UA78522C2 - Benzoxasine and benzothiasine derivatives, method for synthesis thereof and pharmaceutical composition (variants) - Google Patents

Abstract

(I) The present invention relates to novel antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds of formula (I) derivatives thereof, analogs thereof, tautomeric thereof forms, stereoisomers thereof, polymorphs thereof, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them, to a process for preparing such compounds. More particularly, the present invention relates to novel alkyl carboxylic acids of the general, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them, to a process for preparing such compounds. The present invention also relates to processes for the preparation of the compounds of formula (I), novel intermediates, processes for their preparation, their use in the preparation of the above said compounds and their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds.

Description

Description of the invention

The present invention relates to novel antidiabetic, hypolipidemic, hypocholesterolemic compounds and antiobesity agents 2, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutically acceptable compositions containing them, method of obtaining such compounds. More specifically, the present invention relates to novel alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable 70 solvates and pharmaceutically acceptable compositions containing them, and a method of preparing such compounds.

The present invention also relates to new intermediate compounds, methods of their preparation, their use in the manufacture of the above-mentioned compounds and their use as antidiabetic, hypolipidemic, hypocholesterolemic compounds and antiobesity agents.

The compounds of this invention lower plasma glucose, triglycerides, lower total cholesterol 12 (TO) and increase high-density lipoprotein (HDL) and lower low-density lipoprotein (01), which provides a beneficial effect in coronary heart disease and atherosclerosis.

The compounds of the present invention are useful for reducing body weight and for the treatment and/or prevention of diseases such as atherosclerosis, stroke, peripheral vascular disease and related disorders. These compounds are suitable for the treatment of hyperlipidemia, hyperglycemia, hypercholesterolemia, reduction of atherogenic lipoproteins, MI OI. (very low density lipoproteins) and OI. The compounds of the present invention can be used to treat certain kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. These compounds are also suitable. for the treatment and/or prevention of leptin resistance, impaired glucose tolerance, disorders related to syndrome X, such as hypertension, obesity, insulin resistance, coronary heart disease and

Other cardiovascular disorders. These compounds may also be useful as aldose reductase inhibitors, for He) improving cognitive functions in dementia, treating diabetic complications, disorders associated with endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS5), inflammatory bowel disease, osteoporosis, myotonic dystrophy , pancreatitis, arteriosclerosis, retinopathy, xanthoma, eating disorders, inflammation and for the treatment of cancer. The compounds of the present invention are also useful in the treatment and/or prevention of the aforementioned diseases in combination/concomitantly with one or more NMO CoA reductase inhibitors, with hypolipidemic/hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol and probucol ; insulin, sulfonylurea, metformin. at

Atherosclerosis and other peripheral vascular diseases affect the quality of life of millions of people. Therefore, considerable attention is paid to the understanding of the etiology of hypercholesterolemia and hyperlipidemia and the development of effective therapeutic strategies. -

Hypercholesterolemia is defined as a plasma cholesterol level that exceeds a value arbitrarily called a "normal" level. Recently, it has been recognized that "ideal" plasma cholesterol levels are much lower than "normal" cholesterol levels in the general population, and that the risk of coronary artery disease (CA) increases with cholesterol levels above "optimal" (or "ideal"). value. There is an unequivocal causal relationship between hypercholesterolemia and CAO, especially for individuals with multiple risk factors. Most of the cholesterol is in esterified forms with different

With" lipoproteins such as low-density lipoprotein (101), intermediate-density lipoprotein (IM), high-density lipoprotein (HDL), and, in part, very low-density lipoprotein (VLDL). Studies clearly indicate an inverse relationship between CA and atherosclerosis with concentrations

NOI-cholesterol in serum (Ziatrieg ei aiYi., M. EpoiYi. U. Medya., 325 (1991), 373-381), and the risk of SAI increases with increasing levels of IOI. and MI 01.

Ge | With SAU, "fatty streaks" are usually observed in the carotid, coronary, and cerebral arteries, which consist mainly of free and esterified cholesterol. MiMPeg ei aiYi. (Vg. Med. ., 282 (1981), i-th 1741-1744) showed that an increase in the number of NOI particles can reduce the number of areas of stenosis in ka 20 human coronary arteries, and a high level of NOI -cholesterol can prevent the development of atherosclerosis.

Risagdo ei ai., Agpegiozsiegoviz b (1986) 434-441, showed in experiments of ip mygo that NOI is able to remove cholesterol from cells. They -supposed that NOI can cleanse tissues of excess free cholesterol and transfer it to the liver, which is known as reverse cholesterol transport (MasikKippop ei ai.,

U. Vioii. Spent 261 (1986), 2548-2552). Thus, NOI cholesterol-increasing agents will be of therapeutic value in the treatment of hypercholesterolemia and coronary heart disease (CHD).

GF) Obesity is a disease that is highly prevalent in high-affluence societies and in developing countries and is an important cause of morbidity and mortality. It is a state of accumulation of excess fat in the body. o The causes of obesity are not exactly known. It is believed to be genetic in nature or promoted by the interaction between genotype and environment. Regardless of the cause, the result is fat deposition due to an imbalance between energy intake and energy expenditure. Diet, exercise, and appetite suppression are part of the treatment for obesity. There is a need for effective therapy to combat this disease, as it can cause coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility, and many other psychological and social problems.

Diabetes and insulin resistance is another disease that greatly affects the quality of life of a large number of people in the world. Insulin resistance is a reduced ability of insulin to exert its biological effect in a wide range of concentrations. With insulin resistance, the body secretes an abnormally high amount of insulin to compensate for this defect; if it is not possible to achieve this, the concentration of glucose in the plasma inevitably increases and leads to the development of diabetes. In developing countries, diabetes is a very common problem; it is associated with various abnormalities, including obesity, hypertension, hyperlipidemia (9. Siip. Ipmevi, 75 (1985) 809-817; M. Epoi. U. Mea., 317 (1987) 350-357; 9. Siip. EpdosgipoI. Mesyab., 66 (1988) 580-583; 9. Sp. Ipmevi, 68 (1975) 957-969) and other renal complications (patent publication MoUUO 95/21608|. Now the opinion that insulin resistance and relative hyperinsulinemia play a role in obesity, hypertension, atherosclerosis, and type 2 diabetes. 7/0 The association of insulin resistance with obesity, hypertension, and angina has been described as a syndrome whose central pathogenic link is insulin resistance—Syndrome X.

Hyperlipidemia is the main cause of cardiovascular diseases (CVD) and other peripheral vascular diseases. A high risk of SMO is associated with elevated values of Ii. (low-density lipoproteins) and MI 0. (very low-density lipoproteins), observed in hyperlipidemia. Patients with glucose intolerance/insulin resistance, in addition to hyperlipidemia, are at increased risk of SMO. Numerous studies in the past have shown that lowering plasma triglycerides and total cholesterol, in particular, GO. and MI 01, and increased cholesterol NOI. helps prevent cardiovascular diseases.

Peroxisome proliferator-activated receptors (PRAKs) are members of the nuclear receptor superfamily.

It is believed that the gamma isoform (y) of PRAK (PRAKu) is involved in the regulation of adipocyte differentiation (Epdoshypoiyudu, 135 (1994) 798-800) and energy homeostasis (Seyi, 83 (1995) 803-812), while alpha -isoform (0) PRAC (PRACo) mediates the oxidation of fatty acids (Tgepia. Epdoship. Megbar., 4 (1993) 291-296), thereby causing the recovery of circulating free fatty acids in the plasma (Sygepi Vioi., 5 (1995) 618 -621). PRACo agonists have been found to be suitable for the treatment of obesity (MO 97/36579). As recently reported, it has been hypothesized that compounds that are agonists for both PRAC and He

RACU, may be suitable for the treatment of syndrome X (MO 97/25042). A similar effect (5) of the interaction between an insulin sensitizer (PRAC agonist) and an NMO CoA reductase inhibitor was observed, which may be useful for the treatment of atherosclerosis and xanthoma (EP 0753298).

It is known that RRAKU plays an important role in the differentiation of adipocytes (Seyi, 87 (1996) 377-389). Activation

PRAC by ligands is sufficient to induce full terminal differentiation (Cell II, 79 (1994) pp 1147-1156), including cell cycle arrest. PRAK y is stably expressed in certain cells, and activation of this nuclear receptor by PRAK y agonists will stimulate terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristic of a more differentiated, less malignant state (Moiestiag Seyi, (1998), 465-470; Sagsipodepevziv , (1998), 1949 53; Fr

Rhos. May). Aside. Zsi., 94 (1997) 237-241) and inhibit the expression of prostate cancer tissue (Sapseg Kezeagsi, 58

Zo (1998) 3344-3352). This may be useful in the treatment of certain types of cancer that express RCC and may provide a completely non-toxic chemotherapy. .

Leptin resistance is a condition in which target cells are unable to respond to the leptin signal.

This can cause obesity due to excess food intake and reduced energy expenditure, and may lead to impaired glucose tolerance, type 2 diabetes, cardiovascular disease, and other such interrelated complications. KaiЙЙep ей аЙ. (Rhos. May. Asad. Zsi., (1996) 93, 5793-5796) reported that insulin sensitizers, possibly due to the expression of PRAK agonists, reduce leptin concentration in plasma. However, it has recently been reported that compounds that have insulin-sensitizing properties also have leptin-sensitizing properties. They reduce the concentration of leptin circulating in plasma by improving the response of target cells to leptin (MUO 98/02159). - 75 Several alkylcarboxylic acids, their derivatives and their analogs have been reported to be useful in the treatment of hyperglycemia and hypercholesterolemia. Some of such compounds are described in the prior art and (ee) are listed below: sl i) In our (international publication MOUUO 99/085011 we disclosed compounds of the general formula (Ia) ma 70 tsch (a) che Ken scho Ag Their, a " Also in and ZK in

Kk and also , , in which group B", 2, BZ, B and groups KE? and K9, if they are attached to a carbon atom, can be the same (F) or different and denote hydrogen, halogen, hydroxyl group, nitro group, cyano group , formyl or unsubstituted r or substituted groups selected from alkyl, cycloalkyl, alkyl, cycloalkyl, aryl, aryloxy, aralkyl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, br Heteroaryloxy, heteroaralkyl, acyl, acyloxy, amino, acylamino, mono, alkylamino dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, armethoxycarbonyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or derivatives thereof, or sulfonic acid or derivatives thereof; one or both of KE? and 25 may also represent an oxo group if attached to an atom of carbon; KE? and B, if b5 THEY are attached to a nitrogen atom, denote hydrogen, hydroxyl group, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, acyl, acyloxy, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, an aryloxy group, an aralkyl group, a heteroaryloxy group, a heteroaralkyl group, an alkoxycarbonyl, an aryloxycarbonyl, an armethoxycarbonyl, an alkylthio group, a carboxylic acid derivative or a sulfonic acid derivative; X denotes a heteroatom selected from oxygen, sulfur, or MA", where KVK"! represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or armethoxycarbonyl groups; Ag denotes an unsubstituted or substituted divalent monocyclic or condensed aromatic or heterocyclic group; EC" denotes a hydrogen atom, a hydroxyl group, an alkoxy group, a halogen, 70. a lower alkyl, an unsubstituted or substituted aralkyl group, or forms a bond together with an adjacent KZ group; 8 denotes a hydrogen, a hydroxyl group, an alkoxy group, a halogen, a lower alkyl group, acyl, unsubstituted or substituted aralkyl, or KZ forms a bond together with B"7; KU denotes hydrogen, unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, monovalent heterocyclic, heteroaryl or heteroaralkyl groups; BO denotes hydrogen, unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, monovalent heterocyclic, heteroaryl or heteroaralkyl groups; U denotes oxygen or ME!?, where В" denotes hydrogen, -alkyl, aryl, hydroxyalkyl, aralkyl, 2o monovalent heterocyclic, heteroaryl, heteroaralkyl groups; KU and KE" together may form a 5- or b-membered cyclic structure containing carbon atoms and at least one nitrogen atom, and which may optionally contain one or more additional heteroatoms selected from oxygen, sulfur, or nitrogen; and the connecting group, marked -(СНо)й(О)т, can be attached through a nitrogen atom or a carbon atom; n denotes an integer in the interval 1-4 and t denotes an integer 0 or 1. An example of these compounds is represented by the formula (IB)

So (pv) go

Olya

Insi 30. y y y y her) (International publication MoUUO 00/64888) discloses compounds of the general formula (PIs) with in! in EE: I-th (Ps) that dreams uge-ygeya There is | b E | I'm eating ve to me in which Ah! and Ah? independently denote aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, c fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused ts heteroarylcyclenyl or fused heteroarylheterocyclyl; A denotes O, 5, 50, 805, MV", C(O), -" Me is(0),-С(OMe I, Me 'esS(OM(B 7), с('33-M; chemical bond, etc.; B denotes O, 5, ME "U, chemical bond, C(O), M(B 29)3C(0) or C(O)M(B2U); E denotes chemical bond or an ethylene group; a equals 0-6; B - 45 equals 0-4; c equals 0-4; y equals 0-6; d equals 1-5; n equals 1-4; 2", 83, c and BC" independently denote hydrogen, halogen, alkyl, carbonyl, alkoxycarbonyl or aralkyl; 2, 87, 25 and ЕЗ independently denote (ee) -(СН2)д-X; a is 0-3; X denotes hydrogen, halogen, alkyl, alkenyl, cycloalkyl, monovalent sl heterocyclic radical, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyl group, alkoxy group, aralkyl group, heteroaralkyl group, carbonyl, alkoxycarbonyl, tetrazolyl, acyl, acyl-HM5O", etc.; 7 ko) denotes KOS, KOS, cycloimide; SM, K"O28NMSO, K?O25MH, KK" MSO, 0-2 4-thiazolidinonyl or

KZ tetrazolyl.

An example of these compounds is represented by the formula (Ia) o (pa)

N o ii bno din ime) ii) (International publications MoMoUuO 95/03038 and UUO 96/04260) reveal compounds of the formula (Pe) 60 sn, - Sosya (Pe)

VAV chn But OsSnv in which K? stands for 2-benzoxazolyl or 2-pyridyl, and EE? denotes SEz, СНгОСсСН» or СНу. A typical example is (8)-3-I4-(2-(M-(2-benzoxazolyl)-M-methylamino|ethoxy|-phenyl)|-2-(2,2,2-trifluoroethoxy)propionic acid (IV ).

St. Petersburg; Honeycomb: VYT

Xia z

IM) (International publications MoMmouuO 94/13650, UMO 94/01420 and MO 95/17394) reveal compounds of the general formula (Id) ku-Ж- (СН о А А - Я 6) in which A" denotes an aromatic heterocycle, A? denotes a substituted benzene ring and AZ denotes a fragment of the formula (СНо)п-СН-(ОВ 7), where КЕ! denotes alkyl groups, t denotes an integer in the range 1-5, X denotes substituted or unsubstituted M, M denotes C-O or C-5, 2 denotes ОВЗ, where ВЗ can be a hydrogen, alkyl, aralkyl or aryl group, and n denotes an integer in the interval 2 to 6. An example of these compounds 75 is represented by the formula (II)

What a dream DY (t)

Sonia Ztchovy

M) International publication MoOUUO 00/49005) reveal compounds of the general formula (Іи) ке (и) чХ'в-- на- З в - . and c o in which Nei denotes an optionally substituted, saturated, partially saturated or fully unsaturated 8-10-membered bicyclic ring, B" denotes an optionally substituted aryl or optionally substituted heteroaryl, B 2 denotes hydrogen, halogen, lower alkyl or a lower alkoxy group, | denotes the bond -B3-B7, where ВЗ denotes an alkylene, alkenylene or alkynylene and B" denotes a simple bond, cycloalkylene, heterocycloalkylene, arylene, heteroarylidinyl, -C(-72)-МА5 , MV 5-С(-72), -72-, -С(хО), -С(-МОВ5)-, -МВ5-, MA5-с(-72)-МВ5, 505-МВ5 М5-805, EM -0-с(х0)-, -С(50)-О0, -0-С(50)-МЕ?, -МВ?-С(-0)-О-; AND? denotes an optionally substituted alkylene or alkenylene, U denotes a carboxyl group or a bioisoster of an acid and 7" denotes MA? and the corresponding M-oxides, and their prodrugs, and pharmaceutically acceptable salts and solvates. An example of these compounds is represented by the formula (HER) m 47 N (r - A TA dozheh « shi s mi) International publication MoU/O 94/12181) discloses compounds of the general formula (PIK).

B h-u-zh-eryl-ya-v o (Yu

Aryl denotes an aromatic ring that contains 0, 1, 2 or 3 nitrogen atoms and is unsubstituted or substituted by KZ and VU; X denotes MH, MH-C(-MH)-, etc. or a 4-10-membered mono- or polycyclic aromatic or non-aromatic ring system containing 0, 1, 2, C or 4 heteroatoms selected from M, O or 5, and is unsubstituted or substituted; In the selected C Co-alkyl, C. 4o-cycloalkyl, Co-alkyl-MKZ-CO-Co-d-alkyl, and Co-d-alkyl-SOMAZ-Co.c-alkyl, Co-alkyl-0 -Co in-alkyl, Co in-alkyl-Z(O)n-Cov-alkyl, (СНо)о в-aryl-«СНо)о.в, о (СН.О)о в-aryl-5О,- ) with (СНО) в-aryl-CH(OH)-(СН 2)0-в-, (СНо)о-в-СОМН-(СНо)о-в-, Со в-alkyl-505-MAZ-Со в -alkyl,

Co in-alkyl-CO-C o d-alkyl, Co in-alkyl-CH(OH)-Co in-alkyl, where n denotes an integer 0-2; 7 and A are independently selected from (СНо)т. (CHNa) to (CH2g). /(СНадеМАУСНоМ, 0 (СНо)пМАУ(СНо)у, | (СНадпсОМА (СН), 59 (СНА)пСО(СНО)б (СНо)тСВ(СНо), (СНо)дт8ОХ(СНо)в, (СНо) pe(СНо)в / (СНо)тЗО(СНо)в, / (СНо)твО(СНа)в, (Ф) (СнодяЗОо MA (СНо)в, (СНо)нМА805(СНо)в, (СНадтсв Св СН ), (СНо)тос(СНо)в, (СНаИСН(ОНусН») и; where 7t and n each independently denote an integer from 0 to b; aryl denotes a b--linked aromatic ring system containing 0, 1, 2, C or 4 atoms of M and is unsubstituted or substituted P", provided that when A denotes the (CH.)th aryl ring connected to 2 and A, it must contain at least one heteroatom; B denotes the -v" 2 - (sne Vy t or ee vv" . bo 25 v", 8, i, KO and EK"! are independently selected from hydrogen, fluorine, (Si. c)-alkyl, hydroxyl group,

hydroxy-(C-C)-alkyl, carboxy-(C-C)-alkyl, (C4-C)-alkyloxy group, aryl-(C-C)-alkyloxy group, (C3-8)-Cycloalkyl, aryl-(C) -alkyl, (Ci.c)-alkylcarbonyloxy group, (Ci.c)-alkylamino-(Ci)-alkyl, etc. B'? selected from the hydroxyl group, (C..8)-alkyloxy group, aryl-(Cov)-alkyl, etc.; An example of these compounds is represented by the formula (II I) son chNeOVy mii) (International publication MoUUO 93/16697 and US patent Mo5227490 | disclose compounds of the general formula (IPt)

CHI (Fri)

And in

That's all

11th juice

B" is selected from hydrogen, C. c-alkyl, aryl-C. 10o-alkyl, aryl, carboxyl group, C. c-alkyloxy group, carboxy-C. c-alkyl, carboxy-C. c-alkyloxy group, hydroxy-C. c- alkyl, C. /-alkylsulfonyl-C o c-alkyl,

Co d-alkylamino-Co y-alkyl, aryl-Co 10-alkylamino-Co-e-alkyl, C-u-acylamino-Co-b-alkyl, Si-4-carboalkoxy-Co-b-alkyl, halogen, B ? independently selected from hydrogen, halogen, hydroxyl group,

C. dlalkyl, where the alkyl group is substituted or unsubstituted, C. c-alkyloxy groups, aryl-C y-alkyl, aryl-Cov-alkyloxy groups, etc.; KZ denotes hydrogen, C-C-alkyl, aryl-Ci-C-alkyl; 7 denotes MAV"B5 or a 4-9-ene mono- or bicyclic ring system containing 1, 2 or C heteroatoms selected from M, O or 5, and i9) is unsubstituted or substituted; U denotes C-v- alkyl, which is unsubstituted or substituted, C /.8-cycloalkyl, aryl, -С(О)МН-, -МН(С-О)-, etc.; X denotes O, 50, 50", 5, СО, -ME"СО-, СОМВ-, СН», etc.

An example of these compounds is represented by the formula (IIn) He nipple (n) cm about Di I c) p

Several derivatives of B-phenyl-y-oxysubstituted propionic acid were described, which were used as m intermediate compounds for the synthesis of target molecules. Some of such compounds described in the prior art are listed below: i) (European patent application ERO 816316) discloses a compound of formula (Po) « и c! Bosnia? (Po) - i s i sn ;"

The compound of the formula (ma) is further converted into a 1,2-ethanediol derivative of the formula (Pr) - in (Pr)

I he (ee) y s yy y o, y y ; I have) These 1,2-ethanediol derivatives are useful intermediates for pharmaceutical and agricultural

Short-term use of chemicals. her) (Japanese patent application UR 10017540 discloses a compound of the formula (Id)

On Pa)

Not

F) ko o bo; The compound of the formula (IIg) is further converted into the compound of the formula (ma)

In order to obtain new compounds for the treatment and/or prevention of diseases associated with elevated lipid levels, in particular, for the treatment of hypertriglyceridemia and reduction of free fatty acids, for the treatment and/or prevention of diseases described as syndrome X, which include hyperlipidemia, .hyperinsulinemia, obesity, insulin resistance, insulin resistance leading to type 2 diabetes and its diabetic complications, to treat diseases in which insulin resistance is the pathophysiological mechanism, to treat hypertension, atherosclerosis, and coronary artery disease with better efficacy, efficacy, and less toxicity, we have focused our research on obtaining new compounds effective for the treatment of the above-mentioned diseases.

Therefore, the main purpose of this invention is to create new B-aryl-A-oxysubstituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions that contain, or their mixtures.

Another object of this invention is to create new B-aryl-A-oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or mixtures thereof, which can exhibit agonistic activity against PRAC and/or PRAC and, optionally, inhibit NMO CoA reductase in addition to agonistic activity against PRAC and/or PRAC.

Another object of this invention is to create new B-aryl-A-oxysubstituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or from their mixtures, which have increased activity, without toxic effect or with reduced toxic effect. with

Another object of the present invention is to create a method for preparing B-aryl-A-oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates. co

Another object of this invention is to create B-aryl-A-oxysubstituted pharmaceutical compositions

Of the alkylcarboxylic acids, their analogs, their derivatives, their tautomers, their stereoisomers, their polymorphs, their salts, solvates or mixtures thereof, in combination are suitable carriers, solvents, diluents and other means commonly used for the manufacture of such compositions.

Another purpose of this invention is to create new intermediate compounds, a method of their preparation and "use of intermediate compounds in a method of obtaining B-aryl-A-oxysubstituted alkoxycarboxylic acids, their derivatives, their analogues, their tautomers, their stereoisomers, their polymorphs, their salts and their c) with pharmaceutically acceptable solvates, and their use as antidiabetic, hypolipidemic, hypocholesterolemic compounds and antiobesity agents. he ko di sne in Ag udv (ee) p Vchy ot 1 7 50 their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, where Кк 1.82 and КЗ, B, if they are attached to the o) carbon atom, can be the same or different and represent hydrogen, halogen, hydroxyl group, nitro group, cyano group, formyl or substituted or unsubstituted groups selected from a alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, aryloxy, aralkyl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkyl, acyl, acyloxy, o hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylalkyl, aryloxyamino, aryloxyamino , aralkyl, aryloxyalkyl, aryloxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkylamino, carboxylic acid or its derivatives or sulfonic acid or its derivatives; one 60 or both with KZ and KE? can denote an oxo group or a thioxo group if they are attached to a carbon atom;

KZ and c, when attached to a nitrogen atom, represent hydrogen, hydroxyl, formyl, or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkyl, cycloalkyl, aryl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, acyl, acyloxy , hydroxyalkyl, amino group, acylamino group, monoalkylamino group, dialkylamino group, arylamino group, because aralkylamino group, aminoalkyl, aryloxy group, armethoxy group, heteroaryloxy group, heteroaralkyl

alkoxycarbonyl, aryloxycarbonyl, armethoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aroxyalkyl, alkylthio group, thioalkyl group, carboxylic acid derivatives or sulfonic acid derivatives; X denotes a heteroatom selected from oxygen or sulfur; MU denotes MA "2, -C(-0)-(SV 98717) -MV 72, -O-aryl-(SV 98771) -MV "", where B"? represents hydrogen or a substituted or unsubstituted group selected from alkyl, aryl or aralkyl groups; o denotes an integer in the interval 0-6; VO and EV! may be the same or different and represent hydrogen or an unsubstituted or substituted group selected from an alkyl, alkyl, aryl or aralkyl group; Ag denotes a substituted or unsubstituted divalent monocyclic or condensed aromatic or heterocyclic group; KE? denotes a hydrogen atom, a hydroxyl group, an alkoxy group, a halogen, an alkyl, a substituted or unsubstituted aralkyl group, or forms a bond together with an adjacent K 9 group; K9 represents hydrogen, hydroxyl group, alkoxy group, halogen, alkyl group, acyl, substituted or unsubstituted aralkyl, or KZ forms a bond together with

VU; B can be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, monovalent heterocyclic, heteroaryl, heteroaralkyl groups; C can be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, monovalent heterocyclic, heteroaryl or heteroaralkyl groups; U represents oxygen, sulfur, or ME, where CO represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkyl, monovalent heterocyclic, heteroaryl, or heteroaralkyl groups, or ME? denotes a chiral amine, chiral amino alcohols derived from a chiral amino acid; KZ and KU together can form a substituted or unsubstituted 5- or b--cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur, or nitrogen; t and n are integers in the interval 0-6.

Suitable groups represented by 2, b2, b, b can be selected from hydrogen, a halogen atom such as He! fluorine, chlorine, bromine or iodine; hydroxyl group, cyano group, nitro group, formyl, substituted or unsubstituted o (C4-C42)-alkyl group, especially, linear or branched (C4-C.i0)-alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, etc.; cyclo-(C3-C8)-alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and the cycloalkyl group may be substituted; (C4-Cv)-alkyl group, such as methoxy group, ethoxy group, He propyloxy group, butyloxy group, isopropyloxy group and top. which can be substituted; a cyclo-(C3-C)-alkyl group, such as a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, etc., and the cycloalkyloxy group may be substituted; an aryl group such as phenyl, IS o) naphthyl, etc., and the aryl group may be substituted; an aryloxy group, such as a phenoxy group, a naphthyloxy group, etc., and the aryloxy group may be substituted; aralkyl, such as benzyl, phenethyl, co SeNBsSnNosSNosSnH", naphthylmethyl, etc., and the aralkyl group can be substituted; aralkyloxy group, such as benzyloxy group, phenethyloxy group, naphthylmethyloxy group, phenylpropyloxy group, etc. and the aralkyl group can be substituted; a monovalent heterocyclic group such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, etc., and the monovalent heterocyclic group may be substituted; a heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuryl, etc., and the heteroaryl group may be substituted; - c heteroaralkyl group, such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl, etc., and the heteroaralkyl group can be substituted; heteroaryloxy groups and heteroaralkyl groups, where "» heteroaryl and heteroaralkyl fragments have been defined above and may be substituted; acyl groups such as acetyl, propionyl, benzoyl, etc., and the acyl group may be substituted; acyloxy groups such as OOSMe, OOSEI OOSRIII etc., which may be substituted; acylamino groups, such as МНСОСН з, -и МНСОС»ОН, МНСОСЗН;, МНСОСС Нв, etc., which may be substituted; monoalkylamino groups, such as -MNON z, because МНО» Hv, MNezNu, MHC H», etc., which can be substituted; a dialkylamino group, such as M(CH 3)5, MSNU(SeoNv),

M(СоН)», etc., which can be substituted; arylamino group, such as NMS Nv, MONU(SeN), MNOSenNAsSnN", 1 MNSN.-Na! etc., which can be substituted; aralkylamino group, such as C eNeSNoMn, SenH5SsnNoSsnNeMn, t 50 SeNBSNoMSNU and top. that can be substituted; amino groups; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, etc., which may be substituted; aryloxycarbonyl group, such as phenoxycarbonyl, naphthyloxycarbonyl, etc., and the aryloxycarbonyl group may be substituted; aralkyloxycarbonyl group, such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl, etc., which may be substituted; an alkoxyalkyl group, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc., and the alkoxyalkyl group may be substituted; aryloxyalkyl group, such as СНБОсСнН»

SenNBOSNoSNo, naphthyloxymethyl, etc., which may be substituted; aralcoxyalkyl group, such as o SenBSsnNoOoSsNn»o, SeNneSnNoOsNnoSsnN», etc., which may be substituted; hydroxy-C1-C1-alkyl, which may be substituted; thio-(C4-C1)-alkyl, which may be substituted; (C 4-Cv)-alkylthio group, which can be substituted; an alkoxycarbonylamino group, such as МНСООС оН5, МНСООСНУ and top, which may be substituted; 60 aryloxycarbonylamino group, such as МНСООС Нв, МСНЗзСООСоН, МСоНвСООссеНв, МНСООСеН,СН",

MNSOOOSN, OsnN;" etc., which can be substituted; aralkylamino group, such as МНСООСН 2оСеНв,

МНСООСНоСНоСвН, MЩ(СНЗИСОСН»оСН, М(СоН5й)СОосСНосН5, МНСООСНоСНоСН, МНСООСНоСНАОН», etc., which may be substituted; carboxylic acid or its derivatives, such as amides, for example, СОМН», СОМНМе,

SOMMe", SOMNEI, SOMEB, SOMNRA, etc., and carboxylic acid derivatives can be substituted; 65 sulfonic acid or its derivatives, such as ZO OMN»o, 50O2MNMe, ZO2MMe», ZO2MNSE»z, etc., and sulfonic acid derivatives can be substituted.

If the groups represented by B"-BE7 are substituted, then the substituents may be selected from halogen, hydroxyl, nitro, thio, or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkyl, cycloalkyl, aryl, aralkyl, aryloxy, aralkyl , alkoxyalkyl, aryloxyalkyl, aroxyalkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkylthio, carboxylic acid or its derivatives, or sulfonic acid or its derivatives. defined above.

Preferably, the substituents on K1-K7 represent a halogen atom such as fluorine, chlorine or bromine; an alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl; a cycloalkyl group such as cyclopropyl; an aryl group such as phenyl; an aralkyl group such as benzyl; (C 4-C3)-alkyloxy group, benzyloxy group, hydroxyl group, acyl or acyloxy group.

Suitable groups designated X may be selected from oxygen or sulfur.

Suitable groups labeled Ag may be selected from substituted or unsubstituted groups selected from 75 divalent phenylene, naphthylene, pyrrole, opyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl etc. Substituents on the group denoted by Ag can be selected from linear or branched optionally halogenated (C 1-Cv)-alkyl, optionally halogenated (C 41-C3)-alkoxy group, halogen, acyl, amino group, acylamino group, thio group or carboxylic or sulfonic acids and their derivatives.

Substitutes have the values defined for B1-B7,

Preferably, Ag represents substituted or unsubstituted divalent phenylene, naphthylene, benzofuryl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups.

Suitable groups represented by KU can be selected from hydrogen, hydroxyl group, (C4-C8)-alkyl c 29 groups, such as methyl, ethyl, propyl, etc.; (С 41-Са)-alkyl group, such as a methoxy group, an ethoxy group, d) a propoxy group, etc.; a halogen atom such as fluorine, chlorine, bromine or iodine; aralkyl such as benzyl, phenethyl, etc., which may be unsubstituted or substituted, or KE? together with the short circuit denotes the connection. Substituents are selected from halogen, hydroxyl or alkyl groups.

Hydrogen, hydroxyl group, (C4-C)-alkyl groups, such as methyl, ethyl, cm 3o propyl, etc., can be suitable KU; (C4-C3)-Alkoxy group such as methoxy group, ethoxy group, propoxy group, etc.; a halogen atom, Ge such as fluorine, chlorine, bromine or iodine; (C2-C0)-acyl group such as acetyl, propanoyl, butanoyl, pentanoyl, oyu benzoyl, etc.; aralkyl, such as benzyl, phenethyl, etc., which may be unsubstituted or substituted, or VK 5 together with VZ forms a bond. Substituents are selected from halogen, hydroxyl or alkyl groups. co

Suitable groups represented by BK" can be selected from hydrogen, linear or branched - (C.-C.6)-alkyl, preferably, (C1-C12)-alkyl group, such as methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, pentyl, hexyl, octyl, etc., and the alkyl group may be substituted; (C5-C7)-cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl, etc., and the aryl group may be substituted; aralkyl group, such as benzyl, phenethyl, etc., in which the alkyl moiety may contain (C 4-Cv) atoms, and the aryl fragment can be substituted; a heteroaryl group, such as pyridyl, thienyl, pyrrolyl, furyl, etc., and the heteroaryl group can be substituted; a heteroaralkyl group, such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl, etc., and the heteroaralkyl group may be substituted; a monovalent heterocyclic group such as aziridinyl , pyrrolidinyl, piperidinyl, etc., and the monovalent heterocyclic group may be substituted; linear or branched (Co-C16)-acyl group, -| such as acetyl, propanoyl, butanoyl, benzoyl, octanoyl, decanoyl, etc. which can be substituted; for (С4-Св)-alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, etc. and the alkoxycarbonyl group can be substituted; aryloxycarbonyl, such as phenoxycarbonyl, 1-naphthyloxycarbonyl, etc., and the aryl group may be substituted; (C.4-Cv)-alkylaminocarbonyl, and the t 50 alkyl group can be substituted; arylaminocarbonyl, such as RAIMNSO, naphthylaminocarbonyl, etc., and the aryl moiety may be substituted. Substituents may be selected from halogen, hydroxy, nitro, or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, aralkyl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino . o Substitutes have the meanings defined above. where Suitable groups denoted by KU can be selected from hydrogen, linear or branched (C4-C4)-alkyl, preferably (C4-C42)-alkyl, such as methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, pentyl, 60 hexyl, octyl, etc., and the alkyl group may be substituted; (C3-C7)-cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl, etc., and the cycloalkyl group may be substituted; an aryl group such as phenyl, naphthyl, etc., and the aryl group may be substituted; a heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl, etc., and the heteroaryl group may be substituted; a heteroaralkyl group, such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl, etc., and the heteroaralkyl group may be substituted; an aralkyl group, such as benzyl, phenethyl, etc., and the aralkyl group may be substituted; monovalent heterocyclic group, such as aziridinyl, pyrrolidinyl, piperidinyl, etc., and the monovalent heterocyclic group may be substituted. Substituents on KZ can be selected from halogen, hydroxyl group, nitro group, or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkyl group, cycloalkyl group, aryl, aralkyl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, an amino group, an acylamino group, an arylamino group, an aminoalkyl group, an aryloxy group, an aralkoxy group, an alkoxycarbonyl group, an alkylamino group, an alkoxyalkyl group, an alkylthio group, a thioalkyl group, a carboxylic acid or its derivatives, or a sulfonic acid or its derivatives.

Substitutes have the above values.

Suitable groups denoted by KU can be selected from hydrogen, linear or branched (C4-C6)-alkyl, preferably (C-C42)-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, etc.; hydroxy-"C4-C1)-alkyl; an aryl group such as phenyl, naphthyl, etc.; an aralkyl group, such as benzyl, phenethyl, etc.;; a monovalent heterocyclic group such as aziridinyl, pyrrolidinyl, piperidinyl, etc.; a heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl, etc.; heteroaralkyl group, such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl, etc. Substituents may be selected from hydroxyl, halogen, nitro, amino, alkyl, alkoxy or aryl.

Suitable chiral amines labeled ME may be selected from P(u)-A-ethylphenylamine, naphthylethylamine,

C()-phenylethanolamine, cinchonidine, ephedrine, M-octylglucaramine, M-methylglucaramine, etc.; chiral amino alcohols, such as phenylethanolamine, valine, tert-leucine, etc.

Suitable ring structures formed by KZ and KO together may be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and the like.

Suitable groups denoted B'O and B" may be selected from hydrogen or a substituted or unsubstituted linear or branched (C.4-C.42)-alkyl group such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.; (C4-C8)-alkoxy groups such as methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc. .p., which can be substituted; aryl group, such as phenyl, naphthyl, etc., and the aryl group can be substituted; He) aralkyl, such as benzyl, phenethyl, C eNBeCHnoCHnoCH", naphthylmethyl, etc. Substituents may be selected from a hydroxyl group, a halogen, a nitro group, or an amino group.

Suitable groups marked "2" can be selected from hydrogen or a substituted or unsubstituted linear or branched (C.sub.1-C.sub.12)-alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cm tert-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.; an aryl group such as phenyl, sem-naphthyl, etc., and the aryl group may be substituted; an aralkyl group, such as benzyl, phenethyl,

SenNeSnNosSnNo.CHno, naphthylmethyl, etc. Substituents can be selected from a hydroxyl group, a halogen, and a nitro group or an amino group. (uh)

Valid values of H are integers in the range from 0 to 6.

Valid values of n are integers in the range from 0 to 6. -

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases, such as y, Ma, K, Ca, Ma, Be, Si, 7p, My; salts of organic bases, such as

M,M'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, M-ethylmorpholine, « du M-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, with piperidine, procaine, purines, theobromine, ethanolamine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamantylamine, diethanolamine, meglumine, ethylenediamine, M,M'-diphenylethylenediamine, M,M'-:z» dibenzylethylenediamine, M-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine, etc.; chiral bases, such as alkylphenylamine, phenylethanolamine, etc., salts of natural amino acids, such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids, (ee) such as O-isomers or substituted amino acids; guanidine, substituted guanidine, in which the substituents are selected from nitro group, amino group, alkyl, alkenyl, alkynyl, ammonium, or substituted ammonium salts and aluminum salts.

Salts may in certain cases include acid addition salts such as sulfates, nitrates, phosphates, i.e., perchlorates, borates, salts of hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzene sulfonates, ascorbates, glycerophosphates, ketoglutarates, etc. Pharmaceutically acceptable solvates may be hydrates or include other crystallization solvents such as alcohols.

Particularly useful compounds according to the present invention include: (-3-ethyl-3-14-13-(3,4-dihydro-2H-benzoyl|81/11, Zoxazin-4-yl)propylamino)phenyl|-2-ethoxypropionate; (F) ()-ethyl-3-14-(3-(3,4-dihydro-2H-benzo[81(11,Zoxazin-4-yl)/propylamino)phenyl]-2-ethoxypropionate;

He (-)-ethyl-3-14-13-(3,4-dihydro-2H-benzoyl)(1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionate; (--3-I4-(3-(3,4-dihydro-2H-benzo|1/1,Coxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic acid or its salts; in (1)- 3-I4-13-(3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic acid or its salts; (-)-3-I4-43 -(3,4-dihydro-2H-benzo|1/1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic acid or its salts; (i)-ethyl-3-14-N-heptyl-N-[2-(3-oxo-3,4-dihydro-2H-benzo[5)](1,Zoxazin-4-yl)-ethylamino)phenyl| -2-ethoxypropionate; ()-ethyl-3-I4-M-heptyl-M-(2-(3-oxo-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)-ethylamino)phenyl|-2 - ethoxypro 65 pionate; (-)-ethyl-3-I(4-M-heptyl-M-12-(3-oxo-3,4-dihydro-2H-benzoyl)-1I(1,Zoxazin-4-yl)-ethylamino)phenyl| -2-ethoxypropionate; -2-ethoxypropionic acid

Acid or its salts; (1)-3-I(4-M-heptyl-M-12-(3-oxo-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)uethylamino)-phenyl)|- 2-ethoxypropionic acid or its salts; (-)-3-I4-M-heptyl-M-2-(3-oxo-3,4-dihydro-2H-benzo[(1,Zoxazin-4-yl)ethylamino)-phenyl]-2-ethoxypropiono vu acid or its salts; 70 (i)-methyl-2-ethoxy-3-I4-7M-heptyl-M-(2-(3,4-dihydro-2H-benzo|ph|oxazin-4-yl)-2-oxoethyl)iaminomethyl) phenyl|propion at; (1)-methyl-2-ethoxy-3-14-N-heptyl-N-(2-(3,4-dihydro-2H-benzo|in|oxazin-4-yl)-2-oxoethyl)aminomethyluphenyl| propionate; (-)Y-methyl-2-ethoxy-3-I4-7M-heptyl-M-(2-(3,4-dihydro-2H-benzo|p|oxazin-4-yl)-2-oxoethyl)aminomethyluphenyl| propionate; (i)-2-ethoxy-3-14-7M-heptyl-M-(2-(3,4-dihydro-2H-benzo|B|oxazin-4-yl)-2-oxoethyl)-aminomethyl)phenyl| propionic acid or its salts; (1)-2-ethoxy-3-14-7M-heptyl-M-(2-(3,4-dihydro-2H-benzo|ph|oxazin-4-yl)-2-oxoethyl)-aminomethyl)phenyl| propio new acid or its salts; (-)-2-ethoxy-3-(4-7M-heptyl-M-(2-(3,4-dihydro-2H-benzo|p|oxazin-4-yl)-2-oxoethyl)-aminomethyl)phenyl propio new acid or its salts; (-)-methyl-3-14-15-(3,4-dihydro-2H-benzo[5111,Zoxazin-4-yl)-5-oxopentylamino)-phenyl])-2-ethoxypropionate; He (I)-methyl-3-I4-15-(3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)-5-oxopentylamino)-phenyl|-2-ethoxypropionate; (5) (-)-methyl-3-I4-15-(3,4-dihydro-2H-benzo|(B)|1,Doxazin-4-yl)-5--oxopentylamino)-phenyl|-2- ethoxypropionate; (--3-I4-45-(3,4-dihydro-2H-benzo|1/1,Zoxazin-4-yl)-5-oxopentylamino)phenyl|-2-ethoxypropionic acid or its salts; (1)-3-I4-15-(3,4-dihydro-2H-benzoic acid or its salts); ch (-)-3-I4-45-(3,4-dihydro-2H-benzo|1/1,Coxazuin-4-yl)-5-oxopentylamino)phenyl|-2-ethoxypropionic acid or its salts; 10) (-)-methyl-3-I3-(3-(3,4-dihydro-2H-benzo|5111,Zoxazin-4-yl)ipropylamino)phenyl|-2-ethoxypropionate; (i)-methyl-3-(3-(3-(3,4-dihydro-2H-benzoyl)-(11,Doxazin-4-yl)/propylamino)phenyl)-2-ethoxypropionate;

Zo (-)Y-methyl-3-I3-(3-(3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)ipropylamino)phenyl/|-2-ethoxypropionate; v. (- -3-I3-(3-(3,4-dihydro-2H-benzo|1/1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic acid or its salts; (z)-3-( 3-13-(3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic acid or its salts; (-)-3-I3-13-( 3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic acid or its salts; "(-)-methyl-3-I4-(3-(7 -fluoro-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)ipropylamino)-phenyl|-2-ethoxypropionate; 50 (t)-methyl-3-I4-13-(7-fluoro -3,4-dihydro-2H-benzoyl|81/11, Coxazin-4-yl)propylamino)-phenyl()|-2-ethoxypropionate; C c (-N-methyl-3-I4-(3-(7 -fluoro-3,4-dihydro-2H-benzoyl|51(11,Coxazin-4-yl)ipropylamino)-phenyl|-2-ethoxypropionate; "with (--3-I4-43-(7-fluoro-3 ,4-dihydro-2H-benzo|81(11,Coxazin-4-yl)propylamino)phenyl|-2-ethoxypropionic acid or its salts; (1-)-3-I4-73-(7-fluoro-3 ,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)phenyl)|-2-ethoxyp ropionic acid or its salts; - (-3-3-I4-43-(7-fluoro-3,4-dihydro-2H-benzo|(81/1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic (o) acid or Its salts; benzylaminophenyl|propionate; co 20 (α)-methyl-2-ethoxy-3-I4-14-(3-(3,4-dihydro-2H-benzo|β1(1,Zoxazin-4-yl)upropyloxy)-benzyl )aminophenyl|prop "z ionate; (-)U-methyl-2-ethoxy-3-(4-14-(3-(3,4-dihydro-2H-benzoyl)|51(11,Zoxazin-4-yl) /propyloxy)-benzylaminophenyl|prop ionate; )-benzylaminophenyl|propionate; (F) (t)-methyl-2-ethoxy-3-I3-14-(3-(3,4-dihydro-2H-benzo|c)/1,Zoxazin-4-yl) propyloxy)-benzylaminophenyl|prop

He ionate; (-)Y-methyl-2-ethoxy-3-(3-14-(3-(3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)/propyloxy)-benzylaminophenyl|prop vo Ionate; or Its salts; acid or its salts; (-)-2-ethoxy-3-(4-14-(3-(3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)propyloxy)benzyl)-aminophenyl propionic acid or its salts; propionic acid or its salts; |propionic acid or its salts; (-)-2-ethoxy-3-(3-14-(3-(3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)propyloxy)benzyl)-aminophenyl|propionic acid or Its salts; (-)-ethyl-2-ethoxy-3-I4-(3-(3,4-dihydro-2H-benzo|1/1,4)thiazin-4-yl)/propylamino)-phenyl|propionate; 70 ()-ethyl-2-ethoxy-3-(4-13-(3,4-dihydro-2H-benzoyl|b1(1,thiazin-4-yl)/propylamino)-phenyl|propionate; (-)- ethyl 2-ethoxy-3-I4-(3-(3,4-dihydro-2H-benzo|1/1,4)thiazin-4-yl)/propylamino)-phenyl|propionate; (--2-ethoxy-3-(4-13-(3,4-dihydro-2H-benzoyl)(/1,thiazin-4-yl)/propylamino)phenyl|-propionic acid or its salts; () -2-ethoxy-3-I4-73-(3,4-dihydro-2H-benzo|in(/1,4Zthiazin-4-yl)upropylamino)phenyl|-propionic acid or Its salts; (-)-2- ethoxy-3-I(4-13-(3,4-dihydro-2H-benzoi|51I(11,4)hyazin-4-yl)/propylamino)phenyl|-propionic acid or its salts; (-)-ethyl -2-ethoxy-3-I4-(2-(3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)ethylamino)-phenyl|propionate; (t)-ethyl-2-ethoxy- 3-(4-(2-(3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)ethylamino)-phenyl|propionate; (-)-ethyl-2-ethoxy-3-I4- (2-(3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)ethylamino)-phenyl|propionate; (--2-ethoxy-3-(4-12-(3,4- dihydro-2H-benzoi|51(11,Doxazin-4-yl)uethylamino)phenyl|-propionic acid or its salts; ()-2-ethoxy-3-I4-72-(3,4-dihydro-2H-benzo |c)/1,Zoxazin-4-yl)ethylamino)phenyl|-propionic acid or its salts; (-)-2-ethoxy-3-I4-2-(3,4-dihydro-2H-benzoi|c) (1,oxazin-4-yl)ethylamino)phenyl|-propionic acid or its salts; (1)-methyl-2-ethoxy-3-I(4-I(4-72-(3,4 dihydro-2H-benzo[b)/1,Zoxazin-4-yl)ethoxy)-phenylaminomethyl]phenyl|propionate; (t)-methyl-2-ethoxy-3-I4-I4-(2-(3,4-dihydro-2H-benzo|(81(11,Zoxazin-4-yl)ethoxy)-phenylaminomethyl|phenyl|prop ionate c (-)N-methyl-2-ethoxy-3-(4-(4-42-(3,4-dihydro-2H-benzoyl|81(1,Zoxazin-4-yl)ethoxy)-phenylaminomethyl|phenyl |prop o ionate; (i )-2-ethoxy-3-I4-I(4--2-(3,4-dihydro-2H-benzoi| 1/1, Zoxazin-4-yl)ethoxy)-phenylaminomethyl| phenyl|propionic acid or its salts; c ()-2-ethoxy-3-(4-I(4-72-(3,4-dihydro-2H-benzo|b5)/1,Zoxazin-4-yl)ethoxy )-phenylaminomethyl|phenyl|propionic acid or its salts; (-)-2-ethoxy-3-(4-(4-2-(3,4-dihydro-2H-benzoic)|51(11,Doxazin-4- yl)ethoxy)-phenylaminomethyl|phenyl|propionic acid, acid or its salts; co (--ethyl-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoi) 4-yl)propylamino)-phenyl)|-2-ethoxypropionate; 3o ()-ethyl-3-14-(3-(7-fluoro-3,4-dihydro-2H-benzo|8111,Zoxazin-4-yl) )ipropylamino)-phenyl|-2-ethoxypropionate; - (-)-ethyl-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoyl| 51/11, Coxazin-4-yl)propylamino )-phenyl)|-2-ethoxypropionate; (-3-ethyl-3-14-13-(7-fluoro-3,4-dihydro-2 H-benzos 81/11, Coxazin-4-yl)/propylamino)-phenyl|-2-methoxypropionate; ()-ethyl-3-14-(3-(7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)/propylamino)-phenyl|-2-methoxypropionate; " ( -)-ethyl-3-14-13-(7-fluoro-3,4-dihydro-2H-benzoyl(1,Zoxazin-4-yl)/propylamino)-phenyl|-2-methoxypropionate; C 50 ( --3-I4-43-77-fluoro-3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)upropylamino)phenyl|-2-methoxypropionic acid or Its salts; ; with" ( 1)-3-I4-73-177-fluoro-3,4-dihydro-2H-benzoic acid or its salts; (-3-3-I4-43-77-fluoro-3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)ipropylamino)phenyl|-2-methoxypropionic acid or its salts; -i (i (ee) )-ethyl-3-(4-(3--2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl)-1/1, Doxazin-4-yl)-propylamino )phenyl|-2-ethoxypropionate; sl (h)-ethyl-3-I4-3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl|81/1,Doxazin-4-yl)-propylamino)phenyl|-2- ethoxypropionate; ko 20 (-)-ethyl-3-I(4-43-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)-propylamino)phenyl) |-2-ethoxypro "z pionate; (3-3-I4-3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl| 81/11, Coxazin-4-yl)propylamino)- phenyl)|-2-ethoxypropionic 5 acid or its salts; (1)-3-I4-13-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|51/1,Zoxazin-4- yl)propylamino)-phenyl)|-2-ethoxypropiono

HF) acid or its salts;

He (-)-3-I4--3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)-phenyl|-2- ethoxypropionic acid or its salts; in (--ethyl-3-I4-13-(2-methyl-3,4-dihydro-2H-benzo|81(11,Zoxazin-4-yl)/propylamino)-phenyl|-2-ethoxypropionate; () -ethyl-3-I4-3-(2-methyl-3,4-dihydro-2H-benzoyl|b51I(/1,4Zoxazin-4-yl)upropylamino)-phenyl 1|-2-ethoxypropionate; (-)- ethyl 3-I4-13-(2-methyl-3,4-dihydro-2H-benzo|81(11,Zoxazin-4-yl)/propylamino)-phenyl|-2-ethoxypropionate; (-3-3- I4-43-(2-methyl-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)phenyl)|-2-ethoxypropionic acid or its salts; 65 (1)-3 -I4-73-(2-methyl-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)propylamino)phenyl|-2-ethoxypropionic acid or its salts;

(-)-3-I4-43-(2-methyl-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)phenyl)|-2-ethoxypropionic acid or its salts; (-)-ethyl-3-I4-13-(2-methyl-3,4-dihydro-2H-benzo[1/1,Zoxazin-4-yl)/propylamino)-phenyl)|-2-methoxypropionate; ()-ethyl-3-14-3-(2-methyl-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)-phenyl|-2-methoxypropionate; (-)-ethyl-3-I4-13-(2-methyl-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)/propylamino)-phenyl|-2-methoxypropionate; (--3-I4-43-(2-methyl-3,4-dihydro-2H-benzoyl|51/11,Doxazin-4-yl)/propylamino)phenyl)|-2-methoxypropionic acid or its salts; (1)-3-I4-13-(2-methyl-3,4-dihydro-2H-benzo[(1,Zoxazin-4-yl)/propylamino)phenyl]-2-methoxypropionic acid or its salts; (-)-3-I4-43-(2-methyl-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid or its salts; (--ethyl-3|4-(3-(2-propyl-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)-phenyl|-2-ethoxypropionate; (i )-ethyl-3.14-13-(2-propyl-3,4-dihydro-2H-benzoyl|β1/1,oxazin-4-yl)upropylamino)-phenyl|-2-ethoxypropionate; (-)-ethyl -3-(4-3-(2-propyl-3,4-dihydro-2H-benzo|b1(/1,Zoxazin-4-yl)upropylamino)-phenyl)|-2-ethoxypropionate; (--3- I4-43-(2-propyl-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)phenyl)|-2-ethoxypropionic acid or its salts; (1)-3- I4-13-(2-propyl-3,4-dihydro-2H-benzoyl|b1(1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic acid or its salts; (-3-3-I4 -43-(2-propyl-3,4-dihydro-2H-benzoyl|51(1,Zoxazin-4-yl)/propylamino)phenyl)|-2-ethoxypropionic acid or its salts; ( )-ethyl-(25 )-3-I4-13-(2-propyl-3,4-dipdro-2H-benzoyl|in(1,Zoxazin-4-yl)-propylamino)phenyl|-2-methoxypropionate; (t)-ethyl-( 25)-3-I4-3-(2-propyl-3,4-dihydro-2H-benzoyl 5111,Zoxazin-4-yl)-propylamino)phenyl 2-methoxypropionate; o (-)-ethyl-(25)-3-I4-13-(2-propyl-3,4-dihydro-2H-benzoyl|5)(11,Zoxazin-4-yl)-propylamino)phenyl)|- 2-methoxyprop ionate; (--3-I4-43-(2-propyl-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid and its salts; c ( 1) 3-3-I4-73-(2-propyl-3,4-dihydro-2H-benzoyl-1(1,Zoxazin-4-yl)/propylamino)phenyl-2-methoxypropionic acid and its salts; (-)-3-I4-43-(2-propyl-3,4-dihydro-2H-benzoic acid and its salts); co (i

Zo )-ethyl-2-isopropoxy-3-I4-(3-(7-fluoro-3,4-dihydro-2H-benzo|5I(1,Zoxazin-4-yl)-propylamino)phenyl|propionate; - ( t)-ethyl-2-isopropoxy-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzo|(81/1,Zoxazin-4-yl)-propylamino)phenyl|propionate; ( -)-ethyl-2-isopropoxy-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoyl|1/1, Zoxazin-4-yl)-propylamino)phenyl|propionate; (--2-isopropoxy-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)-propylamino|phenyl|Ipropionic acid and its salts; no) with (1)-2-isopropoxy-3-I4-73-(7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)-propylamino|phenyl|propionov : » acid and its salts; (-)-2-isopropoxy-3-(4-73-(7-fluoro-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)-propylamino|phenyl| propionic acid and its salts; propylamino)phenyl|-2-methoxypropionate; (ee) ()-ethyl-3-I4-3-(-2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl| 1/1, Zoxazin-4 -yl)-propylamino)phenyl|-2-methoxypropionate; o (-)-ethyl-3-I4-13-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|81/1, Zoxazin-4-yl)-propylamino)phenyl|-2-methoxyprop 250 opionate;

Kz (3-3-I4-3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl)-1(1,Zoxazin-4-yl)/propylamino)-phenyl|-2-methoxypropion acid and its salts; (1)-3-I4-73-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)propylamino)-phenyl)| -2-methoxypropionic acid and its salts;

HF) (-)-3-I4-43-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)-phenyl|-2- methoxypropion 7 ovo acid and its salts;

I25,M(1K)1-M-(2-hydroxy-1-phentethyl)-2-ethoxy-3-I4-3-(3,4-dipdro-2H-benzo|b1(1,Zoxazin-4-yl )propylamino)phenyl|propanamide; 60 I2A,MI1kK)I-M-(2-hydroxy-1-phentethyl)-2-ethoxy-3-I4-13-(3,4-dipdro-2H-benzoyl|81/1,Doxazin-4-yl) propylamino)phenylpropanamide; (25,M(1K)1-M-(2-hydroxy-1-phentethyl)-2-ethoxy-3-I4-3-(7-fluoro-3,4-dipdro-2H-benzo|c)/1 ,Zoxazin-4-yl)propilamino)phenyl|propanamide;

И2,МИ1кК)И-М-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-(4-13-(7-fluoro-3,4-dihydro-2H-benzoyl) | 81/11, Zoxazin- 4-yl)propanolamino)phenyl|propanamide;

(25,M(1K)1-M-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-I4-13-(3,4-dihydro-2H-benzoi| 81/11, Zoxazin-4- yl)propylamino)phenyl|propanamide hydrochloride salt;

I2,MY1K)I-M-(2-hydroxy-1-phentethyl)-2-ethoxy-3-14-13-(3,4-dihydro-2H-benzoyl|5111,Zoxazin-4-yl)propylamine o)phenyl|Ipropanamide hydrochloride salt.

According to another version of the embodiment of this invention, the compound of the general formula (I), in which B? and KU together denote a bond; U denotes oxygen or sulfur, and MU denotes ME 72, -O-aryl-(СВ ОВ 17) 5-МВ 2-; and all other symbols have the values indicated above, can be obtained in one or more ways shown in

Schemes and below. 70 i v , v y ХА Кк хи му е педа ty and 1 t mm Е A no Кк Нд

PT x ; « but (Pe) | in vo z vovk Od Ko nivy in ni nan ' TIvaH ov! (ntv, ok z I Path 2 i x/i v dya "Z Ku ma nen Z ik v, "

Kv ov'

Way C 1

She gu s

SH ts rus ev aso vyh. at

And I oh t peace, t

Kk Cannes school

Scheme | . high school

Path (1): The reaction of a compound of the general formula (Xa), in which Y represents a leaving group such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, cosulfate, phosphate, hydroxyl, etc. p., and all other symbols have the values indicated above, with the compound of the formula (ШБ), in which МУ denotes МВ 72, -О-aryl-(СВ'ОВ171)5-МА 72-; and all other symbols have the values indicated above, with. the formation of a compound of the general formula (I), where all symbols have the above meanings, can be carried out in the presence of a base, such as metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, etc.; bicarbonates of metals, for example, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, etc.; metal hydrides, for example, MaN or KN; metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, etc.; alkoxides, such as MaOMe, MaovBi, K'VyO, etc.; organic non)c bases, such as guanidine, triethylamine, pyridine, M-methylmorpholine, etc., or their mixtures. The reaction can be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, OME, toluene, benzene, acetone, dimethylacetamide, acetonitrile, etc. or their mixtures. Phase transfer catalysts such as tetraalkylammonium halides or hydroxides may be used. The reaction temperature can be in the -15 range from 09C to 1502C, preferably in the range from 109C to 1202C. If And! denotes a hydroxyl group, then the reaction can also be carried out under Miizipora conditions using such reagents as OEAU, OIAO, etc. (ee) The compound of the formula (Ха) was obtained by reacting the compound of the formula (IMc) і 1 t (Мо) 7 С жех и че) і where all the symbols have the values indicated above, with the compound of the formula (Ма) (Ф) Penn guilty (Ma) ime) where I" and all other symbols have the above values. in Path (2): Reaction of a compound of the general formula (Ps), in which all symbols have the above values, with a compound of the general formula (Pa), in in which I!' represents a leaving group such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate, hydroxyl, etc., and all other symbols have the above meanings, with the formation of the compound of the general formula (I), in which all the symbols have the above meanings, can be carried out in the presence of a base, such as metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, etc.; metal bicarbonates, for example, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, etc.; metal hydrides, for example, Man chi

KN; metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, etc.; alkoxides, such as MaOMe, MaObI, KVa, etc.; organic bases, such as guanidine, triethylamine, pyridine, M-methylmorpholine, etc., or their mixtures. The reaction can be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, OME, toluene, benzene, acetone, dimethylacetamide, acetonitrile, etc. or their mixtures. A phase transfer catalyst such as tetraalkylammonium halides or hydroxides may be used. The reaction temperature can be in the range from 092C to 15023, preferably in the range from 102C to 1002C. If I" denotes a hydroxyl group, then the reaction can also be carried out under Miizipoba conditions using such reagents as OEAU, OIAO, etc.

Path (3): Reaction of a compound of the general formula (Xe), in which all symbols have the values indicated above, with a compound of the formula (IC, in which K 3 denotes a (C,i-Cv)-alkyl group, and all other symbols have the indicated above value, to form a compound of the general formula (I) where EC 9? and K 9U together denote a bond and all other symbols have the above values, can be carried out in the presence of a base such as a metal hydride, for example Mann or KH ; organolithium reagents, such as CH zii Viiii, etc.; alkoxides, such as MaOMe, 79 MaO, K"vyo: and the like, or their mixtures. The reaction can be carried out in the presence of solvents, such as diethyl ether, THF , dioxane, DMF, DMSO, OME, dimethylacetamide, etc., or their mixtures. NMRA can be used as a co-solvent. The reaction temperature can be in the range from -782C to 502C, preferably in the temperature range from -109C to 309C. Reaction proceeds more efficiently under anhydrous conditions.The compound of general formula (PI) can be prepared according to the procedure , (described in the literature (Appaiep. Spetie, (1996) 53, 699) |.

In accordance with another version of the embodiment of this invention, the compound of the general formula (I), in which B? denotes a hydrogen atom, a hydroxyl group, an alkoxy group, a halogen, an alkyl, a substituted or unsubstituted aralkyl group; C represents hydrogen, a hydroxyl group, an alkoxy group, a halogen, an alkyl group, acyl, substituted or unsubstituted aralkyl; M denotes oxygen and MU denotes ME "2, -O-aryl-(СВ 9877) -МВ 72-; and all other symbols have the above meanings, may be obtained according to one or more processes depicted in

Schemes of AI are below. 1 ki e - ev rslsV i ket ud sch cia: o sch (la)

IS)

Path 4 1

U v ky yaz dO (ee)

Kk fcheklyulyacheyatya lyut y

GU x TV

Noya " r t 4 ' x/i shi s Ge Zv div znah - yad som pu :z» tk Shchy sk poi -1 schi Scheme |! so Path (4): Recovery of the compound of the formula (Ma), which is a compound of the formula ( I), in which B 3 and K 9 denote a bond, Y denotes an oxygen atom, and all other symbols have the above meanings, obtained as described above in Scheme I, with the formation of a compound of the general formula (I), in which each with B? and KU represents a hydrogen atom and all of the 50 symbols have the above values, can be carried out in the presence of hydrogen gas and a catalyst such as Ra/C, KP/C, RUS, Raney nickel, etc. Can be used mixture of catalysts.The reaction can o) also be carried out in the presence of solvents such as dioxane, acetic acid, ethyl acetate, methanol, ethanol, isopropanol, etc. A pressure in the range from atmospheric pressure to 0.55 MPa can be used (8 Orzvi).

High pressure can be used to reduce reaction time. The catalyst can be, better, 5-1090

Ppa/C, and the amount of catalyst used can be in the range of 1-5095 wt./wt. The reaction can also

Gee! be carried out by reduction in a solvent with a metal such as magnesium, samarium in alcohol, or sodium amalgam in alcohol, preferably methanol. Hydrogenation can be carried out in the presence of metal catalysts containing chiral ligands to obtain the compound of formula (I) in an optically active form. The metal catalyst can contain rhodium, ruthenium, indium, etc. Chiral ligands may preferably be chiral phosphines such as (25,35)-bisidiphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphosphino)ethane, (-)-2 ,3-isopropylidene-2,3-dihydroxy-1,4-bis(idiphenylphosphino)butane, etc. Any suitable chiral catalysts that provide the desired optical purity of product (I) can be used.

Path (5): The reaction of a compound of the general formula (Xe), in which Y' denotes a leaving group such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate, hydroxyl group, etc. p., and all other symbols have the values indicated above, with the compound of the formula (IM), in which B is hydrogen and all other symbols have the values indicated above, with the formation of a compound of the general formula (I), in which B? and BE? denote a hydrogen atom, and all other symbols have the above meanings, can be carried out in the presence of a base, such as a metal hydride, for example, MaH or KH; organolithium reagents, such as SNU, HIMZh(IRg)", GINMO5, ПИМЗХСХ(ЕХО", MPaNMO5, KNMO5, Vyp, etc.; alkoxides, such as MaOMe, Maoevy, Y-VIOK "7, etc., or mixtures thereof.The reaction may be carried out in the presence of solvents such as diethyl ether, THF, dioxane, DMF, DMSO, OME, dimethylacetamide, etc. or mixtures thereof.

NMRA can be used as a co-solvent. The reaction temperature can be in the range from -782C to 502C, better, in the range from -102C to 302C. The reaction is more efficient in anhydrous conditions.

In accordance with another version of the embodiment of this invention, the compound of the general formula (I), in which U denotes oxygen or sulfur, and MU denotes -С(-0)-(СВ 98 7735-МВ 2-), where o denotes an integer in the interval 0-6 and all other symbols have the values indicated above, can be obtained in a way that includes carrying out the reaction of the compound of the formula (Ша) т5 вх и с (not)

In the same subject matter, "(svv vil ch 4 nk de Y" denotes a leaving group, such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate, hydroxyl, etc., and all others symbols have the above meanings, with the compound of the formula (PV) in two (c) s schiniv points See o od? where M stands for MA "2, VK"? denotes hydrogen and all other symbols have the above meanings, in the presence of a base , such as metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, etc.; metal bicarbonates, for example, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, etc.; metal hydrides, for example, ManH or KN; metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.; alkoxides, such as MaOMe, MaOBBi, K'Vio", etc.; organic bases, such as guanidine, so triethylamine, pyridine, M-methylmorpholine, etc., or mixtures thereof. The reaction can be carried out in the presence of solvents such as THF, d ioxane, DMF, DMSO, OME, toluene, benzene, acetone, dimethylacetamide, acetonitrile, etc. or their mixtures. A phase transfer catalyst such as tetraalkylammonium halides or hydroxides may be used. The reaction temperature can be in the range from 09 to 1502С, better, in the range from 102 to 1202С. If I" denotes a hydroxyl group, then the reaction can also be carried out under the conditions of Miizipora using such reagents as OEAO, OIAO, etc.

In accordance with yet another version of the embodiment of this invention, the compound of the general formula (I), in which U c)c denotes oxygen and M/ denotes -O-aryl-(СК "9 77).-МА 72-; and all other symbols have the above values,

Iz" can be obtained in a way that includes carrying out the reaction of the compound of formula (II) in! d? (iii si y t» - KE Z ioveto- Dema! v? mia 4 (o) no B 1 no . I I 1 kn, in which n and r are integers in the interval of values 0-6, b denotes МН» or formyl, and all other symbols have the values indicated above, with the compound of the formula (PA) except (P) where d denotes an integer in the range of values 0-6, 52 denotes MNO or formyl, and all other symbols have the values indicated above, using solvents such as CH2Cl3, CHCl3, chlorobenzene, benzene, THF, in the presence of a catalyst such as p-toluenesulfonic acid, methanesulfonic acid, TPA, PON, in BEZ3-OBB and etc. The reaction can also be carried out using activated molecular sieves.

The reaction temperature can be in the range from 102C to 1002C, preferably in the range from 109 to 6020.

The initially obtained imine product can be restored using MassM)VvnH 3-HCII (|see: Ni(spiv,

K. Oh, ei ai.,, 9. Ogu. Spet., 1983, moiI.48, 3433-3428), No-Ra/S, No-RYS, No-RB/S, etc. in solvents such as methanol, ethanol, etc. 65 A compound of formula (I), in which K ZU represents a hydrogen atom, can be obtained by hydrolysis, using conventional methods, of a compound of formula (I), in which B Z represents all the groups defined above, except for hydrogen. Hydrolysis can be carried out in the presence of a base such as Ma 2 CO 3 and a suitable solvent such as methanol, ethanol, and the like. or their mixtures. The reaction can be carried out at a temperature in the range of 2020-402C, preferably at 2590-3020. The reaction time can be from 2 to 12 hours, preferably from 4 to 8 hours.

A compound of the general formula (I), in which U represents oxygen, and KZ represents hydrogen or a lower alkyl group, can be converted into a compound of formula (I), in which M represents ME U, by reaction with the corresponding amines of the formula МНЕЗВУ, where KZ and KU? have the above values to form a compound of formula (I) in which U is ME" and all other symbols have the above values. Alternatively, a compound of formula (1) in which UZ is OH can be converted into a halide acids, preferably Uuv8-CI, by reacting with appropriate reagents, such as oxalyl chloride, thionyl chloride, etc., followed by treatment with amines of the formula MNE", where KZ and E? have the above values. According to another option, from the compound of formula (I), in which UZ represents OH and all other symbols have the above values, mixed anhydrides can also be obtained by treatment with acid halides, such as acetyl chloride, acetyl bromide, pivaloyl chloride, 75 dichlorobenzoyl chloride, etc. The reaction can be carried out in the presence of a suitable base such as pyridine, uc triethylamine, diisopropylethylamine, etc. Solvents such as halogenated hydrocarbons, e.g., CHCl3 or CHOCl, hydrocarbons such as benzene, toluene, xylene, etc. may be used. the reaction can be carried out at a temperature in the range from -402C to 402C, better, at a temperature in the range from 02C to 2020. The acid halide anhydride or mixed anhydride obtained in this way can be further treated with the corresponding amines of the formula MNEAZE?U, where KZ and K? have the values indicated above, to form a compound of formula (I) in which U represents ME and all other symbols have the values indicated above.

Another version of the implementation of this invention provides for new intermediate compounds of the formula (name) o (c) s niv pyati ude o) od? their derivatives, their analogues, their tautomeric forms, their stereoisomers, their salts, their solvates, where MU denotes

MA2, B? denotes hydrogen, ВО and Б"! can be the same or different and denote hydrogen or a substituted sc or unsubstituted group selected from an alkyl, alkyl, aryl or aralkyl group; Ag denotes a substituted CM or an unsubstituted divalent monocyclic or condensed aromatic or heterocyclic group; B ? denotes a hydrogen atom, a hydroxyl group, an oxy group, a halogen, an alkyl, a substituted or unsubstituted aralkyl group, or forms a bond together with an adjacent group K 9; 29 denotes a hydrogen, a hydroxyl group, an oxy group, co

335 is halogen, a lower alkyl group, acyl, substituted or unsubstituted aralkyl, or C forms a bond together with 5; IN! i- can be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, monovalent heterocyclic, heteroaryl, heteroaralkyl groups; KZ "can be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, monovalent heterocyclic, heteroaryl or heteroaralkyl groups; M denotes oxygen, sulfur or MA"Z, where KZ denotes hydrogen or substituted or unsubstituted groups selected from alkyl, caryl, hydroxyalkyl, aralkyl, monovalent heterocyclic, heteroaryl or heteroaralkyl -" group; EZ and EZ together can form a substituted or unsubstituted 5- or b-lene cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; t and n are integers in the interval 0-6. -i New intermediate compounds of the formula (NAME), in which t is 0, and all other symbols have the values indicated above, can be obtained by reduction of the compound of the formula (III)) 1 (r mo visk oon sya

Co) where B", 28 and Ag have the above values, in the presence of hydrogen gas and a catalyst such as

Ra/S, Kp/S, RUS, Raney nickel, etc. Mixtures of catalysts may be used. The reaction can also be carried out in the presence of solvents such as dioxane, acetic acid, ethyl acetate, and the like. May be

GF! used pressure from atmospheric pressure to 0.55 MPa (8 Orzi). The catalyst can be, preferably, 5-1095 Ra/C, and the amount of catalyst used can be 1-5095 wt/wt. The reaction can also be carried out by reduction in a solvent with a metal such as magnesium, ferrum, tin, samarium in alcohol, or sodium amalgam in alcohol, preferably methanol. The hydrogenation can be carried out in the presence of metal catalysts containing 60 chiral ligands to obtain the compound of formula (I) in an optically active form. The metal catalyst can contain rhodium, ruthenium, indium, etc. Chiral ligands may preferably be chiral phosphines such as (25,35)-bisidiphenylphosphino)butane, 1,2-bisidiphenylphosphino)ethane, /1,2-bis(2-methoxyphenylphenylphosphino)ethane, (-)-2,3 -isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, etc. See: Rgipsiriev Ge)

Azuttegiszupipevziv, Tei. Ogd. Spent Zegiyev, Moi/.14, pp. 311-316, Ea. Vaidmip 9. E.). because the compound of the formula (II) can be obtained by carrying out the reaction of the compound of the formula (Sh)

Dimnelsno (Sht) where Ag has the values indicated above, with the compound of the formula (PK) poho. eRIOHOV t" (i.e

Rai de KZ denotes a (C.-Cv)-alkyl group, and all other symbols have the values indicated above, in the presence 70 of a base such as a metal hydride, for example, MaH or KH; organolithium reagents, such as CH ions, etc.; alkoxides, such as MaOMe, Maobi, y-BVyO Kk" and top. or their mixtures. The reaction can be carried out in the presence of solvents such as diethyl ether, THF, dioxane, DMF, DMSO, OME, dimethylacetamide, etc. or of their mixtures. NMPA can be used as a co-solvent. The reaction temperature can be in the range from -782C to 509C, preferably in the range from -109C to 302. The reaction proceeds more efficiently under anhydrous conditions. The compound of the general formula (GEN) can be obtained according to the procedure (described in the literature (Appaiep. Spetieee, (1996) 53, 699)).

According to yet another embodiment of the present invention, the compound of the formula (PIB), in which t is 0 and all other symbols have the values indicated above, can be obtained by diazotizing the compound of the formula (PC) to the compound of the formula (II) and reducing the compound of the formula ( AI) with the formation of a compound of the formula (PPB). The reaction is depicted in Scheme III below: di 11 Ya ve oihsvtk A ura s; day A heard

Inni and 7

MN" chiv si

Ku oh! in vo z chan svv A, le sia s ok (v, yu p

Scheme I!

Dianitrogenation of a compound of the formula (PC) to form a compound of the formula (SI) can be carried out using a dianitrogen agent such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite, etc. under acidic conditions using an acid such as sulfuric acid, HCl, acetic acid, etc., in an organic solvent such as alcohols, for example, methanol, ethanol, propanol, etc.; 1,4-dioxane, THF, acetone, etc. " z The residue is esterified with alkyl sulfates such as diethyl sulfate, dimethyl sulfate, etc., or 7 alkyl halides, such as ethyl iodide, methyl iodide, etc., in solvents such as hydrocarbons, for example, with toluene, benzene, etc. or DMF, DMSO, acetonitrile, THF, methyl isobutyl ketone (MIBK), etc., in the presence of alkaline bases, such as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride, potassium hydride, etc.

The reduction of the compound of the formula (II) to the compound of the general formula (PIB) can be carried out in the presence of gaseous hydrogen and a catalyst such as Ra/C, KA/C, RUS, Raney nickel, etc. There may be 75 catalyst mixtures used. The reaction can also be carried out in the presence of solvents such as dioxane, acetic acid, ethyl acetate, etc. Pressure from atmospheric pressure to 0.55 MPa (ee) (8 Org) can be used. The catalyst can be, preferably, 5-1095 Ra/C, and the amount of catalyst used can be 1-5095 wt/wt. The reaction can also be carried out by reduction in a solvent with a metal such as magnesium, iron, tin, samarium in alcohol, or sodium amalgam in alcohol, preferably methanol. Hydrogenation can be carried out in the presence of metal catalysts containing chiral ligands to obtain the compound of formula (I) in an optically active form. The metal catalyst can contain rhodium, ruthenium, indium, etc. Chiral iz ligands may preferably be chiral phosphines such as (25,35)-bisb(idiphenylphosphino)butane, 1,2-bisidiphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane, (-)-2 ,3-isopropylidene-2,3-dihydroxy-1,4-bisidiphenylphosphino)butane and top. |miracle: Rgipsiriev oi Avutteiis 59 zZupipevziv, Tei. Ogd. Spent Zegiev, Moi.14, pp. 311-316, Ea. Vaidmzh/ip 9. E |.

GF) According to yet another embodiment of this invention, the compound of the formula (PPB), in which t is 1-6, and all other t symbols have the values indicated above, can be obtained in the manner shown in Scheme IM below: 60 b5 total. URIYUNOVS by tour From the east and ASSO

OK, it's 5 o'clock

SNO (Svv tA so di yu ( zt Shu 2 pnia zjetvst oo sv! ---- 5 8 , aku) ok o lei l-kn,;

Pe

Ve de di Mk: Z

Ts I chni ba! more

Scheme

The reaction of a compound of the general formula (I), defined above, with a compound of the formula (Pp) to form a compound of the formula (Sho) can be carried out in the presence of a base, such as a metal hydride, for example, Man or Sch

KN; organolithium reagents, such as SNuzi and Vigi, etc.; alkoxides, such as MaOMe, Maoeii, EVIO K" and the like, or their mixtures. The reaction can be carried out in the presence of solvents such as diethyl ether, THF, dioxane, DMF,

DMSO, OMV, dimethylacetamide, etc. or their mixtures. NMRA can be used as a co-solvent.

The reaction temperature can be in the range from -782C to 502C, preferably in the range from -102C; to 3090. сч зо Reduction of the compound of the formula (Sho) with the formation of the compound of the formula (Pr) can be carried out in the presence of gaseous hydrogen and a catalyst such as Ra/C, KpP/C, RUS, Raney nickel, etc. A mixture of catalysts can be used. The reaction can also be carried out in the presence of solvents such as dioxane, acetic acid, ethyl acetate, etc. Pressure from atmospheric pressure to 0.55 MPa (8 Orzvi) can be used.

The catalyst can be, preferably, 5-1095 Pa/C, and the amount of the used catalyst can be 1-5090 sow/wt. The reaction can also be carried out by reduction in a solvent with a metal such as magnesium, iron, tin, samarium in alcohol, or sodium amalgam in alcohol, preferably methanol. The hydrogenation can be carried out in the presence of metal catalysts containing chiral ligands to obtain the compound of formula (I) in an optically active form. The metal catalyst may contain rhodium, ruthenium, indium, etc. Chiral ligands may preferably be chiral phosphines, such as (25,35)-bisb(idiphenylphosphino)butane, "1,2-bisidiphenylphosphino)ethane, 1,2- bis(2-methoxyphenylphenylphosphino)ethane, 2s (-)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, etc.

The reaction of a compound of the general formula (Pr) with a compound of the formula (IPSa) can be carried out using: 3" solvents, such as CH 2 Si", CHCl 3, chlorobenzene, benzene, THF, in the presence of a catalyst, such as p-toluenesulfonic acid, methanesulfonic acid , TRA, TON, ВЕ5-ОЕБ, etc. The reaction can also be carried out using activated molecular sieves. The reaction temperature can be in the range -I from 109 to 1002C, better, in the range from 109 to 602C. The initially obtained imine product can be regenerated using Massm) VNU-NSI | see: Niispipv, K.O. oh oh 9). Ogud Spet., 1983, mo!. 48, 3433-3428), so No-Ra/sS, no-RUS, No-RY/S, etc. in solvents such as methanol, ethanol, etc. According to yet another version of the embodiment of this invention, the compound of the formula (PIB), in which t is 0 or 1, and all 5 or other symbols have the values indicated above, can be obtained by diazotizing the compound of the formula (PC) to the compound of the formula (Ma ), decomposition of the compound of formula (Ma) to the compound of formula (I) in the presence of alcohol, such

IZ as KOH, and reduction of the compound of the formula (PI) to form the compound of the formula (PPB). The reaction sequence is shown in scheme M below:

F) name) 60 b5 vi ao o oil I, -penez oo I At 7" e

In Zh

M tsk) che n (mah o v to oS ov itlye t ud ttn ned МY, ; da ; Uk (now o (y) iz Scheme m

Dianitrogenation of a compound of formula (ShK), in which t is 0, K9 is hydrogen, and all other symbols have the above values, to give a compound of formula (Ma) can be carried out using a dianitrogen agent such as sodium nitrite, isoamyl nitrite, nitrite potassium, ammonium nitrite, etc., in the presence of a catalytic amount of a carboxylic acid, such as acetic acid, propionic acid, etc., in a suitable solvent, such as chloroform, chlorobenzene, dichloroethane, etc. or their mixture, at a temperature in the range from room temperature to the reflux temperature of the used solvent, for a period of time from 0.5 to 16 hours.

Decomposition of an arylalkyldiazoacetate of formula (Ma) to form a compound of formula (I) where K/ has the above values except for hydrogen and all other symbols have the above values can be promoted with a suitable catalyst such as CP(II) acetate ), rural complex Si) or KN) etc., (Vio.. Oga. i)

Honey. Spent Ieiyi, 1996, 2121-2126) in the presence of alcohol of the formula B'OH.

The reduction of the compound of the formula (I) with the formation of the compound of the general formula (PSB), in which all the symbols have the above meanings, can be carried out in the presence of gaseous hydrogen and a catalyst such as Ra/C, CP/C, РУС, Raney nickel etc. Mixtures of catalysts may be used. The reaction can also be carried out in the presence of solvents such as dioxane, acetic acid, ethyl acetate, and the like. Pressure from atmospheric pressure to 0.55 MPa (8 Org) can be used. The catalyst can be, preferably, 5-1095 RA/C, but the amount of the used catalyst can be 1-5095 wt/wt. The reaction can also be carried out by reduction in a solvent with a metal such as magnesium, iron, tin, samarium in alcohol, or sodium amalgam in alcohol, preferably methanol. Hydrogenation can also be carried out using ammonium formate, a hydrogen donor of the cyclohexa-1,4-diene type, under conditions favorable for the use of Ra/C, using solvents such as methanol, ethanol, ethyl acetate, etc.

According to yet another embodiment of the present invention, the compound of the formula (NAME) in its enantiomerically pure form, where "t is 0, v-vo -H, and all other symbols have the values indicated above, can be obtained in the manner depicted in Scheme MI below: - - 132 I two 1 and to z sya" ma, in vv vk , cha che ma ma" -I bo pi satana IYA, 1 cht Ue-- a" mu 0 Ge,

Co.).

KO of the village zhu is o -ioveyatsy and, no chev'edty HER, 7 ag 7 cha o o

HF) Huk) pl z Scheme MI in Dianitrogenation of a compound of formula (Mia), in which all symbols have the above meanings, to form a compound of formula (MIB) can be carried out using a dianitrogen agent such as sodium nitrite, isoamyl nitrite, potassium nitrite , ammonium nitrite, etc., in the presence of aqueous acid using acids such as sulfuric acid, HCl, acetic acid, etc., in an organic solvent such as alcohols, for example, methanol, ethanol, propanol, etc. n.; 1,4-dioxane, THF, acetone, etc. 65 The one-pot esterification and esterification of a compound of the general formula (MIB) to a compound of the general formula (Mis) can be carried out by first deprotonation (MIbB) using a suitable base such as Man, KH, KOH, etc., in a suitable a solvent such as toluene, benzene, diethyl ether, THF, DMF, OME, NMRA, etc., followed by treatment with an alkyl halide such as ethyl iodide or methyl iodide, etc. Other alkylating agents can also be used, such as EG3O"BE,;, MezO BP, dialkyl sulfate. The reaction temperature can vary from 02 to 10096.

Nitration of a compound of the formula (Mis) to a compound of the formula (Mid) in which n is 0 and all other symbols have the values indicated above can be carried out using nitrating agents such as fuming nitric acid, MoOb, a mixture of conc. nitric acid and concentrated sulfuric acid or a mixture of nitric acid and acetic anhydride in the presence of a solvent or in an undiluted state at a temperature in the range from -10907 to room temperature for a period of time from 0.5 to 4 hours. Idiv.: Wow. Have a drink Soy My!.1, 3961.

The reduction of the compound of the formula (MIi) to the compound of the formula (PSHB) can be carried out in the presence of hydrogen gas or hydrogen donors such as ammonium formate, cyclohexa-1,4-diene, etc., and a catalyst such as Ra/C, KpP/S, RUS, Raney nickel, etc. Mixtures of catalysts in the presence of solvents such as methanol, ethanol, dioxane, acetic acid, ethyl acetate, etc. may be used. Can be 72 used pressure from atmospheric pressure to 0.55 MPa (8 Orgi). The catalyst can be, preferably, 5-1095 Ra/C, and the amount of catalyst used can be 1-5095 wt/wt. Alternatively, the reaction may also be carried out by reduction in a solvent with a metal such as magnesium, iron, tin, samarium, indium, sodium amalgam, in an alcohol or other suitable solvent, preferably methanol.

According to yet another embodiment of the present invention, the compound of the formula (NAME) in its enantiomerically pure form, where t is 0, vO-v9-H, and all other symbols have the values indicated above, can be prepared in the manner depicted in Scheme MY below : viko v a - vody" p We WE v shov ucha udvyanta. ОДИСВВt кт сч t cha slov niya in o sloviv) to y U oven ri syu schi s

Ge yuyu pe vo I neo so one syu dnly Kui j ng v'ovtutn A unya - y va von

Cb) "gla, I - c Scheme MI:z" Dianitrogenation of a compound of the formula (MiIa), in which all symbols have the above values, to form a compound of the formula (MB) can be carried out using dianitrogenation agents, such as sodium nitrite, isoamyl nitrite , potassium nitrite, ammonium nitrite, etc. in the presence of aqueous acid using such acids as sulfuric acid, hydrochloric acid, acetic acid, etc., optionally, in the presence of a cosolvent such as alcohols, for example, methanol, ethanol, propanol, etc. ; or ethers, for example, (ee) 1,4-dioxane, THF, etc.; or ketones, for example, acetone, methyl ethyl ketone, etc. sl Esterification of the compound of the formula (MIV) to the compound of the formula (Mis) can be carried out using the appropriate alcohol of the formula E8-OH, where KZ denotes lower alkyl groups, such as methyl, ethyl, propyl, co-isopropyl, n-butyl, tert-butyl etc., in the presence of a suitable catalyst such as concentrated sulfuric acid,

GE dry NSI, VE3-OEB, etc. The reaction can be carried out at the reflux temperature of the used alcohol. Alternatively, such reagents as diazomethane or EBO" VE or MezO VE, etc., can also be used for esterification.

Selective O-alkylation of a compound of the formula (Miiis) to a compound of the formula (MIY) can be carried out using alkyl sulfates, such as diethyl sulfate, dimethyl sulfate, etc., or alkyl halides, such as

F, ethyl iodide, methyl iodide, n-propyl iodide, n-propyl bromide, isopropyl iodide, etc., in solvents such as co-hydrocarbons, for example, toluene, benzene, etc. or acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, etc., in the presence of molecular sieves and an alkaline base, such as sodium carbonate, for potassium carbonate, cesium carbonate, sodium methoxide, sodium hydride, potassium hydride, sodium or potassium hydroxide, etc. .p. Heavy metal oxides, such as A920, RBO, NOO, etc., can be particularly useful for alkylation when used as an alkylating reagent of alkyl halides. Phase transfer catalysts such as tetraalkylammonium hydroxide or tetraalkylammonium halides such as tetrabutylammonium chloride, tetrabutylammonium bromide, and the like may also be used. 65 The reduction of a compound of formula (MIZ) to a compound of formula (PIB) can be carried out in the presence of hydrogen gas or hydrogen donors such as ammonium formate, cyclohexa-1,4-diene, etc., and a catalyst such as Ra/C , KpP/S, RUS, Raney nickel, etc. Mixtures of catalysts in the presence of solvents such as methanol, ethanol, dioxane, acetic acid, ethyl acetate, etc. may be used. A pressure in the range from atmospheric pressure to 0.55 MPa (8 Orgi) can be used. The catalyst can be, preferably, 5-1095 Ra/C, and the amount of catalyst used can be 1-5095 wt/wt. Alternatively, the reaction may also be carried out by reduction in a solvent with a metal such as magnesium, iron, tin, samarium, indium, sodium amalgam, in alcohol or other suitable solvents, preferably methanol.

According to yet another embodiment of the present invention, the compound of the formula (NAME) in its enantiomerically pure form, where t is 0.2-9 -H, and all other symbols have the values indicated above, can be obtained by the method 70 shown in Scheme MI ! below: in V dey oon Z stAtnt udav od Yan uri i shn zn na i slu IM') m dao y t to Odessa in --- n-sve ner te "N (mir 97 lu y in V dva lechu sok a gnav VYNIS uko - t - - t ton nan nai sch panv" te) (8)

R da Arka z povo sp --- new tyai Y uv sa to dyan pia schen yiv) iv)

The scheme of the MI of

Dianitrogenation of a compound of the formula (MiIa), in which all symbols have the above values, to form a compound of the formula (MB) can be carried out using dianitrogenation agents such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite, etc. ., in the presence of aqueous acid, using an acid such as sulfuric acid, hydrochloric acid, acetic acid, etc., optionally, in the presence of a co-solvent such as alcohols, for example, methanol, ethanol, propanol, etc. n.; or ethers, for example, 1,4-dioxane, THF, etc.; or ketones, for example, acetone, methyl ethyl ketone, etc. no) c Esterification of the compound of the formula (MIV) to the compound of the formula (Mis) can be carried out using :c» the corresponding alcohol of the formula E8-OH, where KZ denotes lower alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl , tert-butyl, etc., in the presence of a suitable catalyst such as conc. The reaction can be carried out at the reflux temperature of -1 used alcohol. Alternatively, for esterification, reagents such as diazomethane or EBO" VE, or MesO VE, etc. can also be used for esterification. The reduction of the compound of the formula (Mis) to the compound of the formula (MiIMa) can be carried out in the presence of hydrogen gas or hydrogen donors, such as ammonium formate, cyclohexa-1,4-diene, etc., and 5or catalyst, such as Ra/C, KP/C, RUS, Raney nickel, etc. Can be used a mixture of catalysts in the presence of solvents such as methanol, ethanol, dioxane, acetic acid, ethyl acetate, etc. It can be

Ge used pressure from atmospheric pressure to 0.55 MPa (8 Orzi). The catalyst can be, preferably, 5-1095 Ra/C, and the amount of catalyst used can be 1-5090 wt/wt. Alternatively, the reaction may also be carried out by reduction in a solvent with a metal such as magnesium, iron, tin, samarium, indium, sodium amalgam, in an alcohol or other suitable solvent, preferably methanol.

M,M-Dibenzylation of a compound of formula (MSa) to a compound of formula (MIV) can be carried out with (F) using benzyl halides, such as benzyl bromide, benzyl chloride, etc., in solvents such as hydrocarbons, e.g., toluene, benzene etc., or acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, etc., in the presence of an alkaline base such as sodium carbonate, potassium carbonate, sodium or potassium hydroxide, etc. Phase transfer catalysts may also be used , such as tetraalkylammonium hydroxide or tetraalkylammonium halides, for example, tetrabutylammonium chloride, tetrabutylammonium bromide, etc. The reaction can be carried out in the range from room temperature to the reflux temperature of the solvent used.

The hydrolysis of the compound of the formula (MIV) to the compound of the formula (MI) is carried out using an aqueous base of a white alkali metal, such as lithium carbonate, sodium carbonate, potassium carbonate or potassium bicarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide, etc., in suitable co-solvents, such as methanol, ethanol, THF, etc. or their mixtures. The reaction time can be from 0.5 Bh. up to 24 hours, better, from 0O.5 hours to 3-4 hours. and the reaction temperature can range from 09C to 8090C.

One-pot esterification and esterification of a compound of the formula (Mis) to a compound of the formula (Mii), where the VVR-VE can be carried out by treatment with a base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. .p., in solvents such as hydrocarbons, e.g., toluene, benzene, etc., simple dialkyl ethers, e.g., diethyl ether, tetrahydrofuran, etc., or dimethylformamide, NMPA, followed by treatment with alkyl halides, such as ethyl iodide, methyl iodide, n-propyl iodide, n-propyl bromide, isopropyl iodide, etc., or by alkyl sulfates, such as diethyl sulfate, 70 dimethyl sulfate, etc., or by alkylating agents such as E(Z3O"BE,, MezO" VE, etc. The reaction time can be from 2h to 20h, and the reaction temperature can be from 09C to 8090C.

The debenzylation of a compound of formula (MIY) to a compound of formula (PIB) can be carried out in the presence of hydrogen gas or hydrogen donors such as ammonium formate, cyclohexa-1,4-diene, etc., and a catalyst such as Ra/C, KP/S, RUS, Raney nickel, etc. A mixture of catalysts in the presence of solvents such as methanol, ethanol, dioxane, acetic acid, ethyl acetate, etc. may be used. A pressure in the range from atmospheric pressure to 0.55 MPa (8 Orgi) can be used. The catalyst can be, preferably, 5-10965 Pa/cС, and the amount of catalyst used can be 1-5095 wt/wt.

A new intermediate compound of the formula (PIB), in which MU is ME 72 and K72 is hydrogen, which can be used to prepare the compounds of the present invention, and the method of preparation of the intermediate compound (PIB) are described and disclosed in our PCT application under the title "New B-phenyl-A-oxysubstituted propion derivatives: method of their preparation and their use for the preparation of pharmaceutically important compounds", filed on the same day as this application.

According to yet another version of the embodiment of this invention, a new intermediate compound of the formula (Pa) ch 25 pe do (a) o i i svnin dd s zo is envisaged, its derivatives, its analogues, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, in which Y' denotes a leaving group, such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate or a hydroxyl group; MU denotes MA2, -C(50)-(SV 98 11) 5-MV 12, -O-aryl-(SV OB) MV, where B? CO represents hydrogen or a substituted or unsubstituted group selected from an alkyl, aryl or aralkyl group; o 35 denotes an integer in the interval 0-4; В'О and КЕ"! can be the same or different and denote hydrogen or their unsubstituted or substituted group selected from alkyl, alkyl, aryl or aralkyl groups; Ag denotes a substituted or unsubstituted divalent monocyclic or condensed aromatic or heterocyclic group; B? denotes a hydrogen atom, a hydroxyl group, an alkoxy group, a halogen, an alkyl, a substituted or unsubstituted aralkyl " group or forms a bond together with an adjacent K 9 group; KZ denotes a hydrogen, a hydroxyl group, an alkoxy group, a halogen, a lower alkyl group, acyl, " substituted or unsubstituted aralkyl or KE? forms a connection not with together with KR; K/ can be hydrogen or substituted or unsubstituted groups selected from alkyl, :c» cycloalkyl, aryl, aralkyl, alkyloxyalkyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, monovalent heterocyclic, heteroaryl, heteroaralkyl groups; KZ can be hydrogen or substituted or unsubstituted groups selected from - alkyl, cycloalkyl, aryl, aralkyl monovalent heterocyclic, heteroaryl or heteroaralkyl groups; U denotes oxygen, sulfur or ME, where KO denotes hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl aralkyl monovalent c heterocyclic, heteroaryl or heteroaralkyl groups; VZ and B? together they can form a substituted or unsubstituted 5- or b--cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; t and n are integers in the interval

From values 0-6.

According to yet another version of the embodiment of this invention, a new intermediate compound of the formula (Ча) is provided

S hi a (o)

F. ek Ko (svv С b--(сАВ sy t nok 60) its derivatives, its analogues, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, in which K ", B? and KZ, B", if they are attached to a carbon atom, can be the same or different and denote hydrogen, halogen, hydroxyl group, nitro group, cyano group, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy group, cycloalkyl group, aryl, aryloxy group .

aryloxycarbonyl, armethoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aroxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, armethoxycarbonylamino, carboxylic acid or its derivatives or sulfonic acid or its derivatives; wherein one or both of C and B" may represent an oxo group or a thioxo group when attached to a carbon atom; KZ and EC" when attached to a nitrogen atom represent hydrogen, a hydroxyl group, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxyl group, cycloalkoxy group, aryl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, acyl, acyloxy group, hydroxyalkyl, amino group, acylamino group, monoalkylamino group, dialkylamino group, arylamino group, aralkylamino group, aminoalkyl, aryloxy group, heterooxyaryl group, 70 heterooxyaryl group alkoxycarbonyl, aryloxycarbonyl, armethoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aroxyalkyl, alkylthio group, thioalkyl group, carboxylic acid derivatives or sulfonic acid derivatives; X denotes a heteroatom selected from oxygen or sulfur; CO and K"! can be the same or different and represent hydrogen or a substituted or unsubstituted group selected from an alkyl, alkyl, aryl or aralkyl group; Y" represents a leaving group such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzene sulfonate, acetate, sulfate, phosphate or hydroxyl group; H and o are integers in the range 0-6.

According to another version of the embodiment of this invention, a new intermediate compound of the formula (Pi) and d? (ii

Ken ik Be

KE Z ioveto- Dema! in? me and

NA its derivatives, its analogues, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, in which В "7, В? and ВЗ, ВЕ", if they are attached to a carbon atom, He ) can be the same or different and denote hydrogen, halogen, hydroxyl group, nitro group, cyano group, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy group, cycloalkyl group, aryl, aryloxy group, aralkyl, aralkyl group, monovalent heterocyclic radical, heteroaryl, гетероаралкілу, гетероарилоксигрупи, гетероаралкоксигрупи, ацилу, ацилоксигрупи, гідроксіалкілу, аміногрупи, с ациламіногрупи, моноалкіламіногрупи, діалкіламіногрупи, ариламіногрупи, аралкіламіногрупи, алкоксикарбонілу, с арилоксикарбонілу, аралкоксикарбонілу, алкоксіалкілу, арилоксіалкілу, аралкоксіалкілу, алкілтіогрупи, тіоалкілу, алкоксикарбоніламіногрупи, арилоксикарбоніламіногрупи, аралкоксикарбоніламіногрупи, карбонової о acid or its derivatives or p ulfonic acid or its derivatives; and one or both of C and B" can c5 denote an oxo group or a thioxo group, if they are attached to a carbon atom; KZ and B", if they are attached to a nitrogen atom, denote hydrogen, a hydroxyl group, formyl or optionally substituted groups, selected from alkyl, cycloalkyl, alkyl, cycloalkyl, aryl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aryloxy, heteroaryloxy, " heteroaralkyl group, alkoxycarbonyl, aryloxycarbonyl, -o aralkyl, alkoxyalkyl, aryloxyalkyl, aralkyl, alkylthio group, thioalkyl group, carboxylic acid derivatives or sulfonic acid derivatives; X denotes a heteroatom selected from oxygen or ;" sulfur; CO and K"! can be the same or different and denote hydrogen or a substituted or unsubstituted group selected from alkyl, alkyl, aryl or aralkyl groups; 5" denotes CHO or MNO, ptar is,

Integers in the range 0-6. -I It is assumed that in any of the above reactions, any reactive group in the substrate molecule can be protected in accordance with normal chemical practice. Suitable protecting groups in any of the above reactions are tert-butyldimethylsilyl chloride, methoxymethyl chloride, etc. for the protection of os of the hydroxyl group, M-Vos, M-SrB2, M-Ethos, etc. for amino group protection, acetal protection for aldehyde, kketal protection for ketone, etc. Methods for the formation and removal of such protecting groups are conventional and depend on the molecule being protected.

Kz Pharmaceutically acceptable salts are obtained by reacting a compound of formula (I) with 1-4 equivalents of a base, such as sodium hydroxide, sodium methoxide, sodium hydride, potassium hydroxide, potassium t-butoxide, calcium hydroxide, magnesium hydroxide, etc., in solvents such as ether, THF, methanol, tert-butanol, dioxane, isopropanol, ethanol, toluene, etc. Mixtures of solvents may be used. Organic bases such as lysine, arginine, diethanolamine, choline, guanidine, adamantylamine and their iF) derivatives, etc., may also be used. Alternatively, in appropriate cases, acid addition salts are obtained by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid acid, salicylic acid, oxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, etc., in solvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. p. Mixtures of solvents may also be used.

Stereoisomers of the compounds included in the composition of this invention can be obtained by using in the method, if possible, reagents in the form of separate enantiomers, or by carrying out a reaction in the presence of reagents or catalysts in their separate enantiomeric forms, or by separating a mixture of stereoisomers by conventional methods. Some of the better methods include the use of microbial separation,

separation of diastereomeric salts formed, in appropriate cases, with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, etc., or chiral bases such as brucine, cinchona alkaloids and their derivatives, etc. p. Commonly used methods

Viewed Uadzes ei a). in "Epapioteg5, Kaseta(ez apa Kezoitsop" (Uupeu Ipiegesiepse, 1981). More specifically, the compound of formula (I) in which U Z represents OH can be converted into a 1:1 mixture of diastereomeric amides by treatment with chiral amines, amino acids, amino alcohols , derived from amino acids; conventional reaction conditions can be used to convert the acid to the amide; the diastereomers can be separated by fractional crystallization or chromatography, and the stereoisomers of the compound of formula (I) can be obtained by hydrolysis of the pure diastereomeric amide.

Pharmaceutically acceptable solvates of the compounds of formula (I) included in the present invention can be obtained by conventional methods, such as dissolving the compound of formula (I) in solvents such as water, methanol, ethanol, etc., preferably water, and recrystallization using various crystallization techniques.

Different polymorphs of the compound of the general formula (I), included in the present invention, can be obtained by crystallization of the compound of the formula (I) under different conditions. For example, using different common solvents or their mixtures for recrystallization; by crystallization at different temperatures; with different cooling modes, from very fast to very slow cooling during crystallization. Polymorphs can also be produced by heating or melting the compound followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid-phase methods

NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, X-ray powder diffraction or other similar methods.

The present invention provides a pharmaceutical composition containing compounds of the general formula (1) defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates, in combination with conventional Ha applicable carriers, diluents, etc., suitable for the treatment and/or prevention of such diseases as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and i9) related disorders. These compounds are suitable for the treatment of hyperlipidemia, hyperglycemia, familial hypercholesterolemia, hypertriglyceridemia, reduction of atherogenic lipoproteins, MI OI and GO. The compounds of the present invention can be used for the treatment of certain kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy. The compounds of the general formula (I) are also suitable for the treatment/prophylaxis of insulin resistance (type I diabetes), c leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to the syndrome

X, such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders. These compounds may also be useful as aldose reductase inhibitors, to improve cognitive function in dementia, to treat diabetic complications, disorders associated with endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), inflammatory bowel disease, osteoporosis, myotonic dystrophy, pancreatitis, retinopathy, arteriosclerosis, xanthoma, inflammation, and for the treatment of cancer.

The compounds of the present invention are useful in the treatment and/or prevention of the aforementioned diseases in "combination/concomitant with one or more NMO CoA reductase inhibitors; cholesterol absorption inhibitors; 70 agents for the treatment of obesity; agents for the treatment of lipoprotein disorders; hypoglycemic agents; 8 with insulin; biguanides; sulfonylureas; thiazolidinediones; double ACE inhibitors and or their mixtures. Compounds according to the present invention in combination with NMO CoA reductase inhibitors, cholesterol absorption inhibitors, agents for the treatment of obesity, hypoglycemic agents can be administered simultaneously or during such period of time to ensure their synergistic effect.

The present invention also offers a pharmaceutical composition containing compounds of general formula (1), - I defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their co-pharmaceutically acceptable salts or their pharmaceutically acceptable solvates and one or several NMO inhibitors

CoA reductases; cholesterol absorption inhibitors; anti-obesity means; means for the treatment of 1 lipoprotein disorders; hypoglycemic agents: insulin; biguanides; sulfonylurea; thiazolidinediones; yuyu 50 double PRAKA and in or a mixture thereof in combination with conventional pharmaceutically applicable carriers, diluents, etc.

Co) The pharmaceutical composition may be in commonly used forms, such as tablets, capsules, powders, syrups, solutions, suspensions, etc., may contain flavoring agents, sweeteners, etc. in suitable solid or liquid carriers or diluents, or in a suitable sterile environment for the formation of solutions or suspensions for injection. Such compositions typically contain from 1 to 2095, preferably from 1 to 1095, by weight of the active compound, and the remainder of the composition consists of pharmaceutically acceptable carriers, diluents or solvents. ime) Suitable pharmaceutically acceptable carriers include solid excipients or diluents and sterile aqueous or organic solutions. The active ingredient is part of such pharmaceutical compositions in an amount that is sufficient to provide the desired dose in the range of values indicated above. Thus, for oral administration, the compound of formula (I) can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, etc. Pharmaceutical compositions may, if desired, contain additional components, such as flavoring agents, sweeteners, excipients, etc. For parenteral administration, the polymorph form can be combined with a sterile aqueous or organic medium to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol, etc., as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts or salts of basic forms of compounds can be used. Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil can also be used in injection solutions. Injectable solutions prepared in this manner may then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred for humans.

For nasal administration, the drug may contain polymorphic forms according to the present invention, dissolved or suspended in a liquid carrier, in particular, an aqueous carrier, for aerosol use. The carrier may contain additives such as solubilizers such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.

Particularly suitable for any oral use are tablets, dragees or capsules containing a binder based on talc and/or carbohydrate, etc. Preferably, the carriers for tablets, dragees or capsules include lactose, corn starch and/or potato starch. In cases where a sweetened carrier may be used, a syrup or elixir may be used. 15 A typical example of tablet manufacturing is given below:

An example of vitreous tablets. Ingredients 1-3 are evenly mixed with water and granulated after drying under reduced pressure.

Ingredients 4 and 5 are well mixed with : granules and compressed using a tableting machine to (o) make 1000 tablets, each containing ZOmg of active ingredient. s zo sch and so zv sch

Ingredients 1-4 are evenly moistened with aqueous solution 5 and granulated after drying under reduced pressure. Ingredient 6 is added and the granules are compressed using a tableting machine to produce 1000 tablets containing 30 mg of ingredient 1.

A compound of formula (I) defined above is clinically administered to mammals, including humans, by oral, nasal, pulmonary, transdermal or parenteral routes, rectally, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ocular solution or ointment. Oral administration is preferred "by a route that is more convenient and avoids the pain and irritation possible with injection. However, if the patient is unable to swallow the drug or has impaired absorption after oral administration, whether due to illness or other abnormality , the drug must be administered parenterally. By any route of administration, a dose in the range of from about 0.01 to about 10 ug/kg body weight of the subject per day 7 or, preferably, from about 0.01 to about ZOmg/kg body weight per day, administered as single or multiple doses.(ee) However, the optimal dose for each subject receiving treatment is determined by the person responsible for the treatment, and usually lower doses are administered initially and then gradually are increased to determine the i-th most suitable dose. ko 20 The invention is explained in more detail in the following examples, which are given for illustration only and therefore should not be interpreted as limiting the scope of the invention. i» Synthesis 1 Ethyl-2-ethoxy-3- (4 -aminophenyl)propionate

Co

HF) Stage (i) yuyu The Wittig salt is obtained from triethyl-2-ethoxyphosphonoacetate (26.5g, 1.5eq., 99.3mmol) and Mann (5095 in oil) (5.3g, 2eq., 132.4mmol) in THF (35 Oml) at OS. Solid 4-nitrobenzaldehyde (10g, Tecv., 66b, 2mmol) is added to it in portions at 02C and the resulting solution is stirred at room temperature for 16 hours. bo The reaction mixture is diluted with ethyl acetate and washed with aqueous MN Cl. The crude product contains ethyl-4-nitro-2-ethoxycinnamate as a mixture of 2- and E-stereoisomers (11g).

Stage(s)

Ethyl-4-nitro-2-ethoxycinnamate obtained in step (i) is hydrogenated using Ra (10953/С - H» (414kPa (borge)) (11g) in ethyl acetate (150ml) at room temperature and subjected to chromatography using 65 of a mixture of ethyl acetate/hexane, obtaining the title compound in the form of a viscous oily liquid (9.41 g,

exit 6095).

TN nMR (200MHz, SOSIv) 5: 1.16 (t, 9U-7.0Hz, ZN), 1.22 (t, 9-7.0Hz, ZN), 2.90 (d, U-6.3Hz . .

IR (pure substance) cm": 3372, 1738.

Mass of ti/z (chemical ionization (C1I)): 238 (M.-1), 192 (M-OSONv5B).

Synthesis 2 3-(3,4-Dihydro-2H-benzo|(81(/1,Zoxazin-4-yl)propyl bromide

SI

M sha

A mixture of 3,4-dihydro-2H-benzo[5)(1,Tsoxazine (3.0g, Eq., 22.2mmol), 1,3-dibromopropane (22.5ml, 1Eq., 222mmol) and anhydrous sodium carbonate ( 7.05g, Seq., 66.6mmol) in dry DMF (200ml) is heated at 70°C for 16h. The reaction mixture is diluted with ethyl acetate and washed with water and brine. The residue is subjected to chromatography using ethyl acetate and hexane to give the title compounds as of liquid mass (2.6 g, 47965).

TN o nMR (200 MHz, SOSIi) 8: 2.10-2.30 (m, 2H), 3.37 (t, uU-44Hz, 2H), 3.40-3.56 (m, 4H), 4 .25 (t, 3-4.3Gu, 2H), 6.60-6.90 (m, aromatic nucleus, 4H).

Mass ti/ (SI): 255 (M(Vg)), 256 (M(Vg1), 257 (M(Vg2)), 258 (M(Vg27) 1).

Synthesis of Ethyl-2-ethoxy-3-I4-(-M-heptyl-M-(2'-bromethyl))aminophenyl|propionate

Stage(s)

A mixture of ethyl 2-ethoxy-3-(4-aminophenyl)propionate (5g, Eq., 21mmol), obtained in the synthesis of 1, heptyl bromide (18.8g, bEq., 105mmol), and anhydrous KSO" (14.5g, beq., 105 mmol), heated at 709C. in

DMF (100 ml) for 1 day. The reaction mixture is diluted with ethyl acetate, washed with water and brine. with

The residue was chromatographed using a mixture of ethyl acetate and hexane as eluent to give the monoheptylated product as a viscous liquid (3.85 g, yield 5595).

TN nMR (200MHz, SOSIz) 5: 0.88 (bt, U-6.3Hz, ZN), 1.05-1.42 (m, 15H), 1.42-168 (m, 2H), 2.90 (d, U 3-6.6Hz, 2H), 3.08 (t, uU-6.8Hz, 2H), 3.22-2.42 (m, 1H), 3.44-3, 64 (m, 1H), 3.94 (t, U-6.8Hz, 1H), 4.1 (kv, so

U-7, OGC, 2H), 6.55 (d, U-8.3Hz, 2H), 7.04 (d, U-8.3Hz, 2H).

From IR (pure substance) cm": 3396, 1747. -

Mass t/ (SI): 335 (M'-1), 290 (M-OSON5).

Stage(s)

The monoheptylated product (Zg, eq., 8.98 mmol) obtained in stage (I) is treated with an excess of "dibromoethane (1 eq.) in the presence of anhydrous KSO" (3.72 g, eq., 2/mmol) in DMF (40 ml ), and heated at -70°C for 1 hour. The reaction mixture is diluted with ethyl acetate, washed with water and brine. The residue c was subjected to chromatography using a mixture of ethyl acetate and hexane as an eluent, obtaining: c» ethyl-2-ethoxy-3-14-N-heptyl-N-(2'-bromomethyl))aminophenyl|-propionate in the form of a viscous liquid (1.98 g, output 50965).

TN nMR (200MHz, SOSIv) 5: 0.88 (width, U-6.3Hz, ZN), 1.05-1.42 (m, 14H), 1.42-1.68 (m, 2H ), 2.90 (d, -68.6Hz, 2H), 3.28 (t, U-7.3Hz, 2H), 3.30-3.45 (m, ЗН), 3.50-3, 70 (m, ZN), -3.96 (t, 9U-6.8Hz, 1H), 4.17 (kv, U-7.0Hz, -and 2H), 6.57 (d, U-8, 3Hz, 2H), 7.09 (d, U-8.3Hz, 2H).

IR (pure substance) cm": 1747. so Mass ti/z (SI): 442 (M(Vg)1), 444 (M(Vg 31). 1 Synthesis 4 7 50 2-(3,4-Dihydro- 1H-benzo|5)(1,Zoxazin-4-yl)/carboxymethyl chloride with CO and gave 3,4-Dihydro-2H-benzoi|v1(1,Zoxazin (1.52g, Eq., 11.3mmol), triethylamine (4.73ml, Zeq., 33.9mmol) and

GF) a catalytic amount of LOBSTER is diluted in dry DCM (5 Oml). To this mixture was added 2-chloroacetyl chloride (1.8 ml, with 2 equiv., 22.bmmol) at 02C and the reaction mixture was stirred at 02C for 4 hours. The reaction mixture is diluted

DCM and washed with solution. aqueous NSI, and then MansSO" and brine. The organic layer is dried over anhydrous NaCl and concentrated on a rotary evaporator. The crude compound was chromatographed using ethyl acetate and hexane to give the title compound as a waxy solid (1.54g, yield 6596).

IN NMR (200MHz, SOSI") 5: 3.98 (t, U-4.4Hz, 2H), 4.25-4.40 (m, 4H), 6.90-7.20 (aromatic nucleus, 4H ).

IR (pure substance) cm": 1655. 65 Mass ti/z (SI): 212 (MIS), 214 (M(SIZU 1).

Synthesis 5

Methyl 3-(4-formylphenyl|-2-ethoxypropionate).

SOo.Mme od

Hz!

Stage(s)

The Wittig salt was prepared from triethyl-2-ethoxyphosphonoacetate (25.6 g, 2.0 eq., Ubmmol) and Mann (3.84g, 2 eq., 9 bmmol) in THF (240 mL) at 02С. Monodiethyl acetal of terephthalaldehyde (10 g, 70 equiv., 4 ABmmol) is added to it dropwise at 02С. The resulting solution is stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous MOH. The residue was chromatographed (ethyl acetate and hexane) to give ethyl 4-(diethoxymethyl)-2-ethoxycinnamate as a mixture of 7- and E-stereoisomers (13.9g, yield 9090).

Stage(s)

A dry methanolic (2O0ml) solution of ethyl 4-(diethoxymethyl)-2-ethoxycinnamate (5g, Leq., 15.5mmol) obtained in step () is added to dry methanol (bOml) containing activated magnesium shavings (7, 44 g, 200 equiv., Z'bmmol) and leave with stirring. Gradually, the reaction mixture begins to boil, which requires the use of a reflux condenser. After consuming magnesium with the formation of Moa(OMe) 2 (requires 3-4 hours), it is stirred at room temperature temperature for 16h. The reaction mixture was carefully acidified with conc. HCl and stirred for 2h at room temperature. Finally, ethyl acetate was added and the organic layer was thoroughly washed with water and brine and dried over anhydrous Ma»5O. The residue was subjected to chromatography (EtOAc/hexane ), giving the title compound as a viscous oily liquid (2.92 g, yield 8096).

TN nMR (200MHz, SOSIv) 5: 1.14 (t, 9U-6.8Hz, ZN), 3.00-3.20 (m, 2H), 3.22-3.41 (m, 1), 348-367 (m, p

L1H), 3.73 (s, ЗН), 4.06 (dd, 9-7.8, 5.4Hz, 1H), 6.40 (d, U-8.93Hz, 2H), 7.81 ( d, U-8.3Hz, 2H), 9.99 (s, 1H). at

IR (pure substance) cm": 1751, 1701.

Mass t/dSI): 237 |M'-11.

Synthesis 6

Mothyl-2-ethoxy-3-I4-(M-heptylaminomethyl)phenyl|propionate with

Io)

Sula d) we: - GK u

Stage(s)

Methyl 3-(14-formylphenyl)-2-ethoxypropionate (2 g, Cheq., 8.5 mmol) obtained in the synthesis of 5, heptylamine (978 mg, Cheq., 8.51 mmol) and the cat. amount of p-TON.HO are diluted in DCM (40 mL), along with several pieces of activated molecular sieves (4 A). After 24 h, the reaction mixture is filtered through celite at room temperature and the filtrate is diluted with DCM, washed with aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate to give the crude methyl-2-ethoxy-3-I4-(M-heptyliminomethyl)phenyl|propionate. "» Stage (iii) " Crude methyl-2-ethoxy-3-I4-(«"M-heptyliminomethyl)phenyl|propionate (2.95 g), obtained in stage (ii) above, is dissolved in methanol (40 ml) and processed conc. HCl (85O0μl, Eq., 8.51 mmol) and sodium cyanoborohydride (BZBMg, Eq., 8.51 mmol) at 02 C. The course of the reaction is monitored by TLC. After 2 hours, the reaction mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate (ee). The residue was chromatographed using methanol and chloroform to give the title compound (1.7 1g, yield 6095) as a viscous liquid. n 78 nNMR (200MHz, SOSIS) 8:0 .86 (width, t, 9U-6.3HZ, ZN), 1.14 (t, 9U-6.8HZ, ZN), 1.20-1.40 (m, 9H), name) 20 1.50-1 .70 (m, 2H), 2.60 (t, 9U-74Hz, 2H), 2.98 (d, 9U-6.3HzC 2H), 3.22-3.41 (m, 71H), 3.48- 3.67 (m, 1H), 3.71

Short circuit (c, ZN), 3.89 (c, 2H), 4.02 (t, 9-6.3HuCs, 1H), 7.23 (d, U-7.8HcCs, 2H), 7.30 ( d, U-7.8Hz, 2H).

IR (pure substance) cm": 3500 (width), 1748.

Mass t/z (SI); 336 |M'-11.

Synthesis 7

Methyl 2-ethoxy-3-(4-aminophenyl)propionate

F) ru o nm ov

Ethyl-4-nitro-2-ethoxycinnamate (10g, Eq., 37.7mmol), obtained in stage (I) of synthesis 1, is treated with 60 activated magnesium shavings (18g, 20eq., 754mmol) in dry methanol (40Oml). The reaction mixture is refluxed for 2 hours. And leave with stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and quenched with cold aqueous ammonium chloride.

The organic layer is washed with water and brine. The residue was subjected to chromatography using ethyl acetate and hexane to give the title compound as a liquid (bg, yield 7295). b5 TN nMR (200MHz, SOSIv) 5: 1.64 (t, U-6.8Hz, ZN), 2.90 (d, 9U-6.3Hz, 2H), 3.22-3.42 (m, 1H), 3.42-3.65

(m, 2H), 3.70 (s, ЗН), 3.96 (t, U-6.8Hz, 1H), 6.61 (d, U-8.3Hz, ". 2H), 7.00 (d, U-8.3Hz, 2H).

IR (pure substance) cm": 3350 (width), 1735.

Mass t/z (SI): 224 |M-1).

Synthesis of 8 5-(3,4-Dihydro-2H-benzoyl|51(11,Doxazin-4-yl)-5-oxopentyl bromide

So / see

Stage(s)

To a mixture of 5-bromopentanoic acid (4.63 g, Eq., 25.6 bmmol) and oxalyl chloride (11.2 ml, Bbeq., 128 mmol) in hexane (bml) is added DMF (1 Oml) and the reaction mixture is heated at 7092C for 1 h. Excess oxalyl chloride and hexane were removed by distillation and the residue was distilled under high vacuum to give 75 5-bromopentanoyl chloride as a light yellow liquid (2.1 g, yield 41965).

Stage(s)

To a solution of 3,4-dihydro-2H-benzo|rB|oxazine (50 mg, Eq., 3.7 mmol), triethylamine (1.54 ml, Eq., 11.1 mmol) and a catalytic amount of OMAR in dry DCM (20 ml) is added 5-bromopentanoyl chloride (87 Ωcl, 2 eq., 7.400 mmol) at 092. The reaction mixture was stirred at 09C for 4 hours, and then diluted with an excess of ethyl acetate. The ethyl acetate layer is washed with HCl solution, water, and then brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound (535 mg, yield 5390) as a viscous liquid.

TN nMR (200 MHz, SOSIA) 8: 1.70-2.00 (m, 4H), 2.63 (bt, 9U-5.9Hz, 2H), 3.39 (t, U-5.8Hz , the main rotamer 1.2H), 3.53 (t, U-6.3Hz, rotamer present in smaller amounts, 0О.8H), 3.94 (t, 9-4.4Hz, 2H), 4.29 s (t, ud-4, oHz, 2H), 6.80-7.20 (aromatic core, 4H). at

IR (pure substance) cm": 2936, 1660.

Mass of ti/z (SI): 298 (M(Hg)11, 300 M(ZVh 11.

Synthesis 9

Methyl-2-ethoxy-3-(3-aminophenyl)propionate cm pd soma sch

Where is she?

Stage(s)

The Wittig salt was prepared from triethyl-2-ethoxyphosphonoacetate (34.3 mL, 2 eq., 132 mmol) and Mann (5095 in oil) CO (6.28 g, 2 eq., 132 mmol) in THF (350 mL) at 02C. Solid Z-nitrobenzaldehyde h- (10 g, Eq., bbmmol) is added to it in portions at 09C. The resulting solution is stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with aqueous MH over SI. o The raw product contains ethyl-4-nitro-2-ethoxycinnamate as a mixture of 2- and E-stereoisomers (15g, yield 8695). "

Stage(s)

The crude compound (15g, Eq., 56.b6mmol) obtained in step (i) is dissolved in methanol (250ml). Ammonium formate (35.bg, 10eq., 5ppmmol) and 1095 Ra/C (40g) are added to it, and the reaction mixture is stirred at room temperature for 1h. The catalyst is separated on a filter and the methanol is concentrated on a rotary evaporator. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was subjected to chromatography, obtaining methyl-2-ethoxymetaaminocinnamate in the form of a mixture of (E)- and (2)-isomers (10 g, yield 75905). -i Stage (iii)

Methyl-2-ethoxymetaaminocinnamate (10g, Eq., 42.5mmol), obtained at stage (iii), is treated with magnesium (ee) as well. (20.4g, 2b0eq., 850mmol) and dry methanol (500ml). The reaction mixture is heated to boiling with reflux 1 refrigerator for 2 hours. and leave with stirring at room temperature for 16 hours. 7 50 The reaction mixture was diluted with ethyl acetate and quenched with cold aqueous ammonium chloride. The organic layer is washed with water and brine. The residue is subjected to chromatography using ethyl acetate and hexane,

I" obtaining the title compound in the form of a viscous liquid (8.06 g, yield 80905).

TN nMR (200MHz, SOSIv) 8: 1.15 (t, U-6.8Hz, ZN), 2.96 (d, 9-6.9Hz, 2H), 3.22-3.42 (m, 1H ), 3.42-3.65 (m, 2H), 3.70 (s, ЗН), 4.01 (t, 9U-6.4Htsu, 1H), 6.50-6.62 (aromatic core, ZN), 7.06 (t, 9U-7.8Hz, 1 N).

IR (pure substance) cm": 3360, 1738.

GF) Mass t/z (SI): 224 (M'1).

Synthesis of 10 o 3-(7-Fluoro-3,4-dihydro-2H-benzo|8111,Zoxazin-4-yl)upropyl bromide

Ann I'm OK

M an

Step (i) 65 To a solution of 2-nitro-5-fluorophenol (5g, eq., 31.bmmol) and ethyl 2-bromoacetate (3.vml, 1.1eq., 34.vMmmol) in dry acetone (1bml ) add anhydrous potassium carbonate (8.7 g, 2 eq., 63.2 mmol) and stir at room temperature for 1 hour. The reaction mixture is filtered through celite and then concentrated on a rotary evaporator. The residue was diluted with ethyl acetate and washed with water and brine to give the crude compound (bg, yield 7890), which was used in step (II).

Stage(s)

The crude compound obtained in step (iii) (bg, Tecv., 28.8 mmol) is diluted in dry methanol (150 ml).

Iron powder (8.06 g, eq., 144 mmol) and glacial acetic acid (25 ml, 15 eq., 432 mmol) are added to it and heated at 1102C for 4 hours. Solvents are removed from the reaction mixture and diluted with ethyl acetate.

The ethyl acetate layer is washed with aqueous ammonium chloride, water and brine. The residue was subjected to 7/0 chromatography, obtaining 3Z-oxo-7-fluoro-3,4-dihydro-2H-benzo|BI(/1,4|oxazine in the form of a solid (2.2 g, m.p.: 204- 2062C, exit 46905).

TN nMR (200MHz, SOSIzADMSO-46) 5: 4.52 (s, 2H), 6.60-6.70 (m, 2), 6.88 (dd, U-8.3 and 5.8Hz, 1H ), 10.63 (width, 1H).

IR (KVh) cm"!: 1677, 1622.

Mass t/ (SI): 168 (M'-1).

Stage (its) 3-Oxo-7-fluoro-3,4-dihydro-2H-benzoyl|vI(1, Tsoxazin (2.2 g, Leq., 13.1 mmol), obtained in stage (i), in dry THF (1Oml) is added dropwise to THF (bOml) containing GAN (1.5g, Eq., 39.5mmol) at reflux. Heating to reflux is continued for another h and quenched with ethyl acetate. water (1.5 ml), 1595 sodium hydroxide (1.5 ml) and water (4.5 ml) are added alternately to this mixture. After the formation of a precipitate of AMON) 3-HNO, the mixture is filtered through celite. The filtrate was concentrated on a rotary evaporator and subjected to chromatography (ethyl acetate and hexane) to give 7-fluoro-3,4-dipdro-2H-benzoyl)/1,oxazine (1.3 g, yield 65905) as a yellow oily liquid.

TN nMR (200MHz, SOSIZ) 5: 2.80 (width, 1H), 3.38 (t, 9-44Hz, 2H), 4.24 (t, 9-4.4Hz, 2H), 6, 48-6.56 s (aromatic core, ZN). Gee)

IR (pure substance) cm": 3395 (width), 2957, 1606.

Mass t/z (SI): 154 (Mt).

Stage(s) of high school

A mixture of 7-fluoro-3,4-dihydro-2H-benzo|5I(1,Tsoxazine (1.3g, CHLeq., 8.4Ommol), obtained in step (iii) above, 1,3-dibromopropane (8.bml , 1Eq., 84.9mmol) and anhydrous sodium carbonate (2.7g, Eq. 25.4mmol) in M dry DMF (85ml) are heated at 702 for 1h. The reaction mixture is diluted with ethyl acetate and washed with water and brine. The residue is subjected to chromatography using ethyl acetate and hexane to give the title compound (1.1 g, yield 4790) as a viscous oily liquid.

TN nMR (200 MHz, SOSIi) 8: 2.10-2.28 (m, 2H), 3.30 (t, 9-44Hz, 2H), 3.38 (t, 9U-6.7Hz, 2H), 3.49 (t, cha 9-6.2 Hz, 2H), 4.24 (t, 9-4.4 Hz, 2H), 6.50-6 70 (aromatic nucleus, ЗН).

Mass t/z (SI): 274 (M(?Vg)11, 276 M(ZVg) 1).

Synthesis 11 «

M-((3,4-Dihydro-2H-benzo|ph|oxazin-4-yl)propyl)benzylamine that 7 s M :z» your

Cesium hydroxide monohydrate (288 mg, 1.1 eq., 1.72 mmol) and ground molecular sieves 4A (500 mg) -I are stirred at room temperature in dry DMF (7 ml) for 15 min. Benzylamine (51 µM, Zeq., 4.6 b8 mmol) is added to this mixture, after which it is stirred for another 30 minutes. Finally, 3-(3,4-dipdro-2H-benzoyl|81/1,Zoxazin-4-yl)upropylbromide (40mg, eq., 1.50mmol), obtained in Synthesis 2, is added in DMF (3ml) . After stirring for 1 hour. at room temperature, the reaction mixture is diluted with ethyl acetate and washed with water and brine. The organic layer is concentrated and subjected to chromatography using a chloroform/methanol mixture to give the title compound as a viscous liquid

GI (Z307mg, output 7090). "YAN NMR (200MHz, SOSIV) 8: 1.77 (sq, U-6.8Hz, 2H), 2.00 (width, 1H), 2.67 (t, 9U-7.3Hz, 2H) , 3.20-3.28 (m,

AN), 3.76 (s, 2H), 4.16 (t, U-4.4Hz, 2H), 6.50-6.82 (aromatic core, 4H), 7.18-7.38 (aromatic nucleus, 5H).

IR (pure substance) cm"!: 3311 (width), 2931, 1669. o Mass t/z (SI): 283 (M'1).

Synthesis of 12 ime) Methyl-2-ethoxy-3-14-(4-hydroxybenzyl)aminophenyl)propionate

Som 60 days I no

Methyl 2-ethoxy-3-(4-aminophenyl)upropionate (50mg, Cheq., 2.24mmol) obtained in the synthesis of "LYA, 4-hydroxybenzaldehyde (27Zmg, Cheq., 2.24mmol) and a catalytic amount of p-TON are diluted in DCM (5ml), together b5 With several pieces of molecular sieves (4A) The reaction mixture is stirred at room temperature for 24h, diluted with excess ethyl acetate and washed with aqueous sodium bicarbonate.

The EtOAc layer is dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. The crude substance is dissolved in methanol (10 mL) and treated with MaxsmM)VnH »z (16 mg, 1.2 equiv., 2.64 mmol) in the presence of conc. NSI (220ml) at 02C and stirred for 2 hours. The reaction mixture is diluted with excess ethyl acetate, washed with water and brine. The EtOAc layer is dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. The residue was subjected to chromatography using a mixture of E(OAc/hexane), obtaining the title compound as a solid mass (405 mg, yield 5590, mp: 109-11025),

TN nMR (200MHz, SOSIv) 5: 1.17 (t, U-6.9Hz, ZN), 2.89 (d, 9U-64Hz, 2H), 3.22-3.42 (m, 1H), 3.50-3.65 (m, 1H), 3.70 (width, 5H, COoMe, -OH, -MH-), 3.98 (t, U-6.8HZ, 1H), 4, 20 (s, 2H), 6.56 (d, 9U-8.3Hz, 2H), 6.78 70 (d, 9-8.3Hz, 2H), 7.03 (d, U-8.3Hz, 2H), 7.21 (d, U-8.3 Hz, 2H).

IR (KVh) cm"!: 3369, 1680.

Mass ti/z (SI): 330 |M'-11.

Synthesis 13

Methyl-2-ethoxy-3-(3-(4-hydroxybenzyl)aminophenyl)propionate 75 HO n

IF: - Sokme

WITH

Methyl-2-ethoxy-3-(3-aminophenyl)upropionate (1.0 mg, LEq., 4.4 mmol), obtained in Synthesis 9, 4-hydroxybenzaldehyde (547 mg, Eq., 4.4 mmol), and cat. amount of p-TZON is mixed in СНоСИ» (25 ml) together with several pieces of activated molecular sieves (4A). The reaction mixture is stirred at room temperature for 24 hours, and then diluted with an excess of ethyl acetate and washed with aqueous sodium bicarbonate. The EtOAc layer is dried over anhydrous sodium sulfate, and then concentrated on a rotary evaporator. The crude substance is dissolved in MeOnH (20 ml) and treated with Ma(CM)VN with (415 mg, 1, beq., CM 29 in, mmol) in the presence of conc. NSI (528 μl) at 02С. After 2 hours stirring, the reaction mixture is again diluted with excess ethyl acetate and washed with water and brine. The EUDAs layer is dried over anhydrous sodium sulfate, and then concentrated on a rotary evaporator. The residue was subjected to chromatography using a mixture of E(dAc/hexanes), obtaining the title compound (450 mg, 3095 yield) as a viscous liquid. c

TN NMR (200MHz, SOSIv) 8: 1.19 (t, 9U-7.0Hz, ЗН), 1.29 (s, 1Н, М-Н), 2.96 (d, У-6.3Hz, 2Н ), 3.30-3.50 s (m, 7), 3.50-3.70 (m, 7H), 3.73 (sh.s, ЗН), 4.07 (t, U-6, 6Hz, 1H), 4.21 (s, 2H), 6.50-6.70 (m, ZN), 6.81 (d, --8.9Hz, 2H), 7.11 (t, 9U- 7.8, 1H), 7.22 (d, U-8.3Hz, 2H), 7.39 (c, 1H.-OH). yu

IR (pure substance) cm": 3391, 1738, 1607. (ee)

Mass t/ (SI): 330 |M'-11. what-

Synthesis 14

Z dihydro-2H-benzoi|51(1,4)thiazin-4-yl)upropyl bromide

СО « - s va; A mixture of 3,4-dihydro-2H-benzoyl(1,Chthiazine (2.0 g, 1.0 eq., 13.24 mmol), 1,3-dibromopropane (14 ml, 1 eq., "» 132.4 mmol) and anhydrous Ma»CO»z (4.21 g, 3,Eq., 39.7 mmol) in dry DMF (130 ml) is heated at 709 for 16 h. The reaction mixture is diluted with ethyl acetate (200 ml) and washed with water and brine. The organic layer is dried (Ma »5O)), concentrate, and the residue is subjected to chromatography using ethyl acetate and -1 hexanes, obtaining the title compound in the form of a yellow oily liquid (2.13 g, yield 59965). co TN nNMR (200 MHz, SOCI3) 8: 2, 11-2.25 (m, 2H), 3.02 (t, 9-44Hz, 2H), 3.20-3.28 (m, 4H), 3.62 (t, y-4.4Gu, 2H ), 6.60-6.72 (aromatic core, 2H), 6.90-7.20 (aromatic core, 2H). , 273 (M (285), 271 (M (B) 11. ma 70 Synthesis 15

Kz 2 EDy hydro-2H-benzoi|5111,Zoxazin-4-yl)ethyl bromide in

M iv o A mixture of 3,4-dihydro-2H-benzo|5I(1,Tsoxazine (1.5g, 1.O0eq., 11.12mmol), 1,3-dibromoethane (1Oml, 1Eq., 111.2mmol) and of anhydrous K»CO»z (4.6 g, 3,Eq., 33.3 mmol) in dry DMF (11 Oml) is heated at 702°C for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water and brine. The organic layer was dried (Ma»5O)), concentrated, and the residue chromatographed using ethyl acetate and 60 hexane to give the title compound as a yellow oily liquid (940g, 34905).

TN nMR (200 MHz, SOS) 5: 3.45 (t, 9-44Hz, 2H), 3.50-3.72 (m, 4H), 4.24 (t, U-44Hz, 2H), 6, 65 (t, y-7.8Gu, 2H), 6.78-6.90 (aromatic core, 2H).

Mass of ti/z (SI): 241 IM (B), 242 (M (B), 243 (M (283), 244 (M (B)) 11.

Synthesis of 16 bo 4-(2-(3,4-Dihydro-2H-benzoyl| 1/1, Zoxazin-4-yl)ethoxy)aniline

0

SO ie

WITH

M no

Stage(s)

A mixture of 2-(3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)ethyl bromide (50O0mg, 71.O0eq., 2.07mmol), obtained in

Synthesis of 15, 4-nitrophenol (288 mg, Eq., 2.07 mmol) and anhydrous KSO (857 mg, 3 Eq., 6.21 mmol) in dry acetone (12 ml) were stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate 7/0 (20 Oml), washed with water and brine. The organic layer was dried (Ma»SO)), concentrated. The crude mass was used for stage (iii).

Stage(s)

A methanolic solution (1Oml) of the crude product (b0Omg, eq., 2.0mmol) obtained in step (ii) is hydrogenated at room temperature at atmospheric pressure using ammonium formate (2.6bg, 20eq., 40mmol) and 7/5 1090 ra/C as a catalyst (500mg). After holidays stirring TLC showed the absence of starting material.

The reaction mixture is filtered through celite and concentrated. The residue was chromatographed using ethyl acetate and hexane to give the title compound as a viscous liquid (355 mg, 669).

TN nMR (200MHz, SOSIZ) 5: 3.40 (shr.s, -MNo), 3.51 (t, 9U-4.4Hz, 2H), 3.65 (t, 9-5.8Hz, 2H) , 410 (t, 95.6Hz, 2H). 4.23 (t, U-4.4Hz, 2H), 6.50-6.90 (aromatic core, 4H).

Mass t/z (SI): 270 |MI, 271 |(M--1).

Synthesis of 17 3-(2-Methyl-7-fluoro-3,4-dihydro-2H-benzoyl| 1/1, Zoxazin-4-yl)-propyl bromide peru c o 7 C o be

Stage(s)

anhydrous potassium carbonate (2.63 g, Zeq., 19.08 mmol) and the reaction mixture are heated to boiling under reflux for 1 hour. The reaction mixture is filtered through celite and then concentrated on a rotary evaporator. The residue was diluted with ethyl acetate and washed with water and brine to give ethyl 2-(2-nitro-5-fluorophenoxy)propionate as crude material (1.6bg, yield 9895), which was used in step (ii). co

Stage(s)

Z The crude compound obtained in step (i) (1.6g, eq., 6.22mmol) is diluted in dry methanol (150ml). in.

Iron powder (5.23 g, 15 eq., 93.37 mmol) and glacial acetic acid (5.bml, 15 eq., 93.37 mmol) are added to it and heated at 1102 for 4 hours. Solvents are removed from the reaction mixture and diluted with ethyl acetate. The ethyl acetate layer is washed with aqueous ammonium chloride, water and brine. The residue "F" is subjected to chromatography, obtaining 2-methyl-3-oxo-7-fluoro-3,4-dihydro-2H-benzo|in)(1,Zoxazin in the form of a solid (1.Og, yield 8896). From c T.pl.: 166-1682С with TN NMR (200MHz, SOSIv) 8: 1.59 (d, U-6.9Hz, ZN), 4.67 (q, U-6.9Hz, 1H), 6 ,60-6,80 (aromatic core,

ЗН), 8.61 (width s, 1H).

IR (KVosm"!: 1677, 1610. -1 Mass t/z (SI): 182 (Mt).

Stage (its) (ee) 2-Methyl-3-oxo-7-fluoro-3,4-dihydro-2H-benzo|51(11, Tsoxazin (4.8g, Eq., 26.5mmol), obtained at stage c (i), in dry THF (bOml) was added dropwise to THF (200 ml) containing GAN (6.05 g, b.q., 159.1 mmol) at reflux for 20. Reflux was continued. during the same period) quenched with ethyl acetate and hydrolyzed with saturated aq. sodium sulfate. After the formation of a precipitate (AOH) with NoO, the mixture is filtered through celite. The filtrate is concentrated on a rotary evaporator and subjected to chromatography (ethyl acetate and hexane), obtaining 2-methyl-7-fluoro-3,4-dihydro-2H-benzo|5I(1,Zoxazin (4.3g, yield 9790)) as a yellow oily liquid.The crude product is used for the next reaction.

TN NMR (200MHz, SOSIv) 5: 1.36 (d, 9-6.5Hz, ZN), 3.05 (dd, 9U-11.3, 8.0Hz, 1H), 3.32 (d, 9U -11.8Hz, 1H), 3.60 (width, 1H, M-H), 4.18-4.30 (m, 1H), 6.40-6.60 (aromatic nucleus, Ш). o IR (KVg) cm"!: 3387, 2977, 2933, 1605, 1510. ime) Mass t/z (SI): 168 (Mya1).

Stage (im) 60 Mixture of 2-methyl-7-fluoro-3,4-dihydro-2H-benzo|5I(1,Tsoxazine (4.3g, Leq., 25.74mmol), obtained in the stage (its) above, 1,3-dibromopropane (26.1 ml, 1 Eq., mmol) and anhydrous sodium carbonate (8.2 g, Eq., 77.2 mmol) in dry DMF (260 Oml) are heated at 709 C for 1 h. The reaction mixture is diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound (3.5 g, yield 48905) as a viscous oily liquid. NMR NMR (200 MHz, SOCIv) 5: 1.35 (d, 9-6.7Hz, ZN); 2.02-2.22 (m, 2H); 3.01 (dd, uU-11.3, 8.3Hz, 1H); 3.32

(dd, 9U-11.6, 2.3HZ, 1H); 3.22-3.58 (m, 4H); 4.18-4.35 (m, 1Н), 6.42-6.62 (aromatic core, НН).

Mass t/a (SI): 288 (M("Hg) 11, 290 M(Z'Hg) 11.

Synthesis of 18 3-(2-Methyl-3,4-dihydro-2H-benzoyl|81/1, Doxazin-4-yl)/propyl bromide

CO

I hear you

Stage(s)

Starting with 2-nitrophenol (10g, Eq., 71.Omol) and ethyl 2-bromopropionate (10.2ml, 1.Eq., 79.09mmol), carry out the procedure of stage (i) of Synthesis 17, obtaining ethyl-2- (2-nitrophenoxy)propionate in crude form (16g), which is used for stage (iii).

Stage(s)

The crude compound obtained in stage (i) (16g, ZTeq., 62.2mMmol) is converted into 2-methyl-3-oxo-3,4-dihydro-2H-benzo|5|(1,Zoxazin in the form of a solid (10.0g, output 9895) according to the procedure of stage (ii) of Synthesis 17.

T.pl.: 164-16626.

IN nMR (200MHz, SOSIv) 6: 1.59 (d, 9U-6.7Hz, ZN); 4.67 (sq, 9U-6.7Hz, 1H), 6.80-7.00 (aromatic core, 70 days), 945 (width, 1H).

IR (KVh) cm"; 3500, 3198, 2917, 1675, 1608, 1501. Masat/2(SI): 164 (M-n1).

Stage (ii) 2-Methyl-3-oxo-3,4-dihydro-2H-benzo|5I(1,Zoxazin (5.0g, Chekw., ZO,bmol) obtained in stage (ii), reduced to 2- methyl-3,4-dihydro-2H-benzoic acid (1, Tsoxazine (4.3 g, yield 9095) in the form of a yellow oily liquid according to the procedure of stage (ii) of Synthesis 17. Ho)

TN nMR (200MHz, SOSIv).6: 1.37 (d, 9U-6.1Hz, ZN); 3.10 (dd, 9-11.3, 8.1 GHz, 1); 3.34 (d, 9-11.6, 2.5Hz, 1H); 3.60 (width s, 1H, M-H); 4.18-4.30 (m, 1H), 6.50-6.80 (aromatic core, 4H).

IR (KVg) cm"!: 3389, 2977, 2976, 1608, 1503. s zo Mass t/z (SI): 150 (Myat1).

Stage (im) p

From 2-methyl-3,4-dihydro-2H-benzoyl|51I(1,Tsoxazine (4.5g, Eq., 30.2mmol), obtained in step (ii) above, and 1,3-dibromopropane (ZOml , 1Eq., ZObmmol) obtained by the procedure of stage (m) of Synthesis 17 the title compound (3.5g, yield 4890) in the form of a viscous oily liquid. d, 9-64Hz, ZN); 2.05-2.25 (m, 2H); 3.07 (dd, 9-11.3, 8.3Hz, 1H); 3.24 |- (dd, 9U -11.6, 2.3Hz, 1H); 3.30-3.58 (m, 4H); 4.18-4.35 (m, 1H), 6.50-6.82 (aromatic nucleus, 4H ).

Mass t/z (SI): 270 (M(9Vg)11, 272 |M(ZVg 1).

Synthesis of 19 « 3-(2-Propyl-3,4-Dihydro-2H-benzo|81/1,Zoxazin-4-yl)ipropyl bromide

Su o, - m khz" of the World

Stage(s)

Starting with 2-nitrophenol (1.0 g, Eq., 7.19 mmol) and ethyl 2-bromopentanoate (2.97 ml, Eq., - 21.54 mmol), carry out the procedure of step (i) of Synthesis 17, obtaining ethyl -2-(2-nitrophenoxy)pentanoate (2.0 g) as a crude product used for stage (II).

Stage (ii) o The crude compound obtained in stage (i) (1.7 g, ZTequ., 6.5 mmol) is converted into 7 50 2-propyl-3-oxo-3,4-dihydro-2H-benzo|pI( 1, Shtsoxazine in the form of a solid substance (1.2 g, yield 8790 in 2 stages) according to the procedure of stage (ii) of Synthesis 17. o) M.pl.: 172-17496.

TN nMR (200MHz, SOSIz) 8: 0.98 (d, 9-7.0Hz, ZN); 1.40-1.70 (m, 2H); 1.70-1.98 (m, 2H); 4.59 (t,

U-6.4Gu, 1H); 6.84-7.00 (aromatic core, 4H), 9.00 (width, 1H). 59 IR (KVk) cm": 3198, 2917, 1677, 1611, 1502.

GF) Mass t/z (SI): 192 (Mt). 7 Stage (ii) 2-Propyl-3-oxo-3,4-dihydro-2H-benzo|b1(1,Zoxazin (2.0g, Leq., 104 mmol) obtained in stage (iii), reduced to 2-propyl -3,4-dihydro-2H-benzo|51(11,oxazine (1.65 g, yield 9095) in the form of a crude product according to the 60 procedure of stage (ii) of Synthesis 17 and proceed to the next reaction. Mass t/z: (SI ): 178 (M.-1).

Stage (im)

From 2-propyl-3,4-dihydro-2H-benzo|5I(1,oxazine (1.65g, Leq., 9.mmol), obtained in step (iii) above, and 1,3-dibromopropane (9, 4ml, 1Eq., UZmmol) according to the procedure of stage (im) of Synthesis 17, the title compound (915mg, yield 33905) was obtained as a viscous oily liquid.

TN nMR (200MHz, SOSIi) 8: 0.97 (t, 9U-7.0Hz, ZN); 1.40-1.80 (m, 4H); 2.00-2.25 (m, 2H); 310 (dd,

U-11.6, 8.0Hz, 1H); 3.27 (dd, 9U-11.6, 2.4HZ, 1); 3.35-3.58 (m, 4H); 4.00-4.18 (m, 1H), 6.50-6.90 (aromatic core, 4H).

Mass t/a (SI): 298 (M(?Hg) 11, 300 M(Z'Hg) 11.

Synthesis of 20 (5)-Ethyl-2-ethoxy-3-(4-aminophenyl)propionate

Square nm Ov

Stage(s)

To a solution of (5)-(4-nitrophenyl)alanine (10g, 47.bmol) in a mixture of water (5Oml), H»ZO) (1M, bOml) and acetone (15Oml) at -592C, a nitrite solution is added dropwise with stirring of sodium (9.85 g, 142.8 mmol) in water (40 ml) during a period of 30 min. The reaction mixture is stirred at a temperature from -5 to 02C for another 1.5 hours, and then stirred at room temperature for 1 hour. Acetone is removed, and then the reaction mixture 75 is diluted with 500 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous Ma 2504 and concentrated. The crude mass is purified by crystallization from isopropyl acetate (9.0 g, 9690).

T.pl.: 134-13626.

IAIr:-252 (c 1.0, Men).

IN NMR (SOCIz) 5: 3.04 (dd, 9-14, 7.8Hz, 1H), 3.24 (dd, 9-14, 4.Hz, 1H), 4.39 (dd, 9-7 ,3, 41Hz, 1H). 7.42 (d, 9-8.7Hz, 2H), 8.16 (d, U-8.7Hz, 2H).

IR (pure substance) cm"!: 3485, 3180, 2927, 1715, 1515, 1343.

Mass t/z (SI): 212 (Mt).

Step (ii) ch (5)-2-Hydroxy-3-(4-nitrophenyl)upropionic acid (9.0 g, 42.bmmol), obtained in step (ii) above, is dissolved in dry ETHONE (ZOO ml). To this solution add conc. H2O, (32 bml, 5.9 mmol) and heated to i) reflux for 5 h. The reaction mixture is neutralized with aqueous sodium bicarbonate. Ethanol is concentrated on a rotary evaporator and the residue is dissolved in ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate, water, and brine, then dried over anhydrous NaCl, and concentrated.

The desired product is obtained from the curd by crystallization from isopropyl ether (8.0 g, 78.5905). with

T.pl.: 74-76960, Yu

IAIo: -132 (s 1.0, MeOnH).

IN NMR (SOSIv) 5: 1.30 (t, 9-7 Hz, ЗН), 3.06 (dd, 9-14, 7 Hz, 1Н), 3.25 (dd, 9U-14,4,3 , Hz, 1H), 4.25 (q, so dETHC, 2H), 4.25 (dd, 9-7, 4.3Hz, 1H), 7.42 (d, 9U-8.7Hz, 2H), 8.16 (d, U-8.7Hz, 2H). -

IR (pure substance) cm"!: 3432, 2924, 1736, 1518, 1347.

Mass t/ASI): 240 (M--1).

Stage(s) «

To the mixture of (5)-ethyl-2-hydroxy-3-(4-nitrophenyl)propionate (4.77g, 19.95mmol) obtained in step (ii) above, molecular sieves (4A) (5.0g) and powdered Ad2O (13.8g, 59.8mmol) in dry acetonitrile (100ml) c) with added ethyl iodide (b.4ml, 79.8mmol) at room temperature. The reaction mixture is heated at 60°C for 16 hours. The reaction mixture is filtered through celite and concentrated. The crude mass is subjected to chromatography using ethyl acetate and hexanes, obtaining the desired product as a viscous liquid (3.5 g, yield of isolated substance 67905). Regenerate unreacted starting material (90Omg), which can be reused. 7 (ATo:-26e(c1.0, MeOH). (ee) TN NMR (SOSII) 8: 1.15 (t, 9U-7Hz, ZN); 1.26 (t, 9U-7.1Hz, ZN ); 310 (d, 9-3.8 Hz, 71); 3.13 (s, 1H); sl 3.16-3.35 (m, 1H); 3.45-3.65 (m, 1H) ; 4.03 (dd, 9U-7.5, 554Hz, 1H); 4.21 (q, U-7.2Hz, 2H); 7.43 (d, uU-8.6Hz, 2H); 8, 15 (d, U-8.6Hz, 2H). ko IR (pure substance) cm": 2980, 1747, 1604, 1521, 1347.

GI Mass t/ASI): 268 (M-1).

Stage (im) (5)-Ethyl-2-ethoxy-3-(4-nitrophenyl)propionate (6.0, 25.3 mmol), obtained in stage (ii) above, is dissolved in dry methanol (1000 ml). 1095 Pa/C (2.0 g) is added to this solution and hydrogenated using hydrogen gas (138 kPa (2 Orzi)) for 3-4 hours. The reaction mixture is filtered through celite, and the filtrate (F) is concentrated to obtain a syrupy mass. The product is obtained in quantitative yield. ko IAIr: -14.22 (with 1.0, Men).

Chiral HPLC: e.n. (enantiomeric excess) 298905. in "IN NMR (SOSI»v) 5: 1.16 (t, 9U-7.0Hz, ZN), 1.22 (t, 9-7.0Hz, ZN), 2.90 (d, 9-6.3Hz, 2H), 3.30 (width, 2H, МН»), 3.24-3.42 (m, 71H), 3.50-3.70 (m, 71H ), 3.94 (t, 9U-6.3Hz, 1H), 4.15 (kv, U-7.0Hz, 2H), 6.62 (d, 9U-8.3Hz, 2H), 7.03 (d, U-8.0Hz, 2H).

IR (pure substance) cm": 3372, 1738.

Mass t/ (CI): 238 (M'-1), 192 (M-ОЧН5). 65 Synthesis of 21 (5)-Ethyl-2-methoxy-3-(4-aminophenyl)propionate H Ome

Stage(s)

To the mixture of (5)-ethyl-2-hydroxy-3-(4-nitrophenyl)propionate (12.5 g, 52.3 mmol) obtained in stage (ii)

Synthesis of 20 and powdered AdoO (36.3g, 157mmol) in dry acetonitrile (260ml) was added methyl iodide (13ml, 209.2mmol) at room temperature. Activated molecular sieves (4A) (12.5 g) are added, and then the reaction mixture is stirred at room temperature for 16 h. The reaction mixture was filtered through celite and concentrated. The crude mass was subjected to chromatography using ethyl acetate and hexanes to give the desired product as a viscous liquid (10.Og, 75905).

IATr: -30.12 (with 1.0, MeOnH).

IN NMR (SOSIv) 85: 1.24 (t, 9-7.1 Hz, ZN); 3.09 (d, 9-5.4Hz, 1H); 3.12 (d, 9-2.7Hz, 1H); 3.35 (c, ZN); 3.96 (dd, uU-7.5, 5.1Hz, 1H); 4.19 (sq, U-7.1Hz, 2H); 7.39 (d, U-8.6Hz, 2H); 8.13 (d, U-8.6Hz, 2H).

IR (pure substance) cm"!: 2995, 1747, 1604, 1521, 1343.

Mass t/z (SI): 254 (M'1).

Stage (ii) (5)-Ethyl-2-methoxy-3-(4-nitrophenyl)propionate (8.0, 31.bmol), obtained in stage (ii) above, is dissolved in dry methanol (200 ml). 1095 Ra/s (2.5 g) is added to this solution and hydrogenated using hydrogen gas (138 kPa (2 Orzi)) for 3-4 hours. The reaction mixture is filtered through celite and concentrated to a syrupy mass. After column chromatography using a mixture of ethyl acetate/hexanes, the desired product is isolated as a viscous liquid (7.0 g, quantitative yield).

IAIo: -14.12 (with 1.0, Men).

Chiral HPLC: e.n. 298965. p. 29 "IN NMR (SOSIV) 5: 1.23 (t, 9-7.2Hz, ZN), 2.91 (d, U-6.1Hz, 2H), 3.30 (lat.s, 2Н, МН»), 3.34 (с, ЗН), 3.88 (t, Го)

U-6.2Hz, 1H), 4.17 (q, U-7.2Hz, 2H), 6.62 (d, 9U-8.3Hz, 2H), 7.01 (d, 9-81Hz, 211 ).

IR (pure substance) cm/!!: 3372, 2985, 2932, 1739, 1627, 1519.

Mass t/z (SI): 223 (M), 234 (M.-1), 192 (M-OMe). with

Synthesis 22

Ethyl-2-isopropoxy-3-(4-aminophenyl)propionate

Stage (i) - 4-Nitrophenylalanine (5g, Eq., mmol) is added in portions to a solution of dry ethanol (ml) and thionyl chloride (ml) at -59C. The mixture is stirred at this temperature for another hour and then stirred at room temperature for 1 hour. The reaction mixture is concentrated on a rotary evaporator, subjected to azeotropic distillation with toluene, and then dried using a high-vacuum pump, obtaining C 70 hydrogen chloride salt of the complex ethyl ester of 4-nitrophenylalanine in the form of a white solid substance c (quantitative yield). with" Stage(s)

The hydrogen chloride salt of the complex ethyl ester of 4-nitrophenylalanine (2g, 1.Eq., 7.28mmol), obtained in stage (i), is dissolved in ethyl acetate (1500ml). Add to it Ma»SO» (38bmg, 0,100 mg, 3,64mmol) and stir for 15 minutes. The reaction mixture is washed with aq. Manso from The organic layer is dried (Ma»5O,/) and concentrated, obtaining ethyl ester of 4-nitrophenylalanine in the form of a viscous oily liquid about (1.55 g, 8996).

Stage (ii) i-th Ethyl ester of 4-nitrophenylalanine (1.55 g, 1.0 equiv., 6.51 mmol), obtained in stage (ii) above, is dissolved in chloroform (3 mL). Glacial acetic acid (20 μl, 0.Obeq., 0.3 mmol) and isoamyl nitrite (958 μl, 1.Obq., 7.1 mmol) are added to it, and the reaction mixture is heated to boiling under reflux for 30 min. The reaction mixture is diluted with chloroform and washed with aq. Manso from The organic layer is dried (Ma»5O),) and concentrated (carefully!) to a yellowish liquid.

Stage (im)

The liquid (1.54 g, 71.0 equiv., 6 b, 18 mmol) obtained in this way at stage (ii) is dissolved in dry

HF) isopropanol (3ml), a catalytic amount of KpPo(OAc)/.2H2.O (38 mg, 0.02 eq., 0.12 mmol) is added to it, and the reaction mixture is stirred at room temperature for 16 hours. Isopropanol is concentrated and the reaction mixture is diluted with ethyl acetate. The organic layer was washed with water and brine, dried (Ma 250.) and concentrated. After column chromatography using ethyl acetate and hexanes, the desired compound 60 is obtained - ethyl 2-isopropoxy-3-(4-nitrophenyl)propionate (1.25 g, total yield 6196). 78 iNMR (200MHz, SOSI) 8: 0.92 (d, 9-5.8Hz, ZN), 1.16 (d, 9U-5.8HzC, ZN), 1.27 (t, 9-7.4Hz , ЗН), 3З.00-3.10 (m, 2Н), 3.52 (quintet, 71Н); 4.08 (dd, 9-8.7 and 48Hz, 1), 4.21 (kv, U-74Hz, 2H), 7.43 (d, -8.7Hz, 2H), 8.16 (d, 9-8.7Hz, 2H). 65 IR (pure substance) cm": 2975, 1747, 1602, 1522, 1347.

Mass t/dSI): 282 |M'-11.

Stage (M)

Ethyl 2-isopropoxy-3-(4-nitrophenyl)propionate (1.52 g, 54 mmol), obtained in stage (M), is hydrogenated at a pressure of 9 kPa (1 Org) with molecular hydrogen using 1095 Pa/cС (700 mg) as a catalyst in ethyl acetate (200 ml) at room temperature for 3-4 hours. The desired product is isolated after filtering the reaction mixture and concentrating the filtrate under reduced pressure. Column chromatography of the crude mass using ethyl acetate and hexanes gives the desired compound - ethyl 2-isopropoxy-3-(4-aminophenyl)propionate (1.16g, total yield 86965).

TN about nMR (200 MHz, SOSIi) 8: 0.97 (d, 9U-5.8Hz, ZN), 1.15 (d, 9U-5.8Hz, ZN), 1.23 (t, 9-7, 0 GHz, ZN), 70 2.80-2.95 (m, 2H), 3.49 (quintet, 71H); 3.98 (dd, 9-8.1 and 5.7Hz, 1H), 4.16 (kv, U-7.0Hz, 2H), 6.61 (d, -8, ZHZ, 2H), 7, 03 (d, U-8.3Hz, 2H).

IR (pure substance) cm"!: 3455, 3371, 2975, 2929, 1737, 1626, 1519/

Mass t/ (SI): 252 |M 1).

Example 1

Ethyl-3-I4-3-(3,4-dipdro-2H-benzoyl|51/1,Zoxazin-4-yl)/propylamino)-phenyl|-2-ethoxypropionate c

That's it

SU

Ethyl 2-ethoxy-3-(4-aminophenyl)propionate (2g, Eq., 8.4mmol), obtained in Synthesis 1, 3-(3,4-dihydro-2H-benzo|5)/1,Zoxazin- 4-yl)upropyl bromide (2.36 g, 1.1 eq., 9.0 mmol), obtained in Synthesis 2, and anhydrous CosSoO (3.5 g, eq., 25 mmol) were heated at 702 in DMF (40 Oml) for 24 h. The reaction mixture is diluted with ethyl acetate, washed with water and brine. The residue was chromatographed using a mixture of ethyl acetate and hexane as eluent to give the title compound as a viscous liquid c (1.04 g, yield 3095). Go)

TN NMR (200MHz, SOSIv) 8: 1.17 (t, 9-7.0HzC, ZN), 1.23 (t, 9U-7.0HzC, ZN), 1.92 (kv, U-7.0Hz , 2H), 2.90 (d, 9U-6.8Hz, 2H), 3.20 (t, 9U-7.0Hz, 2H), 3.22-3.41 (m, 5H), 3.45 -3.62 (m, 71H), 3.95 (t, 9U-64Hz, 1), 4.05-4.37 (m, 4H), 6.65 (d, U-8.3Hz, 2H) , 6.61-6.85 (m, 4H), 7.05 (d, U-8.3Hz, 2H).

IR (pure substance) cm": 3396 (width), 1740. cm

Mass ti/l" (SI): 413 (M). high school

Example 2 3-I4-13-(3,4-Dihydro-2H-benzo|5111,Zoxazin-4-yl)upropylamino)phenyl|-2-ethoxypropionic acid o

So som so

S ate -

Ethyl 3-14-13-(3,4-dihydro-2H-benzo[1/1,Coxazin-4-yl)/propylamino)phenyl]-2-ethoxypropionate (700mg, 0.9v8mmol), obtained in Example 1 , hydrolyzed with the help of lithium hydroxide monohydrate (12 mg, 2.9 mmol) in methanol-water at room temperature until the starting material is completely consumed (4-5 hours). The 70% reaction mixture is diluted with water, the solution is acidified. NCI to set the pH to about 4-5, and then extract with ethyl acetate. The ethyl acetate layer is dried over NaClO and concentrated on a rotary evaporator. The residue "c" was subjected to chromatography using methanol and chloroform, obtaining the title compound as a viscous liquid (256 mg, yield 6890).

TN nMR (200 MHz, SOSIv) 85: 1.19 (t, 9U-7.4Hz, ZN), 1.94 (q, 9U-7.4Hz, 2H), 2.90 (dd, U-14.0 and 7.0Hz, -I 1H), 3.05 (dd, 9U-14.0 and 4.9Hz, 1), 3.21 (t, U-6.8Hz, 2H), 3.25-3, 40 (m, 5H), 3.40-3.62 (m, 1H), 4.00-4.17 (m, 1H), 4.18-4.22 (m, 2H), 6.59 ( d, U-8.3Hz, 2H), 6.65-6.85 (m, 4H), 7.06 (d, U-8.3Hz, 2H).

So IR (pure substance) cm": 3500, 1725. "sl Mass t/ (SI): 385 (Mya1).

Example C o Arginine salt of 3-I4-13-(3,4-dihydro-2H-benzoyl|β1(1,Zoxazin-4-yl)-propylamino)phenyl|-2-ethoxypropionic acid from su Son MH

To a solution of 3-I4-13-(3,4-dihydro-2H-benzoic acid 81/11, Coxazin-4-yl)propylamino)-phenyl|-2-ethoxypropionic acid (200 mg, Eq., 0.52 mmol) , obtained in Example 2, in dry methanol:dichloroethane (10:1) (5 ml), add I-arginine (90.5 mg, Eq., 0.52 mmol) and leave with stirring for 3-4 hours. The solvent is removed on a rotary evaporator at 60, and then subjected to azeotropic distillation with benzene. The residue is dried using a high vacuum pump to give the title compound as a free-flowing solid (yield 10090), mp: 92-9496,

DSC: endothermic peak (weak and broad): 66.62С/

X-ray analysis: Amorphous substance. because Example 4

Ethyl 3-I(4-M-heptyl-M-(2-(3-oxo-3,4-dihydro-2H-benzo|51(11,Oxanin-4-yl)ethylamino)phenyl|-2-ethoxypropionate

3-Oxo-3,4-dihydro-2H-benzoyl 81/11, Tsoxazin (185mg, 1.24mmol), ethyl-2-ethoxy-3-I4-7M-heptyl-M-(2'-bromethyl))amshofent|propionate (50Omg, Leq., 1.1Zmmol), received at UU

Synthesis 3, and anhydrous KSO" (468mg, Zeq., 339ummol) are heated at 709 in DMF (bml) for 16 hours. 70 The reaction mixture is diluted with ethyl acetate, washed with water and brine. The residue was chromatographed using a mixture of ethyl acetate and hexanes as eluent to give the title compound as a viscous liquid (Z36Zmg, yield 63965).

TN NMR (200MHz, SOSIZ) 85: 0.88 (width, U-6.3Hz, ZN), 1.05-1.42 (m, 14H), 1.42-1.68 (m, 2H ), 2.92 (d,

U-6.8Hz, 2H), 3.25 (t, 9U-7.3Hz, 2H), 3.30-3.45 (m, 1H), 3.50-3.70 (m, ZN), 3.97 (t, 9U-6.6HzC, 1H), 4.08 (t, iz U-7,ZHC, 2H), 4.17 (kv, U-7,OGcC, 2H), 4.57 ( s, 2H), 6.57 (d, U-8.9Hz, 2H), 6.99 (s, AN), 7.10 (d, U-8.0Hz, 2H).

IR (pure substance) cm": 1747.

Mass t/2 (SI): 511 (M't).

Example 5 3-I4-M-Heptyl-M-12-(3-oxo-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)-ethylamino)phenyl|-2-ethoxypropionic acid

WITH

SH Lochlov

Сас дво ут (о) 3-I(4-M-Heptyl-M-2-(3-oxo-3,4-dihydro-2H-benzo|b1(1,Zoxazin-4-yl)-ethylamino) phenyl|-2-ethoxypropionate (35O0mg, Eq., O0.6v8mmol), obtained in Example 4, is hydrolyzed with the help of lithium hydroxide monohydrate (8bmg, Eq., 2.04mmol) in methanol-water at room temperature until the starting material is completely consumed (4-Bh.). The reaction mixture is diluted with water, acidified with HCl solution to pH 2-3, and then extracted with ethyl acetate.

The ethyl acetate layer is dried over NaCl5O and concentrated on a rotary evaporator. The residue was subjected to chromatography using methanol and chloroform, obtaining the title compound as a resinous mass (197 mg, yield 60905). is)

TN nMR (200MHz, SOSIv) 85: 0.88 (width, U-6.3Hz, ZN), 1.05-1.42 (m, 11H), 1.42-1.68 (m, 2H ), 2.82-3.10 so (m, 2), 3.25 (t, 9U-7.3HZ, 2H), 3.40-3.70 (m, 4H), 3.98-4, 15 (m, ZN), 4.56 (s, 2H), 6.67 (d, 9U-8.3Hz, 2H), 8.98 (s, AN), 7.10 (d, U-8, 0Hz, 2H). in

IR (pure substance) cm": 3500 (width), 1687.

Mass t/z (SI): 483 (M'1).

Example 6 "

Arginine salt -o c 70 3-I4-M-heptyl-M-12-(3-oxo-3,4-dihydro-2H-benzoi|b1(1,Zoxazin-4-yl)ethylamino)phenyl|-2- ethoxypropionic acid o z M red turttrv -k OB Ob:n mn boty -1 395 3-I4-M-Heptyl-M-12-(3-oxo-3,4-dihydro-2H-benzoi|51(11,Zoxazin -4-yl)-ethylamino)phenyl)|-2-ethoxypropionic acid (15mg, eq., 0.3 mmol), obtained in Example 5, and I -arginine (54 mg, eq., 0.3 mmol) are diluted in (ee) dry methanol (2 ml) and stir at room temperature for 2 hours. The solvent is removed on a rotary evaporator, and then subjected to azeotropic distillation with benzene. The residue is dried using a high-vacuum pump, obtaining the title compound as a free-flowing solid (yield: 70 10095), mp: 118-120.

Kz Example 7

Methyl-2-ethoxy-3-14-("M-heptyl-M-(2-(3,4-dipdro-2H-benzo|ph|oxazin-4-yl)-2-oxoethyl)iaminomethyl)phenyl|propio nat o o

2-(3,4-Dihydro-2H-benzo|p|oxazin-4-yl)carboxymethyl chloride (208 mg, Eq., O0.98 mmol) obtained in Synthesis 4 and methyl-2-ethoxy -3-I4-(M-heptylaminomethyl)-phenyl|propionate (ZOOmg, Eq., O0.869mmol), obtained in Synthesis 6, in acetonitrile (bml) is treated with anhydrous sodium carbonate (285mg, Eq., 2.6vmmol). The reaction mixture is stirred at 802C for 4 hours. TLC shows the absence of starting materials. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using ethyl acetate and hexane to give the title compound (25mg, yield 5590) as a viscous liquid.

TN about NMR (200 MHz, SOSIi) 85: 0.86 (width t, 9U-6.3Hz, ZN), 1.14 (t, 9U-6.8Hz, ZN), 1.20-140 (m, 8H), 1.50-1.70 (m, 2H), 2.57 (t, 9U-7.0Hz, 2H), 2.99 (d, 9U-6Hz, 2H), 3.22-4, 40 (m, 11Н), 3.67 (s, ЗН), 6.80-7.26 (aromatic core, 8Н).

IR (pure substance) cm": 1752, 1683.

Mass t/z (SI): 511 MT).

Example 8 2-Ethoxy-3-(4-7M-heptyl-M-(2-(3,4-dihydro-2H-benzo(b|oxazin-4-yl)-2-oxoethyl)aminomethyl)phenyl|propionic 70 acid

SO) Eat

Dena Ha1-

Methyl 2-ethoxy-3-14-M-heptyl-M-(2-(3,4-dihydro-2H-benzo|p|oxazin-4-yl)-2-oxoethyl)aminomethyl)phenyl|propionate (24mg, eq., 0.47mmol), obtained in Example 7, is hydrolyzed with the help of lithium hydroxide monohydrate (99mg, eq., 2.35mmol) in methanol-water at room temperature (takes 4-5 hours). The reaction mixture was acidified with aqueous HCl and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed (ethyl acetate and hexane-»methanol/chloroform) to give the title compound (13mg, yield 56905) as a viscous liquid.

TN nMR (200 MHz, SOSIv) 5: 0.86 (width t, U-6.3 Hz, ZN), 1.10-1.40 (m, 11), 1.40-1.60 (m, 2H ), 2.79 (t, c 29 y-7.5Hz, 2H), 2.90-4.22 (m, 1ZH), 6.80-7.26 (aromatic core, 8H). Gee)

Mass t/z (SI): 497 |MA1).

Example 9

Arginine salt of 2-ethoxy-3-(4-1M-heptyl-M-(2-(3,4-dihydro-2H-benzo|p|oxazin-4-yl)-2-oxoethyl)aminomethyl)phenyl|propionic acid acid Ha

IS) p

2-Ethoxy-3-(4-(M-heptyl-M-(2-(3,4-dipdro-2H-benzo|p|oxazin-4-t)-2 -oxoethyl)aminomethyl)phenyl|propionic acid (9mg, 0.18mmol) obtained in Example 8 and I!-arginine (32mg, 0.18mmol) are diluted in dry methanol (2ml) and stirred at room temperature for 2- Accord The solvent is removed on a rotary evaporator and then azeotroped with benzene.The residue is dried with a high vacuum pump for 8 s to give the title compound as a free-flowing solid (yield

Iz" 10096), t.pl.: 118-12090,

Example 10 15 Methyl 3-14-75-(3,4-dihydro-2H-benzoyl|81/11, Zoxazin-4-yl)-5-oxopentylamino)phenyl)|-2-ethoxypropionate. Solution of methyl-2-ethoxy-3-(4-aminophenyl)propionate (337mg, Eq., 1.51mmol), obtained in Synthesis 7, and name) 5-(3,4- dihydro-2H-benzo(β)/1,Zoxazin-4-yl)-5-oxopentyl bromide (45 Ω, Leq., 1.5 immol), obtained in

GE Synthesis 8, in DMF (bml) is treated with anhydrous potassium carbonate (627mg, Zeq., 4.54mmol) and the reaction mixture is stirred at 702 for bh. The reaction mixture is diluted with ethyl acetate, washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using ethyl acetate and hexane to give the title compound as a viscous liquid (17mg, yield 27905). o TN o nNMR (200MHz, SOSIV) 8: 1.16 (t, 9U-7.0Hz, ZN), 1.50-1.70 (m, 2H), 1.70-1.90 (m, 2H ), 2.64 (t, ime) U-7.0Hz, 2H), 2.89 (d, 9U-6.9Hz, 2H), 3.08 (t, 9U-6.7Hz, 2H), 3 ,22-3.42 (m, 71H), 3.42-3.62 (m, 2H), 3.68 (s,

ЗН), 3.88-4.00 (m, ЗН), 4.26 (t, 9-48, 2Н), 6.50 (d, 9U-7.8Hz, 2Н, aromatic nucleus), 6.82 -7.10 (aromatic 60 core, AN), 7.04 (d, 9-7.8Hz, 2H, aromatic core).

IR (KVh) cm"":3408, 1739, 1683.

Mass t/dSI): 441 MAT).

Example 11 3-I4-15-(3,4-Dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)-5-oxopentylamino)-phenyl|-2-ethoxypropionic acid b5

SO Sen beat rya

And in

Methyl 3-I4-75-(3,4-dihydro-2H-benzoyl| 81/11, Zoxazin-4-yl)-5-oxopentylamino)-phenyl|-2-ethoxypropionate (211 mg, Eq., 0.48 mmol ), obtained in Example 10, is hydrolyzed with the help of lithium hydroxide monohydrate (bomg, Zeq., 1.44 mmol) in methanol-water at room temperature (takes 4-5 hours). The reaction mixture is diluted with water, acidified (pHZ-4) with aqueous NOSI, and then extracted with ethyl acetate. The 7/0 ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed (ethyl acetate and hexane-»methanol/chloroform) to give the title compound (139mg, yield 68905) as a viscous liquid.

TN nMR (200MHz, SOSIv) 8: 1.14 (t, 9U-7.0Hz, ZN), 1.50-1.p90 (m, 2H), 2.62 (t, 9-6.8Hz, 2H ), 2.80-3.15 (m, 4H), 3.22-3.42 (m, 1H), 3.42-3.62 (m, 1H), 3.82-4.00 (m . , 2H, aromatic core), 6.82-7.10 (aromatic core, 4H), 7.04 (d, 9U-7.8Hz, 2H, aromatic core).

IR (KVh) cm"!: 3408, 1719, 1680.

Mass ti/z (SI): 427 |M--1).

Example 12

Arginine salt of 3-I4-15-(3,4-dihydro-2H-benzoyl| 81/11, Zoxazin-4-yl)-5-oxopentylamino)phenyl)|-2-ethoxypropionic acid

So, 3-I4-15-(3,4-Dihydro-2H-benzo|5111,Zoxazin-4-yl)-5-oxopentylamino)phenyl|-2-ethoxypropionic acid (120Omg, Eq., O0.28mmol), obtained in Example 11, and I-arginine (49mg, Eq., 0.28mmol) are diluted in dry methanol (3ml) and stirred at room temperature for 2 hours. The solvent is removed on a rotary evaporator and then subjected to azeotropic distillation with benzene. The residue is dried using an EM high-vacuum pump, obtaining the title compound as a free-flowing solid (yield c 10096), mp: 137-139960,

Example 13 and)

Methyl-3-(3-73-(3,4-dihydro-2H-benzoyl|81(11,Zoxazin-4-yl)propylamino)-phenyl|-2-ethoxypropionate with BI soma -

That

Methyl 2-ethoxy-3-(3-aminophenyl)upropionate (20mg, Cheq., 0.89mmol), obtained in the Synthesis of o, 3-(3,4-dihydro-2H-benzo|5)/1,Zoxazin- 4-yl)upropyl bromide (253 mg, 1.1 equiv., 0.98 mmol), obtained in Synthesis 2, « lo. And anhydrous Ma»CO»z (285 mg, Zeq., 2.6 vmmol) is heated at 702 in DMF (bml) for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The residue was subjected to chromatography using ethyl acetate and hexane, obtaining the title compound (304 mg, yield 8690) as an viscous liquid.

TN nMR (200MHz, SOSIv) 5: 1.17 (t, 9-7Hz, ZN), 1.98 (q, 9U-7Hz, 2H), 2.92 (d, U-6.8Hz, 2H), 3.19 (t, SHETHC, 2H), 3.22-3.41 (m, 5H), 3.45-3.62 (m, 1H), 3.70 (s, ЗН), 4.02 ( t, 9U-64Hz, 1n), 4.22 (t, 9U-4.3Hz, 2H), -| 6.40-6.82 (m, aromatic nucleus, 6H), 6.75 (d, 9U-7.8Hz, 1H), 7.08 (t, U-7.8Hz, 1H). o IR (pure substance) cm": 3380 (width), 1743, 1680.

Mass t/z (SI): 399 (M 1). 1 Example 14 out of 20

Methyl 3-(3-73-(3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionate (35Omg,

Eq., O0.87mmol), obtained in Example 13, hydrolyze with the help of lithium hydroxide monohydrate (11Omg, (F) Eq., 2.64mmol) in methanol-water at room temperature until the starting materials are completely consumed

GI (4-5 hours). The reaction mixture is diluted with water, acidified (pH about 4-5) solution. NSII, and then extracted with ethyl acetate. The ethyl acetate layer is dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was subjected to chromatography using methanol and chloroform to give the title compound (203Zmg, yield 61905) as a viscous oily liquid. "YAN NMR (200MHz, SOSIv) 5: 1.19 (t, 9-7.4Hz, ZN), 1.94 (kv, U-7.4Hz, 2H), 2.85-3.60 (m, ЮН), 4 00-4.17 (m, 1Н), 4.23 (t, У-4.4Гцу, 2Н), 4.95 (shyr.s, МН, СОН), 6.42-7, 20 (aromatic core, 8H).

IR (pure substance) cm'!: 3500 (width), 1727. 65 Mass t/z (SI): 385 (Mya1).

Example 15

Arginine salt of 3-I3-13-(3,4-dihydro-2H-benzoyl|β1(1,Zoxazin-4-yl)-propylamino)phenyl|-2-ethoxypropionic acid

Hn) ; 3-I3-13-(3,4-Dihydro-2H-benzo|8111,Zoxazin-4-yl)ipropylamino)phenyl|-2-ethoxypropionic acid (9Omg,

Teq., 0.2Zmmol) obtained in Example 14, and I-arginine (40.8mg, Teq., 0.2Zmmol) are diluted in dry methanol (bml) and stirred at room temperature for 2 hours. The solvent is removed on a rotary evaporator, and then subjected to azeotropic distillation with benzene. The residue is dried using a high-vacuum pump to give the title compound as a free-flowing solid (yield 10096), mp: 178-180,

Example 16

Methyl 3-I4-73-(7-fluoro-3,4-dihydro-2H-benzo[in]/1,Zoxazin-4-yl)-propylamino)phenyl)|-2-ethoxypropionate

ate by himself

Hm!

Methyl-2-ethoxy-3-(4-aminophenyl)upropionate (405.8 mg, Cheq., 1.82 mmol), obtained in the Synthesis of "17, 3-(7-fluoro-3,4-dihydro-2H-benzoic acid) 51I(1,Zoxazin-4-yl)upropylbromide (50Omg, Leq., 1.82mmol), obtained in

Synthesis 10, and anhydrous Ma»CO»z (572 mg, Eq., 5.4 mmol) are heated at 702C in acetonitrile for 24 hours.

The reaction mixture is diluted with ethyl acetate, washed with water and brine. The residue was subjected to chromatography using ethyl acetate and hexane to give the title compound (3Z3Zmg, yield 4490) as a viscous liquid. se 29 TN nMR (200MHz, SOSIV) 8: 1.17 (t, U-7Hz, ZN), 1.88 (q, U-7HzC, 2H), 2.91 (d, U-6.8Hz, 2H ), 3.10-3.42 g) (m, 7), 3.45-3.65 (m, 1Н), 3.69 (s, ЗН), 3.98 (t, 9U-6.3ГЦ , 1), 4.22 (t, 9U-3.9Hz, 2H), 6.40-6.70 (m, aromatic core, 5H), 7.04 (d, 9U-8.3Hz, 2H).

IR (pure substance) cm": 3382 (width), 1746, 1616.

Mass t/z (SI): 417 (M'1). cm 30 Example 17 sa 3-I4-43-(7-Fluoro-3,4-dihydro-2H-benzoyl|51/1,oxazin-4-yl)propylamino)-phenyl|-2-ethoxypropionic acid

O0 yo roll (ee) 35 shk ov m

Methyl-3-I4-73-(7-fluoro-3,4-dihydro-2H-benzo|v)/1,Zoxazin-4-yl)-propyl-amino)phenyl|-2-ethoxypropionate (180 mg, Eq. . The reaction mixture is diluted with water, acidified (pH about 4-5) solution. NSII, and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue is subjected to chromatography using ethyl acetate and hexanes -» methanol and;» chloroform to give the title compound (121 mg, yield 7095) as a viscous liquid.

TN nMR (200MHz, SOSIi) 8: 1.19 (t, 9-7.4Hz, ZN), 1.94 (quintet, 9-7.4Hz, 2H), 2.85-3.10 (m, 2H ), 45 3.10-3.20 (m, 6H), 3.40-3.70 (m, 2H), 3.90-4.10 (m, 1H), 4.10-4.30 ( m, 2H), 6.20 (shr.s, СО2Н), 6.42-6.70 (m, -| aromatic nucleus, 5Н), 7.07 (d, 9U-8.3Hz, 2Н). about IR (KVh) cm"!: 3394, 1725, 1619.

Mass t/z (SI): 403 (Mya1). 1 Example 18 of 20 Arginine salt of 3-I4-13-(7-fluoro-3,4-dihydro-2H-benzo|5)/1,Zoxazin-4-yl)propylamino)phenyl|-2-ethoxypropionic acid potom n dream Mn, MNN

SYA a Ton Te

N

Gee! 3-I4-13-(7-Fluoro-3,4-dihydro-2H-benzo|(81(/11,Coxazin-4-yl)upropylamino-phenyl|-2-ethoxypropionic acid) (12Omg, Eq., 0.298mmol ), obtained in Example 17, and I -arginine (52 mg, eq., O0.298 mmol) are diluted in dry methanol (2 ml) and stirred at room temperature for 2 h. The solvent is removed on a rotary evaporator, and then subjected to azeotropic distillation with benzene.The residue was dried using a 60 high vacuum pump to give the title compound as a free-flowing solid (yield 10096), mp: 158-160260.

Example 19

Methyl-2-ethoxy-3-I4-14-(3-(3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)-propyloxy)benzylaminophenyl|propionate b5

Fe sSozme z slya in su N

A mixture of methyl-2-ethoxy-3-14-(4-hydroxybenzyl)aminophenyl)ipropionate (b0Omg, Eq., 1.82 mmol) obtained in

Synthesis of 12, 3-(3,4-dihydro-2H-benzoyl|81(11,Zoxazin-4-yl)upropyl bromide (467 mg, Eq., 1.82 mmol), obtained in

Synthesis 2, and anhydrous K»CO»z (755mg, Zeq., 5.4bmmol) in DMF (10ml) was stirred at room temperature for 1h. The reaction mixture is diluted with ethyl acetate, washed with water and brine. The organic layer is then dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using E(OAc/hexanes) to give the title compound (520 mg, 56905 yield) as a viscous liquid.

TN NMR (SOSIZ, 200MHz) 5: 1.19 (t, U-7.0Hz, ZN), 2.00-2.20 (m, 2H), 2.90 (d, 9-6.3Hz, 2H ), 3.30-3.60 (m, 6H), 3.70 (sh. s, ЗН), 3.80-4.10 (m, ЗН ж- МН), 4.10-4.25 ( m, 4H), 6.57 (d, U-8.3Hz, 2H), 6.60-6.90 (m, 6H), 7.04 (d, 9U-8.3Hz, 2H), 7, 28 (d, U-8.3Hz, 2H).

IR (pure substance) cm"!: 3401 (width), 1742, 1614.

Mass pt/ (SI): 504 |MI, 505 |M--11.

Example 20

Methyl-2-ethoxy-3-I3-14-(3-(3,4-Dihydro-2H-benzoyl|51/1,Doxazin-4-yl)-propyloxy)benzylaminophenyl|propionate

M so.me and S a

With high school

The title compound was obtained (34Omg, yield 9090) as a viscous liquid from a mixture of He) methyl-2-ethoxy-3-13-(4-hydroxybenzyl)aminophenyl)-propionate (25Omg, Eq., O0.75mmol) , obtained in Synthesis 13, and 3-(3,4-dihydro-2H-benzoi|51I(/1,Zoxazin-4-yl)upropyl bromide (192 mg, Eq., 0.75 mmol), obtained in

Synthesis 2, following a procedure similar to that described in Example 19.

TN nMR (200MHz, SOSIv) 5: 1.19 (t, 9U-7.0Hz, ZN), 1.95-2.18 (m, 2H), 2.90 (d, 9U-6.3Hz, 2H ), 3.22-3.60 cm (m, 6H), 3.70 (width, ЗН), 3.90-4.10 (m, ЗН), 4.10-4.25 (m, 4H), 6.42-6.90 (aromatic core, 8H), 7.05 (t, He y-7,8,1H), 7.20-7.30 (m, aromatic core, ЗН). yu

IR (pure substance) cm": 3407 (width), 1742, 1607.

Mass p/z (Si): 504 |MI, 505 |M'-11. co

Example 21 chn 2-Ethoxy-3-(4-14-(3-(3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)-propyloxy)benzyl)iaminophsnyl|propionic acid with

Fa son « m suto - s o y ; z» Methyl-2-ethoxy-3-I4-14-(3-(3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)-propyloxy)benzyl)iaminophenyl|propionate (51Omg, Eq., 1.0 mmol), obtained in Example 19, is hydrolyzed with the help of lithium hydroxide monohydrate (127 mg, Eq., 3.0 mmol) in methanol-water at room temperature until the starting material is completely consumed (4-5 hours). The reaction mixture is diluted with water, acidified (pH about 3-4) using a solution. NSI, and then extracted with EUAs. The residue was chromatographed using ethyl acetate/hexanes to give the title compound (oo) as a sticky liquid (250mg, 51965). sl TN NMR (200MHz, SOSIv) 8: 1.18 (t, 9U-6.9Hz, ZN), 1.26 (t, 9U-7.3Hz, МН, М-Н), 1.98-2, 18 (m, 2H), 2.90 (dd, 9-14.1, 7.4Hz, 1H), 3.04 (dd, 9-14.1, 44Hz, 1H), 3.35 (t, 9U -4.2 Hz, 2H), 3.40-3.64 (m, 4H), 3.95-4.10 ime) (m, ZN); 4.10-4.25 (m, 4H), 6.57 (d, 9U-8.3HZ, 2H), 6.60-6.82 (m, 4H), 6.88 (d, 9U-8 ,3Hz, 2H), 7.05 (d,

KZ -8, ZHC, 2H), 7.28 (d,. M - 8.314, 2H).

IR (pure substance) cm": 3407, 1723, 1610.

Mass p/z (SI): 490 |MI, 491 |M--11. 5B Example 22 2-Ethoxy-3-(3-14-(3-(3,4-dihydro-2H-benzo|51(1,Zoxazin-4-yl)-propyloxy)benzyl)iaminophenyl|propionic (F. acid z pa i n zn vo SO Sta se

The title compound was obtained (22Omg, yield 5395) as a viscous liquid from methyl-2-ethoxy-3-I3-4-(3-(3,4-dihydro-2H-benzoi|51(1,Zoxazin- 4-yl)-propyloxy)benzylaminophenyl|propionate (42Omg, 0.83mmol), obtained in Example 20, according to a procedure similar to that described in Example 21. for TN nNMR (200MHz, SOCIv) 5: 1.15 (t, 9U -6.9Hz, ЗН), 1.26 (t, 9-7.3Hz, МН, М-Н), 1.98-2.18 (m, 2Н), 2.90

(dd, 9U-14.1, 7.8HZ, 7H), 3.05 (dd, 9U-13.7, З.9GuЦ, 1Н), 3.30-3.60 (m, b6Н), 3, 70 (width, height), 4.00-4.10 (m,

ЗН), 4.10-4.25 (m, 4Н), 6.42-6.90 (m, aromatic core, 8Н), 7.09 (t, 9У-7.8, 1Н), 7.20 -7.30 (m, aromatic nucleus, ZN).

IR (pure substance) cm": 3407 (width), 1725, 1606.

Mass of ti/z (SI): 491 |M'H1..

Example 23

Arginine salt of 2'ethoxy Z ICH884 dihydro-2H-benzoyl 4Hoxazin 1 yl)propyloxy) benzyl)aminophenylpropionic acid to Fo Hora Mys nm. g KN, god s oon cha 2-Ethoxy-3-(4-14-(3-(3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)ipropyloxy)-benzylaminophenyl|propionov /5 The acid (25mg, Eq., 0.5mmol) obtained in Example 21 and I-arginine (88.7mg, Eq., 0.5mmol) are stirred in dry methanol (3ml) for 3-4 hours at room temperature. Solvent concentrated on a rotary evaporator and then azeotroped with benzene.The residue was dried using a high vacuum pump to give the title compound as a solid (yield 10090), mp: 141-14296.

Example 24

Arginine salt of 2-ethoxy-3-(3-14-(3-(3,4-dihydro-2H-benzoic acid)

There is ZO Meretntvn school

St. 1 «1 soln MH o gl 2-Ethoxy-3-(3-14-(3-(3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)ipropyloxy)-benzylaminophenyl|propionic acid (14mg, Eq., O0.28mmol) obtained in Example 22, and I-arginine (5Omg, Eq., O0.28mmol) are stirred in dry methanol (3ml) for 3-4 hours at room temperature. The solvent is concentrated on a rotary c with the evaporator and then subjected to azeotropic distillation with benzene.

Example 25

Ethyl-2-ethoxy-3-I4-13-(3,4-dihydro-2H-benzoyl|51(11,4)hyazin-4-yl)y-propylamino)phenyl|propionate so

SO m.

M SOY

SANYA Che

NN

A mixture of 3-(3,4-dihydro-2H-benzoyl|51(11,hyazin-4-yl)upropyl bromide (1.7bg, 1.1eq., b,bmmol), obtained in "

Synthesis 14, ethyl-2-ethoxy-3-(4-aminophenyl)-propionate (1.4 g, 1.0 equiv., 5.9 mmol), obtained in Synthesis 1, and anhydrous KSO" (2.45 g, C , Equiv., 17.7 mmol) in dry DMF (3 mL) is stirred at room temperature. within 2 days. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water and brine. The organic layer was dried (Ma»5O)), concentrated and the residue subjected to chromatography using ethyl acetate and hexane to give the title compound as a viscous liquid (50mg, yield 2090).

TN nMR (200MHz, SOSIv) 8: 1.17 (t, 9U-6.8Hz, ZN), 1.23 (t, 9-6.6Hz, ZN), 1.27 (sh.s, 1H, M -H), 1.94 -i (quintet, 6.8Hz, 2H), 2.90 (d, U-6.9Hz, 2H), 3.03 (t, 9U-4.8Hz, 2H), 3 .20 (t, 9U-6.9Hz, 2H), 3.20-3.45 (m, ZN), so 3.45-3.64 (m, ZN), 3.95 (t, U-6 ,4HzC, 1H), 4.16 (q, U-6.9Hz, 2H), 6.50-6.72 (aromatic core, 4H), 6.90-7.10 (aromatic core, 4H). 1 IR (pure substance) cm": 3398, 2926, 1742, 1616. 7 50 Mass p/z (SI): 428 |MI, 429 |M--11.

Example 26

From 2-Ethoxy-3-I(4-13-(3,4-dihydro-2H-benzoyl|51(11,4Cgiazin-4-yl)/propylamino)-phenyl|propionic acid 5

Ethyl-2-ethoxy-3-I4-13-(3,4-dihydro-2H-benzoyl|51(11,4)hyazin-4-yl)upropylamino)-phenyl|Ipropionate (25Omg, imo ) 1.0 beq., O.58 mmol), obtained in Example 25, is hydrolyzed by treating GION-H-O (74 mg, Eq., 1.75 mmol) in a Meon-THF-water solvent mixture at room temperature for 3-4 hours. The reaction mixture is concentrated, 60 diluted with water and acidified (to pH 4) aq. NSI Finally, the crude acid is extracted with ethyl acetate.

The ethyl acetate layer is dried (Ma»5O)), concentrated and subjected to chromatography using as an eluent

Meon and CHO", yielding the title compound as a viscous liquid (152 mg, yield 6895).

TN nMR (200 MHz, SOSIi) 8: 1.17 (t, 9U-6.9Hz, ZN), 1.26 (shr.s, 1H, M-H); 1.93 (quintet, 6.9Hz, 2H), 2.85-3.10 (m, 4H), 3.02 (t, 9-51Hz, 2H), 3.19 (t, 9U-6.9Hz . .72 (aromatic core, 4H), 6.90-7.10 (aromatic core, 4H).

IR (pure substance) cm": 3411, 2929, 1726, 1616.

Mass p/z (SI): 400 |MI, 401 IM--11.

Example 27

Arginine salt of 2-ethoxy-3-(4-13-(3,4-dihydro-2H-benzoyl|β1(1,thiazin-4-yl)/upropylamino)phenyl|propionic acid 2

With soda tmnornn,

Syu ze hundred 70 Mixture of 2-ethoxy-3-(4-13-(3,4-dihydro-2H-benzoyl|51(/1,thiazin-4-yl)/propylamino)-phenyl|propionic acid (110mg, Tekv ., 0.27 mmol), obtained in Example 26, and I-arginine (47.9 mg, Eq., 0.27 mmol) are diluted in dry Meon (2.0 ml) and stirred at room temperature for 2 hours until a clear solution is formed.

The solvent is concentrated, the residue is subjected to azeotropic distillation with dry benzene and dried using a vacuum pump, obtaining the title compound as a solid (10095 yield), mp: 142-14490,

Example 28

Ethyl-2-ethoxy-3-I4-2-(3,4-dihydro-2H-benzoyl|51(11,COxanin-4-yl)-ethylamino)phenyl|propionate

WITH

CO) eye school

Cl

A mixture of 2-(3,4-dihydro-2H-benzoyl|1/1, Tsoxazin-4-yl)ethyl bromide (94Omg, LCequ., 3,bmmol), obtained in

Synthesis 15, ethyl 2-ethoxy-3-(4-aminophenyl)-propionate (1.0g, 1.Eq., 4.2mmol), obtained in Synthesis 1, anhydrous KSO" (1.6g, Eq., 10 .8 mmol) and tetrabutylammonium bromide (265 mg, 0.2 equiv., O0.bmmol) in dry toluene (20 ml) are heated at 902 for 24 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water, brine, and then dried (Ma»3O4) and concentrated. The residue was chromatographed with ethyl acetate and hexanes as eluent to give the desired product as a viscous liquid (9 mg, 60905). o "IN NMR (200MHz, SOSIA) 8: 1.17 (t, U-6.9Hz, ZN), 1.23 (t, 9-6.6Hz, ZN), 1.27 (sh.s, 1H , M-H), 2.90 (d,

U-64HzC, 2H), 3.20-3.65 (m, 8H), 3.95 (t, 9U-64Hzc, 1H), 4.05-425 (m, 4H), 6.56 (d, 9U-8.3Hz, 2H), 6.60-6.85 (aromatic core, 4H), 7.06 (d, U-8.3Hz, 2H). with

IR (pure substance) cm": 3395, 2977, 1740, 1616.

Mass pt/z (SI): 398 |MI, 399 |M--11.

Example 29 And c) 2 roksy ZAV dihydro-7H benzoiBI! loxazine- and yl)ethylamino phenylpropionic acid so

CO Str y-

Gary v

Ethyl 2-ethoxy-3-I4-12-(3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-ylethylamino)-phenyl|propionate (9bOmg, 1.0eq., 2.41mmol), obtained in Example 28, is hydrolyzed by treatment with HION.NoO (35Omg, Zeq., 7.2mMmol)

In a mixture of MeOH-THF-water solvents at room temperature for 3-4 hours. The reaction mixture is concentrated, then diluted with water and acidified (pH about 4-5) aq. NSI Finally, the crude acid is extracted with ethyl acetate. The ethyl acetate layer was dried (Ma»5O)), concentrated and chromatographed using "» Meon and CHCl3 as eluent to give the desired compound as a viscous liquid (37Omg, 42905). "IN NMR (200MHz, SOCl) 8:1 ... 9-14, 4.3Hz, 1H), 3.20-3.65 (m, 8H), 4.02 (dd, 9U-6.49, 4.4HzC, 1H), 4.21 (t, U -4.4Hz, 2H), 5.00 (width, SON), -and 6.58 (d, U-8.9Hz, 2H), 6.60-6.85 (aromatic core, 4H), 7.06 (d, 9U-8.3Hz, 2H).

Go! IR (pure substance) cm"!: 3383 (width), 2927, 1727, 1607.

Mass t/z (SI): 371 MT). 1 Example 30 ko 20 Arginine salt of 2-ethoxy-3-I4-(2-(3,4-dihydro-2H-benzo|81(/1,Zoxazin-4-yl)ethylamino)phenyl|propionic acid b dl tt

Hz se oon 7

The title compound is obtained as a free-flowing solid (m.p.: 142-144 22) from 2-ethoxy-3-(4-2-(3,4-dihydro-2H-benzoyl)|51/11,Doxazin -4-yl)uethylamino)phenyl|ipropionic acid, obtained in iF) Example 29, and I -arginine, according to a procedure similar to that described in Example 27. Example 31

Methyl-2-ethoxy-3-I4-I4-2-43,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)-ethoxy)phenylaminomethyliphenyl|propionate

court

her

A mixture of 4-2-(3,4-dihydro-2H-benzoyl|b1(1,Zoxazin-4-yl)ethoxy)aniline (305 mg, Cheq., 1.133 mmol), obtained 65 in Synthesis 16, methyl-2- ethoxy-3-(4-formylphenyl)propionate (267 mg, Eq., 1.13 mmol), obtained in Synthesis 5, activated molecular sieves (4A) and p-T2OH (21 mg, O, Eq., O0.11 mmol) in dry DCM (4 ml) is stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (10 Oml), washed with aq. sodium bicarbonate, dried (Ma»5O)) and concentrated. The crude mass is dissolved in dry methanol (bml) and conc. NCI (125 μl) at 02С, and then portions of Mav(SM)N with (118mg, 1.eq., 1.87mmol). The reaction mixture was stirred at 02C for 1 h, after which it was diluted with ethyl acetate (100 ml). The organic layer is washed with sodium bicarbonate, dried (Ma»5O)) and concentrated. The residue was chromatographed using ethyl acetate and hexanes to give the title compound as a viscous oily liquid (525mg, 8595). "YAN NMR (200MHz, SOSIV) 8: 1.16 (t, 9-6.9Hz, ZN), 1.25 (width, -MN-), 3.00 (d, 9U-6.8, 2H), 3.22-3.42 (m, 70 1H), 3.49 (t, 9-4.4Hz, 2H), 3.55-3.75 (m, ЗН), 3.71 (s , ZN), 3.99-4.12 (m, ZN), 4.15-4.24 (m, 4H), 6.50-6.90 (aromatic core, 8H), 7.19 (d, U-7.8Hz, 2H), 7.28 (d, U-8.0Hz, 2H).

IR (pure substance) cm"!: 3405 (width), 2927, 1746, 1606.

Mass p/z (SI): 490 |MI, 491 |M--11.

Example 32 2-Ethoxy-3-(4-(4-2-(3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)ethoxy)-phenylaminomethylphenyl|propionic acid)

So unit

And Mn h FI Ok!

Co

Methyl-2-ethoxy-3-I4-I4-(2-(3,4-dihydro-2H-benzoyl|8111,Zoxazin-4-yl)ethoxy)-phenylaminomethyl|phenyl|propionate (52Omg, 1.Eq. , 1.0 bmmol), obtained in Example 31, is hydrolyzed by treatment with HION.NYO (134 mg, Zeq.,

C3.18 mmol) in a Meon-THF-water solvent mixture at room temperature for 3-4 hours. The reaction mixture is concentrated, diluted with water and acidified (pH about 4) aq. NSI Finally, the crude acid is extracted with 29 ethyl acetate. The ethyl acetate layer is dried (ma»zO, 4), concentrated and subjected to chromatography using (3) as eluents MeOnH and CHCl3, obtaining the desired compound in the form of a viscous liquid (15mg, 3090).

TN NMR (200MHZ, SOSIv) 8: 1.18 (t, 9U-6.9Hz, ZN), 1.29 (shyr.s, -MH-), 2.90-3.20 (m, 2H), 3.22-3.75 (m, bH), 4.00-4.18 (m, ЗН), 4.20-4.25 (m, 4H), 6.00 (shyr.s, СО5Н), 6.60-6.90 (aromatic nucleus, 8H), 7.24 (d, 9U-8.3Hz, 2H), 7.29 (d, U-8.3Hz, 2H). with

From IR (pure substance) cm"!: 3390 (width), 2927, 1725, 1605. s

Mass p/z (SI): 476 |MI, 477 (M--11. yu

Example 33

Arginine salt (ee) 2-ethoxy 3408, dihydro 2 benzog BI Poxazin-1 Il) ethoxyuphenylaminomethyl) phenylpropionic acid ich- sh C

S. Z. S

-e ppeutittnn nn « liu | dream we -

A mixture of 2-ethoxy-3-(4-(4-42-(3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)ethoxy)-phenylaminomethyl|phenyl|propionic acid ( 11mg, Eq., O0.23mmol) obtained in Example 32, and I arginine (40mg, Eq., O0.23mmol) are diluted in dry MeonH (2ml) and stirred at room temperature for 2 hours until a clear solution is formed. 415 Solvent concentrated, the residue is subjected to azeotropic distillation from dry benzene and dried with the help of a vacuum pump, obtaining a solid mass (yield 100905), mp: 154-15690,

Example 34 bo (25,M(1K)1-M-(2-Hydroxy-1-phenylethyl)-2-ethoxy-3-(4-13-(3,4-dihydro-1H-benzoyl)|51(11, Doxazin-4-yl)propylamisino)phenyl|propanamide - o t SO SU

Maachsy r os

AND

To a solution of racemic (F. 2-ethoxy-3-(4-13-(3,4-dihydro-2H-benzoi|81/1,Zoxazin-4-yl)/propylamino)phenyl|propionic acid (2,Og, to 1.0 eq., 5.20 mmol) obtained in Example 2, isobutyl chloroformate (1.35 ml, 2 eq., 10.4 mmol) is added dropwise in DCM (26 bml) and triethylamine (3.61 ml, beq., 2 bmmol) at 02 C. The reaction mixture was stirred at room temperature for 30 h, after which (K)-phenylethanolamine (1.42 g, 2 eq., 10.4 mmol) was added. The reaction mixture was further stirred at room temperature for 16 h, and then diluted with DCM, washed with water and brine, dried (Ma»zO)) and concentrated. The residue was chromatographed using ethyl acetate and hexane to give the title compound as the faster-moving (5,K)-diastereomer (620 mg, yield 23.7905), followed by the (K,K)-diastereomer having lower speed (63Omg, output 2495), both in the form of BB VISCOUS liquid. The characterization of the (K,K)-diastereomer is given in Example 35.

TN nMR (200MHz, SOSIv) 5: 1.14 (t, 9-6.8Hz, ZN), 1.24 (s, 1H), 1.91 (quintet, U-6.8Hz, 2H), 2, 90 (dd,

U-12 and 5.8HzC, 71H), 3.06 (dd, 9-12 and Z3.9Hz, 1H), 3.19 (t, U-6.8HzC, 2H), 3.25-3.60 (m, 6H), 3.60-3.70 (m, 2H), 3.97 (dd, 9U-5.8 and Z.9Hz, 1H), 4.22 (t, 9-4.4Hz, 2H), 4.88-5.00 (m, 1H), 6.50-7.40 (aromatic core and amide -MH, 14H).

IR (pure substance) cm": 3393 (width), 2927, 1660.

Mass pt/z (SI): 503 |MI, 504 |M--11.

Example 35

I2A,MY1K)OI-M-(2-Hydroxy-1-phenylethyl)-2-ethoxy-3-I4-(3-(3,4-dihydro-2H-benzo|8111,Zoxazin-4-yl)propylamino )phenyl|propanamide yu . SYA on Sat

Shh

N

The title compound is obtained by a procedure similar to that described in Example 34.

TN NMR (200MHz, SOSIv) 8: 1.16 (t, 9U-6.8Hz, ZN), 1.24 (s, 1H), 1.91 (quintet, U-6.8HzC, 2H), 2, 80 (dd, 9-14, 7.5Hz, 1), 3.06 (dd, 9-14, 39Hz, 1), 3.17 (t, U-6.8Hz, 2H), 3.25-3 .60 (m, 6H), 3.78-3.90 (m, 2H), 3.89 (dd, 9U-7.5, З3.9Hz, 1H), 4.22 (t, U-4, 4Hz, 2H), 4.88-5.00 (m, 1H), 6.45-7.35 (aromatic nucleus and amide -MH, 14H).

IR (pure substance) cm": 3399 (width), 2927, 1660.

Mass pt/z (SI): 503 |MI, 504 |M--11.

Example 36 (25,M(1K)1-M-(2-Hydroxy-1-phenylethyl)-2-ethoxy-3-(4-13-(3,4-dihydro-2H-benzoyl)|51(11,Doxazin -4-yl)propylamine with no)phenyl|propanamide hydrochloride o soy

M year

SAISTIM with

And sch

(25,M(1K)1-M-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-I4-13-(3,4-dihydro-2H-benzoyl |81/11, Coxazin-4-yl)-propylamino) Scheo, phenyl|Ipropanamide (95 mg, 0.19 mmol) obtained in Example 34, and the mixture was stirred at room temperature for 5 min. Then the reaction mixture is concentrated and subjected to azeotropic distillation using dry benzene on a rotary evaporator. The residue is dried under high vacuum, obtaining the title compound Ge as a brown solid (yield 100905, m.p.: 74-7590),

Example 37

I2A,MY1K)OI-M-(2-Hydroxy-1-phenylethyl)-2-ethoxy-3-I4-(3-(3,4-dihydro-2H-benzo|8111,Zoxazin-4-yl)propylami « (no)phenyl|Ipropanamide hydrochloride g.

Г2К,МИ1К)И-М-(2-hydroxy-1-phentethyl)-2-ethoxy-3-(4-(3-(3,4-dipdro-2H-benzoyl)|51/1,Doxazin-4-yl )-propylamino)phe (ee) nyl|Inropanamide (95 mg, 0.19 mmol) obtained in Example 35, and the mixture was stirred at room temperature for 5 min. The reaction mixture was then concentrated and subjected to azeotropic distillation using dry benzene on a rotary evaporator. The residue is dried under high vacuum, obtaining the title compound as a brown solid (yield 100905, m.p.: 69-7090),

Kz Example 38

Magnesium salt of 2-ethoxy-3-I4-13-(3,4-dihydro-2H-benzo|(51/1,Zoxazin-4-yl)/propylamino)phenyl|propionic acid

SO sobu mo? o AD yuyu n ?

A mixture of a methanolic solution (2 ml) of 6vo /2-ethoxy-3-I4-13-(3,4-dihydro-2H-benzo|511/1,oxazin-4-yl)propylamino)phenyl|propionic acid (75mg,

ZTeq., 0.19 mmol), obtained in Example 2, and magnesium hydroxide (5.bmg, 0.beq., 0.095 mmol) are heated at 509C for 5 hours. The resulting solution is concentrated, subjected to azeotropic distillation with benzene, and then finally dried using a high-vacuum pump, obtaining the title compound in the form of a free-flowing solid (yield 100905, m.p.: 1332-1342). 65 Example 39 (25,M(1K3)1-M-(2-Hydroxy-1-phentethyl)-2-ethoxy-3-I4-73-177-fluoro-3,4-dihydro-2H-benzo|c) /1,Tsoxazin-4-yl)pr -BO0-

opylamino)phenyl|Ipropanamide

SO sow them more: Du ' sha: Ov

To a solution of racemic 70 2-ethoxy-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoic|51(1,Zoxazin-4-yl)upropylamino)phenyl|Ipropionic acid (1.8g, 1.0 eq., 4.48 mmol) obtained in Example 17, in DCM (25 bml) and triethylamine (2.4 Uml, 4 eq., 17.92 mmol), isobutyl chloroformate (875 µl, 1.eq., 6.72 mmol) is added dropwise ) at 02. The reaction mixture was stirred at room temperature for 30 h, and then (K)-phenylethanolamine (1.23 g, 2 eq., 8.9 mmol) was added. The reaction mixture is further stirred at room temperature for 16 hours, then diluted with DCM, washed with water and brine for 75 minutes, dried (Ma»5O)) and concentrated. The residue was chromatographed using ethyl acetate and hexane to give the title compound as the faster moving (5,K)-diastereomer (37Omg, yield 32905) followed by the slower moving (K,K)-diastereomer (37Omg, output 3290), both in the form of a viscous liquid. Characterization of the (K,K)-diastereomer is given in Example 40 (next example).

IATo: --7.09 (c, 1.0 SNO").

TN nMR (200MHz, SOSIv) 5: 1.16 (t, U-6.8Hz, ZN), 1.92 (quintet, U-6.8Hz, 2H), 2.92 (dd, 9-14, 5 ,6Hz, 1), 3.08 (dd, 9-14, 3.5Hz, 1H), 3.22 (t, 9U-64Hz, 2H), 3.20-3.40 (m, 4H), 3 ,40-3,80 (m, 4H), 3,99 (t,

U-5.2Hz, 1H), 4.23 (t, 9U-4.4HzC, 2H), 4.88-5.02 (m, 1H), 6.40-6.60 and 6.90-7 ,40 (aromatic core and amide -MH, 13Н). with

IR (pure substance) cm": 3405 (width), 2933, 1660, 1615, 1514. o

Mass t/z (SI): 521 |MI, 522 |M--1).

Example 40

I2A,MY1KOI-M-(2-Hydroxy-1-phentethyl)-2-ethoxy-3-I4-13-(7-fluoro-3,4-dihydro-N-benzo|51/1,Zoxazin-4-yl )about pilamino)phenyl|propanamide with " S y ley y y (action y fev y

At least 35. N o

The title compound is obtained during the synthesis according to Example 39 as the second diastereomer (K,K).

IA1o: 17.4 (c, 1.0 SNI").

TN nMR (200MHz, SOSIv) 5: 1.18 (t, 9-6.8Hz, ZN), 1.91 (quintet, U-6.8Hz, 2H), 2.51 (sh.s, MH, OH ); « du 2.82 (dd, 9U-14.2 and 7.ЗГцЦ, 1H), 3.04 (dd, 9U-14.2 and З4Hz, 1), 3.20 (t, 9U-64Hz, 2Н) , 3.25-3.40 (m, 4H), - 33.42-3.70 (m, 2H), 3.80-3.90 (m, 2H); 3.98 (dd, 9U-7.3 and 4.0Hz, 1H), 4.24 (t, 9-4.8Hz, 2H), 4.88-5.2 (m, 1H), s 6, 4-6.60 and 7.00-7.40 (aromatic core and amide -MH, 13Н). :z" IR (pure substance) cm": 3398 (width), 2929, 1660, 1616, 1513.

Mass t/z (SI): 521 |MI, 522 |M--1).

Example 41 -1 (25,M(1K)1-M-(2-Hydroxy-1-phenylethyl)-2-ethoxy-3-(4-13-(3,4-dihydro-2H-benzoyl)|51(11 ,Doxazin-4-yl)propylamino)phenyl|Ipropanamide hydrochloride with 3 and p СХ y; To Aonov and Gobesh

M

Ko) ii

(25,M(1K)1-M-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-I4-13-(3,4-dihydro-2H-benzoyl |81/11, Coxazin-4-yl)-propylamino)phenyl|Ipropanamide (95 mg, 0.19 mmol) obtained in Example 34, and the mixture was stirred at room temperature for 2 min. The reaction mixture is then concentrated and subjected to azeotropic distillation using dry (F. benzene) on a rotary evaporator. The residue is dried under high vacuum, obtaining the title compound as a brown solid (yield 100905, m.p.: 74-7590) ,

Example 42 in I2A,MI1K)OI-M-(2-Hydroxy-1-phenylethyl)-2-ethoxy-3-I4-(3-(3,4-dihydro-2H-benzo|8111,Zoxazin-4-yl) )propylamino)phenyl|Ipropanamide hydrochloride b5

In o

He (2ml) is added to the dry methanolic solution

I2A,MY1K)I-M-(2-Hydroxy-1-phenylethyl)-2-ethoxy-3-I4-(3-(3,4-dihydro-2H-benzo|81(11,Zoxazin-4-yl) -propylamino)phenyl|Ipropanamide (95mg, 0.19mmol) obtained in Example 35, and the mixture is stirred at room temperature for 25 minutes. The reaction mixture is then concentrated and subjected to azeotropic distillation using dry benzene on a rotary evaporator. The residue is dried under high vacuum , obtaining the title compound as a brown solid (yield 100905, m.p.: 69-7090),

Example 43 (-)3-(5)-3-I4-(3-(3,4-Dihydro-2H-benzoyl)-1(11,Zoxazin-4-yl)propylamino)-phenyl|-2-ethoxypropionic acid

THEM in a dream

Su

IATo:-172(s, 1.0, MeOH).

TN nMR (200 MHz, SOSIv) 85: 1.19 (t, 9U-7.4Hz, ZN), 1.94 (q, 9U-7.4Hz, 2H), 2.90 (dd, U-14.0 and 7.0Hz, 1H), 3.05 (dd, 9U-14.0 and 4.9Hz, 1H), 3.21 (t, U-6.8Hzc, 2H), 3.25-3.40 ( m, 5H), 3.40-3.62 (m, 1H), 4.00-4.17 (m, 1H), 4.18-4.22 (m, 2H), 6.59 (d, U-8.3Hz, 2H), 6.65-6.85 (m, 4H), 7.06 (d, U-8.3Hz, 2H). high school

IR (pure substance) cm": 3500, 1725.

Mass t/ (SI): 385 (Mya1). at

Example 44 (13-(K)-3-(4-13-(3,4-Dihydro-2H-benzo|c)/1,Zoxazin-4-yl)propylamino)-phenyl)|-2-ethoxypropionic acid

So I and z0 ON ch di Drs n yuyu

IAIr: 16.82 (s, 1.0, MeOH). (uh)

TN nMR (200MHz, SOSIv) 5: 1.19 (t, U-7.4Hz, ZN), 1.94 (q, 9U-7.4Hz, 2H). 2.90 (dd, U-14.0 and 7.0Hz, chn 1H), 3.05 (dd, 9U-14.0 and 4.9Hz, 1H), 3.21 (t, U-6.8Hz , 2H), 3.25-3.40 (m, 5H), 3.40-3.62 (m, 1H), 4.00-4.17 (m, 1H), 4.18-4.22 (m, 2H), 6.59 (d, U-8.3Hz, 2H), 6.65-6.85 (m, 4H), 7.06 (d, U-8.3Hz, 2H).

IR (pure substance) cm": 3500, 1725. "

Mass t/ASI): 385 (М.Н1).

Example 45 - with Ethyl-3-I4-73-(7-fluoro-3,4-dihydro-2H-benzo|b)/1,Zoxazin-4-yl)-propylamino)phenyl)|-2-ethoxypropionate. what's the driver

You are NOT

And (5)-Ethyl-2-ethoxy-3-(4-aminophenyl)ipropionate (2.20g, Cheq., 9.28mmol), obtained in Synthesis 20, (ee) 3-(7-fluoro-3, 4-dihydro-2H-benzo[51/1,Coxazin-4-yl)upropyl bromide (3.30g, 1.Eq., 12.0bmmol), obtained in the synthesis of 10, and anhydrous CoCO»z (3.84g, Eq. ., 27.84 mmol) and tetrabutylammonium bromide (597 mg, 0.2 equiv., and 1.85 mmol) are heated at 909C in dry toluene (47 μl) for 20 hours. The reaction mixture was diluted to 50 with ethyl acetate, washed with water and brine. The residue is subjected to chromatography using ethyl acetate

Kz and hexane, obtaining the title compound (1.78g, yield 44.5965) as a viscous liquid.

IAIr: -9.2 (with 1.0, Mmeon).

TN NMR (200MHz, SOSIv) 8: 1.17 (t, 9U-7Hz, ZN), 1.23 (t, 9U-7Hz, ZN), 1.89 (q, U-6.8HzC, 2H), 2.90 (d, vv b Hz, 2H), 3.10-3.42 (m, 7H), 3.45-3.65 (m, 1H). 3.95 (t, 9U-6.7Hz, 1H), 4.10-4.30 (m, 4H), 6.40-6.70 (m, aromatic nucleus, 5H), 7.05 (d, 9U-8.4Hz, 2H). o IR (pure substance) cm": 3394 (width), 2978, 1740, 1617, 1514. ko Mass t/z (SI): 431 (M.-1).

Example 46 60 (5)-3-I4-43-(7-Fluoro-3,4-dihydro-1H-benzoyl|51(11,Zoxazin-4-yl)-propylamino)phenyl|-2-ethoxypropionic acid

E 0

(5)-Ethyl-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoyl| 1/1, Zoxazin-4-yl) -propyl-amino)phenyl|-2-ethoxypropionate

(1.77, eq., 3.95 mmol), obtained in Example 45, is hydrolyzed with the help of lithium hydroxide monohydrate (249 mg, 1.eq., 5.93 mmol) in methanol-THF-water at room temperature until the initial materials (4-5 hours). The reaction mixture is diluted with water, acidified (pH about 4-5) solution. NCI, and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was subjected to chromatography using ethyl acetate and hexanes-» methanol and chloroform to give the title compound (1.5 g, yield 9495) as a viscous liquid.

IAIr: -16.12 (with 1.0, MeOnH).

Chiral HPLC: e.n. 298905.

TN nMR (200MHz, SOSIi) 8: 1.19 (t, 9-7.4Hz, ZN), 1.94 (quintet, 9-7.4Hz, 2H), 2.85-3.10 (m, 2H ), 3.10-3.20 (m, 6H), 3.40-3.70 (m, 2H), 3.90-4.10 (m, 1H), 4.10-4.30 (m .

IR (KVh) cm-": 3394, 1725, 1619.

Mass t/z (SI): 403 (Mya1).

Example 47

I-Arginine salt of (5)-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)/propylamino)phenyl|-1-ethoxypropionic acid and in so, Me"; n (5)-3-I4-13-(7-Fluoro-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)ipropylamino)-phenyl|-2-ethoxypropionic acid (30Omg, Tekv ., 0.74 mmol), obtained in Example 46, and I-arginine (13 Ωg, Eq., 0.74 mmol) are diluted in dry methanol (4 ml) and stirred at room temperature for 2 hours. The solvent is removed on a rotary evaporator and then azeotroped with benzene.The residue was dried using (o) a high vacuum pump to give the title compound as a free flowing solid (yield 10096).Mp: 114-116960.

Example 48 c zo Magnesium salt of (5)-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropion acid with

So what)

ХО слуе has" ee va: But bn i - 2 (5)-3-I4-13-(7-Fluoro-3,4-dihydro-2H-benzoi|51(11,Zoxazin-4-yl)ipropylamino)- phenyl|-2-ethoxypropionic acid (1.13 g, 1.00 equiv., 2.81 mmol), obtained in Example 46, in dry methanol (15 ml) is treated with Ma(OMe) 2 « yu (121 mg, O.bEq., 1 .4 mmol). The resulting mixture is heated at 55-60 for 7-8 hours. The reaction mixture C7Z is concentrated on a rotary evaporator, subjected to azeotropic distillation with benzene, and finally dried with the help of a high-vacuum pump. The sticky mass is triturated with hexanes, obtaining the desired salt in the form :z" of powdery solid substance (quantitative yield). Melting point: 240-2422С (dec.).

Example 49 15 Ethyl-3-I4-73-(7-fluoro-3,4-dihydro-2H-benzo|1/1,Zoxazin-4-yl)-propylamino)phenyl|-2-methoxypropionate o so n Shen ikh Two i-th N ka 20 (5)-Ethyl-2-methoxy-3-(4-aminophenyl)upropionate (800 mg, 1.0 equiv. 3.58 mmol) obtained in Synthesis 21, 3-(7-fluoro-3, 4-dihydro-2H-benzo|51/1,Coxazin-4-yl)iupropyl bromide (1.27g, 1.Eq., 4.b5mmol), obtained in UU from the synthesis of 10, and anhydrous CoCO3 (1.48g, Eq. , 10.79mmol) and tetrabutylammonium bromide (57bmg, 0O.5eq., 1.7U9mmol) are heated at 902C in dry toluene (2O0ml) for hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine. The residue was subjected to chromatography using ethyl acetate 22 and hexane to give the title compound (1.1 g, yield 73905) as a viscous liquid.

HF) IAIr: -4.09 (s 1.0, meon).

He TN NMR (200MHz, SOS) 8: 1.25 (t, 9-7.3HzC, ZN), 1.89 (q, 9U-7.0Hz, 2H), 2.91 (d, U-6, 0Hz, 2H), 3.05-3.42 (m, 6H), 3.36 (s, ZN); 3.90 (t, 9U-6.4 Hz, 1H), 4.10-4.30 (m, 4H), 6.40-6.70 (m, aromatic core, in 5H), 7.05 (aromatic core, 2H).

IR (pure substance) cm-: 3385 (width), 2934, 1741, 1617, 1514.

Mass p/z: (SI): 417(M-1).

Example 50 (5)-3-I4-43-(7-Fluoro-3,4-dipdro-2H-benzo|b1/1,Zoxazin-4-t)-propylamino)phenyl|-2-methoxypropionic acid b5 yoF slu ra n OMme

I

(5)-Ethyl-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoyl|in(1,Zoxazin-4-yl)-propylamino)phenyl|-2-methoxypropionate (1.0g , Teq., 2.4 mmol), obtained in Example 49, is hydrolyzed with the help of lithium hydroxide monohydrate (151 mg, 1, equiv., 3, mmol), in methanol-THF-water at room temperature until the starting materials (4- bghd.). The reaction mixture is diluted with water, acidified (pH about 4-5) solution. NCI, and then 70 is extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was subjected to chromatography using ethyl acetate and hexanes -» methanol and chloroform to give the title compound (65mg, yield 70905) as a viscous liquid.

IAIr: -14.22 (with 1.0, Men).

Chiral HPLC: e.n. 298905. iz TN nMR (200 MHz, SOSIia) 8: 1.9 (quintet, 4-7.4 Hz, 2H), 2.85-3.10 (m, 2H), 3.10-3.38 (m, 6H), 3.40 (s,

ZN); 3.90-4.05 (m, 1H); 4.24 (t, U-4.2Hz, 2H); 6.42-6.70 (m, aromatic nucleus, 5Н); 7.05 (d, U-8.0Hz, 2H).

IR (pure substance) cm"!: 3396, 2936, 1727, 1614, 1513.

Mass t/z (SI): 389 (M'n1).

Example 51

Magnesium salt of (5)-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)/ipropylamino)phenyl|-2-methoxypropionic acid dry : H (o) i (5)-3-I4-43-(7-Fluoro-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)/propylamino)-phenyl|-2- methoxypropionic acid (40Omg, 1.0eq., 1.03mmol), obtained in Example 50, in dry methanol (ml) is treated with Ma(OMe) for 2 s (44.Zmg, O.Beq., O0.5immol). The resulting mixture is heated at 55-609C for 7-8 hours. The reaction mixture c is concentrated on a rotary evaporator, subjected to azeotropic distillation with benzene, and finally dried using a high-vacuum pump. The sticky mass is triturated with hexanes to give the desired salt as a powdery solid (quantitative yield). T.pl.: 210-212 (open). co

Example 52

Zo Ethyl-3-(4-13-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)-propylamino)phenyl|-2-ethoxypropion - at yo u so "

Ethyl 2-ethoxy-3-(4-aminophenyl)propionate (50mg, Teq, 2.1immol) obtained in Synthesis 1, "» 3-(2-methyl-7-fluoro-3, 4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propyl bromide (67Omg, 1, Eq., 2.32mMmol), obtained in Synthesis 17, and anhydrous KSO" (875mg, Eq., b6, 33mmol) and tetrabutylammonium bromide (34Omg, 0O, Beq., 1.05mmol) are heated at 902 in dry toluene (11ml) for 12h. The reaction mixture is diluted with -I ethyl acetate, washed with water and brine. The residue is subjected to chromatography using ethyl acetate and hexane, obtaining the title compound (320 mg, yield 3295) as a mixture of diastereomers as

Me of a viscous liquid. 1 TN NMR (200 MHz, SOSIv) 8: 1.10-1.25 (m, 9H), 1.80-2.00 (m, 2), 2.82-3.02 (m, 2H). 3.10-3.50 (m, 2H), with 50 3.28-3.44 (m, ЗН), 3.50-3.65 (m, 1H); 3.90-4.00 (m, 1H), 4.10-4.30 (m, ЗН), 6.40-6.80 (aromatic core, 5H), 7.00-7.20 (aromatic core , 2H). g" IR (pure substance) cm": 3389 (width), 2929, 1740, 1617, 1515.

Mass p/z: (SI):445 (M--1).

Example 53 3-I4-3-(-2-Methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)-propylamino)phenyl|-2-ethoxypropionic

HF) acid

Kk u vo Stchn pe n

Ethyl-3-14-3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)-propylamino)phenyl|-2-ethoxypropionate (32Omg, eq., 0.72 mmol), obtained in Example 52, is hydrolyzed with the help of lithium hydroxide monohydrate (46 mg, 1.eq., 1.08 mmol) in methanol-THF-water at room temperature until the starting b5 materials are completely consumed (4-5 hours .). The reaction mixture is diluted with water, acidified (pH about 4-5) solution. NSI, and then extracted with ethyl acetate. The ethyl acetate layer is dried over anhydrous sodium sulfate and concentrated to -B4-

rotary evaporator. The residue was chromatographed using methanol and chloroform to give the title compound (190 mg, yield 6490) as a viscous liquid.

TN nMR (200MHz, SOSIv) 8: 1.21 (t, 9-7, 1Hz, ZN), 1.36 (d, U-6.4Hz, ZN), 1.92 (quintet, U-6.8Hz , 2H), 2.90-3.10 (m, 2H), 3.10-3.40 (m, 6H), 3.42-3.60 (m, 2H); 4.06 (dd, 9U-6.8, 3.9Hz, 1H), 4.20-4.35 (m, 1H); 6.50-6.62 (aromatic core, 5H), 7.07 (d, 9U-8.3Hz, 2H).

IR (KVh) cm"!: 3387, 2927, 1726, 1615, 1514.

Mass t/z (SI): 417 (M'1).

Example 54

Magnesium salt of 3-I4-13-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|81(11,Zoxazin-4-yl)upropylamino)phenyl|-2-ethoxypropionic acid

E Mr

S so ma"

Ce 2 3-I4-13-(2-Methyl-7-fluoro-3,4-dihydro-2H-benzoyl|81(11,Doxazin-4-yl)-propyl-amino)phenyl|-2-ethoxypropionic acid ( 17Omg, 1.0 eq., 0.41 mmol), obtained in Example 53, in dry methanol (5 ml) is treated with Moa(OMe) 2 (17.b6mg, 0.bBeq., 0.21 mmol). The resulting mixture is heated at 55-60 for 7-8 hours. The reaction mixture is concentrated on a rotary evaporator, subjected to azeotropic distillation with benzene, and finally dried using a high-vacuum pump. The sticky mass is triturated with hexanes to give the desired salt as a powdery solid (quantitative yield). T.pl.: 110-11296. Ha

Example 55 o

Ethyl 3-I4-73-(2-methyl-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)-propylamino)phenyl|-2-ethoxypropionate

By fate

Si ХГ ze cm

And with

Starting with ethyl 2-ethoxy-3-(4-aminophenyl)propionate (438mg, Eq., 1.85mmol), obtained in Synthesis 1, and 3-(2-methyl-3,4-dihydro-2H-benzo| 51(11,Zoxazin-4-yl)upropyl bromide (550 mg, 1.1 eq., 2.32 mmol), obtained in Synthesis 18, according to the procedure of Example 52, the title compound (ZO0Omg, yield 3595) is obtained as a mixture of diastereomers in the form of "viscous liquid. So

TO nMR (200 MHz, SOSIi) 8: 01.17 (t, 9U-7.0 Hz, ZN); 1.23 (t, 9-7.0 Hz, ZN); 1.35 (d, 9-64 Hz, ZN); i- 1.80-2.00 (m, 2H), 2.91 (d, 9U-6.7Hz, 2H); 3.00-3.42 (m, 7H); 3.45-3.65 (m, 71H); 3.95 (t, 9U-6.7Hz, 1H), 4.10-4.30 (m, ЗН), 6.53 (d, U-8.3Hz, 2H); 6.65 (t, 9U-7.8Hz, 2H); 6.79 (d, U-7.8Hz, 2H); 7.06 (d, U-8.3Hz, 2H).

IR (pure substance) cm": 3400 (width), 2976, 1741, 1616, 1520. "

Mass t/z (SI): 427 (Mt).

Example 56 With c 3-I4-13-(2-Methyl-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)-phenyl|-2-ethoxypropionic acid "» se

Seam 15th E!

B. Ethyl-3-14-73-(2-methyl-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)ipropylamino)-phenyl|-2-ethoxypropionate (ee) (30Omg, Eq., 0.72 mmol), obtained in Example 55, hydrolyzed according to the procedure of Example 53, obtaining the title compound (17Omg, yield 6190) as a viscous liquid.

TN nMR (200MHz, SOSIv) 5: 1.17 (t, 9U-7.0Hz, ZN); 1.34 (d, 9U-6.1Hz, ZN); 1.80-2.00 (m, 2H), 2.80-3.70 o (m, TON); 4.02 (dd, 9U-7.3,4.5Hz, 1H), 4.10-4.30 (m, 1H), 5.6 (shyr.s, 2H, SON, MH); 6.55 (d, U-8.3Hz, 2H); 6.64 (t,

From -7.8Hz, 2H); 6.79 (d, U-7.8Hz, 2H); 7.06 (d, U-8.3Hz, 2H).

IR (KVh) cm": 3393, 2974, 1726, 1617, 1503.

Mass t/ASI): 399 (M.n1).

Example 57

Magnesium salt

Ф, 3-I4-13-(2-methyl-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic acid has) in So so? ma"

AKA be n 2

With 3-14-3-(2-methyl-3,4-dihydro-2H-benzoyl)((1,Zoxazin-4-yl)/propylamino)-phenyl|-2-ethoxypropionic acid (155 mg, 1.0 eq. ., 0.39mmol), obtained in Example 56, and Mo(OMe)" (16.5mg, O.eq., O.20mmol) to obtain the desired salt in the form of a powdery solid (quantitative yield) according to the procedure of Example

54. T.pl.: 102-10426.

Example 58

Ethyl-(25)-3-I4-13-(2-methyl-3,4-dihydro-2H-benzo|8111,Zoxazin-4-yl)-propylamino)phenyl|-2-methoxypropionate

SU m" SEC and that n

Starting from ethyl-(5)-2-methoxy-3-(4-aminophenyl)propionate (50mg, eq., 2.24mmol), obtained in Synthesis /021, and 3-(2-methyl-3,4-dihydro -2H-benzo|51/1,)oxazin-4-yl)propyl bromide (6bbbmg, 1 eq., 2.47mmol) obtained in Synthesis 18 by the procedure of Example 52 gave the title compound (34Omg, yield 3890) as a mixture diastereomers in the form of a viscous liquid.

TN nMR (200MHz, SOSIv) 85: 1.25 (t, 9-7.2Hz, ZN); 1.36 (d, U-6.4 Hz, ZN); 1.80-2.00 (m, 2H), 2.92 (d,

U-6.2Hz, 2H); 3.02-3.50 (m, 9H); 3.90 (t, 9U-6.2Hz, 1), 4.10-4.30 (m, ZN), 6.54 (d, 9U-8.3Hz, 2H); 6.65 (t, 15. BRUSH, 2Gu, 2H); 6.80 (d, 9U-7.2Hz, 2H); 7.05 (d, U-8.3Hz, 2H).

IR (pure substance) cm": 3398 (width), 2928, 1741, 1613, 1520.

Mass t/z (SI): 413 (M'1).

Example 59 (25)-3-I4-13-(2-Methyl-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)-propylamino)phenyl|-2-methoxypropionic acid

So: DREAM

SI bo ch 29 Ethyl-(25)-3-I4-13-(2-methyl-3,4-dihydro-2H-benzo|8111,Zoxazin-4-yl)-propyl-amino)phenyl|-2-methoxypropion He)t (17Omg, Eq., 0.4133mmol) obtained in Example 58 was hydrolyzed according to the procedure of Example 53 to give the title compound (100mg, yield 6390) as a viscous liquid.

TN NMR (200MHz, SOSIi) 8: 1.35 (d, 9U-6.5Hz, ZN); 1.80-2.00 (m, 2H), 2.85-3.60 (m, 11H); 3.98 (dd, sc 20 U-7.0, 4.3Hz, 1H), 4.15-4.30 (m, 1H), 6.55 (d, uU-8.3Hz, 2H); 6.65 (t, 9U-7.2Hz, 2H); 6.79 (d, 9U-7.2Hz, 2H); 7.05 (d, U-8.3Hz, 2H). with

IR (KVh) cm": 3391, 2930, 1727, 1608, 1506.

Mass t/ (SI): 385 (Mya1).

Example 60 so

Magnesium salt of (25)-3-I4-13-(2-methyl-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid

СО шю мух « ваг " - с 2 "» C (25)-3-I4-43-(2-methyl-3,4-dihydro-2H-benzoi|51(11,Zoxazin-4-yl)/propylamino) -phenyl|-2-ethoxypropionic acid (9mg, 1.0eq., 0.233mmol) obtained in Example 59 and Mo(OMe) (10mg, 0.eq., 0.12mmol) give the desired salt in the form of a powdered solid (quantitative yield) according to the procedure of Example 54. Melting point: 1600-1626. w- Example 61

Ho) Ethyl-3-14-73-(2-propyl-3,4-dihydro-2H-benzo|8111,Zoxazin-4-yl)-propylamino)phenyl|-2-ethoxypropionate i-th CO so: ma 7 KK be

Starting from ethyl 2-ethoxy-3-(4-aminophenyl)propionate (325 mg, Eq., 1.37/mmol), obtained in Synthesis 1, and 3-(2-propyl-3,4-dihydro- 2H-benzoyl|81/11, Coxazin-4-yl)upropyl bromide (45mg, 1.1eq., 1.51mmol) obtained in Synthesis 19 by the procedure of Example 52 gives the title compound (34mg, yield 6995) as a mixture 22 diastereomers in the form of a viscous liquid.

HF) TN o nNMR (200MHz, SOSIi) 8: 0.97 (t, 9U7.0Hz, ZNU; 1.17 (t, 9-7.2Hz, ZN); 1.22 (t, 9-7.3Hz , ZN); 7 1.40-1.80 (m, 4H); 1.91 (quintet, U-6.7Hz, 2H), 2.90 (d, U-6.4Hz, 2H); 3, 00-3.42 (m, 7H); 3.45-3.65 (m, 1H); 3.94 (t, 9U-64HZ, 1H), 4.00-4.22 (m, ЗН), 6.52 (d, 9U-8.3Hz, 2H); 6.64 (t, 9-7.0Hz, 2H); 6.78 (d, 9-72Hz, 2H); 7.05 (d, U -8.3Hz, 2H).

IR (pure substance) cm": 3400 (width), 2959, 1741, 1616, 1520.

Mass t/z (SI): 455 (M'1).

Example 62 3-I4-13-(2-Propyl-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)/propylamino)-phenyl|-2-ethoxypropionic acid b5 -58v-

Sa

SO dklvon not

Nn

Ethyl-3-I4-3-(-2-propyl-3,4-dihydro-2H-benzoyl|51/1,Doxazin-4-yl)propylamino)-phenyl|-2-ethoxypropionate (305 mg, Eq., O ,b7mmol) obtained in Example 61 was hydrolyzed according to the procedure of Example 53 to give the title compound (177mg, yield 6290) as a viscous liquid.

TN nMR (200MHz, SOSIi) 8: 0.97 (t, 9U7.0Hz, ZN); 1.18 (t, 9U-7.2Hz, ZN); 1.40-1.80 (m, 4H); 1.92 70 (quintet, U-6.7Hz, 2H), 2.80-3.62 (m, 10H); 3.95-4.15 (m, 2H); 4.60 (width, 2H); 6.55 (d, U-8.3Hz, 2H); 6.64 (t, 9-7.0Hz, 2H); 6.79 (d, U-7.2Hz, 2H); 7.06 (d, U-8.3Hz, 2H).

IR (KVh) cm"!: 3500, 2931, 1724, 1606, 1504.

Mass t/z2 (EB): 427 (M'n1), 853 (Moch1).

Example 63

Magnesium salt of 3-I4-13-(2-propyl-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)propylamino)-phenyl)|-2-ethoxypropionic acid

Sr o m you E: i

With 3-14-13-(2-propyl-7-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)propylamino)-phenyl)-2-ethoxypropionic acid (16b4mg, 1.0eq ., 0.ZOmmol) obtained in Example 62, and Mo(OMe)" (16.5mg, O.beq., O.20mmol) with obtain the desired salt in the form of a powdery solid substance (quantitative yield) according to the procedure of Example 54. T.pl.: 104-10626. at

Example 64

Ethyl-(25)-3-I4-13-(2-propyl-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)-propylamino)phenyl|-2-methoxypropionate

High school, you're fine

Ku tom sch

Ek n iv)

Starting from ethyl-(5)-2-methoxy-3-(4-aminophenyl)propionate (312 mg, Eq., 1.140 mmol) obtained in Synthesis 21, and 3-(2-propyl-3,4-dihydro-2H- benzo|51(11,Coxazin-4-yl)upropyl bromide (46Omg, 1.Eq., 1.54mmol), co obtained in Synthesis 19, according to the procedure of Example 52, the title compound is obtained (255mg, yield 6995) /- as a mixture of diastereomers in the form of a viscous liquid." NN NMR (400MHz, SOSI) 5: 0.99 (t, 9U-6.8Hz, ZN); 1.26 (t,

U-7.2 Hz, ZN); 1.47-1.61 (m, ZN); 1.69-1.74 (m, 71Н); 1.89-1.97 (m, 2H), 2.92 (d, 9U-4.0HZ, 71); 2.93 (d, 3-2.0 Hz, 1H); 3.09 (dd, 9U-11.2, 7.8Hz, 71N); 3.18-3.30 (m, ZN); 3.36 (c, ZN); 3.31-3.48 (m, 2H); 3.90 (t, «

U-6.0Hz, 1H), 4.06-4.10 (m, 1H), 4.19 (kv, U-7.2Hz, 2H); 6.54 (d, 9U-8.8Hz, 2H); 6.55-6.65 (aromatic core, 40.2H); 6.79 (d, 9-7.2Hz, 2H); 7.04 (d, U-8.8Hz, 2H). shi s IR (pure substance) cm": 3396 (width), 2930, 1741, 1613, 1518. "» Mass t/z (SI): 441 (M'1). Example 65 (25)-3-14-13-(2-Propyl-3,4-dihydro-2H-benzo|c)/1,Zoxazin-4-yl)-propylamino)phenyl)|-2-methoxypropionic acid s» so KAS om» t N

GI 20 Ethyl-(25)-3-I4-13-(2-propyl-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)-propyl-amino)phenyl|-2-methoxypropion at (24Omg, Eq., 0.55mmol), obtained in Example 64, is hydrolyzed according to the procedure of Example 53, obtaining the title compound (164mg, yield 7390) as a viscous liquid.

TN nMR (200MHz, SOSIi) 8: 0.96 (t, 9U-7.0Hz, ZN); 1.44-1.67 (m, 4H); 1.91 (quintet, 4-7.0 Hz, 2H), 2.90-3.33 (m, 8H); 3.38 (c, ZN); 3.92-4.06 (m, 2H); 4.60 (width, 2H); 6.55-6.66 (aromatic core, 4H); 6.78 29 (d, 0-7, AHC, 2H); 7.06 (d, U-8.2Hz, 2H). (F) IR (KVh) cm"!: 3397, 2930, 1727, 1606, 1504.

GF Mass t/z2 (EB): 413 (M'n1), 825 (Mo1), 1237 (Mu1).

Example 66 in Magnesium salt of (5)-3-I4-13-(2-propyl-3,4-dihydro-2H-benzoic acid) 51(11,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid soot t no Me 65 M

KU

WITH

(25)-3-I4-13-(2-propyl-7-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)propyl-amino)phenyl)-2-ethoxyprolic acid (14Omg . Example 54. T.pl.: 172-17496.

Example 67

Ethyl-2-isopropoxy-3-(4-73-(7-fluoro-3,4-dihydro-2H-benzo|b)/1,Zoxazin-4-yl)propylamino)phenyl|propionate iodine of Russia

Starting from ethyl 2-isopropoxy-3-(4-aminophenyl)propionate (6b5Omg, Eq., 2.59mmol), obtained in Synthesis 22, and 3-(7-fluoro-3,4-dihydro-2H-benzoic acid) of 1(1,Zoxazin-4-yl)upropyl bromide (781 mg, 1.1 eq., 2.85 mmol), 75 obtained in Synthesis 10, according to the procedure of Example 52, the title compound (700 mg, yield 6195) is obtained as a viscous liquid

TN nMR (200MHz, SOSIZ) 8: 0.98 (d, 9U-6.2Hz, ZN); 1.16 (d, 9U-6.2Hz, ZN); 1.23 (t, 9-7.2 Hz, ZN); 1.81-1.88 (m, 2H); 2.85-2.89 (m, 2H); 3.17-3.24 (m, 4H); 3.33 (t, 9-7.3 Hz, 2H); 3.40-3.60 (m, 1H); 3.99 (t,

U-6, ОГу, 1Н), 4.11-4.23 (m, 4Н), 6.48-6.55 (aromatic nucleus, ЗН); 6.63 (d, 9U-8.3Hz, 2H); 7.08 (d, U-8.3Hz, 2H).

IR (pure substance) cm": 3396 (width), 2939, 1729, 1615, 1514.

Mass t/z (SI): 445 (M'1).

Example 68 2-Ixopropoxy-3-I4-73-(7-fluoro-3,4-dihydro-2H-benzo|51(1,Zoxazin-4-yl)/propylamino)phenyl|propionic acid with io soy o or

And so

Ethyl-2-isopropoxy-3-(4-73-(7-fluoro-3,4-dihydro-2H-benzo|b)/1,Zoxazin-4-yl)propylamino)phenyl|propionate with (6b0Omg, Eq. , 1.35mmol) obtained in Example 67, hydrolyzed according to the procedure of Example 53, obtaining the title compound (24Omg, yield 4390) as a viscous liquid.

TN nMR (200MHz, SOSIv) 8: 1.01 (d, 9-6.2Hz, ZN); 1.16 (d, 9-6.2Hz, ZN); 1.91 (quintet, U-6.7Hz, 2H); at 2.84 (dd, 9-14, 8.1Hz, 1H); 3.00 (dd, 9-14, 4.2 Hz, 1H); 3.16-3.34 (m, 6H); 3.42-3.60 (m, 1H); 4.06 (dd, so 98.1, 4.2HZ, 1H), 4.20-4.25 (m, 2H), 6.09 (shyr.s, 2H); 6.47-6.58 (aromatic core, 5H); 7.06 (d, 9U-8.3Hz, 2H).

IR (pure substance) cm": 3388 (width), 2932, 1722, 1616, 1513. -

Mass t/z (SI): 417 (M'1).

Example 69

Magnesium salt of di 2-isopropoxy-3-I4-(3-(7-fluoro-3,4-dihydro-2H-benzo|51(/1,doxazin-4-yl)/propylamino)phenyl|Ipropionic acid -o 2-isopropoxy-3-(4-(3-(7-riluor-3,4-dihydro-2H-benzo|b1(1,Zoxazin) -4-yl)-propylamino)phenyl|propionic acid (24O0 mg, 1.0 eq., 0.57 mmol) obtained in Example 68 and Mo(OMe)" (25 mg, 0.eq., 0.29 mmol) are obtained the desired salt in the form of a powdered solid (quantitative yield) according to the procedure of Example 1 54.

M.pl.: 11096, o Example 70 that) Ethyl-(25)-3-I4-73-(2-methyl-7-fluoro-3,4-dihydro-1H-benzoyl|51(11,Zoxazin-4 -yl)upropylamino)phenyl|-2-methoxypropionate ioy pen o wag nn Oome imo) Starting with ethyl-(5)-2-methoxy-3-(4-aminophenyl)propionate (50Omg, Eq., 2.24mmol) , obtained in Synthesis 21, and 3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51/1,Doxazin-4-yl)upropyl bromide (711mg, 1,Eq., 2.47mmol ), 60 obtained in Synthesis 17, by the procedure of Example 52, gives the title compound (38Omg, yield 4090) as a mixture of diastereomers in the form of a viscous liquid.

TN nMR (200 MHz, SOSIv) 5: 1.20-1.0 (m, 6H); 1.80-2.00 (m, 2H), 2.90-3.02 (m, 2H); 3.02-3.40 (m, 9H); 3.90 (t, U-6.93Hz, 1H), 4.10-4.30 (m, ZN), 6.40-6.60 (aromatic core, 5H); 7.05 (d, U-8.3Hz, 2H).

IR (pure substance) cm": 3450 (width), 2926, 1740, 1617, 1515. bo Mass t/g (SI): 431 (M-n1).

Example 71 (25)-3-I4-43--2-Methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)-propylamino)phenyl|-2-methoxypropio new acetic acid

S-hNn

KS because

Ethyl-(25)-3-I4-3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)upropylamino)phenyl|-2-methoxypr 70 opionate (38Omg, Teq., 0.88mmol) obtained in Example 70 was hydrolyzed according to the procedure of Example 53 to give the title compound (150mg, yield 4390) as a viscous liquid.

TN nMR (200MHz, SOSIi) 5: 1.37 (d, 9U-6.2Hz, ZN); 1.80-2.00 (m, 2H), 2.90-3.60 (m, 1Z3H); 3.98 (dd, y-7.0, 4.3HZ, 1H), 4.18-4.35 (m, 1H), 6.55-6.70 (aromatic nucleus, 5H); 7.1О( d, U-8.0Hz, 2H).

IR (KVK) cm": 3400 (width), 2930, 1729, 1614, 1513.

Mass t/ (E5): 403.3 (M--1), 805.5 (Mon1).

Example 72

Magnesium salt of (25)-3-I4-13-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropion acid s yo SU boju m

Sk Ome and sch 2

C (8) (25)-3-I4-13-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|1/1,Zoxazin-4-yl)-propylamino)phenyl)-2 -ethoxypropionic acid (15O0mg, 1.0eq., 0.37mmol) obtained in Example 71, and Mo(OMe)" (1bmg, O,eq., 0.185mmMol) give the desired salt in the form of a powdery solid (quantitative yield) according to the procedure of the Example, there are 54.

T.pl.: 208-2105S. with

The compounds of this invention lower random blood sugar, triglycerides, total cholesterol,

GO, MI. and increase NOI... This was demonstrated by experiments on animals ip migo as well as ip mimo.

Demonstration of the effectiveness of the compounds

A) IP myo: h- a) Determination of PRRAK activity

The ligand-binding domain of PRRAKA is fused with the DNA-binding domain of the yeast transcription factor Ca! 4 in a eukaryotic expression vector. NEK-293 cells were transfected with this plasmid and a reporter plasmid containing a luciferase gene driven by a SAI 4-specific promoter using Z!irepesi (Diadep, Septapu) as a transfection reagent. The compound can be added in different concentrations after 42 hours. - s after transfection, and overnight incubation is carried out. Luciferase activity as a function of the compound's ability to bind/activate PRAKA is measured using an analytical kit Raskaga I isike (RaskKaga, "" OBA) in Tor Soshpa (map Zadomuzki, Vgepaap VeiYi, Rebeg Vgoad apa Meimup Noiyiiv. Sep. 1992. 118 : 137-141;

Zirepesi TgapeaHesiop Keadepi Naparook. Rebgoagu 1997. Oiadep, Septapu).

B) Determination of the activity of PRRAKU - and the ligand-binding domain of PRRAKU1 is fused with the DNA-binding domain of the yeast transcription factor SAI 4 so in a eukaryotic expression vector. Using lipofectamine (Sbirso VKI, OBA) as a reagent for transfection, NEK-293 cells are transfected with this plasmid and a reporter plasmid containing 1 luciferase gene controlled by the SAI-4-specific promoter. The compound can be added at a concentration of μm 7 50 After 48 hours. after transfection and incubated overnight. Luciferase activity as a function of the drug's ability to bind/activate PRAK y1 is measured using the RaskKaga assay kit

IR) Gisiye (RasKaga, OBA) in the device of Raskaga Tor Sotspi (I map ZadomuzKki, Vgepdap VeiYi, Rebeg Vgoad apa Meimup

Noiyiv Sepe 1992. 118: 137-141; Scide (about EiKaguoiis Tgapvetesiope m/yip Saiopis Iiriy Keadepiv. | Me

Tesppoiodiez, OPIVSO VK, OA). about t in mm | 46 mm va bo c) Determination of inhibitory activity against NMO CoA-reductase

Liver microsome-bound reductase was obtained from rats fed 295 cholestyramine in the middle of a 65-dark cycle. Spectrophotometric analyzes are carried out in 100 mM KNoRO, 4 mM OT, 0.2 mM MAORN, 0.3 mM NMO

CoA and 125 μg of microsomal liver enzyme. The total volume of the reaction mixture is maintained equal to ml.

The reaction is started by adding NMO CoA. The reaction mixture is incubated at 372C for 30 minutes. and register a decrease in optical density by 3-40 nm. The reaction mixture without a substrate is used as a blank experiment (Soiidviviip, U. Her apa Vgomup, M.5.Rgodgev5v ip ipdegviapaipd (She ОЙ heseriog apa NMO SoA gedisiavze, imo tetrbgape rgoieipz (Shai gedsiage (She riazta spoieviegoi. U. Iiriy Kev., 1984, 25; 1450-1461).The test compounds inhibit the enzyme HMO CoA reductase.

C) Ip mimo a) Efficiency in genetic models

Mutations in laboratory animal colonies and different sensitivities to feeding regimes have made possible 7/0 the development of animal models with non-insulin-dependent diabetes and hyperlipidemia associated with obesity and insulin resistance. Genetic models, such as the db/45 and or/o6 mice (Oiabreyfez, (1982) 31(1): 1-6) and 2isKeg TaLe rats, have been established by various laboratories to understand the pathophysiology of the disease and to test the efficacy of new antidiabetic compounds (Oiabrey ( ez, (1983) 32: 830-838; Appy. Ker. ZapKkuo Kevz. I ab. (1994). 46: 1-57). Homozygous animals - mice C57 VIi/Kvg.)-dr/ar, bred daskvop I aroghaiog (USA), are obese, 75 hyperglycemic, hyperinsulinemic and insulin resistant (U. Siip. Ipmezi,, (1990) 85: 962-967), while heterozygotes are lean and normoglycemic. In the ar/d4r model, mice gradually develop insulinopenia as they age, which is a feature commonly seen in the late stages of type 1 diabetes in humans with insufficient control of blood sugar levels. The state of the pancreas and the course of the process vary depending on the model. Since this model resembles type II diabetes, the compounds of the present invention will be tested for their ability to lower blood sugar and triglycerides.

For the experiment, male C57VI /Kz».)-dr/db mice aged from 8 to 14 weeks, with a body weight in the range from 35 to 60 grams, bred in the animal nursery of Og were used. Kedauz Kezeagsp Roshpadayop (OKR).

Mice were given standard food (Maiyopa! Ipviyshie oi MiigShop (MIM), Nudegabrad, Ipaia) and acidified water ai Irisht. Animals that have more than 35 Ωg of sugar/dl of blood are used for the tests. The number of animals of

In each group is equal to 4.

The test compounds are suspended in 0.2595 carboxymethyl cellulose and administered to the experimental group in a dose from 0.1 mg to about

ZOmg/kg orally by gastric tube for b days. The control group receives the carrier (dose 1Oml/kg). On day 6, blood samples are taken one hour after administration of the test compound/carrier for biological activity analysis. Ha

Random blood sugar and triglyceride levels can be measured by drawing blood (10 µl) through the orbital sinus using a heparinized capillary into tubes containing EDTA, which are then centrifuged to obtain plasma. Levels of glucose and triglycerides in plasma can be measured spectrometrically, according to the methods of Kk! using glucose oxidase and the enzyme glycerol-3-PO /-oxidase/peroxidase (Og. Kedauz I ab. Oiadpoviis Oimiviop Kyiv, Nudegabaa, Ipaia), respectively. co

The activity of test compounds in reducing blood sugar and triglycerides is calculated according to the formula. uh-

In these studies, no undesirable effects were observed for any of the mentioned compounds of the invention. 20 2 s 5-week-old male/female mice were obtained from Votpoidag (Denmark) and used at 8 weeks of age. Obese 7asKeg Tala rats were obtained from Chasstedeau (France) at 10 weeks of age and used at 13 weeks of age. The animals were kept under a 12-hour light-dark cycle at a temperature of 25-10. The animals received standard laboratory food (MIM, Nudeharad, Ipaia) and water ai Iriisht (Rtsimaga, T., Mozpioka, 5., - Mozpioka, I., Ovpiuata, I. apa Nogikovzpi, N. Spagasiegilayop oi pem/ oga! apiidiareis adepi S85-045. 5itsaiev ip KK apa or/or tise apa 7isKeg Tatsu gayiv. YuOiare(ez. 1988. 37: 1549-1558). (o) Test compounds were administered at a dose of 0.1 to ZOmg/kg for 9 days. Control animals received the SL carrier (0.2595 carboxymethyl cellulose, dose 100 ml/kg) through a gastric tube.

Blood samples were collected in the fed state 1 hour after administration of the drug on day 0 and day 9 of the drug administration course. Blood was taken from the retroorbital sinus through a heparinized capillary into test tubes

Kz contain EDTA. After centrifugation, the plasma sample is separated for analysis of triglycerides, glucose, free fatty acids, total cholesterol, and insulin. Measurements of triglycerides, glucose and total cholesterol in plasma are carried out using commercial analytical kits (Og. Kedau's I arogayogu,

Oiadpowiis Oimizviop, Ipaiia). The level of free fatty acids in the plasma is measured using a commercial kit from Voegipdeg Mappneit (Germany). Plasma insulin is measured using a KIA kit (VAKS, (F) Ipaia). The reduction of various studied parameters is calculated according to the following formula.

GI In or/or mice, an oral glucose tolerance test is performed after 9 days of treatment. Mice are starved for B5 hours. and receive a provocation test of Zg/kg of glucose orally. Blood samples for assessment of plasma glucose levels are taken after 0, 15, 30, 60 and 120 minutes.

Experimental results for db/45 mice, or/or mice, and 7!isKeg TaLa rats suggest that the novel compounds of the present invention are also therapeutically useful for prophylactic or regular treatment of diabetes, obesity, cardiovascular disorders such as hypertension, hyperlipidemia and other diseases, since it is known from the literature that such diseases are related to each other. 65 Blood glucose and triglyceride levels are also reduced at doses greater than 1Omg/kg. Of course, the degree of recovery depends on the dose and reaches a plateau at a certain value of the dose.

B) Activity in reducing plasma triglycerides and cholesterol in hypercholesterolemic rat models

Male Zrgadce Juauleu rats (MIM line) are bred in the OKE kennel. Animals are kept under a 12-hour light-dark cycle at a temperature of 25-10. Rats with a body weight in the range of 180-200 grams are used for the experiment. Animals are made hypercholesterolemic by feeding 295 cholesterol and 195 sodium cholate mixed with standard laboratory; by feed (Mayopa! Ipviyshe oi Myigyop (MIM), Nouadegabaad,

Ipaia), within Е days. During the period of the experiment, the animals are kept on the same diet (Reiiii, 0.,

Voppeiiz, M. T., Keu, S, apa Iptapivg, K. EPesiv oi sirgoirgaye op Iimeg Iiridz apa Irorgoiveip zupipeviv ip 70 pogto- apa Nurepiridetis gayiv. Agpegozsiehov. 1988. 74: 215-225).

Test compounds can be administered orally at a dose of 0.1 to 30 mg/kg/day for 3 days. The control group received only the carrier (0.2590 carboxymethyl cellulose; dose 1 Oml/kg).

Blood samples are collected in the fed state 1 hour after drug administration on day 0 and C of the compound administration course. Blood is taken from the retroorbital sinus through a heparinized capillary into tubes containing EDTA. After centrifugation, the plasma sample is separated for analysis of total cholesterol, NOI and triglycerides. Measurements of plasma triglycerides, total cholesterol, and NOI. carried out using commercial sets (Og. Kedauz I arogaiyugu, Oiadpovziis Oimiviop, Ipaiia). The value of cholesterol

GOYS and MINE. calculated from data obtained for total cholesterol, NOI and triglycerides. The reduction of various researched parameters is calculated in accordance with the formula. 7 31118001 yus from 25 y - decrease; 7 - increase (8) c) Activity in reducing plasma triglycerides and total cholesterol in Zmizv albino mice and guinea pigs

Zm/izz male albino mice (ZAM) and male guinea pigs are obtained from MIM and kept in the OKR nursery. All these animals are kept on a 12-hour light-dark cycle at a temperature of 25--126. cm 30 Animals receive standard laboratory feed (MIM, Nuaegabad, Ipaia) and water ai Prisht. They use CM

ZAM with a body weight in the range of 20-25g and guinea pigs with a body weight of 500-700Og (Oiimeg, R., RiapsKe, M.O., oyu

Maghip, O., Siameu, M., Zatsliege5, u. apa Rgasnag, S. ENPesiv oi Tepoibgaye, deptiirgogiY apa pisoyipis asii op riazta Iirorgoiieip Iemeiz ip pogtai apa puregiiridetis tise. Agpegozsiehov. 1988. 70: 107-114). (ee) z Test compounds are administered orally to albino mice Zm/izz at a dose of 0.3 to 30 mg/kg/day for 6 days. M

Control mice received a carrier (0.2595 carboxymethyl cellulose; dose 1 Oml/kg). Test compounds are administered orally to guinea pigs at a dose of 0.3 to ZOmg/kg/day for 6 days. Control animals received a vehicle (0.2590 carboxymethyl cellulose; dose 5 ml/kg).

Blood samples are taken in the fed state 1 hour after administration of the medicinal product on days 0 and 6 of the course of treatment. Blood is taken from the retroorbital sinus through a heparinized capillary to tubes containing EDTA. After centrifugation, the plasma sample is separated for analysis of triglycerides and total cholesterol (Uuieiapa, O. Meijod5z oi Epgutaiys apaiuziv. Wegdegteueg, N.O., Ed., 1963. 211-214; :z» Tgipteg, R. App. Siip. Viospet. 1969. 6: 24-27). Measurements of plasma triglycerides are carried out using commercial kits of reagents (Og. Kedauz Oiadpowiis Oimiziop, Nudegabad, Ipaia). 5 t so 61 sl of 50 a) Effect of body weight reduction in hamsters fed with cholesterol from Male Syrian hamsters were purchased from MEM, Nudegabad (India). The animals were kept in the OKE kennel with a 12-hour light-dark cycle at a temperature of 25-12; with free access to feed and water. Animals receive standard laboratory feed (MIM) with 190 cholesterol from the day of the start of the use of medicinal 959 products.

HF) Test compounds can be administered orally at a dose of 1 to 30 mg/kg/day for 15 days. The control group of animals received a vehicle (Miya water | SO), dose 1 Oml/kg/day). Body weight is measured every 3 days.

Formulas for calculation: o 1. The percentage of reduction in blood sugar / triglycerides / total cholesterol is calculated according to the formula:

Interest rate - |1- 77752 |k100 ts

OS- Value for the control group on day zero

OT: Value for the experimental group on day zero c5 To- Value for the control group on the day of analysis

TT: Value for the experimental group on the day of analysis

2. Cholesterol levels of GO. and MI OI. calculated according to the formulas:

Claims (1)

The formula of the invention 1. Compounds of formula (I) Re 5 ;() В! their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, in which KE" , VK? and KZ, B", if they are attached to a carbon atom, are the same or different and mean hydrogen, halogen, hydroxyl group, nitro group, cyano group, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkyl, cycloalkyl, арилу, арилоксигрупи, аралкілу, аралкоксигрупи, одновалентного гетероциклічного радикала, гетероарилу, гетероаралкілу, гетероарилоксигрупи, гетероаралкоксигрупи, ацилу, ацилоксигрупи, гідроксіалкілу, аміногрупи, ациламіногрупи, моноалкіламіногрупи, діалкіламіногрупи, ариламіногрупи, аралкіламіногрупи, алкоксикарбонілу, арилоксикарбонілу, аралкоксикарбонілу, алкоксіалкілу, арилоксіалкілу, аралкоксіалкілу, alkylthio group, thioalkyl, alkoxycarbonylamino group, aryloxycarbonylamino group, armethoxycarbonylamino group, carbonyl group slots or its derivatives or sulfonic acid or its derivatives; one or both of BZ and E7 means an oxo group or a thioxo group, if they are attached to a carbon atom; B C and K7, when attached to a nitrogen atom, are hydrogen, hydroxyl, formyl or substituted or unsubstituted groups selected from alkyl, C 29 cycloalkyl, alkyl, cycloalkyl, aryl, aralkyl, monovalent heterocyclic (3 radicals, heteroaryl, гетероаралкілу, ацилу, ацилоксигрупи, гідроксіалкілу, аміногрупи, ациламіногрупи, моноалкіламіногрупи, діалкіламіногрупи, ариламіногрупи, аралкіламіногрупи, аміноалкілу, арилоксигрупи, аралкоксигрупи, гетероарилоксигрупи, гетероаралкоксигрупи, алкоксикарбонілу, арилоксикарбонілу, аралкоксикарбонілу, алкоксіалкілу, арилоксіалкілу, аралкоксіалкілу, алкілтіогрупи, тіоалкільної групи, с похідних карбонової acid or sulfonic acid derivatives; X means a heteroatom selected from oxygen, which is sulfur; UM means MA"? , where K" means hydrogen or a substituted or unsubstituted group selected from alkyl, aryl or aralkyl; o means an integer in the range 0-6 ; CO and B"! are the same or different and mean hydrogen or an unsubstituted or substituted group selected from alkyl, alkoxy aryl or aralkyl groups; Ag means a substituted or unsubstituted chn divalent monocyclic or condensed aromatic or heterocyclic group selected from divalent phenylene, naphthylene , pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl or benzoxazolyl group; B? represents a hydrogen atom, a hydroxyl group, « 470 alkoxy group, halogen, alkyl, substituted or unsubstituted an aralkyl group or forms a bond together with the adjacent Э) with a KZ group; KK? means hydrogen, a hydroxyl group, an alkoxy group, a halogen, an alkyl group, acyl, substituted or unsubstituted aralkyl, or a KZ forms a bond together with K?; B" means hydrogen or substituted or unsubstituted "» groups selected from alkyl, cycloalkyl, aryl noy, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, monovalent heterocyclic, heteroaryl, heteroaralkyl groups; BZ means hydrogen or substituted or unsubstituted groups selected from - alkyl, cycloalkyl, aryl, aralkyl, monovalent heterocyclic, heteroaryl, or Ho) heteroaralkyl groups; U means oxygen, sulfur or ME, where is EE? means hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl aralkyl monovalent heterocyclic, and heteroaryl or heteroaralkyl groups, or ME? means chiral amine, chiral amino alcohols derived from ime) 50 chiral amino acids; or VZ and B? together form a substituted or unsubstituted 5- or b-membered cyclic "z structure containing carbon atoms, which optionally contains one or more heteroatoms selected from oxygen, sulfur, or nitrogen; t and n are integers in the range 0-6 . 2. The compound according to claim 1, in which the substituents on К -К? selected from halogen, hydroxyl, nitro, thio, or an unsubstituted or substituted group selected from alkyl, cycloalkyl, alkyl, cycloalkyl, aryl, aralkyl, aryloxy, aralkyl, alkoxyalkyl, aryloxyalkyl, aroxyalkyl, monovalent (F) heterocyclic radical, heteroaryl, heteroaralkyl , acyl, acyloxy group, hydroxyalkyl, amino group, GI acylamino group, arylamino group, aminoalkyl, alkoxycarbonyl, alkylamino group, alkylthio group, carboxylic acid or its derivatives or sulfonic acid or its derivatives; the substituents on K" are selected from alkyl, cycloalkyl, oxy, cycloalkyl, aryl, aralkyl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkyl, alamoxycarbonyl . are different and mean hydrogen, halogen or alkyl; one or both of ЕЗ and КЕ" means an oxo group or a thioxo group, when attached to a carbon atom; BZ and B7, when attached to a nitrogen atom, means hydrogen or alkyl; o means a hydrogen atom or forms a bond together with an adjacent BC group ; 29 means hydrogen or forms a bond together with K?; VK" means hydrogen or substituted or unsubstituted alkyl, aryl or aralkyl; KZ means hydrogen or substituted or unsubstituted groups selected from alkyl, aryl or aralkyl; t and n are integers in the interval 0-2. 4. The compound according to claim 1-3, selected from: (-)-ethyl-3-I4-13-(3,4-dihydro-2H-benzoyl| 1/1, Zoxazin-4-yl)/propylamino)phenyl) |-2-ethoxypropionate, (w)-ethyl-3-I4-(3-(3)4-dihydro-2H-benzo|v)/1,Zoxazin-4-yl)propylamino)phenyl|-2-ethoxypropionate, (-)-ethyl-3-I4-13-(3,4-dihydro-2H-benzoyl|in(1,Zoxazin-4-yl)/propylamino)phenyl)|-2-ethoxypropionate, (z--3- I4-(3-(3,4-dihydro-2H-benzo|(81(11,Zoxazin-4-yl)ipropylamino)phenyl|-2-ethoxypropionic acid or its salts, (z)-3-I4-13- (3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)phenyl)|-2-ethoxypropionic acid or its salts, (-)-3-I4-43-(3,4 -dihydro-2H-benzo(c)/1,Zoxazin-4-yl)propylamino)phenyl|-2-ethoxypropionic acid or 79 Ti salts, ( )-ethyl-3-I4-M-heptyl-M-/2- (3-oxo-3,4-dihydro-2H-benzoyl| 81/11, Zoxazin-4-yl)-ethylamino)phenyl|-2-ethoxypropionate, ()-ethyl-3-14-M-heptyl-M- (2-(3-oxo-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)-ethylamino)phenyl|-2-ethoxypropionate, (-)-ethyl-3-I(4 -M-heptyl-M-12-(3-oxo-3,4-dihydro-2H-benzoyl|in(1,Zoxazin-4-yl)-ethyl) amino)phenyl|-2-ethoxypropionate, (3-3-14-M-heptyl-M-(2-(3-oxo-3,4-dihydro-2H-benzoi|8111,Zoxazin-4-ylethylamino)phenyl |-2-ethoxypropionic acid or its salts, with 29 (1)-3-I4-M-heptyl-M-12-(3-oxo-3,4-dihydro-2H-benzoi|51(11,Doxazin-4 -yl)uethylamino)phenyl|-2-ethoxypropionov Ge) oic acid or its salts, (-)-3-14-M-heptyl-M-/2-(3-oxo-3,4-dihydro-2H-benzo |b1(1,Zoxazin-4-yl)ethylamino)phenyl/|-2-ethoxypropionic acid or its salts, ( c )-methyl-2-ethoxy-3-I4--M-heptyl-M-(2- (3,4-Dihydro-2H-benzo|f|oxazin-4-yl)-2-oxoethyl)aminomethyl)phenyl|propion satu, (1)-methyl-2-ethoxy-3-14--M-heptyl -M-(2-(3,4-dihydro-2H-benzo|in|oxazin-4-yl)-2-oxoethyl)aminomethyluphenyl|n ropionate, (ee) (-)U-methyl-2-ethoxy- 3-I4-7M-heptyl-M-(2-(3,4-dihydro-2H-benzo|p|oxazin-4-yl)-2-oxoethyl)aminomethyluphenyl|propionate, - (i)-2-ethoxy -3-I4-7M-heptyl-M-(2-(3,4-dihydro-2H-benzo|B|oxazin-4-yl)-2-oxoethyl)iaminomethyl)phenyl|propionic acid or its salts, « 20 (g)-2-ethoxy-3-I4-7M-heptyl-M-(2-(3,4-dihydro-2H-benzo|f |oxazin-4-yl)-2-oxoethyl)aminomethyl)phenyl|propionic acid or its salts, with (-)-2-ethoxy-3-(4-7M-heptyl-M-(2-(3 ,4-dihydro-2H-benzo|p|oxazin-4-yl)-2-oxoethyl)aminomethyl)phenyl|propionic acid or its salts, (-)-methyl-3-I4-15-(3 ,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)-5-oxopentylamino)phenyl|-2-ethoxypropionate, (1)-methyl-3-I4-15-(3,4-dihydro- 2H-benzoyl|51(/1,Zoxazin-4-yl)-5-oxopentylamino)phenyl/|-2-ethoxypropionate, -I (-)-methyl-3-I4-15-(3,4-dihydro-2H -benzo|51(11,Tsoxazin-4-yl)-5-oxopentylamino)phenyl|-2-ethoxypropionate, (--3-I4-45-(3,4-dihydro-2H-benzo|81/1,Tsoxazin -4-yl)-5-oxopentylamino)phenyl|-2-ethoxypropionic acid or its salts, with (1)-3-I4-15-(3,4-dihydro-2H-benzoi|51(11,Doxazin- 4-yl)-5-oxopentylamino)phenyl|-2-ethoxypropionic acid OR its salts, co (-)-3-I4-45-(3,4-dihydro-2H-benzo|1/1, Tsoxazin-4 -yl)-5-oxopentylamino)phenyl|-2-ethoxypropionic acid or its salts, (-)-methyl-3-I3-(3-(3,4-dihydro-2H-benzoic acid) yl)upropylamino)phenyl/|-2-eth oxypropionate, (t)-methyl-3-(3-13-(3,4-dihydro-2H-benzoic acid) 1/1, Tsoxazin-4-yl)/propylamino)phenyl)|-2-ethoxypropionate, (-)-methyl-3-I3-(3-(3,4-dihydro-2H-benzo|5111, Tsoxazin-4 -yl)ipropylamino)phenyl/|-2-ethoxypropionate, (z-)-3-I3-(3-(3,4-dihydro-2H-benzo|(81(11,Zoxazin-4-yl)ipropylamino)phenyl |-2-ethoxypropionic acid or iF) its salts, co (z)-3-(3-13-(3,4-dihydro-2H-benzoi|51(11,Doxazin-4-yl)/propylamino)phenyl) |-2-ethoxypropionic acid or its salts, in (-)-3-I3-13-(3,4-dihydro-2H-benzo|in)/1,Zoxazin-4-yl)propylamino)phenyl|-2- ethoxypropionic acid or its salts, (-)-methyl-3-I4-(3-(7-fluoro-3,4-dihydro-2H-benzoi|51(11,Zoxazin-4-yl)/propylamino)phenyl/| -2-ethoxypropionate, (1)-methyl-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoyl| 51/11, Zoxazin-4-yl)/propylamino)phenyl)|-2 -ethoxypropionate, (-)Y-methyl-3-I4-(3-(7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)/propylamino)phenyl/|-2 -ethoxypropionate, 65 (--3-I4-43-(7-fluoro-3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)ipropylamino)phenyl|-2-ethoxypropionic acid or its salts , (1-)-3-I4-73-(7-fluoro-3,4-dihydro-2H-benzoyl|51/1,Doxazin-4-yl)/propylamino)phenyl)|-2-ethoxypropionic acid or its salts , (-)-3-I4-43-(7-fluoro-3,4-dihydro-2H-benzo|81(11,Zoxazin-4-yl)ipropylamino)phenyl|-2-ethoxypropionic acid OR its salts, ( )-methyl-2-ethoxy-3-(4-14-(3-(3,4-dihydro-2H-benzoyl|81/1,Zoxazin-4-yl)/propyloxy)benzylaminophenyl|propionate, (t)- methyl-2-ethoxy-3-I4-(4-(3-(3,4-dihydro-2H-benzoyl) 81/11, Zoxazin-4-yl)propyloxy)benzyl)aminophenyl|propionate, 70 (-) Y-methyl-2-ethoxy-3-(4-14-(3-(3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propyloxy)benzylaminophenyl|propionate, ( )- methyl-2-ethoxy-3-(3-4-(3-(3,4-dihydro-2H-benzoyl|81/1,Zoxazin-4-yl)/propyloxy)benzylaminophenyl|propionate, (t)-methyl- 2-ethoxy-3-I3-4-(3-(3,4-dihydro-2H-benzoyl) 81/11, Zoxazin-4-yl)propyloxy)benzyl)aminophenyl|propionate, (-)-methyl- 2-ethoxy-3-|3-(4-(3-(3,4-dihydro-2H-benzoi|51(11,Zoxazin-4-yl)ipropyloxy)benzylaminophenyl|propionate, ( )-2-ethoxy- 3-I4-14-(3-(3,4-dihydro-2H-benzoic acid) 51(11, Doxazin-4-yl)/propyloxy)benzylaminophenyl|propionic acid or its salts, ()-2-ethoxy-3-I4-14-(3-(3,4-dihydro-2H-benzoi) 51/11, Zoxazin-4-yl)propyloxy)benzyl)iaminophenyl|propionic acid or its salts, (-)-2-ethoxy-3-(4-14-(3-(3,4-dihydro-2H-benzo |51(11,Coxazin-4-yl)propyloxy)benzylaminophenyl|propionic acid or its salts, Ge 25 (- (o) )-2-ethoxy-3-(3-14-(3-(3,4-dihydro -2H-benzoic|51(11,Doxazin-4-yl)/propyloxy)benzylaminophenyl|propionic acid or its salts, ()-2-ethoxy-3-I3-14-(3-(3,4-dihydro-2H -benzoic| 51/11, Coxazin-4-yl)propyloxy)benzyl)iaminophenyl|propionic acid or its salts, with 30 (-)-2-ethoxy-3-I3-4-(3-(3,4-dihydro -2H-benzoic acid or its salts, (-ethyl-2-ethoxy-3-I4-3-(3,4-dihydro-2H -benzoyl|β1(1,4)thiazin-4-yl)/propylamino)phenyl|propionate, IF) (t)-ethyl-2-ethoxy-3-(4-13-(3,4-dihydro-2H- Benzoyl|51(11,thiazin-4-yl)/propylamino)phenyl|propionate, co (-)-ethyl-2-ethoxy-3-I4-(3-(3,4-dihydro-2H-benzo|1/ 1,4)thiazin-4-yl)/upropylamino)phenyl|propionate, 35 (--2-ethoxy-3-(4-13-(3,4-dihydro-2H-benzoyl)/1,thiazin-4-yl)/propylamino)phenyl|propionic acid or its salts, and - ( )-2-ethoxy-3-I4-13-(3,4-dihydro-2H-benzo|β1/1,4)thiazin-4-yl)upropylamino)phenyl|propionic acid or its salts, (-)-2 -ethoxy-3-(4-13-(3,4-dihydro-2H-benzoi|51(11,4)hyazin-4-yl)/propylamino)phenyl|propionic acid or its salts, (-)-ethyl- 2-ethoxy-3-I4-(2-(3,4-dihydro-2H-benzo|81(11,Zoxazin-4-yl)ethylamino)phenyl|propionate, « (t)-ethyl-2-ethoxy-3 -(4-2-(3,4-dihydro-2H-benzoyl|51(11,DCoxazin-4-yl)ethylamino)phenyl|propionate, 40 (-)-ethyl-2-ethoxy-3-I4-(2-(3,4-dihydro-2H-benzo|(81(/11,Zoxazin-4-yl)ethylamino)phenyl|propionate, C c ( --2-ethoxy-3-(4-12-(3,4-dihydro-2H-benzoi|51(11,Doxazin-4-yl)uethylamino)phenyl|propionic acid or its salts, Iz» ()-2 -ethoxy-3-I4-72-(3,4-dihydro-2H-benzo|c)/1,Zoxazin-4-yl)ethylamino)phenyl|propionic acid or its salts, (-)-2-ethoxy-3 -(4-12-(3,4-dihydro-2H-benzoi|51(11,Doxazin-4-yl)ethylamino)phenyl|propionic acid or its salts, ( )-methyl-2-ethoxy-3-(4 -I(4-72-(3,4-dihydro-2H-benzoi|51(11,Zoxazin-4-yl)ethoxy)phenylaminomethyl|phenyl|propionate, - (t)-methyl-2-ethoxy-3-I4 -I4-2-(3,4-dihydro-2H-benzo|b1/1,Zoxazin-4-yl)ethoxy)phenylaminomethyl|phenyl|propy (Fe)onate, (-)U-methyl-2-ethoxy-3 -(4-(4--2-(3,4-dihydro-2H-benzoyl)in(1,Zoxazin-4-yl)ethoxy)phenylaminomethyl|phenyl|propionate, with 50 (- "with ) -2-ethoxy-3-I4-I(4--2-(3,4-dihydro-2H-benzoi| 1/1, Zoxazin-4-yl)ethoxy)phenylaminomethyl|phenyl|propionic acid or its salts, ( )-2-ethoxy-3-(4-I(4-72-(3,4-dihydro-2H-benzo|b5)/1,Zoxa zin-4-yl)ethoxy)phenylaminomethylphenyl|propionic acid or its salts, (-)-2-ethoxy-3-(4-(4-2-(3,4-dihydro-2H-benzoi)|51(11,Doxazin -4-yl)ethoxy)phenylaminomethylIfenyl|propionic HF) acid or Its salts, 7 (--ethyl-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzo|51(/1,Zoxazin -4-yl)propylamino)phenyl|-2-ethoxypropionate, (g)-ethyl-3-I4-(3-(7-fluoro-3,4-dihydro-2H-benzo|8111,Zoxazin-4-yl) upropylamino)phenyl/|-2-ethoxypropionate, in (-)-ethyl-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoyl|51(1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionate, (- -ethyl-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoyl| 81/11, Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionate, (w)-ethyl- 3-I4-(3-(7-fluoro-3,4-dihydro-2H-benzo|81(11,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionate, (-)-ethyl-3- I4-13-(7-fluoro-3,4-dihydro-2H-benzoyl| 81/11, Coxazin-4-yl)/propylamino)phenyl|-2-methoxypropionate, (--3-I4-43-(7 -fluoro-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic 65 Acids OR their salts, (1-)-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzoyl| 1/1, Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid or its salts, (-3-3-I4-43-(7-fluoro-3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid or its salts, ( - )-ethyl-3-I4--3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51(11,Zoxazin-4-yl)-propylamino)phenyl|-2-ethoxypropionate . ethoxypropionate, (-)-ethyl-3-I4-13-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|5111,Zoxazin-4-yl)-propylamino)phenyl|-2- ethoxypro 70 pionate, (3-3-14-3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl| 81/11, Coxazin-4-yl)/propylamino)phenyl|-2 -ethoxypropionic acid or its salts, (1)-3-I4-3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)/propylamino)phenyl |-2-ethoxypropionov 75 OI acid or Its salts, (-)-3-I4-43-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoi|51(11,Doxazin-4-yl )/propylamino)phenyl)|-2-ethoxypropionic acid or its salts, (--ethyl-3-I4-13-(2-methyl-3,4-dihydro-2H-benzo|51(11,Zoxazin-4-yl)ipropylamino)phenyl/|-2-ethoxypropionate, ()-ethyl -3-I4-3-(2-methyl-3,4-dihydro-2H-benzoyl|51/1,Doxazin-4-yl)/propylamino)phenyl)-2-ethoxypropionate, (-)-ethyl-3- I4-13-(2-methyl-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionate, (--3-I4-43-(2 -methyl-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)phenyl)-2-ethoxypropionic acid or its salts, (1)-3-I4-13-(2- methyl-3,4-dihydro-2H-benzo|51(1,Zoxazin-4-yl)/propylamino)phenyl|-2-ethoxypropionic acid or its salts, sa (-3-3-I4-43-(2- methyl-3,4-dihydro-2H-benzoic|51/1,oxazin-4-yl)propylamino)phenyl)|-2-ethoxypropionic (5) acid or its salts, (-)-ethyl-3-I4-13 -(2-methyl-3,4-dihydro-2H-benzo|(81(11,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionate, ()-ethyl-3-I4-3-(2 -methyl-3,4-dihydro-2H-benzoyl|51(11,Doxazin-4-yl)/propylamino)phenyl|-2-methoxypropionate, (-)-ethyl-3-I4-13-(2-methyl- 3,4-dihydro-2H-benzo|81/1,Zoxazin-4-yl)/propylamino)phenyl|-2-metho xypropionate, c (--3-I4-43-(2-methyl-3,4-dihydro-2H-benzoic|51(11,Doxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid or salts, (1)-3-I4-73-(2-methyl-3,4-dihydro-2H-benzoi| 51/11, Coxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid, acid or its salts, co (-)-3-I4-43-(2-methyl-3,4-dihydro-2H- benzoic|51(11,Doxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid or its salts, o (--ethyl-3|4-(3-(2-propyl-3,4-dihydro- 2H-benzoi|51(11,Doxazin-4-yl)/propylamino)phenyl)-2-ethoxypropionate, ()-ethyl-3|4-13-(2-propyl-3,4-dihydro-2H-benzo| 51(1,Zoxazin-4-yl)propylamino)phenyl|-2-ethoxypropionate, (-)-ethyl-3I4-43-(2-propyl-3,4-dihydro-2H-benzoi|51(11,Zoxazin- 4-yl)/propylamino)phenyl/|-2-ethoxypropionate, « (--3-I4-43-(2-propyl-3,4-dihydro-2H-benzoyl)|51(11,Zoxazin-4-yl) /propylamino)phenyl/|-2-ethoxypropionic acid or its salts, but) c (1)-3-I4-13-(2-propyl-3,4-dihydro-2H-benzoi) 81/11, Zoxazin-4 -yl)propylamino)phenyl|-2-ethoxypropionic Iz» acid or its salts, (-)-3-I4-43-(2-propyl-3,4-dihydro-2H-benzoi|51(11,Zoxazin-4 -yl)upropylamino)phenyl|-2-ethoxypropionic acid or its salts, (- - )-ethyl-(25)-3-I4-13-(2-propyl-3,4-dihydro-2H-benzo|81/ 1, Tsoxazin-4-yl )/propylamino)phenyl|-2-methoxypropionate, (ee) (t)-ethyl-(25)-3-I4-13-(2-propyl-3,4-dihydro-2H-benzoi|51(11,Zoxazin -4-yl)/propylamino)phenyl|-2-methoxypropionate, o (-)-ethyl-(25)-3-I4-13-(2-propyl-3,4-dihydro-2H-benzoi| 81/11, Tsoxazin-4-yl)/propylamino)phenyl|-2-methoxypropyl 250 onate, Kz (9)-3Ch-(3(2-propyl-3,4-dihydro-2H-benzoyl)" Tsoxazin-4 -yl)upropylamino)phenyl|-2-methoxypropionic acid and its salts, (1)-3-I4-73-(2-propyl-3,4-dihydro-2H-benzoyl| 81/11, Zoxazin-4-yl )/propylamino)phenyl|-2-methoxypropionic acid and its salts, (-)-3-I4-43-(2-propyl-3,4-dihydro-2H-benzoi|51(11,Zoxazin-4-yl) /propylamino)phenyl|-2-methoxypropionic HF) acid and its salts, ka (-)-ethyl-2-isopropoxy-3-(4-73-(7-fluoro-3,4-dihydro-2H-benzo|51 /1,Zoxazin-4-yl)/propylamino)phenyl|propionate, in (t)-ethyl-2-isopropoxy-3-I4-(3-(7-fluoro-3,4-dihydro-2H-benzo|( 81/1, Coxazin-4-yl)/propylamino)phenyl|propionate, (-)-ethyl-2-isopropoxy-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzo|51 /1,oxazin-4-yl)propylamino)phenyl|propionate, (-2-isopropoxy-3-I(4-13-(7-fluoro-3,4-dihydro-2H-benzoi)|51(11,Zoxazin -4-yl)/propylamino)phenyl|propionic 65 acid and its salts, ()-2-isopropoxy-3-(4-13-(7-fluoro-3,4-dihydro-2H-benzoi)|81/1, coxazin-4-yl) /propylamino)phenyl|propionic acid and its salts, (-)-2-isopropoxy-3-I4-13-(7-fluoro-3,4-dihydro-2H-benzo|51/1,Zoxazin-4-yl) /propylamino)phenyl|propionic acid and its salts, (- )-ethyl-3-I4-73-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoi)|51(11,Doxazin-4- yl)-propylamino)phenyl|-2-methoxypropionate, (I)-ethyl-3-I4-3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl|51(1,oxazin- 4-yl)-propylamino)phenyl|-2-methoxypropionate, 70 (-)-ethyl-3-I4-13-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo|81/1 ,Zoxazin-4-yl)-propylamino)phenyl|-2-methoxypropionate, (3-3-I4-3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoyl) Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid and its salts, (1-)-3-I4-73-(2-methyl-7-fluoro-3,4-dihydro-2H-benzoic acid) 51(1,Zoxazin-4-yl)/propylamino)phenyl|-2-methoxypropionic acid and its salts, (-)-3-I4-43-(2-methyl-7-fluoro-3,4-dihydro- 2H-benzoic acid and its salts, (25,M(1K)1-M-(2-hydroxy-1-phenylethyl) -2-ethoxy-3-I4-13-(3,4-dihydro- 2H-benzos 81/11, Zoxazin-4-yl)propylamino)phenyl|propanamide, I2,MY1kK)I-M-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-(4-13-(3,4 -dihydro-2H-benzoyl|51(11,Doxazin-4-yl)propylamino)phenylpropanamide, (25,M(1K)1-M-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-I4 -73-(7-fluoro-3,4-dihydro-2H-benzo|B5)/1,Zoxazin-4-yl)propylamino)phenyl|propanamide, Ga I2,MY1kK)I-M-(2-hydroxy- 1-phenylethyl)-2-ethoxy-3-(4-13-(7-fluoro-3,4-dihydro-2H-benzoyl| 81/11, Zoxazin-4-yl) propylamino)phenyl|propanamide, and) (25,M(1K)1-M-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-I4-13-(3,4-dihydro-2H-benzoi| 81/11, Zoxazin-4- yl)propylamino)phenyl|Ipropanamide hydrochloride salt, I2,MI1kK)I-M-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-(4-13-(3,4-dihydro-2H-benzoi) |51(11,Doxazin-4-yl)propylamino)phenyl|Ipropanamide hydrochloride salt. 5. The compound according to claim 1, in which the pharmaceutically acceptable salts are salts of ii, Ma, K, Ca, Mp, Re, Si, 7p, Mp; with M,M'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, M-ethylmorpholine, M-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine , triethylamine, trimethylamine, tripropylamine, tromethamine, co-diethanolamine, meglumine, ethylenediamine, M,M'-diphenylethylenediamine, M,M'-dibenzylethylenediamine, h-M-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine; alkylphenylamine, ethanolamine, phenylethanolamine; glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids; O-isomers or substituted amino acids; guanidine, and c substituted guanidine, in which the substituents are selected from nitro group, amino group, alkyl, alkenyl, alkynyl, ammonium c or substituted ammonium salts and aluminum salts; sulfates, nitrates, phosphates, perchlorates, "» borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates, ammonium or substituted ammonium salts or aluminum salts -I 6. The method of obtaining the compound of the formula (I) with the following ingredients: Drennos oven CO with 50% Re YaSe Ov i" defined in claim 1, which includes: a) carrying out the reaction of the compound of the formula (Pa) И З ; (Ша 5 Кк m | (Ша) в" Od en yuyu in Mod in which І" means the leaving group, and all other symbols have the values indicated above, with the compound of the formula (NAME) 60 Ес о ; (ШБ) Е : nysevenogya C, thesis o b5 where MU stands for MA"? or -O-aryl-(СВ 9877) -ME 72 and all symbols have the values indicated above, with the formation of the compound of formula (I) defined above; or B) carrying out the reaction compounds of the formula (Ps) B! m; (Шс) in Мов where all symbols have the values indicated above, with the compound of the formula (Ша) WITH B. "(pa vo (pa) IU-Ly( sv yur 5 --u--(SBYUBBY). du G ' I UEZ o 19 where I means a leaving group, MU means ME"? or -O-aryl-( SK 97) -MVA 77, and all other symbols have the values indicated above, with the formation of a compound of the formula (I); or c) carrying out the reaction of a compound of the formula (Ше) І єв; (Ше) and x in Mov where Я means MV"? or -O-aryl-(СВ'ОВ1)-МВЙ2 and all symbols have the values indicated above, with the EM compound of the formula (PV Ge) according to zutokhovokh (I Ов: сч where К"Z means (C,i-Cv)-alkyl , and all other symbols have the above meanings, with the formation of the compound of formula (I) defined above, and, optionally, the conversion of the compound of formula (I) obtained by any of the methods described above into pharmaceutically acceptable salts or pharmaceutically acceptable solvates; pure salts or pure or s a) reduction of the compound of the formula (Ma) pH and Yuri ЯГ dev vm -- (Sov mog " in Mo ov? - s which means the compound of formula (I), where KE? and KZ together mean a bond, U means an oxygen atom, and all other symbols have the values indicated above, obtained either - by any method stated in claim 5, with the formation of the compound ;" of the formula (I), where each of EB and 5 means a hydrogen atom, and all other symbols have the above values; or e) carrying out the reaction of the compound of the formula (Э) - in ! mo, , (Not) her and Drenevyurti-onnknitv-ono 1 ve: M EE yu where UM means ME"? or -O-aryl-(СВ'9К1)-ME"?, and all other symbols have the above meanings, with Ge compound of the formula (MB) shih (MB) poreogya 55 . Oh, where is BC? means hydrogen and all other symbols are as defined above to form a compound of formula where (I) defined above; or 6o i) carrying out the reaction of the compound of the formula (Sha) in! mo, (Sho) S mn pi ni I! And | (8) dv In Mov where І" means the leaving group, n and о are integers in the interval 0-6, and all other symbols have the values indicated above, with the compound of the formula (NAME) in: ре о ; (IB) Na - - (Svv, -A thesis o where M means ME "2 and all other symbols have the values indicated above, with the formation of a compound of formula (I), where M/ means -С(-0)-(СВ9В7).-МА 77, and all other symbols have the values indicated above; 70 or 9) carrying out the reaction of the compound of the formula (Pi) ! . e mo, ; (Her) C (sov) -a -0 Deyaenyurto r: M v where p and r are integers in the interval 0-6, C! stands for ХО or МН", and all other symbols have the values indicated above, with the compound of the formula (ШЙ) in. ; (PM) r Her r Peteu В I s KE I Ag che Ov where d means an integer in the interval 0-6, 52 means ХО or МН", and all other symbols have the values indicated above, with the formation of the compound of formula (I) , where MU means -O-aryl-(СВ "98 77)5-МВ 7", and all other symbols have the meanings indicated above; or P) () carrying out the reaction of the compound of the formula (I) with - (I sh e o () sch x Re s (svoi) -Uu-- (SVB --A g te yu v: v : і ot so so where all symbols have the above meanings and U is oxygen, or UB8 is a halogen atom, or som is a mixed anhydride group, and all other symbols have the above meanings, with an amine of the formula MNE, where BZ and EE? have the above values, and, necessarily, (i) separation of the compound of formula (I), obtained above, into stereoisomers; or « () carrying out hydrolysis of the compound of formula (I) with Shk 5 ;() I 2 s k m A ro . R. DAYS. what Yuri у ях Also ог: ш- where VZ means unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, Go! monovalent heterocyclic, heteroaryl or heteroaralkyl group, and all other symbols have the above meanings, to the compound of formula (I), where C is hydrogen, and optionally, the transformation of the compound of formula (I) obtained by any of the above methods, on ka 20 pharmaceutically acceptable salts or pharmaceutically acceptable solvates. 7. Intermediate compound of the formula (Ша) Ио в (Ша) ро ' Я т Sort -- жу -- (свой ---дг ' І че о о o its derivatives, its analogues, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, wherein HER | means a leaving group such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, 60 phosphate or a hydroxyl group; MU means ME" . group; o is an integer in the range of 0-4; BO and B"! are the same or different and represent hydrogen or a substituted or unsubstituted group selected from alkyl, alkyl, aryl or aralkyl groups; Ag represents a substituted or unsubstituted divalent monocyclic or a condensed aromatic or heterocyclic group; Vo represents a hydrogen atom, a hydroxyl group, an alkoxy group, a halogen, an alkyl, substituted or unsubstituted aralkyl group or forms a bond together with the neighboring group K 9; 59 represents hydrogen, hydroxyl, alkoxy, halogen, lower alkyl, acyl, substituted or unsubstituted aralkyl, or KE? forms a bond together with E?; B" means hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, monovalent heterocyclic, heteroaryl, heteroaralkyl; BZ means hydrogen or substituted or unsubstituted groups selected from an alkyl, cycloalkyl, aryl, aralkyl, monovalent heterocyclic, heteroaryl, or heteroaralkyl group; U represents oxygen, sulfur, or ME, where VE? represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkyl monovalent heterocyclic, heteroaryl, or heteroaralkyl group; or KZ and KU together form a substituted or unsubstituted 5- or b--cyclic structure containing carbon atoms, which optionally contains one or more heteroatoms selected from oxygen, sulfur or nitrogen; t and n are whole numbers in the interval 0-6. 8. Intermediate compound of the formula (Ша) 9 in hv o , (Mo) C s nn in: M osv its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, in wherein B", K2 and BZ, B", when attached to a carbon atom, are the same or different and represent hydrogen, halogen, hydroxyl, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkyl group, aryl, aryloxy group, aralkyl, aralkyl group, monovalent heterocyclic radical, heteroaryl, c 29 heteroaralkyl, heteroaryloxy group, heteroaralkyl group, acyl, acyloxy group, hydroxyalkyl, amino group, (U acylamino group, monoalkylamino group, dialkylamino group, arylamino group, aralkylaminocarbonyl group, aryloxy, aryloxy Alkoxyalkyl, Aryloxyalkyl, Araloxyalkyl, Alkylthio, Thioalkyl, Alkoxycarbonylamino, Aryloxycarbonylamino, Aralkoxycarbonylamino upy, carboxylic acid or its derivatives or sulfonic acid or its derivatives; one or both of BZ and E7 represent an oxo group or a thioxo group, if they are attached to a carbon atom; B C and VK", if they are attached to a nitrogen atom, c means hydrogen, a hydroxyl group, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkyl, cycloalkyl, aryl, aralkyl, monovalent heterocyclic radical, heteroaryl, гетероаралкілу, ацилу, ацилоксигрупи, гідроксіалкілу, аміногрупи, ациламіногрупи, 00 моноалкіламіногрупи, діалкіламіногрупи, ариламіногрупи, аралкіламіногрупи, аміноалкілу, арилоксигрупи, їч- аралкоксигрупи, гетероарилоксигрупи, гетероаралкоксигрупи, алкоксикарбонілу, арилоксикарбонілу, аралкоксикарбонілу, алкоксіалкілу, арилоксіалкілу, аралкоксіалкілу, алкілтіогрупи, тіоалкільної групи, carboxylic acid derivatives or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; KO and KE"! are the same or different and represent hydrogen or a substituted or unsubstituted group selected from alkyl, alkyl, aryl or aralkyl; Eat! means a leaving group such as a halogen atom, -c methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, c phosphate or a hydroxyl group; n and o are integers in the interval 0-6. "» 9. Intermediate compound of the formula (Her) VE! m ; (Her) 45 С Dsvevnko -0 Deyaenyurto so ve M se s its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts , its pharmaceutically acceptable solvates, in which K 1, 82 and VU, c", if they are attached to a carbon atom, are the same or different and represent hydrogen, halogen, hydroxyl group, nitro group, cyano group, formyl or Kz substituted or unsubstituted groups , selected from alkyl, cycloalkyl, alkyl, cycloalkyl, aryl, aryloxy, aralkyl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylaminocarbyl, arylalkylamino, aryl , aryloxycarbonyl, armethoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aroxyalkyl, alkylthio group, F, thioalkyl, alkoxycarbonylamino group, aryloxycarbonylamino group, aralkylamino group, carboxylic acid or its derivatives or sulfonic acid or its derivatives; one or both of B3 and B7 represent an oxo group or a thioxo group if they are attached to a carbon atom; B C and VK", if they are attached to a nitrogen atom, 60 means hydrogen, hydroxyl group, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkyl, cycloalkyl, aryl, aralkyl, monovalent heterocyclic radical, heteroaryl, heteroaralkyl , ацилу, ацилоксигрупи, гідроксіалкілу, аміногрупи, ациламіногрупи, моноалкіламіногрупи, діалкіламіногрупи, ариламіногрупи, аралкіламіногрупи, аміноалкілу, арилоксигрупи, аралкоксигрупи, гетероарилоксигрупи, гетероаралкоксигрупи, алкоксикарбонілу, арилоксикарбонілу, 65 аралкоксикарбонілу, алкоксіалкілу, арилоксіалкілу, аралкоксіалкілу, алкілтіогрупи, тіоалкільної групи, похідних карбонової кислоти or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; K"O and KE"! are the same or different and represent hydrogen or a substituted or unsubstituted group selected from alkyl, alkyl, aryl or aralkyl groups; Z! represents CHO or MN", n and p are integers in the interval 0-6. 10. A pharmaceutical composition containing a compound of formula (I) defined in claims 1-5 and a pharmaceutically acceptable carrier, diluent, excipient or solvate. 11. A pharmaceutical composition containing a compound of formula (I) defined in claims 1-5 and an inhibitor of NMO CoA reductase; fibrate; nicotinic acid; cholestyramine; colestipol; probucol or combinations thereof and a pharmaceutically acceptable carrier, diluent, excipient or solvate. 70 12. Pharmaceutical composition according to claim 10 or 11 in the form of a tablet, capsule, powder, syrup, solution or suspension. 13. A method of prevention or treatment of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance, or a disease in which insulin resistance is the basic pathophysiological mechanism, which includes the administration of compound 75 of formula (I) defined in claims 1-5, or the pharmaceutical composition according to claim 10 or 11, to a patient in need thereof. 14. The method according to claim 13, in which the disease is type II diabetes, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X, including hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders; kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy; disorders associated with endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS5), dementia, diabetic complications, inflammatory bowel disease, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or osteoporosis, or inflammatory processes. 15. The method according to claim 13, intended for the treatment and/or prevention of disorders related to syndrome X, Ge! which includes the administration of the agonist rrRABo, and/or RRAE»U of the formula (I), defined in claims 1-5, or the pharmaceutical composition according to claim 10 or 11, to a patient in need of it. 16. The method of reducing total cholesterol, body weight, blood plasma glucose, triglycerides, GO, MI OI. or free fatty acids or increase NOI in plasma, which includes the administration of a compound of formula (I) defined in claims 1-5, or a pharmaceutical composition according to claim 10 or 11 to a patient in need thereof. s Zo sch IF) (ee) and - - and? -i (ee) 1 name) Ko) name) 60 b5