RU2543485C2 - Heterocyclic tgr5 bile acid receptor agonists, pharmaceutical composition, methods for preparing and using them - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula I, or their racemic mixture, or their individual optic isomers, or pharmaceutically acceptable salts possessing the properties of TGR bile acid receptor agonist. The invention also refers to methods for preparing the compounds. In general formula I

, X represents amino group R'R"N, wherein the substitutes R' and R" can be optionally identical, or represents hydrogen, C₁-C₆alkyl, C₃-C₆cycloalkyl; substituted C₁-C₆alkyl, wherein the substitute is specified in phenyl or phenoxy, each of which can be substituted by halogen in turn, C₁-C₃alkyl, C₁-C₃alkoxy, phenyloxy, C₃-C₆cycloalkyl, 5-6-merous heteroaryl with 1 nitrogen atom; aryl specified in phenyl optionally substituted by fluorine, C₁-C₃alkyl, C₁-C₃ alkoxy; 5-6-merous heteroaryl with nitrogen atom as heteroatom; C₂-C₄alkenyl, acyl specified in C₁-C₆alkylcarbonyl or C₃-C₆cycloalkylcarbonyl; or substituted oxygroup, which represents hydroxy group, wherein hydrogen is substituted by C₁-C₆alkyl optionally substituted by hydroxy, di(C₁-C₃alkyl)amino, phenyl, which can be substituted by halogen in turn, C₁-C₃alkyl, C₁-C₃alkoxy; C₂-C₄alkenyl; and 5-6-merous heterocyclyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom; R₁a and R₁b represents hydrogen, C₁-C₃alkyl, or R₁a and R₁b together form methylene chain -(CH₂)_n-, wherein n=2-5; R₁c and R₁d represents hydrogen, C₁-C₃alkyl; R2 represents acyl group specified in C₁-C₆alkylcarbonyl, wherein alkyl can be substituted by phenyl or phenoxy, each of which can be substituted by halogen in turn, C₁-C₃alkyl, C₁-C₃alkoxy; C₃-C₆cycloalkylcarbonyl; phenylcarbonyl, which can be substituted by halogen, C₁-C₃alkyl, C₁-C₃alkoxygroup, oxygroup, C₁-C₃alkylene dioxygroup; 5-6-merous heteroarylcarbonyl with nitrogen atom, or oxygen atom, or sulphur atom as heteroatom, optionally substituted by carboxy, halogen or C₁-C₃alkoxycarbonyl, substituted aminocarbonyl group, wherein the substitute can be specified in C₁-C₆alkyl optionally substituted by C₁-C₃alkoxycarbonyl, halogen, 5-6-merous heteroaryl together with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom; C₃-C₆cycloalkyl; phenyl optionally substituted by halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkoxycarbonyl, C₁-C₃alkylenedioxygroup; 5-6-merous heteroarym with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom optionally substituted by carboxy, C₁-C₃alkoxycarbonyl; aminocarbonyl group substituted by C₁-C₃alkyl; sulphonyl group specified in alkylsuphonyl optionally substituted by hydroxyl group, cyano group, phenyl, which is optionally substituted by C₁-C₃alkyl, halogen, C₁-C₃alkoxy group; henylsulphonyl oprtionally substituted by C₁-C₃alkyl, halogen, C₁-C₃alkoxy group, cyano group, C₁-C₃alkylene dioxygroup, or 5-6-merous heteroarylsulphonyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom optionally substituted by halogen, C₁-C₃alkyl, C₁-C₃alkoxy group; R3 represents hydrogen.

EFFECT: compounds can be used for preparing the pharmaceutical composition applicable in treating or preventing metabolic diseases, such as diabetes, obesity, diabetic obesity, metabolic syndrome, hypercholesterolemia, dislipidemia.

14 cl, 17 dwg, 8 tbl, 16 ex

Description

The invention relates to new physiologically active substances, new non-steroidal TGR5 receptor agonists, active ingredients for pharmaceutical compositions, to pharmaceutical compositions and drugs containing a heterocyclic bile acid receptor agonist TGR5, which stimulates the secretion of incretin hormones, a method for treating metabolic diseases such as diabetes, obesity, metabolic syndrome, as well as concomitant cardiovascular and neurodegenerative diseases.

According to the World Health Organization, in 2008, 347 million people worldwide were ill with diabetes [WHO Newsletter No. 312, September 2012], while the number of patients more than doubled compared to 153 million in 1980 [Danaei G, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2-7 million participants. Lancet. 2011; 378 (9785): 31-40]. The spread of diabetes is accelerating. In 2010, diabetes was registered in 6.4% of the global population; in 2030, 7.7% of patients in the world are projected. [Farag Y, Gaballa M. Diabesity: an overview of a rising epidemic. Nephrol Dial Transplant 2011; 26: 28-35.] Diabetes is particularly dangerous when combined with overweight (obesity or obesity), which is the annual cause of death for more than 280 thousand people in the United States. The new scientific and medical term "Diabesity" (in the Russian version - "diabetes mellitus") has become universally recognized, meaning a combination of two interrelated pathologies: diabetes and obesity. At present, diabetes is considered as one of the most serious medical problems of mankind, which has become, in fact, the first non-infectious epidemic [Schmidt MI, Duncan BB. Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med. 2003; 41: 1120-1130], [DangMN, Hashem BE-S. The epidemiology of obesity. Gastroenterol Clin North Am. 2010; 39: 1-7]. Diabetes has become widespread and rapidly spread over the past century. The main causes of this epidemic are a sedentary lifestyle and an improper diet [Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414: 782-787], as well as a genetic predisposition [Ling C, Groop L. Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 2009; 58: 2718-2725]. Diabetes is also an integral component of the metabolic syndrome.

Currently, such simple methods of treating diabetes, such as special diets, do not lead to a solution to the problem - 98% of those who lose weight gain it in excess for 5 years. Various surgical operations in the fight against diabetes (bariatric surgery) have a noticeable effect, however, they are associated with a large number of side effects associated with impaired hormonal homeostasis [Tharakan G, Tan T, Bloom S. Emerging therapies in the treatment of 'diabesity': beyond GLP-1. Trend Pharm Sci. 2011; 32: 8-15]. The many efforts of pharmaceutical companies to create highly effective diabetes and diabetes care products have not yet led to noticeable success. Despite the fact that currently more than 130 new drug candidates are undergoing various tests, no more than ten drugs are approved for use. Clinical trials of a large number of candidates have been suspended due to serious side effects. For example, Avandia, the most promising antidiabetic drug (Rosiglitazone, a PPARgamma receptor agonist), has been shown to increase the risk of heart attack and heart failure [Avorn J. Two centuries of assessing drug risks. New Engl J Med. 2012; 193-197]. The main reasons for the constant failure of researchers are a lack of understanding of the complex picture of the disease, especially the presence of its many signaling mechanisms. Exposure to only one effector target leads to the "escape" of the pathological process due to the activation of other mechanisms. Therefore, one of the main directions in the development of antidiabetic drugs is currently the search for pharmacological agents that can stop the development of pathology. In particular, a search is being made for stimulators of the secretion of incretin proteins, mainly GLP1, as well as YYP and GIP. These properties are possessed by bile acids (FAs), which specifically bind to TGR5 FA GPCR receptors.

TGR5 receptors (also known as GPBAR1, M-BAR, AXOR 109, GPR131 and GPCR19) are class A GPCR receptors linked to Gs proteins [Tiwari A, Maiti P. TGR5: an emerging bile acid GPCR target for the potential treatment of metabolic disorders. Drug Disc Today. 2009; 14: 523]. They are mainly expressed in the gall bladder, gastrointestinal tract, spleen, lungs and placenta [Maruyama T, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002; 298: 714]. The binding of FAs to TGR5 receptors activates adenylate cyclase, which leads to an increase in the intracellular concentration of cAMP followed by activation of the MAP kinase signaling cascade [Pols TWH, et al. The bile acid membrane receptor TGR5: a valuable metabolic target. Dig dis. 2011; 29: 37]. On the other hand, stimulation of TGR5 receptors regulates a number of metabolic processes [Chen X, et al. TGR5: a novel target for weight maintenance and glucose metabolism. Exp Diabetes Res. 2011; ID 853501]. In particular, it was shown that the action of agonists on these receptors of STC-1 enteroendocrine cells significantly increases the secretion of the GLP-1 peptide. [Knop FK. Bile-induced secretion of GLP-1: patophysiological implication in type 2 diabetes? Am J Physiol Endocrinol Metab. 2010; E10-E13]. In turn, the GLP-1 peptide improves glucose homeostasis in several ways, including stimulating insulin secretion and suppressing glucagon secretion, which is extremely important in the treatment of diseases such as diabetes, diabetes and obesity.

Since endogenous FAs, by virtue of their steroidal (hormonal) nature, are able to interact simultaneously with a variety of biotargets (Fig. 1), including nuclear FXR receptors [Prawitt J, et al. Bile acid metabolism and the pathogenesis of type 2 diabetes. Curr Diab Rep. 2011; 11: 160], a search should be made for selective agonists of TGR5 receptors. The most reasonable is the search among small molecules of a non-steroidal nature. The prospects of this approach are confirmed by a series of drug candidates - non-steroidal TGR5 agonists, which are currently at different stages of clinical and laboratory development (Table 1) [1) http://www.integrity.prous.com. 2) Gioiello A, Rosatelli E, Nuti R, Macchiarulo A, Pellicciari R. Patented TGR5 modulators: a review (2006 - present). Expert Opin Ther Patents. 2012; 1-16]. Known patent of the Russian Federation [RU 2456287, publ. 07.27.12], which describes the stimulators of the secretion of incretin hormones, non-steroidal compounds derivatives of 2,3,4,5-tetrahydrobenzo [f] [1, 4] oxazepines, which are of interest as drug substances for the creation of new drugs for prevention and treatment of metabolic diseases. The disadvantage of this series of compounds is the difficulty in obtaining a pure prodrug, since the preparation takes place in several stages: cyclization and reduction with lithium aluminum hydride to obtain an intermediate product, then subsequent acylation of the intermediate product with a biaryl acyl halide. This makes it difficult to obtain a medicinal candidate and conduct clinical trials.

Table 1 Non-steroidal agonists of TGR5 receptors at different stages of clinical and preclinical development as potential antidiabetic agents Compound Structure Test phase Developer Patent / Article SB-756050

Phase I GlaxoSmithKline (Originator) WO 2007127505 818A

Preclinic GlaxoSmithKline (Originator) J Med Chem 2009, 52 (24): 7962 GlaxoSm ithKline

Preclinic GlaxoSmithKline (Originator) Bioorg Med Chem Lett 2010, 20 (4): 1363 Kalypsys-35

Preclinic Kalypsys (Originator) WO 2008097976 RDX-009 The structure is not open Preclinic Ardelyx (Originator) Ardelyx Press Rel.
2011, August 30 XL-475 The structure is not open Phase I Exelixis Exelixis Pharmaceuti cals Web Site 2010, May 25

Table 1 Roche

Test Roche (Originator) WO 1012117000 IRM

Test IRM, LLC (Originator) WO 2012082947 Roche

Test Roche (Originat or) WO 2012007365 Roche

Test Roche (Originator) US 2011178089

Table 1 Exelixis

Test Exelixis Originator) WO 011071565 MSD KK

Test MSD KK WO 2010117090 Exelixis

Test Exelixis WO 2010093845 Takeda

Test Pfizer Takeda (Originator) JP 2006063064 Kalypsys

Test Kalypsys (Originator) WO 2010014739

Table 1 Kalypsys

Test Kalypsys 1 (Originator) WO 009026241 Novartis

Test Novartis (Originator) WO 2008125627 Kalypsys

Test Kalypsys WO 2008067222 Novartis

Test Novartis (Originator) WO 2007110237 Takeda

Test Takeda (Originator) JP 2006063064

Table 1 Takeda

Test Takeda (Originator) WO 2004067008 JP 2006056881 Roche

Test Rpche (Originator) US 2010105906 Banyu

Test Banyu (Originator) WO 2010117084

Thus, the search for effective non-steroidal agonists of TGR5 receptors seems to be an extremely important, relevant and promising task.

In order to develop new highly effective antidiabetic drugs, the authors of this invention performed extensive screening studies of low molecular weight compounds of various classes, hit compounds and leader compounds belonging to several families of heterocyclic compounds were detected, then directed modifications of many positions of the detected structures were performed and tested, the relationship was established “Structure-activity” and the most promising series were selected. As a result, a series of new derivatives are synthesized that are original and highly potent TGR5 receptor agonists. The resulting physiologically active heterocyclic compounds include novel tetrahydrobenzo [f] [1,4] oxazepines derivatives that have not previously been described in the literature. To date, the ability of these compounds to exhibit agonistic properties with respect to TGR5 receptors has also not been known.

The following are definitions of terms that are used in the description of this invention.

“Agonists” means compounds that, by binding to receptors of a certain type, actively promote the transmission of their specific signal by these receptors and thereby elicit a biological response from the cell.

“Azaheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" (C ₁ -C ₆ ) alkyl substituents. Preferred alkyl groups are lower (C ₁ -C ₆ ) alkyl or methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl. Alkyl may have substituents.

"Aliphatic" radical means a radical obtained by removing a hydrogen atom from a non-aromatic CH bond. An aliphatic radical may additionally contain substituents — aliphatic or aromatic radicals defined in this section. aliphatic radicals Representatives include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksialkil, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated arylheterocyclyl, annelated heteroarylheterocyclyl, annelated arylheterocyclenyl, annelated heteroarylheterocyclenyl.

"Alkenyl" means an aliphatic linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and including a carbon-carbon double bond. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. One or more aromatic, cyclic or heterocyclic systems may be attached to an alkenyl group.

″ Active component ″ (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

"Antagonists" means ligands that bind to receptors of a particular type and do not cause an active cellular response. Antagonists inhibit the binding of agonists to receptors and thereby block the transmission of a specific receptor signal.

″ Alkyloxy ″ or ″ Alkoxy ″ means an Alkyl O— group in which alkyl is defined in this section. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and tert-butoxy.

″ Amino group ″ means an R′R ″ N group unsubstituted or optionally substituted with the same substituents R ′ and R ″. An amino group may have substituents.

"Alkylthio" means an alkyl-S group in which the alkyl group is defined in this section.

“Aminocarbonyl ″ means C (= O) N R′R ″ is a group unsubstituted or optionally substituted with the same carbamoyl substituents R ′ and R ″, including hydrogen, methyl, cycloalkyl, which forms a pyrrolidine ring with a nitrogen atom.

″ Annelated cycle ″ (condensed ring) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycycle with which it is ″ annelated ″ have at least two atoms in common. Aromatic, non-aromatic systems and heterocyclic systems can be annelated.

“Aralkyl” means an alkyl group substituted with one or more aryl groups, in which the meanings of aryl and alkyl are defined in this section. Examples of aralkyl groups are optionally substituted benzyl, phenethyl, phenpropyl.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl may contain one or more ″ cyclic system substituents ″ which may be the same or different.

″ Aromatic cycle ″ (aromatic system) means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system including, according to the Hückel rule, (4n + 2) π-electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, and the like. In the case of “heteroaromatic rings”, π-electrons and p-electrons of heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like. The aromatic cycle may have one or more ″ substituents of the cyclic system ″ and can be annelated with a non-aromatic cycle, heteroaromatic or heterocyclic system.

″ Acyl group ″ (Acyl) means HC (= O) -, optionally substituted C ₁ -C ₅ alkyl-C (= O) -, C ₁ -C ₅ alkenyl-C (= O) -, C ₁ -C ₅ cycloalkyl-C (= O) -, (preferably cyclopropyl-C (= O) -, cyclobutyl-C (= O) -); heterocyclyl-C (= O) - (preferably 2-methylfuran), aryl-C (= O) - (aroyl), aralkyl-C (= O) - (preferably 3-phenylpentane-C (= O) -), heteroaryl -C (= O) - (heteroaroyl), heteroarylalkyl-C (= O) -groups in which C ₁ -C ₅ alkyl-, C ₁ -C ₅ alkenyl-, C ₃ -C ₅ cycloalkyl-, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, methoxy group, these groups may have substituents, see ″ substituents of the cyclic system ″, ″ substituted alkyl ″, ″ substituted alkenyl ″, ″ substituents of the heterocyclic system ″ defined in this section.

“Heteroaryl ″ (hetaryl) means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are replaced by heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl can be oxidized to an N-oxide. Heteroaryl may have one or more ″ substituents on the cyclic system ″, which may be the same or different. Preferably, pyrrolyl, furanyl, thienyl, pyridinyl, pyrrolidine, imidazolyl, oxazolyl, benzothiadiazole, benzothiazolyl, quinolinyl, imidazolyl, thienopyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinopyridinyl , thienopyrrolyl, furopyrrolyl, etc.

“Heterocyclyl” means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system containing from 3 to 10 carbon atoms, mainly from 4 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur phosphorus. The prefix "aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclyl may have one or more substituents, which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representative heterocyclyls are piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxan-2-yl, tetrahydrofuryl, tetrahydrothienyl, etc.

″ Substituted alkenyl ″ - substituted alkenyl may also have one or more identical or different substituents, including halogen, alkenyloxy, aroyl, heteroaroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralky alkylsulfonyl, heteroaralkyloxy, etc. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, iso-butenyl, 3-methylbut-2-enyl, n-pentenyl and n-hexenyl.

“Substituted alkyl” - substituted alkyl may have one or more of the same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbon alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy, R′R ″ N-, where R ′ and R ″ independently are ″ amino substituents ″, the meaning of which is defined in this section, for example, a hydrogen atom, an alkyl l, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or R ′ and R ″ together with the N atom to which they are bonded, form through R ′ and R ″ 4-7 membered heterocyclyl or heterocyclenyl. Preferred “alkyl substituents” are aryl, heteroaryl, heterocyclyl, hydroxy, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonylcarbonylcarbonylcarbonylcarbonyl R ″ N-, R′R ″ NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl. Namely, the hydroxy group substituted by fluorophenyl oxy group, mono- and diC ₁ -C ₅ alkylamino group (dimethylamino group, methylamino group), C ₁ -C ₅ alkyloxycarbonyl group (ethyloxycarbonyl), phenyl, chlorophenyl, fluorophenyl, C ₁ -C ₅ alkyl (methyl) substituted phenyl, C ₃ -C ₅ cycloalkyl (cyclopentyl) substituted phenyl, C ₁ -C ₅ alkoxy substituted phenyl (methoxyphenyl), thiophenyl, furanyl, pyrrolidine.

″ Substituents of the amino group ″ - substituents of the amino group R ′ and R ″ are hydrogen, optionally substituted C ₁ -C ₅ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl (see the Deputy of the cyclic system), optionally substituted aryl (see the Deputy of the cyclic system ), optionally substituted heteroaryl (see the Deputy of the cyclic system), optionally substituted heterocyclyl (see the Deputy of the cyclic system), C ₁ -C ₅ alkenyl, acyl, aroyl, heteroaroyl, C ₁ -C ₅ alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkoxycarbo nyl, aryloxycarbonyl, aralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, heterocyclylaminocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylamino optionally. The R′R′′N group may be a non-aromatic azaheterocycle, preferably azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperidine, homopiperazine. Preferred amino substituents are hydrogen, C ₁ -C ₅ alkyl, C ₃ -C ₅ cycloalkyl, substituted C ₁ -C ₅ alkyl ("substituted alkyl"), optionally simultaneously substituted with 1 to 3 radicals, substituted phenyl (C ₁ -C ₅ alkyl , halogen, C ₁ -C ₅ alkoxy group, C ₁ -C ₅ alkyloxycarbonyl), pyridinyl, optionally substituted with thiophenyl, optionally substituted with furanyl (see "cyclic system substituents").

″ Substituents of the cyclic system ″ may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle. Preferably, the cyclic system substituents are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, optionally substituted cycloC ₃ -C ₅ alkyl, C ₁ -C ₅ alkene, hydroxy group, C ₁ -C ₅ alkyloxy group ( methoxy, ethoxy, propoxy, ethylene glycol diester, methanediol diester), cyano, C ₁ -C ₅ alkyloxycarbonyl (methyl, ethyl), alkylthio group (methylthio), carboxy group, aminocarbonyl (see ″ aminocarbonyl ″), phenyl annelated with 5-7 saturated membered ring containing 1-3 heteroatoms (nitrogen, oxygen and sulfur atoms pre respectfully).

"Heterocyclyl substituents" may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle. Preferably, the cyclic system substituents are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, optionally substituted cycloC ₃ -C ₅ alkyl, C ₁ -C ₅ alkene, hydroxy group, C ₁ -C ₅ alkyloxy group ( methoxy, ethoxy, propoxy, ethylene glycol diester, methanediol diester), cyano group, C ₁ -C ₅ alkyloxycarbonyl (methyl, ethyl), alkylthio group (methylthio), carboxy group, aminocarbonyl (see ″ aminocarbonyl ″), 5-7 phenyl annelated saturated membered ring containing 1–3 heteroatoms (nitrogen, oxygen, and sulfur atoms respectfully).

“Substituent ″ means a chemical radical that attaches to a molecular skeleton (scaffold, fragment), for example ″ substituent alkyl ″, ″ substituent of an amino group ″, ″ substituent of carbamoyl ″, ″ substituent of a cyclic system ″, the meanings of which are defined in this section.

″ Substituted amidine group ″ means R′R ″ N- (C = NR ″) - a group in which the substituents R ′, R ″ and R ″ ″ can be represented by optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the meaning of which is defined in this section. The R′R′′N fragment of the amidine group may be a non-aromatic azaheterocycle, preferably azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperidine, homopiperazine.

″ Substituted aminocarbonyl group ″ (aminocarbonyl) means R′R ″ N — C (= O) is a group in which the substituents R ′ and R ″ may be optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the meaning of which is defined in this section. Preferred aminocarbonyl groups are optionally substituted C ₁ -C ₅ alkyl, C ₁ -C ₅ alkenyl, C ₃ -C ₅ cycloalkyl, optionally substituted aryl (see cyclic substituent), optionally substituted hetaryl (see cyclic substituent), optional substituted heterocyclyl (see heterocyclyl substituent) or an amino group R′R ″ N.

″ Substituted aminothiocarbonyl group ″ (aminothiocarbonyl) means R′R ″ NC (= S) is a group in which the substituents R ′ and R ″ may be optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the meaning of which defined in this section. Preferred aminocarbonyl groups are alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, hetarylaminothiocarbonyl and benzylaminothiocarbonyl.

“Substituted oxy group” means a hydroxy group in which hydrogen can be substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkenyl, C ₃ -C ₅ cycloalkyl, aryl, hetaryl and heterocyclyl to form ethers or acyl to form esters or an aminocarbonyl group to form carbamates, or an oxycarbonyl group to form carbonates.

″ Substituted oxycarbonyl group ″ (oxycarbonyl) means R — O — C (═O) - a group in which the substituent R can be represented by optionally substituted alkyl, alkenyl, cycloalkyl, aryl, hetaryl and heterocyclyl, as defined in this section. Preferred hydroxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl and benzyloxycarbonyl.

“Carbamoyl substituent” means a substituent attached to an aminocarbonyl group, the meaning of which is defined in this section. The carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R′R ″ N-, R′R ″ NC (= O) -alkyl, annelylated heteroaryl hetero heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl. Preferred “carbamoyl substituents” are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R′R ″ N-, R′R ″ NC (= O) -alkyl, annelated arylated.

"Bile acids" (endogenous bile acids FA). The main types of bile acids present in the human body are the so-called primary bile acids (primarily secreted by the liver): cholic acid (3α, 7α, 12α-trioxy-5β-cholanic acid) and chenodeoxycholic acid (3α, 7α-dioxi-5β- cholanic acid), as well as secondary (formed from primary bile acids in the colon under the influence of intestinal microflora): deoxycholic acid (3α, 12α-dioxo-5β-cholanoic acid), lithocholic (3α-manooxy-5β-cholanoic acid), allocholic and ursodeoxycholic acid. Of the secondary ones in the intestinal-hepatic circulation, only deoxycholic acid, which is absorbed into the blood and then secreted by the liver as part of the bile, is involved in the amount that affects the physiology. Allocholic, ursodeoxycholic and lithocholic acids are stereoisomers of cholic and deoxycholic acids. All human bile acids have 24 carbon atoms in their molecules. Bile acids are designed to stimulate incretin hormones.

"Carboxyl" means a group -CO ₂ N.

“Combined medicinal product (preparation)” - a combination of several medicinal substances for simultaneous use in the form of tablets, capsules, injections, ointments, rectal suspensions and gels and other finished forms, designed to restore, correct or change physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things. Medicinal substances in one set can be presented in the form of various ready-made forms intended for administration into an animal or human body in various ways, for example, orally and rectally.

"Metabolic diseases" - a group of diseases associated with metabolic disorders. These diseases can be caused by a hereditary predisposition, disruptions in the endocrine and nervous systems, as well as disturbances in the functioning of metabolically active organs. Currently, there are a large number of metabolic disorders, however, this invention mainly addresses diseases associated with the signaling cascade of TGR5 receptors, in particular, such as diabetes, obesity, diabetes, metabolic syndrome, hypercholesterolemia, dyslipidemia, etc.

"Lower alkyl" means a linear or branched alkyl with 1-5 carbon atoms (C ₁ -C ₅ alkyl).

"Neurodegenerative disease" means a specific condition and disease characterized by damage and primary death of populations of nerve cells in certain areas of the central nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's and Parkinson's disease; Huntington's disease (chorea); multiple sclerosis; cerebellar degeneration; amyotrophic lateral sclerosis; dementia with Levy bodies; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis ("mad cow disease", Creutzfeld-Jakob Disease); AIDS-related dementia; multi-infarct dementia; frontotemporal dementia; leukoencephalopathy (a disease of endangered white matter); chronic neurodegenerative diseases; stroke; ischemic, reperfusion, and hypoxic brain damage; epilepsy cerebral ischemia; glaucoma; traumatic brain injury; Down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; Depressed In addition, neurodegenerative diseases include pathological conditions and disorders that develop with hypoxia, substance abuse, exposure to neurotoxins, infectious and oncological diseases of the brain, as well as neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

"Receptors" (from the Latin recipere - to receive, to recognize) are biological macromolecules located on the cytoplasmic membrane of a cell or intracellular, capable of specifically interacting with a limited set of physiologically active substances (ligands) and transforming the signal about this interaction into a specific cellular response.

“TGR5 receptors” receptors (also known as GPBAR1, M-BAR, AXOR 109 and GPCR19) are GsR receptors associated with Gs proteins. They are expressed mainly in the gall bladder, gastrointestinal tract, spleen, lungs, placenta, some parts of the central nervous system, as well as in immune cells (monocytes and dendritic cells).

“Signal cascade” (signal system, signal transmission cascade) means a set of interconnected sequential and parallel molecular processes of regulation of cellular metabolism by external (primary) signals that carry information into the cell, which fundamentally distinguishes them from other chemical compounds entering the cell that serve as its source matter and energy. The molecular mechanisms of transmission (transduction) of external signals into the cell imply not only the transmission of signals as such, but also the whole complex of events associated with it, including amplification, attenuation and suppression (or switching off) of signals.

"Steroids" are a group of natural, semi-synthetic and synthetic compounds - derivatives of partially or fully hydrogenated 1,2-cyclopentenophenanthrene, in the molecular skeleton of which 17 carbon atoms form 4 articulated rings. Steroids are widespread in nature, they are involved in the implementation of a wide variety of biological functions. The steroid nature is sex hormones, vitamin D, adrenal hormones, bile acids, metamorphosis hormones and arthropod repellents, plant phytosteroids, etc. Steroids with a similar structure exhibit very different physiological activity, they are widely used in medicine as anti-inflammatory, cardiac, contraceptive and other agents. When it is necessary to avoid the hormonal effects of steroids, so-called "non-steroidal" drug agents are developed.

"Sulfonyl" means R-SO ₂ - a group in which the substituent R may be optionally substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkenyl, C ₁ -C ₅ cycloalkyl, optionally substituted with aryl (see the Deputy of the cyclic system ), optionally substituted hetaryl (see cyclic system substituent), optionally substituted heterocyclyl (see cyclic system substituent), or R′R′′N amino group, the meanings of which are defined in this section.

“Thioacyl group” (Thioacyl) means optionally substituted alkyl-C (= S) -, alkenyl-C (= S) -, cycloalkyl-C (= S) -, heterocyclyl-C (= S) -, aryl-C ( = S) - aralkyl-C (= S) -, heteroaryl-C (= S) -, heteroarylalkyl-C (= S) groups.

“Cycloalkyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more “ring system substituents”, which may be the same or different. Representative cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Preferred “cyclic system substituents” are alkyl, alkoxy, hydroxy or amino group, the meaning of which is defined in this section.

“Cycloalkenyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms and containing one or more carbon-carbon double bonds. Representatives of cycloalkenyl groups are cyclopentenyl and cyclohexenyl.

"Pharmaceutical composition" means a composition comprising a compound of general formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceptive means, delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterials nye agents, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and way of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms. Pharmaceutical compositions are typically prepared using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier. For the manufacture of suppositories, in addition to the active components, cocoa butter, its alloys with paraffin and hydrogenated fats, vegetable and animal hydrogenated fats, solid fat, lanol, alloys of hydrogenated fats with wax, hard paraffin and other bases approved for medical use are also used.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. (A detailed description of the properties of such salts is given in Berge SM, et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19.) Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, when this can be synthesized metal salts and amines. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids having an early basicity to form a stable salt and suitable for medical use are selected (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

"Pharmaceutically acceptable excipients" by pharmaceutically acceptable excipients refers to pharmaceutical diluents, excipients and / or carriers.

An object of the present invention is to provide novel selective non-steroidal heterocyclic TGR5 receptor agonists.

The goal is achieved by heterocyclic agonists of the bile acid receptors TGR5 of General formula I in the form of free bases, racemic mixtures or individual optical isomers, as well as their pharmaceutically acceptable salts.

The subject of the present invention is the use of a compound of tetrahydrobenzo [f] [1,4] oxazepine derivatives of the general formula I in the form of free bases, racemic mixtures or individual optical isomers, as well as their pharmaceutically acceptable salts, for the preparation of a pharmaceutical composition having properties of bile acid agonist TGR5

Where

X represents an amino group R'R "N, optionally substituted with the same substituents R 'and R", where the amino substituents R' and R "are hydrogen, C ₁ -C ₆ alkyl, substituted C _1- C ₆ alkyl wherein the substituent is selected from phenyl or phenoxy, each of which in turn may be substituted by halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyloxy, C _3- C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl, 5-6-membered heteroaryl with one nitrogen atom; aryl selected from phenyl optionally substituted with fluorine, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy; 5-6 membered heteroaryl with a nitrogen atom as a heteroatom; C ₂ -C ₄ alkenyl; acyl selected from C ₁ -C ₆ alkylcarbonyl or C ₃ -C ₆ cycloalkylcarbonyl; or a substituted oxy group, which is a hydroxy group in which hydrogen is substituted with C ₁ -C ₆ alkyl, optionally substituted with hydroxy, di (C ₁ -C ₃ alkyl) amino, phenyl, which in turn can be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₂ -C ₄ alkenyl; and a 5-6 membered heterocyclyl with a nitrogen or oxygen atom as a heteroatom;

R ₁ a and R ₁ b are hydrogen, C ₁ -C ₃ alkyl; or R ₁ a and R ₁ b together form a polymethylene chain - (CH2) _n -, where n = 2-5; R ₁ c and R ₁ d are hydrogen, C ₁ -C ₃ alkyl;

R2 represents an acyl group selected from C ₁ -C ₆ alkylcarbonyl, where the alkyl may be substituted with phenyl or phenoxy, each of which in turn may be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy; C ₃ -C ₆ cycloalkylcarbonyl; phenylcarbonyl, which may be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxymethylenedioxy; 5-6 membered heteroarylcarbonyl with a nitrogen, oxygen or sulfur atom as a heteroatom, optionally substituted with carboxy or C ₁ -C ₃ alkoxycarbonyl; a substituted aminocarbonyl group, wherein the substituent may be selected from C ₁ -C ₆ alkyl optionally substituted with C ₁ -C ₃ alkoxycarbonyl; C ₃ -C ₆ cycloalkyl; phenyl optionally substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxycarbonyl; A 5-6 membered heteroaryl with a nitrogen or sulfur atom as a heteroatom, possibly substituted by carboxy, C ₁ -C ₃ alkoxycarbonyl; a sulfonyl group selected from C ₁ -C ₃ alkylsulfonyl substituted with phenyl, which is optionally substituted with C _{1 -3} alkyl, halogen, C ₁ -C ₃ alkoxy, cyano; phenylsulfonyl optionally substituted with halogen, C ₁ -C ₃ alkyl, halogen, C ₁ -C ₃ alkoxy, or a 5-membered heteroaryl sulfonyl with a nitrogen, sulfur or oxygen atom as a hetero atom, optionally substituted with halogen, C _1-3 alkyl, C ₁ -C ₃ alkoxy;

R3 is hydrogen.

It is preferable to use tetrahydrobenzo [f] [1,4] oxazepine derivatives of the general formula I.1 and I.2 in the form of free bases, racemic mixtures or individual optical isomers, as well as their pharmaceutically acceptable salts

Where

R ₄ a and R ₄ b are hydrogen or methyl; or R ₄ a and R ₄ b may together form the polymethylene chain -CH2-CH2-; R ₄ c and R ₄ d are hydrogen or methyl;

R5 represents an acyl group selected from C ₁ -C ₆ alkylcarbonyl, where the alkyl may be substituted with phenyl or phenoxy, each of which in turn may be substituted with halogen, C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy; C _{3 -C 6} cycloalkylcarbonyl; phenylcarbonyl, which may be substituted with halogen, C _{1 -C 3} alkyl, C ₁ -C ₃ alkoxymethylenedioxy; 5-6 membered heteroarylcarbonyl with a nitrogen, oxygen or sulfur atom as a heteroatom, optionally substituted with carboxy or C ₁ -C ₃ alkoxycarbonyl; a substituted aminocarbonyl group, wherein the substituent may be selected from C ₁ -C ₆ alkyl optionally substituted with C ₁ -C ₃ alkoxycarbonyl; C _{3 -C 6} cycloalkyl; phenyl optionally substituted with halogen, C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy, C ₁ -C ₃ alkoxycarbonyl; A 5-6 membered heteroaryl with a nitrogen or sulfur atom as a heteroatom, possibly substituted by carboxy, C ₁ -C ₃ alkoxycarbonyl; a sulfonyl group selected from C ₁ -C ₃ alkylsulfonyl substituted with phenyl, which is optionally substituted with C _{1 -C 3} alkyl, halogen, C _{1 -C 3} alkoxy, cyano; phenylsulfonyl optionally substituted with halogen, C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy or a 5-membered heteroarylsulfonyl with a nitrogen, sulfur or oxygen atom as a hetero atom, optionally substituted with halogen, C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy;

R6 represents hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, where the substituent is selected from phenyl or phenoxy, each of which in turn may be substituted with halogen, C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy, phenyloxy, C _{3 -C 6} cycloalkyl, C _{3 -C 6} cycloalkyl, 5-membered heterocyclyl with one nitrogen atom in the ring; an acyl group selected from C ₁ -C ₃ alkylcarbonyl or C _{3 -C 6} cycloalkylcarbonyl;

R7 is hydrogen, C ₁ -C ₆ alkyl; substituted alkyl, where the substituent is selected from phenyl or phenoxy, each of which in turn can be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyloxy, C ₃ -C ₆ cycloalkyl; C ₂ -C ₄ alkenyl; aryl selected from phenyl optionally substituted with halogen, C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy; 5-6 membered heteroaryl with a nitrogen atom as a heteroatom;

R8 is C ₁ -C ₆ alkyl, optionally substituted with hydroxy, di (C ₁ -C ₃ alkyl) amino, phenyl, which in turn may be substituted with halogen, C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy; C ₂ -C ₄ alkenyl; 5-6 membered heterocyclyl with a nitrogen or oxygen atom as a heteroatom.

More preferred is the use of tetrahydrobenzo- [f] [1,4] oxazepine derivatives of the general formula I.1.1, I.1.2, I.1.3, I.2.1, I.2.2 and I.2.3 in the form of free bases, racemic mixtures or individual optical isomers and their pharmaceutically acceptable salts

Where

R ₄ a, R ₄ b, R ₄ c and R ₄ d are as defined above;

R9 represents C ₁ -C ₃ alkyl; C _{3 -C 6} cycloalkyl;

R10 is C ₁ -C ₃ alkyl optionally substituted with phenyl, which may be substituted with halogen; or a 5-6 membered heteroaryl with a nitrogen atom as a heteroatom; C ₂ -C ₄ alkenyl; phenyl optionally substituted with C _{1 -C 3} alkyl;

R11 is C ₁ -C ₄ alkyl optionally substituted with phenyl, optionally substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen; a phenoxy group optionally substituted with a C _{1 -C 3} alkoxy group or halogen, a C _{3 -C 6} cycloalkyl or a 5-6 membered heteroaryl with a nitrogen, sulfur or oxygen atom as a heteroatom; C _{3 -C 6} cycloalkyl; phenyl optionally substituted with C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy, hydroxy or halogen; benzo [d] [1,3] dioxol; 5-6 membered heteroaryl with a nitrogen, sulfur or oxygen atom as a heteroatom, optionally substituted with halogen;

R12 represents hydrogen;

R13 is C ₁ -C ₄ alkyl optionally substituted with a C ₁ -C ₃ alkoxycarbonyl group or phenyl optionally substituted with halogen or a 5-6 membered heteroaryl with a nitrogen, sulfur or oxygen atom as a heteroatom; C _{3 -C 6} cycloalkyl; phenyl optionally substituted with C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy, halogen, C ₁ -C ₃ alkoxycarbonyl group; benzo [d] [1,3] dioxol; 5-6-membered heteroaryl with the nitrogen, sulfur or oxygen atom as the heteroatom, optionally substituted by carboxy, C _1- C ₃ alkoxycarbonyl group, an aminocarbonyl group substituted by C _1- C ₃ alkyl; R14 is C ₁ -C ₄ alkyl optionally substituted with fluoro-substituted phenyl; phenyl optionally substituted with C _{1 -C 3} alkyl, C _{1 -C 3} alkoxy, halogen, cyano;

R15 is C ₁ -C ₆ alkyl optionally substituted with an oxy group, a 5-6 membered heterocyclyl with a nitrogen, sulfur or oxygen atom as a heteroatom, phenyl optionally substituted with a C _{1 -C 3} alkyl, a C _{1 -C 3} alkoxy group, a halogen; C ₂ -C ₄ alkenyl.

The subject of the present invention are tetrahydrobenzo [f] [1,4] oxazepine derivatives:

N- (4-fluorobenzyl) -N '- ({4 - [(3-fluorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) acetamide (I. 1.1-01);

N - {[4- (cyclopropylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) acetamide (I.1.1-02);

N- (4-methylphenyl) -N '- {[4- (2-phenylbutanoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl} acetamide (I.1.1-03 );

N - ({4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N'-phenylcyclopropanecarboxamide (I.1.1-05);

N - {[4- (3-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methyl-N '- (4-methylphenyl) propanamide (I .1.1-06);

N - {[4- (2-furoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) acetamide (I.1.1-07 );

N- (4-methylphenyl) -N - ({4 - [(4-methylphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) acetamide (I.1.1 -08);

N - [(4-isobutyryl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N '- (4-methylphenyl) acetamide (I.1.1-09);

N - [(4-butyryl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -2-methyl-N '- (4-methylphenyl) propanamide (I.1.1-10 );

2-methyl-N- (4-methylphenyl) -N '- {[4- (2-thienylacetyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} propanamide (I .1.1-11);

N- (4-methylphenyl) -N '- {[4- (2-thienylacetyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.1-12 );

N - {[4- (4-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N'-phenyl-cyclopropanecarboxamide (I.1.1-13);

N - {[4- (3-methylbenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N'-phenylcyclopropanecarboxamide (I.1.1-15);

N - {[4- (2,6-difluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) acetamide (I.1.1 -16);

N - {[4- (2,6-difluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methyl-N '- (4-methylphenyl) propanamide (I.1.1-17);

N - {[4- (3-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) acetamide (I.1.1-18 );

N - {[4- (2-furoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methyl-N '- (4-methylphenyl) propanamide (I .1.1-19);

2-methyl-N- (4-methylphenyl) -N '- {[4- (phenoxyacetyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} propanamide (I.1.1 -twenty);

N - ({4 - [(4-methoxyphenoxy) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N '- (phenylcyclopropanecarboxamide (I.1.1-21) ;

N - {[4- (cyclopentylacetyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) acetamide (I.1.1-22);

N - {[4- (2-methylbenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) acetamide (I.1.1-23 );

N - {[4- (cyclobutylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methyl-N '- (4-methylphenyl) propanamide (I.1.1 -24);

N - {[4- (2-fluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) acetamide (I.1.1-25 );

N - {[4- (cyclopentylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) acetamide (I.1.1-26);

N - {[4- (cyclohexylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) acetamide (I.1.1-27);

N - {[4- (4-methylbenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N'-phenyl-cyclopropanecarboxamide (I.1.1-28);

2-methyl-N- (4-methylphenyl) -N '- [(4-propionyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] propanamide (I.1.1-29 );

2-methyl-N - {[4- (3-methylbutanoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methylphenyl) propanamide (I .1.1-30);

N - ([4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl-N '- (methyl) acetamide (I.1.1-31);

N - ([4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (methyl) propanamide (I.1.1-32);

N - ([4-propionyl-2,3,4,5-tetrahydro-1,4-benzoxazepia-7-yl] methyl} N '- (methyl) acetamide (I.1.1-33);

N - ([4-benzoyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (methyl) acetamide (I.1.1-34);

N - {[4- (4-methylbenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methyl) acetamide (I.1.1-35 );

N - {[4- (4-fluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methyl) acetamide (I.1.1-36 );

N - {[4- (2-fluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methyl) acetamide (I.1.1-37 );

N - {[4- (4-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methyl) acetamide (I.1.1-38 );

N - {[4- (4-pyridoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methyl) acetamide (I.1.1-39 );

N - {[4- (thiophen-2-carbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl | methyl} -N '- (4-methyl) acetamide (I.1.1 -40);

N - {[4- (thiophen-3-carbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (4-methyl) propionamide (I.1.1 -41);

N - {[4- (3-pyridoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (methyl) propionamide (I.1.1-42);

N - {[4-phenylacetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (methyl) acetamide (I.1.1-43);

N - {[4- (methylamino) acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (methyl) acetamide (I.1.1-44);

N - {[4- (dimethylamino) acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (methyl) acetamide (I.1.1-45);

N - {[4- (methylamino) acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (2-phenylethyl) acetamide (I.1.1-46) ;

N - {[4- (dimethylamino) acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (2-phenylethyl) acetamide (I.1.1-47) ;

N - {[4- (3-pyridoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl-N '- (ethyl) acetamide (I.1.1-48);

N - {[4- (4-pyridoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl-N '- (ethyl) acetamide (I.1.1-49);

N - {[4- (2-hydroxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N '- (ethyl) acetamide (I.1.1-50);

N- (1- {4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} -1- {methyl} ethyl) -N '- ( 4-methylphenyl) acetamide (I.1.1-51);

N- (1- {4- [4-methoxybenzoyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} -1- {methyl} ethyl) -N '- (4-methylphenyl ) acetamide (I.1.1-52);

N- (1- {4 - [(3-fluorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} -1- {methyl} ethyl) -N '- ( 4-methylphenyl) acetamide (I.1.1-53);

N- (1 - {[4- (cyclopropylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1- (methyl) ethyl} -N '- (4-methylphenyl) acetamide (I.1.1-54);

N- [1- (4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) cyclopropyl] -N '- (4-methylphenyl) acetamide (I.1.1-55) ;

N - [(4-acetyl-5,5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N '- (4-methylphenyl) acetamide (I. 1.1-56);

N- [1 (S) - (4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) ethyl] -N '- (4-methylphenyl) acetamide (I.1.1 -57);

N- [1 (R) - (4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) ethyl] -N '- (4-methylphenyl) acetamide (I.1.1 -58);

N- [1 (S) - (4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) ethyl] -N '- (4-methylphenyl) acetamide (I.1.1 -57 / 58r);

N - [(4-acetyl-5 (S) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N '- (4-methylphenyl) acetamide (I .1.1-59);

N - [(4-acetyl-5 (R) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N '- (4-methylphenyl) acetamide (I .1.1-60);

N - [(4-acetyl-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N '- (4-methylphenyl) acetamide (I.1.1- 59 / 60r);

Methyl 3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophene-2-carboxylate (I .1.2-01);

7 - {[(Cyclopropylcarbonyl) (phenyl) amino] methyl} -N- (4-methylphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-02);

7 - {[isobutyryl (4-methylphenyl) amino] methyl} -N- (3-methylphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-04);

7 - {[isobutyryl (4-methylphenyl) amino] methyl} -N- (4-methylphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-05);

N- (isobutyl) -7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-06);

7 - {[(cyclopropylcarbonyl) - (phenyl) amino] methyl} -N- (3-fluorophenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-07);

N- (4-chlorophenyl) -7 - {[(cyclopropylcarbonyl) - (phenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-08);

N- (3,4-dimethylphenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-09 );

N- (4-fluorobenzyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-10);

7 - {[acetyl (4-methylphenyl) amino] methyl} -N- (3-fluoro-4-methylphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2- 12);

N- (2-fluorophenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-14);

7 - {[acetyl (4-methylphenyl) amino] methyl} -N- (2-ethylphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.1.2-16);

7 - {[isobutyryl (4-methylphenyl) amino] methyl} -N- (3-methoxyphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-17);

N- (sec-butyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-18);

N- (2,5-dimethylphenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-19) ;

N- (tert-butyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-20);

7 - {[acetyl (4-methylphenyl) amino] methyl} -N-cyclopentyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-22);

N- (2-chlorophenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-23);

N- (2,4-dimethylphenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-24) ;

N- (2-furylmethyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-25);

ethyl3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate (I .1.2-26);

3 - ({[[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid dimethylamide (I.1.2-27);

3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid methylamide (I.1.2-28);

3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid N -cyclopentylamide (I.1.2-29);

3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid ( I.1.2-30);

N- [7 - {[Acetyl (methyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-methyl-carboxamide (I.1.2-31);

N- [7 - {[propionyl (methyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-methyl-carboxamide (I.1.2-32);

N- [7 - {[Acetyl (methyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-phenyl-carboxamide (I.1.2-33);

3 - ({[[7 - {[acetyl (methyl) amino] -methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid (I .1.2-34);

Methyl 3 - ({[7 - {[Acetyl (methyl) amino] methyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate (I .1.2-35);

7-N - {[acetyl (methyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (pyridyl-3) -carboxamide (I.1.2-36);

7-N - {[acetyl (methyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (pyridyl-4) -carboxamide (I.1.2-37);

7-N - {[acetyl (methyl) amino] methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)} - N′-benzyl-carboxamide (I.1.2-38);

7-N - {[acetyl (methyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-methylphenyl) carboxamide (I.1.2-39);

7-N - {[acetyl (methyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-fluorophenyl) -carboxamide (I.1.2-40);

7-N - {[acetyl (ethyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (2-fluorophenyl) carboxamide (I.1.2-41);

3 - ({[7 - {[acetyl (ethyl) amino] methyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid (I .1.2-42);

Methyl 3 - ({[7 - {[Acetyl (ethyl) amino] -methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate (I .1.2-43);

3 - ({[7 - {[(2-methylpropionyl) - (ethyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophen-2 β-carboxylic acid (I.1.2-44);

Methyl 3 - ({[7 - {[(2-methylpropionyl) - (ethyl) amino] methyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophene 2-carboxylate (I.1.2-45);

N- [7 - {[Acetyl (2-phenylethyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-methyl-carboxamide (I.1.2-46) ;

N- [7 - {[Acetyl (2-phenylethyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-tert-butyl-carboxamide (I.1.2- 47);

7-N - {[acetyl (ethyl) amino] methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)} - N′-benzyl-carboxamide (I.1.2-48);

7-N - {[acetyl (ethyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (pyridyl-3) -carboxamide (I.1.2-49);

Methyl 3 - ({[7 - {[acetyl (2-phenylethyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate ( I.1.2-50);

Methyl 3 - ({[7 - {[acetyl (methyl) amino] -1- (methyl) ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophene- 2-carboxylate (I.1.2-51);

7 - {[N-acetyl (methyl) amino] -1- (methyl) ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-methylphenyl) -carboxamide ( I.1.2-52);

Methyl 3 - ({[[7 - {[Acetyl (2-phenylethyl) amino] -1 (S) -ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino ) thiophene-2-carboxylate (I.1.2-53);

Methyl 3 - ({[7 - {[Acetyl (2-phenylethyl) amino] -1 (R) -ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate (I.1.2-54);

Methyl 3 - ({[7 - {[Acetyl (2-phenylethyl) amino] -1-ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophen-2 β-carboxylate (I.1.2-53 / 54p);

7 - {[N-acetyl (methyl) amino] methyl} -5 (R) -methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-methylphenyl) -carboxamide (I.1.2-55);

7 - {[N-acetyl (methyl) amino] methyl} -5 (S) -methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-methylphenyl) carboxamide ( I.1.2-56);

7 - {[N-acetyl (methyl) amino] methyl} -5-methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-methylphenyl) -carboxamide (I. 1.2-55 / 56r);

Methyl 3 - ({[7 - {[Acetyl (methyl) amino] methyl} -5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophen-2- carboxylate (I.1.2-57);

Methyl 3 - ({[7 - {[Acetyl (methyl) amino] methyl} -5 (R) -methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene -2-carboxylate (I.1.2-58);

Methyl 3 - ({[7 - {[acetyl (methyl) amino] methyl} -5 (S) -methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene -2-carboxylate (I.1.2-59);

Methyl 3 - ({[7 - {[Acetyl (methyl) amino] methyl} -5-methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophen-2- carboxylate (I.1.2-58 / 59p);

Methyl 3 - ({[7 - {[Acetyl (4-methylphenyl) amino] methyl} -5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophene 2-carboxylate (I.1.2-60);

N - ({4 - [(4-chlorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (4-methylphenyl) acetamide (I.1.3 -01);

N - ({4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (phenyl) cyclopropanecarboxamide (I.1.3-02 );

N - ({4 - [(4-isopropylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (4-methylphenyl) acetamide (I.1.3 -03);

N- (4-fluorobenzyl) -N - ({4 - [(3-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) acetamide (I.1.3 -04);

N- (4-methylphenyl) -N - ({4 - [(4-propylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) acetamide (I.1.3 -05);

N - ({4 - [(3,5-dimethylisoxazol-4-yl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -2-methyl-N- (4-methylphenyl) propanamide (I.1.3-06);

N - ({4 - [(3,4-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (4-fluorobenzyl) acetamide (I .1.3-07);

2-methyl-N- (4-methylphenyl) -N - {[4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} propanamide (I.1.3- 08);

2-methyl-N- (4-methylphenyl) -N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} propanamide (I. 1.3-09);

N - ({4 - [(3-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -2-methyl-N- (4-methylphenyl) propanamide (I.1.3-10);

N - ({4 - [(2,4-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenyl-cyclopropanecarboxamide (I.1.3- eleven);

N - ({4 - [(2-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3-12);

N - ({4 - [(4-ethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3-13);

N - ({4 - [(5-fluoro-2-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3- fourteen);

N - ({4 - [(2-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -2-methyl-N- (4-methylphenyl) propanamide (I.1.3-15);

N - ({4 - [(2-chlorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3-16);

N - ({4 - [(2,4-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (4-fluorobenzyl) acetamide (I .1.3-17);

N - ({4 - [(2,5-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3-18) ;

(2-methyl-N- (4-methylphenyl) -N - {[4- (methylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} propanamide (I1.3 -19);

2-methyl-N - ({4 - [(1-methyl-1H-imidazol-4-yl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) - N- (4-methylphenyl) propanamide (I.1.3-20);

N - ({4 - [(1,2-dimethyl-1H-imidazol-4-yl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- phenylcyclopropanecarboxamide (I.1.3-21);

(N- (4-methylphenyl) -N - {[4- (propylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-22);

N - ({4 - [(3,5-difluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3-23) ;

N - ({4 - [(3,5-dimethylisoxazol-4-yl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I. 1.3-24);

N - {[4- (butylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N-phenylcyclopropanecarboxamide (I.1.3-25);

N- (4-methylphenyl) -N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-26) ;

N-methyl-N - {[4- (methylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-27);

N-methyl-N - {[4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide I.1.3-28);

N-methyl-N - {[4- (4-methylphenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-29);

N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-30);

N-ethyl-N - {[4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-31);

N-ethyl-N - {[4- (4-methylphenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-32);

N-ethyl-N - {[4- (4-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-33);

N-ethyl-N - {[4- (2-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-34);

N-ethyl-N - {[4- (4-methoxyphenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-35);

N-allyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-36);

N-allyl-N - {[4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-37);

N-allyl-N - {[4- (4-methyl-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-38);

N-allyl-N - {[4- (4-fluoro-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-39);

N-allyl-N - {[4- (4-methoxy-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-40);

N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-41);

N-ethyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-42);

N-methyl-N - {[4- (4-chlorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-43);

N-methyl-N - {[4- (4-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-44);

N-methyl-N - {[4- (2-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-45);

N-phenylethyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-46);

N-phenylethyl-N - {[4- (4-chlorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-47);

N-phenylethyl-N - {[4- (4-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-48);

N-phenylethyl-N - {[4- (4-methyl-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-49);

N- [2- (pyrid-3-yl) ethyl] -N - {[4- (4-methoxy-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl } acetamide (I.1.3-50);

N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1-methyl (ethyl)} acetamide (I.1.3- 51);

N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1 (R) -ethyl} acetamide (I.1.3- 52);

N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1 (S) -ethyl} acetamide (I.1.3- 53);

N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1-ethyl} acetamide (I.1.3-52 / 53r );

N-methyl-N - {[4- (2-thienylsulfonyl) -5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-54) ;

N-methyl-N - {[4- (2-thienylsulfonyl) -5 (R) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3 -55);

N-methyl-N - {[4- (2-thienylsulfonyl) -5 (S) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3 -56);

N-methyl-N - {[4- (2-thienylsulfonyl) -5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-55 / 56p);

N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1 (R) -ethyl} acetamide (I. 1.3-57);

N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1 (S) -ethyl} acetamide (I. 1.3-58);

N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1-ethyl} acetamide (I.1.3-57 / 58r);

N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -5 (S) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I .1.3-59);

N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -5 (R) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I .1.3-60);

N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3- 59 / 60r);

7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-01);

7 - {[(4-chlorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-02);

7 - {[(2-chlorobenzyl) oxy] methyl} -4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-03);

7 - {[(4-chlorobenzyl) oxy] methyl} -4- [3- (4-methoxyphenyl) propanoyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-04);

4- (cyclohexylcarbonyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-05);

7 - {[(4-chlorobenzyl) oxy] methyl} -4 - [(3-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-06);

7 - {[(3-fluorobenzyl) oxy] methyl} -4- (3,4,5-trimethoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-07);

7 - {[(3-fluorobenzyl) oxy] methyl} -4- (phenoxyacetyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-08);

7 - {[(4-chlorobenzyl) oxy] methyl} -4- (4-fluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-09);

4- (3-chlorobenzoyl) -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-10);

4- (5-bromo-2-furoyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-11);

7 - {[(4-methylbenzyl) oxy] methyl} -4- (3,4,5-trimethoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-12);

7 - {[(4-chlorobenzyl) oxy] methyl} -4- (2-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-13);

7 - [(benzyloxy) methyl] -4 - [(3-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-14);

7 - {[(3-fluorobenzyl) oxy] methyl} -4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-15);

7 - {[(3-fluorobenzyl) oxy] methyl} -4- (3-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-16);

7 - [(benzyloxy) methyl] -4- (3-phenylpropanoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-17);

7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenoxy) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-18);

4- (2,3-dimethoxybenzoyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-19);

4- (cyclopentylcarbonyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-20);

7 - {[(2-chlorobenzyl) oxy] methyl} -4- (cyclopentylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-21);

7 - {[(4-chlorobenzyl) oxy] methyl} -4- (4-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-22);

7- (methoxymethyl) -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-23);

7- (ethoxymethyl) -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-24);

7- (allyloxymethyl) -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-25);

7- [2-phenylethyloxy (methyl)] - 4 - [(4-methoxybenzoyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-26);

7- [2-phenylethyloxy (methyl)] - 4- (pyridyl-4-carbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-27);

7- [2-phenylethyloxy (methyl)] - 4- (2-hydroxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-28);

7- [2-phenylethyloxy (methyl)] - 4- (2,3-methylenedioxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-29);

7- [2-phenylethyloxy (methyl)] - 4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-30);

7- (allyloxymethyl) -4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-31);

7- [2-phenylethyloxy (methyl)] - 4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-32);

7- [2-dimethylamino-ethyloxy (methyl)] - 4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-33);

7- [2-N-pyrrolidino-ethyloxy (methyl)] - 4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-34);

7- [2-dimethylamino-ethyloxy (methyl)] - 4- (4-pyridylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-35);

7- [2-dimethylamino-ethyloxy (methyl)] - 4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-36);

7- [2-N-pyrrolidino-ethyloxy (methyl)] - 4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-37);

7- [2-N-pyrrolidino-ethyloxy (methyl)] - 4 - [(4-chlorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-38);

7- [2-dimethylamino-ethyloxy (methyl)] - 4 - [(4-chlorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-39);

7- [2-dimethylamino-ethyloxy (methyl)] - 4 - [(4-fluorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-40);

7- [2-hydroxyethyloxy (methyl)] - 4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-41);

7- [2-hydroxyethyloxy (methyl)] - 4 - [(4-chlorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-42);

7- [2-hydroxyethyloxy (methyl)] - 4- (4-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-43);

7- [2-hydroxyethyloxy (methyl)] - 4- (2-hydroxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-44);

7- [2-hydroxyethyloxy (methyl)] - 4-benzoyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-45);

7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-46);

7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4-thienylcarbonyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-47);

7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4- (2-hydroxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-48);

7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4- (4-chlorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-49);

7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4-cyclohexylcarbonyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-50);

7- {1 - [(3-fluorobenzyl) oxy] -1- (methyl}) ethyl-4 - [(4-methoxy-phenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-51);

7- {1 (R) - [(3-fluorobenzyl) oxy] -1- (methyl}) ethyl-4 - [(4-methoxy-phenyl) acetyl] -2,3,4,5-tetrahydro-1, 4-benzoxazepine (I.2.1-52);

7- {1 (S) - [(3-fluorobenzyl) oxy] -1- (methyl}) ethyl-4 - [(4-methoxy-phenyl) acetyl] -2,3,4,5-tetrahydro-1, 4-benzoxazepine (.2.1-53);

7- {1 - [(3-fluorobenzyl) oxy] -1- (methyl}) ethyl-4 - [(4-methoxy-phenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-52 / 53r);

7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-54 );

7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -5 (R) -dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I. 2.1-55);

7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -5 (S) -dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I. 2.1-56);

7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-55 / 56r);

N- (2-ethoxyphenyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-01);

Ethyl 3 - ({[7 - {[(3-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) benzoate (I.2.2-02 );

ethyl 3 - ({[7 - {[(2-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) benzoate (I.2.2-03 );

7 - {[(2-chlorobenzyl) oxy] methyl} -N- (2-methoxyphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-04);

7 - {[(2-fluorobenzyl) oxy] methyl} -N- (2-phenylethyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-05);

7 - {[(3-fluorobenzyl) oxy] methyl} -N- (3-methylphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-06);

7 - {[(3-fluorobenzyl) oxy] methyl} -H-phenyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-07);

7 - {[(2-chlorobenzyl) oxy] methyl} -N- (2,5-dimethoxyphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-08);

ethyl 3 - ({[7 - {[(4-methylbenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) benzoate (I.2.2-09 );

N- (3-fluorophenyl) -7 - {[((4-methylbenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-10);

7 - {[(3-fluorobenzyl) oxy] methyl} -N- (4-fluorophenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-11);

N- (tert-butyl) -7 - {[(4-chlorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-12);

ethyl N - {[7 - {[(4-methylbenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} beta-alaninate (I.2.2-13 );

7 - {[(4-chlorobenzyl) oxy] methyl} -N-phenyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-14);

N- (3,5-dimethoxyphenyl) -7 - {[((4-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-15);

ethyl 2 - ({[7 - {[(4-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) benzoate (I.2.2-16 );

7 - [(benzyloxy) methyl] -N- (2-chlorophenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-17);

7 - {[(4-fluorobenzyl) oxy] methyl} -N- (3-methoxyphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) carboxamide (I.2.2-18);

7 - {[(3-fluorobenzyl) oxy] methyl} -N- (3-methoxyphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) carboxamide (I.2.2-19);

7 - {[(2-fluorobenzyl) oxy] methyl} -N- (4-fluorophenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-20);

N-cyclopentyl-7 - {[(4-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-21);

N-benzyl-7 - {[(4-methylbenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-22);

N- (2,4-difluorophenyl) -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-23);

7 - {[(2-fluorobenzyl) oxy] methyl} -N-phenyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-24);

7 - {[(4-methylbenzyl) oxy] methyl} -N- (4-methylphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-25);

7 - {[(3-fluorobenzyl) oxy] methyl} -N- (3-fluorophenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-26);

7 - {[(4-methylbenzyl) oxy] methyl} -N- (3-methylphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-27);

N-1,3-benzodioxol-5-yl-7 - {[(2-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-28 );

N-cyclohexyl-7 - {[(4-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-29);

7 - {[((4-methylbenzyl) oxy] methyl} -N- (2-phenylethyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide I.2.2-30);

7 - [(benzyloxy) methyl] -N- [3- (methylthio) phenyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-31);

N- (2-ethoxyphenyl) -7-methoxymethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-32);

N- (2-methoxyphenyl) -7-ethoxymethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-33);

N- (2-ethoxyphenyl) -7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-34);

N- (2-methoxyphenyl) -7- (2-phenylethyloxy) methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-35);

N- (2-ethoxyphenyl) -7- (2-dimethylamino-ethyloxy) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-36);

N- (2-methoxyphenyl) -7- (2-H-pyrrolidino-ethyloxy) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-37);

N- (2-ethoxyphenyl) -7- (2-hydroxyethyloxy) methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-38);

N- (2-methoxyphenyl) -7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-39 );

N- (2-methoxyphenyl) -7- [2- (4-chlorophenyl) ethyloxy (methyl)] 2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-40);

Methyl 3 - ([7-methoxymethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate (I.2.2-41);

Methyl 3 - {[7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonylamino} thiophene-2-carboxylate (I.2.2-42);

Methyl 3 - {[7- (2-phenylethyl-hydroxy (methyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl-amino} thiophene-2-carboxylate (I.2.2- 43);

Methyl 3 - {[7- (2-dimethylaminoethyl-hydroxy (methyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl-amino} thiophene-2-carboxylate (I.2.2- 44);

Methyl 3 - {[7- (2-N-pyrrolidino-ethyloxy (methyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl-amino} thiophene-2-carboxylate (I. 2.2-45);

N- (3-methoxycarbonylphenyl) - [7-methoxymethyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)] - carboxamide (I.2.2-46);

N- (3-methoxycarbonylphenyl) - [7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)] - carboxamide (I.2.2-47);

N- (3-methoxycarbonylphenyl) - [7- (2-dimethylamino-ethyloxy) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)] - carboxamide (I.2.2-48);

N- (3-methoxycarbonylphenyl) - [7- (2-N-pyrrolidinoethyloxy) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)] - carboxamide (I.2.2-49);

N- (3-methoxycarbonylphenyl) - [7- (2-phenylethyloxy) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)] - carboxamide (I.2.2-50);

N- (2-ethoxyphenyl) -7- {1 - [(3-fluorobenzyl) oxy] -1- (methyl) ethyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I .2.2-51);

N- (2-ethoxyphenyl) -7- {1 - [(3-fluorobenzyl) oxy] -1 (S) -ethyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I .2.2-52);

N- (2-ethoxyphenyl) -7- {1 - [(3-fluorobenzyl) oxy] -1 (R) -ethyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I .2.2-53);

N- (2-ethoxyphenyl) -7- {1 - [(3-fluorobenzyl) oxy] -1-ethyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2- 52 / 53r);

N- (2-ethoxyphenyl) -7 - [(3-fluorobenzyl) oxymethyl] -5-dimethyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-54);

N- (2-ethoxyphenyl) -7 - [(3-fluorobenzyl) oxymethyl] -5 (S) -methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-55 );

N- (2-ethoxyphenyl) -7 - [(3-fluorobenzyl) oxymethyl] -5 (R) -methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-56 );

N- (2-ethoxyphenyl) -7 - [(3-fluorobenzyl) oxymethyl] -5-methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-55 / 56) ;

Methyl 3 - ({7- [1- (3-fluorobenzyloxy) -1-methylethyl] -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I. 2.2-57);

Methyl 3 - ({7- [1- (3-fluorobenzyloxy) -1 (S) -ethyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I.2.2-58);

Methyl 3 - ({7- [1- (3-fluorobenzyloxy) -1 (R) -ethyl] -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I.2.2-59);

Methyl 3 - ({7- [1- (3-fluorobenzyloxy) -1-ethyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I. 2.2-58 / 59p);

Methyl 3 - {[7- (3-fluorobenzyloxy) methyl] -5-dimethyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I.2.2 -60);

Methyl 3 - {[7- (3-fluorobenzyloxy) methyl] -5 (S) -methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carbonyl} amino) thiophene-2-carboxylate ( I.2.2-61);

Methyl 3 - {[7- (3-fluorobenzyloxy) methyl] -5 (R) -methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carbonyl} amino) thiophene-2-carboxylate ( I.2.2-62);

Methyl 3 - {[7- (3-fluorobenzyloxy) methyl] -5-methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I.2.2 -61 / 62p);

7 - [(benzyloxy) methyl] -4 - [(2-fluorobenzyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-01);

7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(3-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-02);

7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-03);

7 - [(benzyloxy) methyl] -4- (mesitylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-04);

4 - {[7 - [(benzyloxy) methyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] sulfonyl} benzonitrile (I.2.3-05);

7 - {[(2-fluorobenzyl) oxy] methyl} -4 - [(3-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-06);

4 - [(3-chloro-4-fluorophenyl) sulfonyl] -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-07 );

7 - [(benzyloxy) methyl] -4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-08);

7 - {[(2-chlorobenzyl) oxy] methyl} -4- (propylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-09);

7 - {[(4-fluorobenzyl) oxy] methyl} -4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-10);

7 - [(benzyloxy) methyl] -4 - [(3-chloro-4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-11);

7 - [(benzyloxy) methyl] -4 - [(3-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-12);

7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(2,4-difluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-13);

7 - {[(2-chlorobenzyl) oxy] methyl} -4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-14);

4 - [(5-chloro-2-thienyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-15 );

4 - [(2,5-dimethoxyphenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-16);

7 - {[(4-chlorobenzyl) oxy] methyl} -4- (propylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-17);

7 - [(benzyloxy) methyl] -4 - [(5-bromo-2-thienyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-18);

4 - [(5-chloro-2-thienyl) sulfonyl] -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-19 );

7 - {[(4-fluorobenzyl) oxy] methyl} -4 - [(5-fluoro-2-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-20 );

4 - [(3-chloro-4-methoxyphenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-21 );

4 - [(3-chloro-4-methylphenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-22 );

7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(3-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-23);

4 - {[7 - {[(3-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] sulfonyl} benzonitrile (.2.3-24);

4- (2,1,3-benzothiadiazol-4-ylsulfonyl) -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3- 25);

4 - [(3,5-difluorophenyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-26);

7 - {[(4-chlorobenzyl) oxy] methyl} -4 - [(2,4-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-27);

7 - [(benzyloxy) methyl] -4 - [(5-chloro-2-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-28);

4 - [(4-chlorophenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-29);

7 - [(benzyloxy) methyl] -4 - [(4-bromophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-30);

7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(3,5-difluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-31);

4 - [(4-chlorophenyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-32);

4 - [(1,2-dimethyl-1H-imidazol-4-yl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-33);

4 - [(3-chloro-4-methoxyphenyl) sulfonyl] -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-34 );

4- (2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl) -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine ( I.2.3-35);

7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(2-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-36);

7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(3-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-37);

7 - {[(2-chlorobenzyl) oxy] methyl} -4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-38);

4- (2,1,3-benzothiadiazol-4-ylsulfonyl) -7 - [(benzyloxy) methyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-39);

7 - {[(2-fluorobenzyl) oxy] methyl} -4 - [(5-fluoro-2-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-40 );

4 - [(3-chloro-4-fluorophenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-41 );

4 - [(3,5-difluorophenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-42);

7 - [(benzyloxy) methyl] -4- (2,3-dihydro-1,4-benzodioxin-6-yl-sulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3 -43);

4 - [(2,5-dimethylphenyl) sulfonyl] -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-44);

4 - [(2,5-difluorophenyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-45);

7 - [(benzyloxy) methyl] -4 - [(2,4,5-trimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-46);

4 - [(2,4-difluorophenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-47);

4 - [(5-chloro-2-methoxyphenyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-48 );

7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-49);

7 - {[(4-fluorobenzyl) oxy] methyl} -4 - [(4-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-50);

7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-fluoro-phenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-51 );

7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-chloro-phenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-52 );

7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-methoxy-phenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-53 );

7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(2-fluoro-phenylmethyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-54 );

7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(2-thienyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-55);

7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(4-fluoro-phenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3 -56);

7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(4-chloro-phenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3 -57);

7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(4-methoxy-phenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3 -58);

7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(2-fluoro-phenylmethyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3 -59);

7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(2-thienyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-60 );

7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-fluoro-phenyl) sulfonyl] -5 (R) -methyl-2,3,4,5-tetrahydro-1,4- benzoxazepine (I.2.3-61);

7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-fluoro-phenyl) sulfonyl] -5 (S) -methyl-2,3,4,5-tetrahydro-1,4- benzoxazepine (I.2.3-62);

7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-fluoro-phenyl) sulfonyl] -5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I .2.3-61 / 62p).

The subject of this invention is the pharmaceutically acceptable salts of the compounds of general formula I. Some of the compounds of the present invention are neutral molecules and do not form salts, another part contains ionic groups (secondary, tertiary amines or carboxylic acids) and can form salts which were prepared by methods known in the art. this technical field.

The subject of this invention is racemic mixtures and individual optical isomers of compounds of general formula I, since a number of compounds of general formula I have an asymmetric center, and substances can exist in the form of racemic mixtures and isomeric forms.

The subject of this invention is a method for producing derivatives of 2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine of the general formula I.1.1, I.1.2 and I.1.3, starting from Synton A1 (Scheme 1). Acylation of synthon A1 with a suitable acyl halide a2 (acyl chloride, acyl fluoride, acyl bromide) in an aprotic neutral solvent (dichloromethane, dioxane, chloroform and the like) in the presence of a base (triethylamine, DABCO, pyridine and the like) upon cooling leads to a series of substances I.1. The reaction of synton A1 with triphosgene in a neutral aprotic solvent in the presence of a strong non-nucleophilic base (DIPEA, DABCO and the like), followed by the addition of amine a3 in the reaction mixture in an argon atmosphere, leads to a series of substances I.1.2. Exposure to synthon A1 of sulfonic acid a4 in an inert solvent in the presence of a strong base upon cooling leads to a series of substances I.1.3:

Scheme 1

The subject of this invention is a method for producing derivatives of 2,3,4,5-tetrahydrobenzo [1] [1,4] oxazepines of the general formula 1.2.1,1.2.2 and 1.2.3, starting from Synton B1 (Scheme 2). Acylation of synton B1 with a suitable b2 acyl halide (acyl chloride, acyl fluoride, acyl bromide) in an aprotic neutral solvent (dichloromethane, dioxane, chloroform and the like) in the presence of a base (triethylamine, DABCO, pyridine and the like) upon cooling leads to a series of substances 1.2.1. The reaction of synton B1 with triphosgene in a neutral aprotic solvent in the presence of a strong non-nucleophilic base (DIPEA, DABCO and the like), followed by the addition of amine b3 to the reaction mixture in an argon atmosphere, leads to a series of substances 1.2.2. Exposure to synthon B1 sulfochloride b4 in an inert solvent in the presence of a strong base upon cooling leads to a series of substances 1.2.3

The subject of the present invention is an active component having the property of a bile acid receptor agonist TGR5, which is a derivative of 2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine of the general formula I.

Non-steroidal agonists of FA receptors specifically bind to TGR5 receptors and stimulate the secretion of incretin hormones (GLP1, YYP, GIP). Most preferred are TGR5 receptor agonists.

The subject of this invention is a pharmaceutical composition intended for the prevention and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases, containing in an effective amount an active component that is a substituted 2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine of general formula I, in the form of tablets, capsules and injections in a pharmaceutically acceptable package.

The subject of this invention is a pharmaceutical composition intended for the prophylaxis and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases, containing in an effective amount an active component having the property of a bile acid receptor agonist TGR5 and representing substituted 2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine of general formula I.

The subject of this invention is a combination drug intended for the prevention and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases, containing in an effective amount a TGR5 agonist - a derivative of 2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine general formula I and one or more antidiabetic drugs for simultaneous use.

The subject of this invention is a combined pharmaceutical composition intended for the prevention and treatment of metabolic diseases, containing in an effective amount an active component of a TGR5 agonist - a derivative of 2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine of general formula I, and one or several antidiabetic drugs for simultaneous use in the form of tablets, capsules, injections, ointments, rectal suspensions and gels and other finished forms.

The subject of this invention is the aforementioned pharmaceutical compositions in the form of tablets, capsules, ointments, gels, injections and other formulations, placed in a pharmaceutically acceptable package.

The pharmaceutical composition may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field. The pharmaceutical composition, along with the active component of the present invention, may include other active ingredients, provided that they do not cause undesirable effects, such as allergic reactions.

If it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, while they can include traditional pharmaceutical carriers; for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including oral agents using binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless agents flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

A new pharmaceutical composition can be obtained by mixing with an inert excipient and / or solvent of the active component, which is at least one of the compounds of the general formula I.1.1, I.1.2, I.1.3, I.2.1, I.2.2 and I.1.2 .3, as well as their free bases, racemic mixtures or individual optical isomers, as well as their pharmaceutically acceptable salts.

The subject of this invention is a drug.

Medicines may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, topically or rectally). The clinical dosage of the active component (s), pharmaceutical composition or combination drug comprising a pharmaceutically effective amount of the active component in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as depending on the age, sex and stage of the patient’s disease, while the daily dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention in the form of dosage units, the above effective dosage should be taken into account, with each dosage unit of the preparation containing 10 ~ 500 mg, preferably 50 ~ 300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The subject of this invention is a method for the prevention and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases by administering in an effective amount of a new active component or a new pharmaceutical composition.

The subject of this invention is a method for the prevention and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases by administering in an effective amount of a combination drug or a combined pharmaceutical composition.

The invention is illustrated by drawings.

Figure 1 - schematic representation of the functions of FA in the regulation of metabolic pathways through receptors TGR5 and FXR.

Figure 2 - diagram of a 384-well plate with substances.

Figure 3 - concentration dependence of the agonistic activity of the substance I.1.1-01 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Figure 4 - concentration dependence of the agonistic activity of the substance I.1.1-02 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Figure 5 - concentration dependence of the agonistic activity of the substance I.1.1-03 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

6 is a concentration dependence of the agonistic activity of the substance I.1.1-04 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

7 - concentration dependence of the activity of the substance I.1.1-05 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Fig - concentration dependence of the activity of the substance I.1.1-06 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Fig.9 - concentration dependence of the activity of the substance I.1.1-07 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Figure 10 - concentration dependence of the activity of the substance I.1.1-08 in relation to the hTGR.5 receptor. Each concentration point represents an average value for two repetitions.

11 - concentration dependence of the activity of the substance I.1.2-01 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Fig - concentration dependence of the activity of the substance I.1.3-01 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Fig - concentration dependence of the activity of the substance I.1.3-02 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Fig - concentration dependence of the activity of the substance I.1.3-26 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Fig - concentration dependence of the activity of the substance I.2.1-01 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Fig - concentration dependence of the activity of the substance I.2.1-02 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

Fig - concentration dependence of the activity of the substance I.2.2-01 in relation to the hTGR5 receptor. Each concentration point represents an average value for two repetitions.

The following examples illustrate but do not limit the invention.

The structures of the obtained compounds were confirmed by chemical, chromatographic, and spectral analyzes.

Example 1. The general method for synthesizing synthons A1 (R4 = Н; Scheme 1 and Scheme 3)

Synthones A1 were obtained in accordance with scheme 3.

Scheme 3

Compound c2

A solution of compound c1 (150 g, 0.75 mol) and ethanolamine (68.6 g, 1.5 equiv.) In toluene (1 L) was boiled with a Dean-Stark trap for 1 hour. Then the toluene was evaporated, another portion of toluene (0.5 L) was added and evaporated again. The resulting mass was dissolved in ethanol and NaBH ₄ (42.8 g, 1.5 equiv.) Was added portionwise with stirring. After 1 hour of stirring at room temperature, the solvent was evaporated, and the resulting viscous mass was dissolved in aqueous ammonia (0.6 L). The solution was separated from the insoluble precipitate and allowed to crystallize. Received 142.8 g of pure compound c2 (yield - 77%).

Compound c3

To a suspension of c2 (142.8 g, 0.58 mol) in dichloromethane (1 L), triethylamine (116.3 g, 2 equiv.) And boc2O (188.3 g, 1.5 equiv.) Were successively added and stirred overnight at room temperature. Then, the solvent and triethylamine were partially evaporated at 60 ° C, and hexane (0.5 L) was added to the resulting viscous mass. The precipitated solid precipitate was filtered off and washed with hexane (2 × 300 ml). Received 152.4 g of pure product c3 (yield 76%).

Compound c4

DIAD (88.9 g, 0.44 mol) was added in small portions to a solution of c3 (152.4 g, 0.44 mol) and triphenylphosphine (114.7 g, 0.44 mol) in THF (1 L) and stirred overnight at room temperature. Then, the solvent was evaporated, and the resulting mass was chromatographed with ether: hexane (1: 3) on silica gel (6 liters). Received 136.7 g of product c4 (yield 95%).

Compound c5

To a solution of compound c4 (6.3 g, 19 mmol) in 30 ml of THF at -70 ° C was added a 2.5 M solution of BuLi in hexane (a commercial reagent) and after 1 h of exposure to DMF (2.2 ml, 28 mmol). The reaction mass was kept for 2 hours at room temperature, diluted with water and extracted with chloroform (2 × 100 ml). The organic layer was evaporated (78%) and applied to a column (height 70 mm and diameter 100 mm) with silica gel 230-400 M. Eluted with a mixture (328 ml) of hexane: ether (70:30), isolated (after evaporation on a rotor and drying in vacuum) 3.5 g (70%) of compound c5.

Synthons A1

A solution of compound c5 (1.2 g, 4.3 mmol), amine R10-NH2 (4.3 mmol) and TsOH (0.05 g) in toluene (20 ml) was boiled for 2 h with a Dean-Stark nozzle, then completely evaporated, the residue was dissolved in ethanol (15 ml) and a twofold excess of sodium borohydride (commercial reagent) was added. After an hour, the reaction mass was diluted with 5% aqueous potash solution (100 ml) and extracted with chloroform (2 × 100 ml). The organic layer was dried with anhydrous sodium sulfate, evaporated completely, and the obtained technical compound c7 was dissolved in 100 ml of CH2Cl2 and triethylamine (0.62 ml, 4.3 mmol) and acyl chloride R9COCl (4.3 mmol) were added.

The reaction mass was held for 3 hours, completely evaporated, dissolved in 50 ml of methanol and 5 ml of conc. of hydrochloric acid. After 12 hours, the reaction mass was completely evaporated, diluted with water (100 ml), extracted with CH2C12 (2 × 50 ml) and applied to a short column (height 35 mm and diameter 50 mm) with silica gel (230-400 M). Eluted with a mixture (150 ml) of hexane: CH2Cl2: MeOH (5: 5: 1), 0.7 g (52%) of compound A1 was isolated.

Example 2. The general method for synthesizing synthons B1 (R4 = Н; Scheme 2 and Scheme 4)

Synthons B1 were obtained in accordance with scheme 4.

Scheme 4

Compounds d1

R15OH alcohol (3.67 mol) was dissolved in dichloromethane (50 ml) and triethylamine (1.37 g, 13.6 mmol) and trimethylchlorosilane (1.20 g, 11 mmol) were successively added, after which the solution was stirred for 30 min at room temperature. Then, 50 ml of distilled water was added to the reaction mass, and the separated aqueous layer was extracted with dichloromethane (3 × 20 ml). The combined organic layer was dried and evaporated. The resulting product was dissolved in anhydrous dichloromethane (50 ml), cooled to -50 ° C. 5.51 mmol of c5 aldehyde, triethylsilane (641 mg, 5.51 mmol) and trimethylsilyl triflate (408 mg, 1.84 mmol) were successively added to the cooled solution. The mixture was stirred for 15 minutes at the same temperature and then warmed to room temperature. The resulting solution was washed with 2 N. NaOH solution (2 × 30 ml), dried and chromatographed with hexane / ether. Received pure products d1 with a yield of 45-70%.

Synthons B1

5 ml of HCl in dioxane (3 M) was added to compound d1 (0.002 mol), and after 2 hours of stirring at room temperature, the reaction mixture was evaporated on a rotary evaporator. The resulting B1 solid products were used in the following steps without further purification. Yields 70-90%.

Example 3. General method for the synthesis of compounds of General formula I.1.1

The synthesis was carried out in accordance with Scheme 1.

Sinton A1 (0.001 mol) was dissolved in 3 ml of dichloromethane, triethylamine (0.002 mol, 0.202 g) was added and cooled to 0 ° C. With vigorous stirring, 0.0012 mol of a2 chloride was carefully added and the mixture was warmed to room temperature. After three hours, the reaction mass was diluted with dichloromethane (30 ml), washed with 2 N. hydrochloric acid solution (2 × 15 ml), dried over sodium sulfate and chromatographed with a mixture of CH2Cl2 / EtOH (column height 5 cm, width 1 cm). Received pure products I.1.1 with yields of 60-90%.

Thus, the compounds I.1.1-01 - I.1.1-59 / 60r were obtained, which are presented in Table 2.

I.1.1-04

MB 472.59; LC MS m / z 473 (M + 1) A

table 2 I.1.1-05

MB 470.57; LC MS m / z 471 (M + 1l) A I.1.1-06

MB 472.59; LC MS m / z 473 (M + 1) A I.1.1-07

MB 404.47; LC MS m / z 405 (M + 1) A I.1.1-08

MB 442.56; LC MS m / z 443 (M + 1) A I.1.1-09

MB 380.49; LC MS m / z 381 (M + 1) AT

I.1.1-14

MB 462.53; LC MS m / z 463 (M + 1) FROM

table 2 I.1.1-15

MB 440.55; LC MS m / z 441 (m + 1) C I.1.1-16

MB 450.49; LC MS m / z 451 (m + 1) C I.1.1-17

MB 478.54; LC MS m / z 479 (m + 1) C I.1.1-18

MB 444.54; LC MS m / z 445 (m + 1) C I.1.1-19

MB 432.52; LC MS m / z 433 (m + 1) C

table 2 I.1.1-20

MB 472.59; LC MS m / z 473 (M + 1) FROM I.1.1-21

MB 486.57; LC MS m / z 487 (M + 1) FROM I.1.1-22

MB 420.56; LC MS m / z 421 (M + 1) C I.1.1-23

MB 428.54; LC MS m / z 429 (M + 1) C I.1.1-24

MB 420.56; LC MS m / z 421 (M + 1) C

table 2 I.1.1-25

MB 432.50; LC MS m / z 433 (M + 1) D I.1.1-26

MB 406.53; LC MS m / z 407 (M + 1) D I.1.1-27

MB 420.56; LC MS m / z 421 (M + 1) D I.1.1-28

MB 440.55; LC MS m / z 441 (M + 1) D I.1.1-29

MB 394.52; LC MS m / z 395 (M + 1) D I.1.1-30

MB 422.57; LC MS m / z 423 (M + 1) D

table 2 I.1.1-31

MB 276.34; LC MS m / z 277 (M + 1) A I.1.1-32

MB 290.37; LC MS m / z 291 (M + 1) A I.1.1-33

MB 290.37; LC MS m / z 291 (M + 1) AT I.1.1-34

MB 338.41; LC MS m / z 339 (M + l) A I.1.1-35

MB 352.44; LC MS m / z 353 (M + 1) A I.1.1-36

MB 356.40; LC MS m / z 357 (M + 1) A I.1.1-37

MB 356.40; LC MS m / z 357 (M + 1) A

table 2 I.1.1-38

MB 368.44; LC MS m / z 369 (M + 1) FROM I.1.1-39

MB 339.40; LC MS m / z 340 (M + 1) A I.1.1-40

MB 344.44; LC MS m / z 345 (M + 1) AT I.1.1-41

MB 358.46; LC MS m / z 359 (M + 1) AT I.1.1-42

MB 353.43; LC MS m / z 354 (M + 1) A I.1.1-43

MB 352.44; LC MS m / z 353 (M + 1) AT

table 2 I.1.1-44

MB 305.38; LC MS m / z 306 (M + 1) AT I.1.1-45

MB 319.41; LC MS m / z 320 (M + 1) AT I.1.1-46

MB 395.51; LC MS m / z 396 (M + 1) AT I.1.1-47

MB 409.53; LC MS m / z 410 (M + 1) AT I.1.1-48

MB 353.42; LC MS m / z 354 (M + 1) BUT I.1.1-49

MB 353.42; LC MS m / z 354 (M + 1) BUT

table 2 I.1.1-50

MB 368.44; LC MS m / z 369 (m + 1) D I.1.1-51

MB 486.62; LC MS m / z 487 (m + 1) A I.1.1-52

MB 472.59; LC MS m / z 473 (m + 1) A I.1.1-53

MB 474.58; LC MS m / z 475 (m + 1) A I.1.1-54

MB 406.53; LC MS m / z 407 (m + 1) A I.1.1-55

MB 378.48; LC MS m / z 379 (m + 1) A

table 2 I.1.1-56

MB 380.49; LC MS m / z 381 (m + 1) AT I.1.1-57

MB 366.46; LC MS m / z 367 (m + 1) A I.1.1-58

MB 366.46; LC MS m / z 367 (m + 1) A I.1.1-57 / 58r

MB 366.46; LC MS m / z 367 (m + 1) A I.1.1-59

MB 366.46; LC MS m / z 367 (m + 1) A I.1.1-60

MB 366.46; LC MS m / z 367 (m + 1) A I.1.1-59 / 60r

MB 366.46; LC MS m / z 367 (m + 1) A

*) A means activation of hTGR5 receptors by more than 75%, B - more than 50%, C - more than 25%, D - more than 10%.

The structure of a number of compounds 1.1.1 was also confirmed by ¹ H NMR (DMSO-d6, 400 MHz):

I.1.1-02

0.60-0.75 (m, 4H), 1.75 (s, 2H), 1.81-1.98 (m, 1H), 2.30 (s, 3H), 3.17 (s, 2H), 3.57 (s, 2H), 3.79 (m, 1H), 3.99 (m, 1H), 4.06 (d, 1H), 4.50 (s, 1H), 4.70 (m, 3H), 6.86 (t, 1H), 7.00 (d, 2H), 7.16 (d, 2H ), 7.20 (s, 1H).

I.1.1-07

1.80 (s, 2H), 2.24 (s, 3H), 3.18 (s, 3H), 3.57 (s, 1H), 3.75-4.20 (bs, 1H), 4.15 (m, 2H), 4.60-4.93 (bs, 1H), 4.70 (s, 1H), 6.55 (m, 1H), 6.84 (d, 1H), 6.90-7.25 (m, 6H), 7.79 (s, 1H).

I.1.1-08

1.77 (s, 3H), 2.17-2.34 (m, 6H), 3.17 (s, 3H), 3.58 (s, 3H), 3.60 (d, 2H), 3.78 (m, 2H), 3.90 (m, 1H) 4.07 (m, 1H); 4.50 (d, 2H); 4.74 (s, 2H); 6.76-7.32 (m, 11H).

I.1.1-09

0.89 (d, 3H), 1.00 (d, 3H), 1.81 (m, 2H), 2.19 (s, 3H), 2.88 (m, 1H), 3.17 (s, 3H), 3.58 (s, 1H), 3.85 (m, 2H), 4.06 (m, 2H), 4.48 (s, 1H), 4.57 (s, 1H), 4.76 (m, 1H), 6.84 (t, 1H), 6.87-7.17 (m, 5H).

I.1.1-06

0.96 (m, 6H), 2.31 (s, 3H), 2.48 (bs, 1H), 3.19 (m, 4H), 3.57 (s, 1H), 3.76 (m, 4H), 4.01 (bs, 2H), 4.20 (s, 1H), 4.48 (s, 1H), 4.64 (s, 2H), 4.76 (s, 1H), 6.48 (s, 1H), 6.67-7.38 (m, 11H).

I.1.1-05

0.60 (m, 2H), 0.78 (m, 2H), 1.27 (bs, 1H), 2.76 (s, 1H), 2.93 (s, 1H), 3.17 (m, 4H), 3.08 (d, 2H), 3.72 (m, 3H), 3.59 (m, 2H), 3.85 (m, 2H), 4.05 (m, 2H), 4.49 (d, 2H), 4.62 (s, 2H), 6.75-6.98 (m, 3H), 7.04 (m, 4H), 7.38 (d, 2H), 7.25-7.41 (m, 3H).

Example 4. General method for the synthesis of compounds of General formula I.1.2

The synthesis was carried out in accordance with Scheme 1.

To 0.063 g (0.000211 mol) of triphosgene dissolved in 1 ml of dichloromethane, 1 ml of a solution containing compound A1 (0.00057 mol) and diisopropylethylamine DIPEA (0.00126 mol, 0.163 g) was added. The resulting mass was stirred at room temperature under argon for 30 minutes, and then amine a3 (0.00057 mol) and DIPEA (0.081 g, 0.00063 mol) dissolved in 1 ml of dichloromethane were added. The mixture after stirring at room temperature (2 h) was diluted with 30 ml of dichloromethane, washed with 2 N. HCl solution (20 ml), dried over sodium sulfate and chromatographed with CH2Cl2 / EtOH (column height 4 cm, width 1 cm). Received pure products I.1.2 with yields of 30-70%.

Thus, the compounds I.1.2-01 - I.1.2-60 were obtained, are presented in Table 3.

I.1.2-03

MB 485.63; LC MS m / z 486 (M + 1) D

Table 3 I.1.2-04

MB 471.60; LC MS m / z 472 (M + 1) AT I.1.2-05

MB 471.61;
LC MS m / z 472 (M + 1) AT I.1.2-06

MB 409.53; LC MS m / z 410 (M + 1) D I.1.2-07

MB 459.53; LC MS m / z 460 (M + 1) AT

Table 3 I.1.2-23

MB 492.02; LC MS m / z 493 (M + 1) D I.1.2-24

MB 485.63; LC MS m / z 486 (M + 1) D I.1.2-25

MB 461.57; LC MS m / z 462 (M + 1) D I.1.2-26

MB 507.61; LC MS m / z 508 (M + 1l) AT I.1.2-27

MB 506.63; LC MS m / z 507 (M + 1) AT

Table 3 I.1.2-28

MB 492.60; LC MS m / z 493 (M + 1) AT I.1.2-29

MB 532.67; LC MS m / z 533 (M + 1) AT I.1.2-30

MB 479.56; LC MS m / z 480 (M + 1) AT I.1.2-31

MB 291.36; LC MS m / z 292 (M + 1) AT I.1.2-32

MB 305.38; LC MS m / z 306 (M + 1) FROM I.1.2-33

MB 353.42; LC MS m / z 354 (M + 1) BUT

Table 3 I.1.2-34

MB 403.46; LC MS m / z 404 (M + 1) AT I.1.2-35

MB 417.49; LC MS m / z 418 (M + 1) A I.1.2-36

MB 354.41; LC MS m / z 355 (M + 1) A I.1.2-37

MB 354.41; LC MS m / z 355 (M + 1) A I.1.2-38

MB 367.45; LC MS m / z 368 (M + 1) A I.1.2-39

MB 367.45; LC MS m / z 368 (M + 1) A

Table 3 I.1.2-40

MB 371.41; LC MS m / z 372 (M + 1) A I.1.2-41

MB 385.44; LC MS m / z 386 (M + 1) A I.1.2-42

MB 417.49; LC MS m / z 418 (M + 1) AT I.1.2-43

MB 431.51; LC MS m / z 433 (M + 1) A I.1.2-44

MB 445.54; LC MS m / z 447 (M + 1) AT I.1.2-45

MB 459.57; LC MS m / z 461 (M + 1) A

Table 3 I.1.2-46

MB 381.45; LC MS m / z 382 (M + 1) AT I.1.2-47

MB 423.56; LC MS m / z 424 (M + 1) AT I.1.2-48

MB 381.48; LC MS m / z 382 (M + 1) AT I.1.2-49

MB 368.44; LC MS m / z 369 (M + 1) A I.1.2-50

MB 507.61; LC MS m / z 509 (M + 1) A I.1.2-51

MB 445.54; LC MS m / z 447 (M + 1) A

Table 3 I.1.2-52

MB 395.51; LC MS m / z 397 (m + 1) FROM I.1.2-53

MB 431.51; LC MS m / z 433 (m + 1) A I.1.2-54

MB 431.51; LC MS m / z 433 (m + 1) A I.1.2-53 / 54r

MB 431.51; LC MS m / z 433 (m + 1) A I.1.2-55

MB 381.48; LC MS m / z 382 (m + 1) A I.1.2-56

MB 381.48; LC MS m / z 382 (m + 1) A

Table 3 I.1.2-55 / 56r

MB 381.48; LC MS m / z 382 (m + 1) A I.1.2-57

MB 445.54; LC MS m / z 447 (m + 1) A I.1.2-58

MB 431.51; LC MS m / z 433 (m + 1) A I.1.2-59

MB 431.51; LC MS m / z 433 (m + 1) A I.1.2-58 / 59p

MB 431.51; LC MS m / z 433 (m + 1) A I.1.2-60

MB 521.64; LC MS m / z 523 (m + 1) A

The structure of a number of compounds 1.1.2 was also confirmed by ¹ H NMR (DMSO-d6, 400 MHz):

I.1.2-12

1.75 (s, 3H), 2.13 (s, 3H), 2.22 (s, 3H), 3.30 (s, 3H), 3.79 (m, 2H), 4.03 (m, 2H), 4.62 (s, 2H), 4.75 (s, 2H), 6.78-7.19 (m, 8H), 7.24 (s, 1H), 7.35 (d, 1H), 8.68 (s, 1H).

I.1.2-05

0.93 (m, 6H), 2.19 (m, 6H), 2.33 (m, 1H), 3.29 (s, 3H), 3.81 (m, 2H), 4.05 (m, 2H), 4.63 (s, 2H), 4.74 (s, 2H), 6.85-7.03 (m, 8H), 7.17 (s, 1H), 7.32 (m, 2H), 8.47 (s, 1H).

I.1.2-11

0.93 (m, 6H), 3.29 (s, 3H), 3.38 (m, 1H), 3.18 (s, 3H), 3.82 (m, 2H), 4.04 (m, 2H), 4.56 (s, 2H), 3.71 (s, 2H), 6.85-7.09 (m, 8H), 7.09 (s, 1H), 7.36 (m, 1H), 8.27 (s, 1H).

I.1.2-09

0.95 (m, 6H), 2.16 (m, 6H), 2.22 (m, 3H), 3.18 (m, 4H), 3.81 (m, 2H), 4.04 (m, 2H), 4.58 (s, 2H), 4.68 (s, 2H), 6.83-7.00 (m, 7H), 7.13 (d, 1H), 7.19 (d, 2H), 8.31 (s, 1H).

I.1.2-04

0.97 (m, 6H), 2.17 (m, 6H), 2.33 (bs, 1H), 3.34 (m, 2H), 3.80 (m, 2H), 4.06 (m, 2H), 4.61 (s, 1H), 4.73 (s, 2H), 6.72-7.36 (m, 11H), 8.48 (s, 1H).

I.1.2-08

0.60 (m, 2H), 0.91 (s, 2H), 1.29 (s, 1H), 3.18 (s, 3H), 3.82 (m, 2H), 4.04 (m, 2H), 4.59 (s, 2H), 4.82 (s, 2H), 6.88 (dd, 2H), 7.10-7.28 (m, 7H), 7.48 (d, 2H), 8.61 (s, 1H).

Example 5. General method for the synthesis of compounds of General formula I.1.3

The synthesis was carried out in accordance with scheme 1.

Compound A1 (0.001 mol) was dissolved in 3 ml of dichloromethane, triethylamine (0.002 mol, 0.202 g) was added, and 0.0012 mol of a4 sulfochloride was carefully added with vigorous stirring. After 5 hours of stirring at room temperature, the reaction mass was diluted with dichloromethane (30 ml), washed with 2 N. hydrochloric acid solution (2 × 15 ml), dried over sodium sulfate and chromatographed with CH2CL2 / EtOH (column height 5 cm, width 1 cm). Pure I.1.3 products were obtained with yields of 50-65%.

Thus, the compounds I.1.3-01-I.1.3-59 / 60p were obtained, presented in Table 4.

Table 4 Compounds of general formula 1.1.3 their LC MS analysis and activity data Connection number Structure MB, LC MS data % activation at @ 10 µM I.1.3-01

MB 485.01; LC MS m / z 486 (M + 1) A I.1.3-02

MB 480.56; LC MS m / z 481 (M + 1) A I.1.3-03

MB 492.64; LC MS m / z 493 (M + l) A I.1.3-04

MB 482.58; LC MS m / z 483 (M + 1) AT

Table 4 I.1.3-05

MB 492.64; LC MS m / z 493 (M + 1) AT I.1.3-06

MB 497.62; LC MS m / z 498 (M + 1) AT I.1.3-07

MB 496.61; LC MS m / z 497 (M + 1) AT I.1.3-08

MB 478.62; LC MS m / z 479 (M + 1) AT

Table 4 I.1.3-09

MB 484.64; LC MS m / z 485 (M + 1) AT I.1.3-10

MB 496.61; LC MS m / z 497 (M + 1) AT I.1.3-11

MB 490.63; LC MS m / z 491 (M + 1) FROM I.1.3-12

MB 480.56; LC MS m / z 481 (M + 1) AT

Table 4 I.1.3-13

MB 490.63; LC MS m / z 491 (M + 1) AT I.1.3-14

MB 494.59; LC MS m / z 495 (M + 1) FROM I.1.3-15

MB 496.61; LC MS m / z 497 (M + 1) FROM I.1.3-16

MB 497.02; LC MS m / z 498 (M + 1) FROM

Table 4 I.1.3-17

MB 496.61; LC MS m / z 497 (M + 1) FROM I.1.3-18

MB 490.63; LC MS m / z 491 (M + 1) FROM I.1.3-19

MB 416.54; LC MS m / z 417 (M + 1) C I.1.3-20

MB 482.61; LC MS m / z 483 (M + 1) D

Table 4 I.1.3-21

MB 480.59; LC MS m / z 481 (M + 1) D I.1.3-22

MB 416.54; LC MS m / z 417 (M + 1) D I.1.3-23

MB 498.55; LC MS m / z 499 (M + 1) D I.1.3-24

MB 481.58; LC MS m / z 482 (M + 1) D

Table 4 I.1.3-25

MB 442.58; LC MS m / z 443 (M + 1) D I.1.3-26

MB 456.59; LC MS m / z 457 (M + 1) A I.1.3-27

MB 312.39; LC MS m / z 313 (M + 1) FROM I.1.3-28

MB 374.46; LC MS m / z 375 (M + 1) FROM I.1.3-29

MB 388.49; LC MS m / z 389 (M + 1) AT

Table 4 I.1.3-30

MB 380.49; LC MS m / z 381 (M + 1) AT I.1.3-31

MB 388.49; LC MS m / z 389 (M + 1) AT I.1.3-32

MB 402.52; LC MS m / z 404 (M + 1) AT I.1.3-33

MB 406.48; LC MS m / z 407 (M + 1) AT I.1.3-34

MB 406.48; LC MS m / z 407 (M + 1) AT I.1.3-35

MB 418.52; LC MS m / z 420 (M + 1) FROM I.1.3-36

MB 406.53; LC MS m / z 408 (M + 1) FROM

Table 4 I.1.3-37

MB 400.50; LC MS m / z 402 (M + 1) FROM I.1.3-38

MB 414.53; LC MS m / z 416 (M + 1) FROM I.1.3-39

MB 418.50; LC MS m / z 419 (M + 1) AT I.1.3-40

MB 430.53; LC MS m / z 432 (M + 1) AT I.1.3-41

MB 408.54; LC MS m / z 410 (M + 1) AT I.1.3-42

MB 422.57; LC MS m / z 424 (M + 1) AT

Table 4 I.1.3-43

MB 436.96; LC MS m / z 438 (m + 1) FROM I.1.3-44

MB 420.51; LC MS m / z 422 (m + 1) FROM I.1.3-45

MB 420.51; LC MS m / z 422 (m + 1) FROM I.1.3-46

MB 470.61; LC MS m / z 472 (m + 1) FROM I.1.3-47

MB 499.03; LC MS m / z 500 (m + 1) AT I.1.3-48

MB 482.58; LC MS m / z 484 (m + 1) B

Table 4 I.1.3-49

MB 478.62; LC MS m / z 480 (M + 1) AT I.1.3-50

MB 494.61; LC MS m / z 496 (M + 1) AT I.1.3-51

MB 408.54; LC MS m / z 410 (M + 1) AT I.1.3-52

MB 394.52; LC MS m / z 396 (M + 1) A I.1.3-53

MB 394.52; LC MS m / z 396 (M + 1) A I.3-52 / 53r

MB 394.52; LC MS m / z 396 (M + 1) A

Table 4 I.1.3-54

MB 408.54; LC MS m / z 410 (M + 1) A I.1.3-55

MB 394.52; LC MS m / z 396 (M + 1) A I.1.3-56

MB 394.52; LC MS m / z 396 (M + 1) A I.3-55 / 56r

MB 394.52; LC MS m / z 396 (M + 1) A I.1.3-57

MB 422.93; LC MS m / z 424 (M + 1) A I.1.3-58

MB 422.93; LC MS m / z 424 (M + 1) A I.3-57 / 58r

MB 422.93; LC MS m / z 424 (M + 1) A

Table 4 I.1.3-59

MB 422.93; LC MS m / z 424 (M + 1) A I.1.3-60

MB 422.93; LC MS m / z 424 (M + 1) A I.1.3-59 / 60p

MB 422.93; LC MS m / z 424 (M + 1) A

The structure of a number of compounds 1.1.3 was also confirmed by ¹ H NMR (DMSO-d6, 400 MHz):

I.1.3-05

0.91 (t, 3H), 1.62 (m, 2H), 1.80 (s, 3H), 2.32 (s, 3H), 2.58 (m, 2H), 3.07 (m, 1H), 3.53 (m, 2H), 3.58 (s, 2H), 3.95 (m, 2H), 4.33 (s, 2H), 4.77 (s, 2H), 6.74 (m, 1H), 6.95-7.28 (m, 8H), 7.59 (d, 2H).

I.1.3-02

1.82 (s, 3H), 2.28 (s, 3H), 3.57 (m, 5H), 4.00 (m, 2H), 4.36 (m, 2H), 4.77 (s, 2H), 6.79 (d, 1H), 6.95 -7.19 (m, 7H), 7.48 (m, 1H), 7.88 (m, 1H).

I.1.3-03

1.43 (m, 8H), 2.33 (s, 3H), 2.95 (m, 1H), 3.17 (s, 3H), 3.52 (m, 2H), 3.59 (s, 1H), 3.99 (m, 2H), 4.38 (s, 2H), 4.79 (s, 2H), 6.65 (d, 1H), 6.96 (d, 1H), 7.03-7.67 (m, 9H).

I.1.3-06

0.97 (m, 6H), 2.23 (s, 3H), 2.32 (s, 3H), 2.45 (m, 1H), 3.59 (s, 2H), 3.68 (m, 2H), 4.15 (m, 2H), 4.41 (m, 2H), 4.67 (s, 2H), 6.78 (d, 1H), 6.90-7.07 (m, 4H), 7.19 (m, 2H).

I.1.3-26

0.68 (m, 2H), 0.82 (m, 2H), 1.33 (bs, 1H), 3.57 (m, 2H), 3.94 (m, 2H), 4.37 (s, 2H), 4.83 (s, 2H), 6.71 (d, 1H), 6.92 (d, 1H), 7.08 (s, 1H), 7.21 (m, 4H), 7.26-7.41 (m, 3H), 7.72 (t, 2H).

I.1.3-04

2.12 (m, 3H), 2.33 (m, 3H), 3.57 (m, 2H), 3.93 (m, 2H), 4.38-4.51 (m, 6H), 6.67 (dd, 1H), 7.03 (m, 1H) 7.10-7.28 (m, 5H); 7.41-7.57 (m, 4H).

Example 6. General method for the synthesis of compounds of General formula I.2.1

The synthesis was carried out in accordance with scheme 2.

Sinten B1 (0.001 mol) was dissolved in 3 ml of dichloromethane, triethylamine (0.002 mol, 0.202 g) was added and cooled to 0 ° C. With vigorous stirring, 0.0012 mol of b2 chloride was carefully added and the mixture was warmed to room temperature. After three hours, the reaction mass was diluted with dichloromethane (30 ml), washed with 2 N. hydrochloric acid solution (2 × 15 ml), dried over sodium sulfate and chromatographed with a mixture of CH2Cl2 / EtOH (column height 5 cm, width 1 cm). Received pure products 1.2.1 with yields of 60-90%.

Thus, the compounds I.2.1-01-I.2.1-55 / 56r were obtained, which are shown in Table 5.

Table 5 Compounds of general formula 1.2.1 their LC MS analysis and activity data Connection number Structure MB, LC MS data % activation at @ 10 µM I.2.1-01

MB 435.50; LC MS m / z 436 (M + 1) A

Table 5 I.2.1-02

MB 451.95; LC MS m / z 453 (M + 1) A I.2.1-03

MB 413.93; LC MS m / z 415 (M + 1) AT I.2.1-04

MB 465.98; LC MS m / z 467 (M + 1) A I.2.1-05

MB 397.49; LC MS m / z 398 (M + 1) FROM

Table 5 I.2.1-06

MB 451.95; LC MS m / z 453 (M + 1) FROM I.2.1-07

MB 481.53; LC MS m / z 482 (M + 1) FROM I.2.1-08

MB 421.47; LC MS m / z 422 (M + 1) C I.2.1-09

MB 425.89; LC MS m / z 426 (M + 1) C

Table 5 I.2.1-10

MB 425.89; LC MS m / z 426 (M + 1) FROM I.2.1-11

MB 460.30; LC MS m / z 461 (M + 1) FROM I.2.1-12

MB 477.56; LC MS m / z 478 (M + 1) C I.2.1-13

MB 437.93; LC MS m / z 439 (M + 1) C

Table 5 I.2.1-14

MB 417.51; LC MS m / z 419 (M + 1) D I.2.1-15

MB 397.47; LC MS m / z 398 (M + 1) D I.2.1-16

MB 421.47; LC MS m / z 422 (M + 1) D I.2.1-17

MB 401.51; LC MS m / z 402 (M + 1) D I.2.1-18

MB 451.50; LC MS m / z 452 (M + 1) D

Table 5 I.2.1-19

MB 451.50; LC MS m / z 452 (M + 1) D I.2.1-20

MB 383.47; LC MS m / z 384 (M + 1) D I.2.1-21

MB 399.92; LC MS m / z 401 (M + 1) D I.2.1-22

MB 437.93; LC MS m / z 439 (M + 1) D I.2.1-23

MB 341.41; LC MS m / z 342 (M + 1) AT

Table 5 I.2.1-24

MB 355.43; LC MS m / z 356 (M + 1) AT I.2.1-25

MB 367.45; LC MS m / z 368 (M + 1) AT I.2.1-26

MB 417.51; LC MS m / z 419 (M + 1) AT I.2.1-27

MB 388.47; LC MS m / z 389 (M + 1) A I.2.1-28

MB 403.48; LC MS m / z 404 (M + 1) A I.2.1-29

MB 431.49; LC MS m / z 433 (M + 1) A

Table 5 I.2.1-30

MB 431.54; LC MS m / z 433 (M + 1) A I.2.1-31

MB 329.42; LC MS m / z 330 (M + 1) AT I.2.1-32

MB 393.51; LC MS m / z 395 (M + 1) AT I.2.1-33

MB 360.48; LC MS m / z 362 (M + 1) AT I.2.1-34

MB 386.52; LC MS m / z 388 (M + 1) AT I.2.1-35

MB 355.44; LC MS m / z 356 (M + 1) BUT

Table 5 I.2.1-36

MB 398.51; LC MS m / z 400 (M + 1) A I.2.1-37

MB 424.54; LC MS m / z 426 (M + 1) A I.2.1-38

MB 428.96; LC MS m / z 430 (M + 1) A I.2.1-39

MB 402.92; LC MS m / z 404 (M + 1) A I.2.1-40

MB 386.47; LC MS m / z 387 (M + 1) A

Table 5 I.2.1-41

MB 371.44; LC MS m / z 372 (M + 1) AT I.2.1-42

MB 375.86; LC MS m / z 377 (M + 1) AT I.2.1-43

MB 357.41; LC MS m / z 358 (M + 1) AT I.2.1-44

MB 343.38; LC MS m / z 344 (M + 1) AT I.2.1-45

MB 327.38; LC MS m / z 328 (M + 1) AT I.2.1-46

MB 385.46; LC MS m / z 386 (M + 1) AT

Table 5 I.2.1-47

MB 453.56; LC MS m / z 455 (M + 1) A I.2.1-48

MB 463.53; LC MS m / z 465 (M + 1) A I.2.1-49

MB 481.98; LC MS m / z 483 (M + 1) A I.2.1-50

MB 453.58; LC MS m / z 455 (M + 1) FROM I.2.1-51

MB 463.55; LC MS m / z 465 (M + 1) A

Table 5 I.2.1-52

MB 449.53; LC MS m / z 451 (M + 1) A I.2.1-53

MB 449.53; LC MS m / z 451 (M + 1) A I.2.1-52 / 53r

MB 449.53; LC MS m / z 451 (M + 1) A I.2.1-54

MB 463.55; LC MS m / z 465 (M + 1) A I.2.1-55

MB 449.53; LC MS m / z 451 (M + 1) A

Table 5 I.2.1-56

MB 449.53; LC MS m / z 451 (M + 1) A I.2.1-55 / 56r

MB 449.53; LC MS m / z 451 (M + 1) A

The structure of a number of I.2.1 compounds was also confirmed by ¹ H NMR (DMSO-d6, 400 MHz):

I.2.1-06

3.63-3.72 (m, 5H), 3.87 (m, 2H), 3.99 (m, 1H), 4.07 (m, 1H), 4.45-4.68 (m, 6H), 6.75 (m, 3H), 6.96 (m, 1H), 7.15-7.26 (m, 3H), 7.27-7.48 (m, 4H).

I.2.1-03

4.03 (bs, 2H), 4.22 (m, 2H), 4.52 (s, 2H), 4.59 (s, 2H), 4.27 (s, 2H), 6.96 (d, 1H), 7.07 (s, 1H), 7.23 (d, 2H), 7.32-7.53 (m, 5H), 7.23 (m, 1H).

I.2.1-21

1.37-1.75 (m, 8H), 3.00 (m, 1H), 3.84 (m, 2H), 4.07 (m, 2H), 4.55 (m, 5H), 4.17 (s, 1H), 6.93 (m, 1H) 7.16-7.23 (m, 1H); 7.27-7.46 (m, 3H); 7.53 (m, 1H).

I.2.1-11

4.00 (bs, 2H), 4.21 (m, 2H), 4.48 (s, 2H), 4.56 (s, 2H), 4.60 (bs, 2H), 6.75 (m, 1H), 6.95 (d, 1H), 7.03 -7.27 (m, 5H); 7.40 (m, 1H).

I.2.1-10

3.76 (m, 1H), 4.01 (m, 1H), 4.07 (m, 1H), 4.23 (m, 1H), 4.27-4.76 (m, 5H), 6.77 (s, 1H), 6.96-7.53 (m, 10H).

Example 7. General method for the synthesis of compounds of General formula I.2.2

The synthesis was carried out in accordance with scheme 2.

To 0.063 g (0.000211 mol) of triphosgene dissolved in 1 ml of dichloromethane, 1 ml of a solution containing compound B1 (0.00057 mol) and diisopropylethylamine DIPEA (0.00126 mol, 0.163 g) was added. The resulting mass was stirred at room temperature under argon for 30 minutes, and then amine b3 (0.00057 mol) and DIPEA (0.081 g, 0.00063 mol) dissolved in 1 ml of dichloromethane were added. After stirring at room temperature (2 h), the mixture was diluted with 30 ml of dichloromethane, washed with 2 N / HCl solution (20 ml), dried over sodium sulfate and chromatographed with CH2Cl2 / EtOH (column height 4 cm, width 1 cm). Received pure I.2.2 products with yields of 30-70%.

Thus, the compounds I.2.2-01-I.2.2-61 / 62p were obtained, which are shown in Table 6.

Table 6 Compounds of the general formula I.2.2 data on their LC MS analysis and activity Connection number Structure MB, LC MS data % activation at @ 10 µM I.2.2-01

F

F MB 450.52; LC MS m / z 451 (M + 1) A I.2.2-02

MB 478.53; LC MS m / z 479 (M + 1) AT

Table 6 I.2.2-03

MB 478.53; LC MS m / z 479 (M + 1) AT I.2.2-04

MB 452.94; LC MS m / z 454 (M + 1) AT I.2.2-05

MB 434.52; LC MS m / z 435 (M + 1) AT I.2.2-06

MB 420.49; LC MS m / z 421 (M + 1) FROM

Table 6 I.2.2-07

MB 406.46; LC MS m / z 407 (M + 1) FROM I.2.2-08

MB 482.97; LC MS m / z 484 (M + 1) FROM I.2.2-09

MB 474.56; LC MS m / z 475 (M + 1) FROM I.2.2-10

MB 420.49; LC MS m / z 421 (M + 1) FROM

Table 6 I.2.2-11

MB 424.45; LC MS m / z 425 (M + 1) FROM I.2.2-12

MB 402.93; LC MS m / z 403 (M + 1) FROM I.2.2-13

MB 426.52; LC MS m / z 427 (M + 1) FROM I.2.2-14

MB 422.92; LC MS m / z 424 (M + 1) FROM

Table 6 I.2.2-15

MB 466.51; LC MS m / z 467 (M + 1) FROM I.2.2-16

MB 478.53; LC MS m / z 479 (M + 1) FROM I.2.2-17

MB 422.92; LC MS m / z 424 (M + 1) FROM I.2.2-18

MB 436.49; LC MS m / z 437 (M + 1) FROM

Table 6 I.2.2-19

MB 436.49; LC MS m / z 437 (M + 1) FROM I.2.2-20

MB 424.45; LC MS m / z 425 (M + 1) FROM I.2.2-21

MB 398.48; LC MS m / z 399 (M + 1) C I.2.2-22

MB 416.53; LC MS m / z 417 (M + l) D I.2.2-23

MB 442.44; LC MS m / z 443 (M + l) D

Table 6 I.2.2-24

MB 406.46; LC MS m / z 407 (M + 1) D I.2.2-25

MB 416.53; LC MS m / z 417 (M + 1) D I.2.2-26

MB 424.45; LC MS m / z 425 (M + 1) D I.2.2-27

MB 416.53; LC MS m / z 417 (M + 1) D I.2.2-28

MB 450.47; LC MS m / z 451 (M + 1) D

Table 6 I.2.2-29

MB 412.51; LC MS m / z 413 (M + 1) D I.2.2-30

MB 430.55; LC MS m / z 431 (M + 1) D I.2.2-31

MB 434.56; LC MS m / z 436 (M + 1) D I.2.2-32

MB 356.43; LC MS m / z 357 (M + 1) AT

Table 6 I.2.2-33

MB 356.43; LC MS m / z 357 (M + 1) AT I.2.2-34

MB 382.46; LC MS m / z 383 (M + 1) AT I.2.2-35

MB 432.52; LC MS m / z 434 (M + 1) A I.2.2-36

MB 413.52; LC MS m / z 415 (M + 1) A I.2.2-37

MB 425.53; LC MS m / z 427 (M + 1) A I.2.2-38

MB 386.45; LC MS m / z 387 (M + 1) A

Table 6 I.2.2-39

MB 492.58; LC MS m / z 494 (M + 1) A I.2.2-40

MB 480.99; LC MS m / z 482 (M + 1) A I.2.2-41

MB 376.43; LC MS m / z 377 (M + 1) AT I.2.2-42

MB 402.47; LC MS m / z 403 (M + 1) AT I.2.2-43

MB 466.56; LC MS m / z 468 (M + 1) A I.2.2-44

MB 433.53; LC MS m / z 435 (M + 1) A

Table 6 I.2.2-45

MB 459.57; LC MS m / z 461 (M + 1) A I.2.2-46

MB 370.41; LC MS m / z 371 (M + 1) AT I.2.2-47

MB 396.45; LC MS m / z 397 (M + 1) AT I.2.2-48

MB 427.50; LC MS m / z 428 (M + 1) A I.2.2-49

MB 453.54; LC MS m / z 455 (M + 1) A

Table 6 I.2.2-50

MB 460.53; LC MS m / z 462 (M + 1) A I.2.2-51

MB 478.57; LC MS m / z 480 (M + 1) A I.2.2-52

MB 464.54; LC MS m / z 466 (M + 1) A I.2.2-53

MB 464.54; LC MS m / z 466 (M + 1) A I.2.2-
52 / 53r

MB 464.54; LC MS m / z 466 (M + 1) A I.2.2-54

MB 478.57; LC MS m / z 480 (M + 1) A

Table 6 I.2.2-55

MB 464.54; LC MS m / z 466 (M + 1) A I.2.2-56

MB 464.54; LC MS m / z 466 (M + 1) A I.2.2-55 / 56

MB 464.54; LC MS m / z 466 (M + 1) A I.2.2-57

MB 498.58; LC MS m / z 500 (M + 1) A I.2.2-58

MB 484.55; LC MS m / z 486 (M + 1) A I.2.2-59

MB 484.55; LC MS m / z 486 (M + 1) A

Table 6 I.2.2-58 / 59p

MB 484.55; LC MS m / z 486 (m + 1) A I.2.2-60

MB 498.58; LC MS m / z 500 (m + 1) A I.2.2-61

MB 484.55; LC MS m / z 486 (m + 1) A I.2.2-62

MB 484.55; LC MS m / z 486 (m + 1) A I.2.2-61 / 62r

MB 484.55; LC MS m / z 486 (m + 1) A

The structure of a number of compounds 1.2.2 was also confirmed by ¹ H NMR (DMSO-d6, 400 MHz):

I.2.2-04

3.56 (s, 2H), 3.75 (s, 3H), 3.62 (m, 2H), 4.56 (s, 2H), 4.59 (s, 2H), 4.66 (s, 2H), 6.82 (t, 1H), 6.86 (m, 3H), 7.21 (d, 1H), 7.26-7.71 (m, 7H).

I.2.2-08

3.56 (s, 2H), 3.63 (s, 3H), 3.21 (s, 3H), 3.82 (m, 2H), 4.07 (m, 2H), 4.56 (s, 2H), 4.59 (s, 2H), 4.65 (s, 2H), 6.50 (m, 1H), 6.78 (d, 1H), 6.96 (d, 1H), 7.22 (d, 1H), 7.27-7.59 (m, 7H).

I.2.2-07

3.57 (s, 2H), 3.76 (m, 2H), 4.07 (m, 2H), 4.47 (s, 2H), 4.51 (s, 2H), 4.68 (s, 2H), 6.96 (m, 2H), 7.05 -7.47 (m, 7H), 7.40 (m, 4H), 8.51 (s, 1H).

I.2.2-02

3.29 (s, 2H), 3.81 (m, 2H), 4.09 (m, 2H), 4.43 (s, 2H), 4.49 (s, 2H), 4.67 (s, 2H), 6.96 (d, 1H), 7.06 -7.19 (m, 4H), 7.23-7.41 (m, 3H), 7.51 (d, 1H), 7.67 (d, 1H), 8.07 (s, 1H), 8.27 (s, 1H).

I.2.2-05

2.66 (t, 2H), 3.17 (m, 2H), 3.69 (m, 2H), 3.96 (m, 2H), 4.46-4.57 (m, 6H), 6.67 (t, 1H), 6.91 (d, 1H) 7.07-7.43 (m, 10 H); 7.48 (t, 1H).

Example 8. General method for the synthesis of compounds of General formula 1.2.3

The synthesis was carried out in accordance with scheme 2.

Compound B1 (0.001 mol) was dissolved in 3 ml of dichloromethane, triethylamine (0.002 mol, 0.202 g) was added, and 0.0012 mol of b4 sulfochloride was carefully added with vigorous stirring. After 5 hours of stirring at room temperature, the reaction mass was diluted with dichloromethane (30 ml), washed with 2 N. hydrochloric acid solution (2 × 15 ml), dried over sodium sulfate and chromatographed with a mixture of CH2C12 / EtOH (column height 5 cm, width 1 cm). Pure I.2.3 products were obtained with yields of 50-65%.

Thus, the compounds I.2.3-01-I.2.3-61 / 62p were obtained, which are shown in Table 7.

Table 7 Compounds of general formula I.2.3 their LC MS analysis and activity Connection number Structure MB, LC MS data % activation at @ 10 µM I.2.3-01

MB 441.53; LC MS m / z 442 (M + 1) AT I.2.3-02

MB 473.98; LC MS m / z 475 (M + 1) AT I.2.3-03

MB 461.94; LC MS m / z 463 (M + 1) AT

Table 7 I.2.3-04

MB 451.59; LC MS m / z 452 (M + 1) AT I.2.3-05

MB 434.52; LC MS m / z 435 (M + 1) AT I.2.3-06

MB 457.53; LC MS m / z 458 (M + 1) B I.2.3-07

MB 479.93; LC MS m / z 481 (M + 1) C

Table 7 I.2.3-08

MB 415.53; LC MS m / z 416 (M + 1) AT I.2.3-09

MB 409.94; LC MS m / z 411 (M + 1) FROM I.2.3-10

MB 445.49; LC MS m / z 446 (M + 1) AT I.2.3-11

MB 461.94; LC MS m / z 463 (M + 1) AT

Table 7 I.2.3-12

MB 439.54; LC MS m / z 440 (M + 1) FROM I.2.3-13

MB 479.93; LC MS m / z 481 (M + 1) AT I.2.3-14

MB 443.95; LC MS m / z 445 (M + 1) AT I.2.3-15

MB 467.97; LC MS m / z 469 (M + 1) AT

Table 7 I.2.3-16

MB 487.55; LC MS m / z 488 (M + 1) AT I.2.3-17

MB 409.94; LC MS m / z 411 (M +) FROM I.2.3-18

MB 494.43; LC MS m / z 495 (M + 1) C I.2.3-19

MB 467.97; LC MS m / z 469 (M + 1) B

Table 7 I.2.3-20

MB 459.52; LC MS m / z 460 (M + 1) FROM I.2.3-21

MB 491.97; LC MS m / z 493 (M + 1) AT I.2.3-22

MB 475.97; LC MS m / z 477 (M + 1) AT I.2.3-23

MB 457.53; LC MS m / z 458 (M + 1) C

Table 7 I.2.3-24

MB 452.51; LC MS m / z 453 (M + 1) FROM I.2.3-25

MB 485.56; LC MS m / z 486 (M + 1) FROM I.2.3-26

MB 463.48; LC MS m / z 464 (M + 1) C I.2.3-27

MB 472.01; LC MS m / z 473 (M + 1) C

Table 7 I.2.3-28

MB 473.98; LC MS m / z 475 (M + 1) D I.2.3-29

MB 461.94; LC MS m / z 463 (M + 1) D I.2.3-30

MB 478.40; LC MS m / z 479 (M + 1) D I.2.3-31

MB 479.93; LC MS m / z 481 (M + 1) D

Table 7 I.2.3-32

MB 461.94; LC MS m / z 463 (M + 1) D I.2.3-33

MB 445.52; LC MS m / z 446 (M + 1) D I.2.3-34

MB 491.97; LC MS m / z 493 (M + 1) D I.2.3-35

MB 485.54; LC MS m / z 486 (M + 1) D

Table 7 I.2.3-36

MB 461.94; LC MS m / z 463 (M + 1) D I.2.3-37

MB 441.53; LC MS m / z 442 (M + 1) D I.2.3-38

MB 449.98; LC MS m / z 451 (M + 1) D I.2.3-39

MB 467.57; LC MS m / z 468 (M + 1) D

Table 7 I.2.3-40

MB 459.52; LC MS m / z 460 (M + 1) D I.2.3-41

MB 479.93; LC MS m / z 481 (M + 1) D I.2.3-42

MB 463.48; LC MS m / z 464 (M + 1) D I.2.3-43

MB 467.55; LC MS m / z 468 (M + 1) D

Table 7 I.2.3-44

MB 455.55; LC MS m / z 456 (M + 1) D I.2.3-45

MB 463.48; LC MS m / z 464 (M + 1) D I.2.3-46

MB 451.59; LC MS m / z 452 (M + 1) D I.2.3-47

MB 463.48; LC MS m / z 464 (M + 1) D

Table 7 I.2.3-48

MB 491.97; LC MS m / z 493 (M + 1) D I.2.3-49

MB 441.53; LC MS m / z 442 (M + 1) D I.2.3-50

MB 441.53; LC MS m / z 442 (M + 1) D I.2.3-51

MB 408.50; LC MS m / z 410 (M + 1) A

Table 7 I.2.3-52

MB 424.95; LC MS m / z 426 (M + 1) A I.2.3-53

MB 420.53; LC MS m / z 422 (M + 1) AT I.2.3-54

MB 422.52; LC MS m / z 424 (M + 1) AT I.2.3-55

MB 396.53; LC MS m / z 398 (M + 1) AT I.2.3-56

MB 434.53; LC MS m / z 436 (M + 1) AT I.2.3-57

MB 450.99; LC MS m / z 452 (M + 1) AT

Table 7 I.2.3-58

MB 446.57; LC MS m / z 448 (M + 1) AT I.2.3-59

MB 448.56; LC MS m / z 450 (M + 1) AT I.2.3-60

MB 422.57; LC MS m / z 424 (M + 1) AT I.2.3-61

MB 408.50; LC MS m / z 410 (M + 1) A I.2.3-62

MB 408.50; LC MS m / z 410 (M + 1) A I.2.3-61 / 62r

MB 408.50; LC MS m / z 410 (M + 1) A

The structure of a number of compounds 1.2.3 was also confirmed by ¹ H NMR (DMSO-d6, 400 MHz):

I.2.3-09

0.91 (t, 3H), 1.62 (m, 1H), 2.98 (t, 2H), 3.69 (m, 2H), 4.12 (m, 2H), 4.42 (s, 2H), 4.53 (s, 2H), 4.59 (s, 2H), 7.00 (s, 1H), 7.22 (m, 2H), 7.33 (m, 2H), 7.47 (d, 1H), 7.53 (d, 1H).

I.2.3-02

3.57 (m, 2H), 3.76 (s, 3H), 4.01 (m, 2H), 4.44 (s, 2H), 4.53 (s, 2H), 4.59 (s, 2H), 6.84 (d, 1H), 7.17 (m, 3H), 7.26-7.49 (m, 6H), 7.57 (d, 1H).

I.2.3-06

3.63 (m, 2H), 3.74 (s, 3H), 4.01 (m, 2H), 4.43 (s, 2H), 4.48 (s, 2H), 4.58 (s, 2H), 6.83 (d, 1H), 7.07 -7.53 (m, 11H).

I.2.3-05

3.67 (m, 2H), 4.06 (m, 2H), 4.44 (s, 2H), 4.51 (s, 2H), 4.54 (s, 2H), 6.78 (d, 1H), 7.17 (d, 1H), 7.25 -7.43 (m, 6H); 7.87-7.98 (m, 4H).

I.2.3-04

2.25 (s, 3H), 3.51 (m, 2H), 4.12 (m, 2H), 4.41 (s, 2H), 4.46 (s, 2H), 4.51 (s, 2H), 6.98 (d, 1H), 7.06 (s, 2H), 7.13 (s, 1H), 7.21 (d, 1H), 7.26-7.40 (m, 5H).

Example 9. General method for the synthesis of salts of compounds of General formula I

Part of the compounds of the present invention contains ionic groups (secondary and tertiary amines or carboxylic acids) and can form salts, which are obtained by methods known in the art. For this, for example, to a solution of a base in an inert solvent (alcohol, acetone, chloroform, ether, ethyl acetate), a solution of an equivalent amount (sometimes excess) of an organic or inorganic acid in an inert solvent was added and precipitation of the desired salt was achieved. The inorganic acid may be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid or hydroiodic acid. The organic acid may be methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, lactic acid gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid or vanillic acid, n o not limited to them.

Compounds of this invention containing a carboxyl group in their structure can form salts with suitable therapeutically acceptable inorganic and organic bases. Suitable inorganic bases that form salts include, for example, hydroxides, carbonates or bicarbonates of pharmaceutically acceptable alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium, and the like. Suitable organic bases include primary, secondary and tertiary amines such as methylamine, benzathine (N ′, N′-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine , tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol), procaine, triethylamine, etc.

Table 8 presents examples of the obtained pharmaceutically acceptable salts and some of their properties.

Table 8 I.2.2-37c Mesylate 521.6 0.12 BUT I.1.3-50 base 495.6 0.00017 AT I.1.3-50d Hydrochloride 532.1 0.054 AT I.2.3-51 base 408.5 0.00049 BUT I.2.3-51d Hydrochloride 445.0 0.55 BUT I.1.2-30 acid 479.6 0.000026 AT I.1.2-30 Na 501.5 0.20 BUT

Example 10. General method for the synthesis of chiral compounds 1.1-57, 1.1-58, 1.2-53, 1.2-54, 1.3-52, 1.3-53, 1.3-57, 1.3-58 and racemic mixtures 1.1-57 / 58r, 1.2- 53 / 54r, 1.3-52 / 53r, 1.3-57 / 58r of general formula I

Chiral compounds 1.1-57, 1.1-58, 1.2-53, 1.2-54, 1.3-52, 1.3-53, 1.3-57, 1.3-58 and racemic mixtures 1.1-57 / 58r, 1.2-53 / 54r, 1.3- 52 / 53r, 1.3-57 / 58r were obtained in accordance with scheme 1, based on the synths A2-rac, R-A2 and S-A2. Synthesis of synthons A2 was carried out in accordance with scheme 5.

Scheme 5

For this, the available Boc-protected 2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine c8 was acetylated with acetyl halide or acetic anhydride in the presence of a catalyst (aluminum chloride, zinc chloride, magnesium bromide, lithium chloride, etc. ), obtaining acetophenone c9. A series of c10 imines was obtained by condensation of a c9 ketone with suitable amines in the presence of water-removing agents and removal of water (for example, TsOH in toluene, Dean-Stark nozzle, etc.). A series of racemic amines c11-rac was obtained by reduction of c10 imines using suitable reducing agents (e.g., NaBH4, LiBH4, Zn / HOAc, H2 / Pd, etc.). A series of individual optically active amines R-c11 and S-c11 were obtained by methods known in the art, which are described in detail, for example, in ["Stereochemistry of Organic Compounds", Ed. by: E.L. Eliel Wiley, New York, 1994]. In particular, to separate mixtures of c11-rac amines by reaction with chiral tartaric acid, diastereomeric salts were obtained which were separated by chromatography or fractional crystallization.

Acylation of c11 amines with a suitable R9COX acyl halide (acyl chloride, acyl fluoride, acyl bromide) in an aprotic neutral solvent (dichloromethane, dioxane, chloroform and the like) in the presence of a base (triethylamine, DABCO, pyridine and the like) upon cooling-syntheses leads to deprotection and subsequent removal A2-rac, R-A2 and S-A2. LC-MS characteristics of the final racemates and chiral compounds are presented in tables 1-3

Example 11. The general method for the synthesis of chiral compounds 1.1-59, 1.1-60, 1.2-55, 1.2-56, 1.2-58, 1.2-59, 1.3-55, 1.3-56, 1.3-59, 1.3-60, 2.1- 55, 2.1-56, 2.2-55, 2.2-56, 2.2-61, 2.2-62, 2.3-61, 2.3-62 and racemic mixtures 1.1-59 / 60r, 1.2-55 / 56r, 1.2-58 / 59r, 1.3-55 / 56r, 1.3-59 / 60r, 2.1-55 / 56r, 2.2-55 / 56r, 2.2-61 / 62r, 2.3-61 / 62r of general formula I

Chiral compounds 1.1-59, 1.1-60, 1.2-55, 1.2-56, 1.2-58, 1.2-59, 1.3-55, 1.3-56, 1.3-59, 1.3-60, 2.1-55, 2.1-56, 2.2-55, 2.2-56, 2.2-61, 2.2-62, 2.3-61, 2.3-62 and racemic mixtures 1.1-59 / 60r, 1.2-55 / 56r, 1.2-58 / 59r, 1.3-55 / 56r, 1.3-59 / 60r, 2.1-55 / 56r, 2.2-55 / 56r, 2.2-61 / 62r, 2.3-61 / 62r were obtained in accordance with scheme 1, based on the synths A3-gas, R-A3 and S-A3 , or in accordance with Scheme 2, based on B2-rac, R-B2, and S-B2 synths. Sinton A3 received in accordance with scheme 6, synthon B2 - in accordance with scheme 7.

Scheme 6

For this, 2-hydroxyacetophenone e1 was introduced into the Mitsunobu reaction with N-boc-ethanolamine, subsequent cyclocondensation led to the e2 heterocycle, which was reduced with sodium borohydride to amine e3, and the Boc protection of the latter led to the product e4. The subsequent reaction sequence (e4 bromide → aldehyde e5 → imines e6 → amines e7 → racemic synthons A3-rac) corresponded to the synthetic pathway leading to synthons A1 (Scheme 3). A series of individual optically active synthons R-A3 and S-A3 were obtained by methods known in the art, which are described in detail, for example, in ["Stereochemistry of Organic Compounds", Ed. by: E.L. Eliel Wiley, New York, 1994].

Racemic aldehyde e5 (Scheme 6) was reduced and condensed with R15OH alcohol to give d2 esters. Removal of the Boc protection led to racemic B2-rac synthons, the optical cleavage of which led to the chiral R-B2 and S-B2 series. LC-MS characteristics of the final racemates and chiral compounds are presented in tables 1-6.

Example 12. Determination of agonistic activity of compounds with respect to the hTGR5 receptor

A library containing more than 10 thousand substances, including compounds of formula I, was screened using the HEK-293 cell line in which the human TGR5 receptor (hTGR5) was stably expressed. The agonistic activity of the compounds was evaluated by increasing the intracellular concentration of cAMP, since it is known from the literature that activation of the hTGR5 receptor by subsequent activation of cellular adenylate cyclase leads to an increase in the intracellular cAMP content. As an experimental platform, the Lance Ultra cAMP (Perkin Elmer) test system was chosen. Known agonists of the hTGR5 receptor were used as a positive control and to determine the absolute value of the maximum signal of the experiment. The substances were tested at a final concentration of 10 μM at one point. Substances exhibiting agonistic activity of more than 50% of the maximum signal, 3 × SD (minimum signal), were nominated for retest at a concentration of 10 μM in replicates to confirm the activity shown. Data for the most active substances are presented in tables 3-8. And it means the activation of hTGR5 receptors by more than 75%, B - more than 50%, C - more than 25%, D - more than 10%. For the most active compounds, the dependence of the agonistic activity of the substance on the concentration of the substance was analyzed. From the obtained dependency graphs, EC ₅₀ values were determined (the concentration of the substance in micromoles, which causes 50% of the maximum effect).

Cell line: immortalized HEC 293 line stably expressing hTGR5, Millipore, catalog number HTS238L. The cell culture medium was a mixture of DMEM, 10% fetal bovine serum, 1% non-essential amino acids, 2 mM L-glutamine, and 1 μg / ml puromycin / 400 μg / ml C418 / 200 μg / ml hygromycin B as a selective mixture antibiotics.

Preparing cells for the experiment. Cells were thawed in a water bath at 37 ° C, resuspended in 5 ml of Hanks solution, centrifuged and again resuspended in 6 ml of Hanks solution. Thus, the cells were washed from serum and culture medium. The centrifugation step was repeated and the cells were resuspended in the stimulation buffer of the test system (SB). The final cell concentration was 2.00E + 05 cells / ml, which yielded 1000 cells per well. cAMP antibodies were added to the cell suspension in a ratio of 1: 150.

Preparation of tablets with substances. The substances were initially dissolved in DMSO to a concentration of 2.5 mM. Tablets with substances in DMSO were stored at -20 ° C. Figure 2 presents a diagram of a 384-well plate with substances.

Experiment Log

1. On the day of the experiment, the buffer for the experiment (SB) was prepared: l × HBSS, 5 mM HEPES, 0.1% BSA, pH 7.4. 45 ml of HBSS, 225 μl of 1M HEPES and 600 μl of 7.5% BSA were mixed.

2. A cell suspension, including a 4-fold solution of antibodies to cAMP, was added to 384-well plates for the experiment, 5 μl per well using a Biomek 2000 automated system (Beckman Coulter). Centrifuged at 300 rpm for 1 minute.

3. A 2-fold mixture of [SB + substance] was added to the cell suspension using a Biomek FX 384 robotic system. To prepare a 2-fold mixture of [SB + substance] SB was transferred to a 384-well plate, 99 μl / well. 1 μl of a 200-fold working solution of substances in DMSO was transferred to the same 384-well plate. The resulting mixture was thoroughly mixed. 5 μl of a 2-fold mixture of [SB + substance] was added to the cell suspension at 5 μl per well. The experimental plate was centrifuged at 300 rpm for 1 minute. Next, the cell suspension was incubated with substances for 30 minutes at room temperature on a shaker, 300 rpm.

4. The initial solution of the Eu-cAMP tracer was diluted 1: 100 in the buffer for signal detection, obtaining a 2-fold working solution of the tracer. Next, the solution was added to the experimental plate, 10 μl, using a Biomek 2000 robotic system. The cell suspension was incubated with a solution for signal detection for 60 minutes on a shaker, 300 rpm.

5. The essay signal was measured on a Wallac 1420 Victor ³ multifunction reader (Perkin Elmer) using a wavelength of 665 nm, LANCE protocol High Count_665_OptiPlate.

6. The agonistic activity of the substances was calculated using a script for processing Grand CaLculate_0.1.1 data. As the minimum signal of the experiment, the averaged data of wells 23 of the column of the experimental plate containing unstimulated cells were used. As the maximum signal of the experiment, the averaged data of all wells of the 24th column of the experimental plate were used, containing cells stimulated by the known steroid agonist hTGR5.

Example 13. Determination of EC ₅₀ for the most active substances

Data was analyzed using GraphPad Prizm (GraphPad Software, Inc., San Diego, CA). To build the concentration dependence, the equation was chosen

$$Y=Bottom+\frac{(Top-Bottom)}{\mathrm{one}+{10}^{(LogEC\mathrm{fifty}-X)-HillSlope}}$$

The EU _{50 was} determined based on the constructed schedule, as the concentration of a substance that causes 50% of the maximum effect.

Example 14. Metabolic model using DIO mice

DIO mice (Diet Induced Obesity mice) are widely used to model the metabolic syndrome in humans, which is characterized by abdominal obesity, high triglycerides, impaired glucose homeostasis and hyperinsulinemia [Hariri N, Thibault L. High-fat diet -induced obesity in animal models. Nutr Res Rev. 2010; 23 (2): 270-99]. To create the DIO model, C57B L / 6J mice fed a high fat diet (HFD; food includes 58% lard. Diet D12492, Research Diet, New Brunswick, NJ; West D. et al. 1992 ) The HFD diet and water were given to ad libitum animals for 28 days before the start of the experiment. The obtained DIO model was used to study the pharmacological effect of the compounds of general formula I on the secretion of the GLP-1 peptide and glucose metabolism.

Example 15. The study of the pharmacological action of compounds of General formula I on the secretion of incretin peptide GLP-1

Test compound N - ({4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N′-phenylcyclopropanecarboxamide (1.1.1-05 ) of the general formula I (dose 30 mg / kg) in an aqueous solution of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%) was administered orally to DIO mice C57B L / 6J (6 mice per time point) 15 minutes before oral administration of dextrose (2 g / kg in saline). Blood for analysis was collected from the tail vein of animals 5, 10, 15, and 30 minutes after the introduction of sugar. An aqueous solution of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%) was introduced as a control. The experiment was repeated for compounds I.1.2-01, I.1.3-03, I.2.1-02, I.2.2-01, I.2.3-51 of general formula I.

The content of incretin peptide GLP-1 in plasma was determined by standard ELISA. As a result of stimulation of GLP-1 secretion after 15 minutes of the experiment for all compounds: I.1.1-05, I.1.2-01, I.1.3-03, I.2.1-02, I.2.2-01, I.2.3-51 , the content of the incretin peptide GLP-1 in the blood exceeded 6 ng / mmol and 30 minutes after the introduction of sugar for all compounds: I.1.1-05, I.1.2-01, I.1.3-03, I.2.1-02, I .2.2-01, I.2.3-51, the content of the incretin peptide GLP-1 in the blood exceeded 5.5 ng / mmol (or 30 and 45 minutes after administration of the compound). Administration of compounds of general formula I (30 mg / kg) in all cases significantly and statistically significantly stimulates the secretion of the hormone GLP-1.

Example 16. The study of the pharmacological effect of the compounds of General formula I on glucose metabolism (glucose tolerance test GTT)

Test compound N - ({4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N′-phenylcyclopropanecarboxamide (I.1.1-05 ) of general formula I (doses from 5 to 100 mg / kg) in an aqueous solution of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%) was administered orally to C57B L / 6J DIO mice (6 mice per time point) 15 minutes before oral administration of dextrose (2 g / kg in saline). Blood for analysis was collected from the tail vein of animals 0, 5, 10, 20, 30, 60, and 120 minutes after the introduction of sugar. An aqueous solution of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%) was introduced as a control. The experiment was repeated for compounds I.1.2-01, I.1.3-03, I.2.1-02, I.2.2-01, I.2.3-51 of general formula I.

The data obtained as a result of the experiment show a significant statistically significant decrease in the glucose content in the plasma of DIO mice under the action of TGR5 receptor agonists:

plasma glucose 20 minutes after the start of the experiment - 1000 mg / 1L; plasma glucose after 60 minutes after the start of the experiment -800 mg / 1L; plasma glucose after 120 minutes after the start of the experiment -600 mg / 1L.

The results clearly indicate the promise of the proposed approach for the treatment of metabolic diseases.

Claims (14)

1. The use of a compound of general formula I, or a racemic mixture thereof, or individual optical isomers, or pharmaceutically acceptable salts

where X represents an amino group R′R′′N, optionally substituted with the same substituents R ′ and R ′ ′, where
amino substituents R ′ and R ″ are hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl; substituted C ₁ -C ₆ alkyl, where the substituent is selected from phenyl or phenoxy, each of which in turn can be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyloxy, C ₃ -C ₆ cycloalkyl, 5-6 membered heteroaryl with 1 nitrogen atom; aryl selected from phenyl optionally substituted with fluorine, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy; 5-6 membered heteroaryl, with a nitrogen atom as a heteroatom; C ₂ -C ₄ alkenyl, acyl selected from C ₁ -C ₆ alkylcarbonyl or C ₃ -C ₆ cycloalkylcarbonyl;
or a substituted oxy group, which is a hydroxy group in which hydrogen is substituted with C ₁ -C ₆ alkyl, optionally substituted with hydroxy, di (C ₁ -C ₃ alkyl) amino, phenyl, which in turn may be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy; C ₂ -C ₄ alkenyl; and a 5-6 membered heterocyclyl with a nitrogen atom, or sulfur, or oxygen as a heteroatom;
R ₁ a and R ₁ b are hydrogen, C ₁ -C ₃ alkyl, or
R ₁ a and R ₁ b together form a polymethylene chain - (CH ₂ ) _n -, where n = 2-5;
R ₁ c and R ₁ d are hydrogen, C ₁ -C ₃ alkyl;
R2 represents an acyl group selected from C ₁ -C ₆ alkylcarbonyl, where the alkyl may be substituted with phenyl or phenoxy, each of which in turn may be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy; C ₃ -C ₆ cycloalkylcarbonyl; phenylcarbonyl, which may be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy group, hydroxy group, C ₁ -C ₃ alkylenedioxy group; 5-6 membered heteroarylcarbonyl with a nitrogen, oxygen or sulfur atom as a heteroatom, optionally substituted with carboxy, halogen or C ₁ -C ₃ alkoxycarbonyl;
a substituted aminocarbonyl group, wherein the substituent may be selected from C ₁ -C ₆ alkyl, optionally substituted with C ₁ -C ₃ alkoxycarbonyl, halogen, 5-6 membered heteroaryl with a nitrogen, oxygen or sulfur atom as a heteroatom; C ₃ -C ₆ cycloalkyl; phenyl optionally substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₃ alkylenedioxy; A 5-6 membered heteroaryl with a nitrogen, oxygen or sulfur atom as a heteroatom, optionally substituted with a carboxy, C ₁ -C ₃ alkoxycarbonyl; an aminocarbonyl group substituted with C ₁ -C ₃ alkyl;
a sulfonyl group selected from alkylsulfonyl optionally substituted with hydroxy, cyano, phenyl, which is optionally substituted with C ₁ -C ₃ alkyl, halogen, C ₁ -C ₃ alkoxy; phenylsulfonyl optionally substituted with C ₁ -C ₃ alkyl, halogen, C ₁ -C ₃ alkoxy, cyano, C ₁ -C ₃ alkylenedioxy, or 5-6 membered heteroarylsulfonyl with a nitrogen, sulfur or oxygen atom as a hetero atom optionally substituted with halogen, C ₁ -C ₃ alkyl; C ₁ -C ₃ alkoxy;
R3 is hydrogen,
to obtain a pharmaceutical composition having the properties of a TGR5 bile acid agonist. 2. The use of the compound according to claim 1, where the compound corresponds to the General formula I.1 or I.2, or their racemic mixtures, or individual optical isomers or pharmaceutically acceptable salts

Where
R ₄ a and R ₄ b are hydrogen or methyl, or
R ₄ a and R ₄ b together form the polymethylene chain —CH ₂ —CH ₂ -;
R ₄ c and R ₄ d are hydrogen or methyl;
R5 represents an acyl group selected from C ₁ -C ₆ alkylcarbonyl, where the alkyl may be substituted with phenyl or phenoxy, each of which in turn may be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy; C ₃ -C ₆ cycloalkylcarbonyl; phenylcarbonyl, which may be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkylenedioxy; 5-6 membered heteroarylcarbonyl with a nitrogen, oxygen or sulfur atom as a heteroatom, optionally substituted with carboxy or C ₁ -C ₃ alkoxycarbonyl;
a substituted aminocarbonyl group, wherein the substituent may be selected from C ₁ -C ₆ alkyl optionally substituted with C ₁ -C ₃ alkoxycarbonyl; C ₃ -C ₆ cycloalkyl; phenyl optionally substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxycarbonyl; A 5-6 membered heteroaryl with a nitrogen or sulfur atom as a heteroatom, optionally substituted with a carboxy, C ₁ -C ₃ alkoxycarbonyl;
a sulfonyl group selected from alkylsulfonyl substituted with phenyl which is optionally substituted with C ₁ -C ₃ alkyl, halogen, C ₁ -C ₃ alkoxy group, cyano group; phenylsulfonyl optionally substituted with C ₁ -C ₃ alkyl, halogen, C ₁ -C ₃ alkoxy, or a 5-membered heteroaryl sulfonyl with a nitrogen, sulfur or oxygen atom as a hetero atom, optionally substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy;
R6 represents hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, where the substituent is selected from phenyl or phenoxy, each of which in turn can be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyloxy, C ₃ -C ₆ cycloalkyl; C ₃ -C ₆ cycloalkyl, a 5-membered heterocyclyl with one nitrogen atom in the cycle; an acyl group selected from C ₁ -C ₃ alkylcarbonyl or C ₃ -C ₆ cycloalkylcarbonyl;
R7 represents hydrogen, C ₁ -C ₆ alkyl; substituted alkyl, where the substituent is selected from phenyl or phenoxy, each of which in turn can be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenoxy, C ₃ -C ₆ cycloalkyl; C ₂ -C ₄ alkenyl; aryl selected from phenyl optionally substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy; 5-6 membered heteroaryl, with a nitrogen atom as a heteroatom;
R8 is C ₁ -C ₆ alkyl optionally substituted with hydroxy, di (C ₁ -C ₃ alkyl) amino, phenyl, which in turn may be substituted with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy; C ₂ -C ₄ alkenyl; 5-6 membered heterocyclyl with a nitrogen or oxygen atom as a heteroatom. 3. The use of a compound according to claim 1, wherein the compound corresponds to the general formula I.1.1, I.1.2, I.1.3, I.2.1, I.2.2 or I.2.3, or a racemic mixture thereof, or individual optical isomers, or pharmaceutically acceptable salts

where R ₄ a, R ₄ b, R ₄ c and R ₄ d are as defined in claim 2;
R9 represents C ₁ -C ₃ alkyl; C ₃ -C ₆ cycloalkyl;
R10 represents C ₁ -C ₃ alkyl optionally substituted with phenyl, which may be substituted with halogen; or a 5-6 membered heteroaryl with a nitrogen atom as a heteroatom; C ₂ -C ₄ alkenyl; phenyl optionally substituted with C ₁ -C ₃ alkyl;
R11 is C ₁ -C ₄ alkyl optionally substituted with phenyl, optionally substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, phenoxy, optionally substituted with C ₁ -C ₃ alkoxy or halogen; C ₃ -C ₆ cycloalkyl or 5-6 membered heteroaryl with a nitrogen, sulfur or oxygen atom as a heteroatom; C ₃ -C ₆ cycloalkyl; phenyl optionally substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy or halogen; benzo [d] [1,3] dioxol; 5-6 membered heteroaryl with a nitrogen, sulfur or oxygen atom as a heteroatom, optionally substituted with halogen;
R12 represents hydrogen;
R13 is C ₁ -C ₄ alkyl optionally substituted with a C ₁ -C ₃ alkoxycarbonyl group or phenyl optionally substituted with halogen or a 5-6 membered heteroaryl with a nitrogen, sulfur or oxygen atom as a heteroatom; C ₃ -C ₆ cycloalkyl; phenyl optionally substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy group, halogen, C ₁ -C ₃ alkoxycarbonyl group; benzo [d] [1,3] dioxol; A 5-6 membered heteroaryl with a nitrogen, sulfur or oxygen atom as a heteroatom, optionally substituted with a carboxy group, a C ₁ -C ₃ alkoxycarbonyl group, an aminocarbonyl group substituted with a C ₁ -C ₃ alkyl;
R14 is C ₁ -C ₄ alkyl optionally substituted with fluoro-substituted phenyl; phenyl optionally substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, cyano;
R15 is C ₁ -C ₆ alkyl optionally substituted with an oxy group, a 5-6 membered heterocyclyl with a nitrogen, sulfur or oxygen atom as a heteroatom, phenyl optionally substituted with a C ₁ -C ₃ alkyl, a C ₁ -C ₃ alkoxy group, a halogen; C ₂ -C ₄ alkenyl. 4. Compounds representing:
N- (4-fluorobenzyl) -N ′ - ({4 - [(3-fluorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) acetamide (I. 1.1-01);
N - {[4- (cyclopropylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) acetamide (I.1.1-02);
N- (4-methylphenyl) -N ′ - {[4- (2-phenylbutanoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl} acetamide (I.1.1-03 );
N - ({4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N′-phenylcyclopropanecarboxamide (I.1.1-05);
N - {[4- (3-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methyl-N ′ - (4-methylphenyl) propanamide (I .1.1-06);
N - {[4- (2-furoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) acetamide (I.1.1-07 );
N- (4-methylphenyl) -N - ({4 - [(4-methylphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) acetamide (I.1.1 -08);
N - [(4-isobutyryl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N ′ - (4-methylphenyl) acetamide (I.1.1-09);
N - [(4-butyryl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -2-methyl-N ′ - (4-methylphenyl) propanamide (I.1.1-10 );
2-methyl-N- (4-methylphenyl) -N ′ - {[4- (2-thienylacetyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} propanamide (I .1.1-n);
N- (4-methylphenyl) -N ′ - {[4- (2-thienylacetyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.1-12 );
N - {[4- (4-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N′-phenyl-cyclopropanecarboxamide (I.1.1-13);
N - {[4- (3-methylbenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N′-phenylcyclopropanecarboxamide (I.1.1-15);
N - {[4- (2,6-difluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) acetamide (I.1.1 -16);
N - {[4- (2,6-difluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methyl-N ′ - (4-methylphenyl) propanamide (I.1.1-17);
N - {[4- (3-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) acetamide (I.1.1-18 );
N - {[4- (2-furoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methyl-N ′ - (4-methylphenyl) propanamide (I .1.1-19);
2-methyl-N- (4-methylphenyl) -N ′ - {[4- (phenoxyacetyl) -2,3,4,5-tetrahydro-1,4-beisoxazepin-7-yl] methyl} propanamide (I.1.1 -twenty);
N - ({4 - [(4-methoxyphenoxy) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N′-phenylcyclopropanecarboxamide (I.1.1-21);
N - {[4- (cyclopentylacetyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) acetamide (I.1.1-22);
N - {[4- (2-methylbenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) acetamide (I.1.1-23 );
N - {[4- (cyclobutylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methyl-N ′ - (4-methylphenyl) propanamide (I.1.1 -24);
N - {[4- (2-fluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) acetamide (I.1.1-25 );
N - {[4- (cyclopentylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) acetamide (I.1.1-26);
N - {[4- (cyclohexylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) acetamide (I.1.1-27);
N - {[4- (4-methylbenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N′-phenyl-cyclopropanecarboxamide (I.1.1-28);
2-methyl-N- (4-methylphenyl) -N ′ - [(4-propionyl-2,3,4,5-terahydro-1,4-benzoxazepin-7-yl) methyl] propanamide (I.1.1-29 );
2-methyl-N - {[4- (3-methylbutanoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methylphenyl) propanamide (I .1.1-30);
N - ([4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (methyl) acetamide (I.1.1-31);
N - ([4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (methyl) propanamide (I.1.1-32);
N - ([4-propionyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (methyl) acetamide (LI.1-33);
N - ([4-benzoyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (methyl) acetamide (I.1.1-34);
N - {[4- (4-methylbenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methyl) acetamide (I.1.1-35 );
N - {[4- (4-fluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methyl) acetamide (I.1.1-36 );
N - {[4- (2-fluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methyl) acetamide (I.1.1-37 );
N - {[4- (4-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methyl) acetamide (I.1.1-38 );
N - {[4- (4-pyridoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methyl) acetamide (I.1.1-39 );
N - {[4- (thiophen-2-carbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methyl) acetamide (I.1.1 -40);
N - {[4- (thiophen-3-carbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (4-methyl) propionamide (I.1.1 -41);
N - {[4- (3-pyridoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (methyl) propionamide (I.1.1-42);
N - {[4-phenylacetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (methyl) acetamide (I.1.1-43);
N - {[4- (methylamino) acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (methyl) acetamide (I.1.1-44);
N - {[4- (dimethylamino) acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (methyl) acetamide (I.1.1-45);
N - {[4- (methylamino) acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (2-phenylethyl) acetamide (I.1.1-46) ;
N - {[4- (dimethylamino) acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (2-phenylethyl) acetamide (I.1.1-47) ;
N - {[4- (3-pyridoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (ethyl) acetamide (I.1.1-48);
N - {[4- (4-pyridoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (ethyl) acetamide (I.1.1-49);
N - {[4- (2-hydroxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N ′ - (ethyl) acetamide (I.1.1-50);
N- (1- {4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} -1- {methyl} ethyl) -N ′ - ( 4-methylphenyl) acetamide (I.1.1-51);
N- (1- {4- [4-methoxybenzoyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} -1- {methyl} ethyl) -N ′ - (4-methylphenyl ) acetamide (I.1.1-52);
N- (1- {4 - [(3-fluorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} -1- {methyl} ethyl) -N ′ - ( 4-methylphenyl) acetamide (I.1.1-53);
N- (1 - {[4- (cyclopropylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1- (methyl) ethyl} -N ′ - (4-methylphenyl) acetamide (I.1.1-54);
N- [1- (4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) cyclopropyl] -N ′ - (4-methylphenyl) acetamide (I.1.1-55) ;
N - [(4-acetyl-5,5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N ′ - (4-methylphenyl) acetamide (I. 1.1-56);
N- [1 (S) - (4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) ethyl] -N ′ - (4-methylphenyl) acetamide (I.1.1 -57);
N- [1 (R) - (4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) ethyl] -N ′ - (4-methylphenyl) acetamide (I.1.1 -58);
N- [1 (S) - (4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) ethyl] -N ′ - (4-methylphenyl) acetamide (I.1.1 -57 / 58p);
N - [(4-acetyl-5 (S) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N ′ - (4-methylphenyl) acetamide (I. 1.1-59);
N - [(4-acetyl-5 (R) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N ′ - (4-methylphenyl) acetamide (I. 1.1-60);
N - [(4-acetyl-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl) methyl] -N ′ - (4-methylphenyl) acetamide (I.1.1-59 / 60r);
methyl 3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate ( I.1.2-01);
7 - {[(cyclopropylcarbonyl) (phenyl) amino] methyl} -N- (4-methylphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-02);
7 - {[isobutyryl (4-methylphenyl) amino] methyl} -N- (3-methylphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-04);
7 - {[isobutyryl (4-methylphenyl) amino] methyl} -N- (4-methylphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-05);
N- (isobutyl) -7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-06);
7 - {[(cyclopropylcarbonyl) - (phenyl) amino] methyl} -N- (3-fluorophenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-07);
N- (4-chlorophenyl) -7 - {[(cyclopropylcarbonyl) - (phenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-08);
N- (3,4-dimethylphenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-09 );
N- (4-fluorobenzyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-10);
7 - {[acetyl (4-methylphenyl) amino] methyl} -N- (3-fluoro-4-methylphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2- 12);
N- (2-fluorophenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-14);
7 - {[acetyl (4-methylphenyl) amino] methyl} -N- (2-ethylphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.1.2-16);
7 - {[isobutyryl (4-methylphenyl) amino] methyl} -N- (3-methoxyphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-17);
N- (sec-butyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-18);
N- (2,5-dimethylphenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-19) ;
N- (tert-butyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-20);
7 - {[acetyl (4-methylphenyl) amino] methyl} -N-cyclopentyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.1.2-22);
N- (2-chlorophenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-23);
N- (2,4-dimethylphenyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-24) ;
N- (2-furylmethyl) -7 - {[isobutyryl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.1.2-25);
ethyl 3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophene-2-carboxylate ( I.1.2-26);
3 - ({[[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid dimethylamide (I.1.2-27);
3 - ({[[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid methylamide (I.1.2-28);
3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid N -cyclopentylamide (I.1.2-29);
3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid ( I.1.2-30);
N- [7 - {[Acetyl (methyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-methyl-carboxamide (I.1.2-31);
N- [7 - {[propionyl (methyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-methyl-carboxamide (I.1.2-32);
N- [7 - {[Acetyl (methyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-phenyl-carboxamide (I.1.2-33);
3 - ({[[7 - {[acetyl (methyl) amino] -methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid (I .1.2-34);
methyl 3 - ({[7 - {[acetyl (methyl) amino] methyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate (I .1.2-35);
7-N - {[acetyl (methyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (pyridyl-3) -carboxamide (I.1.2-36);
7-N - {[acetyl (methyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (pyridyl-4) -carboxamide (I.1.2-37);
7-N - {[acetyl (methyl) amino] methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)} - N′-benzyl-carboxamide (I.1.2-38);
7-N - {[acetyl (methyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-methylphenyl) -carboxamide (I.1.2-39);
7-N - {[acetyl (methyl) amino [methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-fluorophenyl) carboxamide (I.1.2-40);
7-N - {[acetyl (ethyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (2-fluorophenyl) carboxamide (I.1.2-41);
3 - ({[7 - {[acetyl (ethyl) amino] methyl] -2,3-dihydro-1,4-benzoesazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylic acid (I .1.2-42);
methyl 3 - ({[7 - {[acetyl (ethyl) amino] methyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate (I .1.2-43);
3 - ({[[7 - {[(2-methylpropionyl) - (ethyl) amino] methyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophen-2 β-carboxylic acid (I.1.2-44);
methyl 3 - ({[7 - {[(2-methylpropionyl) - (ethyl) amino] methyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophene 2-carboxylate (I.1.2-45);
N- [7 - {[Acetyl (2-phenylethyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-methyl-carboxamide (I.1.2-46) ;
N- [7 - {[Acetyl (2-phenylethyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H)] - N′-tert-butyl-carboxamide (I.1.2- 47);
7-N - {[acetyl (ethyl) amino] methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)} - N′-benzyl-carboxamide (I.1.2-48);
7-N - {[acetyl (ethyl) amino] methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (pyridyl-3) -carboxamide (I.1.2-49);
methyl 3 - ({[7 - {[acetyl (2-phenylethyl) amino] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate ( I.1.2-50);
methyl 3 - ({[7 - {[acetyl (methyl) amino] -1- (methyl) ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophene- 2-carboxylate (I.1.2-51);
7 - {[N-acetyl (methyl) amino] -1- (methyl) ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-methylphenyl) -carboxamide ( I.1.2-52);
methyl-3 - ({[7 - {[acetyl (2-phenylethyl) amino] -1 (S) -ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino ) thiophene-2-carboxylate (I.1.2-53);
methyl 3 - ({[[7 - {[acetyl (2-phenylethyl) amino] -1 (R) -ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate (I.1.2-54);
methyl 3 - ({[7 - {[acetyl (2-phenylethyl) amino] -1-ethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophen-2 β-carboxylate (I.1.2-53 / 54p);
7 - {[N-acetyl (methyl) amino] methyl} -5 (R) -methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-methylphenyl) -carboxamide (I.1.2-55);
7 - {[N-acetyl (methyl) amino] methyl} -5 (S) -methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-methylphenyl) carboxamide ( I.1.2-56);
7 - {[N-acetyl (methyl) amino] methyl} -5-methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)} - N ′ - (4-megylphenyl) carboxamide (I. 1.2-55 / 56r);
methyl 3 - ({[7 - {[acetyl (methyl) amino] methyl} -5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophen-2- carboxylate (I.1.2-57);
methyl 3 - ({[7 - {[acetyl (methyl) amino] methyl} -5 (R) -methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophene -2-carboxylate (I.1.2-58);
methyl 3 - ({[7 - {[acetyl (methyl) amino] methyl} -5 (S) -methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene -2-carboxylate (I.1.2-59);
methyl 3 - ({[[7 - {[acetyl (methyl) amino] methyl} -5-methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophen-2- carboxylate (I.1.2-58 / 59p);
methyl 3 - ({[7 - {[acetyl (4-methylphenyl) amino] methyl} -5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) thiophene 2-carboxylate (I.1.2-60);
N - ({4 - [(4-chlorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (4-methylphenyl) acetamide (I.1.3 -01);
N - ({4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (phenyl) cyclopropanecarboxamide (I.1.3-02 );
N - ({4 - [(4-isopropylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (4-methylphenyl) acetamide (I.1.3 -03);
N- (4-fluorobenzyl) -N - ({4 - [(3-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) acetamide (I.1.3 -04);
N- (4-methylphenyl) -N - ({4 - [(4-propylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) acetamide (I.1.3 -05);
N - ({4 - [(3,5-dimethylisoxazol-4-yl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -2-methyl-N- (4-methylphenyl) propanamide (I.1.3-06);
N - ({4 - [(3,4-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (4-fluorobenzyl) acetamide (I .1.3-07);
2-methyl-N- (4-methylphenyl) -N - {[4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} propanamide (I.1.3- 08);
2-methyl-N- (4-methylphenyl) -N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} propanamide (I. 1.3-09);
N - ({4 - [(3-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -2-methyl-N- (4-methylphenyl) propanamide (I.1.3-10);
N - ({4 - [(2,4-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenyl-cyclopropanecarboxamide (I.1.3- m);
N - ({4 - [(2-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3-12);
N - ({4 - [(4-ethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3-13);
N - ({4 - [(5-fluoro-2-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3- fourteen);
N - ({4 - [(2-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -2-methyl-N- (4-methylphenyl) propanamide (I.1.3-15);
N - ({4 - [(2-chlorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropaparboxamide (I.1.3-16);
N - ({4 - [(2,4-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- (4-fluorobenzyl) acetamide (I .1.3-17);
N - ({4 - [(2,5-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3-18) ;
(2-methyl-N- (4-methylphenyl) -N - {[4- (methylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} propanamide (I.1.3 -19);
2-methyl-N - ({4 - [(1-methyl-1H-imidazol-4-yl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) - N- (4-methylphenyl) propanamide (I.1.3-20);
N - ({4 - [(1,2-dimethyl-1H-imidazol-4-yl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N- phenylcyclopropanecarboxamide (I.1.3-21);
(N- (4-methylphenyl) -N - {[4- (propylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-22);
N - ({4 - [(3,5-difluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I.1.3-23) ;
N - ({4 - [(3,5-dimethylisoxazol-4-yl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl} methyl) -N-phenylcyclopropanecarboxamide (I. 1.3-24);
N - {[4- (butylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -N-phenylcyclopropanecarboxamide (I.1.3-25);
N- (4-methylphenyl) -N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-26) ;
N-methyl-N - {[4- (methylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-27);
N-methyl-N - {[4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-28);
N-methyl-N - {[4- (4-methylphenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-29);
N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-30);
N-ethyl-N - {[4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-31);
N-ethyl-N - {[4- (4-methylphenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-32);
N-ethyl-N - {[4- (4-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-33);
N-ethyl-N - {[4- (2-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-34);
N-ethyl-N - {[4- (4-methoxyphenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-35);
N-allyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-36);
N-allyl-N - {[4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-37);
N-allyl-N - {[4- (4-methyl-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-38);
N-allyl-N - {[4- (4-fluoro-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-39);
N-allyl-N - {[4- (4-methoxy-phenylsulfonyl) -2,3,4,5-heterohydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-40);
N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-41);
N-ethyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-42);
N-methyl-N - {[4- (4-chlorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-43);
N-methyl-N - {[4- (4-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-44);
N-methyl-N - {[4- (2-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} -2-methylpropanamide (I.1.3-45);
N-phenylethyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-46);
N-phenylethyl-N - {[4- (4-chlorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-47);
N-phenylethyl-N - {[4- (4-fluorophenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-48);
N-phenylethyl-N - {[4- (4-methyl-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-49);
N- [2- (pyrid-3-yl) ethyl] -N - {[4- (4-methoxy-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl } acetamide (I.1.3-50);
N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1-methyl (ethyl)} acetamide (I.1.3- 51);
N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1 (R) -ethyl} acetamide (I.1.3- 52);
N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1 (S) -ethyl} acetamide (I.1.3- 53);
N-methyl-N - {[4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1-ethyl} acetamide (I.1.3-52 / 53r );
N-methyl-N - {[4- (2-thienylsulfonyl) -5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-54) ;
N-methyl-N - {[4- (2-thienylsulfonyl) -5 (R) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3 -55);
N-methyl-N - {[4- (2-thienylsulfonyl) -5 (S) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3 -56);
N-methyl-N - {[4- (2-thienylsulfonyl) -5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3-55 / 56p);
N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1 (R) -ethyl} acetamide (I. 1.3-57);
N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1 (S) -ethyl} acetamide (I. 1.3-58);
N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] -1-ethyl} acetamide (I.1.3-57 / 58r);
N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -5 (S) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I .1.3-59);
N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -5 (R) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I .1.3-60);
N-methyl-N - {[4- (4-chloro-phenylsulfonyl) -5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl] methyl} acetamide (I.1.3- 59 / 60r);
7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-01);
7 - {[(4-chlorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-02);
7 - {[(2-chlorobenzyl) oxy] methyl} -4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-03);
7 - {[(4-chlorobenzyl) oxy] methyl} -4- [3- (4-methoxyphenyl) propanoyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-04);
4- (cyclohexylcarbonyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-05);
7 - {[(4-chlorobenzyl) oxy] methyl} -4 - [(3-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-06);
7 - {[(3-fluorobenzyl) oxy] methyl} -4- (3,4,5-trimethoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-07);
7 - {[(3-fluorobenzyl) oxy] methyl} -4- (phenoxyacetyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-08);
7 - {[(4-chlorobenzyl) oxy] methyl} -4- (4-fluorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-09);
4- (3-chlorobenzoyl) -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-10);
4- (5-bromo-2-furoyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-11);
7 - {[(4-methylbenzyl) oxy] methyl} -4- (3,4,5-trimethoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-12);
7 - {[(4-chlorobenzyl) oxy] methyl} -4- (2-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-13);
7 - [(benzyloxy) methyl] -4 - [(3-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-14);
7 - {[(3-fluorobenzyl) oxy] methyl} -4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-15);
7 - {[(3-fluorobenzyl) oxy] methyl} -4- (3-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-16);
7 - [(benzyloxy) methyl] -4- (3-phenylpropanoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-17);
7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenoxy) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-18);
4- (2,3-dimethoxybenzoyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-19);
4- (cyclopentylcarbonyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-20);
7 - {[(2-chlorobenzyl) oxy] methyl} -4- (cyclopentylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-21);
7 - {[(4-chlorobenzyl) oxy] methyl} -4- (4-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-22);
7- (methoxymethyl) -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-23);
7- (ethoxymethyl) -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-24);
7- (allyloxymethyl) -4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-25);
7- [2-phenylethyloxy (methyl)] - 4 - [(4-methoxybenzoyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-26);
7- [2-phenylethyloxy (methyl)] - 4- (pyridyl-4-carbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-27);
7- [2-phenylethyloxy (methyl)] - 4- (2-hydroxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-28);
7- [2-phenylethyloxy (methyl)] - 4- (2,3-methylenedioxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-29);
7- [2-phenylethyloxy (methyl)] - 4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-30);
7- (allyloxymethyl) -4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-31);
7- [2-phenylethyloxy (methyl)] - 4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-32);
7- [2-dimethylamino-ethyloxy (methyl)] - 4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-33);
7- [2-N-pyrrolidino-ethyloxy (methyl)] - 4- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-34);
7- [2-dimethylamino-ethyloxy (methyl)] - 4- (4-pyridylcarbonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-35);
7- [2-dimethylamino-ethyloxy (methyl)] - 4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-36);
7- [2-N-pyrrolidino-ethyloxy (methyl)] - 4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-37);
7- [2-N-pyrrolidino-ethyloxy (methyl)] - 4 - [(4-chlorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-38);
7- [2-dimethylamino-ethyloxy (methyl)] - 4 - [(4-chlorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-39);
7- [2-dimethylamino-ethyloxy (methyl)] - 4 - [(4-fluorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-40);
7- [2-hydroxyethyloxy (methyl)] - 4 - [(4-methoxyphenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-41);
7- [2-hydroxyethyloxy (methyl)] - 4 - [(4-chlorophenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-42);
7- [2-hydroxyethyloxy (methyl)] - 4- (4-methoxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-43);
7- [2-hydroxyethyloxy (methyl)] - 4- (2-hydroxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-44);
7- [2-hydroxyethyloxy (methyl)] - 4-benzoyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-45);
7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-46);
7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4-thienylcarbonyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-47);
7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4- (2-hydroxybenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-48);
7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4- (4-chlorobenzoyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-49);
7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)] - 4-cyclohexylcarbonyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-50);
7- {1 - [(3-fluorobenzyl) oxy] -1- (methyl}) ethyl-4 - [(4-methoxy-phenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-51);
7- {1 (R) - [(3-fluorobenzyl) oxy] -1- (methyl}) ethyl-4 -] (4-methoxy-phenyl) acetyl] -2,3,4,5-tetrahydro-1, 4-benzoxazepine (I.2.1-52);
7- {1 (S) - [(3-fluorobenzyl) oxy] -1- (methyl}) ethyl-4 -] (4-methoxy-phenyl) acetyl] -2,3,4,5-tetrahydro-1, 4-benzoxazepine (I.2.1-53);
7- {1 - [(3-fluorobenzyl) oxy] -1- (methyl}) ethyl-4 - [(4-methoxy-phenyl) acetyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-52 / 53r);
7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-54 );
7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl) -5 (R) -dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I. 2.1-55);
7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -5 (S) -dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I. 2.1-56);
7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methoxyphenyl) acetyl] -5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.1-55 / 56r);
N- (2-ethoxyphenyl) -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-01);
ethyl 3 - ({[7 - {[(3-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-bepoxoxazepia-4 (5H) -yl] carbonyl} amino) benzoate (I.2.2-02 );
ethyl 3 - ({[7 - {[(2-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) benzoate (I.2.2-03 );
7 - {[(2-chlorobenzyl) oxy] methyl} -N- (2-methoxyphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-04);
7 - {[(2-fluorobenzyl) oxy] methyl} -N- (2-phenylethyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-05);
7 - {[(3-fluorobenzyl) oxy] methyl} -N- (3-methylphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-06);
7 - {[(3-fluorobenzyl) oxy] methyl} -N-phenyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-07);
7 - {[(2-chlorobenzyl) oxy] methyl} -N- (2,5-dimethoxyphenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-08);
ethyl 3 - ({[7 - {[(4-methylbenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) benzoate (I.2.2-09 );
N- (3-fluorophenyl) -7 - {[((4-methylbenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-10);
7 - {[(3-fluorobenzyl) oxy] methyl} -N- (4-fluorophenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-11);
N- (tert-butyl) -7 - {[(4-chlorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-12);
ethyl N - {[7 - {[(4-methylbenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} beta-alaninate (I.2.2-13 );
7 - {[(4-chlorobenzyl) oxy] methyl} -N-phenyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-14);
N- (3,5-dimethoxyphenyl) -7 - {[((4-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-15);
ethyl 2 - ({[7 - {[(4-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) yl] carbonyl} amino) benzoate (I.2.2-16 );
7 - [(benzyloxy) methyl] -N- (2-chlorophenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-17);
7 - {[(4-fluorobenzyl) oxy] methyl} -N- (3-methoxyphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-18);
7 - {[(3-fluorobenzyl) oxy] methyl} -N- (3-methoxyphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-19);
7 - {[(2-fluorobenzyl) oxy] methyl} -N- (4-fluorophenyl) -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-20);
N-cyclopentyl-7 - {[(4-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-21);
N-benzyl-7 - {[(4-methylbenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-22);
N- (2,4-difluorophenyl) -7 - {[((2-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-23);
7 - {[(2-fluorobenzyl) oxy] methyl} -N-phenyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-24);
7 - {[(4-methylbenzyl) oxy] methyl} -N- (4-methylphenyl) -2,3-dihydro-1,4-benzoxazspin-4 (5H) -carboxamide (I.2.2-25);
7 - {[(3-fluorobenzyl) oxy] methyl} -N- (3-fluorophenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-26);
7 - {[(4-methylbenzyl) oxy] methyl} -N- (3-methylphenyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-27);
N-1,3-benzodioxol-5-yl-7 - {[(2-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-28 );
N-cyclohexyl-7 - {[(4-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-29);
7 - {[(4-methylbenzyl) oxy] methyl} -N- (2-phenylethyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-30);
7 - [(benzyloxy) methyl] -N- [3- (methylthio) phenyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-31);
N- (2-ethoxyphenyl) -7-methoxymethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-32);
N- (2-methoxyphenyl) -7-ethoxymethyl-2,3-dihydro-l, 4-benzoxazepin-4 (5H) -carboxamide (I.2.2-33);
N- (2-ethoxyphenyl) -7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-34);
N- (2-methoxyphenyl) -7- (2-phenylethyloxy) methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-35);
N- (2-ethoxyphenyl) -7- (2-dimethylamino-ethyloxy) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-36);
N- (2-methoxyphenyl) -7- (2-N-pyrrolidino-ethyloxy) methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carboxamide (I.2.2-37);
N- (2-ethoxyphenyl) -7- (2-hydroxyethyloxy) methyl-2,3-dihydro-l, 4-benzoxazepine-4 (5H) -carboxamide (I.2.2-38);
N- (2-methoxyphenyl) -7- [2- (2,3-dimethoxyphenyl) ethyloxy (methyl)) - 2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-39 );
N- (2-methoxyphenyl) -7- [2- (4-chlorophenyl) ethyloxy (methyl)] - 2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-40);
methyl 3 - ([7-methoxymethyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl} amino) thiophene-2-carboxylate (I.2.2-41);
methyl 3 - {[7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl-amino} thiophene-2-carboxylate (I.2.2-42);
methyl 3 - {[7- (2-phenylethyl-hydroxy (methyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl-amino} thiophene-2-carboxylate (I.2.2- 43);
methyl 3 - {[7- (2-dimethylaminoethyl-hydroxy (methyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl-amino} thiophene-2-carboxylate (I.2.2- 44);
methyl 3 - {[7- (2-N-pyrrolidino-ethyloxy (methyl) -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] carbonyl-amino} thiophene-2-carboxylate (I. 2.2-45);
N- (3-methoxycarbonylphenyl) - [7-methoxymethyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)] - carboxamide (I.2.2-46);
N- (3-methoxycarbonylphenyl) - [7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H)] - carboxamide (I.2.2-47);
N- (3-methoxycarbonylphenyl) - [7- (2-dimethylamino-ethyloxy) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)] - carboxamide (I.2.2-48);
N- (3-methoxycarbonylphenyl) - [7- (2-N-pyrrolidium-ethyloxy) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)] carboxamide (I.2.2-49);
N- (3-methoxycarbonylphenyl) - [7- (2-phenylethyloxy) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H)] - carboxamide (I.2.2-50);
N- (2-ethoxyphenyl) -7- {1 - [(3-fluorobenzyl) oxy] -1- (methyl) ethyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I .2.2-51);
N- (2-ethoxyphenyl) -7- {1 - [(3-fluorobenzyl) oxy] -1 (S) -ethyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I .2.2-52);
N- (2-ethoxyphenyl) -7- {1 - [(3-fluorobenzyl) oxy] -1 (R) -ethyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I .2.2-53);
N- (2-ethoxyphenyl) -7- {1 - [(3-fluorobenzyl) oxy] -1-ethyl} -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2- 52 / 53r);
N- (2-ethoxyphenyl) -7 - [(3-fluorobenzyl) oxymethyl] -5-dimethyl-2,3-dihydro-1,4-beisoxazepin-4 (5H) -carboxamide (I.2.2-54);
N- (2-ethoxyphenyl) -7 - [(3-fluorobenzyl) oxymethyl] -5 (S) -methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-55 );
N- (2-ethoxyphenyl) -7 - [(3-fluorobenzyl) oxymethyl] -5 (R) -methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-56 );
N- (2-ethoxyphenyl) -7 - [(3-fluorobenzyl) oxymethyl] -5-methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carboxamide (I.2.2-55 / 56) ;
methyl 3 - ({7- [1- (3-fluorobenzyloxy) -1-methylethyl] -2,3-dihydro-1,4-benzoxazepine-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I. 2.2-57);
methyl 3 - ({7- [1- (3-fluorobenzyloxy) -1 (S) -ethyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I.2.2-58);
methyl 3 - ({7- [1- (3-fluorobenzyloxy) -1 (R) -ethyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I.2.2-59);
methyl 3 - ({7- [1- (3-fluorobenzyloxy) -1-ethyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I. 2.2-58 / 59p);
methyl 3 - {[7- (3-fluorobenzyloxy) methyl] -5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I.2.2 -60);
methyl 3 - {[7- (3-fluorobenzyloxy) methyl] -5 (S) methyl-2,3-dihydro-1,4-benzoxazepin-4 (5H) -carbonyl} amino) thiophene-2-carboxylate ( I.2.2-61);
methyl 3 - {[7- (3-fluorobenzyloxy) methyl] -5 (R) methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carbonyl} amino) thiophene-2-carboxylate ( I.2.2-62);
methyl 3 - {[7- (3-fluorobenzyloxy) methyl] -5-methyl-2,3-dihydro-1,4-benzoxazepine-4 (5H) -carbonyl} amino) thiophene-2-carboxylate (I.2.2 -61 / 62p);
7 - [(benzyloxy) methyl] -4 - [(2-fluorobenzyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-01);
7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(3-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-02);
7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-03);
7 - [(benzyloxy) methyl] -4- (mesitylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-04);
4 - {[7 - [(benzyloxy) methyl] -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] sulfonyl} benzonitrile (I.2.3-05);
7 - {[(2-fluorobenzyl) oxy] methyl} -4 - [(3-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-06);
4 - [(3-chloro-4-fluorophenyl) sulfonyl] -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-07 );
7 - [(benzyloxy) methyl] -4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-08);
7 - {[(2-chlorobenzyl) oxy] methyl} -4- (propylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-09);
7 - {[(4-fluorobenzyl) oxy] methyl} -4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-10);
7 - [(benzyloxy) methyl] -4 - [(3-chloro-4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-11);
7 - [(benzyloxy) methyl] -4 - [(3-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-12);
7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(2,4-difluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-13);
7 - {[(2-chlorobenzyl) oxy] methyl} -4- (phenylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-14);
4 - [(5-chloro-2-thienyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-15 );
4 - [(2,5-dimethoxyphenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy) methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-16);
7 - {[(4-chlorobenzyl) oxy] methyl} -4- (propylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-17);
7 - [(benzyloxy) methyl] -4 - [(5-bromo-2-thienyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-18);
4 - [(5-chloro-2-thienyl) sulfonyl1-7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-19) ;
7 - {[(4-fluorobenzyl) oxy] methyl} -4 - [(5-fluoro-2-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-20 );
4 - [(3-chloro-4-methoxyphenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-21 );
4 - [(3-chloro-4-methylphenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-22 );
7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(3-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-23);
4 - {[7 - {[(3-fluorobenzyl) oxy] methyl} -2,3-dihydro-1,4-benzoxazepin-4 (5H) -yl] sulfonyl} benzonitrile (I.2.3-24);
4- (2,1,3-benzothiadiazol-4-ylsulfonyl) -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3- 25);
4 - [(3,5-difluorophenyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-26);
7 - {[(4-chlorobenzyl) oxy] methyl} -4 - [(2,4-dimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-27);
7 - [(benzyloxy) methyl] -4 - [(5-chloro-2-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-28);
4 - [(4-chlorophenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-29);
7 - [(benzyloxy) methyl] -4 - [(4-bromophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-30);
7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(3,5-difluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-31);
4 - [(4-chlorophenyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-32);
4 - [(1,2-dimethyl-1H-imidazol-4-yl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-33);
4 - [(3-chloro-4-methoxyphenyl) sulfonyl] -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-34 );
4- (2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl) -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine ( I.2.3-35);
7 - {[(2-chlorobenzyl) oxy] methyl} -4 - [(2-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-36);
7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(3-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-37);
7 - {[(2-chlorobenzyl) oxy] methyl} -4- (2-thienylsulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-38);
4- (2,1,3-benzothiadiazol-4-ylsulfonyl) -7 - [(benzyloxy) methyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-39);
7 - {[(2-fluorobenzyl) oxy] methyl} -4 - [(5-fluoro-2-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-40 );
4 - [(3-chloro-4-fluorophenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-41 );
4 - [(3,5-difluorophenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-42);
7 - [(benzyloxy) methyl] -4- (2,3-dihydro-1,4-benzodioxin-6-yl-sulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3 -43);
4 - [(2,5-dimethylphenyl) sulfonyl] -7 - {[(2-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-44);
4 - [(2,5-difluorophenyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-45);
7 - [(benzyloxy) methyl] -4 - [(2,4,5-trimethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-46);
4 - [(2,4-difluorophenyl) sulfonyl] -7 - {[(4-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-47);
4 - [(5-chloro-2-methoxyphenyl) sulfonyl] -7 - {[(3-fluorobenzyl) oxy] methyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-48 );
7 - {[(3-fluorobenzyl) oxy] methyl} -4 - [(4-methylphenyl) sulfonyl] -2,3,4,5-terahydro-1,4-benzoxazepine (I.2.3-49);
7 - {[(4-fluorobenzyl) oxy] methyl} -4 - [(4-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-50);
7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-51);
7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-chlorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-52);
7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-53);
7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(2-fluorophenylmethyl) sulfonyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-54);
7- {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(2-thienyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-55);
7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-56 );
7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(4-chloro-phenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3 -57);
7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(4-methoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-58 );
7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(2-fluorophenylmethyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-59 );
7 - {[(2-N-pyrrolidino-ethyl) oxy] methyl} -4 - [(2-thienyl) sulfonyl] -2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3-60 );
7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-fluorophenyl) sulfonyl] -5 (R) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine ( I.2.3-61);
7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-fluorophenyl) sulfonyl] -5 (S) -methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine ( I.2.3-62);
7 - {[(2-dimethylamino-ethyl) oxy] methyl} -4 - [(4-fluorophenyl) sulfonyl] -5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (I.2.3 -61 / 62p); 5. The method of obtaining compounds of General formula I.1.1, which consists in the acylation of synthon A1 acyl halide A2 in a neutral solvent in the presence of a base

where R ₄ a, R ₄ b, R ₄ c, R ₄ d, R9, R10, R11 have the above meanings. 6. A method of producing compounds of general formula I.1.2, which consists in the sequential interaction of synton A1 with triphosgene in a neutral solvent in the presence of a strong base and amine a3 in an inert atmosphere

where R ₄ a, R ₄ b, R ₄ c, R ₄ d, R9, R10, R12, R13 have the above meanings. 7. A method of obtaining compounds of General formula I.1.3, which consists in the interaction of synton A1 and sulfonic acid a4 in an inert solvent in the presence of a strong base

where R ₄ a, R ₄ b, R ₄ c, R ₄ d, R9, R10 and R14 have the above meanings. 8. The method of obtaining compounds of General formula I.2.1, which consists in the acylation of synthon B1 acyl halide b2 in a neutral solvent in the presence of a strong base

where R ₄ a, R ₄ b, R ₄ c, R ₄ d, R11 and R15 have the above meanings. 9. A method for producing compounds of general formula I.2.2, which consists in the sequential interaction of synton B1 with triphosgene in the presence of a strong base and amine b3 in an inert atmosphere

where R ₄ a, R ₄ b, R ₄ c, R ₄ d, R12, R13 and R15 have the above meanings. 10. The method of obtaining compounds of General formula I.2.3, which consists in the interaction of synton B1 and sulfochloride b4 in an inert solvent in the presence of a base

where R ₄ a, R ₄ b, R ₄ c, R ₄ d, R14, R15 have the meanings defined above. 11. The active component having the property of an agonist of bile acid receptors TGR5, which is a compound of General formula I according to any one of claims 1 to 4. 12. A pharmaceutical composition for the prevention and treatment of metabolic diseases, such as diabetes, obesity, diabetes, metabolic syndrome, hypercholesterolemia, dyslipidemia, containing in an effective amount the active component according to claim 11. 13. The pharmaceutical composition according to item 12 in the form of tablets, capsules, injections, ointments, rectal suspensions and gels, placed in a pharmaceutically acceptable package. 14. A method for the prevention and treatment of metabolic diseases, such as diabetes, obesity, diabetes, metabolic syndrome, hypercholesterolemia, dyslipidemia, the introduction of an effective amount of a new active component according to claim 11 or the pharmaceutical composition according to claims 12, 13.

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