title compound was prepared following the procedure in Step 2 of Example 467, but replacing 4- (4-chlorophenyl) -4-fluoropiperidine with 4- (4-chlorophenyl) piperidin-3,4-diol.

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.51 (s, 6H), 1.80 (broad d, 1H), 2.03-2.11 (m, 1H), 2.56 ( q, 2H), 2.68-3.12 (m, 6H), 4.00 (dd, 1H), 5.00-5.50 (br s, 2H), 6.17 (t, 1H) 6.76 (d, 2H), 7.27 (dd, 1H), 7.33 (dd, 2H), 7.44-7.49 (m, 4H), 7.80 (dd, 1H), 8.48 (dd, 1H). MS t / ζ: 521 (M + 1).

Example 471. 4- (4-Chlorophenyl) -3-ethyl-1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene -5-ylidene] propyl} piperidin-4-ol.

Stage 1

A solution of 4-oxopiperidin-1-carboxylic acid tert-butyl ester (5 g, 25.1 mmol), pyrrolidine (5 ml) and p-toluenesulfonic acid (25 mg) in benzene (100 ml) is heated under reflux in for 16 hours with azeotropic distillation of water. The resulting enamine solution was cooled to room temperature and concentrated. The crude enamine is dissolved in acetonitrile (50 ml); iodoethane (4.67 g, 30.1 mmol) was added and the mixture was heated at 100 ° C. for 0.5 h, cooled to room temperature and concentrated. The mixture was dissolved in ethyl acetate (200 ml), washed with 1-normal hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The extract was dried over magnesium sulfate, filtered and concentrated. The crude compound was purified by chromatography on silica gel eluted with hexane-ethyl acetate (80% / 20%) to give 3-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (680 mg).

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 0.95 (t, 3H), 1.26-1.42 (m, 1H), 1.50 (s, 9H), 1.69-1, 85 (m, 1H), 2.30 (br s, 1H), 2.43 (q, 2H), 2.90-4.36 (m, 4H).

Stage 2

4- (4-Chlorophenyl) -3-ethyl-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester was prepared by following the procedure in Step 2 of Example 502, replacing 3,3-dimethyl-4-oxopiperidin-1 tert-butyl ester -carboxylic acid on 3-ethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester.

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 0.80 (t, 3H), 0.91-1.13 (m, 2H), 1.18-1.28 (m, 1H), 1, 48 (s, 9H), 1.57-1.64 (broad d, 1H), 1.75-1.91 (m, 2H), 2.79 (t, 1H), 3.14 (ddd, 1H), 4.02 (broad d, 1H), 4.19 (broad d, 1H), 7.28-7.37 (m, 4H).

Stage 3.

4- (4-Chlorophenyl) -3-ethylpiperidin-4-ol was prepared according to the procedure for Step 3 in Example 502, replacing 4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-carboxylic tert-butyl ester acids on 4- (4-chlorophenyl) -3-ethyl-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester.

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 0.75 (t, 3H), 0.88-1.17 (m, 2H), 1.26 (t, 1H), 1.65 (br. d, 2H),

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1.83-2.02 (m, 2H), 2.75 (t, 1H), 2.95-3.21 (m, 3H), 7.32 (d, 2H), 7.40 (d, 2H). MS m ^: 240 (M + 1).

Stage 4.

The title compound was prepared following the procedure for Step 5 of Example 502, replacing 4- (4chlorophenyl) -3,3-dimethylpiperidin-4-ol with 4- (4-chlorophenyl) -3-ethylpiperidin-4-ol.

NMR / I spectrum (SPS1 ₃ , 300 MHz) δ: 0.70 (t, 3H), 0.81-1.11 (m, 3H), 1.56-1.64 (m, 7H), 1, 77-2.09 (m, 4H), 2.23-2.86 (m, 7H), 5.00-5.60 (m, 2H), 6.13 (t, 1H), 6.83 ( d, 1H), 7.23-7.47 (m, 6H), 7.46 (d, 1H), 7.59 (dd, 1H), 8.49 (dd, 1H). MS t / ζ: 533 (M + 1).

Example 472. 5-Chloro-1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene 5-ylidene] propyl} spiro [3 oxo-1,3-dihydroisobenzofuran-1,4'-piperidine].

Stage 1

To a suspension of 2-bromo-5-chlorobenzoic acid (1.5 g, 6.4 mmol) in 15 ml of methylene chloride, oxalyl chloride (969 mg, 666 μl, 7.64 mmol) and 2 drops of dimethylformamide are added at room temperature; bubbling begins and the mixture finally becomes homogeneous. The mixture was stirred at room temperature for 7 hours and concentrated. The resulting acid chloride residue was dissolved in methylene chloride (15 ml). Triethylamine (325 mg, 450 μl, 3.2 mmol) was added, followed by 2-amino-2-methyl-1-propanol (627 mg, 672 μl, 7.04 mmol), and the reaction mixture was kept at room temperature for 3 hours temperature and stirring. The mixture was poured into 1-normal hydrochloric acid (50 ml), extracted with methylene chloride (2 times 75 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, concentrated and dried in vacuo. The residue of the crude amide was dissolved in methylene chloride (15 ml) and thionyl chloride (1.29 g, 794 μl, 10.9 mmol) was added. The mixture was stirred at room temperature for 4 hours, and then the mixture was poured into saturated sodium bicarbonate solution (50 ml). The pH is adjusted to 9 by adding solid sodium bicarbonate and further alkalinized by adding several milliliters of aqueous 5N. sodium hydroxide solution. The biphasic mixture was extracted with methylene chloride (150 + 50 ml). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a crude residue, which was purified by chromatography on silica gel eluted with a concentration gradient (hexane / ethyl acetate 80% / 20%) to obtain 2- (2-bromo- 5-chlorophenyl) -4,4-dimethyl-4,5-dihydrooxazole (1.15 g, 62%).

NMR spectrum ^! H (СОС1 ₃ , 300 MHz) δ: 1.42 (s, 6H), 4.14 (s, 2H), 7.25 (dd, 1H), 7.55 m (d, 1H), 7.67 (d, 1H).

Stage 2

To a solution of the product obtained in stage 1 (1.09 g, 4.63 mmol) cooled in -78 ° C in anhydrous tetrahydrofuran (10 ml), a solution of n-butyllithium (1.6 mol / L in hexane, 2, 89 ml, 4.63 mmol) and the reaction mixture was allowed to react for 0.5 h. A solution of 4-oxopiperidin-1-carboxylic acid tert-butyl ester (922 mg, 4.63 mmol) in tetrahydrofuran (10 ml) was added. and the combined contents are stirred for 2 hours at -78 ° C. The reaction was interrupted by adding a saturated aqueous solution of ammonium chloride (30 ml), followed by warming to room temperature. The biphasic mixture was extracted with ethyl acetate (150 ml); washed with water and brine; dried over magnesium sulfate; filtered and concentrated. 4- [4-chloro-2- (4,4dimethyl-4,5-dihydrooxazol-2-yl) phenyl] -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester was isolated (412 mg, 22%) by chromatography on silica gel eluted with a mixture (80% hexane / 20% ethyl acetate).

¹ H NMR spectrum (СОС1 ₃ , 300 MHz, mixture; spectrum of the main component) δ: 1.36 (s, 6H), 1.50 (s, 9H), 1.66 (d, 2H), 1.96 ( dd, 2H), 3.19 (broad d, 2H), 3.42 (d, 2H), 4.24 (broad s, 2H), 7.16 (d, 1H), 7.45 (dd , 1H); 7.71 (br s, 1H). MS t / ζ: 409 (M + 1).

Stage 3.

Water (5 ml) and oxalic acid (300 mg) are added to a solution of the product from step 2 (200 mg, 0.49 mmol) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for approximately 4 days. The solid is isolated and dissolved in ethyl acetate (50 ml); the resulting solution was washed with saturated aqueous sodium bicarbonate and brine. The extracts are dried over magnesium sulfate, filtered and concentrated. Thus, 5chlorospiro [3-oxo-1,3-dihydroisobenzofuran-1,4′-piperidine] -1-carboxylic acid tert-butyl ester is obtained (100 mg, 61%) and is used without further purification.

Ί1 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.49 (s, 9H), 1.67 (d, 2H), 2.04 (ddd, 2H), 3.24 (dd, 2H), 4, 21 (br.s, 2 N), 7.32 (d, 1H), 7.64 (dd, 1H), 7.85 (d, 1 H). MS t / ζ: 238 (M + 1-100).

Stage 4.

5-Chlorospiro [3-oxo-1,3-dihydroisobenzofuran-1,4'-piperidine] was prepared according to the procedure for Step 3 in Example 502 using 5-chlorospiro [3-oxo-1,3-dihydroisobenzofuran tert-butyl ester -1,4'-piperidine] -1-carboxylic acid, instead of 4- (4-chlorophenyl) 4-hydroxy-3,3-dimethylpiperidin-1-carboxylic acid tert-butyl ester.

NMR spectrum ^! H (SPS1 ₃ , 300 MHz) δ: 1.71 (d, 2H), 2.09-2.22 (m, 2H), 3.13-3.28 (m, 4H), 7.37 (d , 1H),

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7.64 (dd, 1H); 7.84 (d, 1H). MS m / ζ: 238 (M + 1).

Stage 5.

The title compound was prepared according to the procedure for Step 2 of Example 467, replacing 4- (4-chlorophenyl) -4-fluoropiperidine with 5-chlorospiro [3-oxo-1,3-dihydroisobenzofuran-1,4′-piperidine].

NMR spectrum ^! H (C0C1 ₃ , 300 MHz) δ: 1.58 (s, 6H), 1.64 (d, 2H), 2.04-2.15 (m, 3H), 2.33-2.50 (m , 3H), 2.57 (t, 2H), 2.76 (d, 2H), 5.20-5.50 (br s, 2H), 6.12 (t, 1H), 6.81 ( d, 1H), 7.22-7.34 (m, 3H), 7.45 (d, 2H), 7.55-7.63 (m, 2H), 7.81 (d, 1H), 8 48 (dd, 1H). MS t / ζ: 531 (M + 1).

Example 473. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} -4-methoxy-3-methylpiperidin-3-ol.

Stage 1

Triethylamine (3.6 g, 4.9 ml, 35 mmol) was added to a suspension of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (5 g, 21.8 mmol) in methylene chloride (100 ml). The resulting solution is cooled to a temperature of 0 ° C in a water bath with ice. Di-tert-butyl dicarbonate (5.4 g, 25 mmol) was added and the resulting reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture is poured into 100 ml of a solution of (1: 1) 1 N. hydrochloric acid in brine and diluted with methylene chloride (300 ml). The organic phases are washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated to give 4- (4-chlorophenyl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (6 , 68 g, 93%) as a colorless oil, which is used without further purification.

NMR spectrum ^! H (СОС1 ₃ , 300 MHz) δ: 1.48 (s, 9H), 2.45-2.55 (m, 2H), 3.63 (t, 2H), 4.07 (q, 2H), 6.03 (br s, 1H); 7.29 (m, 4H).

Stage 2

In a solution of 4- (4-chlorophenyl) -3,6-dihydro-2H-pyridine-1 carboxylic acid tert-butyl ester (7.10 g, approximately 24.1 mmol) in methylene chloride (150 ml), cooled to 0 ° C a solution of 3-chloroperbenzoic acid (75%, 8.34 g, 36.2 mmol) in methylene chloride (120 ml) for 40 minutes. The mixture was warmed to room temperature and stirred overnight (16 hours). The solution is washed 2 times with a half-saturated aqueous solution of sodium bisulfite in order to decompose the excess oxidizing agent. Then the mixture is washed 2 times with a half-saturated aqueous solution of potassium carbonate and brine. The extracts were dried over magnesium sulfate, filtered and concentrated to give a crude oil, which was purified chromatographically on silica gel eluting with a gradient mixture (100% hexane - 80% hexane / 20% ethyl acetate) to obtain pure tert-butyl ether 6- (4 -chlorophenyl) -7oxa-3-azabicyclo [4.1.0] heptane-3-carboxylic acid (5.34 g, 71%) as a clear, colorless oil that solidifies upon standing.

NMR spectrum ^! H (СОС1 ₃ , 300 MHz) δ: 1.48 (s, 9H), 2.06-2.22 (m, 1H), 2.42 (ddd, 1H), 3.08-3.23 (m , 2H); 3.57-4.19 (m, 3H); 7.26-7.36 (m, 4H).

Stage 3.

To a solution of 6- (4-chlorophenyl) -7-oxa-3-aza-bicyclo [4.1.0] heptane-3-carboxylic acid tert-butyl ester (2.4 g, 7.8 mmol) in methanol (100 ml ) add a catalytic amount of p-toluenesulfonic acid (about 50 mg). The resulting solution was heated at reflux for 24 hours, cooled and concentrated. The crude residue was purified by chromatography on silica gel eluting with a gradient mixture (100% hexane - 80% hexane / 20% ethyl acetate) to obtain 4- (4-chlorophenyl) -3-hydroxy-4-methoxypiperidine-1-carboxylic tert-butyl ester acid (2.05 g, 77%). It is noted that the diol has a trans orientation.

NMR spectrum ^! H (SPS1 ₃ , 300 MHz) δ: 1.47 (s, 9H), 1.95 (d, 1H), 2.37 (ddd, 1H), 2.97 (s, 3H), 3.47 ( d, 1H), 3.67 (br s, 1H), 3.98-4.17 (m, 3H), 7.29-7.42 (m, 4H).

Stage 4.

A solution of 4- (4-chlorophenyl) -3-hydroxy-4-methoxypiperidin-1-carboxylic acid tert-butyl ester (2.05 g, 6.0 mmol) in methylene chloride (75 ml) was cooled to 0 ° C. Periodin Ee55Magbp (3.30 g, 7.8 mmol) was added, followed by water (200 μl) and the reaction mixture was allowed to stir for 2 hours at room temperature. The reaction is interrupted by the addition of a solution containing equal amounts of a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate. The resulting reaction mixture is stirred until two homogeneous phases form in it. These phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to give the isolated starting material (1.17 g, 57%) and 4- (4-chlorophenyl) -4-methoxy-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (540 mg, 27% (62%, br. M)).

NMR spectrum ^! H (SPS1 ₃ , 300 MHz) δ: 1.43 (s, 9H), 2.16-2.40 (m, 2H), 3.12 (s, 3H), 3.55 (ddd, 1H), 3.80 (br s, 1H), 3.96 (d, 1H), 4.34 (br s, 1H), 7.23-7.40 (m, 4H).

Stage 5.

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To a solution of 4- (4-chlorophenyl) -4-methoxy-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (470 mg, 1.38 mmol) in anhydrous tetrahydrofuran (10 ml) at a temperature of 0 ° C, 2, 96 ml of methylmagnesium bromide (in diethyl ether, 1.4 mol / L, 4.15 mmol) and the resulting mixture was stirred at this temperature for 3 hours. The excess organomagnesium was quenched by adding a saturated aqueous solution of ammonium chloride, and the reaction mixture was allowed to warm to room temperature. Water and ethyl acetate are added to the biphasic mixture. The phases are separated and the organic phase is washed with brine, dried over magnesium sulfate, filtered, dried and concentrated to obtain a crude residue, which is purified by chromatography on silica gel eluted with a gradient mixture (100% methylene chloride - 97.5% methylene chloride / 2.5% methanol ) to obtain pure 4- (4-chlorophenyl) -3-hydroxy-4-methoxy-3-methylpiperidin-1-carboxylic acid tert-butyl ester (269 mg, 58%).

Я NMR spectrum (SIS1 ₃ , 300 MHz) δ: 0.97 (s, 3H), 1.50 (s, 9H), 1.81 (d, 1H), 2.59 (ddd, 1H), 2, 96 (br t, 1H), 3.11 (s, 3H), 3.31 (s, 3H), 3.72-3.88 (m, 1H), 7.27-7.37 (m, 4H).

Stage 6.

4- (4-Chlorophenyl) -3-hydroxy-4-methoxy-3-methylpiperidin-1-carboxylic acid tert-butyl ester (260 mg, 0.74 mmol) was dissolved in methylene chloride (5 ml) and the resulting solution was cooled to 0 ° C. Trifluoroacetic acid (1 ml) was added and the mixture was stirred for 2 hours. Then the solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. Water and a 6-normal aqueous sodium hydroxide solution are added to pH 10. The organic phase is washed with brine and dried over magnesium sulfate, filtered and concentrated to give 4- (4-chlorophenyl) -4-methoxy-3methylpiperidin-3-ol.

Я NMR spectrum (SIS1 ₃ , 300 MHz) δ: 0.94 (s, 3H), 1.91 (d, 1H), 2.65-2.81 (m, 2H), 2.94 (ddd, 1H ), 3.13 (s, 3H), 3.25 (d, 1H), 3.30 (m, 1H), 7.37 (s, 4H). MS t / ζ: 256 (M + 1).

Stage 7.

To a solution of 4- (4-chlorophenyl) -4-methoxy-3-methylpiperidin-3-ol (206 mg, 1.24 mmol) in a mixture of acetonitrile / water (4: 1, 20 ml), potassium carbonate (171 mg, 1.24 mmol) followed by the addition of 2 [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a.b | cyclohepten-7-yl] propan-2-ol (417 mg, 1.12 mmol). The mixture was stirred at room temperature for 40 hours and concentrated. The remainder of the product was partitioned between ethyl acetate and water, and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel eluting with a gradient mixture (100% methylene chloride - 90% methylene chloride / 10% methanol) to give the title compound (232 mg, 35%) as an off-white solid.

Я NMR spectrum (SIS1 ₃ , 300 MHz) δ: 0.83 (s, 3H), 1.57 (s, 6H), 1.76-1.94 (m, 2H), 2.20 (t, 1H ), 2,292.72 (m, 7H), 3.06 (s, 3H), 3.39 (br s, 1H), 5.19-5.54 (br s, 2H), 6.12 ( t, 1H), 6.82 (d, 1H), 7.21-7.34 (m, 6H), 7.46 (d, 1H), 7.58 (d, 1H), 8.51 (d , 1H). MS t / ζ: 549 (M + 1).

Example 474. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} -4-methoxypiperidin-3-ol.

Stage 1

4- (4-Chlorophenyl) -4-methoxypiperidin-3-ol is prepared following the procedure of Step 6 in Example 473, replacing 4- (4-chlorophenyl) -3-hydroxy-4-methoxy-3-methylpiperidin- tert-butyl ester 1-carboxylic acid, on 4- (4-chlorophenyl) -3-hydroxy-4-methoxypiperidin-1-carboxylic acid tert-butyl ester. MS t / ζ: 242 (M + 1).

Stage 2

The title compound was prepared following the procedure for Step 7 in Example 473 and replacing 4 (4-chlorophenyl) -4-methoxy-3-methylpiperidin-3-ol with the product of Step 1 in Example 474.

М NMR spectrum (SIS1 ₃ , 300 MHz) δ: 1.58 (s, 6H), 1.63-1.82 (m, 3H), 1.95 (d, 1H), 2.21-2.78 (m, 8H), 2.91 (s, 3H), 3.63 (br s, 1H), 5.32 (br s, 2H), 6.11 (t, 1H), 6.81 ( d, 1H), 7.21-7.37 (m, 6H), 7.44 (d, 1H), 7.57 (dd, 1H), 8.51 (dd, 1H). MS t / ζ: 535 (M + 1).

Example 475. 2- (5- {3- [4- (4-Chlorophenyl) -3,4-dimethoxypiperidin-1-yl] propylidene} -5,11-dihydro10-oxa-1-aza-dibenzo [a, b ] cyclohepten-7-yl) propan-2-ol.

Stage 1

The product of stage 3 in example 473 (259 mg, 0.76 mmol) was dissolved in tetrahydrofuran (5 ml) and cooled to 0 ° C. The dispersion of sodium hydride (60% in mineral oil, 46 mg, 1.15 mmol) is added as one portion and the mixture is stirred for 5 minutes. Methyl iodide was added and the mixture was warmed to room temperature and stirred for 48 hours. The excess base was quenched by the addition of a saturated aqueous IN ₄ C1 solution and water. The biphasic mixture was extracted twice with ethyl acetate. The extracts are combined, washed with brine and dried over sodium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel eluting with a gradient mixture (hexane - 80% hexane / 20% ethyl acetate) to give 4- (4-chlorophenyl) -3,4-dimethoxypiperidine-1-carboxylic acid tert-butyl ester (191 mg, 71 %).

Я NMR spectrum (SIS1 ₃ 300 MHz) δ: 1.47 (s, 9H), 1.90 (d, 1H), 2.31 (ddd, 1H), 2.91-3.38 (m, 9H) 3.934.37 (br m, 2H); 7.24-7.37 (m, 4H).

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Stage 2

4- (4-Chlorophenyl) -3,4-dimethoxypiperidine is prepared following the procedure of Step 6 in Example 473, replacing 4- (4-chlorophenyl) -3-hydroxy-4-methoxy-3-methylpiperidin-1- tert-butyl ester carboxylic acid per stage 1 product.

NMR spectrum '11 (C1) _; C) 1X 300 MHz) δ: 1.96 (d, 1H), 2.27 (ddd.d, 1H), 2.71-3.03 (m, 9H), 3.04-3.15 (m , 2H); 7.30-7.41 (m, 4H). MS tA: 256 (M + 1).

Stage 3.

The title compound was prepared following the procedure for Step 7 in Example 473 and replacing 4 (4-chlorophenyl) -4-methoxy-3-methylpiperidin-3-ol with the product of Step 2.

Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ ) δ: 1.58 (s, 6H), 1.67 (br s, 2H), 1.77 (s, 1H), 1.91 (d, 1H), 2.18 -2.31 (m, 1H), 2.33-2.47 (m, 2H), 2.48-2.62 (m, 2H), 2.65-2.75 (m, 1H), 2 83-2.90 (m, 4H), 2.92 (s, 3H), 3.07 (br s, 1H), 5.06-5.57 (br s, 2H), 6.10 (t, 1H), 6.82 (d, 1H), 7.22-7.35 (m, 6H), 7.44 (d, 1H), 7.59 (d, 1H), 8.50 ( d, 1H). MS t / ζ: 549 (M + 1).

Example 476. 3-Azido-4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene -5-ylidene} propyl} piperidin-4-ol.

Stage 1

4- (4-Chlorophenyl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester.

Add to a solution of di-tert-butyl dicarbonate (9.96 g, 45.6 mmol) in methylene chloride (500 ml) 10.00 g of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (43.5 mmol) and 12.42 ml of triethylamine (89 mmol). The solution was stirred at room temperature for 4 hours. Gas evolution was observed. The reaction is interrupted by adding 1N. HC1 acid and extracted 3 times with methylene chloride. The organic layers were collected together, dried over magnesium sulfate and evaporated in vacuo. The residue was purified to give the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum Ή (SPS1 ₃ ) δ: 1.50 (9H, s), 2.46 (2H, br s), 3.62 (2H, br s), 4.05 (2H, br s) 6.01 (1H, br s); 7.25 (4H, s).

Stage 2

6- (4-Chlorophenyl) -7-oxa-3-aza-bicyclo [4.1.0] heptane-3-carboxylic acid tert-butyl ester.

A solution of 4- (4-chlorophenyl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (4.0 g, 13.6 mmol) in methylene chloride (136 ml) is cooled to 0 ° C . 3-Chloroperbenzoic acid (4.07 g, 20.4 mmol) was dissolved in methylene chloride and added in portions over 45 minutes. The formation of a white precipitate is observed. The solution was allowed to stir at room temperature for 14 hours. The reaction mixture was washed 1 time with 10% solution of No. 5O ₃ . 1 time with a 10% solution of #CO ₃ . 1 time with brine and dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was purified in a Vu1ade Πηδίι system (90% hexane / 10% ethyl acetate to 80% hexane / 20% ethyl acetate) to obtain the title compound as a colorless oil (2.75 g, 65%).

Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ ) δ: 1.50 (9Н, s), 2.15 (1Н, m), 3.15 (2Н, m), 3.6-4.2 (4Н, m), 7 31 (4H, s).

Stage 3. 4-Azido-4- (4-chlorophenyl) -3-hydroxypiperidin-1-carboxylic acid and 3-azido-4- (4-chlorophenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester.

Into a solution of 6- (4-chlorophenyl) -7-oxa-3-aza-bicyclo [4.1.0] heptane-3-carboxylic acid tert-butyl ester (0.960 g, 3.1 mmol) in 31 ml of dimethyl sulfoxide (DMSO ) sodium azide (0.970 g, 14.9 mmol) is added. The solution was allowed to warm to 100 ° C for 24 hours and cooled to room temperature. The reaction mixture was washed with water, dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was purified in a Vyuade GYN system (from 90% hexane / 10% ethyl acetate to 80% hexane / 20% ethyl acetate, to 70% hexane / 30% ethyl acetate) to obtain two compounds. The more easily eluting isomer is 4-azido-4- (4-chlorophenyl) -3-hydroxypiperidin-1-carboxylic acid tert-butyl ester (0.010 g, 9%).

Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ ) δ: 1.46 (s, 9H), 1.93 (d, 1H), 2.51 (dt, 1H), 3.10 (br t, 1H), 3.34 (d , 1H), 3.80 (br s, 1H), 4.08 (m, 2H), 7.41 (s, 4H).

The slowly eluting isomer is 3-azido-4- (4chlorophenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (0.361 g, 33%)

Я NMR spectrum (SPS1 ₃ ) δ: 1.43 (s, 9H), 1.57 (m, 1H), 2.40 (t, 1H), 2.93 (m, 1H), 3.11 (t 11H), 3.50 (s, 1H), 3.56 (d, 1H), 4.07 (m, 2H), 7.33 (d, 2H), 7.40 (d, 2H).

Stage 4.

The azido alcohol (0.184 g, 0.5 mmol) protected by a butoxycarbonyl group was dissolved in dichloromethane (2 ml) and cooled to 0 ° C, and trifluoroacetic acid (0.790 ml) was added. The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo, and the residue was partitioned between aqueous solution No. ₁ HCO ₃ and CH ₂ Cl ₂ . The aqueous solution was extracted (3 times) and then washed with brine and dried over sodium sulfate. The residue is used in the next step, without further purification.

Stage 5.

To a solution of azidopiperidine (0.142 g, 0.56 mmol) in isopropanol (5.6 ml) was added 2,6-lutidine

- 84 008060 (0.066 ml, 0.8 mmol) and the catalyst is potassium iodide.

This mixture is heated to 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol ( 0.025 g, 0.067 mmol), which is added in parts over 2 hours. Then the solution is stirred at 80 ° C for another 14 hours. The reaction mixture is concentrated in vacuo, then purified in the system Vyuade Pak11 (from 75% ethyl acetate / 25% hexane to 100% ethyl acetate) to obtain the title compound (0.135 g, 66%).

¹ H NMR (SOS1 ₃₎ δ: 1,56 (6H, s), 1.65 (d, 1H), 1.85 (s, 1H), 2.13 (s, 1H), 2,36- 2.94 (m, 8H), 3.51 (s, 1H), 5.24 (br s, 2H), 6.16 (t, 1H), 6.80 (d, 1H), 7.21 -7.45 (m, 7H), 7.58 (d, 1H), 8.44 (d, 1H). EMC t / ζ: 546 (M + 1), retention time 1.55.

Example 477. 4-Azido-4- (4-chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene -5-ylidene] propyl} piperidin-3-ol.

Stage 1

The azido alcohol (Example 476, step 3) (0.050 g, 0.2 mmol) protected by a butoxycarbonyl group was dissolved in methylene chloride (2 ml), cooled to 0 ° C and trifluoroacetic acid (0.2 ml) was added. The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between an aqueous solution of NaHCO ₃ and CH ₂ Cl ₂ . The aqueous solution was extracted (3 times) and then washed with brine and dried over sodium sulfate. The residue is used in the next step without further purification.

Stage 2

To a solution of azidopiperidine (0.025 g, 0.1 mmol) in isopropanol (1.0 ml) was added 2,6-lutidine (0.012 ml, 0.1 mmol) and the catalyst was potassium iodide. This mixture is heated to 80 ° C and treated with 2- [5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol ( 0.025 g, 0.067 mmol), which is added in parts over 2 hours. Then, the solution is stirred at 80 ° C. for another 14 hours. The reaction mixture is concentrated in vacuo, then purified in a NaClade system (100% ethyl acetate) to obtain the above the title compound (0.013 g, 36%).

¹ H NMR (SOS1 ₃₎ δ: 1,56 (6H, s), 1.65 (d, 1H), 1.85 (s, 1H), 2.13 (s, 1H), 2,36- 2.94 (m, 8H), 3.51 (s, 1H), 5.24 (br s, 2H), 6.16 (t, 1H), 6.80 (d, 1H), 6.93 (d, 1H), 7.21-7.46 (m, 8H), 7.58 (d, 1H), 8.42 (d, 1H). EMC t / ζ: 546 (M + 1), retention time 1.71.

Example 478

No. [4- (4-Chlorophenyl) -4-hydroxy-1- {3- [7- (hydroxy-1-methylethyl) -11Н-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5- ylidene] propyl} piperidin-3-yl) propionamide.

Stage 1

3-amino-4- (4-chlorophenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester.

3-Azido-4- (4-chlorophenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (0.67 g, 0.2 mmol) is dissolved in diethyl ether (2 ml), cooled to 0 ° C and lithium aluminum hydride (0.280 ml, 0.23 mmol) is added. The solution was allowed to warm to room temperature and stirred for 2 hours. A white precipitate formed. The reaction was stopped by adding water and the mixture was extracted 3 times with diethyl ether. The organic layers were collected together, dried over magnesium sulfate and evaporated in vacuo to give an amino alcohol, which was used directly in the next reaction.

Stage 2

4- (4-Chlorophenyl) -4-hydroxy 3-propionylaminopiperidin-1-carboxylic acid tert-butyl ester.

3-amino-4- (4-chlorophenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (0.116 g, 0.35 mmol) is dissolved in chloromethylene. Propionyl chloride (0.034 ml, 0.39 mmol) and triethylamine (0.109 ml, 0.78 mmol) are added and the solution is stirred for 24 hours at room temperature. The reaction mixture was concentrated in vacuo, then purified by flash chromatography (from 30% ethyl acetate / 70% hexane to 50% ethyl acetate / 50% hexane) in a Vu1ade system to give the title compound (0.133 g, 97%).

¹ H NMR spectrum (SPS1 ₃ ) δ: 0.87 (t, 3H), 1.44 (s, 9H), 1.78-1.95 (m, 3H), 2.20 (dt, 1H), 3.24 (t, 1H), 3.50 (d, 1H), 3.90 (t, 1H), 4.08 (q, 2H), 4.28 (d, 1H), 5.48 (broad d, 1H), 7.26 (d, 2H), 7.37 (d, 2H). EMC t / ζ: 383 (M + 1), retention time 2.21.

Stage 3.

Protected with butoxycarbonyl group, 3-Y-acyl alcohol (0.180 g, 0.47 mmol) was dissolved in methylene chloride (5 ml), cooled to 0 ° C and trifluoroacetic acid (2 ml) was added. The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between NaHCO ₃ solution and methylene chloride. The aqueous solution was extracted (3 times), then washed with brine and dried over sodium sulfate. The residue is then transferred to the next step without further purification.

Stage 4.

To a solution of No. [4- (4-chlorophenyl) -4-hydroxypiperidin-3-yl] propionamide (0.133 g, 0.47 mmol) in isopropanol (5.0 ml) was added 2.6-lutidine (0.055 ml, 0, 47 mmol) and the catalyst is potassium iodide. This

- 85 008060 the mixture is heated to a temperature of 80 ° C, treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.176 g, 0.35 mmol), which is added in parts over 2 hours. Then the solution is stirred at 80 ° C. for another 14 hours. The reaction mixture is concentrated in vacuo, then purified by chromatography (HPLC, acetonitrile / water / formic acid) to give the title compound as a white salt of formic acid (0.085 g, 27%).

'11 NMR spectrum (СОС1 ₃ ) δ: 0.780 (t, 3H), 1.55 (s, 6H), 1.90 (m, 3H), 2.60 (m, 2H), 2.92-3, 28 (m, 6H), 4.50 (d, 1H), 5.26 (br.s, 2H), 6.00 (t, 1H), 6.82 (d, 1H), 7.22- 7.37 (m, 6H), 7.44 (s, 1H), 7.56 (d, 1H), 8.20 (d, 1H), 8.34 (s, 1H), 8.47 (d , 1H). EMC m / ζ: 576 (M + 1), retention time 1.43.

Example 479. trans-4- (4-Chlorophenyl) -4-hydroxy-1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1aza-dibenzo [a, b] cycloheptene -5-ylidene] propyl} piperidin-3-carbonitrile.

Stage 1

cis and trans-4- (4-chlorophenyl) -3-cyano-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester.

Acetone cyanohydrin (0.917 ml, 10 mmol) was added to 22 ml of tetrahydrofuran and the solution was cooled to 0 ° C. Lithium hydride (0.077 g, 9.7 mmol) is added to the solution in several portions over 20 minutes and then stirred at room temperature for 1 hour. 6- (4chlorophenyl) -7-oxa-3-aza-bicyclo tert-butyl ether [4.1.0] heptane-3-carboxylic acid (1.00 g, 3.2 mmol) was dissolved in THF (10 ml), added to the above solution and heated to boiling for 7.5 hours. The reaction mixture was diluted with water and extracted (3 times). The reaction mixture was washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified in a Vu1ade G1a8k system (from 90% hexane / 10% ethyl acetate to 80% hexane / 20% ethyl acetate to 70% hexane / 30% ethyl acetate) to obtain two compounds. The more easily eluting isomer is the tis-butyl ester of cis- (4chlorophenyl) -3-cyano-4-hydroxypiperidin-1-carboxylic acid (0.210 g, 19%).

'11 NMR spectrum (СОС1 ₃ ) δ: 1.35 (s, 9H), 1.59-1.86 (m, 2H), 2.83-3.30 (m, 3H), 3.88 (w) ss, 2H), 4.16 (m, 1H), 7.23 (d, 2H), 7.33 (d, 2H).

The second eluting isomer is trans-4- (4-chlorophenyl) -3-cyano-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (0.560 g, 51%).

'11 (ΟΌΟ1 ₃ ) δ NMR spectrum: δ 1.43 (s, 9H), 1.70 (d, 1H), 2.47 (dt, 1H), 2.7 6 (br s, 2H), 3.10-3.54 (m, 2H), 4.18 (m, 2H), 7.31 (d, 2H), 7.44 (d, 2H).

Stage 2

trans-4- (4-chlorophenyl) -3-cyano-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (0.210 g, 0.62 mmol) is dissolved in methylene chloride (5 ml), cooled to 0 ° C and trifluoroacetic acid (1.0 ml) was added. The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between NaHCO ₃ solution and methylene chloride. The aqueous solution was extracted (3 times), then washed with brine and dried over sodium sulfate. The residue is transferred to the next step without further purification.

Stage 3.

To a solution of trans-3-cyano-4-hydroxypiperidine (0.137 g, 0.58 mmol) in isopropanol (5.7 ml) was added 2.6-lutidine (0.067 ml, 0.58 mmol) and the catalyst was potassium iodide. This mixture is heated to a temperature of 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.108 g, 0.29 mmol) added in portions over 2 hours. Then the solution was stirred at 80 ° C for another 14 hours. The reaction mixture was concentrated in vacuo, then purified in a Vu1ade system by flash chromatography (from 50% ethyl acetate / 50% hexane to 75% ethyl acetate / 25% hexane) to give the title compound (0.040 g, 26%).

'11 (ΟΌΟ1 ₃ ) δ NMR spectrum: 1.50 (d, 6H), 1.63 (s, 1H), 1.78 (d, 1H), 2.08 (s, 1H), 2.35 ( m, 2H), 2.51-3.03 (m, 6H), 3.48 (s, 1H), 5.29 (br.s, 2H), 6.42 (t, 1H), 6, 79 (d, 1H), 7.15 (d, 1H), 7.28 (m, 1H), 7.37 (d, 2H), 7.50 (d, 2H), 7.55 (s, 1H ), 7.58 (d, 1H), 8.46 (d, 1H). EMC t / ζ: 530.2 (M + 1), retention time 1.50.

Example 480. cis-4- (4-Chlorophenyl) -4-hydroxy-1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene -5-ylidene] propyl} piperidin-3-carbonitrile.

Stage 1

cis-4- (4-chlorophenyl) -3-cyano-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (0.210 g, 0.62 mmol) was dissolved in methylene chloride (3 ml), cooled to 0 ° C, and trifluoroacetic acid (1 ml) was added. The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between NaHCO ₃ solution and methylene chloride. The aqueous solution was extracted (3 times), then washed with brine and dried over sodium sulfate. The residue is transferred to the next step without further purification.

Stage 2

To a solution of cis-3-cyano-4-hydroxypiperidine (0.125 g, 0.53 mmol) in isopropanol (5.8 ml) was added 2.6-lutidine (0.061 ml, 0.53 mmol) and the catalyst was potassium iodide. This mixture is heated to a temperature of 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2 -ol (0.100 g, 0.26 mmol) added in portions over 2 hours.

- 86 008060 was stirred at 80 ° C for another 14 hours. The reaction mixture was concentrated in vacuo, then purified in a ΒίοΙη ^ system by flash chromatography (from 50% ethyl acetate / 50% hexane to 75% ethyl acetate / 25% hexane and up to 100 % ethyl acetate) to obtain the title compound (0.050 g, 35%).

'11 NMR spectrum (CBC1 ₃ ) δ: 1.53 (d, 1H), 1.57 (s, 6H), 1.74 (d, 1H), 1.89 (s, 1H), 2.35- 2.68 (m, 7H), 2.88 (d, 1H), 3.11 (d, 1H), 5.30 (br.s, 2H), 6.11 (t, 1H), 6, 82 (d, 1H), 7.23-7.45 (m, 7H), 7.57 (d, 1H), 8.48 (d, 1H). EMC m / ζ: 530.2 (M + 1), retention time 1.58.

Example 481. 4- (4-Chlorophenyl) -4-hydroxy-1- {3- [7- (hydroxy-1-methylethyl) -11H-10oxa-1-aza-dibenzo [a, th] cycloheptene-5 methyl ester -ilidene] propyl} -3-methylpiperidin-3-carboxylic acid.

Stage 1

4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ether 3-methyl ester

Methyl 4-oxo-3-piperidine carboxylate hydrochloride (2.6 g, 13.4 mmol) and triethylamine are added to a solution of di-tert-butyl dicarbonate (3.08 g, 14.1 mmol) in methylene chloride (134 ml). (3.84 ml, 27.5 mmol). The solution was stirred at room temperature for 12 hours. Gas evolution was observed. The reaction is interrupted by adding 1N. hydrochloric acid, the mixture is extracted 3 times with methylene chloride. The organic layers were collected together, dried over magnesium sulfate and evaporated in vacuo. The residue was purified to give the title compound as a colorless oil.

'11 NMR spectrum (СОС1 ₃ ) δ: 1.46 (s, 9H), 2.36 (t, 2H), 3.55 (t, 2H), 3.77 (s, 4H), 4.04 ( s, 2H).

Stage 2

3-methyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ether 3-methyl ester.

4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ether 3-methyl ester (2.00 g, 6.8 mmol) was dissolved in tetrahydrofuran and cooled to 0 ° C. NaH (0.300 g, 12.5 mmol) is added in portions to this solution over 1 hour. Hydrogen gas is released upon addition. The reaction mixture was allowed to stir for 30 minutes at 0 ° C, then methyl iodide (0.422 ml, 6.8 mmol) was added and the mixture was allowed to stir at room temperature for 13 hours. The reaction was stopped by adding ice water and the mixture was concentrated. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3 times), the organic layers were collected together, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (10% ethyl acetate / 90% hexane) in the Bu1ade system to obtain the title compound (1.1 g, 52%).

'11 NMR spectrum (SPS1 ₃ ) δ: 1.29 (s, 3H), 1.47 (s, 9H), 2.47 (dt, 1H), 2.76 (m, 1H), 3.07 ( d, 1H), 3.33 (dt, 1H), 3.71 (s, 3H), 4.11 (m, 1H), 4.50 (d, 1H).

Stage 3.

4-(4-chlorophenyl) -4-hydroxy-3-methylpiperidin-1,3-dicarboxylic acid 1-tert-butyl ether 3-methyl ester.

1-tert-Butyl ether, 3-methyl-3-methyl-4-oxopiperidin-1,3-dicarboxylic acid methyl ester (1.1 g, 4.07 mmol) was dissolved in tetrahydrofuran and cooled to 0 ° C. 4chlorophenylmagnesium bromide (12.2 ml, 12.2 mmol) was added to the solution, dropwise for approximately 1/2 hour and then stirred at 0 ° C for 1 hour. The reaction was quenched by adding a saturated aqueous solution of Ο ₄ Ο, and the mixture was extracted ethyl acetate (3 times). The organic layers were collected, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified using flash chromatography (10% ethyl acetate / 90% hexane to 20% ethyl acetate / 80% hexane) in a 13ο13 ^ system to obtain the title compound (1, 1 g, 70%).

'11 NMR spectrum (COS1 ₃ ) δ: 1.17 (s, 3H), 1.44 (s, 9H), 1.55 (m, 1H), 1.96 (d, 1H), 3.00 ( m, 1H), 3.37 (m, 2H), 3.53 (s, 3H), 3.91 (m, 2H), 4.07 (d, 1H), 7.27 (d, 2H), 7.43 (d, 2H). EMC t / ζ: 384.1 (M + 1), retention time 2.95.

Stage 4.

1-tert-Butyl ether 3- methyl ester of 4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidin-1,3-dicarboxylic acid (1.1 g, 2.87 mmol) was dissolved in methylene chloride (35 ml), cooled to 0 ° C. and trifluoroacetic acid (8 ml) was added dropwise. The solution was allowed to stir at 0 ° C. for 1 hour. The solvent was evaporated in vacuo and the residue was partitioned between 1N. solution No. 1OH and methylene chloride. The aqueous solution was extracted (3 times), then washed with brine and dried over sodium sulfate. The residue is transferred to the next step without further purification.

Stage 5.

To a solution of 4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidin-3-carboxylic acid methyl ester (0.71 g, 2.5 mmol) in 25 ml of acetonitrile / water (8: 2) was added To ₂ CO ₃ (1.40 g, 10.0 mmol) and 2- [5- (3 bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, th] cyclohepten-7-yl] propane -2-ol (0.937 g, 2.5 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers are collected together, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified using flash chromatography in a 13ο13 ^ system (from 50% ethyl acetate / 50% hexane to 75% ethyl acetate / 25% hexane and up to 100% ethyl acetate), receiving the title compound (0.835

- 87 008060 g, 58%).

Nuclear Magnetic Resonance Spectrum Ή (SBS1 ₃ ) δ: 1.30 (s, 3Η), 1.57 (s, 6H), 1.76 (d, 1Η), 2.24-2.53 (m, 7H), 2 65 (d, 1H), 2.86 (d, 2H), 3.44 (s, 3Η), 5.30 (br.s, 2H), 6.16 (d, 1H), 6.82 (d, 1H), 7.26 (m, 4H), 7.45 (s, 1H), 7.53 (d, 1Η), 7.58 (d, 1Η), 8.49 (d, 1H) . EMC t / ζ: 577 (M + 1), retention time 1.50.

Example 482. 4- (4-Chlorophenyl) -3-hydroxymethyl-1- {3- [7- (hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene ] propyl} -3-methylpiperidin-4-ol.

4- (4-Chlorophenyl) -4-hydroxy-1- {3- [7- (hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene methyl ester] propyl} -3-methylpiperidin-3-carboxylic acid (0.250 g, 0.43 mmol) was dissolved in tetrahydrofuran and cooled to 0 ° C. Lithium aluminum hydride (1.3 ml, 1.3 mmol) was added dropwise to this solution, and the reaction mixture was allowed to stir at 0 ° C. for 3 hours. The reaction was quenched by the addition of ice water slowly and the mixture was diluted with ethyl acetate. The reaction mixture was allowed to stir at room temperature for 45 minutes to decompose all aluminum complex compounds. The organic layers were separated and the aqueous layer was further extracted (2 times). All organic layers were collected, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography in a Vu1ade system (from 50% ethyl acetate / 50% hexane to 75% ethyl acetate / 25% hexane) to give the title compound ( 0.103 g, 43%).

¹ H NMR spectrum (SPS1 ₃ ) δ: 0.53 (s, 3Η), 1.55 (d, 6H), 1.62 (m, 1H), 2.40 (q, 2H), 2.55 ( q, 3Η), 2,722.86 (m, 10 4H), 3.19 (dd, 1H), 3.24 (d, 1H), 3.41 (d, 1H), 5.33 (br.s. , 2H), 6.17 (t, 1H), 6.44 (br.s, 1Η), 6.79 (d, 1H), 7.17 (d, 1H), 7.26-7.59 (m, 7H), 8.50 (d, 1H). EMC t / ζ: 549 (M + 1), retention time 1.39.

Example 483-1, example 483-2.

The racemic mixture of 4- (4-chlorophenyl) -3-hydroxymethyl-1- {3- [7- (hydroxy-1-methylethyl) -11H-10oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene] propyl} -3-methylpiperidin-4-ol is cleaved using a chromatographic column Syga1Pak ΆΌ, eluted with 5/5/90 methanol / ethanol / hexane. The first peak represents the more active enantiomer, example 483-1, the second peak refers to the less active enantiomer, example 483-2.

Example 484. 4- (4-Chlorophenyl) -3-ethoxymethyl-1- {3 [7- (hydroxy-1-methylethyl) -1Sh-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5- ylidene] propyl} -3-methylpiperidin-4-ol.

Stage 1

Sodium hydride (Ν · 1Η) is added to a solution of 4- (4-chlorophenyl) -4-hydroxy-3-hydroxymethyl-3-methylpiperidin1-carboxylic acid tert-butyl ester (0.270 g, 0.76 mmol) in 4.8 ml THF 0.075 g, 1.9 mmol) and the mixture was stirred for 20 minutes at room temperature. Ethyl iodide (0.066 ml, 0.83 mmol) was added and the solution was heated to 50 ° C. for 1 h. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate (3 times). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography in a Vu1ade system (from 10% ethyl acetate / 90% hexane to 20% ethyl acetate / 80% hexane and up to 30% ethyl acetate / 70% hexane) getting the title compound (0.110 g, 3 37%).

NMR spectrum Ή (SPS1 ₃ ) δ: 0.79 (s, 3Η), 1.10 (t, 3Η), 1.26 (s, 1H), 1.45 (s, 9H), 1.84 (s, 1H ), 2.74 (m, 2H), 2.98 (d, 1H), 3.18 (m, 1Η), 3.28 (q, 2H), 3.97 (d, 2H), 7.26 -7.39 (m, 4H).

Stage 2

4- (4-Chlorophenyl) -3-ethoxymethyl-4-hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.052 g, 0.14 mmol) was dissolved in methylene chloride (3 ml), the solution was cooled to 0 ° C and trifluoroacetic acid (1 ml) was added. The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo and used directly in the next reaction.

Stage 3.

To a solution of 4- (4-chlorophenyl) -3-ethoxymethyl-3-methylpiperidin-4-ol (0.038 g, 0.13 mmol) in 1.3 ml of a mixture of acetonitrile / water (8: 2) was added To ₂ CO ₃ ( 0.075 g, 0.53 mmol) and 2- [5- (3-bromopropylidene) -5.11 dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol ( 0.050 g, 0.13 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers were collected, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (75% ethyl acetate / 25% hexane) in the Vu1ade system to give the title compound in 65% yield.

Я NMR spectrum (SPS1 ₃ ) δ: 0.81 (s, 3Η), 0.98 (t, 3Η), 1.58 (s, 6H), 1.84 (s, 1H), 2.31-2 49 (m, 5H), 2.58 (d, 1H), 2.67 (s, 1H), 2.77 (d, 2H), 3.26 (q, 2H), 3.65 (d, 2H), 5.33 (br s, 2H), 6.16 (t, 1Η), 6.82 (d, 1H), 7.22-7.36 (m, 7H), 7.45 ( d, 1H); 7.60 (d, 1H). EMC t / ζ: 577 (M + 1), retention time 1.58.

Example 485. Ethyl ether (4- (4-chlorophenyl) -4-hydroxy-1- {3 [7- (1-hydroxy-1-methylethyl) -1Sh-10oxa-1-aza-dibenzo [a, b] cycloheptene -5-ylidene] propyl} -3-methylpiperidin-3-ylmethoxy) acetic acid.

Stage 1

To a solution of 4- (4-chlorophenyl) -4-hydroxy-3-hydroxymethyl-3-methylpiperidine tert-butyl ether

- 88 008060

1-carboxylic acid (0.080 g, 0.22 mmol) of THF (2.2 ml) was added No. 1H (0.031 g, 0.78 mmol) and stirred for 20 min at room temperature. Ethyl bromoacetate (0.027 ml, 0.30 mmol) was added and the solution was heated to 50 ° C. for 1 h. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate (3 times). The organic layers were collected together, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography in a Vu1ads system (from 10% ethyl acetate / 90% hexane to 20% ethyl acetate / 80% hexane) to give ethyl ether (0.050 g , fifty %).

Я NMR spectrum (SPS1 ₃ ) δ: 0.85 (br s, 3H), 1.22 (t, 3H), 1.45 (s, 9H), 1.66 (s, 1H), 2, 64-3.39 (m, 6H), 3.96 (d, 2H), 4.12 (q, 2H), 7.26-7.38 (m, 4H).

Stage 2

4- (4-Chlorophenyl) -3-ethoxycarbonylmethoxymethyl-4-hydroxy-3-methylpiperidin-1-carboxylic acid tert-butyl ester (0.060 g, 0.14 mmol) is dissolved in methylene chloride (3 ml), cooled to 0 ° C and trifluoroacetic acid (1 ml) was added. The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo and used directly in the next reaction.

Stage 3.

To a solution of 4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidinyl-3-methoxyacetic acid ethyl ester (0.046 g, 0.13 mmol) in 1.3 ml of an acetonitrile / water mixture (8: 2) was added K ₂ CO ₃ (0.075 g, 0.53 mmol) and 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, 6] cyclohepten-7-yl] propane -2ol (0.051 g, 0.13 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water and extracted with ethyl acetate (3 times). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (75% ethyl acetate / 25% hexane) in a Vu1ads system to give the title compound in 54% yield.

Я NMR spectrum (SPS1 ₃ ) δ: 0.86 (s, 3H), 1.16 (s, 3H), 1.57 (s, 6H), 1.78 (s, 1H), 2.37 (t , 1H), 2.46-2.71 (m, 5H), 2.81 (t, 1H), 3.80 (d, 2H), 3.97 (d, 2H), 4.06 (q, 2H), 5.30 (br s, 2H), 6.18 (t, 1H), 6.82 (d, 1H), 7.22 (dd, 1H), 7.26-7.36 ( m, 7H), 7.47 (d, 1H), 7.60 (d, 1H). EMC t / ζ: 635 (M + 1), retention time 1.62.

Example 486. 4- (4-Chlorophenyl) -3- (2-diethylaminoethoxymethyl) -4-hydroxy-3methylpiperidine-1-carboxylic acid tert-butyl ester.

Stage 1

To a solution of 4- (4-chlorophenyl) -4-hydroxy-3-hydroxymethyl-3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.071 g, 0.15 mmol) THF (1.5 ml) was added N34 (0.016 g, 0.39 mmol) and stirred for 20 min at room temperature. 2-Bromo- ^ diethylethylamine hydrobromide was added (0.044 ml, 0.17 mol) and the solution was heated to 50 ° C for 1 h. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate (3 times). The organic layers were collected, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (10% ethyl acetate / 90% hexane to 20% ethyl acetate / 80% hexane) in a Vu1ads system to give diethylamine (0.035 g).

Stage 2

4- (4-Chlorophenyl) -3- (2-diethylaminoethoxymethyl) -4-hydroxy-3methylpiperidin-1-carboxylic acid tert-butyl ester (0.035 g, 0.62 mmol) in dichloromethane (3 ml) was dissolved, cooled to 0 ° C and trifluoroacetic acid (1 ml) was added. The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo and the substance was used directly in the next reaction.

Stage 3.

To a solution of 4- (4-chlorophenyl) -3- (2-diethylaminoethoxymethyl) -3-methylpiperidin-4-ol in 3.2 ml of a mixture of acetonitrile / water (8: 2), K ₂ CO ₃ and 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1azadibenzo [a, 6] cyclohepten-7-yl] propan-2-ol. The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers are collected, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography in a Vu1ads system (gradient from 5% methanol / 95% methylene chloride to 10% methanol / 90% methylene chloride and up to 15% methanol / 85% methylene chloride) to give the title compound.

Nuclear Magnetic Resonance Spectrum Ή (SHS1 ₃ ) δ: 0.50 (s, 3H), 0.97 (t, 6H), 1.52 (s, 6H), 2.40-2.66 (m, 12H), 3.16 -3.30 (m, 6H), 5.32 (br s, 2H), 6.06 (t, 1H), 6.80 (t, 1H), 7.20 (dd, 1H), 7.29 (dd, 1H), 7.29-7.31 (m, 6H), 7.58 (d, 2H), 8.51 (d, 1H). EMC t / ζ: 648 (M + 1), retention time 1.19.

Example 487. 2- [5- (3- {4 - [(4-Chlorobenzyl) ethylamino] piperidin-1-yl} propylidene) -5,11-dihydro-10oxa-1-aza-dibenzo [a, 6] cycloheptene -7-yl] propan-2-ol.

Stage 1

4- (4-Chlorobenzylamino) piperidine-1-carboxylic acid tert-butyl ester.

4-amino-1-N-butoxycarbonylpiperidine (1.80 g, 8.9 mmol) and 4chlorobenzyl bromide (1.84 g, 8.9 mmol) are dissolved in methylene chloride and triethylamine (1.25 ml, 8.9 mmol) is added. . The solution is left

- 89 008060 stirred for 14 hours at room temperature, evaporated in vacuo and partitioned between ether and 1-normal solution of ΝαΝ. The aqueous layer was removed, the ether layer was washed with brine and dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (5% methanol / 95% methylene chloride) in a Vu1ade system to give the title compound (0.800 g, 27 %).

Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ ) δ: 1.26 (m, 1Н), 1.44 (s, 9Н), 1.83 (d, 2Н), 2.63 (t, 1Н), 2.78 (t , 2H), 3.46 (s, 2H), 3.78 (s, 2H), 4.00 (br s, 2H), 7.26 (br s, 4H). EMC t / ζ: 325.1 (M + 1), retention time 1.86.

Stage 2

(4-Chlorobenzyl) ethylamino] piperidine-1-carboxylic acid tert-butyl ester (0.500 g 1.4 mmol) is dissolved in 100 ml of a solution of Ηί, Ί in dioxane (4 mol / l). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as a hydrochloride salt.

Stage 3.

(4-Chlorobenzyl) ethylpiperidinyl-4-amine tert-butyl ether.

4- (4-Chlorobenzylamino) piperidine-1-carboxylic acid tert-butyl ester is dissolved in methylene chloride and acetaldehyde (0.678 g, 3.2 mmol), sodium triacetate borohydride (0.163 g, 3.7 mmol) and 1 drop of acetic acid are added . The solution was stirred in a sealed vessel for 10 hours. The reaction mixture was washed with 1N. ΝαΟΗ solution, brine and dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (15% ethyl acetate / 85% hexane) in the Vu1ade system to give the title compound (0.350 g, 40%).

Stage 4.

To a solution of (4-chlorobenzyl) ethylpiperidin-4-yl-amine hydrochloride (0.200 g, 0.83 mmol) in 8 ml of an acetonitrile / water mixture are added To ₂ CO ₃ (0.476 g, 3.4 mmol) and 2- [5 - (3-bromopropylidene) -5,11-dihydro-10oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.282 g, 7.5 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic scrap was collected, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (from 5% methanol / 95% methylene chloride to 10% methanol / 90% methylene chloride) in a Vu1ade system to give the title compound (0.240 g, yield 60%).

Nuclear Magnetic Resonance Spectrum Ή (ΟΌΟ1 ₃ ) δ: 0.988 (t, 3 с), 1.57 (s, 6H), 1.67 (d, 2H), 1.85 (t, 2H), 2.32-2.46 (m, 5H), 2.51 (q, 2H), 5 2.84 (d, 2H), 3.47 (s, 2H), 3.56 (s, 2H), 5.29 (br s ., 2H), 6.07 (t, 1H), 6.80 (d, 1Η), 7.21-7.28 (m, 6H), 7.42 (s, 1H), 7.56 (d, 1H) ), 8.48 (d, 1H). EMC t / ζ: 546 (M + 1), retention time 1.87.

Example 488. 1- {3- [7- (1-Hydroxy-1-methylethyl) -1Sh-10-oxa-1-aza-dibenzo [a, b] cyclohepten-5-ylidene] propyl} -4-phenylpiperidine 4-ol

To a solution of 4-phenylpiperidin-4-ol (0.212 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.240 ml, 2.1 mmol) and the catalyst was potassium iodide. This mixture is heated to 80 ° C and treated with 2- [5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol ( 0.224 g, 0.6 mmol), which is added in parts over 1 hour. Then the solution is stirred at 80 ° C for another 14 hours. The reaction mixture is concentrated in vacuo, then purified by flash chromatography 18CO (15% methanol / 85% methylene chloride) to give the title compound (0.140 g, 50%).

Nuclear Magnetic Resonance Spectrum Ή (1,11 ₃ ) δ: 1.12 (t, 3Η), 1.57 (s, 6H), 2.67-2.80 (m, 4H), 1.95-2.11 (m, 2H), 2.34-2.41 (m, 2H), 2.43-2.54 (m, 2H), 2.88 (d, 2H), 3.22 (q, 2H), 3.43 (m, 1H), 5.28 (br s, 2H), 6.12 (t, 1Η), 6.60 (d, 2H), 6.80 (d, 1H), 7.13 (d , 2H), 7.21-7.30 (m, 2H), 7.45 (s, 1H), 7.56 (d, 1H), 8.48 (dd, 1Η). EMC t / ζ: 534 (M + 1), retention time 2.47.

Example 489. 4- (2-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -1 Ш-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} piperidin-4-ol.

Stage 1

0.238 g of magnesium (9.8 mmol) and an iodide catalyst at room temperature for 2 hours are added to a solution of 1-bromo-2-chlorobenzene (0.97 ml, 8.3 mmol) in ether. This mixture is cooled to 0 ° C, treated with 4-oxopiperidin-1-carboxylic acid tert-butyl ether (1.5 g, 7.5 mmol) dissolved in ether (8 ml), and slowly added to the reaction mixture. This reaction mixture was heated at the boiling point for 1 hour. The reaction was quenched by the addition of a solution of ammonium chloride, and the aqueous phase was extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified in an 18Co Pa811 system (75% hexane / 25% ethyl acetate) to give an alcohol (0.600 g, 38%).

Stage 2

4- (2-Chlorophenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (0.600 g, 1.9 mmol) was dissolved in methylene chloride (19 ml), cooled to 0 ° C and trifluoroacetic acid (4 ml) was added ) The solution was allowed to stir at 0 ° C for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between an aqueous solution of ΝαΗί.Ό ₃ and methylene chloride.

- 90 008060

The aqueous solution was extracted (3 times) and then washed with brine and dried over sodium sulfate. The residue is transferred to the next step without further purification.

Stage 3.

To a solution of 4- (2-chlorophenyl) -piperidin-4-ol (0.210 g, 1.0 mmol) in isopropanol was added 2.6 lutidine (0.31 ml, 2.7 mmol) and the catalyst was potassium iodide. This mixture is heated at 80 ° C and treated with 2 [5- (3-bromo-propylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2- ol (0.287 g, 0.77 mmol), which is added in portions over 1 h. Then the solution is stirred at 80 ° C for another 14 h. The reaction mixture is concentrated in vacuo, then purified in a PSO system by flash chromatography ( 15% methanol / 85% methylene chloride) to give the title compound (0.200 g, 52%).

'11 NMR spectrum (SPS1 ₃ ) δ: 1.55 (s, 6H), 1.70 (d, 2H), 2.10-2.30 (m, 2H), 2.36-2.54 (m , 2H), 2.57-2.92 (m, 6H), 5.30 (br s, 2H), 6.16 (t, 1H), 6.77 (d, 1H), 7.16 -7.36 (m, 5H), 7.48 (s, 2H), 7.58 (d, 1H), 8.37 (dd, 1H). EMC t / ζ: 505 (M + 1), retention time 1.48.

Example 490. 4- (4-Chloro-2-methylphenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene -5-ylidene] propyl} piperidin-4-ol.

Stage 1

To a solution of 4-chloro-2-methylphenylmagnesium bromide (15 ml, 7.5 mmol) in ether, cooled to 0 ° C., 4-oxopiperidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) was added ) within 30 minutes The resulting solution was heated at the boiling point for 1 h. The reaction was quenched by adding a solution of ammonium chloride, and the aqueous phase was extracted with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is purified in the PSO Duck system! (75% hexane / 25% ethyl acetate) to obtain the indicated alcohol (0.534 g, 33%).

Stage 2

4- (4-Chloro-2-methyl-phenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (0.534 g, 1.6 mmol) was dissolved in methylene chloride (16 ml), cooled to 0 ° C and trifluoroacetic acid was added acid (3 ml). The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between NaHCO ₃ solution and methylene chloride. The aqueous solution was extracted (3 times), then washed with brine and dried over sodium sulfate. The residue is transferred to the next step without further purification.

Stage 3.

To a solution of 4- (4-chloro-2-methylphenyl) piperidin-4-ol (0.160 g, 0.71 mmol) in isopropanol was added 2,6-lutidine (0.24 ml, 2.1 mmol) and the iodide catalyst potassium. This mixture is heated to 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2ol (0.221 g 0.59 mmol), which is added in parts over 1 hour. Then the solution is stirred at 80 ° C for another 14 hours. The reaction mixture is concentrated in vacuo, then purified in a GSO system by flash chromatography (15% methanol / 85% methylene chloride) to give the title compound (0.130 g, 36%).

'11 NMR spectrum (SPS1 ₃ ) δ: 1.57 (s, 6H), 1.92 (d, 2H), 2.30 (t, 2H), 2.49 (s 3H), 2.48-2 63 (m, 2H), 2,743.11 (m, 6H), 3.40 (s, 1H), 5.21 (br s, 2H), 6.09 (t, 1H), 6.75 (d, 1H), 7.06 (d, 1H), 7.08 (s, 1H), 7.20 (d, 2H), 7.227.36 (m, 1H), 7.57 (d, 1H) 8.36 (dd, 1H). EMC t / ζ: 519 (M + 1), retention time 1.61.

Example 491. 4- (3,4-Dichlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene ] propyl} piperidin-4-ol.

Stage 1

To a solution of 3,4-dichlorophenylmagnesium bromide (7.5 ml, 7.5 mmol) in ether, cooled to 0 ° C., 4-oxopiperidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) is added ) within 30 minutes The resulting solution was heated at the boiling point for 1 h. The reaction was quenched by adding a solution of ammonium chloride and the aqueous phase was extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is purified in the PSO Duck system! (75% hexane / 25% ethyl acetate) to obtain the indicated alcohol (0.630 g, 36%).

Stage 2

4- (3,4-Dichlorophenyl) -4-hydroxy-sheridin-1-carboxylic acid tert-butyl ester (0.630 g, 1.8 mmol) was dissolved in methylene chloride, cooled to 0 ° C and trifluoroacetic acid (3 ml) was added. The solution was allowed to stir at 0 ° C. for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between NaHCO ₃ solution and methylene chloride. The aqueous solution was extracted (3 times) and then washed with brine and dried over sodium sulfate. The residue is transferred to the next step without further purification.

Stage 3.

To a solution of 4- (4-chloro-2-methylphenyl) piperidin-4-ol (0.140 g, 0.57 mmol) in isopropanol was added 2,6-lutidine (0.23 ml, 2.0 mmol) and the iodide catalyst potassium. This mixture is heated to 80 ° C, treated with 2- [5- (3-bromopropylpden) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2ol (0.213 g 0.57 mmol), which is added in parts over 1 hour. Then the solution is stirred

- 91 008060 at a temperature of 80 ° C for another 14 hours. The reaction mixture was concentrated in vacuo, then purified in an LCO system by flash chromatography (15% methanol / 85% methylene chloride) to give the title compound (0.110 g, 36% )

'11 NMR spectrum (COC1 ₃ ) δ: 1.55 (s, 6H), 1.70 (d, 2H), 2.10-2.30 (m, 2H), 2.45 (m, 2H), 2.57-2.92 (m, 6H), 5.30 (br s, 2H), 6.16 (t, 1H), 6.7-7.15 (d, 1H), 7.16 -7.40 (m, 4H), 7.08 (s, 1H), 7.57 (s, 2H), 8.36 (dd, 1H). EMC t / ζ: 539 (Μ + 1), retention time 1.72.

Example 492. 4- (4-Chloro-3-nitrophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b) cycloheptene -5-ylidene] propyl} piperidin-4-ol.

Stage 1

4- (4-chlorophenyl) piperidin-4-ol is added to fuming nitric acid (20 ml) at 0 ° C and stirred for 5 minutes. The solution was carefully neutralized with sodium carbonate and filtered. The resulting solid was triturated with water and then filtered to give a yellow solid. This solid was dissolved in a saturated NaHCO ₃ solution and extracted with ethyl acetate (3 times). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo to give the 4-chloro-3-nitro compound (1.1 g, 18%).

Stage 2

To a solution of 4- (4-chloro-3-nitrophenyl) piperidin-4-ol (0.295 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.225 ml, 2.1 mmol) and the catalyst was potassium iodide. This mixture is heated to 80 ° C, treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol ( 0.224 g, 0.6 mmol), which is added in parts over 1 hour. Then the solution is stirred at 80 ° C for another 14 hours. The reaction mixture is concentrated in vacuo, then purified in a LCO system by flash chromatography (15% methanol / 85% methylene chloride) to give the title compound (0.100 g, 30%).

'11 NMR spectrum (СОС1 ₃ ) δ: 1.53 (s, 6Н), 1.70 (d, 2Н), 1.81-2.18 (m, 4Н), 2.3-2.44 (m) 4H), 2.56 (t, 2H), 2.69 (d, 2H), 5.32 (br s, 2H), 6.16 (t, 1H), 6.81 (d, 1H) ), 7.28 (t, 2H), 7.48 (t, 2H), 7.58 (t, 2H), 8.06 (s 1H). EMC t / ζ: 550 (Μ + 1), retention time 1.51.

Example 493. 2- [5- (3- {4 - [(4-Chlorophenyl) ethylamino] piperidin-1-yl} propylidene) -5,11-dihydro-10oxa-1-aza-dibenzo [a, b] cycloheptene -7-yl] propan-2-ol.

Stage 1

4-aminopiperidin-1-carboxylic acid tert-butyl ester (1.58 g, 7.9 mmol) and acetaldehyde (0.417 g, 9.48 mmol) are mixed with sodium triacetoxyborohydride (3.35 g, 15.8 mmol) in dichloroethane containing acetic acid (1%), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. The reaction mixture was concentrated in vacuo, then purified in an LCO system by flash chromatography (10% methanol / 90% methylene chloride / ammonium hydroxide) to obtain the indicated tert-butyl ether (0.71 g, 39%).

Stage 2

4-Ethylaminopiperidin-1-carboxylic acid tert-butyl ester (0.694 g, 3.04 mmol) and 1-bromo-4-chlorobenzene (0.582, 3.04 mmol) are dissolved in toluene together with sodium tert-butoxide (0.41 g, 4.26 mmol), tris- (dibenzylideneacetone) dipalladium (Ρ6 ₂ (ΌΒΑ) ₃ , 0.055 g, 0.061 mmol) and ΒΙΝΑΡ (0.037 g, 0.061 mmol). The solution was heated to 70 ° C for 2 days, then filtered and the reaction mixture was concentrated in vacuo, then purified in a LCO system by flash chromatography (50% ethyl acetate / 50% hexane) to give the indicated tert-butyl ether (0.25 g , 24%).

Stage 3.

4- (Ethylphenylamino) piperidine-1-carboxylic acid tert-butyl ester (0.251 g, 1.0 mmol) is dissolved in 10 ml of a solution of HCl in dioxane (4 mol / L). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as a hydrochloride salt.

Stage 4.

To a solution of (4-chlorophenyl) ethylpiperidinyl-4-amine (0.150 g, 0.63 mmol) in isopropanol was added 2,6-lutidine (0.24 ml, 2.1 mmol) and the catalyst was potassium iodide. This mixture is heated to 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol ( 0.221 g, 0.6 mmol), which is added in parts over 1 hour. Then the solution is stirred at 80 ° C for another 14 hours. The reaction mixture is concentrated in vacuo, then purified in a LCO system by flash chromatography (15% methanol / 85% methylene chloride) to give the title compound (0.108 g, 34%).

'11 NMR spectrum (SPS1 ₃ ) δ: 1.12 (t, 3H), 1.57 (s, 6H), 2.67-2.80 (m, 4H), 2.00 (m, 2H), 2.34-2.41 (m, 2H), 2.43-2.54 (m, 2H), 2.88 (d, 2H), 3.22 (q, 2H), 3.37-3, 51 (m, 1H), 5.28 (br s, 2H), 6.12 (t, 1H), 6.60 (d, 2H), 6.80 (d, 1H), 7.13 ( d, 2H), 7.21-7.30 (m, 2H), 7.45 (s, 1H), 7.56 (d, 1H), 8.48 (dd, 1H). EMC t / ζ: 532 (Μ + 1), retention time 2.47.

Example 494. 2- (5- {3- [4- (4-Chlorophenyl) -4-methoxypiperidin-1-yl] propylidene} -5.11-dihydro-10

- 92 008060 oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl) propan-2-ol.

Stage 1

4- (4-Chlorophenyl) -4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (200 mg, 0.641 mmol) is added in parts as a solid to a suspension of sodium hydride (0.018 g, 0.770 mmol) in dimethylformamide (6 ml ) at room temperature. After 30 minutes, methyl iodide (0.109 g, 60 μl, 0.770 mmol) was added and the mixture was stirred overnight. The mixture was poured into an equal volume of water, and extracted with ethyl acetate (2 times 10 ml). The ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give a brownish oil. The crude oil is purified by chromatography on silica gel (hexane to 60:40 hexane / ethyl acetate gradient) to give 4- (4-chlorophenyl) -4-methoxypiperidin-1-carboxylic acid tert-butyl ester as a clear oil (108 mg, 52%).

Я NMR spectrum (SES1 ₃ ) δ: 1.45 (s, 9H), 1.80 (td, 2H), 1.97 (bd, 2H), 2.96 (s, 3H), 3.16 (td) , 2H), 3.90 (bd, 2H), 7.36 (s, 4H). MS t / ζ: 326 (M + 1).

Stage 2

4- (4-Chlorophenyl) -4-methoxypiperidin-1-carboxylic acid tert-butyl ester (0.108 g, 0.331 mmol) was dissolved in methylene chloride (6 ml) and cooled in an ice bath. Trifluoroacetic acid (2 ml) was added dropwise slowly. The mixture was warmed to room temperature with stirring for 2 hours. The reaction mixture was concentrated in vacuo and then redissolved in methylene chloride and washed with saturated sodium bicarbonate solution (2 x 10 ml). The combined aqueous layers were extracted with methylene chloride (2 times 10 ml). The methylene chloride extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give 4- (4-chlorophenyl) -4 methoxy piperidine as a clear oil (72 mg, 97%).

Я NMR spectrum (SES1 ₃ ) δ: 1.92 (m, 4H), 2.98 (s, 3H), 3.07 (m, 4H), 4.50 (br.s, 1H), 7, 30 (s, 4H). MS t / ζ: 226 (M + 1).

Stage 3.

4- (4-Chlorophenyl) -4-methoxypiperidine (0.072 g, 0.319 mmol) was dissolved in isopropanol (5 ml) and 2.6-lutidine (0.034, 37 μl, 0.319 mmol) was added. In addition, add a catalyst - iodine. The resulting suspension is heated to 80 ° C. Solid 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.060 g, 0.160 mmol) is added in approximately equal parts for 2 hours. Stirring is continued for another 20 hours at a temperature of 80 ° C. The mixture was concentrated and the resulting residue was purified by silica gel chromatography (gradient from ethyl acetate to 87/10/3 ethyl acetate / methanol / triethylamine) to obtain the title compound (70 mg, 42%).

Nuclear Magnetic Resonance Spectrum Ή (SES1 ₃ ) δ: 1.67 (s, 6H), 1.99-2.86 (m, 12H), 2.98 (s, 3H), 5.32 (br s, 2H) 6.16 (t, 1H), 6.81 (d, 1H), 7.25-7.40 (m, 6H), 7.50 (s, 1H), 7.66 (d, 1H), 7.59 (d, 1H). MS t / ζ: 519 (M + 1).

Example 495. 2- (5- {3- [4- (2-Chlorophenoxy) piperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cycloheptene-7 - il) propan-2-ol.

4- (2-Chlorophenoxy) piperidine hydrochloride (0.067 g, 0.268 mmol) was dissolved in a mixture of acetonitrile (1.32 ml) and water (0.17 ml). To this mixture was added 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.050 g, 0.134 mmol) and potassium carbonate (0.074 g, 0.536 mmol). The mixture was stirred at room temperature for 24 hours and then concentrated in vacuo. The resulting white solid was suspended in ethyl acetate (5 ml) and an equal volume of water was added. The product is extracted with ethyl acetate (2 times in 5 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. The residue was purified by silica gel chromatography (gradient from ethyl acetate to 87/10/3 ethyl acetate: methanol: triethylamine) to obtain the title compound (46 mg, 68%).

Я NMR spectrum (SES1 ₃ ) δ: 1.58 (s, 6H), 1.7-2.9 (m, 12H), 4.42 (br s, 1H), 5.34 (br s, 2H), 6.1 (t, 1H), 6.75 (d, 1H), 6.88 (d, 2H), 6.9-7.3 (m, 4H), 7.32 (s, 1H) ), 7.58 (d, 1H), 8.55 (d, 1H); MS t / ζ: 506 (M + 1).

Example 496. (4-Chlorophenyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cyclohepten-5-ylidene] propyl} piperidin-4-yl) methanone.

The title compound was prepared following the procedure of Example 494, step 3, but replacing 4 (4-chlorophenyl) -4-methoxypiperidine with (4-chlorophenyl) piperidinyl-4-methanone.

М NMR spectrum (SES1 ₃ ) δ: 1.45 (s, 6H), 2.05 (m, 2H), 2.55 (m, 2H), 2.71 (m, 2H), 3.05 (m , 2H), 3.20 (m, 2H), 3.61 (m, 2H), 5.20 (m, 2H), 6.05 (t, 1H), 6.77 (d, 1H), 7 35-7.60 (m, 6H), 7.82 (d, 1H), 8.35 (br s, 1H), 8.52 (d, 1H); MS t / ζ: 517 (M + 1).

Example 497. 2- (5- {3- [4- (4-Trifluoromethylphenoxy) piperidin-1-yl] propylidene} -5,11-dihydro-10oxa-1-aza-dibenzo [a, b] cycloheptene-7- il) propan-2-ol.

The title compound was prepared following the procedure of Example 495, but replacing 4- (2-chlorophenoxy) piperidine hydrochloride with 4- (4-trifluoromethylphenoxy) piperidine.

Nuclear Magnetic Resonance Spectrum Ή (SES1 ₃ ) δ: 1.62 (s, 6H), 2.15 (broad d, 2H), 2.60-3.15 (m, 8H), 3.3 (wide d, 2H), 4.74 (s, 1H), 6.07 (t, 1H), 6.84 (d, 1H), 6.91 (d, 2H), 7.10-7.24 (m, 5H) ), 7.40 (s, 1H), 7.55 (m, 3H), 8.52 (d, 1H); MS t / ζ:

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539 (M + 1).

Example 498. 4- (4-Chlorobenzyl) -3- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5- ylidene] propyl} piperidin-4-yl) oxazolidin-2-one.

Stage 1

2-amino-3- (4-chlorophenyl) propan-1-ol and 4-oxopiperidin-1-carboxylic acid tert-butyl ester are dissolved in 12 ml of methylene chloride. Sodium triacetoxyborohydride (1.03 g, 0.00487 mol) was added in solid form, followed by the addition of a catalyst, acetic acid. The reaction mixture was stirred overnight at room temperature. The reaction is interrupted by the addition of 12 ml of 1 N. sodium hydroxide solution. The intermediate alcohol was extracted with methylene chloride (3 times 12 ml), the organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the intermediate alcohol as a clear yellow oil (1.1 g, 86%). This oil is used without further identification. 4- [1- (4-chlorobenzyl) -2-hydroxyethylamino] piperidine-1-carboxylic acid tert-butyl ester and the intermediate alcohol are dissolved in 15 ml of methylene chloride. Triethylamine (0.423 g, 0.00418 mol, 583 μl 1.2 eq.) Was added, followed by the addition of carbonyldiimidazole (0.68 g, 0.00418 mol, 1.2 eq.) In portions. The mixture was stirred at room temperature and then quenched with water (15 ml). The organic layers were separated and the remaining aqueous layer was extracted with methylene chloride (3 times 15 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow solid. The crude oil is purified by chromatography on silica gel (gradient from methylene chloride to 10% methanol in methylene chloride) to give 4- [4- (4-chlorobenzyl) -2-oxooxazolidin-3-yl] piperidine-1-carboxylic acid tert-butyl ester in as a white solid (1.1 g, 80%).

'11 NMR spectrum (SPS1 ₃ ) δ: 1.40 (s, 9H), 1.70-2.10 (m, 4H), 2.75 (m, 2H), 2.72 (td, 1H), 4.11 (m, 3H), 4.15 (br t, 2H), 7.05 (d, 2H), 7.45 (d, 2H); MS t / ζ: 395 (M + 1).

Stage 2

4- [4- (4-chlorobenzyl) -2-oxo-oxazolidin-3-yl] piperidine-1-carboxylic acid tert-butyl ester (0.9 g, 0.002279 mol) was dissolved in methylene chloride (41 ml). The solution was cooled to the temperature of an ice bath, trifluoroacetic acid (14 ml) was added and the reaction mixture was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo to give the trifluoroacetate salt of the product as an oil. This salt is transferred to the free base by adding a saturated solution of sodium bicarbonate (50 ml), then extracted with methylene chloride (2 times 50 ml). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give 4- (4chlorobenzyl) -3-piperidin-4-yloxazolidin-2-one as an off-white foam (560 mg, 84%).

'11 NMR spectrum (SPS1 ₃ ) δ: 1.70-2.15 (m, 4H), 2.60-2.80 (m, 4H), 3.05-3.30 (m, 2H), 3 55 (br s, 1H), 3.71 (m, 1H), 3.87 (m, 2H), 7.01 (d, 2H), 7.23 (d, 2H). MS t / ζ: 295 (M + 1).

Stage 3.

The title compound was prepared following the procedure of Example 495, but replacing 4- (2-chlorophenoxy) piperidine hydrochloride with 4- (4-chlorobenzyl) -3-piperidinyl-4-oxazolidin-2-one.

NMR spectrum 41 (SPS1 ₃ ) δ: 1.60 (s, 6H), 1.97-3.10 (m, 14H), 3.75 (br s, 2H), 4.10 (br s, 2H), 5.98 (t, 1H), 6.80 (d, 1H), 7.00-7.20 (m, 8H), 7.40 (s, 1H), 7.62 (d, 1H) ), 8.60 (d, 1H). MS t / ζ: 590 (M + 1).

Example 499. 1- {4- (4-Chlorophenyl) -1- [3- (7-isopropenyl-11H-10-oxa-1-azadibenzo [a, b] cyclohepten-5ylidene) propyl] piperidin-4-yl} ethanol.

The product from example 457 (64 mg, 0.12 mmol) was dissolved in anhydrous methanol (2.5 ml) and the resulting solution was cooled to 0 ° C. Sodium borohydride (37 mg, 1 mmol) was added in portions over 5 hours. The reaction was quenched by the addition of water and the mixture was concentrated. The residue of the crude product is purified by reverse phase HPLC chromatography (gradient: water, acetonitrile, formic acid) to obtain the title compound (cleavage of tertiary benzyl alcohol is noted). MS t / ζ: 515 (M + 1).

Example 500. Methyl ester [(4-chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1azadibenzo [a, b] cycloheptene-5-ylidene] propyl } piperidin-4-yl) amino] acetic acid.

Stage 1

To a solution of 4-chlorobenzylamine (859 mg, 6.07 mmol) in 1,2-dichloroethane (20 ml) was added tert-butyl 4-oxopiperidin-1-carboxylate (1.451 g, 7.282 mmol), acetic acid (400 μl) and triacetoxyborohydride sodium (1.800 g, 8.497 mmol). The mixture was stirred at room temperature under nitrogen for 2 hours, diluted with ethyl acetate, washed three times with saturated sodium bicarbonate and dried over magnesium sulfate. The extracts are filtered and concentrated to give 4- (4-chlorobenzylamino) piperidine-1-carboxylic acid tert-butyl ester (2.49 g,> 100%) as a yellow oil, which, according to H-NMR, is pure enough to be used. no additional cleaning.

NMR spectrum 41 (SPS1 ₃ ) δ: 1.44 (s, 9H), 1.56-1.70 (br s, 2H), 1.81-1.90 (br d, 2H), 2, 63 (dddd, 1H), 2.78 (dd, 2H), 3.72 (s, 1H), 3.78 (s, 1H), 4.00 (br s, 2H), 7.16 -7 25 (m, 4H). MS t / ζ: 325 (M + 1).

Stage 2

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Triethylamine (0.386 g, 532 μl, 3.82 mmol) was added to a solution of the product from stage 1 (620 mg, 1.91 mmol) in tetrahydrofuran (20 ml), followed by methyl bromoacetate (0.584 g, 361 μl, 3.82 mmol) ) The resulting mixture was heated at 55 ° C for 2 days, then at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over magnesium sulfate, filtered and concentrated. The resulting crude 4 - [(4-chlorobenzyl) methoxycarbonylmethylamino] piperidine-1-carboxylic acid tert-butyl ester (0.697 g, 92%) is pure enough to be used without further purification.

Nuclear Magnetic Resonance Spectrum Ή (SPS1 ₃ ) δ: 1.44 (s, 9H), 1.78-1.95 (m, 2H), 2.60-2.83 (m, 2H), 3.3-4, 2 (m, 12H); 7.247.36 (m, 4H). MS t / ζ: 397 (M + 1).

Stage 3.

To a solution of the product from step 2 (0.270 g, 0.681 mmol) in methanol (6 ml) was added a 4 molar solution of hydrogen chloride in dioxane (340 μl, 1.36 mmol). After stirring at room temperature for 3 hours, an additional aliquot (1 ml) of a solution of HCl in dioxane was added and the mixture was allowed to stir at room temperature overnight. The mixture was concentrated under reduced pressure to obtain [(4-chlorobenzyl) piperidin-4-ylamino] -acetic acid methyl ester, which was used without further purification. MS t / ζ: 297 (M + 1).

Stage 4.

To a solution of the product from step 3 (0.251 g, 0.680 mmol) in acetonitrile (4 ml), potassium carbonate (0.310 g, 2.24 mmol) in water (2 ml) was added, followed by 2- [5- (3-bromopropylidene) -5.11 dihydro-10-oxa-1-aza-dibenzo [a, th] cyclohepten-7-yl] propan-2-ol (170 mg, 448 mmol). The resulting orange solution was stirred at room temperature for 13 days. The mixture was diluted with ethyl acetate and washed with water and brine. The washed extracts are dried over magnesium sulfate, filtered and concentrated. The title pure compound (107 mg, 41%) was obtained by silica gel chromatography of a crude material (with a methylene chloride gradient of 98/2 methylene chloride / methanol).

Nuclear Magnetic Resonance Spectrum Ή (SPS1 ₃ ) δ: 1.56 (s, 6H), 1.74-1.92 (m, 6H), 2.28-2.48 (m, 4H), 2.53-2, 66 (m, 2H), 2.82 (br.

d, 2H), 3.30 (s, 2H), 3.63 (s, 3H), 3.77 (s, 2H), 5.21-5.39 (br s, 2H), 6.07 (t, 1H), 6.80 (d, 1H), 7.21-7.32 (m, 6H), 7.42 (d, 1H), 7.55 (dd, 1H), 8.50 ( dd, 1H). MS t / ζ: 590.

Example 501. [(4-Chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, th] cyclohepten-5-ylidene] propyl } piperidin-4-yl) amino] acetic acid.

To the solution of the product from step 4 of Example 500 (209 mg, 0.353 mmol) in dioxane (5 ml) and water (2.5 ml) lithium hydroxide (59 mg, 1.41 mmol) was added. The reaction mixture was allowed to stir at room temperature for 24 hours, concentrated and purified by reverse phase HPLC (gradient: water, acetonitrile, formic acid) to give the title compound (44 mg, 22%) as a white solid .

Nuclear Magnetic Resonance Spectrum Ή (СОС1 ₃ , 300 MHz) δ: 1.49 (s, 6Н), 1.69 (d, 2Н), 2.05 (d, 2Н), 2.28-2.53 (m, 5Н) ), 2.82 (m, 3H), 3.14-3.20 (4H), 4.06 (s, 2H), 5.18-5.36 (br d, 2H), 6.12 ( t, 1H), 6.76 (d, 1H), 7.25 (dd, 1H), 7.32-7.40 (m, 2H), 7.45-7.51 (m, 4H), 7 78 (dd, 1H), 8.49 (dd, 1H). MS t / ζ: 576 (M + 1).

Example 502. 5-4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, th] cycloheptene-5-ylidene ] propyl} -3,3-dimethylpiperidin-4-ol.

Stage 1

In a dry, 2-liter, two-necked, round-bottom flask equipped with a magnetic stirrer, a refrigerator and a large water bath (at 10 ° C), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (125 g, 628 mmol) and anhydrous tetrahydrofuran (1 l) are added ) Methyl iodide (85 ml, 1365 mmol) is added to the resulting yellow solution. Sodium tert-butoxide (150 g, 1560 mmol) is then added in portions over 30 minutes. Heat is noted, especially at the beginning of the addition. The reaction mixture is heated to a slight boil (reflux), and the boiling rate is controlled by the addition of a base. The mixture is stirred for an additional 30 minutes. The solvent is removed in vacuo. The oily residue is treated with an aqueous solution of IN ₄ C1 (500 ml) and extracted with ether (3 times 200 ml). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered through a short layer of silica gel. The solvent is removed in vacuo and crystallization of the resulting yellow oil is caused. It is left in high vacuum overnight. The mixture was suspended in hexane (50-100 ml) and sonicated for 1 min. The yellow solid was collected by filtration and washed with hexane (100 ml).

The first collection of 3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester yields a yellow solid (see, preparation (37) in Uye, 8. e1 a1., 1. Ogd. Syet., Νο1 66, pp. 2487-2492 (2001)).

Я NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.13 (s, 6H), 1.49 (s, 9H), 2.49 (t, 2H), 3.43 (br s, 2H) 3.73 (t, 2H).

Stage 2

A two-necked, 2-liter round-bottom flask is equipped with two dropping funnels (125 ml each) and a stirring rod (magnetic stirrer). The unit is dried in a flame in an atmosphere of dry

- 95 008060 nitrogen. THF (700 ml) and 4-bromo-chlorobenzene (33.7 g, 176 mmol, 2.5 eq.) Are charged into the flask. The resulting solution is cooled to a temperature of minus 78 ° C in a dry ice / acetone bath. A solution of butyllithium in hexane (2.5 mol / L, 70 ml, 175 mmol, 2.5 equiv.) From a syringe is added to one of the dropping funnels. A solution of butyllithium is slowly added to a cold solution in THF over 1 hour. Stirring is continued for another 0.5 hour to form a white suspension. A solution of 3,3-dimethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (16.0 g, 70.5 mmol, 1 eq.) In THF (100 ml) is obtained and it is added to the reaction mixture from a second drop funnel for 1.75 hours. The resulting mixture was stirred at -78 ° C for 2 hours, at this point the reaction, apparently, is completely completed according to the analysis by TLC. A saturated aqueous solution of \ H4C1 (150 ml) was added and the reaction mixture was allowed to warm to room temperature. Water (150 ml) was added and the mixture was extracted with ethyl acetate (2 + 1 L). The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The solid residue was triturated with ethyl acetate and filtered. The supernatant was concentrated and triturated with ether. The resulting liquid over the precipitate was then triturated with diethyl ether / petroleum ether. The solids formed are combined to give 4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1 carboxylic acid tert-butyl ester (17.52 g, 51.6 mmol, 73%) as a whitish solid .

NMR spectrum ^! H (SPS1 ₃ , 300 MHz) δ: 0.82 (s, 6H), 1.34-1.44 (m, 2H), 1.49 (s, 9H), 2.67 (ddd, 1H), 3.103.70 (m, 3H), 4.00-4.30 (m, 1H), 7.31 (d, 2H), 7.39 (d, 2H).

Stage 3.

Trifluoroacetic acid (60 ml) was slowly added to a cooled (to 0 ° C) solution of the compound obtained in stage 2 (10.42 g, 30.7 mmol) in methylene chloride (300 ml) over a period of 1.25 hours. The resulting yellow solution stirred at a temperature of 0 ° C for another 1.5 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (1.2 L), washed with aqueous 1N. sodium hydroxide solution (150 ml). The aqueous layer was extracted with additional ethyl acetate (200 ml) and the combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ether to give 4- (4chlorophenyl) -3,3-dimethylpiperidin-4-ol (6.94 g, 29.0 mmol, 94%) as an off-white solid.

^! H-NMR (C1O1). 300 MHz) δ: 0.73 (s, 3H), 0.85 (s, 3H), 1.42 (ddd, 1H), 2.36 (d, 1H), 2.61 (ddd, 1H), 2.91 (broad dd, 1H), 3.08-3.19 (m, 2H), 7.26-7.32 (m, 2H), 7.44-7.50 (m, 2H). MS t / ζ: 240 (M + 1).

Stage 4.

A noticeably transparent 3-necked flask (5 l) is equipped with an overhead stirrer and purged with nitrogen for 20 minutes. 4- (4-chlorophenyl) -3,3-dimethylpiperidin-4-ol (202 g, 843 mmol), 114 g of b - (+) tartaric acid (759 mmol) and 4040 ml of the mixture (9: 1) are added to the flask. ) butanone: water. The mixture is heated at boiling point. Water (202 ml) was added in portions over 45 minutes (6: 1 ratio of butanone to water) in order to completely dissolve the mixture of solids. Refluxing is continued for another 45 minutes, then the heat source is turned off and the flask is allowed to slowly cool to room temperature overnight. The solid was removed by suction filtration and dried for 3 days in vacuo to give the 8-enantiomer (134.4 g, 41%) as the b - (+) tartaric acid salt. The above salt was partitioned between a \ aOH solution (1 mol / L) and methylene chloride (washed with brine and dried with sodium sulfate) to give a free base.

^! H-NMR (C1O1). 300 MHz) δ: 0.73 (s, 3H), 0.85 (s, 3H), 1.42 (ddd, 1H), 2.36 (d, 1H), 2.61 (ddd, 1H), 2.91 (broad dd, 1H), 3.08-3.19 (m, 2H), 7.26-7.32 (m, 2H), 7.44-7.50 (m, 2H). MS t / ζ: 240 (M + 1).

Stage 5.

Potassium carbonate (1.39 g, 10 mmol) was added to a solution of the homochiral product of step 4 (2.40 g, 10 mmol) in a mixture of acetonitrile (80 ml) and water (20 ml), followed by 2- [5- (3 -bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (2.49 g, 6.67 mmol). The biphasic mixture was stirred at room temperature for 48 hours. Acetonitrile was removed on a rotary evaporator and the resulting suspension was partitioned between ethyl acetate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give an oily solid, which was purified by chromatography on silica gel (gradient: methylene chloride 90/10 methylene chloride / methanol) to give the title compound as an off-white powder (2.63 g, 74%).

^! H-NMR (C1O1). 300 MHz) δ: 0.71 (s, 3H), 0.84 (s, 3H), 1.4-1.55 (m, 9H), 2.18-2.81 (m, 9H), 5.155 40 (br s, 2H), 6.23 (t, 1H), 6.74 (d, 1H), 7.23-7.31 (m, 3H), 7.42-7.50 (m 4H), 7.80 (dd, 1H), 8.47 (dd, 1H). MS t / ζ: 533 (M + 1).

Example 503. K-4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene ] propyl} -3,3-dimethylpiperidin-4-ol.

Stage 1

Racemic 4- (4-chlorophenyl) -3,3-dimethylpiperidin-4-ol (0.500 g, 2.086 mmol) is dissolved in a minimum amount of hot isopropyl alcohol (approximately 5 ml). The hot solution is filtered through a layer of cotton and transferred to a solution of (18) - (+) - 10-camphorsulfonic acid (0.484 g,

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2.086 mmol) in isopropyl alcohol (approximately 3 ml). The mixture was vigorously stirred for several minutes during which time a dense precipitate formed and the mixture was allowed to cool to room temperature over 0.25 hours. The solid was removed by suction filtration and dried in vacuo. The dried salt was dissolved in hot isopropyl alcohol (approximately 50 ml), filtered through a layer of cotton and allowed to slowly cool to room temperature without stirring overnight. The solid formed during cooling (95 mg, 19% of theory) is removed by filtration with pumping, and according to analytical data from HPLC it is enantiomerically pure. This salt is suspended in ethyl acetate and neutralized with sodium hydroxide (1N solution). The homogeneous organic phase is washed with water and brine, dried over sodium sulfate, filtered and dried to obtain K-4- (4-chlorophenyl) -3,3-dimethylpiperidin-4-ol.

^! H-NMR (CO ₃ OE. 300 MHz) δ: 0.73 (s, 3H), 0.85 (s, 3H), 1.42 (ddd, 1H), 2.36 (d, 1H), 2 61 (ddd, 1H), 2.91 (broad dd, 1H), 3.08-3.19 (m, 2H), 7.26-7.32 (m, 2H), 7.44-7 50 (m, 2H). MS t / ζ: 240 (M + 1).

Stage 2

The title compound was prepared following the procedure in Step 5 of Example 502, replacing 5'4- (4-chlorophenyl) -3,3-dimethylpiperidin-4-ol with K-4- (4-chlorophenyl) -3,3-dimethyl piperidin-4-ol.

^! H-NMR (C1) _; O1). 300 MHz) δ: 0.71 (s, 3H), 0.84 (s, 3H), 1.4-1.55 (m, 9H), 2.18-2.81 (m, 9H), 5.155 40 (br s, 2H), 6.23 (t, 1H), 6.74 (d, 1H), 7.23-7.31 (m, 3H), 7.42-7.50 (m 4H), 7.80 (dd, 1H), 8.47 (dd, 1H). MS t / ζ: 533 (M + 1).

Example 504. 8-1 - (5- {3 - [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylsperidin-1-yl] propylidene} 5.11-dihydro-10-oxa-1 - aza-dibenzo [a, b] cyclohepten-7-yl) ethanone.

To a solution of 8-4- (4-chlorophenyl) -3,3-dimethylpiperidin-4-ol (180 mg, 0.75 mmol) in a mixture of acetonitrile / water (4/1) is added potassium carbonate (120 mg, 0.86 mmol) followed by the addition of 1- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] ethanone (214 mg, 0.6 mmol). The reaction mixture was stirred at 50 ° C for 8 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. The solvent was evaporated from the combined dried (MD8O4) organic extracts and the residue was purified by chromatography on silica gel eluting with dichloromethane-methanol (96: 4) to give the title compound (217 mg, 70%).

NMR spectrum ^! N (SPS1 ₃ , 300 MHz) δ: 0.6-0.9 (6H, d), 1.2-1.6 (4H, m), 2.2-2.4 (4H, m), 2 55 (3H, s), 2.8 (2H, d), 5.3 (2H, br s), 6.25 (1H, t), 6.85 (1H, d), 7.27- 7.4 (6H, m), 7.6-7.8 (2H, m), 8.0 (1H, d), 8.5 (1H, d). MS t / ζ: 517 (M + 1).

Example 505. K-1- (5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} 5.11-dihydro-10-oxa-1 - aza-dibenzo [a, b | cyclohepten-7-yl) ethanone.

To a solution of K-4- (4-chlorophenyl) -3,3-dimethylpiperidin-4-ol (100 mg, 0.417 mmol) in a mixture of acetonitrile / water (4/1), potassium carbonate (57 mg, 0.413 mmol) was added followed by by adding 1- [5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b) cyclohepten-7-yl] ethanone (100 mg, 0.279 mmol). The reaction mixture was stirred at 50 ° C for 8 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. The solvent was evaporated from the combined dried (MD8O4) organic extracts and the residue was purified by chromatography on silica gel eluting with dichloromethane-methanol (96: 4) to give the title compound (102 mg, 71%).

NMR spectrum ^! N (SPS1 ₃ , 300 MHz) δ: 0.6-0.9 (6H, d), 1.2-1.6 (4H, m), 2.2-2.4 (4H, m), 2 55 (3H, 1s), 2.8 (2H, d), 5.3 (2H, br s), 6.25 (1H, t), 6.85 (1H, d), 7.27- 7.4 (6H, m), 7.6-7.8 (2H, m), 8.0 (1H, d), 8.5 (1H, d). MS t / ζ: 517 (M + 1).

Example 506. Ethyl 2- (5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1 -aza-dibenzo [a, b] cycloheptenyl-7-hydroxy) acetic acid.

To a solution of 5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a , b] cycloheptene-7-ol (64.5 mg, 0.131 mmol) in Ν, Ν-dimethylformamide (2.5 ml) add 60% dispersion of sodium hydride (6 mg, 0.158 mmol) in mineral oil, then 2-ethyl acetate acid (17 μl, 0.158 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen. The reaction was interrupted the next day by adding water, and the mixture was diluted with ethyl acetate. The organic layer is washed twice with water, then with brine. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound, 132 mg (100%).

NMR spectrum ^! N (СОС1 ₃ , 300 MHz) δ: 1.73-1.90 (4Н, m), 2.07-2.90 (4Н, s), 2.29-2.79 (6Н, m), 4.114 14 (2H, pcs), 4.36-4.40 (2H, pcs), 5.23-5.30 (2H, bs), 6.10-6.15 (1H, t), 6.73-6.84 (3H, m), 7.24-7.39 (10H, m), 7.56-7.59 (1H, dd), 8.47-8.50 (1H, dd ) MS t / ζ: 577 (M).

Example 507. 4- (4-Chlorophenyl) -1- {3- [7- (2-hydroxyethoxy) -11H-10-oxa-1-aza-dibenzo [a, b] cyclohepten-5-ylidene] propyl} - 3,3-dimethylpiperidin-4-ol.

To a solution of 75.8 mg (0.1314 mmol) of ethyl 2- (5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5.11 - dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptenyl-7-hydroxy)

97 008060 acetic acid (Example 10) in ethanol (5 ml) was added a 15% solution of sodium hydroxide in water (2 ml). The reaction mixture is heated at boiling point for 30 minutes, during which time the reaction is complete according to liquid chromatography-mass spectrometry (LC / MS). After cooling to room temperature, the reaction mixture was treated by diluting with ethyl acetate and washing with water and brine. The combined aqueous layers were again extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography (reverse phase HPLC) to give the title compound (42 mg, 60%).

NMR spectrum ^! H (SIS1 ₃ , 300 MHz) δ: 0.821 (3H, s), 0.975 (3H, s), 2.56-5.64 (2H, bq), 2.68-2.74 (1H, bld), 2.80-3.08 (5H, m), 3.30-3.38 (1H, bd), 3.62-3.67 (2H, t), 4.04-4.08 (2H, t ), 5.19-5.32 (2H, br.s), 5.946.00 (1H, t), 6.79-6.87 (4H, m), 7.26-7.40 (4H, m) 7.56-7.60 (1H, bd), 8.35-8.37 (1H, s), 8.50-8.53 (1H, dd). MS t / ζ: 535 (M).

Example 508. 4- (4-Chlorophenyl) -1- {3- [7- (2-methoxy-ethoxy) -11H-10-oxa-1-aza-dibenzo- [a, b] cycloheptene-5-ylidene] propyl} -3,3-dimethylpiperidin-4-ol.

The title compound was prepared following the procedure of Example 506, but replacing 2-bromoethyl ester of acetic acid with 1-bromo-2-methoxyethane. The residue was purified by chromatography (reverse phase HPLC) to give the title compound (27 mg, 39%).

NMR spectrum ^! H (SIS1 ₃ , 300 MHz) δ: 0.79-0.85 (3H, s), 0.95-1.03 (3H, s), 2.55-3.12 (8H, m), 3.283 45 (2H, m), 3.48 (3H, b.s.), 3.70-3.78 (2H, b.s.), 4.06-4.13 (2H, b.s. ), 5.18-5.28 (2H, br.s), 5.92-6.01 (1H, pc), 6.75-6.88 (3H, m), 7.25-7, 43 (4H, m), 7.55-7.63 (1H, bd), 8.48-8.55 (2H, bd). MS ν / ζ: 549 (M).

Example 509. 5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11 dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-ol.

The title compound was prepared following the procedure in Step 5 of Example 502, replacing 2 [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl ] propan-2-ol on 5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-ol, and the racemic mixture was cleaved to 8-piperidine.

NMR spectrum ^! H (SIS1 ₃ , 300 MHz) δ: 0.74 (s, 3H), 0.88 (s, 3H), 1.45 (m, 1H), 2.20-2.54 (m, 7H), 2,662.77 (m, 2H), 5.27 (br s, 2H), 6.11 (t, 1H), 6.67 (dd, 1H), 5 6.74-6.79 (m, 2 H), 7.25-7.31 (m, 3H), 7.36-7.42 (m, 2H), 7.59 (d, 1H), 8.50 (dd, 1H). MS t / ζ: 491 (M + 1).

Example 510. 2- (5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1 ethyl ester -aza-dibenzo [a, b] cyclohepten-7-yloxy) -2-methylpropionic acid.

To a solution of 5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5.11-dihydro-10-oxa-1 cooled to a temperature of 0 ° C -azadibenzo [a, b] cyclohepten-7-ol (250 mg, 0.51 mmol) in dimethylformamide (7 ml) add sodium hydride (60%, dispersion in oil, 31 mg, 0.76 mmol). The resulting mixture was stirred at 0 ° C for 10 minutes. Ethyl 2-bromo-2-methylpropionate (149 mg, 0.76 mmol) was added. Stirring at 0 ° C was continued for 10 minutes, then the mixture was warmed to room temperature and stirred for 4 hours. Then the reaction mixture was partitioned between ethyl acetate and water; the aqueous phases are extracted again by adding ethyl acetate. The combined organic phases are washed three times with water, brine and dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient: methylene chloride — 95: 5 methylene chloride: methanol) to give the title compound (233 mg, 76%).

NMR spectrum ^! H (SIS1 ₃ , 300 MHz) δ: 0.74 (s, 3H), 0.87 (s, 3H), 1.27 (t, 3H), 1.41 (d, 1H), 1.50 ( broad s, 1H), 1.55 (s, 6H), 2.18-2.56 (m, 7H), 2.64-2.78 (m, 2H), 4.24 (q, 2H) , 5.27 (br s, 1H), 6.09 (t, 1H), 6.67-6.76 (m, 2H), 6.87 (d, 1H), 7.25-7.31 (m, 2H), 7.37-7.42 (m, 2H), 7.57 (d, 2H), 8.01 (s, 1H), 8.50 (d, 1H). MS t / ζ: 605 (M + 1).

Example 511. 4- (4-Chlorophenyl) -1- {3- [7- (2-hydroxy-1,1-dimethylethoxy) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene ] propyl} -3,3-dimethylpiperidin-4-ol.

To a cooled (to a temperature of 0 ° C) solution of ethyl 2- (5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5.11-dihydro- 10-oxa-1-azadibenzo [a, b] cyclohepten7-yloxy) -2-methylpropionic acid (117 mg, 0.193 mmol) in tetrahydrofuran (5 ml) add a solution of lithium aluminum hydride (1.0 mol / l) in tetrahydrofuran (0, 39 ml, 0.39 mmol). The reaction mixture was allowed to stir at 0 ° C. for 2 hours. Excess hydride was quenched by the addition of a saturated aqueous solution of potassium / sodium tartrate. The mixture was stirred at room temperature until two transparent phases formed. The mixture was diluted with ethyl acetate and shaken. The extracts are dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (gradient: methylene chloride 90:10 methylene chloride / methanol) to give the title compound (102 mg, 94%).

NMR spectrum ^! H (SIS1 ₃ , 300 MHz) δ: 0.74 (s, 3H), 0.87 (s, 3H), 1.25 (s, 6H), 1.41 (d, 1H), 2.18- 2.55 (m, 9H), 2.65-2.79 (m, 2H), 3.58 (d, 2H), 5.20-5.40 (br s, 2H), 6.12 ( t, 1H), 6.74-6.84 (m, 2H), 6.92 (d, 1H), 7.257.32 (m, 3H), 7.36-7.42 (m, 2H), 7 60 (dd, 1H); 8.51 (dd, 1H). MS t / ζ: 563 (M + 1).

Example 512. 2- (5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5.11

- 98 008060 dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yloxy) -2-methylpropionic acid.

Into a solution of ethyl 2- (5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1- azadibenzo [a, b] cyclohepten-7-yloxy) -2-methylpropionic acid (158 mg, 0.261 mmol) in methanol (3 ml) add 1 ml of an aqueous solution of sodium hydroxide (1N.). After a slight heat release, the mixture becomes transparent. After 1 h, add another aliquot (1 ml) of 1N. sodium hydroxide solution and the mixture was allowed to stir for another 1 h at room temperature. The solvents were evaporated under reduced pressure and the residue was dissolved in water (2.5 ml). The alkaline solution is neutralized (to pH = 7) with hydrochloric acid (1N), while the title compound precipitates and is collected by filtration with evacuation (86 mg, 57%).

^! H-NMR (HALF. 300 MHz) δ: 0.80 (s, 3H), 0.91 (s, 3H), 1.47 (s, 6H), 1.72 (d, 1H), 2.56 -2.72 (m, 2H), 2.833.00 (m, 2H), 3.15-3.24 (m, 3H), 3.32-3.48 (m, 2H), 5.18 (broad s, 2H), 6.04 (t, 1H), 6.69-6.84 (m, 2H), 6.97 (d, 1H), 7.28-7.37 (m, 3H), 7.40-7.47 (m, 2H), 7.67 (dd, 1H), 8.42 (dd, 1H). MS t / ζ: 577 (M + 1).

Example 513. 2- (5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5.11 dihydro-10-oxa-1-aza dibenzo [a, b] cyclohepten-7-yloxy) -2-methylpropionamide.

To a solution of 2- (5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11 dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yloxy) -2-methylpropionic acid (72 mg, 0.125 mmol) in dimethylformamide (3 ml) add 1- (3-dimethylaminopropyl) -3 ethylcarbodiimide hydrochloride (48 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol) and ammonium hydroxide (170 μl, 0.50 mmol) and triethylamine (100 μl). Stirred at room temperature for 48 hours. The mixture was poured into chloroform and washed with water. The organic phase is washed by adding water and brine; dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel (methylene chloride-90:10 methylene chloride / methanol gradient) to give the title compound (22 mg, 31%).

'11 NMR spectrum (ΟΌΟ1 ₃ , 300 MHz) δ: 0.74 (s, 3H), 0.87 (s, 3H), 1.42 (broad d, 1H), 1.49 (s, 6H) , 2.162.61 (m, 7H), 2.63-2.78 (m, 2H), 5.20-5.40 (br s, 2H), 5.50 (br s, 1H), 6 11 (t, 1H), 6.68-6.82 (m, 3H), 6.91 (dd, 1H), 7.26-7.33 (m, 4H), 7.36-7.43 (m, 2H), 7.60 (dd, 1H), 8.51 (dd, 1H). MS t / ζ: 576 (M + 1).

Example 514. (5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-methyl ester -dibenzo [a, b] cycloheptenyl-7-hydroxy) acetic acid.

5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene -7-ol (0.4 g, 0.814 mmol) was dissolved in dimethylformamide (10 ml). 48 mg of sodium hydride (0.029 g, 1.22 mmol, 1.5 g-equiv, 60% suspension in mineral oil) was added at room temperature and gas evolution was observed. Methyl bromoacetate (0.187 g, 1.22 mmol, 116 μl) was added and the mixture was stirred at room temperature. After stirring overnight at room temperature, the reaction was quenched by adding water (10 ml). The resulting suspension was extracted with ethyl acetate (3 times 10 ml). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. The crude oil is purified by chromatography on silica gel (gradient: from methylene chloride to 10% methanol in methylene chloride) to give the title compound as a white solid (222 mg, 48%).

'11 NMR spectrum (ΟΌΟ1 ₃ , 300 MHz) δ: 0.7 (s, 3H), 1.2 (s, 3H), 1.30-1.70 (m, 3H), 2.62 -3, 51 (m, 9H), 3.82 (s, 3H), 4.55 (s, 2H), 5.22 (br s, 1H), 5.88 (t, 1H), 6.85 (m , 2H), 7.15-7.33 (m, 6H), 7.62 (d, 1H), 8.43 (d, 1H); MS t / ζ: 564 (M + 1).

Example 515. (5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11 dihydro-10-oxa-1-aza-dibenzo [a , b] cycloheptenyl-7-hydroxy) acetic acid.

(5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene methyl ester} -

5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yloxy) acetic acid (0.060 g, 0.107 mmol) was dissolved in methanol (1.5 ml). Add 150 μl of the prepared sodium hydroxide solution (1 N), and the resulting mixture was stirred at room temperature. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo to give a yellow oil. The oil is suspended in water (2 ml) and then washed with ethyl acetate (3 times 3 ml). Then the aqueous layer was acidified to pH = 2 and extracted with ethyl acetate (3 times 5 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid (55 mg, 94%).

'11 NMR spectrum (ΟΌΟ1 ₃ , 300 MHz) δ: 0.8 (s, 3H), 0.92 (s, 3H), 1.12 - 1.31 (m, 6H), 2.68 (br. d, 2H), 3.89 (m, 1H), 2.95 (d, 1H), 3.10 - 3.36 (m, 2H), 4.45 (s, 1H), 5.20 (broad s, 2H), 5.98 (t, 1H), 6.81 (m, 2H), 6.96 (d, 1H), 7.40 (d, 2H), 7.40 (m, 3H) 7.83 (d, 1H); 8.44 (d, 1H); MS t / ζ: 550 (M + 1).

Example 516. 2- (5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,1,1 dihydro-10-oxa-1 - aza-dibenzo [a, b] cyclohepten-7-yloxy) acetamide.

The title compound was prepared following the procedure of Example 514, but replacing methyl bromoacetate with bromoacetamide. 58 mg of the title compound are obtained after chromatographic purification (52%).

'11 NMR spectrum (ΟΌΟ1 ₃ , 300 MHz) δ: 0.5 (br s, 6H), 0.78-2.90 (m, 10H), 4.35 (s, 1H), 5.22 ( broad s, 2H),

- 99 008060

5.74 (br s, 1H), 6.11 (br s, 1H), 6.55 (br s, 1H), 6.82 (m, 3H), 7.33 (d, 3H) 7.25 (d, 2H); 7.65, (d, 1H); 8.55 (d, 1H); MS t / ζ: 549 (M + 1).

Example 517. 4- (4-Chlorophenyl) -1- {3- [7- (2-hydroxy-2-methylpropoxy) -11H-10-oxa-1-azadibenzo [a, b] cyclohepten-5-ylidene] propyl } -3,3-dimethylpiperidin-4-ol.

Methyl ester (5 - {3 - [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -

5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yloxy) acetic acid (52 mg, 0.0923 mmol) was dissolved in tetrahydrofuran (2 ml). The resulting solution was cooled to the temperature of an ice bath and 264 μl of a solution (1.4 mol / L) of methyl magnesium bromide (0.369 mmol) in toluene / tetrahydrofuran mixture was added dropwise. The reaction mixture was stirred for 4 hours at ice bath temperature and then warmed to room temperature overnight. Tetrahydrofuran is removed by concentration in vacuo. The resulting solid was dissolved in ethyl acetate (10 ml) and washed with a saturated solution of ammonium chloride (10 ml). The ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. This crude oil is purified by chromatography on silica gel (gradient: from methylene chloride to 10% methanol in methylene chloride) to give the title compound as a white solid (40 mg, 77%).

¹ H NMR spectrum (SPS1 ₃ , 300 MHz) δ: 0.92 (d, 6H), 1.34 (s, 6H), 1.62, (br s, 2H), 2.24 (m, 9H ), 3.78 (s, 2H), 6.82 (m, 3H), 7.22-7.41 (m, 7H), 7.62 (d, 1H), 8.52 (d, 1H) ; MS t / ζ: 564 (M + 1).

Example 518. 3- (5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5.11 dihydro-10-oxa-1-azadibenzo [ a, b] cyclohepten-7-yl) propan-1,2-diol.

1- [3- (Allyl-11H-10-oxa-1-aza-dibenzo [a, b] cyclohepten-5-ylidene) propyl] -4- (4-chlorophenyl) -3,3-dimethylpiperidin-4-ol (0.044 g, 0.08 mmol) was dissolved in a mixture of THF (2 ml) / water (0.5 ml) and cooled to 0 ° C. To the solution was added 1.07 ml of a solution of ОГО ₄ (2.5% ОГО ₄ ) in tert-butanol and stirred at room temperature for 4 hours. The reaction mixture was diluted with saturated sodium bisulfite solution, the organic layer was removed, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified in a Vu1ade system by flash chromatography (gradient: from 5% methanol / 95% methylene chloride to 7.5% methanol / 92.5% methylene chloride and up to 15% methanol / 85% methylene chloride ) yielding the title compound (0.025 g, 53%).

М NMR spectrum (SPS1 ₃ , 300 MHz) δ: 0.74 (ss, 3H), 0.87 (s, 3H), 1.22 (d, 1H), 1.41 (s, 1H), 1, 44 (d, 1H), 2.26-2.77 (m, 9H), 3.53 (d, 1H), 3.70 (dd, 1H), 3.93 (s, 1H), 5.30 (br.s, 2H), 6.14 (t, 1H), 6.79 (d, 1H), 7.02 (d, 1H), 7.16 (s, 1H), 7.27 (d , 3H), 7.37 (d, 2H), 7.58 (d, 1H), 8.48 (dd, 1H). EMC t / ζ: 515 (M +1), retention time 1.72.

Example 519. 2- (5- {3- [4- (4-Chlorophenyl) -3-methylpiperazin-1-yl] propylidene} -5,11-dihydro-10-oxa-

1-aza-dibenzo [a, b] cyclohepten-7-yl) propan-2-ol.

Stage 1

4- (4-Chlorophenyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester.

Sodium tert-butoxide (0.96 g, 10 mmol), palladium is added to a solution of 3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5 mmol) and 4 bromochlorobenzene (0.77 g, 4 mmol) (P) dibenzylideneacetone ((Pb ₂ (OHL) ₃ , 0.09 g, 0.1 mmol) and ΒΙΝΑΡ (0.19 g, 0.3 mmol). The suspension was stirred at 120 ° C. for 10 hours. the mixture was filtered through celite and evaporated in vacuo.The residue was purified by silica gel chromatography (gradient from hexane to ethyl acetate) to obtain 0.84 g (68%) of the title compound.

Я NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.00 (3H, m), 1.74 (9H, s), 3.10 (3H, m), 3.30 (1H, m), 3, 80 (2H, m), 4.10 (1H, br s), 6.85 (2H, d), 7.20 (2H, d).

Stage 2

1- (4-Chlorophenyl) -2-methylpiperazine.

4- (4-Chlorophenyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.83 g, 0.68 mmol) was dissolved in 8 ml of a solution of HC1 in dioxane (4 mol / l) and stirred for 2 h at room temperature. The mixture was then evaporated in vacuo, basified with 50 ml of an aqueous solution of sodium hydroxide (1 mol / l) and extracted with ethyl acetate (3 times 100 ml). The organic layers were evaporated and the crude residue was used in the next step (0.56 g, brown oil).

Stage 3.

2- (5- {3- [4- (4-Chlorophenyl) -3-methylpiperazin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene- 7-yl) propan-2-ol.

Solution 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-

2-ol (0.24 g, 0.64 mmol) in isopropanol (5 ml) is treated with 1- (4-chlorophenyl) -2-methylpiperazine (0.25 g, 1.2 mmol) and potassium iodide catalyst is introduced. The solution was stirred at 80 ° C. for 5 hours and evaporated in vacuo. The residue was purified by chromatography on silica gel (gradient: ethyl acetate to 87: 10: 3 ethyl acetate / methanol / triethylamine) to give 0.22 g (69%) of the title compound.

М NMR spectrum (ССО1 ₃ , 300 MHz) δ: 1.00 (3Н, m), 1.60 (6Н, s), 2.20-2.70 (8Н, m), 3.10 (2Н, m ), 3.75 (1H, m), 5.30 (2H, br s), 6.12 (1H, t), 6.87 (4H, d), 7.18-7.32 (3H, m), 7.45 (1H, s), 7.70 (1H, d), 8.55 (1H, d). EMC

- 100 008060 t / ζ: 504 [M + 1].

The free base is converted into a formic acid salt by treatment with a formic acid / methanol mixture. A 0ΉΝ assay corresponds to compound * 0.4 of formic acid.

Example 520. 2- (5- {3- [6-Chloro-1,2-dihydro-2-oxospiro [4H-3,1-benzoxazin-4,4'-piperidine] -1-yl] propylidene} -5 , 11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl) propan-2-ol.

A solution of 6-chloro-1,2-dihydro-2-oxo-spiro [4H-3,1-benzoxazine-4,4'-piperidine] (0.25 g, 0.7 mmol) (obtained by the method of Wax, e1 A1., patent CB 2355465, 2- [5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propane is treated in isopropanol (5 ml) -2-ol (0.19 g, 0.50 mmol) and potassium iodide catalyst was added. The solution was stirred at 80 ° C. for 5 hours and evaporated in vacuo. The residue was purified by chromatography (preparative reverse phase HPLC), receiving 0.029 g (10%) of the title compound.

¹ H-NMR (COOC) δ: 1.50 (3H, s), 2.18 (2H, br s), 2.95-3.2 (6H, m), 5.30 (2H, br. s), 6.18 (1H, m), 6.79 (1H, m), 6.92 (1H, m), 7.12 (1H, m), 7.38 (2H, m), 7, 48 (2H, m), 7.81 10 (2H, m), 8.31 (1H, m), 8.55 (1H, d). EMC t / ζ: 546 [M + 1].

Example 521. 2- (5- {3- [4- (2-Chlorophenyl) -4-methylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene -7-yl) propan-2-ol.

Stage 1

1-Benzyl-4-methylpiperidin-4-ol.

A solution of 1-benzyl-4-piperidone (4.9 ml, 26.5 mmol) in anhydrous diethyl ether (50 ml) was cooled to -78 ° C and treated with a solution of methyl lithium (1.4 mol / L, 21 ml, 29 mmol ) This mixture was stirred for 2.5 hours at −78 ° C., then the reaction was quenched by the addition of aqueous brine, and the mixture was extracted with ethyl acetate (3 times 100 ml). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (gradient: from methylene chloride to 90: 10: 1 methylene chloride / methanol / MH ₄ OH) to give 4.5 g (83%) of the title compound. EMC t / ζ: 206 [M + 1].

Stage 2

1- Benzyl-4- (2-chlorophenyl) -4-methylpiperidine.

A solution of 1-benzyl-4-methylpiperidin-4-ol (4.5 g, 22 mmol) in chlorobenzene (60 ml) is treated with anhydrous A1Cl ₃ (15 g, 110 mmol). This mixture was stirred for 3 hours at reflux, then quenched by pouring onto ice (250 g), made basic with sodium hydroxide and extracted with ethyl acetate (3 times 100 ml). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (from methylene chloride to a 90:10 mixture of methylene chloride / methanol) to give 0.59 g (10%) of the title compound. EMC t / ζ: 300 [M + 1].

Stage 3.

4- (2-Chlorophenyl) -4-methylpiperidine.

A solution of 1-benzyl-4- (2-chlorophenyl) -4-methylpiperidine (0.59 g, 1.95 mmol) in 1,2-dichloroethane (10 ml) is treated with 1-chloroethyl chloroformate (0.28 ml, 2.6 mmol). This mixture was stirred for 12 hours at boiling point, then evaporated in vacuo. The residue was redissolved in methanol (10 ml) and heated at the boiling point for 1 h, then evaporated in vacuo. The resulting brown solid (hydrochloride salt) was washed with ethyl acetate, then taken up in the free base, treated with ethyl acetate / sodium hydroxide to give 0.30 g (72%) of the title compound. EMC t / ζ: 246 [M + 1].

Stage 4.

2- (5- {3- [4- (2-Chlorophenyl) -4-methylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cycloheptene-7- il) propan-2-ol.

A solution of 4- (2-chlorophenyl) -4-methylpiperidine (0.29 g, 1.38 mmol) in isopropanol (5 ml) is treated with 2- [5 - (3-bromopropylidene) -5.11-dihydro-10-oxa -1 -ase-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.19 g, 0.50 mmol) and the catalyst is potassium iodide. The solution was stirred at 80 ° C for 12 hours and evaporated in vacuo. The residue was purified by silica gel chromatography (from ethyl acetate to 87: 10: 3 ethyl acetate / methanol / triethylamine) to obtain 0.062 g (25%) of the title compound.

¹ H NMR (SOS1 _3, 300 MHz) δ: M: 1.10 (3H, s), 1.58 (6H, s), 1.78 (2H, m), 1.90 (1H, m) , 2.10 (2H, m), 2.40 (8H, m), 5.30 (2H, br s), 6.18 (1H, t), 6.79 (1H, m), 6, 92 (1H, m), 7.19-7.39 (6H, m), 7.42 (1H, m), 7.55 (1H, m), 8.55 (1H, d). EMC t / ζ: 503 [M + 1].

Example 522. 4- (4-Chlorophenyl) -1- {3- [7- (2-hydroxy-2-methylpropoxy) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene] propyl } -3-methylpiperidin-4-ol.

Stage 1

(5- {3- [4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo methyl ester [a, b] cyclohepten-7-yloxy) acetic acid.

Solution 5- {3- [4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidin-1-yl] propylidene} -5,11-dihydro-10oxa-1-aza-dibenzo [a, b] cycloheptene- 7-ol (0.14 g, 0.28 mmol) in dimethylformamide (3 ml) is treated

- 101 008060 sodium hydride (60% in mineral oil, 0.016 g, 0.4 mmol) and methyl bromoacetate (0.038 ml, 0.4 mmol). The mixture was allowed to stir at room temperature for 2 hours, then it was quenched by adding aqueous brine and extracted with ethyl acetate (3 times 10 ml). The combined organic layers were washed several times with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (from ethyl acetate to 87: 10: 3 ethyl acetate / methanol / triethylamine), to give 0.07 g (50%) of the title compound. EMC t / ζ: 549 [M + 1].

Stage 2

4- (4-Chlorophenyl) -1- {3- [7- (2-hydroxy-2-methylpropoxy) -11H-10-oxa-1-aza-dibenzo [a, th] cyclohepten-5-ylidene] propyl} -3-methylpiperidin-4-ol.

(5- {3- [4- (4-chlorophenyl) -4-hydroxy-3-methylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo methyl ester solution [a , th] cyclohepten-7-yloxy) acetic acid (0.07 g, 0.13 mmol) in THF (3 ml) is treated with 0.15 ml of a solution of methylmagnesium bromide (3 mol / l, 0.45 mmol). The solution was stirred at room temperature for 2 hours and quenched with brine. The aqueous residue was extracted with ethyl acetate (3 times 10 ml) and the combined organic layers were evaporated in vacuo. The residue was purified by silica gel chromatography (from ethyl acetate to 87: 10: 3 ethyl acetate / methanol / triethylamine) to obtain 0.038 g (50%) of the title compound.

М NMR spectrum (SPS1 ₃ , 300 MHz) δ: M: 0.6 (3H, s), 1.37 (6H, s), 1.66 (2H, m), 1.99-2.80 (9H , m), 3.78 (2H, s), 5.30 (2H, br s), 6.18 (1H, t), 6.79-6.89 (3H, m), 6.92 ( 1H, m), 7.25-7.45 (6H, m), 7.55 (1H, m), 8.55 (1H, d). EMC t / ζ: 549 [M + 1].

Example 523. 4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -1-hydroxy-11H-10-oxa-1-aza-dibenzo [a, d] cycloheptene -5-ylidene] propyl} -3,3-dimethylpiperidin-4-ol.

Stage 1

1- [5- (3-Bromopropylidene) - 1-hydroxy-5,11-dihydro-10-oxa-1-azadibenzo [a, th] cyclohepten-7-yl] ethanone.

Solution of 1- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, th] cyclohepten-7-yl] ethanone (1.5 g, 4.2 mmol) in chloride methylene (10 ml) is treated with methachloroperbenzoic acid (77%, 1.2 g, 5.0 mmol). The mixture was allowed to stir at room temperature for 12 hours, then quenched by adding aqueous brine and extracted with methylene chloride (3 times 30 ml). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The resulting brown foam (1.5 g, 95%) is transferred to the next step without purification. EMC t / ζ: 374 [M + 1].

Stage 2

1- (5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -1-hydroxy-5,11-dihydro-10-oxa-1 - aza-dibenzo [a, th] cyclohepten-7-yl) ethanone.

Solution 1 - [5 - (3-bromopropylidene) -1-hydroxy-5,11-dihydro-10-oxa-1-aza-dibenzo [a, th] cyclohepten-7-yl] ethanone (1.4 g, 3 , 8 mmol) in a mixture of acetonitrile / water (12 ml / 3 ml) is treated with 4- (4-chlorophenyl) -3,3dimethylpiperidin-4-ol (1.0 g, 4.2 mmol) and potassium carbonate (1.1 g, 7.6 mmol). The suspension was stirred at room temperature for 72 hours and evaporated in vacuo. The residue was purified by silica gel chromatography (from ethyl acetate to 87: 10: 3 ethyl acetate / methanol / triethylamine) to obtain 1.2 g (58%) of the title compound. EMC t / ζ: 533 [M + 1].

Stage 3.

4- (4-Chlorophenyl) -1- {3- [7- (1-hydroxy-1-methylethyl) -1-hydroxy-11H-10-oxa-1-aza-dibenzo [a, th] cycloheptene-5- ylidene] propyl} -3,3-dimethylpiperidin-4-ol.

Solution 1- (5- {3 - [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -1-hydroxy-

5,11-dihydro-10-oxa-1-azadibenzo [a, th] cyclohepten-7-yl) ethanone (0.43 g, 0.81 mmol) in THF (3 ml) is treated with 0.74 ml of a solution of methylmagnesium bromide ( 1.4 mol / L, 1.0 mmol). The solution was stirred at room temperature for 48 hours and quenched with brine. The aqueous residue was extracted with ethyl acetate (3 times 10 ml) and the combined organic layers were evaporated in vacuo. The residue was purified by silica gel chromatography (gradient: from ethyl acetate to a mixture of 87: 10: 3 ethyl acetate / methanol / triethylamine) to obtain 0.10 g (25%) of the title compound.

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: M: 0.6 (3H, s), 0.9 (3H, s), 1.55 (6H, s), 1.99-2.80 ( 10H, m), 5.30 (2H, br s), 6.18 (1H, br), 6.89 (1H, m), 7.25-7.45 (7H, m), 7, 50 (1H, m), 8.55 (1H, d). EMC t / ζ: 549 [M + 1].

Example 524. (K) -2- [5- (3- {3 - [(4-Chlorobenzyl) ethylamino] pyrrolidin-1-yl} propylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, th] cyclohepten-7-yl] propan-2-ol.

(K) -pyrrolidin-3-yl-carbamic acid tert-butyl ester (7.85 g, 42.1 mmol) was dissolved in methylene chloride at 0 ° C and triethylamine (11.72 ml, 84.3 mmol) and ethyl chloroformate were added. (8.06 ml, 84.3 mmol). The solution was warmed to room temperature and stirred for 30 minutes, the reaction mixture was washed with NaHCO3 solution. The organic layers were combined and dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was purified in ^ ο Pa ^ H system (70% hexane / 30% ethyl acetate) to obtain the indicated ester (7.73 g, 71%).

Part 2.

(K) -3-tert-butoxycarbonylaminopyrrolidine-1-carboxylic acid ethyl ester (7.73 g, 29.9

- 102 008060 mmol) is dissolved in a solution (4 mol / l) ΗΟ in dioxane. This solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as the hydrochloride salt.

Part 3

(K) -3-aminopyrrolidine-1-carboxylic acid ethyl ester and acetaldehyde (1.76 ml, 31.43 mmol) are mixed with sodium triacetoxyborohydride (9.54 g, 45 mmol) in dichloroethane (200 ml) containing acetic acid (1%), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with a solution of Ν; · ιΘΗ (1N) and brine and dried over magnesium sulfate. The reaction mixture was concentrated in vacuo. The residue was used directly in the next reaction (4.0 g, 72%)

Part 4

(K) -3-Ethylaminopyrrolidine-1-carboxylic acid ethyl ester (1.00 g, 5.4 mmol) was dissolved in acetonitrile (100 ml) and potassium carbonate (3.7 g, 27 mmol) was added, ΚΣ (0.050 mg ) and 1-bromomethyl-4chlorobenzene (1.1 g, 5.4 mmol). The solution was heated at 60 ° C for 20 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on an iSO system (75% hexane / 25% ethyl acetate) to give a paired product (0.410 g, 25%).

Part 5

(K) -3 - [(4-chlorobenzyl) ethylamino] pyrrolidine-1-carboxylic acid ethyl ester (4.00 g, 1.29 mmol) was dissolved in 15 ml of ethanol and potassium hydroxide (1.5 g, 26, 7 mmol) in water (8 ml). The solution was heated at boiling point for 14 hours and ethanol was removed in vacuo. The residue was partitioned between water and methylene chloride. The organic layers are removed and washed with saturated NaΗCO3 solution and brine, then dried over magnesium sulfate. The reaction mixture was concentrated in vacuo (0.253 g, 82%).

Part 6

To a solution of (K) - (4-chlorobenzyl) ethylpyrrolidinyl-3-amine (0.253 g, 1.06 mmol) in isopropanol was added 2,6-lutidine (0.225 g, 2.1 mmol) and the catalyst was potassium iodide. This mixture is heated to 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol ( 0.224 g, 0.6 mmol), which is added in parts over 1 hour. Then, the solution is stirred at 80 ° C for another 14 hours. The reaction mixture is concentrated in vacuo, then purified in flash with flash chromatography (15%) methanol / 85% methylene chloride) to give the title compound (0.100 g, 31%).

Ή-NMR (MeOE): δ 0.94 (t, 3Η), 1.40 (s, 6H), 1.88-2.01 (m, 1Η), 2.02-2.18 (m, 1H ), 2.42-2.67 (m, 4H), 3.033.36 (m, 7H), 3.56 (d, 1H), 3.72 (d, 1Η), 5.16 (br s. , 2H), 6.03 (t, 1H), 6.77 (d, 1H), 7.22-7.37 (m, 4H), 7.38-7.47 (m, 2H), 7.69 ( d, 1H), 8.30 (s, 1Η), 8.37 (dd, 1Η). EMC t / ζ: 534 (M + 1), retention time 1.22.

Example 525. (K) -2- [5- (3- {3 - [(4-Chlorophenyl) ethylamino] pyrrolidin-1-yl} propylidene) -5,11-dihydro10-oxa-1-aza-dibenzo [a b) cyclohepten-7-yl] propan-2-ol.

Part 1.

(K) -3-Ethylaminopyrrolidine-1-carboxylic acid ethyl ester (2.0 g, 10.8 mmol) and 1-bromo-4-chlorobenzene (2.06 g, 10.8 mmol) are dissolved in toluene together with tert-butoxide sodium (1.45 g, 15.12 mmol), Ρά ₂ (ΌΒΆ) ₃ (0.195 g, 0.21 mmol) and ΒΓΝΆΡ (0.13 g, 0.21 mmol). The solution was heated to 100 ° C for 2 days, then filtered and the reaction mixture was concentrated in vacuo and then purified using a flash chromatography method (50% ethyl acetate / 50% hexane) to give the product (0.536 g, 17%).

Part 2.

(K) -3 - [(4-chlorophenyl) ethylamino] pyrrolidine-1-carboxylic acid ethyl ester (0.536 g, 1.8 mmol) was dissolved in 15 ml of ethanol and potassium hydroxide (2.05 g, 36.2 mmol) was added. ) in water (8 ml). The solution was heated at boiling point for 14 hours and ethanol was removed in vacuo. The residue was partitioned between water and methylene chloride. The organic layers are removed and washed with saturated NaΗCO ₃ solution and brine, then dried over magnesium sulfate. The reaction mixture was concentrated in vacuo (0.273 g, 67%).

Part 3

To a solution of (K) - (4-chlorophenyl) ethylpyrrolidinyl-3-amine (0.270 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.20 g, 1.7 mmol) and the catalyst was potassium iodide. This mixture is heated to 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan2-ol (0.180 g , 0.48 mmol), which is added in parts over 1 hour. Then the solution is stirred at 80 ° C for another 14 hours. The reaction mixture is concentrated in vacuo, then purified in the iso system by flash chromatography (15% methanol / 85% methylene chloride) to give the title compound (0.180 g, 72%).

Я NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.08 (t, 3Η), 1.54 (s, 6H), 1.68-1.92 (m, 2H), 2.08-2.25 (m, 1H), 2,362.92 (m, 7H), 3.26 (q, 2H), 4.28 (t, 1H), 5.29 (br s, 2H), 6.12 (t, 1H) ), 6.74 (d, 2H), 6.82 (d, 1H), 7.08 (d, 2H), 7.137.31 (m, 20 2H), 7.44 (s, 1Η), 7, 52 (d, 1H), 8.48 (dd, 1H). EMC t / ζ: 520 (M + 1), retention time 2.01.

- 103 008060

Example 526. (K) -2- {5- [3- (3 - {[(4-Chlorobenzyl) ethylamino] methyl} pyrrolidin-1-yl) propylidene] 5.11 dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl} propan-2-ol.

Part 1.

(K) -3-aminomethylpyrrolidine-1-carboxylic acid tert-butyl ester (0.385 g, 1.92 mmol) and 1-bromomethyl-4-chlorobenzene (0.395 g, 1.92 mmol) are dissolved in 10 ml of acetonitrile at a temperature of 0 ° C and triethylamine (0.793 ml, 5.76 mmol) was added. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and partitioned between a solution of ΝαΟΗ (1N) and extracted with methylene chloride (3 times). The organic layers were combined and dried over Md8Ο _4, filtered and evaporated in vacuo. The residue was purified in a 18co system by flash chromatography (20% hexane / 80% ethyl acetate) to give the product (0.35 g, 57%).

Part 2.

(K) -3 - [(4-chlorobenzylamino) methyl] pyrrolidine-1-carboxylic acid tert-butyl ether (0.35 g, 0.1 mmol) and acetaldehyde (0.15 ml, 0.15 mmol) are mixed with sodium triacetoxyborohydride (0.35 g, 0.15 mmol) in dichloroethane (15 ml) containing acetic acid (1%), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with (1N) ΝαΝ solution and brine and dried over magnesium sulfate. The reaction mixture was concentrated in vacuo. The residue was used directly in the next reaction (0.34 g, 100%).

Part 3

3 - {[((4-chlorobenzyl) ethylamino] methyl} pyrrolidine-1-carboxylic acid tert-butyl ether (0.34 g, 0.98 mmol) was dissolved in a solution of Ηί, Ί in dioxane (4 mol / l). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as the hydrochloride salt.

Part 4

To a solution of (K) - (4-chlorobenzyl) ethylpyrrolidinyl-3-methylamine in a mixture of acetonitrile and water (8: 2) (10 ml) was added To ₂ CO ₃ (0.54 g, 3.9 mmol) and 2- [ 5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.368 g, 0.98 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified using flash chromatography (5% methanol / 95% methylene chloride / ammonium hydroxide) in the 18co system to give the title compound (0.110 g, 33%) .

Я NMR spectrum (ΟΌΟ1 ₃ , 300 MHz) δ: 0.94 (t, 3Η), 1.37 (m, 1H), 1.48 (s, 6H), 1.76-2.15 (m, 4H), 2.222.68 (m, 10Η), 3.41 (d, 1Η), 3.52 (d, 1Η), 5.28 10 (br s, 2H), 6.11 (t, 1H), 6 82 (d, 1H), 7.14-7.32 (m, 6H), 7.48 (s, 1Η), 7.54 (d, 1H), 8.51 (dd, 1H). EMC t / ζ: 548 (M + 1), retention time 1.02.

Example 527. (K) -5- (3- {3 - [(4-Chlorobenzyl) ethylamino] pyrrolidin-1-yl} propylidene) -5,11-dihydro10-oxa-1-aza-dibenzo [a, b] cycloheptene-7-carboxylic acid.

Part 1.

To a solution of (K) - (4-chlorobenzyl) ethylpyrrolidinyl-3-amine (0.43 g, 1.8 mmol) in acetonitrile / water (8: 2) was added To ₂ CO ₃ (0.99 g, 7, 2 mmol) and 1- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1azadibenzo [a, b] cyclohepten-7-yl] ethanone (0.65 g, 1.8 mmol) . The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water and the mixture was extracted with ethyl acetate (3 times). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified using flash chromatography (5% methanol / 95% methylene chloride / ammonium hydroxide) in the 18co system to give a tricyclic ketone (0.683 g, 73%).

Ή-NMR (ΧΚ'ΟΙ)) δ: 0.96 (t, 3Η), 1.39 (dd, 1H), 1.48 (dd, 1H), 1.84 (s, 1Η), 1.81 (m, 1H), 1.94 (m, 1H), 2,332.47 (m, 2H), 2.53 (s, 3Η), 2.58-2.66 (m, 2H), 2.68- 2.86 (m, 4H), 5.42 (br s, 2H), 6.24 (t, 1H), 6.81 (d, 1Η), 7.177.32 (m, 4H), 7, 46 (dd, 1H), 7.77 (t, 2H), 7.96 (s, 1H), 8.48 (d, 1H). EMC t / ζ: 517 (M + 1), retention time 2.61.

Part 2.

Bromine (0.13 ml, 2.5 mmol) was added dropwise to a solution of ΝηΟΗ (0.332 g, 8.3 mmol) in water (3 ml) at 10 ° C. The solution was cooled to 0 ° C. and 0.43 g of (K) -1- [5- (3- {3 - [(4chlorobenzyl) ethylamino] pyrrolidin-1-yl} propylidene) -5.11 was added dropwise. -dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] ethanone (0.83 mmol) dissolved in dioxane (8 ml). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was evaporated in vacuo and purified by HPLC.

Ή-NMR (ΧΚ'ΟΙ)) δ: 0.96 (t, 3Η), 1.37 (m, 1H), 1.48 (m, 1H), 1.95 (s, 1H), 1.94 (m, 1H), 2.10 (m, 1Η), 2.422.63 (m, 3Η), 2.90 (t, 1H), 2.97-3.23 (m, 3Η), 5.82 ( b.s., 2H), 6.26 (t, 1Η), 6.65 (d, 1Η), 7.13-7.31 (m, 4H), 7.39 (t, 1H), 7, 61 (d, 1H), 7.67 (d, 1Η), 7.86 (s, 1H), 8.37 (d, 1H). EMC t / ζ: 519 (M + 1), retention time 1.91.

Example 528. 2- {5- [3- (3 - {[2- (4-Chlorophenyl) ethyl] ethylamino} pyrrolidin-1-yl) propylidene] -5.11

- 104 008060 dihydro-10-oxa-1-aza-dibenzo [a.b | cyclohepten-7-yl} propan-2-ol.

Part 1.

To a solution of 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (0.300 g, 1.37 mmol) in dimethylformamide was added To ₂ CO ₃ (0.567 g, 4.11 mmol) and 1- (2-bromoethyl) -4- chlorobenzene (0.30 g, 1.37 mmol). The solution was heated to 60 ° C for 2 days and then concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers were collected together, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (60% ethyl acetate / 40% hexane) in a 1xo system to give an intermediate (0.263 g, 59%).

Part 2.

(B) -3- [2- (4-chlorophenyl) ethylamino] pyrrolidine-1-carboxylic acid tert-butyl ester (0.263 g, 0.81 mmol) and acetaldehyde (0.068 ml, 1.2 mmol) are mixed with sodium triacetoxyborohydride (0.25 g, 1.2 mmol) in dichloroethane containing acetic acid (1%), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with a solution of (1 N.) No. 1OH and brine and dried over magnesium sulfate. The reaction mixture was concentrated in vacuo. The residue was used directly in the next reaction (0.24 g, 85%).

Part 3

(B) -3 - {[[2- (4-chlorophenyl) ethyl] ethylamino} pyrrolidine-1-carboxylic acid tert-butyl ester (0.242 g) was dissolved in a 4 molar solution of HCl in dioxane. The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as the hydrochloride salt.

Part 4

To a solution of (B) - [2- (4-chlorophenyl) ethyl] ethylpyrrolidinyl-3-amine (0.100 g, 0.39 mmol) in a mixture of acetonitrile and water (8: 2) (10 ml) was added To ₂ CO ₃ ( 0.837 g, 6.06 mmol) and 2- [5- (3-bromopropylidene) -5.11 dihydro-10-oxa-1-azadibenzo [a, 6] cyclohepten-7-yl] propan-2-ol (0.100 g 0.26 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers were collected together, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified in a 1x system using flash chromatography (5% methanol / 95% methylene chloride / ammonium hydroxide) to give the title compound (0.048 g, 33%) .

Я NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.06 (t, 3H), 1.52 (s, 6H), 1.58 (m, 1H), 2.10 (m, 1H), 2.20- 2.78 (m, 13H), 3.30 (m, 1H), 5.28 (br s, 2H), 6.12 (t, 1H), 6.80 (d, 1H), 7, 06 (d, 2H), 7.14-7.30 (m, 4H), 7.46 (s, 1H), 7.52 (d, 1H), 8.52 (dd, 1H). EMC t / ζ: 548 (M + 1), retention time 1.35.

Example 529. (8) -2- (5- {3- [3- (4-Chlorobenzyloxy) pyrrolidin-1-yl] propylidene} -5,11-dihydro-10oxa-1-aza-dibenzo [a, 6] cyclohepten-7-yl) propan-2-ol.

To a solution of (8) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.67 mmol) in THF (10 ml) was added NaH (0.128 g, 3.2 mmol) (60% dispersion) In oil). The resulting solution was stirred for 5 minutes and bromomethyl-4-chlorobenzene (0.658 g, 3.2 mmol) dissolved in THF (5 ml) was added. The reaction mixture was stirred overnight. The reaction was stopped by adding water, and the mixture was extracted with ethyl acetate (3 times). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (15% ethyl acetate / 85% hexane) in a 1xo system to give an intermediate (0.48 g, 58%).

Part 2.

(8) -3- (4-chlorobenzyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester (0.48 g) was dissolved in a 4 molar solution of HCl in dioxane. The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was used directly in the next step without further purification as the hydrochloride salt.

Part 3

To a solution of (8) -3- (4-chlorobenzyloxy) pyrrolidine (0.38 g, 1.54 mmol) in 10 ml of a mixture of acetonitrile and water (8: 2) was added To ₂ CO ₃ (0.85 g, 6, 15 mmol) and 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, 6] cyclohepten-7-yl] propan-2-ol (0.575 g, 1, 54 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers were collected together, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified in a 1x system using flash chromatography (5% methanol / 95%) methylene chloride / ammonium hydroxide) to give the title compound (0.112 g, 14%).

М NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.54 (s, 6H), 1.81 (m, 1H), 1.94 - 2.12 (m, 2H), 2.31 (t, 3H) ), 2,482.72 (m, 4H), 4.10 (m, 1H), 4.38 (q, 2H), 5.28 (br s, 2H), 6.12 (t, 1H), 6.84 (d, 1H), 7.16-7.30 (m, 6H), 7.48 (s, 1H), 7.56 (d, 1H), 8.52 (dd, 1H). EMC t / ζ: 507 (M + 1), retention time 1.56.

Example 530. 4-Chlorobenzylamide 1- {3- [7- (1-hydroxy-1-methylethyl-11H-10-oxa-1-aza-dibenzo [a, 6] cycloheptene-5-ylidene] propyl} pyrrolidin-3- carboxylic acid.

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Stage 1

3- (4-Chlorobenzylcarbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of di-tert-butyl dicarbonate (1.86 g, 8.5 mmol) in dioxane (100 ml) was added 3-pyrrolidinecarboxylic acid (1.0 g, 8.5 mmol) and 1N. solution No. YUN (5 ml). The solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and 1N. hydrochloric acid. The reaction is interrupted by adding 1N. HC1 acid, and the mixture is extracted with ethyl acetate (3 times) and the organic layers are collected together, dried over Ο§δΟ ₄ and evaporated in vacuo. The residue is used directly in the next reaction.

Stage 2

Pyrrolidine-1,3-dicarboxylic acid (1.59 g, 7.3 mmol) was dissolved in methylene chloride and EECS (2.53 g, 13.2 mmol), НΟВΐ (1.48 g, 10.9 mmol) were added. and 4-chlorobenzylamine (0.97 ml, 8.05 mmol). The solution was allowed to stir at room temperature for 10 hours and then washed with 1N. NaΟH solution (1 time), 1N. HC1 acid (1 time) and brine (1 time). The organic layers were dried over Μ ^ δΟ ₄ and evaporated in vacuo, then purified by flash chromatography (50% ethyl acetate / 50% hexane) in a Vu1ade system to give the title compound (1.50 g, 62%).

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.43 (s, 9H), 2.07 (m, 2H), 2.85 (quint, 1H), 3.30 (q, 1H), 3 49 (q, 1H), 3.55 (q, 2H), 4.38 (d, 2H), 6.16 (br s, 1H), 7.17 (d, 2H), 7.27 (d, 2H).

3- (4-Chlorobenzylcarbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.707 g, 2.07 mmol) was dissolved in a solution of HC1 (4 mol / L) in dioxane (5 ml). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as the hydrochloride salt.

To a solution of 4-chlorobenzylamide hydrochloride of pyrrolidine-3-carboxylic acid (0.2 g, 0.83 mmol) in acetonitrile / water (8: 2) (8 ml) was added To ₂ CO ₃ (0.476 g, 3.4 mmol) and 2- [5- (3-bromopropylidene) -

5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.282 g, 0.83 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (from 5% methanol / 95% methylene chloride to 10% methanol / 90% methylene chloride) in a Vu1ade system to give the title compound ( 0.240 g, 60%).

'11 NMR spectrum (СОС1 ₃ , 300 MHz) δ: 1.54 (s, 6Н), 1.93 (m, 1Н), 2.12 (m, 2Н), 2.29-2.82 (m, 10H), 4.26 (br.s, 2H), 5.26 (br.s, 1H), 6.05 (t, 1H), 6.79 (d, 1H), 7.03 (d , 2H), 7.19-7.26 (m, 4H), 7.42 (s, 1H), 7.51 (d, 1H), 8.46 (d, 1H). EMC t / ζ: 532.05 (Μ + 1), retention time 1.68.

Example 531. (4-Chlorophenyl) ethylamide 1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cyclohepten-5-ylidene] propyl } pyrrolidine-3-carboxylic acid.

Stage 1

3 - [(4-Chlorophenyl) ethylcarbamoyl)] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of di-tert-butyl dicarbonate (1.86 g, 8.5 mmol) in dioxane (100 ml) was added 3pyrrolidine carboxylic acid (1.0 g, 8.5 mmol) and 1N. NaΟH solution (5 ml). The solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and 1N. HC1 acid. The reaction is interrupted by adding 1N. HC1 acid, and the mixture is extracted with ethyl acetate (3 times) and the organic layers are collected together, dried over Ο§δΟ ₄ and evaporated in vacuo. The residue is used directly in the next reaction.

Stage 2

Pyrrolidine-1,3-dicarboxylic acid (0.300 g, 1.4 mmol) was dissolved in methylene chloride and EECC (0.477 g, 2.4 mmol), HΟBΐ (0.280 g, 2.1 mmol) and Y-ethyl-4 were added. -chloraniline (0.236 g, 1.5 mmol). The solution was allowed to stir at room temperature for 24 hours and then washed with 1N. NaΟH solution (1 time), 1 N HC1 acid (1 time) and brine (1 time). The organic layers were dried over Μ§δΟ ₄ and evaporated in vacuo, then purified by flash chromatography (from 30% ethyl acetate / 70% hexane to 40% ethyl acetate / 60% hexane) in a Vu1ade system to give the title compound (0.040 g, 38%).

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.08 (t, 3H), 1.41 (s, 9H), 1.78 (m, 1H), 2.13 (m, 1H), 2 76 (quint, 1H), 3.10 (q, 1H), 3.36 (quint, 2H), 3.50 (t, 1H), 3.73 (m, 2H), 7.09 (d, 2H), 7.42 (d, 2H).

3 - [(4-Chlorophenyl) ethylcarbamoyl)] pyrrolidine-1-carboxylic acid tert-butyl ether (0.040 g, 0.1 mmol) was dissolved in a solution (4 mol / L) of HC1 in dioxane (2 ml). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as the hydrochloride salt.

To a solution of (4-chlorophenyl) ethyl chloride pyrrolidin-3-carboxylic acid ethyl chloride (0.033 g, 0.11 mmol) in a mixture of acetonitrile / water (8: 2) (2 ml) add To ₂ CO ₃ (0.125 g, 0.89 mmol) and 2- [5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.042 g, 0.11 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times).

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The organic layers are collected together, dried over magnesium sulfate, filtered and evaporated in vacuo; then purified using flash chromatography in a Vu1ade system (2.5% methanol / 97.5% methylene chloride to 5% methanol / 95% methylene chloride) to give the title compound (0.028 g, 46%).

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.07 (t, 3H), 1.55 (6H, s), 1.62 (m, 1H), 1.99 (m, 3H), 2 30 (quint, 3H), 2.47-2.77 (m, 5H), 3.68 (m, 2H), 5.26 (br s, 2H), 6.09 (t, 1H) 6.79 (d, 1H), 7.03 (d, 2H), 7.24 (m, 2H), 7.37 (d, 2H), 7.42 (s, 1H), 7.52 (d, 1H), 8.47 (d, 1H). EMC t / ζ: 546.04 (M + 1), retention time 1.44.

Example 532. (K) -2- (5- {3- [3- (5-Chloro-1,3-dihydroisoindol-2-yl) pyrrolin-1-yl] propylidene-5.11 dihydro-10-oxa-1 -aza-dibenzo [a, b] cyclohepten-7-yl-propan-2-ol.

Part 1.

(K) -3 - (5-chloro-1,3-dioxo-1,3-dihydroisoindol-2-yl) pyrrolidin-1-carboxylic acid tert-butyl ester.

The monosodium salt of 4-chlorophthalic acid (2.00 g, 8.9 mmol) and PC1 ₅ (5.61 g, 26.9 mmol) are added to the flask in a pure form and heated to a temperature of 180 ° C (caution: the initial mixture of acid and PC1 ₅ is very exothermic). The mixture was heated for 3 hours and then the suspension was diluted with toluene and filtered. The reaction mixture was concentrated and used without further purification.

Part 2.

(K) -4-Chlorophthaloyl dichloride (0.556 g, 2.3 mmol) and (K) -3-amino-1-N-butoxy-carbonylpyrrolidine (0.400 g, 2.1 mmol) are dissolved in 21 ml of pyridine and heated to 80 ° C for 2.5 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layers are combined and washed with 1N. HC1 acid, 1n. solution No. OH, brine and dried over magnesium sulfate, filtered and evaporated in vacuo. It is then purified in a Vu1ade system by flash chromatography (from 5% methanol / 95% methylene chloride, up to 10% ethyl acetate / 90% hexane and up to 20% ethyl acetate / 80% hexane) to give the title compound (0.200 g, 26%) .

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.46 (s, 9H), 2.12 (m, 1H), 2.59 (quint, 1H), 3.38 (quartet, 1H), 3 71 (m, 3H), 4.83 (quint, 1H), 7.69 (d, 1H), 7.77 (d, 1H), 7.80 (s, 1H). EMC t / ζ: 351 (M + 1), retention time 2.73.

(K) -3- (5-chloro-1,3-dihydroisoindol-2-yl) pyrrolidin-1-carboxylic acid tert-butyl ester.

(K) -3- (5-chloro-1,3-dioxo-1,3-dihydroisoindol-2-yl) pyrrolidin-1-carboxylic acid tert-butyl ester (0.200 g, 0.57 mmol) is dissolved in ether, cooled to 0 ° C. and lithium aluminum hydride (2.85 ml, 2.8 mmol) was added dropwise, followed by A1C1 ₃ (0.380 g, 2.8 mmol). The solution was allowed to stir at 0 ° C. for 1½ hours and then the reaction was slowly interrupted with water and the mixture was extracted with ethyl acetate (3 times). The organic layers were combined and dried over magnesium sulfate, filtered and evaporated in vacuo to give the title compound (0.076 g, 41%) without further purification. EMC t / ζ: 323 (M + 1), retention time 1.27.

(K) -3- (5-chloro-1,3-dihydroisoindol-2-yl) pyrrolidin-1-carboxylic acid tert-butyl ester (0.076 g, 0.23 mmol) is dissolved in a 4 molar solution of HCl in dioxane ( 2 ml). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as the hydrochloride salt.

Stage 2

To a solution of (K) -5-chloro-2-pyrrolin-3-yl-2,3-dihydro-1H-isoindole hydrochloride (0.052 g, 0.23 mmol) in acetonitrile / water (8: 2) (2 ml) ) add To ₂ CO ₃ (0.215 g, 1.5 mmol) and 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene-7 -yl] propan-2-ol (0.079 g, 0.21 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers were collected together, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (from 5% methanol / 95% methylene chloride, up to 10% methanol / 90% methylene chloride and up to 15% methanol). / 85% methylene chloride) to give the title compound (0.055 g, 55%).

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.55 (s, 9H), 1.77 (m, 1H), 2.02 (m, 2H), 2.37 (quint, 3H), 2.422 64 (m, 4H), 2.81 (t, 1H), 3.17 (quint, 1H), 3.43 (s, 3H), 3.84 (s, 4H), 5.26 (br. s., 2H), 6.11 (t, 1H), 6.79 (d, 1H), 7.08-7.28 (m, 5H), 7.43 (s, 1H), 7.56 ( d, 1H), 8.46 (d, 1H). EMC t / ζ: 516.02 (M + 1), retention time 1.26.

Example 533. (K) -1- (4-Chlorobenzyl) -1- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cyclohepten-5-ylidene] propyl} pyrrolidin-3-yl) urea.

Part 1.

(I) -1- (4-Chlorobenzyl) -1-pyrrolidin-3-yl-urea.

(K) -3- (4-chlorobenzylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (0.690 g, 2.2 mmol) was dissolved in methylene chloride with a few drops of isopropanol and trimethylsilyl isocyanate (0.365 ml, 2.6 mmol) was added. . The solution was allowed to stir at room temperature for 12 hours, the reaction mixture was concentrated and used directly in the next reaction. EMC t / ζ: 354 (M + 1), retention time 2.15.

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Part 2.

(K) -3- [1 (4-chlorobenzyl) ureido] pyrrolidine-1-carboxylic acid tert-butyl ester (0.300 g, 0.84 mmol) was dissolved in a 4 molar solution of HCl in dioxane (2 ml). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as the hydrochloride salt.

To a solution of (K) -1- (4-chlorobenzyl) -1-pyrrolidin-3-yl-urea (0.200 g, 0.78 mmol) in a mixture of acetonitrile and water (8: 2) (8 ml) was added K ₂ CO ₃ (0.449 g, 3.2 mmol) and 2- [5- (3-bromopropylidene) -5.11 dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol ( 0.267 g, 0.71 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers were collected together, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (from 5% methanol / 95% methylene chloride to 10% methanol / 90% methylene chloride) in the Vukade system to give the title compound ( 0.231 g, 60%).

'11 NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.55 (s, 6H), 1.88 (quint, 1H), 2.01-2.28 (m, 5H), 2.53 (quint, 6H), 3.12 (t, 1H), 3.14 (t, 1H), 3.83 (q, 1H), 4.37 (s, 1H), 4.53 (s, 2H), 5, 28 (br s, 2H), 6.18 (t, 1H), 6.78 (d, 1H), 7.11 (dd, 1H), 7.16 (s, 1H), 7.18- 7.27 (m, 4H), 7.49 (d, 1H), 7.51 (s, 1H), 8.47 (dd, 1H). EMC t / ζ: 547.06 (M + 1), retention time 1.65.

Example 534. (K) -8-Chloro-4- (1- {3 [7 - (- hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5- ylidene] propyl} pyrrolidin-3-yl) -1,3,4,5-tetrahydrobenzo [e] [1,4] diazhesh-2-one.

Stage 1

3- (4-Chloro-2-nitro-benzylamino) pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) in methanol (20 ml) was added 4-chloro-2-nitrobenzaldehyde (1.98 g, 10.7 mmol). The resulting solution was heated at a temperature of 60 ° C. overnight. The reaction mixture is cooled to 0 ° C and No. 1BN is added to it. - | (629 mg, 10 mmol). After 1 h, the reaction was quenched by adding a saturated aqueous solution of HCO ₃ and the mixture was extracted with ethyl acetate. The organic extracts were dried over MgSO ₄ , filtered and concentrated to give the crude product as an oil. This crude product is used in the next reaction without further purification. LC / MS (retention time = 1.28, E8 +; 356).

Stage 2

3 - [(4-Chlorobenzyl) methoxycarbonylmethylamino] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3- (4-chloro-2-nitrobenzylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (3.8 g, 10.7 mmol) in DMF (40 ml) was added methyl bromoacetic acid ester (1.01 ml 10.7 mmol) and K2CO3 (1.48 g, 10.7 mmol). The resulting suspension was stirred at 70 ° C. overnight. The reaction mixture was diluted with water and diethyl ether. The organic extract was dried over Md8O _4, filtered and concentrated to give the desired product as an oil. The crude product is purified on 81O ₂ and concentrated to obtain the desired product as an oil (2 g, 44%). LC / MS (retention time = 3.03, E8 +; 428).

Stage 3.

3- (8-Chloro-2-oxo-1,2,3,5-tetrahydrobenzo [e] [1,4] diazepin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3 - [(4-chloro-2-nitrobenzyl) methoxycarbonylmethylamino] pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g, 2.4 mmol) in ethyl acetate (20 ml) was added a 10% Pb / C catalyst. Hydrogenolysis of the reaction solution at room temperature and atmospheric pressure provides the desired product after 1.5 hours. The reaction mixture is filtered through a celite pad and concentrated. The crude product (662 mg, 1.7 mmol) was dissolved in DMF (5 ml) and a 60% dispersion of NaH in oil (100 mg, 2.5 mmol) was added to the solution. The resulting solution was stirred at room temperature overnight. The reaction was interrupted by adding water, and the mixture was extracted with diethyl ether. The organic extract was dried over Md8O _4, filtered and concentrated to give the crude product. Purification at 81O ₂ provides the desired product. LC / MS (retention time = 1.89, E8 +; 310).

(K) -3- (8-chloro-2-oxo-1,2,3,5-tetrahydrobenzo [e] [1,4] diazepin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.210 g, 0.57 mmol) was dissolved in a 4 molar solution of HCl in dioxane (5.7 ml). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as the hydrochloride salt.

Stage 2

To a solution of (K) -8-chloro-4-pyrrolidin-3-yl-1,3,4,5-tetrahydrobenzo [e] [1,4] diazepin-2-one (0.198 g, 0.58 mmol) in mixtures of acetonitrile and water (8: 2) (5.8 ml) are added to ₂ CO ₃ (0.655 g, 4.6 mmol) and 2- [5- (3 bromopropylidene) -5.11-dihydro-10-oxa-1 -aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.183 g, 0.48 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times).

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The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified in a Vu1ade system using flash chromatography (from 5% methanol / 95% methylene chloride, up to 10% methanol / 90% methylene chloride and up to 15% methanol / 85% methylene chloride) to give the title compound (0.077 g, 28%).

'11 NMR spectrum (СОС1 ₃ , 300 MHz) δ: 1.55 (s, 6Н), 1.74 (septet, 1Н), 2.01 (sextet, 1Н), 2.32-2.60 (m, 6H), 2.76 (t, 1H), 3.26 (quint, 1H), 3.43 (d, 1H), 3.46 (s, 2H), 3.74 (s, 2H), 5, 27 (br s, 2H), 6.12 (t, 1H), 6.78 (d, 1H), 6.96 (s, 1H), 7.06 (dd, 1H), 7.13 ( d, 1H), 7.19-7.27 (m, 2H), 7.44 (d, 1H), 7.55 (yes, 1H), 8.47 (dd, 1H), 8.49 (s, 1H) ) EMC t / ζ: 559 (M + 1), retention time 1.24.

Example 535. (K) -8-Chloro-1-ethyl-4- (1- {3 [7- (hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5 -ilidene] propyl} pyrrolidin-3-yl) -1,3,4,5-tetrahydrobenzo [e] [1,4] diazepin-2-one.

Stage 1

(K) -3- (8-chloro-1-ethyl-2-oxo-1,2,3,5-tetrahydrobenzo [e] [1,4] diazepin-4-yl) pyrrolidin-1- tert-butyl ether carboxylic acid.

(K) -3- (8-chloro-2-oxo-1,2,3,5-tetrahydrobenzo [e] [1,4] diazepin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.258 g, 0.70 mmol) is dissolved in THF (7 ml) and cooled to 0 ° C. NaH (0.042 g, 1.0 mmol) was added to the solution and stirred for 15 minutes, followed by the addition of ethyl iodide (0.085 ml, 1.0 mmol). The solution was allowed to slowly warm to room temperature, then stirred at room temperature for 14 hours. The reaction was quenched by adding water, and the mixture was extracted with ethyl acetate (3 times). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography (75% ethyl acetate / 25% ethyl acetate to 100% ethyl acetate) in a Vu1ade system to give the title compound (0.130 g, 47%) .

Я NMR spectrum (SPS1 ₃ , 300 MHz) δ: 1.16 (t, 3H), 1.43 (s, 9H), 1.75 (sext, 1H), 2.18 (quint, 1H), 3.053, 9 (m, 1H); 7.20 (m, 3H). EMC t / ζ: 394 (M + 1), retention time 2.25.

(B) -3- (8-chloro-1-ethyl-2-oxo-1,2,3,5-tetrahydrobenzo [e] [1,4] diazepin-4-yl) pyrrolidin-1- tert-butyl ether carboxylic acid (0.130 g, 0.32 mmol) is dissolved in 3.2 ml of a solution of HCl in dioxane (4 mol / l). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the mixture was transferred to the next step without further purification as the hydrochloride salt.

Stage 2

To a solution of (B) -8-chloro-1-ethyl-4-pyrrolidin-3-yl-1,3,4,5-tetrahydrobenzo [e] [1,4] diazepin-2-one (0.121 g, 0 , 32 mmol) in a mixture of acetonitrile and water (8: 2) (3.2 ml) add To ₂ CO ₃ (0.368 g, 2.6 mmol) and 2- [5- (3-bromopropylidene) -5.11- dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.102 g, 0.27 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water, extracted with ethyl acetate (3 times). The organic layers were collected together, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified by flash chromatography in a Vu1ade system (from 5% methanol / 95% methylene chloride to 10% methanol / 90% methylene chloride and up to 15% methanol / 85% methylene chloride) to give the title compound (0.033 g, 21%).

Я NMR spectrum (ССО1 ₃ , 300 MHz) δ: 1.17 (t, 3Н), 1.55 (s, 6Н), 1.73 (septet, 1Н), 2.08 (m, 1Н), 2, 34 (quint, 2H), 2.43-2.61 (m, 4H), 2.85 (t, 1H), 2.92 (d, 1H), 3.10 (q, 1H), 3.22 (m, 1H), 3.52 (q, 2H),

3.91 (septet, 2H), 5.29 (br s, 2H), 6.12 (t, 1H), 6.79 (dd, 1H), 7.15-7.28 (m, 5H) ), 7.44 (s, 1H), 7.56 (d, 1H), 8.47 (d, 1H). EMC t / ζ: 587 (M + 1), retention time 1.37.

Example 536. [(4-Chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1azadibenzo [a, b] cycloheptene-5-ylidene] propyl methyl ether } pyrrolidin-3-yl) amino] acetic acid.

Stage 1

3- (4-Chlorobenzylamino) pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) in methanol (20 ml) was added 4-chlorobenzaldehyde (1.5 g, 10.7 mmol). The resulting solution was heated at 60 ° C. overnight. The reaction mixture was cooled to 0 ° C. and NaBH ₄ (629 mg, 10 mmol) was added to it. After 1 h, the reaction was quenched by adding a saturated NaHCO ₃ solution, and the mixture was extracted with ethyl acetate. The organic extract was dried over MgSO ₄ , filtered and concentrated to give the crude product as an oil. This crude product is used in the next reaction without further purification. LC / MS (retention time = 1.27, E8 +; 311)

Stage 2

3 - [(4-Chlorobenzyl) methoxycarbonylmethylamino] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3- (4-chlorobenzylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 10.7 mmol) in DMF (40 ml) was added methyl bromoacetate (1.01 ml, 10.7 mmol) and K2CO3 (1.48 g, 10.7 mmol). The resulting suspension was stirred at 70 ° C. overnight. The reaction mixture was diluted with water and diethyl ether. The organic extract was dried over MgO ₄ , filter

109 008060 and concentrated to obtain the desired product as an oil. The crude product is purified on 81O ₂ and concentrated to obtain the desired product as an oil (3.5 g, 87%). LC / MS (retention time = 2.96, E8 +; 383).

Stage 3.

[(4-Chlorobenzyl) pyrrolidinyl-3-amino] acetic acid methyl ester.

3 - [(4-Chlorobenzyl) methoxycarbonylmethylamino] pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g, 9.1 mmol) was dissolved in 4N. a solution of HCl in dioxane (60 ml). The resulting solution was stirred for 2 hours at room temperature, then concentrated to obtain the desired product as a white solid. LC / MS (retention time = 1.26, E8 +; 283).

Stage 4.

Methyl ester [(4-chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene] propyl} pyrrolidin-3-yl) amino] acetic acid.

To a solution of [(4-chlorobenzyl) pyrrolidin-3-yl-amino] acetic acid methyl ester (188 mg, 0.67 mmol) in isopropanol (5 ml) was added 2.6-lutidine (186 μl, 1.6 mmol) and a catalytic amount of potassium iodide. The resulting solution is heated at a temperature of 80 ° C and 2- [5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2 is added to it -ol (149 mg, 0.4 mmol) in portions for 0.5 h. The reaction solution was heated overnight, then partitioned between water and ethyl acetate. The product is purified on 81O ₂ (ethyl acetate: methanol: triethylamine = 95: 4.5: 0.4) and isolated in the form of a film. LC / MS (retention time = 1.84, E8 +; 576).

NMR spectrum ^! H (C1) _; O1)) δ: 8.46 (1H, d), 7.45 (2H, m), 7.23 (5H, m), 6.74 (1H, d), 6.15 (1H, m), 3.72 (2H, m), 3.60 (4H, s), 3.30 (6H, m), 2.78 (4H, m), 2.42 (2H, m), 2.05 (1H , m), 1.82 (1H, m), 1.50 (6H, s).

Example 537. [(4-Chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cyclohepten-5-ylidene] propyl } pyrrolidin-3-yl) amino] acetic acid.

Stage 1

[(4-Chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5ylidene] propyl} pyrrolidine- 3-yl) amino] acetic acid ..

To a solution of methyl ester [(4-chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11Н-10-oxa-1aza-dibenzo [a, b] cycloheptene-5-ylidene] propyl} pyrrolidin-3-yl) amino] acetic acid (116 mg, 0.2 mmol) in a mixture of THF: water (4: 1, total volume 10 ml), lithium hydroxide monohydrate (17 mg, 0.4 mmol) was added. The resulting solution was stirred at room temperature for 3 hours. The reaction in the solution was interrupted by adding 1 N. HCl acid and extracted with diethyl ether, dried over MgSO ₄ , filtered and concentrated. The final product is filtered through filter paper and concentrated again. This product is used without further purification.

NMR spectrum ^! H (C1) _; O1)) δ: 8.48 (1H, d), 7.78 (1H, d), 7.48 (2H, m), 7.31 (5H, m), 6.76 (1H, d), 6.15 (1H, t), 3.85 (2H, dd), 3.60 (2H, m), 3.30 (7H, m), 3.24 (1H, s), 3.18 (1H , m), 3.06 (1H, m), 2.58 (1H, m), 2.48 (1H, t), 2.06 (2H, m), 1.50 (6H, s).

Example 538

2- (5- {3- [4- (3,4-Dichlorophenyl) piperazin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene-7 -yl) propan-2-ol.

To a solution of 1- (3,4-dichlorophenyl) piperazine (0.14 g, 0.601 mmol) in isopropanol (6.0 ml) was added 2,6-lutidine (95 μl, 0.802 mmol) and the catalyst was potassium iodide. This mixture is heated to 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2ol ( 0.37 g, 1.0 mmol), added in three parts over 2 hours. Then the reaction mixture was stirred at 80 ° C for 18 hours. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate / 5% methanol to 90% ethyl acetate / 10% methanol) to give the title compound as a white solid (0.15 g, 69%).

¹ H-NMR (MeOE) δ: 1.55 (6H, s), 2.35-2.65 (8H, m), 3.15-3.25 (4H, m), 5.30 (2H, br s), 6.20 (1H, t), 6.82 (1H, dd), 7.23-7.55 (5H, m), 7.59 (1H, d), 8.50 (1H , dd). EMC t / ζ: 524 (M + 1), ϋΥ retention time: 1.66 min.

Example 539. 2- (5- {3- [4- (4-Chloro-2-methylphenyl) piperazin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl) propan-2-ol.

Stage 1

4- (4-chloro-2-methylphenyl) piperazine-1-carboxylic acid tert-butyl ester.

2-Bromo-5-chlorotoluene (0.82 g, 4 mmol) and tert-butyl-1-piperazinecarboxylate (0.89 g, 2.32 mmol) are added to the solution of tri-tert-butylphosphine (0.033 g, 4 mmol). %), tris- (dibenzylideneacetone) dipalladium (0) (0.075 g, 2.0 mmol.%) and cesium carbonate (1.95 g, 6.0 mmol) in toluene and heated at 80 ° C overnight. The reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified on silica gel (gradient elution from 20% ethyl acetate in hexane to 50% ethyl acetate in hexane) to give the title compound in 20% yield. EMC m / ζ: 311 (M + 1), υV retention time: 3.49 min.

- 110 008060

Stage 2

1- (4-Chloro-2-methylphenyl) piperazine.

A solution of 4- (4-chloro-2-methylphenyl) piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 0.837 mmol) in dichloromethane, cooled at 0 ° C, is treated with trifluoroacetic acid (20%) and the mixture is heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by treatment with 10% aqueous sodium bicarbonate solution. The organic layers were isolated and dried over sodium sulfate and concentrated. This product is used without further purification. EMC t / ζ: 211 (M + 1), υν retention time: 1.25 min.

Stage 3.

2- (5- {3- [4- (4-Chloro-2-methylphenyl) piperazin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene -7-yl) propan-2-ol.

To a solution of 1- (4-chloro-2-methylphenyl) piperazine (0.13 g, 0.6 mmol) in isopropanol (6.0 ml) was added 2.6-lutidine (95 μl, 0.802 mmol) and the iodide catalyst potassium. This mixture is heated to 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan2-ol ( 0.15 g, 0.4 mmol), which is added in parts over 2 hours. Then the solution is stirred at 80 ° C for another 12 hours. The reaction mixture is concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate / 5% methanol to 90% ethyl acetate / 10% methanol) to give the title compound (0.11 g, 54%).

Я-NMR in dimethyl sulfoxide (DMSO) δ: 1.45 (6H, s), 2.30-2.65 (8H, m), 2.75-2.85 (4H, m), 3.30 (3H d) 5.30 (2H, br s), 6.20 (1H, t), 6.75 (1H, d), 7.00-7.47 (6H, m), 7.80 ( 1H, dd), 8.50 (1H, dd). EMC t / ζ: 504 (M + 1), υν retention time: 1.65 min.

Example 540. 5-Chloro-2- (4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene] propyl} piperazin-1-yl) benzonitrile.

Stage 1

4- (2-Cyanophenyl) piperazine-1-carboxylic acid tert-butyl ester.

To a solution of 2-piperazinyl-1-benzonitrile (1.1 g, 5.87 mmol) in dichloromethane (10 ml), diisopropylethylamine (3.1 ml, 17.62 mmol) was added followed by di-tert-butyl dicarbonate (1, 28 g, 5.87 mmol) and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was again extracted twice with ethyl acetate. The organic layers are combined, dried over sodium sulfate and concentrated in vacuo. The crude product is purified using a short layer of silica gel and the solvent is hexane / ethyl acetate (50%).

Nuclear Magnetic Resonance Spectrum Ή (СОСО1 ₃ ) δ: 1.47 (9Н, s), 3.12-3.16 (4Н, m), 3.61-3.65 (4Н, m), 6.90-7, 05 (2H, m), 7.477.70 (2H, m). EMC t / ζ: 288 (M + 1), υν: 2.75 min.

Stage 2

4- (4-chloro-2-cyanophenyl) piperazine-1-carboxylic acid tert-butyl ester.

To a solution of 4- (2-cyanophenyl) piperazine-1-carboxylic acid tert-butyl ester (7.1 g, 24.72 mmol) in acetonitrile (120 ml) was added Ν-chlorosuccinimide (3.96 g, 29.66 mmol) ) and the resulting mixture was slowly heated to 80 ° C and stirred for 1.5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate. The aqueous layer was again extracted 2 times with dichloromethane. The organic layers are combined, dried over sodium sulfate and concentrated in vacuo. The crude product is purified using a short layer of silica gel and gradient elution (mixtures: hexane / ether (10%) to hexane / ether (40%)) to give a parachloro isomer in 50% yield.

NMR spectrum р (СОСО1 ₃ ) δ: 1.48 (9Н, s), 3.10-3.38 (4Н, m), 3.60-3.70 (4Н, m), 6.85-7, 18 (1H, m), 7,407.60 (2H, m). EMC m / ζ: 322 (M + 1), υν retention time: 3.07 min.

Stage 3.

5-chloro-2-piperazinyl-1-benzonitrile.

A solution of 4- (4-chloro-2-cyanophenyl) piperazine-1-carboxylic acid tert-butyl ester (0.32 g, 1 mmol) in dichloromethane, cooled at 0 ° C, is treated with trifluoroacetic acid (20%) and the mixture warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by treating the mixture with 10% aqueous sodium bicarbonate solution. The organic layers were separated and dried over sodium sulfate and concentrated in vacuo. This product is used without further purification. EMC m / ζ: 222 (M + 1), υν retention time: 1.05 min.

Stage 4.

5-Chloro-2- (4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene] propyl} piperazin-1 -yl) benzonitrile.

To a solution of 5-chloro-2-piperazin-1-yl-benzonitrile (0.22 g, 1 mmol) in isopropanol (8 ml) was added 2,6-lutidine (0.16 ml, 1.33 mmol) and the catalyst potassium iodide. This mixture is heated to 80 ° C and about

- 111 008060 work in portions of 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7yl] propan-2-ol (0.26 g, 0 , 67 mmol) for 2 hours. Then the solution was stirred at 80 ° C for another 18 hours. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate / 5% methanol to 90% ethyl acetate / 10% methanol) to obtain the title compound (0.11 g, 54%).

^! H-NMR (MeOI) δ: 1.40 (6H, s), 2.30-2.58 (8H, m), 3.00-3.15 (4H, m), 5.20 (1H, broad) s) 6.18 (1H, d), 6.70 (1H, dd), 7.18-7.84 (7H, m), 8.50 (1H, dd). EMC t / ζ: 515 (M + 1), DUT retention time: 1.75 min.

Example 541. 5-Chloro-2- (4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene] methyl ester] propyl} piperazin-1-yl) benzoic acid.

Stage 1

4- (2-Carboxy-4-chlorophenyl) piperazine-1-carboxylic acid tert-butyl ester.

To a solution of 4- (4-chloro-2-cyanophenyl) piperazine-1-carboxylic acid tert-butyl ester (0.6 g, 1.86 mmol) in methanol (4.0 ml) was added 1.0N. NaOH solution (4.0 ml, 4.0 mmol) and the resulting mixture was heated at boiling point (80 ° C) for 36 hours. An additional 2.0 ml of 1N was added. NaOH solution (2.0 mmol) and the reaction mixture is boiled for another 18 hours. The reaction mixture is concentrated and acidified to pH 4.0-5.0 using 1.0 normal HC1 acid, and the mixture is extracted with chloroform (5 times ) The combined organic layers were dried over sodium sulfate, concentrated and dried in vacuo overnight. A product containing approximately 20% amide is recovered after esterification in the next step. EMC m / ζ: 341 (M + 1), DUT retention time: 2.33 min.

Stage 2

4- (4-Chloro-2-methoxycarbonylphenyl) piperazine-1-carboxylic acid tert-butyl ester.

To a solution of 4- (2-carboxy-4-chlorophenyl) piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 1.88 mmol) in a toluene: methanol (9: 1) mixture was added trimethylsilyldiazomethane (2.0 M in hexane) (1.05 ml, 2.07 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane / ethyl acetate (10%) to hexane / ethyl acetate (fifty%).

NMR ^! H (SPS1 ₃ ) δ: 1.45 (9H, s), 2.90-3.00 (4H, m), 3.50-3.60 (4H, m), 3.90 (3H, s) 6.90-7.00 (1H, d), 7.357.45 (1H, dd), 7.80 (1H, d). EMC t / ζ: 355 (M + 1), DUT retention time: 3.11 min.

Stage 3.

5-Chloro-2-piperazinyl-1-benzoic acid methyl ester.

A solution of 4- (4-chloro-2-methoxycarbonylphenyl) piperazine-1-carboxylic acid tert-butyl ester (0.32 g, 0.92 mmol) in dichloromethane (5.0 ml), cooled at a temperature of 0 ° C, is treated trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The organic layers were separated and dried over sodium sulfate and concentrated in vacuo. This product is used without any further purification. EMC t / ζ: 255 (M + 1), DUT retention time: 1.14 min.

Stage 4. Methyl ether 5-chloro-2- (4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene] propyl} piperazin-1-yl) benzoic acid.

To a solution of 5-chloro-2-piperazin-1-yl-benzoic acid methyl ester (0.23 g, 0.916 mmol) in isopropanol (8.0 ml) was added 2.6-lutidine (0.16 ml, 1.33 mmol) and the catalyst is potassium iodide. This mixture is heated to a temperature of 80 ° C and treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.26 g, 0.67 mmol), which is added in parts over 2 hours. Then the solution is stirred at 80 ° C for another 18 hours. The reaction mixture is concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate / 5% methanol to 90% ethyl acetate / 10% methanol) to obtain the title compound.

^! H-NMR (DMSO) δ: 1.40 (6H, s), 2.15-2.55 (8H, m), 2.75-2.95 (4H, m), 3.75 (3H, s ), 5.20 (2H, br s), 6.10 (1H, t), 6.65 (1H, dd), 7.00-7.60 (6H, m), 7.70 (1H, dd), 8.50 (1H, dd). EMC t / ζ: 548 (M + 1), DUT retention time: 1.56 min.

Example 542. 2- (4-Chlorophenyl) -Y- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5- ylidene] propyl} piperidin-4-yl) acetamide.

Stage 1

4- [2- (4-Chlorophenyl) acetylamino] piperidine-1-carboxylic acid tert-butyl ester.

To a solution of 4-aminopiperidin-1-carboxylic acid tert-butyl ester (0.44 g, 2.2 mmol) and 4chlorophenylacetic acid (0.34 g, 2 mmol) in dichloromethane (10 ml), ΕΌί, Ί (0, 55 g, 2.8 mmol), HOBT (0.42 g, 2.8 mmol) and Ν-methylmorpholine (0.6 g, 6 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate. The aqueous layer was again extracted with dichloromethane (2 times). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product is purified using a short layer of silica gel and

- 112 008060 ethyl acetate to obtain the desired product.

NMR ¹ H (SPS1 ₃ ) δ: 1.15-1.25 (2H, m), 1.40 (9H, s), 1.80-1.90 (2H, m), 2.85 (2H, dd), 3.5 (2H, s), 4.00 (1H, br s), 5.20 (1H, d), 7.15-7.35 (4H, m). EMC t / ζ: 353 (M + 1), DUT retention time: 2.47 min.

Stage 2

2- (4-Chlorophenyl) -I-piperidin-4-yl-acetamide.

A solution of 4- [2- (4-chlorophenyl) acetylamino] piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.54 mmol) in dichloromethane (8.0 ml), cooled at 0 ° C, is treated trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product is purified on silica gel using gradient elution (from ethyl acetate: methanol (2%) to ethyl acetate: methanol (20%)).

NMR ¹ H (SPS1 ₃ ) δ: 1.15-1.25 (2H, m), 1.80-1.90 (2H, m), 2.60-2.75 (2H, m), 2, 90-3.10 (2H, m), 3.5 (2H, s), 3.85 (1H, m), 5.20 (1H, d), 7.15-7.35 (4H, m) . EMC t / ζ: 253 (M + 1), DUT retention time: 0.87 min.

Stage 3.

2- (4-Chlorophenyl) -I- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene 5-ylidene] propyl } piperidin-4-yl) acetamide.

To a solution of 2- (4-chlorophenyl) -I-piperidinyl-4-acetamide (0.2 g, 0.8 mmol) in isopropanol (6.0 ml) was added 2.6-lutidine (0.095 ml, 0.8 mmol) ) and the catalyst is potassium iodide. This mixture is heated to 80 ° C. and treated with portions of 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7yl] propan-2-ol (0 15 g, 0.4 mmol) for 2 hours. Then the solution was stirred at 80 ° C for another 18 hours. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate / 5% methanol up to 90% ethyl acetate / 20% methanol) to give the title compound.

NMR ¹ H (SPS1 ₃ ) δ: 1.15-1.50 (4H, m), 1.60 (6H, s), 1.80-2.85 (8H, m), 3.50 (2H, s), 3.70-3.90 (1H, m), 5.20 (2H, br s), 6.05 (1H, t), 6.80 (1H, d), 7.20-7 40 (7H, m) 7.60 (1H, dd), 8.50 (1H, dd). EMC t / ζ: 546 (M + 1), DUT retention time: 1.24 min.

Example 543. 2- {5- [3 - ({2 - [(4-Chlorophenyl) ethylamino] ethyl} ethylamino) propylidene] -5,11-dihydro-10oxa-1-aza-dibenzo [a, b] cycloheptene- 7-yl} propan-2-ol.

Stage 1

2- (5- {3- [2- (4-Chlorophenylamino) ethylamino] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl) propan-2 -ol.

To a solution of No. (4-chlorophenyl) ethane-1,2-diamine (0.68 g, 3.96 mmol) in isopropanol (8.0 ml) was added 2,6-lutidine (0.31 ml, 2.64 mmol ) and the catalyst is potassium iodide. This mixture is heated to 80 ° C and then treated with portions of 2- [5- (3-bromo-propylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten7-yl] propan-2- ol (0.15 g, 0.4 mmol) for 2 hours. Then the solution was stirred at 80 ° C for another 18 hours. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate (5% methanol to 90% ethyl acetate / 20% methanol) to give the title compound.

¹ H-NMR (DMSO) δ: 1.40 (6H, s), 2.20-2.40 (2H, m), 2.70-2.90 (3H, m), 3.10-3, 30 (3H, m), 5.20 (2H, broad, s), 5.80 (1H, m), 6.15 (1H, t), 6.60-6.70 (1H, m), 7, 10-7.30 (4H, m) 7.50 (2H, m), 7.80 (1H, dd), 8.50 (1H, dd). EMC t / ζ: 464 (M + 1), DUT retention time: 1.40 min.

Stage 2

2- {5- [3 - ({2 - [(4-Chlorophenyl) ethylamino] ethyl} ethylamino) propylidene] -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl } propan-2-ol.

To a solution of 2- (5- {3- [2- (4-chlorophenylamino) ethylamino] propylidene} -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl) propan-2 -ol (0.13 g, 0.27 mmol) in dichloroethane (5.0 ml) was added acetaldehyde (0.045 ml, 0.81 mmol), sodium triacetoxyborohydride (0.17 g, 0.81 mmol) and the catalyst was acetic acid, and stir the mixture at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product is purified on silica gel using gradient elution (from ethyl acetate (100%) to ethyl acetate / methanol (5%)).

¹ H NMR (SPS1 ₃ ) δ: 0.90-1.20 (6H, 2 x t), 1.60 (6H, s), 2.20-2.40 (2H, m), 2.45- 2.65 (6H, m), 3.20-3.40 (4H, 2 x q), 5.30 (2H, br., S), 6.10 (1H, t), 6.50 (2H dd), 6.80 (1H, d), 7.10 (2H, dd) 7.20-7.35 (2H, m), 7.45 (1H, dd), 7.55 (1H, dd ), 8.50 (1H, dd). EMC t / ζ: 520 (M + 1), DUT retention time: 1.51 min.

Example 544. Amide 1- (4-chlorophenyl) -4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5- ylidene] propyl} piperazine-2-carboxylic acid.

Stage 1

1- (4-Chlorophenyl) -4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5ylidene] propyl} piperazine- 2-carbonitrile.

- 113 008060

To a solution of 2- (5- {3- [2- (4-chlorophenylamino) ethylamino] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl) propane -2-ol (0.4 g, 0.86 mmol) in toluene (6 ml) add triethylamine (0.48 ml, 3.44 mmol) and 2,3-dibromopropionitrile (0.19 ml, 1.72 mmol) ) and the reaction mixture was heated to 110 ° C (refluxing) and stirred overnight for 18 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and extracted with 1.0 N solution No. 1OH. The aqueous layer was again extracted (2 times) with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified using a short layer of silica gel and ethyl acetate to give the title compound.

NMR Ή (SBS1 ₃ ) δ: 1.05 (6H, s), 2.20-2.70 (8H, 2 x m), 3.00 (1H, m), 3.10-3.40 (3H , 2 x m), 4.50 (1H, br. S), 5.30 (2H, br. S), 6.20 (1H, t), 6.70-6.90 (3H, 2 x d), 7.10-7.35 (4H, m), 7.50 (2H, d), 8.50 (1H, dd). EMC m / ζ: 515 (M + 1), υν retention time: 2.36 min.

Stage 2

Amide 1- (4-chlorophenyl) -4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene] propyl } piperazine-2-carboxylic acid.

To a solution of 1- (4-chlorophenyl) -4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene] propyl} piperazine-2-carbonitrile (0.12 g, 0.23 mmol) in methanol (0.5 ml) and tetrahydrofuran (0.5 ml) add 1.0N. No. 1OH (0.5 ml, 0.5 mmol) and the resulting mixture were heated to boiling at 80 ° C for 18 hours. An additional 0.5 ml of 2.0 N was added to the reaction mixture. solution No. 1OH (0.5 mmol) and refluxed for another 18 hours. The reaction mixture was concentrated, acidified to pH 5.0 using 1.0N. HC1 acid, and extracted with ethyl acetate (3 times). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified on silica gel (short layer) using gradient elution (mixture of ethyl acetate and 2-10% methanol) to give the title compound.

NMR Ή (SBS1 ₃ ) δ: 1.05 (6H, s), 2.20-2.70 (8H, 2 x m), 3.00 (1H, m), 3.10-3.40 (3H , 2 x m), 4.50 (1H, br., S), 5.30 (2H, br., S), 6.00 (1H, br., S), 6.20 (1H, t) 6.40 (1H, broad, s), 6.70-6.90 (3H, 2 x d), 7.10-7.35 (4H, m), 7.50 (2H, d), 8.50 (1H, dd). EMC t / ζ: 515 (M + 1), υν retention time: 1.32 min.

Example 545. 1- (4-Chlorophenyl) -4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-15-dibenzo [a, b] cycloheptene-5 -ilidene] propyl} piperazine-2-carbonitrile.

To a solution of 2- (5- {3- [2- (4-chlorophenylamino) ethylamino] propylidene} -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl) propan-2 -ol (0.4 g, 0.87 mmol) in toluene (6 ml) add triethylamine (0.48 ml, 3.44 mmol) and 2,3-dibromopropionitrile (0.19 ml, 1.72 mmol) and the reaction mixture was heated at 110 ° C (boiling) and stirred overnight for 18 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and extracted with 1.0N. solution No. 1OH. The aqueous layer was again extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude product is purified using a short layer of silica gel and ethyl acetate to obtain the desired product.

NMR Ή (SBS1 ₃ ) δ: 1.05 (6H, s), 2.20-2.70 (8H, 2 x m), 3.00 (1H, m), 3.10-3.40 (3H , 2 x m), 4.50 (1H, br. S), 5.30 (2H, br. S), 6.20 (1H, t), 6.70-6.90 (3H, 2 x d), 7.10-7.35 (4H, m), 7.50 (2H, d), 8.50 (1H, dd). EMC t / ζ: 515 (M + 1), υν retention time: 2.36 min.

Example 546. 1- (4-Chlorophenyl) -4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1aza-dibenzo [a, b] cycloheptene-5-ylide methyl ester ] propyl} piperazine-2-carboxylic acid.

Stage 1

1-tert-Butyl ether, 4- (9H-fluoren-9-yl) methyl ether, piperazine-1,2,4-tricarboxylic acid 2-methyl ester.

To a solution of 1-tert-butyl, 4- (9H-fluoren-9-yl) piperazine-1,2,4-tricarboxylic acid methyl ester (2.21 mmol) in toluene: methanol (9: 1) was added an equimolar amount trimethylsilyldiazomethane (2.0 mol / L in hexane) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and purified using gradient elution (from hexane / ethyl acetate (5%) to hexane / ethyl acetate (30%)). EMC t / ζ: 467 (M + 1), υν retention time: 3.04 min.

Stage 2

Piperazine-1,2-dicarboxylic acid 1-tert-butyl-, 2-methyl ester.

To a solution of 1-tert-butyl-, 4- (9H-fluoren-9-yl) methyl-, 2-methyl ester shesherazine 1,2,4-tricarboxylic acid (2.03 mmol) in DMF (4.0 ml) was added diethylamine (5%) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified using ethyl acetate / methanol (10%). EMC t / ζ: 245 (M + 1), υν retention time: 0.78 min.

Stage 3.

4- (4-Chlorophenyl) piperazine-1,3-dicarboxylic acid 1-tert-butyl, 3-methyl ester.

4-Chlorophenylboronic acid (2.0 eq, 3.68 mmol) and 1-tert-butyl, 2-methyl-piperazine-1,2-dicarboxylic acid ester (1.0 eq, 1.84 mmol) are dissolved in dichloromethane with subsequent

- 114 008060 by the addition of copper acetate (1.0 equiv.), Molecular sieve 4A and pyridine (2.0 equiv.). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, filtered through celite and concentrated. The crude product is purified using gradient elution (from hexane / ethyl acetate (5%) to hexane / ethyl acetate (20%)). EMC t / ζ: 354 (M + 1), υν retention time: 2.88 min. Reference: Tetraiebgop Leyegck, 2001, v. 42, p. 3415-3418.

Stage 4.

1- (4-Chlorophenyl) piperazine-2-carboxylic acid methyl ester.

A solution of 4- (4-chlorophenyl) piperazine-1,3-dicarboxylic acid tert-butyl 3-methyl ester (0.4 g, 1.13 mmol) in dichloromethane (5.0 ml) was cooled at 0 ° C, treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The combined organic layers were dried over sodium sulfate and concentrated. The product is used without any further purification. EMC m ”: 254 (M + 1), υν retention time: 1.01 min.

Stage 5.

1- (4-Chlorophenyl) -4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene methyl ester] propyl} piperazine-2-carboxylic acid.

To a solution of 1- (4-chlorophenyl) piperazine-2-carboxylic acid methyl ester (0.14 g, 0.53 mmol) in a mixture of acetonitrile: water (4: 1), potassium carbonate (0.083 g, 0.6 mmol) is added and (E) -2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (150 mg 0.4 mmol) and the resulting mixture was stirred at 50 ° C for 5 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product is purified by flash chromatography on silica gel using gradient elution (from ethyl acetate (100%) to ethyl acetate / 5% methanol).

NMR ^! H (SPS1 ₃ ) δ: 1.05 (6H, s), 2.20-2.70 (8H, 2 x 1m), 3.00 (1H, m), 3.10-3.40 (3H, 2 x m), 3.55 (3H, s), 4.50 (1H, br., S), 5.30 (2H, br., S), 6.20 (1H, t), 6.70 -6.90 (3H, 2 x d), 7.10-7.35 (4H, m), 7.50 (2H, d), 8.50 (1H, dd). EMC m / ζ: 548 (M + 1), υν retention time: 1.62 min.

Example 547. 5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11 dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl ester of isopropylcarbamic acid.

5- {3- [4- (4-Chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cycloheptene -7-ol (0.27 mmol, 1.0 equiv.) Is dissolved in tetrahydrofuran and treated with triethylamine (1.50 equiv.) And isopropylisocyanate (0.4 mmol, 1.50 equiv.). The resulting mixture was heated to 50 ° C. for 18 hours. The reaction mixture was concentrated and the crude product was purified on silica gel using gradient elution from ethyl acetate (100%) and ethyl acetate / methanol (5%).

NMR ^! H (SPS1 ₃ ) δ: 0.70 (3H, s), 0.90 (3H, s), 1.1 (3H, d), 1.25 (3H, d), 1.4 (1H, m ), 1.6 (1H, m), 2.302.50 (8H, m), 2.70 (2H, m), 3.80-4.00 (3H, m), 3.55 (3H, s) 4.85 (1H, m), 5.30 (2H, broad, s), 6.20 (1H, t), 6.807.00 (2H, dd), 7.20-7.45 (6H, m), 7.60 (1H, dd), 8.50 (1H, dd). EMC m / ζ: 576 (M + 1), υν retention time: 1.58 min.

Example 548. 3- (4-Chlorophenyl) -1-ethyl-1- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cyclohepten-5-ylidene] propyl} pyrrolidin-3-yl) urea.

Stage 1. tert-Butyl ether, 3-ethylaminopyrrolidine-1-carboxylic acid.

To a solution of (K) -3-amino-1-N-butoxycarbonylpyrrolidine (1 equiv., 5.37 mmol) in methanol (20 ml) was added acetaldehyde (0.95 equiv.) And the resulting mixture was heated to 80 ° C and stirred in for 2 hours, then stirred at room temperature overnight. Sodium borohydride (0.95 equiv, 5.1 mmol) was added and the reaction mixture was stirred for another 2 hours. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product was purified on silica gel using eluents: hexane / ethyl acetate (10%) to hexane / ethyl acetate (50%).

NMR ^! H (SPS1 ₃ ) δ: 1.05 (3H, t), 1.45 (9H, s), 1.60-1.75 (1H, m), 2.00-2.10 (1H, m) 2.68 (4H, q), 2.903.15 (1H, m), 3.25-3.65 (4H, m). EMC t / ζ: 215 (M + 1), υν retention time: 0.75 min.

Stage 2

3- [3- (4-Chlorophenyl) -1-ethylureido] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3-ethylaminopyrrolidine-1-carboxylic acid tert-butyl ester (0.33 g, 1.5 mmol) in DMF (5.0 ml) was added dropwise a solution of 4-chlorophenyl-isocyanate (0.23 g, 1, 51 mmol) in DMF (2.5 ml) at room temperature and the resulting mixture was stirred for 3 hours. The reaction mixture was concentrated in vacuo and the crude product was purified on silica gel using hexane / ethyl acetate (50%) and then pure ethyl acetate (100% ) to obtain the desired product as a white foamy solid. EMC t / ζ: 368 (M + 1), υν retention time: 2.61 min.

Stage 3.

3- (4-Chlorophenyl) -1-ethyl-1-pyrrolidinyl-3-urea.

Solution of 3- [3- (4-chlorophenyl) -1-ethylureido] pyrrolidine-1-carboxylic acid tert-butyl ester

115 008060 ty (0.4 g, 1.08 mmol) in dichloromethane (5.0 ml), cooled at 0 ° С, treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 hours. the mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The combined organic layers are dried over sodium sulfate. This product is used without any further purification. EMC t / ζ: 268 (M + 1), DUT retention time: 1.02 min.

Stage 4.

3- (4-Chlorophenyl) -1-ethyl-1- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, d] cycloheptene -5-ylidene] propyl} pyrrolidin-3-yl) urea.

To a solution of 3- (4-chlorophenyl) -1-ethyl-1-pyrrolidin-3-yl-urea (0.21 g, 0.8 mmol) in a mixture of acetonitrile zod (4: 1), potassium carbonate (0.16 g , 0.8 mmol) and (E) -2- [5- (3-bromopropylidene) -5,11 dihydro-10-oxa-1-azadibenzo [a, th] cyclohepten-7-yl] propan-2-ol (0, 15 g, 0.4 mmol) and the resulting mixture was stirred at 50 ° C for 24 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel using gradient elution (from ethyl acetate / methanol (5%) to ethyl acetate / methanol (10%)) to obtain the desired product as a yellow solid.

NMR Ή (SPS1 ₃ ) δ: 1.05 (3H, s), 1.40 (6H, s), 1.80 (1H, m), 2.20-2.40 (3H, m), 2, 50-3.00 (8H, m), 3.40 (4H, q and m), 4.20 (1H, m), 5.20 (2H, br., S), 6.20 (1H, t ), 6.65 (1H, d), 7.00 (2H, dd), 7.20-7.40 (5H, m), 7.70 (1H, dd), 8.50 (1H, dd) 9.80 (1H, br s). EMC t / ζ: 561 (M + 1), DUT retention time: 1.45 min.

Example 549. 2- (5- {3- [3- (4-Chlorobenzyloxy) pyrrolidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1aza-dibenzo [a, th] cycloheptene-7- il) propan-2-ol.

Stage 1

(K) -3- (4-chlorobenzyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester.

A solution of (K) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.14 mmol, 1.0 eq.) In THF (2.5 ml) was added to a suspension of sodium hydride (1.15 eq.) In THF (2.5 ml) cooled at 0 ° C and the resulting mixture was stirred for 45 minutes. Then, a solution of 4chlorobenzyl bromide (1.31 mmol, 1.15 equiv.) In THF (2.0 ml) was added dropwise and the reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with water (1.0 ml) ) and diluted with ethyl acetate. The combined organic layers are dried over sodium sulfate. The crude product is purified on silica gel using gradient elution (from hexane / ethyl acetate (10%) to hexane / ethyl acetate (30%)).

NMR '11 (SBS _{1 3} ) δ: 1.45 (9H, s), 1.80-2.05 (2H, m), 3.30-3.55 (4H, m), 4.05 (1H, m), 4.45 (2H, s), 7.157.30 (4H, m). EMC m / x: 311 (M + 1), DUT retention time: 2.94 min.

Stage 2

(K) -3- (4-Chlorobenzyloxy) pyrrolidine.

A solution of (K) -3- (4-chlorobenzyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester (0.88 mmol) in dichloromethane, cooled at 0 ° C, is treated with trifluoroacetic acid (20%), warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The combined organic layers are dried over sodium sulfate. This product is used without any further purification. EMC t / ζ: 211 (M + 1), DUT retention time: 0.97 min.

Stage 3.

2- (5- {3- [3- (4-Chlorobenzyloxy) pyrrolidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-aza-dibenzo [a, th] cyclohepten-7-yl ) propan-2-ol.

To a solution of (K) -3- (4-chlorobenzyloxy) pyrrolidine (0.88 mmol, 2.0 equiv.) In a mixture of acetonitrile: water (4: 1), potassium carbonate (0.88 mmol, 2.0 equiv. ) and (E) -2- [5- (3-bromopropylidene) -5,11-dihydro-10oxa-1-azadibenzo [a, th] cyclohepten-7-yl] propan-2-ol and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product is purified by reverse phase HPLC.

NMR '11 (SBS _{1 3} ) δ: 1.40 (6H, s), 1.15-1.35 (1H, m), 1.85-2.05 (1H, m), 2.20-2, 40 (1H, m), 2.35-2.65 (8H, m), 3.90-4.10 (1H, m), 4.30-4.50 (2H, d), 5.10- 5.30 (2H, broad, s), 6.05 (1H, d), 6.50 (1H, dd), 7.10-7.50 (4H, m), 7.70 (1H, dd ), 8.50 (1H, dd). EMC t / ζ: 505 (M + 1), DUT retention time: 1.52 min.

Example 550. 2- [5- (3- {3 - [(4-Chlorobenzyl) isobutylamino] pyrrolidin-1-yl} propylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, th ] cyclohepten-7-yl] propan-2-ol.

Stage 1

3- (4-Chlorobenzylamino) pyrrolidine-1-carboxylic acid tert-butyl ester.

(K) -3-amino-1-no. Butoxycarbonylpyrrolidine (1.0 eq., 2.68 mmol), 4-chlorobenzyl bromide (1.0 eq., 2.68 mmol) and potassium carbonate (1.75 eq.) mixed in ethanol (10 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel using ethyl acetate. EMC t / ζ: 311 (M + 1), DUT retention time: 1.18

- 116 008060 minutes

Stage 2

3 - [(4-chlorobenzyl) isobutylamino] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3- (4-chlorobenzylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.28 mmol) and isobutyraldehyde (0.14 g, 1.92 mmol) in dichloroethane is added sodium triacetoxyborohydride (0 , 81 g, 3.85 mmol) and the catalyst is acetic acid. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product was purified on silica gel using gradient elution (from hexane / ethyl acetate (10%) to hexane / ethyl acetate (50%)).

NMR '11 (ΟΌΟ1 ₃ ) δ: 0.80 (6H, 2 x d), 1.45 (9H, s), 1.60-1.90 (2H, m), 2.20 (2H, d) 3.00-3.70 (7H, m); 7.20 (4H, s). EMC t / ζ: 367 (M + 1), DUT retention time: 1.89 min.

Stage 3.

(4-Chlorobenzyl) isobutylpyrrolidin-3-yl-amine.

To a solution of 3 - [(4-chlorobenzyl) isobutylamino] pyrrolidine-1-carboxylic acid tert-butyl ester in dichloromethane, cooled at 0 ° С, trifluoroacetic acid (20%) was added and heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The combined organic layers were dried over sodium sulfate and concentrated. This product is used without any further purification. EMC t / ζ: 267 (M + 1), DUT retention time: 0.93 min.

Stage 4.

2- [5- (3- {3 - [(4-Chlorobenzyl) isobutylamino] pyrrolidin-1-yl} propylidene) -5,11-dihydro-10-oxa-1aza-dibenzo [a, b] cycloheptene-7- il] propan-2-ol.

To a solution of (4-chlorobenzyl) isobutylpyrrolidinyl-3-amine (0.16 g, 0.6 mmol) in a mixture of acetonitrile: water (4: 1), potassium carbonate (0.8 mmol) and (E) -2- [ 5- (3-bromopropylidene) -5,11-dihydro-10oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.15 g, 0.4 mmol), and the resulting mixture stirred at a temperature of 50 ° C for 24 hours. The reaction mixture was concentrated, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified by flash chromatography using ethyl acetate / methanol (5%).

NMR '11 (ΟΌΟ1 ₃ ) δ: 0.80 (6H, d), 1.55 (6H, s), 1.60-1.90 (4H, m), 2.15 (1H, d), 2 , 20-2.60 (6H, m), 3.253.60 (2H, m), 5.30 (2H, broad, s), 6.10 (1H, t), 6.80 (1H, dd) 7.15-7.30 (6H, m), 7.40 (1H, d), 7.55 (1H, dd), 8.45 (1H, dd). EMC t / ζ: 560 (M + 1), DUT retention time: 1.66 min.

Example 551. 2- [5- (3 - {3 - [(4-Chlorobenzyl) isopropylamino] pyrrolidin-1-yl} propylidene) -5.11 dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol.

Stage 1

3-Isopropylaminopyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of (K) -3-amino-1-Y-butoxycarbonylpyrrolidine (1.0 eq., 2.68 mmol) in methanol (15 ml) was added acetone (1.07 eq.), Sodium cyanoborohydride (2.0 eq. .) and a few drops of acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product is purified on silica gel using gradient elution (from hexane / ethyl acetate (5%) to hexane / ethyl acetate (30%)).

NMR '11 (СОС1 ₃ ) δ: 1.05 (6Н, d), 1.45 (9Н, s), 1.60 (1Н, m), 2.80-3.00 (2Н, m), 3 20-3.70 (4H, m). EMC t / ζ: 229 (M + 1), yw retention time: 0.77 min.

Stage 2

3 - [(4-Chlorobenzyl) isopropylamino] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of isopropylpyrrolidinyl-3-amine (0.3 g, 1.31 mmol) in dichloroethane (5.0 ml) was added

4-chlorobenzaldehyde (0.22 g, 1.57 mmol), sodium triacetoxyborohydride (0.83 g, 3.93 mmol) and acetic acid catalyst, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product was purified on silica gel using hexane / ethyl acetate (50%).

NMR / 1 (ΟΌΟ1 ₃ ) δ: 1.05 (6H, d), 1.45 (9H, s), 1.60 (1H, m), 2.80-3.00 (2H, m), 3 20-3.70 (4H, m); 7.20 (4H, m). EMC t / ζ: 353 (M + 1), DUT retention time: 1.49 min.

Stage 3.

(4-Chlorobenzyl) isopropylpyrrolidinyl-3-amine.

A solution of 3 - [(4-chlorobenzyl) isopropylamino] pyrrolidine-1-carboxylic acid tert-butyl ester in dichloromethane, cooled at 0 ° C, is treated with trifluoroacetic acid (20%), heated

117 008060 was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate. The combined organic layers are dried over sodium sulfate. The product is used without any further purification. EMC t / ζ: 253 (M + 1), DUT retention time: 0.59 min.

Stage 4.

2- [5- (3- {3 - [(4-Chlorobenzyl) isopropylamino] pyrrolidin-1-yl} propylidene) -5,11-dihydro-10-oxa-1 aza-dibenzo [a, b] cycloheptene-7 -yl] propan-2-ol.

To a solution of (4-chlorobenzyl) isopropylpyrrolidinyl-3-amine (0.68 mmol, 1.7 equiv.) In a mixture of acetonitrile: water (4: 1), potassium carbonate (0.8 mmol, 2 equiv.) And (E ) -2- [5- (3-bromopropylidene) -5.11 dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.4 mmol, 1.0 equiv .), and the resulting mixture was stirred at 50 ° C for 24 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product is purified by flash chromatography using ethyl acetate / methanol.

NMR Ή (SBS1 ₃ ) δ: 0.85 (6H, d), 1.50-1.90 (10Η, m), 2.10-2.60 (8H, m), 3.50 (3Η, m) ), 5.30 (2H, broad, s), 6.10 (1H, t), 6.80 (1H, dd), 7.10-7.40 (8H, m), 7.50 (1Η d), 8.50 (1Η, dd). EMC t / ζ: 546 (M + 1), DUT retention time: 1.40 min.

Example 552. 2 - [(4-Chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene ] propyl} pyrrolidin-3-yl) amino] acetamide.

Stage 1

3- (carbamoylmethylamino) pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of (K) -3-amino-1-N-butoxycarbonylpyrrolidine (0.5 g, 2.68 mmol) and 2-bromoacetamide (0.44 g, 3.21 mmol) in DMF (6.0 ml) was added carbonate potassium (1.11 g, 8.04 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and redissolved in dichloromethane. Potassium carbonate was filtered off and the filtrate was concentrated and purified using ethyl acetate / methanol (5%).

NMR Ή (СОС1 ₃ ) δ: 1.50 (9Н, s), 1.60-1.80 (2Н, m), 2.10 (1Н, m), 3.10-3.60 (6Н, m ), 5.65 (1 H, broad s), 6.90 (1 шир, broad s). EMC t / ζ: 367 (M + 1), DUT retention time: 0.61 min.

Stage 2

3- [Carbamoylmethyl- (4-chlorobenzyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3- (carbamoylmethylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 2.03 mmol) in dichloroethane (5.0 ml) was added 4-chlorobenzaldehyde 0.34 g, 2.44 mmol) , sodium triacetoxyborohydride (0.86 g, 4.06 mmol) and acetic acid catalyst and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product is purified on silica gel using ethyl acetate.

NMR Ή (СОС1 ₃ ) δ: 1.50 (9Н, s), 1.60-1.80 (2Н, m), 2.10 (1Н, m), 3.10-3.60 (8Н, m ), 5.65 (1H, broad, s), 6.90 (1Η, broad, s) 7.20-7.40 (4H, m). EMC t / ζ: 367 (M + 1), DUT retention time: 1.94 min.

Stage 3.

2 - [(4-Chlorobenzyl) pyrrolidinyl-3-amino] acetamide.

A solution of 3- [carbamoylmethyl- (4-chlorobenzyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 1.32 mmol) in dichloromethane, cooled at 0 ° C, is treated with trifluoroacetic acid (20%) . The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The combined organic layers are dried over sodium sulfate. The product is used without any further purification. EMC t / ζ: 267 (M + 1), DUT retention time: 0.82 min.

Stage 4.

2 - [(4-Chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -1Sh-10-oxa-1-azadibenzo [a, b] cycloheptene-5ylidene] propyl} pyrrolidine- 3-yl) amino] acetamide.

To a solution of 2 - [(4-chlorobenzyl) pyrrolidin-3-yl-amino] acetamide (0.21 g, 0.8 mmol) in a mixture of acetonitrile: water (4: 1), potassium carbonate (0.6 mmol) was added and (E) -2- [5- (3-bromopropylidene) -5,11-dihydro-10oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50 ° C for 24 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product is purified by HPLC.

NMR Ή (SPS1 ₃ ) δ: 1.35 (6H, s), 1.55-1.75 (1Η, m), 1.80-2.00 (1H, m), 2.20-2.85 (8H, m), 2.90-3.10 (2H, d), 3.30-3.50 (1Η, m), 3.60 (1H, d), 4.80-5.30 (2H broad, s), 6.10 (1H, t), 6.70 (1H, dd), 7.00-7.45 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). EMC t / ζ: 562 (M + 1), DUT retention time: 1.31 min.

Example 553. 2 - [(4-Chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene ] propyl} pyrrolidin-3-yl) amino] -noethylacetamide.

Stage 1

- 118 008060 3- (methoxycarbonylmethylamino) pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of (K.) - 3-amino-1-I-butoxycarbonylpyrrolidine (0.5 g, 2.68 mmol) and methyl bromoacetate (0.49 g, 2.95 mmol) in DMF (6.0 ml) was added carbonate potassium (1.11 g, 8.04 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and redissolved in dichloromethane. Potassium carbonate was filtered off and the filtrate was concentrated and purified using gradient elution (from hexane / ethyl acetate (10%) to hexane / ethyl acetate (50%)).

NMR Ή (СОС1 ₃ ) δ: 1.40 (9Н, s), 1.70 (2Н, m), 2.00 (1Н, m), 3.20-3.60 (5Н, m), 3, 79 (3H, br s). EMC t / ζ: 258 (M + 1), υν retention time: 0.74 min.

Stage 2

3 - [(4-Chlorobenzyl) methoxycarbonylmethylamino] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3- (methoxycarbonylmethylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.03 mmol) in dichloroethane (5.0 ml) was added 4-chlorobenzaldehyde (0.34 g, 2.44 mmol) ), sodium triacetoxyborohydride (0.86 g, 4.06 mmol) and an acetic acid catalyst, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product is purified on silica gel using ethyl acetate.

NMR Ή (SHS1 ₃ ) δ: 1.40 (9H, s), 1.80 (1H, m), 2.10 (1H, m), 3.00-3.80 (7H, m), 4, 70 (1H, br. S), 7.20 (4H, m). EMC m / ζ: 383 (M + 1), υν: retention time: 2.91 min.

Stage 3.

3- [Carboxymethyl- (4-chlorobenzyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester.

A solution of 3 - [(4-chlorobenzyl) methoxycarbonylmethylamino] pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.31 mmol) in methanol (4.00 ml) and 1.0N. aqueous solution No. 1OH (4.00 ml) was heated at boiling point (80 ° C) for 2.5 hours. The reaction mixture was concentrated, acidified to pH 5.0 using 1.0N. HC1 acid, and extracted with dichloromethane (3 times). This product is used in the next step without further purification. EMC t / ζ: 369 (M + 1), υν retention time: 1.85 min.

Stage 4.

3 - [(4-Chlorobenzyl) ethylcarbamoylmethylamino] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3- [carboxymethyl- (4-chlorobenzyl) amino] pyrrolidine-1 carboxylic acid tert-butyl ester (0.48 g, 1.30 mmol) in tetrahydrofuran (10 ml) was added ΕΌί.Ί (0.39 g, 1 , 95 mmol), NOVT (0.26 g, 1.95 mmol) and stirred for 30 minutes, followed by the addition of Ν methylmorpholine (0.43 ml, 3.90 mmol) and Ν-ethylamine (0.1 ml, 1, 95 mmol). The reaction mixture was stirred at room temperature for 18 hours. After concentration, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product is purified on silica gel using gradient elution (from hexane / ethyl acetate (50%) to pure ethyl acetate). EMC m / ζ: 396 (M + 1), υν retention time: 2.18 min.

Stage 5.

2 - [(4-Chlorobenzyl) pyrrolidin-3-yl-amino] -Y-ethylacetamide.

A solution of 3 - [(4-chlorobenzyl) ethylcarbamoylmethylamino] pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.31 mmol) in dichloromethane, cooled at 0 ° C., is treated with trifluoroacetic acid (20%). The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The combined organic layers are dried over sodium sulfate. This product is used without any further purification. EMC t / ζ: 296 (M + 1), υν retention time: 1.02 min.

Stage 6.

2 - [(4-Chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, 6] cycloheptene-5ylidene] propyl} pyrrolidin-3-yl) amino] -Y-ethylacetamide.

To a solution of 2 - [(4-chlorobenzyl) pyrrolidin-3-yl-amino] -Y-ethylacetamide (0.09 g, 0.31 mmol) in a mixture of acetonitrile: water (4: 1) is added potassium carbonate (0.07 g, 0.51 mmol) and (E) -2- [5- (3-bromopropylidene) 5,11-dihydro-10-oxa-1-aza-dibenzo [a, 6] cyclohepten-7-yl] propan- 2-ol (0.095 g, 0.25 mmol) and the resulting mixture was stirred at 50 ° C for 24 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product is purified on silica gel using ethyl acetate.

NMR Ή (SHS1 ₃ ) δ: 0.90 (3H, s), 1.40 (6H, s), 1.60 (1H, m), 1.85 (1H, m), 2.10-2, 55 (8H, m), 2.90-3.10 (4H, m), 3.25-3.40 (4H, m), 3.55 (2H, d), 4.95 (2H, s) 5.10 (2H, br s), 6.10 (1H, d), 6.70 (1H, dd), 7.15-7.25 (1H, dd), 7.25-7.45 (4H, m), 7.55-7.75 (2H, m), 8.50 (1H, dd). EMC t / ζ: 589 (M + 1), υν retention time: 1.42 min.

- 119 008060

Example 554. 2- [5- (3- {3 - [(4-Chlorobenzyl) - (2-hydroxyethyl) amino] pyrrolidin-1-yl} propylidene) 5,11-dihydro-10-oxa-1-aza dibenzo [a, b] cyclohepten-7-yl] propan-2-ol.

Stage 1

3 - [(4-chlorobenzyl) - (2-hydroxyethyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3 - [(4-chlorobenzyl) methoxycarbonylmethylamino] pyrrolidine-1 carboxylic acid tert-butyl ester (0.44 g, 1.15 mmol) in methanol, cooled to 0 ° C, sodium borohydride (0.13 g, 3 , 45 mmol) and the resulting mixture was heated to 65 ° C for 16 hours. More sodium borohydride (0.26 g, 6.90 mmol) was added to the reaction mixture, and the mixture was stirred for an additional 18 hours at 65 ° C. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate. The crude product is purified on silica gel using gradient elution (from hexane / ethyl acetate (50%) to pure ethyl acetate). EMC m / ζ: 355 (M + 1), DUT retention time: 1.27 min.

Stage 2

2 - [(4-Chlorobenzyl) pyrrolidinyl-3-amino] ethanol.

A solution of 3 - [(4-chlorobenzyl) - (2-hydroxyethyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 0.6 mmol) in dichloromethane, cooled at 0 ° C, is treated with trifluoroacetic acid (twenty%). The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The combined organic layers are dried over sodium sulfate. This product is used without any further purification. EMC t / ζ: 255 (M + 1), DUT retention time: 0.34 min.

Stage 3.

2- [5- (3- {3 - [(4-Chlorobenzyl) - (2-hydroxyethyl) amino] pyrrolidin-1-yl} propylidene) -5,11-dihydro-10oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol.

To a solution of 2 - [(4-chlorobenzyl) pyrrolidin-3-yl-amino] ethanol (0.15 g, 0.6 mmol) in a mixture of acetonitrile: water (4: 1), potassium carbonate (0.11 g, 0 , 8 mmol) and (E) -2- [5- (3-bromopropylidene) -5,11-dihydro10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0, 15 g, 0.4 mmol) and the resulting mixture was stirred at 50 ° C for 24 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product is purified on silica gel.

NMR '11 (SPS1 ₃ ) δ: 1.40 (6H, s), 1.60 (1H, m), 1.80 (1H, m), 2.10-2.60 (8H, m), 3 , 20-3.40 (6H, m), 3.50 (2H, m), 5.20 (2H, br s), 6.15 (1H, t), 6.70 (1H, t), 7.18-7.42 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). EMC t / ζ: 548 (M + 1), yw retention time: 1.26 min.

Example 555. Methyl ester 3 - [(4-chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1azadibenzo [a, b] cycloheptene-5-ylidene ] propyl} pyrrolidin-3-yl) amino] propionic acid.

Stage 1

3- (2-Methoxycarbonylethylamino) pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of (K) -3-amino-1-Y-butoxycarbonylpyrrolidine (0.5 g, 2.68 mmol) and 3-bromopropionate (0.49 g, 2.95 mmol) in DMF (6.0 ml) was added potassium carbonate (1.11 g, 8.04 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and redissolved in dichloromethane. Potassium carbonate was filtered off, the filtrate was concentrated, and the crude product was used in the next step. EMC t / ζ: 272 (M + 1), DUT retention time: 1.28 min.

Stage 2

3 - [(4-Chlorobenzyl) - (2-methoxycarbonylethyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of 3- (2-methoxycarbonylethylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (0.73 g, 2.68 mmol) in dichloroethane (10.0 ml) was added 4-chlorobenzaldehyde (0.42 g, 2, 95 mmol), sodium triacetoxyborohydride (1.71 g, 8.04 mmol) and an acetic acid catalyst, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product is purified on silica gel using gradient elution (from hexane / ethyl acetate (15%) to hexane / ethyl acetate (50%)).

NMR '11 (SPS1 ₃ ) δ: 1.35 (9H, s), 1.80 (1H, m), 1.90 (1H, m), 2.40 (2H, t), 2.85 (2H , t), 3.00-3.80 (7H, m), 4.70 (1H, d), 7.20 (4H, m). EMC t / ζ: 397 (M + 1), DUT retention time: 1.99 min.

Stage 3.

3 - [(4-Chlorobenzyl) pyrrolidinyl-3-amino] propionic acid methyl ester.

A solution of tert-butyl ether 3 - [(4-chlorobenzyl) - (2-methoxycarbonylethyl) amino] pyrrolidine-1 carboxylic acid (0.08 g, 0.2 mmol) in dichloromethane, cooled at 0 ° C, is treated with trifto

- 120 008060 acetic acid (20%).

The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the free base was isolated by adding 10% aqueous sodium bicarbonate solution. The combined organic layers are dried over sodium sulfate. The product is used without any further purification. EMC t / ζ: 297 (Μ + 1), DUT retention time: 1.05 min.

Stage 4.

Methyl ester 3 - [(4-chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11Н-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5 - ylidene] propyl} pyrrolidin-3-yl) amino] propionic acid.

To a solution of 3 - [(4-chlorobenzyl) pyrrolidin-3-yl-amino] propionic acid methyl ester (0.06 g, 0.2 mmol) in a mixture of acetonitrile: water (3: 1), potassium carbonate (0.056 g, 0.4 mmol) and (E) -2- [5- (3bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.065 g, 0.17 mmol) and the reaction mixture was stirred at 50 ° C. for 24 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel using ethyl acetate / methanol (5%).

NMR '11 (SPS1 ₃ ) δ: 1.40 (6H, s), 1.60 (1H, m), 1.80 (1H, m), 2.10-2.60 (8H, m), 3 , 20-3.40 (6H, m), 3.50 (2H, m; 2H, s), 5.20 (2H, br s), 6.15 (1H, t), 6.70 (1H , t), 7.18-7.42 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). EMC t / ζ: 590 (Μ + 1), and Y retention time: 1.51 min.

Example 556. 2- (5- {3- [4- (4-Chlorophenyl) -3- (8) methylpiperazin-1-yl] propylidene} -5,11-dihydro-10oxa-1-aza-dibenzo [a , b] cyclohepten-7-yl) propan-2-ol.

Stage 1

3- (§) -methylpiperazine-1-carboxylic acid tert-butyl ester.

Triethylamine (3 g, 4.2 ml, 30 mmol) is added to a solution of 2- (§) methylpiperazine (2 g, 20 mmol) in dichloromethane (40 ml), followed by the addition of di-tert-butyl dicarbonate (4.8 g, 22 mmol). The reaction mixture was stirred at room temperature for 20 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The crude product is purified using a short layer of silica gel using a mixture of hexane / ethyl acetate (1: 1).

NMR 11 (SPS1 ₃ ) δ: 1.03 (3H, d), 1.45 (9H, s), 1.65 (1H, s), 2.35-2.42 (1H, m), 2, 66-2.80 (3H, m), 2.922.95 (1H, m), 3.92 (2H, br s). EMC t / ζ: 201 (M + 1).

Stage 2

4- (4-Chlorophenyl) -3- (8) -methylpiperazine-1-carboxylic acid tert-butyl ester.

To a mixture of 4-chlorobromobenzene (1.05 g, 5.5 mmol) and 3- (§) methylpiperazine-1 carboxylic acid tert-butyl ester (1 g, 5 mmol) in toluene (30 ml), tris (dibenzylideneacetone) dipalladium (0) (0.057 g, 0.063 mmol), ΒΙΝΑΡ (0.12 g, 0.19 mmol) and sodium tert-butoxide (2.02 g, 21 mmol). The resulting mixture was heated at 110 ° C for 20 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Chromatographic purification (eluent -10% ethyl acetate in hexane) gives 0.79 g (51%) of the title compound.

NMR '11 (SPS1 ₃ ) δ: 0.97 (3H, s), 1.48 (9H, s), 3.00-3.24 (3H, m), 3.32-3.38 (1H, m), 3.72-3.79 (2H, m), 3.884.05 (1H, m), 6.81 (2H, d), 7.21 (2H, d). EMC t / ζ: 311 (M), DUT retention time: 3.2 min.

Stage 3.

2- (5- {3- [4- (4-Chlorophenyl) -3- (8) methylpiperazin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl) propan-2-ol.

4- (4-Chlorophenyl) -3- (8) -methylpiperazine-1-carboxylic acid tert-butyl ester (0.79 g, 2.6 mmol) was treated with a 4M solution of HC1 in dioxane (20 ml) at room temperature for 3 hours. The solvent was evaporated and the residue was dissolved in dichloromethane and washed several times with saturated sodium bicarbonate solution. The combined organic phases are dried over sodium sulfate. The residue is transferred to the next step without further purification.

To a solution of 4- (4-chlorophenyl) -3- (8) methylpiperazine (0.56 g, 2.6 mmol) in isopropanol (20 ml) was added 2,6-lutidine (0.305 ml, 2.6 mmol) and the catalyst is potassium iodide. This mixture is heated to 80 ° C. and then treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7yl] propan-2-ol (0.64 g, 1.7 mmol), which is added in parts over 2 hours. Then the solution is stirred at 80 ° C for another 20 hours. The reaction mixture is concentrated in vacuo and purified by flash chromatography (from pure dichloromethane up to 2% methanol in dichloromethane) to give the title compound (0.151 g, 18%).

NMR '11 (SPS1 ₃ ) δ: 1.0 (3H, d), 1.57 (6H, s), 1.79 (s, 1H), 2.25-2.52 (7H, m), 2 66-2.69 (1H, m), 2.983.12 (2H, m), 3.68-3.73 (1H, m), 5.32 (2H, broad s), 6.17 (1H , t), 6.82 (3H, d), 7.18-7.31 (4H, m), 7.44 (1H, d), 7.567.60 (1H, m), 8.50 (1H, dd). EMC t / ζ: 504 (M), DUT retention time: 1.49 min.

Example 557. 2- (5- {3- [4- (4-Chlorophenyl) -3- (P) -methylpiperazin-1-yl] propylidene} -5,11-dihydro-10oxa-1-aza-dibenzo [a , b] cyclohepten-7-yl) propan-2-ol.

- 121 008060

Stage 1

3- (K) -methylpiperazine-1-carboxylic acid tert-butyl ester.

Triethylamine (3 g, 4.2 ml, 30 mmol) was added to a solution of (K) -2-methylpiperazine (2 g, 20 mmol) in dichloromethane (40 ml) followed by di-tert-butyl dicarbonate (4.8 g, 22 mmol). The reaction mixture was stirred at room temperature for 20 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The crude product is purified using a short layer of silica gel and a mixture of hexane / ethyl acetate (1: 1).

NMR Ή (SPS1 ₃ ) δ: 1.05 (3H, d), 1.45 (9H, s), 2.11 (1H, s), 2.37-2.44 (1H, m), 2.66- 2.79 (3H, m), 2.932.96 (1H, m), 3.93 (2H, br s). EMC t / ζ: 201 (M + 1).

Stage 2

4- (4-Chlorophenyl) -3- (K) -methylpiperazine-1-carboxylic acid tert-butyl ester.

To a mixture of 4-chlorobromobenzene (0.53 g, 2.75 mmol) and 3- (K) -methylpiperazine-1-carboxylic acid tert-butyl ester (0.5 g, 2.5 mmol) in toluene (20 ml) is added Tris (dibenzylideneacetone) dipalladium (0) (0.029 g, 0.032 mmol), ΒΙΝΑΡ (0.058 g, 0.093 mmol) and sodium tert-butoxide (1.01 g, 10.5 mmol). The resulting mixture was heated at 110 ° C for 20 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Chromatographic purification (eluent 10% ethyl acetate in hexane) gave the title compound.

NMR Ή (SPS1 ₃ ) δ: 0.98 (3H, s), 1.48 (9H, s), 3.04-3.21 (3H, m), 3.34-3.38 (1H, m ), 3.72-3.76 (2H, m), 3.804.05 (1H, m), 6.81 (2H, d), 7.21 (2H, d). EMC t / ζ: 311 (M), υν retention time: 3.21 min.

Stage 3.

2- (5- {3- [4- (4-Chlorophenyl) -3- (B) methylpiperazin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl) propan-2-ol.

4- (4-Chlorophenyl) -3- (B) -methylpiperazine-1-carboxylic acid tert-butyl ester (0.36 g, 2.6 mmol) was treated with a 4M solution of HC1 in dioxane (10 ml) at room temperature for 3 hours. The solvent was evaporated and the residue was dissolved in dichloromethane and washed several times with saturated aqueous sodium bicarbonate. The combined organic phases are dried over sodium sulfate. The residue is transferred to the next step without further purification.

To a solution of 4- (4-chlorophenyl) -3- (K) -methylpiperazine (0.2 g, 0.95 mmol) in isopropanol (20 ml) was added 2.6-lutidine (0.11 ml, 0.94 mmol) ) and the catalyst is potassium iodide. This mixture is heated to 80 ° C. and then treated with 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-azadibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.24 g, 0.63 mmol), which is added in parts over 2 hours. Then the solution is stirred at 80 ° C. for another 20 hours. The reaction mixture is concentrated in vacuo and purified by flash chromatography (from 100% dichloromethane to 2% methanol in dichloromethane) to give the title compound.

NMR Ή (SPS1 ₃ ) δ: 1.0 (3H, d), 1.57 (6H, s), 1.72 (s, 1H), 2.25-2.55 (7H, m), 2, 61-2.73 (1H, m), 2.963.17 (2H, m), 3.66-3.77 (1H, m), 5.3 (2H, br s), 6.16 (1H, t), 6.77-6.87 (3H, m), 7.17-7.31 (4H, m), 7.45 (1H, d), 7.59 (1H, dd), 8.51 (1H, dd). EMC t / ζ: 504 (M), υν retention time: 1.50 min.

Example 558. Methyl ester (1- (4-chlorophenyl) -4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1azadibenzo [a, b] cycloheptene-5-ylidene] propyl} piperazin-2-yl) acetic acid.

Stage 1

4- (4-Chlorophenyl) -3-methoxycarbonylmethylpiperazine-1-carboxylic acid tert-butyl ester.

4-Chlorophenylboronic acid (1.08 g, 6.97 mmol) and 3-methoxycarbonylmethylpiperazine-1-carboxylic acid tert-butyl ester (0.9 g, 3.48 mmol) are dissolved in dichloromethane. To this mixture were added copper acetate (0.63 g, 3.48 mmol), a 4A molecular sieve and pyridine (0.56 ml, 6.97 mmol) and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuum and dissolved in ethyl acetate, filtered through celite and concentrated. The crude product is purified using gradient elution (from hexane / ethyl acetate (5%) to hexane / ethyl acetate (20%)).

EMC t / ζ: 369 (M + 1), υν retention time: 2.97 min.

Stage 2

(1- (4-Chlorophenyl) -4- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene] propyl methyl ether } piperazin-2-yl) acetic acid.

4- (4-Chlorophenyl) -3-methoxycarbonylmethylpiperazine-1-carboxylic acid tert-butyl ester (0.19 g, 0.5 mmol) was treated with a 4M solution of HC1 in dioxane (10 ml) at room temperature for 3 hours. Solvent evaporated and the residue was dissolved in dichloromethane and washed several times with saturated sodium bicarbonate solution. The combined organic phases are dried over sodium sulfate. The residue is transferred to the next step without further purification.

To a solution of 4- (4-chlorophenyl) -3-methoxycarbonylmethylpiperazine (0.13 g, 0.5 mmol) in acetonitrile / water (8: 2) (10 ml) was added To ₂ CO ₃ (0.2 g, 0 , 42 mmol) and 2- [5- (3-bromopropylidene) -5,11-dihydro

- 122 008060

10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2-ol (0.16 g, 0.42 mmol). The solution was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated, partitioned between ethyl acetate and water and extracted with ethyl acetate (3 times). The organic phases are combined, dried over magnesium sulfate, filtered and evaporated in vacuo, then purified in a Vu1ade system by flash chromatography (from 50% ethyl acetate / 50% hexane to 75% ethyl acetate / 25% hexane, to 100% ethyl acetate) to obtain the indicated in the connection header.

NMR Ή (ΟΌΟ1 ₃ ) δ: 1.57 (6H, s), 2.16-2.49 (8H, m), 2.78-3.01 (4H, m), 3.22 (1H, d ), 3.54 (3Η, s), 4.214.24 (1H, m), 5.29 (2H, br s), 6.19 (1H, t), 6.77-6.82 (3Η, m), 7.17-7.30 (4H, m), 7.48 (1H, d), 7.58 (1Η, dd), 8.51 (1Η, dd). EMC t / ζ: 562 (M), DUT retention time: 1.63 min.

Example 559. 4- (4-Chlorophenyl) -3,3-dimethyl-1- {3- [7- (2-morpholinyl-4-ethoxy) -11H-10-oxa-1-aza-dibenzo [a, b ] cyclohepten-5-ylidene] propyl} piperidin-4-ol.

To a solution of 5- {3- [4- (4-chlorophenyl) -4-hydroxy-3,3-dimethylpiperidin-1-yl] propylidene} -5,11-dihydro-10-oxa-1-azadibenzo [a, b ] cyclohepten-7-ol (0.15 g, 0.28 mmol) in DMF (1.5 ml) was added NaΗ (0.034 g, 0.84 mmol) and stirred for 20 min at room temperature. 4- (2-Chloroethyl) morpholine hydrochloride (0.063 g, 0.34 mmol) was added and the solution was heated to 50 ° C for 16 hours. The reaction was stopped by adding water and the mixture was extracted with ethyl acetate (3 times). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated, then purified by flash chromatography in a Vu1ade system (5-10% methanol in dichloromethane) to give the title compound (0.050 g).

NMR Ή (MeOO) δ: 0.73 (3Η, s), 0.85 (3Η, s), 2.39-2.90 (11H, m), 3.29-3.31 (3Η, m) 3.69-3.72 (4H, m), 4.1 (2H, t), 5.20 (2H, br s), 6.18 (1H, t), 6.74-6.79 (2H, m), 6.89 (1H, d), 7.27-7.30 (2H, m), 7.43-7.47 (3Η, m), 7.79 (1H, dd), 8.46 (1H, dd). EMC t / ζ: 604 (M), DUT retention time: 1.20 min.

Examples 560-571. General techniques.

An amine protected with Ν-butoxycarbonyl (0.0565-0.6911 mmol) was treated with 1N. ΝηΟΗ solution. extracted with dichloromethane, washed with brine, dried over magnesium sulfate and filtered. The solution was evaporated in a constant stream of nitrogen. To the residue was added the corresponding bromide (0.8 eq), potassium carbonate (1.0 eq.), 11 ml of acetonitrile and 2.75 ml of water. The resulting solution was stirred in an orbital shaker for 48 hours. The ampoules were transferred to a heating plate and stirred at 50 ° C for 48 hours. The solutions were quenched with a 1: 1 brine / water mixture, washed with 1N. ΝηΟΗ solution, dried over magnesium sulfate, filtered and concentrated in a constant stream of nitrogen. The residue was dissolved in dichloromethane and subjected to column chromatography (8ίΟ ₂ VyuEsche 12M; eluent - 95% dichloromethane / 5% methanol with 0.1% triethylamine) to give the desired product.

Example 560. L- (4-Chlorobenzyl) -M- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5- ylidene] propyl} pyrrolidin-3-yl) -2-methylbutyramide.

In a heated (77 ° C) stirred solution of 1- (4-chlorophenyl) -2-imidazolidin-1-yl-4-methylhexan-3-one (110 mg, 0.374 mmol), 2,6-lutidine (130 μl, 11.229 mmol) and 5 ml of isopropanol are added in portions 2- [5- (3-bromopropylidene) -5,11-dihydro-10-oxa-1-aza-dibenzo [a, b] cyclohepten-7-yl] propan-2ol ( 70 mg, 0.187 mmol) for 30 minutes. The resulting solution was analyzed using thin layer chromatography and allowed to stir it at 77 ° C for 16 hours. The solution was concentrated in vacuo at 35 ° C. The residue is dissolved in ethyl acetate and subjected to column chromatography (8ίΟ ₂ Vyu1ade 12M, gradient elution from 100% ethyl acetate to 92% ethyl acetate / 8% methanol with 1% triethylamine) to obtain 54 mg of 1- (4-chlorophenyl) -2- (3- {3- [7- (1-hydroxy-1methylethyl) -11H- 10-oxa-1-azadibenzo [a, b] cyclohepten-5-ylidene] propyl} imidazolidin-1-yl) -4-methylhexan-3-one as a light brown enes.

LC / MS: CIU) = 1.68 min, t / ζ = 588 ami (atomic mass unit).

Example 561. Y- (4-Chlorobenzyl) -MH- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene- 5-ylidene] propyl} pyrrolidin-3-yl) acetamide.

LC / MS: 1 (CC) = 1.66 min, t / ζ = 546 am. NMR Ή ((ΟΌ ₃ ) ₂ 8Ο): δ 8.54 (1H, d), 7.70 (1H, m), 7.44 (3Η, m), 7.28 (3Η, m), 7, 13 (1Η, m), 6.76 (1H, d), 6.12 (1H, d), 5.21 (3Η, m), 5.00 (1H, s), 4.63 (2Η, m ), 4.50 (2Η, m), 3.12 (2H, d), 2.39 (4Η, m), 2.27 (2Η, m), 2.18 (3Η, s), 1.90 (5Η, m), 1.60 (2Η, m), 1.43 (6H, s), 1.21 (2Η, t), 0.92 (1Η, m).

Example 562. Y- (4-Chlorobenzyl) -M- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5- ylidene] propyl} pyrrolidin-3-yl) isobutyramide.

LC / MS: 1 (DI) = 1.56 min, t / ζ = 574 am. NMR Ή ((ΟΌ ₃ ) ₂ 8Ο): δ 8.51 (1H, d), 7.66 (1H, d), 7.42 (3Η, m), 7.25 (2Η, t), 7, 12 (1Η, m), 7.04 (1H, d), 6.74 (1H, d), 6.11 (1Η, m), 5.18 (2Η, m), 4.98 (2H, s ), 4.91 (2Η, m), 4.48 (1H, s), 3.04 (1Η, m), 2.40 (5Η, m), 2.14 (4Η, m), 1.40 (6H, s), 1.04 (3Η, d), 0.90 (3Η, m).

Example 563. Y- (4-Chlorobenzyl) -M- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5- ylidene] propyl} pyrrolidin-3-yl) propionamide.

LC / MS: 1 (DI) = 1.49 min, t / ζ = 560 am. NMR Ή ((ΟΌ ₃ ) ₂ 8Ο): δ 8.48 (1H, d), 7.64 (1H, d), 7.40 (3Η, m), 7.27 (2Η, t), 7, 07 (2Η, m), 6.72 (1H, d), 6.10 (1Η, m), 5.17 (3Η, m), 4.96 (2H, s), 4.52 (4Η, m) ), 2.35 (3Η, m), 2.12 (5Η, m), 1.52 (1Η, m), 1.34 (6H, s), 1.00 (2Η, t), 0.89 (1Η, m).

- 123 008060

Example 564. Amide (4-chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} pyrrolidin-3-yl) cyclopentanecarboxylic acid.

LC / MS: 1 (U) = 1.73 min, ιιι / ζ 600 ai. NMR ¹ H (^ 3) 2 ^): δ 8.50 (1H, d), 7.65 (1H, d), 7.40 (3H, m), 7.24 (2H, t), 7, 11 (1H, m), 7.02 (1H, d), 6.72 (1H, d), 6.11 (1H, m), 5.14 (3H, m), 4.96 (1H, s ), 4.82 (1H, m), 4.64 (2H, m), 4.46 (1H, s), 3.13 (1H, m), 2.34 (3H, t), 2.19 (2H, m), 2.06 (2H, m), 1.71 (2H, m), 1.57 (7H, m), 1.39 (6H, s).

Example 565. Amide (4-chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cycloheptene-5-ylidene ] propyl} pyrrolidin-3-yl) cyclopentanecarboxylic acid.

LC / MS: 1 (UI) = 1.79 min, ιιι / ζ614 a.m. NMR ¹ H (^ 3) 2 ^): δ 8.48 (1H, d), 7.64 (1H, d), 7.39 (3H, m), 7.23 (2H, t), 7, 10 (1H, m), 7.00 (1H, d), 6.69 (1H, d), 6.08 (1H, m), 5.13 (2H, m), 4.95 (1H, s ), 4.58 (2H, m), 4.43 (1H, s), 2.73 (1H, m), 2.34 (3H, m), 2.12 (4H, m), 1.67 (7H, m), 1.38 (6H, s), 1.29 (3H, m), 1.03 (3H, m).

Example 566. (4-Chlorobenzyl) - (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cyclohepten-5-ylidene] propyl} pyrrolidin-3-yl) amide 2-ethylhexanol acid.

LC / MS: 1 (UI) = 1.92 min, ιιιΖζ 630 am. NMR ¹ H ((SP ₃ ) ₂ 8O): δ 8.44 (1H, m), 7.61 (1H, m), 7.35 (3H, m), 7.20 (2H, m), 7 11 (1H, m), 7.02 (1H, d), 6.68 (1H, d), 6.05 (1H, m), 5.10 (3H, m), 4.91 (1H, s), 4.61 (2H, m), 4.44 (1H, s), 2.66 (3H, m), 2.32 (3H, m), 2.07 (4H, m), 1, 46 (3H, m), 1.34 (6H, s), 1.17 (4H, m), 0.94 (2H, m), 0.75 (4H, m), 0.60 (1H, m )

Example 567. 1- (4-Chlorobenzyl) -1- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5- ylidene] propyl} pyrrolidin-3-yl) -3-isopropylurea.

LC / MS: 1 (UI) = 1.53 min, ιινζ589 aem. NMR ¹ H (^ 3) 2 ^): δ 8.50 (1H, m), 7.69 (1H, d), 7.40 (2H, m), 7.32 (2H, d), 7, 19 (3H, m), 6.71 (1H, d), 6.09 (1H, m), 5.17 (2H, m), 4.95 (1H, s), 4.41 (2H, s ), 4.12 (1H, m), 3.69 (1H, m), 3.05 (2H, m), 2.78 (2H, m), 2.58 (1H, m), 2.26 (2H, m), 1.91 (2¾ m), 1.61 (1H, m), 1.38 (6H, s), 1.16 (1H, m), 0.92 (6H, m).

Example 568. 1 - (4-Chlorobenzyl) -3-cyclohexyl-1- (1- {3- [7- (1-hydroxy-1-methylethyl) -11 H-10-oxa-1 azadibenzo [a, b] cyclohepten-5-ylidene] propyl} pyrrolidin-3-yl) urea.

LC / MS: 1 (U) = 1.70 min, 1 ^ 629 am. NMR ¹ H (^ 3) 2 ^): δ 8.50 (1H, d), 7.69 (1H, d), 7.40 (2H, m), 7.32 (4H, m), 7, 18 (3H, m), 6.70 (1H, d), 6.10 (1H, m), 5.16 (2H, m), 4.95 (1H, s), 4.43 (2H, m ), 4.02 (1H, m), 3.14 (1H, m), 2.71 (3H, m), 2.22 (3H, m), 1.87 (2H, m), 1.62 (5H, m), 1.38 (6H, s), 0.98 (8H, m).

Example 569. 1- (4-Chlorobenzyl) -3-ethyl-1- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-aza-dibenzo [a, b] cyclohepten-5-ylidene] propyl} pyrrolidin-3-yl) urea.

LC / MS: 1 (U) = 1.46 min, v / ζ 575 am. NMR ¹ H (^ 3) 2 ^): δ 8.52 (1H, d), 7.70 (1H, d), 7.43 (2H, m), 7.33 (2H, d), 7, 23 (1H, dd), 7.17 (2H, d), 6.73 (1H, d), 6.13 (1H, t), 5.19 (2H, m), 4.98 (1H, s ), 4.43 (2H, s), 4.20 (1H, m), 2.96 (4H, m), 2.71 (2H, m), 2.26 (3H, m), 1.95 (2H, m), 1.61 (1H, m), 1.41 (6H, s), 1.19 (1H, m), 1.01 (1H, m), 0.85 (2H, m) .

Example 570. 1- (4-Chlorobenzyl) -1- (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5- ylidene] propyl} pyrrolidin-3-yl) -3- (1,1,3,3-tetramethylbutyl) urea.

LC / MS: 1 (U) = 2.05 min, v / ζ 659 am.

Example 571. No. (4-Chlorobenzyl) -№ (1- {3- [7- (1-hydroxy-1-methylethyl) -11H-10-oxa-1-azadibenzo [a, b] cycloheptene-5-ylidene] propyl} pyrrolidin-3-yl) methanesulfonamide.

LC / MS: 1 (U) = 1.49 min, v / ζ 582 aem.

According to the circuits shown in FIG. 1-5, 7, 8A-8C, 9A-9E, 10A-10b and 12-19 and additional compounds of this invention can be obtained by the methods described therein.

Skilled artisans will be able to understand or verify, using no more than routine experimentation, that there are many equivalents to the specific embodiments of the invention described herein that fall within the scope of the claims below.

Claims (48)

CLAIM 1. The compound having the formula or its physiologically acceptable salt, in which η is a number from one to four; M represents> ΝΚ ² or> SK? K ² ; K ¹ represents —H, —OH, —Ν ₃ , a halogen atom, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O— (aliphatic group), —O— (substituted aliphatic - 124 008060 group), -8Н, -8- (aliphatic group), -8- (substituted aliphatic group), -ОС (О) (aliphatic group), -О-С (О) - (substituted aliphatic group), —C (O) O (aliphatic group), —C (O) O (substituted aliphatic group), —COOH, ΚΝ, —CO — NOK ³ K ⁴ , —ΝΚ ³ Κ ⁴ or K ¹ represents a covalent bond between a ring atom at M and an adjacent carbon atom in a ring that contains M; K ² represents an —OH group, a halogen atom, an acyl group, a substituted acyl group, a —ΝΚ ⁵ Κ ⁶ group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, substituted non-aromatic heterocyclic group, -O (substituted or unsubstituted aromatic group), -O- (substituted or unsubstituted aliphatic group), -C (O) - (substituted or unsubstituted aromatic group) or -C (O) - (for eschennuyu or unsubstituted aliphatic group); K ³ , K ⁴ , K ⁵ and K ⁶ independently represent —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or K ¹ and K ² , K ³ and K ⁴ or K ⁵ and K ⁶ , taken together with the atom with which they are attached, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring; K ⁷⁰ and K ⁷¹ independently represent -H, -OH, -Ν3, a halogen atom, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -O- (aliphatic group), -O (substituted aliphatic group), -8H, - 8- (aliphatic group), -8- (substituted aliphatic group), -OC (O) - (aliphatic group), -O-C (O) - (substituted aliphatic group), -C (O) O (aliphatic group ), -C (O) O (substituted aliphatic group), -COOH, ΚΝ, -CO-NPK ³ K ^4, K ³ * K ^4, an acyl group, a substituted acyl group, a benzyl group, a substituted benzyl group, nearomatiches th heterocyclic group, substituted non-aromatic heterocyclic group, -O- (substituted or unsubstituted aromatic group); K ⁷² and K ⁷³ independently represent a —OH, —Ν ₃ group, a halogen atom, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O- (aliphatic group), —O (substituted aliphatic group), -8H, -8 - (aliphatic group), -8- (substituted aliphatic group), -O-C (O) - (aliphatic group), -O-C (O) - (substituted aliphatic group), -C (O) O (aliphatic group), -C (O) O (substituted aliphatic group), -COOH, ΚΝ, -CO-NOK ³ K ⁴ , ^ K ³ K ⁴ , acyl group, substituted acyl group, benzyl group, substituted benzyl group, nonaroma a tical heterocyclic group, a substituted non-aromatic heterocyclic group, -O- (substituted or unsubstituted aromatic group); Ζ represents X1 represents -CH2-O-, -O-CH2-, -8-, -CH2-, -CH2-CH2-, -CH2-8-, -8-CH2-, -ΝΚ-OD-, -OD groups -ΝΚ-, -8O-OD-, -OD-8O-, -8 (O) 2-CH2-, -OD-8OD-, -CH = CH-, -ΝΚ-CO-, bond, -O- or -CO-ΝΚ-; Kc is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; rings A and B are independently unsubstituted or substituted; said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl; said aliphatic group is a _C1-C6 alkyl, alkenyl or alkynyl; said aromatic group is selected from the group consisting of phenyl, 1-naphthyl, 2 naphthyl, 1-anthracyl, 2-anthracyl, Ν-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2thienyl, 3-thienyl, 2-furanyl , 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2oxazolyl, 4-oxazolyl, 5-oxazolyl, tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2 benzofuranyl , 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2 benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, aridi -benzisoxazolyl, benzocyclopentyl, benzocyclohexyl; said non-aromatic heterocyclic group is a five to eight membered non-aromatic ring which contains one or more heteroatoms independently selected from the group consisting of a nitrogen, oxygen or sulfur atom; the specified substituted aliphatic group is substituted by one or more substituents, you - 125 008060 selected from the group consisting of an oxo group, an epoxy group, a non-aromatic heterocyclic ring, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group, an electron-withdrawing group, a halogen atom, an azido group, -СЫ, -СОЯК ²⁴ К ²⁵ , -ΝΚ ²⁴ Κ ²⁵ , -Ο8 (0) 2ΝΚ ²⁴ Κ ²⁵ , -8 (О) 2ЫК ²⁴ К ²⁵ , -8О3Н, guanidino group, oxalyl group, -C groups (= LK ⁶⁰ ) LK ²¹ К ²² , ΝΙΝ, - (О ) and- (СН ₂ ) ₁ -С (О) ОК ²⁰ , - (О) and- (СН2) 1-ОС (О) К ²⁰ , - (О) и- (СН ₂ ) ₁ -С (О) -YK ²¹ K ²² , - (O) and (CH2) 1-YNS (O) O-K ²⁰ , -PH, -P- (aliphatic group), - (/ - (mixed aliphatic group py), -P (aryl), ^ - (aromatic group), -P- (substituted aromatic group), -P- (CH2) _p - (substituted or unsubstituted aromatic group), -P- (non-aromatic heterocyclic group) or -P (CH ₂ ) _p - (non-aromatic heterocyclic group); the specified substituted non-aromatic heterocyclic ring is substituted by one or more substituents selected from the group consisting of = O, = 8, an electron withdrawing group, a halogen atom, an azido group, —CY, —SOYC ²⁴ K ²⁵ , —ΝΚ ²⁴ Κ ²⁵ , —O8 (O ) 2K ²⁴ K ²⁵ , -8 (О) 2 K ²⁴ K ²⁵ , -8О3Н, guanidino group, oxalyl group, -C (= LK ⁶⁰ ) LK ²¹ K ²² , ΝΙΝ, - (O) and - (CH2) HS (O ) OK ²⁰ , - (О) и- (СН ₂ ) ₁ -ОС (О) К ²⁰ , - (О) t- (СН2) 1-С (О) -ЫК ²¹ К ²² , - (Ο) и- (CH ₂ ) _ΐ -NHC (Ο) Ο-Κ ²⁰ . -P-H, -P- (aliphatic group), -P- (substituted aliphatic group), -P- (aryl), ^ - (aromatic group), -P- (substituted aromatic group), -P- (CH ₂ ) _p - (substituted or unsubstituted aromatic group), -P- (non-aromatic heterocyclic group) or -P- (CH ₂ ) _p - (non-aromatic heterocyclic group); said substituted aromatic group, substituted benzyl group, ring A when substituted, and ring B when substituted, are substituted by one or more substituents selected from the group consisting of an electron-withdrawing group, an aliphatic group, a substituted aliphatic group, an aromatic group, substituted aromatic group, halogen atom, azido group, -ΟΝ, -CONK ^ K ²⁵ , -ΝΚ ²⁴ Κ ²⁵ , -О ^ ОДН ^ К ²⁵ , - ^ (ОГКК ²⁴ ^ ²⁵ , -8О3Н, guanidino group, oxalyl group, ^ ( = ΝΚ ⁶⁰ ) ΝΚ ²¹ Κ ²² , ΝΚ ^6. - (O) and- (CH ₂ ) ₁ -C (O) OK ²⁰ , - (O) and- (CH2) 1-OS (O) K ²⁰ , - (0) u (CH _{2) ΐ} -C (Ο) -NΚ Κ ^{21 22} -. (Ο) u (CH2) ^ NHC (Ο) Ο-Κ ²⁰ p-H, -P- (. aliphatic group), -P- (substituted aliphatic group), -P- (aryl), ^ - (aromatic group), -P- (substituted aromatic group), -P- (CH2) _p - (substituted or unsubstituted aromatic group ), -P- (non-aromatic heterocyclic group) or -P- (CH ₂ ) _p - (non-aromatic heterocyclic group); p represents the groups —O—, —8—, —8 (O) -, —8 (O) ₂ -, —O8 (O) ₂ -, —C (O) -, —OC (O) -, - С (О) О, -С (О) С (О) О-, -О-С (О) С (О), -ХН ^ О) -, -ОС ^ НН-, ^ - ^) ^ -, -8 (Ο) ₂ NH-. -NH8 (Ο) ₂ -. -C (NΚ ²³ ) NHNH-. -ΝΙ ΙΝΙ [SSKhK ² ) -, -ΝΈΤΑ)) - or -ΝΙΝΝΗ)) -; K ²⁰ , K ²¹ and K ²² independently represent —H, an aliphatic group, an aromatic group, a non-aromatic heterocyclic group, —CHS (O) —O— (an aliphatic group), —CHNS (O) —O (an aromatic group), or - CNS (O) -O- (non-aromatic heterocyclic group) or K ²¹ and K ²² taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring; K ²³ represents —H, an aliphatic group, a benzyl group, an aryl group or a non-aromatic heterocyclic group; K ²⁴ and K ²⁵ independently represent —H, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, a non-aromatic heterocyclic group, or K ²⁴ and K ²⁵ taken together with the nitrogen atom to which they are attached can form a substituted or unsubstituted non-aromatic heterocyclic ring; K ⁶⁰ represents —H, —OH, —ΝΙ K aromatic group or substituted aromatic group, ΐ is a number from zero to three; and is zero or one; p is a number from zero to five. 2. The compound according to claim 1, in which ring A is unsubstituted and ring B is substituted in the para position to the carbon atom of ring B, which is bonded to group X! in ring C, and group Ζ is represented by the structural formula in which K ⁴⁰ represents —OH, —COOH, —ΝΌ2, a halogen atom, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, —MK ²⁴ K ²⁵ , —COIC ^ K ²⁵ , -NK. ²⁴ C (O) - (aliphatic group), -ХК ²⁴ С (О) - (substituted aliphatic group), -ХК ²⁴ 8 (О) 2- (aliphatic group), -ХК ²⁴ 8 (О) ₂ - (substituted aliphatic group) -C (O) O (aliphatic group), -C (O) O- (substituted aliphatic group), -C (O) - (aliphatic group), -C (O) - (substituted aliphatic group), -O- (aliphatic group), -O- (substituted aliphatic group), -O- (aromatic group), -O- (substituted aromatic group), electron - 126 008060 acceptor group, - (О) _and - (СН ₂ ) _Г С (О) ОК ²⁰ , - (О) и- (СН2) ГСО (О) К ²⁰ , - (О) и- (СН ₂ ) _Г С (О) - \ К ²¹ К ²² or - (О) _and (СН2) _Г \ НС (О) О-К ²⁰ ; 20 21 22 K, K, or K independently represent —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, or a non-aromatic heterocyclic group; or K ²¹ and K ²² taken together with the nitrogen atom to which they are bonded form a non-aromatic heterocyclic ring; K ²⁴ and K ²⁵ independently represent —H, an aliphatic group or a substituted aliphatic group; and is zero or one, and ΐ is a number from zero to three. 3. The compound according to claim 2, in which M represents> SK ¹ To ² ; K ¹ represents —H or —OH and K ² is a substituted aromatic group in which said substituted aromatic group is 4-halo phenyl. 4. The compound according to claim 3, in which the specified 4-halogenated is selected from the group consisting of 4chlorophenyl, 4-bromophenyl and 4-fluorophenyl. 5. The compound according to claim 4, in which the specified 4-halogenated is 4-chlorophenyl. 6. The compound according to claim 3, in which X ₁ represents-CH ₂ -O-. 7. The compound according to claim 2, in which at least one of the substituents K ⁷⁰ , K ⁷¹ , K ⁷² and K ⁷³ represents an aliphatic group or a substituted aliphatic group; wherein said aliphatic group is C ₁ -C ₆ alkyl and said substituted aliphatic group is C ₁ -C ₆ alkyl substituted with a substituent selected from the group consisting of —OH, - (O) _and - (CH ₂ ) _G C (O) OK ²⁰ and —O— (aliphatic group); ΐ is a number from zero to three; and is zero or one and K ²⁰ is C1-C6 alkyl. 8. The compound according to claim 7, in which both substituents K ⁷⁰ and K ⁷¹ represent -H; K ⁷² and K ^{73 are} independently selected from the group consisting of C ₁ -C ₆ alkyl and substituted C ₁ -C ₆ alkyl. 9. The compound of claim 8, wherein K ⁷² is —CH3. 10. The compound having the formula or its physiologically acceptable salt, in which η is a number from one to four; M represents> SK ¹ K ² ; K ¹ is —OH; K ² is 4-halo phenyl; K ⁷⁰ and K ⁷¹ are —H and K ⁷² and K ⁷³ are —CH ₃ ; or K ⁷⁰ and K ⁷¹ are —CH ₃ and K ⁷² and K ⁷³ are —H; Ζ represents K ^{40 is} selected from the group consisting of - 127 008060 11. The compound of claim 10, in which K ⁴⁰ represents IT 12. The compound of claim 10, wherein said 4-halo phenyl is selected from the group consisting of 4 chlorophenyl, 4-bromophenyl and 4-fluorophenyl. 13. The compound of claim 12, wherein said 4-halo phenyl is 4-chlorophenyl. 14. The compound of claim 13, wherein K ⁷⁰ and K ⁷¹ are —H, K ⁷² and K ⁷³ are —CH ₃ , η is two, and the compound has the structure 15. The compound of claim 14, wherein K ⁴⁰ is IT 16. A compound having a structure or a physiologically acceptable salt thereof, wherein K ² is 4-halo phenyl and K ^{40 is} selected from the group consisting of - 128 008060 17. The compound according to clause 16, in which K ⁴⁰ represents he 18. The compound of claim 16, wherein K ^{2 is} selected from the group consisting of 4-chlorophenyl, 4 bromophenyl and 4-fluorophenyl. 19. The compound of claim 18, wherein K ² is 4-chlorophenyl. 20. The compound according to 17, in which K ² represents 4-chlorophenyl. 21. A method of treating a disease associated with impaired leukocyte recovery, impaired leukocyte activation, or impaired leukocyte recovery and activation, which consists in administering to a needy subject an effective amount of a compound according to claims 1, 10 or 15. 22. The method according to item 21, in which the specified disease is selected from the group consisting of atherosclerosis, arteriosclerosis, restenosis, ischemic / reperfusion injury, diabetic mellitis, psoriasis, inflammatory disease of the intestinal tract, rejection of transplanted organs or tissues, transplant versus host, allergies and asthma. 23. A method for treating a disease associated with impaired leukocyte recovery, impaired activation, or with impaired leukocyte recovery and activation, which consists in administering to a needy subject an effective amount of a compound according to claim 16 or 20. 24. The method according to claim 23, wherein said disease is selected from the group consisting of atherosclerosis, arteriosclerosis, restenosis, ischemic / reperfusion injury, diabetic mellitis, psoriasis, inflammatory bowel disease, rejection of transplanted organs or tissues, transplant versus host, allergies and asthma. 25. A method of treating a chronic inflammatory disease, which consists in administering to a needy subject an effective amount of a compound according to claims 1, 10 or 15. 26. A method of treating a chronic inflammatory disease, which consists in administering to a needy subject an effective amount of a compound according to claim 16 or 20. 27. A method of treating arthritis, which consists in administering to a needy subject an effective amount of a compound according to claims 1.10 or 15. 28. The method of claim 27, wherein said arthritis is rheumatoid arthritis. 29. A method of treating arthritis, which consists in administering to a needy subject an effective amount of a compound according to claim 16 or 20. 30. The method according to clause 29, wherein said arthritis is rheumatoid arthritis. 31. A method for the treatment of multiple sclerosis, which consists in introducing to a needy subject an effective amount of a compound according to claims 1, 10 or 15. 32. A method of treating multiple sclerosis, which consists in administering to a needy subject an effective amount of a compound according to claim 16 or 20. 33. The use of a compound according to claims 1, 10 or 15 for the manufacture of a medicament for the treatment of a disease associated with impaired leukocyte recovery, impaired leukocyte activation, or impaired leukocyte recovery and activation. 34. The use of claim 33 wherein said disease is selected from the group consisting of atherosclerosis, arteriosclerosis, restenosis, ischemic / reperfusion injury, diabetic mellitis, psoriasis, inflammatory disease of the intestinal tract, rejection of transplanted organs or tissues, transplant versus host, allergy and asthma. 35. The use of a compound according to claim 16 or 20 for the manufacture of a medicament for the treatment of a disease associated with impaired leukocyte recovery, impaired leukocyte activation, or impaired leukocyte recovery and activation. 36. The use of claim 35, wherein said disease is selected from the group consisting of atherosclerosis, arteriosclerosis, restenosis, ischemic / reperfusion injury, diabetic - 129 008060 th mellitis, psoriasis, inflammatory bowel disease, rejection of transplanted organs or tissues, graft versus host disease, allergies and asthma. 37. The use of a compound according to claims 1, 10 or 15 for the manufacture of a medicament for the treatment of a chronic inflammatory disease. 38. The use of a compound according to claims 16 or 20 for the manufacture of a medicament for the treatment of a chronic inflammatory disease. 39. The use of compounds according to claims 1, 10 or 15 for the manufacture of a medicinal product for the treatment of arthritis. 40. The use of claim 39, wherein said arthritis is rheumatoid arthritis. 41. The use of a compound according to claim 16 or 20 for the manufacture of a medicament for the treatment of arthritis. 42. The application of paragraph 41, wherein said arthritis is rheumatoid arthritis. 43. The use of a compound according to claims 1, 10 or 15 for the manufacture of a medicament for the treatment of multiple sclerosis. 44. The use of a compound according to claim 16 or 20 for the manufacture of a medicament for the treatment of multiple sclerosis. 45. The compound according to claims 1, 10 or 15 for use in therapy. 46. The compound of claim 16 or 20 for use in therapy. 47. A pharmaceutical composition comprising a compound according to claims 1, 10 or 15 and a physiologically acceptable carrier. 48. A pharmaceutical composition comprising a compound according to claim 16 or 20 and a physiologically acceptable carrier.