Substituted pyrrolidine-2-carboxamides

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula

in which
X is selected from the group comprising H, F, Cl, Br, I;
Y represents from 1 to 4 groups independently selected from the group comprising H, F, Cl, Br, I, ness. alkyl and NISS. alkoxygroup,
one of R1and R2selected from the group comprising ness. alkyl, substituted ness. alkyl, NISS. alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and substituted cycloalkyl, and the other denotes hydrogen or nits. alkyl;
R3denotes H or nits. alkyl;
one of R4and R5selected from the group comprising ness. alkyl, substituted ness. alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, and the other represents hydrogen;
R6and R7selected from the group on the expectation (CH 2)n-R', (CH2)n-R NR'r", (CH2)n-NR'r COR", (CH2)n-NR'r SO2R", (CH2)n-COOH, (CH2)n-COOR', (CH2)n-CONR'R", (CH2)n-OR', (CH2)n-SR', (CH2)n-SOR', (CH2)n-SO2R', (CH2)n-COR', (CH2)n-SO3H, (CH2)n-SONR'R", (CH2)n-SO2NR'r R", (CH2CH2O)m-(CH2)n-R', (CH2CH2O)m-(CH2)n-OH, (CH2CH2O)m-(CH2)n-OR', (CH2CH2O)m-(CH2)n-R NR'r", (CH2CH2O)m-(CH2)n-NR'r COR", (CH2CH2O)m-(CH2)n-NR'r SO2R", (CH2CH2O)m-(CH2)n-COOH, (CH2CH2O)m-(CH2)n-COOR', (CH2CH2O)m-(CH2)n-CONR'R", (CH2CH2O)m-(CH2)n-SO2R', (CH2CH2O)m-(CH2)n-COR', (CH2CH2O)m-(CH2)n-SONR'R", (CH2CH2O)m-(CH2)n-SO2NR'r R", (CH2)p-(CH2CH2O)m-(CH2)n-R', (CH2)p-(CH2CH2O)m-(CH2)n-OH, (CH2)p-(CH2CH2O)m-(CH2)n-OR', (CH2)p-(CH2CH2O)m-(CH2)n-R NR'r", (CH2)p-(CH2 2O)m-(CH2)n-NR'r COR", (CH2)p-(CH2CH2O)m-(CH2)n-NR'r SO2R", (CH2)p-(CH2CH2O)m-(CH2)n-COOH, (CH2)p-(CH2CH2O)m-(CH2)n-COOR', (CH2)p-(CH2CH2O)m-(CH2)n-CONR'R", (CH2)p-(CH2CH2O)m-(CH2)n-SO2R', (CH2)p-(CH2CH2O)m-(CH2)n-COR', (CH2)p-(CH2CH2O)m-(CH2)n-SONR'R", (CH2)p-(CH2CH2O)m-(CH2)n-SO2NR'r R',- COR', -SOR' and SO2R',
where R' and R" are independently selected from the group comprising H, substituted or unsubstituted ness. alkyl, substituted or unsubstituted ness. cycloalkyl, substituted or unsubstituted ness. cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted a heterocycle;
or R' and R" can independently communicate with the formation of a cyclic structure selected from the group comprising substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted a heterocycle;
m, n and p is independently equal to 0 to 6;
where "aryl" means a 6-10-membered aromatic ring system which he;
"heteroaryl" means a 5-10 membered aromatic mono - or bicyclic aromatic hydrocarbon, in which from 1 to 3 carbon atoms replaced by a heteroatom selected from a nitrogen atom, oxygen or sulfur;
"heterocycle" means a 5-to 10-membered mono - or bicyclic non-aromatic hydrocarbon, in which from 1 to 3 carbon atoms replaced by a heteroatom selected from a nitrogen atom, oxygen or sulfur;
and where this is specified, different groups can contain 1-3 substituent, independently selected from the group comprising halogen, NISS. alkoxygroup, NISS. alkyl, hydroxycarbonyl, carboxypropyl, carboxy-ness. alkoxygroup, oxoprop and CN;
and its pharmaceutically acceptable salts.

2. The compound according to claim 1 of the formula

in which
X is selected from the group comprising H, F, Cl, Br, I;
Y represents from 1 to 4 groups independently selected from the group comprising H, F, Cl, Br, I, ness. alkyl and NISS. alkoxygroup;
R1selected from the group comprising ness. alkyl, substituted ness. alkyl, NISS. alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and substituted cycloalkyl;
R2denotes hydrogen or nits. alkyl;
R3denotes H or nits. alkyl;
R5selected from the group comprising ness. alkyl, substituted ness. alkyl, aryl, substituted aryl, heteroaryl and substituted heteros is aryl;
R4denotes hydrogen;
R6and R7selected from the group comprising (CH2)n-R', (CH2)n-R NR'r", (CH2)n-NR'r COR", (CH2)n-NR'r SO2R", (CH2)n-COOH, (CH2)n-COOR', (CH2)n-CONR'R", (CH2)n-OR', (CH2)n-SR', (CH2)n-SOR', (CH2)n-SO2R', (CH2)n-COR', (CH2)n-SO3H, (CH2)n-SONR'R", (CH2)n-SO2NR'r R", (CH2CH2O)m-(CH2)n-R', (CH2CH2O)m-(CH2)n-OH, (CH2CH2O)m-(CH2)n-OR', (CH2CH2O)m-(CH2)n-R NR'r", (CH2CH2O)m-(CH2)n-NR'r COR", (CH2CH2O)m-(CH2)n-NR'r SO2R", (CH2CH2O)m-(CH2)n-COOH, (CH2CH2O)m-(CH2)n-COOR', (CH2CH2O)m-(CH2)n-CONR'R", (CH2CH2O)m-(CH2)n-SO2R', (CH2CH2O)m-(CH2)n-COR', (CH2CH2O)m-(CH2)n-SONR'R", (CH2CH2O)m-(CH2)n-SO2NR'r R", (CH2)p-(CH2CH2O)m-(CH2)n-R', (CH2)p-(CH2CH2O)m-(CH2)n-OH, (CH2)p-(CH2CH2O)m-(CH2)n-OR', (CH )p-(CH2CH2O)m-(CH2)n-R NR'r", (CH2)p-(CH2CH2O)m-(CH2)n-NR'r COR", (CH2)p-(CH2CH2O)m-(CH2)n-NR'r SO2R", (CH2)p-(CH2CH2O)m-(CH2)n-COOH, (CH2)p-(CH2CH2O)m-(CH2)n-COOR', (CH2)p-(CH2CH2O)m-(CH2)n-CONR'R", (CH2)p-(CH2CH2O)m-(CH2)n-SO2R', (CH2)p-(CH2CH2O)m-(CH2)n-COR', (CH2)p-(CH2CH2O)m-(CH2)n-SONR'R", (CH2)p-(CH2CH2O)m-(CH2)n-SO2NR'r R',- COR', -SOR' and SO2R',
where R' and R" are independently selected from the group comprising H or substituted or unsubstituted ness. alkyl, substituted or unsubstituted ness. cycloalkyl, substituted or unsubstituted ness. cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted a heterocycle;
or R' and R" can independently communicate with the formation of a cyclic structure selected from the group comprising substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted a heterocycle;
, n and p independently is from 0 to 6; and
its pharmaceutically acceptable salt.

3. The compound according to claim 2, in which
X denotes F, Cl or Br;
Y represents from 1 to 2 groups independently selected from the group comprising H, F, Cl, Br, I, ness. alkyl and NISS. alkoxygroup;
R1selected from the group comprising ness. alkyl, substituted ness. alkyl, NISS. alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and substituted cycloalkyl;
R2denotes hydrogen;
R3denotes H;
R5selected from the group comprising aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R4denotes hydrogen;
R6and R7selected from the group comprising (CH2)n-R', (CH2)n-R NR'r", (CH2)n-NR'r COR", (CH2)n-NR'r SO2R", (CH2)n-COOH, (CH2)n-COOR', (CH2)n-CONR'R", (CH2)n-OR', (CH2)n-SR', (CH2)n-SOR', (CH2)n-SO2R', (CH2)n-COR', (CH2)n-SO3H, (CH2)n-SONR'R", (CH2)n-SO2NR'r R", (CH2CH2O)m-(CH2)n-R', (CH2CH2O)m-(CH2)n-OH, (CH2CH2O)m-(CH2)n-OR', (CH2CH2O)m-(CH2)n-R NR'r", (CH2CH2O)m-(CH2)n-NR'r COR", (CH2CH2O)m-(CH2 )n-NR'r SO2R", (CH2CH2O)m-(CH2)n-COOH, (CH2CH2O)m-(CH2)n-COOR', (CH2CH2O)m-(CH2)n-CONR'R", (CH2CH2O)m-(CH2)n-SO2R', (CH2CH2O)m-(CH2)n-COR', (CH2CH2O)m-(CH2)n-SONR'R", (CH2CH2O)m-(CH2)n-SO2NR'r R", (CH2)p-(CH2CH2O)m-(CH2)n-R', (CH2)p-(CH2CH2O)m-(CH2)n-OH, (CH2)p-(CH2CH2O)m-(CH2)n-OR', (CH2)p-(CH2CH2O)m-(CH2)n-R NR'r", (CH2)p-(CH2CH2O)m-(CH2)n-NR'r COR", (CH2)p-(CH2CH2O)m-(CH2)n-NR'r SO2R", (CH2)p-(CH2CH2O)m-(CH2)n-COOH, (CH2)p-(CH2CH2O)m-(CH2)n-COOR', (CH2)p-(CH2CH2O)m-(CH2)n-CONR'R", (CH2)p-(CH2CH2O)m-(CH2)n-SO2R', (CH2)p-(CH2CH2O)m-(CH2)n-COR', (CH2)p-(CH2CH2O)m-(CH2)n-SONR'R", (CH2)p-(CH2CH2O)m-(CH2)n-SO2NR'r R',- COR', -SOR' and SO2R';
where R and R" are independently selected from the group including H or substituted or unsubstituted ness. alkyl, substituted or unsubstituted ness. cycloalkyl, substituted or unsubstituted ness. cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted a heterocycle;
or R' and R" can independently communicate with the formation of a cyclic structure selected from the group comprising substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted a heterocycle;
m, n and p is independently equal to 0 to 6; and
its pharmaceutically acceptable salt.

4. The compound according to claim 2, in which
X denotes F, Cl or Br;
Y represents monosubstituted group selected from H or F; and
R1selected from the group comprising ness. alkyl, substituted ness. alkyl, NISS. alkenyl, cycloalkyl and substituted cycloalkyl.

5. The compound according to claim 2, in which
R1denotes a substituted ness. the alkyl of the formula

where R8, R9both represent methyl;
R10means (CH2)m-R11;
m is 0, 1 or 2,
R11selected from the group comprising hydrogen, NISS. alkyl, NISS. alkoxygroup;
R2denotes H;
R3denotes H;
R5denotes a substituted phenyl selected from the group, Lucaya
or;
W denotes F, Cl or Br;
V denotes H or F;
R4denotes hydrogen;
one of R6and R7denotes hydrogen and the other represents (CH2)n-R';
n is 0 or 1; and
R' is selected from the group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle.

6. The compound according to claim 1, selected from the group including
rat-(2-morpholine-4-retil)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
(2-morpholine-4-retil)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-dimethylamide (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2S,3R,4R,5R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2,2-dimethylpropyl)-5-[4-(2-morpholine-4-yl-2-oxoethyl)-piperazine-1-carbonyl]-pyrrolidin-3-carbonitril,
rat-(2S,3R,4R,5R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2,2-dimethylpropyl)-5-[4-(2-oxo-2-pyrrolidin-1-retil)-piperazine-1-to rbony]-pyrrolidin-3-carbonitril,
rat-(2S,3R,4R,5R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2,2-dimethylpropyl)-5-[4-(2-hydroxyethyl)-piperazine-1-carbonyl]-pyrrolidin-3-carbonitril,
rat-(4-hydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid, and
rat-(2-pyrrolidin-1-retil)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

7. The compound according to claim 1, selected from the group including
rat-(2-piperazine-1-retil)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
methyl ester of (S)-2-{[(2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-3-methylmalonic acid,
(S)-2-{[(2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-3-methylmalonyl acid,
rat-(1-hydroxymethylpropane)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(1-hydroxymethylbutyrate)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(3,3-dimethylbutyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-carboxylic acid,
rat-(2,2-dimethylpropyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-the feast of ridin-2-carboxylic acid,
(2S,3R,4R,5R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2,2-dimethylpropyl)-5-((S)-2-hydroxyethylpyrrolidine-1-carbonyl)pyrrolidin-3-carbonitril, and
rat-2-(3,4-acid)ethylamide (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

8. The compound according to claim 1, selected from the group including
((R)-1-hydroxymethyl-3-methylbutyl)-amide (2S,3S,4S,5R)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(3-hydroxypropyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[2-(CIS-2,6-dimethylmorpholine-4-yl)-ethyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2-cyclopropylethyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-tert-butyl ester (3-{[(2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamino acid,
rat-(3-aminopropyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[3-(1-acetylpiperidine-4-ylamino)-propyl]-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(3-hydroxypropyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorphen is)-4-cyano-5-isobutylpyrazine-2-carboxylic acid,
rat-(3-hydroxypropyl)-amide and (2R,3R,4R,5R)-5-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-3-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-(3-hydroxypropyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-2-methylpyrrolidine-2-carboxylic acid.

9. The compound according to claim 1, selected from the group including
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-cyclopentylmethyl-2-carboxylic acid,
rat-(2-hydroxy-1,1-dimethylethyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(3-hydroxy-2,2-dimethylpropyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[2-(2-hydroxyethoxy)-ethyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2-acetylamino)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(3-imidazol-1-ylpropyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((R)-4-hydroxy-3-methylbutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-cyclopropylmethoxy (2R,3S,4R,5S)-3-(3-chloro-2-perfe who yl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[2-((S)-2,2-dimethyl-[1,3]dioxolane-4-yl)-ethyl]-amide and (2R,3R,4R,5S) - for 3,5-bis-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyanopyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S) - for 3,5-bis-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyanopyrrolidine-2-carboxylic acid and
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(1-ethylpropyl)-pyrrolidin-2-carboxylic acid.

10. The compound according to claim 1, selected from the group including
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-isobutylpyrazine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5R)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-isobutylpyrazine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5R)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(1-ethylpropyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5,5-diarylpyrimidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-isopropylpyridine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)s is (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-cyclohexylpiperidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-5-tert-butyl-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyanopyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

11. The compound according to claim 1, selected from the group including
rat-((S)-3,4-dihydroxybutyl)-amide (2S,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-4-(4-bromophenyl)-3-(3-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-4-(4-forfinal)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-cyano-4-(2,4-dichlorophenyl)-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-cyano-4-(2,4-dichlorophenyl)-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-were)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide (2,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-cyclohexylpiperidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide (2S,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-cyclohexylpiperidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-4-(4-chloro-2-forfinal)-4-cyano-3-(2,3-differenl)-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-4-(4-chloro-2-forfinal)-4-cyano-3-(2,3-differenl)-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-bromo-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-bromo-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

12. The compound according to claim 1, selected from the group including
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-4-(4-chloro-2-forfinal)-3-(3-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-4-(4-chloro-2-forfinal)-3-(3-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-3-(3-forfinal)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-bromophenyl)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide (2S,3R,4R,5S)-3-(3-what Ravenel)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-4-(4-chloro-2-forfinal)-4-cyano-3-(3,4-dichlorophenyl)-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chloro-4-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chloro-4-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(4-bromothiophene-2-yl)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((R)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chloro-4-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((R)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2,3-trimethylbutane)-pyrrolidin-2-carboxylic acid,
((R)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chloro-4-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((R)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((R)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((R)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-4-(4-chloro-2-forfinal)-3-(3-chlorphen is)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((R)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-((R)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

13. The compound according to claim 1, selected from the group including
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2,3-trimethylbutane)-pyrrolidin-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2,3-trimethylbutane)-pyrrolidin-2-carboxylic acid,
rat-((R)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2,3-trimethylbutane)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylbutyl-3-enyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylbutyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2-methyl-2-phenylpropyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-4-(4-chloro-2-forfinal)-3-(5-chloro-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(inolin-3-ylmethyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-4-hydroxybenzamide (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2-ethylbutyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-3-(3-chloro-5-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-4-(4-chloro-2-forfinal)-3-[5-chloro-2-(2-hydroxyethoxy)-phenyl]-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-tert-butyl ester 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-carboxylic acid,
salt piperidine-4-ylamide rat-(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid with triperoxonane acid,
rat-(1-methanesulfonamido-4-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(1-methylcarbonate-4-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(1-benzoylpiperidine-4-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-isopr pyramid 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-carboxylic acid.

14. The compound according to claim 1, selected from the group including
rat-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-yl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
chiral [1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-yl]-amide 2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
chiral [1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-yl]-amide (2S,3R,4S,5R)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-{1-[2-methyl-2-((R)-1-oxiranylmethyl)-propyl]-1H-pyrazole-3-yl}-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-{1-[2-((R)-3-amino-2-hydroxypropoxy)-2-methylpropyl]-1H-pyrazole-3-yl}-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(1-{2-[(R)-2-hydroxy-3-(3-hydroxypropylamino)-propoxy]-2-methylpropyl}-1H-pyrazole-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(1-{2-[(R)-2-hydroxy-3-(2-hydroxy-1-hydroxymethylamino)-propoxy]-2-methylpropyl}-1H-pyrazole-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-{-[2-methyl-2-((S)-1-oxiranylmethyl)-propyl]-1H-pyrazole-3-yl}-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-{1-[2-((S)-3-amino-2-hydroxypropoxy)-2-methylpropyl]-1H-pyrazole-3-yl}-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-{1-[2-((S)-2,3-dihydroxypropane)-2-methylpropyl]-1H-pyrazole-3-yl}-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-{1-[2-((5)-3-dimethylamino-2-hydroxypropoxy)-2-methylpropyl]-1H-pyrazole-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

15. The compound according to claim 1, selected from the group including
rat-{(5)-3-[2-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-pyrazole-1-yl)-1,1-dimethylmethoxy]-2-hydroxypropylamino}-acetic acid,
rat-{1-[2-((S)-2-hydroxy-3-methylaminopropane)-2-methylpropyl]-1H-pyrazole-3-yl}-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-carboxylic acid,
rat-{1-[2-((R)-3-dimethylamino-2-hydroxypropoxy)-2-methylpropyl]-1H-pyrazole-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[1-((R)-2,3-dihydroxypropyl)-1H-pyrazole-3-yl]-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[1-(2-what hydroxyethyl)-1H-pyrazole-3-yl]-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-2,3-dihydroxypropyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-2,3-dihydroxypropyl)-amide (2S,3S,4S,5R)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[1-((R)-2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-1H-pyrazole-3-yl]-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-2-triptoreline (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-4-(2-oxopyrrolidin-1-yl)-benzylamine (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-(tetrahydropyran-4-ylmethyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

16. The compound according to claim 1, selected from the group including
rat-(3-hydroxy-2-hydroxymethylpropane)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[2-(2-aminoethoxy)-ethyl]-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(3-methanesulphonyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2-methanesulfonyl)-amide and (2R,3R,4R,5S)-3-(3-chlorp the Nile)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-tert-butyl ester 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-cyclohexylamino-1-carboxylic acid,
rat-salt 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-TRANS-cyclohexylamine with triperoxonane acid,
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-TRANS-cyclohexyl-N-methanesulfonamide,
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-TRANS-cyclohexyl-M-methanesulfonamide,
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-TRANS-cyclohexyl-(1,1-dioxo)-2-isothiazolin,
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-TRANS-cyclohexylamine and
rat-N-[1-(2-hydroxyethyl)-piperidine-4-yl]amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

17. The compound according to claim 1, selected from the group including
rat-amid-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-sulfonic acid,
rat-3-{4-[(2R,3S,4R,5S)-3-(3-chloro-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperazine-1-yl}-acetic acid,
rat-3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperazine-1-yl}-N,N-bis-(2-methoxyethyl)-ndimethylacetamide,
rat-3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperazine-1-yl}-N,N-bis-(2-hydroxyethyl)-acetamide", she
rat-3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperazine-1-yl}-N-(3-methoxypropyl)-ndimethylacetamide,
rat-2-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperazine-1-yl}-acetamide", she
rat-(2S,3R,4S,5R)-4-(3-chloro-2-forfinal)-3-(4-chloro-2-forfinal)-2-(2,2-dimethylpropyl)-5-[4-(2-morpholine-4-yl-2-oxoethyl)-piperazine-1-carbonyl]-pyrrolidin-3-carbonitril,
rat-2-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperazine-1-yl}-N-[2-((S)-2,2-dimethyl-[1,3]dioxolane-4-yl)-ethyl]-acetamide", she
rat-2-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro
2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperazine-1-yl}-N-((S)-3,4-dihydroxybutyl)-ndimethylacetamide,
rat-methyl ether {1-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperidine-4-yl}-acetic acid and
rat-hydrochloride{1-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidin--carbonyl]-piperidine-4-yl}-acetic acid.

18. The compound according to claim 1, selected from the group including
rat-2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperidine-4-yl}-acetamide", she
rat-2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperidine-4-yl}-N,N-bis-(2-hydroxyethyl)-acetamide", she
rat-2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperidine-4-yl}-N-(2-hydroxyethyl)-N-methylacetamide,
rat-2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-piperidine-4-yl}-N-(2-hydroxypropyl)-acetamide", she
rat-tert-butyl ester {[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-acetic acid,
rat-Sol {[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-acetic acid with triperoxonane acid,
rat-carbamoylmethyl (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
Sol {[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-acetic acid with triperoxonane acid,
rat-ethyl ester 3-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-qi is but-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
rat-(3-carbamoylphenoxy)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-tert-butyl ester 3-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.

19. The compound according to claim 1, selected from the group including
rat-3-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
rat-(3-hydroxymethylene)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-tert-butyl ester (3-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamino acid,
rat-(3-aminopropyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[3-(aminosulfonyl)-propyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-tert-butyl ester 2-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
rat-tert-butyl ester 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-Pierre is lidin-2-carbonyl]-amino}-benzoic acid,
rat-ethyl ester 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
rat-(2-carbamoylethyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(4-carbamoylphenoxy)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-ethyl ester 2-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.

20. The compound according to claim 1, selected from the group including
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
rat-2-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
rat-(3-cyanophenyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2-hydroxy-2-methylpropyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-2-hydroxy-2-methylpropionic ester 3-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,br/> rat-(3-methanesulfonylaminoethyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(1H-tetrazol-5-ylmethyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(3-ureidopropionic)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(3-methylsulfinylphenyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(3-methanesulphonyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-(3-methanesulfonyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

21. The compound according to claim 1, selected from the group including
3-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
(3-carbamoylphenoxy)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[3-(1H-tetrazol-5-yl)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[4-(1H-tet the azole-5-yl)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(4-AMINOPHENYL)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(4-acetylaminophenol)-amide and (2R,35,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-ethyl ester 2-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-thiazole-4-carboxylic acid,
rat-(1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(6-oxo-1,6-dihydropyridines-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
(6-oxo-1,6-dihydropyridines-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-(4-methylsulfinylphenyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

22. The compound according to claim 1, selected from the group including
rat-(4-methanesulphonyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
tert-butyl ether 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidin-carbonyl]-amino}-benzoic acid,
4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
4-{[(2S,3R,4S,5R)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
(4-carbamoylphenoxy)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
(4-carbamoylphenoxy)-amide (2S,3R,4S,5R)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(4-methanesulfonylaminoethyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(4-triftormetilfullerenov)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide and (2R,3R,4R,5S)-4-(4-chloro-2-forfinal)-3-(3-chloro-2-were)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[3-(2-methyl-1H-tetrazol-5-yl)-phenyl]-amide and (2R,3R,4R,5S)-4-(4-chloro-2-forfinal)-3-(3-chloro-2-were)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
(6-oxo-1,6-dihydropyridines-3-yl)-amide (2S,3R,4S,5R)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

23. The compound according to claim 1, selected from the group include the her
[4-(1H-tetrazol-5-yl)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
[4-(1H-tetrazol-5-yl)-phenyl]-amide (2S,3R,4S,5R)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[4-(2-methyl-1H-tetrazol-5-yl)-phenyl]-amide and (2R,3R,4R,5S)-4-(4-chloro-2-forfinal)-3-(3-chloro-2-were)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[4-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide and (2R,3R,4R,5S)-4-(4-chloro-2-forfinal)-3-(3-chloro-2-were)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-ethyl ester 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-2-fermenting acid,
[3-(1H-tetrazol-5-yl)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
[3-(1H-tetrazol-5-yl)-phenyl]-amide (2S,3R,4S,5R)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
(4-carbarnoyl-3-chlorophenyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[3-chloro-4-(1H-tetrazol-5-yl)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(4-forfinal)-amide (R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-(3-forfinal)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

24. The compound according to claim 1, selected from the group including
rat-(3-chlorophenyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(4-chlorophenyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-tert-butyl ester 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-2-fermenting acid,
rat-(4-ethylcarbazole-3-forfinal)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-2-fermenting acid,
rat-(6-methoxypyridine-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-methyl ether 3-({[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid,
rat-methyl ester 4-({[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzo who Inoi acid,
rat-(4-chlorophenyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
(4-chlorophenyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
(4-chlorophenyl)-amide (2S,3R,4S,5R)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

25. The compound according to claim 1, selected from the group including
rat-methyl ester 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-2-methoxybenzoic acid,
rat-3-({[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid,
rat-4-({[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid,
(4-acetylaminophenol)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
(4-acetylaminophenol)-amide (2S,3R,4S,5R)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
(4-methanesulphonyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
(4-methanesulphonyl)-amide (2S,3R,4S,5R)-3-(-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-2-methoxybenzoic acid,
rat-methyl ester 5-bromo-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-2-methoxybenzoic acid,
rat-methyl ester 4- {[(2R,3 8,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-2-methylbenzoic acid and
rat-methyl ester 2-chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.

26. The compound according to claim 1, selected from the group including
rat-methyl ester 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-2-triftorperasin acid,
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-2-methylbenzoic acid,
rat-2-chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
rat-[4-(2H-[1,2,4]triazole-3-yl)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[4-(5-oxo-2,5-dihydro-1H-[1,2,4]triazole-3-yl)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-fluoro who enyl)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(5-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,35,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2-cyclopropyl-2-methylpropyl)-pyrrolidin-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2-cyclopropyl-2-methylpropyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-3-were)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(tetrahydropyran-4-ylmethyl)-pyrrolidin-2-carboxylic acid and
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-methylcyclohexyl)-pyrrolidin-2-carboxylic acid.

27. The compound of formula 1 selected from the group including
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-methylcyclohexyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methylpropyl)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyanopyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-perfe who yl)-4-cyano-5-(2-methoxycarbonyl-2-methylpropyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-hydroxy-2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-hydroxy-2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-diethylbutyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2-ethyl-2-methylbutyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-4-(4-chloro-2,6-differenl)-3-(3-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3R,4R,5S)-4-(4-chloro-2,5-differenl)-3-(3-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-methoxy-2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid, and
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-methoxy-2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

28. The compound according to claim 1, selected from the group including
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2-ethyl-2-hydroxymethyl who util)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-methyloxiran-3-ylmethyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-atiaxiety-3-ylmethyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-hydroxymethylpropane)-pyrrolidin-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-hydroxymethylpropane)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-hydroxymethylbutyrate)-pyrrolidin-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-hydroxymethylbutyrate)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(4-hydroxy-2,2-dimethylbutyl)-pyrrolidin-2-carboxylic acid,
((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(4-hydroxy-2,2-dimethylbutyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-hydroxymethylene the CEN-3-animetal)-pyrrolidin-2-carboxylic acid and
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-hydroxymethylglycinate)-pyrrolidin-2-carboxylic acid.

29. The compound according to claim 1, selected from the group including
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-[4-(2-hydroxyethoxy)-2,2-dimethylbutyl]-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-5-(4-azido-2,2-dimethylbutyl)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyanopyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-5-(4-amino-2,2-dimethylbutyl)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyanopyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethylbutyl)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyanopyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(4-methanesulfonamido-2,2-dimethylbutyl)-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-5-(4-benzoylamine 2,2-dimethylbutyl)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyanopyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-[2-methyl-2-(5-methylfuran-2-yl)-propyl]-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)and the ID (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-[3-(4-methoxyphenyl)-2,2-dimethylpropyl]-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydropyridine-4-yl)-2-methylpropyl]-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyanopyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-5-[2-(1-benzylpiperidine-4-yl)-2-methylpropyl]-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyanopyrrolidine-2-carboxylic acid and
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-[2-(3,b-dihydro-2H-Piran-4-yl)-2-methylpropyl]-pyrrolidin-2-carboxylic acid.

30. The compound according to claim 1, selected from the group including
rat-((S)-3,4-dihydroxybutyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-[2-methyl-2-(tetrahydropyran-4-yl)-propyl]-pyrrolidin-2-carboxylic acid,
rat-((S)-3,4-dihydroxy-4-methylpentyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-hydroxy-2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((S)-3,4-dihydroxy-4-methylpentyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-4)terphenyl)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-hydroxy-2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-((S)-3,4-dihydroxy-4-methylpentyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
((S)-3,4-dihydroxy-4-methylpentyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid is you,
rat-((S)-3,4-dihydroxy-4-methylpentyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-methylcyclohexyl)-pyrrolidin-2-carboxylic acid,
((S)-3,4-dihydroxy-4-methylpentyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-methylcyclohexyl)-pyrrolidin-2-carboxylic acid,
rat-(2S,3R,4S,5P)-4-(3-chloro-2-forfinal)-3-(4-chloro-2-forfinal)-2-(2,2-dimethylpropyl)-5-(3-hydroxyazetidine-1-carbonyl)-pyrrolidin-3-carbonitril,
rat-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-yl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-hydroxy-2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
[1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-yl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(3-hydroxy-2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

31. The compound according to claim 1, selected from the group including
rat-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-yl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(4-hydroxy-2,2-dimethylbutyl)-pyrrolidin-2-carboxylic acid,
[1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-yl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(4-hydroxy-2,2-dimethylbutyl)-pyrrolidin-2-carboxylic acid,
rat-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-methyl ether 6-{[(2R,3S,4R,5S)-3-3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid,
rat-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-N-(2-hydroxy-1,1-dimethylethyl)-nicotinamide,
rat-(6-acetylpiperidine-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[5-((S)-1,2-dihydroxyethyl)-pyrazin-2-yl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(4-hydroxy-2,2-dimethylbutyl)-pyrrolidin-2-carboxylic acid and
rat-methyl ester 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid.

32. The compound according to claim 1, selected from the group including
rat-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid,
rat-amide 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-terphenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid,
rat-(6-chloropyridin-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2-methylpyridin-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[4-(2-hydroxyethoxy)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
[4-(2-hydroxyethoxy)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-methyl ester 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid,
rat-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid,
5-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid,
rat-(2-methoxypyridine-4-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-(2-hydroxypyridine-4-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

33. The compound according to claim 1, selected from the group including
rat-(4-acetylphenyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[4-(2-bromoacetyl)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-[4-(2-dimethylaminoacetyl)-phenyl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(5-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-4H-[1,2,4]triazole-3-yl)-acetic acid,
rat-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-pyrazole-1-yl)-acetic acid,
rat-(1H-imidazol-4-ylmethyl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2R,3S,4R,5S)-4-(3-chloro-2-forfinal)-3-(4-chloro-2-forfinal)-2-(2,2-dimethylpropyl)-5-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-pyrrolidin-3-carbonitril,
rat-1-[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-azetidin-3-carboxylic acid
rat-(2-[1,2,3]triazole-1-retil)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(1-carbamoylmethyl-1H-pyrazole-3-yl)-amide and (2R,3S,4R,5S)-3-(chlor-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid and
rat-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-yl]-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid.

34. The compound according to claim 1, selected from the group including
rat-(3-methanesulfonylaminoethyl)-amide and (2R,3R,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
chiral {1-[2-((S)-3-dimethylamino-2-hydroxypropoxy)-2-methylpropyl]-1H-pyrazole-3-yl}-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
chiral {1-[2-((S)-3-dimethylamino-2-hydroxypropoxy)-2-methylpropyl]-1H-pyrazole-3-yl}-amide (2S,3R,4S,5R)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-1-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-cyclopropanecarbonyl acid,
rat-[1-(4-hydroxypiperidine-4-ylmethyl)-1H-pyrazole-3-yl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2-acetylthio-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-(2-carbamoylation-3-yl)-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
the AC-[1-((S)-3-dimethylamino-2-hydroxypropyl)-1H-pyrazole-3-yl]-amide and (2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid,
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-methylcyclohexyl)-pyrrolidin-2-carbonyl]-amino}-benzoic acid and
rat-[4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-pyrazole-1-ylmethyl)-4-hydroxypiperidine-1-yl]-acetic acid.

35. The compound according to claim 1, selected from the group including
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-methylcyclohexyl)-pyrrolidin-2-carbonyl]-amino}-benzoic acid,
rat-methyl ester 4-{[(2R,3S,4R,5S)-3-(5-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
rat-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid,
rat-methyl ester 4-{[(2R,3R,4R,5S)-3-(3-chloro-4-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-carbonyl]amino}-benzoic acid,
rat-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-carbonyl]amino}benzoic acid,
rat-methyl ester 4-{[(2R,3R,4R,5S)-3-(3-bromophenyl)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-carbonyl]amino}-benzoic acid,
rat-4-{[(2R,3R,4R,5S)-3-(3-bromophenyl)-4-(4-chloro-2-forfinal)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-carbonyl]amino}benzoic acid is,
rat-methyl ester 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-carbonyl]amino}-benzoic acid,
rat-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chlorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carbonyl]amino}benzoic acid and
rat-methyl ester 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-forfinal)-4-(4-chloro-2-forfinal)-4-cyano-5-(1-methylcyclohexylamine)pyrrolidin-2-carbonyl]-amino}benzoic acid.

36. The pharmaceutical composition inhibiting the interaction of MDM2-p53 containing compound according to claims 1 to 35, together with pharmaceutically acceptable inert excipients or carriers.

37. The compound according to any one of claims 1 to 35, intended for use as a drug for the treatment of cell proliferative disorders.

38. The compound according to any one of claims 1 to 35 for use as a medicinal product intended for the treatment of cancer, preferably solid tumors, more preferably tumors of the breast, colon, lung and prostate.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel acyl thiourea derivatives of formula or a pharmaceutically acceptable salt thereo, where R1 is a hydrogen atom or a C1-3 alkyl group; R2 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C6-14 aromatic hydrocarbon group or an optionally substituted saturated or unsaturated 5-7-member heterocyclic group containing 1 or 2 nitrogen or sulphur atoms, or R1 and R2, together with the nitrogen atom which they are bonded, can form an optionally substituted nitrogen-containing saturated heterocyclic group selected from a group comprising pyrrolinyl, piperidinyl, piperazinyl or morpholino group; where the substitute is selected from a group comprising a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkanoyl group, a C1-6 alkyl group, a C3-10 cycloalkyl group, a C2-6 alkenyl group, C1-6 alkoxy group, an amino group, a C1-6 alkylamino group, a C1-6 alkanoylamino group, a C1-6 alkylaminocarbonyl group, a C1-6 alkylsulphonyl group, a C6-14 aromatic group, a saturated or unsaturated 5-7-member heterocyclic group containing 1-4 nitrogen and/or oxygen atoms, a saturated or unsaturated 5-7-member heterocycyl-carbonyl group containing 1 or 2 nitrogen and/or oxygen atoms, and an oxo group; R3 is a C1-6 alkyl group; and R4 is a halogen atom; R5 and R6, which can be identical or different from each other, denote a hydrogen atom, a halogen atom, a C1-3 alkyl group which can be substituted with a halogen atom, or a C1-6 alkoxy group. The invention also relates to a pharmaceutical or anti-tumour agent based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel acetyl thiourea derivatives having c-Met inhibiting activity are obtained.

11 cl, 2 dwg, 4 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to sulphonamide compounds of formula or pharmaceutically acceptable salts thereof, wherein A is phenyl, optionally substituted with 1 or 2 halogen atoms, C1-6 alkyl group, trifluoromethyl group, C1-6 alkoxy group or -SCH3 group, thiophenyl, optionally substituted with a C1-C6 alkyl group or a halogen atom, pyridinyl, optionally substituted with a halogen atom, naphthalenyl or dihydroindenyl; R1 denotes the following formulae or [in formulae (R1a) and (R1b) Ar1 denotes the following formulae , or (each R5 and R6 independently denotes a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted with up to three halogen atoms, C1-6 lower alkoxy group optionally substituted with up to three halogen atoms); Ar2 denotes the following formulae , or (each R7 and R8 independently denotes a hydrogen atom, a hydroxyl group, a halogen atom, a C1-6 alkyl group optionally substituted with up to three halogen atoms or a C1-6 lower alkoxy group optionally substituted with up to three halogen atoms, an amine group, a nitro group, a C2-6 acyl group, or R7 and R8 together form -CH2CH2O-; R9 is a hydrogen atom or - J-COOR10; J is a covalent bond, alkylene containing 1 to 5 carbon atoms, alkenylene containing 2 to 5 carbon atoms or alkynylene containing 2 to 5 carbon atoms, where one carbon atom in said alkylene groups can be substituted with an oxygen atom, a sulphur atom, NR11, CONR11 or NR11CO in any chemically acceptable position; R11 is a hydrogen atom; and R10 is a hydrogen atom); and p equals 0 or 1]; R2 is a C1-6 alkyl group; each R3 and R4 is independently a C1-6 alkyl group; * denotes an asymmetric carbon atom; and m equals an integer from 1 to 3. The invention also relates to a medicinal agent for stimulating PTH secretion.

EFFECT: obtaining novel compounds which can be used in medicine to prevent or treat primary or secondary osteoporosis.

29 cl, 15 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-R- amides of (Z)-2-[(3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thien-2-yl)amino]-4-phenyl-4-oxobut-2-enoic acids (1-4) of general formula:

.

Acid amides (1-4) are obtained by reacting ethyl ether of 2-[(2-oxo-5-phenyl-(2H)-furanylidene)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid with R-amines in a medium of pure toluene at 25-110°C, followed by separation of the end product using known techniques.

EFFECT: obtaining novel compounds with high output, having marked analgesic activity and low toxicity.

2 tbl, 5 ex

FIELD: chemistry.

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

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

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1) or salts thereof, where in formula (1) R1 is a lower C1-C6alkyl group, a lower C3-C6cycloalkyl group, a phenyl group, a heterocyclic group, which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom and a sulphur atom, or a phenyl(C1-C6alkyl) group; in cases when R1 is a lower C1-C6alkyl group, that lower C1-C6alkyl group can have, as substitute(s), one, two or three groups selected from a halogen atom, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one or two heteroatoms in the ring, selected from a nitrogen atom and an oxygen atom, a carboxyl group, a lower C1-C6alkoxycarbonyl group, a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a phenyl group; in cases when R1 is a phenyl group, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom or a sulphur atom, or a phenyl(C1-C6alkyl) group, that phenyl, heterocyclic or phenyl(C1-C6alkyl) group can contain, as substitute(s), one, two or three groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group or a lower C1-C6alkoxy group; R2 is a hydrogen atom or a lower C1-C6alkyl group; R3 is a hydrogen atom or a lower C1-C6alkyl group; R4 and R5 can be identical or different and are a hydrogen atom or a lower C1-C6alkyl group; R6 is a hydrogen atom or a lower C1-C6alkyl group; R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom; in cases where R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom, that phenyl or heterocyclic group can contain, as substitute(s), one or two groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group, a lower C1-C6alkoxy group and a nitro group; W is an oxygen atom or NR8; R8 is a hydrogen atom or a lower C1-C6alkyl group; X is an oxygen atom or a sulphur atom; Y is a lower C1-C6alkylene group; Z is an oxygen atom, a sulphur atom, NR9 or OCO; R9 is a hydrogen atom or a lower C1-C6alkyl group. The invention also relates to a pharmaceutical composition based on said compounds, having GR binding activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as glucocorticoid receptor modulators.

10 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new uracil derivatives possessing human dUTPase inhibitory activity. In formula (I) n is equal to an integer 1 to 3; X member a bond, an oxygen atom, a sulphur atom, an alkenyl group containing 2 to 6 carbon atoms, a bivalent aromatic hydrocarbon group containing 6 to 14 carbon atoms, or a bivalent 5-7-merous saturated or unsaturated heterocyclic group containing 1 nitrogen or sulphur atom; Y means a bond or a linear or branched alkylene group containing 1 to 8 carbon atoms optionally having a cycloalkylydene structure containing 3 to 6 carbon atoms on one carbon atom; and Z means -SO2NR1R2 or -NR3SO2-R4, wherein R4 means an aromatic hydrocarbon group containing 6 to 14 carbon atoms which is optionally substituted by 1-2 substitutes, or an unsaturated 5-7-member heterocyclic group containing 1 nitrogen or sulphur atom which is optionally substituted by 1-2 halogen atoms; the radical values R1, R2 and the substitutes of the group R4 are presented in the patent claim.

EFFECT: invention relates to a pharmaceutical compositions comprising said compounds, to a human dUTPase inhibitor and a method of treating a human dUTPase-associated disease.

10 cl, 85 tbl, 179 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel of 2,4-pyrimidine diamine compounds of formula I, which inhibit degranulation of immune cells and can be used in treating cell reactions mediated by FcεRI or FcγRl receptors. In formula (I) each R2 and R4 is independently phenyl substituted with one or more R8 groups or a heteroaryl selected from a group consisting of , where the heteroaryl is optionally substituted with one or more R8 groups and at least one of R2 and R4 is a heteroaryl; R5 is selected from a group consisting of (C1-C6)alkyl, optionally substituted with one or more identical or different R8 groups, -ORd, -SRd, fluorine, (C1-C3)halogenalkyloxy, (C1-C3)perhalogenalkyloxy, -NRcRc, (C1-C3)halogenalkyl, -CN, -NO2, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc; -OC(NH)NRcRc, - [NHC(O)]nORd, R35 is hydrogen or R8; each Y is independently selected from a group consisting of O, S and NH; each Y1 is independently selected from a group consisting of O, S and NH; each Y2 is independently selected from a group consisting of CH, CH2, S, N, NH and NR37. Other values of radicals are given in the claim.

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: chemistry.

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

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

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

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

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

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

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole derivatives of the formula (1): or pharmaceutically acceptable salts thereof, where: R1 denotes H, halogen; R2 denotes an 8-10-member bicyclic hydrocarbon group, optionally substituted, or a bicyclic heterocyclic group consisting of one or two atoms selected from nitrogen, oxygen and sulphur and 5-9 carbon atoms, optionally substituted, where the optional substitute is halogen, lower alkyl, OH, lower alkoxy, oxo, NO2, CN; R3 denotes H.

EFFECT: compounds have inhibiting action of production of IL-6, which enables use thereof in a pharmaceutical composition and when treating a range of diseases.

12 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole compounds of formula I or pharmaceutically acceptable salts thereof: I, where: Ar denotes phenyl, thiophenyl; R1 denotes imidazolyl, imidazolyl substituted with C1-C6alkyl, chlorine, bromine, fluorine, hydroxy group, methoxy group; R2 denotes H, CH3, Cl, F, OH, OCH3, OC2H5, propoxy group, carbamoyl, dimethylamino group, NH2, formamide group, CF3; X denotes CO and SO2. The compounds inhibit S-nitrosoglutathione reductase (GSNOR).

EFFECT: using the compound to produce a pharmaceutical composition and for treating asthma.

17 cl, 1 tbl, 14 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new phenylimidazole derivatives of general formula , wherein R1 represents a hydrogen atom, a phenyl lower-alkyl group or a pyridyl lower-alkyl group with a benzene ring and a pyridine ring are optionally substituted by 1 or 2 substitutes specified in a group consisting of halogen atoms, cyano group and halogen-substituted lower-alkyl groups; one or R2 and R3 represents a hydrogen atom, and another one represents a lower alkoxy group; R4 represents a lower-alkyl group, a difurylglyoxal group, a thienyl group or a phenyl group optionally substituted by 1 or 2 substitutes specified in a group consisting of lower-alkyl groups, lower-alkoxy groups, halogen atoms, a carboxyl group, lower alkoxycarbonyl groups, and halogen-substituted lower-alkyl groups; R5 and R6 are identical or different, and represent a hydrogen atom or a lower alkyl group; R7 and R8 are identical or different, and represent a hydrogen atom or a lower alkoxy group; provided R1 represents an unsubstituted phenyl lower-alkyl group, R2 represents a lower alkoxy group, R3 represents a hydrogen atom, R4 represents an unsubstituted phenyl group or a phenyl group containing 1 or 2 halogen-substituted lower-alkyl groups, and R5 represents a hydrogen atom, then R6 is other than a hydrogen atom. Also, the invention refers to an LPL activator, an agent for preventing or treating hyperlipidaemia, an agent for treating arteriosclerosis, and an agent for treating obesity on the basis of the compound of formula (1).

EFFECT: there are prepared new phenylimidazole derivatives effective for LPL activation.

23 cl, 10 tbl, 7 ex

FIELD: medicine, pharmaceutics.

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

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

67 cl, 1 tbl, 4393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - 5-hydroxy-6-methyl-1-(thietanyl-3)pyrimidine-2,4(1H,3H)-dione of formula , which inhibits generation of active forms of oxygen and has antioxidant activity.

EFFECT: improved properties of compounds.

2 cl, 1 dwg, 1 tbl, 2 ex

FIELD: chemistry.

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

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

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

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

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

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

46 cl, 3 dwg, 38 tbl, 89 ex

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