Derivants of 2, 4, 5-triphenylimidazoline as inactivators of interaction between p53 and mdm2 proteins designed for application as anticancer drugs

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

 

Protein p53 is a suppressor protein, which plays a major role in protecting against cancer. He maintains the integrity of the cells and prevents reproduction steadfastly damaged cell clones by inducing stop growth or apoptosis. At the molecular level of p53 is a transcription factor that activates a group of genes involved in cell cycle regulation and apoptosis. p53 Is an active inhibitor of the cell cycle, which at the cellular level is strictly regulated by MDM2. MDM2 and p53 form a loop regulation with feedback. MDM2 can bind p53 and inhibit its ability to transactivate genes regulated by p53. In addition, MDM2 mediates dependent ubiquitin decomposition of p53. p53 Can activate the expression of the MDM2 gene and thereby to increase the protein content of MDM2 in the cell. This loop regulation with feedback leads to the fact that in normal proliferating cells, the content and MDM2, and p53 is maintained at low level. MDM2 is also a cofactor for E2F, which plays a major role in the regulation of cell cycle.

In many cancers the number of MDM2 to the amount of p53 (E2F) rosregulirovanie. For example, it is shown that often arise in the locus of p16INK4/p19ARF molecular defects affect the degradation of protein MDM2. Inhibition of vzaimode istia MDM2-p53 in wild-type cells leads to accumulation of p53, the cell cycle arrest and/or apoptosis. Therefore, antagonists of MDM2 can lead to a new approach to the treatment of cancer using them as the sole means or in combination with a wide range of other anticancer agents. The applicability of this strategy was demonstrated by the use of various macromolecular means of inhibiting the interaction of MDM2-p53 (e.g., antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F using conservative binding site, as p53 and activates E2F-dependent transcription cyclina well, and this shows that MDM2 antagonists can affect cells with mutant p53.

Wells et al. J. Org. Chem. 1972, 37, 2158-2161 described the synthesis of imidazoline. Hunter et al. Can. J. Chem. 1972, 50, 669-77 described receiving Marinov and solarino that previously studied by chemiluminescence (McCapra et al. Photochem. and Photobiol. 1965, 4, 1111-1121). Zupanc et al. Bull. Soc. Chem. & Tech. (Yugoslavia) 1980-81, 27/28, 71-80 has described the use of triarylmethane as starting materials for the production of derivatives of EDTA (ethylenediaminetetraacetic acid).

In EP 363061 issued to Matsumoto described imidazoline derivatives applicable as immunomodulators. It is shown that these compounds have low toxicity. The possibility of treatment and/or prevention of rheumatoid arthritis, multiple sclerosis, with the intended lupus erythematosus, eritematoso and rheumatic polyarthritis. In WO 00/78725 issued Choueiry et al., described is a method of obtaining substituted amidino and indicated that the compounds of the imidazoline type can be applicable for the treatment of diabetes and related diseases, including breach of excretion of glucose.

In the US 6617346 B1 (issued September 9, 2003), US 6734302 B2 (issued may 11, 2004), US 20040259884 A1 (published on 23 December 2004), US 20040259867 A1 (published on 23 December 2004), US 20050282803 A1 (published 22 December 2005) and US 20050288287 A1 (published December 29, 2005) revealed cognate CIS-imidazoline.

The present invention relates to chiral CIS-imidazolines, which are small molecules inhibitors of the interaction between MDM2-p53. When studies without using the cell shown that the compounds proposed in the present invention inhibit the interaction of MDM2 protein with a peptide-type p53 activity, about 100 times higher than that of a peptide derived from p53. When studies using cells, these compounds exhibit mechanistic activity. Incubation of cancer cells with wild type p53 leads to the accumulation of p53 protein, induction regulated by p53 gene P21 and cell cycle arrest in the G1 phase and G2, which leads to significant antiproliferative activity against cells with p53 wild tee is and in vitro. In contrast with comparable concentrations of compounds such activity was not observed for cancer cells with mutant p53.

Therefore, the activity of MDM2 antagonists, probably linked with the mechanism of action. These connections can be active and selective anticancer agents.

The present invention relates to at least one compound of the formula I

in which

X1and X2denote halogen, acetylene, cyano, trifluoromethyl or nitro-group;

R1and R2selected from the group comprising-H, -CH3, -CH2CH3, -CH2HE and

-CH2Och3provided that R1and R2both represent hydrogen;

R3denotes-H or-C(=O)-R7;

and if R6denotes hydrogen, then

R4represents-och3, -Och2CH3, -OCH2CH2F, -och2CH2Och3or-och(CH3)2;

R5means

Mr.

-halogen,

-CH3,

-CF3,

-Och3,

- (CH3)2,

-cyclopropyl,

a cyano,

- (CH3)3,

- (CH3)2OR (where R is-H, -CH3or-CH2CH3),

- (CH3)2CH-OR (where R is-H, -CH3, -CH(CH3)2, -CH2CH2OH, or

CH 2CH2OCH3),

- (CH3)2CN,

- (CH3)2COR (where R is-CH3),

- (CH3)2COOR (where R represents-H, -CH3, -CH2CH3or-CH(CH3)2),

-C(CH3)2CONRaRb(where Radenotes-H or-CH3and Rb=-H or-CH3),

-SR (where R denotes-CH3or-CH2CH3or

-SO2R (where R denotes-CH3, -CH2CH31 is pyrrolidine, -NH-tert-butyl, or-N(CH3)2);

and if R6does not denote hydrogen, then

R4represents-och3, -Och2CH3, -OCH2CH2F, -OCH2CH2OCH3or-och(CH3)2;

R5denotes hydrogen, -Cl, -och3, tert-butyl, or-N(CH3)2;

R6represents-Cl, cyclopropyl, -SO2R (where R denotes-CH3, -CH2CH31 is pyrrolidine, -NH-tert-butyl, -NH2or-N(CH3)2);

and R7selected from the group including

(i)- (CH3, -CH(CH3)2, -CH2CH(CH3)2cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted by chlorine, -och3or cyano,

ii) 4-morpholinyl, 1-piperidinyl, 4-thiomorpholine or 4-thiomorpholine-1,1-dioxide,

iii) -NRc2(where Rcdenotes hydrogen, -sub> 3, -CH2CH3, -CH2CH2OH, -CH2CH2OCH3or-CH2CH(OH)CH2OH),

iv) substituted piperazine of the formula

in which R is selected from the group including

a) hydrogen,

b) ness. alkyl,

c) -CH(CH3)2,

d) -CH(CH2CH3)2,

e) cyclopentyl,

f) -CH2CH(OH)CH3,

g) -CH2CF3,

h) -CH2CH(OH)CF3,

(i)- (CH2C(CH3)2OH,

j) -CH2-[4-N-methylpiperidine],

k) -CH2CH2Rd(where Rdrepresents-OH, -och3, -OCH2CH2OH, -OCH2CH2OCH3, -CN, -CF3, -SO2CH3, -SO2NH2, -SO2N(CH3)2, -CONH2, -CON(CH3)2, -NH2, -NHCOCH3, -NHSO2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)21 is pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 2-isothiazoline-1,1-dioxide or 2-tetrahydrofuranyl),

l) -CH2CH2CH2Re(where Rerepresents-OH, -och3, -SO2CH3, -SO2CH2CH3, -SO2H(CH3)2, -CN, -N(CH3)2, -N(CH2CH2CH3)21-imidazolyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, SOON3-SOON2CH3, -SOOS(CH3)3 , -CON(CH3)2, -CO-Rf(where Rfdenotes-CH3, -CH2CH3cyclopropyl, phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl), -COCH2-Rg(where Rgdenotes H, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCH2CH2N(CH3)21 is piperidinyl, 1-(piperidinyl-4-methanol), 4-morpholinyl or-N(CH3)-(3-(1-methylpyrrolidinyl)),

m) -CH2-CO-Rh(where Rhrepresents-och3, -Och2CH3, -NH2, -NHCH2CH(CH3)2, -NHCH2CF3, -NH-cyclopropyl, -NH-tert-butyl, -NHCH2CH2CH2OH, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2OH)2, -N(CH2CH2OCH3)2, -N(CH3)CH2CH2OH, -N(CH3)CH2CH2OCH3, -NHCH2CH2OCH31 is pyrrolidinyl, 1-piperidinyl, 1-(piperidinyl-4-methanol), 1-(piperidinyl-3-carboxamide), 4-morpholinyl, 4-thiomorpholine, 4-thiomorpholine-1,1-dioxide, 1-piperazinil, 1-(4-acetylpiperidine), 1-(3-oxopiperidine),

n) -SO2Rl(where Rldenotes-CH3, -CH2CH3, -CH(CH3)2, phenyl, 4-were, 4-propylphenyl, -CF32-thienyl, 3-thienyl, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH2OCH3, -N(CH2CH2OCH3)21 is pyrrolidinyl, 1-piperidinyl, 4-Mor is oliner, 1-piperazin-4-ethanol, 1-(4-acetylpiperidine), 1-(3-oxopiperidine)),

on-CORj(where Rjdenotes-CH3, -CH2CH3, -CH(CH3)22-tetrahydrofuranyl, 2-thienyl, 3-thienyl, -NH2, -NHCH3, -N(CH3)21 is pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinil-4-ethanol, 1-(4-acetylpiperidine) or 1-(3-oxopiperidine)),

R) 4-tetrahydro-2H-tiopronin-1,1-dioxide,

q) 4-piperidinyl-1-acetyl,

r) 4-piperidinyl-1-dimethylcarbamyl, and

s) 3-tetrahydrothiophene-1,1-dioxide;

v) substituted oxopiperidin formula

in which R represents-H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2OH or-CH2CH2OCH3;

and

vi) a substituted piperidine of the formula

in which R represents-H, -SOON3-SOON2CH3, -CONH2, -OH, -CH2OH, -CH2CH2OH, -CH2-N(CH2CH3)2, -CH2-(1-piperazinil), -CH2-(1-(3-oxopiperidine)), -NH2, -NHCOCH3, -NHCOCH2NH2, -NHCOCH2NHCH3, -NHCOCH2H(CH3)2, -NHCOCH2N(CH2CH2OH)2, -NHCOCH2N(CH2CH2OCH3)2, -NHCOCH2NHCH2CH2OH, -NHCOCH2-(1-(4-acetylpiperidine)), -NHCOCH2-(1-(3-oxopiperidine)), -NHCOCH 2-(1-piperazinecarboxamide), -NHCOCH2-(N,N-diethyl-1-piperazinecarboxamide), -NHCOCH2-(1-(3-hydroxypiperidine)), -NHCOCH2-(1-(piperidinyl-4-methanol)), -NHCON(CH3)2, -NHCSNHCH3, -NHCSNHPh, -NHCH2CONH21 is pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazine) or 4-morpholinyl;

and its pharmaceutically acceptable salts and esters.

More preferred compounds are those in which X1and X2sterling is Cl.

More preferred compounds are those in which R3denotes-C(=O)-R7.

More preferred compounds are those in which R6denotes hydrogen; R4represents-och3, -Och2CH3or-och(CH3)2; and R5denotes-C(CH3)3- (CH3)2OR (where R is-H or-CH3), -C(CH3)2CH-OR (where R is-H or-CH3), -C(CH3)2CN, -C(CH3)2COR (where R is-CH3), -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl or N(CH3)2).

The preferred compounds are those in which R4represents-och3, -Och2CH3or-och(CH3)2; R5means-Cl; and R6means-SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-is util, -NH2or-N(CH3)2).

More preferred compounds are those in which R7means

where R is-CH2CORh.

Even more preferred compounds are those in which Rhdenotes 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl, -NH2or-N(CH3)2.

More preferred compounds are those in which R7means

where R is-CH2CH2CH2Re.

Even more preferred compounds are those in which Remeans-SO2CH3or-SO2CH2CH3.

More preferred compounds are those in which R7means

where R is-CH2CH2Rd.

Even more preferred compounds are those in which Rdmeans-SO2CH3, -NHSO2CH3, -NHCOCH3or-CF3.

More preferred compounds are those in which R7means

where R is 4-tetrahydro-2H-tiopronin-1,1-dioxide.

Another embodiment of the present invention are the compounds of formula I, in which

X1and X mean-Cl;

R1and R2selected from the group comprising-H, -CH3, -CH2CH3, -CH2HE and CH2Och3provided that R1and R2both represent hydrogen;

R3denotes-C(O)-R7;

R4represents-och3, -Och2CH3or-och(CH3)2;

R5denotes-C(CH3)3- (CH3)2OR (where R is-H or-CH3), -C(CH3)2CH-OR (where R is-H or-CH3), -C(CH3)2CN, -C(CH3)2COR (where R is-CH3), -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, or-N(CH3)2);

R6denotes hydrogen;

R7means

(where R denotes-CHCORh);

Rhdenotes 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl, -NH2or-N(CH3)2; and

their pharmaceutically acceptable salts and esters.

Another embodiment of the present invention are the compounds of formula I, in which

X1and X2mean-Cl;

R1and R2selected from the group comprising-H, -CH3, -CH2CH3, -CH2OH and-CH2OCH3provided that R1and R2both represent hydrogen;

R3denotes-C(O)-R7;

R4oznachaet-och 3, -Och2CH3or-och(CH3)2;

R5denotes-C(CH3)3- (CH3)2OR (where R is-H or-CH3), -C(CH3)2CH-OR (where R is-H or-CH3), -C(CH3)2CN, -C(CH3)2COR (where R is-CH3), -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, or-N(CH3)2);

R6denotes hydrogen;

R7means

(where R denotes-CH2CH2CH2Re);

Remeans-SO2CH3or-SO2CH2CH3; and

their pharmaceutically acceptable salts and esters.

Another embodiment of the present invention are the compounds of formula I, in which

X1and X2mean-Cl;

R1and R2selected from the group comprising-H, -CH3, -CH2CH3, -CH3HE and CH2Och3provided that R1and R2both represent hydrogen;

R3denotes-C(O)-R7;

R4represents-och3, -Och2CH3or-och(CH3)2;

R5denotes-C(CH3)3- (CH3)2OR (where R is-H or-CH3), -C(CH3)2CH-OR (where R is-H or-CH3), -C(CH3)2CN, -C(CH3) 2COR (where R is-CH3), -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, or-N(CH3)2);

R6denotes hydrogen;

R7means

(where R denotes-CH2CH2Rd);

R6means-SO2CH3, -NHSO2CH3, -NHCOCH3or-CF3; and

their pharmaceutically acceptable salts and esters.

Another embodiment of the present invention are the compounds of formula I, in which

X1and X2mean-Cl;

R1and R2selected from the group comprising-H, -CH3, -CH2CH3, -CH2OH and-CH2OCH3provided that R1and R2both represent hydrogen;

R3denotes-C(O)-R7;

R4represents-och3, -Och2CH3or-och(CH3)2;

R5means-Cl;

R6means-SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, -NH2or-N(CH3)2);

R7means

(where R denotes-CHCORh);

Rhdenotes 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl, -NH2or-N(CH3)2; and

their pharmaceutically acceptable salts and esters.

Another way of implementing this is part II of the invention are the compounds of formula I, in which

X1and X2mean-Cl;

R1and R2selected from the group comprising-H, -CH3, -CH2CH3, -CH2HE and CH2Och3provided that R1and R2both represent hydrogen;

R3denotes-C(O)-R7;

R4represents-och3, -Och2CH3or-och(CH3)2;

R5means-Cl;

R6means-SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, -NH2or-N(CH3)2);

R7means

(where R denotes-CH2CH2CH2Re);

Remeans-SO2CH3or-SO2CH2CH3; and

their pharmaceutically acceptable salts and esters.

Another embodiment of the present invention are the compounds of formula I, in which

X1and X2mean-Cl;

R1and R2selected from the group comprising-H, -CH3, -CH2CH3, -CH3HE and CH2Och3provided that R1and R2both represent hydrogen;

R3denotes-C(O)-R7;

R4represents-och3, -Och2CH3or-och(CH3)2;

R5means-Cl;

R6means-SO2R (where R denotes-CH31-Pyrrhus is lidin, -NH-tert-butyl, -NH2or-N(CH3)2);

R7means

(where R denotes-CH2CH2Rd);

Rdmeans-SO2CH3, -NHSO2CH3, -NHCOCH3or-CF3; and

their pharmaceutically acceptable salts and esters.

Especially preferred compounds selected from the group including:

rat-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole,

(4S,5R)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-carbonylchloride,

(4S,5R)-4-[[4-[[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]carbonyl]-1-piperazinil]acetyl]-morpholine,

(4S,5R)-4-[[4-[[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]carbonyl]-1-piperidine,

(4S,5R)-1-[[4-[[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]]-carbonyl]-4-[3-(methylsulphonyl)propyl]-piperazine,

(4S,5R)-1-[[4-[[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]]-carbonyl]-4-[3,3,3-cryptochromes]-piperazine,

2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she

2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-di is hydromedusa-1-carbonyl]-piperazine-1-yl}-1-pyrrolidin-1-ylatason,

N-(2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ethyl)-acetamide", she

N-(2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ethyl)-methanesulfonamide,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-hydroxyethyl)-piperazine-1-yl]-methanon,

methyl ester of (S)-4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-1-methylpiperazin-2-carboxylic acid,

5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-2-tert-butyl-4-ethoxy-N,N-dimethylbenzenesulfonamide,

rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-2-methylpropionitrile,

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile,

N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-methanesulfonamide,

N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-acetamide", she

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(2-hydroxyethyl)-piperazin-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile,

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile,

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she

2-[4-((4S,5R)-4,5-bis-(4-chlorophenyl)-1-{4-[2-(1,1-dioxothiazolidine-2-yl)-ethyl]-piperazine-1-carbonyl}-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-3-ethoxyphenyl]-2-methylpropionitrile,

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-1-[4-(2-oxo-2-pyrrolidin-1-retil)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile,

2-{4-[(4S,5R)-1-[4-(1-acetylpiperidine-4-yl)-piperazine-1-carbonyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-2-methylpropionitrile,

isopropylated 4-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-piperidine-1-carboxylic acid,

rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole,

rat-(4S*,5R*)-4-[(4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-3-ethoxybenzaldehyde,

{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

2-(4-{(4S,5R)-4,bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-1-pyrrolidin-1-ylatason,

N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl)-piperazine-1-yl)-ethyl]-methanesulfonamide,

N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-acetamide", she

{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(2-hydroxyethyl)-piperazine-1-yl]-methanon,

4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-3-ethoxybenzaldehyde,

2-{4-[(4S,5R)-2-(4-tert-butylsulfonyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she

rat-(4S*,5R*)-5-[4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde,

5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde,

5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(2-methanesulfonylaminoethyl)piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde the Ministry of foreign Affairs,

N-{(4S,5R)-(2-{4-[2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}ethyl)acetamide", she

5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde,

5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-1-[4-(2-oxo-2-pyrrolidin-1-retil)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde,

2-{4-[(4S,5R)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she

methyl ester of (S)-4-[(4S,5R)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-1-methylpiperazin-2-carboxylic acid,

rat-(4S*,5R*)-2-[4-chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole,

5-{(4S,5R)-2-[4-chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]metano,

rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole,

{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]meth is non,

rat-(4S*,5R*)-2-(4-chloro-2-ethoxy-5-methanesulfonyl)4,5-bis-(4-chlorophenyl)4,5-dimethyl-4,5-dihydro-1H-imidazole,

[(4S,5R)-2-(4-chloro-2-ethoxy-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]metano,

rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole,

{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]metano,

rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxybenzonitrile,

4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxybenzonitrile,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone,

1-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,

N-tert-butyl-2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she

rat-(4S*,5R*)-2-(4-bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole,

rat-(4S*,5R*)-2-(4-bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperaz the n-1-yl]-methanon,

rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-propan-2-ol,

[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

2-{4-[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she

{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she

{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(2-hydroxyethyl)-piperazine-1-yl]-methanon,

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-1-pyrrolidin-1-ylatason,

N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-acetamide", she

N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-methanesulfonamide,

{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-yl]-methanon,

rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole,

rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she

rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,

rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-it,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-methanesulfonyl)-piperazine-1-yl]-methanon,

rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole,

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she

{rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)piperazine-1-yl]-methanon,

rat-1-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-Etalon,

1-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-cyclopropylmethanol,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-cyclobutylamine,

1-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-3-methylbutane-1-he,

1-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-3-phenylpropane-1-he,

4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-benzonitrile,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-furan-2-ylmethanone,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-phenylmethanone,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-methoxyphenyl)-methanon,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-chlorophenyl)-methanon,

rat-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole,

[(4S,5R)-2(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

2-{4-[(4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she

rat-(2-{4-[48*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,

rat-[(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-dimethylamino-piperidine-1-yl)-methanon,

rat-[(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-pyrrolidin-1-reparacin-1-yl)-methanon,

rat-[1,4']bipyridinyl-1'-yl-[(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-methanon,

tert-butyl ether rat-{1-[(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-yl}-carbamino acid,

rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydro-1H-imidazole,

rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-it,

rat-1-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,

[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl is)-piperazine-1-yl]-methanon,

rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,

rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-acanaloniidae-1-yl)-methanon,

(1-methanesulfonamido-4-yl)-amide rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(4-methylpiperazin-1-yl)-piperidine-1-yl]-methanon,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-(morpholine-4-reparacin-1-yl)-methanon,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-hydroxy-piperidine-1-yl)-methanon,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-hydroxyethylpiperazine-1-yl)-methanon,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-hydroxyethyl)-piperidine-1-yl]-methanon,

amide rat-1-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carboxylic acid,

bis-(2-hydroxyethyl)-amide rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)--(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid,

(2,3-dihydroxypropyl)-amide rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid,

3-{4-[4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-3-methylbutane-2-it,

3-(4-{4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-3-methylbutane-2-it,

3-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-3-methylbutane-2-it,

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she

rat-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole,

rat-1-{4-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-isopropylpiperazine-1-yl)-methanon,

rat-4-{4-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-butyronitrile,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methoxypropyl)-piperazine-1-yl]-meta is he,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-morpholine-4-retil)-piperazine-1-yl]-methanon,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-ylmethyl)-piperazine-1-yl]-methanon,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(hexahydropyrazino[1,2-a]pyrazin-2-yl)-methanon,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(octahedrite[1,2-a]pyrazin-2-yl)-methanon,

rat-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid bis-(2-methoxyethyl)-amide,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-methoxyethyl)-piperazine-1-yl]-methanon,

[(4S,5R)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-isopropylphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-2-(5-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-4,5-bis-(4-chlorphen is)-2-(2-ethoxy-5-methanesulfonyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methanesulfonyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(4-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(5-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(4-econsultancy-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-diethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethylsulfanyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-2-(4-tert-butyl-2-methoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

[(4S,5R)-2-(4-chloro-2-ethoxy-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-yl]-methanon,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(1,1-dioxotetrahydrofuran-3-yl)-piperazine-1-yl]-methanon,

[(4S,5R)-2-(4-t the et-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-acanaloniidae)-piperazine-1-yl]-methanon,

2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-acanaloniidae)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile,

(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-imidazole,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone,

[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone,

amide 1-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carboxylic acid,

1-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,

(2-dimethylaminoethyl)-amide rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carboxylic acid,

rat-4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-it,

rat-2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,

rat-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-(4-methanesulfonylaminoethyl-1-yl)-methanon,

rat-2-{4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-1-pyrrolidin-1-ylatason,

rat-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-carbonyl)-piperazine-1-yl]-methanon,

dimethylamide rat-4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-carboxylic acid,

rat-2-{4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she

rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-pyrrolidin-1-ylatason,

rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-it,

rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-(4-methanesulfonylaminoethyl-1-yl)-methanon,

rat-1-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-carbonyl)-piperazine-1-yl]-methanon,

rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-to rbony]-piperazine-1-yl}-acetamide", she

dimethylamide rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-carboxylic acid,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone,

(2-dimethylaminoethyl)-amide rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carboxylic acid,

amide rat-1-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carboxylic acid,

rat-4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-it,

amide rat-1-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carboxylic acid,

rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-carbonyl)-piperazine-1-yl]-methanon,

rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason and

dimethylamide rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazo the-1-carbonyl]-piperazine-1-carboxylic acid.

The term "alkyl" means having a linear or branched chain saturated hydrocarbon groups containing from 1 to about 20 carbon atoms, preferably from 1 to 12, more preferably from 1 to about 7 carbon atoms. In some embodiments, the implementation of the alkyl substituents can be ness. alkyl substituents. The term "ness. alkyl" means alkyl groups containing from 1 to 6 carbon atoms, and in some embodiments, the implementation from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, SIM-butyl, tert-butyl, n-pentyl and Siem pencil.

When used in the present invention "cycloalkyl" shall mean any stable monocyclic or polycyclic system, which consists only of carbon atoms, the rings of which are saturated. Preferably, if such cycloalkyl are 3-14-membered, more preferably 3-10-membered mono - or bicyclic systems. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, substituted, cyclooctyl, bicycloalkyl, including bicyclobutane, such as [2.2.2]bicicletta or [3.3.0]bicicletta, bicycleonly, such as [4.3.0]bicycleand, and bicyclobutane such to the to [4.4.0]bellocan (decalin), or spiraeoideae.

The term "halogen" as used in the definition means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

"Alkoxygroup, alkoxyl or nits. alkoxygroup" means any of the above nits. alkyl groups attached to the oxygen atom. Typical ness. alkoxygroup include methoxy, ethoxy, isopropoxy - or propoxy-, butylacrylate etc. In the meaning of the term "alkoxygroup" is also included containing several groups alkoxide side chains, for example, ethoxyethoxy, methoxyethoxy, methoxyethoxyethoxy and the like, and substituted alkoxide side chains, for example, dimethylaminoethoxy, diethylaminoethoxy, diethoxyphosphoryloxy etc.

The compounds of formula I and their salts containing at least one asymmetric carbon atom may be in the form of racemic mixtures or different stereoisomers. Various isomers can be distinguished by using known separation techniques such as chromatography.

Connections proposed in the present invention and vpisivaushiesya the above formula I, can be characterized by fotometria or structural isomerism. It is implied that the present invention encompasses any tautomeric or structural isomeric forms of these compounds and mixtures of such forms and is not limited to any who Automoney or structural isomeric form, described by the above formula I.

Connections proposed in the present invention, applicable for the treatment of cell proliferative disorders, in particular cancer disorders, or fight with them. These compounds and drugs containing these compounds, can be used to treat solid tumors, such as tumors of the breast, colon, lung and prostate cancer, or fighting them.

A therapeutically effective amount of the compounds in the context of the present invention means the number of connections, which is effective to prevent, alleviate or ameliorate symptoms of disease or for increasing the life expectancy of the subject undergoing treatment. Determination of therapeutically effective amount is within the competence of a person skilled in the technical field.

Therapeutically effective amount or dosage of the compounds proposed in the present invention, may vary within wide limits and can be identified by methods known in the art. This dosage should be selected in accordance with the individual requirements in each particular case, taking into account what specific connection (connection) is entered, the route of administration, treated pathological condition, and ACC is lauderee treatment of the patient. Usually by oral or parenteral administration to adult humans weighing approximately 70 kg may be a suitable daily dose is from about 10 to about 10000 mg, preferably from about 200 to about 1000 mg, although there are indications the upper limit value may be exceeded. The daily dose can be administered as a single dose or divided doses and parenteral you can enter it in the form of a continuous infusion.

Drugs proposed in the present invention include intended for oral, nasal, local (including transbukkalno and sublingual), rectal, vaginal and/or parenteral administration. The preparations can be prepared in the form of a single dosage forms and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient which can be combined with the media to produce a single dosage form will vary depending on the treated recipient, and the particular route of administration. The amount of active ingredient which can be combined with the media to produce a single dosage form will generally be that amount of a formula I compound, which leads to a therapeutic effect. Usually this number varies in the range from about 1 to about 99%of active ingredient, preferably from about 5 to about 70%, most preferably from about 10 to about 30%.

Methods of preparing these preparations or compositions include the stage of combining the compounds proposed in the present invention, with a carrier and optionally with one or more accessory ingredients. Usually the drugs are prepared by uniformly and thoroughly merge joins, proposed in the present invention with liquid carriers or finely ground solid carriers or both of those, and other, if necessary with subsequent formation of the product.

Drugs proposed in the present invention suitable for oral administration can be a capsule, pellet, wafer, pill, tablet, lozenge-shaped tablet (using a flavoring, normally sucrose or gum acacia, or tragacanth gum), powders, granules or in solution or suspension in aqueous or non-aqueous liquid, or a liquid emulsion of the type oil-in-water or water-in-oil, or elixirs, or syrups or lozenges (using an inert base, such as gelatin or glycerin, or sucrose, or gum acacia) and/or as a gargle for mouth and the like, each of which contains a given number of connections proposed in the present invention, as active and is gradient. The connection proposed in the present invention, it is also possible to enter bolus, electuary or paste.

"Pharmaceutically acceptable ester" means ordinary way esterified compound of the formula I containing carboxypropyl, and these esters retain the biological effectiveness and characteristics of the compounds of the formula I and in vivo (in the body) are oxidized with the release of the corresponding active carboxylic acid.

Information about similar esters and the use of esters for the delivery of pharmaceutical compounds are given in the publication " Design of Prodrugs. Bundgaard H ed. (Elsevier, 1985). Cm. also .Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp.108-109; Krogsgaard-Larsen, et al., In Textbook of Drug Design and Development (2d Ed. 1996) at pp.152-191.

"Pharmaceutically acceptable salt" means ordinary salt accession with acids or salts attach to bases that retain the biological effectiveness and characteristics of the compounds proposed in the present invention, and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Suitable salts of joining with acids include formed from inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, sulfamic acid, f is sforna acid and nitric acid, or from organic acids such as p-toluensulfonate acid, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. Samples salts joining with bases include obtained from the hydroxides of ammonium, potassium, sodium and Quaternary ammonium compounds, such as, for example, Tetramethylammonium. Chemical transformation of pharmaceutical compounds (i.e. medicines) in salt is a technique well known to chemists pharmacists and intended to improve the mechanical and chemical stability, hygroscopic characteristics, flowability and solubility of compounds. See, for example, .Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp.196 and 1456-1457.

"Pharmaceutically acceptable"such as pharmaceutically acceptable carrier, excipient and the like, means pharmacologically acceptable and generally non-toxic to the subject, which impose a particular connection.

"Substituted" means substitution can occur at one or more positions, unless otherwise stated, and that the substituents in each position of the substitution is independently selected from the specified group.

"Therapeutically effective amount" means an amount of at least one specified the CSOs connection that significantly inhibits proliferation and/or prevents differentiation of human tumor cells, including line human tumor cells.

Connections proposed in the present invention, are given as preferred examples have values IC50equal to from about 1 to about 1000 nm.

The present invention also relates to pharmaceutical compositions comprising at least one compound of formula I or its pharmaceutically acceptable salt or ester and a pharmaceutically acceptable carrier or excipient.

General methods of preparing compounds of formula (I) is shown in schemes 1, 2, 3 and 4, where, if not explicitly stated otherwise, all of the substituents (X1X2, R1, R2, R3, R4, R5and R6) have the above values.

Briefly, the method includes obtaining imidazoline (V) or by condensation of Tetra-substituted 1,2-diamine (II) with aromatic acid (III) with the formation of a derivative monoamide (IV) with subsequent cyclodehydration (method 1, scheme 1), or by the reaction of Tetra-substituted 1,2-diamine (II) with aromatic ether complex (VI) in the presence of trialkylamine (method 2, scheme 2).

Imidazolin (V) enter into reaction with phosgene to form carbamylcholine (VII), which is then injected into the reaction with amyamyamy formula RaRbNH with formation of the corresponding urea derivatives of the formula (I), i.e. such derivatives, in which R3denotes the group-C(O)-R7and R7has the values specified in sections ii)-vi)above (path (A) in scheme 3).

Imidazolin (V) you can also enter into reaction with anhydrides of the acids of formula (VIII) in the presence of a base, such as triethylamine, with formation of the corresponding derivatives of the amides of formula (I), i.e., those derivatives in which R denotes the group-C(O)-R7and R7has the values specified in section i)above (path (C) in scheme 3).

The absolute stereochemical configuration of the active enantiomer (I) determined on the basis of the crystal structure of its complex with MDM2 (see Vassilev, L. et al. Science 2004, 303, 844-848).

Getting imidazoline

Method 1: Interaction of diamines with acids

Scheme 1

Method 2: Interaction of diamines with esters

Scheme 2

Getting imidazoline derivatives

Scheme 3

Group RaRbNH figure 3 indicates primary or secondary (and cyclic) amino group corresponding to the definitions of R7sections ii)-(vi), respectively.

The group R" in the formula (VIII) in scheme 3 refers to the group corresponding to section i) for R7above.

Obtaining p is omegatech diamines

The intermediate diamines received or by using a restorative combination of Iminov according to the method described in the publication Volckaerts [Sugase, E.Volckaerts, ...Lenstra, H.J.Geise, H.J., Bulletin des Societes Chimiques Beiges, 1990, 99, 797-801] (method 3), or by the reaction of 1,2,5-thiadiazole-1,1-dioxides with Grignard reagents according to the method described in the publication Pansare [S.V.Pansare, A.N.Rai, S.N.Kate, Synlett, 1998, 623-624] (method 4).

Method 3:

Scheme 4

Method 4:

Scheme 5

The following examples and links are intended to facilitate understanding of the present invention, the precise scope of which is indicated in the accompanying claims.

General provisions: In the examples, temperatures are in degrees Celsius. The values of the mass spectroscopic characteristics are shown for ion MH+/Z obtained by elektrorazpredelenie in the positive mode ionization mass spectrometer Micromass Platform II.

Example 1

Meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine

A mixture of 15.0 g (97,3 mmole) of trichloride titanium and 480 ml of tetrahydrofuran in an argon atmosphere was cooled to -15°C. and then was added dropwise 48,64 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran. The mixture was stirred for 10 minutes, then boiled under reflux for 1 h the Mixture was cooled to room temperature and rest the market 50 ml of ammonia in 192 ml of tetrahydrofuran and 15,04 g (97,3 mmole) of 4-chloroacetophenone in 240 ml of tetrahydrofuran was added at the same time for 40 minutes The mixture was stirred over night at room temperature, then was cooled to 0°C. and acidified by adding 2 M hydrochloric acid. The aqueous phase was extracted with dichloromethane, then podslushivaet by adding 2 M sodium hydroxide solution and was extracted with dichloromethane. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and was received with 4.64 g of 2,3-bis-(4-chlorophenyl)-2,3-butanediamine in the form of a mixture of meso and d1-isomers. This substance was used without further purification in subsequent reactions.

Example 2

rat-(4S*,5R*)-4,5-Bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol

Method 1:

For 30 min at room temperature carried out the reaction of a mixture of meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (70 mg, 0,226 mmole, example 1) and triethylamine (62 μl, 0,226 mmole) in 2 ml of dichloromethane with 0.225 mmole of 4-(tert-butyl)-2-ethoxybenzonitrile (obtained by the reaction of 0.225 mmole of 4-(tert-butyl)-2-ethoxybenzoyl acid and 0.34 mmole of oxalicacid). The mixture was subjected to distribution between 10% sodium bicarbonate solution and dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and obtained the crude mixture am the Dov. Purification via chromatography on silica gel with elution by the mixture hexane-ethyl acetate (3:1) gave 20 mg of N-[2-amino-1,2-bis-(4-chlorophenyl)-1-methylpropyl]-4-(tert-butyl)-2-ethoxybenzene. The intermediate substance is boiled under reflux in an argon atmosphere with 0.5 mg of the monohydrate toluensulfonate acid and 7 ml of toluene for 3.5 h, then was cooled, dissolved in ethyl acetate and sequentially washed with a saturated solution of sodium bicarbonate, water and brine. An ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via chromatography on silica gel with elution by ethyl acetate, then with a mixture of ethyl acetate : methanol (95:5) gave 9.5 mg rat-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole. HP-MS (mass spectroscopy low-resolution): 495,0 [(M+N)+].

Method 2:

A solution of meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (2.5 g, 8,08 mmole, example 1) in 100 ml of toluene was added to a solution of trimethylaluminum (4 ml, 2 M solution in toluene, Aldrich) in 24 ml of toluene at 0°C. the Mixture was stirred for 10 min at 0°C, 20 min at room temperature and then was added the methyl ester of 4-(tert-butyl)-2-ethoxybenzoyl acid (2.1 g, 8.9 mmole) in 10 ml of toluene. The mixture was boiled under reflux for 2.5 h, then was cooled to 0°C and R. the action stopped, dropwise adding a saturated solution of sodium tartrate. The mixture was extracted with ethyl acetate and an ethyl acetate layer was sequentially washed with 10% sodium bicarbonate solution and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via chromatography on silica gel with elution by the mixture hexane-ethyl acetate (1:1) to give 710 mg of rat-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole. HP-MS: 495,0 [(M+N)+].

Example 3

rat-(4S*,5R*)-4,5-Bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-carbonylchloride

To a solution of rat-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (710 mg, 1,43 mmole, example 2) and triethylamine (400 μl, 2.86 mmole) in 12 ml of dichloromethane at 0°C was added 1.13 ml of a 1.9 M solution of phosgene in toluene (Fluka). After stirring for 30 min the mixture was dissolved in dichloromethane and washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via chromatography on silica gel with elution by the mixture hexane-ethyl acetate (4:1) gave 689 mg rat-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-carbonylchloride in the form of a white solid which CSOs substances.

Example 4

(4S,5R)-4,5-Bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-carbonylchloride

Chiral separation of rat-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-carbonylchloride (example 4) using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 15% acetonitrile in carbon dioxide) gave the desired compound.

Example 5

(4S,5R)-4-[[4-[[4,5-Bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]carbonyl]-1-piperazinil]acetyl]-morpholine

To a solution of rat-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-carbonylchloride (50 mg, and 0.09 mmole, example 4) in 5 ml dichloromethane at 0°C were added triethylamine (165 μl, 1,186 mmole) and 4-(1-piperazinylmethyl)-morpholine (20 mg (0,097 mmole, Oakwood Products). The reaction mixture was carried out for 20 h and then dissolved in dichloromethane and then washed with 10% sodium bicarbonate solution and water. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via chromatography on silica gel with elution with a mixture of ethyl acetate : methanol (95:5) gave a 55.4 mg rat-(4S*,5R*)-4-[4-[[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]carbonyl]-1-piperazinil]acetyl]-the research. Separation of enantiomers using chiral HPLC (high performance liquid chromatography) gave 24 mg of (4S,5R)-4-[[4-[[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]carbonyl]-1-piperazinil]acetyl]-the research. BP-MS (mass spectroscopy high resolution) (IE (electrospray ionization), m/z) calculated for C40H50N5O4Cl2[(M+N)+] 734,3235 found 734,3237.

Example 6

(4S,5R)-4-[[4-[[4,5-Bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]carbonyl]-1-piperidine

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-carbonylchloride (50 mg, and 0.09 mmole) was injected into the reaction with piperidine (Aldrich) and after chiral separation received 24 mg of the desired compound. BP-MS (EI, m/z) calculated for C35H42N3O2Cl2[(M+N)+] 606,2649 found 606,2650.

Example 7

(4S,5R)-1-[[4-[[4,5-Bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]]-carbonyl]-4-[3-(methylsulphonyl)propyl]-piperazine

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-carbonylchloride (50 mg, 0,mole) were introduced in the reaction with 4-[3-(methylsulphonyl)propyl]-piperazine (0,09 mmole, obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and after chiral separation received 24 mg of the desired compound. BP-MS (EI, m/z) calculated for C38H49N4O4SCl2[(M+N)+] 727,2846 found 727,2846.

Example 8

(4S,5R)-1-[[4-[[4,5-Bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]]-carbonyl]-4-[3,3,3-cryptochromes]-piperazine

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-carbonylchloride (50 mg, and 0.09 mmole) was injected into the reaction with 4-[3-(methylsulphonyl)-propyl]-piperazine (0,09 mmole, obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and after chiral separation was received 38 mg of the desired compound. BP-MS (EI, m/z) calculated for C37H44N4O2F3Cl2[(M+N)+] 727,2846 found 727,2846.

Example 9

2-{4-[(48,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 4) were introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired connection. BP-MS (EI, /z) calculated for C 36H44H5O3Cl2[(M+N)+] 664,2816 found 664,2810.

Example 10

2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-pyrrolidin-1-ylatason

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 4) were introduced in the reaction with 2-piperazine-1-yl-1-pyrrolidin-1-ratanana (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C40H50N5O3Cl2[(M+N)+] 718,3285 found 718,3286.

Example 11

N-(2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ethyl)-ndimethylacetamide

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 4) were introduced in the reaction with N-(2-piperazine-1-retil)-acetamidocinnamate (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired connection. BP-MS (EI, m/z) calculated for C38H48H5O3Cl2[(M+N)+] 692,3129 found 692,3125.

Example 12

N-(2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-ethyl)-methanesulfonamide

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 4) were introduced in the reaction with N-(2-piperazine-1-retil)-methanesulfonamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired connection. BP-MS (EI, m/z) calculated for C37H48N5O4SCl2[(M+N)+] 782,2799 found 782,2787.

Example 13

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-hydroxyethyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 4) were introduced in the reaction with 2-piperazine-1-ilathalam (Chemical Dynamics) and got the desired connection. BP-MS (EI, m/z) calculated for C36H45N4O3Cl2[(M+N)+] 651,2863 found 651,2863.

Example 14

Methyl ester of (S)-4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-1-methylpiperazin-2-carboxylic acid

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbon is chloride (example 4) were introduced in the reaction with methyl ether (S)-1-methylpiperazin-2-carboxylic acid (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C37H45H4O4Cl2[(M+N)+] 679,2813 found 679,2805.

Example 15

5-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-2-tert-butyl-4-ethoxy-N,N-dimethylbenzenesulfonamide

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) were introduced in the reaction with methyl ester 4-tert-butyl-5-dimethylsulphamoyl-2-ethoxybenzoyl acid (obtained by the procedure similar to that described in example 43) in the presence of trimethylaluminum and got rat-5-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-N,N-dimethylbenzenesulfonamide.

According to the method similar to that described in example 3, RAC-5-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-N,N-dimethylbenzenesulfonamide was introduced in the reaction with phosgene in the presence of triethylamine and got rat-(4S*,5R*)-2-(4-tert-butyl-5-dimethylsulphamoyl-2-ethoxyphenyl)-4,5 bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride. Then carbamoylated was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) in the presence of triethylamine and got the desired compound in the form of racemic mixtures. the ATEM enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C40H53H5O6S2Cl2[(M+N)+] 834,2887 found 834,2878.

Example 16

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-2-methylpropionitrile

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with methyl ester of 4-(centimetres)-2-ethoxybenzoyl acid (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) in the presence of trimethylaluminum and got the desired connection. HP-MS: 506,0 [(M+N)+].

Example 17

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, 2-{4-[rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-2-methylpropionitrile (example 17) was introduced into the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 18

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile

By the method similar to described the example 5, rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 35% methanol in carbon dioxide). HP-MS: 738,0 [(M+N)+].

Example 19

N-[2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-methanesulfonamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced into the reaction with M-(2-piperazine-1-retil)-methanesulfonamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide). HP-MS: 739,3 [(M+N)+].

Example 20

N-[2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[4-(tzia is dimethylethyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with N-(2-piperazine-1-retil)-acetamidocinnamate (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 35% methanol in carbon dioxide). HP-MS: 703,3 [(M+N)+].

Example 21

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(2-hydroxyethyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-ilathalam (Chemical Dynamics) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide). HP-MS: 662,2 [(M+N)+].

Example 22

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(1,1-dioxo is etrahydro-2H-thiopyran-4-yl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile

With stirring to a solution of tetrahydrothiopyran-4-one (5.30 g, 43,1 mmole, Aldrich) in 50 ml of ethyl acetate was added dropwise 32% peracetic acid (24 g, 110 mmole) with speed, eliminating the boil. After the addition the mixture was cooled to room temperature and the solid was filtered and obtained 1,1-dioxotetrahydrofuran-4-one as a white solid (5,69 g, 89%).

Tetrahydro-4H-thiopyran-4-one (6 g, 40.5 mmole) at low heating was dissolved in 1,2-dichloroethane (250 ml). When the temperature was decreased to room temperature, was added 1-BOC-piperazine (7,62 g, 41 mmole), triacetoxyborohydride sodium (17,01 g, 56,7 mmole)and then glacial acetic acid (2.4 g, 41 mmole). The reaction mixture was stirred at room temperature overnight. The reaction was stopped with water and the layers were separated. The aqueous layer was extracted with 1,2-dichloroethane (3×20 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated and received a white solid. White solid was purified using flash chromatography (ISCO, silica gel, with elution with a mixture of 2-7% methanol-ethyl acetate for 30 min) and was obtained tert-butyl ester 4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-carboxylic acid as a white solid (9.3 g, 69%). HP-MS: 334 [(M+N)+].

PR is stirring to a solution of tert-butyl ester 4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-carboxylic acid (8,02 g, 25 mmole) in methanol at 45°C. (150 ml) was added 4 N. hydrochloric acid in 1,4-dioxane (100 mmole, 25 ml, Aldrich). The mixture was stirred at 45°C for 7 hours until thin layer chromatography (5% methanol in ethyl acetate) showed that the reaction was completed. The solvent was removed under reduced pressure and obtained 1-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazineethanol in the form of a white solid substance (of 7.24 g of 99.5%). HP-MS: 218 [(M+N)+].

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazinecarboxamide and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide). HP-MS: 749,63 [(M+N)+].

Example 23

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-PIP the Razin-1-yl-acetamidomalonate (Matrix Scientific) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide). HP-MS: 675,2 [(M+N)+].

Example 24

2-[4-((4S,5R)-4,5-Bis-(4-chlorophenyl)-1-{4-[2-(1,1-dioxothiazolidine-2-yl)-ethyl]-piperazine-1-carbonyl}-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-3-ethoxyphenyl]-2-methylpropionitrile

With stirring to a solution of 1-BOC-4-(2-amino-ethyl)-piperazine (1.26 g, 6.8 mmole, Aldrich) and triethylamine (1 ml) in tetrahydrofuran (10 ml) at room temperature was slowly added 3-chloropropanesulfonyl (0.68 ml, 6,94 mmole, Aldrich). The mixture was stirred for 30 min at room temperature and the reaction was stopped with water. It was extracted with ethyl acetate and the extracts were combined and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo and obtained tert-butyl ester 4-[2-(3-chloro-propane-1-sulfonylamino)-ethyl]-piperazine-1-carboxylic acid. It was dissolved in tetrahydrofuran (20 ml) was added cesium carbonate (500 mg) and sodium iodide (80 mg) and the mixture was stirred while boiling under reflux overnight. The mixture was cooled to room temperature and poured into water. It was extracted with ethyl acetate (3×15 ml) and the extracts were combined and dried the hell anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuum and got a 2.01 g of tert-butyl ester 4-[2-(1,1-dioxothiazolidine-2-yl)-ethyl]-piperazine-1-carboxylic acid in the form of solids. HP-MS: 334 [(M+N)+].

Tert-butyl ester 4-[2-(1,1-dioxothiazolidine-2-yl)-ethyl]-piperazine-1-carboxylic acid (2,01 g) was treated with 30% triperoxonane acid in dichloromethane (10 ml) and the mixture was stirred at room temperature for 30 minutes the Mixture was concentrated in vacuo and got to 2.46 g of 1-[2-(1,1-dioxothiazolidine-2-yl)-ethyl]-piperidinecarboxylate in the form of solids. HP-MS: 234 [(M+N)+].

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-[2-(1,1-dioxothiazolidine-2-yl)-ethyl]-piperazineethanol and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 35% methanol in carbon dioxide). HP-MS: 765,0 [(M+N)+].

Example 25

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-1-[4-(2-oxo-2-pyrrolidin-1-retil)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-1-pyrrolidin-1-ratanana (Aldrich) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 20% methanol in carbon dioxide). HP-MS: 729,4 [(M+N)+].

Example 26

2-{4-[(4S,5R)-1-[4-(1-Acetylpiperidine-4-yl)-piperazine-1-carbonyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-2-methylpropionitrile

N-tert-butoxycarbonylmethyl (1.86 g, 10 mmole, Lancaster), N-Fmoc-4-oxo-piperidine (3,21 g, 10 mmole, Aldrich) and isopropoxide titanium(IV) (3,72 ml, Aldrich) were combined and the mixture was stirred at room temperature for 1 h Then was added ethanol (10 ml), and then cyanoborohydride sodium (0,47 g of 7.48 mmole, Aldrich) and the mixture was stirred over night. Was added water (2 ml) and the mixture was filtered. The solid is washed with ethanol and the filtrates were combined. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (ISCO, silica gel, elution with 20% ethyl acetate in hexane for 30 m is n) and obtained tert-butyl ester 4-(1-Fmoc-piperidine-4-yl)-piperazine-1-carboxylic acid as a white foam substances (1,02 g).

Tert-butyl ester 4-(1-Fmoc-piperidine-4-yl)-piperazine-1-carboxylic acid (0.3 g, and 0.61 mmole) was stirred with 20% piperidine in methylene chloride for 40 minutes the Mixture was concentrated to dryness and was obtained tert-butyl ether 4-piperidine-4-reparation-1-carboxylic acid. Then it was dissolved in tetrahydrofuran (5 ml) was added triethylamine (308 mg, of 3.05 mmole) and acetic anhydride (86 mg, 0.9 mmole). Then the reaction mixture was stirred for 2 h, were added water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated and was obtained tert-butyl ester 4-(1-acetylpiperidine-4-yl)-piperazine-1-carboxylic acid. It was dissolved in methylene chloride (7 ml), cooled in a bath of ice and added triperoxonane acid. The reaction mixture was stirred for 30 min and the solvent was removed. The residue is triturated with diethyl ether and the solvent was removed and obtained 1-(4-piperazine-1-reparacin-1-yl)-atlanticocean in the form of a light yellow foam substances (151 mg, 76%). HP-MS: 212 [(M+N)+]

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(4-PIP the Razin-1-reparacin-1-yl)-atlanticocean and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide). HP-MS: 743,4 [(M+N)+].

Example 27

4-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-piperidine-1-carboxylic acid Isopropylamine

To a solution of tert-butyl methyl ether 4-piperidine-4-reparation-1-carboxylic acid (108 mg, 0.4 mmole, example 27) in dichloromethane (2 ml) was added isopropyltoluene. The mixture was stirred for 1 h and the reaction was stopped with water. After treatment with water and dichloromethane organic layers were dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated and was obtained tert-butyl ester 4-(1-isopropylcarbodiimide-4-yl)-piperazine-1-carboxylic acid as a viscous oil.

According to the method similar to that described in example 27, tert-butyl ester 4-(1-isopropylcarbodiimide-4-yl)-piperazine-1-carboxylic acid were processed triperoxonane acid and got isopropylpiperazine 4-piperazine-1-reparacin-1-carboxylic acid as a yellow solid. HP-MS: 255 [(M+N)+].

According to the method similar to that described in example 5, RAC-(4S*,5R*)-45-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with isopropylpiperazine 4-piperazine-1-reparacin-1-carboxylic acid and was obtained the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 30% methanol in carbon dioxide). HP-MS: 786,0 [(M+N)+].

Example 28

Methyl ester 2-ethoxy-4-(pyrrolidin-1-sulfonyl)-benzoic acid

2 Ethoxy-4-thiobenzoic acid (1.6 g, 8,08 mmole, obtained in accordance with the publication Robertson, D. et al. J. Med. Chem. 1985, 28, 717-727) was dissolved in methanol (80 ml) and cooled to 0°C. was Slowly added thionyl chloride (1.2 ml, 16.2 mmole). The reaction mixture gave to slowly warm to room temperature and was stirred overnight. Evaporation of the solvent gave a mixture of sulfide and disulfide methyl ester (1.9 g, 100%) as a yellow oil, which was used without further purification. This crude sulfide/disulfide ester was dissolved in acetic acid and cooled to 0°C. a Small amount of toluene was added to the reaction mixture to prevent freezing of the reaction mixture. Gaseous chlorine (Cl2) was passed through the reaction mixture until thin layer chromatography (50% ethyl acetate in hexano) not found magazine is empty, the original substance. To remove excess chlorine through the reaction mixture missed argon (Ar). The reaction mixture was concentrate which has demonstrated to dryness in a vacuum and with a quantitative yield was obtained methyl-4-chlorosulfonyl-2-ethoxybenzoate. It was dissolved in anhydrous methylene chloride (50 ml) and cooled to 0°C. were Added triethylamine (8.5 ml, 62 mmole) and pyrrolidine (2.7 ml, and 32.3 mmole). The reaction mixture gave to slowly warm to room temperature and it was stirred at room temperature for 16 hours the Reaction mixture was washed with water, dried over magnesium sulfate and concentrated. Purification of the crude residue using flash column-chromatography (40 g silica gel, elution with 15-30% ethyl acetate in hexano) gave methyl ether, ethoxy-4-(pyrrolidin-1-sulfonyl)-benzoic acid. BP-MS (EI, m/z) calculated for C14H20NO5[(M+N)+] 314,1057 found 314,1056.

Example 29

Methyl ester 4-tert-butylsulfonyl-2-ethoxybenzoyl acid

According to the method similar to that described in example 29, methyl-4-chlorosulfonyl-2-ethoxybenzoate was introduced into the reaction with tert-butylamine was obtained methyl ester 4-tert-butylsulfonyl-2-ethoxybenzoyl acid.

Example 30

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with methyl ether 2-ethoxy-4-(pyrrolidin-1-sulfonyl)-benzoic acid in the presence of trimet aluminia and got the desired connection. BP-MS (EI, m/z) calculated for C29H32N3O3SCl2[(M+N)+] 572,1536 found 572,1534.

Example 31

rat-(4S*,5R*)-4-[(4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-3-ethoxybenzaldehyde

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with methyl ester 4-tert-butylsulfonyl-2-ethoxybenzoyl acid in the presence of trimethylaluminum and got the desired connection. BP-MS (EI, m/z) calculated for C29H34N3O3SCl2[(M+N)+] 574,1693 found 574,1589.

Example 32

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole (example 31) were introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 33

rat-(4S*,5R*)-2-(4-tert-Butylsulfonyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-4-[(4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-3-oxybenzenesulfonate (example 32) was introduced into the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 34

{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 25% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C38H47N6O5S2Cl2[(M+N)+] 804,2418 found 804,2413.

Example 35

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired compound in the form of racemic the tion mixture. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 25% of a mixture of 1:1 ethanol/acetonitrile in carbon dioxide). BP-MS (EI, m/z) calculated for C36H42N6O5SCl2[(M+N)+] 741,2387 found 741,2379.

Example 36

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-1-pyrrolidin-1-ylatason

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-1-pyrrolidin-1-ratanana (Aldrich) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% of a mixture of 1:1 ethanol/acetonitrile in carbon dioxide). BP-MS (EI, m/z) calculated for C40H48H6O5SCl2[(M+N)+] 795,2857 found 795,2851.

Example 37

N-[2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-methanesulfonamide

On m is todica, similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with N-(2-piperazine-1-retil)-methanesulfonamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C37H46N6O6S2Cl2[(M+N)+] 805,2370 found 805,2372.

Example 38

N-[2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with N-(2-piperazine-1-retil)-acetamidocinnamate (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and suirou the AI using 25% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C38H46H6O5SCl2[(M+N)+] 769,2700 found 769,2697.

Example 39

{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(2-hydroxyethyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-ilathalam (Chemical Dynamics) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C36H43N5O5SCl2[(M+N)+] 728,2435 found 728,2431.

Example 40

4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-3-ethoxybenzaldehyde

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butylsulfonyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained, as is written in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 35% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C38H49H5O6S2Cl2[(M+N)+] 806,2574 found 806,2579.

Example 41

2-{4-[(4S,5R)-2-(4-tert-Butylsulfonyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butylsulfonyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C36H44H6O5SCl2[(M+N)+] 743,2544 found 743,2538.

Example 42

Methyl ester 5-tert-butylsulfonyl-4-chloro-2-ethoxybenzoyl acid

4-Chlorosalicylic acid (15 g, Aldrich, 87.5MHz mmole) and Atila the bits (35,7 g, 230 mmole) was dissolved in dimethylformamide (400 ml) and vigorous stirring blade device the solution was cooled to 0°C (from acetone bath with ice). The two portions was added sodium hydride (10.5 g, Aldrich, 50% in oil, 220 mmole). Cooling was stopped after 10 min and the reaction mixture was slowly heated to 30°C and then heated at 50-60°C for 2 h, the Reaction mixture was cooled and poured into a mixture of ice water and was extracted with dichloromethane (3×500 ml). The organic layer was washed with water (2×500 ml), washed with brine, dried over magnesium sulfate and evaporated to dryness and received ethyl ester 4-chloro-2-ethoxybenzoyl acid.

Ethyl ester of 4-chloro-2-ethoxybenzoyl acid (~18 g) suspended in ethanol (500 ml). He was treated with potassium hydroxide (200 ml, 2 M solution) and boiled under reflux for 1 h the Reaction mixture was cooled and poured into cold aqueous hydrochloric acid solution (300 ml, 3 M solution) and was extracted with dichloromethane (3×500 ml). Dichloromethane was washed with water (500 ml) and dried over magnesium sulfate and evaporated to dryness and received 4-chloro-2-ethoxybenzoyl acid in the form of solids.

4-Chloro-2-ethoxybenzoyl acid (9.4 g, 47 mmole) in several portions was added to the cold chlorosulfonic acid (55 ml, Aldrich)was stirred at 0-10°C. and the resulting solution was heated at -60°C in the tip is of 2 hours Received the dark solution was poured into ice (800 g) and then was added 500 ml of dichloromethane. After stirring for 15 min the layers were separated and the aqueous layer was extracted with 200 ml dichloromethane. The organic layers were successively washed with brine, combined, dried over magnesium sulfate, filtered and concentrated at room temperature. Crystallization from a mixture of ether/hexane gave 3.4 g of 4-chloro-5-chlorosulfonyl-2-ethoxybenzoyl acid.

A solution of 4-chloro-6-chlorosulfonyl-2-ethoxybenzoyl acid (1.0 g, 3,34 mmole) and tert-butyl amine (2.0 ml) in 20 ml of tetrahydrofuran was heated under reflux for 4 h and concentrated. The residue in water was acidified and extracted with ether, the extract washed with water, brine, dried over magnesium sulfate, filtered and evaporated. Deposition from a mixture of ether/hexane gave 0.8 g of the crude 5-tert-butylsulfonyl-4-chloro-2-ethoxybenzoyl acid.

5-tert-Butylsulfonyl-4-chloro-2-ethoxybenzoyl acid (0.8 g, 24 mmole) in 10 ml of tetrahydrofuran at room temperature was treated with diazomethane (15 ml, ~2-3 M in ether, obtained from N-methyl-N-nitroso-p-toluensulfonate, Aldrich) and stirred for 0.5 h the Mixture was concentrated and the residue was purified using flash chromatography (silica gel, elution with 20% ethyl acetate in hexane) was obtained 0.45 g of methyl ester 5-tert-Buti is sulfamoyl-4-chloro-2-ethoxybenzoyl acid in the form of solids.

Example 43

rat-(4S*,5R*)-5-[4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-2-chloro-4-ethoxybenzylidene

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) were introduced in the reaction with methyl ester 5-tert-butylsulfonyl-4-chloro-2-ethoxybenzoyl acid (example 43) in the presence of trimethylaluminum and got the desired connection. BP-MS (EI, m/z) calculated for C29H33N3O3SCl3[(M+N)+] 608,1303 found 608,1300.

Example 44

rat-(4S*,5R*)-2-(5-tert-Butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-5-[4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde (example 44) was introduced into the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 45

5-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzylidene

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazo the l-1-carbonylchloride (260 mg, to 0.39 mmole, example 45) and triethylamine (350 mg, 3,34 mmole) in methylene chloride (10 ml) was treated with 1-(3-methanesulfonyl)-piperazinecarboxamide (110 mg, of 0.39 mmole, obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C38H49H5O6S2Cl3[(M+N)+] 840,2185 found 840,2179.

Example 46

5-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(2-methanesulfonylaminoethyl)piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzylidene

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 45) was introduced in the reaction with N-(2-piperazine-1-retil)-methanesulfonamide (obtained as described in the publication Fotouhi, N. et at. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide is carbon). BP-MS (EI, m/z) calculated for C37H48N6O6S2Cl3[(M+N)+] 841,2137 found 841,2129.

Example 47

N-{(4S,5R)-(2-{4-[2-(5-tert-Butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}ethyl)ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 45) was introduced in the reaction with N-(2-piperazine-1-retil)-acetamidocinnamate (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 25% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C37H48N6O5SCl3[(M+N)+] 805,2460 found 805,2467.

Example 48

5-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzylidene

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl arid (example 45) was introduced in the reaction with 2-piperazine-1-ilathalam (Chemical Dynamics) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 25% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C36H45N5O5SCl3[(M+N)+] 764,2202 found 764,2198.

Example 49

5-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-1-[4-(2-oxo-2-pyrrolidin-1-retil)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzylidene

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 45) was introduced in the reaction with 2-piperazine-1-yl-1-pyrrolidin-1-ratanana (Aldrich) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OJ-H 3×25 cm, 35°C at 100 bar and elution with 15% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C40H50N6O5SCl3[(M+N)+] 831,2624 found 831,2625.

Example 50

2-{4-[(4S,5R)-2-(5-tert-Butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide

By the method similar to OPI is Anna in example 5, rat-(4S*,5R*)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 45) was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 25% of a mixture of 1:1 acetonitrile/ethanol carbon dioxide). BP-MS (EI, m/z) calculated for C36H44N6O5SCl3[(M+N)+] 777,2154 found 777,2146.

Example 51

Methyl ester of (S)-4-[(4S,5R)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-1-methylpiperazin-2-carboxylic acid

According to the method similar to that described in example 5, pan-(4S*,5R*)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 45) was introduced in the reaction with methyl ether (S)-1-methylpiperazin-2-carboxylic acid and was obtained the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 25% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for 37H45N5O6SCl3[(M+N)+] 792,2151 found 792,2148.

Example 52

rat-(4S*,5R*)-2-[4-Chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) were introduced in the reaction with methyl ether 4-chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)benzoic acid (obtained by the procedure similar to that described in example 43) in the presence of trimethylaluminum and got the desired connection. BP-MS (EI, m/z) calculated for C29H33N3O3SCl3[(M+N)+] 608,1303 found 608,1300.

Example 53

rat-(4S*,5R*)-[-2-[4-Chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-2-[4-chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (example 53) was introduced into the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 54

5-{(4S,5R)-2-[4-Chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]metano

According to the method, a similar description is authorized in example 5, rat-(4S*,5R*)-2-[4-chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 54) was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 35% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C38H47N5O6S2Cl3[(M+N)+] 838,2028 found 838,2025.

Example 55

Methyl ester 2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)benzoic acid

4-Metoxisalicilice acid (10 g, 59 mmole, Aldrich) and ethyliodide (23,2 g, 150 mmole, Aldrich) under vigorous stirring paddle device was dissolved in dimethylformamide (300 ml) and the solution was cooled to 0°C. (bath with ice). The two portions was added sodium hydride (6.2 g, 130 mmole, 50% in mineral oil, Aldrich). Bath ice was removed after 10 min and the reaction mixture was slowly heated to 30°C and then heated to raise the temperature to 50-60°C. After 2 h the reaction mixture was cooled and poured into a mixture of ice water and was extracted with dichloromethane (2×500 ml). The organic layer was washed in the water (2×500 ml), brine and was dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate is evaporated to dryness and received the ethyl ester of 2-ethoxy-4-methoxybenzoic acid.

Ethyl ester of 2-ethoxy-4-methoxybenzoic acid (13 g, 58 mmole) suspended in ethanol (150 ml). He was treated with potassium hydroxide (40 ml, ~4 M) and boiled under reflux for 1 h the Reaction mixture was cooled and poured into cold aqueous hydrochloric acid solution (300 ml, 2 M) and was extracted with dichloromethane (3×200 ml). The organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate is evaporated to dryness and got 2 ethoxy-4-methoxybenzoic acid (9.5 g, white solid).

2 Ethoxy-4-methoxybenzoic acid (9.5 g, 48.5 mmole) portions was added to the cold chlorosulfonic acid (60 ml, Aldrich), stirred at a temperature of from -3 to 0°C (from acetone bath with ice) for 15 min and was heated slowly to room temperature and was heated at 60-65°C for 40 minutes Received a dark solution with stirring carefully poured into a large excess of ice and then added 500 ml of dichloromethane. After stirring for 15 min the layers were separated and the aqueous layer was extracted with dichloromethane (3×250 ml). The organic layers were washed with brine and dried over anhydrous is magnesium sulfate. The solids were filtered off and the filtrate evaporated to a small volume. It is rubbed with a mixture of ether/hexane and was filtered and received 5-chlorosulfonyl-2-ethoxy-4-methoxybenzoic acid as a colourless solid (13,4 g, 94%).

A solution of 5-chlorosulfonyl-2-ethoxy-4-methoxybenzoic acid (13 g, 44 mmole) and then it is carbonated bustard wound was cooled to 5°C. and treated with excess diazomethane dissolved in ether (obtained from N-methyl-N-nitroso-p-toluensulfonate, Aldrich) and stirred for 10 minutes, the Solvent and excess diazomethane was removed with a rotary evaporator. The obtained residue was dissolved in dichloromethane and filtered through a layer of silica gel and evaporated. The solids triturated with a mixture of ether/hexane and obtained 13 g of methyl ester of 5-chlorosulfonyl-2-ethoxy-4-methoxybenzoic acid as colorless solid.

According to the method similar to that described in example 33, methyl ester 5-chlorosulfonyl-2-ethoxy-4-methoxybenzoic acid was introduced into the reaction with pyrrolidine and got the desired connection.

Example 56

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with methyl avirom-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)benzoic acid in the presence of trimethylaluminum and got the desired connection. HP-MS: 602 (M+N)+.

Example 57

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 58

{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]metano

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C39H50N5O7S2Cl2[(M+N)+] 834,2523 found 834,2524.

Example 59

Methyl ether 4-chloro-2-ethoxy-5-methysulfonylmethane acid

A solution of sodium bicarbonate (5.0 g, 60 mmole) and sodium sulfite (2.4 g, 19 mmole) in water (25 ml) at 70-75°C. was treated with 4-chloro-5-chlorosulfonyl-2-ethoxybenzoyl acid (6.2 g, 21 mmole, example 43) portions according to the method described in the publication Imamura, S. et al. (Bioorg. Med. Chem. 2005, 12, 397-416). After 1 h at 75°C with three portions was carefully added Chloroacetic acid (3.0 g, 32 mmole), and then an aqueous solution of sodium hydroxide (1.28 g, 32 mmole/4 ml water) and stirred at 100°C for 16 hours the Mixture was cooled and poured into 2 N. hydrochloric acid (100 ml) and was extracted with ethyl acetate (2x). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated at room temperature to a small volume. Their triturated with ether and filtered and obtained methyl ether 4-chloro-2-ethoxy-5-methysulfonylmethane acid as a colourless solid (5.2 g, 89%).

A solution of 4-chloro-2-ethoxy-5-methysulfonylmethane acid (2.5 g, 9.0 mmole) in tetrahydrofuran was cooled to 5°C. and treated with excess diazomethane dissolved in ether (obtained from N-methyl-N-nitroso-p-toluensulfonate, Aldrich), and stirred for 10 minutes, the Solvent and excess diazomethane was removed with a rotary evaporator. The floor is obtained residue was dissolved in dichloromethane and filtered through a layer of silica gel and evaporated. The solids triturated with a mixture of ether/hexane and was obtained methyl ether 4-chloro-2-ethoxy-5-methysulfonylmethane acid (2.1 g, colorless solid).

Example 60

rat-(4S*,5R*)-2-(4-Chloro-2-ethoxy-5-methanesulfonyl)4,5-bis-(4-chlorophenyl)4,5-dimethyl-4,5-dihydro-1H-imidazol

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with methyl ether 4-chloro-2-ethoxy-5-methysulfonylmethane acid in the presence of trimethylaluminum and got the desired connection. BP-MS (EI, m/z) calculated for C26H26N2O3SCl3[(M+N)+] 551,0724 found 551,0721.

Example 61

rat-(4S*,5R*)-2-(4-Chloro-2-ethoxy-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-2-(4-chloro-2-ethoxy-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 62

[(4S,5R)-2-(4-Chloro-2-ethoxy-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]metano

According to the method similar to that described in example 5, 2-(4-chloro-2-etox the-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 30% of a mixture of 1:1 ethanol/acetonitrile in carbon dioxide). BP-MS (EI, m/z) calculated for C35H42H4O6S2Cl3[(M+N)+] 783,1606 found 783,1596.

Example 63

Ethyl ester of 2-ethoxy-5-(pyrrolidin-1-sulfonyl)benzoic acid

A solution of 5-chlorosulfonyl-2-hydroxybenzoic acid (0.52 g, 2.0 mmole, Matrix Scientific) in tetrahydrofuran (10 ml) was treated with pyrrolidine (1.5 g, 21 mmole) and boiled under reflux for 2 hours It was cooled and poured into dilute aqueous hydrochloric acid solution and was extracted with dichloromethane (2×50 ml). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated and received solid. His triturated with ether and was obtained 2-hydroxy-5-(pyrrolidin-1-sulfonyl)benzoic acid as a solid substance. Then it turned to the ethyl ester of 2-ethoxy-5-(pyrrolidin-1-sulfonyl)benzoic acid by the procedure similar to that described in example 33.

Example 64

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidin-1-sulf the Nile)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with ethyl ester of 2-ethoxy-5-(pyrrolidin-1-sulfonyl)benzoic acid in the presence of trimethylaluminum and got the desired connection.

Example 65

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 66

{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]metano

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instruent Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C38H48H5O6S2Cl2[(M+N)+] 804,2418 found 804,2413.

Example 67

Methyl ester of 4-cyano-2-ethoxybenzoyl acid

2 Ethoxy-4-nitrobenzoic acid (20 g, 94 mmole, Aldrich) suspended in ethanol (170 ml) and combined with saturated aqueous ammonium chloride (100 ml). With vigorous stirring portions was added iron dust (13.3 g, 239 mmole). The temperature was raised to 80°C for 1 h the Cooled suspension was filtered through celite and the filter cake was washed with dichloromethane (150 ml). The filtrate was diluted with dichloromethane and washed with brine, dried over magnesium sulfate, filtered and evaporated. The brown solid is triturated with dichloromethane and filtered and received 15 g of 4-amino-2-ethoxybenzoyl acid (88%).

A suspension of 4-amino-2-ethoxybenzoyl acid (20 g, 110 mmole) in 2 N. hydrochloric acid (200 ml) was vigorously stirred while cooling in a bath of ice. To it was added sodium nitrite (to 7.68 g, 111 mmole) in 22 ml of water. After stirring for 5 min was added solid sodium carbonate to bring the pH to 9-10. Separate copper chloride (14.2 g, 143 mmole) in 200 ml of water was slowly added to a solution of sodium cyanide ((18,28 g, mol) in 200 ml of water at 0-5°C and was stirred for 2 hours A cold solution of nitrite was slowly added to the cyanide solution and stirred at 0-5°C for 15 min and then at 25°C for 2 hours It was filtered and the pH value of the aqueous solution was brought to 2 with concentrated hydrochloric acid. It was extracted with ethyl acetate (4 l). The organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated and obtained 19 g of crude 4-cyano-2-ethoxybenzoyl acid.

The crude 4-cyano-2-ethoxybenzoyl acid (19 g) was dissolved in a mixture of benzene (446 ml) and methanol (111 ml). At 0°C was slowly added (trimethylsilyl)diazomethane (76 ml, 2.0 M in ether, Aldrich) and then at room temperature. The solvent was removed and the residue was purified using flash chromatography (silica gel, elution with 25% ethyl acetate in hexane) was obtained methyl ester of 4-cyano-2-ethoxybenzoyl acid as a solid (15.5 g, 74%).

Example 68

rat-4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxybenzonitrile

To dry toluene (6 ml) was added trimethylaluminum (0.7 ml, of 0.14 mmole, 2.0 M in toluene, Aldrich). At 0°C for 10 min was added meso-2,3-bis-(4-chlorophenyl)-butane-2,3-diamine (0.28 g, 0,091 mmole) in toluene (7 ml). The mixture was heated to room temperature within 1 the. Was added methyl ether 4-cyano-2-ethoxybenzoyl acid (0.34 g, 0,166 mmole)suspended in toluene (6 ml)and the mixture is boiled under reflux for 16 hours, the Reaction mixture was cooled and was added 3 ml of Rochelle salt and was stirred for 2 hours, the Reaction mixture was diluted with ethyl acetate (20 ml) and was stirred for 10 minutes the Organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification of the residue via flash chromatography (silica gel, elution with 20-50% mixture of ethyl acetate/hexane) gave 250 mg of the desired compound.

Example 69

4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxybenzonitrile

A solution of rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxybenzonitrile (190 mg, 0.31 in mmole) in dichloromethane was cooled to 0°C and treated with phosgene (2.5 ml, of 0.47 mmole, 1.9 M in toluene) and triethylamine (0.66 g, 0.65 mmole). After 1 h to the reaction mixture was added the same amount of phosgene and triethylamine. After another 1 h at 0°C. the reaction mixture was treated with a mixture of ice water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated and the obtained oil. It was purified by thin layer silica gel (elution with POM is using a 20% mixture of ethyl acetate/hexane) and got rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(4-cyano-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride.

A solution of rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(4-cyano-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (~175 mg of 0.26 mmole) in dichloromethane (10 ml) and triethylamine (0.35 g, 3,34 mmole) at 0°C for 0.5 h and treated with 1-(3-methanesulfonyl)piperazine (0.11 g, of 0.39 mmole, obtained as described in the publication Fotouhi, N. et al. WO 2005110996). The reaction mixture was washed with cold water, dried over anhydrous magnesium sulfate, filtered and evaporated and received solid. Rubbing with ether and filtration gave the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C35H40N5O4SCl2[(M+N)+] 696,2173 found 696,2167.

Example 70

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 4) was introduced into the reaction with piperazine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C34H41N4O2Cl2[(M+N)+] 607,2601, Nai is prohibited 607,2603.

Example 71

1-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-alanon

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 4) were introduced in the reaction with 1-acetylpiperidine (Aldrich) and got the desired connection. HP-MS: 649,2 [(M+N)+].

Example 72

N-tert-Butyl-2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 4) was introduced into the reaction with K-tert-butyl-2-piperazine-1-yl-ndimethylacetamide (Enamine-BB) and got the desired connection.

Example 73

Ethyl ester of 4-bromo-2-ethoxybenzoyl acid

Sodium (1,815 g, 78,9 mmole, Aldrich) were cut into small pieces and added to ethanol (100 ml). After dissolution of all the pieces of the clear solution was added to a solution of ethyl-4-bromo-2-perbenzoate (13 g, 52,6 mmole) in ethanol (20 ml), cooled to 0°C. Then the bath with ice was removed and the mixture was stirred at room temperature for 12 hours, the Reaction mixture the concentration of Aravali in vacuum and the residue was treated with water and a mixture of 20% ethyl acetate-hexane. The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuum. Purification of the crude residue using flash chromatography (120 g of silica gel, elution with 10-15% ethyl acetate in hexane) gave ethyl ester 4-bromo-2-ethoxybenzoyl acid as a white solid (11,020 g, 77%).

Example 74

rat-(4S*,5R*)-2-(4-Bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol

To a solution of meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (3 g, example 1) in toluene, cooled to 0°C, was added dropwise a 2 M solution of trimethylaluminum in toluene (5,33 ml, 10,66 mmole). After the addition the mixture was stirred at 0°C for 15 min, then bath with ice was removed. After 30 min the mixture was heated to 80-100°C for about 30 min and then slowly cooled to room temperature. At room temperature was added a solution of ethyl ester of 4-bromo-2-ethoxybenzoyl acid (3,18 g, 11,64 mmole) in toluene (10 ml) and the yellow reaction mixture is boiled under reflux for 48 hours After cooling to room temperature, was added 1 M solution of Rochelle salt (~20 ml) and ethyl acetate (~50 ml). A two-phase mixture was vigorously stirred at room temperature for 3 hours the LOI were separated and the aqueous layer was extracted with ethyl acetate (1×100 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (1×20 ml), brine (1×20 ml), dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated to dryness. Purification of the crude residue using flash chromatography (120 g of silica gel, elution with 5-10%, 20%, 40%, then 80% ethyl acetate in hexane) gave the desired compound as light yellow foam substances (3.25 g, 65%). BP-MS (EI, m/z) calculated for C25H24N2OCl2Br [(M+N)+] 517,0444 found 517,0443.

Example 75

rat-(4S*,5R*)-2-(4-Bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-2-(4-bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 76

rat-(4S*,5R*)-2-(4-Bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (received, ka is described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired connection. BP-MS (EI, m/z) calculated for C36H41N5O4Cl2Br [(M+N)+] 756,1714 found 756,1720.

Example 77

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-propan-2-ol

To a solution of n-utility (to 11.6 ml, 28,95 mmole, 2.5 M solution in hexane, Aldrich) in tetrahydrofuran (50 ml) at -78°C was added dropwise a solution of rat-(4S*,5R*)-2-(4-bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (1.5 g, 2,894 mmole, example 74) in tetrahydrofuran (50 ml). The brown reaction mixture was stirred at -78°C for 15 min, and then dropwise added acetone (2,12 ml, 28,94 mmole). At the end of the addition, the color was yellow. The reaction mixture was stirred at -78°C for 30 min then the reaction was stopped with water. Bath ice was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was treated with water and ethyl acetate. The organic layers were washed with brine and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated and received a yellow residue. Purification of the crude residue using flash chromatography (120 g of silica gel, elution with 100% ethyl acetate, 2-5% methanol in ethyl acetate) gave the desired compound (702 mg, 49%). BP-MS (EI, mz) calculated for C 28H31N2O2Cl2[(M+N)+] 497,1757 found 497,1758.

Also received a small amount of by-product, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (187 mg, 15%). BP-MS (EI, m/z) calculated for C25H25N2OCl2[(M+N)+] 439,1339 found 439,1339.

Example 78

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-propan-2-ol was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 79

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 80

[(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorp the Nile)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 25% of a mixture of 1:1 ethanol/acetonitrile in carbon dioxide). BP-MS (EI, m/z) calculated for C34H41N4O4SCl2[(M+N)+] 671,2220 found 671,2218.

Example 81

2-{4-[(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 35% of a mixture of 1:1 ethanol/acetonitrile in carbon dioxide). BP-MS (EI, m/z) calculated for C32H36N5O3Cl2[(M+N)+] 608,2190 found 608,2190.

Example 82

{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon/p>

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% of a mixture of 1:1 ethanol/acetonitrile in carbon dioxide). BP-MS (EI, m/z) calculated for C37H47H4O5SCl2[(M+N)+] 729,2639 found 729,2634.

Example 83

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with what omashu 45% of a mixture of 1:1 ethanol/acetonitrile in carbon dioxide). BP-MS (EI, m/z) calculated for C35H42N5O4Cl2[(M+N)+] 666,2609 found 666,2606.

Example 84

{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(2-hydroxyethyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-retinol (Chemical Dynamics) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C35H43H4O4Cl2[(M+N)+] 653,2656 found 653,2657.

Example 85

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-1-pyrrolidin-1-ylatason

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-1-pyrrolidin-1-ylatason (Aldrich) and got the desired joint is in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 25% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C39H48N5O4Cl2[(M+N)+] 720,3078 found 720,3072.

Example 86

N-[2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with N-(2-piperazine-1-retil)-acetamidocinnamate (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C37H46H5O4Cl2[(M+N)+] 694,2922 found 694,2918.

Example 87

N-[2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-methanesulfonamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with N-(2-piperazine-1-retil)-methanesulfonamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C36H45N5O5SCl2[(M+N)+] 730,2591 found 730,2585.

Example 88

{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazinecarboxamide (example 22) was obtained the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and buyrevia by using 35% of a mixture of 1:1 ethanol/acetonitrile in carbon dioxide). BP-MS (EI, m/z) calculated for C38H47H4O5SCl2[(M+N)+] 741,2639 found 741,263 7.

Example 89

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with methyl ether 2-isopropoxy-4-methoxybenzoic acid (obtained by the procedure similar to that described in example 56) in the presence of trimethylaluminum and got the desired connection. BP-MS (EI, m/z) calculated for C29H34N3O3SCl2[(M+N)+] 574,1693 found 574,1589.

Example 90

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 91

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-label iphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired connection. BP-MS (EI, m/z) calculated for C36H45N4O5SCl2[(M+N)+] 715,2482 found 715,2485.

Example 92

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired connection. BP-MS (EI, m/z) calculated for C34H40N5O4Cl2[(M+N)+] 652,2452 found 652,2451.

Example 93

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-morpholine-4-yl-2-piperazine-1-ratanana (Oakwood Products) and got the desired connection. BP-MS (EI, m/z) calculated for C38H46H5O5Cl2[(M+N)+] 722,2871 found 722,2874.

Example 94

rat-4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-what isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-he

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazinone (Avocado Organics) and got the desired connection. BP-MS (EI, m/z) calculated for C32H35H4O4Cl2[(M+N)+] 609,2030 found 609,2025.

Example 95

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(2-methanesulfonyl)-piperazine (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired connection. BP-MS (EI, m/z) calculated for C35H43N4O5SCl2[(M+N)+] 701,2326 found 701,2325.

Example 96

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol

To a solution of 1-bromo-3-ethoxybenzene (20 g, 99,473 mmole) in anhydrous tetrahydrofuran (300 ml), cooled to -78°C. was added 2.5 M n-utility in hexane (39,8 ml, 99,473 mmole, Aldrich). The reaction mixture was stirred at -8°C for 5 min, then was added acetone (43,8 ml, 596,838 mmole). After 30 min at -78°C bath with ice was removed and for stopping the reaction was added a saturated solution of ammonium chloride. The product was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with brine (1×50 ml) and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuum. Purification of the crude residue using flash chromatography (silica gel, elution with 15-25% ethyl acetate in hexane) gave 2-(3-ethoxyphenyl)-propan-2-ol as a clear oil (10,930 g, 61%).

Sodium hydride (3,261 g, 81,54 mmole, 60% in mineral oil, Aldrich) was twice washed with hexane and added tetrahydrofuran (60 ml). To this suspension was added 2-(3-ethoxyphenyl)-propan-2-ol (4.9 g, 27.18 per mmole). The mixture was stirred at 45°C for 1.5 h before the termination of allocation of bubbles. It was cooled to 0°C and added logmean (5,08 ml, 81,54 mmole, Aldrich). After stirring for 4 h at room temperature was added another portion of iodomethane (5,08 ml, 81,54 mmole). The mixture was stirred at room temperature for 4 days, then the reaction was stopped at 0°C cold 20% solution of ammonium chloride. The product was extracted with ethyl acetate (2×1 l). The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Solids of otfiltrovana the filtrate was concentrated in vacuum and received 1 ethoxy-3-(1-methoxy-1-methylethyl)-benzene (5,15 g, 97%).

To a solution of 1-ethoxy-3-(1-methoxy-1-methylethyl)-benzene (5,15 g, 26,51 mmole) in acetonitrile (60 ml) was added N-jodatime (8,349 g, 37,11 mmole) and triperoxonane acid (1,02 ml, 13,26 mmole). The mixture was stirred at room temperature overnight. It was then concentrated in vacuo and the residue was dissolved in ethyl acetate. After washing with saturated sodium bicarbonate solution, water and brine the organic layer was dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuum and received 9,39 g 2 ethoxy-1-iodine-4-(1-methoxy-1-methylethyl)-benzene in the form of a light brown oil.

Diisopropylethylamine (10,15 ml, 58,10 mmole) was added to a solution of 2-ethoxy-1-iodine-4-(1-methoxy-1-methylethyl)-benzene (9.3 g, 29,05 mmole) in methanol (60 ml). Through the mixture for 30 min missed argon was added palladium(II) acetate (653 mg, only 2.91 mmole). The reaction mixture several times quickly blew carbon monoxide, and then stirred at 60°C for 18 h under a pressure of carbon monoxide (40 lbs/inch2). The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. It was washed with water, brine and dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue using flash chromatography (silica gel, elution with 10-30% ethyl acetate in hexane for 30 m is n) gave methyl ether 2-ethoxy-4-(1-methoxy-1-methylethyl)-benzoic acid (2,81 g).

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with methyl ether 2-ethoxy-4-(1-methoxy-1-methylethyl)-benzoic acid in the presence of trimethylaluminum and got the desired connection.

Example 97

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 98

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ndimethylacetamide

According to the method similar to that described in example 5 4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/z) calculated the ANO for C 36H44N5O4Cl2[(M+N)+] 680,2765 found 680,2767.

Example 99

{rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5 4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C38H49N4O5SCl2[(M+N)+] 743,2795 found 743,2795.

Example 100

{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5 4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(1,1-dioxotetrahydrofuran-2H-ti is Piran-4-yl)-piperazinecarboxamide (example 22) was obtained the desired compound in the form of racemic mixtures. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 35% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C39H49N4O5SCl2[(M+N)+] 755,2795 found 755,2792.

Example 101

rat-1-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-alanon

To a solution of rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (70 mg, of 0.13 mmole, example 2) and triethylamine (92 μl, 0.65 mmole) in methylene chloride (3 ml) were added acetylchloride (59 μl, Aldrich). The reaction mixture was stirred at room temperature overnight, then concentrated. Purification of the crude residue via flash chromatography (12 g of silica gel, elution with 5-30% ethyl acetate in hexane) gave the desired compound (56,1 mg, 80%). BP-MS (EI, m/z) calculated for C31H34N2O2Cl2[(M+N)+] 537,2070 found 537,2068.

Example 102

1-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imides the l was injected into the reaction with Isobutyraldehyde (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C33H37N2O2Cl2[(M+N)+] 565,2383 found 565,2384.

Example 103

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-cyclopropylmethanol

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with cyclopropanecarbonitrile (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C33H37N2O2Cl2[(M+N)+] 563,2227 found 563,2224.

Example 104

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-cyclobutylmethyl

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with cyclobutanecarbonitrile (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C34H39N2O2Cl2[(M+N)+] 577,2383 found 577,2382.

Example 105

1-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-3-methylbutane-1-he

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 3-methylbutyraldehyde (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C34H41N2O2Cl2[(M+N)+] 579,2540 found 579,2543.

Example 106

1-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-3-phenylpropane-1-he

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 3-phenylpropionylamino (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C38H41N2O2Cl2[(M+N)+] 627,2540 found 627,2541.

Example 107

4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-benzonitrile

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 4-cyanobenzaldehyde (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C37H36N3O2Cl2[(M+N)+] 624,2179 found 624,2177.

Example 108

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-furan-2-ylmethanol

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorine is phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced into the reaction with furan-2-carbonylchloride (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C34H35N2O3Cl2[(M+N)+] 589,2019 found 589,2017.

Example 109

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-phenylmethanone

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with benzoyl chloride (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C36H37N2O2Cl2[(M+N)+] 599,2227 found 599,2223.

Example 110

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-methoxyphenyl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 4-methoxybenzylamine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C37H39N2O3Cl2[(M+N)+] 629,2332 found 629,2337.

Example 111

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-chlorophenyl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 4-chlorobenzylchloride (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C36H36N2O3Cl3[(M+N)+] 633,1837 found 633,1838.

Example 112

rat-(4S*,5R*)-2-(4-tert-Butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with methyl ester 4-tert-butyl-5-chloro-2-ethoxybenzoyl acid (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) in the presence of trimethylaluminum and got the desired connection.

Example 113

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 114

[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 1-(3-methanesulfonyl who drank)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and received racemic rat-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon. Chiral separation of enantiomers using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 25% methanol in carbon dioxide) gave the desired compound. BP-MS (EI, m/z) calculated for C38H48N4O4SCl3[(M+N)+] 761,2457 found 761,2460.

Example 115

2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and received racemic 2-rat-{4-[(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide. Chiral separation of enantiomers using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 25% methanol in carbon dioxide) gave the desired compound. BP-MS IE, m/z) calculated for C36H43H5O3Cl3[(M+N)+] 698,2426 found 698,2431.

Example 116

rat-(2-{4-[4S*,5R*)-2-(4-tert-Butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 1-morpholine-4-yl-2-piperazine-1-ratanana (Oakwood Products) and got the desired connection. BP-MS (EI, m/z) calculated for C40H49N5O4Cl3[(M+N)+] 768,2845 found 768,2845.

Example 117

rat-[(4S*,5R*)-2-(4-tert-Butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-dimethylamino-piperidine-1-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole were introduced into the reaction dimethylpiperidin-4-yl-amine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C37H46H4O2Cl3[(M+N)+] 683,2681 found 683,2681.

Example 118

rat-[(4S*,5R*)-2-(4-tert-Butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-pyrrolidin-1-reparacin-1-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 4-pyrrolidin-1-ipipeline (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C39H48N4O2Cl3[(M+N)+] 709,2838 found 709,2836.

Example 119

rat-[1,4']Bipyridinyl-1'-yl-[(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with [1,4']bipyridinyl (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C40H50N4O2Cl3[(M+N)+] 723,2994 found 723,2997.

Example 120

Tert-butyl ether rat-{1-[(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-yl}-carbamino acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced into the reaction with tert-butyl ether piperidine-4-yl-carbamino acid (Aldrich) and got the desired connection. BP-MS (THE UH, m/z) calculated for C40H50H4O4Cl3[(M+N)+] 755,2892 found 755,2895.

Example 121

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydro-1H-imidazol

To a solution of 2-hydroxy-4-triftorperasin acid (5 g, 24,258 mmole, Matrix Scientific) in ethanol (50 ml) were added potassium carbonate (scored 8.38 g, 60,645 mmole) and ethyliodide (7.68 per ml, 97,032 mmole). The reaction mixture was slowly heated under reflux for 4 h, then concentrated in vacuo. The residue was treated with petroleum ether and water and the layers were separated. The product was extracted with petroleum ether (1x). The organic layers were washed with brine (1x), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the crude residue using flash chromatography (40 g silica gel, elution with 10% ethyl acetate in hexane) gave ethyl ester 2-ethoxy-4-triftorperasin acid as a colourless oil (4.68 g, 74%).

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with ethyl ester of 2-ethoxy-4-triftorperasin acid in the presence of trimethylaluminum and got the desired connection. BP-MS (EI, m/z) calculated for C26H24N2OF3Cl2[(M+N)+] 507,1213 found 507,1207.

Example 122

the AC-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 123

rat-4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-he

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazinone (Avocado Organics) and got the desired connection. BP-MS (EI, m/z) calculated for C31H30N4O3F3Cl2[(M+N)+] 633,1642 found 633,1638.

Example 124

rat-1-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-alanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-acetylpiperidine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C33H34N4O3F3Cl2[(M+N)+] 661,1955 found 661,1947.

Example 125

[(4S,5R)-4,-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and received racemic rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon. Chiral separation of enantiomers using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 25% methanol in carbon dioxide) gave the desired compound. BP-MS (EI, m/z) calculated for C35H40N4O4SF3Cl2[(M+N)+] 739,2094 found 739,2094.

Example 126

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-morpholine-4-yl-2-piperazine-1-ratanana (Oakwood Products) and got the desired connection. BP-MS (EI, m/z) calculated for C37H41N5O F3Cl2[(M+N)+] 746,2482 found 746,2483.

Example 127

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-acanaloniidae-1-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-acanaloniidae (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C33H36H4O4SF3Cl2[(M+N)+] 711,1781 found 711,1786.

Example 128

(1-Methanesulfonamido-4-yl)-amide rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-methanesulfonamido-4-aluminum (obtained as described in the publication Bartkovitz, D. J. et al. WO 2004069139) and got the desired connection. BP-MS (EI, m/z) calculated for C33H36N4O4SF3Cl2[(M+N)+] 711,1781 found 711,1778.

Example 129

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(4-methylp perazin-1-yl)-piperidine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-methyl-4-piperidine-4-reparation (Oakwood Products) and got the desired connection. BP-MS (EI, m/z) calculated for C37H43N5O2F3Cl2[(M+N)+] 716,2741 found 716,2746.

Example 130

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-(morpholine-4-reparacin-1-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 4-piperidine-4-yl-morpholine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C36H40N4O3F3Cl2[(M+N)+] 703,2424 found 703,2419.

Example 131

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-hydroxy-piperidine-1-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 4-hydroxy-piperidine (Aldrich) and the floor is Ali the desired connection. BP-MS (EI, m/z) calculated for C32H33N3O3F3Cl2[(M+N)+] 634,1846 found 634,1846.

Example 132

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-hydroxyethylpiperazine-1-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced into the reaction with piperidine-4-ylmethanol (Lancaster) and got the desired connection. BP-MS (EI, m/z) calculated for C33H35H43O3F3Cl2[(M+N)+] 648,2002 found 648,2006.

Example 133

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-hydroxyethyl)-piperidine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced into the reaction with piperidine-4-ilathalam (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C34H37N3O3F3Cl2[(M+N)+] 662,2159 found 662,2158.

Example 134

Amide rat-1-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carb is new acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with Amida piperidine-4-carboxylic acid (isonipecotamide, Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C33H34N4O3F3Cl2[(M+N)+] 661,1955 found 662,1955.

Example 135

Bis-(2-hydroxyethyl)-amide rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in a reaction with bis-(2-hydroxyethyl)-amine (Sigma) and got the desired connection. BP-MS (EI, m/z) calculated for C31H33N3O4F3Cl2[(M+N)+] 638,1795 found 638,1797.

Example 136

(2,3-Dihydroxypropyl)-amide rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 3-amino-p is open-1,2-diola (Aldrich) and got the desired compound in the form of a mixture of diastereoisomers. BP-MS (EI, m/z) calculated for C30H31N3O4F3Cl2[(M+N)+] 624,1638 found 624,1641.

Example 137

3-{4-[4,5-Bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-3-methylbutane-2-he

Sodium hydride (3,65 g, 91,347 mmole, 60% in mineral oil, Aldrich) were placed in a round bottom flask and washed with hexane. Then was added a tetrahydrofuran (80 ml). To a suspension of sodium hydride in tetrahydrofuran, cooled to 0°C, was added a solution of 1-(3-methoxyphenyl)-propane-2-she (6 g, 36,539 mmole, Lancaster) in 1 ml of tetrahydrofuran. Bath ice was removed and the mixture was stirred at room temperature for 30 minutes At 0°C was added methyliodide (6,82 ml, 109,6 mmole, Aldrich) and the mixture was stirred at room temperature for 48 hours the Reaction was stopped with saturated solution of ammonium chloride and was treated with water and ethyl acetate. The product was extracted with ethyl acetate (1x). The organic layers were washed with brine (1x), dried over anhydrous sodium sulfate and concentrated. The residue was purified using column flash chromatography (40 g silica gel, elution with 3-5% ethyl acetate in hexane) was obtained 3-(3-methoxyphenyl)-3-methylbutane-2-it is in the form of a clear oil (6,603 g, 94%).

To a solution of 3-(3-methoxyphenyl)-3-methylbutane-2-it (6,570 g, 34,172 mmole) in methylene chloride (100 ml), cooled to -7°C, were added tribromide boron (102 ml, 1 M solution in methylene chloride, Aldrich). The mixture was stirred at -78°C for 1 h, warmed up to 0°C for 1 h and then kept in the freezer (-20°C) for 72 hours At 0°C. water was added to decompose the excess tribromide boron (WARNING: violent reaction). The product was extracted with petroleum ether. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified using flash chromatography (40 g silica gel, elution with 5-20% ethyl acetate in hexane) was obtained 3-(3-hydroxyphenyl)-3-methylbutane-2-it is in the form of a yellow oil (5 g, 82%).

A mixture of 3-(3-hydroxyphenyl)-3-methylbutane-2-she (3.4 g, 19,08 mmole), Diisopropylamine (16,7 ml, 95,4 mmole) and ethyliodide (6.2 ml, 76,32 mmole) in 60 ml of ethanol was boiled under reflux overnight. Thin layer chromatography was still found the original substance. Were added potassium carbonate (9 g) and the mixture is boiled under reflux for 12 hours It was concentrated in vacuum and the residue was dissolved in ethyl acetate. After washing with water and brine the organic layer was dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated and received 3,727 g of 3-(3-ethoxyphenyl)-3-methylbutane-2-it is in the form of a light brown oil. It was used without additional purification.

<> To a solution of 3-(3-ethoxyphenyl)-3-methylbutane-2-it (3,720 g, 18,03 mmole) in acetonitrile (40 ml) under stirring in an argon atmosphere was added N-jodatime (5,679 g, 25,24 mmole) and triperoxonane acid (0.7 ml, 9,02 mmole). The reaction mixture was stirred at room temperature for 10 min, then at 50°C for 1 h After cooling to room temperature it was diluted with 10% ethyl acetate in hexane and filtered through a layer of celite and silica gel. The filtrate was washed with water (1x), saturated sodium bicarbonate solution (1x), 5% sodium thiosulfate solution (1x), brine (1x), dried over anhydrous sodium sulfate and concentrated in vacuum. Purification of the crude residue using flash chromatography (330 g of silica gel, elution with 30% ethyl acetate in hexane for 30 min) to give 4.83 g of 3-(3-ethoxy-4-iodine-phenyl)-3-methylbutane-2-it looks almost white solid.

In a dry test tube high pressure with stirring was injected anhydrous acetonitrile (10 ml), 3-(3-ethoxy-4-iodine-phenyl)-3-methylbutane-2-he (450 mg, of 1.35 mmole), diphenylpropylamine (77 mg, 0,34 mmole) and triethylamine (470 μl, 3,37 mmole). Through the solution for 10 min missed argon, then was added palladium acetate (76 mg, 0.34 in mmole). The system was pumped to a high vacuum and filled with carbon monoxide (40 lbs/inch2). After 10 min was added trihexoside is (960 μl, 2.7 mmole). The system re-filled carbon monoxide (60 pound-force/inch2) and was stirred at 60°C over night. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The mixture was filtered through a thin layer of silica gel. The filtrate was washed with water (2x), brine (1x), dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuum. The crude residue was purified using flash chromatography (80 g silica gel, elution with 10-30% ethyl acetate in hexane over 35 min) and received 150 mg of 4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxybenzaldehyde.

To a solution of 4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxybenzaldehyde (145 mg, of 0.62 mmole) in anhydrous 1,2-dichloroethane (2 ml), cooled to 0°C, was added meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (191 mg, of 0.62 mmole). The mixture was stirred at room temperature for 4 days. At 0°C was added N-bromosuccinimide (x mg, x mmole) and the mixture was stirred at room temperature for 1.5 hours a Saturated solution of sodium carbonate was added to alkalizing and the product was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuum. The crude residue was purified using flash chromatography (45 g silica gel, elution with 0-30% ethyl acetate in hexane over 25 mi is) and received 217 mg of the desired product as a pale yellow solid.

Example 138

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3 3-{4-[4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-3-methylbutane-2-he was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 139

3-(4-{4,5-Bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-3-methylbutane-2-he

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired product as a racemic mixture. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 25% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C39H49N4O5SCl2[(M+N)+] 775,2795 found 775,2795.

Example 140

3-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazin the-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-3-methylbutane-2-he

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazinecarboxamide (example 22) was obtained the desired product as a racemic mixture. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 35% methanol in carbon dioxide). BP-MS (EI, m/z) calculated for C40H49N4O5SCl2[(M+N)+] 767,2795 found 767,2790.

Example 141

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired product as a racemic mixture. Then the enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% methanol in carbon dioxide). BP-MS (EI, m/) calculated for C 37H44H5O4Cl2[(M+N)+] 692,2765 found 692,2762.

Example 142

rat-(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol

According to the method similar to that described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine was introduced in the reaction with methyl ester 4-tert-butyl-2-isopropoxybenzoic acid (obtained from 3-tert-butylphenol and isopropylated, as described in the publication Fotouhi, N. et al. WO 2005110996) in the presence of trimethylaluminum and got the desired connection. BP-MS (EI, m/z) calculated for C30H35N2OCl2[(M+N)+] 509,2121 found 509,2121.

Example 143

rat-(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 144

rat-1-{4-[(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-alanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorp the Nile)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-acetylpiperidine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C37H55H4O3Cl2[(M+N)+] 663,2863 found 663,2857.

Example 145

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-isopropylpiperazine-1-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-isopropylpiperazine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C38H49N4O2Cl2[(M+N)+] 663,3227 found 663,3228.

Example 146

rat-4-{4-[(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-butyronitrile

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 4-piperazine-1-illusionarium (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C39H48N5O2Cl2[(M+N)+] 688,3180 found 688,3186.

Example 147

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methoxypropyl)-piperazine-1-yl]-methanon/p>

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methoxypropyl)-piperazine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C39H51N4O3Cl2[(M+N)+] 693,3333 found 693,3334.

Example 148

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-morpholine-4-retil)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 4-(2-piperazine-1-retil)-morpholine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C41H54N5O3Cl2[(M+N)+] 734,3598 found 734,3600.

Example 149

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-ylmethyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(tetrahydrofur the EN-2-ylmethyl)-piperazine (Aldrich) and got the desired compound in the form of a mixture of diastereoisomers. BP-MS (EI, m/z) calculated for C40H51N4O3Cl2[(M+N)+] 705,3333 found 705,3332.

Example 150

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(hexahydropyrazino[1,2-a]pyrazin-2-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with octahedral[1,2-a]pyrazino (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C38H47H4O3Cl2[(M+N)+] 661,3071 found 661,3073.

Example 151

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(octahedrite[1,2-a]pyrazin-2-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced into the reaction with octahedrite[1,2-a]pyrazino (Aldrich) and got the desired compound in the form of a mixture of diastereoisomers. BP-MS (EI, m/z) calculated for C39H49N4O2Cl2[(M+N)+] 675,3227 found 675,3224.

Example 152

Bis-(2-methoxyethyl)-amide rat-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorphen the l)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in a reaction with bis-(2-methoxyethyl)-amine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C37H49N4O5SCl2[(M+N)+] 668,3017 found 668,3010.

Example 153

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-methoxyethyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(2-methoxyethyl)-piperazine (Aldrich) and got the desired connection. BP-MS (EI, m/z) calculated for C38H49H4O3Cl2[(M+N)+] 679,3176 found 679,3180.

Example 154

[(4S,5R)-2-(4-tert-Butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazine what hydrochloridum (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 25% isopropanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C39H51N4O4SCl2[(M+N)+] 741,3003 found 741,2998.

Example 155

[(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-isopropylphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-isopropylphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was obtained from 2-ethoxy-4-isopropylbenzylamine (obtained from 2-hydroxy-4-isopropylbenzoic acid in stage 3) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) according to the method similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-isopropylphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-isopropylphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-Pipa is sindikalizam (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OJ-H 3×25 cm, 35°C at 100 bar and elution with 15% mixture of 1:1 ethanol/acetonitrile in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C37H47N4O4SCl2[(M+N)+] 713,2690 found 713,2692.

Example 156

[(4S,5R)-2-(5-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

Rat-(4S*,5R*)-2-(5-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was obtained from 5-tert-butyl-2-ethoxybenzonitrile (obtained from 5-tert-butyl-2-hydroxybenzoic acid) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) according to the method similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-2-(5-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(5-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl who yl)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 20% mixture of 1:1 ethanol/acetonitrile in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C38H49N4O4SCl2[(M+N)+] 727,2846 found 727,2847.

Example 157

[(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-5-methanesulfonyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methanesulfonyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was obtained from 2-ethoxy-5-methysulfonylmethane (obtained from 2-ethoxybenzoyl acid by the procedure similar to that described in example 59) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) according to the method similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methanesulfonyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methanesulfonyl)-4,5-dimethyl-4,5-dihydroimidazole-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 25% of a mixture of 1:1 ethanol/acetonitrile in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C35H43H4O6S2Cl2[(M+N)+] 749,1996 found 749,1991.

Example 158

[(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-methanesulfonyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methanesulfonyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was obtained from 2-ethoxy-4-methysulfonylmethane (obtained from ethyl 2-ethoxy-4-fluoro-benzoate and timelocked sodium (stage 4) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) according to the method similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methanesulfonyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methanesulfonyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carb is Nellore was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 30% methanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C35H43N4O6S2Cl2[(M+N)+] 749,1996 found 749,1995.

Example 159

[(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-(4-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(4-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was obtained from 4-cyclopropyl-2-ethoxybenzonitrile (obtained from 4-bromo-2-hydroxybenzoic acid by alkylation with jumatano, combination by Suzuki with cyclopropylboronic acid, subsequent saponification and conversion to acid chloride) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) the method is similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(4-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,-bis-(4-chlorophenyl)-2-(4-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbamoylated was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% methanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C37H44N4O4SCl2[(M+N)+] 711,2533 found 711,2533.

Example 160

[(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-(5-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(5-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was obtained from 5-cyclopropyl-2-ethoxybenzonitrile (obtained from 5-bromo-2-hydroxybenzoic acid by alkylation with jumatano, combination by Suzuki with cyclopropylboronic acid, subsequent saponification and conversion to acid chloride) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) the method is similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(5-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-x is arvanil)-2-(5-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% isopropanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C37H44N4O4SCl2[(M+N)+] 711,2533 found 711,2536.

Example 161

[(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-(4-econsultancy-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(4-econsultancy-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was obtained from 4-econsultancy-2-ethoxybenzonitrile (obtained from ethyl 2-ethoxy-4-fluoro-benzoate and attentionate sodium) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) according to the method similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(4-econsultancy-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(4-econsultancy-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-meta is sulfonylated)-piperazinecarboxamide (received as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 30% methanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C36H53N4O4SCl2[(M+N)+] 763,2152 found 763,2150.

Example 162

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-diethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

1-(4-Chlorophenyl)propane-1-he (8,4 g, 50 mmole) was combined with hydroxylaminopurine (4.0 g, 58 mmole), pyridine (4.6 g, 58 mmole) and ethanol (75 ml). The mixture was boiled under reflux for 3 hours, the Solvent evaporated and the residue was diluted with water and was extracted with a mixture of diethyl ether/hexane (1:1). The organic extracts were washed with water, brine and dried over anhydrous magnesium sulfate. Crystallization from cold hexane gave 5.0 g of 1-(4-chlorophenyl)propane-1-noxema.

1-(4-Chlorophenyl)propane-1-ONEXIM (5.0 g, 27.3 mmole) was dissolved in acetonitrile (200 ml) was added zinc dust (8.8 g, 136 mmol). Under mechanical stirring at -15°C for 0.5 h was added methanesulfonyl acid (13 g, 136 mmole). Was peremeshivaya.prokipevshie at room temperature for 16 hours Under stirring was added water (100 ml) and the mixture was filtered through celite. Volatiles evaporated and the aqueous portion was diluted 3 N. a solution of sodium hydroxide (100 ml). The mixture was extracted with diethyl ether (2x). The organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate and concentrated. The crude residue was partially purified using flash chromatography and got ~2 g of a mixture of threo - and Erythro-isomers (ratio 8:1). Crystallization from a mixture of diethyl ether/hexane gave pure threo-isomer) (1.4 g), and the crystallization mother solutions gave Erythro-3,4-bis-(4-chlorophenyl)hexane-3,4-diamine (310 mg, purity 90%).

Rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-diethyl-4,5-dihydro-1H-imidazole was obtained from 4-tert-butyl-2-ethoxybenzonitrile and meso-3,4-bis-(4-chlorophenyl)-hexane-3,4-diamine by the procedure similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-diethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, carbamoylated was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic with the art. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 25% isopropanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C40H53N4O4SCl2[(M+N)+] 755,3159 found 755,3157.

Example 163

[(4S,5R)-4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethylsulfanyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethylsulfanyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was obtained from 2-ethoxy-4-metilsulfonilmetane (obtained from ethyl 2-ethoxy-4-fluoro-benzoate and attentionate sodium) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) according to the method similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethylsulfanyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethylsulfanyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and p who were given the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 35% methanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C36H45N4O4S2Cl2[(M+N)+] 731,2254 found 731,2259.

Example 164

[(4S,5R)-2-(4-tert-Butyl-2-methoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

Rat-(4S*,5R*)-2-(4-tert-butyl-2-methoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was obtained from 4-tert-butyl-2-methoxybenzonitrile (obtained from 4-tert-butyl-2-hydroxybenzoic acid) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) according to the method similar to that described in example 2 (method 1).

Rat-(4S*,5R*)-2-(4-tert-butyl-2-methoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and received the appropriate carbamoylated.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-methoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired soybean is inania in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 35% methanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C37H47N4O4SCl2[(M+N)+] 713,2690 found 713,2690.

Example 165

[(4S,5R)-2-(4-Chloro-2-ethoxy-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-chloro-2-ethoxy-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 61) was introduced in the reaction with 1-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazinecarboxamide (example 22) was obtained the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Regis Technologies Whelk-01 3×25 cm, 35°C at 100 bar and elution with 40% methanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C36H42N4O6S2Cl3[(M+N)+] 795,1606 found 795,1605.

Example 166

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(1,1-dioxotetrahydrofuran-3-the l)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with 1-(1,1-dioxotetrahydrofuran-3-yl)-piperazine (Enamine-BB) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OJ-H 3×25 cm, 35°C. at 100 bar and elution with 20% isopropanol in carbon dioxide), which gave the desired compound in the form of a mixture of diastereoisomers. BP-MS (EI, m/z) calculated for C38H46H4O4SCl2[(M+N)+] 725,2690 found 725,2692.

Example 167

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-acanaloniidae)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (example 4) were introduced in the reaction with 1-(3-acanaloniidae)-piperazinecarboxamide (obtained from 3-ethylsulfanyl-propan-1-ol by the procedure analogous to that described for 1-(3-methane sulfonylated)-piperazinecarboxamide) and got the desired connection. BP-MS (EI, m/z) calculated for C39H51N4O4SCl2[(M+N)+] 741,3003 found 7412998.

Example 168

2-(4-{(4S,5R)-4,5-Bis-(4-chlorophenyl)-1-[4-(3-acanaloniidae)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile

Enantiomers rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride (example 17) were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 18% acetonitrile in carbon dioxide).

According to the method similar to that described in example 5 (4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(piandimeleto)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-acanaloniidae)-piperazinecarboxamide (example 167) and got the desired connection. BP-MS (EI, m/z) calculated for C38H48N5O4SCl2[(M+N)+] 752,2799 found 752,2799.

Example 169

3,4-Bis(4-chlorophenyl)-1,2,5-thiadiazole-1,1-dioxide

To a solution of 4-chlorobenzaldehyde (240 g, 1,707 mol) in 144 ml of methanol for 6 min was added to 2.40 g of potassium cyanide in 4.8 ml of water. The mixture was boiled under reflux for a further 50 minutes (the mixture became dark red), cooled, then concentrated under reduced pressure. The red residue was dissolved in 1500 ml of a mixture of hexane-ethyl acetate (1:1) is then washed with water (1×150 ml), 20% sodium bisulfite (6×150 ml), brine (1×150 ml) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure the product was boiled in 400 ml of hexane to remove small amounts of 4-chlorobenzaldehyde. The mixture was cooled and the white solid was collected by filtration with suction and received 183,94 g of 4,4'-dichlorbenzene (76%). This technique was a modification of the method, taken from the publication Lutz et al. J. Am. Chem. Soc. 1949, 77, 478.

To a solution of 4,4'-dichlorbenzene (183,94 g to 0.645 mole) in 1400 ml of ethyl acetate for 2 min was added 109,785 g (0,687 mole) of bromine. The mixture was stirred for 1.5 h, and during this time a dark color, caused by the bromine grew lighter, and the solution was separated crystals (it is recommended to use mechanical mixing). The mixture was cooled in a bath with ice for 10 minutes and the solids were collected by filtration with suction and washed with 800 ml of diethyl ether and received 149,01 g of 4,4'-dichlorobenzil in the form of a yellow crystalline substance (81%).

A mixture of 4,4'-dichlorobenzil (55,824 g of 0.20 mol), sulphonamide (24,028 g of 0.25 mole), triethylamine (at 8.36 ml of 0.06 mol) and absolute ethanol (1200 ml) was boiled under reflux in an argon atmosphere for 18 h, then ~600 ml and drove the remaining volatiles were removed under reduced pressure. LC-MS (liquid chrome is ografia - mass spectroscopy showed that the reaction was not completed, so I added an additional amount of sulphonamide (4,806 g, 0.05 m), triethylamine (at 8.36 ml of 0.06 mol) and absolute ethanol (1200 ml). The mixture was heated under reflux in an argon atmosphere for 22 hours Approximately 600 ml of volatile substances were released and the remaining volatiles were removed under reduced pressure. Addition was added acetonitrile and the mixture is again concentrated under reduced pressure. The residue was dissolved in 1000 ml of ethyl acetate, then washed with saturated sodium bicarbonate solution (1×250 ml), water (3×250 ml), brine (1×250 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue re-evaporated with acetonitrile and then was dissolved in 450 ml of diethyl ether and was stirred for 30 minutes, the Solids were collected by filtration with suction and received 56,14 g of 3,4-bis-(4-chlorophenyl)-1,2,5-thiadiazole-1,1-dioxide in the form of a yellowish-brown solid (82%).

Example 170

Rat-(1R*,2S*)-1,2-bis-(4-chlorophenyl)-propane-1,2-diamine

A solution of 5.0 g (14.7 mmole) of 3,4-bis-(4-chlorophenyl)-1,2,5-thiadiazole-1,1-dioxide in 55 ml of anhydrous tetrahydrofuran in an argon atmosphere was cooled to 0°C and then for 5 min was added dropwise to 12.9 ml of 1.4 M Rast is ora (1:3 tetrahydrofuran-toluene) methylacrylamide. The mixture was stirred for 35 min and then was poured into 100 g of ice, to which are added 55 ml of 1 M hydrochloric acid. The mixture was dissolved in 1000 ml of ethyl acetate and the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure received 5,38 g of 2,3-dihydro-3-methyl-3,4-bis(4-chlorophenyl)-1,2,5-thiadiazole-1,1-dioxide. This substance is used directly in the next stage without additional purification.

To a solution of 3,4-bis-(4-chlorophenyl)-3-methyl-2,3-dihydro-[1,2,5]-thiadiazole-1,1-dioxide (5,38 g of 15.1 mmole) in 91 ml of ethanol, cooled to 0°C, portions for 7 min was added to borohydride sodium (0,30 g, 61 mmole). After stirring at 0°C for another 45 min the mixture was allowed to warm to room temperature and was stirred for 3.5 h Then the reaction mixture was cooled to 0°C and the reaction was stopped by dropwise adding 1 M hydrochloric acid (38 ml). The reaction mixture was dissolved in 500 ml ethyl acetate, then washed with water (300 ml) and brine (300 ml), dried over anhydrous sodium sulfate and concentrated. The crude residue was purified using flash column-chromatography (silica gel, elution with 3:1 heptane-ethyl acetate) and got rat-(3R*,4S*)-3,4-bis(4-chlorophenyl)-3-methyl-1,2,5-thiadiazolidine-1,1-dioxide (4.3 g).

A suspension of rat-(3R*,4S*)-3,4-bis(4-shall lorgeril)-3-methyl-1,2,5-thiadiazolidine-1,1-dioxide (3,71 g, of 10.4 mmole) and phenol (a 4.86 g, 52 mmole) in 48% Hydrobromic acid (13.56MHz ml) and acetic acid (46,44 ml) was stirred at 130°C for 40 min (the reaction was monitored using TLC (thin layer chromatography), then it was allowed to cool to room temperature. The crude reaction mixture was subjected to distribution between ethyl acetate and water and the aqueous phase was twice washed with ethyl acetate. Then the aqueous phase was podslushivaet by slow addition of solid sodium hydroxide (60 g; CAUTION! exothermic reaction) and was extracted with diethyl ether (3×500 ml). The combined ether extracts were washed with 2 M sodium hydroxide solution (100 ml), then dried over anhydrous sodium sulfate (with the addition of a few pellets of solid sodium hydroxide) and evaporated and obtained the desired compound (1.56 g). This substance was used in the next stage without any further purification.

Example 171

(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-imidazol

According to the method similar to that described in example 2, RAC-(1R*,2S*)-1,2-bis-(4-chlorophenyl)-propane-1,2-diamine was introduced in the reaction with methyl ester 4-tert-butyl-2-ethoxybenzoyl acid (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) in the presence of trimethylaluminum and got the desired connection in the form of racemic mixtures.

The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C. at 100 bar and elution with 25% methanol and 0.2% Isopropylamine in carbon dioxide) and received (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-imidazole. BP-MS (EI, m/z) calculated for C28H31H2OCl2[(M+N)+] 481,1808 found 481,1801.

Example 172

Rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 173

(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride

According to the method similar to that described in example 3 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got the desired connection.

Example 174

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone

According to the method similar about vannoy in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired connection. BP-MS (EI, m/z) calculated for C37H47N4O4SCl2[(M+N)+] 713,2690 found 713,2687.

Example 175

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with piperazine (Aldrich) and got the desired connection. LC-MS: 593,2 [(M+N)+].

Example 176

Amide 1-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carboxylic acid

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-piperidine-4-ratanana (Aldrich) and got the desired connection. LC-MS: 635,2 [(M+N)+].

Example 177

1-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-alanon

According to the method similar to that described in example 5 (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-acetylpiperidine (Aldrich) and got the desired connection. LC-MS: 635,2 [(M+N)+].

Example 178

(2-Dimethylaminoethyl)-amide rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with N,N-dimethyl-1,2-atendimento (Aldrich) and got the desired connection. LC-MS: 595,2 [(M+N)+].

Example 179

rat-4-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-he

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazinone (Avocado Organics) and got the desired connection. LC-MS: 607,2 [(M+N)+].

Example 180

rat-2-{4-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason

According to the method similar to that described Primera 5, rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-morpholine-4-yl-2-piperazine-1-ratanana (Oakwood Products) and got the desired connection. LC-MS: 720,3 [(M+N)+].

Example 181

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-(4-methanesulfonylaminoethyl-1-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-methylsulfonylamino (Aldrich) and got the desired connection. LC-MS: 671,2 [(M+N)+].

Example 182

rat-2-{4-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-pyrrolidin-1-ylatason

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-1-pyrrolidin-1-ratanana (Aldrich) and got the desired connection. LC-MS: 704,3 [(M+N)+].

Example 183

rat-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-carbonyl)-piperazine-1-yl]-methanon

According to met the dick, similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with piperazine-1-yl-(tetrahydrofuran-2-yl)-Metronom (Aldrich) and got the desired connection. LC-MS: 691,3 [(M+N)+].

Example 184

Dimethylamide rat-4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with dimethylamide piperazine-1-carboxylic acid (Aldrich) and got the desired connection. LC-MS: 664,3 [(M+N)+].

Example 185

rat-2-{4-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired connection. LC-MS: 650,3 [(M+N)+].

Example 186

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-pyrrolin the n-1-ylatason

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-imidazole was obtained from the rat-(1R*,2S*)-1,2-bis-(4-chlorophenyl)-propane-1,2-diamine and methyl-2-isopropoxy-4-methoxybenzoate in the presence of trimethylaluminum according to the method described in example 2. He was then introduced to react with phosgene in the presence of triethylamine and got rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride (example 3).

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-1-pyrrolidin-1-ratanana (Aldrich) and got the desired connection. LC-MS: 692,3 [(M+N)+].

Example 187

rat-4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-he

rat-(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-imidazole was obtained from the rat-(1R*,2S*)-1,2-bis-(4-chlorophenyl)-propane-1,2-diamine and methyl-2-isopropoxy-4-methoxybenzoate in the presence of trimethylaluminum according to the method described in example 2. He was then introduced to react with phosgene in the presence of triethylamine and got rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,dihydroimidazole-1-carbonylchloride (example 3).

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazinone (Avocado Organics) and got the desired connection. LC-MS: 595,2 [(M+N)+].

Example 188

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-morpholine-4-yl-2-piperazine-1-ratanana (Oakwood Products) and got the desired connection. LC-MS: USD 708.3 [(M+N)+].

Example 189

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-(4-methanesulfonylaminoethyl-1-yl)-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-methylsulfonylamino (Aldrich) and got the desired connection. LC-MS: 659,2 [(M+N)+].

Example 190

rat-1-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-alanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-acetylpiperidine (Aldrich) and got the desired connection. LC-MS: 623,2 [(M+N)+].

Example 191

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-carbonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with piperazine-1-yl-(tetrahydrofuran-2-yl)-Metronom (Aldrich) and got the desired connection. LC-MS: OF 679.2 [(M+N)+].

Example 192

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazine-1-yl-acetamidomalonate (Matrix Scientific) and got the desired connection. LC-MS: 638,2 [(M+N)+].

Example 193

Dimethylamide rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-Pipera the Jn-1-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with dimethylamide piperazine-1-carboxylic acid (Aldrich) and got the desired connection. LC-MS: 652,2 [(M+N)+].

Example 194

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired connection. LC-MS: 701,2 [(M+N)+].

Example 195

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with piperazine (Aldrich) and got the desired connection. LC-MS: 581,2 [(M+N)+].

Example 196

(2-Dimethylaminoethyl)-amide rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-and is propoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carboxylic acid

According to the method similar to that described in example 5, RAC-(45*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with N,N-dimethyl-1,2-atendimento (Aldrich) and got the desired connection. LC-MS: 583,2 [(M+N)+].

Example 197

Amide rat-1-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-piperidine-4-ratanana (Aldrich) and got the desired connection. LC-MS: 623,3 [(M+N)+].

Example 198

rat-4-[(4S*,5R*)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-he

Rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-dihydro-1H-imidazole was obtained from the rat-(1R*,2S*)-1,2-bis-(4-chlorophenyl)-butane-1,2-diamine (obtained from 3,4-bis-aryl-1,2,5-thiadiazole-1,1-dioxide and ethylacetamide as described in example 170) and methyl-2-isopropoxy-4-methoxybenzoate in the presence of trimethylaluminum according to the method described in example 2. He was then introduced to react with phosgene in the presence of triethylamine and got rat(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-dihydroimidazole-1-carbonylchloride.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 2-piperazinone (Avocado Organics) and got the desired connection. LC-MS: 621,2 [(M+N)+].

Example 199

Amide rat-1-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-piperidine-4-ratanana (Aldrich) and got the desired connection. LC-MS: 649,3 [(M+N)+].

Example 200

rat-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-carbonyl)-piperazine-1-yl]-methanon

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with piperazine-1-yl-(tetrahydrofuran-2-yl)-Metronom (Aldrich) and got the desired connection. LC-MS: OF 693, 3 [(M+N)+].

Example 201

rat-2-{4-[(4S*,5R*)-4,5-Bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-morpholine-4-yl-2-piperazine-1-ratanana (Oakwood Products) and got the desired connection. LC-MS: 722,3 [(M+N)+].

Example 202

Dimethylamide rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-carboxylic acid

According to the method similar to that described in example 5, RAC-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonylchloride introduced into reaction with dimethylamide piperazine-1-carboxylic acid (Aldrich) and got the desired connection. LC-MS: 666,3 [(M+N)+].

Example 203

[(4S,5R)-2-(4-tert-Butyl-2-ethoxyphenyl)-4,5-bis-(4-forfinal)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon

Meso-2,3-bis-(4-forfinal)-2,3-butanediamine was obtained from 4,4'-diferencia according to the method similar to that described in examples 169 and 170. Then it was introduced into the reaction with 2-ethoxybenzonitrile according to the method described in example 2 (method 1), and got rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-forfinal)-4,5-dimethyl-4,5-dihydro-1H-imidazole.

Then pan-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-perfe who yl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was introduced in the reaction with phosgene in the presence of triethylamine and got rat-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-forfinal)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride.

According to the method similar to that described in example 5, RAC-(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-forfinal)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonylchloride was introduced in the reaction with 1-(3-methanesulfonyl)-piperazinecarboxamide (obtained as described in the publication Fotouhi, N. et al. WO 2005110996) and got the desired compound in the form of racemic mixtures. The enantiomers were separated using supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35°C at 100 bar and elution with 30% methanol in carbon dioxide), which gave the desired compound. BP-MS (EI, m/z) calculated for C38H49N4O4SF2[(M+N)+] 695,3437 found 695,3433.

Example 204

Research activity in vitro

The ability of compounds to inhibit the interaction between proteins p53 and MDM2 was investigated using analysis based on HTRF (homogeneous fluorescence with time resolution), in which recombinant MDM2 with attached GST binds to the peptide, which is similar to the plot of p53 interacting with MDM2 (Lane et al.). Binding of the protein GST-MDM2 and p53 peptide (biotinylated at the end atom N) are recorded using FRET (resonance energy transfer fluorescence) between labeled with europium (EU) anti-GST antibodies and conjugated with streptavidin-allophycocyanin (ARS).

Studies in black flat-bottom 384-l the night plates (Costar) at full volume, equal to 40 μl, comprising: 90 nm biotinylated peptide, 160 ng/ml GST-MDM2, 20 nm streptavidin-APC (PerkinElmerWallac), 2 nm labeled UOM anti-GST antibodies (PerkinElmerWallac), and 0.2% bovine serum albumin (BSA), 1 mm dithiothreitol (DTT) and 20 mm Tris-borate saline buffer (TBS) is conducted as follows. In each well put 10 ál of GST-MDM2 (working solution concentration of 640 ng/ml) in the buffer for the reaction. In each well put 10 μl of the diluted compounds (dilution ratio 1:5 in buffer for the reaction, mix by shaking. In each well put 20 ál of the biotinylated peptide p53 (working solution 180 nm) in buffer for the reaction and stirred device for shaking. Incubated at 37°C for 1 h was Added 20 μl of a mixture of streptavidin-APC and Eu-anti-GST antibodies (6 nm Eu-anti-GST and 60 nm working solution of streptavidin-APC) in TBS buffer with addition of 0.2% BSA, shaken at room temperature for 30 minutes and read using a reader tablets, suitable for use at different wavelengths, at 665 and 615 nm (5 Victor, Perkin ElmerWallac). Unless otherwise stated, reagents were purchased from the company Sigma Chemical Co.

The values of the IC50characterizing the biological activity of the compounds which are the object of the present invention are in the range of from about 1 to when is Erno 1000 nm. Specific data for some compounds of the examples below:

ExampleIC50(µm)
50,019
60,344
80,046
350,017
1770,107
1900,048

1. The compound of the formula

in which X1and X2denote halogen;
R1and R2selected from the group comprising-H, -CH3, -CH2CH3when
the condition that R1and R2both represent hydrogen;
R3denotes-H or-C(=O)-R7;
and if R6denotes hydrogen, then
R4represents-och3, -OCH2CH3or-och(CH3)2;
R5does
- N
- halogen,
- CF3,
- Ons,
- (CH3)2,
- cyclopropyl,
a cyano,
- (CH3)3,
- (CH3)2OR (where R denotes-H),
- (CH3)2CH-OR (where R denotes-CH3),
- (CH3)2CN,
- (CH3)2R (where R hereafter which denotes-CH 3),
- SR (where R denotes-CH2CH3or
- SO2R (where R denotes-CH3, -CH2CH31 is pyrrolidine, -NH-tert-butyl);
and if R6does not denote hydrogen, then
R4represents-och2CH3;
R5denotes hydrogen, -Cl, -och3, tert-butyl;
R6represents-Cl, cyclopropyl, -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, or-N(CH3)2);
and R7selected from the group including
(i)- (CH3, -CH(CH3)2, -CH2CH(CH3)2cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted by chlorine, -och3or cyano,
ii) 1-piperidinyl,
iii) -NRc2(where Rcdenotes-CH2CH2OH, -CH2CH2OCH3or-CH2CH(OH)CH2OH),
iv) substituted piperazine of the formula

in which R is selected from the group including
a) hydrogen,
C) -CH(CH3)2,
k) -CH2CH2Rd(where Rdrepresents-OH, -och3, -CF3, -SO2CH3, -NH2, NHCOCH3, -NHSO2CH3, 4-morpholinyl, 2-isothiazoline-1,1-dioxide),
l) -CH2CH2CH2Re(where Rerepresents-och3, -SO2CH3, -SO2CH2CH3, -CN).
m) -CH2-CO-Rh(where Rhputting the AET-NH 21 is pyrrolidinyl, 4-morpholinyl),
n) -SO2Ri(where Ridenotes-CH3, -CH2CH3),
on-CORj(where Rjdenotes-CH32-tetrahydrofuranyl, -NH2, -N(CH3)2),
R) 4-tetrahydro-2H-tiopronin-1,1-dioxide,
q) 4-piperidinyl-1-acetyl,
r) 4-piperidinyl-1-dimethylcarbamyl, and
s) 3-tetrahydrothiophene-1,1-dioxide;
v) substituted oxopiperidin formula

in which R denotes H;
and (vi) a substituted piperidine of the formula

in which R represents-CONH2HE-HE2HE, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazine) or 4-morpholinyl;
and its pharmaceutically acceptable salts.

2. The compound according to claim 1, in which X1and X2sterling is Cl.

3. The compound according to claim 2, in which R3denotes-C(=O)-R7.

4. The compound according to claim 3 in which R6denotes hydrogen; R4represents-och3,
-Och2CH3or-och(CH3)2; and R5denotes-C(CH3)3- (CH3)2OR (where R denotes
-H,- (CH3)2CH-OR (where R denotes-CH3), -C(CH3)2CN, -C(CH3)2COR (where R is-CH3), -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl).

5. The compound according to claim 3 in which R4 represents-och2CH3; R5means-Cl; and R6means-SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl or
-N(CH3)2).

6. The compound according to claim 3 in which R7doesand in which R denotes a-CH2CORh.

7. The connection according to claim 6, in which Rhdenotes 4-morpholinyl, 1-pyrrolidinyl,
-NH2.

8. The compound according to claim 3 in which R7doesand in which R denotes a-CH2CH2CH2Re.

9. The connection of claim 8, in which Remeans-SO2CH3or-SO2CH2CH3.

10. The compound according to claim 3 in which R7doesand in which R denotes a-CH2CH2Rd.

11. The connection of claim 10, in which Rdmeans-SO2CH3, -NHSO2CH3, -NHCOCH3or-CF3.

12. The compound according to claim 3 in which R7doesand R represents 4-tetrahydro-2H-tiopronin-1,1-dioxide.

13. The compound according to claim 1, in which
X1and X2mean-Cl;
R3denotes-C(O)-R7;
R4represents-och3, -Och2CH3or-och(CH3)2;
R5denotes-C(CH3)3- (CH3)2OR (where R is-H,- (CH3) 2CH-OR (where R denotes-CH3), -C(CH3)2CN, -C(CH3)2COR (where R is-CH3), -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl);
R6denotes hydrogen;
R7does(where R denotes-CH2CORh);
Rhdenotes 4-morpholinyl, 1-pyrrolidinyl, -NH2;
R1and R2have the meanings specified in claim 1; and
its pharmaceutically acceptable salt.

14. The compound according to claim 1, in which
X1and X2mean-Cl;
R3denotes-C(O)-R;
R4represents-och3, -Och2CH3or-och(CH3)2;
R5denotes-C(CH3)3- (CH3)2OR (where R is-H,- (CH3)2CH-OR (where R denotes-CH3), -C(CH3)2CN, -C(CH3)2COR (where R is-CH3), -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl);
R6denotes hydrogen;
R7does(where R denotes-CH2CH2CH2Re);
Remeans-SO2CH3or-SO2CH2CH3;
R1and R2have the meanings specified in claim 1; and
its pharmaceutically acceptable salt.

15. The compound according to claim 1, in which
X1and X2mean-Cl;
R denotes-C(O)-R7;
R4represents-och3, -Och2CH3or-och(CH3)2;
R5denotes-C(CH3)3- (CH3)2OR (where R is-H,- (CH3)2CH-OR (where R denotes-CH3), -C(CH3)2CN, -C(CH3)2COR (where R is-CH3), -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl);
R6denotes hydrogen;
R7does(where R denotes-CH2CH2Rd);
Rdmeans SO2CH3, -NHSO2CH3, -NHCOCH3or-CF3;
R1and R2have the meanings specified in claim 1; and its pharmaceutically acceptable salts.

16. The compound according to claim 1, in which X1and X2mean-Cl;
R3denotes-C(O)-R7;
R4represents-och2CH3;
R5means-Cl;
R6means-SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, or-N(CH3)2);
R7does(where R denotes-CH2CORh);
Rhdenotes 4-morpholinyl, 1-pyrrolidinyl, -NH2;
R1and R2have the meanings specified in claim 1; and
its pharmaceutically acceptable salt.

17. The compound according to claim 1, in which
X1and X2denote-C;
R3denotes-C(O)-R7;
R4represents-och2CH3;
R5means-Cl;
R6means-SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, or-N(CH3)2);
R7does(where R denotes-CH2CH2CH2Re);
Remeans-SO2CH3or-SO2CH2CH3; and R1and R2have the meanings specified in claim 1; and its pharmaceutically acceptable salts.

18. The compound according to claim 1, in which X1and X2mean-Cl;
R3denotes-C(O)-R7;
R4represents-och2CH3;
R5means-Cl;
R6means-SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, or
-N(CH3)2);
R7does(where R denotes-CH2CH2Rd);
Rdmeans-SO2CH3, -NHSO2CH3, -NHCOCH3or-CF3and
R1and R2have the meanings specified in claim 1; and
its pharmaceutically acceptable salt.

19. The compound according to claim 1, selected from the group including:
rat-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole,
(4S,5R)-4-[[4-[[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-yl]carbonyl]-1-piperazinil]acetyl]-morpholine,
(4S,5R)-4-[4-[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]carbonyl]-1-piperidine,
(4S,5R)-1-[4-[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]-carbonyl]-4-[3-(methylsulphonyl)propyl]-piperazine,
(4S,5R)-1-[4-[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]-carbonyl]-4-[3,3,3-cryptochromes]-piperazine,
2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she
2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-pyrrolidin-1-ylatason and
N-(2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ethyl)-ndimethylacetamide.

20. The compound according to claim 1, selected from the group including
N-(2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ethyl)-methanesulfonamide,
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-hydroxyethyl)-piperazine-1-yl]-methanon,
5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-2-tert-butyl-4-ethoxy-N,N-dimethylbenzenesulfonamide,
rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-di is Idro-1H-imidazol-2-yl]-3-ethoxyphenyl}-2-methylpropionitrile,
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile,
N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(piandimeleto)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-methanesulfonamide,
N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(piandimeleto)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-ndimethylacetamide and
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(2-hydroxyethyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile.

21. The compound according to claim 1, selected from the group including
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile,
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she
2-[4-((4S,5R)-4,5-bis-(4-chlorophenyl)-1-{4-[2-(1,1-dioxothiazolidine-2-yl)-ethyl]-piperazine-1-carbonyl}-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-3-ethoxyphenyl]-2-methylpropionitrile,
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-1-[4-(2-oxo-2-pyrrolidin-1-retil)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile,
2-{4-[(4S,5R)-1-[4-(1-acetylpiperidine-4-yl)-piperazine-1-carbonyl]-4,5-bis-(4-chlorophenyl)-45-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-2-methylpropionitrile,
4-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(centimetres)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-piperidine-1-carboxylic acid Isopropylamine,
rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole and
rat-(4S*,5R*)-4-[(4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-3-ethoxybenzaldehyde.

22. The compound according to claim 1, selected from the group including
{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-1-pyrrolidin-1-ylatason,
N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-methanesulfonamide,
N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-acetamide", she
{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(2-hydroxyethyl)-piperazine-1-yl]-methanon,
4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-3-ethoxybenzaldehyde,
2-{4-[(4S,5R)-2-(4-tert-butylsulfonyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she
rat-(4S*,5R*)-5-[4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde and
5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde.

23. The compound according to claim 1, selected from the group including
5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(2-methanesulfonylaminoethyl)piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde,
N-{(4S,5R)-(2-{4-[2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}ethyl}acetamide", she
5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde,
5-{(4S,5R)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-1-[4-(2-oxo-2-pyrrolidin-1-retil)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxybenzaldehyde,
2-{4-[(4S,5R)-2-(5-tert-butylsulfonyl-4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she
rat-(4S*,5R*)-2-[4-chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihyd the o-1H-imidazole,
5-[(4S,5R)-2-[4-chloro-2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]metano and
rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole.

24. The compound according to claim 1, selected from the group including
{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidin-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]metano,
rat-(4S*,5R*)-2-(4-chloro-2-ethoxy-5-methanesulfonyl)4,5-bis-(4-chlorophenyl)4,5-dimethyl-4,5-dihydro-1H-imidazole,
[(4S,5R)-2-(4-chloro-2-ethoxy-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]metano,
{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidin-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]metano and
4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxybenzonitrile.

25. The compound according to claim 1, selected from the group including
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone,
1-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,
RA is-(4S*,5R*)-2-(4-bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole,
rat-[(4S*,5R*)-2-(4-bromo-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}-propan-2-ol and
[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon.

26. The compound according to claim 1, selected from the group including
2-{4-[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she
{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she
{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(2-hydroxyethyl)-piperazine-1-yl]-methanon,
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-1-pyrrolidin-1-ylatason,
N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-acetamide", she
N-[2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-ethyl]-methanesulfonamide,
{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-yl]-methanon,
rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole.

27. The compound according to claim 1, selected from the group including
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she
rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,
rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-it,
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-methanesulfonyl)-piperazine-1-yl]-methanon,
rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole,
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she
{rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-Digi ronidazole-1-yl}-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon and
{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-methoxy-1-methylethyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-yl}-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-yl]-methanon.

28. The compound according to claim 1, selected from the group including
rat-1-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-Etalon,
1-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-cyclopropylmethanol,
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-cyclobutylamine,
1-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-3-methylbutane-1-he,
1-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-3-phenylpropane-1-he,
4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-benzonitrile,
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-furan-2-ylmethanone,
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-phenylmethanone and
rat-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-methoxyphenyl)-methanon.

29. Connection p., selected from the group including
rat-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-chlorophenyl)-methanon,
[(4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
2-{4-[(4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she
rat-(2-{4-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,
rat-[(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-pyrrolidin-1-reparacin-1-yl)-methanon and
rat-[1,4']bipyridinyl-1'-yl-[(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-methanon.

30. The compound according to claim 1, selected from the group including
rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydro-1H-imidazole,
rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-it,
rat-1-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,
[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazo the l-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,
rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-acanaloniidae-1-yl)-methanon,
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(4-methylpiperazin-1-yl)-piperidine-1-yl]-methanon and
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-(morpholine-4-reparacin-1-yl)-methanon.

31. The compound according to claim 1, selected from the group including
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-hydroxy-piperidine-1-yl)-methanon,
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-hydroxyethylpiperazine-1-yl)-methanon,
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-hydroxyethyl)-piperidine-1-yl]-methanon,
amide rat-1-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carboxylic acid,
bis-(2-hydroxyethyl)-amide rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid,
(2,3-dihydroxypropyl)-am is on rat-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-triptoreline)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid,
3-(4-{4,5-bis-(4-chlorophenyl)-1-[4-(3-methanesulfonyl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-3-methylbutane-2-he
3-(4-{(4S,5R-)-4,5-bis-(4-chlorophenyl)-1-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-3-methylbutane-2-it.

32. The compound according to claim 1, selected from the group including
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxyphenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl}-piperazine-1-yl)-acetamide", she
rat-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole,
rat-1-{4-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,
rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-(4-isopropylpiperazine-1-yl)-methanon,
rat-4-{4-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-butyronitrile,
rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methoxypropyl)-piperazine-1-yl]-methanon and
rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-morpholine-4-retil)-piperazine-1-yl]-methanon.

33. The compound according to claim 1, selected from the GRU is dust, including
bis-(2-methoxyethyl)-amide rat-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carboxylic acid,
rat-[(4S*,5R*)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(2-methoxyethyl)-piperazine-1-yl]-methanon,
[(4S,5R)-2-(4-tert-butyl-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-isopropylphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methanesulfonyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(4-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon, and
[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(5-cyclopropyl-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon.

34. The compound according to claim 1, selected from the group including
[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(4-econsultancy-2-ethoxyphenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-diethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazin the-1-yl]-methanon,
[(4S,5R)-4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethylsulfanyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
[(4S,5R)-2-(4-tert-butyl-2-methoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
[(4S,5R)-2-(4-chloro-2-ethoxy-5-methanesulfonyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)-piperazine-1-yl]-methanon,
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(1,1-dioxotetrahydrofuran-3-yl)-piperazine-1-yl]-methanon,
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-yl]-[4-(3-acanaloniidae)-piperazine-1-yl]-methanon,
2-(4-{(4S,5R)-4,5-bis-(4-chlorophenyl)-1-[4-(3-acanaloniidae)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxyphenyl)-2-methylpropionitrile and
(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-imidazole.

35. The compound according to claim 1, selected from the group including
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone,
[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone,
amide 1-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-to rbony]-piperidine-4-carboxylic acid,
1-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,
rat-4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-it,
rat-2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,
rat-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-(4-methanesulfonylaminoethyl-1-yl)-methanon,
rat-2-{4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-pyrrolidin-1-ylatason, and
rat-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-carbonyl)-piperazine-1-yl]-methanon.

36. The compound according to claim 1, selected from the group including
dimethylamide rat-4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-carboxylic acid,
rat-2-{4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-acetamide", she
rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-pyrrolidin-1-ylatason,
rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydr is imidazol-1-carbonyl]-piperazine-2-it,
rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason,
rat-1-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-Etalon,
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-carbonyl)-piperazine-1-yl]-methanon,
rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-ndimethylacetamide and
dimethylamide rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-carboxylic acid.

37. The compound according to claim 1, selected from the group including
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-[4-(3-methanesulfonyl)-piperazine-1-yl]-methanon,
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone,
amide rat-1-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4-methyl-4,5-dihydroimidazole-1-carbonyl]-piperidine-4-carboxylic acid,
rat-4-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-dihydroimidazole-1-carbonyl]-piperazine-2-it,
amide rat-1-[(4S*,5R*)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4-ethyl-4,5-is hydromedusa-1-carbonyl]-piperidine-4-carboxylic acid,
rat-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-[4-(tetrahydrofuran-2-carbonyl)-piperazine-1-yl]-methanon,
rat-2-{4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-yl}-1-morpholine-4-ylatason and
dimethylamide rat-4-[(4S*,5R*)-4,5-bis-(4-chlorophenyl)-4-ethyl-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-piperazine-1-carboxylic acid.

38. The compound according to any one of claims 1 to 37, intended for use as a drug that inhibits the interaction between proteins p53 and MDM2.

39. The compound according to any one of claims 1 to 37, intended for the treatment of cancer, preferably solid tumors, more preferably tumors of the breast, colon, lung and prostate cancer, or fighting them.

40. Pharmaceutical composition having the ability to inhibit the interaction between proteins p53 and MDM2, comprising the compound of the formula

in which X1and X2denote halogen;
R1and R2selected from the group comprising-H, -CH3, -CH2CH3provided that R1and R2both represent hydrogen;
R3denotes-H or-C(=O)-R7;
and if R6denotes hydrogen, then
R4represents-och3, -Och CH3or-och(CH3)2;
R5does
- H
- halogen,
- CF3,
- Och3,
- (CH3)2,
- cyclopropyl,
a cyano,
- (CH3)3,
- (CH3)2OR (where R denotes-H),
- (CH3)2CH-OR (where R denotes-CH3),
- (CH3)2CN,
- (CH3)2COR (where R is-CH3),
-SR (where R denotes-CH2CH3or
-SO2R (where R denotes-CH3, -CH2CH31 is pyrrolidine, -NH-tert-butyl);
and if R6does not denote hydrogen, then
R4represents-och2CH3;
R5denotes hydrogen, -Cl, -och3, tert-butyl;
R6represents-Cl, cyclopropyl, -SO2R (where R denotes-CH31 is pyrrolidine, -NH-tert-butyl, or-N(CH3)2);
and R7selected from the group including
(i)- (CH3, -CH(CH3)2, -CH2CH(CH3)2cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted by chlorine, -och3or cyano,
ii) 1-piperidinyl,
iii) -NRc2(where Rcdenotes-CH2CH2OH, -CH2CH2OCH3or-CH2CH(OH)CH2OH),
iv) substituted piperazine of the formula

in which R is selected from the group including
a) hydrogen,
C) -CH(CH3)2 ,
k) -CH2CH2Rd(where Rdrepresents-OH, -och3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morpholinyl, 2-isothiazoline-1,1-dioxide),
l) -CH2CH2CH2Re(where Rerepresents-och3, -SO2CH3, -SO2CH2CH3, -CN),
m) -CH2-CO-Rh(where Rhdenotes-NH21 is pyrrolidinyl, 4-morpholinyl),
n) -SO2Ri(where Ridenotes-CH3, -CH2CH3),
on-CORj(where Rjdenotes-CH32-tetrahydrofuranyl, -NH2, -N(CH3)2),
R) 4-tetrahydro-2H-tiopronin-1,1-dioxide,
q) 4-piperidinyl-1-acetyl,
r) 4-piperidinyl-1-dimethylcarbamyl, and
s) 3-tetrahydrothiophene-1,1-dioxide;
v) substituted oxopiperidin formula

in which R denotes H;
and (vi) a substituted piperidine of the formula

in which R represents-CONH2, -OH, -CH2OH, -CH2CH2HE, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazine) or 4-morpholinyl;
and its pharmaceutically acceptable salt together with a pharmaceutically acceptable inert filler.

41. The pharmaceutical composition according p intended for the treatment of cancer, preferably solid tumors, more preferably of mammary glands is, colon, lung and prostate cancer, or fighting them.

42. The use of compounds according to any one of claims 1 to 37 for the preparation of medicines intended for the treatment of cancer, preferably solid tumors, more preferably tumors of the breast, colon, lung and prostate cancer, or fighting them.

43. The method of obtaining the compounds of formula (I) according to claim 1, in which (a) imidazolin formula (V), i.e. the compound of formula (I)in which R3denotes hydrogen,

get through
i) condensation of Tetra-substituted 1,2-diamine of the formula (II)

with aromatic acid of the formula (III)

with the formation of a derivative monoamide formula (IV)

with the subsequent cyclodehydration with obtaining the compounds of formula (V) and
b) the compound of formula (V) enter into reaction with phosgene to form carbamoylated formula (VII)

which is then injected into the reaction with primary or secondary amines with the formation of the corresponding compounds of formula (I)in which R3does not denote hydrogen; and
(C) the specified connection formula (I) is optionally converted into pharmaceutically acceptable salt; where all substitutes shall C what aczeniami, specified in claim 1.

44. The method of obtaining the compounds of formula (I) according to claim 1, in which (a) imidazolin formula (V), i.e. the compound of formula (I)in which R3denotes hydrogen,

get through
ii) reaction of the Tetra-substituted 1,2-diamine of the formula (II)

with complex aromatic ether of the formula (VI)

in the presence of trialkylamine getting imidazoline of the formula (V); and
b) the compound of formula (V) enter into reaction with phosgene to form carbamoylated formula (VII)

which is then injected into the reaction with primary or secondary amines with the formation of the corresponding compounds of formula (I)in which R3does not denote hydrogen; and
c) the compound of formula (I) is optionally converted into pharmaceutically acceptable salt; where
all substituents have the meanings indicated in claim 1.



 

Same patents:

FIELD: pharmachology.

SUBSTANCE: invention describes new compounds with general formula (I-c) Where R1 is a radical (d-1) or (d-2) (radical values are given in the invention formula) and pharmaceutical composition containing them. The described compounds are the hepatitis C inhibitors and can be used in medicine.

EFFECT: enhanced hepatitis C inhibition.

5 cl, 1 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds selected from a group consisting of compounds of formula: and or to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, as well as to using at least one compound under cl.1 and/or its pharmaceutically acceptable salts.

EFFECT: preparing new biologically active compounds which exhibit the properties of cycline-dependent kinase inhibitors.

11 cl, 86 tbl

Kinase inhibitors // 2440352

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula : a pharmaceutically acceptable salt or solvate thereof, having Syk kinase inhibiting properties. The invention also relates to a pharmaceutical composition containing said compound, methods of treating diseases whose development is aided by c-kit receptor activity, such as arthritis, rheumatoid arthritis, tumours, mantle cell lymphoma, as well as a method of inhibiting angiogenesis.

EFFECT: improved method.

13 cl, 4 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula in which is or (values of radicals are given in the claim), a method of producing said compounds, a pharmaceutical composition containing said compounds and therapeutic application thereof.

EFFECT: compounds are cysteine protease inhibitors and can be used in medicine.

25 cl, 1 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril). The reaction takes place at 80°C for 60 minutes, where concentrated sulphuric acid is used in an aqueous medium and reagents are taken in the following molar ratios: glyoxal 2.0; urea 4.0; sulphuric acid 0.4; water 12, and the freshly prepared glyoxal solution is added while stirring for 20 minutes, after which the mixture is stirred for 40 more minutes.

EFFECT: novel method of producing glycoluril, which increases output of the end product and is simpler.

1 cl, 1 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of formulae pharmaceutically acceptable salts or stereoisomers thereof, where R1 = -OR5, -NH-SO2R6; R2 = hydrogen; R3 = C1-6-alkyl; R4 = isoquinolinyl, possibly substituted; n equals 4 or 5; R5 = hydrogen; R6 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: novel compounds have hepatitis C virus replication inhibitory action and can be used in medicine.

6 cl, 32 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes a compound of general formula where A1 is selected from the following formula R1c denotes a hydrogen atom, a lower alkenyl group or a -Q3-A3(R1d)R1e group; A3 denotes a methane or lower alkyl group; Q3 denotes a single bond; R1d and R1e independently denote a hydrogen atom, hydroxyl group, lower alkyl group or hydroxyl-containing lower alkyl group, or together form a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1 denotes a lower alkenyl group or a lower alkynyl group; R2 denotes a phenyl, pyridyl or thienyl group, which can contain a -Q4-A4(R1g)R1h group; A4 denotes a nitrogen atom, a lower alkyl group optionally substituted with a hydroxy-lower alkyl group, or a methane group optionally substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q denotes a single bond or a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1g and R1h independently denote a hydrogen atom, a lower alkyl group or a lower alkylsulphonyl group; R5 and R6 independently denote a hydrogen atom, a lower alkyl group or a hydroxyl-containing lower alkyl group, or a pharmaceutically acceptable salt thereof. The invention also describes a pharmaceutical composition based on compounds of formula I, having anti-cancer activity, an anticancer agent, a codrug, as well as an exposure sensitising agent containing the pharmaceutical composition.

EFFECT: novel compounds are obtained and described, having excellent Well-kinase inhibitory action and can therefore be used in medicine, especially when treating different malignant tumours.

13 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of general formulae (I-c) (I-d), pharmaceutically acceptable salt or stereoisomer thereof, where R1 = -OR11 or -NH-SO2R12; R2 = hydrogen and R3 =C1-6-alkyl; n = 3-6; W is a radical of formula , where R5 = phenyl, possibly substituted with C1-6alkyl or alkoxy; thiazolyl, possibly substituted with C1-6alkyl; or pyridyl; R11 denotes hydrogen; R12 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: said compounds are hepatitis C virus inhibitors and can be used in medicine.

3 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antiviral active components - substituted indoles of general formula 1 and pharmaceutically acceptable salts thereof, which can be used to treat and/or prevent viral diseases caused by hepatitis C virus (HCV). In general formula , R1 denotes a hydrogen atom, optionally substituted C1-C4alkyl, C6cycloalkyl, phenyl, ethoxycarbonyl, nitro group; R2 denotes a hydrogen atom; R3 denotes N-mono- or N,N-disubstituted 1-methylene-piperidine-3-carboxamide of general formula 1a or N-mono- or N,N-disubstituted 1-methylene-piperdine-4-carboxamide of general formula 1b; R4 denotes a hydrogen atom, optionally substituted C2-C3alkyl, a -CH2-R12 group, where R12 denotes a hydrogen atom or phenyl which is optionally substituted with halogen or C1-C4alkyl; or R2, R3, and R4 together with atoms with which they are bonded form a substituted azaheterocycle of general formula 1.2; or R2 and R3 together with carbon atoms with which they are bonded form a substituted 2,3,4,9-tetrahydro-1H-carbazole of general formula 1.1, in which R1 denotes methyl, ethoxycarbonyl, nitro group; R4 denotes a hydrogen atom, methyl, C2-C3alkyl substituted with N-benzylamine; R7 and R8 denote hydrogen atoms or R7 and R8 together with a carbon atom with which they are bonded form a C=O group; R5 and R6, which are optionally identical, denote a hydrogen atom, optionally substituted C1-C3alkyl or C3-C6cycloalkyl; or R5 and R6 together with a nitrogen atom with which they are bonded form an optionally substituted 5- or 6-member azaheterocyclyl containing one or two nitrogen atoms, etc.

EFFECT: improved properties of compounds.

11 cl, 1 tbl, 6 ex

Antiviral compouds // 2441869

FIELD: pharmacology.

SUBSTANCE: invention refers to the new compounds or its pharmaceutically acceptable salts where the compound has formula I possessing the activity towards hepatitis C virus (HCV). In the compound of formula I, Each W1 and W2 means nitrogen, W3 is chosen out of group consisting of nitrogen and -CH-, and W4 is -CH-; A is phenyl and is not mandatory substituted, X is chosen out of group consisting out of bond, -O- and -S-, Z is chosen out of group consisting of -CH2- and -NH-; R22 is chosen out of group consisting of hydrogen, benzimidazole, indole and thiophene, where R22 is not mandatory substituted, Y is chosen out of group consisting of C(O)N(R15)- and -N(R15)C(O)-, where R15 in each case is chosen out of group consisting of hydrogen and C1-C6alkyl; R50 is -L1-A1 where L1 is chosen out of group consisting of bond and C1-C6alkylene, and A1 is chosen out of group consisting of phenyl, pyridyl, benzothiazolyl, thiadiazole, isothiazole and thiophene, where A1 is not mandatory replaced, each R10 and R35 means hydrogen; R17 is C1-C6alkyl; and each C3-C18carbocyclil and M3-M18heterocyclil in -LE-Q-LE-(C3-C18carbocyclil) and -LE-Q-LE-( M3-M18heterocyclil) is not mandatory independently substituted in each case.

EFFECT: enhanced cure of hepatitis C.

13 cl, 12 dwg, 459 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazopyridines of formula I

and to their pharmaceutically acceptable salts where Z1 represents CR1; R1 represents H; R1' represents H; Z2 represents CR2; Z3 represents CR3 or N; R2 and R3 are independently selected from H, halogen; R4 represents H; Y represents W-C(O)-; W represents or , R5 represents H; X1 is selected from R11' and -OR11'; each R11 independently represents H, C1-C12alkyl, C2-C8alkenyl; X4 represents , R6 represents H, halogen, cyclopropyl or -(CR19R20)n-SR16; R6 represents H, halogen; p represents 0, 1, 2 or 3; n represents 0, 1 or 2; where each specified alkyl in R11 is independently substituted by one or two groups independently selected from halogen, -(CR19R20)nOR16 and R21; each R16 independently represents H, C1-C12alkyl; R19 and R20 are independently selected from H, C1-C12alkyl; R21 represents cyclopropyl.

EFFECT: invention refers to a pharmaceutical composition for treating hyperproliferative disorder.

10 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula:

in which: X represents one of the following groups: - a phenyl group optionally substituted by one or more groups, optionally selected from one of the following atoms and groups: halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, NRaRb, R1 represents hydrogen atom, halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, amino, the group NRcRd; with the alkyl and alkoxy groups being optionally substituted by one or more halogens, hydroxy, amino or (C1-C6)alkoxy, R2 represents one of the following groups: -hydrogen atom, - (C1-C6)alkyl group optionally substituted by one or more groups optionally substituted by hydroxy, halogen, amino, the group NRaRb, the phenyl group, the - (C1-C3)alkoxygroup optionally substituted by one or more groups independently selected from hydroxy, halogen, amino, the group NRaRb, - (C3-C7)cycloalkyl((C1-C6)alkyl, - (C3-C7)cycloalkyl(C1-C6)alkoxy, -(C2-C6)alkenyl, - (C2-C6)alkinyl, - the group -CO-R5,- the group -CO-NR6R7,- the group -CO-O-R8,- the group -NR9-CO-R10,- the group -NR11R12,- halogen atom,- the cyanogroup,- the phenyl group optionally substituted by one or more groups optionally selected from the following atoms and groups: halogen, (C1-C6)alkoxy, NRaRb, -CO-R5, -CO-NR6R7, -CO-O-R8, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkyl group optionally substituted by one or more hydroxy groups or NRaRb R3 represents hydrogen atom, (C1-C6)alkyl, (C1-C6)alkoxy or halogen atom, R4 represents hydrogen atom, (C1-C4)alkyl, (C1-C4)alkoxy or fluorine atom, R5 represents hydrogen atom, the phenyl group or (C1-C6)alkyl, R6 and R7, the same or different represents hydrogen atom or (C1-C6)alkyl, or together with nitrogen atom forms a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S,R8 represents (C1-C6)alkyl, R9 and R10, the same or different, represent hydrogen atom or (C1-C6)alkyl, R11 and R12, the same or different, represent (C1-C6)alkyl, or together with nitrogen atom form a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S, Ra and Rb independently represent hydrogen atom, (C1-C6)alkyl or together with nitrogen atom form a 4-7-member cycle, Rc represent hydrogen atom, and Rd represents (C1-C6)alkyl and at least one of the substitutes R1, R2, R3 and R4 are different from hydrogen; and when R3 means methyl, X is unsubstituted; when R1 means methyl, X is unsubstituted; when R2 means chlorine, X is other than parafluorophenyl; in the form of a base or an acid addition salt. The invention also refers to the compounds selected from the group, to a drug, to a pharmaceutical composition, as well as to application of the compounds of formula (I) by any of cl. 1-4.

EFFECT: preparing new biologically active compounds for treating or preventing the diseases associated with nuclear receptor NOT.

13 cl, 18 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel synthesis of 11H-indolo[2,3-c]quinoline derivatives of formula I, which can be used in synthesis of novel preparations for pharmaceutical purposes. In the method of producing 11H-indolo[2,3-c]quinoline derivatives of general formula I

indexRR1R2НННIbClННIcClОСН3ОСН3IdСН3ННIeНОСН3Н

, the corresponding 4-[2-(2-nitrophenyl)-1H-indol-3-yl]-but-3-en-2-ones II are boiled in acetic acid in the presence of twenty-fold molar excess of carbonyl iron for 5 minutes.

EFFECT: method widens the range of obtained products and simplifies the process owing to use of other initial compounds and conditions.

1 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered an agent showing properties of a cognitive function activator representing 1,3-dimethyl-5-(pyridyl-4-amino)methylene-barbituric acid

and an agent of the same purpose, 4-amino-1-(3-nitro-2-oxo-1-phenyl-1,2-dihydronaphthiridinyl)pyridinium chloride -versions.

EFFECT: high biological activity in scopolamine amnesia of the offered agents is presented.

2 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of bicyclic imdazo-3-lylamines of general formula and corresponding physiologically transportable salts thereof, where A1 denotes a nitrogen atom or a C-R1a-group, A2 denotes a nitrogen atom or a C-R1b-group, A3 denotes a C-R1c-group, A4 denotes a nitrogen atom or a C-R1d-group, R1a, R1b, R1c, R1d independently denote hydrogen, halogen, -C(=O)-OR12, -OR16, a straight or branched, saturated, unsubstituted or halogen-tri-substituted C1-10-aliphatic residue, or an unsubstituted phenyl residue which can be bonded through a straight or branched C1-5-alkylene group, or R1b and R1c or R1c and R1d together with a C-C-bridge bonded to them optionally form an unsubstituted annelated phenyl residue, R2 and R3 independently denote hydrogen, -C(=O)-R2b, (CH2)q -C(=O)-R21, where q equals 1, -(CH2)r- C(=O)-O-R22, where r equals 1, a straight or branched, saturated unsubstituted C1-16-aliphatic residue, saturated, unsubstituted C4-8-cycloaliphatic residue which can be bonded through a straight or branched C1-5-alkylene group, or an unsubstituted or at least mono-substituted phenyl or heteroaryl residue which can be bonded through a straight or branched C1-5-alkylene group, or R2 and R3 together with the nitrogen atom with which they are bonded to as a ring member form a saturated heterocycloaliphatic residue which is piperidine or pyrrolidine, R12, R16, R20, R21 and R22 independently denote hydrogen, straight or branched, saturated C1-4-aliphatic residue or an unsubstituted or at least mono-substituted phenyl residue, which can be bonded through a straight or branched C1-5-alkylene group, M1 denotes a phenyl or heteroaryl residue which can be substituted with an additional substitute which is methyl or -CH2-CN, M2 denotes an unsubstituted or at least mono-substituted phenyl or heteroaryl residue, wherein the heteroaryl is selected from a group consisting of the following residues: furyl (furanyl), thienyl (thiophenyl), imidazolyl, thiazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl and quinolyl, the expression "at least mono-substituted" in association with "phenyl" or "heteroaryl" relates to a phenyl or heteroaryl residue which can be substituted with 1 or 2 substitutes independently selected from a group comprising halogen, , -CN, -NO2, -OH, -NH2, -CH2-NH2, -C(=O)-OH, C1-C5alkyl, -CH2-O-C1-C5alkyl, -C2-C5alkenyl, -S-C1-C5alkyl, -O-C1-C5alkyl, -CF3, -O-CF3, -NH-C1-C5alkyl, -N-(C1-C5alkyl)2, -C(=O)-O-C1-C5alkyl, -C(=O)-H, -C(=O)-C1-C5alkyl, -NH-S(=O)2-C1-C5alkyl, -NH-C(O)-C1-C5alkyl, -S(=O)2-NH2,-S(=O)2-NH-C1-C5alkyl, -CH2OH, -C(=O)-NH2, -Si(phenyl)2[C1-C5alkyl], (1,3)-dioxolanyl, phenyl and pyrrolyl. The invention also relates to methods of producing compounds of formula I, a medicinal agent based on compounds of formula I, use of compounds of formula I to prepare the medicinal agent.

EFFECT: obtaining novel derivatives of bicyclic imidazo-3-ylamines of general formula I, used to regulate the mGluR5-receptor.

30 cl, 3 tbl, 365 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I): or its pharmaceutically acceptable salt where Q is 2,6-pyrimidyl; where Q is optionally substituted by 1-5 substitutes JQ; Z is a link or NH; R1 is H; R2 is H; R3 is halogen or -(U)m-X where m is equal to 0; X is H or halogen; JQ is halogen, OCF3, -(Vn)-R", -(Vn)-CN or -(Vn)-(C1-4 halogenaliphatic group) where JQ is not H; V is C1-10aliphatic group where up to three methylene groups are substituted by GV where Gv is selected from -NH-, -NR-, -O-, -S-, -CO2-, -C(O)CO-, -C(O), -C(O)NH-, -C(O)NR-, -C(=N-CN)-, -NHCO-, -NRCO-, -NHSO2-, -NRSO2-, -NHC(O)NH-, -NRC(O)NH-, -NHC(O)NR-, -NRC(O)NR or -SO2-; and where V is optionally substituted by 1-6 substitutes JV; R" is H or an optionally substituted group selected from C1-6aliphatic group, C3-10cycloaliphatic group, C6-10aryl, 5-10-member heteroaryl or 5-10-member heterocyclyl; or two R" groups on the same substitute or various substitutes together with atom (s) whereto each group R" is attached, form optionally substituted 3-8-member heterocyclyl; where each optionally substituted R" group is independently and optionally substituted by 1-6 substitutes JR; R is an optionally substituted group selected from C1-6aliphatic group and C6-10aryl where each group R is independently and optionally substituted by 1-4 substitutes JR; each Jv and JR are independently selected from halogen, L, - (Ln)-R', - (Ln)-N(R')2, -(Ln)-OR', C1-4haloalkyl, -(Ln)-CN, - (Ln)-OH, -CO2R', -CO2H or -COR'; or two Jv, JR groups on the same substitute or various substitutes together with atom (s) whereto each group JV and JR is attached, form a 5-7-member saturated, unsaturated or partially saturated ring; R' is H or C1-6aliphatic group; L is C1-6aliphatic group where up to three methylene units are substituted by -C(O)-; each n is independently equal to 0 or 1. Besides, an invention refers to of a pharmaceutical composition for ROCK or JAK kinase inhibition on the basis of the given compounds, to a method of ROCK or JAK kinase activity inhibition, and also to application of the compounds of formula I, for preparing a drug where Q, Z, R1, R2 and R3 are those as described in cl. 1 of the patent claim, effective as protein kinase inhibitors, especially JAK and ROCK families kinase inhibitors.

EFFECT: there are prepared and described new compounds which can find the application in medicine.

42 cl, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

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