Cetp inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

 

The technical field to which the invention relates

The present invention relates to the class of chemical compounds that inhibit protein-a carrier of aethers of cholesterol (SETR) and, thus, suitable for raising the level of HDL-cholesterol, reducing LDL-cholesterol, and for treating and preventing atherosclerosis.

The level of technology

Atherosclerosis and its clinical consequences of coronary heart disease (CHD), stroke and peripheral vascular disease, form a truly monstrous burden on the health systems of industrialized countries. Only in the United States diagnosed with CHD delivered approximately 13 million patients annually and at the expense of CHD include more than half a million deaths. Moreover, it is expected that this tribute will increase over the next quarter century, as the epidemic of obesity and diabetes continues to spread.

It has long been noted that in mammals variation profiles of circulating lipoproteins correlate with the risk of atherosclerosis and coronary heart disease. The clinical success of inhibitors of HMG-CoA reductase inhibitor, in particular statins, to reduce the incidence of coronary diseases is based on the reduction of circulating cholesterol low-density lipoprotein (LDL-C)levels directly correlate with an increased risk of developing ater the sclerosis. Recently conducted epidemiological studies have shown that there is an inverse relationship between the levels of cholesterol in high density lipoprotein (HDL-C) and the development of atherosclerosis, and this forces us to conclude that low levels of HDL-C in serum are associated with an increased risk of developing coronary artery disease.

Metabolic regulation of the levels of lipoproteins is a complex and dynamic process involving many factors. One of the important factors regulating metabolism in humans is a protein-a carrier of aethers of cholesterol (SETR) - located in the plasma glycoprotein that catalyzes the movement of cholesterol esters from HDL to apoB-containing lipoproteins, including VLDL (see Hesler, C.B. et al (1987) Purification and characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem. 262(5), 2275-2282)). In physiological terms, the following interaction is gitarooman, which SETR transfers triglyceride from apoB-containing lipoproteins to HDL and transports cholesterol from HDL to apoB to myprotein.

People SETR performs the function of treatment of transfer of cholesterol by which cholesterol is returned to the liver from peripheral tissues. It is interesting to note that many animals do not have SETR, including animals, which have high levels of HDL, but as you know, are resistant to the development of coronary heart disease,for example, rodents (see Guyard-Dangremont, V. et al., (1998) Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 120(3), 517-525). There have been numerous epidemiological studies relating the effect of natural variations in activity SETR with the risk of coronary heart disease, including the study of a small number of known null mutations (see Harada, K.-I., Yamashita, S. and Matsuzawa, Y. (2000) Pros and cons of inhibiting cholesteryl ester transfer protein, Curr. Opin. Lipidol. 11(6), 589-596). These studies suggest a strong inverse relationship between the concentration of HDL-C in plasma and the activity of SETR (see see Inazu, A., et al. (2000) Cholesteryl ester transfer protein and atherosclerosis, Curr. Opin. Lipidol. 11(4), 389-396) and lead to the hypothesis that pharmacological inhibition activity SETR in lipid transfer can have a beneficial effect on people by increasing levels of HDL-C while lowering LDL levels.

Despite significant therapeutic advances that provide statins, such as simvastatin (ZOCOR®), statins may reduce risk of only about one third of the attempts at treatment and prevention of atherosclerosis and called atherosclerosis diseases. Currently little available pharmacological treatments, which markedly increase the circulating levels of HDL-C. Certain statins and some fibrates give moderate the expansion of the HDL-C. Niacin, providing the most effective therapeutic effect on increasing HDL-C, which has been documented in clinical conditions, has the disadvantage that is associated with patients ' adherence to the regimens and regimens, in part because of side effects such as hot flashes. A tool that safely and effectively increases the levels of HDL, would solve a significant, but as yet unmet medical need due to the development of pharmacological therapies that could significantly improve the profile of circulating lipids through a mechanism that complements existing methods of treatment.

New classes of chemical compounds that inhibit SER, are investigated in various pharmaceutical companies or undergoing clinical trials. On the market there is currently no inhibitors SER. Clinical trials torcetrapib representing inhibitor SETR, Pfizer was recently discontinued due to the high mortality rate of patients who took the specified medication in the process of conducting studies on the consequences of his actions. Need new connection in order to receive one or more pharmaceutical compounds that are safe and effective. New connections given in this description is, are very effective inhibitors SER.

The invention

Compounds having Formula I, including pharmaceutically acceptable salts of these compounds are inhibitors SETR, which is suitable for the following use, where:

Y is selected from a group that includes-C(=O)- and -(CRR1)-;

X is selected from a group that includes-O-, -NH-, -N(C1-C5alkyl) -, and -(CRR6)-;

Z is selected from a group that includes-C(=O)-, -S(O)2and

-C(=N-R9), where R9selected from the group which consists of H, -CN and

C1-C5alkyl, optionally substituted by 1-11 halogen atoms;

each R is independently selected from the group which includes H,

C1-C5alkyl and halogen atom, where C1-C5alkyl optionally substituted by 1-11 halogen atoms;

In selected from the group which includes And1and2where And1has the structure:

R1and R6each selected from the group which includes H,

-C1-C5alkyl, halogen atom and -- (C(R)2)nA2where-C1-C5alkyl optionally substituted by 1-11 halogen atoms;

R2selected from the group which includes H, -C1-C5alkyl, halogen atom, And1and -(C(R)2)nA2where-C1-C5Ala is l is optionally substituted 1 to 11 halogen atoms;

where one of the b and R2identifies And1; and one of B, R1, R2and R6identifies And2or -(C(R)2)nA2; so that the compound of Formula I includes one group And1and one group And2;

And3selected from the group which includes:

(a) an aromatic cycle, selected from phenyl and naphthyl;

(b) phenyl cycle, condensed with (5-7)-membered nonaromatic cycloalkyl, which optionally contains 1-2 double bonds;

(c) from 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of connection And3to the phenyl cycle that is attached And3is a carbon atom; and

(d) benzoheterocycles, including phenyl cycle, condensed with a 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from O, N and-S(O)x-, and optionally 1-2 double bonds, where the point of connection And3to the phenyl cycle that is attached And3is a carbon atom;

at the same time3substituted by one group And4and optionally substituted by 1-4 groups Ra;

And2selected from the group which includes:

(a) an aromatic cycle, selected from phenyl and naphthyl;

(b) phenyl cycle, condensed with (5-7)-membered ring is nonaromatic cycloalkyl, which optionally contains 1-2 double bonds;

(c) from 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group;

(d) benzoheterocycles, including phenyl cycle, condensed with a 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from O, N and S, and optionally 1-2 double bonds; and

(e) -C3-C8cycloalkyl, optionally containing 1-3 double bonds;

at the same time2optionally substituted by 1-5 substituting groups independently selected from Ra;

And4selected from the group which includes:

(a) an aromatic cycle, selected from phenyl and naphthyl;

(b) phenyl cycle, condensed with (5-7)-membered nonaromatic cycloalkyl, which optionally contains 1-2 double bonds;

(c) from 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group;

(d) benzoheterocycles, including phenyl cycle, condensed with a 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from O, N and-S(O)x-, and optionally 1-2 double bonds;

in the case when A4means: (a) an aromatic cycle, selected from phenyl and naphthyl; (b) familycircle, condensed with (5-7)-membered nonaromatic cycloalkyl, which optionally contains 1-2 double bonds; (c) from 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of attachment of the heterocycle to a3is the atom N And4; or (d) benzoheterocycles, including phenyl cycle, condensed with a 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from O, N and-S(O)x-, and optionally 1-2 double bonds; And4optionally substituted by 1-5 groups Ra;

and when And4means (5-6)-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of attachment of the heterocycle to a3is the carbon atom in the a4a4substituted with one Reand optionally also substituted by 1-4 groups independently selected from Ra;

each Raindependently selected from the group which includes-C1-C6alkyl, -C2-C6alkenyl, -C2-C6quinil, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS1-C6alkyl, -OS2-C6alkenyl, -OS2-C6quinil, -OS3-C8cloaker, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -C(=O)C3-C8cycloalkyl, -C(=O)H, -CO2H,-CO2C1-C6alkyl, -C(=O)SC1-C6alkyl, -OH, -NR3R4, -C(=O)NR3R4, -NR3C(=O)OS1-C6alkyl, -NR3C(=O)NR3R4, -S(O)xC1-C6alkyl, -S(O)yNR3R4, -NR3S(O)yNR3R4, halogen atom, -CN, -NO2and 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S and O, with the specified heterocycle optionally also includes a carbonyl group and optionally also includes 1-3 double bonds, where the connection point is specified heterocycle to the loop that is attached to Rais a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom, -C1-C3the alkyl and-OC1-C3of alkyl, C1-C3alkyl, and-OC1-C3alkyl optionally substituted by 1 to 7 halogen atoms;

for compounds in which Raselected from the group comprising-C1-C6alkyl, -C2-C6alkenyl, -C2-C6quinil, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS1-C6alkyl, -OS2-C6alkenyl, -OS2-C quinil, -OS3-C8cycloalkyl, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -C(=O)C3-C8cycloalkyl, -CO2C1-C6alkyl, -C(=O)SC1-C6alkyl, -NR3C(=O)OS1-C6alkyl and-S(O)xC1-C6alkyl, Raoptionally substituted by 1-15 atoms, halogen, and optionally substituted 1-3 substituting groups, independently selected from: (a) HE, (b) -CN, (c) -NR3R4, (d) -C3-C8cycloalkyl, optionally containing 1-3 double bonds and optionally substituted by 1-15 atoms of halogen, (e) -OS1-C4the alkyl, optionally substituted by 1-9 halogen atoms and optionally substituted by 1-2 substitute groups independently selected from-OC1-C2the alkyl and phenyl, (f) -OS3-C8cycloalkyl, optionally containing 1-3 double bonds and optionally substituted by 1-15 atoms of halogen, (g) -CO2H (h) -C(=O)CH3(i) -CO2C1-C4of alkyl, which is optionally substituted by 1-9 halogen atoms, and (j) phenyl which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3;

each Reindependently selected from the group which includes-C2-C6alkenyl, -C2-C6quinil, -C3-C8cycloalkyl, optional soda is containing 1-3 double bonds, -OS2-C6alkenyl, -OS2-C6quinil, -OS3-C8cycloalkyl, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -C(=O)C3-C8cycloalkyl, -C(=O)H, -CO2H, -CO2C1-C6alkyl, -C(=O)SC1-C6alkyl, -OH, -NR3R4, -C(=O)NR3R4, -NR3C(=O)OS1-C6alkyl, -NR3C(=O)NR3R4, -S(O)xC1-C6alkyl, -S(O)yNR3R4, -NR3S(O)yNR3R4, -CN, -NO2and 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S and O, with the specified heterocycle optionally also includes a carbonyl group and optionally also includes 1-3 double bonds, where the connection point is specified heterocycle to the loop that is attached to Reis a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom, -C1-C3the alkyl and-OC1-C3of alkyl, C1-C3alkyl, and-OC1-C3alkyl optionally substituted by 1 to 7 halogen atoms;

for compounds in which Reselected from the group comprising-C2-C6alkenyl, -C2-C6quinil, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS2-C62-C6quinil, -OS3-C8cycloalkyl, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -C(=O)C3-C8cycloalkyl, -CO2C1-C6alkyl, -C(=O)SC1-C6alkyl, -NR3C(=O)OS1-C6alkyl and-S(O)xC1-C6alkyl, Reoptionally substituted by 1-15 atoms, halogen, and optionally substituted 1-3 substituting groups, independently selected from: (a) HE, (b) -CN, (c) -NR3R4, (d) -C3-C8cycloalkyl, optionally containing 1-3 double bonds and optionally substituted by 1-15 atoms of halogen, (e) -OS1-C4the alkyl, optionally substituted by 1-9 halogen atoms and optionally substituted by 1-2 substitute groups independently selected from-OC1-C2the alkyl and phenyl, (f) -OS3-C8cycloalkyl, optionally containing 1-3 double bonds and optionally substituted by 1-15 atoms of halogen, (g) -CO2H (h) -C(=O)CH3(i) -CO2C1-C4of alkyl, which is optionally substituted by 1-9 halogen atoms, and (j) phenyl which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3;

n denotes 0 or 1;

p denotes an integer equal 0-4;

x denotes 0, 1 or 2;

y denotes 1 or 2;

R3and R4each independently researched the Simo selected from H, -C1-C5of alkyl, -C(=O)C1-C5the alkyl and-S(O)yC1-C5of alkyl, C1-C5alkyl in all instances is optional substituted 1 to 11 halogen atoms; and

R5selected from the group which includes H, -OH, -C1-C5alkyl and halogen atom, a C1-C5alkyl optionally substituted by 1-11 halogen atoms.

All of the compounds of Formula I and the following compounds, alkyl, alkeline and alkyline group, if not stated otherwise, can be linear or branched.

Detailed description of the invention

In the ways of implementation of the present invention the compounds have the Formula Ia, Ib or Id, including represent a pharmaceutically acceptable salt.

In the ways of implementation of the present invention groups in the structures independently from each other are the following groups:

Y represents -(CRR1)-.

R and R6each independently selected from the group which includes N and-C1-C5alkyl, C1-C5alkyl optionally substituted by 1-11 halogen atoms.

R1selected from the group which includes H, -C1-C5alkyl and

-(C(R)2)nA2where-C1-C5alkyl optionally substituted by 1-11 halogen atoms;

where one of the b and R2identifies And1; and one of B, R 1and R2represents A2or -(C(R)2)nA2; so that the compound of Formula I includes one group And1and one group And2.

And3selected from the group which includes:

(a) an aromatic cycle, selected from phenyl and naphthyl;

(b) from 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of connection And3to the phenyl cycle that is attached And3is a carbon atom; and

(C) benzoheterocycles, including phenyl cycle, condensed with a 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from O, N and-S(O)x-, and optionally 1-2 double bonds, where the point of connection And3to the phenyl cycle that is attached And3is a carbon atom;

at the same time3substituted by one group And4and optionally substituted by 1-4 groups Ra.

And2selected from the group which includes:

(a) an aromatic cycle, selected from phenyl and naphthyl;

(b) from 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group;

(C) benzoheterocycles, including phenyl cycle, condensed with a 5 to 6-membered heterocycle is, containing 1-2 heteroatoms independently selected from O, N and S, and optionally 1-2 double bonds; and

(d) -C3-C8cycloalkyl, optionally containing 1-3 double bonds;

at the same time2optionally substituted by 1-5 substituting groups independently selected from Ra.

Each Raindependently selected from the group which includes-C1-C6alkyl, -C2-C6alkenyl, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)H, -CO2H, -CO2C1-C6alkyl, -OH, -NR3R4, -NR3C(=O)OS1-C6alkyl, -S(O)xC1-C6alkyl, halogen atom, -CN, -NO2and 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S and O, with the specified heterocycle optionally also includes a carbonyl group and optionally also includes 1-3 double bonds, where the connection point is specified heterocycle to the loop that is attached to Rais a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom, -C1-C3the alkyl and-OC1-C3of alkyl, C1-C3alkyl, and-OC1-C3alkyl optionally substituted by 1 to 7 halogen atoms;

for with the of dinani, in which Raselected from the group comprising-C1-C6alkyl, -C2-C6alkenyl, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS1-C6alkyl, -C(=O)C1-C6alkyl, -CO2C1-C6alkyl, -NR3C(=O)OS1-C6alkyl and-S(O)xC1-C6alkyl, Raoptionally substituted by 1-15 atoms, halogen, and optionally substituted by one substituting group selected from: (a) HE, (b) -NR3R4, (s) -OS1-C4the alkyl, optionally substituted by 1-9 halogen atoms and optionally substituted by 1-2 substitute groups independently selected from-OC1-C2the alkyl and phenyl, and (d) phenyl, which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3.

Each Reindependently selected from the group which includes-C2-C6alkenyl, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -C(=O)H, -CO2H, -CO2C1-C6alkyl, -OH, -NR3R4, -NR3C(=O)OS1-C6alkyl, -S(O)xC1-C6alkyl, -CN, -NO2and 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S and O, with the specified heterocycle optionally includes also Carbo is safe group and optionally also includes 1-3 double bonds, where the connection point is specified heterocycle to the loop that is attached to Reis a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom, -C1-C3the alkyl and-OC1-C3of alkyl, C1-C3alkyl, and-OC1-C3alkyl optionally substituted by 1 to 7 halogen atoms;

for compounds in which Reselected from the group comprising-C2-C6alkenyl, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -CO2C1-C6alkyl, -NR3C(=O)OS1-C6alkyl and-S(O)xC1-C6alkyl, Reoptionally substituted by 1-15 atoms, halogen, and optionally substituted by one substituting group selected from: (a) HE, (b) -NR3R4, (s) -OS1-C4the alkyl, optionally substituted by 1-9 halogen atoms and optionally also substituted with 1-2 substitute groups independently selected from-OC1-C2the alkyl and phenyl, and (d) phenyl, which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3.

p denotes an integer equal to 0-2.

R3and R4each independently selected from H and-C1-C5of alkyl, where

-C 1-C5alkyl in all instances is optional substituted 1 to 11 halogen atoms.

R5selected from the group which includes H, -OH, -C1-C5alkyl, C1-C5alkyl optionally substituted by 1-11 halogen atoms.

Z is selected from a group that includes-C(=O)-, -S(O)2and

-C(=N-R9), where R9selected from the group comprising H, -CN and CH3.

Each R is independently selected from the group comprising H and-C1-C2alkyl.

R6selected from the group comprising H and-C1-C3alkyl, C1-C3alkyl optionally substituted by 1-5 halogen atoms.

R1selected from the group comprising H and-C1-C3alkyl and -(C(R)2)nA2where-C1-C5alkyl optionally substituted by 1-5 halogen atoms.

R2selected from the group which includes H, -C1-C3alkyl, And1and

-(C(R)2)nA2where-C1-C3alkyl optionally substituted by 1-5 halogen atoms, where one of the b and R2identifies And1and one of In, R1and R2identifies And2or -(C(R)2)nA2; so that the compound of Formula I includes one group And1and one group And2.

And3selected from the group which includes:

(a) phenyl;

(b) from 5 to 6-membered aromatic heterocycle containing 1-2 heteroatoms independently selected from N, S, OI-N(O)-, where the attachment point And3to the phenyl cycle that is attached And3is a carbon atom; and

(C) benzoheterocycles, including phenyl cycle fused with 5-membered aromatic heterocycle containing 1-2 heteroatoms independently selected from O, N and-S(O)x-where the attachment point And3to the phenyl cycle that is attached And3is a carbon atom;

at the same time3substituted by one group And4and optionally substituted by 1-4 groups Ra.

And2selected from the group which includes:

(a) phenyl;

(b) from 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds;

(C) benzoheterocycles, including phenyl cycle fused with 5-membered heterocycle containing 1-2 heteroatoms independently selected from O, N and S; and

(d) -C5-C6cycloalkyl;

at the same time2optionally substituted by 1-5 substituting groups independently selected from Ra.

Each Raindependently selected from the group which includes-C1-C4alkyl, -C2-C4alkenyl, cyclopropyl, -OS1-C2alkyl, -C(=O)C1-C2alkyl, -C(=O)H, -CO2H, -CO2C1-C4alkyl, -OH, -NR3R4, -NR3C(=O)OS1-C4alkyl, -S(O)xC 1-C2alkyl, halogen atom, -CN, -NO2and 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from N, S and O, where the connection point is specified heterocycle to the loop that is attached to Rais a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom;

for compounds in which Raselected from the group comprising-C1-C4alkyl, -C2-C4alkenyl, -OS1-C2alkyl, -C(=O)C1-C2alkyl, -CO2C1-C4alkyl, -NR3C(=O)OS1-C4alkyl and-S(O)xC1-C2alkyl, the alkyl group in Raoptionally substituted by 1-5 halogen atoms, and optionally substituted by one substituting group selected from: (a) HE, (b) -NR3R4, (s) -och3, optionally substituted by 1-3 fluorine atoms and optionally substituted by one phenyl group, and (d) phenyl, which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3.

Each Reindependently selected from the group which includes-C2-C4alkenyl, cyclopropyl, -C(=O)C1-C2alkyl, -C(=O)H, -CO2H, -CO2C1-C4alkyl, -OH, -NR3R4, -NR3C(=O)OS1 4alkyl, -S(O)xC1-C2alkyl,-CN, -NO2and 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from N, S and O, where the connection point is specified heterocycle to the loop that is attached to Reis a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom;

for compounds in which Reselected from the group comprising-C2-C4alkenyl, -C(=O)C1-C2alkyl, -CO2C1-C4alkyl, -NR3C(=O)OS1-C4alkyl and-S(O)xC1-C2alkyl, the alkyl group in Reoptionally substituted by 1-5 halogen atoms, and optionally substituted by one substituting group selected from: (a) HE, (b) -NR3R4, (s) -och3, optionally substituted by 1-3 fluorine atoms and optionally substituted with one phenyl group, and (d) phenyl, which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3.

p denotes an integer equal to 0-2.

R3, R4and R5each independently selected from H and-C1-C3the alkyl.

There are many ways of implementing the present invention uses the following definitions:

X represents-O-;

Z represents-C(=O)-;

Y represents-R1where R1selected from C1-C2of alkyl;

R and R5denote H;

R2and In each selected from And1and2where one of R2and denote As1and the other of R2and denote As2;

And2selected from the group comprising phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imidazolyl;

And3selected from the group comprising phenyl, thiazolyl and pyrazolyl;

And4selected from the group comprising phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and azetidines;

And2optionally substituted by 1-3 substituents, independently selected from a halogen atom, -co3and-CF3and-C1-C3the alkyl, optionally substituted by 1 to 3 halogen atoms;

And3substituted by one group And4and optionally substituted with 1-2 substituents independently selected halogen atom, -OH, -CF3and

-C1-C3the alkyl, optionally substituted by 1 to 3 halogen atoms;

And4optionally substituted by 1-3 substituents, independently selected from the group which includes: (a)- (C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted by a group- (b)- (C2-C4alkenyl, optionally substituted by 1 to 3 halogen atoms, (C) -C(=O)C1-C2the alkyl, optional the part substituted by 1-3 halogen atoms and optionally substituted by one group, selected from-OH, -CO2CH3-C(=O)CH3, -NR3R4and-OS1-C2alkylene1-C2of alkyl, (d) -C(=O)H, (e) -CO2N (f) -CO2C1-C4alkyl, optionally substituted by one group selected from-C(=O)C1-C2of alkyl, -OH, -CO2CH3, -CO2H, -NR3R4and-OS1-C2alkylene1-C2of alkyl, (g), (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4(m) -OS1-C2alkylene1-C2alkyl, (n) -OS1-C3alkyl, optionally substituted by 1 to 3 halogen atoms, (o) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted by one group selected from-OH, -CO2CH3, -NR3R4and-OS1-C2alkylene1-C2of alkyl, (R) -NR3C(=O)OS1-C2alkyl, (q) -NR3R4and (r) -S(O)xNR3R4,

provided that if a4denotes a heterocyclic group attached to And3through a ring carbon atom in the a4then, at least one Deputy in A4must be selected from Rewhere Reselected from the group which includes: (a)- (C1-C5alkyl, substituted by a group-HE, and optionally substituted by 1 to 3 halogen atoms, (b)- (C2 -C4alkenyl, optionally substituted by 1 to 3 halogen atoms, (C) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted by one group selected from-OH, -CO2CH3-C(=O)CH3, -NR3R4and-OS1-C2alkylene1-C2of alkyl, (d) -C(=O)H, (e) -CO2N (f) -CO2C1-C4alkyl, optionally substituted by one group selected from-C(=O)C1-C2of alkyl, -OH, -CO2CH3, -CO2H, -NR3R4and-OS1-C2alkylene1-C2of alkyl, (g), (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OS1-C2alkylene1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted by one group selected from-OH, -CO2CH3, -NR3R4and-OS1-C2alkylene1-C2of alkyl, (n) -NR3C(=O)OS1-C2alkyl, (o) -NR3R4and (p) -S(O)xNR3R4;

Raselected from a halogen atom, -CH3, -CF3, -Och3and-CF3;

R3and R4each independently selected from N and CH3; and

x is 0, 1 or 2.

In embodiments implementing the present invention identifies And1and R2identifies And2.

In Varian the Ah implementation of the present invention identifies And 2and R2identifies And1.

In embodiments implementing the present invention And2And3and4denote phenyl.

In embodiments implementing the present invention each Raselected from the group which contains (a)- (C1-C4alkyl, optionally substituted by 1-5 fluorine atoms and optionally substituted by one group selected from-OH, -och3and-NR3R4; (b) -OS1-C2alkyl, optionally substituted by 1-3 fluorine atoms; (C) -C2-C4alkenyl; (d) -C1-C2alkyl-O-C1-C2alkylphenyl; (e) cyclopropyl; (f) -C(=O)H; (g) CO2N; (h) -CO2C1-C4alkyl; (i) -OH; (j) -NR3R4; (k) -S(O)xC1-C2alkyl; (l) a halogen atom; (m) -CN; (n) -NO2and (about) 5 to 6-membered heterocycle comprising 1-2 oxygen atom, which is optionally substituted C1-C2the alkyl.

In other embodiments, implementation of the present invention the compounds have the Formula Ic, including their pharmaceutically acceptable salt,

where one of the1and2means

and the other In1and2denotes Ar1(Rc)u;

Ar1selected from the group which includes:

(a) an aromatic cycle, selected from phenyl and naphthyl;

(b) phenyl cycle, condenser the cell with (5-7)-membered nonaromatic cycloalkyl, which optionally contains 1-2 double bonds;

(c) from 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group;

(d) benzoheterocycles, including phenyl cycle, condensed with a 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from O, N and S, and optionally 1-2 double bonds; and

(e) -C3-C8cycloalkyl, optionally containing 1-3 double bonds;

AG2selected from the group which includes:

(a) an aromatic cycle, selected from phenyl and naphthyl;

(b) phenyl cycle, condensed with (5-7)-membered nonaromatic cycloalkyl, which optionally contains 1-2 double bonds;

(c) benzoheterocycles, including phenyl cycle, condensed with a 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from O, N and S, and optionally 1-2 double bonds; and

(d) 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group;

R1selected from the group which includes H, -C1-C5alkyl and halogen atom, a C1-C5alkyl optionally substituted by 1-11 halogen atoms;

R3and R4each independently selected from H, -C1-C5is Lila, -C(=O)C1-C5the alkyl and-S(O)yC1-C5of alkyl, C1-C5alkyl in all instances is optional substituted 1 to 11 halogen atoms;

each Ra, Rb, Rcand Rdindependently selected from the group which includes-C1-C6alkyl, -C2-C6alkenyl, -C2-C6quinil, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS1-C6alkyl, -OS2-C6alkenyl, -OS2-C6quinil, -OS3-C8cycloalkyl, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -C(=O)C3-C8cycloalkyl, -C(=O)H, -CO2H, -CO2C1-C6alkyl, -C(=O)SC1-C6alkyl, -OH, -NR3R4, -C(=O)NR3R4, -NR3C(=O)OS1-C6alkyl, -NR3C(=O)NR3R4, -S(O)xC1-C6alkyl, -S(O)yNR3R4, -NR3S(O)yNR3R4, halogen atom, -CN, -NO2and 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S and O, with the specified heterocycle optionally also includes a carbonyl group and optionally also includes 1-3 double bonds, where the connection point is specified heterocycle to the loop that is attached to Ra, Rb, Rcor Rdis a carbon atom, with the specified GE is erotic optionally substituted by 1-5 substituting groups, independently selected from a halogen atom, -C1-C3the alkyl and-OC1-C3of alkyl, C1-C3alkyl, and-OC1-C3alkyl optionally substituted by 1 to 7 halogen atoms;

in this case, when Ra, Rb, Rcand Rdselected from the group comprising-C1-C6alkyl, -C2-C6alkenyl, -C2-C6quinil, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS1-C6alkyl, -OS2-C6alkenyl, -OS2-C6quinil, -OS3-C8cycloalkyl, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -C(=O)C3-C8cycloalkyl, -CO2C1-C6alkyl, -C(=O)SC1-C6alkyl, -NR3C(=O)OS1-C6alkyl and-S(O)xC1-C6alkyl, Ra, Rb, Rcand Rdoptionally substituted by 1-15 atoms, halogen, and optionally substituted 1-3 substituting groups, independently selected from: (a) HE, (b) -CN, (c) -NR3R4, (d) -C3-C8cycloalkyl, optionally containing 1-3 double bonds and optionally substituted by 1-15 atoms of halogen, (e) -OS1-C4the alkyl, optionally substituted by 1-9 halogen atoms and optionally substituted by 1-2 substitute groups independently selected from-OC1-C2the alkyl and phenyl, (f) -OS3-C8is cloacina, optionally containing 1-3 double bonds and optionally substituted by 1-15 atoms of halogen, (g) -CO2H (h) -C(=O)CH3(i) -CO2C1-C4of alkyl, which is optionally substituted by 1-9 halogen atoms, and (j) phenyl which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3;

Reindependently selected from the group which includes-C2-C6alkenyl, -C2-C6quinil, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS2-C6alkenyl, -OS2-C6quinil, -OS3-C8cycloalkyl, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -C(=O)C3-C8cycloalkyl, -C(=O)H, -CO2H, -CO2C1-C6alkyl, -C(=O)SC1-C6alkyl, -OH, -NR3R4, -C(=O)NR3R4, -NR3C(=O)OS1-C6alkyl, -NR3C(=O)NR3R4, -S(O)xC1-C6alkyl, -S(O)yNR3R4, -NR3S(O)yNR3R4, -CN, -NO2and 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S and O, with the specified heterocycle optionally also includes a carbonyl group and optionally also includes 1-3 double bonds, where the connection point is specified heterocycle to cycle to motorolaringtones R eis a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom, -C1-C3the alkyl and-OC1-C3of alkyl, C1-C3alkyl, and-OC1-C3alkyl optionally substituted by 1 to 7 halogen atoms;

in this case, when Reselected from the group comprising-C2-C6alkenyl, -C2-C6quinil, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS2-C6alkenyl, -OS2-C6quinil, -OS3-C8cycloalkyl, optionally containing 1-3 double bonds, -C(=O)C1-C6alkyl, -C(=O)C3-C8cycloalkyl, -CO2C1-C6alkyl, -C(=O)SC1-C6alkyl, -NR3C(=O)OS1-C6alkyl and-S(O)xC1-C6alkyl, Reoptionally substituted by 1-15 atoms, halogen, and optionally substituted 1-3 substituting groups independently selected from (a) HE, (b) -CN, (c) -NR3R4, (d) -C3-C8cycloalkyl, optionally containing 1-3 double bonds and optionally substituted by 1-15 atoms of halogen, (e) -OS1-C4the alkyl, optionally substituted by 1-9 halogen atoms and optionally substituted by 1-2 substitute groups independently selected from-OC1-C2the alkyl and phenyl, (f) -OS3-C8C is kloeckera, optionally containing 1-3 double bonds and optionally substituted by 1-15 atoms of halogen, (g) -CO2H (h) -C(=O)CH3(i) -CO2C1-C4of alkyl, which is optionally substituted by 1-9 halogen atoms, and (j) phenyl which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3;

p denotes an integer equal 0-4;

q denotes an integer equal 0-4;

u denotes an integer equal to 0-5;

x is 0, 1 or 2; and

y is 1 or 2;

in this case, when AG2selected from the group which includes:

(a) an aromatic cycle, selected from phenyl and naphthyl;

(b) phenyl cycle, condensed with (5-7)-membered nonaromatic cycloalkyl, which optionally contains 1-2 double bonds;

(c) benzoheterocycles, including phenyl cycle, condensed with a 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from O, N and S, and optionally 1-2 double bonds; and

(d) 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group, where the connection point is specified heterocycle to the phenyl group to which is attached a heterocycle is a heteroatom of the heterocycle, t denotes an integer equal to 0 to 5, and w is 0;

and the hen AG 2means (5-6)-membered heterocycle containing 1-4 heteroatoms independently selected from N, S, O, and-N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group, where the connection point is specified heterocycle to the phenyl group to which is attached a heterocycle, is the carbon atom in the heterocycle, t denotes an integer equal to 0-4, and w is 1.

Variants of the compounds have the Formula Ie, including their pharmaceutically acceptable salts:

In the variants of implementation of the present invention the compound has the Formula If, including its pharmaceutically acceptable salt:

In the variants of implementation of the present invention the compound has Formula Ig, including its pharmaceutically acceptable salt:

In embodiments implementing the present invention each Rdindependently selected from the group which includes-C1-C4alkyl, -C2-C4alkenyl, cyclopropyl, -OS1-C4alkyl, -C(=O)C1-C4alkyl, -C(=O)H, -CO2H, -CO2C1-C4alkyl, -OH, -NR3R4, -NR3C(=O)OS1-C4alkyl, -S(O)xC1-C2alkyl, halogen atom, -CN, -NO2and 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from N, S and O, where the point process the organisations specified heterocycle to cycle, attached to Rdis a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom;

in this case, when Rdselected from the group comprising-C1-C4alkyl, -C2-C4alkenyl, cyclopropyl, -OS1-C4alkyl, -C(=O)C1-C4alkyl, -CO2C1-C4alkyl, -NR3C(=O)OS1-C4alkyl and-S(O)xC1-C2alkyl, alkyl, Alchemilla and cyclopropyl group in Rdoptionally substituted by 1-5 halogen atoms and optionally substituted by one substituting group selected from: (a) HE, (b) -NR3R4, (s) -och3, optionally substituted by 1-3 fluorine atoms and optionally substituted with one phenyl group, and (d) phenyl, which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3; and

t denotes an integer equal to 0-5.

Embodiments of the present invention can have the Formula Ih or represent its pharmaceutically acceptable salt:

In independent variants of implementation of the present invention, including pharmaceutically acceptable salts:

R1selected from the group which consists of H and-C1-C5alkyl, C1 -C5alkyl optionally substituted by 1-11 halogen atoms;

R3and R4each independently selected from H and-C1-C5of alkyl, C1-C5alkyl in all instances is optional substituted 1 to 11 halogen atoms;

each Ra, Rband Rcindependently selected from the group which includes-C1-C6alkyl, -C2-C6alkenyl, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)H, -CO2H, -CO2C1-C6alkyl, -OH, -NR3R4, -NR3C(=O)OS1-C6alkyl, -S(O)xC1-C6alkyl, halogen atom, -CN, -NO2and 5 to 6-membered heterocycle containing 1-4 heteroatoms independently selected from N, S and O, with the specified heterocycle optionally also includes a carbonyl group and optionally also includes 1-3 double bonds, where the connection point is specified heterocycle to the loop that is attached to Rais a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom, -C1-C3the alkyl and-OC1-C3of alkyl, C1-C3alkyl, and-OC1-C3alkyl optionally substituted by 1 to 7 halogen atoms;

in this case, when Ra, Rband Rcselect the HN group, includes-C1-C6alkyl, -C2-C6alkenyl, -C3-C8cycloalkyl, optionally containing 1-3 double bonds, -OS1-C6alkyl, -C(=O)C1-C6alkyl, -CO2C1-C6alkyl, -NR3C(=O)OS1-C6alkyl and-S(O)xC1-C6alkyl, Ra, Rband Rdoptionally substituted by 1-15 atoms, halogen, and optionally substituted by one substituting group selected from: (a) HE, (b) -NR3R4, (s) -OS1-C4the alkyl, optionally substituted by 1-9 halogen atoms and optionally substituted by 1-2 substitute groups independently selected from-OC1-C2the alkyl and phenyl, and (d) phenyl, which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3.

Each Rdindependently selected from the group which includes-C1-C4alkyl, -C2-C4alkenyl, -OS1-C2alkyl, -C(=O)C1-C2alkyl, -C(=O)H, -CO2H, -CO2C1-C4alkyl, -OH, -NR3R4, -NR3C(=O)OS1-C4alkyl, -S(O)xC1-C2alkyl, halogen atom, -CN, -NO2and 5 to 6-membered heterocycle containing 1-2 heteroatoms independently selected from N, S and O, where the connection point is specified to the ring heterocycle is attached to Rthe is a carbon atom, with the specified heterocycle optionally substituted by 1-5 substituting groups, independently selected from a halogen atom;

in this case, when Rdselected from the group comprising-C1-C4alkyl, -C2-C4alkenyl, -OS1-C2alkyl, -C(=O)C1-C2alkyl, -CO2C1-C4alkyl, -NR3C(=O)OS1-C4alkyl and-S(O)xC1-C2alkyl, alkyl or Alchemilla group in Rdoptionally substituted by 1-5 halogen atoms and optionally substituted by one substituting group selected from (a) HE, (b) -NR3R4, (s) -och3, optionally substituted by 1-3 fluorine atoms and optionally substituted with one phenyl group, and (d) phenyl, which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3.

In embodiments implementing the present invention:

p denotes an integer equal to 0-2.

q denotes an integer equal to 0-2.

t denotes an integer equal to 0 to 3.

u denotes an integer equal to 0-2.

x is 0, 1 or 2.

y is 1 or 2.

In independent variants of implementation of the present invention, including pharmaceutically acceptable salts:

R1selected from H and-C1-C2the alkyl.

R3and R4each independently selected and is H and-C 1-C3the alkyl.

Each Ra, Rband Rcindependently selected from the group which includes-C1-C4alkyl, -C2-C4alkenyl, -OS1-C2alkyl, -C(=O)C1-C2alkyl, -C(=O)H, -CO2H, -CO2C1-C4alkyl, -OH, -NR3R4, -NR3C(=O)OS1-C4alkyl, -S(O)xC1-C2alkyl, halogen atom, -CN, -NO2;

in this case, when Ra, Rband Rcselected from C1-C4of alkyl, -C2-C4alkenyl, -OS1-C2of alkyl, -C(=O)C1-C2of alkyl, -CO2C1-C4of alkyl, -NR3C(=O)OS1-C4the alkyl and-S(O)xC1-C2of alkyl, alkyl and Alchemilla group in Ra, Rband Rwithoptionally substituted by 1-5 halogen atoms and optionally substituted by one group selected from: (a) HE, (b) -NR3R4, (s) -och3, optionally substituted by 1-3 fluorine atoms and optionally substituted with one phenyl group, and (d) phenyl, which is optionally substituted by 1-3 groups independently chosen from a halogen atom, -CH3, -CF3, -Och3and-CF3.

Rdselected from the group which includes-C1-C4alkyl, -C2-C4alkenyl, -NR3R4-C(=O)H, -CO2H, -CO2C1-C4alkyl, -HE, halogen atom, -CN and-NO2where-Csub> 1-C4alkyl and-C2-C4alkenyl in all cases optionally substituted by 1-5 fluorine atoms.

p denotes an integer equal 1-2.

q denotes an integer equal 1-2.

t denotes an integer equal to 0 to 3.

u denotes an integer equal 1-2.

x is 0, 1 or 2.

In additional embodiments, the implementation of the present invention, including pharmaceutically acceptable salts:

R1, R3and R4each independently selected from H and-CH3.

Ra, Rband Rceach independently selected from the group which includes-C1-C3alkyl, -OS1-C2alkyl, halogen atom, and HE is, where-C1-C3alkyl, and-OC1-C2alkyl optionally substituted by 1-3 fluorine atoms.

Rdselected from the group which includes-C1-C3alkyl, -NR3R4, -CO2H, -CO2C1-C3alkyl, halogen atom and -- CN, where C1-C3alkyl and-CO2C1-C3alkyl optionally substituted by 1-3 fluorine atoms.

p denotes an integer equal 1-2.

q denotes an integer equal 1-2.

t denotes an integer equal to 0 to 3.

u denotes an integer equal 1-2.

Definition

“Ac” means acetyl, which is a group CH3C(=O)-.

“Alkyl” means carbon chains which may be linear or R is svetlanyi, or a combination thereof, if the carbon chain is not defined in any way. Other groups having the prefix “ALK”, such as alkoxy and alkanoyl, can also be linear or branched or a combination thereof, if the carbon chain is not defined in any way. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl etc.

“Alkylene” groups are alkyl groups which are bifunctionality, not monofunctional. For example, methyl is an alkyl group, and a methylene (-CH2-) is the corresponding alkalinous group.

“Alkenyl” means carbon chains which contain at least one double carbon-carbon bond and which may be linear or branched or a combination thereof. Examples alkenyl include vinyl, allyl, Isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl etc.

“Quinil” means carbon chains which contain at least one triple carbon-carbon bond and which may be linear or branched or a combination thereof. Examples of quinil include ethinyl, propargyl, 3-methyl-1-pentenyl, 2-heptenyl etc.

“Cycloalkyl” means a saturated carbocycle, containing the rd from 3 to 8 carbon atoms, if not specified otherwise (in particular, cycloalkyl can be defined as containing one or more double bonds). This term also includes cycloalkyl condensed with an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl etc. “Cycloalkyl” means nonaromatic carbocycle containing one or more double bonds.

“Aryl” (and “Allen”), when used to describe a substituent or a group in the structures, means a monocyclic or bicyclic compound in which the cycles are aromatic and which contains in a cycle of only carbon atoms. The term “aryl” may also refer to an aryl group which is condensed with cycloalkyl or heterocycle. Predpochtitelnye “Allami” are phenyl and naphthyl. Phenyl in General is the most preferred group.

“EDC” means 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

“Heterocyclyl”, “heterocycle” and “heterocyclic” means a fully or partially saturated or aromatic 5 to 6-membered cycle, containing 1-4 heteroatoms independently selected from N, S and O, unless otherwise specified.

“Benzoheterocycles” represents a phenyl cycle, condensed with a 5 to 6-membered heterocycle containing 1-2 heteroatoms, each of which represents the Oh Oh N or S, where the heterocycle may be saturated or unsaturated. Examples include indole, benzofuran, 2,3-dihydrobenzofuran and quinoline.

“DIPEA” means diisopropylethylamine.

“Halogen atom” includes fluorine, chlorine, bromine and iodine.

“HOBT” refers to 1-hydroxybenzotriazole.

“IPAC” means isopropylacetate.

“Me” means methyl.

“Amin Weinrebe” means N,O-dimethylhydroxylamine.

The term “composition” is a pharmaceutical composition and assumes that it covers the product, which includes the active(s) ingredient(s), inert(s) ingredient(s)that make up the carrier, as well as any product which is formed, directly or indirectly, from combination, kompleksowe, or aggregation of any two or more ingredients or dissociation of one or more ingredients, or when passing any other types of reactions or interactions of one or more ingredients. Thus, the pharmaceutical compositions of the present invention encompass any composition, which is obtained by mixing the compounds of the present invention and a pharmaceutically acceptable carrier.

Deputy “tetrazol” means 2N-tetrazol-5-ilen replacement group and its tautomers.

Optical isomers, the Diastereomers and Geometric isomers - Tautomers

<> The compounds of Formula I can contain one or more asymmetric centers and may thus exist in the form of the racemates, racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers. It is anticipated that this invention includes all such isomeric forms of the compounds of the Formula I and all mixtures of compounds. In the case where the structure shown in the form of stereochemical representation, other stereochemical structures, such as enantiomers, diastereoisomers (where possible diastereoisomers and mixtures of enantiomers and/or diastereomers, including racemic mixtures, are also included individually or collectively.

Some of the compounds described here may contain olefinic double bonds, and unless specified otherwise, it is assumed that they include both E and Z geometric isomers.

Some of the described compounds can exist as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. The compounds of Formula I encompass individual tautomers, and mixtures thereof.

The compounds of Formula I having one or more asymmetric centers can be divided into diastereoisomers, enantiomers, etc. using methods that are well known from the technical field.

Alternatively, enantiomers and other compounds with chiral centers can be synthesized by stereospecific synthesis using optically pure starting substances and/or reagents of known configuration.

Some of biphenylene or bearily compounds observed in NMR spectra as mixtures of atropisomers (rotamers). Individual atropoisomeric, as well as mixtures thereof are encompassed with compounds of the present invention.

Salt

The term “pharmaceutically acceptable salt” refers to salts derived from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum salts, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(III), manganese(II), potassium, sodium, zinc, etc. the Most preferred salts are the ammonium, calcium, magnesium, potassium and sodium. Salt in solid form can exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, Ilichevsky amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamin, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polianinova resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine and the like

In the case where the connection of the present invention is based, can be obtained salt from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzosulfimide, benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate acid, etc. Most preferred are citric, Hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acid.

It should be understood that in this description, references to the compounds of Formula I include pharmaceutically acceptable salts.

Metabolites, Prodrugs

Therapeutically AK is active metabolites, the metabolites included in the scope of the claimed invention are the compounds of the present invention. Prodrugs, which are compounds that are converted to the claimed connection with the introduction of their patient or after they have been introduced to the patient, are also compounds of the present invention.

Application

Compounds of the present invention are effective inhibitors SER. They are therefore suitable for the treatment of diseases or conditions that can be treated with inhibitors SER.

One aspect of the present invention relates to a method of treating or reducing the risk of developing the disease or condition that can be treated or prevented by inhibition SETR by introducing the required treatment to the patient a therapeutically effective amount of the compounds of the present invention. The patient is a human or a mammal, and most often people. “Therapeutically effective amount” is an amount of compound that is effective for obtaining the desired clinical outcome in the treatment of specific diseases.

Disease or condition that can be treated with compounds of the present invention, or the same disease or condition, the risk of which patientsyears as a result of treatment using the compounds of the present invention, include: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterinemia, hypertriglyceridemia, inherited hypercholesterinemia, cardiovascular disease, angina, coronary heart disease, stroke, myocardial infarction, lesions result in reperfusion injury, restenosis during angioplasty, hypertension, vascular complications in diabetes, obesity, the presence in the blood of toxins and metabolic syndrome.

Compounds of the present invention is most effective for raising HDL-C and/or reducing the relationship of HDL-C to LDL-C. Compounds are effective to reduce the level of LDL-C. These changes in HDL-C and LDL-C may be beneficial for the treatment of atherosclerosis, lowering, or returning to a previous state in the development of atherosclerosis, while reducing the risk of atherosclerosis, or preventing atherosclerosis.

The routes of administration

To ensure a mammal, preferably a human, an effective dose of a compound of the present invention can use any suitable method of drug administration. For example, can be used for oral, rectal, local, parenteral, intraocular, intra-lungs, nasal, etc. as a way of introduction. Dosage forms include tablets, hearts and, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. of Compounds of Formula I are preferably administered orally.

The effective dose of the active ingredient may vary depending on the specific compound, the route of administration, the condition, the treatment is carried out, and the severity of the condition, the treatment is carried out. Such doses can easily be installed by a professional.

In the treatment of diseases for which illustrates the compounds of Formula I, in General satisfactory results are obtained when the compounds of the present invention is administered in the form of daily daily dose comprising from about 0.01 mg to about 100 mg per kilogram of body weight of the animal or human, which is mostly administered in single daily dose or as divided a total dose of from two to six times a day, or in the form slow release of the drug. In the case of an adult with a mass of 70 kg total daily dose in General will be from about 0.5 mg to about 500 mg. For the most effective compounds dosage for an adult can be lower down to 0.1 mg. Modes introduction of medicines, you can find within a specified range or outside of the specified range is it so, to obtain the optimum therapeutic response.

Oral administration is usually performed with the use of tablets. Examples of doses in tablet form in 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 250 mg and 500 mg Other oral forms (in particular, capsules) can also have the same ranges.

The pharmaceutical composition

Another aspect of the present invention relates to pharmaceutical compositions that include a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention as an active ingredient contain the compound of Formula I or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term “pharmaceutically acceptable salt” refers to salts derived from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. If appointed, the prodrug, the pharmaceutical composition may also include a prodrug or pharmaceutically acceptable salt. Pharmaceutical compositions can also comprise the majority of the compounds of Formula I and a pharmaceutically acceptable carrier and does not contain other therapeutic ingredients.

The composition includes the t of the composition, suitable for oral, rectal, local, parenteral (including subcutaneous, intramuscular or intravenous), ocular (ophthalmic), pulmonary (nasal or transbukkalno inhalation), or nasal introduction, although the most suitable route of administration will depend on the type and severity of the condition, the treatment is carried out, and the type of active ingredient. They are for convenience can be a standard dosage form and may be prepared by any known from the field of pharmacy way.

In practice, the compounds of Formula I in accordance with the usual methods of making the pharmaceutical compositions can be obtained in the form of a carefully prepared mixture of active ingredients with the pharmaceutical carrier. The media may take a variety of forms depending on the required for the introduction of forms, including oral, or parenteral (including intravenous) administration. When preparing the compositions for oral dosage forms can be used any pharmaceutical environment, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, dyes, etc. in the case of oral liquid preparations such as suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, shall zbavitel, granulating tools, lubricants, binders, disintegrating agents and the like, in the case of oral solid preparations such as powders, hard or soft capsules and tablets, with oral solid preparations are preferred over the liquid preparations.

Due to the ease of their administration tablets and capsules represent the most convenient standard oral dosage forms, and in this case, obviously, use solid pharmaceutical carriers. If necessary, the tablets can be coated with coating using standard aqueous and non-aqueous methods. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of active compound in these compositions may, of course, be varied and may for convenience be in the range of from about 2% to about 60% by weight of the dosage unit. The number of active connections in such suitable for therapeutic use of the compositions is such that you get an effective dose. The active compounds can also be administered intranasally, for example in the form of liquid drops or spray.

Tablets, pills, capsules and the like may also contain a binder such as resin tragakant, Arabian gum, corn starch or gelatin; excipients, such as the dicalcium phosphate; baking powder, such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and a sweetener, such as sucrose or saccharin. In that case, if a dosage form is a capsule, it may, in addition to the above substances to contain a liquid carrier such as fatty acid.

Various other substances may be contained as a coating or modify the physical form standard dosing unit. For example, tablets may be coated with shellac, sugar or both at the same time. A syrup or elixir in addition to the active ingredient may contain sucrose as a sweetener, methyl - or propylparaben as preservatives, coloring or flavoring, such as odorant with a cherry flavor or aroma of orange.

The compounds of Formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be obtained in water usually by mixing with surface-active substance, such as hydroxypropylcellulose. Dispersion can also be obtained in glycerol, liquid polyethylene glycols and their mixtures in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Suitable for injection pharmaceutical fo what we include sterile aqueous solutions or dispersions and sterile powders for impromptu preparation of sterile solutions or dispersions. In all cases, the dosage form must be sterile and must be fluid to the extent that it could easily dial in the syringe. It must be stable under the conditions of preparation and storage and must be protected from contaminating action of microorganisms, such as bacteria or fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (in particular, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures and vegetable oil.

Combination therapy

Compounds of the present invention (in particular the compounds of Formula I and Ia-Ij) can be used in combination with other drugs that may also be suitable for treating or reducing the intensity of symptoms of the diseases or conditions for which suitable compounds of Formula I. Such other drugs may be injected in the way and quantity in which they are typically used simultaneously or sequentially with the compound of the Formula I. when a compound of the Formula I is administered with one or more other drugs, preferred is a pharmaceutical composition in the form of a standard dosage form containing such other drugs and the compound of Formula I. However, m is her combination therapy also includes therapies in which the compound of Formula I and one or more other medicines prescribed by different schemes taking medication.

If use of oral formulations, the drug can be combined into a single combination tablet or other oral dosage forms or medication may be Packed together in the form of separate tablets and other oral dosage forms. It is also assumed that when used in combination with one or more active ingredients, the compounds of the present invention and other active ingredients can be used in lower doses than when each is used individually. Thus, the pharmaceutical compositions of the present invention include pharmaceutical compositions which in addition to the compounds of Formula I contain one or more active ingredients.

Examples of other active ingredients which may be administered in combination with the compound of the present invention (in particular, a compound of Formula (I) and which is administered either separately or as part of the same pharmaceutical compositions, include, but not limited to, other compounds that improve the lipid profile of the patient, such as: (i) and hibitory HMG-CoA-reductase (they generally represent statins, including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, mevastatin, pitavastatin, pitavastatin and other statins), (ii) substances that increase the excretion of bile acids (cholestyramine, colestipol, dialkylaminoalkyl derivatives containing cross connection dextran, Colestid®, LoCholest®, (iii) Niacin and related compounds, such as nicotinebuy alcohol, nicotinamide and nicotinic acid and its salts, (iv) PPARα agonists such as gemfibrozil and derived fenofibric acid (fibrates), including clofibrate, fenofibrate, bezafibrat, ciprofibrate and etofibrate, (v) inhibitors of cholesterol absorption, such as esters of stanol, beta-sitosterol, Sterol glycosides such as tiqueside; and azetidinone, such as ezetimibe, (vi) inhibitors of acyl-COA:cholesterol-acyltransferase (AST), such as avasimibe and melinamide, and including selective inhibitors of ACAT-1 and ACAT-2 and dual inhibitors, (vii) phenolic antioxidants, such as probucol, (viii) the secretion inhibitors of microsomal protein carrier of triglycerides (MTP)/Ares, (ix) vitamin antioxidants, such as vitamin C and E and beta-carotene, (x) thyromimetics, (xi) receptor inducers of LDL (low density lipoprotein), (xii) inhibitors of the aggregation of platelets, for example antagonists of the receptor glycoprotein IIb/IIIa fibrinogen and aspirin, (xiii) the vitamin is 12 (also known as cyanocobalamin), (xiv) folic acid or its pharmaceutically acceptable salt or ester, such as sodium salt and the methylglucamine salt, (xv) the ligands of FXR and LXR, including both inhibitors and agonists, (xvi) agents that enhance gene expression ASA, and (xvii) the vector of bile acids in the ileum.

Preferred classes of therapeutic compounds that can be used with the compounds of the present invention, with the aim of improving the lipid profile of the patient (i.e. increase HDL-C and lower LDL-C) include one or two of the statin and inhibitors of cholesterol absorption. Most preferred are combinations of compounds of the present invention with simvastatin, ezetimibe or simvastatin and ezetimibe together. Preferred are combinations of compounds of the present invention with statins other than simvastatin, such as lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, mevastatin, pitavastatin and ZD-4522.

Finally, the compounds of the present invention can be used with compounds that are suitable for treatment of other diseases, such as diabetes, hypertension and obesity, as well as with other anti-atherosclerotic compounds. Such combinations can be used to treat one or more diseases such as dia is no, obesity, atherosclerosis and dyslipidemia, or several diseases associated with metabolic syndrome. These combinations can exhibit synergistic activity in the treatment of these diseases, which allows you to assign a reduced dose of the active ingredients, such as dose, which otherwise would be subtherapeutic.

Examples of other active ingredients which may be administered in combination with the compound of the present invention, include, but not limited to, compounds that are mainly anti-diabetic compounds, including:

(a) agonists and partial agonists of PPAR-gamma, including glitazone and not glitazone (in particular, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512, and LY-818;

(b) biguanides, such as Metformin and phenformin;

(C) inhibitors of protein-TRAINFORTRADE-1B (PTP-1B);

(d) inhibitors dipeptidylpeptidase IV (DP-IV), including vitality, sitagliptin, saxagliptin;

(e) insulin and insulin mimetics, such as, for example, insulin lispro, insulin glargine, insulin zinc suspension and formulations of insulin for inhalation;

(f) sulfonylureas such as tolbutamide, glipizide, glimepiride, acetohexamide, hlorpropamid, glibenclamide and related substances;

(g) inhibitors of α-glucosidase (so the e as acarbose, adipsin, camiglibose, emiglitate, miglitol, voglibose, bradikinin-Q and substation);

(h) dual antagonists of PPAR-α/γ, such as muraglitazar, tesaglitazar, farglitazar and naveglitazar;

(i) antagonists of PPAR-δ, such as GW501516 disclosed in WO 97/28149;

(j) receptor antagonists of glucagon;

(k) GLP-1; derivatives of GLP-1; analogues of GLP-1, such as exendin, such as exenatide (Byetta); and nematodirinae receptor agonists GLP-1;

(l) GIP-1; and

(m) non-sulfonylureas tools that enhance insulin secretion, such as meglitinide (in particular, nateglinide and Repaglinide).

These active ingredients that can be used in combination with the present invention also include compounds against obesity, including inhibitors of 5-HT (serotonin), inhibitors of neuropeptide Y5 (NPY5)receptor agonists melakarta 4 (Mc4r)antagonists/inverse agonists of cannabinoid receptor 1 (CB-1) and agonists β3-adrenergic receptor. They later more detailed in this section.

These other active ingredients include active ingredients that are used to treat inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine and selective inhibitors of cyclooxygenase-2 (MOR-2), including etoricoxib, celek is xib, rofecoksib and Bextra.

Antihypertensive compounds useful in combination therapy with compounds of the present invention. Examples of antihypertensive compounds that can be used with the compounds of the present invention include (1) antagonists of angiotensin II, such as losartan; (2) inhibitors angiotensin-converting enzyme (ACE inhibitors)such as enalapril and captopril; (3) calcium channel blockers such as nifedipine and diltiazam; and (4) endothelial antagonists.

Connection against obesity may be administered in combination with compounds of the present invention, including: (1) tools that increase the secretion of growth hormone, and agonists/antagonists of the receptor means, amplifying secretion of growth hormone, such as NN703, hexarelin, MK-0677; inhibitors of protein-tyrosine phosphatase-1B (PTP-1B); (3) the ligands of cannabinoid receptor, such as antagonists or inverse agonists of the receptor cannabinoid ST1such as rimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4) serotonergic anti-obesity, such as fenfluramine, dexfenfluramin, phentermine, and sibutramine; (5) agonists, β3-adrenergic receptors, such as AD9677/TAK677 (Dainippon/Takeda), CL-316243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114 and SR 59119A; (6) inhibitors of pancreatic who lipase, such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teaspoon and diethylaminophenyl phosphate; (7) antagonists of the neuropeptide Y1, such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A; (8) antagonists of neuropeptide Y5, such as GW-A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104; (9) antagonists factor receptor accumulation of melamine (sit); (10) antagonists factor receptor accumulation of melamine 1 (1R), such as T-226296 (Takeda); (11) agonists/antagonists factor receptor accumulation of melamine 2 (2R); (12) receptor antagonists orexin-1, such as SB-334867-A; (13) agonists melanocortin, such as Melanotan II; (14) other Mc4r agonists (receptor melanocortin 4)such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron), PT-141, and PT-14 (Palatin); (15) agonists NT-2; (16) agonists NTS (2C receptor serotonin), such as BVT933, DPCA37215, WAY161503 and R-1065; (17) antagonists Galanina; (18) CCK agonists; (19) agonists, CCK-a (cholecystokinin-A), such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR146131; (20) agonists GLP-1; (21) antagonists of corticotropin-releasing hormone; (22) modulators of receptor-3 histamine (H3)antagonists/inverse agonists of the receptor-3 histamine (H3), such as hyperemia, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, closedprofit, jodieproffit, impressive and GT2394 (Gliatech); (24) inhibitors, β-hydroxysteroid-dehydrogenase-1 inhibitors 1β-HSD-1), such as BVT 3498 and BVT 2733; (25) inhibitors PDE (phosphodiesterase), such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram and cilomilast; (26) inhibitors of phosphodiesterase-3B (PDE3B); (27) inhibitors transfer NE (norepinephrine), such as GW 320659, despiramine, talsupram and nomifensine; (28) antagonists, ghrelin receptor; (29) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl leptin person (Amgen); (30) derived leptin; (31) BRS3 agonist (subtype 3 receptor bombezin), such as [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13)propylamide; (32) CNTF (ciliary neurotrophic factors)such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), Buchbinder, PD170292 and PD 149164 (Pfizer); (33) CNTF derivatives, such as axokine (Regeneron); (34) inhibitors reuptake monoamine, such as sibutramine; (35) activators UCP-1 (uncoupling protein-1, 2 or 3), such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid; (36) agonists thyroid hormone β, such as the KV-2611 (KaroBioBMS); (37) inhibitors of FAS (synthase fatty acids), such as Cerulenin and C75; (38) inhibitors DGAT1 (diacylglycerol acyltransferase 1); (39) inhibitors DGAT2 (diacylglycerol acyltransferase 2); (40) inhibitors ACS (acetyl-coenzyme A. carboxylase-2); (41) antagonists glucocorticoid; (42) allestree, t is the cue as oleoyl-estrone; (43) inhibitors vector of in primary forms; (44) peptide YY, PYY 3-36, analogs, derivatives and fragments of peptide YY, such as BIM 43073D, BIM-43004C; (45) agonists of the receptor neuropeptide Y2 (NPY2), such as NPY3-36, N acetyl [Leu(28,31)]NPY24-36, TASP-V and cyclo-(28/32)-AC-[Lys28-Glu32]-(25-36)-pNPY; (46) agonists, neuropeptide Y4 (NPY4), such as pancreatic peptide (PP); (47) antagonists of neuropeptide Y1 (NPY1), such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A; (48) opioid antagonists such as nalmefene (Revex®), 3-methoxyestradiol, naloxone, and naltrexone; (49) inhibitors vector glucose; (50) inhibitors vector phosphate; (51) inhibitors of 5-HT (serotonin); (52) beta-blockers; (53) receptor antagonists neirokinina-1 (antagonists of NK-1); (54) clobenzorex; (55) klotrix; (56) glominerals; (57) clortermine; (58) cilexetil; (59) dextroamphetamine; (60) diphemethoxidine; (61) N-ethylamphetamine; (62) fenbutrazate; (63) penetrex; (64) fenproporex; (65) fluorex; (66) glominerals; (67) furfurylmercaptan; (68) levamfetamine; (69) levorotatory; (70) mefenorex; (71) metamfepramone; (72) methamphetamine; (73) norpseudoephedrine; (74) pentrex; (75) phendimetrazine; (76) phenmetrazine; (77) pillories; (78) Vitapharm 57; (79) zonisamide; (80) Aminorex; (81) amflora; (82) amphetamine; (83) benzphetamine and (84) chlorphentermine.

The above combination therapy, in which the use of the compounds of the present invention may be suitable for L. the treatment of metabolic syndrome. According to one widely used definition the patient with metabolic syndrome characterized by the presence of three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low cholesterol high density lipoprotein (HDL); (4) high blood pressure; and (5) elevated levels of glucose on an empty stomach, which may be in the range characteristic of type 2 diabetes, if the patient is also diabetic. Each of these symptoms has received clinical definition in the recently published devoted to cholesterol the Third report of the national program of training of specialists on the detection, evaluation and treatment of high blood cholesterol in adults (III Council on the treatment of adults, or ATP III), national Institute of health, 2001, NIH Publication No. 01-3670. Patients with metabolic syndrome have an increased risk of macrovascular or microvascular complications listed above, including atherosclerosis and coronary heart disease. The above combination can reduce the intensity of more than one symptom of metabolic syndrome (in particular, two symptom, three symptom, four symptom or all five symptoms).

Analysis SETR

Continuous in vitro EN is Liz for determining the value of the IC 50with the aim to identify compounds that are inhibitors SETR, carried out by a modified method described in Epps et al., with the use of BODIPY®-CE as a source of lipid donor of ester cholesterol and BODIPY®-TG as a lipid donor triglycerides. Cm. Epps et al. (1995) Method for measuring the activities of cholesteryl ester transfer protein (lipid transfer protein), Chem. Phys. Lipids, 77, 51-63.

Particles used to conduct this analysis, is obtained from the following substances using probe ultrasonic processing in accordance with the methodology described in Epps et al. Particles of synthetic complex of cholesterol ester (CE) as a donor HDL containing DOPC (dioleoyl the phosphatidyl choline), BODIPY®-CE (Molcular Probes C-3927), triolein (triglyceride), dabcyl diacetylated (ndifundisa molecule quencher to reduce background luminescence) and apoHDL. Particles of synthetic triglycerides (TG) as a donor HDL containing DOPC, BODIPY®-TG and apoHDL. BODIPY®-TG synthesized at room temperature from diolein and BODIPY containing similar fatty acid 4,4-debtor-5-(2-thienyl)-4-Bora-3A,4A-diaza-s-indocin-3-dodecanol acid (Molcular Probes) in methylene chloride in the presence of dicyclohexylcarbodiimide. Dabcyl diacetylated obtained by heating dabcyl n-succinimide with diacetylenes in DMF at a temperature of 95°C overnight in the presence of Diisopropylamine as a cat who lyst. As particles acceptor use of native lipoproteins isolated from human blood. Particles with a density less than 1,063 g/ml allocate ultracentrifugation. These particles contain VLDL, IDL and LDL. The concentration of particles is expressed as the concentration of protein, which is determined using the ICA assay (Pierce, USA). Particles before use store at 4°C.

Tests conducted on 96-well tablets Dynex Microfluor 2 black U-shaped bottom (# 7205 catalog). For analysis prepare a cocktail containing SER, buffer 1X SETR (50 mm Tris, pH 7.4, 100 mm NaCl, 1 mm etc), 3% human serum and half of the final particle concentration of the acceptor, and in each well of the tablet add 100 ál of cocktail for analysis. Test compounds in DMSO added in a volume of 3 μl. The contents of the tablet mixed in a rocking chair for tablets, and then incubated at 25°C for 1 hour. Prepare a second cocktail for analysis containing particles of the donor, the remaining particles of the acceptor and the buffer 1X SER. To begin the analysis, 47 μl of the second cocktail for analysis add in the holes in which carry out the reaction. Tests conducted in the final volume of 150 μl. Reactions transfer COE carried out as follows: final concentration of substances are: 2.5 ng/ál particles donor BEHOLD, 7.5 ng/μl of acceptor particles (each expressed with what uranium protein), buffer 1X SER, 14-30 nm recombinant SETR person (Express in cells of SNO and partially purified) and up to 2% DMSO, when conducting the test compounds; reactions monitored with fluorescent tablet reader (Molcular Devices Spectramax GeminiXS), which establish the running time 45 min at 25°C, and the samples read every 45 sec for Ex=480 nm and Em=511 nm cut-off filter at 495 nm, setting the photomultiplier tube set in the middle range, and when the calibration is performed in 6 reads for each hole. The reaction of transfer of TG were carried out as described above, except that use 2.5 ng/ál particles donor TG. The transfer of TG is measured by the length of the excitation 538 nm, and reading is performed on the length of the emission 568 nm every 45 sec for 45 min at 37°C with a cut-off filter at 550 nm.

Assessing data, determining the initial velocity, which is expressed in relative fluorescence units per second, for pseudolinear portion of the curve, often in the range of 0-500 or 1000 sec. Comparison of velocity samples containing inhibitors, with eingeborenen (containing only DMSO) positive control gives the percentage of inhibition. To calculate the magnitude IC50use a graph of percent inhibition from the logarithm of the concentration of the inhibitor, to the which well describes the 4-parameter sigmoidal equation.

EXAMPLES

The following schemes and examples are given for a more complete explanation and understanding of the present invention. Educt get famous or on the following methods.

The examples should not be construed as in any way limiting the present invention. Scope of the present invention is defined by the attached claims. Compounds of the present invention have values IC50determined for the reaction of transfer of CE, the reaction of transfer of TG or both, as described above, which comprise less than or equal to 50 μm. The value of the IC50one or both of the reactions are usually in the range of 5 nm to 15 μm and preferably be in the range of 5 nm - 5 μm, more preferably in the range of 5 nm - 1 μm, more preferably in the range of 5 nm - 200 nm, and most preferably in the range of 5 nm - 100 nm.

Scheme 1

Intermediate compounds 1-2, 1-3, 1-4, 1-5, 1-6 and 1-7, which use the present invention, where a value of Randdefined in the claims, can be purchased or obtained, as shown in figure 1. Appropriately substituted 2-halogenation 1-1, where the halogen atom is preferably an iodine atom or bromine, interacts with CuCN in DMF at elevated temperature formed with the eating of the corresponding 2-cyanoaniline 1-2. Otherwise, the nitrile can be obtained by the interaction 1-1 with KCN and CuI in the presence of salts of palladium(II) or in the presence of certain complexes of copper or Nickel (see: Smith, M. and March, J. “March's Advanced Organic Chemistry, 5thEd., John Wiley and Sons, New York, pp. 867 (2001) and in the references). The iodides 1-3 get reactions 1-2 solidities, n-pentylnitrates, tert-butylnitrite etc. in diiodomethane (see, for example, Smith et al., J. Org. Chem. 55, 2543 (1990) and in the references). Alternatively, the iodide can be obtained by formation of a first page using isoamylamine, n-pentylnitrate, tert-butylnitrite, sodium nitrite, nitrous acid and the like, followed by heating in the presence of iodide, such as copper iodide, sodium iodide, potassium iodide, tetrabutylammonium etc. Hydrolysis of idolatrie 1-3 is carried out using potassium hydroxide in isopropanol and water, and get iodoacetate 1-4. Subsequent recovery borane, lithium aluminum hydride, lithium borohydride and the like in ether, tetrahydrofuran, dimethoxyethane etc. gives 2-idespite 1-5. Intermediate compounds 1-5 can be converted to benzylbromide 1-6 using such reagents as triphenylphosphine and tetrabromide carbon in solvents such as dichloromethane and the like (see Smith, M. and March, J. “March's Advanced Organic Chemistry, 5thEd., John Wiley and Sons, New York, pp. 518-199 (2001) and in the references). Intermediate with the organisations 1-6 can also be converted into aldehydes 1-7 interaction with periodinane reaction dessa-Martin or under oxidation conditions in Turn interact with perruthenate of tetrapropylammonium, chlorbromuron pyridinium, a complex of a sulfur trioxide-pyridine and the like (see Smith, M. and March, J. “March's Advanced Organic Chemistry, 5thEd., John Wiley and Sons, New York, pp. 1167-1171 (2001) and in the references).

Scheme 2

The intermediate 2-2 and 2-3, which use the present invention, where the values of Rand, Rband Ar2defined in the claims, can be obtained as shown in Scheme 2. Benzyl alcohols 2-1 can be purchased or obtained in accordance with the methodology described in Scheme 1. The intermediate 2-2 can be obtained by Suzuki reaction, in which the connection 2-1 combined with appropriately substituted arylboronic acid or arylboronic ether in the presence of palladium catalyst. The reaction mix can be made using acetate Pd(II) and potassium carbonate by boiling in aqueous acetone. Otherwise, the reaction can be used tetrakis(triphenylphosphine)palladium in a mixture of ethanol/toluene in the presence of sodium carbonate. As an alternative, which is practiced by professionals in the reaction, you can use a series of compounds of palladium(0) and salts of palladium(II) in several solvents in the presence of various ligands, bases and promoters, usually, but not exclusively, by heating and/or when using RF radiation. Some the suitable conditions for the reaction can be found in the description, shown in Miyaua et al., Chem. Rev. 95, 2457 (1995) and in the references, as well as in monographs in Smith, M. and March, J. “March's Advanced Organic Chemistry, 5thEd., John Wiley and Sons, New York, pp. 868-869 (2001) and in the references. Compounds 2-3 produced from intermediates 2-2, as shown in figure 1.

Scheme 3

The intermediate 3-4 of the present invention, where the values of R1and Ar1defined in the claims, can be obtained as shown in Scheme 3. The interaction of N-carbarnoyl-(N-methoxy-N-methyl)amide amino acids 3-1, which can be purchased or obtained by known methods, with a Grignard reagent or other ORGANOMETALLIC reagent such as an organolithium compound, receive the corresponding ketone 3-2. Restore the specified ketone with sodium borohydride or zinc borohydride in an alcohol solvent or THF or the like or restoration with the help of another reducing agent, such as phenyldimethylsilane in THF, gives the alcohol 3-3, which can be cilitate in oxazolidinone 3-4 treatment with base, such as KOH, in a solvent such as MeOH, EtOH and the like, and THF, dioxane, dimethoxyethane etc.

Scheme 4

Compounds of the present invention 4-3, where the values of R1, Rand, Rb, Ar1and Ar2defined in f is rule of the invention, can be obtained as shown in Scheme 4. Oxazolidinone 4-2 obtained as shown in Scheme 3, can be alkilirovanii benzylbromide 4-1, which receive, as shown in Scheme 1, using bases, such as hexamethyldisilazide sodium or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether and the like, and to get the products 4-3.

Scheme 5

Connection 5-4 of the present invention, where the values of R1, Rand, Rb, Ar1and Ar2defined in the claims, can be obtained as shown in Scheme 5. Oxazolidinone 5-2 obtained, as shown in Schemes 10 and 11, can be alkilirovanii benzylbromide 5-1, which receive, as shown in Scheme 1, using bases, such as hexamethyldisilazide sodium or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether and the like, and to get the products 5-3. Then get a connection 5-5 on the Suzuki reaction or the reaction of Steele or their variations using catalyzed by palladium cross-combination of iodide 5-3 with an appropriately substituted aryl - or heteroaryl-Bronevoy acid-boronate ether or triamcinolonum, as described in Miyaua et al., Chem. Rev. 95, 2457 (1995) and in the references, and as described in Meijere, A. And Diedrich, F., “Metal-Catalyzed Cross Couplig Reactions”, 2ndEd., WILEY-VCH Verlag GmbH & Co. KgaA, Weinheim (2004) and in the references. Otherwise arylboronic acid or arylboronic esters can be obtained by the reaction of helgaleena 5-3 with a suitable reagent such as DIBORANE, cilivian or scandivian and the like, in the presence of palladium or platinum catalyst or metallogenesis exchange and processing of suitable electrophilic boron derivative, as described in Meijere, A. and Diedrich, F., “Metal-Catalyzed Cross Coupling Reactions”, 2ndEd., WILEY-VCH Verlag GmbH & Co. KgaA, Weinheim (2004), Chapter 2. Arylboronic reagent 5-4 can then enter in the interaction with the appropriately substituted helgaleena in the presence of a suitable palladium catalyst and receive connections 5-5.

Scheme 6

Connection 6-5 of the present invention, where the values of R1, Rand, Rb, Ar1and Ar2defined in the claims, can be obtained as shown in Scheme 6. Benzyl alcohols 6-1 can be purchased, or obtained by the method shown in Scheme 2. The interaction of compounds 6-1 to periodinane dessa-Martin receive appropriate benzaldehyde 6-2. You can also use other methods of oxidation of the primary hydroxyl group in aldehydes, for example to carry out the reaction under oxidizing conditions in Turn, to use perruthenate tetrapropylene the Oia, chlorproma pyridinium, a complex of a sulfur trioxide-pyridine and the like (see Smith, M. and March, J. “March's Advanced Organic Chemistry, 5thEd., John Wiley and Sons, New York, pp. 1167-1171 (2001) and in the references). 2-Amino-1-phenylethanol 6-3 can be obtained from compounds 6-2, through the intermediate formed corresponding sililirovany cyanohydrin, interaction with trimethylsilylcyanation and a catalytic amount of zinc iodide and subsequent reduction with lithium aluminum hydride or similar reducing agent. Otherwise 2-a Mino-1-phenylethanol 6-3 can be obtained from compounds 6-2, through the intermediate formed corresponding cyanohydrin, interaction with potassium cyanide and subsequent recovery. 2-Amino-1-phenylethanol 6-3 can be cilitate in oxazolidinone 6-4 using such reagents as phosgene (Y=Cl), triphosgene (Y=OCCl3or carbonyldiimidazole (Y=imidazole)with bases such as triethylamine, diisopropylethylamine and the like, in solvents such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane etc. Oxazolidinone 6-4 can be alkilirovanii alkyl-, heteroalkyl-, aryl - or heteroarylboronic using bases, such as hexamethyldisilazide sodium or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether and the like, and to get the products 6-5. Enantioface products can be obtained by using myotherarray chromatography.

Scheme 7

Connection 6-6 of the present invention, where the values of R1, Rand, Rb, Ar1and Ar2defined in the claims, can be obtained as shown in Scheme 7. Aldehydes 7-1 can be purchased or obtained, as shown in figure 1. The condensation of compound 7-1 to nitroalkanes get replaced nitroalkanes 7-2. This reaction can kataliziruetsa aqueous solutions of bases, such as sodium hydroxide and the like, in solvents such as ethanol, methanol, etc. Nitroalkanes 7-2 can be restored to the aminoalcohols 7-3 reductants such as Raney Nickel, palladium on charcoal or platinum oxide, in the presence of hydrogen gas and an aqueous solution of an acid in an alcohol solvent such as methanol, ethanol and the like (see: Langer, O., et al., Bioorg. Med. Chem., 2001, 9, 677-694). The aminoalcohols 7-3 can be cilitate in oxazolidinone 7-4 using such reagents as phosgene (Y=Cl), triphosgene (Y=OCCl3or carbonyldiimidazole (Y=imidazole)with bases such as triethylamine, diisopropylethylamine and the like, in solvents such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane etc. Oxazolidinone 7-5 win a Suzuki reaction or the reaction of Steele or their variations using catalyzed by palladium cross-combination of iodides 7-4 with testwuide follows substituted aryl - or heteroaryl-baronowie acids, -barhatnymi esters or derivatives-triamcinolone, as described in Miyaura et al., Chem. Rev. 95, 2457 (1995) and in the references, and as described in Smith, M. and March, J. “March's Advanced Organic Chemistry, 5thEd., John Wiley and Sons, New York, pp. 868-869 (2001) and in the references. Oxazolidinone 7-5 you can alkilirovanii alkyl-, heteroalkyl-, aryl - or heteroarylboronic using bases, such as hexamethyldisilazide sodium or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether and the like, and to get the products 7-6. Enantioface products can be obtained using the method of chiral chromatography.

Scheme 8

Connections 8-5 of the present invention, where the values of R, R1, Rand, A2, A3and n are defined in the claims, can be obtained as shown in Scheme 8. Aldehydes 8-1 can be purchased or obtained by the method shown in Scheme 1. Condensation of compound 8-1 with chiral N-allocationally gives adducts of aldos 8-2, as described in Evans, D.A. et al., J. Am. Chem. Soc., 2002, 124, 392-3. Chiral N-allocational you can purchase or receive, as described in Ager, D.J.; Allen, D.A.; Schaad, D.R. Synthesis 1996, 1283-5. Connection 8-2 can hydrolyze to the corresponding acid, and then to enter into interaction with diphenyltetrazolium and trialkylamine base with C is poured implementation rearrangement of kurzius and to obtain chiral oxazolidinone 8-3. Oxazolidinone 8-4 win a Suzuki reaction or the reaction of Steele or their variations using catalyzed by palladium cross-combination of iodides 8-3 with an appropriately substituted aryl - or heteroaryl-baronowie acids-barhatnymi esters or derivatives-triamcinolone, as described in Miyaura et al., Chem. Rev. 95, 2457 (1995) and in the references, and as described in Smith, M. and March, J. “March's Advanced Organic Chemistry, 5thEd., John Wiley and Sons, New York, pp. 868-869 (2001) and in the references. Oxazolidinone 8-4 can be alkilirovanii alkyl-, heteroalkyl-, aryl - or heteroarylboronic using bases, such as hexamethyldisilazide sodium or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether and the like, and to get the products 8-5. Alternatively, oxazolidinone 8-3 alkylate the corresponding bromides and receive connections 8-6, which is administered in the Suzuki reaction or the reaction of Steele or their variations with an appropriately substituted aryl - or heteroaryl-baronowie acids-barhatnymi esters or derivatives-triamcinolone, and receive the products 8-5.

The intermediate connection 1

2-Amino-5-(trifluoromethyl)benzonitrile

A 2-liter flask, 100 g (0,348 mol) 4-amino-3-iodobenzonitrile, 40 g of CuCN and 750 ml of DMF. The mixture is heated is up to the boil, and then refluxed for 1 hour. The reaction mixture is cooled and poured into 3 l of water containing 300 ml of concentrated ammonium hydroxide. To the mixture was added 1 l of CH2Cl2. The mixture is then filtered through celite. The layers are separated and the aqueous layer was again extracted with CH2Cl2. The organic extracts are combined and the solvent is removed under reduced pressure. The residue is dissolved in 1.5 liters of diethyl ether and the resulting solution was washed with a 1N solution of ammonium hydroxide, an aqueous solution of sodium bisulfite, 1N aqueous HCl solution and a saturated salt solution. The solution is dried over anhydrous MgSO4and filtered through a thick layer of silica gel containing top layer MgSO4. The layer of silica gel is washed with 0.5 l of ether. The ether solutions are combined and concentrated to 750 ml, and then leave at room temperature. After 2 days, the obtained solid substance was separated, washed with hexane and dried under reduced pressure, obtaining 2-amino-5-(trifluoromethyl)benzonitrile. Range1H NMR (CDCl3, 500 MHz) δ 7,68 (s, 1H), 7,58 (d, J=8.5 Hz, 1H), for 6.81 (d, J=8.5 Hz, 1H), 4,80 (Shir. s, 2H).

Intermediate compound 2

2-Iodine-5-(trifluoromethyl)benzonitrile

To a solution of 2-amino-5-(trifluoromethyl)benzonitrile (Intermediate compound 7, 15,1 g) and deitmer is on (24 ml) in acetonitrile (150 ml) at 35°C are added dropwise tert-butylnitrite (21 ml). During the addition the temperature of the support at approximately 35°C. the Reaction mixture was kept for 30 min, and then heated to 60°C for 30 minutes, the Reaction mixture was cooled, diluted with ether and washed twice with water, washed twice with an aqueous solution of sodium bisulfite, water and saturated salt solution. The solution is dried over anhydrous MgSO4, filtered through a thick layer of silica gel and concentrate, getting the oil red. The product was then purified by chromatography on silica gel, consistently elwira hexane, a mixture of 3:1 hexane/CH2Cl2and a mixture of 1:1 hexane/CH2Cl2and get 2-iodine-5-(trifluoromethyl)benzonitrile. Range1H NMR (CDCl3, 500 MHz) δ 8,10 (d, J=8.5 Hz, 1H), a 7.85 (d, J=1.8 Hz, 1H), 7,52 (DD, J=8,5, 1.8 Hz, 1H).

Intermediate compound 3

2-Iodine-5-(trifluoromethyl)benzoic acid

Potassium hydroxide (of 3.78 g; 0,0673 mol) is added to a stirred solution of 2-iodine-5-(trifluoromethyl)benzonitrile (Intermediate compound 8, 4 g, 0,0135 mol) in a solution of isopropanol:water 1:1 (60 ml). The reaction mixture was refluxed for 14 h, and then redistributed between the H2About (50 ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (50 ml) and acidified to pH 5 with 6N HCl solution. The aqueous layer was additionally extracted with EtOAc(4×50 ml), the extracts are combined and washed with saturated salt solution (50 ml), dried over MgSO4, filtered and concentrated in vacuo, obtaining 2-iodine-5-(trifluoromethyl)benzoic acid in a solid yellow color. IHMS = 317,0 (M+1)+. Range1H NMR (CDCl3, 500 MHz) δ of 8.27 (d, J=1.6 Hz, 1H), 8,25 (d, J= 8,2 Hz, 1H), 7,47 (DD, J=8,2, 1.8 Hz, 1H).

Intermediate compound 4

[2-Iodine-5-(trifluoromethyl)phenyl]methanol

Borane-THF (1.0 M solution in THF; 94 ml, 94 mmol) under nitrogen atmosphere add to the mix a solution of 2-iodine-5-(trifter-methyl)benzoic acid (Intermediate compound 3, 2,97 g; 9.4 mmol) in THF (300 ml) at 0°C. the Reaction mixture is refluxed for 90 min, and then gently interrupt the reaction using 6N HCl solution up until the gas is completely stopped. The reaction mixture was diluted with water (250 ml) and extracted with EtOAc (3×250 ml). The extracts are combined, washed with saturated salt solution (300 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude substance is purified flash chromatography on silica gel (gradient of 0-25% EtOAc/hexane) and receive [2-iodine-5-(trifluoromethyl)phenyl]methanol in a solid white color. IHMS = 285,0 (M-17)+. Range1H NMR (CDCl3, 500 MHz) δ of 7.97 (d, J=8,3 Hz, 1H), 7,79 (s, 1H), 7,28 (d, J=8,4 Hz, 1H), and 4.75 (s, 2H).

Intermediate compound 5

2-(methyl bromide)-1-iodine-4-(trifluoromethyl)benzene

Tetrabromide carbon (1.86 g; 5.6 mmol) and triphenylphosphine (1.47 g; 5.6 mmol) are successively added to a stirred solution of [2-iodine-5-(trifluoromethyl)phenyl]methanol (Intermediate compound 10, 1.13 g; 3,74 mmol) in CH2Cl2(25 ml) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 48 hours. Add a second equivalent of tetrabromide carbon (1.2 g; 3,74 mmol) and triphenylphosphine (0,98 g; 3,74 mmol) and the reaction mixture is stirred for 14 hours. The solvent is removed in vacuo and the residue purified flash chromatography on silica gel (gradient of 0-25% EtOAc/hexane) and get 2-(methyl bromide)-1-iodine-4-(trifluoromethyl)benzene as a clear oil. Range1H NMR (CDCl3, 500 MHz) δ 8,02 (d, J=8,2 Hz, 1H), 7,73 (d, J=1.8 Hz, 1H), 7,26 (DD, J=8,3, 1.8 Hz, 1H), with 4.64 (s, 2H).

The intermediate compound 6

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-ONU (400 mg, 1.28 mmol) is added NaH (60% in oil, 128 mg, 3.2 mmol) and 2-(methyl bromide)-1-iodine-4-(trifluoromethyl)benzene (Example 70, 466 mg, 1.28 mol)as described in Example 66, and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-ACS who solidin-2-it looks like a solid white color. IHMS = 598,0 (M+1)+. Range1H NMR (CDCl3, 500 MHz) δ of 8.06 (d, J=8,2 Hz, 1H), to 7.93 (s, 1H), 7,82 (s, 2H), to 7.61 (s, 1H), 7,33 (DD, J=8,2, and 1.4 Hz, 1H), 5,79 (d, J=7.8 Hz, 1H), 4,91 (d, J=16 Hz, 1H), and 4.40 (d, J=16 Hz, 1H), 4,16-4,06 (m, 1H), 0,83 (d, J=6,4 Hz, 3H).

Intermediate compound 7

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-he

Specified intermediate connection are directly from chiral starting compound CBZ-L-alanine three-stage synthesis, which are listed below. The compound (4R,5S)-5-[3,5-bis(tri-permitil)phenyl]-4-methyl-1,3-oxazolidin-2-it can be obtained similarly using as starting compound CBZ-D-alanine.

Stage 1

CBZ-L-alanine (6.5 kg, 28.5 mol), NOT-hydrate (4.8 kg, 34.8 mol), salt with HCl amine Weinrebe (3.4 kg, and 36.2 mol) and THF (32 l) is placed in a flask in nitrogen atmosphere (Amin Weinrebe represents N,O-dimethylhydroxylamine). The mixture is cooled to 0-10°C., and then maintaining the temperature not exceeding 25°C, slowly add DIPEA (12,4 l). Then when cooled to 15-25°C. slowly added EDC-HCl (7 kg, and 36.2 mol). The resulting slurry is mixed overnight at 20-25°C. the mixture is Then cooled to 0-10°C. and slowly added 3N HCl solution (12 l). After that add IPAC (32 l) and the layers separated. The organic layer once the industry is up with HCl (13 l) and twice with 8%solution of NaHCO 3(caution: foaming is observed). Then the organic layer was concentrated in vacuo at 50°C to approximately the volume of 15 liters Clear solution is slowly cooled to room temperature, allowing the product to crystallize. Slowly add heptane (~70 l). The suspension is filtered, washed with heptane (18 l) and dried at room temperature on the filter. Get the product of >99.9% of AI according to chiral HPLC.

Stage 2

Amide Weinrebe with stage 1 (6 kg to 22.5 mol) and 3,5-bis(trifluoromethyl)brobinson (4.8 l, 28.1 mol) is dissolved in anhydrous THF (24 l). The solution is blown with nitrogen to remove oxygen. At this point, the water content should be <500 ppm, if necessary, can lead azeotropic removal of water by distillation at atmospheric pressure. The solution is cooled to minus 10°C and slowly (over 2 hours) using a dropping funnel add iso-PrMgCl in THF (of 56.4 mol), maintaining the reaction temperature at the level of ≤-5°C. Allow the solution to warm to 20°C and left overnight at 20°C, while the amide will not be <0.5 to LCAP. Then the reaction mixture in a stream of nitrogen is cooled to minus 10°C and slowly over 2 hours interrupt the reaction by adding 5N HCl (14 l) so that the temperature was maintained at 0-5°C. Add MTBE (12 l) and biphasic see what camping is stirred for 5 minutes After heating up to 20-25°C. allow the mixture to settle for 30 min and the layers separated. The organic layer is washed twice with water (12 l).

The organic layer through the built-in PTFE filter with a pore size of 1 μm using a vacuum filtered to a distillation flask and concentrated in vacuo to a volume of ~12 l (temperature <40°C) up to the minimum capable of mixed volume. Then the solution is dried by azeotropic distillation with toluene and again brought to a minimum can mix the volume of the resulting solution was directly used in the next stage.

Stage 3: Recovery of the ketone (stage 2) in the chiral oxazolidinone:

The ketone from the previous stage (6 kg) is heated at 50°C with 0.3 EQ. Al(O-i-Pr)3(790 g) in 12 l of isopropyl alcohol (IPA) and 18 l of toluene in the course of 15.5 hours. The solution is cooled to room temperature and with vigorous stirring, slowly add granules of solid KOH (1.35 kg), maintaining the temperature at <25°C. after About 2 hours, when the analysis method HPLC shows >99.5% of completion of the cyclization, to interrupt the reaction, add 33 l of 1N HCl, the temperature of the support at the level of <25°C. If the image of cereals layer of solids, it should be filtered. Flocculent layer represents the Oh racemic oxazolidinone, and its removal increases the enantiomeric excess. The organic layer is then washed first with 36 l 0,5N HCl solution, then with 6 l IPS with 45 l of water and finally with 6 l IPS with 36 l of water. The organic layer is filtered through a built-in filter. The solvent is replaced by heptane (final volume of ~42 l) at a temperature of ~40°C, until there is <2% toluene. Leave for 2 hours at room temperature and obtain the Intermediate compound 7.

Intermediate compound 8

2-Methoxy-4-fluoro-5-(2'-were)baronova acid

Stage A: 2-fluoro-2'-methylbiphenyl-4-yl methyl ether

A mixture of 4-bromo-3-fernicola, 2-methylphenylacetic acid, tetrakis(triphenylphosphine)palladium (5 mol%) and sodium carbonate (0,23 g, 2.1 mmol) in 20 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 5 hours. Analysis by thin layer chromatography (TLC) (EtOAc:hexane/2:98) shows that the reaction is complete. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×50 ml). Extraction of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after purification by the method of preparative TLC using 2% EtOAc in hexane as eluent.

Stage b: 2-fluoro-5-IO is -2'-methylbiphenyl-4-yl methyl ether

To a mixture of silver sulfate (0.34 g, 1.11 mmol), iodine (0.28 g, 1.11 mmol) in Meon (10 ml) at room temperature is added dropwise a solution obtained above 2-fluoro-2'-methylbiphenyl-4-yl methyl ester (0.24 g, 1.11 mmol) in Meon (5 ml). The mixture is stirred at room temperature for 4 hours before until the mixture acquires a light yellow color. The solids are filtered and the filtrate concentrated. The residue is purified column flash chromatography using hexane as eluent, and get listed in the name of the connection.

Stage C: 2-methoxy-4-fluoro-5-(2'-were)baronova acid

To a solution of 2-fluoro-5-iodine-2'-methylbiphenyl-4-yl methyl ester (0.32 g, of 0.93 mmol) in THF at a temperature of minus 78°C dropwise with a syringe add n-BuLi (of 0.48 ml, 1,22 mmol,2.5 M solution in hexane). The solution is stirred at minus 78°C for 30 minutes Add trimethylboron (at 0.31 ml, 2.8 mmol). The resulting mixture was stirred at minus 78°C for 3 hours. The reaction is interrupted by a saturated solution of ammonium chloride. The mixture is extracted with EtOAc (3×15 ml). Layers EtOAc combined and dried over sodium sulfate. Indicated in the name of the connection is then used after removal of solvent.

Intermediate compound 9

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan the-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-he

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he (Intermediate compound 6, 0.75 g, 1.25 mmol), bis(pinacolato)diboron (339 mg, 1.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (214 mg, 0,262 mmol), potassium acetate (257 mg, 2,616 mmol) and 1,4-dioxane (2.5 ml), sealed in a vessel for RF heating. The reaction mixture is subjected to RF heating to a temperature of 140°C for 20 min, and then to a temperature of 130°C for 30 minutes the Crude product is washed with saturated salt solution, and then extracted with ethyl acetate. The extracts are combined and dried over Na2SO4and then filtered and concentrated in vacuo, obtaining oil is dark in color. The resulting mixture was used in the next stage without further purification.

Intermediate compound 10

Methyl 2-chloro-3'-iodine-4'-methoxybiphenyl-4-carboxylate

Stage A: methyl 4-iodine-3-chlorobenzoate

A mixture of methyl 4-amino-3-chlorobenzoate (1.0 g, 5.4 mmol), n-pentylnitrate (0.95 g, 8.1 mmol) and iodine (1.78 g, 7.0 mmol) is stirred while boiling under reflux for 1 hour. The mixture is diluted with methylene chloride (30 ml). The resulting solution was pink washed with saturated sodium thiosulfate solution, saturated salt solution and dried over sodium sulfate. Specified trade names in the connection receive after conducting column flash chromatography, using EtOAc:hexane/2:98 as eluent.

Stage b: methyl 2-chloro-4'-methoxybiphenyl-4-carboxylate

A mixture of methyl 4-iodine-3-chlorobenzoate (1.20 g, of 4.05 mmol)obtained in stage A, 4-methoxyphenylacetic acid (1.23 g, 8.1 mmol), tetrakis(triphenylphosphine)palladium (0,23 g, 5%mol.) and sodium carbonate (0,94 g, 8.9 mmol) in 50 ml of a mixture of water/EtOH/toluene (1:2:4) leave overnight to boil under reflux. The analysis method TLC (EtOAc:hexane/1:9) shows that the reaction is complete. The solvents are removed. Add water (30 ml). Organic matter is extracted with methylene chloride (3×50 ml). Extraction of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after purification by the method column flash chromatography using EtOAc:hexane/1:9 as eluent. Range1H NMR (CDCl3, 500 MHz) δ is 8.16 (d, J=1.5 Hz, 1H), of 7.97 (DD, J=8, 1,5Hz, 1H), 7,43 (m, 3H), 7,01 (d, J=6,5 Hz, 2H), 4.00 points (s, 3H), 3,91 (s, 3H).

Stage C: methyl 2-chloro-3'-iodine-4'-methoxybiphenyl-4-carboxylate

To a mixture of sulphate of silver (0.97 g 3.11 mmol) and iodine (0,79 g, 3.11 mmol) in Meon (20 ml) at room temperature add a solution of methyl 2-chloro-4'-methoxybiphenyl-4-carboxylate (0,86 g, 3.11 mmol) in a mixture 1:1 Meon/EtOH (10 ml). The mixture is stirred at room temperature for 6 hours before until the reaction mixture is colorless. Solid is e substance is filtered off and the filtrate concentrated. Specified in the title compound is obtained after purification by the method column flash chromatography using EtOAc:hexane/5:95 as eluent. Range1H NMR (CDCl3, 500 MHz) δ of 8.15 (d, J=1.5 Hz, 1H), of 7.97 (DD, J=8, 2 Hz, 1H), 7,89 (d, J=2 Hz, 1H), 7,46 (DD, J=8,5, 2 Hz, 1H), 7,40 (d, J=8 Hz, 1H), 6,91 (d, J=8 Hz, 1H), 3,98 (s, 6H).

Intermediate compound 11

Methyl 4'-methoxy-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate

3'-Iodine-4'-methoxy-2-methylbiphenyl-4-carboxylate (500 mg, 1,308 mmol), bis(pinacolato)diboron (353 mg, 1.57 mmol), 1,1'-bis(diphenyl-phosphino)ferrocene-palladium dichloride dichloromethane adduct (214 mg, 0,262 mmol), potassium acetate (257 mg, 2,616 mmol) and 1,4-dioxane (2.5 ml) is placed in a hermetically closed tube and subjected to RF heating to a temperature of 140°C for 20 min, and then to temperature 130°C for 30 minutes the Crude product is washed with saturated salt solution, and then extracted with ethyl acetate. The extracts are combined and dried over Na2SO4and then filtered and concentrated in vacuo, obtaining methyl 4'-methoxy-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate in the form of oil is dark in color, which is used in the next stage without further purification. JHMS: calculated = 382,20; found = 383,41 (M+1)+.

Intermediate compound 12

p> (4R,5R)-5-[2-Iodine-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-he

Stage A: 2-iodine-5-(trifluoromethyl)benzaldehyde

To a solution of 2-iodine-5-(trifluoromethyl)benzonitrile (Intermediate compound 2, 42 g) in CH2Cl2(300 ml) at minus 78°C. add a solution of DIBAL in CH2Cl2(175 ml, 1 M) for 30 minutes, a precipitate may form. The reaction mixture is heated to 0°C. dropwise Addition over 30 min add 25 ml of a solution of DIBAL. The reaction mixture is poured into 200 ml of 2N aqueous HCl, diluted with ether and stirred for 1 hour. Analysis by TLC shows that Imin still present; in addition, add 100 ml of 2N aqueous HCl and the reaction mixture is left to mix overnight. According to TLC, Imin still present, so additional add 200 ml of 2N aqueous HCl and the reaction mixture is stirred for 2 hours. The layers are separated and the aqueous layer was additionally extracted with ether. The ether extracts are combined, washed with saturated salt solution, dried over anhydrous MgSO4filter and concentrate. The product was then purified by chromatography on silica gel, elwira a mixture of 95:5 hexane/EtOAc, and get 2-iodine-5-(trifluoromethyl)benzaldehyde in the form of a solid white color. Range1H NMR (500 MHz, CDCl3) δ 10,00 (s, 1H), 8,12 (s, 1H), 8,11 (d, J=8 Hz, 1H), 7,53 (DD, J=2 Hz, 8 Hz, 1H).

Stage b: (4S)-4-Ben the Il-3-{(2R,3S)-3-hydroxy-3-[2-iodine-5-(trifter-methyl)phenyl]-2-methylpropanoyl}-1,3-oxazolidin-2-he

A mixture of 1.8 g of 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde (stage A), of 1.16 g of (4S)-4-benzyl-3-propionyl 1,3-oxazolidin-2-it, 0,048 g of magnesium chloride, of 1.40 ml of triethylamine and of 0.91 ml of chlorotrimethylsilane in 10 ml of EtOAc was stirred at room temperature for 24 hours, and then filtered through a thick layer of 10×10 cm silica gel, elwira with 400 ml Et2O. the Filtrate is concentrated and add 10 ml Meon together with 2 drops of triperoxonane acid. The resulting solution was stirred at room temperature for 30 min and concentrated, obtaining the oil is pale yellow in color. The resulting solution was purified flash chromatography on a column (Biotage Horizon, 65i, elwira 10%solution of acetone in hexane 15 column volumes, and obtain 1.42 g (53%) specified in the connection name. Mass spectrum (ESI) 516,2 (M-OH). Range1H NMR (500 MHz, CDCl3) δ of 8.00 (d, J=8.5 Hz, 1H), 7,76 (d, J=2 Hz, 1H), 7,22-to 7.32 (m, 4H), 7,07 (Shir. d, J=6,5 Hz, 2H), by 5.18 (DD, J=6,5 Hz, 7.5 Hz, 1H), 4,67 (m, 1H), 4,46 (DQC, J=6,5 Hz, 7.5 Hz, 1H), 4,17 (t, J=9 Hz, 1H), 4,11 (DD, J=3 Hz, 9 Hz, 1H), 3,97 (d, J=8 Hz, 1H), 3,19 (DD, J=7 Hz, 13.5 Hz, 1H), to 2.57 (DD, J=9.5 Hz and 13.5 Hz, 1H), 1,34 (d, J=7.5 Hz, 3H).

Stage C: (4R,5R)-5-[2-iodine-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-he

To a cooled to 0°C. a solution of (4S)-4-benzyl-3-{(2R,3S)-3-hydroxy-3-[2-iodine-5-(trifluoromethyl)phenyl]-2-methylpropanoyl}-1,3-oxazolidin-2-it in 6 ml of a mixture of 3:1 tetrahedr the furan-water type is 0.102 g of lithium hydroxide in 1.5 ml of water, then add 0,554 ml of 30%aqueous hydrogen peroxide solution. The resulting solution was stirred at 0°C for 1 h, whereupon analysis by LC/MS shows the absence of starting materials. To the cold solution was added a 1.5 M solution of sodium sulfite (3,7 ml), transfer the solution into a separating funnel and extracted with 2×10 ml of CH2Cl2. Extracts CH2Cl2unite and again extracted with 20 ml of a mixture of 3:1 saturated aqueous solution of NaHCO3. The aqueous layers are combined and acidified (pH < 1) with 6N HCl solution and extracted with 4×10 ml of EtOAc. The EtOAc extracts are combined, washed with 10 ml of saturated salt solution, dried over Na2SO4and concentrate. The residue is dissolved in 10 ml of toluene. Add diphenylphosphinite (0,315 ml) and 0.24 ml of triethylamine and the mixture is left to mix overnight at a temperature of 100°C, and then cooled and concentrated. The residue is purified flash chromatography on a column (Biotage Horizon, 40S, elwira 5%solution of EtOAc in hexane at a rate of 1 column volume, followed by a gradient elution EtOAc in hexane from 5 to 100% and get 0,302 g (67%) specified in the connection name. Mass spectrum (ESI) 372,1 (M+1). Range1H NMR (500 MHz, CDCl3) δ 8,02 (d, J=8 Hz, 1H), to 7.61 (d, J=1.5 Hz, 1H), 7,32 (DD, J=2 Hz, 8 Hz, 1H), 6,16 (s, 1H), 5,39 (d, J=4 Hz, 1H), 3,76 (DQC, J=6 Hz, 4.5 Hz, 1H), 1,62 (d, J=6 Hz, 3H).

Analytical HPLC n the column Chiralpak AD, a 4.6×250 mm, elution with 4%ethanol in heptane at a speed of 0.75 ml/min (tR=21,56 for R,R; tR=18,00 for S,S) gives 98% E...

Intermediate compound 13

Methyl 2-(methyl bromide)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

Stage A: methyl 4'-methoxy-2-methylbiphenyl-4-carboxylate

To methyl 4-bromo-3-methylbenzoate (92 g, 0,402 mol), (4-methoxyphenyl)Bronevoy acid (61,1 g, 0,402 mol), Na2CO3(to 85.2 g, 0,804 mol) and PdCl2(PPh3)2(1410 mg, a 2.01 mmol) is added EtOH (1,23 l) and water (0,61 l). The reaction mixture is heated to 80°C for 1 hour. The reaction mixture is cooled to room temperature, add 550 ml of water and the mixture is left for 1 hour. The resulting solids filtered and washed with EtOH solution in N2About (1:1, 750 ml). Solids are crushed using a mortar and pestle, and then suspended in 250 ml of N2About at room temperature for 1 hour, then filtered off, washed with water (2×125 ml) and dried, obtaining methyl 4'-methoxy-2-methylbiphenyl-4-carboxylate. Range1H NMR (400 MHz, CDCl3) δ of 7.95 (s, 1H), 7,89 (d, J=7.9 Hz, 1H), 7,29 (d, J=7.9 Hz, 1H), 7,27 (d, J=8.7 Hz, 2H), 6,98 (d, J=8.7 Hz, 2H), of 3.94 (s, 3H), a 3.87 (s, 3H), of 2.33 (s, 3H).

Stage b: methyl 3'-bromo-4'-methoxy-2-methylbiphenyl-4-carboxylate

To a solution of methyl 4'-methoxy-2-methylbiphenyl-4-carboxylate (71,5 g of 0.79 mol) in acetonitrile (1,43 l) and water (572 ml) add Oxon (180,1 g, 0,293 mol). Then within 30 minutes, slowly add a solution of KBr (38,2 g, 0,321 mol) in water (143 ml). The reaction mixture is stirred for 2.5 hours, then add water (715 ml) and the mixture is left for 1 hour. Solids filtered and washed as follows: a solution of MeCN/water (1:1, 350 ml, twice), water (700 ml, twice, then 350 ml) and dried, obtaining methyl 3'-bromo-4'-methoxy-2-methylbiphenyl-4-carboxylate. Range1H NMR (400 MHz, CDCl3) δ 7,94 (s, 1H), 7,89 (d, J=8,1 Hz, 1H), 7,53 (d, J=2.2 Hz, 1H), and 7.3 to 7.2 (m, 2H), 6,97 (d, J=8,4 Hz, 1H), 3.96 points (s, 3H), of 3.94 (s, 3H), 2,32 (s, 3H).

Stage C: methyl 2-(hydroxymethyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

To methyl 3'-bromo-4'-methoxy-2-methylbiphenyl-4-carboxylate (80,0 g, 0,239 mol), pinacolborane (72,8 g, 0,287 mol), Pd(dba)2(4120 mg, 7,17 mmol), P(Cy)3(2140 mg, 7,65 mmol) and Kaas (70,3 g, 0,717 mol) are added dioxane (1.2 l). The reaction mixture is heated up to 80°C and stirred for 3 hours. Then the reaction mixture is cooled to room temperature and filtered. Solids dissolved in EtOAc (800 ml), washed with saturated salt solution (400 ml, twice) and concentrate.

The residue is dissolved in THF (300 ml) and add the [2-chloro-5-(trifluoromethyl)phenyl]methanol (47,1 g, 0,223 mol) and (t-Bu2P)2ferrocene PdCl2. Add the solution To a2CO3(83,7 g, 0,606 mol) in water (214 ml) and the mixture is heated to 45°C and AC who're asked for 9 hours. The reaction mixture is cooled to room temperature, diluted with EtOAc (428 ml) and washed with water (428 ml) and saturated salt solution (428 ml). To add organic matter to 21.5 g of activated carbon (a mixture of Darco KB-100) and the mixture is stirred for 1 hour. The mixture is filtered, the solid washed with EtOAc (428 ml). The filtrate is concentrated and re-dissolved in Meon (677 ml) and leave for 1 hour. To the mixture add water (169 ml) for 2 h and then the mixture is left for 1 hour. The obtained solid substance was washed with a solution of the Meon in the water (4:1, 170 ml, three times) and dried, obtaining methyl 2-(hydroxymethyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate.

Stage D: methyl 2-(methyl bromide)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

To a cooled to 0°C. a solution of methyl 2-(hydroxymethyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (1,500 g, 3,49 mmol) in CH2Cl2(14 ml) is added GVS4(2,429 g, 7,33 mmol), and then a solution of triphenylphosphine (1,830 g, 6,98 mmol) in CH2Cl2(15 ml). The solution is heated to room temperature and stirred for twelve hours. The reaction mixture is concentrated and the residue purified flash chromatography on silica gel (0 to 25% EtOAc/hexane) and get methyl 2-(methyl bromide)-4'-methoxy-2-methyl-4"-(trifter-methyl)-1,1':3',1"-terphenyl-4-carb is kilat. Rf=0,59 (50% EtOAc/hexane). IHMS=494,8 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ of 7.95 (s, 1H), 7,89 (d, J=8.0 Hz, 1H), 7,80 (s, 1H), to 7.59 (d, J=7,6 Hz, 1H), 7,40-7,33 (m, 3H), 7,21 (d, J=2.3 Hz, 1H), 7,06 (d, J=8.5 Hz, 1H), of 4.44-4,39 (m, 2H), 3,93 (s, 3H), 3,82 (s, 3H), is 2.37 (s, 3H).

Intermediate compound 14

(5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)barrel-2-yl]}-4,4-dimethyl-1,3-oxazolidin-2-he

Stage A: benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate

N-Methylmorpholin (682 mg, 741 μl, 6,74 mmol) and isobutylparaben (460 mg, 441 μl, 3,37 mmol) are successively added to a stirred solution of N-carbobenzoxy-2-methylalanine (0.64 g, 2,69 mmol) in dry CH2Cl2at 0°C under nitrogen atmosphere. The obtained turbid mixture was stirred at 0°C for 90 minutes added in several Portions of the hydrochloride of N,O-dimethylhydroxylamine (316 mg, 3,24 mmol) and the mixture is heated to room temperature and stirred for 3 hours. The mixture was poured in 1N HCl (30 ml) and extracted with CH2Cl2(3×40 ml). The extracts are combined washed with 1N HCl solution (30 ml), dried over Na2SO4) and concentrated in vacuum to give crude product. Its clean flash chromatography (Si, 40×160 mm, the gradient of 0-80% EtOAc in hexane) and receive benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate. Rf= 0,47 (50% EtOAc who hexane). JHMS: calculated = 303,1; found = 303,2 (M+Na)+. Range1H NMR (500 MHz, CDCl3) δ 7,37-7,29 (m, 5H), of 5.82 (s, 1H), 5,09 (s, 2H), 3,60 (s, 3H), 3,18 (s, 3H), 1,60 (s, 6H).

Stage b: benzyl (1,1-dimethyl-2-oxoethyl)carbamate

Diisobutylaluminum (1.77 ml, 1 M solution in toluene, 0,708 mmol) is added to a stirred solution of benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate (198,5 mg, 0,708 mmol) in dry TGF (7,1 ml) at minus 78°C. in a nitrogen atmosphere. The reaction mixture is stirred at minus 78°C for 4 hours. Add Meon (100 ml) and 1N HCl (250 μl) and the reaction mixture allowed to warm to room temperature. The mixture was diluted with Et2O (50 ml) and washed with 1N HCl solution (2×50 ml), 50%saturated solution of NaHCO3(50 ml) and water (50 ml), then dried (MgSO4) and concentrated in vacuo, getting benzyl (1,1-dimethyl-2-oxoethyl)carbamate. Rf= 0,40 (20% EtOAc in hexane). JHMS: calculated = to 244.1; found = to 244.1 (M+Na)+. Range1H NMR (500 MHz, CDCl3) δ 9,43 (s, 1H), 7,38-7,30 (m, 5H), of 5.34 (s, 1H), 5,09 (s, 2H), of 1.37 (s, 6H).

Stage C: benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate

Ethylmagnesium (1,63 ml, 1 M solution in THF, to 1.63 mmol) dropwise with stirring to a solution of 1-iodine-3,5-bis(tri-permitil)benzene (608 mg, 317 μl, to 1.79 mmol) in dry THF (1 ml) at room temperature under nitrogen atmosphere and the reaction to shift the ü is stirred for 30 minutes The resulting solution was added to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (163,5 mg, 0,739 mmol) in dry THF (1 ml) at minus 20°C and the reaction mixture for 3 hours, allowed to warm to room temperature. Add a saturated solution of NH4Cl (10 ml) and water (10 ml) and the mixture extracted with EtOAc (3×20 ml). The combined extracts are dried over Na2SO4) and concentrated in vacuum to give crude product. Its clean flash chromatography (Si, 25×160 mm, gradient 0-40% EtOAc in hexane) and receive benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate. Rf= 0,40 (20% EtOAc in hexane). JHMS: calculated = 436,1; found = km 436.0 (M+1)+. Range1H NMR (600 MHz, CDCl3) δ 7,80 (s, 1H), to 7.77 (s, 2H), 7,39-7,33 (m, 5H), 5,12-5,08 (m, 2H), 1,36 (s, 1H), 4,90 (d, J=4.4 Hz, 1H), 4,81 (s, 1H), 1,36 (s,3H), of 1.23 (s,3H).

Intermediate compound 15

(4S,5R)-4-Methyl-5-pyridin-4-yl-1,3-oxazolidin-2-he

Stage A: benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate

CBZ-L-alanine (6.5 kg, 28.5 mol), NOT-hydrate (4.8 kg, 34.8 mol), Me(MeO)NH2Cl (3.4 kg, and 36.2 mol) and THF (32 l) placed under nitrogen in a clean flask. The mixture is cooled to 0-10°C. and slowly add diisopropylethylamine (12,4 l), keeping the temperature not more than 20°C. When a little cooled to 15-25°C. slowly added EDC-HCl (7 kg, and 36.2 mol). The slurry on OCI at a temperature of 20-25°C. The mixture is cooled to 0-10°C. and slowly added 3N HCl (13 l). Add isopropylacetate (45,5 l) and the layers separated. The organic layer is washed once with HCl (13 l) and double-8% NaHCO3(13 l). The organic layer is concentrated at 50°C under vacuum to a volume of <20 HP Clear solution is slowly cooled to room temperature, allowing the product to crystallize. Slowly add heptane (~70 l). The suspension is filtered, washed with heptane (18 l) and dried at room temperature on the filter. Receive benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate with >99.9% of AI according to chiral HPLC.

Stage b: benzyl [(1S)-1-methyl-2-oxo-2-pyridin-4-ileti]carbamate

The solution isopropylacrylamide (1.6 ml, 1 M in THF, 3,23 mmol) under stirring in nitrogen atmosphere is added dropwise to a solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (879 mg, 3,30 mmol) in dry THF (4,2 ml) at a temperature of minus 15°C. the Reaction mixture is stirred at minus 15°C for 30 min, and then the cannula added dropwise a suspension of 4-pyridylmethylamine in dry THF (receive, adding ethylmagnesium (6 ml, 2 M in THF, 6,00 mmol) to a stirred solution of 4-iodopyridine (1.35 g, 6,60 mmol) in dry THF (45 ml) at room temperature in a nitrogen atmosphere, and then stirred for 30 min). The reaction mixture is allowed to warm up to CONTROLTEMPLATES and stirred for 5 hours. To interrupt the reaction, add 1N HCl (15 ml) and the mixture is alkalinized with saturated solution of NaHCO3. The mixture is extracted with EtOAc (2×50 ml) and CH2Cl2(3×50 ml). The EtOAc extracts and CH2Cl2separately washed with saturated salt solution, dried over Na2SO4), are combined and concentrated in vacuum to give crude product. Its clean flash chromatography (Si, 40×160 mm, gradient 0-100% EtOAc in hexane) and obtain benzyl [(2R)-1-methyl-2-oxo-2-pyridin-4-ileti]carbamate as a colourless solid. Rf=0,33 (50% EtOAc/hexane). JHMS: calculated = 285,1; found = 285,3 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ cent to 8.85 (d, J=3.3 Hz, 2H), 7,76 (d, J=5.5 Hz, 2H), was 7.36-to 7.32 (m, 5H), 5,70 (d, J=6,8 Hz, 1H), 5,31-a 5.25 (m, 1H), 5,13 (s, 2H), USD 1.43 (s, 3H).

Stage C: benzyl [(1S,2R)-2-hydroxy-1-methyl-2-pyridine-4-ileti]carbamate

Three-tert-butoxylated lithium (964 mg, with 3.79 mmol) in nitrogen atmosphere at a temperature of minus 78°C is added to a solution of benzyl [(2R)-1-methyl-2-oxo-2-pyridin-4-ileti]carbamate (539,1 mg, 1,90 mmol) in dry EtOH (40 ml). The reaction mixture is stirred at minus 78°C for 2 hours. To interrupt the reaction, add 2%aqueous solution of acetic acid and the mixture is alkalinized with saturated solution of NaHCO3(~50 ml). The mixture is extracted with EtOAc (3×100 ml), the extracts combined and washed with saturated salt solution (50 ml), dried over Na2SO 4) and concentrated in vacuum to give crude product. Its clean flash chromatography (Si, 40×160 mm, gradient 0-100% EtOAc in hexane) and obtain benzyl [(1S,2R)-2-hydroxy-1-methyl-2-pyridine-4-ileti]carbamate as a colourless solid. Rf=0,49 (EtOAc). JHMS: calculated = 287,1; found = 287,3 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ to 8.41 (d, J=5.7 Hz, 2H), was 7.36-to 7.32 (m, 7H), 5,27 (d, J= 7,4 Hz, 1H), 5,10 (s, 2H), 4,89 (s, 1H), was 4.02 (Shir. s, 1H), of 0.96 (d, J=6,7 Hz, 3H).

Stage D: (4S,5R)-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-he

A solution of benzyl [(1S,2R)-2-hydroxy-1-methyl-2-pyridine-4-ileti]carbamate 7,5N aqueous mixture of KOH/Meon/THF (1:2:4, 7 ml) and left overnight to mix at room temperature. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The organic layers are combined, dried over Na2SO4) and concentrated in vacuo, obtaining (4S,5R)-4-methyl-5-phenyl-1,3-oxazolidin-2-it. JHMS: calculated = 179,1; found = 179,2 (M+1)+.

The intermediate connection 16

Methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

In a round bottom flask was placed methyl 4-bromo-3-methylbenzoate (200 mg, of 0.878 mmol), bis(pinacolato)diboron (277 mg, 1,089 mmol), PdCl2(dppf)CH2Cl2(70 mg, 0,0873 mmol), COAs (171 mg, about 1.75 mmol) and DMSO (10 ml). The reaction mixture Tegaserod with N2and heated to 40°With the a period of 1 hour, to 60°C for 1 hour, and then 80°C for 12 hours. The reaction mixture was diluted with EtOAc (25 ml) and hexane (75 ml) and the organic extracts washed with water (2×25 ml) and saturated salt solution (50 ml). The organic layer is dried over Na2SO4filter and concentrate. The residue is purified flash chromatography on silica gel (0 to 15% EtOAc/hexane) and obtain methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. Range1H NMR (500 MHz, CDCl3) δ of 7.82 (s, 1H), 7,80 (s, 2H), 3,91 (s, 3H), 2.57 m (s, 3H), of 1.35 (s, 12H).

Intermediate compound 17

4-(2-Fluoro-4-methoxyphenyl)piperidine

Stage A: 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidine-4-ol

To a cooled (0°C.) solution of 4-bromo-3-fernicola (1 g, 4,88 mmol) in anhydrous THF (7 ml) with stirring, added dropwise to isopropylaniline (2.0 m in THF; 2,22 ml; 4,43 mmol). The reaction mixture was stirred at room temperature for 30 min and cooled to 0°C. added dropwise 1-benzyl-4-piperidone (0,72 ml; a 4.03 mmol) and the reaction mixture was stirred at room temperature for 14 hours. Interrupt the reaction with a saturated solution of NH4Cl and the reaction mixture is redistributed between EtOAc (50 ml) and N2O (30 ml). The aqueous layer was extracted with EtOAc (3×50 ml), the extracts combined and washed with a saturated solution of salt (50) - Rev. l), dried over MgSO4), filtered and concentrated in vacuo. The residue is purified flash chromatography on silica gel (gradient from 0 to 50% EtOAc/hexane) and get 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidine-4-ol in the form of a solid light orange color. IHMS = 315,9 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ 7,38-7,31 (m, 5H), 7,28-7,24 (m, 1H), 6,66 (DD, J=8,7,2,5 Hz, 1H), is 6.61 (DD, J=14,4, 2.5 Hz, 1H), 3,79 (s, 3H), of 3.56 (s, 2H), 2,77 (Shir. d, J=10,6 Hz, 2H), 2,54-2,48 (m, 2H), 2,31-of 2.24 (m, 2H), 1,84(d, J=12.3 Hz, 2H).

Stage b: 1-benzyl-4-(2-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine

A mixture of 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidine-4-ol (stage A; 300 mg; 0,952 mmol) and monohydrate p-toluensulfonate acid (18 mg; 0,0952 mmol) in benzene (20 ml) with stirring and heated to 80°C for 14 hours. Additionally, add 100 mg of the monohydrate of p-toluensulfonate acid and the reaction mixture is heated to 80°C for 1 hour. The reaction mixture is redistributed between EtOAc (50 ml) and N2About (50 ml). The aqueous layer was extracted with EtOAc (3×50 ml), the extracts combined and washed with water (3×50 ml) and saturated salt solution (50 ml), dried over MgSO4), filtered and concentrated in vacuo. The residue is purified flash chromatography on silica gel (gradient 0-10% EtOAc/hexane) and get 1-benzyl-4-(2-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine in the form of a yellow oil. IHMS = 297,9 (M+1)+. Range13) δ 9,56 (Shir. s, 1H), 7,42-7,38 (m, 2H), 7,34 (t, J=7,3 Hz, 2H), 7,28 (d, J=7,3 Hz, 1H), 7,17 (t, J=8.7 Hz, 1H), only 6.64 (DD, J=8,7, 2.5 Hz, 1H), 6,59 (DD, J=13,0, 2.5 Hz, 1H), 5,91-of 5.89 (m, 1H), of 3.78 (s, 3H), 3,66 (Shir. s, 2H), 3,18 (Shir. s, 2H), 2,71 (Shir. s, 2H), 2,54 (Shir. s, 2H).

Stage C: 4-(2-fluoro-4-methoxyphenyl)piperidine

To a solution of 1-benzyl-4-(2-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (stage V; 117 mg; 0,393 mmol) in Meon (10 ml) is added a catalytic amount of 10% Pd/C and the reaction mixture is placed in an atmosphere of H2(Parr apparatus at the rocking chair; 45 psi) for 48 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The residue is purified flash chromatography on silica gel (gradient from 0-100% EtOAc/hexane) and receive a 4-(2-fluoro-4-methoxyphenyl)piperidine in the form of a solid brown color. IHMS = 210,1 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ 7,16 (t, J=8.7 Hz, 1H), of 6.68 (DD, J=8,7, 2.5 Hz, 1H), 6,60 (DD, J=12,3, 2.5 Hz, 1H), of 3.78 (s, 3H), 3,63 (d, J=12,6 Hz, 2H), 3,09 are 2.98 (m, 2H), 2,18 (kV, J=12.1 Hz, 2H), 2,02 (d, J=13.3 Hz, 2H).

Intermediate compound 18

Ethyl [4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine-1-yl]acetate

Stage A: ethyl [4-(2-fluoro-4-methoxyphenyl)piperidine-1-yl]acetate

To a solution of 4-(2-fluoro-4-methoxyphenyl)piperidine (40 mg; 0,19 mmol) in DMF (1 ml) with stirring in an atmosphere of N2add N,N-diisopropylethylamine (33 μl; 0,19 mmol), and the eating ethylbromoacetate (21 μl; 0,19 mmol). The resulting solution was stirred at room temperature for 2.5 hours. The reaction mixture is redistributed between EtOAc (10 ml) and N2About (10 ml). The aqueous layer was extracted with EtOAc (3×10 ml), the extracts combined and washed with saturated salt solution (10 ml), dried over Na2SO4), filtered and concentrated in vacuo. The residue is purified flash chromatography on silica gel (gradient of 0-25% EtOAc/hexane) and obtain ethyl [4-(2-fluoro-4-methoxy-phenyl)piperidine-1-yl]acetate as a colourless oil. IHMS = 295,9 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ 7,14 (t, J=8.7 Hz, 1H), 6,65 (DD, J=8,5, 2.5 Hz, 1H), return of 6.58 (DD, J=12,43, 2.5 Hz, 1H), 4,20 (kV, J=7,1 Hz, 2H), of 3.77 (s, 3H), 3,26 (s, 2H), 3,06 (d, J=11,4 Hz, 2H), 2,80 (TT, J=12.1 is of 3.7 Hz, 1H), 2,32 (t, J=11.2 Hz, 2H), 1,87 (arcs, J=12,3, 3,3 Hz, 2H), 1,78 (d, J=12.1 Hz, 2H), 1,29 (t, J=7,1 Hz, 3H).

Stage b: ethyl [4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine-1-yl]acetate

A mixture of ethyl [4-(2-fluoro-4-methoxyphenyl)piperidine-1-yl]acetate (stage A; to 21.6 mg; 0,073 mmol), iodine (45,6 mg; 0,146 mmol) and silver sulfate (37 mg; 0,146 mmol) in Meon (1.5 ml) was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The residue is again dissolved in ether (25 ml) and washed with water (25 ml). The aqueous layer was extracted with ether (3×25 ml), the extracts combined and washed with saturated salt solution (25 ml), dried over MgSO4)has shown that the comfort and concentrated in vacuo. The residue is purified flash chromatography on silica gel (gradient 0-10% EtOAc/hexane) and obtain ethyl [4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine-1-yl]acetate as yellow oil. IHMS = 421,8 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ to 7.61 (d, J=8,3 Hz, 1H), 6,45 (d, J=11,9 Hz, 1H), 4,21 (kV, J=7,1 Hz, 2H), of 3.84 (s, 3H), 3,26 (s, 2H), 3,05 (d, J=11.2 Hz, 2H), 2,80 (TT, J=12,0, 3,9 Hz, 1H), 2,33 (t, J=10,6 Hz, 2H), 1,87 (arcs, J=12,3, 3,2 Hz 2N), of 1.78 (d, J=12.1 Hz, 2H), 1,29 (t, J=7,1 Hz, 3H).

Intermediate compound 19

4-(2-Fluoro-5-iodine-4-methoxyphenyl)piperidine

Stage A: tert-butyl 4-(2-fluoro-4-methoxyphenyl)piperidine-1-carboxylate

To a mixture of 4-(2-fluoro-4-methoxyphenyl)piperidine (200 mg; 0,957 mmol) and N,N-diisopropylethylamine (183 μl; 1,053 mmol) is added di-tert-BUTYLCARBAMATE (230 mg; 1,053 mmol), as described previously, and obtain tert-butyl 4-(2-fluoro-4-methoxyphenyl)piperidine-1-carboxylate as a colourless oil. IHMS = 254,0 (M+1-100+44)+. Range1H NMR (500 MHz, CDCl3) δ 7,07 (t, J=8.7 Hz, 1H), 6,65 (DD, J=8,5, 2.3 Hz, 1H), 6,59 (DD, J=12,3,2,3 Hz, 1H), 4,23 (Shir. s, 2H), of 3.78 (s, 3H), 2.91 in (TT, J=12,2, 3.2 Hz, 1H), 2,84 was 2.76 (m, 2H), 1,79 is 1.75 (m, 2H), 1,65-of 1.56 (m, 2H), to 1.48 (s, 9H).

Stage b: 4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine and tert-butyl 4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine-1-carboxylate

To a mixture of tert-butyl 4-(2-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (stage A; 255 mg; 0,825 mmol) in Meon (15 ml) under stirring until ablaut iodine (345 mg; 1,107 mmol) and silver sulfate (281 mg; 1,107 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The residue is again dissolved in ether 50 ml) and washed with water (50 ml). The aqueous layer was extracted with ether (3×50 ml), the extracts combined and washed with saturated salt solution (50 ml), dried over MgSO4), filtered and concentrated in vacuo. The residue is purified flash chromatography on silica gel (gradient from 0-10% EtOAc/hexane) and obtain tert-butyl 4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine-1-carboxylate as a colorless glassy substance. The aqueous layer was again extracted with EtOAc (3×100 ml), the extracts combined, dried over MgSO4), filtered and the solvent is removed under reduced pressure until, until you begin to form the precipitate. The formed solid is filtered off and dried in a vacuum Cabinet, receiving 4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine in the form of a whitish substance.

tert-butyl 4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine-1-carboxylate:IHMS=379,7 (M+1-100+44)+. Range1H NMR (500 MHz, CDCl3) δ rate of 7.54 (d, J=8,3 Hz, 1H), 6,55 (d, J=and 12.2 Hz, 1H), 4,23 (Shir. s, 2H), 3,85 (s, 3H), 2.91 in (TT, J=12,3, 3.5 Hz, 1H), and 2.79 (t, J=12.1 Hz, 2H), 1,78-of 1.74 (m, 2H), 1,59 (arcs, J=12,6, 4,1 Hz, 2H), to 1.48 (s, 9H).

4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine:IHMS=335,7 (M+1)+. the range of 1H NMR (500 MHz, CDCl3) δ 9,62 (Shir. s, 1H), to 7.59 (d, J=8,3 Hz, 1H), 6,56 (d, J=and 12.2 Hz, 1H), 3,85 (s, 3H), of 3.64 (d, J=12.1 Hz, 2H), 3,06-of 3.97 (m, 3H), 2.21 are a 2.12 (m, 2H), 2.05 is is 2.00 (m, 2H).

Intermediate compound 20

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-(2-bromobutyryl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he

Stage A: methyl 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzoate

The palladium (II) acetate (0,109 g, 0,486 mmol), DPPF (0,269 g, 0,486 mmol), K2CO3(2,013 g of 14.57 mmol) and Et3N (0,677 ml, a 4.86 mmol) are added to a solution of (4S,5R)5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he (2.9 g, a 4.86 mmol) in MeCN (30 ml) and Meon (10 ml). The reaction mixture is blown with nitrogen, the flask is closed with a lid and attach it to the tank WITH. After transmission for 5 min through a solution WITH gaseous via connected to the needle cylinder, the mixture is left overnight to be heated at 70°C WITH current from a cylinder. The mixture was diluted with EtOAc (300 ml), filtered through celite and then washed with water (3×50 ml), saturated salt solution (1×), dried over Na2SO4), filtered and the solvent evaporated in vacuum. The residue is purified flash chromatography on silica gel and get methyl 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(triptime who yl)benzoate. JHMS: calculated = 530,1; found = 529,9 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ of 8.09 (d, J=8,1 Hz, 1H); 7,92 (s, 1H); of 7.82 (s, 2H); 7,79 (s, 1H); of 7.69 (d, J=8,1 Hz, 1H); of 5.75 (d, J=7.8 Hz, 1H); 5,10 (d, J=16.2 Hz, 1H); to 4.81 (d, J=16.2 Hz, 1H); 4,19-4,11 (m, 1H); 3,99 (s, 3H); 0,81 (d, J=6.5 Hz, 3H).

Stage A: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(hydroxymethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he

To a solution of methyl 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzoate (1.55 g, with 2.93 mmol) in THF (65 ml) at 0°C in an atmosphere of nitrogen was added dropwise 1N solution of super-hydride in THF (5,86 ml, 5,86 mmol). The reaction mixture was stirred at 0°C for 1 hour. To complete the reaction adds extra superseded.

The reaction gently interrupt water and the aqueous layer was extracted with EtOAc (3×). The organic layers are combined and washed with saturated salt solution, dried over Na2SO4), filtered and the solvent evaporated in vacuum. The residue is purified flash chromatography on silica gel and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(hydroxymethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-it. JHMS: calculated = 502,1; found = 502,0 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ to $ 7.91 (s, 1H); for 7.78 (s, 2H); the 7.65 (t, J=9.5 Hz, 2H); at 7.55 (s, 1H); 5,72 (d, J=8,1 Hz, 1H); 5,09 (d, J=15,5 Hz, 1H); a 4.86 (d, J=3,7 Hz, 2H); 4,29 (d, J=15,5 Hz, 1H); 4,06-4,00 (m, 1H); 2,59 (s, 1H); 0,8 (d, J=6.6 Hz, 3H).

Stage C: 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzaldehyde

To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(hydroxymethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (510 mg, 1,017 mmol) in CH2Cl2(20 ml) at 0°C in nitrogen atmosphere are added in several portions periodinane dessa-Martin (647 mg, 1,526 mmol). The reaction mixture was stirred at 0°C for 1 hour. The reaction gently interrupt a saturated solution of NaHCO3and the aqueous layer was extracted with CH2Cl2. The organic layers are combined, washed with saturated salt solution, dried over Na2SO4), filtered and the solvent evaporated in vacuum. The residue is purified flash chromatography on silica gel and get 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzaldehyde as solid white. JHMS: calculated = 500,1; found = 500,0 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ 10,29 (s, 1H); 8,04 (d, J=7.8 Hz, 1H); to 7.93 (s, 1H); a 7.85 (d, J=8.0 Hz, 1H); 7,83 (s, 1H); of 7.82 (s, 2H); 5,77 (d, J=7.9 Hz, 1H); 5,11 (d,J=16.5 Hz, 1H); 4,94 (d, J=16.5 Hz, 1H); 4,23-4,18 (m, 1H); 0,84 (d, J=6.5 Hz, 3H).

Stage D: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-butyryl-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he

To a solution of 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}METI is)-4-(trifluoromethyl)benzaldehyde (654 mg, 1,310 mmol) in toluene (25 ml) at minus 78°C in an atmosphere of nitrogen was added dropwise a 2 M solution of n-propylaniline (0,655 ml, 1,310 mmol). The reaction mixture is stirred at minus 78°C for 4 hours. The reaction gently interrupt water and the aqueous layer was extracted with EtOAc. The organic layers are combined and washed with saturated salt solution, dried over Na2SO4), filtered and the solvent evaporated in vacuum, obtaining a mixture of the product (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-butyryl-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-it is a by-product, (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(hydroxymethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-it is in the ratio of 3 to 1. The resulting mixture was dissolved in CH2Cl2(50 ml) at 0°C under nitrogen atmosphere and portions add periodinane dessa-Martin (834 mg, 1,965 mmol). The reaction mixture was stirred at 0°C for 1 hour. The reaction gently interrupt a saturated solution of NaHCO3and the aqueous layer was extracted with CH2Cl2(3×). The organic layers are combined, washed with saturated salt solution, dried over Na2SO4), filtered and the solvent evaporated in vacuum. The residue is purified flash chromatography on silica gel and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-butyryl-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-it. JHMS: calculated = 542,1; on the Deno = 542,0 (M+1) +. Range1H NMR (500 MHz, CDCl3) δ to $ 7.91 (s, 1H); 7,81 (s, 2H); 7,79 (d, J=8,2 Hz, 2H); of 7.69 (d,J=8.0 Hz, 1H); 5,74 (d,J=7.8 Hz, 1H); 4,91 (d, J=16.1 Hz, 1H); of 4.57 (d,J=16.1 Hz, 1H); 4,24-4,19 (m, 1H); 3,01-2,89 (m, 2H); 1,82-1,72 (m, 2H); of 1.03 (t, J=7,4 Hz, 3H); to 0.80 (d,J=6.5 Hz, 3H).

Stage E: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-bromobutyryl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he

To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-butyryl-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (300 mg, 0,554 mmol) in CHCl3(3 ml) at 0°C in an atmosphere of nitrogen was added dropwise a solution of bromine (0,030 ml, 0,582 mmol) in CHCl3(2 ml). The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture is evaporated in vacuum. The residue is purified flash chromatography on silica gel and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-bromobutyryl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-it looks like a solid white color. JHMS: calculated = 622,0; found = 621,7 (M+1)+. Range1H NMR (500 MHz, CDCl3that 1:1 mixture of atropisomers) δ to $ 7.91 (s, 1H); a 7.85 (d, J=5,1 Hz, 1H); 7,83-to 7.77 (m, 2,5H); 7,74-of 7.69 (m, 1,5H); 5,79 (d, J=7.8 Hz, 0,5H); 5,74 (d, J=7.9 Hz, 0,5H); 5,06 to 4.92 (m, 2H); of 4.57 (d, J=16.4 Hz, 0,5H); 4,47 (d, J=16.0 Hz, 0,5H); 4,24-4,16 (m, 1H); 2,35 was 2.25 (m, 1H); 2,19-of 2.09 (m, 1H); 1,18-of 1.16 (m, 3H); to 0.80 (d, J=6,6 Hz, 1,5H); 0,78 (d, J=6,6 Hz, 1,5H).

The intermediate connection 21

Methyl 4-(iminocarbonothioyl)-3-methylbenzoate

Stage A: methyl 4-cyan is-3-methylbenzoate

In the receiver for RF heating place of methyl 4-bromo-3-methylbenzoate (100 mg, 0,437 mmol), Pd(Ph3P)4of 25.2 mg, of 0.022 mmol), Zn(CN)2(51.3 mg, 0,437 mmol) and DMF (2 ml). The mixture is blown with nitrogen and sealed. The reaction mixture is subjected to RF radiation at 150°C for 5 minutes the Mixture is diluted with EtOAc and washed with water. The organic layer is dried over Na2SO4), filtered and the solvent evaporated in vacuum. The residue is purified flash chromatography on silica gel and obtain methyl 4-cyano-3-methylbenzoate. JHMS: calculated = 176,1; found = 176,1 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ 8,02 (s, 1H); to 7.95 (d, J=8,1 Hz, 1H); 7,71 (d, J=8.0 Hz, 1H); 7.29 trend (s, 1H); 3,98 (s,3H); of 2.64 (s, 3H).

Stage b: methyl 4-(iminocarbonothioyl)-3-methylbenzoate

To a solution of methyl 4-cyano-3-methylbenzoate (36 mg, 0,205 mmol) in 1,4-dioxane (0.5 ml) and water (0,500 ml) is added sodium hydrosulfide is 0.019 ml, 0,616 mmol) and triethylamine hydrochloride (170 mg, 1,233 mmol). The reaction mixture is left overnight to be heated at a temperature of 55°C. Allow the mixture to cool and add water. The mixture is extracted with EtOAc. The organic layers are combined, dried over Na2SO4), filtered and the solvent evaporated in vacuum, obtaining the product in a solid yellow color. JHMS: calculated = 210,1; found = 210,2 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ 7,86 (s, 1H); to 7.84 (d, J=8,1 Hz, 1H) 7,42 (d, J=7.9 Hz, 1H); 7,16 (s, 2H); 3,93 (s, 3H); of 2.51 (s, 3H).

Intermediate compound 22

Methyl 2',4'-debtor-2-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate

Stage A: methyl 5'-amino-2',4'-debtor-2-methylbiphenyl-4-carboxylate

5-Bromo-2,4-diptiranjan (500 mg, is 2.40 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Intermediate compound 16, 797 mg, is 2.88 mmol), sodium carbonate (2,40 ml aqueous solution of 2 M, is 2.88 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (196 mg, 0.24 mmol) and ethanol (15 ml) is heated to 80°C in oil bath for 3 hour, and then left overnight to cool to room temperature. Volatiles are removed under reduced pressure. The resulting residue is treated according to the scheme DCM/saturated salt solution/Na2SO4/filtration/concentration and get oil dark color. The resulting oil purified flash chromatography (SiO2cartridge Biotage 40+M). Column elute with a mixture of EtOAc/hexane in a gradient from 0% to 40%. Collecting appropriate fractions, and concentrate under vacuum, obtaining specified in the title compound. JHMS: calculated = 277,09; found = 278,03(M+1)+.

Stage b: methyl 2',4'-debtor-5'-iodine-2-methylbiphenyl-4-carboxylate

Mate the 5'-amino-2',4'-debtor-2-methylbiphenyl-4-carboxylate (stage A, 500 mg of 1.80 mmol), 3-methylbutyronitrile (317 mg, a 2.71 mmol), iodine (549 mg, of 2.16 mmol) and chloroform (15 ml) is refluxed on an oil bath for 5 hours and then left overnight to cool to room temperature. The crude product was purified flash chromatography (SiO2cartridge Biotage 40+M), performing a gradient elution with mixture of EtOAc/hexane. Collecting appropriate fractions, and concentrate under vacuum, obtaining specified in the title compound. IHMS (ESI): calculated = 387,98; found = 388,92(M+1)+.

Stage C: methyl 2',4'-debtor-2-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate

Methyl 2',4'-debtor-5'-iodine-2-methylbiphenyl-4-carboxylate (stage, 1,551 g, 4,55 mmol), bis(pinacolato)diboron (1,385 g, 5.46 mmol), potassium acetate (0,892 g, 9.09 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (0,743 g, 0,909 mmol) and 1,4-dioxane (10 ml) is placed in a sealed tube and heated in a microwave oven to a temperature of 140°C for 30 minutes Analysis method IHMS aliquots taken from the reaction mixture shows the formation of dibromononane side of the product and the desired borate/Bronevoy acid. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate is washed with saturated salt solution, extracted with ethyl acetate, dried over Na2SO4that is altroot and evaporated, getting the balance of dark color, representing the crude mixture indicated in the title compound, which in this form is used in the next stage. IHMS (ESI): calculated = 388,17; found = 389,11(M+1)+.

Intermediate compound 23

The above triarylmethyl get through the following sequential process:

Buildingcommunity alcohol 1

In a vessel with a capacity of 100 liters, equipped with a top stirrer, a thermocouple, a pipe for input of nitrogen, a dropping funnel and a shirt, steam heated, placed 30 l of DMF, 8 l of water GMP 5000 g source benzyl alcohol and 4458 g of potassium acetate. The mixture Tegaserod, blowing with nitrogen, and then leave in a nitrogen atmosphere. To the reaction mixture are added PdCl2(DTBPF) (64,8 g) and the resulting portion is heated to 40-45°C. (DTBPF is a 1,1'-bis(di-tert-butylphosphino)ferrocene).

In a vessel with a capacity of 20 liters, equipped with a top stirrer and a tube for input of nitrogen, placed 10 l of DMF and 4114 g dichlorophenylamino acid. The solution Tegaserod, blowing with nitrogen, and then leave in a nitrogen atmosphere. The resulting solution slowly over 1 hour using a dropping funnel added to this reaction mixture. Over the course of the reaction is monitored by HPLC; the reaction ends in PR is approximately 2 hours. After completion of the reaction, to the reaction mixture are added toluene (20 l) and 0.2 M solution of acetic acid (20 l). A two-phase mixture is transferred into the cylinder with a capacity of 170 liters In capacity, where there was a reaction, add toluene (20 l) and 0.2 M solution of acetic acid (20 l) and this mixture is also transferred to the cylinder capacity of 170 HP Layers are separated and the organic (upper) layer was washed with 10%aqueous solution of sodium chloride (2×40 l)and then water GMP (40 l). Then the organic phase is filtered through a thick layer of silica gel (3 kg) and the silica gel was additionally washed with toluene (2×20 l) for the complete removal of the product. Toluene solution portions are concentrated to a volume of 20 l, and then washed with portions 2×50 l of heptane. The volume of the mixture is brought to 60 liters and heated to completely dissolve any precipitated in the sediment amount of the product.

In the kneading put the seed crystals obtained from earlier portions, and leave to cool overnight. The mixture is cooled to 0°C and filtered. Wet the filter cake was washed with cold heptane (0°C, 15 l) and dried in a stream of nitrogen under vacuum, obtaining the required biodiversify alcohol 1.

Barilani benzoate 2

In a vessel with a capacity of 100 liters, equipped with a top stirrer, a thermocouple, a pipe for input of nitrogen, a dropping funnel and a shirt with a steam heating, pomeshaut l of toluene, 4869 ml of triethylamine, 5100 g periventricular alcohol 1 obtained at the previous stage, and 102 g of 4-dimethylaminopyridine (DMAP). The solution is cooled to 0°C. To the mixture using a dropping funnel slowly for about 1 hour add benzoyl chloride (2120 ml). The addition is accompanied by heat. When you are finished adding portion is heated to room temperature. Forming a thick suspension. Over the course of the reaction is monitored by HPLC; the reaction ends after approximately 2 hours after heating to room temperature.

In the reaction vessel is added an aqueous solution of HCl (1.0 M, 20 l), and a portion is transferred to the extractor with a capacity of 100 l of the Lower aqueous layer is separated, a portion sequentially washed with 2×12 l of 1.0 M HCl solution, and then 2×12 l water GMP. Toluene solution is dried over anhydrous sodium sulfate and filtered through a funnel with a glass bottom. Toluene solution portions are concentrated to a volume of 10 l, and then add 51 l of heptane, maintaining the temperature at 40-45°C. Leave the dough overnight to cool to room temperature. Then the batch is cooled to minus 5°C and filtered. Wet the filter cake was washed with cold heptane (-5°C, 16 l) and dried in a stream of nitrogen under vacuum, getting barilani benzoate 2.

Baronova acid 3

In a flask with a capacity of 3 l, snabzhenna is with a mechanical stirrer, thermocouple and addition funnel, was placed 100 g of solid methyl ester 4-iodine-3-methylbenzoic acid and 1.0 l of dry THF. The mixture is cooled to minus 25°C and then added dropwise over 25 min add 218 ml of a solution of i-PrMgCl (2 M in THF), maintaining the temperature at <-15°C. the Mixture after addition of the Grignard reagent was incubated for 1 hour at <-10°C. analysis of a hydrolyzed aliquot shows that the degree of deiodinase is 97%.

Then the reaction mixture is cooled to approximately minus 20°C and complete the reaction, adding trimethylboron (77 g). Adding trimethylborane accompanied by an exothermic reaction. In the process of adding over 3 minutes and the temperature rises to approximately minus 4°C. the resulting solution was left for 1 hour at a temperature <0°C. Then the mixture is cooled to approximately minus 20°C and optionally terminate the reaction by adding 1.0 l of 1 M solution of N3RHO4. This process is also exothermic, the temperature by the end of the add increased to 3°C. the Mixture left overnight at room temperature.

THF is removed by distillation at a temperature of <45°C under reduced pressure. The resulting suspension is allowed to cool down to room temperature, and then filtered. The precipitate on the filter is washed with water (3×500 ml) and toluene (2×250 ml), and dried in vacuum at current I is the same for 18 h, getting Bronevoy acid 3 in the form of a whitish crystalline substance.

Triarylbismuth 4

First, in a glove box filled with nitrogen, to prepare the catalyst, placing bis(acetonitrile)palladium dichloride (107 mg) and 1,2-bis(di-tert-butyrophenone)benzene (292 mg) in a vessel equipped with a magnetic stirrer. Then add acetonitrile (35 ml). The resulting suspension before use was stirred at room temperature for ~2 hours.

In the bottle Slanka capacity of 100 ml, equipped with a magnetic stirrer, a tube for supplying nitrogen/vacuum and a septum, placed Bronevoy acid 3 (6,79 g, 35,3 mmol) and bioalberta 2 (9.45 in). The vessel is rinsed with nitrogen and transferred into a glove box. The suspension of catalyst, which is prepared as described in the previous paragraph, then in the glove box is transferred into the flask Slanka. The vessel, which was preparing a suspension of the catalyst, rinse with acetonitrile (5 ml); the washing solution is also transferred into the flask Slanka.

To a viscous suspension in the flask Slanka at room temperature in a glove box add the aqueous solution To a3RHO4(15.0 g of 50 wt%. To3RHO4, 7.5 g3RHO4). Vessel Slanka sealed, removed from the glove box and connected to a nitrogen bubbler. The obtained two-phase mixture plumage is eshivot and heated for 22 h at an oil bath the temperature is 55°C, then according to the analysis by HPLC, the amount of unreacted biodiversity 1.7% in relation to the product, triarylbismuth. At a temperature of ~30°C add acetonitrile (40 ml) and the lower aqueous layer was separated. The aqueous layer was again extracted with acetonitrile (3 ml) and the resulting extract is combined with the main organic layer. The reaction mixture was concentrated to ~40% of the original volume, maintaining the external temperature and pressure at 40-42°C and 190-200 mbar. The batch is cooled to ~30° and the organic layer filtered through a funnel with a glass filter bottom directly into the vessel to conduct crystallization. The reaction vessel is washed with CH3CN (17 ml), and wash solution is filtered into a reaction vessel. Once the dough has cooled, there is a rapid crystallization of triarylbismuth 4.

Fast crystallizing the mixture, which is contained in a 3-necked round bottom flask with a capacity of 100 ml, equipped with a mechanical stirrer, a tube for input and bubbler for nitrogen and addition funnel, diluted, further adding 43 ml of CH3CN, and receive the results of the analysis of ~6 ml of CH3CN/g of product in the form of triarylbismuth. To the thick slurry at room temperature for 60 min add water (25 ml) in order to get ~27%. in the water (with respect to CH 3CN). The suspension is stirred at room temperature until such time as the concentration of triarylbismuth in the liquid above the sediment will not be approximately 5.5 g/l according to the analysis by HPLC (leave overnight). Portion is cooled in a bath with ice to ~2°C and stirred for approximately 2 hours, after which the concentration of triarylbismuth 4 in the liquid above the sediment is ~1.6 g/l, the Suspension is filtered through a funnel with a filter bottom and the filter cake is washed with 46 ml of a cold mixture of 75:25./about. CH3CN:water, which also allows to replace the solvent. Sludge triarylbismuth on the filter is dried in vacuum in a stream of nitrogen at room temperature until constant weight.

Triarray alcohol (5)

In a vessel with a capacity of 100 liters, equipped with a top stirrer, a line for supplying nitrogen and a thermometer, put 2 kg solid triarylbismuth (4) and dry methanol (20 l). Under stirring bubbled nitrogen through the suspension for 5 minutes To a suspension add sodium methoxide (30 wt%. the solution in the Meon, 210 ml) and the reaction mixture was kept at room temperature until, until there <0.15% of the original triarylbismuth (approximately 3-4 hours). Approximately 1 hour before the end of the reaction, the reaction mixture becomes homogeneous. Added 5M HCl solution (250 ml), then tolua is (10 l) and water (15 l). The phases are separated, the organic layer once washed with water (10 l). Then a portion of the concentrate to remove water and residual methanol. Triarray alcohol 5 used in the next stage without further purification.

Triarylmethyl 6

In a round-bottom vessel with a capacity of 75 litres, fitted top with a stirrer, a line for nitrogen supply, thermocouple, and addition funnel, is placed 1490 g treillage alcohol 5 in toluene (22,2 l). To the solution was added TsCl (1232 g) and stirred, and then using a dropping funnel for 3 minutes and add a solution of triethylamine (1197 ml), DABCO (19.3 g) and toluene (2.5 l). The inside temperature of the mixture rises to 32°C. the reaction course is monitored by HPLC, and the degree of conversion of >99.7% of achieved within 2 hours.

After the initial triarray alcohol will completely react, the solution is filtered through a layer of silica gel (1700 g, Merck Grade 9385) so cloudy suspension became a clear solution. The filter cake is washed with 5.0 l of toluene, washing solutions are combined and transferred into a 100-liter reactor/extractor. The solution with stirring, mixed with 6.0 l of 10% vol./about. NaHSO4(900 g 9.0 l of water GMP), and then vigorously stirred. The phases are separated and the aqueous phase is discarded (pH 1). The organic (upper) layer was washed with water GMP (2×9,0 l) and the aqueous layer is separated is. The pH value of the two leaching is 1 and 4, respectively.

The organic layer is concentrated to the formation of the oil and dissolved in 10-14 volumes 3-7% solution of toluene in heptane. Organic matter is heated up until the solution is clear and homogeneous (in the range 60-80°C depending on the concentration of toluene), and then slowly cooled to room temperature. The seed using a seed crystal of the substance of the previously received portions) are placed in solution at 50°C, and then immediately starts the growth of crystals. Leave overnight to cool to room temperature, the mother liquor is decanted and the crystals washed with 10.0 l of a 10%toluene/heptane, and then with 6.0 liters of heptane. Solid bright white, dried for 72 hours in a vacuum in a stream of nitrogen and receive toilet 6.

EXAMPLE 1

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-methoxy-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

Stage And

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5'-bromo-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(tri-permitil)benzyl]-4-methyl-1,3-oxazolidin-2-she (to 6.80 g, is 11.39 mmol), 2-methoxy-5-brompheniramine acid (3.00 g, 12,99 mmol) and K is rbonate sodium (2.65 g, 25,0 mmol) in 200 ml of a mixture of 1:2:4 water:EtOH:toluene is stirred at room temperature for 30 minutes Add a catalytic amount of tetrakis(triphenyl-phosphine)palladium (0.66 g, 5 mol%). The mixture is stirred while boiling under reflux for 24 hours. Analysis by TLC (CH2Cl2:hexane/1:1) shows the absence of starting materials. The solvent is removed. Add water (100 ml). The mixture is extracted with methylene chloride (3×100 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using CH2Cl2:hexane/6:4 as eluent. Range1H NMR (CDCl3, 500 MHz, 1:1 mixture of atropisomers) δ 7,88 (s, 1H), 7,74 (s, 1H), 7,72 (s, 1H), to 7.67 (t, J=1 Hz, 1H), 7.62mm (s, 1H), 7,54 (m, 1H), 7,37-7,42 (m, 1H), 7,31-7,34 (m, 1H), 6.90 to-6,93 (m, 1H), 5,63 (d, J=8 Hz, 0,5H), 5.25-inch (d, J=8 Hz, 0,5H), to 4.98 (d, J=15,5 Hz, 0,5H), 4,88 (d, J=16 Hz, 0,5H), of 4.12 (d, J=15,5 Hz, 0,5H), 3,88 (d, J=16.5 Hz, 0,5H), of 3.84 (s, 3H), 3,81 (s, 3H), of 3.73 (m, 1H), 0,59 (d, J=6,5 Hz, 1,5H), 0,45 (d, J=6,5 Hz, 1,5H).

Stage A: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-methoxy-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

A mixture of compound from step A (0.05 g, 0,076 mmol), fibranova acid (0.14 g, 0.11 mmol), tetrakis(triphenylphosphine)palladium (5 mol%) and sodium carbonate (0,018 g, 0,17 mmol) in 7 ml of a mixture water:EtOH:toluene (1:2:4) is boiled with milk products is the first refrigerator for 4 hours. Analysis by TLC (CH2Cl2:hexane/1:1) shows that the reaction is complete. The solvents are removed. Add water (30 ml). Organic matter is extracted with methylene chloride (3×40 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound obtained after preparative TLC using CH2Cl2:hexane/6:4 as eluent. Range1H NMR (CDCl3, 500 MHz, 1:1 mixture of atropisomers) δ 7,86(s, 0,5H), to 7.84(s, 0,5H), 7,26-7,71 (m, 10H), 7,10 (DD, J=8,5, 3 Hz, 1H), of 6.96 (t, J=7.5 Hz, 1H), 6,86 (d, J=9 Hz, 1H), to 5.57 (d, J=8 Hz, 0,5H), 5,10 (d, J=7.5 Hz, 0,5H), of 5.05 (d, J=16 Hz, 0,5H), to 4.92 (d, J=16 Hz, 0,5H), 4,19 (d, J=15,5 Hz, 0,5H), 3,99 (d, J=16 Hz, 0,5H), 3,90(s, 1,5H), 3,88(s, 1,5H), and 3.72 (m, 1H), 0,564(d, J=6,5 Hz, L5H), and 0.40 (d, J=6,5 Hz, 1,5H).

LC-MS (M+1): 654,3.

The following compounds (table 1) are obtained by the same method, as shown in Example 1.

Table 1
ExampleR1Data LC/MS

2668,0
3 722,1
4706,0
5672,0
6of 679.2
7684,0
8688,1
9672,0
10682,5
11702,3
12671,98

13689,9
14us 726.2
15711,95
16712,2
17USD 708.3
18668,4
19668,2
20712,2

EXAMPLE 21

Stage And

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5'-bromo-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he (500 mg, 0,762 mmol), bis(pinacolato)diboron (388 mg, 1.53 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct(150 mg, 0,184 mmol), potassium acetate (150 mg, 1.53 mmol) and 1,4-dioxane (5 ml), sealed in a vessel for RF heating. The reaction mixture is subjected to RF heating to a temperature of 140°C for 40 minutes Add a further quantity of bis(pinacolato)diboron (388 mg, 1.53 mmol) and the reaction mixture is subjected to RF heating to a temperature of 140°C for 20 minutes Add a further quantity of potassium acetate (150 mg, 1.53 mmol) and the reaction mixture is subjected to RF heating to a temperature of 140°C for 20 minutes the Crude product is washed with water. The resulting mixture was extracted using EtOAc. The organic extracts are combined and dried over Na2SO4and then filtered and concentrated, gaining a solid dark color. The solid is purified preparative HPLC with reversed phase (column: Kromasil 100-5C18, 100×21,1 mm), elwira in the gradient mixture of MeCN/H2O, and get (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-it is in the form of a dark oil. JHMS: calculated = 703,22; found = 704,47 (M+1)+.

Stage

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(4,4,5,tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-she (60 mg, of 0.085 mmol), methyl 4-bromo-3-methylbenzoate (29 mg, 0,128 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (28 mg, 30%), an aqueous solution of potassium hydroxide (57 μl, 3 M, 0,171 mmol) and 1,4-dioxane (1 ml) is placed in a hermetically closed tube and subjected to RF heating to a temperature of 140°C for 15 min the Crude reaction mixture is purified by the method of preparative TLC on SiO2(elute 30%solution of EtOAc in hexane) and get methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate as a dark foam. JHMS: calculated = 725,18; found = 726,49 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ 7,94 (d, J=8.5 Hz, 1H), 7,88-7,83 (m, 2H), 7,71 (s, 0,5H), 7,69 (s, 0,5H), 7.68 per-of 7.60 (m, 2H), 7,45-7,39 (m, 2H), 7,38, 7,37 (d, J=2 Hz, 1H), 7,28 (d, J=8 Hz, 0,5H), from 7.24 (d, J=8 Hz, 0,5H), 7,14 (d, J=2 Hz, 1H), 7,07 (t, J=8 Hz, 1H), 5,58 (d, J=8,5 Hz, 0,5H), 5,28 (d, J=8 Hz, 0,5H), 4,96 (d, J=10 Hz, 0,5H), is 4.93 (d, J=9.5 Hz, 0,5H), 4,16 (d, J=15,5 Hz, 0,5H), 3.96 points (d, J=16 Hz, 0,5H), to 3.92 (s, 3H), 3,86 (s, 3H), 3,82-3,93 (m, 1H), 2,37 (s, 1,5H), 2,31 (s, 1,5H), 0,54 (d, J=6,5 Hz, 1,5H), 0,42 (d, J=6,5 Hz, 1,5H).

EXAMPLE 22

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-chloro-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

Stage And

(4S,5R)-5-[3,5-Bis(thrift rmutil)phenyl]-3-{[2'-chloro-5'-nitro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2'-iodine-5-(tri-permitil)benzyl]-4-methyl-1,3-oxazolidin-2-she (1.0 g, by 1.68 mmol), 2-chloro-5-nitrophenylacetic acid (0,67 g, 3.3 mmol), tetrakis(triphenylphosphine)palladium (97 mg, 5%mol.) and sodium carbonate (0.39 g, 3,68 mmol) in 50 ml of a mixture water:EtOH:toluene (1:2:4) is refluxed for 4 hours. Analysis by TLC (CH2Cl2:hexane/1:1) shows that the reaction is complete. The solvents are removed. Add water (30 ml). Organic matter is extracted with methylene chloride (3×40 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash chromatography using CH2Cl2:hexane/6:4 as eluent. Range1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers 8,16-8,31 (m, 1H), 8,21 (d, J=2.5 Hz, 1/2H), 8,16 (d, J=2.5 Hz, 1/2H)a, of 7.90 (s, 1H), 7,71 for 7.78 (m, 5H), 7,42-7,46 (m, 1H), to 5.66 (d, J=4.5 Hz, 1/2H), 5,64 (d, J=4.5 Hz, 1/2H), is 4.93 (d, J=15,5 Hz, 1/2H), 4,79 (d, J=16 Hz, 1/2H), a 4.03 (d, J=16hz, 1/2H), 3,94 (m, 1H), 3,91 (d, J= 15,5 Hz, 1/2H), 0,70 (d, J=6,5 Hz, 1,5H), of 0.64 (d, J=6,5 Hz, 1,5H).

Stage

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2'-chloro-5'-iodine-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

To a mixture of compound indicated in the title on the Stage And (1,14 g, 1.82 mmol)in EtOH (20 ml) at room temperature add SnCl2·H2O ( EQ.). The resulting solution was stirred at room temperature for 4 hours. Analysis by TLC (CH2Cl2:hexane/1:1) shows that the reaction is complete. Add EtOAc (50 ml). The mixture was washed with water (2×20 ml), saturated salt solution and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue was diluted with chloroform (30 ml). Add n-internetit (0,36 ml, 2,73 mmol) and iodine (0.55 g, to 2.18 mmol). The mixture with stirring, refluxed for 1 hour. The mixture is diluted with methylene chloride (30 ml). The resulting solution was pink washed with saturated sodium thiosulfate solution, saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using EtOAc:hexane/2:98 as eluent. Range1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of atropisomers of 7.90 (s, 1H), to 7.77 (s, 1H), 7,70 to 7.75 (m, 4H), of 7.65 (d, J=2.5 Hz, 1/2H), to 7.61 (d, J=2.5 Hz, 1/2H), 7,40 (m, 1H), 7,28 (m, 1H), to 5.66 (d, J=8 Hz, 1/2H), 5,64 (d, J=8 Hz, 1/2H), around 4.85 (d, J=15,5 Hz, 1/2H), 4,82 (d, J=14 Hz, 1/2H), was 4.02 (d, J=16 Hz, 1/2H), 3.96 points (m, 1/2H), 3,95 (d, J=15,5 Hz, 1/2H), 3,79 (m, 1/2H), 0,64 (d, J=6,5 Hz, 1,5 H), or 0.57 (d, J=6,5 Hz, 1,5H).

Stage C: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6'-chloro-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

A mixture of the connection specified by name on Stage (0,064 g, 0.9 mmol), 2-methylphenylimino sour is you (0,018 g, 0.14 mmol), tetrakis(triphenylphosphine)palladium (10 mg, 5%mol.) and sodium carbonate (0,048 g, 0.45 mmol) in 7 ml of a mixture water:EtOH:toluene (1:2:4) is refluxed for 2 hours. Analysis by TLC (CH2Cl2:hexane/8:2) shows that the reaction is complete. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×20 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after purification by the method of preparative TLC, using a solution of 18% EtOAc in hexane as eluent. Range1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of atropisomers 7,89 (s, 1H), 7,72 (m, 3H), 7,60 (d, J=1.5 Hz, 0,5H), 7,67,59(d, J=1.5 Hz, 0,5H), of 7.48 (m, 1H), 7,38 (m, 1H), 7,21-to 7.32 (m, 4H), 7,14 (d, J=7.5 Hz, 0,5H), 7,10 (t, J=7.5 Hz, 0,5H), 6.87 in (t, J=7.5 Hz, 0,5H), to 6.80 (d, J=7,5 Hz, 0,5H), 5,62 (t, J=8.0 Hz, 1H), 5,00 (d, J=15,5 Hz, 0,5H), of 4.83 (d, J=16 Hz, 0,5H), of 4.12 (d, J=16 Hz, 0,5H), was 4.02 (d, J=15,5 Hz, 0,5H), 3,95 (m, 0,5H), a 3.87 (m, 0,5H), 2,33 (s, 1,5H), 2,33 (s, 1,5H), and 0.61 (d, J=6,5 Hz, 1,5H), 0,57 (d, J=6,5 Hz, 1,5H).

LC-MS (M+): 672,2

EXAMPLE 23

The following connection receive the above methods (LC/MS 730,4):

The specified connection (Example 23) can also be obtained by the method described for Intermediate compounds 7 and 23:

Chiral oxazolidinone (Intermediate joint is 7) (1.35 kg) and dry DMF (30,8 l) is placed in a container with a capacity of 100 liters After cooling to a temperature in the range from minus 15 to minus 20°C added NaHMDS (1,96 l 2 M solution) and the mixture is stirred for 15-30 minutes To the resulting sodium salt oxazolidinone add triarylmethyl (Intermediate compound 23, 2.2 kg) in DMF and the mixture allowed to warm to a temperature in the range from 0 to 5°C. After triarylmethyl fully react, add 2,44 l 5 M HCl solution, and then 22 liters of 20% solution of heptane/ethyl acetate. Finally, slowly add water (11 l). The layers separated, the organic layer is washed twice with a mixture of DMF:water and then twice with water. Analyze organic layer to determine the output, and then filtered through a layer of silica gel to remove excess oxazolidinone. After that, the solvent was changed to methanol in order to use the product on other stages.

EXAMPLE 24

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4"-chloro-4'-methoxy-2-methyl-1,1':3',1"-terphenyl-4-carboxylate

Stage A: 1-bromo-2-(methyl bromide)-4-chlorobenzene

A mixture of 2-bromo-5-chlorotoluene (2.00 g, of 9.75 mmol), NBS (2,08 g, 11.7 mmol) and catalytic amount of AIBN in carbon tetrachloride (50 ml) is heated to boiling and refluxed for 4 hours. Analysis by TLC (EtOAc:hexane/5:95) shows the absence of starting substances the. The mixture is filtered and the filtrate concentrated. Specified in the title compound obtained as a solid substance of white color (2.20 g) after flash chromatography using EtOAc:hexane/5:95 as eluent. Range1H NMR (CDCl3, 500 MHz) δ 7,53 (d, J=9.0 Hz,1H), 7,47 (d, J=2.5 Hz, 1H), 7,18 (DD, J=8,5, 2.5 Hz, 1H), 4,60 (s, 2H).

Stage A: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-Chlorobenzyl)-4-methyl-1,3-oxazolidin-2-he

To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-it (0,050 g, 0.16 mmol) in THF (1 ml) at 0°With added NaH (7,6 mg, 0,19 mmol,60%). The mixture is stirred at 0°C for 30 minutes Add specified in the name of the connection on Stage And (0,059 g, 0.21 mmol). The resulting mixture was stirred at 0°C for 1 hour for 4 hours, warmed to room temperature. The reaction is interrupted with a saturated solution of ammonium chloride. Organic matter is extracted with ethyl acetate (3×15 ml). Layers ethyl acetate unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after purification by the method of preparative TLC using EtOAc:hexane/2:8 as eluent. Range1H NMR (CDCl3, 500 MHz) δ a 7.92 (s, 1H), 7,82 (s, 2H), 7,55 (d, J=8.5 Hz, 1H), 7,43 (d, J=2.5 Hz, 1H), 7.23 percent (DD, J=8,5, 2.5 Hz, 1H), 5,77(d, J=8.0 Hz, 1H), a 4.86 (d, J=16.0 Hz, 1H), 4,36 (d, J=16.0 Hz, 1H), 4,11 (m, 1H), of 0.82 (d, J=6.5 Hz, 3H).

Stage C: methyl 2"-({(4S,5R)-5-[3,5-is IP(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4"-chloro-4'-methoxy-2-methyl-1,1':3',1"-terphenyl-4-carboxylate

A mixture of the connection specified by name on Stage (0,068 g, 0.13 mmol), methyl 4'-methoxy-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (Intermediate compound 11) (0.075 g, 0,19 mmol), tetrakis(triphenylphosphine)palladium (15 mg, 5%mol.) and sodium carbonate (0.07 g, of 0.65 mmol) in 7 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 5 hours. Analysis by TLC (EtOAc:hexane/1:3) shows that the reaction is complete. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×20 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after purification by the method of preparative TLC using 10% EtOAc in hexane as eluent. Range1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of atropisomers of 7.96 (d, J=9 Hz, 1H), 7,88 (m, 2H), 7,72 (s, 1H), 7,65 (s, 1H), 7,49 (d, J=2Hz, 0,5H), 7,39 (m, 2H), was 7.36 (d, J= 2 Hz, 0,5H), 7.24 to 7,28 (m, 2H), 7,15 (m, 1H), of 7.70 (m, 1H), 5,62 (d, J=8 Hz, 0,5H), 5,52 (d, J=8 Hz, 0,5H), 4,91 (t, J=16 Hz, 1H), 4,08 (d, J=15,5 Hz, 0,5H), of 3.95 (s, 3H), 3,88 (s, 3H), a 3.87(d, J=16 Hz, 0,5H), of 3.84 (m, 1H), 2,39(s, 1,5H), 2,33 (C, 1,5H), of 0.56 (d, J=7 Hz, 1,5H), 0,43 (d, J=6,5 Hz, 1,5H).

EXAMPLE 25

The specified connection receive according to the method described in Example 24, taking as a starting compound (4S,5R)-5-[3,5-bis(chloro)phenyl]-4-methyl-1,3-oxazolidin-2-it. Range1H NMR (CDClsub> 3, 500 MHz) δ 1:1 mixture of atropisomers of 7.96 (d, J=6,5 Hz, 1H), 7,89 (DD, J=8,1 Hz, 1H), 7,45 (m, 2H), 7,34-7,40 (m, 3H), 7,22-7,31 (m, 2H), 7,13 (d, J=2,5 Hz, 0,5H), 7,12 (d, J=2,5 Hz, 0,5H), 7,01-7,07 (m, 2H), of 5.45 (d, J=8,5 Hz, 0,5H), 5,20 (d, J=8 Hz, 0,5H), 4,88 (d, J=16 Hz, 0,5H), of 4.83 (d, J=15,5 Hz, 0,5H), 4,08 (d, J=15,5 Hz, 0,5H), of 3.95 (s, 3H), a 3.87 (s, 3H), 3,85 (d, J=16 Hz, 0,5H), of 3.75 (m, 1H), of 2.38 (s, 1,5H), 2,33 (s, 1,5H), of 0.58 (d, J=6,5 Hz, 1,5H), of 0.44 (d, J=6 Hz, 1,5H).

LC-MS (M+1): 626,38

EXAMPLE 26

Methyl 2"-{[(4S,5R)-5-[3,5-dichlorophenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

(4S,5R)-5-(3,5-Dichlorophenyl)-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he (100 mg, 0,1886 mmol), methyl 4'-methoxy-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (108 mg, 0,283 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (46 mg, 0,056 mmol), aqueous sodium carbonate solution (190 μl, 2 M, 0,380 mmol) and 1,4-dioxane (2 ml) is placed in a hermetically closed tube and subjected to RF heating to a temperature of 130°C for 30 min, and then to a temperature of 135°C for 15 min to complete the reaction. The reaction mixture is purified by the method of preparative TLC on SiO2(sequentially elute 30%solution of EtOAc in hexane, 70%solution of dichloromethane in hexane, and then 80%dichloromethane solution in hexane) and get methyl 2"-{[(4S,5R)-5-[3,5-dichlorophenyl]-4-methyl-2-oxo-1,3-about Catholicon-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate in the form of a solid white color. JHMS: calculated = 657,13; found = 658,46 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ 7,94 (d, J=7 Hz, 1H), 7,87 (d, J=8,5Hz, 1H), of 7.70 (s, 0,5H), 7,65-to 7.61 (m, 1,5H), 7,47 and 7.36 (m, 3H), 7,32 (d, 7=2 Hz, 0,5H), 7,29-of 7.23 (m, 1,5H), 7,11 (DD, J=6,3, 2.0 Hz, 1H), 7,08-7,02 (m, 1,5H), 7,00 (DD, J=8,3, 2.0 Hz, 0,5H), 5,41 (d, J=8,5 Hz, 0,5H), 5,16 (d, J=8.0 Hz, 0,5H), 4,91 (d, J=16 Hz, 0,5H), is 4.85 (d, J=16.5 Hz, 0,5H), 4,17 (d, J=16 Hz, 0,5H), 3,98-3,90 (m, 3,5H), 3,856, 3,851 (s, 3H), 3,74-3,66 (m, 1H), 2,36, 2,32 (s, 3H), of 0.55 (d, J=7 Hz, 1,5H), 0,43 (d, J=6 Hz, 1,5H).

EXAMPLE 27

Stage And

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl)-3-(2-bromo-5-terbisil)-4-methyl-1,3-oxazolidin-2-he

To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-she (2.0 g, to 6.39 mmol) in THF (40 ml) at 0°C in one step add NaH (285 mg, 60% wt. in mineral oil, 7,13 mmol,1.1 EQ.). The obtained foamed mass is stirred while cooling in a bath with ice. The reaction mixture was added an additional amount of THF (50 ml). The reaction mixture was stirred at 0°C for 30 minutes, Add a solution of 2-bromo-5-ftorangidridy (1,712 g, to 6.39 mmol) in THF (20 ml). The resulting mixture upon cooling, stirred for 30 min, and then allow it to warm to room temperature. The reaction is finished after 3 hours. The reaction is interrupted with NH4Cl (saturated is odny solution 80 ml). Volatiles removed in vacuum. The reaction mixture was extracted with EtOAc and dried over Na2SO4. The residue is purified flash chromatography on SiO2(cartridge Biotage 40+M, spend gradient elution with mixture of EtOAc/hexane). (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl)-3-(2-bromo-5-terbisil)-4-methyl-1,3-oxazolidin-2-he receives in the form of a clear oil. LC-MS: 500,09 (M+1)+. Range1H NMR (CDCl3, 500 MHz) δ 7,88 (s, 1H), 7,79 (s, 2H), 7,55 (DD, J=8,8, 5,2 Hz, 1H), 7,17 (DD, J=8,7, and 4.5 Hz, 1H), 6,95 (m, 1H), 5,74 (d, J=8.0 Hz, 1H), a 4.83 (d, J=15,8, 1H), 4,54 (d, J=16.0 Hz, 1H), 4,11 (m, 1H), 0,80 (d, J=6.6 Hz, 3H).

Stage

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl)-3-[(5'-bromo-4-fluoro-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-he

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluoro-benzyl)-4-methyl-1,3-oxazolidin-2-er (600 mg, 1.2 mmol), (5-bromo-2-methoxyphenyl)baronova acid (319 mg, 1.38 mmol), an aqueous solution of sodium carbonate (1,27 ml, 2 M, 2.54 mmol), toluene (3.5 ml) and ethanol (400 μl) is mixed and stirred at room temperature for 45 min, and then added tetrakis(triphenylphosphine)palladium(0) (87 mg, and 4.5 mol%). The mixture to complete the reaction is heated on an oil bath to a temperature of 90°C for 24 hours. The crude reaction mixture is diluted with saturated salt solution and extracted with ethyl acetate. The extracts are combined, dried over Na2SO 4and then filtered and concentrated in vacuo, obtaining oil is dark in color. Crude oil is purified preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), performing a gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./about.) get (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl)-3-[(5'-bromo-4-fluoro-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-it. JHMS: calculated = 607,04; found = 607,98 (M+1)+.

Stage C: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-fluoro-6'-methoxy-2"-methyl-1,1':3',1"-terphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-he

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl)-3-[(5'-bromo-4-fluoro-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-he (50 mg, 0,082 mmol), (2-were)baronova acid (22 mg, 0,165 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (20 mg, 0,024 mmol), aqueous solution potassium hydroxide (55 μl, 3 M, 0,165 mmol) and 1,4-dioxane (1 ml) is placed in a hermetically closed tube and subjected to RF heating to a temperature of 140°C for 20 min to complete the reaction. The reaction mixture is purified by the method of preparative TLC on SiO2(elute 20%solution of EtOAc in hexane) and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-fluoro-6'-methoxy-2"-methyl-1,1':3',1"-terphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-it is in the form of a transparent glassy substance. JHMS: calculated = 617,18; found = 618,16 (M+1)+. The signal SP is CTRE 1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ to 7.84 (s, 1H), 7,68 (s, 1H), 7.62mm (s, 1H), was 7.36-7,32 (m, 1H), 7,30-7,22 (m, 4H), 7,22-to 7.18 (m, 1,5H), 7.18 in-7,14 (m, 0,5H), 7,14-7,11 (m, 1H), 7,11-7,05 (m, 1H), 7,02 (t, J=8.0 Hz, 1H), 5,58 (d, J=8,5 Hz, 0,55H), 5,28 (d, J=8 Hz, 0,45H), the 4.90 (d, J=3.5 Hz, 0,45H), 4.09 to (d, J=15,5 Hz, 0,45H), 3,88 (d, J=16.5 Hz, O,55H), 3,844, 3,838 (s, 3H), 3,82 of 3.75 (m, 1H), 2,32, of 2.56 (s, 3H), 0,52 (d, J=6,5 Hz, 1,35H), 0,38 (d, J=6,5 Hz, 1,65H).

EXAMPLE 28

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-fluoro-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

Stage And

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl)-3-{[5'-bromo-2'-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl)-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he (500 mg, 0,837 mmol) is mixed with (5-bromo-2-forfinal)Bronevoy acid (211 mg, 0,963 mmol), toluene (5 ml), ethanol (278 μl) and an aqueous solution of sodium carbonate (2 M, of 0.89 ml, 1.78 mmol). The resulting mixture was stirred at 20°C for 30 min, and then added tetrakis(triphenylphosphine)palladium(0) (43,5 mg, 0,0376 mmol,4,5%mol.). The mixture to complete the reaction is heated on an oil bath to a temperature of 90°C for 40 hours. The reaction mixture was purified flash chromatography (SiO2cartridge Biotage 40+M). Column elute with a mixture of ethyl acetate/hexane. Choosing the appropriate fractions are combined and concentrated in vacuo, receiving (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl)-3-{[5'-bromo-2'-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-it. JHMS: calculated = 645,02; found = 645,94 (M+1)+.

Stage A: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-fluoro-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl)-3-{[5'-bromo-2'-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he (79 mg, 0,123 mmol), (2-were)baronova acid (25 mg, of 0.182 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (10 mg, 0,0122 mmol), an aqueous solution of potassium hydroxide (82 μl, 3 M, 0,246 mmol) and 1,4-dioxane (1 ml) is placed in a hermetically closed tube and subjected to RF heating to a temperature of 140°C for 15 min to complete the reaction. The crude reaction mixture is purified by the method of preparative TLC on SiO2(elute 30%solution of EtOAc in hexane) and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6'-fluoro-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-it is in the form of a transparent glassy substance. JHMS: calculated = 655,16; found = 656,11 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ 7,86 (s, 1H), 7,73 (s, 1H), 7,72-7,66 (m, 2H), of 7.48 (d, J=8 Hz, 1H), 7,41 and 7.36 (m, 1H), 7,29-of 7.23 (m, 4H), 7,19-of 7.23 (m, 3H), 5.56mm (Shir. s, 1H), 4,96 (Shir. s, 1H), 4,13 (Shir. d, J=46,5 Hz, H), 3,83 (Shir. d, J=43,5 Hz, 1H), to 2.29 (s, 3H), 0,56, 0,51 (Shir. s, 3H).

EXAMPLE 29

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-6'-methoxy-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl)-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-it (0,050 g 0,084 mmol), 2-methoxy-4-fluoro-5-(2'-were)Bronevoy acid (excess), tetrakis(triphenylphosphine)palladium (5 mol%) and sodium carbonate (19.5 mg, 0.18 mmol) in 7 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 4 hours. Analysis by TLC (CH2Cl2:hexane/1:1) shows that the reaction is complete. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using CH2Cl2:hexane/6:4 as eluent. LC-MS (M+1): 686,1.

EXAMPLE 30

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifter-m is Teal)-1,1':3',1"-terphenyl-4-carboxylate (20 mg, 0,0276 mmol), aqueous potassium hydroxide solution (300 μl, 3 M, 0.90 mmol) and ethanol (2 ml) is stirred at 20°C for 2 hours and 20 minutes to complete the hydrolysis. The reaction mixture is acidified with acetic acid. The mixture was purified preparative TLC on silica gel (elute with a mixture of Asón/EtOAc/hexane = 5/25/70, vol./about.) and get 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}IU-Tyl)-4'-methoxy-2-methyl"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. JHMS: calculated = 711,17; found = 712,10 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ to 7.99 (d, J=8.0 Hz, 1H), 7,92 (d, J=8.5 Hz, 1H), a 7.85 (d, J=5 Hz, 1H), 7,72-to 7.68 (m, 1,5H), to 7.67-of 7.60 (m, 2,5H), 7,47 and 7.36 (m, 2H), 7,32 (d, J=8.0 Hz, 0,5H), 7,28 (d, J= 8.0 Hz, 0,5H), to 7.15 (s, 1H), was 7.08 (d, J=8,5, 7,0 Hz, 1H), 5,58 (d, J=8.0 Hz, 0,5H), from 5.29 (d, J=6,5 Hz, 0,5H), equal to 4.97 (d, J=15,5 Hz, 0,5H), 4,94 (d, J=14 Hz, 0,5H), 4,16 (d, J=16 Hz, 0,5H), of 3.96 (d, J=15,5 Hz, 0,5H), a 3.87 (s, 3H), 3,83-3,74 (m, 1H), 2,38, of 2.33 (s, 3H), of 0.55 (d, J=6,5 Hz, 1,5H), 0,42 (d, J=1 Hz, 1,5H).

EXAMPLE 31

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-2-carboxylic acid

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-2-carboxylate (50 mg, 0.07 mmol), aqueous solution of potassium hydroxide (1.1 ml, 3 M, 3.3 mmol), water (1,5 ml) and ethanol (3,6 ml) is stirred at 20°C for 23 hours. The reaction mixture is acidified with HCl (aqueous solution, 1N). Volatiles are removed under reduced pressure. The resulting mixture was extracted with ethyl acetate and washed with a saturated solution of salt. The combined organic extracts dried over Na2SO4, filtered and concentrated, obtaining oil. Specified oil purified preparative HPLC with reversed phase (column: Kromasil 100-5C18, 100×21,1 mm)through gradient elution with a mixture of MeCN (0,1% vol./about. TFA buffer)/N2On (0,1% vol./about. TFA buffer), and get 2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-2-carboxylic acid. JHMS: calculated = 697,15; found = 698,16 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ 7,94 (t, J=7,0 Hz, 1H), a 7.85 (d, J=7,0 Hz, 1H), 7.68 per-7,63 (m, 2,5H), 7,63-to 7.59 (m, 1,5H), to 7.59-rate of 7.54 (m, 1H), 7,47-7,35 (m, 4H), 7,14 (DD, J=8,0, 2.0 Hz, 1H),? 7.04 baby mortality (d, J=8.5 Hz, 1H), of 5.53 (d, J=8,0 Hz, 0,4H), 5,42 (d, J=8.0 Hz, 0,6H), 5,02 (d, J=15,5 Hz, 0,6H), is 4.85 (d, J=15,5 Hz, 0,4H), 4,11-was 4.02 (m, 0,4H), a 3.87-of 3.77 (m, 3,6H), 0,99 (d, J=6,5 Hz, 0,6H), of 0.93 (d, J=7,0 Hz, 0,4H), of 0.58 (d, J=7,0 Hz, 1,2H), 0,54 (d, J=6,5 Hz, 1,8H).

EXAMPLE 32

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-3-carboxylic acid

Specified in the title compound from Example 15 ostal the Ute overnight at room temperature, mixed with LiOH (3 EQ.) in a mixture of 2:1 dioxane and water. The solvent is removed and the aqueous solution acidified with 1N HCl solution to pH ~4. The mixture is extracted with EtOAc (3×10 ml). Layers EtOAc combined and dried over sodium sulfate. Specified in the title compound obtained after preparative TLC on silica gel using EtOAc:hexane/1:1 as eluent. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric 8,32 (s, 0,5H), 8,29 (s, 0,5H), 8,08 (m, 1H), 7,46-a 7.85 (m, 10H), 5,61 (d, J=8 Hz, 0,5H), 5,20 (d, J=8 Hz, 0,5H), 5,04 (d, J=16 Hz, 0,5H), of 4.95 (d, J=15,5 Hz, 0,5H), to 4.17 (d, J=16 Hz, 0,5H), of 3.97 (d, J=15,5 Hz, 0,5H), 3,91 (s, 1,5H), 3,83 (s, 1,5H), with 3.79 (m, 1H), 0,58 (d, J=6,5 Hz, 1,5H), 0,42 (d, J=6,5 Hz, 1,5H).

LC-MS (M+1): 698,18.

EXAMPLE 33

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (10 mg, 0.014 mmol), aqueous potassium hydroxide solution (150 μl, 3 M, 0.45 mmol) and ethanol (1 ml) is stirred at 20°C for 2 hours and 30 minutes to complete the hydrolysis. The reaction mixture is acidified with HCl (aqueous solution, 1N), and then alkalinized with sodium bicarbonate. Volatiles are removed under reduced pressure. The resulting mixture was extracted with ethyl acetate and washed with a saturated solution of salt. United'or is adicheskie extracts dried over Na 2SO4, filtered and concentrated, obtaining oil. Specified oil purified preparative TLC on silica gel (elute with 50% EtOAc in hexane) and get 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. JHMS: calculated = 697,15; found = 698,03 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ 8,16-8,11 (m, 2H), 7,83 (d, J=8.0 Hz, 1H), 7,74-of 7.69 (m, 2H), 7,69-the 7.65 (m, 2,5H), 7,65-to 7.61 (m, 1,5H), EUR 7.57 (s, 1H), of 7.48-7,42 (m, 2,0H), 7,11 (DD, J=8,8, 2.5 Hz, 1H), to 5.57 (d, J=8.0 Hz, 0,5H), to 5.17 (d, J=8.0 Hz, 0,5H), equal to 4.97 (d, J=15,5 Hz, 0,5H), is 4.93 (d, J=15,5 Hz, 0,5H), 4,16 (d, J=16 Hz, 0,5H), 3,95 (d, J=16.0 Hz, 0,5H), 3,88, a 3.87 (s, 3H), 3,80-and 3.72 (m, 1H), 0,55 (d, J=6,5 Hz, 1,5H), 0,41 (d, J=6,5 Hz, 1,5H).

EXAMPLE 34

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (25 mg, 0,034 mmol), aqueous potassium hydroxide solution (300 μl, 3 M, 0.90 mmol) and ethanol (2 ml) leave at night mixed at a temperature of 20°C. Volatiles are removed under reduced pressure. The resulting residue is treated with saturated salt solution and extracted with ethyl acetate. the joint extracts dried over Na 2SO4, filtered and concentrated in vacuo, obtaining oil. Specified oil purified preparative TLC on SiO2(elute 50% EtOAc in hexane) and get a clear oil. Specified oil additionally purified preparative HPLC with reversed phase (column: Kromasil 100-5C18, 100×21,1 mm)through gradient elution with a mixture of MeCN (0,1% vol./about. TFA)/N2On (0,1% vol./about. TFA), and get 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. JHMS: calculated = 715,12; found = 716,12 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ to 7.99 (d, J=8.0 Hz, 1H), 7,92 (d, J=8.5 Hz, 1H), a 7.85 (d, J=5 Hz, 1H), 7,72-to 7.68 (m, 1,5H), to 7.67-of 7.60 (m, 2,5H), 7,47 and 7.36 (m, 2H), 7,32 (d, J=8.0 Hz, 0,5H), 7,28 (d, J=8.0 Hz, 0,5H), to 7.15 (s, 1H), was 7.08 (DD, J=8,5, 7,0 Hz, 1H), 5,58 (d, J=8.0 Hz, 0,5H), from 5.29 (d, J=6,5 Hz, 0,5H), equal to 4.97 (d, J=15,5 Hz, 0,5H), 4,94 (d, J=14 Hz, 0,5H), 4,16 (d, J=16 Hz, 0,5H), of 3.96 (d, J=15,5 Hz, 0,5H), a 3.87 (s, 3H), 3,83-3,74 (m, 1H), 2,38, of 2.33 (s, 3H), of 0.55 (d, J=6,5 Hz, 1,5H), 0,42 (d, J=7 Hz, 1,5H).

The above compound (example 34) was obtained from its methyl ester (Example 23) by the following procedure:

In a vessel with a capacity of 75 litres, equipped with a top stirrer, a thermocouple, a pipe for input of nitrogen, a dropping funnel and a shirt with a steam heating, which contains approximately 12 l methanolic solution of methyl e is the Ira of trialisation (Example 23, 2190 g, 3 mol), placed THF (12 l). Add hydrogen peroxide (1800 ml of 35%aqueous solution. The addition is accompanied by an exothermic reaction so that the temperature of the mixture rises from 16°C to 23°C.

Then the reaction vessel was placed a monohydrate of lithium hydroxide (378 g, 9 mol) and the reaction mixture heated to 60°C. the reaction course is monitored by HPLC; the reaction ends after 15-16 hours. The reaction mixture is cooled to 0-10°C. and added slowly an aqueous solution of sodium bisulfite (2185 g approximately 18 liters of water)to decompose hydrogen peroxide. The addition is accompanied by a vigorous exothermic reaction. The absence of hydrogen peroxide confirm using indicator papers EM Quant Peroxide.

Next add MTBE (22 l) GMP and water (8 l) and the mixture is transferred into the reactor with a capacity of 100 liters of Bottom water layer in the reactor is removed and the upper organic layer is washed with 10%solution of salt (2010 NaCl at about 18 l of water GMP). The bottom layer was removed and the cloudy organic layer is dried over anhydrous sodium sulfate.

The dried organic phase with built-in filter (1 micron) filter in a vessel with a capacity of 100 l, connected to a hub. MTBE is removed and replaced by cyclohexane. The volume was adjusted to 20 L. the Mixture is heated to 50-65°C to completely dissolve any precipitated in the sludge solids, and then ohla the give about 60°C and make the seed crystals, obtained from a previous batch. The solution is left overnight to cool to room temperature and get a solid white color. Specified white solid is separated by filtration, washed with 2×2 l of cyclohexane and dried in a nitrogen atmosphere under vacuum.

Obtained in this way solid carboxylic acid is a mixture of anhydrous product and MES with cyclohexane (typically 3-5% cyclohexane), MES transferred to the anhydrous product by drying in a vacuum thermal cupboard at a temperature of 110-135°C, the exact temperature depends on the design and size of the used thermal Cabinet.

EXAMPLE 35

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-chloro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage A: methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-chloro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

A mixture of Intermediate 9 (0.1 g), Intermediate 10 (0.1 g, 0.25 mmol), tetrakis(triphenylphosphine)palladium (5 mol%) and sodium carbonate (58 mg, 0.55 mmol) in 7 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 2 hours. Analysis by TLC (EtOAc:hexane/1:9) shows that the reaction is complete. Rest ritali removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×15 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using CH2Cl2:hexane/8:2 as eluent. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric 7,10-to 8.20 (m, N), the ceiling of 5.60 (d, J=8,5 Hz, 0,5H), from 5.29 (d, J=8 Hz, 0,5H), free 5.01 (d, J=16.5 Hz, 0,5H), equal to 4.97 (d,J=16.5 Hz, 0,5H), is 4.21 (d, J=16 Hz, 0,5H), 4.00 points (d, J=16 Hz, 0,5H), of 3.97 (s, 3H), 3,91 (s, 1,5H), 3,90 (s, 1,5H), of 3.78 (m, 1H), 0,55 (d, J=7 Hz, 1,5H), 0,43 (d, J=6,5 Hz, 1,5H).

Stage b: 2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-chloro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Specified in the title compound from Example 25 leave for the night mixed with LiOH (5 EQ.) in a mixture of 2:1 dioxane and water at room temperature. The solvent is removed and the aqueous solution is acidified with 1N HCl solution to pH ~4. Organic matter extracted with EtOAc (3×10 ml). Layers EtOAc combined and dried over sodium sulfate. Specified in the title compound obtained after preparative HPLC with reversed phase. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric 8,21 (d, J=12 Hz, 1H), 8,04 (d, J=8 Hz, 1H), 7,87 (d, J=5.5 Hz, 1H), 7,76 (s, 0,5H), 7,72 (s, 1H), 7,69 (s, 0.5 H), to 7.67 (d, J=3.5 Hz, 1H), 7,65 (s, 1H), 7,44-7,58 (m, 3H, 7,37 (d, J=2 Hz, 0,5H), 7,35 (d, J=0.5 Hz, 0,5H), 7,13 (d, J=4 Hz, 0,5H), 7,12 (d, J=5 Hz, 0,5H), 5,61 (d, J=8 Hz, 0,5H), and 5.30 (d, J=12,5 Hz, 0,5H), free 5.01 (d, J=12,5 Hz, 0,5H), to 4.98 (d, J=13 Hz, 0,5H), is 4.21 (d, J=15,5 Hz, 0,5H), 4.00 points (d, J=16hz, 0,5H), 3,91 (s, 1,5H), 3,90 (s, 1,5H), 3,80 (m, 1H), 0,56 (d, J=6,5 Hz, 1,5H), of 0.44 (d, J=6,5 Hz, 1,5H).

LC-MS (M+1): 732,1.

EXAMPLE 36

Specified in the title compound from Example 24 leave for the night mixed with LiOH (3 EQ.) in a mixture of 2:1 dioxane and water at room temperature. The solvent is removed and the aqueous solution is acidified with 1N HCl solution to pH ~4. Organic matter extracted with EtOAc (3×10 ml). Layers EtOAc combined and dried over sodium sulfate. Specified in the title compound obtained after preparative TLC plates using EtOAc:hexane/1:1 as eluent. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric 8,02 (d, J=7.5 Hz, 1H), 7,95 (d, J=7.5 Hz, 1H), 7,87 (s, 1H), 7,72 (s, 1H), 7,66 (s, 1H), 7,49 (s, 1H), 7.24 to 7,41 (m, 4H), to 7.15 (s, 1H), was 7.08 (d, J= 7 Hz, 0,5H), 7,06 (d, J=8 Hz, 0,5H), 5,62 (d, J=8,5Hz, 0,5H), to 5.35 (d, J=8 Hz, 0,5H), is 4.93 (d, J=16 Hz, 0,5H), of 4.90 (d, J=15,5 Hz, 0,5H), 4,08 (d, J=15,5 Hz, 0,5H), 3,88 (s, 3H), 3,85 (m, 1,5H), 2,39 (s, 1,5H), was 2.34 (s, 1,5H), 0,57 (d, J=6,5 Hz, 1,5H), of 0.44 (d, J=6,5 Hz, 1,5H).

LC-MS (M+1): 678,3.

EXAMPLE 37

Specified in the title compound from Example 25 leave for the night mixed with LiOH (3 EQ.) in a mixture of 2:1 dioxane and water at room temperature. The solvent is removed the aqueous solution is acidified with 1N HCl solution to pH ~4. Organic matter extracted with EtOAc (3×10 ml). Layers EtOAc combined and dried over sodium sulfate. Specified in the title compound obtained after preparative TLC plates using EtOAc:hexane/1:1 as eluent. LC-MS (M+1): 612,0.

EXAMPLE 38

2"-{[(4S,5R)-5-(3,5-Dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Methyl 2"-{[(4S,5R)-5-[3,5-dichlorophenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (Example 26) (50 mg, 0,076 mmol), aqueous potassium hydroxide solution (600 μl, 3 M, 1.8 mmol) and ethanol (4 ml) is stirred at 20°C for 6 hours. The reaction mixture is acidified with HCl (aqueous solution, 1N), and then alkalinized with sodium bicarbonate. Volatiles are removed under reduced pressure. The resulting mixture was extracted with ethyl acetate and washed with a saturated solution of salt. The organic extracts are combined and dried over Na2SO4, filtered and concentrated, obtaining oil. Specified oil purified preparative TLC (elute with a mixture of EtOAc/hexane) and get 2"-{[(4S,5R)-5-[3,5-dichlorophenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. JHMS: calculated = 643,11; found = 644,14 (M+1) +. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ 8,01 (d, J=5.5 Hz, 1H), 7,94 (d, J=8.0 Hz, 1H), of 7.70 (s, 1H), 7,65-to 7.61 (m, 1,5H), 7,44-7,37 (m, 3H), 7,34-7,31 (m, 1H), 7,29 (d, J=8.0 Hz, 0,5H), 7,29 (d, J=8.0 Hz, 0,5H), 7,27-7,24 (m, 0,5H), 7,14 (DD, J=7,0, 2.5 Hz, 1H), to 7.09-7.03 is (m, 1,5H), 7,00 (DD, J=8,25, 2.0 Hz, 1H), 5,42 (d, J=8,5 Hz, 0,55H), to 5.17 (d, J=8.0 Hz, 0,45H), to 4.92 (d, J=16.0 Hz, 0,55H), a 4.86 (d, J=16.0 Hz, 0,45H), 4,18 (d, J=15,5 Hz, 0,55H), of 3.96 (d, J=15,5 Hz, 0,45H), 3,86 (s, 3H), 3.75 to 3,66 (m, 1H), 2,38, was 2.34 (s, 3H), of 0.56 (d, J=6,5 Hz, 1,35H), of 0.44 (d, J=6,5 Hz, 1,65H).

EXAMPLE 39

5-[2'-{[(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]-6-methylpyridin-2-carboxylic acid

Stage And

5-(4-methoxyphenyl)-6-methylpyridin-2-amine

(4-Methoxyphenyl)baronova acid (1 g, to 6.58 mmol), 5-bromo-6-methylpyridin-2-amine (1.23 g, to 6.58 mmol), 1,1'-bis(diphenyl-phosphino)ferrocene-palladium dichloride dichloromethane adduct (537 mg, 0,658 mmol), potassium acetate (1.29 g, 13,16 mmol) and 1,4-dioxane (5 ml) is placed in a hermetically closed tube and the mixture is subjected to RF heating to a temperature of 140°C for 30 min the Crude reaction mixture was purified column flash chromatography on SiO2(cartridge Biotage 40+M in ethyl acetate) and receive 5-(4-methoxyphenyl)-6-methylpyridin-2-amine in the form of a solid pink color. JHMS: calculated = 214,11; found =215,17 (M+1) +.

Stage

6-Iodine-3-(4-methoxyphenyl)-2-methylpyridin

5-(4-Methoxyphenyl)-6-methylpyridin-2-amine (500 mg, of 2.33 mmol) and iodine (710 mg, 2.8 mmol) was stirred in chloroform (10 ml) at room temperature for 12 min, and then add n-amyl nitrite (545,9 mg of 4.66 mmol). The resulting mixture is heated on an oil bath to 82°C for 1.5 hours to complete the conversion. The reaction is interrupted by adding saturated aqueous solution of Na2S2O3. The reaction mixture is extracted with dichloromethane. The organic extracts are combined and dried over Na2SO4and then filtered and concentrated. The resulting residue is purified column flash chromatography on SiO2(cartridge Biotage 40+M, gradient elution in a mixture of dichloromethane/hexane) and receive a yellow oil. The specified oil is further purified by the method of preparative TLC on SiO2(elute 80%dichloromethane in hexane) and receive a 6-iodine-3-(4-methoxyphenyl)-2-methylpyridin. JHMS: calculated = 325,00; found = 326,06 (M+1)+.

Stage

Benzyl 5-(4-methoxyphenyl)-6-methylpyridin-2-carboxylate

6-Iodine-3-(4-methoxyphenyl)-2-methylpyridine (100 mg, 0,308 mmol), bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0,031 mmol), triethylamine (46,7 mg, 0,462 mmol) and benzyl alcohol (1 ml, to 9.66 mmol) mix the acetonitrile (3 ml). The mixture for 18 hours placed in an atmosphere of carbon monoxide under a pressure of 45 pounds per square inch at a temperature of 60°C. the reaction mixture is purified by the method of preparative TLC on SiO2(elute with 25% ethyl acetate in hexane, then 10% of triethylamine, 20% ethyl acetate in hexane) and receive benzyl 5-(4-methoxyphenyl)-6-methylpyridin-2-carboxylate. JHMS: calculated = 333,14; found = 334,13 (M+1)+.

Stage D

Benzyl 5-(3-iodine-4-methoxyphenyl)-6-methylpyridin-2-carboxylate

Benzyl 5-(4-methoxyphenyl)-6-methylpyridin-2-carboxylate (150 mg, 0.45 mmol), iodine (228 mg, 0,898 mmol), silver sulfate (402 mg, 1,29 mmol) leave much to be mixed in methanol (3 ml) overnight at room temperature. After 25 hours, the reaction mixture was additionally added iodine (57 mg, 0.22 mmol) and silver sulfate (100 mg, 0.32 mmol). After 1.5 hours the reaction mixture was added an aqueous solution of NaHSO3(saturated solution, 20 ml)to terminate the reaction. The reaction mixture was extracted with ethyl acetate. The extracts are combined and dried over Na2SO4and then filtered and concentrated, obtaining a clear oil. The crude oil purified by the method of preparative TLC on SiO2(elute 30% ethyl acetate in hexane) and receive benzyl 5-(3-iodine-4-methoxyphenyl)-6-methylpyridin-2-carboxylate. JHMS: calculated = 459,03; found = 460,17 (M+1)+

Stage E

Benzyl 5-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]-6-methylpyridin-2-carboxylate

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-it - methane (385 mg, 0,644 mmol) (Intermediate compound 9), benzyl 5-(3-iodine-4-methoxyphenyl)-6-methylpyridin-2-carboxylate (148 mg, 0,322 mmol), 1,1'bis(diphenylphosphino)ferrocene-palladium dichloride (71 mg, 0,097 mmol), aqueous solution of potassium hydroxide (215 μl, 3 M, to 0.645 mmol) and 1,4-dioxane (2 ml) is placed in the tube. The vessel is rinsed with nitrogen and sealed. The reaction mixture is subjected to RF heating to a temperature of 120°C for 20 min, and then to a temperature of 140°C for 30 minutes To the reaction mixture are added water and then extracted with ethyl acetate. The extracts are combined and dried over Na2SO4and then filtered and concentrated in vacuo, obtaining oil is dark in color. Specified oil cleanse method preparative TLC on SiO2(elute 45% ethyl acetate in hexane) and get oil dark color. The oil obtained is further purified preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), performing a gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./about). The appropriate fractions unite and evaporated, receiving the oil is dark in color. The resulting oil is treated with an aqueous solution of sodium bicarbonate (saturated solution), and then extracted with ethyl acetate. The extracts are combined and dried over Na2SO4and then filtered and concentrated in vacuo, obtaining oil is dark in color. This oil still contains alkaline impurities. The oil obtained is again purified by the method of preparative TLC on SiO2(elute 50% ethyl acetate in hexane) and receive benzyl 5-[2'-{[(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]-6-methylpyridin-2-carboxylate. JHMS: calculated = 802,21; found = 803,21 (M+1)+.

Stage F: 5-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]-6-methylpyridin-2-carboxylic acid

Benzyl 5-[2'-{[(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]-6-methylpyridin-2-carboxylate (52 mg, 0,065 mmol) and palladium/activated carbon (10% wt.) (25 mg) are mixed in ethanol. The resulting mixture Tegaserod and serves N2under pressure of 45 pounds per square inch at room temperature for 3 h in a Parr apparatus in the rocking chair until the reaction is complete. The reaction mixture was filtered through celite (521). The filtrate was concentrated in vacuo and get a stack is noobraznoe substance light brown color. The residue is purified preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), performing a gradient elution in a mixture of MeCN/H2O. the Appropriate fractions are collected and combined and then evaporated, obtaining water-containing residue. The obtained residue lyophilized and get 5-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]-6-methylpyridin-2-carboxylic acid. JHMS: calculated = 712,16; found = 713,19 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ 8,07 (s, 1H), 7,86 (s, 1H), to 7.77 (s, 1H), 7,71 to 7.62 (m, 4H), 7,45 was 7.36 (m, 2H), 7,19-7,07 (m, 2H), of 5.55 (d, J=7,0 Hz, 0,55H), 5,42 (d, J=7 Hz, 0,45H), 4,99 (d, J=13 Hz, 0,5H), is 4.85 (d, J=12,5 Hz, 0,5H), 4,14 (d, J=13.5 Hz, 0,5H), 3,95 (d, J=13.5 Hz, 0,5H), 3,92-of 3.80 (m, 4H), 2,61, of 2.58 (s, 3H), of 0.58 (d, J=5.0 Hz, 1,35H), 0,49 (d, J=5.5 Hz, 1,65H).

EXAMPLE 40

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6 ' -iodine-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage And

2-Methyl-4-triptorelin

A mixture of 2-iodine-4-triptorelin (5.0 g, 17,42 mmol), trimethylboroxine (3,64 ml of 26.1 mmol), tetrakis(triphenylphosphine)palladium (1.0 g, 0.87 mmol) and potassium carbonate (4,82 g, 34,8) in DMF (10 ml) is heated to 100°C for 48 hours. The reaction abortion is jut, adding water (50 ml), and extracted with EtOAc (3×50 ml). Layers EtOAc unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using EtOAc:hexane/1:9 as eluent. Range1H NMR (CDCl3, 500 MHz) δ 7,13 (s, 1H), 7,30 (d, J=8 Hz, 1H), of 6.71 (d, J=8 Hz, 1H), 3,98 (Shir. s,2H), of 2.21 (s, 3H).

Stage b: 2-methyl-4-triptoreline iodide

To a solution of 2-methyl-4-triptorelin (stage A) (2.2 g, 12.6 mmol) in chloroform (20 ml) at room temperature add p-internetit (2.2 g, to 18.9 mmol) and iodine (6,38 g, a 25.1 mmol). The mixture is refluxed for 1 hour. Dilute the mixture with methylene chloride (50 ml). The resulting solution was washed with saturated aqueous sodium thiosulfate, saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using hexane as eluent.

Stage C: 2-methyl-4-trifluoromethyl-6-nitrophenyl iodide

A mixture of 1:1 H2SO4/HNO3(20 ml) at 0°C is added to 2-methyl-4-triptoreline the iodide. The mixture was stirred at 0°C. and then left overnight to warm to room temperature. Analysis by LC/MS shows the absence of starting materials. The mixture is diluted with water and extracted with EtOAc (3×50 ml). Layers tOAc unite, washed with sodium bicarbonate solution and a saturated saline solution and then dried over sodium sulfate. Specified in the title compound is obtained after the removal of solvent. Range1H NMR (CDCl3, 500 MHz) δ 7,71 (s, 1H), 7,69 (s, 1H), 2,68 (s, 3H).

Stage D

1-(methyl bromide)-2-iodine-3-nitro-5-(trifluoromethyl)benzene

A mixture of the connection specified by name on Stage With (0,38 g, 1.15 mmol), NBS (0.24 g, 1.38 mmol) and catalytic amount of AIBN in carbon tetrachloride (5 ml) is refluxed for 3 days. During this period daily add an additional amount of AIBN. The mixture is cooled and concentrated. Specified in the title compound is obtained after flash column-chromatography using hexane as eluent. Range1H NMR (CDCl3, 500 MHz) δ to $ 7.91 (s, 1H), 7,80 (s, 1H), and 4.75 (s, 2H).

Stage E

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-iodine-3-nitro-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he

To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-she (0.14 g, 0.44 mmol) in THF (3 ml) at 0°C. add NaH (21 mg, of 0.53 mmol,60%). The mixture is stirred at 0°C for 30 minutes, Add a solution of the compound indicated in the title at the Stage D (0.15 g, of 0.37 mmol)in THF (1 ml). The mixture is left overnight to mix in to the room temperature. The reaction is interrupted by adding saturated aqueous solution of ammonium chloride (5 ml) and extracted with EtOAc (3×15 ml). Layers EtOAc unite, washed with saturated salt solution and then dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using EtOAc:hexane/15:85 as eluent. Range1H NMR (CDCl3, 500 MHz) δ of 7.95 (s, 1H), 7,87(d, J=1.5 Hz, 1H), 7,83 (s, 2H), 7,79 (d, J=1.5 Hz, 1H), of 5.83 (d, J=8 Hz, 1H), 4.95 points (d, J=16.5 Hz, 1H), 4,53 (d, J=16.5 Hz, 1H), 4,19 (m, 1H), 0,87 (d, J=6.5 Hz, 3H).

Stage F

Methyl 2-amino-6"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

To a solution of the compound indicated in the title at the Stage E (0.17 g, 0.26 mmol)in EtOH (5 ml), add chloride dihydrate tin (0,30 g of 1.32 mmol). The mixture is stirred at room temperature for 4 hours. Analysis by LC-MS shows complete consumption of the starting materials. EtOH is removed. To the residue add EtOAc (20 ml). The mixture is washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive a solid white color that is mixed with methyl 4'-methoxy-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (Intermediate compound 11, excess), tetrakis(trifinio the fin)palladium (5 mol%) and sodium carbonate (0,062 g, of 0.58 mmol) in 7 ml of a mixture of water/EtOH/toluene (1:2:4) and refluxed for 2 hours. Analysis by TLC (EtOAc:hexane/1:3) shows that the reaction is complete. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×20 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after purification by the method of preparative TLC using 20% EtOAc in hexane as eluent. Range1H NMR (CDCl3, 500 MHz) δ blend 2:1: atropoisomeric of 7.96 (m, 1H), 7,88 (m, 2H), 7,73 (s, 0,66H), 7,66 (s, 0,33H), 7,44 (m, 1H), 7,28 (m, 2H), 7,16 (m, 2H), 7,02-7,07 (m, 2H), 5,59 (d, J=8 Hz, 0,66H), 5,42 (d, J=8 Hz, 0,33H), 4,80 (d, J=12 Hz, 0,33H), of 4.77 (d, J=12 Hz, 0,66H), of 3.95 (s, 3H), of 3.94 (m, 1H), 3,90 (s, 2H), a 3.87 (s, 1H), 3,82 (d, J=12 Hz, 1H), 2,38 (s, 1H), 2,37 (s, 2H), 0,59 (d, J=6,5 Hz, 1H), 0,54 (d, J=6,5 Hz, 2H).

Stage G

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6 ' -iodine-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

To a solution of the compound indicated in the title at the Stage F (0.10 g, is 0.135 mmol)in chloroform (5 ml) at room temperature add p-internetit (0,024 g, 0.20 mmol) and iodine (0,044 g, 0,17 mmol). The mixture is refluxed for 1 hour. Dilute the mixture with methylene chloride (10 ml). The resulting solution was washed with saturated is one solution of sodium thiosulfate, saturated salt solution and dried over sodium sulfate. The residue is purified preparative HPLC with reversed phase and get listed in the name of the connection. Range1H NMR (CDCl3, 500 MHz) δ blend 2:1: atropoisomeric 8,21 (s, 1H), of 7.97 (s, 1H), 7,88 (s, 2H), 7,72 (s, 1H), 7,76 (m, 1H), 7,44 (m, 1H), 7,29 (m, 1H), 7,20 (m, 1H), 7,12 (m, 1H), 7,00 (m, 1H), 5,59 (d, J=8 Hz, 0,66H), of 5.53 (d, J=8 Hz, 0,33H), 4,80 (d, J=16 Hz, 1H), 3.96 points (d, J=15,5 Hz, 1H), 3,95 (s, 3H), 3,90 (m, 1H), with 3.89 (s, 2H), 3,86 (s, 1H), 2,04 (s, 1H), 2,38 (s, 2H), 0,60 (d, J=6,5 Hz, 1H), 0,54 (d, J=6,5 Hz, 2H). LC-MS (M+1): 852,1.

Stage H: 2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6 ' -iodine-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

To a solution of the compound indicated in the title at the Stage of G (0,016 g, 0,0188 mmol), in dioxane (2 ml) at room temperature, add aqueous solution of LiOH·H2On (0,007 g, 0.16 mmol). The mixture is stirred at room temperature for 5 hours. Analysis by TLC (EtOAc:hexane/2:8) shows the absence of starting materials. The solvent is removed. Add 1N HCl (1 ml). The mixture is extracted with EtOAc (3×15 ml). Layers EtOAc combined and dried over sodium sulfate. Specified in the title compound obtained after preparative HPLC with reversed phase. Range1H NMR (CDCl3, 500 MHz) δ blend 2:1: atropoisomeric 8,21 (s, 1H), 8,01 (s, 1H), 7,94 (d, J=7.5 Hz, 1H), 7,89 (s, 1H), 7,72 (s, 1H), 7,69 (s, 1H), 7,66 (d, J=7.5 Hz, 1H), 7,45 (m, 1H), 7,37 (m, N), 7,14 (m, 1H), 7,00 (m, 1H), ceiling of 5.60 (d, J=8 Hz, 0,66H), 5,54 (d, J=8 Hz, 0,33H), 4,82 (d, J=7.5 Hz, 0,33H), 4,79 (d, J=8 Hz, 0,66H), 3,99 (d, J=10 Hz, O,33H), of 3.96 (d, J=9.5 Hz, 0,66H), 3,91 (m, 1H), 3,90 (s, 2H), 3,86 (s, 1H), 2,42 (s, 1H), 2,41 (s, 2H), 0,60 (d, J=7 Hz, 1H), 0,55 (d, J=6,5 Hz, 2H).

EXAMPLE 41

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-hydroxy-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

To a cooled solution (bath temperature of -78°C) of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6'-methoxy-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-she (75 mg, 0.11 mmol) in dichloromethane (1 ml) add tribromide boron (106,6 mg, mmol 0,426). The resulting mixture was stirred under cooling (at a bath temperature of -78°C) for 1 hour, and then left overnight to warm to room temperature. The reaction is interrupted by adding ice, and then extracted with dichloromethane. The extracts are combined, washed with saturated salt solution and dried over Na2SO4. The resulting mixture was filtered and concentrated. The residue is purified by the method of preparative TLC on SiO2(elute 30% solution of ethyl acetate in hexane) and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6'-hydroxy-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-it. JHMS: calculated = 653,16; found = 654,19 (M+1)+. The signals in the spectrum of1H NMR double due atrophy is homerism. Range1H NMR (CDCl3, 500 MHz) δ 7,87-to 7.84 (m, 1H), 7,76 (s, 0,5H), 7,72-the 7.65 (m, 2,5H), 7,63 (s, 1H), 7,53-7,47 (m, 1H), 7,33-of 7.23 (m, 3H), 7.23 percent-7,16 (m, 2H), 7,12 (DD, J=a 10.5, 2.5 Hz, 1H),? 7.04 baby mortality (d, J=8.0 Hz, 0,5H), 7,02 (d, J=8,5 Hz, 0,5H), 5,64 (d, J=8.0 Hz, 0,5H), 5,32 (d, J=7.5 Hz, 0,5H), 4,98, to 4.92 (d, J=16hz, 1H), 4,23 (d, J=15,5 Hz, 0,5H), 4,07 (d, J=15,5 Hz, 0,5H), 3,89-3,82 (m, 0,5H), 3,74-to 3.67 (m, 0,5H), 2,32, of 2.28 (s, 3H), of 0.58 (d, J=7 Hz, 1,5H), 0,49 (d, J=6,5 Hz, 1,5H).

EXAMPLE 42

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-3-{[3'-(1H-pyrazole-1-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-he

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (0.05 g, 0,084 mmol), 3-(1H-pyrazole-1-yl)phenylboronic acid (0,031 g, 0,167 mmol), tetrakis(triphenylphosphine)palladium (5 mol%) and sodium carbonate is 0.019 g, 0.18 mmol) in 7 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 4 hours. Analysis by TLC (EtOAc:hexane/1:1) shows that the reaction is complete. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after purification by the method column flash chromatography using EtOAc:hexane/1:1 as eluent. Range1H NMR (CDCl3, 500 MHz) δ 8,02 (d, J=2.5 Hz, 1H), 7,88 (s, 1H), to 7.84 (s, 1H), to 7.77 (s, 1H), 7,76 (s, 1H), 7,75 (2H), 7,73 (m, 1H), 7,71 (m, 1H), to 7.61 (t, J=7.5 Hz, 1H), 7,53 (d, J=7.5 Hz, 1H), 7,26 (m, 1H), 6,54 (t, J=2 Hz, 1H), 5,55 (d, J=7.5 Hz, 1H), 5,02 (d, J=16 Hz, 1H), is 4.21 (q,j=16 Hz, 1H), 3,82 (m, 1H), 0,54 (d, J=6.5 Hz, 3H).

LC-MS (M+1): 614,3.

EXAMPLE 43

Ethyl 4-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]-5-methyl-1,3-thiazole-2-carboxylate

Stage And

2'-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-carbaldehyde

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (0.50 g, 0.84 mmol), 5-formyl-2-methoxyphenylacetic acid (0,22 g, 1.25 mmol), tetrakis(triphenylphosphine)palladium (48 mg, 5%mol.) and sodium carbonate (0,19 g of 1.84 mmol) in 20 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 4 hours. Analysis by TLC (CH2Cl2:hexane/1:1) shows that the reaction is complete. The solvents are removed. Add water (30 ml). Organic matter is extracted with methylene chloride (3×40 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using EtOAc:hexane/3:7 as eluent. Range1H NMR (CDCl3, 00 MHz) δ a mixture of 1:1: atropoisomeric 9,95 (s, 1H), 7,62-7,98 (m, 6H), 7,42 (m, 1H), 7,17 (m, 2H), 5,65 (d, J=8 Hz, 0,5H), 5,20 (d, J=8 Hz, 0,5H), 4,96 (d, J=15,5 Hz, 0,5H), to 4.92 (d, J=16.5 Hz, 0,5H), 3,85-4,10 (m, 2H), 3,98 (s, 1,5H), to 3.92 (s, 1,5H), 0,59 (d, J=6,5 Hz, 1,5H), 0,42 (d, J=6 Hz, 1,5H).

Stage

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5'-(1-hydroxypropyl)-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

To a solution of the compound indicated in the title on the Stage And (0,44 g, 0.73 mmol)in THF at 0°C is added EtMgBr (of 0.87 ml, 0.87 mmol,1 M in THF). The solution was stirred at 0°C for 2 hours. The reaction is interrupted with a saturated aqueous solution of ammonium chloride (10 ml). Organic matter extracted with EtOAc (3×15 ml). Layers EtOAc unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using EtOAc:hexane/1:1 as eluent. Range1H NMR (CDCl3, 500 MHz) δ mixture of atropisomers and diastereomers 7,86 (s, 1H), to 7.61-7,71 (m, 4H), 7.18 in-7,47 (m, 4H), of 6.99 (m, 1H), 5,28-5,49 (m, 1H), 4,92 is 5.07 (m, 1H), br4.61 (m, 1H), 3,92-to 4.14 (m, 1H), 3,97 (m, 3H), 3,66-with 3.79 (m, 1H), 1,80 (m 2H), and 0.98 (m, 3H), 0.50 to 0.60 (m, 3H).

Stage

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-propionyl 4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

To a solution of the compound indicated in the title at the Stage In (0.32 g, 0.50 mmol, in methylene chloride (10 ml) at room temperature add periodinane dessa-Martin (0.28 g, 0.50 mmol). The mixture is stirred at room temperature for 4 hours. Analysis by TLC (EtOAc:hexane/2:8) shows that the reaction is complete. The mixture is filtered and the filtrate evaporated. Specified in the title compound is obtained after flash column-chromatography using EtOAc:hexane/2:8 as eluent. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1 atropoisomeric of 8.06 (m, 1H), 7,86 (m, 2H), 7,62 to 7.75 (m, 4H), 7,40 (m, 1H), 7,07 (m, 1H), 5,65 (d, J=8 Hz, 0,5H), 5,20 (d, J=8 Hz, 0,5H), equal to 4.97 (d, J=15 Hz, 0,5H), of 4.90 (d, J=15,5 Hz, 0,5H), 4.09 to (d, J=15 Hz, 0,5H), of 3.94 (s, 1,5H), 3,90 (s, 1,5H), of 3.84 (d, J=15,5 Hz, 0,5H), 3,70-3,82 (m, 1H), 3,00 (m, 2H), 1,22 (m, 3H), 0,59 (d, J=7 Hz, 1,5H), 0,41 (d, J=6,5 Hz, 1,5H).

Stage D

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5'-(2-bromopropane)-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

To a solution of the compound indicated in the title on the Stage With (0.28 g, 0.44 mmol)in a mixture of 1:1 Meon/CH2Cl2(5 ml) at room temperature add tetrabutylammonium tribromide (0.28 g, or 0.57 mmol). The mixture is stirred at room temperature for 24 hours. Add the water. The mixture is extracted with EtOAc (3×15 ml). Layers EtOAc unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after column F. the ash-chromatography using EtOAc:hexane/2:8 as eluent. Range1H NMR (CDCl3, 500 MHz) δ mixture of atropisomers and diastereomers 8,10-8,18 (m, 1H), 7,85-7,98 (m, 2H), 7,62-to 7.77 (m, 4H), 7,39-7,46 (m, 1H), 7,08 for 7.12 (m, 1H), 4,88-the 5.65 (m, 3H), 4,06-4,12 (m, 1H), 3,90 (m, 3H), 3,65-3,86 (m, 2H), 1,90 (m, 3H), 0.37 to 0.59 is (m, 3H).

Stage E: ethyl 4-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]-5-methyl-1,3-thiazole-2-carboxylate

The mixture of the compounds mentioned in the title at the Stage D of Example 67 (0,040 g 0,056 mmol), and ethyl of thiooxamate (11 mg, 0,084 mmol) in EtOH (2 ml) is refluxed overnight. The reaction mixture was concentrated. Specified in the title compound obtained after preparative TLC plates using EtOAc:hexane/3:7 as eluent. LC-MS (M+1): 747,2.

EXAMPLE 44

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-piperidine-1-yl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (0.05 g, 0,084 mmol), 3-(piperidino)phenylboronic acid (0,040 g, 0,167 mmol), tetrakis(triphenylphosphine)palladium (5 mol%) and sodium carbonate is 0.019 g, 0.18 mmol) in 7 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 4 hours. Analysis by TLC (EtOAc:hexane/1:1) shows that the reaction of the law is Chen. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using EtOAc:hexane/6:4 as eluent. LC-MS (M+1): 631,1.

EXAMPLE 45

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-3-{[3'-pyrrolidin-1-yl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-he

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (0.05 g, 0,084 mmol), 3-(pyrrolidino)phenylboronic acid (0,032 g, 0,167 mmol), tetrakis(triphenylphosphine)palladium (5 mol%) and sodium carbonate is 0.019 g, 0.18 mmol) in 7 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 4 hours. Analysis by TLC (EtOAc:hexane/1:1) shows that the reaction is complete. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using EtOAc:hexane/6:4 as eluent. LC-MS (M+1): 617,0.

EXAMPLE 46

2"-({(4R,5R)-3-[3,5-is IP(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage And

Methyl 4'-methoxy-2-methyl-2"-[(4R,5R)-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

(4R,5R)-5-[2-Iodine-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-he (Intermediate compound 12, 100 mg, 0,269 mmol), methyl 4'-methoxy-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (Intermediate compound 11, 124 mg, 0,323 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (44 mg, 0,054 mmol), aqueous solution of potassium carbonate (270 μl, 2 M, 0,538 mmol) and 1,4-dioxane (2 ml), sealed in a vessel for RF heating. The vessel is heated in a microwave oven to a temperature of 140°C for 30 minutes Analysis of aliquots taken from the reaction mixture, the method IHMS shows total expenditures source of iodide. The crude mixture was purified on SiO2(preparative TLC on plates, 50% ethyl acetate in hexane) and get a glassy substance. The residue is optionally purified on SiO2(preparative TLC on plates, 10% ethyl acetate in dichloromethane) and obtain methyl 4'-methoxy-2-methyl-2"-[(4R,5R)-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. JHMS: calculated = 499,16; found = 500,08 (M+1).

Stage

Methyl 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-yl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

The source of methyl 4'-methoxy-2-methyl-2"-[(4R,5R)-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (40 mg, 0,080 mmol) dissolved in anhydrous THF (1 ml) and cooled in a bath with ice. To the mixture is added sodium hydride (60% wt. in mineral oil, 3.5 mg, 0,088 mmol). The reaction mixture upon cooling (in a bath with ice) is stirred for 10 min, and then add 1-(methyl bromide)for 3,5-bis(trifluoromethyl)benzene (22 μl, to 36.8 mg, 0,120 mmol). The resulting mixture when cooled stirred for 20 min, then bath is removed. The analysis method IHMS aliquots taken from the reaction mixture after 2.5 h, indicates the degree of conversion of about 50%. The reaction mixture is cooled (in a bath with ice) and interrupt the reaction with NH4Cl (saturated aqueous solution). The obtained two-phase mixture is extracted with ethyl acetate. The organic extracts are combined and dried over Na2SO4, filtered and concentrated, obtaining oil. Specified oil cleanse method preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), performing a gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions are combined and evaporated, obtaining methyl 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. There is also neproreagirovavshimi the e educt. JHMS: calculated = 725,18; found = 726,19 (M+1).

Stage

2"-{(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Methyl 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (21 mg, 0,029 mmol), monohydrate of lithium hydroxide (9 mg, 0.21 mmol), water (0.4 ml) and 1,4-dioxane (1 ml) stirred at a temperature of 20°C for 2 h to complete the hydrolysis. The reaction mixture is acidified with HCl (aqueous, 1 ml). The resulting mixture was extracted with ethyl acetate. The organic extracts are combined and dried over Na2SO4, filtered and concentrated, obtaining a clear oil. Specified oil cleanse method preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), performing a gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions are combined and evaporated, receiving the 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. JHMS: calculated = 711,17; found = 712,28 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ 8,01 (s, 0,4H), of 7.97 (s, 0,6H, of 7.95 (d, J=7,0 Hz, 0,4H), to 7.93 (d, J=6,5 Hz, 0,6H), 7,81 (s, 0,4H), to 7.77 (s, 0,6H), of 7.75 (s, 0,4H), 7,71 (s, 0,6H), to 7.68 (d, J=6,5 Hz, 0,6H), 7,66 (d, J=6,5 Hz, 0,4H), a 7.62 (s, 1H), 7,55 (s, 1H), 7,41-7,35 (m, 2H), 7,32 (d, J=6,5 Hz, 0,4H), of 7.23 (d, J=6,5 Hz, 0,6H), 7,16 (d, J=2 Hz, 0,4H), was 7.08 (d, J=7.5 Hz, 0,6H), 7,02 (d, J=7.5 Hz, 0,4H), 6,98 (d, J=2.0 Hz, 0,6H), 5,22 (d, J=4 Hz, 0,6H), 5,13 (d, J=4.5 Hz, 0,4H), 4,82,4,75 (d, J=13.5 Hz, 1H), 4,29,4,26 (d, J=15,5 Hz, 1H), 3,86 (s, 1,8H)and 3.59 (s, 1,2H), 3,53-of 3.48 (m, 0,4H), 3,30-3,24 (m, 0,6N), 2,36, 2,22 (s, 3H), 0,89, of 0.75 (d, J=5.5 Hz, 3H).

EXAMPLE 47

Stage And

(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-5-[2-iodine-5-(trifter-methyl)phenyl]-4-methyl-1,3-oxazolidin-2-he

(4R,5R)-5-[2-Iodine-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-he (Intermediate compound 12, 1,451 g 3,910 mmol) dissolved in anhydrous THF (30 ml) and cooled in a bath with ice. At one time in the reaction mixture was added sodium hydride (60% wt. in mineral oil, 172 mg, at 4,301 mmol). The reaction mixture upon cooling (in a bath with ice) is stirred for 30 min, and then add 1-(methyl bromide)for 3,5-bis(trifluoromethyl)benzene (1,078 ml, 1.80 mg, 5,865 mmol). After 5 hours the reaction mixture is cooled (in a bath with ice) and terminate the reaction by adding NH4Cl (saturated aqueous solution). The reaction mixture was extracted with ethyl acetate. The organic extracts are combined and dried over Na2SO4, filtered and concentrated, obtaining oil. Specified oil clean flash x is omatography (SiO 2cartridge Biotage 40+M, EtOAc:hexane) and receive (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodine-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-it. JHMS: calculated = 596,98; found = 598,05 (M+1)+. There is also to 132.6 mg of the original substance.

Stage

(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-5-[5'-bromo-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-he

(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-5-[2-iodine-5-(trifter-methyl)phenyl]-4-methyl-1,3-oxazolidin-2-he (500 mg, 0,837 mmol), (5-bromo-2-methoxyphenyl)baronova acid (222 mg, 0,962 mmol), an aqueous solution of sodium carbonate (0,885 ml, 2 M, 1.77 mmol), ethanol (300 μl) and toluene (2.5 ml) is stirred at room temperature for 0.5 hour, and then add tetrakis(triphenylphosphine)palladium(0) (44 mg, and 4.5 mol%). The resulting mixture was heated to 90°C in oil bath for 28.5 hours and then left overnight to mix at room temperature. To the reaction mixture are added water and then extracted with ethyl acetate. The extracts are combined, dried over Na2SO4, filtered and concentrated under reduced pressure, obtaining a yellow oil. Specified oil purified flash chromatography (SiO2cartridge Biotage 40+M, EtOAc:hexane, gradient elution) and receive (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-bromo-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxa who ridin-2-it. JHMS: calculated = 657,04; found = 597,95 (M+1)+.

Stage

Methyl 2-amino-2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

Mix (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-bromo-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-he (358 mg, 0,545 mmol), [2-amino-4-(methoxycarbonyl)phenyl]Bronevoy acid (214 mg, 1.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (76,5 mg, mmol 0,109), an aqueous solution of potassium carbonate (545 μl, 2 M of 1.09 mmol) and ethanol (5 ml) and heated to 80°C in oil bath. Aliquots taken after 2 hours and 3.5 hours after the start of the reaction, show about 6% of unreacted starting materials. Add an additional amount of [2-amino-4-(methoxy-carbonyl)phenyl]Bronevoy acid (50 mg, 0,256 mmol), when the time for the reaction is 3 hours 45 minutes an Aliquot shows no further development of the reaction. The reaction mixture is cooled and mixed with a saturated solution of salt. Volatile substances are removed from the mixture under reduced pressure. To the resulting mixture are added water and extracted with ethyl acetate. The extracts are combined, dried over Na2SO4, filtered and concentrated under reduced pressure, obtaining the oil is dark in color. Specified oil clean flash chromate what graphy (SiO 2cartridge Biotage 40+M, EtOAc:hexane, gradient elution)and then by the method of preparative TLC (SiO2, 10% ethyl acetate in dichloromethane) and get methyl 2-amino-2"-{(4R,5R)-3-[3,5-bis(tri-permitil)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. JHMS: calculated = 726,18; found = 727,29 (M+1)+.

Stage D

Methyl 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-2-chloro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

Amyl nitrate (33 μl, 29 mg, 0,248 mmol) and copper chloride(II) (27 mg, 0,198 mmol) dissolved in anhydrous acetonitrile (1 ml) and sealed in a vessel for RF heating. The vessel is heated on an oil bath to 65°C. To the hot solution for approximately 1 min add the source of methyl 2-amino-2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (120 mg, 0,165 mmol,in 1 ml MeCN). Then hermetically closed vessel is heated on an oil bath to 65°C for 1 hour. Analysis of aliquots (IHMS) indicates complete reaction. The solution is filtered and purified by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), performing a gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions combined Aut and evaporated in vacuum, receiving methyl 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-2-chloro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. JHMS: calculated = 745,13; found = 746,12 (M+1)+.

Stage E: 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-2-chloro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

To a solution of the original methyl 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-2-chloro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (65 mg, 0,087 mmol) in 1,4-dioxane (2 ml) add a solution of the monohydrate of lithium hydroxide (to 36.5 mg, 0.87 mmol) in water (1 ml). The mixture becomes cloudy and acquires a pinkish color (from the original light yellow solution). An aliquot taken after 22 min after start of the reaction, indicates the completion of the reaction. The reaction mixture is acidified (1N HCl, aqueous solution). From the reaction mixture to remove volatile substances. The resulting mixture was purified by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), performing a gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions are combined and evaporated in vacuum, obtaining a colorless glassy substance. Specified glassy substance is dissolved in dichloromethane and washed with water. The organic layer is separated, dried over Na2SO4/sub> , filtered and concentrated in vacuo, receiving the 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-2-chloro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. JHMS: calculated = 731,11; found = 732,08 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ by 8.22, 8,13 (d, J=1.5 Hz, 1H), 8,05-to 7.99 (m, 1H), 7,79 (s, 1H), 7,74 (s, 1H), 7,70-to 7.64 (m, 1H), 7,60 (s, 0,6H), 7,54-7,51 (m, 1,8H), 7,50-7,44 (m, 1H), 7,42-7,30 (m, 2H), 7,13 (d, J=2,5 Hz, 0,6H), 7,10 (d, J=9,0 Hz, 0,6H), 7,17 (d, J=8,5 Hz, 0,4H), 5,22 (d, J=4.5 Hz, 1H), 4,82, of 4.77 (d, J=16 Hz, 1H), 4,27,4,22 (d, J=16 Hz, 1H), a 3.87 (s, 1,8H)and 3.59 (s, 1,2H), 3,49-of 3.43 (m, 0,4H), 3,32-of 3.25 (m, 0,6H), 0,86 (d, J=6.0 Hz, 1,2H), 0,73 (d, J=6,5 Hz, 1,8H).

EXAMPLE 48

Stage And

Methyl 3'-amino-4'-chloro-2-methylbiphenyl-4-carboxylate

Mix (3-amino-4-chlorophenyl)baronova acid (1.0 g, 5,834 mmol), methyl 4-bromo-3-methylbenzoate (1,337 g 5,834 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (476 mg, 0,583 mmol), aqueous potassium carbonate solution (11,57 ml, 1 M, 11,57 mmol) and acetone (53 ml) and heated on an oil bath to 70°C for 1.5 for completion of the reaction combinations. Volatile substances are removed from the mixture under reduced pressure. To the resulting mixture are added water and then extracted with ethyl acetate. The extracts are combined, dried over Na2SO4filter and will contentresult under reduced pressure, receiving the oil is dark in color. Specified oil purified flash chromatography (SiO2cartridge Biotage 40+M, 0-40% EtOAc in hexane) and obtain methyl 3'-amino-4'-chloro-2-methylbiphenyl-4-carboxylate. JHMS: calculated = 275,07; found = 276,23 (M+1)+.

Stage

Methyl 3'-bromo-4'-chloro-2-methylbiphenyl-4-carboxylate

Methyl 3'-amino-4'-chloro-2-methylbiphenyl-4-carboxylate (946 mg, of 3.43 mmol) dissolved in a mixture of CHBr3(5 ml) and dichloromethane (5 ml). To the resulting mixture of tert-butylnitrite (680 μl, 530,6 mg, 5,145 mmol). The reaction mixture is heated to 80°C for 30 minutes Analysis of aliquots (IHMS) indicates complete consumption of the starting materials. The crude mixture was purified flash chromatography (SiO2cartridge Biotage 40+S) and obtain methyl 3'-bromo-4'-chloro-2-methylbiphenyl-4-carboxylate. JHMS: calculated = 339,97; found = 340,98 (M+1)+.

Stage

Methyl 4'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate

Methyl 3'-bromo-4'-chloro-2-methylbiphenyl-4-carboxylate (699 mg, of 2.06 mmol), bis(pinacolato)diboron (556 mg, 2,47 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (226 mg, 0,277 mmol), potassium acetate (404 mg, 4,12 mmol) and 1,4-dioxane (10 ml), sealed in a vessel for RF heating. The vessel is heated in a microwave oven until the temperature is 140°C for 45 minutes Analysis of aliquots (IHMS) indicates the completion of the reaction. To the reaction mixture are added water and then extracted with ethyl acetate. The extracts are combined, dried over Na2SO4, filtered and concentrated, obtaining the oil is dark in color, representing a crude mixture of methyl 4'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate, which is used in the next stage without further purification. JHMS: calculated = 386,15; found = 387,13 (M+1)+.

Stage D

Methyl 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-5-[2-iodine-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-he (103 mg, 0,172 mmol,515 μl of toluene), methyl 4'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (100 mg, 0,259 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (14 mg, 10%), aqueous solution of potassium carbonate (344 μl, 2 M, 0,688 mmol) and ethanol (2 ml), sealed in a vessel for RF heating. The vessel is heated using RF heating to a temperature of 140°C for 45 minutes Analysis by LC/MS shows complete consumption of the starting materials. The crude mixture was purified on SiO2(preparative TLC on plates, 50% ethyl acetate in hexane) and the floor is with a glassy substance. The residue is optionally purified on SiO2(preparative TLC, 30% EtOAc/hexane). The residue is then purified by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), performing a gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.), and get methyl 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. JHMS: calculated = 729,13; found = 730,14 (M+1)+.

Stage E

2"-{(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

To a solution of methyl 2"-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (65 mg, 0,089 mmol) in 1,4-dioxane (3 ml) add a solution of the monohydrate of lithium hydroxide (26 mg, 0,623 mmol) in water (1.2 ml). An aliquot taken after 2 hours after the start of the reaction, indicates the end of the reaction (there are atropoisomeric). The crude mixture is acidified with HCl (1N aqueous solution, 1 ml), Muddy residue was dissolved in MeCN (2 ml). The resulting solution was purified by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), performing a gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.), and get 2"-{(4R,5R-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. JHMS: calculated = 715,12; found = 716,20 (M+1)+. The signals in the spectrum of1H NMR double due atropoisomeric. Range1H NMR (CDCl3, 500 MHz) δ 8,04 (s, 0,5H), 8,00 (s, 0,5H), 7,98-to 7.93 (m, 1H), 7,80 to 7.75 (m, 1,5H), of 7.75 (s, 0,5H), 7,74-of 7.69 (m, 1H), 7,63-to 7.59 (m, 2H), 7,58, 7,56 (d, J=3.5 Hz, 1H), 7,42 (d, J=7.5 Hz, 0,5H), 7,40-7,34 (m, 1,5H), 7,31 (d, J=7.5 Hz, 0,4H), 7,28 (d, J=2 Hz, 0,6H), from 7.24 (d, J=8.0 Hz, 0,6H), to 7.09 (d, J=2,5 Hz, 0,4H), 5,14 (d, J=5.5 Hz, 0,4H), 5,10 (d, J=4.5 Hz, 0,6H), of 4.83 (d, J=16 Hz, 0,6H), to 4.73 (d, J=16 Hz, 0,4H), 4,28 (d, J=16 Hz, 1H), 3,57-3,51 (m, 0,4H), 3,42-to 3.35 (m, 0,6H), 2,35, of 2.25 (s, 3H), of 0.91 (d, J=6,5 Hz, 1,8H), of 0.85 (d, J=6 Hz, 1,2H).

EXAMPLE 49

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-chloro-4-(hydroxymethyl)-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

To a solution of the acid from Example 34 (1.0 g, of 1.40 mmol) in THF (15 ml) at a temperature of minus 78°C. add borane (and 2.79 ml, and 2.79 mol, 1 M solution in THF). The solution is stirred at minus 78°C for 30 min and slowly for 2 hours, warmed to room temperature. Analysis by TLC shows the absence of the original substances (EtOAc/hexane 3:7). Add water (10 ml). The mixture is extracted with EtOAc (3×20 ml). Layers EtOAc unite, washed with saturated sodium bicarbonate solution, saturated salt solution and dried over sodium sulfate. The solvent is removed and the residue purified column flash chromatography on silica gel, elwira a mixture of EtOAc/hexane (30:70), and produces the t specified in the title compound as a colourless solid. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric 7,89 (s, 1H), 7,73 (s, 1H), 7,72 (s, 2H), of 7.70 (m, 1H), to 7.59 (d, J=8.0 Hz, 1H), 7,49 (d, J=8,5 Hz, 0,5H), 7,47 (d, J=8.0 Hz, 0,5H), 7,39 was 7.36 (m, 2H), 7,32 (s, 1H), 7,25 (m 1,5H), 7,20 (d, J= 2.0 Hz, 0,5H), 5,62 (d, J=8.0 Hz, 1H), 4,99 (d, J=15,0 Hz, 0,5H), of 4.83 (d, J=16.0 Hz, 0,5H), to 4.73 (s, 2H), 4,15 (s, 1H), 4,10 (d, J=16.0 Hz, 0,5H), to 4.01 (d, J=15,5 Hz, 0,5H), 3.96 points (m, 0,5H), 3,86(m, 0,5H), was 2.34 (s, 1,5H), 2,33 (s, 1,5H), and 0.61 (d, J=6,5 Hz, 1,5H), of 0.58 (d, J=6,5 Hz, 1,5H).

EXAMPLE 50

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carbaldehyde

Periodinane dessa-Martin (145 mg, 0.34 mmol) are added to a solution of the alcohol from Example 49 (200 mg, 0,285 mmol) in methylene chloride (5 ml) at room temperature. The resulting suspension is stirred at room temperature for 1 hour. Analysis by TLC shows the absence of the original substances (EtOAc/hexane 2:8). Solids filtered off. The filtrate is concentrated. The residue is purified column flash chromatography on silica gel, elwira a mixture of EtOAc/hexane (30:70), and get mentioned in the title compound as a colourless solid. Range1H NMR (CDCl3, 500 MHz) δ mix 6:4: atropoisomeric there is a 10.03 (s, 1H), of 7.90 (s, 2/5H), 7,89 (s, 3/5H), 7,83 (s, 1H), 7,78 (d, J=8.0 Hz, 3/5H), of 7.75 (d, J=8.0 Hz, 2/5 H), 7,74 (s, 1,2H), 7,73 (s, 0,8H), 7,72 (s, 2/5H), 7,70 (, 3/5H), to 7.64 (d, J= 8.0 Hz, 1H), 7,52 (d, J=8.0 Hz, 3/5H), 7,47 (d, J=8.0 Hz, 2/5H), 7,46 (d, J=8.0 Hz, 3/5H), the 7.43 (d, J= 8.0 Hz, 2/5H),7,40 (m, 1H), 7,28 (m, 1,5H), of 7.23 (d, J=2.0 Hz, 0,5H), 5,64 (d, J=8.0 Hz, 1H), 5,04 (d, J=15,5 Hz, 3/5H), of 4.83 (d, J=16 Hz, 2/5H), 4.09 to (d, J=16 Hz, 2/5H), 4,01 (d, J=15,0 Hz, 3/5H), of 4.00 (m, 2/5H), 3,91 (m, 3/5H), 2,43 (s, 1,8H), is 2.41 (s, 1,2H), 0,65 (d, J=6,5 Hz, 1,8H), and 0.61 (d, J=7,0 Hz, 1,2H).

EXAMPLE 51

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-chloro-4"-(1-hydroxyethyl)-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

MeMgBr (0,274 ml, 0,274 mmol,1 M solution) are added to a solution of the aldehyde from Example 50 (160 mg, 0,229 mmol) in THF (3 ml) at minus 78°C. the Solution is stirred at minus 78°C for 2 hours. Add a saturated solution of ammonium chloride. The mixture is extracted with EtOAc (3×10 ml). Layers EtOAc unite, washed with saturated salt solution and dried over sodium sulfate. The residue is purified column flash chromatography on silica gel, elwira a mixture of EtOAc/hexane (30:70), and get mentioned in the title compound as a colourless solid. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric 7,89 (s, 1H), 7,72 (m, 4H), 7,58 (d, J= 8.5 Hz, 1H), of 7.48 (t, 1H), 7,38 (m, 1H), 7,32 -7,20 (m, 4H), 5,62 (d, J=8.0 Hz, 1H), 5,00 (d, J=15,5 Hz, 0,5H), is 4.93 (m, 1H), 4,82 (d, J=16.0 Hz, 0,5H), 4,10 (d, J=15,5 Hz, 0,5H), to 4.01 (d, J=15,5 Hz, 0,5H), 3,88 (m, 0,5H), a 3.87 (m, 0,5H), was 2.34 (s, 1,5H), 2,33 (s, 1,5H), of 1.55 (m, 3H), and 0.61 (d, J=6,5 Hz, 1,5H), of 0.58 (d, J=6,5 Hz, 1,5H).

LC/MS: M+-18: 698,16.

EXAMPLE 52

(4S,5R)-3-{[4"-Acetyl'-chloro-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-he

Periodinane dessa-Martin (58,3 mg, 0,137 mmol) are added to a solution of the alcohol from Example 51 (82 mg, 0,115 mmol) in methylene chloride (5 ml) at room temperature. The resulting suspension is stirred at room temperature for 1 hour. Analysis by TLC shows the absence of the original substances (EtOAc/hexane 2:8). Solids filtered off. The filtrate is concentrated. The residue is purified column flash chromatography on silica gel, elwira a mixture of EtOAc/hexane (20:80), and get mentioned in the title compound as a colourless solid. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric of 7.90 (s, 1H), 7,89 (s, 1H), to 7.84 (d, J=8 Hz, 1H), 7,72 (m, 4H), a 7.62 (d, J=8.5 Hz, 1H), 7,51 (d, J=8.0 Hz, 0,5H), 7,46 (d, J=8.0 Hz, 0,5H), 7,40-7,34 (m, 2H), 7,26 (d, J=2,5 Hz, 0,5H), 7,21 (d, J=2,5 Hz, 0,5H), 5,62 (d, J=8.0 Hz, 1H), 5,02 (d,J= 15,5 Hz, 0,5H), of 4.83 (d, J=16.0 Hz, 0,5H), 4,08 (d, J=16.0 Hz, 0,5H), to 4.01 (d, J=15,5 Hz, 0,5H), 3,99 (m, 0,5H), 3,90(m, 0,5H), of 2.64 (s, 3H), 2.40 a (C, 1,5H), 2,39 (s, 1,5H), of 0.64 (d, J=6,5 Hz, 1,5H), and 0.62 (d, J=6,5 Hz, 1,5H).

LC/MS: M+: 714,01.

EXAMPLE 53

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-chloro-4"-(1-hydroxy-1-methylethyl)-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

MeMgBr (has 0.168 ml, has 0.168 mmol,1 M solution) are added to a solution of the ketone from Example 52 (80 mg, 0,112 mmol) in THF (3 ml) at minus 78°C. the Solution is stirred at minus 78°C for 2 hours. Add saturated the initial solution of ammonium chloride. The mixture is extracted with EtOAc (3×10 ml). Layers EtOAc unite, washed with saturated salt solution and dried over sodium sulfate. The residue is purified column flash chromatography on silica gel, elwira a mixture of EtOAc/hexane (30:70), and get mentioned in the title compound as a colourless solid. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric 7,89 (s, 2H), 7,83 (d, J=8 Hz, 1H), 7,72 (m, 4H), 7,63 (d, J=8.5 Hz, 1H), 7,51 (d, J=8.0 Hz, 0,5H), 7,46 (d, J=8.0 Hz, 0,5H), 7,40-7,34 (m, 2H), 7,27 (d, J=2.0 Hz, 0,5H), 7,21 (d, J=2,5 Hz, 0,5H), 5,64 (d, J=8.0 Hz, 0,5H), 5,63 (d, J=8.0 Hz, 0,5H), 5,02 (d, J=16.0 Hz, 0,5H), of 4.83 (d, J=16.0 Hz, 0,5H), 4,08 (d, J=16.0 Hz, 0,5H), to 4.01 (d, J=15,5 Hz, 0,5H), 4,00 (m, 0,5H), 3,90(m, 0,5H), is 2.41 (s, 1,5H), 2,39 (s, 1,5H), to 1.60 (m, 3H), 1.28 (in m, 3H), of 0.64 (d, J=6,5 Hz, 1,5H), and 0.62 (d, J=6,5 Hz, 1,5H).

EXAMPLE 54

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6'-fluoro-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage A: methyl 2'-fluoro-4'-methoxy-2-methylbiphenyl-4-carboxylate

A mixture of 4-bromo-3-fernicola (500 mg, of 2.44 mmol), methyl 4'-methoxy-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (875 mg, 3,17 mmol), tetrakis(triphenylphosphine)palladium (282 mg, 5%mol.) and sodium carbonate (569 mg, 5.37 mmol) in 20 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 4 hours. Analysis by TLC (CH Cl2:hexane/1:1) shows that the reaction is complete. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×10 ml). Extraction of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using a mixture of CH2Cl2:hexane/6:4 as eluent. Range1H NMR (CDCl3, 500 MHz) δ 7,98 (s, 1H), 7,92 (DD, J=8,0, 1.5 Hz, 1H), 7,29 (d, J=8.0 Hz, 1H), 7,16 (t, J=8.5 Hz, 1H), 6,80 (DD, J=8,5, 2.5 Hz, 1H), 6,77 (DD, J=a 11.5 and 2.5 Hz, 1H), 3,95(s, 3H), 3,88 (s, 3H), of 2.28 (s, 3H).

Stage b: methyl 2'-fluoro-5'-iodine-4'-methoxy-2-methylbiphenyl-4-carboxylate

A solution of compound from step A (1.30 grams, 4,74 mmol) in a mixture of Meon/EtOAc (10:1) (10 ml) is added to a mixture of Ag2SO4(1.47 g, 4,74 mmol) and (I2(1.20 g, 4,74 mmol) in Meon (20 ml) at room temperature. The mixture is stirred at room temperature for 4 hours. The color of the solution changed from brown to light yellow. The mixture is filtered. The filtrate is concentrated. The residue is purified flash chromatography, elwira a mixture of EtOAc/hexane (5:95), and get mentioned in the title compound as a colourless solid. Range1H NMR (CDCl3, 500 MHz) δ 7,98 (s, 1H), 7,92 (DD, J=8,0, 2.0 Hz, 1H), to 7.67 (d, J=8.5 Hz, 1H), 7,28 (d, J=9,0 Hz, 1H), 6,69 (d, J=11.5 Hz, 1H), 3.96 points(s, 3H), of 3.95 (s, 3H), and 2.27(s, 3H)./p>

Stage C: methyl 2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6'-fluoro-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-it - methane (1.30 grams, to 2.18 mmol) (Intermediate compound 9), is indicated in the name of the connection on Stage (1,30 g, 3.25 mmol), tetrakis(triphenylphosphine)palladium (250 mg, 10%mol.) and sodium carbonate (507 mg, 4,79 mmol) in 50 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 4 hours. Analysis by TLC (CH2Cl2:hexane/1:1) shows that the reaction is complete. The solvents are removed. Add water (20 ml). Organic matter is extracted with methylene chloride (3×30 ml). Extraction of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using a mixture of CH2Cl2:hexane/8:2 as eluent. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric 7,98 (d, J=4.5 Hz, 1H), 7,89 (s, 2H), 7,68 (m, 4H), 7,42 (t, J=6.0 Hz, 1H), 7,30 (d, J=7.5 Hz, 0,5H), 7,26 (d, J=7.5 Hz, 0,5H), 7,07 (t, J=8.0 Hz, 1H), 6.87 in (d, J=5.5 Hz, 0,5H), 6,85 (d, J= 6.0 Hz, 0,5H), 5,63 (d, J=8.0 Hz, 0,5H), 5,41 (d, J=8.0 Hz, 0,5H), 5,00 (d, J=15,5 Hz, 0,5H), to 4.92 (d, J=16.0 Hz, 0,5H), 4,17 (d, J=15,5 Hz, 0,5H), 3,95 (d, J=16.0 Hz, 0,H), of 3.95 (s, 3H), 3,88 (s, 3H), of 3.84(m, 1H), 2,32 (s, 1,5H), 2,28 (s, 1,5H), of 0.64 (d, J=7,0 Hz, 1,5H), and 0.62 (d, J=6,5 Hz, 1,5H).

LC/MS: M+: 744,2.

Stage D: 2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6'-fluoro-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Specified in the name of the connection on Stage With (1.97 g) leave much to be mixed on the night of LiOH (5 EQ.) in a mixture of 2:1 dioxane and water at room temperature. The solvent is removed, and the aqueous phase is acidified with 1N HCl solution to pH ~4. Organic matter extracted with EtOAc (3×30 ml). Layers EtOAc unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography, elwira a mixture of EtOAc/hexane (1:1). Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1 atropoisomeric 8,03 (d, J=4.5 Hz, 1H), 7,95 (d, J=8.5 Hz, 1H), 7,89 (s, 1H), 7,73-the 7.65 (m, 4H), 7,43 (m, 1H), 7,34 (d, J=7.5 Hz, 0,5H), 7,29 (d, J=7.5 Hz, 0,5H), was 7.08 (t, J=8.5 Hz, 1H), 6,88 (d, J=5.5 Hz, 0,5H), 6,86 (d, J=6,5 Hz, 0,5H), 5,63 (d, J=8.0 Hz, 0,5H), 5,42 (d, J=8,5 Hz, 0,5H), free 5.01 (d, J=16.0 Hz, 0,5H), is 4.93 (d, J=16.0 Hz, 0,5H), 4,17 (d, J=16.0 Hz, 0,5H), 3,95 (d, J=16.0 Hz, 0,5H), to 3.89 (s, 3H), of 3.84(m, 1H), 2,34 (C31,5H), 2,30 (s, 1,5H), and 0.61 (d, J=7,0 Hz, 1,5H), and 0.50 (d, J=6,5 Hz, 1,5H).

EXAMPLE 55

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-t is henyl-4-carboxylic acid

Stage A: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3'-bromo-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (2.0 g, 3.35 mmol), 3-brompheniramine acid (0.74 g, 3,68 mmol) and sodium carbonate (0.71 g, 6,70 mmol) in 21 ml of a mixture of 1:2:4 water:EtOH:toluene is stirred at room temperature for 30 minutes Add a catalytic amount of tetrakis(triphenylphosphine)palladium (0,193 g, 5 mol%). The resulting mixture was refluxed with stirring for 3 hours. The solvents are removed. Add water (10 ml). The mixture is extracted with methylene chloride (3×30 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using a mixture of CH2Cl2:hexane/1:1 as eluent.

Stage b: methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

A mixture of methyl 4'-methoxy-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (150 mg, 0,542 mmol), the connection specified by name on Stage And (224 mg, 0,358 mmol), tetrakis(triphenylphospine (20,66 mg, 5%mol.) and sodium carbonate (76 mg, 0,715 mmol) in 14 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 1 hour. Analysis by TLC (CH2Cl2:hexane/1:1) shows that the reaction is complete. The solvents are removed. Add water (10 ml). Organic matter is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using a mixture of CH2Cl2:hexane/8:2 as eluent. Range1H NMR (CDCl3, 500 MHz) δ to 7.99 (s, 1H), 7,92 (DD, J=7,5, 1.5 Hz, 1H), 7,88(s, 1H), of 7.75 (s, 1H), 7,71 (s, 2H), to 7.67 (m, 1H), EUR 7.57 (t, J=7.5 Hz, 1H), 7,50 (d, J=8.0 Hz, 1H), 7,42 (m, 1H), 7,35-7,28 (m, 3H), of 5.53 (d, J=8.0 Hz, 1H), equal to 4.97 (d, J=15,5 Hz, 1H), 4,25 (d, J=16.0 Hz, 1H), 3,95 (s, 3H), 3,80 (m, 1H), a 2.36 (s, 3H), of 0.48 (d, J=6.5 Hz, 3H).

Stage C: 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Specified in the name of the connection on Stage (30 mg, 0,043 mmol) leave much to be mixed on the night of LiOH (5 EQ.) in a mixture of 2:1 dioxane and water at room temperature. The solvent was removed and the aqueous solution is acidified with 1N HCl solution to pH ~4. Organic matter extracted with EtOAc (3×10 ml). Layers EtOAc unite, washed with saturated RA is tworoom salt and dried over sodium sulfate. Specified in the title compound as a colourless solid substance obtained after HPLC with reversed phase. Range1H NMR (CDCl3, 500 MHz) δ with 8.05 (s, 1H), to 7.99 (d, J=8.0 Hz, 1H), of 7.90(s, 1H), of 7.75 (s, 1H), 7,72 (s, 2H), to 7.67 (m, 1H), to 7.59 (t, J=7.5 Hz, 1H), 7,51 (d, J=8.0 Hz, 1H), 7,44 (m, 1H), 7,37 (m, 2H),7,30 (m, 1H), 5,54 (d, J=8.0 Hz, 1H), to 4.98 (d, J=15,5 Hz, 1H), 4,25 (d, J=16.0 Hz, 1H), 3,81 (m, 1H), 2.40 a (s, 3H), 0,49 (d, J=6.5 Hz, 3H).

LC/MS (M+1) 682,1.

EXAMPLE 56

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6'-fluoro-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage A: (4S,5R)-3-{[3'-amino-4'-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-he

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (1.1 g, of 1.84 mmol), 3-amino-4-ftorhinolonovy acid (0,43 g, was 2.76 mmol), sodium carbonate (0.39 g, 3,68 mmol) and catalytic amount of tetrakis(triphenylphosphine)palladium (0,213 g, 10%mol.) in 14 ml of a mixture of 1:2:4 water:EtOH:toluene is refluxed with stirring for 2 hours. The solvents are removed. Add water (10 ml). The mixture is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Indicated in the name of the connection will receive the Le column flash chromatography, using a mixture of CH2Cl2:hexane/7:3 as eluent. Range1H NMR (CDCl3, 500 MHz) δ 7,89 (s, 1H), 7,73 (s, 2H), of 7.70 (s, 1H), to 7.64 (d, J=8.5 Hz, 1H), 7,42 (d, J=8.0 Hz, 1H), to 7.09 (DD, J=11, 8.5 Hz, 1H), 6,74 (DD, J=8,0,2,5 Hz, 1H), 6,62 (m, 1H), 5,55 (d, J=8.5 Hz, 1H), 4,94 (d, J=15,5 Hz, 1H), 4,23 (d, J=16.0 Hz, 1H), 3,80 (m, 1H), 1,60 (Shir. s, 2H), 0,51 (d, J=6.5 Hz, 3H).

Stage A: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-iodine-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

n-Internetit (0,42 g, 3.58 mmol) and iodine (0.68 g, 2,69 mmol) are added to a solution of the compound indicated in the title on the Stage And (1.04 g, to 1.79 mmol) in chloroform (10 ml). The mixture is stirred at the boil under reflux for 1 hour. The reaction mixture is diluted with methylene chloride (10 ml). The resulting solution was pink washed with saturated sodium thiosulfate solution, saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after carrying out column flash chromatography using EtOAc:hexane/1:9 as eluent. Range1H NMR (CDCl3, 500 MHz) δ of 7.90 (s, 1H), of 7.75 (s, 2H), 7,74 (m, 1H), to 7.67 (d, J=8.0 Hz, 1H), 7,42 (d, J=7.5 Hz, 1H), 7,30 (m, 2H), 7,20 (t, J=8,0 Hz, 1H), 5,55 (d, J=8.0 Hz, 1H), 4,89 (d, J=16.0 Hz, 1H), 4,15 (d, J=16.0 Hz, 1H), 3,84 (m, 1H), 0,51 (d, J=6.5 Hz, 3H).

Stage C: methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}IU the Il)-6'-fluoro-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

The mixture of compounds listed in the title at the Stage In (60 mg, 0,087 mmol), 4-methoxycarbonylpropionyl acid (31,2 mg, 0,174 mmol), sodium carbonate (to 18.4 mg, 0,174 mmol) and catalytic amount of tetrakis(triphenylphosphine)palladium (20 mg, 20%mol.) in 7 ml of a mixture of water/EtOH/toluene (1:2:4) is refluxed for 2 hours. The solvents are removed. Add water (10 ml). The mixture is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after carrying out column flash chromatography using a mixture of CH2Cl2:hexane/7:3 as eluent. Range1H NMR (CDCl3, 500 MHz) δ of 8.15 (d,J= 8.5 Hz, 2H), 7,89(s, 1H), 7,74 (s, 1H), 7,72 (s, 2H), to 7.67 (m, 2H), 7,49 (d, J=8.0 Hz, 1H), 7,43 (d, J=7.5 Hz, 1H), 7,32 (d, J=8.0 Hz, 2H), to 5.57 (d, J=8.0 Hz, 1H), equal to 4.97 (d, J=16,0 Ng, 1H), 4,23 (d, J=16.0 Hz, 1H), of 3.97 (s, 3H), 3,85 (m, 1H), 0,53 (d, J=6.5 Hz, 3H).

Stage D: 2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6'-fluoro-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Specified in the name of the connection on Stage (60 mg, 0,086 mmol) leave much to be mixed at night with LiOH (10 equiv.) in a mixture of 2:1 dioxane and water at room temperature. The solvent was removed and the aqueous solution is acidified with 1N HCl solution to pH ~4. Organically the substances extracted with EtOAc (3×10 ml). Layers EtOAc unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound as a colorless solid substance obtained after HPLC with reversed phase. Range1H NMR (CDCl3, 500 MHz) δ 8,18 (d, J=7,0 Hz, 2H), 7,87(s, 1H), 7,72 (s, 1H), of 7.70 (s, 2H), 7,68 (m, 2H), 7,47 (d, J=6,5 Hz, 1H), 7,42 (d,J=5.5 Hz, 1H), 7,32 (d, J=6,5 Hz, 2H), of 5.55 (d, J=6,5 Hz, 1H)74,96 (d, J=13,0 Hz, 1H), 4,21 (d, J=13,0 Hz, 1H), 3,85 (m, 1H), 0,52 (d, J=5.0 Hz, 3H).

LC/MS M+ 686,06.

The following examples are carried out in accordance with the General methodology described in Example 56.

ExampleRGHMC (M+1)+
57Me700,09
58Cl720,07

The following examples are carried out using (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he (100 mg, 0.14 mmol) from Example 21 with Stage a and the corresponding bromides in accordance with the General methodology described in Example 56 on Stage With.

Example
RGHMC (M+Na)+
59734,20

60734,20

EXAMPLE 61

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-chloro-6-iodine-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage A: methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-chloro-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

To a solution of the compound indicated in the title of Example 40 at Stage E (500 mg, 0,779 mmol) in EtOH (10 ml) add the chloride dihydrate tin (1.64 g, 7,27 mmol). The mixture is stirred at room temperature for 2 hours. Analysis by LC-MS shows complete consumption of the starting materials. EtOH is removed. To the residue add EtOAc (200 ml). The mixture is washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent get a solid substance that is mixed with methyl 4'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-the l)biphenyl-4-carboxylate (Example 48, Stage, 281 mg, 0,727 mmol), tetrakis(triphenylphosphine)palladium (10 mol%) and sodium carbonate (0,154 g, 1,45 mmol) in 32 ml of a mixture of water/EtOH/toluene (1:2:4) and refluxed for 48 hours. Analysis by TLC (EtOAc:hexane/2:8) shows that the reaction is complete. The solvents are removed. Add water (10 ml). The mixture is extracted with methylene chloride (3×30 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after purification column flash chromatography using 20% EtOAc in hexane as eluent. Range1H NMR (CDCl3, 500 MHz) δ to 7.99 (s, 1H), to $ 7.91 (DD, J=8,0, 2.0 Hz, 1H), 7,88(s, 1H), 7,74 (s, 2H), to 7.67 (d, J=8.0 Hz, 1H), 7,42 (DD, J=8,5, 2.0 Hz, 1H), was 7.36 (d, J=8.0 Hz, 1H), 7,30-7,24 (m, 1H), 7,07 (s, 1H), 7,01 (s, 1H), 5,70 (d, J=8.0 Hz, 1H), a 4.83 (d, J=to 15.0 Hz, 1H), 4,01 (m, 1H), 3.96 points (s, 3H), 3,83 (d, J=to 15.0 Hz, 1H), 3,81 (Shir. s, 2H), 2,42 (s, 3H), of 0.68 (d, J=6.0 Hz, 3H).

Stage b: methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-chloro-6-iodine-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

To a solution of the compound indicated in the title at the Stage (285 mg, 0,383 mmol) in chloroform (10 ml) at room temperature add n-internetit (67.2 per mg, 0,574 mmol) and iodine (126 mg, 0,497 mmol). The mixture is refluxed for 1 hour. The reaction mixture is diluted with methylenchlorid the Ohm (10 ml). The resulting solution was washed with saturated sodium thiosulfate solution, saturated salt solution and dried over sodium sulfate. Specified in the title compound as a colourless solid substance obtained after carrying out HPLC with reversed phase. Range1H NMR (CDCl3, 500 MHz) δ 8,24 (s, 1H), to 7.99 (s, 1H), 7,92 (d, J=8,0 Hz, 1H), of 7.90(s, 1H), 7,74 (s, 2H), 7,66 (s, 1H), 7,42 (DD, J=8,5, 2.5 Hz, 1H), 7,34 (d, J=8.0 Hz, 1H), 7,28 (m, 1H), 7,21-7,14 (m, 1H), 5,71 (d, J=8.0 Hz, 1H), 4,78 (d, J=15,5 Hz, 1H), 3,99 (m, 2H), 3.96 points (s, 3H), 2,41 (s, 3H), of 0.65 (d, J=6.5 Hz, 3H).

Stage C: 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-chloro-6-iodine-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

To a solution of the connection specified by name on Stage (30 mg, 0.035 mmol)in dioxane (2 ml) at room temperature, add aqueous solution of LiOH·H2(7.36 mg, 0,175 mmol). The mixture is left overnight to mix at room temperature. Analysis by TLC (EtOAc:hexane/2:8) shows the absence of starting materials. The solvent is removed. Add 1N HCl (1 ml). The mixture is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound as a colourless solid substance obtained after carrying out HPLC with reversed phase.

EXAMPLE 62/b>

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4',6'-debtor-6"-iodine-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Specified in the title compound, receive, using the compound from Example 40 with Stage E, and methyl 4'-fluoro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (Intermediate compound 22), in accordance with the methodology described in Example 61. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1: atropoisomeric compared to 8.26 (s, 0,5H), 8,24 (s, 0,5H), of 8.06 (s, 1H), 7,98 (d, J=8.0 Hz, 1H), to $ 7.91 (s, 1H), of 7.75 (s, 2H), 7,69 (s, 0.5 H), the 7.65 (s, 0,5H), 7,39 (m, 1H), 7,16? 7.04 baby mortality (m, 2H), to 5.66 (d, J=8,0 Hz, 0,5H), 5,64 (d, J=8,5 Hz, 0,5H), 4,88 (d, J=15,5 Hz, 0,5H), to 4.81 (d, J=16.0 Hz, 0,5H), was 4.02 (m, 1H), 3,91(m, 1H), 2,39 (s, 1,5H), a 2.36 (s, 1,5H), 0,70 (d, J=6,5 Hz, 1,5H), 0.69 (d, J=6,5 Hz, 1,5H).

LC/MS (M+1) 844,04.

The following examples are carried out using the compound of Example 56 from the Stage and In the appropriate boranova acid, in accordance with the General methodology described in Example 56 to Stage C.

ExampleRLC/MS
63CF3725,77 (M+)
64Me 672,17 (M+1)+

EXAMPLE 65

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[4"-hydroxy-6'-methoxy-2",4-bis(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl}-4-methyl-1,3-oxazolidin-2-he

Specified in the title compound, receive, using the intermediate compound from Example 1 with Stage a and 4-hydroxy-2-triftormetilfullerenov acid, in accordance with the methodology described in Example 56 to Stage C.

LC/MS (M+1) 737,98.

EXAMPLE 66

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6'-chloro-4"-hydroxy-2",4-bis(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

Specified in the title compound, receive, using the intermediate compound from Example 22 with Stage and 4-hydroxy-2-triftormetilfullerenov acid, in accordance with the methodology described in Example 56 to Stage C.

LC/MS (M+1) 741,70.

EXAMPLE 68

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-sulfonamide

To a solution of 4-bromo-3-methylbenzenesulfonamide (120 mg, of 0.37 mmol) in dioxane (5 ml) at room temperature add concentrated NH4OH (1 ml). The mixture is stirred at room temperature for 4 hours. A solution of compounds of the decree is tion in the name of Example 21 at Stage A (100 mg, 0.14 mmol), sodium carbonate (30 mg, 0.28 mmol) and catalytic amount of tetrakis(triphenylphosphine)palladium (5 mol%) in 14 ml of a mixture of 1:2:4 water/EtOH/toluene is refluxed with stirring for 6 hours. The solvents are removed. Add water (10 ml). The mixture is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after carrying out HPLC with reversed phase. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1 atropoisomeric 7,89 (s, 1H), 7,86 (d, J=7.5 Hz, 1H), 7,79 (d, J=8.0 Hz, 1H), 7,72 (s, 2H), 7,68 (m, 2H), 7,45 (t, J=8.0 Hz, 1H), 7,39 (m, 2H), 7,13 (m, 2H), ceiling of 5.60 (d, J=8,5 Hz, 0,5H), 5,38 (d, J=8,5 Hz, 0,5H), 5,00 (d, J=16.0 Hz, 0,5H), 4,94 (d, J=16.0 Hz, 0,5H), 4,17 (d, J=16.0 Hz, 0,5H), 3,99 (d, J=16.0 Hz, 0,5H), 3,90 (s, 1,5H), to 3.89(s, 1,5H), of 3.84 (m, 1H),2,42 (s, 1,5H), 2,37 (s, 1.5), 1,75 (Shir. s, 2H), 0,59 (d, J=6,5 Hz, 1,5H), of 0.48 (d, J=7,0 Hz, 1,5H).

LC/MS (M+1) 747,20.

EXAMPLE 69

5-[2'-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloro-4'-(trifluoromethyl)biphenyl-3-yl]-1H-1,2,4-triazole-3-carboxamide

Stage A: 2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloro-4'-(trifluoromethyl)biphenyl-3-carbonitril

A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodine-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (0.5 g, 0,837 mmol, 2-chloro-5-cyanophenylacetic acid (0,228 g of 1.26 mmol), sodium carbonate (0.18 g, 1,67 mmol) and catalytic amount of tetrakis(triphenylphosphine)palladium (0,097 g, 10%mol.) in 14 ml of a mixture of 1:2:4 water:EtOH:toluene is refluxed with stirring for 2 hours. The solvents are removed. Add water (10 ml). The mixture is extracted with methylene chloride (3×10 ml). Layers of methylene chloride unite, washed with saturated salt solution and dried over sodium sulfate. Specified in the title compound is obtained after flash column-chromatography using a mixture of CH2Cl2:hexane/8:2 as eluent. Range1H NMR (CDCl3, 500 MHz) δ a mixture of 1:1 atropoisomeric to $ 7.91 (s, 1H), to 7.77-of 7.69 (m, 6H), to 7.61 (d, J=2.0 Hz, 0,5H), 7,58 (d, J=2.0 Hz, 0,5H), 7,42 (d, J=8.0 Hz, 0,5H), 7,38 (d, J=8.0 Hz, 0,5H), of 5.68 (d, J=8.0 Hz, 0,5H), the 5.65 (d, J=8.0 Hz, 0,5H), 4,89 (d, J=15,5 Hz, 0,5H), 4,74 (d, J=16.0 Hz, 0,5H), is 4.03 (d, J=16.0 Hz, 0,5H), 4.00 points (m, 0,5H), 3,91 (d, J=16.0 Hz, 0,5H), 3,90 (m, 0,5H), of 0.67 (d, J=6,5 Hz, 1,5H), 0,65 (d, J=6,5 Hz, 1,5H).

Stage b: ethyl 2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloro-4'-(trifluoromethyl)biphenyl-3-carboximide hydrochloride

The compound obtained in stage A (100 mg, 0,165 mmol) is stirred with a saturated solution of HCl in EtOH (10 ml). The solvent is stirred at room temperature for 2 hours. According to TLC (EtOAc/hexane 2:8), the original substance is absent. Races shall foretell removed and receive a white solid. The resulting material is used for the next stage without purification.

Stage C: 5-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloro-4'-(trifluoromethyl)biphenyl-3-yl]-1H-1,2,4-triazole-3-carboxamide

A mixture of the connection specified by name on Stage (100 mg, 0,145 mmol), hydrazide Aksakovo acid (16.5 mg, 0.16 mmol) and Kaas (17,1 mg, 0,174 mmol) in EtOH (5 ml) is refluxed with stirring for 2 hours. Analysis by LC/MS shows that the reaction is complete. The solvent is removed and indicated in the title compound is obtained after purification by HPLC with reversed phase.

LC/MS (M+1)+692,38.

EXAMPLE 70

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[4-(hydroxymethyl)-6'-methoxy-4"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid (2 g, of 2.81 mmol) and THF (18,74 ml) stirred at 0°C. (bath with ice). To the resulting mixture for 3 min add the complex of borane and tetrahydrofuran (5,90 ml 5,90 mmol). The resulting mixture was stirred at 0°C for 15 min Bath with ice removed. The reaction mixture is additionally stirred at room themes is the temperature value within 1 hour. Analysis by TLC indicates completion of the reaction. The reaction is interrupted by adding water (bath with ice). To the reaction mixture an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated, obtaining a mixture of dark colors. The obtained dark mixture was purified flash chromatography (SiO2cartridge Biotage 40+M). Column elute with a mixture of EtOAc/hexane (0% to 40%). Collect the appropriate fractions are pooled and evaporated, getting listed in the name of the connection. IHMS (ESI): calculated = 697,19; found = 680,29 (M-HE-)+. Range1H NMR (CDCl3, 400 MHz, mixture 1:1 of atropisomers) δ 7,83 (d, J=4 Hz, 1H), 7,71 (s, 0,5H), to 7.67 (s, 1H), 7,66-7,58 (m, 2,5H) 7,43 (d, J=8 Hz, 0,5H), 7,40 (d, J=8 Hz, 0,5H), 7,38-7,32 (m, 1H), 7,28-of 7.23 (m, 1H), 7,22-7,14 (m, 2H), 7,12 (s, 1H), 7,05 (d, J=5,GC, 0,5H), 7,03 (d, J=5.6 Hz, 0,5H), to 5.56 (d, J=8,4 Hz, 0,5H), 5,23 (d, J=8 Hz, 0,5H), equal to 4.97 (d, J=10,8 Hz, 0,5H), is 4.93 (d, J=10,8 Hz, 0,5H), and 4.68 (s, 2H), 4,15 (d, J=15.6 Hz, 0,5H), 3,95 (d, J= 15.6 Hz, 0,5H), 3,85 (s, 1,5H), 3,83 (s, 1,5H), 3,80-3,66 (m, 1H), 2,32 (s, 1,5H), and 2.26 (s, 1,5H), 0,52 (d, J=6,8 Hz, 1,5H), 0,38 (d, J=6,8 Hz, 1,5H).

EXAMPLE 71

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2',6'-debtor-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage A: 2-(2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

1-Bromo-2-fluoro-4-methoxybenzo (750 mg, 3.65 mmol), potassium acetate (718 mg, to 7.32 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (300 mg, 0,367 mmol), bis(pinacolato)diboron (984 mg, 4,39 mmol) and 1,4-dioxane (10 ml), sealed in a vessel for RF heating and subjected to RF heating to a temperature of 140°C in total for 50 min (40 min + 10 min). Analysis of the aliquot method IHMS indicates complete consumption of the starting materials. The reaction mixture was filtered through a layer of celite (521). The filtrate is washed with saturated salt solution, extracted with EtOAc, dried over Na2SO4, filtered, evaporated and get the mixture mentioned in the title compound as a dark oil. It is used as is in the next stage. IHMS (ESI): calculated = 252,13; found = 253,09 (M+1)+.

Stage b: methyl 2,2'-debtor-4'-methoxybiphenyl-4-carboxylate

2-(2-Fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (600 mg, of 2.38 mmol), methyl 4-bromo-3-perbenzoate (665 mg, 2,856 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (292 mg, 0,358 mmol), potassium carbonate (2.38 ml, aqueous solution, 2 M, 4.76 mmol) and 1,4-dioxane (10 ml), sealed and subjected to RF heating to a temperature of 145°C for 15 minutes Analysis of an aliquot indicates the formation of the desired connection. TLC (20% EtOAc/hexane) gives a bright pink spot @ Rf=0.4 are. React the mixture was dried over Na 2SO4and then purified flash chromatography (SiO2cartridge Biotage 40+M). Column elute the mixture from 0% to 20% EtOAc/hexane. Collect the appropriate fractions are pooled and concentrated in vacuo, getting listed in the name of the connection. IHMS (ESI): calculated = 278,08; found = 279,09 (M+1)+.

Stage C: methyl 2,2'-debtor-5'-iodine-4'-methoxybiphenyl-4-carboxylate

Methyl 2,2'-debtor-4'-methoxybiphenyl-4-carboxylate (585 mg, 2.10 mmol), methanol (10 ml), iodine (534 mg, 2.10 mmol), silver sulfate (655 mg, 2.10 mmol) was stirred at room temperature. IHMS indicates the formation of the desired connection. The reaction mixture is washed with NaHSO3(saturated aqueous solution). The resulting mixture is remove all volatiles. The residue is successively treated with Na2SO4/EtOAc/filtration/concentration and get a solid light brown color. The crude product was purified flash chromatography (SiO2cartridge Biotage 40+M). Column elute the mixture from 0% to 20% EtOAc/hexane. 5 major fractions were accidentally spilled. Other appropriate fractions are combined and concentrated in vacuo, getting listed in the name of the connection. IHMS (ESI): calculated = 403,97; found = 404,92 (M+1)+.

Stage D: methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)Fe is Il]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2',6'-debtor-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

Methyl 2,2'-debtor-5'-iodine-4'-methoxybiphenyl-4-carboxylate (100 mg, 0,247 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-he (Intermediate compound 9, 179,2 mg, 0.30 mmol), sodium carbonate (247 μl, aqueous solution, 2 M, 0,494 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (40 mg, 0,049 mmol) and 1,4-dioxane (2.1 ml) is heated to 80°C in oil bath for 8 hours. Analysis of an aliquot indicates the formation of the desired product. The reaction mixture was concentrated under reduced pressure. The residue is treated sequentially N2O/EtOAc/Na2SO4/filtration followed by concentration and get a dark oil. The resulting oil purified by HPLC with reversed phase (Waters SunFire PrepC18 OBD 5 μm, 30×100 mm), performing a gradient elution with a mixture of MeCN (0.05% of TFA, vol./vol.)/H2About (0.05% of TFA, vol./about.) (from 10 to 100% over 12 min, maintain 100% for 3 min). The appropriate fractions are collected, combined and evaporated in vacuum, obtaining a dark oil. The specified oil is further purified on SiO2(preparative TLC, 30% EtOAc/hexane) and get listed in the name of the connection. IHMS (ESI): calculated = 747,15; found = 748,20 (M+1)+.

Stage E: 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin the-3-yl}methyl)-2',6'-debtor-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2',6'-debtor-4'-methoxy-4"-(three-permitil)-1,1':3',1"-terphenyl-4-carboxylate (50 mg, 0,067 mmol), monohydrate of lithium hydroxide (28 mg, 0.67 mmol), water (1 ml) and 1,4-dioxane (2 ml) was stirred at room temperature for 2.5 hours. Analysis of the aliquot method IHMS indicates the formation of the desired product and the complete withdrawal of the original substances. The reaction mixture is acidified (1N HCl, aqueous solution). Volatiles are removed under reduced pressure. The residue is dissolved in MeCN and purified by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), elwira a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions are collected, combined and evaporated in vacuum, obtaining a mixture. The resulting mixture was extracted with EtOAc. The organic phase is separated, washed again with water, separated, dried over Na2SO4, filtered and evaporated, getting listed in the name of the connection. IHMS (ESI): calculated = 733,13; found = 734,14 (M+1)+. Range1H NMR (CDCl3, 500 MHz, mixture 1:1 of atropisomers) δ of 7.95 (t, J=6 Hz, 1H), 7,89-7,83 (m, 2H), 7,73 (s, 0,5H), 7,71 (s, 1H), 7.68 per-to 7.64 (m, 2H), 7.62mm (s, 0,5H) 7,58 (t, J=7 Hz, 0,5H), 7,53 (t, J=7.5 Hz, 0,5H), 7,42 (d, J=8 Hz, 0,5H), 7,39 (d, J=8 Hz, 0,5H), 7,31-of 7.23 (m, 1H), 6.89 in (d, J=4 Hz, 0,5H), 6.87 in (d, J=3,5 Hz, 0,5H), 5,61 (d, J=8 Hz, 0,5H), from 5.29 (d, J=8 Hz, 0,5H), of 5.05 (d, J=16 Hz, 0,5H)that is 4.93 (d, J=16 Hz, 0,5H), 4,16 (d, J=16.5 Hz, 0,5H), of 3.94 (d,J=16 Hz, 0,5H), to 3.89 (s, 1,5H), a 3.87 (s, 1,5H), 3,85-and 3.72 (m, 1H), 0,59 (d, J=Hz, 1,5H), 0,43 (d, J=6 Hz, 1,5H).

EXAMPLE 72

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-chloro-6'-fluoro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage A: methyl 2-amino-2'-fluoro-4'-methoxybiphenyl-4-carboxylate

1-Bromo-2-fluoro-4-methoxybenzo (750 mg, 3,66 mmol), [2-amino-4-(methoxycarbonyl)phenyl]Bronevoy acid (856 mg, 4,39 mol), potassium acetate (3,66 ml, 2 M aqueous solution, to 7.32 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (299 mg, 10%mol.) and ethanol (30 ml) is heated on an oil bath to 80°C for 3 hours. The reaction mixture is washed with saturated salt solution, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated and get a dark oil. Specified oil purified on SiO2(Biotage Horizon Flash system, the cartridge 40+M, 0-25% EtOAc/hexane, vol./about.) and get listed in the name of the connection. IHMS (ESI): calculated = 275,10; found = 276,09 (M+1)+.

Stage b: methyl 2-chloro-2'-fluoro-4'-methoxybiphenyl-4-carboxylate

Amyl nitrate (420 μl, 3,19 mmol) and copper chloride(II) (343 mg, 2.55 mmol) suspended in acetonitrile (5 ml) and heated to 65°C. on an oil bath under stirring on a magnetic stirrer. To pointed to by the second hot mixture is added methyl 2-amino-2'-fluoro-4'-methoxybiphenyl-4-carboxylate (585 mg, 2,13 mmol,in 5 ml MeCN) for about 1 min the resulting mixture was heated to 65°C. on an oil bath for 2 hours. The reaction mixture is purified on SiO2(Biotage Horizon Flash system, the cartridge 40+M, 0-20% EtOAc/hexane, vol./about.) and get listed in the name of the connection. IHMS (ESI): calculated = 294,05; found = 295,03 (M+1)+.

Stage C: methyl 2-chloro-2'-fluoro-5'-iodine-4'-methoxybiphenyl-4-carboxylate

Methyl 2-chloro-2'-fluoro-4'-methoxybiphenyl-4-carboxylate (550 mg, of 1.87 mmol), methanol (8 ml), iodine (474 mg, of 1.87 mmol) and silver sulfate (583 mg, of 1.87 mmol) was stirred at room temperature for 2 hours. The reaction mixture is washed with NaHSO3(saturated aqueous solution). From the resulting mixture under reduced pressure to remove volatile substances. The residue is washed with saturated salt solution, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated, getting a solid light brown color. Specified, the solid is purified on SiO2(Biotage Horizon Flash system, the cartridge 40+M, 0-20% EtOAc/hexane, vol./about.) and get listed in the name of the connection. IHMS (ESI): calculated = 419,94; found = 420,86 (M+1)+.

Stage D: methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-chloro-6'-fluoro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxyl the t

Methyl 2-chloro-2'-fluoro-5'-iodine-4'-methoxybiphenyl-4-carboxylate (177 mg, 0.42 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-he (Intermediate compound 9, 250 mg, 0.42 mmol), potassium carbonate (0,42 µl aqueous solution, 2 M, 0.84 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (51 mg, 0.06 mmol) and 1,4-dioxane (2 ml), sealed and subjected to RF heating to 140°C for 15 min Analysis aliquots (IHMS) indicates complete consumption of starting compounds and the formation of the desired product. The reaction mixture was sequentially treated with N2O/EtOAc/Na2SO4/filtration/concentration and get a dark oil. The resulting oil purified on SiO2(preparative TLC, 5% EtOAc/5% hexane/90% DCM) and receive the product and impurities in the form of a dark oil. Specified oil cleanse method preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm)through gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions are collected, combined and evaporated in a vacuum, receiving 250 mg of glassy substances dark green color. Analysis by TLC (30% EtOAc/hexane) gives a dark main spot and traces of impurities below and above the spot connection. Specified glassy substance dark green color is the further purified on SiO 2(preparative TLC, 100% DCM) and get listed in the name of the connection. IHMS (ESI): calculated = 763,12; found = 764,09 (M+1)+.

Stage E: 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-chloro-6'-fluoro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-chloro-6'-fluoro-4'-methoxy-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (84,5 mg, 0.11 mmol), monohydrate of lithium hydroxide (46.2 mg, 1.1 mmol), water (1 ml) and 1,4-dioxane (2 ml) was stirred at room temperature. The analysis method IHMS aliquots taken after 2 hours from the start of the reaction, indicates completion of the reaction. Volatiles are removed under reduced pressure. The residue is dissolved in MeCN and acidified with HCl (1N solution)to give a clear solution. This solution purified by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm)through gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions are collected, combined and evaporated in vacuum, obtaining a colorless glassy substance. Specified glassy substance is dissolved in DCM and washed with water. The organic extracts are combined, dried over Na2SO4, filtered and evaporated, the floor, the tea is indicated in the name connection. IHMS (ESI): calculated = 749,10; found = 750,06 (M+1)+. Range1H NMR (CDCl3, 500 MHz, mixture 1:1 of atropisomers) δ 8,21 (DD, J=10, 2 Hz, 1H), 8,03 (DD, J=8,2 Hz, 1H), 7,86 (s, 1H), 7,73-to 7.68 (m, 1,5H), 7.68 per to 7.62 (m, 2,5H), of 7.48 (t, J=7.5 Hz, 1H), 7,41 (DD, J=11, 8 Hz, 1H), 7,17 (DD, J=8,5, 2 Hz, 1H), 6,86 (DD, J=11 and 3.5 Hz, 1H), 6,60 (d, J=8 Hz, 0,5H), of 5.40 (d, J=8 Hz, 0,5H), 4,94 (t, J=15 Hz, 1H), 4,18 (d, J=16 Hz, 0,5H), 3,95 (d, J=16 Hz, 0,5H), a 3.87 (s, 3H), 3,85-3,74 (m, 1H), 0,56 (d, J=6,5 Hz, 1,5H), and 0.46 (d, J=6,5 Hz, 1,5H).

EXAMPLE 73

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4',6'-debtor-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage A: methyl 5'-amino-2',4'-debtor-2-methylbiphenyl-4-carboxylate

1-Bromo-2,4-diptiranjan (500 mg, is 2.40 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Intermediate compound 16, 797 mg, is 2.88 mmol), sodium carbonate (2,40 ml, 2 M aqueous solution, is 2.88 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (196 mg, 0.24 mmol) and ethanol (15 ml) is heated to 80°C in oil bath for 3 hour, and then left overnight to cool to room temperature. Volatiles are removed under reduced pressure. The residue is successively subjected to treatments DCM/saturated salt solution/Na2SO4/filtration/concentration and get a dark oil. Specified oil clean the lash-by chromatography (SiO 2cartridge Biotage 40+M). The column is washed in a gradient from 0% to 40% EtOAc/hexane. The appropriate fractions are collected and concentrated in vacuo, getting listed in the name of the connection. IHMS (ESI): calculated = 277,09; found = 278,03 (M+1)+.

Stage b: methyl 2',4'-debtor-5'-iodine-4'-methylbiphenyl-4-carboxylate

Methyl 5'-amino-2',4'-debtor-2-methylbiphenyl-4-carboxylate (550 mg, of 1.80 mmol), 3-methylbutyronitrile (317 mg, a 2.71 mmol), iodine (549 mg, of 2.16 mmol) and chloroform (15 ml) is refluxed on an oil bath for 5 hours and then left overnight to cool to room temperature. The reaction mixture was purified flash chromatography (SiO2cartridge Biotage 40+M) gradient elution in a mixture of EtOAc/hexane. The appropriate fractions are collected and concentrated in vacuo, getting listed in the name of the connection. IHMS (ESI): calculated = 387,98; found = 388,92 (M+1)+.

Stage C: methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4',6'-debtor-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

Methyl 2',4'-debtor-5'-iodine-4'-methylbiphenyl-4-carboxylate (100 mg, 0.26 mmol,dissolved in 1 ml ethanol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-he (Intermediate compound , 185 mg, 0.31 mmol,dissolved in 2.2 ml of 1,4-dioxane), sodium carbonate (258 μl, 2 M aqueous solution, 0,516 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (42 mg, 0.05 mmol) is heated to 80°C for 2 hours. Analysis of the aliquot method IHMS indicates complete reaction. The reaction mixture is dried/Na2SO4and then put on 2 plates preparative TLC (SiO2). Records show a mixture of 20% EtOAc/hexane and receive a colorless glassy substance. Specified glassy substance is additionally cleaned by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm)through gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions are collected, combined and evaporated in vacuum, obtaining a colorless glassy substance. Specified glassy substance is dissolved in DCM and washed with water. The organic extracts are combined, dried over Na2SO4, filtered and evaporated, getting listed in the name of the connection. IHMS (ESI): calculated = 731,15; found = 732,06 (M+1)+.

Stage D: 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4',6'-debtor-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazol the DIN-3-yl}methyl)-4',6'-debtor-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (of 73.5 mg, 0.10 mmol), monohydrate of lithium hydroxide (42 mg, 1 mmol), water (1 ml) and 1,4-dioxane (2 ml) was stirred at room temperature for 2 hours. Volatiles are removed under reduced pressure. The residue is dissolved in a mixture of MeCN/1N HCl (aqueous solution) and purified by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm)through gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions are collected, combined and evaporated in a vacuum, getting listed in the name of the connection. IHMS (ESI): calculated = 717,14; found = 718,17 (M+1)+. Range1H NMR (CDCl3, 500 MHz) δ of 8.04 (s, 1H), of 7.97 (d, J=8 Hz, 1H), 7,88 (s, 1H), 7,74-to 7.67 (m,4H), 7,51 was 7.45 (m, 1H), 7,34 (d, J=8 Hz, 1H), 7,19 (Shir. s, 1H), to 7.09 (t, J=9 Hz, 1H), 5,59 (d, J=8 Hz, 1H), 5.08 to 4,80 (m, 1H), 4,20-of 3.78 (m, 2H), 2,32 (s, 3H), and 0.62 (s, 3H).

EXAMPLE 74

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6'-fluoro-4'-methoxy-3-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Stage A: 2'-fluoro-4'-methoxy-3-methylbiphenyl-4-amine

(2-Fluoro-4-methoxyphenyl)baronova acid (356,7 mg, 2.1 mmol), 4-bromo-2-methylaniline (391 mg, 2.1 mmol), potassium carbonate (3.15 ml, 2 M aqueous solution, 6.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (257 mg, 0.31 in%mol.) and ethanol (12 ml) is heated to 80°C in oil the bath. According to TLC (40% EtOAc/hexane) and IHMS reaction was completed after 1 hour. Volatiles are removed under reduced pressure. The residue is successively subjected to treatments DCM/saturated salt solution/Na2SO4/filtration/concentration and get a dark oil. Specified oil purified flash chromatography (SiO2cartridge Biotage 40+M). The column is washed in a gradient from 0% to 40% EtOAc/hexane. The appropriate fractions are collected and concentrated in vacuo, getting listed in the name of the connection. IHMS (ESI): calculated = 231,11; found = 232,09 (M+1)+.

Stage b: 2'-fluoro-4'-iodine-3-methylbiphenyl-4-yl methyl ether

2'-Fluoro-4'-methoxy-3-methylbiphenyl-4-amine (190 mg, 0,822 mmol), 3-methylbutyronitrile (144,4 mg, 1,233 mmol), iodine (251 mg, 0,986 mmol) and chloroform (7 ml) is refluxed on an oil bath for 3.5 hours and then left overnight to cool to room temperature. The reaction mixture was purified flash chromatography (SiO2cartridge Biotage 40+M)through gradient elution with mixture of EtOAc/hexane. The appropriate fractions are collected and concentrated in vacuo, getting listed in the name of the connection. The analysis method IHMS shows that the solid material has a purity of about 70 %. IHMS (ESI): calculated = 341,99; found = 241,94 (M)+.

Stage C: methyl 2'-fluoro-4'-methoxy-3-methylbiphenyl-4-carboxylate

2'-Fluoro-4'-iodine-3-methylbiphenyl-4-yl methyl ester (289 mg, 0,845 mmol), chloride TRANS-bis(triphenylphosphine)palladium(II) (59.3 mg, 0.08 mmol), triethylamine (177 μl, of 1.27 mmol) and methanol (5 ml) is shaken in an atmosphere of carbon monoxide (50 psi) at 60°C for 17 hours. Analysis of an aliquot indicates complete consumption of starting compounds and gives the peak m/e 275 (main peak). The reaction mixture is purified on SiO2(preparative TLC, 20% EtOAc/hexane) and get listed in the name of the connection. IHMS (ESI): calculated = 274,10; found = 275,09 (M+1)+.

Stage D: methyl 2'-fluoro-5'-iodine-4'-methoxy-3-methylbiphenyl-4-carboxylate

Methyl 2'-fluoro-4'-methoxy-3-methylbiphenyl-4-carboxylate (100 mg, 0,365 mmol), methanol (3 ml), iodine (93 mg, 0,366 mmol) and silver sulfate (114 mg, 0,366 mmol) was stirred at room temperature for 1.5 hour. The reaction is interrupted by adding Na2SO3(saturated aqueous solution). Volatile substances are removed from the grey-brown mixture. The residue is successively subjected to the treatments of N2O/EtOAc/Na2SO4/filtration/concentration and get listed in the name of the connection. IHMS (ESI): calculated = 400,00; found = 400,96 (M+1)+.

Stage E: methyl 2"-({(4S,5R)-5-[3,5-bis(three is tormentil)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6'-fluoro-4'-methoxy-3-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

Methyl 2'-fluoro-5'-iodine-4'-methoxy-3-methylbiphenyl-4-carboxylate (135 mg, of 0.337 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-he (Intermediate compound 9, 403 mg, 0,675 mmol,dissolved 2.75 ml 1,4-dioxane), sodium carbonate (337 μl, 2 M aqueous solution, 0,674 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (55 mg, 0.07 mmol) is heated on an oil bath to 80°C for 2 h and then left overnight to cool to room temperature. Add a further amount of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-she (Intermediate compound 9, 200 mg, 0,335 mmol,dissolved 2.35 ml of 1,4-dioxane) and continue heating for another 2 hours. Analysis of an aliquot indicates the presence of M+23 (IHMS). The reaction mixture is cooled, dried/Na2SO4and then put on a plate preparative TLC (SiO2). Records show a mixture of 30% DCM/hexane and receive 350 mg oil green colors. Specified green oil/glassy substance is additionally cleaned by the method of preparative TLC (SiO2, 20% EtOAc/hexane) and get listed in the name of the connection. IHMS (ESI): calculated = 743,17; found = 744 (M+1)+.

Stage F: 2"-({(4S,5)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6'-fluoro-4'-methoxy-3-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

Methyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6'-fluoro-4'-methoxy-3-methyl-4"-(three-permitil)-1,1':3',1"-terphenyl-4-carboxylate (55 mg, 0,074 mmol), monohydrate of lithium hydroxide (31 mg, of 0.74 mmol), water (1 ml) and 1,4-dioxane (2 ml) and left overnight to mix at room temperature. Analysis of the aliquot method IHMS indicates complete reaction. The reaction mixture is acidified with HCl (1N aqueous solution). Volatiles are removed under reduced pressure. The residue is dissolved in a mixture of water/MeCN and purified by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm)through gradient elution with a mixture of MeCN (0.1% of TFA, vol./vol.)/H2About (0.1% of TFA, vol./vol.). The appropriate fractions are collected, combined and evaporated in vacuum, obtaining a glassy substance is light yellow in color. The specified residue is dissolved in EtOAc and washed with water (10 ml ×2), separated, dried over Na2SO4filter and concentrate, getting listed in the name of the connection.

IHMS (ESI): calculated = 729,16; found = 730,15 (M+1)+Spectr1H NMR (CDCl3, 500 MHz, mixture 1:1 of atropisomers) δ 8,10 (t, J=7.8 Hz, 1H), a 7.85 (d, J=5 Hz, 1H), of 7.70 (s, 1,5H), 7,66 (d, J=8 Hz, 1H), 7.62mm (s, 1,5H), 7,47-7,38 (m, 3H), 7,30-7,25 (m, 1H), 6,85 (DD, J=12,5,3 Hz, 1H), 5,61 (d, J=8gts, 0,5H), 5,31 (d,J= 8 Hz, 0,5H), 4,94 (d, J=4.5 Hz, 0,5H), 4,91 (d, J=4 Hz, 0,5H), is 4.15 (d, J=16.5 Hz, 0,5H), 3,93 (d, J=16 Hz, 0,5H), 3,86 (s, 3H), 3,86 is 3.76 (m, 1H), 2,68 (s, 3H), or 0.57 (d, J6,5 Hz, 1,5H), and 0.46 (d, J=6,5 Hz, 1,5H).

EXAMPLE 75

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-N,N,2-trimethyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxamid

2"-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid (Example 30, 300 mg, 0.42 mmol), hydrochloride N-methylmethanamine (41 mg, 0.50 mmol), hydrochloride of N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide (121 mg, 0,63 mmol), hydrate 1H-1,2,3-benzotriazol-1-ol (86 mg, 0,56 mmol) and triethylamine (146 μl, 1.05 mmol) was stirred in DCM (5 ml) at room temperature for 1.5 hour. Analysis of aliquots taken after the specified time, shows the formation of the desired product and the complete withdrawal of the original substances. The reaction mixture was diluted with MeCN and purified by the method of preparative HPLC with a reversed phase Kromasil 100-5C18, 100×21,1 mm), elwira mixture (acetonitrile + 0.1% of TFA, vol./vol.)/(H2O + 0.1% of TFA, vol./about.) (from 10% to 100% during 10 min, then put in 100% for 2 min, 20 ml/min) and get a solid substance in the form of foam. The above foam was dissolved in EtOAc and washed with NaHCO3(saturated aqueous solution), and then water. The aqueous phase is separated from the extracts. The aqueous phase are combined and again extracted with EtOAc. Extracts of Yedinaya, dried over Na2SO4, filtered and concentrated in vacuo, getting listed in the name of the connection. IHMS (ESI): calculated = 738,21; found = 739,41 (M+1)+. Range1H NMR (CDCl3, 500 MHz, mixture 1:1 of atropisomers) δ a 7.85 (s, 0,5H), 7,71 (s, 0,5H), of 7.69 (s, 1H), to 7.67 to 7.62 (m, 2,5H), 7,44 (d, J=8 Hz, 0,5H), 7,41 (d, J=8,5 Hz, 0,5H), was 7.36 (t, J=7.5 Hz, 1H), 7,32 (d, J=8 Hz, 1H), 7,25 (s, 0,5H), of 7.23 (s, 1H), 7,19 (d, J=8 Hz, 0,5H), 7,12 (t, J= 2 Hz, 1H), 7,07 (d, J=7 Hz, 0,5H), 7,05 (d, J=7 Hz, 0,5H), to 5.58 (d, J=8 Hz, 0,5H), and 5.30 (d, J=8 Hz, 0,5H), 4,96 (d, J=16 Hz, 1H), 4.16 the (d, J=16 Hz, 0,5H), of 3.97 (d, J=15,5 Hz, 0,5H), 3,86 (s, 3H), 3,81-to 3.73 (m, 1H), 3,11 (s, 3H), to 3.02 (s, 3H), 2,33 (s, 1,5H), and 2.27 (s, 1,5H), 0,54 (d,J=6,5 Hz, 1,5H), 0,41 (d, J=6,5 Hz, 1,5H).

The following connections receive in accordance with the General methodology described in Example 21.

ExampleRxData LC/MS
76685,1
77726,1
78732,0
8016,2

The following connections receive in accordance with the General methodology described in Example 1.

ExampleRxData LC/MS
81670,3
82671,3

EXAMPLE 83

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-(1-glycopolypeptides-4-yl)-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

Stage A: 2-[4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine-1-yl]-2-oxoethyl acetate

To a stirred solution of 4-(2-fluoro-5-iodine-4-methoxy-phenyl)piperidine (50 mg; 0,149 mmol) in DMF (1.2 ml) in an atmosphere of nitrogen was added N,N-diisopropylethylamine (26 μl; 0,149 mmol), and then acetoxyacetyl (16 μl, 0,149 mmol). The resulting solution was stirred at room temperature for 5 hours. The reaction mixture is redistributed between EtOAc (25 ml) and a saturated solution of NaHCO3(25 ml). The aqueous layer was extracted with EtOAc (3×25 ml), the organic fractions are combined and washed with water and saturated the second salt solution each time (25 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified flash chromatography on silica gel, elwira a mixture of EtOAc/hexane, and get 2-[4-(2-fluoro-5-iodine-4-methoxyphenyl]piperidine-1-yl-2-oxoethyl acetate as a colorless oil. IHMS = 435,8 (M+1)+. Range1H NMR (CDCl3, 500 MHz) δ 7,52 (d, J=8,2 Hz, 1H), 6,56 (d, J=and 12.2 Hz, 1H), amounts to 4.76 (s, 2H), 4,76-4,70 (m, 1H), 3,85 (s, 3H), 3,76 (Shir. d, J=13 Hz, 1H), 3,17 (t, J=12,6 Hz, 1H), 2,98 (TT, J=12.1 is of 3.4 Hz, 1H), 2,68 (t, J=12,4 Hz, 1H), measuring 2.20 (s, 3H), 1,90-to 1.82 (m, 2H), 1.70 to of 1.62 (m, 2H).

Stage b: 2-{4-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]piperidine-1-yl}-2-oxoethyl acetate

To a mixture of 2-[4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine-1-yl]-2-oxoethyl acetate (stage A; 33 mg; 0,076 mmol) and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-she (Intermediate connection 9, 68 mg, 0,114 mmol) is added 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (~5 mg), as described previously. The product was then purified by the method of chiral HPLC (column ChiralPak IA, 15% isopropanol/heptane) and get 2-{4-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]piperidine-1-yl}-2-oxoethyl acetate as a colourless glassy substance. IHMS = 779,0 (M+1)+. Range1 H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7,86 (s, 1H), 7,69 (s, 2H), 7.68 per-of 7.60 (m, 2H), 7,32 (d, J=7.8 Hz, 1H), of 6.96-6,91 (m, 1H), 6,72 (DD, J=11,9, and 2.1 Hz, 1H), 5,59 is 5.54 (m, 1H), 4,90 (d, J=15.6 Hz, 1H), 4.80 to the 4.65 (m, 3H), 4,13-4,04 (m, 1H), 3,88-and 3.72 (m, 2H), of 3.78 (s, 3H), 3,21 totaling 3.04 (m, 2H), 2,72-to 2.67 (m, 1H), 2,17 (s, 3H), 1,96 of-1.83 (m, 2H), 1.70 to to 1.59 (m, 2H), 0,42 to 0.39 (m, 3H).

Stage C: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-(1-glycopolypeptides-4-yl)-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-he

To a stirred solution of 2-{4-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]piperidine-1-yl}-2-oxoethyl acetate (24 mg, 0,031 mmol) in Meon (1 ml) under nitrogen atmosphere add the methoxide sodium (6,66 mg, 0,031 mmol). The resulting mixture was stirred at room temperature for 15 minutes Add water (10 ml) and the mixture extracted with EtOAc (3×10 ml). The organic fractions are combined and washed with saturated salt solution (10 ml), dried over MgSO4), filtered and concentrated in vacuo. The residue is purified flash chromatography on silica gel (0-100% EtOAc/hexane) and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-(1-glycopolypeptides-4-yl)-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-it is in the form of a yellow resin. IHMS = 737,1 (M+1)+. Range1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7,87 (s, 1H), 7,69 (s, 2H), 7.68 per-7,0 (m, 2H), 7,34-7,30 (m, 1H), of 6.96-6,91 (m, 1H), 6,72 (d, J=11,9 Hz, 1H), 5,44 (d, J=7.8 Hz, 1H), 4,90 (d, J=15,8 Hz, 1H), 4,78-4,70 (m, 1H), 4,18 is 4.13 (m, 2H), of 3.78 (s, 3H), 3,62-of 3.54 (m, 1H), 3.15 and was 3.05 (m, 2H), 2,82-by 2.73 (m, 1H), 1,96-of 1.84 (m, 2H), 1.70 to of 1.52 (m, 4 H), of 0.43 to 0.39 (m, 3H).

The following compounds receive in accordance with the General method outlined in Example 83.

ExampleRGHMC (M+1)+
84721,0
85isomer And735,2
86isomer735,2
87
isomer
735,2

88
the D isomer
735,2
89703,0
90719,2
91
racemic mixture
737,5
92751,2
93765,5

EXAMPLE 94

tert-Butyl 4-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]piperidine-1-carboxylate

To a mixture of tert-butyl 4-(2-fluoro-5-iodine-4-methoxyphenyl)piperidine-1-carboxylate (58 mg, 0.133 mmol) and (4S,5R)-5-[3,5-bis(tri-permitil)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-she (111 mg, 0,187 mmol) is added 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (~10 mg), as described previously. The product was then purified by the method of chiral HPLC (column ChiralPak OD, 10% isopropanol/heptane) and obtain tert-butyl 4-[2'-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]piperidine-1-carboxylate as a colorless glassy substance. IHMS = 678,8 (M+1-100)+. Range1H NMR (CDCl 3, 500 MHz, mixture of atropisomers) δ 7,86 (s, 1H), 7,69 (s, 2H), of 7.64-to 7.61 (m, 2H), 7,32 (d, J=8 Hz, 1H), of 6.96 (d, J=8,4 Hz, 1H), 6,70 (d, J=11,9 Hz, 1H), to 5.57 (d, J=8 Hz, 1H), 4,88 (d, J=15,8 Hz, 1H), 4.26 deaths-4,17 (m, 2H), 3,86 (d, J=15,8 Hz, 1H), 3,83-of 3.78 (m, 1H), of 3.77 (s, 3H), 3,01-of 2.93 (m, 1H), 2,84 is 2.75 (m, 2H), 1,84 was 1.69 (m, 2H), 1,64 of 1.50 (m, 2H), 1,45 (s, 9 H), 0,38 (d, J=6,7 Hz, 3H).

EXAMPLE 95

Methyl 2"-{[(4S,5R)-5-(3-forfinal)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

At 0°C to a solution of (4S,5R)-5-(3-forfinal)-4-methyl-1,3-oxazolidin-2-it (16.2 mg, 0,0830 mmol) in DMF (1 ml) was added NaHMDS (83 μl, 0,083 mmol). Then the cannula add a solution of methyl 2-(methyl bromide)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (49 mg, 0,0996 mmol) in DMF (1 ml). After 5 min the reaction is interrupted with a saturated solution of NH4Cl (10 ml) and diluted with EtOAc (20 ml). The aqueous layer was extracted with EtOAc (20 ml) and the organic fractions combined, washed with saturated salt solution (10 ml), dried over Na2SO4filter and concentrate. The residue is purified flash chromatography on silica gel (5 to 25% EtOAc/hexane) and get methyl 2"-{[(4S,5R)-5-(3-forfinal)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. IHMS = 608,2 (M+1-100)+. Range1H NMR (CDCl3, 500 MHz, there are rotamer) δ 7,94 (d, J=59 Hz, 1H), 7,87 (d, J=7.8 Hz, 1H), 7,71-to 7.61 (m, 2H), 7,41 and 7.36 (m, 2H), 7,33-7,24 (m, 2H), 7,14-7,12 (m, 1H), 7,07-7,05 (m, 1H), 7,02-of 6.90 (m, 3H), 5,46 (d, J=8,2 Hz), 5,24 (d, J=8,2 Hz), the 4.90 (d, J=15,8 Hz), 4,82 (d, J=15,8 Hz), 4,20 (d, J=15,8 Hz), of 3.97 (d, J=15,8 Hz)to 3.92 (s, 3H), of 3.95 (s, 3H), 3.75 to at 3.69 (m, 1H), 2,36 (C)2,31 (C)of 0.53 (d, J=6.6 Hz), 0,43 (d, J=6,6 Hz).

EXAMPLE 96

Methyl 2"-{[(4S,5S)-5-(5-chloro-2-thienyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

To a solution of (4S,5S)-5-(5-chloro-2-thienyl)-4-methyl-1,3-oxazolidin-2-it (39.9 mg, 0,184 mmol) in DMF (1.8 ml) is added t-BuOK (21.1 mg, 0,183 mmol). The reaction mixture was stirred for 15 min, and then the cannula add a solution of methyl 2-(methyl bromide)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (90 mg, 0,184 mmol) in DMF (2 ml). The reaction mixture was stirred at room temperature for 1 hour, and then interrupt the reaction with a saturated solution of NH4Cl (10 ml) and diluted with EtOAc (20 ml), washed with saturated salt solution (10 ml), dried over Na2SO4filter and concentrate. The residue is purified by chromatography with reversed phase (C-18, 10 to 95% MeCN/water with 0.1% TFA) and get methyl 2"-{[(4S,5S)-5-(5-chloro-2-thienyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. Rf= 0,43 (50% EtOAc/hexane). IHMS = 629,7 (M+1)+. Range1H NMR (CDCl3 , 500 MHz, there are rotamer) δ 7,88-7,71 (m, 3H), to 7.67-of 7.48 (m, 2H), 7,28 for 7.12 (m, 2H), 7,00-6,92 (m, 2H), 6,66-6,55 (m, 2H), 5,42 (d, J=8.0 Hz), to 5.21 (d, J=8.0 Hz), 4,70 (d, J=16.0 Hz), 4,58 (d, J=16.0 Hz), 4,14 (d, J=16,0 Hz), 3,88 (d, J=16.0 Hz), with 3.79 (m, 3H), 3.72 points-3,71 (m, 3H), to 3.58-3,55 (m, 1H), 2.23 to (C)of 2.20 (C)of 0.59 (d, J=6.4 Hz), of 0.51 (d, J=6,4 Hz).

Similarly synthesize the following compound:

ConnectionMolecular structureGHMC (M+1)+
97to $ 591.1

EXAMPLE 98

Methyl 4'-methoxy-2"-{[(4S,5R)-5-(3-methoxyphenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

At 0°C to a solution of benzyl [(1S,2R)-2-hydroxy-2-(3-methoxyphenyl)-1-methylethyl]carbamate (40 mg, 0,126 mmol) in DMF (1.5 ml) is added NaHMDS (0,246 ml of 1 M solution in THF, 0,246 mmol). After 5 min through a cannula add a solution of methyl 2-(methyl bromide)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (68 mg, was 0.138 mmol) in DMF (2.5 ml). After 5 min the reaction is interrupted by adding a saturated solution of NH4Cl (10 ml), diluted with EtOAc (20 ml), washed with saturated salt solution (10 ml), dried over Na2SO4filter and concentrate. About ISDA residue flash chromatography on silica gel (0 to 25% acetone/hexane) followed by chromatography with reversed phase (C-18, from 10 to 95% MeCN/water with 0.1% TFA) to give methyl 4'-methoxy-2"-{[(4S,5R)-5-(3-methoxyphenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. IHMS = 644,0 (M+1)+. Range1H NMR (CDCl3, 500 MHz, there are rotamer) δ 7,94-7,86 (m, 2H), 7,71 to 7.62 (m, 2H), 7,43 and 7.36 (m, 2H), 7,31-7,22 (m, 2H), and 7.3 (m, 1H), 7,08-7,05 (m, 1H), 6,85-6,83 (m, 1H), 6.75 in of 6.68 (m, 2H), of 5.45 (d, J=8.0 Hz), 5,23 (d, J=8.0 Hz), 4,89 (d, J=16.0 Hz), 4,82 (d, J=16.0 Hz), 4,20 (d, J=15,8 Hz), 3.96 points (d, J=15,8 Hz), 3,91 (s, 3H), 3,85 (s, 3H), of 3.77 of 3.75 (m, 3H), 3.72 points at 3.69 (m, 1H), 2,31 (C)of 2.08 (C)of 0.54 (d, J=6.4 Hz), 0,44 (d, J=6,4 Hz).

Similarly synthesize the following compound:

ConnectionMolecular structureGHMC (M+1)+
99620,0

EXAMPLE 100

4'-Methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-2-oxo-5-(3,4,5-tryptophanyl)-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

To a solution of methyl 4'-methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-2-oxo-5-(3,4,5-tryptophanyl)-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (23 mg, 0,0358 mmol) in Meon (1 ml) is added 4 M solution of KOH (0.5 ml). The reaction mixture was stirred at room temperature for 3 hours, and then terminate the reaction by adding 1N HCl (5 ml), and diluted with EtOAc (15 ml). The aqueous layer was extracted with EtOAc (10 ml), the organic extracts are combined, washed with saturated salt solution (10 ml), dried over Na2SO4filter and concentrate. The residue is purified by chromatography with reversed phase (C-18, 10 to 95% MeCN/water with 0.1% TFA) and get 4'-methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-2-oxo-5-(3,4,5-tryptophanyl)-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. IHMS = 629,9 (M+1)+. Range1H NMR (CDCl3, 500 MHz, there are rotamer) δ 8,01-to 7.93 (m, 2H), 7,70 to 7.62 (m, 2H), 7,43-7,38 (m, 2H), 7,33-7,30 (m, 1H), 7,14-7,12 (m, 1H), 7,09-7,06 (m, 1H), 6,88-to 6.80 (m, 2H), 5,39 (d, J=8.0 Hz), 5,15 (d, J=8.0 Hz), to 4.92 (d, J=15.6 Hz), a 4.86 (d, J=15.6 Hz), 4,16 (d, J=15,8 Hz), 3,95 (d, J=15,8 Hz), 3,86 (m, 3H), 3.72 points at 3.69 (m, 1H), 2,38 (C), 2,34 (C)of 0.57 (d, J=6.6 Hz), and 0.46 (d, J=6,6 Hz).

Similarly synthesize the following compounds:

ConnectionMolecular structureGHMC (M+1)+
101593,9
102606,4
103 576,9
104616,0

EXAMPLE 105

2"-{[(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

To a solution of (4S)-4-benzyl-1,3-oxazolidin-2-it (29,8 mg, has 0.168 mmol) in DMF (1.5 ml) is added t-BuOK (17.5 mg, 0,152 mmol). After 10 min via cannula add a solution of methyl 2-(methyl bromide)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (75 mg, 0,152 mmol) in DMF (1.5 ml). The reaction mixture was stirred for 30 min, and then terminate the reaction by adding a saturated solution of NH4Cl (10 ml), diluted with EtOAc (15 ml), washed with saturated salt solution (10 ml), dried over Na2SO4filter and concentrate. The residue is dissolved in Meon (2 ml) is added 4 M solution of KOH (0.5 ml). The reaction mixture was stirred at room temperature for 2 hours, and then placed in a refrigerator for 16 hours. The reaction mixture is allowed to warm to room temperature and stirred for another 2 hours. Terminate the reaction by adding 1N HCl (5 ml), diluted with EtOAc (15 ml), washed with saturated salt solution (5 ml), dried over Na2SO4filter and will centerour. The residue is purified by chromatography with reversed phase (C-18, 10 to 95% MeCN/water with 0.1% TFA) followed by lyophilization and get 2"-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. IHMS = 576,0 (M+1)+. Range1H NMR (CDCl3, 500 MHz, there are rotamer) δ 8,01-7,86 (m, 2H), to 7.67-to 7.50 (m, 2H), 7,44-to 7.32 (m, 3H), 7.23 percent-7,07 (m, 5H), 6,91-6,85 (m, 2H), 4.92 in-4,58 (m, 2H), 4,27 (d, J=15.6 Hz), 4,11 (d, J=15.6 Hz), 4,06-3,82 (m, 5H), 3,64-3,51 (m, 1H), 2,86-a 2.71 (m, 1H), 2,47-of 2.28 (m, 4H).

Similarly synthesize the following compound:

ConnectionMolecular structureGHMC (M+1)+
106610,1

EXAMPLE 107

2"-{[(4S,5R)-5-(3-Chloro-4-forfinal)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

At 0°C to a solution of benzyl [(1S,2R)-2-(3-chloro-4-forfinal)-2-hydroxy-1-methylethyl]carbamate (51,4 mg, 0,152 mmol) in DMF (1.5 ml) is added NaHMDS (0,296 ml of 1 M solution in THF, 0,296 mmol). After 5 min through a cannula add a solution of methyl 2-(methyl bromide)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (75 mg,0,152 mmol) in DMF (2.5 ml). After 5 min add a saturated solution of NaOH (3 ml) and the mixture allowed to warm to room temperature. After 3 hours the mixture is acidified with 6N HCl solution and concentrated. The residue is purified by chromatography with reversed phase (C-18, 10 to 95% MeCN/water with 0.1% TFA) followed by lyophilization and get 2"-{[(4S,5R)-5-(3-chloro-4-forfinal)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. IHMS = 627,9 (M+1)+. Range1H NMR (CDCl3, 500 MHz, there are rotamer) δ 7.95 is to 7.62 (m, 2H), 7,69-7,52 (m, 2H), 7,43-7,37 (m, 2H), 7,30-7,24 (m, 1H), 7.18 in-7,11 (m, 2H), 7,08-6,86 (m, 3H), 5,44 (d, J=8.0 Hz), 5,18 (d, J=8.0 Hz), 4.92 in-4,85 (m, 1H), 4,18 (d, J=15,5), of 3.96 (d, J=15,5), 3,93-of 3.85 (m, 3H), of 3.73-3,66 (m, 1H), 2,36 (C), 2,32 (C)of 0.55 (d, J=6.6 Hz), 0,44 (d, J=6,6 Hz).

EXAMPLE 108

2"-({5-[3,5-Bis(trifluoromethyl)phenyl]-4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

To a solution of benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate (65 mg, 0,149 mmol) in THF (1.5 ml) is added NaH (13 mg, 0,542 mmol) and methyl 2-(methyl bromide)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (to 91.1 mg, 0.185 mmol). The reaction mixture is stirred for 72 hours, and then add an additional amount of NaH (36.2 mg and 1.51 mmol). Stirred at room temperature for 6 hours, the reaction Ave is current, adding a saturated solution of NH4Cl (10 ml) and diluted with EtOAc (20 ml). The aqueous layer was extracted with EtOAc (20 ml), the organic extracts are combined, washed with saturated salt solution (10 ml), dried over Na2SO4filter and concentrate. The residue is purified by chromatography with reversed phase (C-18, 10 to 95% MeCN/water with 0.1% TFA) and get 2"-({5-[3,5-bis(tri-permitil)phenyl]-4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. IHMS = 726,0 (M+1)+. Range1H NMR (CDCl3, 500 MHz, there are rotamer) δ 8,03-8,02 (m, 1H), 7,80-of 7.96 (m, 1H), 7,89 (s, 1H), 7,79-7,76 (m, 2H), 7,62-to 7.59 (m, 1H), 7,42-7,31 (m, 3H), 7,22-was 7.08 (m, 3H), 5,26 is 5.28 (m, 1H), 4,81 (d, J=16.6 Hz), of 4.44 was 4.42 (m, 1H), was 4.02 (d, J=16.6 Hz), 3,85 (s, 3H), 2,37 to 2.35 (m, 3H), 1,24 (s)of 1.06 (C), up 0,56 0,54 (m, 3H).

EXAMPLE 109

4-{2-[2-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-3-methylbenzoic acid

Stage 1: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-bromo-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he

The tube is placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(tri-permitil)benzyl]-1,3-oxazolidin-2-he (59 mg, 0,099 mmol), 2,4-dibromothiazole (60 mg, 0,247 mmol), DME (420 ml), EtOH (140 ml) and 1 M solution of Na2CO3(296 μl, 0,296 the mol). The mixture Tegaserod with N2and then add Pd(PPh3)4(5.7 mg, 4,94×10-3mmol). The mixture is again Tegaserod with N2and then the tube is sealed and the reaction mixture is heated to 100°C for 90 min, the Reaction mixture was cooled to room temperature and diluted with EtOAc (30 ml). The organic layers are combined, washed with water and saturated salt solution (each time 10 ml), dried over Na2SO4filter and concentrate. The residue is purified flash chromatography on silica gel (5 to 25% EtOAc/hexane) and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-bromo-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-it. Rf= 0,33 (25% EtOAc/hexane). IHMS = 635,0 (M+1)+. Range1H NMR (CDCl3, 500 MHz) δ 7,89 (Sirs, 2H), 7,78 (s, 2H), of 7.75 (d, J=8,3 Hz, 1H), 7,68 (DD, J=8,1, 1.0 Hz, 1H), 7,41 (s, 1H), to 5.66 (d, J=8.0 Hz, 1H), 5,02 (d, J=15,8 Hz, 1H), 4,84 (d,J=15,8 Hz, 1H), 4,20 (m, 1H), 0,78 (d, J=6,7 Hz, 3H).

Stage 2: methyl 4-{2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-3-methylbenzoate

The tube is placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-bromo-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he (to 46.0 mg, 0,073 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (30 mg, 0.11 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (5 mg, 7,3×10-3 mmol), THF (1 ml) and 1 M solution of K2CO3(1 ml, 1 mmol). The mixture Tegaserod with N2and then the tube is sealed and the reaction mixture is heated to 90°C for 90 min, the Reaction mixture was cooled to room temperature and diluted with EtOAc (30 ml). The organic layers are combined, washed with water and saturated salt solution (each time 10 ml), dried over Na2SO4filter and concentrate. The residue is purified flash chromatography on silica gel (5 to 40% EtOAc/hexane) and obtain methyl 4-{2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-3-methylbenzoate. Rf= 0,29 (25% EtOAc/hexane). IHMS = 702,9 (M+1)+. Range1H NMR (CDCl3, 600 MHz) δ of 7.97 (s, 1H), 7,92 (DD, J=8.0 a, and 1.4 Hz, 1H), 7,85-7,86 (m, 3H), 7,69-7,72 (m, 4H), 7,53(s, 1H), to 5.66 (d, J=8.0 Hz, 1H), 5,11 (d, J=16.2 Hz, 1H), 4.95 points (d, J=16.2 Hz, 1H), 4,11 (m, 1H), 3,93 (s, 3H), of 2.54 (s, 3H), of 0.60 (d, J=6.6 Hz, 3H).

Stage 3: 4-{2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-3-methylbenzoic acid

To a solution of 4-{2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-3-methylbenzoate (35.2 mg, 0.05 mmol) in THF (2 ml) is added water (800 ml), 4N KOH solution (75 μl, 0.3 mmol) and EtOH (200 µl). The reaction mixture was stirred at room temperature the re within 24 hours, and then acidified with 1N HCl solution and extracted with EtOAc (30 ml). The organic layers washed with water and saturated salt solution (each time 10 ml), dried over Na2SO4filter and concentrate. The residue is purified flash chromatography on silica gel (10 to 100% EtOAc/hexane) and receive 4-{2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-3-methylbenzoic acid. IHMS = 688,8 (M+1)+. Range1H NMR (CDCl3, 500 MHz) δ of 8.04 (s, 1H), to 7.99 (d, J=8.0 Hz, 1H), 7,84-7,87 (m, 3H), 7,70 to 7.75 (m, 4H), 7,56 (s, 1H), 5,67 (d, J=8,1 Hz, 1H), 5,14 (d, J=16.2 Hz, 1H), 4,96 (d, J=16.2 Hz, 1H), 4,10 (m, 1H), has 2.56 (s, 3H), 0,62 (d, J=6.6 Hz, 3H).

EXAMPLE 110

Methyl 2"-{[(4S,5R)-5-(2-chloropyridin-4-yl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

To a solution of 4'-methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-2-oxo-5-pyridin-4-yl-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (175 mg, 0,296 mmol) in CH2Cl2(15 ml) at 0°C in an atmosphere of N2add 3-chlormadinone acid (146 mg, 0,593 mmol) in powder form. The mixture is stirred at 0°C for 15 minutes the mixture is allowed to warm to room temperature and stirred for another 2 hours. The reaction mixture was diluted with CH2Cl2and washed with saturated solution of Na2 SO3(1×)and then with saturated solution of K2CO3(2×). The organic layer is dried over Na2SO4), filtered and the solvent evaporated in vacuum. The resulting residue is dissolved in POCl3(10 ml). The resulting solution was heated to 110°C under nitrogen for 2 hours. The mixture is allowed to cool to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (50 ml) and water (10 ml) and washed with saturated solution of NaHCO3(20 ml). The aqueous layer was extracted with EtOAc (2×40 ml). The organic layers are combined, dried over Na2SO4), filtered and the solvent evaporated in vacuum. The residue is purified flash chromatography on silica gel and get methyl 2"-{[(4S,5R)-5-(2-chloropyridin-4-yl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. JHMS: calculated = 625,2; found = 625,0 (M+1)+. Range1H NMR (500 MHz, CDCl3mixture 1:1 of atropisomers) δ of 8.40 (s, 0.5 H); 8,39 (s, 0.5 H); of 7.97 (s, 1H); of 7.90 (t, J=5.8 Hz, 1H); 7,72 (s, 0.5 H); 7,69-7,63 (m, 1.5 H); of 7.48 (d, J=11.8 Hz, 0.5 H); 7,44 (s, 0.5 H); 7,43-7,37 (m, 1H); 7,32-7,26 (m, 1H); from 7.24 (s, 0.5 H); 7,20 (s, 0.5 H); 7,16 (d, J=2.2 Hz, 0.5 H); 7,14 (d, J=2.2 Hz, 0.5 H); 7,12-7,06 (m, 1.5 H); 7,05 (d, J=5,1 Hz, 0,5H); 5,42 (d, J=8,1 Hz, 0.5 H); is 5.18 (d, J=8,1 Hz, 0.5 H); to 4.92 (DD, J=15,9, of 18.5 Hz, 1H); 4,19 (d, J=15,8 Hz, 0.5 H); 3,99 (d, J=15,8 Hz, 0.5 H); of 3.95 (s, 3H); 3,88 (s, 3H); 3,81 of 3.75 (m, 1H); 2,39 (s, 1.5 H); 2,35 (s, 1.5 H); 0,60 (d, J=6,5 Hz, 1,5 H); 0,49 (d, J=6,5 Hz, 1,5 H.

EXAMPLE 111

Methyl 4'-methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

To a solution of methyl 2"-{[(4S,5R)-5-(2-chloropyridin-4-yl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (48 mg, 0,077 mmol) in THF (1 ml) and K2CO3(1N) (1 ml) add trimethylboroxine (0,107 ml, 0,768 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (7,1 mg, to 0.011 mmol). The mixture was sealed and left overnight to warm to 80°C. the Mixture is diluted with water and EtOAc and filtered through celite. The organic layer is separated and the aqueous layer extracted with EtOAc (2×). The organic layers are combined, washed with saturated salt solution (1×), dried over Na2SO4), filtered and the solvent evaporated in vacuum. The residue is purified flash chromatography on silica gel and obtain methyl 4'-methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate. JHMS: calculated = 605,2; found = 605,0 (M+1)+. Range1H NMR (500 MHz, CDCl3mixture 1:1 of atropisomers) δ 8,49 (t, J=4.3 Hz, 1H); 7,98 (t, J=6,6 Hz, 1H); to $ 7.91 (t, J=10.0 Hz, 1H); 7,73 (s, 0.5 H); to 7.67 (s, 0.5 H); the 7.65 (s, 1H); 7,47-7,39 (m, 2H); 7,33-7,26 (m, 1H); to 7.15 (DD, J=2.2, while the 5.7 Hz, 1H); 7,09 (DD, J=6,8, and 8.4 Hz, 1H); 7,06 (s, 0,5H); 7,00, 0,5H); to 6.95 (d, J=4,8 Hz, 0,5H); make 6.90 (d, J=4,7 Hz, 0.5 H); 5,43 (d, J=8,2 Hz, 0,5H); by 5.18 (d, J=8,1 Hz, 0,5H); to 4.92 (d,J=15,8 Hz, 0,5H); to 4.87 (d, J=15,8 Hz, 0,5H); 4,22 (d, J=15,8 Hz, 0,5H); 4,00 (d, J=15,8 Hz, 0,5H); of 3.95 (s, 3H); to 3.89 (s, 1,5H); 3,88 (s, 1,5H); 3,81-to 3.73 (m, 1H); 2.57 m (s, 1,5H); 2,56 (s, 1,5H); 2,39 (s, 1,5H); of 2.34 (s, 1,5H); 0,57 (d, J=6,6 Hz, 1,5H); 0,47 (d, J=6,6 Hz, 1,5H).

EXAMPLE 112

4'-Methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid

To a solution of methyl 4'-methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate (30.1 mg, 0,050 mmol) in 1,4-dioxane (1.5 ml) and water (1.5 ml) was added 1 M aqueous LiOH solution (0,498 ml, 0,498 mmol). The mixture is stirred at room temperature for 4 hours. The mixture is acidified with 1N HCl solution. The aqueous layer was extracted with EtOAc (3×). The organic layers are combined, dried over Na2SO4, filtered and the solvent evaporated in vacuum. The crude product is purified preparative HPLC with reversed phase (C-18), elwira a mixture of MeCN/water. Fractions are collected and lyophilized, receiving 4'-methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid. JHMS: calculated = 591,2; found = to $ 591.1 (M+1)+. Range1H NMR (500 MHz, CDCl3mixture 1:1 of atropisomers) δ 8,83 (s, 1H); 802 (C, 1H); 7,94 (t, J=10.0 Hz, 1H); 7,72 (s, 0.5 H); of 7.69 (t, J=6.0 Hz, 1H); to 7.64 (s, 0,5H); 7,49-the 7.43 (m, 3H); 7,40 (d, J=5,2 Hz, 0,5H); to 7.35 (d, J=5.4 Hz, 0,5H); 7,31 (m, 1H); 7,16 (DD, J=2.1 a, 6,0 Hz, 1H); for 7.12 (t, J=8,8 Hz, 1H); to 5.56 (d, J=8,1 Hz, 0,5H); 5,26 (d, J=8,2 Hz, 0,5H); 4,94 (DD, J=8,7, 15.7 Hz, 1H); 4,77 (Sirs, 1H); 4,20 (d, J=15,8 Hz, 0,5H); 4,00 (d, J=15.7 Hz, 0,5H); 3,90 (s, 1,5H); the 3.89 (s, 1,5H); 3,89-3,81 (m, 1H); 2,82 (s, 1,5H); 2,81 (s, 1,5H); to 2.41 (s, 1,5H); a 2.36 (s, 1,5H); and 0.62 (d, J=6,5 Hz, 1,5H); 0,49 (d, J=6,5 Hz, 1,5H).

EXAMPLE 113

4'-Methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxamid

To a solution of 4'-methoxy-2-methyl-2"-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid (15 mg, of 0.025 mmol) in CH2Cl2(2 ml) is added 2 M solution of oxalicacid in CH2Cl2(0,038 ml, 0,076 mmol) and 2 drops of DMF. The mixture under nitrogen was stirred at room temperature for 30 minutes, the Reaction mixture was concentrated in vacuo. The residue is again dissolved in THF (2 ml), and then add ammonium hydroxide (or 0.035 ml, 0,254 mmol) and diisopropylethylamine (of 0.013 ml, 0,076 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue purified preparative HPLC with reversed phase (C-18), elwira a mixture of MeCN/water. Fractions are collected and lyophilized, receiving 4'-methoxy-2-methyl-2"-{[(S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxamide in the form of a white powder. JHMS: calculated = 590,2; found = 590,0 (M+1)+. Range1H NMR (500 MHz, CDCl3mixture 1:1 of atropisomers) δ 8,49 (t, J=4.3 Hz, 1H); to 7.77 (Sirs, 1H); 7,72 (s, 0,5H); 7,66 (Sirs, 1,5H); 7,46-7,38 (m, 3H); 7,33-7,29 (m, 1H); 7,14 (DD, J=2,2, 7.7 Hz, 1H); to 7.09 (DD, J=6,2, 8.5 Hz, 1H); 7,06 (s, 0,5H); 7,01 (s, 0,5H); to 6.95 (d, J=4.3 Hz, 0,5H); make 6.90 (d, J=4.4 Hz, 0,5H); 6,17 (Sirs, 1H); 5,79 (Sirs, 1H); 5,43 (d, J=8,1 Hz, 0,5H); 5,20 (d, J=8.0 Hz, 0,5H); to 4.92 (d, J=15,9 Hz, 0,5H); a 4.86 (d, J=15,8 Hz, 0,5H); 4,22 (d, J=15,8 Hz, 0,5H); 4,00 (d, J=15,8 Hz, 0,5H); 3,88 (s, 1,5H); a 3.87 (s, 1,5H); 3,80 of 3.75 (m, 1H); 2.57 m (s, 1,5H); 2,56 (s, 1,5H); 2,39 (s, 1,5H); 2,35 (s, 1,5H); 0,58 (d, J=6,5 Hz, 1,5H); 0,47 (d, J=6,5 Hz, 1,5H).

The following examples 114-123 carried out in accordance with the above methods.

ExampleRR'GHMC (M+1)+
114OCH3608,1
115OCH3594.1 nm
116OCH3608,1
117 OCH3595,1
118HE594.1 nm
119HE580,1
120HE594.1 nm
121HE581,1
122NH2579,0
123NH2593,0

EXAMPLE 124

Methyl 4-{4-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoate

A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-bromobutane the l)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-it (25 mg, 0.040 mmol) and methyl 4-(iminocarbonothioyl)-3-methylbenzoate (16,87 mg of 0.081 mmol) in EtOH (450 μl) and left overnight to warm to a temperature of 70°C. the Reaction mixture was concentrated in vacuo and the residue purified by the method of preparative TLC (Si, 1000 μm, hexane/EtOAc (80:20)) and obtain methyl 4-{4-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoate in the form of a colorless oil. JHMS: calculated = 731,2; found = 731,0 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ to 7.99 (s, 1H); 7,92 (d, J=8,1 Hz, 1H); 7,86 (d, J=8.0 Hz, 2H); 7,79 (s, 1H); 7,72 (d, J=7.9 Hz, 1H); of 7.69 (s, 1H); at 7.55 (d, J=7.9 Hz, 1H); 7.29 trend (s, 1H); 5,59 (d, J=8.0 Hz, 1H); 4,91 (d, J=15.7 Hz, 1H); 4,27 (d, J=15.7 Hz, 1H); 4.04 the-3,99 (m, 1H); of 3.95 (s, 3H); 2,88 was 2.76 (m, 2H); in 2.68 (s, 3H); of 1.36 (t, J=7.5 Hz, 3H); 0,57 (d, J=6.5 Hz, 3H).

EXAMPLE 125

4-{4-[2-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoic acid

To a solution of methyl 4-{4-[2-({(4S,5R)-5-[3,5-bis(tri-permitil)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoate (11 mg, 0.015 mmol) in 1,4-dioxane (0.4 ml) and water (0.4 ml) was added 1 M an aqueous solution of LiOH (0,151 ml, 0,151 mmol). The mixture is stirred at room temperature for 2 hours. The mixture is acidified with 1N HCl solution. The aqueous layer was extracted with EtOAc (3×). the content of inorganic fillers layers combine, dried over Na2SO4), filtered and the solvent evaporated in vacuum. The crude product is purified preparative HPLC with reversed phase (C-18), elwira a mixture of MeCN/water containing 0.1% TFA. Fractions are collected and lyophilized, receiving 4-{4-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoic acid. JHMS: calculated = 717,1; found = 717,0 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ with 8.05 (s, 1H); to 7.99 (d, J=8,1 Hz, 1H); 7,89 (d, J=8,1 Hz, 1H); 7,87 (s, 1H); for 7.78 (s, 1H); 7,74 (d, J=8.0 Hz, 1H); 7,71 (s, 2H); EUR 7.57 (d, J=7.9 Hz, 1H); 5,61 (d, J=8.0 Hz, 1H); 4,94 (d, J=15.7 Hz, 1H); of 4.25 (d, J=15.7 Hz, 1H); 4.04 the-3,98 (m, 1H); 2,89 was 2.76 (m, 2H); 2,69 (s, 3H); to 1.37 (t, J=7.5 Hz, 3H); 0,60 (d, J=6.5 Hz, 3H).

The following compounds are synthesized according to the method described in Example 124, the Intermediate connection 20 and the corresponding thioamides.

M

EXAMPLE 136

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-(4-ethyl-1-phenyl-1H-pyrazole-3-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-he

To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-butyryl-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-she (300 mg, 0,554 mmol) (46,3 mg, 0,086 mmol)) in dimethylacetal N,N-dimethylformamide (0.5 ml, of 3.78 mmol) left overnight to warm what about the temperature of 110°C. The reaction mixture was concentrated in vacuo and receive raw enamine. The resulting enamine dissolved in EtOH (200 ml) and added phenylhydrazine (16,97 μl, 0,171 mmol). The mixture is heated to a temperature of 80°C for 3 hours. The reaction mixture was concentrated in vacuo and the residue purified preparative HPLC with reversed phase (C-18), elwira a mixture of MeCN/water. Fractions of a second in order aliremove peak is collected and lyophilized, receiving a mixture of diastereoisomers specified in the connection name. Diastereoisomer divide by the method of preparative TLC (Si, 1000 μm, hexane/EtOAc (70:30)) and receive (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-ethyl-1-phenyl-1H-pyrazole-3-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-it. JHMS: calculated = 642,2; found = 641,9 (M+1)+. Range1H NMR (500 MHz, CDCl3) δ 7,89 (s, 1H); 7,87 (s, 1H); to 7.84 (s, 1H); 7,74-the 7.65 (m, 5 H); EUR 7.57 (d, J=7.9 Hz, 1H); 7,46 (t, J=7.9 Hz, 2H); 7,31 (d, J=7.9 Hz, 1H); 5,59 (d, J=8.0 Hz, 1H); equal to 4.97 (d, J=15,5 Hz, 1H); 4,36 (d, J=15,5 Hz, 1H); 4,05-4,00 (m, 1H); 2,50 (kV, J=7.5 Hz, 2H); 1,22 (t, J=7.5 Hz, 3H); 0,53 (d, J=6.5 Hz, 3H).

EXAMPLE 137

The specified connection receive according to the method described in Example 75. LC/MS 725,2.

EXAMPLE 138

2-Methoxy-2-oxoethyl 2"-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate

2"-({(4S,5)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid (Example 30, 200 mg, 0,281 mmol), methylhydroxylamine (0,22 ml, 0,281 mmol), hydrochloride of N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide (81 mg, 0,422 mmol) and triethylamine (0,059 ml; 0,422 mmol) was stirred in DCM (2,811 ml) at room temperature over night. Analysis of the aliquot method IHMS indicates the formation of the desired product and the complete withdrawal of the original substances. From the reaction mixture to remove volatile substances. The residue is purified by the method of preparative HPLC and get listed in the title compound in the form of a solid of light yellow color. IHMS (ESI): calculated = 783,19; found = 784,0 (M+1)+. Range1H NMR (CDCl3, 400 MHz, mixture 1:1 of atropisomers) δ to 7.99 (d, J=6,8 Hz, 1H), 7,92 (d, J=8 Hz, 1H), a 7.85 (s, 1H), 7,72-to 7.68 (m, 1,5H), to 7.67-to 7.61 (m, 2,5H), 7,45 was 7.36 (m, 2H), 7,32-7,26 (m, 1H), 7,13 (s, 1H), was 7.08 (d, J=5.6 Hz, 0,5H), 7,06 (d, J=5.6 Hz, 0,5H), 5,59 (d, J=8 Hz, 0,5H), and 5.30 (d, J=8 Hz, 0,5H), equal to 4.97 (d, J=14 Hz, 0,5H), is 4.93 (d, J=14 Hz, 0,5H), to 4.87 (s, 2H), 4.16 the (d, J=15.6 Hz, 0,5H), 3,95 (d, J=16 Hz, 0,5H), 3,86 (s, 3H), of 3.80 (s, 3H), 3,80 of 3.75 (m, 1H), 2,37 (s, 1,5H), 2,32 (s, 1,5H), 0,54 (d, J=6,8 Hz, 1,5 H)0,42 (d, J=6,8 Hz, 1,5H).

The following connections receive in accordance with the General methodology described in Example 138.

ExampleRxData LC/MS
139 836,0 (M + Na)
140783,0

1. The compound having the Formula I, or its pharmaceutically acceptable salt, where:

X is-O-;
Z represents-C(=O)-;
Y represents -(CRR1)-, where R1selected from C1-C2of alkyl;
R denotes H or-C1-C5alkyl;
R5denotes H;
R2and B are each selected from A1and A2where one of R2and B denote A1and the other of R2and B denote A2;
where A1has the structure:

A2selected from the group comprising phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imidazolyl;
A3selected from the group comprising phenyl, thiazolyl and pyrazolyl;
A4selected from the group comprising phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and azetidines;
A2optionally substituted by 1-3 substituents, independently selected from a halogen atom, -OCH3and-OCF3and-C1-C3the alkyl, optionally substituted by 1 to 3 halogen atoms;
A3substituted by one group A4and optionally substituted with 1-2 substituents independently selected from a halogen atom, -OH, -OCH3, -OCF3 and-C1-C3the alkyl, optionally substituted by 1 to 3 halogen atoms;
A4optionally substituted by 1-3 substituents, independently selected from the group which includes (a)- (C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted by a group-OH, (b)- (C2-C4alkenyl, optionally substituted by 1 to 3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted by one group selected from-OH, -CO2CH3, -C(=O)CH3, -NR3R4and-OC1-C2alkylene1-C2of alkyl, (d) -C(=O)H, (e) -CO2H (f) -CO2With1-C4alkyl, optionally substituted by one group selected from-C(=O)C1-C2of alkyl, -OH, -CO2CH3, -CO2H, -NR3R4and-OC1-C2alkylene1-C2of alkyl, (g) OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4(m) -OC1-C2alkylene1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted by 1 to 3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted by one group selected from-OH, -CO2CH3, -NR3R4and-OC1-C2alkylene1-C2of alkyl, (q) -NR3R4and (r-S(O) xNR3R4,
provided that if a4denotes a heterocyclic group attached to And3through a ring carbon atom in the a4then, at least one Deputy in A4must be selected from Rewhere Reselected from the group which includes (a)- (C1-C5alkyl, substituted by a group-OH and optionally substituted by 1 to 3 halogen atoms, (b)- (C2-C4alkenyl, optionally substituted by 1 to 3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted by one group selected from-OH, -CO2CH3, -C(=O)CH3, -NR3R4and-OC1-C2alkylene1-C2of alkyl, (d) -C(=O)H, (e) -CO2H (f) -CO2C1-C4alkyl, optionally substituted by one group selected from-C(=O)C1-C2of alkyl, -OH, -CO2CH3, -CO2H, -NR3R4and-OC1-C2alkylene1-C2of alkyl, (g) OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkylene1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted by one group selected from-OH, -CO2CH3, -NR3R4and-OC1-C2alkylene1-C2of alkyl, (n) -NR3 R4(=O)OC1-C2alkyl, (o) -NR3R4and (p) -S(O)xNR3R4;
p is 0, 1 or 2; and
Raselected from a halogen atom, -CH3, -CF3, -OCH3and-OCF3;
R3and R4each independently selected from H and CH3;
x is 0, 1 or 2.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where B denotes A1and R2represents A2.

3. The compound according to claim 1 or its pharmaceutically acceptable salt, where B denotes A2and R2represents A1.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, where A2, A3and A4denote phenyl.

5. Pharmaceutical composition having the properties of an inhibitor SETR comprising the compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

6. The compound according to claim 1, which is selected from the group comprising the following compounds, or pharmaceutically acceptable salt:




































7. The compound according to claim 1, which is selected from the group comprising the following compounds, or pharmaceutically acceptable salt:
(a)

where R1selected from the group which includes:

Example 2Example 3
Example 4 Example 5

Example 6Example 7
Example 8Example 9
Example 10Example 11
Example 12Example 13
Example 14Example 15
Example 16Example 17
Example 18 Example 19and

Example 20

(b)

where R is selected from the group which includes:
57Me, and
58Cl

(C)

where R is selected from the group which includes:
59and
60

(d)

where R is selected from the group which includes:
63CF3and
64Me

(e)

where Rxselected from the group which includes:
76

78
80
81and
82

(f)

where R is selected from the group which includes:
84
85, 86, 87, 88
4 isomer,
89
90
91
racemic mixture
92
93

(g)

where R R' are defined as follows:
ExampleRR'
114OCH3,
115OCH3,
116OCH3,
117OCH3,
118OH,
119OH,
120OH,
121OH,
122NH2
123 NH2;

(h)

where R is selected from the group which includes:
126
127
128
129
130
131
132
133
134and
135and

(i)

where Rxselected from the group which includes:
139and
140

8. The use of compounds according to claim 1 or its pharmaceutically acceptable salt for the manufacture of medicaments for increasing HDL-C.

9. The use of compounds according to claim 1 or its pharmaceutically acceptable salt for the manufacture of a medicine for lowering LDL-C.

10. The use of compounds according to claim 1 or its pharmaceutically acceptable salt for the manufacture of a medicinal product having the properties of an inhibitor SER.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where "----" denotes a bond or is absent; R1 is a C1-4alkoxy group or halogen; R1b is H or C1-3alkyl; U and V each independently denote CH or N; W is CH or N, or, if "----" is absent, W is CH2 or NH; under the condition that at least one of U, V and W is CH or CH2; A is -CH2-CH(R2)-B-NH-* or -CH(R3)-CH2-N(R4)-[CH2]m-*; where asterisks indicate a bond which binds said fragments through a CH2-group with an oxazolidinone fragment; B is CH2 or CO; and R2 is hydrogen, OH or NH2; R3 and R4 both denote hydrogen, or R3 and R4 together form a methylene bridge; m equals 0, 1 or 2; and G is a phenyl which is monosubstituted in position 3 or 4, or disubstituted in positions 3 and 4, where each substitute is independently selected from a group comprising C1-4alkyl, C1-3alkoxy group and halogen; or G is a group selected from groups G1 and G5 where M is CH or N; Q' is S or O; Z1 is N, Z2 is CH and Z3 is CH; or Z1 is CH, Z2 is N and Z3 is CH or N; or Z1 is CH, Z2 is CR5 and Z3 is CH; or Z1 is CH, Z2 is CH and Z3 is N; and R5 is hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof are used as a medicinal agent for preventing or treating bacterial infections.

EFFECT: oxazolidinone derivatives used as antimicrobial agents.

15 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyridin-2-one and pyridazin-3-one derivatives, having Btk inhibiting activity. In formulae I-IV:

,

R denotes -R1-R2-R3 or -R2-R3; R1 denotes a heteroaryl containing 6 ring atoms, including one N heteroatom; R2 denotes -C(=O), -C(=O)N(R2'), where R2' denotes H; R3 denotes R4; where R4 is a lower alkyl, heterocycloalkyl, (lower alkyl) heterocycloalkyl or heterocycloalkyl (lower alkyl), where the heterocycloalkyl contains 6 ring atoms, including two heteroatoms selected from N and O; and where R4 can be substituted with one or more substitutes selected from lower alkyl, oxo group and lower alkoxy group; X denotes CH or N; Y1 denotes lower alkyl; n and m are equal to 0; values of radicals Y2, Y4 are given in the claim.

EFFECT: improved properties of compounds.

6 cl, 2 tbl, 42 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I , where R1 and R2 independently denote hydrogen, C3-C7cycloalkyl, C1-C6alkyl, C2-C6alkynyl, hydrogen or pyridine; or R1 and R2 together with a nitrogen atom which binds them form a pyrroline group; R3 denotes hydrogen, C1-C6halogenalkyl, C1-C6alkyl, halogen, cyano group, nitro group, C1-C4alkoxy group, phenyl, halogen-substituted phenyl, (R51)(R52)(R53)Si-(C2-C6alkynyl)-, where R51, R52, R53 independently denote halogen, cyano group, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, C2-C6alkynyl, C1-C6alkoxy group, benzyl or phenyl; R4 denotes hydrogen, halogen, phenyl, imidazolyl, amino group, C1-C6alkoxy group or C1-C6alkyl; R5 denotes C1-C12alkyl or a group A, where A denotes a 3-10-member monocyclic or condensed bicyclic ring system which can be aromatic, partially unsaturated or completely saturated, where said 3-10-member ring system can be mono- or polysubstituted with substitutes independently selected from a group comprising halogen, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy group and C1-C6alkylthio group; R6 denotes hydrogen; and R7 denotes hydrogen or C1-C6alkyl and agronomically acceptable salts/metal complexes/metalloid complexes/isomers/structural isomers/stereoisomers. The invention also relates to methods of controlling infection of useful plants by phytopathogenic microorganisms by applying a compound of formula I onto the plants, a part thereof or place where said plants grow, as well as a composition for controlling infection by phytopathogenic microorganisms.

EFFECT: novel compounds which are suitable for use as microbiocides are obtained and described.

7 cl, 48 ex, 151 tbl

Amide compound // 2479576

FIELD: chemistry.

SUBSTANCE: compounds exhibit antagonistic activity towards the EP4 receptor, which enables use thereof as an active ingredient in a pharmaceutical composition for treating chronic kidney disease or diabetic nephropathy.

EFFECT: high efficiency of the compounds.

27 cl, 228 tbl, 86 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-(1,2-phenylene)-bis-1,5,3-dithiazepinane and 3,3'-[methylene-bis-(1,4-phenylene)]-bis-1,5,3-dithiazepinane of general formula (1):

, R=1,2-C6H4; 4-C6H4-CH2C6H4-4, which lies in the following: α,ω-diamines (1,2-phenylenediamine or 4,4'-diaminodiphenylmethane) is subjected to interaction with 1,3,6-oxadithiapinane in presence of catalyst Sm(NO3)3·6H2O in mole ratio α,ω-diamine : 1,3,6-oxadithiapinane : Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) in chlorophorm and argon atmosphere for 2.5-3.5 h.

EFFECT: elaborated is method of obtaining novel compounds, which cam be applied as antibacterial, antifungal and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for suppression of vital activity of bacteria in various technical media.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopropylamine derivatives of formula: or its pharmaceutically acceptable salt, wherein: one of R1 and R2 means a group of formula -L2-R6a-L3-R6b; the other of R1 and R2 means H, C1-10alkyl, C1-10alkoxy, halogen, CN; each R3, R3a R3b independently means H, C1-6alkyl, trifluoromethyl, C1-10alkoxy, CN; R4 and R5 taken together with a nitrogen atom whereto each attached form a non-aromatic cycle of formula: R7, R8, R9 and R10 each H, C1-10alkyl; R6a means cyanophenyl, phenyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, azepanyl, azetidinyl, azetidin-2-onyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrrolidin-2-onyl, benzothiazolyl wherein the pyridinyl and pyrimidinyl groups optionally contain 1-3 substitutes specified in a group consisting of C1-10alkyl and C1-10alkoxy; R6b means H; L means - [C(R16)(R17)]k; L2 means a bond, C2-10alkylene, -O-, -C(=O)-, -NH-, -N(R16)C(=O), -C(=O)N(R16) and -N(C1-6alkyl)-;L3 means a bond; R15 means H, C1-6alkyl, C1-6alkoxycarbonyl, amido and formyl R16 , R17 in each specific case means H, C1-6alkyl; Rx and Ry in each specific case independently mean H, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, fluorine, diC1-6alkylamino; k is equal to 1, 2 or 3; m is equal to 2.

EFFECT: compounds show H3 receptor inhibitory activity that makes them applicable in a pharmaceutical composition.

10 cl, 7 dwg, 44 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where R1 denotes C1-C8-alkylaminocarbonyl, which is optionally substituted with a 5- or 6-member heterocyclic ring containing 3-4 ring heteroatoms selected from a group consisting of oxygen, nitrogen and sulphur, where the ring can be optionally substituted with C1-C8-alkyl or C1-C8-alkoxy group ; R2 denotes C1-C3-alkyl or a halogen; one of R3 and R4 denotes R6, and the other denotes R7; R5 denotes hydrogen or halogen; R6 denotes hydrogen, hydroxy group amino group, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxy, -OR8 or C1-C8-halogenalkyl; R7 denotes hydrogen, OR11, halogen, carboxy, -SO2R8, cyanogroup or C1-C8-halogenalkyl, or when R4 denotes R7, then R7 can also denote -NR12 R13 ; R8 R11 independently denote C1-C8-alkyl or C3-C8-cycloalkyl, which can be optionally substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group or di-C1-C8-alkyl)amino group; any R9 denotes C1-C8-alkyl or C3-C8-cycloalkyl, which can optionally be substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group, di(C1-C8-alkyl)amino group or a 5- or 6-member heterocyclic ring containing one or two ring heteroatoms selected from a group consisting of oxygen and nitrogen, where the ring can optionally be substituted with C1-C8-alkyl, and R10 denotes hydrogen or C1-C8-alkyl; or R9 and R10 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which can contain one or two additional nitrogen heteroatoms, where the ring can be optionally substituted with C1-C8-alkyl; any R12 denotes C1-C8-alkyl or C3-C8-cycloalkyl which can be optionally substituted with di(C1-C8-alkyl)aminogroup, and R13 denotes hydrogen or C1-C8-alkyl; or R12 and R13 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which contains one or two additional nitrogen heteroatoms, where the ring can optionally be substituted with C1-C8-alkyl.

EFFECT: possibility of using the compounds to produce a pharmaceutical agent for treating diseases mediated by phosphatidylinositol-3 kinase.

6 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to oxazolidinone derivatives of formula (I) or pharmaceutically acceptable salts thereof, synthesis method thereof and pharmaceutical compositions containing said derivatives which are used as an antibiotic. Oxazolidinone derivatives, where R1 and R1' independently denote hydrogen or fluorine; R2 denotes -OR7, fluorine, monophosphate or metal phosphate; and R7 denotes hydrogen, C1-3alkyl or an acylated amino acid group, where the amino acid is alanine, glycine, proline, proline, isoleucine, leucine, phenylalanine, β-alanine or valine; R3 denotes hydrogen, a C1-4alkyl group which is unsubstituted or substituted cyano, , -(CH2)m-OR7 (m equals 0, 1, 2, 3, 4) or a ketone group. Oxazolidinone derivatives of formula (I) have antibacterial activity against different human and animal pathogens.

EFFECT: oxazolidinone derivatives, having inhibiting activity towards a wide range of bacteria and having low toxicity.

27 cl, 4 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

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