Proline derivatives as cathepsin inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula

,

where values A, R1-R6 are given in i.1 of the invention formula. Methods of obtaining the formula (I) compound are described.

EFFECT: compounds demonstrate an inhibiting activity of the cathepsin enzyme, which makes it possible to use them for the preparation of a pharmaceutical composition and for the preparation of a medication.

38 cl, 12 dwg, 495 ex

 

The present invention relates to compounds, which are the preferred inhibitors cysteinate cathepsin, in particular cysteinate cathepsin S or L.

The present invention particularly relates to compounds of formula (I)

in which

R1denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cycloalkyl, cycloalkenyl, alkylsilanes, halogenallylacetic, phenylcyclohexyl, halogenosilanes, phenylalanyl, halogennitroalkane, alkoxycarbonylmethyl, cyanoacrylates, halogenfrei, pyridinylmethyl, aminocyclohexanol, aminocarbonylmethyl, halogensilberemulsionen, alkylphenolethoxylates, bis(halogenfree)alkyl, phenylcyclohexyl, alkylresorcinols, halogennitroalkane, halogenerator, aftercollege, halogenbenzonitriles, benzo[1,3]dioxole, naftiliaki, halogen-1H-indazole, galogenangidridy, (halogenfree)(alkoxycarbonyl)alkyl, alkylresorcinols, halogenopyrimidines, (halogenfree)(amino)alkyl, (halogenfree)(halogenosilanes)alkyl, halogenallylacetic, (halogenfree)(alkoxycarbonylmethyl), (halogenfree)(morpholinyl)alkyl, halogenanlagen, alkylene cycloalkyl, hydroxyalkyloxy, (halogenfree)(alkanolamine)alkyl, alkoxycarbonylmethyl, gamogenetically, galopenforceskyblogcom, vinyltetrahydrofuran or R11;

And denotes-CH2-, -CH2CH2-, carbonyl, -C(O)O-, -SO2- or is absent;

R2denotes hydrogen, alkyl, halogenated, cycloalkyl, phenyl, phenylalkyl or phenylsulfonyl;

or A, R1and R2together form-CH2Cl2-, -CH2CF2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-; -CH2CH2OCH2- or-CH2CH2CH(CN)-;

R3denotes alkyl, hydroxyalkyl, cycloalkyl, phenyl or substituted phenyl, where the substituted phenyl is a phenyl containing from 1 to 3 substituents independently selected from the group comprising alkyl, halogenated, hydroxyalkyl, alkoxygroup, halogenaryloxy, halogen, pyrazolyl, alkylphenolic, imidazolyl, benzoimidazolyl, 6-oxo-6N-pyridazinyl, alkyl-6-oxo-6N-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, ecomorphology, oxopyridine, 2-oxo-2H-pyrazinyl, deformabilities, galogenangidridy, piperidinecarboxylate, acetamidoxime, alkylphenolic, loginpanel, alkylpyridine, cycloalkyl, cycloalkenyl, halogenfree, alkylarylsulphonates, halogenatedbiphenyls, alkylamino, alkoxycarbonyl, cycloalkylcarbonyl, hexahydropyrazino[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, alkylimidazole, azetidine, cycloalkylcarbonyl, alkylimidazole, alkoxyalkyl, imidazo[4,5-C]pyridinyl, alkylpiperazine, hexahydropyrazino[1,2-a]pyrazinyl, halogenations, pyrimidinyl and alkenylacyl;

R4denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cycloalkyl, cycloalkylation, phenyl, alkylphenyl, halogenfree, fenoxaprop or halogenerator;

R5and R6independently selected from the group comprising hydrogen, alkyl, cycloalkyl, alkyloxy, hydroxyalkyl, halogenated, halogenaryloxy, phenyl and phenylalkylamine;

or R5and R6together with the carbon atom to which they are attached, form cycloalkyl, pyrrolidinyl or piperidinyl; and

R11denotes phenyl, substituted phenyl, tetrahydropyranyl, pyridinyl, alkylpyridine, galgenlieder, oxetanyl, alkyloxyaryl, pyrrolidinyl, alkylpyridine, pyrimidinyl, halogensilberemulsionen, alkylpiperidines, naphthyl, biphenyl, halogenated-[1,3,4]thiadiazolyl, Alcock carbonyldiimidazole, halogen-[1,2,4]thiadiazolyl, pyrazolyl or substituted pyrazolyl, where the substituted phenyl and substituted pyrazolyl represent phenyl and pyrazolyl, each of which contains from 1 to 3 substituents independently selected from the group comprising alkyl, halogen, halogenated, alkoxygroup, alkoxycarbonyl, halogenfree, halogenopyrimidines, oxopiperidine, a nitrogroup, thiazolyl, halogenosilanes, alkylphenyl, phenyl, alkylpyridine, tetrahydropyranyl, pyridinyl, cycloalkyl, phenylalkyl, oxazolyl, alkoxyphenyl, chinoline, allylcarbosilane, halogenlampe, alkylsulfonyl, generalquartiermeister, piperidinyl, tiopronin, dioxathiapine, morpholinylmethyl and alkylimidazole;

or their pharmaceutically acceptable salts.

Connections proposed in the present invention are the preferred inhibitors cysteinate cathepsin (Cat), in particular, cathepsin S or cathepsin L and therefore applicable for the treatment of metabolic diseases such as diabetes, atherosclerosis, aneurysm of the abdominal aorta, the disease of the peripheral arteries, cancer, reducing the incidence of cardiovascular disorders in chronic kidney disease and diabetic nephropathy. In addition, immune diseases such as rheumatoid arthritis, multiple sclerosis, Sjogren syndrome, to the ACLs lupus, neuropathic pain, a type I diabetic, asthma and allergies and associated with skin immune diseases are suitable for treatment with an inhibitor of cathepsin S.

Objects of the present invention are compounds of formula I and their aforementioned salts themselves and their use as therapeutically active substances, the method of obtaining these compounds, intermediates, pharmaceutical compositions, drugs containing these compounds, their pharmaceutically acceptable salts, the use of such compounds and salts for the prophylaxis and/or treatment of diseases, particularly for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, diseases of the peripheral arteries, cancer, reducing the incidence of cardiovascular disorders in chronic kidney disease and diabetic nephropathy, and the use of such compounds and salts for the preparation of drugs intended for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, diseases of the peripheral arteries, cancer, reducing the incidence of cardiovascular disorders in chronic kidney disease and diabetic nephropathy.

The mammalian cathepsins are cysteine proteases of the type involved in the key stages of the biological and pathologic the ski manifestations. Cathepsins considered suitable targets for drugs, because of the inhibition of their enzymatic activity of small molecules and it is of interest to the pharmaceutical industry (Bromme 2001; Roberts 2005).

Cathepsin S markedly expressed in the cells that produce antigen, such as macrophages and dendritic cells and smooth muscle cells. (Hsing and Rudensky 2005; Rudensky and Beers 2006). Although cathepsin S only weakly expressed in the tissue of healthy arteries in atherosclerotic arteries there is a significant increase regulation (Liu et al. 2006; Sukhova et al. 1998).

Data preclinical studies suggest that the function of cathepsin S critical to atherosclerosis, since according to the data obtained with the use of appropriate models in mice, in mice with deficiency of cathepsin S decreases the frequency of atherosclerotic phenotype. Reported that in mice with deficiency of LDL-Rec, there is a reduced lipid accumulation, destruction of elastin fibers and chronic inflammation of the arteries. Reported that in mice with deficiency of APO E was observed a significant decrease in the frequency of acute rupture of plaques. When creating chronic kidney disease in mice with deficiency of cathepsin S/In the APO-E with maximum protivoateroskleroticheskim activity in the arteries and heart valves there is ALOS significant decrease accelerated calcification (Aikawa et al. 2009; de Nooijer et al. 2009; Rodgers et al. 2006; Sukhova et al. 2003). This shows that the potential inhibitor of cathepsin S must stabilize atherosclerotic plaque by reducing the frequency of the destruction of the extracellular matrix, by reducing Pro-inflammatory state and by reducing accelerated calcification and subsequent clinical manifestations.

These phenotypes described in models of atherosclerosis, consistent with the known functions of cathepsin S in the cells. First, cathepsin S participates in the destruction of the extracellular matrix that stabilizes the plaque. In particular, cathepsin S has expressed latinalicious activity and can show it in a neutral environment that distinguishes cathepsin S from all other cathepsins. Secondly, cathepsin S is the major protease involved in the processing of antigen, in particular, the splitting constant circuit in the cells that produce antigen, which leads to the reduction of the contribution of T cells in chronic inflammation of the atherosclerotic tissue. Increased inflammation leads to subsequent oxidative and proteolytic to tissue damage and subsequent destabilization of plaques (Cheng et al. 2004; Driessen et al. 1999; Rudensky and Beers 2006).

Anti-inflammatory and protivoastmatichesky the ability of the inhibitor Cat S also makes it an important target for chronic obstructive is zabolevanii light (Williams et al. 2009). In addition, due to its role in degradation of extracellular matrix, inhibition of cathepsin S will lead to the formation of neointima and angiogenesis (Burns-Kurtis et al. 2004; Cheng et al. 2004; Shi et al. 2003; Wang et al. 2006). Therefore, the inhibitor of cathepsin S may be applied in various diseases.

Cathepsin S also plays a role in the attenuation of tumor growth and invasion of tumor cells, as described in the publication Roberta E. Burden in Clin Cancer Res 2009; 15(19). In addition, in mice with remote kidneys, deprived of cathepsin S, there is a significant decrease of calcification of the arteries compared with wild-type mice with remote kidneys. This shows that inhibition of cathepsin S may have a beneficial effect on reducing the incidence of cardiovascular disorders in patients with chronic kidney disease (Elena Aikawa, Circulation, 2009, 1785-1794).

Cathepsin L is characterized by a broader expression profile than cathepsin S, and there are also data that indicate a role of cathepsin L in atherosclerosis, for example, in mice with deficiency of LDLrec & Cat L decreases the frequency of atherosclerotic phenotype (Kitamoto et al. 2007). In addition, it was suggested that Cat L participates in the metabolic syndrome, because it regulates lipogenesis and peripheral glucose tolerance. Reported that kidney disease of cathepsin L regulates the function podocyte is by proteolytic processing dinamina and thereby regulates proteinuria (Sever et al. 2007).

For cathepsin L described effects in cells, leading to tissue remodeling and destruction of the extracellular matrix, generation of active neuropeptides and participate in the development of antigen in the epithelial cells of the thymus gland (Funkelstein et al. 2008; Rudensky and Beers 2006).

In the present description, the term "alkyl", alone or in combination, means having a linear or branched chain alkyl group containing from 1 to 8 carbon atoms, preferably having a linear or branched chain alkyl group containing from 1 to 6 carbon atoms, and especially preferably having a linear or branched chain alkyl group containing from 1 to 4 carbon atoms. Examples with linear or branched chain C1-C8-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric of Penteli, isomeric sexily, isomeric Gately and the isomeric octile, preferably methyl, ethyl, propyl, isopropyl, isobutyl and tert-butyl.

The term "cycloalkyl", separately or in combination, means cycloalkyl ring containing from 3 to 8 carbon atoms and preferably cycloalkyl ring containing from 3 to 6 carbon atoms. Examples3-C8-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohe the silt and cyclooctyl. The preferred cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "alkoxygroup", separately or in combination, signifies a group of the formula alkyl-O-, in which the term "alkyl" has the previously listed values, such as a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl and tert-butoxypropyl, preferably a methoxy group, ethoxypropan, propoxylate, isopropoxy and tert-butoxypropan.

The term "cycloalkylation", separately or in combination, signifies a group of formula cycloalkyl-O-, in which the term "cycloalkyl" has the above meaning, such as cyclobutylamine, cyclopentylamine or cyclohexyloxy.

The term "fenoxaprop", separately or in combination, means a phenyl-O-.

The term "oxygraph", separately or in combination, signifies a group-O-.

The term "halogen", alone or in combination, means fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine.

The terms "halogenated", "halogenosilanes" and "halogenlampe", separately or in combination, means an alkyl group, cycloalkyl group and alkoxygroup, substituted by at least one halogen, preferably substituted 1-5 Gal the genes. Foralkyl is a subgroup of halogenoalkane. The preferred halogenation are deformity, trifluoromethyl, triptorelin, cryptochromes, pentafluoroethyl and pentafluoropropyl. Vertikaalsel is a subgroup of halogennitroalkane. The preferred forcecoercion is diversicolor. The preferred halogenation are deformity, trifluoromethyl, triptorelin, cryptochromes, pentafluoroethyl and pentafluoropropyl.

The term "carbonyl", alone or in combination, signifies a group-C(O)-.

The term "carboxypropyl", separately or in combination, signifies a group-COOH.

The term "pharmaceutically acceptable salt" means those salts which retain the biological effectiveness and characteristics of the free bases or free acids and which are not undesirable in biological or another. These salts are formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, limo is Naya acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, N-acetylcysteine, etc., in Addition, these salts can be obtained by adding an inorganic base or organic base to the free acid. Salts formed from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, etc. Salts formed from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resin, etc., the Compound of formula (I) may also be contained in the form zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride, formate, sulfate, phosphate, and mesylates, more preferred hydrochloride and formate.

One embodiment of the present invention are the compounds of formula (I) in which:

R1denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cloacal, cycloalkenyl, alkylsilanes, halogenallylacetic, phenylcyclohexyl, halogenosilanes, phenylalanyl or R11;

And denotes-CH2-, -CH2CH2-, carbonyl, -C(O)O-, -SO2- or is absent;

R2denotes hydrogen, alkyl, halogenated, cycloalkyl, phenyl or phenylalkyl;

or A, R1and R2together form-CH2CH2-, -CH2CF2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- or-CH2CH2OCH2-;

R3denotes alkyl, hydroxyalkyl, cycloalkyl, phenyl, phenylalkyl or substituted phenyl, where the substituted phenyl is a phenyl containing from 1 to 3 substituents independently selected from the group comprising alkyl, halogenated, hydroxyalkyl, halogenaryloxy, halogen, pyrazolyl, imidazolyl, benzoimidazolyl, 6-oxo-6N-pyridazinyl, alkyl-6-oxo-6N-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, ecomorphology, oxopyridine, 2-oxo-2H-pyrazinyl, ceftobiprole, galogenangidridy, piperidinecarboxylate and oceanologique;

R4denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cycloalkyl, cycloalkylation, phenyl, halogene the sludge, fenoxaprop or halogenerator;

R5and R6independently selected from the group comprising hydrogen, alkyl, cycloalkyl, alkyloxy, hydroxyalkyl, halogenated, halogenaryloxy, phenyl and phenylalkylamine;

or R5and R6together with the carbon atom to which they are attached, form cycloalkyl, pyrrolidinyl or piperidinyl; and

R11denotes phenyl, substituted phenyl, tetrahydropyranyl, pyridinyl, alkylpyridine, galgenlieder, oxetanyl, pyrrolidinyl, alkylpyridine, pyrimidinyl, halogensilberemulsionen, alkylpiperidines, pyrazolyl or substituted pyrazolyl, where the substituted phenyl and substituted pyrazolyl represent phenyl and pyrazolyl containing from 1 to 3 substituents independently selected from the group comprising alkyl, halogen, halogenated, alkoxygroup, alkoxycarbonyl, halogenfree, halogenopyrimidines, oxopiperidine and the nitro-group;

or their pharmaceutically acceptable salt.

In another embodiment, the present invention R1denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cycloalkyl, cycloalkenyl, alkylsilanes, halogenallylacetic, phenylcyclohexyl, halogenosilanes, phenylalanyl or R11.

In another embodiment, the present image is placed R 1denotes hydrogen, alkyl, foralkyl, finalforce, alkoxygroup, alkoxymethyl, alkylsilanes, divorcecare, cryptomaterial, vinylcyclopropyl, chlorophenylsulfonyl, cyclobutyl, cyclohexyl, cryptometrics, cryptomaterial or cyclopentyloxy.

In addition, in another embodiment, R1denotes hydrogen, methyl, ethyl, propyl, butyl, deformity, trifluoromethyl, triptorelin, pentafluoroethyl, cryptochromes, denitrifier, a methoxy group, propyloxy, butylacrylate, methoxymethyl, methylcyclopropyl, divorcecare, cryptomaterial, vinylcyclopropyl, chlorophenylsulfonyl, cyclobutyl, cyclohexyl, cryptometrics, cryptomaterial or cyclopentyloxy.

In another embodiment, the present invention R1represents tert-butyl, cryptomaterial, methylcyclopropyl or chlorophenylacetyl.

The compound of formula (I) in which R1denotes alkyl, halogenallylacetic, alkylsilanes or halogennitroalkane is another embodiment of the present invention.

The compound of formula (I) in which R1denotes alkyl, peralkylated, alkylsilanes or chlorophenylsulfonyl is another embodiment n is standing inventions.

In addition, in the preferred embodiment of the present invention And represents-CH2-, -CH2CH2-, carbonyl or absent.

In another embodiment of the present invention And indicates the carbonyl.

The compound of formula (I) in which R2denotes hydrogen or alkyl, is another embodiment of the present invention.

The compound of formula (I) in which R2denotes hydrogen, a preferred embodiment of the present invention.

In a preferred embodiment of the present invention, the alkyl in R2represents butyl, preferably isobutyl.

In addition, in another embodiment of the present invention And, R1and R2together form-CH2CH2-, -CH2CF2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- or-CH2CH2OCH2-. In this case, the compound of formula (I) in which A, R1and R2together form-CH2CF2CH2- is the preferred embodiment of the present invention.

In another embodiment, the present invention R3denotes alkyl, hydroxyalkyl, cycloalkyl, phenyl or substituted phenyl, where the substituted phenyl is a phenyl, with the containing a series of from 1 to 3 substituents, independently selected from the group comprising alkyl, halogenated, halogenlampe, hydroxyalkyl, halogen, pyrazolyl, imidazolyl, benzoimidazolyl, 6-oxo-6N-pyridazinyl, alkyl-6-oxo-6N-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, ecomorphology, oxopyridine, 2-oxo-2H-pyrazinyl, ceftobiprole, triftormetilfullerenov, piperidinyloxy and oceanologique.

In addition, in another embodiment, R3denotes alkyl, hydroxyalkyl, cycloalkyl, phenyl or substituted phenyl, where the substituted phenyl is a phenyl containing from 1 to 3 substituents independently selected from the group comprising methyl, trifluoromethyl, tripterocarpa, cryptometer, hydroxymethyl, fluorine, bromine, chlorine, pyrazolyl, imidazolyl, benzoimidazolyl, 6-oxo-6N-pyridazinyl, alkyl-6-oxo-6N-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, ecomorphology, oxopyridine, 2-oxo-2H-pyrazinyl, ceftobiprole, triftormetilfullerenov, piperidinyloxy and oceanologique.

The compound of formula (I) in which R3denotes phenyl containing 1 or 2 substituent independently in the curse of the group, including chlorine, trifluoromethyl, cryptometer, tripterocarpa and pyrazolyl, is the preferred embodiment of the present invention.

In addition, the compound of formula (I) in which R3means dichlorophenyl, (chloro)(pyrazolyl)phenyl, (chloro)(triptoreline)phenyl, (chloro)(cryptochrome)phenyl, triptoreline (triptoreline)(trifluoromethyl)phenyl or chlorophenyl, is another preferred embodiment of the present invention.

The compound of formula (I) in which R3denotes phenyl containing 1 or 2 substituent, independently selected from the group comprising halogen, halogenated, halogenlampe and pyrazolyl, is also the embodiment of the present invention.

In a preferred embodiment of the present invention R4denotes hydrogen.

In another embodiment, the present invention R5denotes hydrogen, alkyl, cycloalkyl or phenyl.

In another embodiment, the present invention R5denotes hydrogen, methyl, cyclopropyl or phenyl.

In yet another embodiment, the present invention R6denotes hydrogen.

In one embodiment of the present invention R5and R6together with the carbon atom to which they are attached, about atout cycloalkyl.

In addition, the compound of formula (I) in which R5and R6together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, or cyclohexyl, a preferred embodiment of the present invention.

The compound of formula (I) in which R5and R6together with the carbon atom to which they are attached, form cyclopropyl is another embodiment of the present invention.

In a preferred embodiment of the present invention R11denotes phenyl, substituted phenyl, tetrahydropyranyl, pyridinyl, alkylpyridine, alkylpyridine, oxetanyl, pyrrolidinyl, alkylpyridine, pyrimidinyl, halogensilberemulsionen, alkylpiperidines, pyrazolyl or substituted pyrazolyl, where the substituted phenyl and substituted pyrazolyl represent phenyl and pyrazolyl, each of which contains from 1 to 3 substituents independently selected from the group comprising halogenated, halogen, alkoxygroup, alkoxycarbonyl, halogenlampe, halogenated, halogenfree, halogenopyrimidines, oxopiperidine and the nitro-group.

In another preferred embodiment of the present invention R11denotes phenyl, substituted phenyl, tetrahydropyranyl, pyridinyl, methylpyrimidine, cryptomaterial, oxea the sludge, pyrrolidinyl, methylpyrrolidinyl, pyrimidinyl, cryptomaterial, methylpiperidine, pyrazolyl or substituted pyrazolyl, where the substituted phenyl and substituted pyrazolyl represent phenyl and pyrazolyl, each of which contains from 1 to 3 substituents independently selected from the group comprising methyl, fluorine, methoxy group, methoxycarbonyl, cryptometer, trifluoromethyl, chlorophenyl, forfinal, chloropyridinyl, oxopiperidine and the nitro-group.

In another embodiment, the present invention R11denotes phenyl, forfinal, chlorophenyl, methoxyphenyl, ethoxycarbonylphenyl, triptoreline, nitrophenyl, tetrahydropyranyl, pyridinyl, methylpyrimidine, cryptomaterial, oxetanyl, pyrrolidinyl, methylpyrrolidinyl, pyrimidinyl, cryptomaterial, methylpiperidine, pyrazolyl, methylvinylpyridine, globaldeleteatom, chlorophenylpiperazine, performativity or oxodehydroepiandrosterone.

The following compounds of formula (I) are the preferred options for implementation of the present invention:

cyanomethylene (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid;

cyanomethylene (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid;

cyanomethylene (2S,4R)-4-benzazolyl-1-cycle is getselectionrange-2-carboxylic acid;

cyanomethylene (2S,4R)-4-benzazolyl-1-(2,2,2-Cryptor-1-phenylethyl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-4-benzazolyl-1-cyclohexanecarbonitrile-2-carboxylic acid;

cyanomethylene (2S,4R)-1-benzoyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-(tetrahydropyran-4-carbonyl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-Cryptor-1-phenylethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-perbenzoic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(4-perbenzoic)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(4-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocycline who yl)-amide (2S,4R)-1-(2,2,3,3,3-pentafluoropropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-benzoyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexanecarbonitrile-2-carboxylic acid;

ethyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

cyclopentyloxy ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

4-forfinally ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-pyridin-4-iletilenlerin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-ethylpyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-phenotypically-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclobutylmethyl-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexylpiperidine-2-carboxylic acid;

(1-cyanocyclohexyl)-methylamide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-methylpyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-triptorelin)-pyrrolidin-2-carboxylic acid;

(1-cyanocycline is)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2-dottorati)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-perbenzoic)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexanecarbonitrile-2-carboxylic acid;

cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-propenylboronic-2-carboxylic acid;

cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-methoxyacetyl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-oxetan-3-iparralde-2-carboxylic acid;

cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(tetrahydropyran-4-yl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-1-benzoyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-1-(4-perbenzoic)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-1-(4-methylbenzoyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-1-(tetrahydropyran-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-1-(pyridine-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-1-(1-methylpiperidin-4-carbonyl)-4-(2-t is attorneysanafranil)-pyrrolidin-2-carboxylic acid;

cyclopentyloxy ester (2S,4R)-2-(cyanomethylene)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,3,3,3-pentafluoropropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-Cryptor-2-methylpropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-cryptochromes)-pyrrolidin-2-carboxylic acid;

cyanomethylene 6-benzazolyl-2,2-divorceregistration-7a-carboxylic acid;

cyanomethylene 1-benzazolyl-6,6-divorceregistration-7a-carboxylic acid;

cyanomethylene 1-benzazolyl-6,6-divorceregistration-7a-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

isopropyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-TRIFLUOROACETYL)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidin-1-carboxylic acid;

(1-C is ansiklopedi)-amide (2S,4R)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(cianfanelli)-carbarnoyl]-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(cyanomethylene)-carbarnoyl]-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-benzyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-pyridin-4-ylmethyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(cianfanelli)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(cyanomethylene)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2,2-TRIFLUOROACETYL)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-methylpyrrolidine-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(centimetres)-carbarnoyl]-pyrrolidin-1-carboxylic to the slots;

tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexyl)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(centimetres)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (R)-4-(2-chlorobenzenesulfonyl)-1-((S)-1-methylpyrrolidine-2-carbonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-propionyl 4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-methylpiperidin-4-carbonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-methoxyethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-ethylbenzonitrile)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R-2-(1-cyanocyclohexane)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-hydroxymethanesulfinic)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-hydroxymethanesulfinic)-pyrrolidin-2-carboxylic acid;

methyl ester of 4-[(2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carbonyl]-benzoic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-phenyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-differentiality)-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(4-imidazol-1-eventality)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-differentlal the Nile)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-2-[(cyanocobalamin)-carbarnoyl]-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-imidazol-1-eventality)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-(4-bromo-2-trifloromethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-formylpyridine-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4S,5R)-5-(4-forfinal)-2-isobutyl-4-methanesulfonamide-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-(2-chloro-4-permentantly)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2R,4S,5R)-2-(1-cyanocyclohexane)-5-(4-forfinal)-2-isobutyl-4-methanesulfonyl pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4S,5R)-4-benzazolyl-5-(4-forfinal)-2-isobutylpyrazine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-formyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-(4-benzimidazole-1-yl-2-trifloromethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(3-methyl-6-oxo-6N-pyridazin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidin-2-carbon is th acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-[2-chloro-4-(3,3-debtorprovidian-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chloro-4-piperidine-1-eventality)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-benzimidazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(3,3-debtorprovidian-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid;

methyl ester of 4-[(2S,4R)-2-(cyanomethylene)-4-(2-trifloromethyl)-p is Raiden-1-carbonyl]-benzoic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(3-methyl-6-oxo-6N-pyridazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-4-[2-chloro-4-(2-piperidine-1-ylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-Mei-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-phenylimidazol-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-oxopyrrolidin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-oxoacridine-3-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(3,3-debtorprovidian-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-(morpholine-4-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(3-exmortis-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-oxo-2H-pyridin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-oxo-2H-pyrazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-formylpyridine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-1-formylpyridine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-benzazolyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-formylpyridine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-formylpyridine-2-carboxylic acid;

cyanomethylene (2S,4R)-1-phenyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-[2-chloro-4-(4,4-deformability-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

tert-butyl ester (2S,4R)-4-[2-chloro-4-(4-triftormetilfosfinov-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-triftormetilfosfinov-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4,4-deformability-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-triftormetilfosfinov-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4,4-deformability-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-Pierre is lidin-2-carboxylic acid;

tert-butyl ester (2S,4S)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4S)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(4-methoxyphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-morpholine-4-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-4-(2-chloro-4-morpholine-4-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperazine-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

cyanomethylene (2S,4R)-1-(2-nitrophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-nitrophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(2-nitrophenyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-t is ftormetilirovaniya)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-triftoratsetilatsetonom)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(2,2-divorcecelebration)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-[2-chloro-4-(oxetan-3-yloxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzene is sulfonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-isobutylpyrazine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(3-methylbutyryl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(oxetan-3-yloxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-formylpyridine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(2-cryptomaterial-4-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-phenyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-chlorophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-forfinal)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2-oxo-1,2-dihydropyridines-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-cyclopropanecarbonitrile-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1-methyl is toxi)-benzazolyl]-1-cyclopropanecarbonitrile-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(oxetan-3-yloxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(3,3,3-triptocaine)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-2-(1-cenotillo OpenCalais)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2-dimethylpropanoyl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2-dimethylpropanoyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-isobutylpyrazine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide(2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-triptocaine)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-methylbutyryl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-[4-chloro-2-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-isobutylpyrazine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3,3,3-triptocaine)-pyrrolidin-2-carboxylic acid; and

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3-methylbutyryl)-pyrrolidin-2-carboxylic acid.

The following compounds of formula (I) are the other preferred options for implementation of the present invention:

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-(1-triftormetilfullerenov carbonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid is you;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2-dimethylpropanoyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid; and

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid.

The following compounds of formula (I) are other variants of implementation of the present invention:

tert-butyl ester (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2-oxo-1,2-dihydropyridines-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-chlorophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-thiazol-2-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2,4-dipteran alsultany)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(1-methyl-1H-pyrazole-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(3,4-dichlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2,2-divorcecelebration)-pyrrolidin-2-carboxylic acid;

tert-butyl ether ({1-[(2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carbonyl]-cyclopropyl}-carbamino acids;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-cyanocyclohexane)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-chlorophenyl)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-karbonovoi acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-chloropyridin-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-methylpyridin-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(1-methyl-1H-pyrazole-4-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-pyridine-4-enciclopediaper)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2,2-debtor-2-phenylacetyl)-pyrrolidin-2-carboxylic acid;

4-hlorfenilovy ester (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid is you;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-cyclopropyl-2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2-methylpyridin-4-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-chloropyridin-4-yl)-2-trifloromethyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2',4'-debtor-3-triptorelin-4-sulfonyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(',4'-debtor-3-triptorelin-4-sulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

tert-butyl ester (4-{2-[(2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-yl]-2-oxoethyl}-cyclohexyl)-carbamino acids;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-aminocyclohexane)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-cyclopropyl-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carbon is howling acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-bromophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-acetylaminophenol)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2,2-bis-(4-chlorophenyl)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-m-tolyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-carbamoylphenoxy)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclobutanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-chlorophenyl)-2-methylpropionyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4S)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-trifloromethyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-methylpropionyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclobutanecarbonyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(3,4-dichlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-pyridine-4-enciclopediaper)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(4-vinyltetrahydrofuran-4-carbonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-{1-[4-(1-methyl-1H-pyrazole-4-yl)-phenyl]-cyclopropanecarbonyl}-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2-methylpyridin-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-{2-chloro-4-[4-(2,2,2-triptorelin)-piperazine-1-yl]-benzazolyl}-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-the foreign Ministry (2S,4R)-4-(2-chloro-4-dimethylaminobenzylidene)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-isopropylpiperazine-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(3-methyloxiran-3-carbonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(4-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-{2-chloro-4-[4-(2-methoxyethyl)-piperazine-1-yl]-benzazolyl}-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-cyclopropylmethyl-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-((S)-2-chloro-4-hexahydropyrazino[1,2-a]pyrazin-2-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,5-dimethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-benzols hanil]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopentanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-phenylcyclohexanecarboxylic)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-p-tooltipcontent)-pyrrolidin-2-carboxylic acid

(1-cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(4-triptoreline)-eloprofessional]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(3-triptoreline)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclohexanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(biphenyl-4-sulfonyl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-pyridazin-3-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-to benovoy acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-oxazol-5-eventality)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazol-1-eventality)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-Mei-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-azetidin-1-yl-2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4[2-chloro-4-(4-cyclopropylmethyl-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(3-chlorophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(3-bromophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-isopropylimidazole-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-tert-butyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-ISO is util-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-methoxyethoxy)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide 1-biphenyl-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide 1-naphthalene-1-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-bromophenyl)-[1,3]dioxolane-2-carbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-naphthalene-1-enciclopediaper)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-naphthalene-2-enciclopediaper)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazo[4,5-C]pyridine-1-eventality)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazo[4,5-C]pyridine-5-albenza sulfonyl)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-quinoline-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide 4-(2-trifloromethyl)-1-(3-triptoreline)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide 1-(2-tert-butylphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide 1-(3-cyanophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclobutanecarbonyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-unoticable)-amide (2S,4R)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide 1-(tetrahydropyran-4-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-cyclopropyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

tert-butyl ester 4-[2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-yl]-piperidine-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropylmethyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide 1-(3-trifloromethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-isopropylpiperazine-1-yl)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-Carbo the OIC acid; compound with formic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-{2-chloro-4-[4-(2-methoxyethyl)-piperazine-1-yl]-benzazolyl}-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-((S)-2-chloro-4-hexahydropyrazino[1,2-a]pyrazin-2-eventality)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-cyclopropylmethyl-1-yl)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-methoxybenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chloro-4-methoxybenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (R)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(2-methoxy who toxi)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazol-1-eventality)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (6R,7aS)-6-(2-chloro-4-permentantly)-1-cyano-tetrahydropyrazin-7a-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-benzo[1,3]dioxol-5-enciclopediaper)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;

tert-butyl ester (2S,4R)-4-(2-chloro-4-methoxybenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-CEC is avutil-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-naphthalene-1-yl-[1,3]dioxolane-2-carbonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-methyl-5-(tetrahydropyran-4-yl)-1H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide and (2R,4S)-1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-cyclobutyl-5-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic sour is s;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(3-methanesulfonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(3,3-diversecity-1-yl)-2-trifloromethyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

benzyl ether of 4-{5-[(2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-piperidine-1-carboxylic acid;

(1-cyan is cyclopropyl)-amide (2S,4R)-1-(5-methyl-2-piperidine-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-pyrimidine-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-methanesulfonamide-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(6-chloro-1H-indazol-3-carbonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[(R)-2-(4-chlorophenyl)-2-hydroxyacetic]-pyrrolidin-2-carboxylic acid;

tert-butyl ester [(R)-2-[(2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-yl]-1-(4-chlorophenyl)-2-oxoethyl]-carbamino acids;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-methylthiazole-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(5-chloropyridin-2-yl)-acetyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(3,3-diversecity-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[(R)-2-amino-2-(4-chlorophenyl)-acetyl]-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carbon is Oh acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-Chlorobenzyl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-pyrimidine-4-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;

(2S,4R)-N-(1-cyanocyclohexyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)-4-(4-(1-methyl-1H-pyrazole-5-yl)-2-(trifluoromethyl)phenylsulfonyl)pyrrolidin-2-carboxamide;

(1-cyanocyclohexyl)-amide (R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-(2,2,2-triptoreline)-acetyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(3-cryptomaterial-1-yl)-acetyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-cyclopropanesulfonyl-2-carboxylic acid;

(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-(4-forfinal)cyclopropanecarbonyl)pyrrolidin-2-carboxamide;

(2S,4R)-1-(1-(4-bromophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;

(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-(4-(trifluoromethyl)phenyl)cyclopropanecarbonyl)pyrrolidin-2-carbox the ID;

(2S,4R)-1-(1-(3-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;

(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-(3-(trifluoromethyl)phenyl)cyclopropanecarbonyl)pyrrolidin-2-carboxamide;

(2S,4R)-1-(2-(4-chlorophenyl)propanol)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;

(2S,4R)-1-(2-(4-chlorophenyl)propanol)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;

(2S,4R)-1-(2-(4-chlorophenyl)-3-methylbutanoyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;

tert-butyl 4-(4-chlorophenyl)-4-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclohexane)pyrrolidin-1-carbonyl)piperidine-1-carboxylate;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-morpholine-4-ylacetic]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-morpholine-4-ylacetic]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-morpholine-4-ylacetic]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(3,4-dichlorophenyl)-2,2-divercity]-pyrrolidin-2-carboxylic acid;

(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-p-tooltipcontent)pyrrolidin-2-carbox the ID;

(2S,4R)-1-(1-(4-chloro-2-forfinal)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;

(1-cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;

(2S,4R,5S)-5-(4-tert-butylphenyl)-N-(1-cyanocyclohexyl)-4-(phenylsulfonyl)-2-(2-(phenylsulfonyl)ethyl)pyrrolidin-2-carboxamide;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2,2-divercity]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(2,4-dichlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chloro-3-forfinal)-acetyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chloro-3-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide 4-benzazolyl-5-(4-tert-butylphenyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-ka is oil acid;

tert-butyl ester (2S,4R)-4-(2-allyloxymethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-hydroxymethylpropane)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-hydroxymethylpropane)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-allyloxymethyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[(R)-2-allylamino-2-(4-chlorophenyl)-acetyl]-4-(2-allyloxymethyl)-pyrrolidin-2-carboxylic acid;

(2S,4R)-4-(2-chloro-4-(3,3-diversecity-1-yl)phenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide;

(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)-4-(phenylsulfonyl)pyrrolidin-2-carboxamide;

(2S,4R)-4-(benzylmethyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-itfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl the l)-1-[1-(2,4-dichloro-5-methoxyphenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(2,4-dichloro-5-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-methanesulfonamide-2-carboxylic acid;

(2S,4R)-4-(2-chloro-4-(3,3-diversecity-1-yl)phenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide;

(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide;

(1-cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-cyclopropanesulfonyl-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-the l-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-does not depend-1-yl)-cyclopropanecarbonyl]-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorphenoxy)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(diphenylmethylene)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromophenylacetonitrile)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-phenylmethanesulfonyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(4R)-4-[(2-chlorophenyl)sulfonyl]-N-(1-cyanocyclohexyl)-1-[1-(1,1-dissidocerida-2H-thiopyran-4-yl)-3-methyl-1H-pyrazole-5-yl]-L-prolinamide;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(3,3-diversecity-1-yl)-benzazolyl]-1-(2-cyclobutyl-5-methyl-2H-Piras the l-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(3,3-diversecity-1-yl)-benzazolyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-pyrrolidin-2-carboxylic acid;

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(3-phenylpropyl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid; and

(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(2-morpholine-4-retil)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid.

Soy is inane, proposed in the present invention, can be obtained, for example, according to the General methods of synthesis described below.

Scheme 1

Orthogonally protected CIS-4-hydroxy Proline, such as 1-tert-butyl ester (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid is introduced into reaction with a suitable derivative of aminoacetonitrile in the presence of one of the various reagents in combination with amide formation, such as BGP-Cl, TBTU, BOP, Rumor, HATU, EDCI/HOBT, DICK (diisopropylcarbodiimide)/NOUT; DCC (dicyclohexylcarbodiimide)/NOUT, etc. and receive the corresponding amide. Amide is introduced into the reaction sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or anhydride triftormetilfullerenov acid and get the connection A. the Reaction with thiols in the presence of a suitable base, such as NaH, LiHMDS, DIPEA (N,N,N-diisopropylethylamine), tea, etc., gives compounds of type C. the Oxidation of the obtained simple tiefer conduct an appropriate oxidizing reagent such as H2About2, Oxon, MJPBK etc., network connection With. the Protective group is removed, in the case of Boc as a protective group using TFA, HCl, or formic acid in a suitable solvent, such as THF, dioxane, CH2Cl2and so on, and get the ultimate connection D.

Scheme 2

PG = protective group (for example the EP, Cbz, Boc, Fmoc); LG = useplease group (for example, F, Cl, Br, I).

Orthogonally protected CIS-4-hydroxy Proline, such as 1-tert-butyl ether,2-methyl ester (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid is introduced into reaction with a suitable sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or anhydride triftormetilfullerenov acid and get a connection that is the Reaction of E with thiols in the presence of a suitable base, such as NaH, LiHMDS, DIPEA, tea, etc., gives compounds of type F. the Oxidation of the obtained simple tiefer conduct an appropriate oxidizing reagent, such as H2About2, Oxon, MJPBK, etc. and receive connections G. Saponification base, such as LiOH, NaOH, KOH or2CO3, Na2CO3Cs2CO3and so on, or acids network connection N. The reaction mix with the formation of amide N derived aminoacetonitrile is performed using one of the various reagent combinations, such as BGP-Cl, TBTU, BOP, Rumor, HATU, EDCI/HOBT, DICK/NOT; DC/NEWT, etc. and get a connection I. Connections To get by removal of the protective group of compound I with acids such as TFA, formic acid, HCl, etc., or bases, such as piperidine. Prolinamide To then you can modify alkylating reagents, such as R1-Hal (Hal = Cl, Br, I, TfO, etc.,) and aldehydes/ketones or acelerou what they reagents, such as carboxylic acids, carboxylic acid anhydrides, anhydrides, mixed anhydrides, sulphonylchloride, etc. and get connection L.

In addition, the compounds proposed in the present invention, can be obtained according to the methods below.

Scheme 3

Raand Rbindependently selected from the group comprising hydrogen and fluorine. Rcdenotes alkyl or benzyl, preferably methyl, ethyl or benzyl.

Optionally substituted with protected carboxypropyl derived cyclic amino acids, such as methyl ester of L-Proline, benzyl ester of L-Proline, ethyl ester of L-Proline, methyl ester of 4,4-debtor-L-Proline, ethyl ester of 4,4-debtor-L-Proline, benzyl ester 4,4-debtor-L-Proline, and the corresponding samopromzvolny Proline condense with formaldehyde in the presence of a suitable vinylsulfonic. The resulting regioisomers of pyrrolizine M and N amyraut base, such as LiOH, NaOH, KOH or2CO3, Na2CO3Cs2CO3and so on, or by acid or by catalytic hydrogenation to obtain the corresponding acid, which is introduced into reaction with derivatives of aminoacetonitrile when the combination with the amide formation in the presence of one of the various reagent combinations, such as BGP-Cl, TBTU, BOP, Rumor, HATU, EDCI/HOBT, DICK/BUT THE T; DC/NEWT, etc. and receive connections and R.

Scheme 4

R denotes methyl, ethyl, isopropyl or tert-butyl.

Connection type 1, obtained according to the methods described above, or by similar methods, can be converted into N-arylphosphonate type 2 (where R1=R11) by methods well known in the art, for example, catalyzed by copper or palladium N-arilirovaniya using arylboronic acids or arylboronic esters as a source of aryl and different types of salts of palladium or copper with ligands or without them, possibly in the presence of additives, such as a base or oxygen. Alternatively, compounds of type 2, in which R1=R11can be obtained by nucleophilic aromatic substitution of suitable donors aryl. Such reaction is carried out at room temperature or by heating, possibly in the presence of a base. Saponification base, such as LiOH, NaOH, KOH or2CO3, Na2CO3Cs2CO3and so on, or acid gives compound 3. The reaction mix with the formation of amide 3 derivative of aminoacetonitrile is performed using one of the various reagent combinations, such as BGP-Cl, TBTU, BOP, Rumor, HATU, EDCI/HOBT, DICK/NOT; DC/NOT, etc., or by formation of a mixed anhydride with alkyl what orformula, such as ethylchloride or isobutylparaben followed by reaction with aminoacetonitrile obtaining compounds 4.

Scheme 5

R denotes methyl, ethyl, isopropyl or tert-butyl.

R8denotes alkyl, phenyl, p-toluyl, m-toluyl, p-halogenfrei, p-nitrophenyl or m-nitrophenyl, preferably methyl, ethyl, phenyl, p-toluyl, m-toluyl, p-bromophenyl, p-nitrophenyl or m-nitrophenyl. Rddenotes hydrogen, methyl, fluorine, chlorine or trifluoromethyl. Redenotes alkyl, halogenated, hydroxyalkyl, halogenaryloxy, halogen, pyrazolyl, imidazolyl, benzoimidazolyl, 6-oxo-6N-pyridazinyl, alkyl-6-oxo-6N-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, ecomorphology, oxopyridine, 2-oxo-2H-pyrazinyl, ceftobiprole, galogenangidridy, piperidinecarboxylate or oceanologique. Repreferably denotes methyl, trifluoromethyl, tripterocarpa, cryptometer, hydroxymethyl, fluorine, bromine, chlorine, pyrazolyl, imidazolyl, benzoimidazolyl, 6-oxo-6N-pyridazinyl, alkyl-6-oxo-6N-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, OK is morpholinyl, oxopyridine, 2-oxo-2H-pyrazinyl, ceftobiprole, triftormetilfullerenov, piperidinyloxy or oceanologique.

CIS-hydroxyprolisilane ester 5 can be converted into compounds of type 6, in which R1=R11by techniques well known in the art, for example, catalyzed by copper or palladium N-arilirovaniya using arylboronic acids or arylboronic esters as a source of aryl and different types of salts of palladium or copper with ligands or without them, possibly in the presence of additives, such as a base or oxygen. Alternatively, compounds of type 6, in which R1=R11can be obtained by nucleophilic aromatic substitution of suitable donors aryl. Such reaction is carried out at room temperature or by heating, possibly in the presence of a base. Connection type 6 is introduced into reaction with the appropriate sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or anhydride triftormetilfullerenov acid and get the connection 7. The reaction of 7 with thiophenolate, which may contain a suitable useplease group (for example, F, Cl, Br, I, etc.,), in the presence of a suitable base, such as NaH, LiHMDS, DIPEA, tea, etc., gives compounds of type 8. Oxidation of the obtained simple tiefer conduct an appropriate oxidizing reagent, takimag H 2About2, Oxon, MJPBK, etc. and receive connections 9. Saponification base, such as LiOH, NaOH, KOH or2CO3, Na2CO3Cs2CO3and so on, or acids network connection 10. The reaction mix with the formation of amide 10 derivative of aminoacetonitrile is performed using one of the various reagent combinations, such as BGP-Cl, TBTU, BOP, Rumor, HATU, EDCI/HOBT, DICK/NOT; DC/NOT, etc., or by formation of a mixed anhydride with alkylchlorosilanes, such as ethylchloride or isobutylparaben followed by reaction with aminoacetonitrile with obtaining the compound (11). The remainder Reoptionally, you can enter or by aromatic nucleophilic substitution of amines, alcohols or heteroaromatic fragments in the presence of a base (for example, DIEA, tea, K2CO3, Na2CO3Cs2CO3and so on) or catalyzed by metal reactions combination and get a connection 12.

Scheme 6

R, Rdand Reare as defined above.

Rf, Rgand Rhindependently selected from the group comprising alkyl, halogen, halogenated, alkoxygroup, alkoxycarbonyl, halogenfree, halogenopyrimidines, oxopiperidine and the nitrogroup, preferably independently selected from the group comprising ethyl, fluorine, methoxy group, methoxycarbonyl, cryptometer, trifluoromethyl, chlorophenyl, forfinal, chloropyridinyl, oxopiperidine and the nitro-group.

Compounds of type 13, obtained according to the methods described above, or by similar methods, can be converted into β-ketoamide type 14 by reaction with a suitable complex β-ketefian, typically tert-butyl complex β-ketefian under conditions of thermal exchange by methods known in the art. The transformation into the corresponding thioamide 15 can be easily carried out, for example, by using a reagent Lawesson. The cyclization in the pyrazoles 16 is carried out by treatment with hydrazine when heated. The optional conversion of β-ketoamide 14 pyrazoles 16 also can be performed at dorectory technique. Saponification base, such as LiOH, NaOH, KOH or2CO3, Na2CO3Cs2CO3and so on, or acids network connection 17. The reaction mix with the formation of amide 17 derivative of aminoacetonitrile is performed using one of the various reagent combinations, such as BGP-Cl, TBTU, BOP, Rumor, HATU, EDCI/HOBT, DICK/NOT; DC/NOT, etc., or by formation of a mixed anhydride with alkylchlorosilanes, such as ethylchloride or isobutylparaben followed by reaction with aminoacetonitrile obtaining compounds 18.

Scheme 7

PG = protective group (for example, Cbz, Boc, Fmoc); LG = useplease group (for example, F, Cl, Br, I). Ri= methyl, ethyl, CF3, isopropyl, phenyl, 4-were, 3-were, 4-nitrophenyl, 3-nitrophenyl, 4-bromophenyl or 3-bromophenyl.

Orthogonally protected CIS-4-hydroxy Proline, such as 1-tert-butyl ether, 2-methyl ester (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid is introduced into reaction with a suitable sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or anhydride triftormetilfullerenov acid and get a connection 19. Reaction of 19 with thiophenolate that contain suitable useplease group (for example, F, Cl, Br, I, etc.,), in the presence of a suitable base, such as NaH, LiHMDS, DIPEA, tea, etc., network connection 20. Oxidation of the obtained simple tiefer conduct an appropriate oxidizing reagent such as H2About2, Oxon, MJPBK, etc. and get a connection 21. The remainder Reyou can enter or by aromatic nucleophilic substitution of amines, alcohols or heteroaromatic fragments in the presence of a base (for example, DIEA, tea, K2CO3, Na2CO3Cs2CO3and so on) or catalyzed by metal reactions combination and get a connection 22. Saponification base, such as LiOH, NaOH, KOH or2CO3, Na2CO3Cs2CO3and so what., or acids network connection 23. The reaction mix with the formation of amide 23 derivative of aminoacetonitrile is performed using one of the various reagent combinations, such as BGP-Cl, TBTU, BOP, Rumor, HATU, EDCI/HOBT, DICK/NOT; DC/NEWT, etc. and get a connection 24. Compound 25 is obtained by removal of the protective group of compound 24 with acids such as TFA, formic acid, HCl, etc., or bases, such as piperidine. Prolinamide 25 you can then modify alkylating reagents, such as R1-Hal (Hal = Cl, Br, I, TfO, etc.,) and aldehydes/ketones or allerease reagents such as carboxylic acids, carboxylic acid anhydrides, anhydrides, mixed anhydrides, sulphonylchloride, etc. and to obtain compound 26.

Alternative compounds can be obtained by using the sequence of reactions shown in scheme 8, using reaction conditions similar to those described above. In this sequence, Reintroduced at the final stage of transformation 33, 34.

Scheme 8

Alternative compounds can be obtained by using the sequence of reactions shown in scheme 9, using reaction conditions similar to those described above. In this sequence of H2N-C(R5R6)-CN injected at the final stage of turning 41, 42.

Scheme 9

Scheme 10

Tetra-substituted derivatives of pyrrolidine was obtained by methods similar to those described in the publication J. C. Carretero et al., Org. Lett., Vol.8, No.9, 2006, 1795-1798. Suitable amino acid condenses with the aldehyde and receive appropriate Imin in the presence of a dehydrating reagent, such as Na2SO4, CaCl2, MgCl2, molecular sieves, etc., In the presence of a source of Cu(I), such as CuClO4, CuOAc, or source of Ag(I), substituted vinylsulfonic and chiral ligand, such as Binap, Chiraphos, Norphos, Josiphos, Mandyphos, Taniaphos, etc. flows through the reaction of 1,3-dipolar cycloaddition. The subsequent introduction of a suitable protective group such as Boc, Fmoc, Cbz, etc., and saponification with LiOH, NaOH, etc., gives the corresponding protected on the N atom of the amino acid. The reaction of amino acids with cyclopropanecarbonitrile in the presence of a suitable reagent combination with amide formation, such as the OED, EDCI, DICK, DCC, HATU, TBTU, BOP, Rumor, and the subsequent removal of the protective group makes the final connection.

Scheme 11

Figure 11 R1and R2independently selected from the group comprising hydrogen and alkyl. R4denotes alkyl or benzyl, preferably methyl, ethyl or benzyl. R5and R6are as defined above. Rzdenotes CN, COOR, C(O)ONH or SO 2R (R = alkyl, alkylaryl, aryl, heteroaryl).

Arylsulfonamides derivatives protected by carboxylate cyclic amino acid X condense during the catalysis acid (TFA, MesOS, triftormetilfullerenov acid, HCl, HBr, H2SO4H3PO4and so on) with formaldehyde or aldehydes or ketones Y in the presence of a suitable activated vinylphosphonic Z. Derived derived pyrrolizine omelet base, such as LiOH, NaOH, KOH or2CO3, Na2CO3Cs2CO3and so on, or acids or subjected to catalytic hydrogenation and obtain the corresponding acid, which is introduced into reaction with derivatives of aminoacetonitrile when the combination with the amide formation in the presence of one of the various reagent combinations, such as BGP-Cl, TBTU, BOP, Rumor, HATU, EDCI/HOBT, DICK/NOT, DCC/NEWT, etc. and get the ultimate connection. If the connection Z contains a functional group that is unstable or reaktsionnosposobnykh when the conditions of the one or more reaction stages, before a critical stage by methods well known in the art, it is possible to introduce a suitable protective group (PG) (as described, for example, "Protective Groups in Organic Chemistry" by T. W. Greene and P. G. M. Wutts, 2nd Ed., 1991, Wiley N. Y.). Such protective group mo is but to remove at a later stage of the synthesis by standard methods, described in the literature.

Scheme 12

Figure 12 presents a modification of the above-described synthesis. It used the known ability of methansulfonate (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-3-one, 43 (registration No. CAS: 769167-53-5) to establish the relative and absolute configuration. After the introduction of the substituent on the N atom conduct combined with aminoacetonitrile and get hydroxyamide 45 using, for example, 2-ethylhexanoate sodium in the water. The free hydroxy-group 45 activate using, for example, chlorophenylsulfonyl. The sulfonate is substituted for the reaction SN2for the introduction of a simple thioester group. This simple thioether 47 is then oxidised in sulfon 48 using, for example, Oxon.

The present invention also relates to a method for obtaining compounds of formula (I) comprising one of the following stages:

(a) reaction of compounds of formula (Ia)

in the presence of a reagent that removes the protective group of amino group;

(b) reaction of compounds of formula (Ib)

in the presence of R1-A-X; or

(c) reaction of compounds of formula (Ic)

in the presence of H2N-CR5R6-CN;

in which A, R1-R6are as defined above and in which Y about the mean of the protective group of amino group.

Examples of the reagent, removing the protective group of the amino group, are TFA, HCl, MeSO3H, HBr/Asón, HCOOH, TBAF, hexafluoroisopropanol, piperidine and Pd(PPH3)4/Bu3SnH.

Examples of suitable protective groups for the amino groups are Z (benzyloxycarbonyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl), theos (trimethylsilylethynyl), Trt (trityl), Moz (4-methoxyphenylacetylene) and Alloc (allyloxycarbonyl).

Stage (a) is preferably carried out in a solvent selected from the group comprising dichloromethane, dioxane, acetonitrile, toluene, DMF, DMA, NMP, THF or acetic acid. The temperature of stage (a) is preferably equal to from -10 to +100°C.

Stage (b) is preferably carried out in a solvent selected from the group comprising dichloromethane, dioxane, acetonitrile, toluene, DMF, DMA, NMP and THF. The temperature of stage (b) is preferably equal to from -10 to +100°C.

Stage (C) is preferably carried out in a solvent selected from the group comprising dichloromethane, dioxane, acetonitrile, toluene, DMF, DMA, NMP and THF. The temperature of stage (C) is preferably equal to from -10 to +100°C and more preferably from -10 to +50°C.

The present invention also relates to the compound of formula (I) intended for use as therapeutically active substances.

In addition, the pharmaceutical composition, with whom containing a series connection of the formula (I) and a therapeutically inert carrier, also an object of the present invention.

The present invention also relates to the use of compounds of formula (I) for the preparation of drugs intended for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm disease peripheral artery or diabetic nephropathy.

The compounds of formula (I) can be used to treat cancer or reduce the incidence of cardiovascular disorders or diseases in patients with chronic kidney disease.

The compound of formula (I) obtained by the method proposed in the present invention, also is an object of the present invention.

In addition, the present invention also relates to a method of treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm disease peripheral artery or diabetic nephropathy, which includes the introduction of the compounds of formula (I) in an effective amount.

The present invention is illustrated by the following examples which are not limiting.

Examples

Abbreviations

Atsn: acetonitrile;

THIEF: benzotriazolyl-N-oxy-Tris(dimethylamino)-phosphodiesterase;

THIEF-Cl: acid chloride bis-(2-oxo-3-oxazolidinyl)-phosphinic acid;

CBI: 1,1'-carbonyldiimidazole;

DIA: Diisopropylamine is in;

DMA: N,N-dimethylacetamide;

DMF: N,N-dimethylformamide;

EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide;

HATU: O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyleneglutaric;

NOT: 1-hydroxybenzotriazole;

iPrOAc: isopropylacetate

LiHMDS: bis(trimethylsilyl)amide lithium;

MJPBK: 3-chloroperbenzoic acid;

Mes-Cl: methylchloride;

Na2SO4: sodium sulfate

NMP = N-methylpyrrolidone;

Nos-Cl: 3-nitrobenzenesulfonamide;

Rumor: benzotriazol-1-electropermeabilization;

The tea: triethylamine;

TBAF: tetrabutylammonium;

TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine;

THF: tetrahydrofuran;

TFK: triperoxonane acid; and

Tos-Cl: toluene-4-sulphonylchloride.

A. Synthesis of intermediate product, tert-butyl ester (2S,4S)-2-(1-cyanocyclohexane)-4-methanesulfonylaminoethyl-1-carboxylic acid And

A1. A mixture of tert-butyl ester (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (2.2 mmole) and 1-aminocyclohexanecarboxylic (2.2 mmole) in acetonitrile (5 ml) was sequentially treated with diisopropylethylamine (10.8 mmole), 1-hydroxybenzotriazole (2.2 mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (ejh, 2.4 mmole) and stirring was continued at 22°C for 4 h the Mixture was subjected to what the distribution between ethyl acetate and aqueous solution of sodium carbonate (1 N), organic matter was dried and evaporated. The residue was chromatographically on silica using a mixture of ethyl acetate/methanol (95:5) was obtained tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-hydroxypyrrolidine-1-carboxylic acid (390 mg) as a white solid. MS (mass spectrometry): 196,2 [M+H-BOC]+.

A2. To a solution of methanesulfonic acid (1.6 mmole) in THF (3 ml) was added triethylamine (1.6 mmole) and triphenylphosphine (1.7 mmole) and the mixture was stirred at 22°C for 30 minutes the Mixture to the solution was added tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-hydroxypyrrolidine-1-carboxylic acid (1.3 mmole) in THF (10 ml), then added diisopropylethylamine (1.7 mmole) and stirring was continued while boiling under reflux for 3 days. The reaction mixture was subjected to distribution between ethyl acetate and aqueous solution of KHSO4, the organic layer was dried, evaporated and the residue was chromatographically on silica using a mixture of cyclohexane/ethyl acetate (1:2) and obtained the desired compound (273 mg), containing small amounts of triphenylphosphine, in the form of a white solid. MS: 372,3 [M-N]-.

C. Synthesis of intermediate simple thioethers

General methods

To a solution of thiol (0,41 mmole) in THF (4 ml) was added NaH (55% in oil, 0,41 mmole) PR is 22°C and stirring was continued until gas evolution stops. To the mixture was added a solution of tert-butyl ester (2S,4S)-2-(1-cyanocyclohexane)-4-methanesulfonylaminoethyl-1-carboxylic acid (0,28 mmole, obtained in experiment A2) in THF (4 ml) and stirring continued at 50°C. until completion of reaction. The mixture was subjected to distribution between ethyl acetate and water, the organic layer was dried, evaporated and the residue was chromatographically on silica using mixtures of cyclohexane and ethyl acetate and received simple thioethers Century

B1. The reaction nelfinavir, obtained in experiment A2, 2-ethylbenzoyl gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-ethylvanillin)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 414,4 [M-N]-.

B2. The reaction nelfinavir, obtained in experiment A2, 2-mercaptobenzyl alcohol gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-hydroxymethanesulfinic)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 416,5 [M-N]-.

B3. The reaction nelfinavir, obtained in experiment A2, 2-cryptomaterial gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-cryptomaterial)-pyrrolidin-1-carboxylic acid as a colourless foam substances, MS: 470,3 [M-N]-.

B4. The reaction nelfinavir, obtained in experiment A2, 4 is imidazol-1-eventation (received in accordance with the patent application FR 2267101, 1975) gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(4-imidazol-1-intenlational)-pyrrolidin-1-carboxylic acid as a colourless foam substance. MS: 454,2 [M+H]+.

B5. The reaction nelfinavir, obtained in experiment A2, 2,4-dichlorodiphenyl gave tert-butyl ester ((2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 454.,3 [M-N]-.

B6. The reaction nelfinavir obtained in the experiment A2 with 2,6-dichlorodiphenyl gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid as a white solid. MS: 454,4 [M-N]-.

V7. The reaction nelfinavir, obtained in experiment A2, 2,4-Divertimento gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-differentsurfaces)-pyrrolidin-1-carboxylic acid as a colourless foam substance. MS: 422,2 [M-N]-.

B8. To a solution of 4-bromo-2-triftormetilfullerenov (4,85 g) in dioxane (29 ml) at 22°C was added water (6.5 ml) and Tris-(2-carboxyethyl)fosphenytoin (17.3 g) and the mixture is boiled under reflux for 6 hours, the Cooled mixture was subjected to distribution between water and dichloromethane, the organic layer was washed with water, dried and evaporated and received net Brom-2-trifloromethyl (of 3.85 g) as a colourless liquid. MS: 257,2 and 255,1 [M-N]-.

The reaction nelfinavir, obtained in experiment A2, 4-bromo-2-triftoratsetilatsetonom gave tert-butyl ester (2S,4R)-4-(4-bromo-2-triftormetilfullerenov)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as a colourless foam substance. MS: 436,2 and 434,2 [M+H-Boc]+.

C. Synthesis of sulfones With

General methods

The solution is simple thioethers (0.1 mmole) in dichloromethane (1 ml) was added a solution of m-chloroperbenzoic acid (70%, 0.4 mmole) in dichloromethane (2 ml) and stirring was continued at 22°C to complete the reaction. The mixture was vigorously shaken with an aqueous solution of NaHSO3, the organic layer was washed with an aqueous solution of Na2CO3and water, the organic layer was dried, evaporated and the residue was chromatographically on silica using mixtures of cyclohexane and ethyl acetate and received sulfones C.

C1. The oxidation of simple tiefer obtained in experiment B1, gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-ethylbenzonitrile)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 348,2 [M+H-BOC]+.

Example 1

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-hydroxymethanesulfinic)-pyrrolidin-1-carboxylic acid

C2. The oxidation of simple tiefer obtained the experiment B2, gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-hydroxymethanesulfinic)-pyrrolidin-1-carboxylic acid as a colourless foam substance. MS: 448,4 [M-N]-.

Example 2

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid

C3. The oxidation of simple tiefer obtained in the experiment B3, gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid as a colourless foam substance. MS: 502,4 [M-N]-.

Example 3

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(4-imidazol-1-eventality)-pyrrolidin-1-carboxylic acid

C4. The oxidation of simple tiefer obtained in the experiment B4, gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(4-imidazol-1-eventality)-pyrrolidin-1-carboxylic acid as a white solid. MS: 484,3 [M-N]-.

Example 4

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid

C5. The oxidation of simple tiefer obtained in experiment B5, gave tert-butyl ester (2S,4R)-2-(1-Ciani cloprostenol)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid as a white solid. MS: 486,5 [M-N]-.

Example 5

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid

C6. The oxidation of simple tiefer obtained in the experiment B6, gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 486,5 [M-N]-.

Example 6

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-differentiality)-pyrrolidin-1-carboxylic acid

C7. The oxidation of simple tiefer obtained in the experiment V7, gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-differentiality)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 454,4 [M-N]-.

Example 7

Tert-butyl ester (2S,4R)-4-(4-bromo-2-trifloromethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

C8. The oxidation of simple tiefer obtained in the experiment B8, gave tert-butyl ester (2S,4R)-4-(4-bromo-2-trifloromethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as a white solid. MS: 566,2 and 564,2 [M-N]-.

C9. A mixture of bromide (0,18 mmole) obtained in experiments the e C8, 1H-pyrazole (0,20 mmole)2CO3(30 mg) and CuI (7 mg) in N,N-dimethylformamide (1 ml) was treated with microwave radiation at 140°C to complete the reaction. The mixture was subjected to distribution between water and ethyl acetate, the organic layer was dried and evaporated. The residue was purified using preparative HPLC on a column of RP-18 in gradient mode using a mixture of acetonitrile and water were obtained tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-1-carboxylic acid as a pale yellow solid. MS: 552,2 [M-N]-.

C10. Reaction of the bromide obtained in the experiment C8 and 1H-imidazole carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-1-carboxylic acid as a yellow oil. MS: 554,3 [M+H]+.

Example 8

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid

C11. Reaction of the bromide obtained in the experiment C8 and 1-methylpiperazine carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(4-methylpiperazin-1-yl)-2-cryptomaterial is of IMT]-pyrrolidin-1-carboxylic acid as a white powder. MS: 586,2 [M+H]+.

Example 9

Tert-butyl ester (2S,4R)-4-(4-benzimidazole-1-yl-2-trifloromethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

C12. Reaction of the bromide obtained in the experiment C8 and 1H-benzimidazole carried out according to experiment C9 gave tert-butyl ester (2S,4R)-4-(4-benzimidazole-1-yl-2-trifloromethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as a yellow solid. MS: 604,3 [M+H]+.

Example 10

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(3-methyl-6-oxo-6N-pyridazin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid

C13. Reaction of the bromide obtained in the experiment C8 and 6-methyl-2H-pyridazin-3-it is carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(3-methyl-6-oxo-6N-pyridazin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid as a white powder. MS: 596,2 [M+H]+.

C14. Reaction of the bromide obtained in the experiment C8 and 2-methyl-1H-imidazole carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(2-Mei-1-yl)-2-cryptomaterial Lionel]-pyrrolidin-1-carboxylic acid as a pale yellow oil. MS: 568,3 [M+H]+.

15. Reaction of the bromide obtained in the experiment C8 and 2-phenyl-1H-imidazole carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(2-phenylimidazol-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid as a pale yellow oil. MS: 630,3 [M+H]+.

C16. Reaction of the bromide obtained in the experiment C8 and pyrrolidin-2-it is carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(2-oxopyrrolidin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid as colorless oil. MS: 471,3 [M+H-BOC]+.

C17. Reaction of the bromide obtained in the experiment C8 and oxazolidin-2-it is carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(2-oxoacridine-3-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid as a pale yellow oil. MS: 571,5 [M-N]-.

C18. Reaction of the bromide obtained in the experiment C8 and 3,3-debtorprovidian carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(3,3-debtorprovidian-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid as a pale yellow oil. MS: 493,2 [M+H-BOC]+ .

C19. Reaction of the bromide obtained in the experiment C8 and the research, carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(4-(morpholine-4-yl-2-trifloromethyl)-pyrrolidin-1-carboxylic acid as a pale red oil. MS: 473,1 [M+H-BOC]+.

C20. Reaction of the bromide obtained in the experiment C8 and morpholine-3-it is carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(3-exmortis-4-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid as a pale yellow oil. MS: 487,3 [M+H-BOC]+.

C21. Reaction of the bromide obtained in the experiment C8 and 1H-pyridine-2-it is carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(2-oxo-2H-pyridin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid as colorless oil. MS: 481,2 [M+H-BOC]+.

C22. Reaction of the bromide obtained in the experiment C8 and 1H-pyrazin-2-it is carried out according to experiment C9 gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(2-oxo-2H-pyrazin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid as a yellow oil. MS: 482,1 [M+H-BOC]+.

D. Synthesis of prolinol D

General methods

the solution sulfones (0.1 mmole) in 1,4-dioxane (2 ml) was added a solution of 4M HCl in 1,4-dioxane (0.8 mmole) and stirring was continued at 22°C to complete the reaction. The mixture was diluted with diethyl ether (8 ml), the suspension was filtered and the residue was dried and got Proline D.

Example 11

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-ethylbenzonitrile)-pyrrolidin-2-carboxylic acid

D1. Cleavage of the protective group of the sulfone obtained in the experiment C1, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-ethylbenzonitrile)-pyrrolidin-2-carboxylic acid as a white solid. MS: 346,3 [M-N]-.

Example 12

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-hydroxymethanesulfinic)-pyrrolidin-2-carboxylic acid

D2. Cleavage of the protective group of the sulfone obtained in experiment C2, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-hydroxymethanesulfinic)-pyrrolidin-2-carboxylic acid as a white solid. MS: 348,3 [M-N]-.

Example 13

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

D3. Cleavage of the protective group of the sulfone obtained in the experiment C3, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 404,3 [M+H]+.

Example 14

(1 Cyanotic propyl)-amidogidrolaza (2S,4R)-4-(4-imidazol-1-eventality)-pyrrolidin-2-carboxylic acid

D4. Cleavage of the protective group of the sulfone obtained in the experiment C4, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-imidazol-1-eventality)-pyrrolidin-2-carboxylic acid as a pale yellow solid. MS: 386,1 [M+H]+.

Example 15

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

D5. Cleavage of the protective group of the sulfone obtained in the experiment C5, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 388,1 [M+H]+.

Example 16

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

D6. Cleavage of the protective group of the sulfone obtained in the experiment C6, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 388,1 [M+H]+.

Example 17

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2,4-differentiality)-pyrrolidin-2-carboxylic acid

D7. Cleavage of the protective group of the sulfone obtained in the experiment C7, gave (1-cyanocyclohexyl)-amide is hydrochlorid (2S,4R)-4-(2,4-differentiality)-pyrrolidin-2-carboxylic acid as a white solid. MS: 356,1 [M+H]+.

Example 18

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-bromo-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

D8. Cleavage of the protective group of the sulfone obtained in the experiment C8, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-bromo-2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 468,0 and 466,1 [M+H]+.

Example 19

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

D9. Cleavage of the protective group of the sulfone obtained in the experiment C9 gave (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a pale yellow foam substance. MS: 454,2 [M+H]+.

Example 20

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

D10. Cleavage of the protective group of the sulfone obtained in the experiment C10, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a pale yellow solid. MS: 454,2 [M+H]+.

Example 21

(Cyanocobalamin)-amidogidrolaza (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

D11. Cleavage of the protective group of the sulfone obtained in the experiment C11, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a white solid. MS: 486,3 [M+H]+.

Example 22

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-benzimidazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

D12. Cleavage of the protective group of the sulfone obtained in the experiment C12, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-benzimidazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 504,1 [M+H]+.

Example 23

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(3-methyl-6-oxo-6N-pyridazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

D13. Cleavage of the protective group of the sulfone obtained in the experiment C13, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(3-methyl-6-oxo-6N-pyridazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a white solid. MS: 496,3 [M+H]+.

Example 24

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-Mei-1-yl)-2-trifloromethyl]-Pierre is lidin-2-carboxylic acid

D14. Cleavage of the protective group of the sulfone obtained in the experiment C14, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-Mei-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a pale yellow solid. MS: 468,2 [M+H]+.

Example 25

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-phenylimidazol-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

D15. Cleavage of the protective group of the sulfone obtained in the experiment C15, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-phenylimidazol-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a pale yellow solid. MS: 530,1 [M+H]+.

Example 26

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-oxopyrrolidin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

D16. Cleavage of the protective group of the sulfone obtained in the experiment C16, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-oxopyrrolidin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a yellow oil. MS: 471,3 [M+H]+.

Example 27

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-oxoacridine-3-yl)-2-trifloromethyl]-pyrrole the Jn-2-carboxylic acid

D17. Cleavage of the protective group of the sulfone obtained in the experiment C17, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-oxoacridine-3-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a yellow oil. MS: 473,1 [M+H]+.

Example 28

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(3,3-debtorprovidian-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

D18. Cleavage of the protective group of the sulfone obtained in the experiment C18, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(3,3-debtorprovidian-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a yellow oil. MS: 493,2 [M+H]+.

Example 29

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-(morpholine-4-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

D19. Cleavage of the protective group of the sulfone obtained in the experiment C19, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-(morpholine-4-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a pale brown solid. MS: 473,2 [M+H]+.

Example 30

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(3-exmortis-4-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

D20. Cleavage of the protective group of the sulfone obtained in the experiment C20, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(3-exmortis-4-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a yellow solid. MS: 487,3 [M+H]+.

Example 31

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-oxo-2H-pyridin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

D21. Cleavage of the protective group of the sulfone obtained in the experiment C21, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-oxo-2H-pyridin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a yellow solid. MS: 481,2 [M+H]+.

Example 32

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-oxo-2H-pyrazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

D22. Cleavage of the protective group of the sulfone obtained in the experiment C22, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-[4-(2-oxo-2H-pyrazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as a yellow oil. MS: 482,1 [M+H]+.

E. Synthesis of the intermediate product, 1-tert-butyl ether,2-methyl ester (2S,4S)-4-methanesulfonylaminoethyl-1,2-dicarboxylic acid of the Sabbath.

The desired compound was obtained from 1-tert-butyl ether,2-methyl ester (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid according to method A2. MS: 324,4 [M+H]+.

F. Synthesis of intermediate simple thioethers F

General methods

Simple thioethers F was obtained from 1-tert-butyl ether,2-methyl ester (2S,4S)-4-methanesulfonylaminoethyl-1,2-dicarboxylic acid obtained in the experiment E, and thiols using General method C.

F1. The reaction nelfinavir with bentolila gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-phenolsulfonephthalein-1,2-dicarboxylic acid in the form of a pale yellow oil. MS: 338,4 [M+H]+.

F2. The reaction nelfinavir with 2-chloro-bentolila gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2-chlorophenylsulfonyl)-pyrrolidine-1,2-dicarboxylic acid as a white solid. MS: 372,1 [M+H]+.

F3. The reaction nelfinavir with 2 triftoratsetilatsetonom gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2-triftormetilfullerenov)-pyrrolidine-1,2-dicarboxylic acid in the form of a colorless oil. MS: 406,2 [M+H]+.

F4. The reaction nelfinavir with 2,4-dimethylbenzoyl gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid in the form of a colorless oil. MS: 366,2 [M+H]+.

F5. The reaction nelfinavir with 4-chloro-2-methylbenzothiazol gave the 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(4-chloro-2-methylphenylsulfonyl)-pyrrolidine-1,2-dicarboxylic acid in the form of a colorless oil. MS: 386,2 [M+H]+.

F6. The reaction nelfinavir with 2,3-dichloro-bentolila gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid in the form of a pale yellow oil. MS: 306,1 [M+H-BOC]+.

G. Synthesis of intermediate sulfonic esters G

Sulfonic esters G were obtained from simple thioethers F using General method C.

G1. The oxidation of simple tiefer obtained in the experiment F1, gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-benzensulphochloramide-1,2-dicarboxylic acid in the form of a colorless oil. MS: 370,1 [M+H]+.

G2. The oxidation of simple tiefer obtained in experiment F2, gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid in the form of a colorless oil. MS: 404,5 [M+H]+.

G3. The oxidation of simple tiefer obtained in the experiment F3, gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid in the form of a colorless oil. MS: 438,1 [M+H]+.

G4. The oxidation of simple tiefer obtained in the experiment F4, gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid in the form of a colorless oil. MS: 298,3 [M+H-BOC]+.

G5. The oxidation of simple tiefer obtained in the experiment F5 gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid in the form of a colorless oil. MS: 318,1 [M+H-BOC]+.

G6. The oxidation of simple tiefer obtained in the experiment F6, gave 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid in the form of a colorless oil. MS: 338,1 [M+H-BOC]+.

N. Synthesis of intermediate acids N

General methods

To a solution of sulfonic esters G (of 1.35 mmole) in THF (10 ml) was added a solution of LiOH (3.0 mmole) in water (3 ml) and methanol (3 ml) and stirring was continued at 22°C to complete the reaction. The mixture is evaporated and the residue was subjected to distribution between ethyl acetate and hydrochloric acid (0.1 N.). The organic layer was dried, evaporated and the residue triturated with ether or pentane and got acid N.

H1. Hydrolysis of ester sulfone obtained in the experiment G1, gave 1-tert-butyl ester (2S,4R)-4-benzensulphochloramide-1,2-dicarboxylic acid in the form of an amorphous white solid. MS: 354,4 [M-N]-.

H2. Hydrolysis of ester sulfone obtained in experiment G2, gave 1-tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid as a colourless foam substance. MS: 289,9 [M+H-Boc]+.

H3. Hydrolysis of the complex is Fira sulfone, obtained in the experiment G3, gave 1-tert-butyl ester (2S,4R)-4-(2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid as a white solid. MS: 422,3 [M-N]-.

H4. Hydrolysis of ester sulfone obtained in experiment G4, gave 1-tert-butyl ester (2S,4R)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid as a white solid. MS: 382,4 [M-N]-.

H5. Hydrolysis of ester sulfone obtained in the experiment G5, gave 1-tert-butyl ester (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid as a white solid. MS: 402,4 [M-N]-.

N6. Hydrolysis of ester sulfone obtained in the experiment G6, gave 1-tert-butyl ester (2S,4R)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid as a white solid. MS: 424,2 [M-N]-.

I. Synthesis of NITRILES I

General methods

To a solution of the acid H (10 mmole) and 4-methylmorpholine (30 mmole) in THF (50 ml) at -15°C was added isobutylparaben (12 mmole) and stirring was continued until the formation of the intermediate mixed anhydride. The mixture was treated at the same temperature a solution of aminonicotinamide (12 mmole) in dimethylformamide (17 ml) and stirring was continued until completion of the reaction. The mixture was subjected to distribution between ethyl acetate and aq is m solution of NH 4Cl, the organic layer was washed in an aqueous solution of NaHCO3, dried, evaporated and the residue was chromatographically on silica using mixtures of ethyl acetate and n-heptane and got NITRILES I.

I1. The reaction mix acid obtained in the experiment H2, and aminoacetonitrile gave tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(cyanomethylene)-pyrrolidin-1-carboxylic acid as white amorphous solids. MS: TO 426.2 [M-N]-.

I2. The reaction mix acid obtained in the experiment H3, and aminoacetonitrile gave tert-butyl ester (2S,4R)-2-(cyanomethylene)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid as white amorphous solids. MS: 460,5 [M-N]-.

I3. The reaction mix acid obtained in the experiment H1, and 1-aminocyclohexanecarboxylic gave tert-butyl ester (2S,4R)-4-benzazolyl-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as white amorphous solids. MS: 320,1 [M+H-Boc]+.

I4. The reaction mix acid obtained in the experiment H2, and 1-aminocyclohexanecarboxylic gave tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as a colourless foam substance. MS:354,1 [M+H-Boc] +.

I5. The reaction mix acid obtained in the experiment H3, and 1-aminocyclohexanecarboxylic gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid as a white solid. MS: 486,5 [M-N]-.

Example 33

Tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(centimetres)-carbarnoyl]-pyrrolidin-1-carboxylic acid

I6. The reaction mix acid obtained in the experiment H2, and 2-amino-2-methylpropionitrile gave tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(centimetres)-carbarnoyl]-pyrrolidin-1-carboxylic acid as colorless oil. MS: 456,2 [M+H]+.

Example 34

Tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

I7. The reaction mix acid obtained in the experiment H2, and 1-aminocyclohexanecarboxylic gave tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as a colourless oil, MS: 468,2 [M+H]+.

Example 35

Tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexyl)-pyrrolidin-1-carboxylic acid

I8. The reaction mix acid obtained in the experiment H2, and 1-aminocyclohexanecarboxylic gave tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexyl)-pyrrolidin-1-carboxylic acid as colorless solid. MS: 496,3 [M+H]+.

Example 36

Tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(cianfanelli)-carbarnoyl]-pyrrolidin-1-carboxylic acid

I9. The reaction mix acid obtained in the experiment H2, and rat-aminophenylacetylene gave tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(cianfanelli)-carbarnoyl]-pyrrolidin-1-carboxylic acid as a colourless foam substance. MS: 504,1 [M+H]+.

Example 37

Tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(cyanomethylene)-carbarnoyl]-pyrrolidin-1-carboxylic acid

I10. The reaction mix acid obtained in the experiment H2, and rat-2-amino-2-phenylpropionaldehyde gave tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(cyanomethylene)-carbarnoyl]-pyrrolidin-1-carboxylic acid as a pale yellow solid. MS: 518,2 [M+H]+.

Example 38

Tert-butyl ester (2S,4R)-2-[(cyanocobalamin)-carbarnoyl]-4-(2-trifloromethyl)-Pirro is one-1-carboxylic acid

I11. The reaction mix acid obtained in the experiment H3, and rat-aminocyclohexanecarboxylic (receipt described in T. Gabriel et al., application for international patent WO 2004106285, 2004) gave tert-butyl ester (2S,4R)-2-[(cyanocobalamin)-carbarnoyl]-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 402,2 [M+H-BOC]+.

Example 39

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidin-1-carboxylic acid

I12. The reaction mix acid obtained in the experiment H4, and 1-aminocyclohexanecarboxylic gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 348,2 [M+H-Boc]+.

Example 40

Tert-butyl ester (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

I13. The reaction mix acid obtained in the experiment H5 and 1-aminocyclohexanecarboxylic gave tert-butyl ester (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as white amorphous solids. MS: 368,0 [M+H-BOC]sup> +.

Example 41

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid

I14. The reaction mix acid obtained in the experiment N6, and 1-aminocyclohexanecarboxylic gave tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid as white amorphous solids. MS: 388,1 [M+H-Boc]+.

K. Synthesis of prolinol To

Proline To received from NITRILES I using General method D.

K1. Cleavage of the protective group of the nitrile obtained in experiment I1, gave cyanomethaemoglobin (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 328,1 [M+H]+.

K2. Cleavage of the protective group of the nitrile obtained in the experiment I2, gave cyanomethaemoglobin (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 362,2 [M+H]+.

K3. Cleavage of the protective group of the nitrile obtained in the experiment I3 held in triperoxonane acid at 22°C and received (1-cyanocyclohexyl)-nitrilotriacetate (2S,4R)-4-benzensulphochloramide-2-carboxylic acid as colorless oil. MS: 320,0 [M+H]+.

Example 42

(1-Cenotillo ropyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

Q4. Cleavage of the protective group of the nitrile obtained in the experiment, I4, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as colorless solid. MS: 354,1 [M+H]+.

Example 43

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

K5. Cleavage of the protective group of the nitrile obtained in the experiment I5, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless solid. MS: 388,1 [M+H]+.

Example 44

(Centimetres)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

K6. Cleavage of the protective group of the nitrile obtained in the experiment I6, gave (centimetres)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 356,0 [M+H]+.

Example 45

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

C7. Cleavage of the protective group of the nitrile obtained in the experiment I7, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorine is benzazolyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 368,1 [M+H]+.

Example 46

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

K8. Cleavage of the protective group of the nitrile obtained in the experiment I8, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 396,1 [M+H]+.

Example 47

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid

K9. Cleavage of the protective group of the nitrile obtained in the experiment I9, gave a 1:1 mixture of epimeres (cianfanelli)-americanled (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a pale yellow solid. MS: 404,2 [M+H]+.

Example 48

(Cyanomethylene)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

K10. Cleavage of the protective group of the nitrile obtained in the experiment I10, gave a 1:1 mixture of epimeres (cyanomethylene)-americanled (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a pale yellow solid. MS: 418,2 [M+H]+.

Example 49

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2,4-dimethylbenzoic Lionel)-pyrrolidin-2-carboxylic acid

C. Cleavage of the protective group of the nitrile obtained in the experiment I12, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 348,1 [M+H]+.

Example 50

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid

K12. Cleavage of the protective group of the nitrile obtained in the experiment I13, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 368,0 [M+H]+.

Example 51

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

K13. Cleavage of the protective group of the nitrile obtained in the experiment I14, gave (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 388,1 [M+H]+.

L. Synthesis of prolinol L

Proline L was obtained from prolinol To

Example 52

Cyanomethylene (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid

L1. Cyanomethaemoglobin (2S,4R)-4-benzensulphochloramide-2-carb is a new acid, obtained by analogy with the experiment K1, was introduced in the reaction mix with benzoic acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-benzoyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as colorless solid. MS: 458,2 [M+H]+.

Example 53

Cyanomethylene (2S,4R)-4-benzazolyl-1-cyclohexanecarbonitrile-2-carboxylic acid

L2. Cyanomethaemoglobin (2S,4R)-4-benzensulphochloramide-2-carboxylic acid, obtained by analogy with the experiment K1, was introduced in the reaction mix with cyclohexanecarbonyl acid analogously to experiment A1 and received cyanomethylene (2S,4R)-4-benzazolyl-1-cyclohexanecarbonitrile-2-carboxylic acid as a white solid. MS: 404,3 [M+H]+.

Example 54

Cyanomethylene (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid

L3. To a suspension of cyanomethaemoglobin (2S,4R)-4-benzensulphochloramide-2-carboxylic acid (0,13 mmole), obtained by analogy with the experiment K1, in THF (1 ml) was added acetic acid (15 ml), then was added benzaldehyde (of 0.14 mmole) and stirring was continued at 22°C for 1 h to One portion was added triacetoxyborohydride sodium (or 0.38 mmole) and stirring was continued is at 22°C for 3 hours The reaction was stopped with an aqueous solution of HCL and the Meon and the solution was purified using preparative HPLC (RP-18) using a mixture of acetonitrile and water and got cyanomethylene (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid as colorless oil. MS: 384,1 [M+H]+.

Example 55

Cyanomethylene (2S,4R)-4-benzazolyl-1-cyclohexylpiperidine-2-carboxylic acid

L4. Cyanomethaemoglobin (2S,4R)-4-benzensulphochloramide-2-carboxylic acid, obtained by analogy with the experiment K1, subjected recovery aminating cyclohexanecarboxaldehyde similar to the L3 experiment and received cyanomethylene (2S,4R)-4-benzazolyl-1-cyclohexylpiperidine-2-carboxylic acid as a white solid. MS: RUR 390.4 [M+H]+.

Example 56

Cyanomethylene (2S,4R)-4-benzazolyl-1-(2,2,2-Cryptor-1-phenylethyl)-pyrrolidin-2-carboxylic acid

L5. To a solution of 1-phenyl-2,2,2-triptoreline (0.4 mmole) in dichloromethane (1.4 ml) at -50°C was added diisopropylethylamine (2.0 mmole) and the anhydride triftormetilfullerenov acid (at 0.42 mmole) and stirring was continued at -50° for 1 hour To the mixture at -50°C was added a solution of cyanomethaemoglobin (2S,4R)-4-benzensulphochloramide-2-carboxylic acid (0.4 mmole), obtained what about the analogy with the experiment K1, in dichloromethane (0.4 ml) and stirring was continued at 22°C for 2 days. The mixture was subjected to distribution between ethyl acetate and water, the organic layer was dried, evaporated and the residue was chromatographically on the silicon dioxide and got cyanomethylene (2S,4R)-4-benzazolyl-1-(2,2,2-Cryptor-1-phenylethyl)-pyrrolidin-2-carboxylic acid as colorless solid. MS: 452,1 [M+H]+.

Example 57

Cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-Cryptor-1-phenylethyl)-pyrrolidin-2-carboxylic acid

L6. Cyanomethaemoglobin (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K1, was introduced in the reaction with 1-phenyl-2,2,2-triptoreline as described in experiment L5, and got cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-Cryptor-1-phenylethyl)-pyrrolidin-2-carboxylic acid as white amorphous solids. MS: 486,2 [M+H]+.

Example 58

Cyanomethylene (2S,4R)-1-benzoyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

L7. Cyanomethaemoglobin (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K1, was introduced in the reaction mix with benzoic acid analogously to experiment A1 and received cyanomethylene (2S,4R)-1-benzoyl-4-(2-chlorbenzoyl who were radioactive)-pyrrolidin-2-carboxylic acid as an amorphous solid. MS: 432,2 [M+H]+.

Example 59

Cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-perbenzoic)-pyrrolidin-2-carboxylic acid

L8. Cyanomethaemoglobin (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K1, was introduced in the reaction mix with 4-fermenting acid analogously to experiment A1 and received cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-perbenzoic)-pyrrolidin-2-carboxylic acid as colorless oil. MS: OF 450.1 [M+H]+.

Example 60

Cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexanecarbonitrile-2-carboxylic acid

L9. Cyanomethaemoglobin (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K1, was introduced in the reaction mix with cyclohexanecarbonyl acid analogously to experiment A1 and received cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexanecarbonitrile-2-carboxylic acid as colorless oil. MS: 438,1 [M+H]+.

Example 61

Cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-propenylboronic-2-carboxylic acid

L10. Cyanomethaemoglobin (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K1, was introduced in the region who share the combination with propionic acid analogously to experiment A1 and received cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-propenylboronic-2-carboxylic acid as colorless oil. MS: 384,1 [M+H]+.

Example 62

Cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-methoxyacetyl)-pyrrolidin-2-carboxylic acid

L11. Cyanomethaemoglobin (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K1, was introduced in the reaction mix with methoxybutanol acid analogously to experiment A1 and received cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-methoxyacetyl)-pyrrolidin-2-carboxylic acid as a colourless foam substance. MS: 400,1 [M+H]+.

Example 63

Cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-oxetan-3-iparralde-2-carboxylic acid

L12. Cyanomethaemoglobin (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K1 subjected recovery aminating oxetan-3-one (obtained in accordance with the publication of G. Wuitschik et al., Angewandte Chemie, International Edition(2006), 45(46), 7736) similarly, the L3 experiment and received cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-oxetan-3-iparralde-2-carboxylic acid as a colourless foam substance. MS: 384,1 [M+H]+.

Example 64

Cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(tetrahydropyran-4-yl)-pyrrolidin-2-carboxylic acid

L13. Cyanomethylene drochloride (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid, obtained in the experiment K1 subjected recovery aminating tetrahydro-4H-Piran-4-one similar to the L3 experiment and received cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(tetrahydropyran-4-yl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 412,1 [M+H]+.

Example 65

Cyanomethylene (2S,4R)-1-(4-perbenzoic)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L14. Cyanomethaemoglobin (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K2, was introduced in the reaction mix with 4-fermenting acid analogously to experiment A1 and received cyanomethylene (2S,4R)-1-(4-perbenzoic)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: Ozenmunaygas given KZT 484.1 ecological [M+H]+.

Example 66

Cyanomethylene (2S,4R)-1-(4-methylbenzoyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L15. Cyanomethaemoglobin (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K2, was introduced in the reaction mix with 4-methylbenzoic acid analogously to experiment A1 and received cyanomethylene (2S,4R)-1-(4-methylbenzoyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid in the form of bescoto the oil. MS: 480,1 [M+H]+.

Example 67

Cyanomethylene (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L16. Cyanomethaemoglobin (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K2, was introduced in the reaction mix with cyclohexanecarbonyl acid analogously to experiment A1 and received cyanomethylene (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 472,2 [M+H]+.

Example 68

Cyanomethylene (2S,4R)-1-(tetrahydropyran-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L17. Cyanomethaemoglobin (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K2, was introduced in the reaction mix with tetrahydropyran-4-carboxylic acid analogously to experiment A1 and received cyanomethylene (2S,4R)-1-(tetrahydropyran-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 474,1 [M+H]+.

Example 69

Cyanomethylene (2S,4R)-1-(pyridine-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L18. Cyanomethylene the hydrochloride, (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid, obtained in the experiment K2, was introduced in the reaction mix with isonicotinic acid analogously to experiment A1 and received cyanomethylene (2S,4R)-1-(pyridine-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 467,2 [M+H]+.

Example 70

Cyanopyrimidine (2S,4R)-1-(1-methylpiperidin-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L19. Cyanomethaemoglobin (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K2, was introduced in the reaction mix with 1 methylpiperidin-4-carboxylic acid analogously to experiment A1 and received cyanomethylene (2S,4R)-1-(1-methylpiperidin-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid, salt with formic acid as a colourless oil. MS: 487,3 [M+H]+.

Example 71

Cyanomethylene (2S,4R)-1-benzoyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L20. Cyanomethaemoglobin (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K2, was introduced in the reaction mix with benzoic acid analogously to experiment A1 and received cyanomethylene (2S,4R)-1-benzoyl-4-(2-trifloromethyl)-the feast of ridin-2-carboxylic acid as colorless oil. MS: 466,2 [M+H]+.

Example 72

cyclopentyloxy ester (2S,4R)-2-(cyanomethylene)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid

L21. To a suspension of cyanomethaemoglobin (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (0,13 mmole) obtained in the experiment K2, in acetonitrile (1 ml) at 22°C was added diisopropylethylamine (0.40 mmole) and cyclopentylamine (0.15 mmole) and stirring was continued for 2 hours the Reaction was stopped with methanol, acidified with acetic acid and purified using preparative HPLC (RP-18) using a mixture of acetonitrile and water and received cyclopentyloxy ester (2S,4R)-2-(cyanomethylene)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 474,1 [M+H]+.

Example 73

(1-Cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid

L22. (1-Cyanocyclohexyl)-nitrilotriacetate (2S,4R)-4-benzensulphochloramide-2-carboxylic acid obtained in the experiment K3, was introduced in the reaction mix with benzoic acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid as a pale yellow solid. MS: 424,2 [M+H]+ .

Example 74

(1-Cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-(tetrahydropyran-4-carbonyl)-pyrrolidin-2-carboxylic acid

L23. (1-Cyanocyclohexyl)-nitrilotriacetate (2S,4R)-4-benzensulphochloramide-2-carboxylic acid obtained in the experiment K3, was introduced in the reaction mix with tetrahydropyran-4-carboxylic acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-(tetrahydropyran-4-carbonyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 432,3 [M+H]+.

Example 75

(1-Cyanocyclohexyl)-amide (2S,4R)-1-benzoyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

L24. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was introduced in the reaction mix with benzoic acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-benzoyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as colorless solid. MS: 458,2 [M+H]+.

Example 76

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-perbenzoic)-pyrrolidin-2-carboxylic acid

L25. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-arbonboy acid, obtained in the experiment K4 was introduced in the reaction mix with 4-fermenting acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-perbenzoic)-pyrrolidin-2-carboxylic acid as white amorphous solids. MS: 476,0 [M+H]+.

Example 77

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexanecarbonitrile-2-carboxylic acid

L26. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was introduced in the reaction mix with cyclohexanecarbonyl acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexanecarbonitrile-2-carboxylic acid as colorless oil. MS: 464,1 [M+H]+.

Example 78

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-formylpyridine-2-carboxylic acid

L27. To a solution of (1-cyanocyclohexyl)-americanled (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid (0.12 mmole) obtained in the experiment K4, in acetonitrile (1.0 ml) at 22°C was added N,N-diisopropylethylamine (range 0.38 mmole) and p-nitrophenylphosphate (of 0.14 mmole) and stirring was continued for 2 hours the Mixture is evaporated, the residue is has vergili distribution between ethyl acetate and aqueous solution of sodium carbonate, the organic layer was washed with water, dried and evaporated. The residue was purified using preparative HPLC (RP-18) using a mixture of acetonitrile and water were obtained (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-formylpyridine-2-carboxylic acid as colorless oil. MS: 482,3 [M+H]+.

Example 79

(1-Cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

L28. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was introduced in the reaction mix with acetic acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid as colorless solid. MS: 496,0 [M+H]+.

Example 80

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-TRIFLUOROACETYL)-pyrrolidin-2-carboxylic acid

L29. To a mixture of (1-cyanocyclohexyl)-americanled (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid (0,13 mmole) obtained in the experiment K4 in acetonitrile (2.0 ml) at 22°C was added N,N-diisopropylethylamine (0.77 mmole) and triperoxonane anhydride (0,61 mmole) and stirring was continued for 3 hours the Mixture is evaporated, the remainder of the basement is RGALI distribution between ethyl acetate and water, the organic layer was dried and evaporated. The residue was purified by chromatography using a mixture of cyclohexane/ethyl acetate (1:1) and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-TRIFLUOROACETYL)-pyrrolidin-2-carboxylic acid as a pale yellow oil. MS: OF 450.1 [M+H]+.

Example 81

(1-Cyanocyclohexyl)-midformat (R)-4-(2-chlorobenzenesulfonyl)-1-((S)-1-methylpyrrolidine-2-carbonyl)-pyrrolidin-2-carboxylic acid

L30. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was introduced in the reaction mix with (S)-1-methylpyrrolidinone acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (R)-4-(2-chlorobenzenesulfonyl)-1-((S)-1-methylpyrrolidine-2-carbonyl)-pyrrolidin-2-carboxylic acid, salt with formic acid as colorless solid. MS: 465,2 [M+H]+.

Example 82

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-methylpiperidin-4-carbonyl)-pyrrolidin-2-carboxylic acid

L31. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was introduced in the reaction mix with 1 methylpiperidin-4-carboxylic acid analogously experimenta and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-methylpiperidin-4-carbonyl)-pyrrolidin-2-carboxylic acid as a white solid. MS: 479,1 [M+H]+.

Example 83

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-ethylpyrrolidin-2-carboxylic acid

L32. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was subjected to reductive aminating the acetaldehyde is similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-ethylpyrrolidin-2-carboxylic acid as colorless oil. MS: 382,3 [M+H]+.

Example 84

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclobutylmethyl-2-carboxylic acid

L33. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was subjected to reductive aminating cyclobutanones similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclobutylmethyl-2-carboxylic acid as colorless oil. MS: 408,3 [M+H]+.

Example 85

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexylpiperidine-2-carboxylic acid

L34. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid, n is obtained in the experiment K4 was subjected to reductive aminating cyclohexanone similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexylpiperidine-2-carboxylic acid in the form of a colorless oil. MS: 436,2 [M+H]+.

Example 86

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-pyridin-4-iletilenlerin-2-carboxylic acid

L35. (2S,4R)-4-(2-chloro-benzazolyl)-pyrrolidin-2-carboxylic acid (1-cyanocyclohexyl)-amidogidrolaza obtained in the experiment K4 was subjected to reductive aminating 4-pyridinecarboxamide similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-pyridin-4-iletilenlerin-2-carboxylic acid as colorless oil. MS: 445,3 [M+H]+.

Example 87

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-phenotypically-2-carboxylic acid

L36. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was subjected to reductive aminating phenylacetaldehyde similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-phenotypically-2-carboxylic acid as colorless oil. MS: 458,2 [M+H]+.

Example 88

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2-dottorati)-pyrrolidin-2-carboxylic acid

L37. To a suspension of (1-cyanocyclohexyl) s the hydrochloride (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid (0,13 mmole), obtained in the experiment K4, in THF (2 ml) at 22°C was added diisopropylethylamine (0.75 mmole) and 2,2-differetiated (0.60 mmole) and stirring was continued at 60°C for 24 h the Reaction was stopped with methanol, acidified with acetic acid and purified using preparative HPLC (RP-18) using a mixture of acetonitrile and water were obtained (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2-dottorati)-pyrrolidin-2-carboxylic acid as colorless oil. MC: 418,2 [M+H]+.

Example 89

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-triptorelin)-pyrrolidin-2-carboxylic acid

L38. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4, alkilirovanie 2,2,2-triftoratsetata similar to experiment L37 and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-triptorelin)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 436,2 [M+H]+.

Example 90

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-Cryptor-2-methylpropyl)-pyrrolidin-2-carboxylic acid

L39 are effective. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was subjected to reset mobitelea alkylation of rat-2-methyltryptamine aldehyde similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-Cryptor-2-methylpropyl)-pyrrolidin-2-carboxylic acid in the form of a colorless solid. MS: 464,1 [M+H]+.

Example 91

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-cryptochromes)-pyrrolidin-2-carboxylic acid

L40. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was subjected to reductive alkylation 3,3,3-cryptosporidum aldehyde similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-cryptochromes)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 450,2 [M+H]+.

Example 92

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,3,3,3-pentafluoropropyl)-pyrrolidin-2-carboxylic acid

L41. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4, alkilirovanie 2,2,3,3,3-pentafluoropropanol similar to experiment L37 and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,3,3,3-pentafluoropropyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 486,2 [M+H]+.

Example 93

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-methylpyrrolidine-2-carboxylic acid

L42. (1-Cyano shall ecoprofile)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid, obtained in the experiment K4 was subjected to reductive alkylation with an aqueous solution of formaldehyde similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-methylpyrrolidine-2-carboxylic acid as colorless oil. MS: 368,0 [M+H]+.

Example 94

(1-Cyanocyclohexyl)-mediametrie (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-methylpyrrolidine-2-carboxylic acid

The second fraction contained (1-cyanocyclohexyl)-methylamide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-methylpyrrolidine-2-carboxylic acid as colorless oil. MS: 382,3 [M+H]+.

Example 95

Methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

L43. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was etilirovany methylchloroform similar to experiment L21 and received methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 412,1 [M+H]+.

Example 96

Ethyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

L44. (1-Cyanocyclohexyl)amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid, obtained in the experiment K4 was etilirovany etelcharge.com similar to experiment L21 and received ethyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 426,0 [M+H]+.

Example 97

Isopropyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

L45. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was etilirovany isopropylcarbamate similar to experiment L21 and received isopropyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 440,2 [M+H]+.

Example 98

Cyclopentyloxy ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

L46. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was etilirovany cyclopentylpropionate similar to experiment L21 and received cyclopentyloxy ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 466,2 [M+H]+/sup> .

Example 99

4-Forfinally ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

L47. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K4 was etilirovany 4-vtorganichoney.com similar to experiment L21 and received 4-forfinally ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid as colorless oil. MS: 492,1 [M+H]+.

Example 100

(1-Cyanocyclohexyl)-amide (2S,4R)-1-formyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L48. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was introduced in the reaction mix with p-nitrophenylphosphate similar to experiment L27 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-formyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 416,2 [M+H]+.

Example 101

(1-Cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L49. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-Pierre is lidin-2-carboxylic acid, obtained in the experiment K5 was etilirovany acetic anhydride analogously to experiment L29 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless solid. MS: 430,2 [M+H]+.

Example 102

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2,2,2-TRIFLUOROACETYL)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L50. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was etilirovany triperoxonane anhydride analogously to experiment L29 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2,2-TRIFLUOROACETYL)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a pale yellow solid. MS: Ozenmunaygas given KZT 484.1 ecological [M+H]+.

Example 103

(1-Cyanocyclohexyl)-amide (2S,4R)-1-propionyl 4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L51. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was etilirovany propionic anhydride analogously to experiment L29 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-propionyl 4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid VI is e a colorless oil. MS: 444,3 [M+H]+.

Example 104

(1-Cyanocyclohexyl)-amide (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L52. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was introduced in the reaction mix with cyclohexanecarbonyl acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as an amorphous pale yellow solid. MS: 498,3 [M+H]+.

Example 105

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(4-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

L53. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was introduced in the reaction mix with 4-(trifluoromethyl)-cyclohexanecarbonyl acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(4-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid as a pale yellow oil. MS: 566,3 [M+H]+.

Example 106

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(4-perbenzoic)-4-(2-t is attorneysanafranil)-pyrrolidin-2-carboxylic acid

L54. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was introduced in the reaction mix with 4-fermenting acid analogously to experiment A1 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-(4-perbenzoic)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a pale yellow solid. MS: 510,2 [M+H]+.

Example 107

(1-Cyanocyclohexyl)-amide (2S,4R)-1-benzyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L55. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was subjected to reductive aminating the benzaldehyde analogous to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-1-benzyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 478,1 [M+H]+.

Example 108

(1-Cyanocyclohexyl)-amide (2S,4R)-1-pyridin-4-ylmethyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L56. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was subjected to restore the valid aminating pyridine-4-carbaldehyde similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-1-pyridin-4-ylmethyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 479,1 [M+H]+.

Example 109

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2,2,3,3,3-pentafluoropropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L57. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was subjected to reductive aminating 2,2,3,3,3-pentafluorobenzenesulfonyl similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2,3,3,3-pentafluoropropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as pale brown oil. MS: 520,1 [M+H]+.

Example 110

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-methoxyethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L58. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment K5 was subjected to reductive aminating methoxyacetanilide similar to the L3 experiment and received (1-cyanocyclohexyl)-amide (2S,4R)-1-(2-methoxyethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless oil. MS: 446,3 [M+H]+.

Example 111

(1-Cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(4-(pyrazole-1-yl-2-trifloromethyl)pyrrolidin-2-carboxylic acid

L59. (1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment D9, etilirovany acetic anhydride analogously to experiment L29 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless solid. MS: 496,3 [M+H]+.

Example 112

(1-Cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

L60. (1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid obtained in the experiment D10, etilirovany acetic anhydride analogously to experiment L29 and received (1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless solid. MS: 496,3 [M+H]+.

Example 113

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-1-carboxylic acid

L61. Tert-butyl ester (2S,4S)-2-(1-cyanocyclohexane)-4-methanesulfonylaminoethyl-1-carboxylic acid, obtained in experiment A2, introduced the reaction with 2-methyl-1-propandiol according to the General procedure b and obtained tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-isobutylacetophenone-1-carboxylic acid as a white solid. MS: 366,3 [M-N]-.

Intermediate simple thioether was oxidized with m-chloroperbenzoic acid according to the General procedure C and was obtained tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-1-carboxylic acid as a white foam substance. MS: 400,2 [M+H]+.

Example 114

(1-Cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-2-carboxylic acid

L62. From tert-butyl ether (2S,4R)-2-(1-cyanocyclohexane)-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-1-carboxylic acid, obtained in the experiment L61, removing the protective group according to the General procedure D and received (1-cyanocyclohexyl)-amidogidrolaza (2S,4R)-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-2-carboxylic acid as a pale yellow solid. MS: 300,0 [M+H]+.

Example 115

Cyanomethylene 6-benzazolyl-2,2-divorceregistration-7a-carboxylic acid

a) a Mixture of isomers of benzyl ester 6-benzazolyl-2,2-divorceregistration-7a-carboxylic acid (a) and benzyl ester 1-benzazolyl-6,6-divorceregistration-7a-carboxylic acid (a)

Hydrochloride benzyl ester (R)-4,4-debtorprovidian-2-carboxylic acid (500 mg) suspended in THF (5 ml) was added DIEA (1.8 ml). To receive the resultant solution was added an aqueous solution of formaldehyde (36.5% of wt./wt.) and the solution was stirred for 15 min at 25°C. Then to the reaction mixture was added TFA (20.5 mg) and a solution of phenylenesulfonyl (303 mg) in THF (5 ml). The reaction mixture was stirred for 18 h at 25°C. Then, according to analysis with LC-MS (LC - liquid chromatography) was formed product (m/z = 422,1 [M+H]++). To complete the reaction, the reaction mixture was heated for 2 h at 60°C. Then the mixture was cooled to 25°C., evaporated to dryness, dissolved in AcOEt and washed with an aqueous solution of NH4Cl, a solution of Na2CO3and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The resulting oil was purified using flash chromatography on a column of silica gel (20 g) in gradient mode n-heptane : AcOEt (100:0) → n-heptane : AcOEt (50:50) for 1 h, it was Possible to distinguish two isomer, about 32 mg (4%) each in the form of an almost white solid. MS (IER - electrospray ionization): m/z = 422,1 [M+H]+.

b) Cyanomethylene 6-benzazolyl-2,2-divorceregistration-7a-carboxylic acid

The compound of example 115 (A1) (30 mg) was dissolved in THF (2 ml) and to the solution was added aqueous NaOH solution (2 N., 107 μl). The mixture was stirred for 18 h at 25°C. Analysis by LC-MS indicated complete conversion of ester to the corresponding acid. Then the solution is evaporated to dryness using toluene to remove water. Stausee is I, the solid is suspended in acetonitrile (2 ml) and EDCI (27 mg), NOT (19 mg) and DIEA (50 μl; 2 EQ.) added. The mixture was stirred for 1 h at 25°C. Aminoacetonitrile (13 mg) suspended in atsn (2 ml) and DIEA (50 μl; 2 EQ.) added. The resulting solution was added to the activated acid. The reaction mixture was stirred for 3 days at 25°C. the Reaction mixture is evaporated to dryness and dissolved in DMSO (dimethyl sulfoxide) (1 ml) and purified using preparative HPLC and was obtained the desired compound as a light brown foam material (12 mg; 45%). MS (IER): m/z = 370,4 [M+H]+.

Example 116

Cyanomethylene 1-benzazolyl-6,6-divorceregistration-7a-carboxylic acid, diastereoisomer Δ1

The compound of example 115 (A2) (30 mg) was dissolved in THF (2 ml) and to the solution was added aqueous NaOH solution (2 N., 107 μl). The mixture was stirred for 18 h at 25°C. Analysis by LC-MS indicated complete conversion of ester to the corresponding acid. Then the solution is evaporated to dryness using toluene to remove water. The remaining solid is suspended in acetonitrile (2 ml) was added EDCI (27 mg), NOT (19 mg) and DIEA (50 μl; 2 EQ.). The mixture was stirred for 1 h at 25°C. was Added aminoacetonitrile (13 mg), suspended in atsn (2 ml) and DIEA (50 μl; 2 EQ.). The resulting solution was added to the activated key is lot. The reaction mixture was stirred for 3 days at 25°C. the Reaction mixture is evaporated to dryness and dissolved in DMSO (1 ml) and purified using preparative HPLC and was obtained the desired compound as light yellow foam material (12 mg; 45%). MS (IER): m/z = 370,4 [M+H]+.

Example 117

Cyanomethylene 1-benzazolyl-6,6-divorceregistration-7a-carboxylic acid, diastereoisomer Δ2

The desired compound was obtained in the form of the isomer in the synthesis of the compound of example 116 was obtained a light yellow foam substance (4,6 mg; 16%). MS (IER): m/z = 370,4 [M+H]+.

Example 118

Methyl ester of 4-[(2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carbonyl]-benzoic acid

The desired compound was obtained analogously to receive in example 106 using methyl-4-chlorocarbonate, triethylamine and dimethylaminopyridine. MS (IER): m/z = 550,2 [M+H]+.

Example 119

(1-Cyanocyclohexyl)-amide (2S,4R)-1-phenyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 151 (see diagram AB) using 1-aminocyclohexanecarboxylic instead of 2-aminoacetonitrile on stage C. MS (IER): m/z = 464,1 [M+H]+ .

Example 120

Tert-butyl ester (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

a) 1-Tert-butyl ether,2-methyl ester (2S,4S)-4-(3-nitrobenzenesulfonate)-pyrrolidine-1,2-dicarboxylic acid

Methyl ester of N-BOC-CIS-4-hydroxyproline (1.0 EQ., 6.0 g) was dissolved in MeCl2(60,0 ml) was added 3-nitrobenzenesulfonamide (1.06 equiv.; 5,747 g). This clear, colorless solution was cooled to 0-5°C and carefully added Et3N (3.0 EQ,, 10,19 ml). After 0.5 h was formed yellowish liquid suspension, which was stirred for 18 h at ambient temperature. The mixture is then turned into a light brown suspension. Analysis using LC-MS showed that the reaction was completed. The reaction mixture was further diluted with MeCl2(100 ml), then was extracted with 0.5 N. aqueous solution of HCl, 10% Na2CO3. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness and the received light brown viscous oil (10.8 g; 102%). MS (IER): m/z = 331,2 [M+H-BOC]+

b) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-(2-chloro-4-perpenicular)-pyrrolidine-1,2-dicarboxylic acid

The compound of example 120A (10.8 g) was dissolved in propionitrile (10.0 ml), to light what about the brown solution was added 2-chloro-4-portifino (4.35 g) and tea (10,43 ml). The reaction mixture was stirred at 110°C for 18 hours Analysis by LC/MS indicated complete conversion. Then the reaction mixture was diluted with AcOEt (250 ml) were extracted sequentially with an aqueous solution of 10% Na2CO3then the aqueous layer 3 times washed with AcOEt, the combined organic layers were washed with saturated solution of NaCl, dried over Na2SO4, filtered and evaporated, then purified by silica using a mixture of AcOEt : n-heptane was obtained the desired compound as colorless resinous substance (8.8 g; 88%). MS (IER): m/z = 390,1 [M+H]+.

c) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-(2-chloro-4-permentantly)-pyrrolidine-1,2-dicarboxylic acid

Connection example 120b (8.5 g) was dissolved in MeCl2(50,0 ml) at ambient temperature, then 3-chloroperbenzoic acid (9.4 g, 2.5 EQ.) added to the light yellow solution, which after 1 h was turned into a white suspension. The reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with MeCl2(150 ml) and was extracted twice with an aqueous solution of 10% Na2CO3(100 ml), washed with saturated solution of NaCl, dried over Na2SO4, filtered and evaporated to dryness and got the desired compound in the form of a colourless resin (9,05 g; 98%). MS (IER): m/z = 3222 [M+H-Boc] +.

d) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidine-1,2-dicarboxylic acid

Connection example 120C (0.6 g) was dissolved in DMA (10.0 ml) at ambient temperature. To this solution was added pyrazole (0,116 g; 1.2 EQ.) and Cs2CO3(0,463 g; 1.2 EQ.). The reaction mixture was stirred in the microwave at 140°C for 30 minutes and Then the reaction mixture was cooled to room temperature and the reaction mixture is evaporated to dryness under reduced pressure. The remaining solid is suspended in CH2Cl2(50 ml) were extracted sequentially with 0.5 N. aqueous solution of HCl (30 ml) and brine. The aqueous layer was twice washed with CH2Cl2(100 ml), the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to dryness. Then the crude product was purified on silica gel using a mixture of n-heptane : AcOEt and got the desired compound as a colourless foam substances (0,48 g; 72%). MS (IER): m/z = 370,1 [M+H-Boc]+.

e) (2S,4R)-1-Tert-butoxycarbonyl-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidin-2-carboxylate lithium

To a colorless solution of the compound of example 120d (to 0.480 g) in THF (2.0 ml) at ambient temperature under inert atmosphere was added a solution of lithium hydroxide (0,051 g; 1.2 EQ.) in N2About (3 ml). Astor was stirred at ambient temperature for 18 hours throughout the night. Then to the specified solution was additionally added lithium hydroxide (0.5 EQ. + 0.2 EQ.) and was stirred for 5 h at ambient temperature. Then the reaction mixture is evaporated to dryness and got the desired compound as a white solid (0,49 g, 103%). The crude product was used without additional purification. MS (IER): m/z = 456,2 [M-H-Li]-.

f) Tert-butyl ester (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

Connection example a (480 mg) suspended in DMF (5 ml). HATU (3.0 equiv.) to the suspension was added DIEA (3.0 EQ.) and 1-amino-1-cyclopropanecarbonitrile (1.5 EQ.). After addition of HATU were formed dark yellow suspension. The reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture is evaporated to dryness and then purified by silica gel using a mixture of n-heptane : AcOEt and got the desired compound as a colourless foam substances (536 mg; 99%). MS (IER): m/z = 520,3 [M+H]+.

Example 121

Tert-butyl ester (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

a) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-pyrrolidine-1,2-dicarboxylic KIS is the notes

Connection example 120C (500 mg) was dissolved in DMA (10.0 ml) at ambient temperature. To this solution was added piperidine (97 mg; 1,2 eq) and Cs2CO3(371 mg; 1.2 EQ.). The reaction mixture was stirred in the microwave at 140°C for 30 minutes, the Reaction mixture was cooled to ambient temperature. Then the reaction mixture is evaporated to dryness, dissolved in CH2Cl2(50 ml) were extracted sequentially with 0.5 N. aqueous solution of HCl (30 ml) and brine. The aqueous layer was twice washed with CH2Cl2(100 ml), organic layers were washed with brine, the combined organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel using a mixture of n-heptane : AcOEt and got the desired compound as a colourless foam substances (453 mg; 78%). MS (IER): m/z = 487,4 [M+H]+.

b) (2S,4R)-1-Tert-butoxycarbonyl-4-(2-chloro-4-piperidine-1-eventality)-pyrrolidin-2-carboxylate lithium

Connection example 121b was obtained from the compound of example 99a (450 mg) by the procedure described in example I, and obtained the desired compound as a white solid (460 mg, 104%). MS (IER): m/z = 402,2 [M-H-Boc-Li]-.

c) Tert-butyl ester (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

With the gathering of example 121 was obtained from the compound of example 121b (460 mg) by the procedure described in example 98f, and received the target compound as a colourless foam substances (510 mg; 98%). MS (IER): m/z = 537,3 [M+H]+.

Example 122

Tert-butyl ester (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

a) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidine-1,2-dicarboxylic acid

Connection example a was obtained from the compound of example 120C (500 mg) by the method similar to that described in example a using 1,1,1-tripersonal instead of piperidine was obtained the desired compound as a colourless foam substances (433 mg; 71%). MS (IER): m/z = 516,4 [M+H]+.

b) (2S,4R)-1-Tert-butoxycarbonyl-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylate lithium

Connection example 122b was obtained from the compound of example 100A (430 mg) by the procedure described in example I, and obtained the desired compound as a white solid (435 mg, 103%). MS (IER): m/z = 402,2 [M-H-Boc-Li]-.

c) Tert-butyl ester (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The compound of example 122 was obtained from the compound of example 100b (435 mg) by the method described in note the re 120f, and received the target compound as a colourless foam substances (327 mg; 67%). MS (IER): m/z = 566,3 [M+H]+.

Example 123

(1-Cyanocyclohexyl)-amide and (2R,4S,5R)-5-(4-forfinal)-2-isobutyl-4-methanesulfonamide-2-carboxylic acid

a) Methyl ester of (S)-2-{[1-(4-forfinal)-meth-(E)-ilidene]-amino}-4-methylpentanoic acid

The hydrochloride of the methyl ester of L-leucine (3,65 g) was dissolved in methanol (35 ml) was added 4-forbindelse (2.65 ml) and Na2CO3(4.0 g). The mixture was stirred at ambient temperature for 3 days. Then, the mixture was filtered, evaporated to dryness. The residue was dissolved in TBME (tert-butyl methyl ether). The precipitate was filtered. The solution in TBME evaporated to dryness and got the desired compound as a colourless oil (of 4.66 g; 92%). MS (IER): m/z = 252,3 [M+H]+.

b) Methyl ester of (2R,4S,5R)-5-(4-forfinal)-2-isobutyl-4-methanesulfonamide-2-carboxylic acid

Taniaphos (registration number CAS 255884-98-1; 61 mg) and copper acetate(I) (10 mg) was dissolved in THF (2 ml) at ambient temperature and was stirred for 30 minutes was Added a solution of compound of example 101A (390 mg) and tea (20 μl) in THF (4 ml). The reaction mixture was cooled to 0°C was added methylphenylsulfonyl (165 mg), dissolved in THF (2 ml). The resulting mixture was stirred at ambient temperature for 6 days. ZAT is m and the mixture was filtered through dicalite and evaporated to dryness. The obtained solid was purified using flash chromatography (n-heptane : ethyl acetate) was obtained the desired compound as a pale yellow oil (361 mg; 65%). MS (IER): m/z = 358,2 [M+H]+.

c) 1-Tert-butyl ether,2-methyl ester (2R,4S,5R)-5-(4-forfinal)-2-isobutyl-4-methanesulfonanilide-1,2-dicarboxylic acid

The compound of example 123b (472 mg) was dissolved in acetonitrile (5 ml). To the solution was added di-tert-BUTYLCARBAMATE (365 mg) and K2CO3(432 mg). The reaction mixture was stirred at ambient temperature for 24 hours Then further added di-tert-BUTYLCARBAMATE (1.5 EQ.) and the mixture was stirred for 24 h at ambient temperature. Just after 68 h, the reaction analysis using LC-MS indicated complete conversion to the desired compound. The reaction mixture is evaporated to dryness and purified using flash chromatography (n-heptane : ethyl acetate). A large part of the substance was re-decomposed with the formation of the original substance, which was used without further purification. MS (IER): m/z = 458,2 [M+H]+.

d) (2R,4S,5R)-5-(4-Forfinal)-2-isobutyl-4-methanesulfonamide-2-carboxylate lithium

The mixture obtained in example C (120 mg), was dissolved in a mixture of THF/water (4 ml/0.4 ml), and then to the solution was added LiOH hydrate (17 mg; 1.2 EQ.). The mixture was stirred for 23 h at temperatureincrease environment. To the mixture was further added LiOH hydrate (0.2 EQ.). After 3 h to complete the reaction the mixture was further added LiOH hydrate (0.2 EQ.). After stirring for 1 h at ambient temperature the mixture is evaporated to dryness and received a yellow solid (145 mg, 123%), which was used without further purification. MS (IER): m/z = 342,4 [M-N]-.

e) (1-Cyanocyclohexyl)-amide and (2R,4S,5R)-5-(4-forfinal)-2-isobutyl-4-methanesulfonamide-2-carboxylic acid

Connection example 123d (145 mg) was dissolved in DMF (2 ml). Then to the mixture was added cyclopropanecarbonitrile (150 mg), DIEA (180 μl) and HATU (561 mg). The reaction mixture was stirred for 18 h at ambient temperature. Then the mixture was purified using preparative HPLC and was obtained the desired compound as a pale yellow solid (45 mg, 26%). MS (IER): m/z = 408,5 [M+H]+.

Example 124

Tert-butyl ester (2S,4R)-4-(2-chloro-4-permentantly)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The desired compound was obtained from the compound of example 120C according to the methods described in the examples e and 120f, and received the compound of example 124 in the form of a colorless solid. MS (IER): m/z = 472,3 [M+H]+.

Example 125

Tert-butyl ester (2R,4S,5R)-2-(1-cyanocyclohexane)-5-(4-forfinal)-2-Isobe the Il-4-methanesulfonamido-1-carboxylic acid

The desired compound was obtained as a side product during the synthesis of the compound of example 123. MS (IER): m/z = 508,5 [M+H]+.

Example 126

(1-Cyanocyclohexyl)-amide and (2R,4S,5R)-4-benzazolyl-5-(4-forfinal)-2-isobutylpyrazine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 123 using phenylenesulfonyl instead of methylphenylsulfonyl on stage 123b and got the desired compound in the form of a viscous yellow oil (36 mg, 24%). MS (IER): m/z = 470,3 [M+H]+.

Example 127

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-pyrrolidin-2-carboxylic acid

The compound of example 121 (480 mg) was dissolved in formic acid (10 ml) and stirred at room temperature for 3.5 hours and Then the reaction mixture is evaporated to half volume, then diluted with AcOEt (30 ml) and was extracted with 10% aqueous solution of Na2CO3(40 ml). The aqueous phase was washed with AcOEt (30 ml), the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness and got the desired compound as a colorless amorphous substance (231 mg; 59%). MS (IER): m/z = 437,3 [M+H]+.

Example 128

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-benzazolyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained in accordance with the procedures described in example 127, using as the starting material compound of example 120 (390 mg) and amorphous colourless solid (236 mg; 75%) MS (IER): m/z = 420,2 [M+H]+.

Example 129

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained in accordance with the procedures described in example 127, using as the starting material compound of example 122 (310 mg) and amorphous colourless solid (220 mg; 86%) MS (IER): m/z = 466,2 [M+H]+.

Example 130

Tert-butyl ester (2S,4R)-4-[2-chloro-4-(3,3-debtorprovidian-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The compound of example 124 (100 mg) was dissolved in 2.0 ml of DMA at RT. To this solution was added a salt of 3,3-debtorprovidian with HCl (1.2 EQ.; 0.037 g) and Cs2CO3(2.4 equiv.; 0,166 g). The reaction mixture was stirred in the microwave at 140°C for 2×30 min (until completion of the conversion of the compound of example 124). The reaction mixture was diluted with CH2Cl2(20 ml) and was extracted with water, 0.1 G. of aqueous HCl solution and brine. Organic SL is th evaporated to dryness and received a concentrated solution in DMA. The solution was diluted to 2.5 ml with DMA and directly purified using preparative HPLC. MS (IER): m/z = 559,2 [M+H]+isotopes Cl-; 503,2 [M+H-tBu]+isotopes Cl-; 459,3 [M+H-BOC]+isotopes Cl-.

Example 131

(1-Cyanocyclohexyl)-midformat (2S,4R)-1-acetyl-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidin-2-carboxylic acid

The compound of example 128 (90 mg) was dissolved in CH2Cl2(2 ml), to the solution was added Et3N (2.0 EQ., 43 mg) and acetylchloride (1.3 equiv.; 22 mg) and was stirred over night at ambient temperature. The solvent is evaporated to dryness, the remaining solid was dissolved in DMF and purified using preparative HPLC and was obtained the desired compound in the form of colorless amorphous solid substance in the form of a salt with formic acid (61 mg; 61%). MS (IER): m/z = 462,3 [M+H]+.

Example 132

(1-Cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 131, using the compound of example 129 (90 mg) as a starting substance was obtained 56 mg (57%) of colorless amorphous solid. MS (IER): m/z = 508,2 [M+H]+.

Example 133

(1-Cyanocyclohexyl)-midformat (2S,4R)-1-acetyl-4-(2-chloro-4-piperidine-1-IV solarpanel)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 131, using the compound of example 127 (100 mg) as a starting substance was obtained 82 mg (75%) of colorless amorphous solid. MS (IER): m/z = 479,1 [M+H]+.

Example 134

(1-Cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 131, using the compound of example 144 (30 mg) as a starting substance and received 19 mg (57%) of colorless amorphous solid. MS (IER): m/z = level of 414.2 [M+H]+.

Example 135

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The compound of example 127 (70 mg) was dissolved in DMF (2 ml). To this solution was added HATU (122 mg), DIEA (41 mg) and 1-(trifluoromethyl)-cyclopropane-1-carboxylic acid (30 mg) and was stirred for 18 h at ambient temperature. The reaction mixture was purified using preparative HPLC and was obtained the desired compound in the form of colorless amorphous solid (42 mg, 46%). MS (IER): m/z = 573,3 [M+H]+.

Example 136

(1-Cyanocyclohexyl)-midformat (2S,4R)-4-[2-chloro-4-(3,3-debtorprovidian-1-yl)-endolsulfan]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 127 using the compound of example 130 (18 mg) as a starting substance and received 16 mg (96%) of colorless amorphous solid. MS (IER): m/z = 459,3 [M+H]+.

Example 137

Methyl ester of 4-[(2S,4R)-2-(cyanomethylene)-4-(2-trifloromethyl)-pyrrolidin-1-carbonyl]-benzoic acid

The desired compound was obtained analogously to receive in example 118, using methyl-4-chlorocarbonate, triethylamine and dimethylaminopyridine at the last stage. MS (IER): m/z = 524,3 [M+H]+.

Example 138

Tert-butyl ester (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The desired compound was obtained analogously to receive in example 130 using the compound of example 124 (100 mg) and N-ethylpiperazine (29 mg) as starting compounds and received 54 mg (45%) of colorless amorphous solid. MS (IER): m/z = 566,4 [M+H]+.

Example 139

Tert-butyl ester (2S,4R)-4-[2-chloro-4-(2-piperidine-1-ylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The desired compound was obtained similarly polucheniya example 130 using the compound of example 124 (100 mg) and 1-(2-hydroxyethyl)piperidine (33 mg) as starting compounds and received 0.5 mg (0.2%) of a light brown resin. MS (IER): m/z = 581,4 [M+H]+.

Example 140

(1-Cyanocyclohexyl)-midformat (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 127 using the compound of example 138 (52 mg) as a starting substance and received 47 mg (99%) of a yellow resin. MS (IER): m/z = 466,2 [M+H]+.

Example 141

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 135 using the compound of example 140 (37 mg) as a starting substance and received 6 mg (13%) amorphous light yellow solid. MS (IER): m/z = 602,2 [M+H]+.

Example 142

(1-Cyanocyclohexyl)-midformat (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid (alternative way of obtaining the compound of example 141)

The compound of example 145 (200 mg) was dissolved in DMA (4 ml). Was added N-ethylpiperazine (0.06 ml) and Cs2CO3(0,154 g). The reaction mixture was stirred in the microwave at 140°C for 30 minutes, the Reaction mixture was purified using the reparative HPLC and was obtained the desired compound (101 mg, 40%) as a colorless amorphous solid substance in the form of a salt with formic acid. MS (IER): m/z = 602,2 [M+H]+.

Example 143

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-formylpyridine-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 141 and received 14 mg (39%) colorless amorphous solid. MS (IER): m/z = 494,2 [M+H]+.

Example 144

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 127 using the compound of example 124 (500 mg) as a starting substance and received 345 mg (88%) of colorless foam substance. MS (IER): m/z = 372,2 [M+H]+.

Example 145

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 135 using the compound of example 144 (340 mg) as a starting substance and received 313 mg (67%) of an amorphous light yellow solid. MS (IER): m/z = 508,2 [M+H]+.

Example 146

(1-Cyanocyclohexyl)-midformat (2S,4R)-4-(2-chloro-4-PIP is ridin-1-eventality)-1-formylpyridine-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 135 and received 7 mg (8%) colorless amorphous solid. MS (IER): m/z = 465,3 [M+H]+.

Example 147

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 135 using the compound of example 128 (128 mg) as a starting substance and received 103 mg (61%) of colorless amorphous solid. MS (IER): m/z = 556,3 [M+H]+.

Example 148

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-formylpyridine-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 147 and received 13 mg (10%) of colorless amorphous solid. MS (IER): m/z = USD 448,2 [M+H]+.

Example 149

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 135 using the compound of example 129 (110 mg) as starting substances is a and received 65 mg (46%) of colorless amorphous solid. MS (IER): m/z = 602,2 [M+H]+.

Example 150

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-formylpyridine-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 149 and received 25 mg (21%) of an amorphous light yellow solid. MS (IER): m/z = 494,2 [M+H]+.

Example 151

Cyanomethylene (2S,4R)-1-phenyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) methyl ester of (2S,4R)-1-phenyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

To a solution of methyl ester (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (see example XX) (1,03 g, 1.0 EQ.) in dry dichloromethane (25 ml) was added segerstrale molecular sieves (2,88 g). Added phenylboronic acid (0.74 g, 2.0 EQ.), then triethylamine (of 0.62 g, 2.0 EQ.) and copper acetate(II) (0,61 g, 1.1 EQ.). Through the reaction mixture for 5 min missed the oxygen. The flask was sealed with a rubber membrane and kept in an atmosphere of oxygen supplied from a cylinder. After stirring at room temperature for 24 h the mixture was filtered and the filtrate was treated with water and re-filtered. The phases were separated and the organic phase was dried over sodium sulfate, filter is Ali and evaporated. Purification using flash chromatography on silica gel in a gradient mode using a mixture of heptane/ethyl acetate gave the desired compound as a pale yellow solid (0,23 g, 18%). MS (IER): m/z = level of 414.2 [M+H]+.

b) (2S,4R)-1-Phenyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

A (0.14 g, 1.0 EQ.) suspended in methanol (3.4 ml) and THF (1.0 ml). Added LiOH 1 N. (0,66 ml, 2.0 EQ.) and the reaction mixture was stirred at RT for 2 h Analysis using TLC (thin layer chromatography) and MS showed that the reaction was completed. The solvents are evaporated and the resulting residue suspended in water and acidified 1 N. aqueous solution of HCl to pH 1. The desired acid was precipitated, was filtered off, washed with water. The desired compound was obtained as a white solid (0.12 g, 94%) and used without further purification. MS (IER): m/z = 400,1 [M+H]+.

(C) Cyanomethylene (2S,4R)-1-phenyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

151b (0.15 g, 1.0 EQ.) was dissolved in dry DMF (3.0 ml) in an argon atmosphere and treated with diisopropylethylamine (0.24 g, 5.0 EQ.) and HATU (0.17 g, 1.2 EQ.). The mixture was stirred at RT for 2 h, then was treated with 2-aminoacetonitrile (0.05 g, 1.5 EQ.). The mixture was stirred at RT overnight, then was diluted with water and extracted with ethyl acetate. Merged the content of inorganic fillers phase was washed with water and saturated NaCl solution, was dried over sodium sulfate and evaporated. Purification using flash chromatography on silica gel in a gradient mode using a mixture of heptane/ethyl acetate gave the desired compound as a white solid (0.03 g, 19%). MS (IER): m/z = 438,2 [M+H]+.

Example 152

Tert-butyl ester (2S,4R)-4-[2-chloro-4-(4,4-deformability-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The desired compound was obtained analogously to receive in example 130 using the compound of example 124 (400 mg), and salts of 4,4-ceftobiprole with HCl (187 mg) as a starting substance and received 66 mg (14%) of an amorphous yellow solid. MS (IER): m/z = RUB 573.4 [M+H]+.

Example 153

Tert-butyl ester (2S,4R)-4-[2-chloro-4-(4-triftormetilfosfinov-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The desired compound was obtained analogously to receive in example 130 using the compound of example 124 (400 mg), and salts of 4-triftormetilfullerenov with HCl (225 mg) as a starting substance and received 102 mg (20%) of an amorphous yellow solid. MS (IER): m/z = 605,3 [M+H]+.

Example 154

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-triftormetilfosfinov-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 137, by using the compound of example 153 (95 mg) as a starting substance and received 75 mg (95%) of light yellow solid. MS (IER): m/z = 505,2 [M+H]+.

Example 155

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4,4-deformability-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 127 using the compound of example 152 (62 mg) as a starting substance and received 36 mg (70%) of light yellow solid. MS (IER): m/z = 473,3 [M+H]+.

Example 156

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-triftormetilfosfinov-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 135 using the compound of example 154 (70 mg) as a starting substance and received 34 mg (38%) of light yellow solid. MS (IER): m/z = 641,2 [M+H]+.

Example 157

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4,4-deformability-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 135 the BL is reattaching the compound of example 155 (35 mg) as a starting substance and was sentenced to 9 mg (20%) of light yellow solid. MS (IER): m/z = 609,3 [M+H]+.

Example 158

Tert-butyl ester (2S,4S)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid

The desired compound was obtained analogously to receive in example 124, using 1-tert-butyl ether,2-methyl ester (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid as the starting material instead of 1-tert-butyl ether,2-methyl ester (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid and was obtained the desired compound (130 mg, 31%) as a white solid. MS (IER): m/z = 488,5 [M+H]+.

Example 159

(1-Cyanocyclohexyl)-amide (2S,4S)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 127 using the compound of example 158 (120 mg) as a starting substance and received 20 mg (21%) of colorless solid. MS (IER): m/z = 388,2 [M+H]+.

Example 160

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(4-methoxyphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 151. 4-Methoxyphenylalanine acid used at the stage instead of phenylboronic acid and 1-aminocyclopropane unitelligable used instead of 2-aminoacetonitrile at stage C. MS (IER): m/z = 494,2 [M+H]+.

Example 161

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-morpholine-4-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 142 using the compound of example 145 (250 mg) as a starting substance and received 87 mg (31%) of light yellow solid. MS (IER): m/z = 575,3 [M+H]+.

Example 162

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-(2-chloro-4-morpholine-4-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 161 and received 17 mg (6%) amorphous light yellow solid. MS (IER): m/z = 494,2 [M+H]+.

Example 163

(1-Cyanocyclohexyl)-midformat (2S,4R)-4-(2-chloro-4-piperazine-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 142 using the compound of example 145 (250 mg) as a starting substance and received 186 mg (66%) of light yellow oil. MS (IER): m/z = 574,3 [M+H]+.

Example 164

Cyanomethylene (2S,4R)-1-(2-nitrophenyl)-4-(2-trifloromethyl)-Pirro is one-2-carboxylic acid

a) Methyl ester of (2S,4S)-4-hydroxy-1-(2-nitrophenyl)-pyrrolidin-2-carboxylic acid

A suspension of methyl ester hydrochloride (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (4.0 g, 1.0 EQ.) in acetonitrile (55 ml) was treated with tea (3.8 g, 1,36 EQ.) and 1-chloro-2-nitrobenzene (4.1 g, of 1.05 EQ.). Formed solution, then quickly formed a white precipitate. The mixture was stirred at 60°C for 22 h and then poured into 1 n HCl solution (60 ml) and was extracted several times with ether. The combined organic extracts were dried over sodium sulfate and evaporated. Purification using flash chromatography on silica gel in a gradient mode using a mixture of heptane/ethyl acetate gave the desired compound as a white solid (5.8 g, 79%).

b) Methyl ester of (2S,4S)-4-(3-nitrobenzenesulfonate)-1-(2-nitrophenyl)-pyrrolidin-2-carboxylic acid

A (5.8 g, 1.0 EQ.) was dissolved in dichloromethane (60 ml) and was treated with 3-nitrobenzenesulfonamide (5,1 g, 1.06 EQ.). The mixture was cooled to 0°C and treated with triethylamine (6.6 g, 3.0 EQ.), which was added dropwise over 20 minutes and the Mixture was stirred at RT overnight, then was diluted with dichloromethane (60 ml) and washed with a 0.5 N. HCl (45 ml), a saturated solution of sodium carbonate (60 ml) and brine. The organic phase was dried over sodium sulfate and evaporated and received the desired compound as an orange foam substances (9.2 grams, 94%). The compound was used without further purification. MS (IER): m/z = 452,1 [M+H]+.

c) Methyl ester of (2S,4R)-1-(2-nitrophenyl)-4-(2-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

Sodium hydride (55% in mineral oil, 1.3 g, 1.5 EQ.) suspended in dry tetrahydrofuran (200 ml) in an argon atmosphere. Within 10 min was added dropwise 2-(trifluoromethyl)thiophenol (5.6 g, 1.5 EQ.). The mixture was stirred at RT for 2 h 164b (9.0 g, 1.0 EQ.) was dissolved in dry THF (50 ml) and the solution was added dropwise to the reaction mixture for 10 min. the Reaction mixture was stirred at 50°C for 2 h after which formed a white suspension. After cooling to CT and the mixture was poured into water (400 ml) and was extracted twice with ethyl acetate (2×300 ml). The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The desired compound was obtained as an orange solid (10.2 g, 107%) and used without further purification. MS (IER): m/z = 427,1 [M+H]+.

d) Methyl ester of (2S,4R)-1-(2-nitrophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

164 ° C. (5,3 g, 1.0 EQ.) was dissolved in dichloromethane (125 ml) and was treated with 3-chloroperbenzoic acid, which portions were added within 10 minutes and the Mixture was stirred at RT overnight, then was treated with 1 n sodium carbonate. The phase section is ranged and the aqueous phase is once was extracted with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. Purification using flash chromatography on silica gel in a gradient mode using a mixture of heptane/ethyl acetate gave the desired compound as an orange foam substances (5,3 g, 54%). MS (IER): m/z = 459,2 [M+H]+.

e) (2S,4R)-1-(2-Nitrophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

164d (1.0 g, 1.0 EQ.) suspended in ethanol (50 ml) and treated with LiOH 1 N. (4.3 ml, 2.0 EQ.). The mixture was stirred at RT over night. After dilution with water and acidification with 1 N. HCl to pH 1 acid was precipitated, was filtered off, washed with water. The desired compound was obtained as a yellow solid (0,83 g, 86%). MS (IER): m/z = 445,3 [M+H]+.

f) Cyanomethylene (2S,4R)-1-(2-nitrophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

E (0,19 g, 1.0 EQ.) was dissolved in argon atmosphere in dry DMF (4.0 ml) and treated with diisopropylethylamine (0.27 g, 5.0 EQ.) and HATU (0,19 g, 1.2 EQ.). The mixture was stirred at RT for 1 h, then was treated with aminoacetonitrile (0.06 g, 1.5 EQ.). After stirring at RT overnight was added water and the mixture was twice extracted with ethyl acetate. The combined organic phases are washed three times with water and once with brine, dried over sodium sulfate and perivale. Purification using flash chromatography on silica gel in a gradient mode using a mixture of heptane/ethyl acetate gave the desired compound as a yellow solid (0.10 g, 51%). MS (IER): m/z = 483,3 [M+H]+.

Example 165

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 147 and amorphous light yellow solid. MS (IER): m/z = 556,2 [M+H]+.

Example 166

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-nitrophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 164. The last stage was carried out as follows:

The solution e (0.20 g, 1.0 EQ.) in dry THF (6.5 ml) was treated with 4-methylmorpholine (0.14 g, 3.0 EQ.) and cooled to 0°C. for 5 min was added dropwise isobutylparaben (0,074 g, 1.2 EQ.). The mixture was stirred at 0°C for 1.5 h, then at RT for 1 h After re-cooling to 0°C was added dropwise a solution of 1-aminocyclohexanecarboxylic (0,064 g, 1.2 EQ.) in dry DMF (3.0 ml). The mixture was stirred at RT over night. After adding a saturated solution of lorida ammonium and water, the mixture was twice extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. Purification using flash chromatography on silica gel in a gradient mode using a mixture of heptane/ethyl acetate/formic acid gave the desired compound as a yellow solid (0,051 g, 22%). MS (IER): m/z = 509,1 [M+H]+

Example 167

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(2-nitrophenyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 164 and 166 with the use of 2,4-Dichlorotoluene on stage 164 ° C.. MS (IER): m/z = 509,1 [M+H]+.

Example 168

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 145, using the compound of example 15 (250 mg) as a starting substance and received 36 mg (11%) of light yellow solid. MS (IER): m/z = 524,1 [M+H]+.

Example 169

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-triftoratsetilatsetonom)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in the example 168 using the compound of example 15 (250 mg) and 1-(trifluoromethyl)-1-cyclobutanecarbonyl acid (167 mg) as a starting substance and received 73 mg (21%) of light yellow solid. MS (IER): m/z = 538,1 [M+H]+.

Example 170

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(2,2-divorcecelebration)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in the example 168 using the compound of example 15 (250 mg) and 2,2-divorcecare-1-carboxylic acid (118 mg) as a starting substance was obtained 41 mg (13%) of light yellow solid. MS (IER): m/z = 492,0 [M+H]+.

Example 171

Tert-butyl ester (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The desired compound was obtained by using the sequence of reactions similar to those described in example 122, using 2,2,2-triptoreline instead of 1,1,1-tryptophan-2-ol as starting substance and received a white foam substance. MS (IER): m/z = 552,1 [M+H]+.

Example 172

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 173 (56 mg) as a starting substance and received 11 mg (15%) of a white solid matter what. MS (IER): m/z = 588,1 [M+H]+.

Example 173

(1-Cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 171 (86 mg) as a starting substance was obtained 56 mg (79%) of light yellow solid. MS (IER): m/z = 452,1 [M+H]+.

Example 174

Tert-butyl ester (2S,4R)-4-[2-chloro-4-(oxetan-3-yloxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The desired compound was obtained by the sequence of reactions similar to those described in example 122 using 3-hydroxyacetone instead of 1,1,1-tryptophan-2-ol as starting substances and received almost white amorphous substance. MS (IER): m/z = to 526.4 [M+H]+.

Example 175

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 173 (100 mg) as a starting substance and received 21 mg (18%) of white solids. MS (IER): m/z = 534,1 [M+H]+.

Example 176

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-x is the PR-4-(2,2,2-triptoreline)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 173 (100 mg) as a starting substance and received 14 mg (12%) almost white amorphous substance. MS (IER): m/z = 536,1 [M+H]+.

Example 177

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 173 (100 mg) as a starting substance and received 53 mg (38%), almost white amorphous substance. MS (IER): m/z = 624,2 [M+H]+.

Example 178

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 173 (100 mg) as a starting substance and received 54 mg (39%) almost white amorphous substance. MS (IER): m/z = 630,1 [M+H]+.

Example 179

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-isobutylpyrazine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149 and with the use of the compound of example 173 (100 mg) as a starting substance and received 39 mg (34%) of nearly white solid. MS (IER): m/z = 522,2 [M+H]+.

Example 180

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(3-methylbutyryl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 173 (100 mg) as a starting substance and received 29 mg (24%) of nearly white solid. MS (IER): m/z = 536,1 [M+H]+.

Example 181

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(oxetan-3-yloxy)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 127 using the compound of example 174 (261 mg) as a starting substance and received 179 mg (85%) of white solids. MS (IER): m/z = 426,1 [M+H]+.

Example 182

(1-Cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-formylpyridine-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 175 was obtained 33 mg (31%) of nearly white solid. MS (IER): m/z = 426,1 [M+H]+.

Example 183

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

a) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidine-1,2-dicarboxylic acid

Connection example 120C (3.0 g) was dissolved in DMA (30 ml) at RT. To this solution was added (S)-2,2,2-tripolitana (1.2 EQ.; 0,973 g) and Cs2CO3(1.2 EQ.; 2,78 g). The reaction mixture was stirred in the microwave at 140°C for 30 minutes Then the reaction mixture was further added (S)-2,2,2-tripolitana (0.4 equiv.; 0,324 g) and was stirred in the microwave at 140°C for 30 minutes the Reaction mixture is evaporated, the residue was dissolved in CH2Cl2(250 ml) were extracted sequentially with 0.5 N. aqueous solution of HCl (100 ml) and brine. The aqueous layer was twice washed with CH2Cl2(150 ml), washed with brine, the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified on silica gel using a mixture of n-heptane : AcOEt and received 2.66 g (73%) 183a as colorless resinous substance. MS (IER): m/z = 416,1 [M+H-BOC]+.

b) Methyl ester of (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid

Connection example 183a (0.5 g) was dissolved in CH2Cl2(5 ml), clear, colorless solution was added TFA (10.0 equiv.; 0,74 ml). The reaction mixture was stirred during the course the e night at ambient temperature. Formed transparent light-yellow solution. The reaction mixture was diluted with CH2Cl2(20 ml), was extracted with 10% aqueous solution of Na2CO3, the aqueous layer was twice washed with CH2Cl2combined organic layers were washed with brine, dried over Na2SO4was filtered and evaporated and received 407 mg (100%) of the desired compound as a colourless viscous oil. MS (IER): m/z = 416,1 [M+H]+.

C) Methyl ester of (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

Connection example 183b (400 mg) was dissolved in DMF (4.0 ml). To the suspension was added HATU (732 mg), DIEA (249 mg) and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (178 mg) (after adding HATU formed light yellow suspension). The reaction mixture was stirred over night at ambient temperature. The solvent is evaporated to dryness, the residue was dissolved in CH2Cl2(25 ml) were extracted sequentially with 0.5 N. aqueous solution of HCl, 10% aqueous solution of Na2CO3and brine. The aqueous layers were washed with CH2Cl2(100 ml), the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel using a mixture of n-heptane : AcOEt and the floor is Ali 219 mg (41%) of the desired compound as colorless amorphous solid. MS (IER): m/z = 552,1 [M+H]+.

d) (2S,4R)-4-[2-Chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylate lithium

To a colorless solution of the compound of example C (0.21 g) in THF (0.8 ml) at ambient temperature under inert atmosphere was added a solution of lithium hydroxide (1.9 equiv.; 17 mg) in water (1.2 ml). The solution was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and got 205 mg (99%) of the desired compound as a white solid. MS (IER): m/z = 538,1 [M-N-Vos]-.

To obtain (1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid the compound of example C (200 mg) was dissolved in DMF (2.0 ml). To the solution was added HATU (420 mg), DIEA (143 mg) and 1-amino-1-cyclopropanecarbonitrile. The resulting suspension was stirred at ambient temperature for 2 hours the solvent is Then evaporated to dryness under reduced pressure. The residue was dissolved in CH2Cl2(25 ml) were extracted sequentially with 0.5 N. aqueous solution of HCl, aqueous solution 10% Na2CO3and brine. The aqueous layers were washed with CH2Cl2(50 ml), the combined organic layers were dried over Na2SO4was filtered and perivale. The residue was purified by chromatography on silica gel using a mixture of n-heptane : AcOEt and received 130 mg (59%) of the desired compound as colorless amorphous solid. MS (IER): m/z = 602,1 [M+H]+.

Example 184

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 183 and amorphous colorless solid. MS (IER): m/z = 602,1 [M+H]+.

Example 185

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(2-cryptomaterial-4-yl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 186 using 4-chloro-2-(trifluoromethyl)pyrimidine stage and. MS (IER): m/z = 534,2 [M+H]+.

Example 186 example 187

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid

and

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid

a) ethyl ester of (2S,4R)-4-(2-cryptomaterial the Nile)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid and ethyl ester of (2R,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid

A solution of compound e (0.20 g, 1.0 EQ.) in acetonitrile (0.3 ml) was treated with 2-chloro-3-(trifluoromethyl)pyridine (0,72 g, 7.0 EQ.) and triethylamine (0.14 g, 2.5 EQ.). The mixture was irradiated in a microwave oven at 190°C for 1 h and then at 200°C for 30 minutes the Solvent is evaporated and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and evaporated. Purification using flash chromatography on silica gel in a gradient mode using a mixture of toluene/ethyl acetate gave ethyl ester (2S,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid as a pale yellow oil (0,048 g, 17%) and ethyl ester of (2R,4R-)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid as a white solid (0.025 g, 8%). MS (IER): m/z = 497,0 [M+H]+.

b) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid and (1-cyanocyclohexyl)-amide and (2R,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid

Ethyl ester of (2S,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid (0,043 g, 1.0 EQ.) was dissolved in ethanol (2.0 ml) and treated with 1 N. LiOH (0.17 ml, 2.0 EQ.). The mixture was stirred when It is over 4.5 hours The solvent is evaporated and the residue suspended in water and acidified to pH 1 using 1 N. HCl. Osadovskaya acid was filtered and washed with water and got a white solid (0,034 g, 84%). The solid was dissolved in dry THF (1.0 ml) and was treated with N-methylmorpholine (0,022 g, 3.0 EQ.). The mixture was cooled to 0°C and treated with isobutylphthalate (0,012 g, 1.2 EQ.). The mixture was stirred at 0°C for 2 h and then there was bright red. 1-Aminocyclohexanecarboxylic (0,010 g, 1.2 EQ.) was dissolved in dry DMF (1 ml) and then this solution was added dropwise, bath with ice was removed and the reaction mixture was stirred at RT over night. The mixture was treated with a saturated solution of ammonium chloride and water and was extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. Purification using flash chromatography on silica gel in a gradient mode using a mixture of toluene/acetonitrile gave (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid as a pale yellow oil (0.005 g, 13%) and (1-cyanocyclohexyl)-amide and (2R,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid as a white solid (0.004 g, 10%). MS (IER): m/z = 533,1 cleaboy compounds [M+H] +.

Example 188 and example 189

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid

and

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid

The desired compounds were obtained analogously to receive in example 164 and 166 using 2-chloro-3-triptoreline on stage a and 2,4-Dichlorotoluene on stage 164 ° C.. The final stage was conducted as in example 166, and got both compounds, which could be separated using serial twofold flash chromatography on silica gel in a gradient mode using a mixture of dichloromethane/methanol in a gradient mode using a mixture of toluene/acetonitrile. MS (IER): m/z = 533,3 [M+H]+and 533,1 [M+H]+.

Example 190 and the example 191

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid

and

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid

A solution of (1-cyanocyclohexyl)-amide 4-(2-chloro-4-permentantly)-1-(3-triform terpyridine-2-yl)-pyrrolidin-2-carboxylic acid (0,084 g, 1.0 EQ.) in dry DMA (1.5 ml) was treated with N-ethylpiperazine (0,032 g, 1.7 EQ.) and cesium carbonate (0.09 g, 1.7 EQ.) and was stirred for 3 days at RT. The mixture was filtered and the filtrate evaporated. Double purification using flash chromatography on silica gel in a gradient mode using a mixture of dichloromethane/methanol and only dichloromethane gave the desired compound as white solids: (1 cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid (0.003 g, 3%) and (1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid (0.002 g, 2%). MS (IER): m/z = 611,2 [M+H]+for both compounds.

(1-Cyanocyclohexyl)-amide 4-(2-chloro-4-permentantly)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid was obtained similarly to the receipt in the examples 164 and 166 using 2-chloro-4-portifino on stage 164 ° C..

Example 192

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-phenyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

1-Tert-butyl ether,2-ethyl ester (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid

With stirring to a solution of 1-tert-butyl ester (2S,4S)-4-hydroxypyrrolidine-1,2-dicarba the OIC acid (1.0 EQ., 5.0 g) in ethyl acetate (250 ml) was added dicyclohexylamine (2.0 EQ., to 8.62 ml) and the reaction mixture was stirred for 5 min and during this time he formed a white precipitate. Part of the ethyl acetate is evaporated and the suspension was kept for 30 min, then filtered and washed with diethyl ether (30 ml). The filtrate is briefly dried under high vacuum and then suspended in anhydrous DMF (50 ml). Then the reaction mixture was treated with ethylbromide (4.0 EQ., 6,46 ml) and stirred in a sealed flask for 18 hours TLC and MS showed that the reaction was completed. The reaction mixture was filtered and washed with ethyl acetate (2×20 ml). Then the filtrate is evaporated to dryness, the residue was transferred into ethyl acetate (50 ml) and the organic layer was washed once with water and once with brine, dried over sodium sulfate, filtered and evaporated and obtained colorless oil (4,87 g; 87%). The crude product was used without additional purification. MS (IER): m/z = to 204.1 [M+H-BOC]+.

1-Tert-butyl ether,2-ethyl ester (2S,4S)-4-(3-nitrobenzenesulfonate)-pyrrolidine-1,2-dicarboxylic acid

A (4,87 g, 1 EQ.) was dissolved in dichloromethane (50 ml) and was treated with 3-nitrobenzenesulfonamide (5,25 g, 1.20 equiv.). Then the reaction mixture was cooled to 0°C. using a bath of ice and within 10 min dropwise added triethylamine (7,81 ml, 3.0 EQ.). Observed changed the e color from colorless to bright yellow. Then the reaction mixture gave re-heated to CT (even in the bath with ice) and was stirred over night. Formed dark orange solution. Analysis by TLC and MS showed that the reaction was completed. The reaction mixture was further diluted with dichloromethane (50 ml), then was extracted with 0.5 M aqueous HCl solution and a saturated solution of sodium carbonate. Then the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated and received a brown resin (8,45 g, 101%). The crude product was used without additional purification. MS (IER): m/z = 445,2 [M+H]+.

1-Tert-butyl ether,2-ethyl ester (2S,4R)-4-(2-triftormetilfullerenov)-pyrrolidine-1,2-dicarboxylic acid

NaH (1.24 g, 1.50 EQ.) suspended in dry THF (220 ml) in an argon atmosphere. In an argon atmosphere for 10 min was added dropwise 2-triptoreline (3,76 ml, 1.50 EQ.) and the reaction mixture was stirred at RT for 2 h 192b (8,45 g, 1 EQ.) was diluted with THF (50 ml) and the solution in an argon atmosphere for 10 min was added to the reaction mixture. Then the reaction mixture was stirred at 50°C for 2 h and during this time he formed a white suspension. Analysis by TLC and MS showed that the reaction was completed. At RT the reaction mixture was poured into water (450 ml) and was extracted with ethyl acetate (2 the 350 ml). Then the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated and got an orange oil (9,11 g; 114%). The crude product was used without additional purification. MS (IER): m/z = 419,9 [M+H]+.

1-Tert-butyl ether,2-ethyl ester (2S,4R)-4-(2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid

S (9,11 g, 1 EQ.) was dissolved in dichloromethane (65 ml), to which for 20 min at RT portions was added m-chloroperbenzoic acid (13,4 g, 2.5 EQ.). Then the reaction mixture was stirred at for 17 h at RT and during this time he formed a white precipitate. The precipitate was filtered and washed with dichloromethane (30 ml). Then the filtrate was slightly diluted with dichloromethane (30 ml) and treated with a saturated solution of sodium carbonate (50 ml). Then the aqueous phase was extracted three times with dichloromethane (3×40 ml) and the combined organic phases were dried over sodium sulfate, filtered and evaporated and received a yellow oil (8,30 g). The crude product was purified on silica gel in a gradient mode using a mixture of n-heptane : ethyl acetate and obtained the desired compound as colorless resinous substance (5,14 g; 52%). MS (IER): m/z = 452,1 [M+H]+.

Ethyl ester of (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

192d (5,14 g, 1 EQ.) was diluted with dichloromethane 35 ml), to which was added TFA (10,98 ml, 12,60 EQ.). Then the reaction mixture was stirred at RT for 1.5 h Then the reaction mixture is evaporated to dryness and the residue was transferred to a dichloromethane (40 ml) and was extracted twice with saturated sodium bicarbonate solution (30 ml). Then the combined organic phases were dried over sodium sulfate, filtered and evaporated and obtained white solid (3,96 g; 99%). The crude product was used without additional purification. MS (IER): m/z = 352,2 [M+H]+.

Ethyl ester of (2S,4R)-1-(3-oxobutyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

E (3.0 g, 1 EQ.) was dissolved in toluene (70 ml), to which under stirring was added tert-butylacetoacetate (1,42 ml, 1 EQ.). The reaction mixture was stirred at 100°C during the night. Over the course of the reaction was monitored by TLC and MS. After completion of the reaction the solvent is evaporated and received a brown oil (4.1 g). The crude product was purified on silica gel in a gradient mode using a mixture of n-heptane : ethyl acetate and obtained the desired compound in the form of a viscous brown oil (3.1 g, 84%). MS (IER): m/z = 436,1 [M+H]+.

Ethyl ester of (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

192f (3.1 g, 1 EQ.) was diluted with toluene (120 ml) in an argon atmosphere, to which under stirring on balali the reagent Lawesson (1.45 g, 0.5 EQ.). Then the reaction mixture was stirred at 75°C during the night. Over the course of the reaction was monitored by TLC and MS. After completion of the reaction the solvent is evaporated and was given a dark red oil (5.0 g). The crude product was purified on silica gel in a gradient mode using a mixture of n-heptane : ethyl acetate and obtained the desired compound as a brown solid (2,18 g, 67%). MS (IER): m/z = 452,0 [M+H]+.

Ethyl ester of (2S,4R)-1-(5-methyl-2-phenyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

192g (0,290 g, 1 EQ.) suspended in toluene (12 ml) under nitrogen atmosphere, to which was added phenylhydrazine (0,08 ml, 1.2 EQ.) and the reaction mixture was stirred at 90°C for 2 hours Analysis by TLC and MS showed that the reaction was completed. The reaction mixture was diluted with toluene (30 ml) and was extracted with 0.5 N. aqueous solution of HCl and once washed with brine. The combined organic layers were dried over sodium sulfate, filtered and evaporated and received a brown oil (0.35 g). The crude product was purified on silica gel in a gradient mode using a mixture of n-heptane : ethyl acetate and obtained the desired compound as an orange solid (0.17 g, 51%). MS (IER): m/z = 508,2 [M+H]+.

(2S,4R)-1-(5-Methyl-2-phenyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-to robonova acid

192h (0.17 g, 1 EQ.) suspended in methanol (20 ml). Added 1 N. LiOH (0,66 ml, 2 EQ.) and the reaction mixture was stirred at RT over night. Analysis by TLC and MS showed that the reaction was completed. The methanol evaporated and the obtained residue was dissolved in water (25 ml). Then the solution was acidified aqueous solution of 1 N. HCl. The desired acid was not deposited completely, so the aqueous phase was extracted three times with ethyl acetate (3×30 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated and obtained colorless oil (0.12 g; 75%). The crude product was used without additional purification. MS (IER): m/z = of 480.2 [M+H]+

j) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-phenyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

192i (0.12 g, 1 EQ.) was diluted with dry THF (5 ml) under nitrogen atmosphere, to which was added 4-methylmorpholine (0,08 ml, 3 EQ.). In nitrogen atmosphere, the reaction mixture was cooled to -15°C. using a bath of ice and salt. Then for 3 min was added dropwise isobutylparaben (0.04 ml, 1.2 EQ.) and the reaction mixture was stirred at -15°C for 2 hours 1-Aminocyclohexanecarboxylic (0.035 g, 1.2 EQ.) was dissolved in dry DMF (2 ml) and then this solution was added dropwise, bath with ice and salt was removed and the reaction mixture was stirred at RT for but is I. Over the course of the reaction was monitored by TLC and MS. After completion of the reaction the solvent is evaporated and received a brown oil (0,200 g). The crude product was purified on silica gel in a gradient mode using a mixture of n-heptane : ethyl acetate and obtained the desired compound as a colourless solid (amount of 0.118 g, 87%). MS (IER): m/z = 544,1 [M+H]+.

Example 193

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 192, replacing phenylhydrazine (2-chloropyridin-4-yl)-hydrazine at stage h. MS (IER): m/z = 579,1, 581,0 [M+H]+.

Example 194

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-chlorophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 192, replacing phenylhydrazine by 4-chlorophenylhydrazone at stage h. MS (IER): m/z = 578,1, 580,0 [M+H]+.

Example 195

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-forfinal)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 192, replacing phenylhydrazine the 4-forfamilies at stage h. MS (IER): m/z = 562,2 [M+H]+.

Example 196

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2-oxo-1,2-dihydropyridines-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 192, replacing phenylhydrazine by 4-hydrazino-1H-pyridine-2-being h. MS (IER): m/z = 561,2 [M+H]+.

Example 197

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-cyclopropanecarbonitrile-2-carboxylic acid

The desired compound was obtained from the compound of example 183a according to the method described in example 149, through intermediate products a ((2S,4R)-1-tert-butoxycarbonyl-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylate lithium), 197b (tert-butyl ether (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid) and s ((1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid; 150 mg) was obtained 76 mg (44%) of colorless amorphous solid. MS (IER): m/z = 534,2 [M+H]+.

Example 198

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-cyclopropanecarbonitrile-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 197 and amorphous colorless solid. MS (IER): m/z = 534,2 [M+H]+.

Example 199

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 197, using the compounds of example C (150 mg) as a starting substance and received 101 mg (57%) of a colorless resin. MS (IER): m/z = 548,2 [M+H]+.

Example 200

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 199 and amorphous colorless solid. MS (IER): m/z = 548,2 [M+H]+.

Example 201

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(oxetan-3-yloxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 181 (90 mg) as a starting substance and is Uchali 10 mg (8%) of white solids. MS (IER): m/z = 562,2 [M+H]+.

Example 202

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 43 (160 mg) as a starting substance and received 161 mg (75%) of white solids. MS (IER): m/z = 566,2 [M+H]+.

Example 203

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 197, using the compounds of example C (150 mg) as a starting substance was obtained 63 mg (36%) of colorless amorphous solid. MS (IER): m/z = 550,2 [M+H]+.

Example 204

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid

The desired compound was obtained as a byproduct in the synthesis of the compound of example 203 and amorphous colorless solid. MS (IER): m/z = 550,3 [M+H]+.

Example 205

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(1-triftormetilfullerenov the carbonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 43 (80 mg) as a starting substance and received 44 mg (45%) of nearly white solid. MS (IER): m/z = 524,1 [M+H]+.

Example 206

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(3,3,3-triptocaine)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 43 (80 mg) as a starting substance was obtained 56 mg (60%) of a white solid. MS (IER): m/z = 498,1 [M+H]+.

Example 207

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 43 (80 mg) as a starting substance and received 47 mg (53%) of amorphous solids. MS (IER): m/z = 470,1 [M+H]+.

Example 208

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid

a) 4-fluoro-2-trifloromethyl

4-fluoro-2-(trifluoromethyl)benzoylformate (2.0 g) Rast is oral in dioxane (12 ml) in an atmosphere of N 2when the ambient temperature. Then added water (3.0 ml) and Tris-(2-carboxyethyl)fosphenytoin (8,73 g). The reaction mixture was stirred while boiling under reflux for 6 hours, the Reaction mixture was cooled to 25°C and dissolved in water (30 ml). The product was extracted several times with CH2Cl2(100 ml). The combined organic layers were washed with water and dried over Na2SO4. The organic layer was filtered and evaporated to dryness and obtained 1.27 g (85%) of colorless liquid, which was used without further purification. MS (IER): m/z = 194,9 [M-H]-.

b) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-(4-fluoro-2-triftormetilfullerenov)-pyrrolidine-1,2-dicarboxylic acid

The desired compound was obtained from the compound of example 120A (1.1 g) and example a (0.6 g) by the method similar to that described in example 120b, and obtained the desired compound as a colourless viscous oil (0,93 g; 86%). MS (IER): m/z = 332,2 [M+H]+.

c) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid

The desired compound was obtained from the compound of example 208b (0,932 g) by the method similar to that described in example 120C, and obtained the desired compound as light yellow viscous oil (0,958 g; 96%). MS (IER): m/z = 456,1 [M+H]+.

d) 1-Tert-butyl ether,2-methyl shall ester (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidine-1,2-dicarboxylic acid

The desired compound was obtained from the compound of example C (0.5 g) and 2,2,2-triptoreline (0,132 g) by the method similar to that described in example a, and obtained the desired compound as a brown oil (0,587 g; 99%). MS (IER): m/z = 536,1 [M+H]+.

e) 1-Tert-butyl ester (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidine-1,2-dicarboxylic acid

The desired compound was obtained from the compound of example 208d (0,587 g) by the method similar to that described in example 122b. The obtained lithium salt was treated with CH2Cl2and was extracted with 0.1 M aqueous HCl solution and brine. The organic layer was dried over Na2SO4. The organic layer was filtered and evaporated to dryness and got the desired compound in the form of an almost white solid (0,587 g; 100%). MS (IER): m/z = 544,1 [M+Na]+.

Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid

The target compound 208 was obtained from the compound of example e (0,587 g) by the method similar to that described in example 122, and received 0,544 g (84%) of nearly white amorphous solid. MS (IER): m/z = 586,1 [M+H]+.

Example 209

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

a) 1-Tert-butyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid

The desired compound was obtained from the compound of example C (250 mg) by the procedure similar to that described in example I, and received 236 mg (97%) of white solids. MS (IER): m/z = 342,0 [M+H-BOC]+.

b) Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-1-carboxylic acid

The desired compound was obtained from the compound of example a (236 mg) by the procedure similar to that described in example 208, and received 373 mg (138%) of colorless viscous oil. MS (IER): m/z = 504,1 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

Connection example C was obtained from the compound of example 209b (373 mg) by the method similar to that described in example C, and received 318 mg (106%) of an amorphous brown solid. MS (IER): m/z = 404,1 [M+H]+.

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The target compound of example 209 was obtained from the compound of example C (106 mg) by the method similar to that described in example 135, and obtained 42 mg (30%) of a white solid. MS (IER): m/z = USD 542.3 [M+H]+.

Example 210

(1-Cyanocyclohexyl)amide (2S,4R)-1-(2,2-dimethylpropanoyl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained from the compound of example C (106 mg) by the method similar to that described in example 209, and received 14 mg (11%) of colorless solid. MS (IER): m/z = 490,2 [M+H]+.

Example 211

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

a) (1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained from the compound of example 208 (389 mg) by the method similar to that described in example C, and received example 211A (258 mg; 80%) as a pale yellow amorphous substance. MS (IER): m/z = 486,2 [M+H]+.

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

The target compound of example 211 was obtained from the compound of example 211A (100 mg) by the method similar to that described in example 210, and received 85 mg (73%) as a pale yellow amorphous substance. MS (IER): m/z = 568,3 [M+H]+.

Example 212

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2,2-dimethylpropanoyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

The suit is my connection was obtained from the compound of example 211a (100 mg) by the method similar to that described in example 211, and received 78 mg (67%) as a pale yellow amorphous substance. MS (IER): m/z = 570,3 [M+H]+.

Example 213

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 42 (100 mg) as a starting substance and received 90 mg (72%) of white solids. MS (IER): m/z = 490,2 [M+H]+.

Example 214

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 42 (100 mg) as a starting substance and received 83 mg (75%) of white solids. MS (IER): m/z = 436,2 [M+H]+.

Example 215

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 42 (100 mg) as a starting substance and received 113 mg (83%) of white solids. MS (IER): m/z = 532,1 [M+H]+.

Example 216

(1-Cenotillo ropyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 42 (100 mg) as a starting substance and received 97 mg (76%) of white solids. MS (IER): m/z = 498,2 [M+H]+.

Example 217

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 42 (100 mg) as a starting substance was obtained 72 mg (64%) of amorphous solids. MS (IER): m/z = 438,2 [M+H]+.

Example 218

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-isobutylpyrazine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 42 (100 mg) as a starting substance and received 86 mg (79%) of white solids. MS (IER): m/z = 424,2 [M+H]+.

Example 219

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-triptocaine)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 42 (100 mg) as a starting substance and received 89 mg (75%) of amorn the th light-yellow solid. MS (IER): m/z = 464,1 [M+H]+.

Example 220

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-methylbutyryl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149, using the compound of example 42 (100 mg) as a starting substance and received 83 mg (74%) of an amorphous light yellow solid. MS (IER): m/z = 438,2 [M+H]+.

Example 221

Tert-butyl ester (2S,4R)-4-[4-chloro-2-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The desired compound was isolated as a side product during the synthesis of the compound of example 171 using as a starting material 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid instead of 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2-chloro-4-permentantly)-pyrrolidine-1,2-dicarboxylic acid, and received 341 mg (25%) of colorless foam substance. MS (IER): m/z = 552,2 [M+H]+.

Example 222

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 149 using with the unity of example 15 in the form of the free base (150 mg) as a starting substance and received 117 mg (64%) of colorless solid. MS (IER): m/z = 470,1 [M+H]+.

Example 223

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 222 using the compounds of example 15 in the form of the free base (150 mg) as a starting substance and received 143 mg (65%) of colorless solid. MS (IER): m/z = 568,2 [M+H]+.

Example 224

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 222 using the compounds of example 15 in the form of the free base (150 mg) as a starting substance and received 131 mg (64%) of colorless solid. MS (IER): m/z = 532,1 [M+H]+.

Example 225

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 222 using the compounds of example 15 in the form of the free base (150 mg) as a starting substance and received 99 mg (54%) of colorless foam substance. MS (IER): m/z = 472,1 [M+H]+.

Example 226

(1-Cyano shall ecoprofile)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-isobutylpyrazine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 222 using the compounds of example 15 in the form of the free base (150 mg) as a starting substance and received 103 mg (58%) of colorless amorphous solid. MS (IER): m/z = 458,1 [M+H]+.

Example 227

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3,3,3-triptocaine)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 222 using the compounds of example 15 in the form of the free base (150 mg) as a starting substance and received 98 mg (51%) of colorless foam substance. MS (IER): m/z = 498,0 [M+H]+.

Example 228

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3-methylbutyryl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 222 using the compounds of example 15 in the form of the free base (150 mg) as a starting substance and received 90 mg (49%) of colorless amorphous substance. MS (IER): m/z = 472,1 [M+H]+.

Example 229

Tert-butyl ester (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

IP is omogo compound was obtained analogously to receive in example 122 using (S)-tripersonal as the initial substance and got 74% colorless foam substance. MS (IER): m/z = 566,1 [M+H]+.

Example 230

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid

The compound of example 229 (8.1 g) was dissolved in formic acid (40,0 ml) and stirred at ambient temperature during the whole of 8.0 hours the Reaction mixture was carefully treated with cold 10% aqueous solution of Na2CO3(400 ml) to pH=8. The mixture was extracted with CH2Cl2(500 ml). The aqueous phase was washed a total of 4 times with CH2Cl2combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness and got to 6.43 g (96%) of colorless amorphous substance. MS (IER): m/z = 466,1 [M+H]+.

Example 231

Isobutyl ether 4-{5-[(2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-2-oxo-2H-pyridine-1-carboxylic acid

The desired compound was obtained analogously to receive in example 192, replacing phenylhydrazine by 4-hydrazino-1H-pyridine-2-being h. MS (IER): m/z = 661 [M+H]+.

Example 232

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

+.

Example 233

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-chlorophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 192, replacing phenylhydrazine by 3-chlorophenylhydrazone at stage h. MS (IER): m/z = 578,1 [M+H]+.

Example 234

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-thiazol-2-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 192, replacing phenylhydrazine 2 hydrazino-1,3-thiazol at stage h. MS (IER): m/z = 551,1 [M+H]+.

Example 235

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2,4-differentiality)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compounds of example 17 (44 mg) as a starting substance and received 25 mg (42%) of colorless solid. MS (IER): m/z = 534,1 [M+H]+.

Example 236

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 114 (28 mg) as a starting substance and received 25 mg (63%) of colorless solid. MS (IER): m/z = 472,1 [M+H]+.

Example 237

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid (20 mg, 41 μmol; the compound of example 211A) was dissolved in DMF (0.4 ml) in an atmosphere of N2when the ambient temperature. Was added 1-trifluoromethyl-cyclopropanecarbonyl acid (10 mg, 62 μmol; registration number CAS 277756-46-4), HATU (23 mg, 62 μmol) and DIEA (10 μl, 62 mmol) and the reaction mixture was stirred for 48 h at ambient temperature. Was added a mixture of water/brine 1/1 and iPrOAc and the layers were separated. The aqueous layer was once again extracted with iPrOAc, the combined organic layers were washed with a mixture of water with ice/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and were awarded a yellow oil, which was purified using preparative thin-layer chromatography (silica gel, iPrOAc/heptane) and obtained the desired compound (13 mg, 21 mmol; 51%) as best is to maintain solids, MS (IER): m/z = 622,3 [M+H]+.

Example 238

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(1-methyl-1H-pyrazole-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

a) Synthesis of (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

Connection example I got like getting in example 145, using the compound of example 18 (375 mg) as a starting substance and received 297 mg (61%) of white foam substance. MS (IER): m/z = 604,0 [M+H]+.

b) Synthesis of (1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(1-methyl-1H-pyrazole-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

Argon was passed for 15 minutes through a mixture a (0,100 g), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan)-1H-pyrazole (0,048 g, 1.4 EQ.) and Na2CO3(0,048 g, 2.7 EQ.) in DMF (3.0 ml) and water (226 μl). Then add the complex [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride with CH2Cl2composition 1:1 (of 0.014 g, 0.1 EQ.) and the orange mixture was heated at 80°C for 3 h (analysis by TLC showed that the reaction was completed). The mixture was cooled to 25°C., then poured into a mixture of 5% aqueous solution of NaHCO3/ice and extrage is ovali with EtOAc (3×50 ml). The organic layers were washed with water and brine, dried over Na2SO4, filtered and evaporated. The crude substance was adsorbing on Si-amine silica gel and once was purified using flash chromatography (20 g of Si-Amin CH2Cl2/EtOAc). Then the resulting mixture was purified using chiral preparative HPLC and was obtained on 17 mg (17%) colorless amorphous substance. MS (IER): m/z = 604,2 [M+H]+.

Example 239

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(3,4-dichlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The compound of example 173 (75 mg) was dissolved in acetonitrile (1 ml). To this solution was added 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylhexadecane) (126 mg), diisopropylethylamine (44 mg) and 1-(3,4-dichlorophenyl)cyclopropanecarbonyl acid (46 mg) and was stirred for 24 h at ambient temperature. The reaction mixture was purified by chromatography on silica gel and got the desired compound as a colourless semi-solid substances (79 mg; 68%). MS (IER): m/z = 664,1 [M-N]-.

Example 240

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid

The desired compound was obtained in a similar way to gaining the example 239 using the compound of example 173 (75 mg) and 1-phenyl-1-cyclopropanecarbonyl acids and received 53 mg (53%) of colorless semisolid substances. MS (IER): m/z = 696,12 [M+H]+.

Example 241

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2,2-divorcecelebration)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 2,2-divertikulyarnoy acids and received 59 mg (59%) of colorless semisolid substances. MS (IER): m/z = 554,0 [M-N]-.

Example 242

Tert-butyl ether ({1-[(2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carbonyl]-cyclopropyl}-carbamino acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1 - [(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid and was obtained 30 mg (27%) of white solids. MS (IER): m/z = 657,1 [M+Na]+.

Example 243

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-cyanocyclohexane)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-sapotaceous acid and obtained 55 mg (58%) of colorless semisolid substances. MS (IER): z = 662,1 [M+Na] +.

Example 244

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-chlorophenyl)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 4-chlorophenylalanine acid and obtained 100 mg (quantitative yield) of colorless liquid. MS (IER): m/z = 604,1 [M+H]+.

Example 245

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-chloropyridin-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 238 using the compounds of example a) (100 mg) as a starting substance and received 53 mg (50%) of colorless amorphous substance. MS (IER): m/z = 634,1 [M+H]+.

Example 246

2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid (1-cyanocyclohexyl)-amide

The compound of example 173 (75 mg) was dissolved in acetonitrile (1 ml). To this solution was added 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylhexadecane) (126 mg), diisopropylethylamine (44 mg) and TRANS-2-phenyl-1-cyclopropanecarbonyl acid (32 mg) and was stirred for 24 h at tempera the ur environment. The reaction mixture was purified by chromatography on silica gel and the obtained mixture diastereoisomers. This mixture was further purified using preparative chiral HPLC (chiral stationary phase reprosil NR; solvent: ethanol/heptane 3:7) and got the desired compound, which was loirevalley first; white solid (21 mg; 28%). MS (IER): m/z = 596,1 [M+H]+.

Example 247

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-pyridine-4-enciclopediaper)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 246 and got the desired compound, which was loirevalley second; white solid (24 mg; 32%). MS (IER): m/z = 596,1 [M+H]+.

Example 248

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-methylpyridin-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 238 using the compounds of example a) (100 mg) as a starting substance and received 46 mg (45%) of colorless amorphous substance. MS (IER): m/z = 615,1 [M+H]+.

Example 249

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(1-methyl-1H-pyrazole-4-yl)-2-trifloromethyl]-pyrrolidin-2-carbon is acid

The desired compound was obtained analogously to receive in example 238 using (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid (example 270, 120 mg) as a starting substance and received 111 mg (92%) of light brown solid. MS (IER): m/z = 550,2 [M+H]+.

Example 250

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-methylpyridin-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-(pyridine-4-yl)cyclopropanecarbonyl acids and received 114 mg (99%) of an orange foam substance. MS (IER): m/z = 597,1,1 [M+H]+.

Example 251

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2,2-debtor-2-phenylacetyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 2,2-debtor-2-phenylacetic acid and received 86 mg (86%) of a white foam substance. MS (IER): m/z = 623,1 [M+Na]+.

Example 252

4-Hlorfenilovy ester (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-bensalah the Nile]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The compound of example 173 (75 mg) was dissolved in acetonitrile (1 ml). To this solution was added 4-chlorphtorcarbon (39 mg) and diisopropylethylamine (44 mg) and was stirred for 6 h at ambient temperature. The reaction mixture was purified by chromatography on silica gel and got the desired compound as colorless resinous substance (86 mg; 84%). MS (IER): m/z = 623,1 [M+NH4]+.

Example 253

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

It chilled with ice to a solution of 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid (2,97 g, 7 mmole; the compound of example I4) in dichloromethane (25 ml) in an argon atmosphere was added triperoxonane acid (2,82 ml, 37 mmole). The reaction mixture was stirred for 14 h at ambient temperature. The solvent was removed under reduced pressure. The residue was dissolved in iPrOAc (200 ml) and cooled to 0°C. was Carefully added to saturated aqueous solution of sodium carbonate (100 ml) and the layers were separated. The aqueous layer was extracted 2 more times with iPrOAc, the combined organic layers Ave is mawali water with ice and brine and dried over sodium sulfate. The solvent was removed under reduced pressure and obtained the desired compound (1.8 g, 7 mmole; 81%) as a red oil, which was sufficiently pure for use in the next stage. MS (IER): m/z = 304,1 [M+H]+.

b) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with tert-butylacetoacetate and got the desired compound as a yellow solid.

c) methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192 g, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson and got the desired compound as a red solid. MS (IER): m/z = 404,1 [M+H]+.

d) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 4-(trifluoromethyl)phenylhydrazine (registration number CAS 368-90-1) and got the desired connection is tion in the form of a colorless solid. MS (IER): m/z = 528,2 [M+H]+.

e) (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

Methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid (27 mg, 51 μmol) was dissolved in THF (0.2 ml). Was added to the solution of the monohydrate of lithium hydroxide (3 mg, 72 μmol) in water (0.2 ml) and the mixture was stirred at ambient temperature for 14 hours was Added a mixture of water with ice/0.1 N. aqueous HCl solution 1/1 and iPrOAc and the layers were separated. The aqueous layer was once again extracted with iPrOAc, the combined organic layers were washed with a mixture of water with ice/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and obtained the desired compound (26 mg, 51 μmol; quantitative yield) as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z = 514,3 [M+H]+.

f) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in Pris is accordance HATU, DIEA and got the desired compound as a colourless solid. MS (IER): m/z = 578,1 [M+H]+.

Example 254

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with (2-chloropyridin-4-yl)-hydrazine (registration number CAS 700811-29-6) and got the desired compound as a colourless solid. MS (IER): m/z = 495,1 [M+H]+.

b) (2S,4R)-4-(2-Chlorobenzenesulfonyl)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil. MS (IER): m/z = 481,0 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(2-chloropyridin-4-yl)-5-IU the Il-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless solid substances. MS (IER): m/z = 545,2 [M+H]+.

Example 255

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with methylhydrazine (registration number CAS 60-34-4) and got the desired compound as a yellow solid. MS (IER): m/z = 432,1 [M+H]+.

b) (2S,4R)-1-(1,5-Dimethyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound in the form of an almost white solid. MS (IER): m/z = 418,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin the-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = RUB 482.2 [M+H]+.

Example 256

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-cyclopropyl-2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

Connection example a) (50 mg) was dissolved in toluene (2.0 ml) and water (0.1 ml) in a sealed tube. Argon was injected within 15 minutes To the solution in a stream of argon was added tricyclohexylphosphine (0,15 equiv.) tribalistas (3.5 EQ.) and palladium(II) acetate (0.1 EQ.). The mixture was stirred at 100°C for 4 h, then at 25°C during the night. Analysis using LC-MS indicated complete depletion of the original substance. The reaction mixture was dissolved in AcOEt (10 ml) and was extracted with N2About (2×5 ml). The aqueous layers were washed with AcOEt, the combined organic layers were washed with brine, dried over Na2SO4, was filtered and evaporated to dryness. The reaction mixture was purified using flash chromatography (4 g SiO2in gradient mode, n-heptane 15% → n-heptane/EtOAc 1:4 for 45 min) and received 32 mg (68%) of colorless amorphous substance. MS (IER): m/z = 564,2 [M+H]+.

Example 257

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2-methylpyridin-4-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained anal is Gino getting in example 249 using (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid (example 270, 100 mg) as a starting substance and received 84 mg (82%) of light brown foam substance. MS (IER): m/z = 561,2 [M+H]+.

Example 258

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-chloropyridin-4-yl)-2-trifloromethyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 249 using (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid (example 270, 100 mg) as a starting substance was obtained 64 mg (60%) of nearly white solid. MS (IER): m/z = 581,2 [M+H]+.

Example 259

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2',4'-debtor-3-triptorelin-4-sulfonyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 249 using (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid (example 270, 100 mg) as a starting substance and received 90 mg (85%) of light brown foam substance. MS (IER): m/z = 582,2 [M+H]+.

Example 260

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-1-(1-trip armadillidiidae)-pyrrolidin-2-carboxylic acid

Connection example a) (70 mg) was dissolved in atsn (2 ml). To the solution at 25°C was added 1-methylpiperazine (0,02 ml, 1.4 EQ.) and base Hunya (0.05 ml, 2 EQ.). The mixture was stirred over night. Analysis using LC-MS indicated no reaction. Therefore, the reaction mixture was further added 1-methylpiperazine (0.5 EQ.) and the mixture was stirred at 55°C for 24 hours Since the reaction was still not completed, the solution was further added 1-methylpiperazine (0.2 EQ.) and stirred at 80°C for 24 h, the Reaction mixture was cooled to 25°C and purified using preparative HPLC and was obtained on 17 mg (20%) colorless amorphous substance. MS (IER): m/z = 622,4 [M+H]+.

Example 261

(1-Cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-benzensulphochloramide-1,2-dicarboxylic acid

According to the General method 1-tert-butyl ether,2-methyl ester (2S,4R)-4-phenolsulfonephthalein-1,2-dicarboxylic acid (Kyle, Donald James; Hiner, Roger Neal PCT Int. Appl. (1992), WO 9218155 A1) was oxidized with m-chloroperbenzoic acid and was obtained the desired compound as a yellow oil. MS (IER): m/z = 370,1 [M+H]+.

b) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic to the slots

According to the method similar to that described in example I, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-benzensulphochloramide-1,2-dicarboxylic acid was treated triperoxonane acid in dichloromethane and got the desired compound as a yellow oil. MS (IER): m/z = 270,2 [M+H]+.

c) Methyl ester of (2S,4R)-4-benzazolyl-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-benzensulphochloramide-2-carboxylic acid were introduced into a reaction with tert-butylacetoacetate and got the desired compound as a yellow solid.

d) Methyl ester of (2S,4R)-4-benzazolyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example h, methyl ester (2S,4R)-4-benzazolyl-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson and got the desired compound as a red oil.

e) Methyl ester of (2S,4R)-4-benzazolyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-benzazolyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 4-(trifluoromethyl)phenylhydrazine (registration number CAS 368-90-1) and got the desired connection in vitilligo solids. MS (IER): m/z = 394,1 [M+H]+.

f) (2S,4R)-4-Benzazolyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-benzazolyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid. MS (IER): m/z = 480,1 [M+H]+.

g) (1-Cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-benzazolyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow solid. MS (IER): m/z = 544,2 [M+H]+.

Example 262

(1-Cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-benzazolyl-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-benzazolyl-1(3-occationally)-pyrrolidin-2-carboxylic acid (example 261d) were introduced in the reaction with (2-chloropyridin-4-yl)-hydrazine (registration number CAS 700811-29-6) and got the desired compound as a yellow solid. MS (IER): m/z = 461,3 [M+H]+.

b) (2S,4R)-4-Benzazolyl-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-benzazolyl-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid. MS (IER): m/z = 447,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-benzazolyl-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow oil. MS (IER): m/z = 511,2 [M+H]+.

Example 263

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2',4'-debtor-3-triptorelin-4-sulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 238 using the compounds of example a) (100 mg) as a starting substance and received 92 mg (87%) of colorless foam substance. MS (IER): m/z = 36,2 [M+H] +.

Example 264

Tert-butyl ester (4-{2-[(2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-yl]-2-oxoethyl}-cyclohexyl)-carbamino acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and TRANS-4-tert-butoxycarbonylmethylene acids and received 107 mg (33%) of a white foam substance. MS (IER): m/z = 691,1 [M+H]+.

Example 265

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-aminocyclohexane)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The compound of example 264 (87 mg) was dissolved in formic acid (0.4 ml) and was stirred over night at ambient temperature. The reaction mixture was subjected to distribution between water ice and dichloromethane. The pH value was set equal to 10 by adding solid sodium carbonate. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, concentrated to dryness and purified via chromatography on silica gel and got the desired compound as colorless resinous substance (74 mg; 96%). MS (IER): m/z = 591,3 [M+H]+.

Example 266

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-m is Teal-2H-pyrazole-3-yl]-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid (example C) was treated triperoxonane acid in dichloromethane and got the desired compound as a yellow oil. MS (IER): m/z = 356,1 [M+H]+.

b) Methyl ester of (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with tert-butylacetoacetate and got the desired compound as a yellow oil. MS (IER): m/z = 440,2 [M+H]+.

c) Methyl ester of (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example h, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson and got the desired compound as a brown solid.

d) Methyl ester of (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(4-fluoro-2-triftoratsetata hanil)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid were introduced into a reaction with (2-chloropyridin-4-yl)-hydrazine (registration number CAS 700811-29-6) and got the desired compound as a colourless solid. MS (IER): m/z = 547,2 [M+H]+.

e) (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid. MS (IER): m/z = 533,1 [M+H]+.

f) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless solid. MS (IER): m/z = 597,2 [M+H]+ .

Example 267

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with 4-(trifluoromethyl)phenylhydrazine (registration number CAS 368-90-1) and got the desired compound as a yellow solid. MS (IER): m/z = 580,3 [M+H]+.

b) (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil. MS (IER): m/z = 566,1 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

By the method similar to OPI is Anna in example 237, (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow solid. MS (IER): m/z = 630,2 [M+H]+.

Example 268

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with isopropylidenediphenol (registration number CAS 16726-41-3) and got the desired compound as a yellow solid. MS (IER): m/z = 460,3 [M+H]+.

b) (2S,4R)-1-(2-Isopropyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and recip is whether the desired compound as a yellow solid. MS (IER): m/z = 446,3 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless solid. MS (IER): m/z = 510,2 [M+H]+.

Example 269

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) methyl ester of (2S,4R)-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with 2,2,2-cryptgetkeyparam (registration number CAS 5042-30-8) and got the desired compound as a yellow solid. MS (IER): m/z = 500,2 [M+H]+.

b) (2S,4R)-1-[5-Methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

what about the method, similar to that described in example I, methyl ester (2S,4R)-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid. MS (IER): m/z = 486,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 550,1 [M+H]+.

Example 270

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example a) and received 1230 mg (76%) of white foam substance. MS (IER): m/z = 548,0 [M+H]+.

Example 271

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-cyclopropyl-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 256, and received 13 mg (23%) of nearly white waxy substance. MS (IER): m/z = 510,2 [M+H]+.

Example 272

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 260 and received 32 mg (31%) as a light red solid. MS (IER): m/z = 568,4 [M+H]+.

Example 273

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-bromophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (1.0 g) and 1-(4-bromophenyl)cyclopropanecarbonitrile acids and received 1.24 g (83%) of a white foam substance. MS (IER): m/z = 676,0 [M+H]+.

Example 274

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-acetylaminophenol)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 252, using the compound of example 265 (41 mg) and acetylchloride and received 34 mg (77%) of white solids. MS (IER): m/z = 633,0 [M+H +.

Example 275

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2,2-bis-(4-chlorophenyl)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (200 mg) and bis-(4-chlorophenyl)-acetic acid and received 264 mg (84%) of a white foam substance. MS (IER): m/z = 716,10 [M+H]+.

Example 276

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-m-tolyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(5-methyl-2-m-tolyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with 3-methylphenylhydrazine (registration number CAS 637-04-7) and got the desired compound as a yellow solid. MS (IER): m/z = 508,1 [M+H]+.

b) (2S,4R)-1-(5-Methyl-2-m-tolyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(5-methyl-2-m-tolyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-Pirro is one-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid. MS (IER): m/z = 494,1 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-m-tolyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(5-methyl-2-m-tolyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow solid. MS (IER): m/z = 558,2 [M+H]+.

Example 277

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-carbamoylphenoxy)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The compound of example 273 (200 mg), hexacarbonyl molybdenum (209 mg), catalyst Herrman (36 mg), tri-tert-butylmethylether (23 mg), gidroxinimesoulid (220 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (0,235 ml) and diisopropylethylamine (365 mg) suspended in dioxane (4 ml). The reaction mixture was irradiated in a microwave reactor at 120°C for 20 minutes and Then the reaction mixture was filtered through a layer dicalite. Layer was washed with dichloromethane, ethyl acetate. The crude mixture was concentrated to dryness and purified via chromatography on silica gel and got the desired compound in the form of colourless what about a resinous substance (42 mg; 21%). MS (IER): m/z = 638,1 [M+H]+.

Example 278

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclobutanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-(4-chlorophenyl)-1-cyclobutanecarbonyl acid and was obtained 78 mg (73%) of a white waxy substance. MS (IER): m/z = 644,10 [M+H]+.

Example 279

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-chlorophenyl)-2-methylpropionyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 4-chlorodimethylvinylsilane acid and was obtained 51 mg (49%) of white foam substance. MS (IER): m/z = 632,10 [M+H]+.

Example 280

(1-Cyanocyclohexyl)-amide and (2R,4S)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-trifluoromethyl-cyclopropanecarbonyl acid and was obtained 50 mg (50%) of rose oil. MS (IER): m/z = 605,1 [M+NH4]+.

Note the p 281

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-trifloromethyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (100 mg) as a starting substance and received 78 mg (47%) of colorless amorphous substance. MS (IER): m/z = 582,2 [M+H]+.

Example 282

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-methylpropionyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (100 mg) as a starting substance and received 24 mg (16%) of colorless amorphous substance. MS (IER): m/z = 534,1 [M+H]+.

Example 283

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclobutanecarbonyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (100 mg) as a starting substance and received 92 mg (60%) of colorless amorphous substance. MS (IER): m/z = 546,2 [M+H]+.

Example 284

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-what lebensalter)-1-[1-(3,4-dichlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (100 mg) as a starting substance was obtained 57 mg (36%) of colorless amorphous substance. MS (IER): m/z = 568,2 [M+H]+.

Example 285

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-pyridine-4-enciclopediaper)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (100 mg) as a starting substance was obtained 33 mg (23%) of colorless foam substance. MS (IER): m/z = 499,2 [M+H]+.

Example 286

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(5-methyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with hydrazinoacetate (registration number CAS 7803-57-8) and got the desired compound as a yellow solid.

b) (2S,4R)-1-(5-Methyl-1 is-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(5-methyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid. MS (IER): m/z = 404,4 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(5-methyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a brown solid. MS (IER): m/z = 468,2 [M+H]+.

Example 287

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(4-vinyltetrahydrofuran-4-carbonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (90 mg) and 1-phenylcyclohexanecarboxylic acid [registration no CAS 1135-67-7] and obtained 28 mg (22%) yellow solid. MS (IER): m/z = 640,1 [M+H]+.

Example 288

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzolamide the l]-1-{1-[4-(1-methyl-1H-pyrazole-4-yl)-phenyl]-cyclopropanecarbonyl}-pyrrolidin-2-carboxylic acid

The compound of example 273 (200 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole, (89 mg), sodium carbonate (85 mg), the complex [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)chloride with dichloromethane composition of 1:1 (24 mg) suspended in dimethylformamide (4 ml) and water (0.4 ml) was then degirolami nitrogen. The reaction mixture was stirred at 75°C for 2 days. The reaction mixture was subjected to distribution between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water. The crude mixture was concentrated to dryness and was purified by HPLC and was obtained the desired compound as a pale yellow solid (10 mg; 5%). MS (IER): m/z = 674,3 [M-N]-.

Example 289

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2-methylpyridin-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-[5-methyl-2-(2-methylpyridin-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with 2-hydrazino-2-methylpyridine (Regis is operating CAS no 100518-39-6) and got the desired compound as a brown solid. MS (IER): m/z = 509,3 [M+H]+.

b) (2S,4R)-1-[5-Methyl-2-(2-methylpyridin-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-[5-methyl-2-(2-methylpyridin-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid. MS (IER): m/z = 495,2 [M+H]+.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2-methylpyridin-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[5-methyl-2-(2-methylpyridin-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a brown solid. MS (IER): m/z = 559,2 [M+H]+.

Example 290

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The compound of example 145 (40 mg) was dissolved in acetonitrile (2 ml), was added to the base Hunya (30 μl) and 1-methylpiperazine (16 mg). Rea is operating and the mixture was stirred for 24 h at 25°C. LC/MS showed that it still contained the original substance. Additionally added 1-methylpiperazine (16 mg, 2.0 EQ.) and was stirred for 24 h at 25°C. LC/MS showed that it still contained the original substance. Additionally added 1-methylpiperazine (16 mg, 2.0 EQ.) and was stirred for 48 h at 25°C. LC/MS indicated complete conversion. The reaction mixture was purified using preparative HPLC and was obtained 38 mg (82%) of nearly white solid. MS (IER): m/z = 588,2 [M+H]+.

Example 291

(1-Cyanocyclohexyl)-amide (2S,4R)-4-{2-chloro-4-[4-(2,2,2-triptorelin)-piperazine-1-yl]-benzazolyl}-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 290 using the compound of example 145 (80 mg) as a starting substance and received 7 mg (7%) of light brown solid. MS (IER): m/z = 656,3 [M+H]+.

Example 292

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-dimethylaminobenzylidene)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained as a side product in example 301 and received 27 mg (32%) of white foam substance. MS (IER): m/z = 533,1 [M+H]+.

Example 293

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-of propylpiperazine-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 290 using the compound of example 145 (20 mg) as a starting substance and received 16 mg (66%) of white solids. MS (IER): m/z = 616,3 [M+H]+.

Example 294

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(3-methyloxiran-3-carbonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 3-acetocarmine acid (23 mg) and received 90 mg (99%) of yellow oil. MS (IER): m/z = 567,1 [M+NH4]+.

Example 295

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(4-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-(4-forfinal)-cyclopropanecarboxylic acid (36 mg) and received 81 mg (76%) as a light yellow foam substance. MS (IER): m/z = 612,2 [M-N]-.

Example 296

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The search is connected to the e was obtained similarly to the receipt in example 290 using the compound of example 145 (60 mg) as a starting substance and received 74 mg (99%) of nearly white solid. MS (IER): m/z = 630,5 [M+H]+.

Example 297

(1-Cyanocyclohexyl)-amide (2S,4R)-4-{2-chloro-4-[4-(2-methoxyethyl)-piperazine-1-yl]-benzazolyl}-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 290 using the compound of example 145 (60 mg) as a starting substance was obtained 57 mg (76%) of nearly white solid. MS (IER): m/z = 632,4 [M+H]+.

Example 298

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-cyclopropylmethyl-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 290 using the compound of example 145 (60 mg) as a starting substance was obtained 51 mg (70%) of nearly white solid. MS (IER): m/z = 614,2 [M+H]+.

Example 299

(1-Cyanocyclohexyl)-amide (2S,4R)-4-((S)-2-chloro-4-hexahydropyrazino[1,2-a]pyrazin-2-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 290 using the compound of example 145 (60 mg) as a starting substance and received 59 mg (81%) of nearly white solid. MS (IER): m/z = 614,2 [M+H]+

Example 300

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2,5-dimethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-[3-(tert-butoxycarbonylmethylene)-dibutyryl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with tert-butyl ether N-methylhydrocinnamic acid (registration number CAS 21075-83-2) and got the desired compound in the form of an almost white solid. MS (IER): m/z = 566,2 [M+H]+.

b) Methyl ester of (2S,4R)-1-(2,5-dimethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

Triperoxonane acid (61 μl, 0.8 mmole) in argon atmosphere was added to a solution of methyl ester (2S,4R)-1-[3-(tert-butoxycarbonylmethylene)-dibutyryl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (90 mg, 160 μmol) in dichloromethane (0.3 ml). The mixture was stirred at ambient temperature for 72 hours was Added a mixture of water with ice/10% aqueous sodium carbonate solution 1/1 and iPrOAc and the layers were separated. The aqueous layer was extracted 4 times with iPrOAc, the combined organic layers about ivali a mixture of water with ice/brine 1/1 and dried over Na 2SO4. The solvent was removed under reduced pressure and obtained a brown oil, which was purified using preparative thin-layer chromatography (silica gel, iPrOAc), and obtained the desired compound (20 mg, 46 μmol; 29%) as a yellow solid. MS (IER): m/z = 432,1 [M+H]+.

c) (2S,4R)-1-(2,5-Dimethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(2,5-dimethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound in the form of an almost white solid. MS (IER): m/z = 418,2 [M+H]+.

d) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2,5-dimethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(2,5-dimethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a brown solid. MS (IER): m/z = 482,1 [M+H]+.

Example 301

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-benzazolyl]-1-(1-triptime cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 290 using the compound of example 145 (20 mg) as a starting substance and stirring for 48 h at 70°C and received 6 mg (25%) of nearly white solid. MS (IER): m/z = 612,2 [M+H]+.

Example 302

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopentanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-(4-chlorophenyl)-1-cyclopentanecarbonyl acid (46 mg) and received 47 mg (43%) of a white foam substance. MS (IER): m/z = 658,2 [M+H]+.

Example 303

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-phenylcyclohexanecarboxylic)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-phenyl-1-cyclohexanecarboxylic acid (43 mg) and received 15 mg (14%) of a white foam substance. MS (IER): m/z = 638,2 [M+H]+.

Example 304

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-p-tooltipcontent)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 288 using the compound of example 273 (200 mg) and trimethylboroxine in tetrahydrofuran (50% wt./wt., 104 mg) and received 12 mg (7%) of colorless oil. MS (IER): m/z = 608,1 [M-N]-.

Example 305

(1-Cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

The desired compound was obtained as a side product during the synthesis of the compound of example 290 using the compound of example 145 (60 mg) as a starting substance and was sentenced to 9 mg (10%) of light brown solid. MS (IER): m/z = 588,1 [M+H]+.

Example 306

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

2,2,2-Triptoreline (2,2 μl, 29 mmol) and cesium carbonate (9 mg, 29 μmol) in argon atmosphere was added to a solution of (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid (15 mg, 24 µmol; the compound of example C) in N,N-dimethylacetamide (0.2 ml). The mixture was stirred for 12 h at ambient temperature and for 5 hours at 40 the S. Was added a mixture of water with ice/0.1 N. aqueous HCl solution 1/1 and iPrOAc and the layers were separated. The aqueous layer was once again extracted with iPrOAc, the combined organic layers were washed with a mixture of water with ice/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and were awarded a yellow oil, which was purified using preparative thin-layer chromatography (silica gel, iPrOAc/heptane) and obtained the desired compound (7 mg, 9.9 mmol; 44%) as a colourless oil. MS (IER): m/z = 710,1 [M+H]+.

Example 307

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with (tetrahydropyran-4-yl)hydrazinecarboxamide (registration number CAS 194543-22-1) and got the desired compound as an orange oil. MS (IER): m/z = 502,1 [M+H]+.

b) (2S,4R)-1-[5-Methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method, and is similar to the one described in example I, methyl ester (2S,4R)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as an orange oil.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless oil. MS (IER): m/z = 552,3 [M+H]+.

Example 308

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

a) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidine-1,2-dicarboxylic acid

According to the method similar to that described in example 306, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid (example C) was treated with 2,2,2-triptorelin and carbonate C is Zia and received a mixture of the desired compounds and source materials in the form of a yellow oil. MS (IER): m/z = 436,1 [M+H]+.

b) Methyl ester of (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidine-1,2-dicarboxylic acid, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid, processed triperoxonane acid in dichloromethane and the obtained mixture of the desired compounds and methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a yellow oil. MS (IER): m/z = 436,2 [M+H]+.

c) Methyl ester of (2S,4R)-1-(3-oxobutyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with tert-butylacetoacetate and received a mixture of the desired compounds and methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid as colorless oil. MS (IER): m/z = 520, [M+H] +.

d) Methyl ester of (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

The reagent Lawesson (39 mg, 106 μmol; registration number CAS 19172-47-5) and isopropylideneglycerol (12 mg, 106 μmol; registration number CAS 16726-41-3) in an argon atmosphere was added to a solution of methyl ester (2S,4R)-1-(3-oxobutyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid (50 mg, 96 μmol) in tetrahydrofuran (2.9 ml) and pyridine (0.1 ml). The mixture was stirred for 16 h at 55°C and for a further 48 h at ambient temperature. Was added a mixture of water with ice/0.1 N. aqueous HCl solution 1/1 and iPrOAc and the layers were separated. The aqueous layer was once again extracted with iPrOAc, the combined organic layers were washed with a mixture of water with ice/10% aqueous solution of sodium carbonate, the mixture of water with ice/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and were awarded a yellow oil, which was purified using preparative thin-layer chromatography (silica gel, iPrOAc/heptane) and received a mixture of the desired compounds and methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-Pierre is lidin-2-carboxylic acid (39 mg, 70 mmol; 73%) as a colourless oil. MS (IER): m/z = 558,2 [M+H]+.

e) Methyl ester of (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 306, a mixture of methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid methyl ester (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid was treated with 2,2,2-triptorelin and cesium carbonate and received a mixture of the desired compounds and methyl ester (2R,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid as colorless oil. MS (IER): m/z = 558,2 [M+H]+.

f) (2S,4R)-1-(2-Isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, a mixture of methyl ester (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid methyl ester (2R,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid ω is ranged in the presence of lithium hydroxide and obtained the desired compound as a colourless solid. MS (IER): m/z = 544,2 [M+H]+.

g) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after purification using preparative thin layer chromatography (silica gel, iPrOAc) was obtained the desired compound as a colourless oil. MS (IER): m/z = 608,2 [M+H]+.

Example 309

(1-Cyanocyclohexyl)-amide and (2R,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid (example 308f) was introduced in R. the share 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after purification using preparative thin layer chromatography (silica gel, iPrOAc) was obtained the desired compound as a colourless oil. MS (IER): m/z = 608,3 [M+H]+.

Example 310

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(4-triptoreline)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-(4-trifluoromethyl)phenylcyclopropanecarboxylic acid (48 mg) and received 119 mg (98%) of a white foam substance. MS (IER): m/z = 664,1 [M+H]+.

Example 311

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(3-triptoreline)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-(3-trifluoromethyl)phenylcyclopropanecarboxylic acid (48 mg) and received 112 mg (93%) of a white foam substance. MS (IER): m/z = 664,1 [M+H]+.

Example 312

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 144 (1.8 g) as a starting substance is received 1.8 g (68%) of white foam substance. MS (IER): m/z = 550,2 [M+H]+.

Example 313

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-carboxylic acid

The compound of example 42 in the form of the free base (70 mg) was dissolved in THF (4 ml). Was added 2-naphthalenesulfonate (54 mg) and the base Hunya (70 μl). The mixture was stirred for 18 h at room temperature. The reaction mixture is evaporated to dryness and was purified using preparative HPLC and was obtained 92 mg (85%) of the desired compound as a colourless foam substance. MS (IER): m/z = 544,2 [M+H]+.

Example 314

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclohexanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-(4-chlorophenyl)-1-cyclohexanecarboxylic acid (50 mg) and 17 mg (15%) of a colorless resin. MS (IER): m/z = 670,3 [M-N]-.

Example 315

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 313 using CH2Cl2(2 ml) instead of THF as a solvent and which has alocale 91 mg (87%) of a white foam substance. MS (IER): m/z = 528,1 [M+H]+.

Example 316

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(biphenyl-4-sulfonyl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 315 and received 54 mg (48%) of white foam substance. MS (IER): m/z = 570,2 [M+H]+.

Example 317

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-pyridazin-3-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(5-methyl-2-pyridazin-3-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction pyridazin-3-algerina (registration number CAS 40972-16-5) and got the desired compound as a colourless oil. MS (IER): m/z = 496,3 [M+H]+.

b) (2S,4R)-1-(5-Methyl-2-pyridazin-3-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(5-methyl-2-pyridazin-3-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide. Reacciona the mixture was dried to dryness and got the desired compound in the form of its lithium salt as a yellow solid. MS (IER): m/z = RUB 482.2 [M+H]+.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-pyridazin-3-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(5-methyl-2-pyridazin-3-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless oil. MS (IER): m/z = 546,3 [M+H]+.

Example 318

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 308d, a mixture of methyl ester (2S,4R)-1-(3-oxobutyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example 192f) and methyl ester (2R,4R)-1-(3-oxobutyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson (registration number CAS 19172-47-5) and cyclohexanedimethanol (registration number CAS 24214-73-1) and received a mixture of the desired compounds and methyl ester of (R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a brown oil. MS (IER): m/z = 500,3 [M+H]+.

b) (2S,4R)-1-(2-Cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, a mixture of methyl ester (2S,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid methyl ester (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and received a mixture of the desired compound and (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as colorless solid, which was used in the next stage without additional purification.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using hyalinobatrachium HPLC was obtained the desired compound as a colourless oil. MS (IER): m/z = 550,2 [M+H]+.

Example 319

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, a mixture of methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) and methyl ester (2R,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with benzyltrimethylammonium (registration number CAS 20570-96-1) and received a mixture of the desired compounds and methyl ester (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as an orange oil. MS (IER): m/z = 508,2 [M+H]+.

b) (2S,4R)-1-(2-Benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, a mixture of methyl ester (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid methyl ester (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid on ilali in the presence of lithium hydroxide and received a mixture of the desired compound and (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as an orange oil, which was used in the next stage without additional purification. MS (IER): m/z = 492,3 [M-N]-.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a colourless oil. MS (IER): m/z = 558,2 [M+H]+.

Example 320

(1-Cyanocyclohexyl)-amide and (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) presence in the AI HATU, DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a colourless oil. MS (IER): m/z = 550,2 [M+H]+.

Example 321

(1-Cyanocyclohexyl)-amide and (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a colourless oil. MS (IER): m/z = 558,2 [M+H]+.

Example 322

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 308d, a mixture of methyl ester (2S,4R)-1-(3-oxobutyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example 192f) and methyl ester (2R,4R)-1-(3-oxobutyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid in the-Odile in the reaction with the reagent Lawesson (registration number CAS 19172-47-5) and cyclobutanecarbonitrile (registration number CAS 158001-21-9) and received a mixture of the desired compounds and methyl ester (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid in the form of a white solid. MS (IER): m/z = 472,3 [M+H]+.

b) (2S,4R)-1-(2-Cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, a mixture of methyl ester (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid methyl ester (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and received a mixture of the desired compound and (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a white solid, which was used in the next stage without additional purification. MS (IER): m/z = 456,1 [M-N]-.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in PR is the absence of HATU, DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a yellow solid. MS (IER): m/z = 522,3 [M+H]+.

Example 323

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-oxazol-5-eventality)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 315 and received 60 mg (54%) of white foam substance. MS (IER): m/z = 570,2 [M+H]+.

Example 324

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The compound of example 312 (100 mg) was dissolved in acetonitrile (4 ml). Added base Hunya (60 μl) and 1-methylpiperazine (40 μl). The reaction mixture was stirred for 24 h at 25°C. the Reaction was not completed. Therefore, in addition was added 1-methylpiperazine (40 μl, 2.0 EQ.) and the mixture was stirred for 24 h at 25°C. the Reaction was not yet completed. Additionally added 1-methylpiperazine (40 μl, 2.0 EQ.) and the mixture was stirred for 24 h at 25°C. According to analysis with LC-MS, the reaction was completed. The reaction mixture was purified using preparative HPLC and was obtained the desired compound (104 mg, 91%) as a white solid. MS (IER): m/z = 630,1 [M+H]+.

Example 325

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazol-1-eventality)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrole the h-2-carboxylic acid

The compound of example 312 (100 mg) was dissolved in acetonitrile (4 ml). Added base Hunya (60 ml) and imidazole (25 mg). The reaction mixture was stirred for 24 h at 25°C. the Reaction mixture contained only the original substance. Therefore, in addition was added imidazole (25 mg, 2.0 EQ.) and the mixture was stirred for 24 h at 80°C. the Reaction was not yet completed. Additionally added imidazole (50 mg, 4.0 EQ.) and the mixture was stirred for 3 days at 80°C. According to analysis with LC-MS, the reaction was completed. The reaction mixture was purified using preparative HPLC and was obtained the desired compound (51 mg, 47%) as a white foam substance. MS (IER): m/z = 598,2 [M+H]+.

Example 326

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-Mei-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 325 and received 67 mg (60%) of a white foam substance. MS (IER): m/z = 612,2 [M+H]+.

Example 327

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidin-2-carboxylic acid

The compound of example 312 (50 mg) was dissolved in DMA (2 ml). Added cesium carbonate (59 mg) and pyrazole (12 mg).The reaction mixture was stirred in the microwave at 80°C for 30 min at 80°C. The reaction mixture was purified using preparative HPLC and was obtained the desired compound (32 mg, 59%) as a white foam substance. MS (IER): m/z = 598,2 [M+H]+.

Example 328

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-azetidin-1-yl-2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The compound of example 312 (100 mg) was dissolved in acetonitrile (4 ml). Added base Hunya (60 μl) and azetidin (20 µl). The reaction mixture was stirred for 2 h at 25°C. Then was additionally added azetidine (20 μl, 2.0 EQ.) and the mixture was stirred for 24 h at 40°C. the Reaction mixture was purified using preparative HPLC and was obtained the desired compound (90 mg, 84%) as a white foam substance. MS (IER): m/z = 587,1 [M+H]+.

Example 329

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 328 and received 80 mg (65%) of a white foam substance. MS (IER): m/z = 672,2 [M+H]+.

Example 330

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-cyclopropylmethyl-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The compound of example 312 (100 mg) was dissolved in acetonitrile (4 ml). Added base Hunya (60 μl) and 1-cyclopropanecarbonitrile (72 mg). The reaction mixture was stirred for 2 h at 25°C. Then further added 1-cyclopropanecarbonitrile (72 mg, 2.0 EQ.) and base Hunya (60 μl) and the mixture was stirred for 24 h at 80°C. Then was further added 1-cyclopropanecarbonitrile (72 mg, 2.0 EQ.) and base Hunya (60 μl) and the mixture was stirred for 24 h at 80°C. the Reaction mixture was purified using preparative HPLC and was obtained the desired compound (68 mg, 57%) as a light brown foam substance. MS (IER): m/z = 656,2 [M+H]+.

Example 331

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(3-chlorophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-(3-chlorophenyl)-1-cyclopropanecarboxylic acid (39 mg) and received 94 mg (90%) of a white foam substance. MS (IER): m/z = 630,0 [M+H]+.

Example 332

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(3-bromophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

the Desired compound was obtained analogously to receive in example 239 using the compound of example 173 (200 mg) and 1-(3-bromophenyl)-cyclopropanecarboxylic acid (128 mg) and received 238 mg (80%) of a white solid. MS (IER): m/z = 698,0 [M+Na]+.

Example 333

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, a mixture of methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) and methyl ester (2R,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 3-methoxyphenylacetonitrile (registration number CAS 39232-91-2) and received a mixture of the desired compounds and methyl ester (2R,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as an orange oil. MS (IER): m/z = 524,3 [M+H]+.

b) (2S,4R)-1-[2-(3-Methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, a mixture of methyl ester (2S,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid methyl ester (2R,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-tripto methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and received a mixture of the desired compound and (2R,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as an orange solid, which was used in the next stage without additional purification. MS (IER): m/z = 510,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a colourless oil. MS (IER): m/z = 574,2 [M+H]+.

Example 334

(1-Cyanocyclohexyl)-amide and (2R,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example 333b) were introduced in the Rea is tion with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a colourless oil. MS (IER): m/z = 574,3 [M+H]+.

Example 335

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-trifloromethyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid

The potassium fluoride (26 mg, 445 mmol) and triethylamine (62 μl, 445 mmol) was added to a solution of methyl ester (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (50 mg, 148 mmol; prepared as described for the corresponding ethyl ester of (2S,4S)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid in example e) and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (31 mg, 163 µmol; registration number CAS 53645-98-0) in N,N-dimethylacetamide (1 ml). The reaction mixture was heated in a microwave oven at 120°C for 90 minutes was Added a mixture of water with ice/0.1 N. aqueous HCl solution 1/1 and iPrOAc and the layers were separated. The aqueous layer was once again extracted with iPrOAc, the combined organic layers were washed with a mixture of water with ice/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and obtained the desired compound as yellow solid (50 mg, 102 μmol; 69%) which was sufficiently pure for use in the next stage of the reaction. MS (IER): m/z = 558,2 [M+H]+ .

b) (2S,4R)-4-(2-Trifloromethyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-trifloromethyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid. MS (IER): m/z = 476,0 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-trifloromethyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a red solid. MS (IER): m/z = 540,2 [M+H]+.

Example 336

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-isopropylimidazole-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The compound of example 312 (50 mg) was dissolved in DMA (2 ml). Added cesium carbonate (59 mg) and 2-isopropylimidazole (20 mg). The reaction mixture was stirred in the microwave at 80°C for 30 minutes, the Reaction mixture was purified using preparative HPLC and was obtained the desired compound (32 mg, 59%) as a light brown solid. MS (IER): m/z = 642,2 [M+H]+.

Example 337

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, a mixture of methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) and methyl ester (2R,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 2-penicillinresistant (registration number CAS 56-51-4) and received a mixture of the desired compounds and methyl ester (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as an orange oil. MS (IER): m/z = 522,3 [M+H]+.

b) (2S,4R)-1-(5-Methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, a mixture of methyl ester (2S,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid methyl ester (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-triptoreline solarpanel)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and received a mixture of the desired compound and (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a yellow oil, which was used in the next stage without additional purification.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a colourless oil. MS (IER): m/z = 572,3 [M+H]+.

Example 338

(1-Cyanocyclohexyl)-amide and (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example 337b) introduced in the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of the tvii HATU, DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a colourless solid. MS (IER): m/z = 572,3 [M+H]+.

Example 339

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-tert-butyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-tert-butyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with tert-butylhydroperoxide (registration number CAS 7400-27-3) and got the desired compound as a brown solid. MS (IER): m/z = 474,2 [M+H]+.

b) (2S,4R)-1-(2-Tert-butyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(2-tert-butyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid, which was used in the next stage without additional purification. MS (IER): m/z = 458,1 [M-N]-.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-tert-butyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

P is the method similar to that described in example 237, (2S,4R)-1-(2-tert-butyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow solid. MS (IER): m/z = 524,3 [M+H]+.

Example 340

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 308d, a mixture of methyl ester (2S,4R)-1-(3-oxobutyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example 192f) and methyl ester (2R,4R)-1-(3-oxobutyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson (registration number CAS 19172-47-5) and (2-methylpropyl)-hydrazine 4-methylbenzenesulfonate (registration number CAS 112306-59-9) and received a mixture of the desired compounds and methyl ester (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a yellow solid. MS (IER): m/z = 474,2 [M+H]+.

b) (2S,R)-1-(2-Isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, a mixture of methyl ester (2S,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid methyl ester (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and received a mixture of the desired compound and (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a colourless oil, which was used in the next stage without additional purification. MS (IER): m/z = 460,4 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a yellow oil. MS (IER): m/z = 524,2 [M+H]+.

Example 341

(1-Cyanocyclohexyl)-amide and (2R,4R)-1-(-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a yellow solid. MS (IER): m/z=524,2 [M+H]+.

Example 342

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-methoxyethoxy)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The compound of example 312 (50 mg) was dissolved in DMA (2 ml). Added cesium carbonate (59 mg) and 2-methoxyethanol (14 μl). The reaction mixture was stirred at 25°C for 96 hours, the Reaction mixture was purified using preparative HPLC and was obtained the desired compound (22 mg, 40%) as a white solid. MS (IER): m/z = 606,2 [M+H]+.

Example 343

(1-Cyanocyclohexyl)-amide 1-biphenyl-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) 1-(2-Bromethalin)-2-cryptomaterial

With stirring to a solution of 2-(reformer)thiophenol (2,96 ml, 22 mmole; registration number CAS 13333-97-6) in DMF (65 ml) was added 1,2-dibromoethane (9,67 ml, 112 mmole) and potassium carbonate (3,41 g, 25 mmole). The reaction mixture was stirred for 2 h 30 min at ambient temperature. Added AcOEt (30 ml) and water (30 ml) and the layers were separated. The aqueous layer was extracted three times with AcOEt (3×20 ml). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and obtained the desired compound as a yellow oil (6.0 g, 22 mmole; quantitative yield), which was sufficiently pure for use in the next stage.

b) 1-(2-Bromethalin)-2-cryptomaterial

With stirring to a solution of 1-(2-bromethalin)-2-triptoreline (6.0 g, 22 mmole) in dichloromethane (50 ml) in four portions over 8 min was added MJPBK (9,68 g, 56 mmole). The reaction mixture was stirred at ambient temperature for 12 h and filtered to remove solids. The filtrate was diluted with dichloromethane (50 ml) was added 1 M aqueous solution of sodium carbonate (30 ml) and the layers were separated. The aqueous layer was 2 more times was extracted with dichloromethane (70 ml). The combined extracts were washed with water (50 ml), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and obtained the desired compound in the form of almost Belogorodka substances (5,4 g, 19 mmole; 84%), which was used in the next stage without additional purification.

c) 1-Atenolol-2-cryptomaterial

With stirring to a solution of 1-(2-bromethalin)-2-triptoreline (5,4 g, 19 mmole) in dichloromethane (50 ml) was added triethylamine (of 4.66 ml, 34 mmole). The reaction mixture is boiled under reflux at 50°C for 12 h the Solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/heptane) and obtained the desired compound (3,68 g, 16 mmole; 69%) in the form of almost white semi-liquid substances. MS (IER): m/z = 254,1 [M+NH4]+.

d) Ethyl ester of 1-biphenyl-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

Paraformaldehyde (74 mg, 2.4 mmole) in argon atmosphere was added to a solution of ethyl ester (biphenyl-2-ylamino)-acetic acid (125 mg, 490 μmol; registration number CAS 39950-19-1) in toluene (9 ml). The mixture was stirred for 1 h at ambient temperature. Solution was added 1-atenolol-2-triptoreline (231 mg, 979 µmol) in toluene (1 ml) and acetic acid (10 μl, 98 mmol) and the reaction mixture is boiled under reflux at 120°C for 12 h the Solvent was removed under reduced pressure and was purified by column chromatography (silica gel, EtOAc/heptane) and obtained the desired compound (47 mg, 93 mmol is; 19%) as a colourless oil. MS (IER): m/z = 504,1 [M+H]+.

e) 1-Biphenyl-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 1-biphenyl-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a white solid, which was used in the next stage without additional purification. MS (IER): m/z = 476,1 [M+H]+.

f) (1-Cyanocyclohexyl)-amide 1-biphenyl-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 1-biphenyl-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 540,4 [M+H]+.

Example 344

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

a) Synthesis of 4-fluoro-2-trifloromethyl

4-fluoro-2-(trifluoromethyl)benzoylformate (2 g) was dissolved in 1,4-dioxane (12 ml) and water (3 ml) under nitrogen atmosphere. Added Tris-(2-carboxyethyl)fo is vingerklip (8,73 g) and the mixture was stirred while boiling under reflux for 6 hours The reaction mixture was cooled to 25°C and was added water (20 ml). Product 3 times were extracted with CH2Cl2(20 ml). The combined organic layers were dried over Na2SO4was filtered and evaporated to dryness and got the desired compound (1.27 g, 85%) as a colourless liquid. MS (IER): m/z = 194,9 [M-N]-.

b) Synthesis of (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 207 using the compound of example a) as the initial substance and received 16 mg (13%) of white solids. MS (IER): m/z = 488,3 [M+H]+.

Example 345

(1-Cyanocyclohexyl)-amide 1-naphthalene-1-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Ethyl ester of 1-naphthalene-1-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 343d, ethyl ester (naphthalene-1-ylamino)-acetic acid (registration number CAS 107456-67-7) were introduced in the reaction with paraformaldehyde and 1-atenolol-2-triftorperasin (example s) and got the desired compound as a brown oil. MS (IER): m/z = 478,2 [M+H]+.

b) 1-Naphthalene-1-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic Ki is a lot

According to the method similar to that described in example e, ethyl ester 1-naphthalene-1-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = of 450.1 [M+H]+.

c) (1-Cyanocyclohexyl)-amide 1-naphthalene-1-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 1-naphthalene-1-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 514,5 [M+H]+.

Example 346

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-bromophenyl)-[1,3]dioxolane-2-carbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

a) Ethyl ester of 2-(4-bromophenyl)-[1,3]dioxolane-2-carboxylic acid

To a solution of ethyl-4-bromobenzonitrile (940 mg) and 2-chloroethanol (0,360 ml) in a mixture of 2:1 dimethylformamide : tetrahydrofuran (2.1 ml) at -60°C was added dropwise a solution of tert-butanolate potassium (0,597 mg) in dimethylformamide (2 ml). The reaction mixture was stirred is at -60°C for 4 h and then it was allowed to warm to room temperature and was stirred at room temperature overnight. The reaction mixture was subjected to distribution between the aqueous solution of ammonium chloride and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine. The crude mixture was concentrated to dryness and purified via chromatography on silica gel and got the desired compound as a colourless liquid (616 mg; 58%). MS (IER): m/z = 300,8 [M+H]+.

b) 2-(4-Bromophenyl)-[1,3]dioxolane-2-carboxylic acid

To a solution of ethyl ester of 2-(4-bromophenyl)-[1,3]dioxolane-2-carboxylic acid (example 346a plug), 300 mg) in tetrahydrofuran (2 ml) and water (2 ml) in two portions was added lithium hydroxide (41 mg). The reaction mixture was stirred at room temperature for 2 days and then concentrated in vacuum. The residue was acidified to pH=1 with an aqueous solution of hydrochloric acid (0.1 N.) and was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in a vacuum and got the desired compound as a colourless oil (225 mg; 66%). MS (IER): m/z = 271,1 [M-N]-.

(C) (1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-bromophenyl)-[1,3]dioxolane-2-carbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 2-(4-shall Romper)-[1,3]dioxolane-2-carboxylic acid (example 346b); 68 mg) and received 39 mg (30%) of a white solid. MS (IER): m/z = 708,0 [M+H]+.

Example 347

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-naphthalene-1-enciclopediaper)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-naphthalene-1-yl-cyclopropanecarboxylic acid (registration number CAS [124276-38-6]; 42 mg) and received 53 mg (49%) of a yellow oil. MS (IER): m/z = 646,14 [M+H]+.

Example 348

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-naphthalene-2-enciclopediaper)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-naphthalene-2-yl-cyclopropanecarboxylic acid (registration number CAS [623583-91-5]; 42 mg) and received 70 mg (65%) of a yellow oil. MS (IER): m/z = 646,14 [M+H]+.

Example 349

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazo[4,5-C]pyridine-1-eventality)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The compound of example 312 (100 mg) was dissolved in acetonitrile (4 ml). Added base Hunya (60 μl) and 5-azobenzenes (43 mg). Reaction the Yu and the mixture was stirred for 2 h at 25°C. Then further added 5-azobenzenes (43 mg, 2.0 EQ.) and the mixture was stirred for 24 h at 25°C. Then was further added 5-azobenzenes (43 mg, 2.0 EQ.) and the mixture was stirred for 24 h at 25°C. the Reaction mixture was purified using preparative HPLC and was obtained the desired compound (7 mg, 6%) as a white solid. MS (IER): m/z = 649,3 [M+H]+.

Example 350

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazo[4,5-C]pyridine-5-eventality)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained as a side product during the synthesis of the compound of example 349 and received 16 mg (14%) of white solids. MS (IER): m/z = 649,3 [M+H]+.

Example 351

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-[2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with (2,6-dimethylpyridin-4-yl)-hydrazinecarboxamide (re istruzioni CAS no 1187853-32-2) and got the desired compound as a brown oil. MS (IER): m/z = 523,2 [M+H]+.

b) (2S,4R)-1-[2-(2,6-Dimethylpyridin-4-yl)-5-metal-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-[2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide. The reaction mixture is evaporated to dryness and got the desired compound in the form of its lithium salt as a red solid, which was used in the next stage without additional purification. MS (IER): m/z = 509,3 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as an orange oil. MS (IER): m/z = 573,2 [M+H]+.

Example 352

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-quinoline-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) M is tilby ester (2S,4R)-1-(5-methyl-2-quinoline-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with quinoline-4-inheritancerelated (registration number CAS 68500-41-4) and got the desired compound as an orange oil. MS (IER): m/z = 545,2 [M+H]+.

b) (2S,4R)-1-(5-Methyl-2-quinoline-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(5-methyl-2-quinoline-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a red solid, which was used in the next stage without additional purification.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-quinoline-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(5-methyl-2-quinoline-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a brown oil. MS (IER): m/z = 595,4 [M+H]+.

Example 353

a) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with cyclobutanecarbonitrile (registration number CAS 158001-21-9) and got the desired compound as an orange oil. MS (IER): m/z = 438,3 [M+H]+.

b) (2S,4R)-4-(2-Chlorobenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z = 424,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in Pris is accordance HATU, DIEA and got the desired compound as a yellow oil. MS (IER): m/z = 488,4 [M+H]+.

Example 354

(1-Cyanocyclohexyl)-amide 4-(2-trifloromethyl)-1-(3-triptoreline)-pyrrolidin-2-carboxylic acid

a) Ethyl ester of 4-(2-trifloromethyl)-1-(3-triptoreline)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 343d, ethyl ester (3-triptoreline)-acetic acid (registration number CAS 2445-84-3) were introduced in the reaction with paraformaldehyde and 1-atenolol-2-triftorperasin (example s) and got the desired compound in the form of an almost white solid. MS (IER): m/z = 496,3 [M+H]+.

b) 4-(2-Trifloromethyl)-1-(3-triptoreline)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 4-(2-trifloromethyl)-1-(3-triptoreline)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a white solid, which was used in the next stage without additional purification. MS (IER): m/z = 468,1 [M+H]+.

c) (1-Cyanocyclohexyl)-amide 4-(2-trifloromethyl)-1-(3-triptoreline)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 4-(2-trifloromethyl)-1-(3-triptoreline)-Pirro is one-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 532,0 [M+H]+.

Example 355

(1-Cyanocyclohexyl)-amide 1-(2-tert-butylphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Ethyl ester of 1-(2-tert-butylphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 343d, ethyl ester (2-tert-butylbenzylamine)-acetic acid (registration number CAS 959563-17-8) were introduced in the reaction with paraformaldehyde and 1-atenolol-2-triftorperasin (example s) and got the desired compound as a colourless oil. MS (IER): m/z = 484,4 [M+H]+.

b) 1-(2-Tert-butylphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 1-(2-tert-butylphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 456,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide 1-(2-tert-butylphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 1-(2-tert-butylphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid which was taken in the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 520,2 [M+H]+.

Example 356

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 308d, a mixture of methyl ester (2S,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) and methyl ester (2R,4R)-1-(3-occationally)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with N-(3-hydrazinophenyl)-acetamidomalonate (registration number CAS 1187369-44-3) and received a mixture of the desired compounds and methyl ester (2R,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as a yellow solid. MS (IER): m/z = 551,2 [M+H]+.

b) (2S,4R)-1-[2-(3-Acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, a mixture of methyl ester (2S,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid methyl ester (2R,4R)-1-[2-(3-acetyl is inopril)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and received a mixture of the desired compound and (2R,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid as an orange solid, which was used in the next stage without additional purification. MS (IER): m/z = 537,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as an orange oil. MS (IER): m/z = 601,4 [M+H]+.

Example 357

(1-Cyanocyclohexyl)-amide and (2R,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, a mixture of (2S,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid and (2R,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid is introduced into the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after cleaning using chiral preparative HPLC was obtained the desired compound as a yellow oil. MS (IER): m/z = 601,3 [M+H]+.

Example 358

(1-Cyanocyclohexyl)-amide 1-(3-cyanophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Ethyl ester of 1-(3-cyanophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 343d, ethyl ester (3-cyanovinylene)-acetic acid (registration number CAS 92316-76-2) were introduced in the reaction with paraformaldehyde and 1-atenolol-2-triftorperasin (example s) and got the desired compound as a brown oil. MS (IER): m/z = 453,1 [M+H]+.

b) 1-(3-Cyanophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 1-(3-cyanophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 425,1 [M+H]+.

c) (1-Cyanocyclohexyl)-amide 1-(3-cyanophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 1-(3-cyanophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclo what apunkabollywood (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 489,3 [M+H]+.

Example 359

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with 2-penicillinresistant (registration number CAS 56-51-4) and got the desired compound as an orange oil. MS (IER): m/z = 488,3 [M+H]+.

b) (2S,4R)-4-(2-Chlorobenzenesulfonyl)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a brown oil, which was used in the next stage without additional purification. MS (IER): m/z = 472,2 [M-N]-.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-methyl-2-phenethyl-2 is-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as an orange oil. MS (IER): m/z = 538,4 [M+H]+.

Example 360

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclobutanecarbonyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The compound of example 43 (100 mg) suspended in DMF (1.5 ml). To the suspension was added HATU (196 mg), base Hunya (90 μl) and 1-(4-chlorophenyl)-1-cyclobutanecarbonyl acid (71 mg). The reaction mixture was stirred for 18 h at 25°C. the Reaction mixture was purified using preparative HPLC and was obtained the desired compound (85 mg, 57%) as a colorless amorphous solid. MS (IER): m/z = 580,3 [M+H]+.

Example 361

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 360, using 1-(6-chloropyridin-3-yl)-cyclopropanecarboxylic acid (registration number CAS 854267-90-6) as the initial substance and received 75 mg (51%) of colorless amorphous substance. MS (IER): m/z = 567,3 [M+H]+.

Example 362

(1-Cyanocyclohexyl)-amide 1-(tetrahydropyran-4-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Ethyl ester of 1-(tetrahydropyran-4-yl)-4-(2-trifloromethyl)-pyrrol the DIN-2-carboxylic acid

According to the method similar to that described in example 343d, ethyl ester (tetrahydropyran-4-ylamino)-acetic acid (registration number CAS 1153226-50-6) were introduced in the reaction with paraformaldehyde and 1-atenolol-2-triftorperasin (example s) and got the desired connection.

b) 1-(Tetrahydropyran-4-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 1-(tetrahydropyran-4-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a white solid, which was used in the next stage without additional purification. MS (IER): m/z = 408,4 [M+H]+.

c) (1-Cyanocyclohexyl)-amide 1-(tetrahydropyran-4-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 1-(tetrahydropyran-4-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white foam substance. MS (IER): m/z = 472,3 [M+H]+.

Example 363

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-cyclopropyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-triftoratsetata hanil)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(3-cyclopropyl-3-oxopropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example I) were introduced in the reaction with tert-butyl ether 3-cyclopropyl-3-oxopropionate acid (registration number CAS 134302-07-1) and got the desired compound as a brown oil. MS (IER): m/z = 448,1 [M+H]+.

b) Methyl ester of (2S,4R)-1-[5-cyclopropyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-cyclopropyl-3-oxopropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson (registration number CAS 19172-47-5) and 4-(trifluoromethyl)phenylhydrazine (registration number CAS 368-90-1) and got the desired compound as a yellow oil.

c) (2S,4R)-1-[5-Cyclopropyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-[5-cyclopropyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid is omilami in the presence of lithium hydroxide and obtained the desired compound as a white solid, which was used in the next stage without additional purification. MS (IER): m/z = 574,3 [M+H]+.

d) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[5-cyclopropyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[5-cyclopropyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 638,2 [M+H]+.

Example 364

Tert-butyl ester 4-[2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-yl]-piperidine-1-carboxylic acid

a) Tert-butyl ester 4-[2-etoxycarbonyl-4-(2-trifloromethyl)-pyrrolidin-1-yl]-piperidine-1-carboxylic acid

According to the method similar to that described in example 343d, tert-butyl ester 4-(ethoxycarbonylmethylene)-piperidine-1-carboxylic acid (registration number CAS 177276-49-2) were introduced in the reaction with paraformaldehyde and 1-atenolol-2-triftorperasin (example s) and got the desired connection.

b) Tert-butyl ester 4-[2-carboxy-4-(2-trifloromethyl)-pyrrolidin-yl]-piperidine-1-carboxylic acid

According to the method similar to that described in example I, tert-butyl ester 4-[2-etoxycarbonyl-4-(2-trifloromethyl)-pyrrolidin-1-yl]-piperidine-1-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 507,3 [M+H]+.

c) Tert-butyl ester 4-[2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-yl]-piperidine-1-carboxylic acid

According to the method similar to that described in example 237, tert-butyl ester 4-[2-carboxy-4-(2-trifloromethyl)-pyrrolidin-1-yl]-piperidine-1-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 571,3 [M+H]+.

Example 365

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropylmethyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The compound of example 173 (50 mg) and 1-(4-chlorophenyl)-cyclopropanecarboxaldehyde (registration number CAS 100845-90-7; 22 mg) suspended in tetrahydrofuran (1.2 ml) and stirred at 80°C for 1 h, the Reaction mixture was cooled to room so the temperature, then add acetoxyvalerenic sodium (52 mg) and the reaction mixture was stirred at 80°C for 20 hours, the Reaction mixture was subjected to distribution between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous solution of sodium bicarbonate. The crude mixture was concentrated to dryness and purified via chromatography on silica gel and got the desired compound as a colourless oil (40 mg; 59%). MS (IER): m/z = 616,1 [M+H]+.

Example 366

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example a, (1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid (example 211A) were introduced in the reaction with 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (registration number CAS 53645-98-0) swinging the reactor at 55°C for 12 h, and was obtained the desired compound as a yellow solid. MS (IER): m/z = 638,1 [M+H]+.

Example 367

(1-Cyanocyclohexyl)-amide 1-(3-trifloromethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) e is silt ester 1-(3-trifloromethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 343d, ethyl ester (3-triphtalocyaninine)-acetic acid (registration number CAS 1021237-80-8) were introduced in the reaction with paraformaldehyde and 1-atenolol-2-triftorperasin (example s) and got the desired compound in the form of an almost white solid. MS (IER): m/z = 512,3 [M+H]+.

b) 1-(3-Trifloromethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 1-(3-trifloromethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z = 484,2 [M+H]+.

c) (1-cyanocyclohexyl)-amide 1-(3-trifloromethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 1-(3-trifloromethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 548,2 [M+H]+.

Example 368

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-Forbes sulfonyl)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 312 was obtained 2.1 g (52%) of white solids. MS (IER): m/z = 551,2 [M+H]+.

Example 369

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid

The compound of example 368 (100 mg) was dissolved in atsn (1.5 ml) at 25°C. To the resulting solution was added 1-methylpiperazine (0.04 ml) and the base Hunya (0.06 ml). The reaction mixture was stirred at 25°C for 96 hours Then the reaction mixture was further added 1-methylpiperazine (0.01 ml) and was stirred for 18 h at 25°C. Then the mixture was purified using preparative HPLC and was obtained the desired compound (101 mg; 84%) as a colorless amorphous solid. MS (IER): m/z = 631,3 [M+H]+.

Example 370

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-isopropylpiperazine-1-yl)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid

The desired compound was obtained analogously to receive in example 369 and obtained 76 mg (63%) of colorless amorphous substance. MS (IER): m/z = 659,3 [M+H]+.

Example 371

(1-Cyanocyclohexyl)-the foreign Ministry (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; connection with formic acid

The desired compound was obtained analogously to receive in example 369 and received 117 mg (96%) of colorless amorphous substance. MS (IER): m/z = 673,4 [M+H]+.

Example 372

(1-Cyanocyclohexyl)-amide (2S,4R)-4-{2-chloro-4-[4-(2-methoxyethyl)-piperazine-1-yl]-benzazolyl}-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid

The desired compound was obtained analogously to receive in example 369 and received 86 mg (66%) of colorless amorphous substance. MS (IER): m/z = 675,3 [M+H]+.

Example 373

(1-Cyanocyclohexyl)-amide (2S,4R)-4-((S)-2-chloro-4-hexahydropyrazino[1,2-a]pyrazin-2-eventality)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid

The desired compound was obtained analogously to receive in example 369 and received 108 mg (91%) of colorless amorphous substance. MS (IER): m/z = 657,3 [M+H]+.

Example 374

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-cyclopropylmethyl-1-yl)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid

The desired compound was obtained analogously to receive in the use of the e 369 and received 78 mg (65%) of colorless amorphous substance. MS (IER): m/z = 657,3 [M+H]+.

Example 375

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-methoxybenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2-chloro-4-permentantly)-pyrrolidine-1,2-dicarboxylic acid (example 171) was treated triperoxonane acid in dichloromethane and got the desired compound as a colourless oil. MS (IER): m/z = 322,2 [M+H]+.

b) Methyl ester of (2S,4R)-4-(2-chloro-4-permentantly)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid were introduced into a reaction with tert-butylacetoacetate and got the desired compound as a yellow foam substance. MS (IER): m/z = 406,3 [M+H]+.

c) Methyl ester of (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(2-chloro-4-permentantly)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson (Regis is operating CAS no 19172-47-5) and cyclobutanecarbonitrile (registration number CAS 158001-21-9) and got the desired compound as a colourless oil. MS (IER): m/z = 456,2 [M+H]+.

d) (2S,4R)-4-(2-Chloro-4-methoxybenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a brown oil, which was used in the next stage without additional purification.

e) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-methoxybenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chloro-4-methoxybenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 518,2 [M+H]+.

Example 376

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chloro-4-methoxybenzenesulfonyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid

According to the method similar is written in the example 192h, methyl ester (2S,4R)-4-(2-chloro-4-permentantly)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid (example 375b) were introduced in the reaction with the reagent Lawesson (registration number CAS 19172-47-5) and benzyltrimethylammonium (registration number CAS 20570-96-1) and got the desired compound as a yellow oil. MS (IER): m/z = 492,3 [M+H]+.

b) (2S,4R)-1-(2-Benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chloro-4-methoxybenzenesulfonyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a white solid, which was used in the next stage without additional purification. MS (IER): m/z = 490,3 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chloro-4-methoxybenzenesulfonyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chloro-4-methoxybenzenesulfonyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless foam substance. MS (IER): m/z = 554,4 [M+H]+.

The use of the 377

(1-Cyanocyclohexyl)-amide (R)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The compound of example 368 (80 mg) was dissolved in DMF (1.0 ml) at 25°C. To the solution was added 2,2,2-triptoreline (0,020 ml) and cesium carbonate (95 mg). The reaction mixture was stirred at 25°C for 96 hours and Then the mixture was purified using preparative HPLC and was obtained the desired compound (59 mg; 64%) as a colorless amorphous solid. MS (IER): m/z = of 631.2 [M+H]+.

Example 378

(1-Cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(2-methoxyethoxy)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 377 and received 62 mg (70%) of colorless amorphous substance. MS (IER): m/z = 607,3 [M+H]+.

Example 379

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-gorbansolton)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example is C) were introduced in the reaction with benzyltrimethylammonium (registration number CAS 20570-96-1) and got the desired compound as an orange oil. MS (IER): m/z = 474,2 [M+H]+.

b) (2S,4R)-1-(2-Benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z = 460,3 [M+H]+.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless oil. MS (IER): m/z = 524,3 [M+H]+.

Example 380

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The compound of example 368 (80 mg) was dissolved in DMA (2.0 ml) at 25°C. To the solution was added pyrazole (18 mg) and cesium carbonate (95 mg). The reaction mixture was stirred at 100°C within 30 min in a microwave oven. To the suspension was additionally added pyrazole (0.2 EQ.) and the mixture was heated twice in a microwave oven at 100°C for 30 minutes Then the mixture was purified using preparative HPLC and was obtained the desired compound (31 mg; 36%) as a colorless amorphous solid. MS (IER): m/z = 599,2 [M+H]+.

Example 381

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 380 and obtained 42 mg (45%) of colorless amorphous substance. MS (IER): m/z = 645,1 [M+H]+.

Example 382

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazol-1-eventality)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The compound of example 368 (80 mg) was dissolved in acetonitrile (1.0 ml) at 25°C. To the resulting solution were added imidazole (20 mg) and the base Hunya (0.05 ml). The reaction mixture was stirred at 25°C for 96 hours and Then the mixture was stirred at 90°C for 72 hours Then the mixture was purified using preparative HPLC and was obtained the desired compound (31 mg; 36%) as a colorless amorphous solid. MS (IER): m/z = 599,2 [M+H]+.

Example 383

(1-Cyanocyclohexyl)-amide (6R,7aS)-6-(2-chloro-4-torrentsolder)-1-cyano-tetrahydropyrazin-7a-carboxylic acid

a) Methyl ester of (6R,7aR)-6-(2-chloro-4-permentantly)-1-cyano-tetrahydropyrazin-7a-carboxylic acid

Methyl ester (2S,4R)-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid (380 mg) was dissolved in THF (10 ml). Was added formaldehyde (120 μl; of 36.5% aqueous solution), Acrylonitrile (80 μl) and TFA (10 μl). The reaction mixture was stirred for 12 h at 65°C. the Reaction mixture was purified using preparative HPLC and was obtained the desired compound (mixture of epimeres; 130 mg, 28%) as a light brown viscous oil. MS (IER): m/z = 387,1 [M+H]+.

b) (6R,7aR)-6-(2-Chloro-4-permentantly)-1-cyano-tetrahydropyrazin-7a-carboxylic acid

Connection example a) (125 mg) and lithium hydroxide (13 mg) was dissolved in a mixture of THF/water (7 ml; 4:1). The reaction mixture was stirred for 18 h at 25°C. Then the pH value of the reaction mixture is brought up to 3 0,5 N. aqueous solution of HCl and was extracted with CH2Cl2. The combined organic layers were washed with brine. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness and the obtained compound of example 383b) (101 mg, 84%) as a colourless solid. MS (IER): m/z = 371,0 [M-N]-.

c) (1-Cyanocyclohexyl)-amide (6R,7aS)-6-(2-chloro-4-permentantly)-1-cyano-tetrahydropyrazin-7a-carboxylic acid

Soy is inania example 383b) (101 mg), HATU (206 mg) and 1-amino-1-cyclopropanecarbonitrile (39 mg) was dissolved in acetonitrile (7 ml). Added base Hunya (60 μl) and the reaction mixture was stirred for 20 h at 25°C. the Solvent is evaporated, the residue was dissolved in AcOEt (15 ml) and was extracted with 10% aqueous solution of Na2CO3, 0,5 N. aqueous HCl solution and brine. The organic layers were dried over Na2SO4, was filtered and evaporated to dryness. The desired compound was purified using preparative HPLC and was obtained 38 mg (32%) of colorless solid. MS (IER): m/z = 437,1 [M+H]+.

Example 384

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(1-benzo[1,3]dioxol-5-enciclopediaper)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (75 mg) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (registration number CAS [862574-89-8]; 41 mg) and received 105 mg (99%) of a white foam substance. MS (IER): m/z = 640,11 [M+H]+.

Example 385

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

a) (2S,4R)-4-(2-Chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic Ki is a lot

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid (example C) omilami in the presence of lithium hydroxide instead of using methanol as co-solvent, and obtained the desired compound as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z = 442,2 [M+H]+.

b) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless foam substance. MS (IER): m/z = 506,2 [M+H]+.

Example 386

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 173 (37 mg) and 3-(tert-butyl)-1H-pyrazole-5-carboxylic acid (19 mg) and received 47 mg (93%) be the CSOs foamed substance. MS (IER): m/z = 616,16 [M+H]+.

Example 387

Tert-butyl ester (2S,4R)-4-(2-chloro-4-methoxybenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

The desired compound was obtained as a side product during the synthesis of the compound of example 124 and received 18% almost white foam substance. MS (IER): m/z = Ozenmunaygas given KZT 484.1 ecological [M+H]+.

Example 388

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid (example C) was treated triperoxonane acid in dichloromethane and got the desired compound as a yellow oil. MS (IER): m/z = 356,1 [M+H]+.

b) Methyl ester of (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidine-1,2-dicarboxylic acid was treated triperoxonane acid in dichloromethane and received the suit is my connection in the form of a yellow oil. MS (IER): m/z = 356,1 [M+H]+.

c) Methyl ester of (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with tert-butylacetoacetate and got the desired compound as a yellow oil. MS (IER): m/z = 440,2 [M+H]+.

d) Methyl ester of (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson and got the desired compound as a brown solid.

e) Methyl ester of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid were introduced into a reaction with cyclobutanecarbonitrile (registration number CAS 158001-21-9) and got the desired compound as a yellow oil. MS (IER): m/z = 490,1 [M+H]+.

f) (2S,4R)-1-(2-Cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-Tr is formative.nathaniel)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide instead of using methanol as co-solvent, and obtained the desired compound as a yellow foam substance that is used in the next stage without additional purification. MS (IER): m/z = 476,2 [M+H]+.

g) (1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a brown oil. MS (IER): m/z = 540,2 [M+H]+.

Example 389

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

1-Methylpiperazine (10 μl, 116 μmol; registration number CAS 109-01-3), DIEA (20 ml, 93 mmol) in an argon atmosphere was added to a solution of (1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cycle is butyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid (25 mg, 46 micromole; compound of example 388 g) in acetonitrile (400 μl). The reaction mixture was stirred at ambient temperature for 72 h, the solvent was removed under reduced pressure and the residue was purified using preparative HPLC and was obtained the desired compound (14 mg, 23 mmol; 49%) as a colourless oil. MS (IER): m/z = 618,2 [M-N]-.

Example 390

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-naphthalene-1-yl-[1,3]dioxolane-2-carbonyl)-pyrrolidin-2-carboxylic acid

a) Ethyl ester of 2-naphthalene-1-yl-[1,3]dioxolane-2-carboxylic acid

The desired compound was obtained analogously to receive in example 346a plug) using ethyl-2-(1-naphthyl)glyoxylate (500 mg) and received 439 mg (77%) as a colourless liquid. MS (IER): m/z = 199 [M-CO2Et]+.

b) 2-Naphthalene-1-yl-[1,3]dioxolane-2-carboxylic acid

The desired compound was obtained analogously to receive in example 346b) using the ethyl ester of 2-naphthalene-1-yl-[1,3]dioxolane-2-carboxylic acid (400 mg) and received 331 mg (92%) of white solids. MS (IER): m/z = 243,07 [M-H]-.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-naphthalene-1-yl-[1,3]dioxolane-2-carbonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the soedineniya example 173 (50 mg) and 2-naphthalene-1-yl-[1,3]dioxolane-2-carboxylic acid (example 390b), 32 mg) and received 55 mg (73%) of white solids. MS (IER): m/z = 678,13 [M+H]+.

Example 391

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

2,2,2-Triptoreline (10 μl, 137 μmol; registration number CAS 75-89-899) and cesium carbonate (45 mg, 137 μmol) in argon atmosphere was added to a solution of (1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid (37 mg, 69 μmol; the compound of example 388 g) in DMF (500 μl). The reaction mixture was stirred for 72 h at ambient temperature and subjected to distribution between the mixture of water with ice/brine 1/1 and iPrOAc. The layers were separated and the aqueous layer was once again extracted with iPrOAc. The combined extracts were washed with a mixture of water with ice/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and were awarded a yellow foam substance, which was purified using preparative chiral HPLC and was obtained the desired compound (13 mg, 21 mmol; 31%) as a colourless foam substance. MS (IER): m/z = 620,2 [M+H]+.

Example 392

(1-Cyanocyclohexyl)-amide and (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifluoromethyl who endolsulfan]-pyrrolidin-2-carboxylic acid

2,2,2-Triptoreline (10 μl, 137 μmol; registration number CAS 75-89-899) and cesium carbonate (45 mg, 137 μmol) in argon atmosphere was added to a solution of (1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid (37 mg, 69 μmol; the compound of example 388 g) in DMF (500 μl). The reaction mixture was stirred for 72 h at ambient temperature and subjected to distribution between the mixture of water with ice/brine 1/1 and iPrOAc. The layers were separated and the aqueous layer was once again extracted with iPrOAc. The combined extracts were washed with a mixture of water with ice/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and were awarded a yellow foam substance, which was purified using preparative chiral HPLC and was obtained the desired compound (6 mg, 10 µmol; 14%) as a colourless oil. MS (IER): m/z = 620,2 [M+H]+.

Example 393

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-methyl-5-(tetrahydropyran-4-yl)-1H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) 2,2-Dimethyl-5-(tetrahydropyran-4-carbonyl)-[1,3]dioxane-4,6-dione

Pyridine (1.26 in ml, 16 mmole) in argon atmosphere was added to a cooled with ice to a solution of 2,2-dimethyl-[1,3]dioxane-4,6-dione (750 mg, 5 mmole; registracionnyy CAS no 2033-24-1) in dichloromethane (5.3 ml). For 30 min was added dropwise tetrahydropyran-4-carbonylchloride (1 g, 7 mmole; registration number CAS 40191-32-0), maintaining the temperature of 0°C. the Mixture was stirred for 2 h at 0°C. was carefully added 1 N. aqueous HCl solution to establish a pH value equal to 1. Added dichloromethane (25 ml) and the layers were separated. The aqueous layer was 2 more times was extracted with dichloromethane (2×25 ml). The combined extracts were washed with brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and obtained the desired compound (1.24 g, 5 mmole; 93%) as a yellow oil which was sufficiently pure for use in the next stage of the reaction. MS (IER): m/z = 255,1 [M-N]-.

b) Tert-butyl ether 3-oxo-3-(tetrahydropyran-4-yl)-propionic acid

Tert-butanol (600 μl, 6 mmole) was added to a solution of 2,2-dimethyl-5-(tetrahydropyran-4-carbonyl)-[1,3]dioxane-4,6-dione (1.1 g, 4 mmole) in toluene (9.6 ml). The reaction mixture is boiled under reflux for 6 h and subjected to distribution between the mixture of water with ice/brine 1/1 and iPrOAc. The layers were separated and the aqueous layer was once again extracted with iPrOAc. The combined extracts were washed with a mixture of water with ice/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and obtained the desired compound (891 mg, 3.9 mmole; 91%) as to ichnevogo oil, which was sufficiently pure for use in the next stage of the reaction. MS (EI): m/z = 228 [M]+.

c) Methyl ester of (2S,4R)-1-[3-oxo-3-(tetrahydropyran-4-yl)-propionyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example I) were introduced in the reaction with tert-butyl ester 3-oxo-3-(tetrahydropyran-4-yl)-propionic acid was obtained the desired compound as a yellow foam substance. MS (IER): m/z = 492,2 [M+H]+.

d) Methyl ester of (2S,4R)-1-[3-oxo-3-(tetrahydropyran-4-yl)-thiopropionic]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-1-[3-oxo-3-(tetrahydropyran-4-yl)-propionyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson and got the desired compound as a yellow oil. MS (IER): m/z = 508,1 [M+H]+.

e) Methyl ester of (2S,4R)-1-[1-methyl-5-(tetrahydropyran-4-yl)-1H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-[3-oxo-3-(tetrahydropyran-4-yl)-thiopropionic]-4-(2-trifloromethyl)-pyrrolidin-2-CT is about acid were introduced into a reaction with methylhydrazine (registration number CAS 60-34-4) and got the desired compound as a colourless foam substance. MS (IER): m/z = 502,2 [M+H]+.

f) (2S,4R)-1-[1-Methyl-5-(tetrahydropyran-4-yl)-1H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-[1-methyl-5-(tetrahydropyran-4-yl)-1H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z = 488,3 [M+H]+.

g) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-methyl-5-(tetrahydropyran-4-yl)-1H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[1-methyl-5-(tetrahydropyran-4-yl)-1H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless foam substance. MS (IER): m/z = 552,2 [M+H]+.

Example 394

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Ethyl ester of 1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carb is new acid

According to the method similar to that described in example 343d, ethyl ester (3-chloro-4-forgenerating)-acetic acid (registration number CAS 2344-98-1) were introduced in the reaction with paraformaldehyde and 1-atenolol-2-triftorperasin (example s) and got the desired compound in the form of an almost white solid.

b) 1-(3-Chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid, which was used in the next stage without additional purification.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and received (1-cyanocyclohexyl)-amide 1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid in the form of a mixture of stereoisomers, which was purified using preparative chiral HPLC and received and komoe compound as a white solid. MS (EI): m/z = 515 [M]+.

Example 395

(1-Cyanocyclohexyl)-amide and (2R,4S)-1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and received (1-cyanocyclohexyl)-amide 1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid in the form of a mixture of stereoisomers, which was purified using preparative chiral HPLC and was obtained the desired compound as a white solid. MS (IER): m/z = 516,1 [M+H]+.

Example 396

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example 388d) were introduced in the reaction with (tetrahydropyran-4-yl)-geringere what oridam (registration number CAS 116312-69-7) and got the desired compound as a brown solid. MS (IER): m/z = 520,3 [M+H]+.

b) (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide instead of using methanol as co-solvent, and obtained the desired compound as a yellow foam substance that is used in the next stage without additional purification. MS (IER): m/z = 506,1 [M+H]+.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless foam substance. MS (IER): m/z = 570,3 [M+H]+.

Example 397

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-cyclobutyl-5-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid/p>

a) Methyl ester of (2S,4R)-1-[2-cyclobutyl-5-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-[3-oxo-3-(tetrahydropyran-4-yl)-thiopropionic]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example 393d) were introduced in the reaction with cyclobutanecarbonitrile (registration number CAS 158001-21-9) and got the desired compound as a yellow oil. MS (IER): m/z = 542,4 [M+H]+.

b) (2S,4R)-1-[2-Cyclobutyl-5-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-[2-cyclobutyl-5-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z = consists 528.3 [M+H]+.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-cyclobutyl-5-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[2-cyclobutyl-5-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-triform telesolutions)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of colorless foamed substance. MS (IER): m/z = 592,3 [M+H]+.

Example 398

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(3-cyclopropyl-3-associational)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-1-(3-cyclopropyl-3-oxopropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example 363a) were introduced in the reaction with the reagent Lawesson and got the desired compound as a brown oil. MS (IER): m/z = 364,1 [M+H]+.

b) Methyl ester of (2S,4R)-1-(2-cyclobutyl-5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-cyclopropyl-3-associational)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with cyclobutanecarbonitrile (registration number CAS 158001-21-9) and got the desired compound as a yellow foam substance.

c) (2S,4R)-1-(2-Cyclobutyl-5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl EF the p (2S,4R)-1-(2-cyclobutyl-5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid, which was used in the next stage without additional purification.

d) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(2-cyclobutyl-5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow oil. MS (IER): m/z = 548,2 [M+H]+.

Example 399

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid (example a) were introduced in the reaction with 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (registration number CAS 53645-98-0) swinging the reactor at 55°C for 12 h, and was obtained the desired compound as an orange oil. MS (IER): m/z = 456,0 [M+H]+.

b) (2S,4R)-4-(2-Chlorobenzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic who Isleta

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil. MS (IER): m/z = 442,0 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a colourless oil. MS (IER): m/z = 506,0 [M+H]+.

Example 400

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-1-(3-cyclopropyl-3-associational)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example a) were introduced in the reaction with hydrazinehydrate (registration number CAS 2644-70-4) who received the desired compound as a brown oil.

b) (2S,4R)-1-(5-Cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a brown solid, which was used in the next stage without additional purification.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow solid. MS (IER): m/z = 494,2 [M+H]+.

Example 401

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 389, (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carbon is th acid (example 385b) were introduced in the reaction with 1-methylpiperazine (registration number CAS 109-01-3) and got the desired compound as a colourless foam substance. MS (IER): m/z = 586,1 [M+H]+.

Example 402

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(3-methanesulfonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Ethyl ester of (3-methanesulfonamido)-acetic acid

0.5 M Solution of ethylglycol in toluene (0.95 ml, 5 mmole; registration number CAS 924-44-7) and acetic acid (0.4 ml) in an argon atmosphere was added to a cooled with ice to a solution of 3-(methylsulphonyl)aniline (500 mg, 2 mmole; registration number CAS 5470-49-5) in methanol (6.3 ml). Cyanoborohydride sodium (356 mg, 5 mmole) was added in 3 portions over 10 minutes, the Reaction mixture was stirred for 45 min at 0°C. and then at ambient temperature overnight. The reaction mixture was poured into a mixture of ice water (100 ml). Added iPrOAc (100 ml) and the layers were separated. The aqueous layer was once again extracted with iPrOAc (100 ml). The combined extracts 2 times washed with a mixture of water with ice/brine 1/1 and dried over sodium sulfate. After filtration the solvent was removed under reduced pressure and obtained crude product as a yellow foam substance, which was purified by column chromatography (silica gel, iPrOAc/n-heptane) and obtained the desired compound (350 mg, 1 mmole; 56%) as a white solid. MS (IER): m/z = 258,2 [M+H]+.

b) Ethyl ester of 1-(3-methanesulfonyl enyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 343d, ethyl ester (3-methanesulfonamido)-acetic acid were introduced into a reaction with paraformaldehyde and 1-atenolol-2-triftorperasin (example s) and got the desired compound as a yellow oil. MS (IER): m/z = 506,1 [M+H]+.

c) 1-(3-Methanesulfonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 1-(3-methanesulfonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a white solid, which was used in the next stage without additional purification. MS (IER): m/z = 476,1 [M-N]-.

d) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(3-methanesulfonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 1-(3-methanesulfonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and received (1-cyanocyclohexyl)-amide 1-(3-methanesulfonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid in the form of a mixture of stereoisomers, which was purified by preparation is effective chiral HPLC and was obtained the desired compound as a white solid. MS (IER): m/z = 542 [M+H]+.

Example 403

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(3,3-diversecity-1-yl)-2-trifloromethyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 389, (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with 3,3-diversityconservation (registration number CAS 288315-03-7) in acetonitrile at 55°C for 48 h, and was obtained the desired compound as a colourless foam substance. MS (IER): m/z = 643,3 [M+H]+.

Example 404

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 389, (1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with 1-methylpiperazine (registration number CAS 109-01-3) and got the desired compound as a colourless foam substance. MS (IER): m/z = 650,4 [M+H]+.

Example 405

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(chlor-[1,2,4]thiadiazole-5-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (prepared as described for the corresponding ethyl ester of (2S,4S)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid in example I) were introduced in the reaction with 3,5-dichloro-[1,2,4]thiadiazole (registration number CAS 2254-88-8) swinging the reactor at 55°C for 12 h, and was obtained the desired compound as an orange solid. MS (IER): m/z = 456,2 [M+H]+.

b) (2S,4R)-1-(3-Chloro-[1,2,4]thiadiazole-5-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a brown solid. MS (IER): m/z = 442,1 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carbonophobia was introduced in the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow foam substance. MS (IER): m/z = 506,0 [M+H]+.

Example 406

Benzyl ether of 4-{5-[(2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-piperidine-1-carboxylic acid

a) Benzyl ether of 4-{5-[(2S,4R)-2-methoxycarbonyl-4-(2-trifloromethyl)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-piperidine-1-carboxylic acid

According to the method similar to that described in example 308d, methyl ester (2S,4R)-1-(3-oxobutyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example 192f) were introduced in the reaction with the reagent Lawesson (registration number CAS 19172-47-5) and benzyl ether 4-hydrazinopyridazine-1-carboxylic acid (registration number CAS 280111-51-5) and got the desired compound as a yellow oil.

b) Benzyl ether of 4-{5-[(2S,4R)-2-carboxy-4-(2-trifloromethyl)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-piperidine-1-carboxylic acid

According to the method similar to that described in example I, benzyl ether of 4-{5-[(2S,4R)-2-methoxycarbonyl-4-(2-trifloromethyl)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-piperidine-1-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid. MS (IER): m/z = 619,4 [M-N]-.

c) Benzyl ether of 4-{5-[(2S,4R)-2-(1-cyanocyclohexane)-4-(2-triftormyetil who were radioactive)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-piperidine-1-carboxylic acid

According to the method similar to that described in example 237, benzyl ether of 4-{5-[(2S,4R)-2-carboxy-4-(2-trifloromethyl)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-piperidine-1-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow resinous substance. MS (IER): m/z = 685,2 [M+H]+.

Example 407

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-piperidine-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

Palladium on charcoal 10% (5 mg) was added to a solution of benzyl ester 4-{5-[(2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-piperidine-1-carboxylic acid (12 mg, 18 µmol; the compound of example C) in ethanol (1 ml). The reaction mixture was placed in an atmosphere of hydrogen and stirred at ambient temperature for 12 hours After filtration through dicalite the filtrate was dried to dryness and got the desired compound (4.4 mg, 8 mmol; 46%) as a white solid. MS (IER): m/z = 551 [M+H]+.

Example 408

(1-Cyanocyclohexyl)-amide (2S,4R)-1-pyrimidine-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Metrowater (2S,4R)-1-pyrimidine-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid (prepared as described for the corresponding ethyl ester of (2S,4S)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid in example I) were introduced in the reaction with 2-chloropyrimidine (registration number CAS 1722-12-9) in the swing reactor at 150°C for 48 h, and was obtained the desired compound as a yellow oil. MS (IER): m/z = 416,1 [M+H]+.

b) (2S,4R)-1-Pyrimidine-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-pyrimidine-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a white solid. MS (IER): m/z = 402,1 [M+H]+.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-pyrimidine-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-pyrimidine-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow oil. MS (IER): m/z = 466,2 [M+H]+.

Example 409

<> (1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-methanesulfonamide-2-carboxylic acid

a) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-mercaptopyrimidine-1,2-dicarboxylic acid

To a solution of 1-tert-butyl ether,2-methyl ester (2S,4R)-4-acetylsulfapyridine-1,2-dicarboxylic acid (12.5 g, 41 mmole; registration number CAS 188111-18-4) in the Meon (200 ml) and dichloromethane (20 ml) at 0°C was added potassium carbonate (5.7 g, 41,2 mmole). The resulting mixture was stirred at 0°C for 1 h After consumption of the original substance, the solvent is evaporated. The residue was dissolved in water and was extracted with EtOAc (2×200 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated and obtained the crude desired compound (9.5 g, 36,1 mmole; 88%), which was used in the next stage without additional purification. MS (IER): m/z = 262,0 [M+H]+.

b) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-methylsulfinylpropyl-1,2-dicarboxylic acid

To a solution of 1-tert-butyl ether,2-methyl ester (2S,4R)-4-mercaptopyrimidine-1,2-dicarboxylic acid (9.5 g, 35,4 mmole) in Meon (300 ml) was added methyliodide (24 ml, 363,5 mmole) and NaHCO3(3.4 g, 39,98 mmole). The reaction mixture was stirred for 12 h at 25°C. After depletion recognize the aqueous substance, the solvent was removed under reduced pressure and obtained crude substance, which was purified by column chromatography on silica gel (25-40% EtOAc/hexane) and was obtained the desired compound as a white solid (6.9 g, is 24.4 mmole; 69%). MS (IER): m/z = 276,4 [M+H]+.

c) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-methanesulfonanilide-1,2-dicarboxylic acid

To a solution of 1-tert-butyl ether,2-methyl ester (2S,4R)-4-methylsulfinylpropyl-1,2-dicarboxylic acid (6.6 g, 23,96 mmole) in dichloromethane at 0°C was added MJPBK (20.7 g, 119,8 mmole) and the mixture was stirred for 16 h at 25°C. the Suspension was filtered; the filtrate was poured into a mixture of ice/water solution of Na2CO3. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×150 ml). The combined organic layers were washed with an aqueous solution of Na2CO3and brine, dried over anhydrous sodium sulfate and evaporated and obtained crude compound (9.7 g), which was purified by column chromatography on silica gel (25-50% EtOAc/hexane) and was obtained the desired compound as a white solid (6.9 g, 22.4 mmole; 94%). MS (IER): m/z = 308,2 [M+H]+.

d) 1-Tert-butyl ester (2S,4R)-4-methanesulfonanilide-1,2-dicarboxylic acid

According to the method similar to that described in example I, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-methanesulfonanilide-1,2-dicarboxylic acid omilami in the presence of hydroc the IDA lithium and received the desired compound as a yellow solid. MS (IER): m/z = 294,2 [M+H]+.

e) Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-methanesulfonamido-1-carboxylic acid

According to the method similar to that described in example 237, 1-tert-butyl ester (2S,4R)-4-methanesulfonanilide-1,2-dicarboxylic acid was introduced into the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 358,4 [M+H]+.

f) (1-Cyanocyclohexyl)-nitrilotriacetate (2S,4R)-4-methanesulfonamide-2-carboxylic acid

To a solution of tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-methanesulfonamido-1-carboxylic acid (500 mg, of 1.39 mmole) in dichloromethane at 0°C was added triperoxonane acid (0.5 ml, 6,99 mmole). The resulting mixture was stirred at 25°C for 16 hours After depletion of the original substance, the reaction mixture was evaporated in vacuum and got the crude desired compound (500 mg, of 1.39 mmole; quantitative yield) which was used in the next stage without additional purification. MS: m/z = 258,0 [M+H]+.

g) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-methanesulfonamide-2-carboxylic acid

According to the method similar to that described in example 237, (1-cyanocyclohexyl)-amitriptyli the (2S,4R)-4-methanesulfonamide-2-carboxylic acid were introduced into a reaction with 1-(4-chlorophenyl)-cyclopropanecarboxylic acid (registration number CAS 72934-37-3) in the presence of HATU and DIEA and got the desired compound as a white solid substances. MS (IER): m/z = 436,2 [M+H]+.

Example 410

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(6-chloro-1H-indazol-3-carbonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 and received 26 mg (17%) of colorless amorphous substance. MS (IER): m/z = M+N 532,1 [M+H]+.

Example 411

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[(R)-2-(4-chlorophenyl)-2-hydroxyacetic]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (100 mg) as a starting substance and received 85 mg (57.6%) of a colorless amorphous substance. MS (IER): m/z = M+N 522,1 [M+H]+.

Example 412

Tert-butyl ester [(R)-2-[(2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-yl]-1-(4-chlorophenyl)-2-oxoethyl]-carbamino acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (150 mg) as a starting substance and received 91 mg (52%) of colorless amorphous substance. MS (IER): m/z = M+N 521,1 (M-BOC), M+N 621,3472,1 [M+H]+.

Example 413

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzylthio the Il)-1-[1-(4-methylthiazole-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

a) Synthesis of ethyl ester of 1-(4-methylthiazole-2-yl)-cyclopropanecarbonyl acid

Ethyl-2-(4-methylthiazole-2-yl)acetate (1 g, 5.4 mmole, 1.00 EQ.) was dissolved in DMF (5 ml). Added 1,2-dibromoethane (1,62 g, 744 μl, 8,64 mmole, 1,60 EQ.) and Cs2CO3(4.4 g, 13.5 mmole, 2.50 EQ.). The reaction mixture was stirred for 48 h at RT. The reaction mixture was poured into 0.5 M aqueous HCl solution (100 ml) and was extracted with EtOAc (3×50 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude substance was purified using flash chromatography (silica gel, 50 g, from 0 to 50% EtOAc in heptane) and got to 1.14 g (73,6%) light yellow liquid. MS (IER): m/z = 212,0 [M+H]+.

b) Synthesis of 1-(4-methylthiazole-2-yl)-cyclopropanecarbonyl acid

Connection example a) (840 mg, 3,98 mmole, 1.00 EQ.) was dissolved in THF (5 ml) and water (7.5 ml). Then was added LiOH (162 mg, 6,76 mmole, 1.7 EQ.) and the reaction mixture was stirred for 3 h at RT. The reaction mixture was extracted with a mixture of 10% aqueous solution of Na2CO3/CH2Cl2, a mixture of 0.5 N. aqueous solution of HCl/CH2Cl2. The organic layers were dried over Na2SO4, was filtered and was concentrated in vacuum and received 650 mg (89%) of white solids. MS (IER): m/z = 181,8 [M-N]-.

c) Synthesis of the desired compounds (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-Harb solarpanel)-1-[1-(4-methylthiazole-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (100 mg) as a starting substance and received 69 mg (47%) of oil. MS (IER): m/z = 519,1 [M+H]+.

Example 414

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(5-chloropyridin-2-yl)-acetyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (100 mg) as a starting substance and received 89 mg (62%) of nearly white foam substance. MS (IER): m/z = 508,0 [M+H]+.

Example 415

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(3,3-diversecity-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 389, (1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example g) were introduced in the reaction with 3,3-diversityconservation (registration number CAS 288315-03-7) in acetonitrile at 90°C for 48 h, and was obtained the desired compound as a colourless oil. MS (IER): m/z = 613,1 [M+H]+.

Example 416

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-ethyl-2H-pyrazole-3-yl)-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

Pyrazole (5 mg, 67 μmol; registration number CAS 288-11-9) and cesium carbonate (18 mg, 56 μmol) in argon atmosphere was added to a solution of (1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid (30 mg, 56 umol; the compound of example 388 g) in DMA (0.9 ml). The mixture was heated for 48 h at 90°C and for a further 4 h at 120°C in a swinging reactor. Was added a mixture of water/brine 1/1 and iPrOAc and the layers were separated. The aqueous layer was once again extracted with iPrOAc. The combined extracts were washed with a mixture of water with ice/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and obtained a brown oil, which was purified using preparative HPLC and was obtained the desired compound (6.5 mg, 11 mmol; 20%) as a colourless oil. MS (IER): m/z = 588,4 [M+H]+.

Example 417

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[(R)-2-amino-2-(4-chlorophenyl)-acetyl]-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

Connection example 412 (80 mg, 129 μmol, 1.00 EQ.) was dissolved in formic acid (1.8 g, 1.5 ml, 39.1 mmole, 304 EQ.) and was stirred at 25°C for 4 h ice 10% aqueous solution of Na2CO3the pH value of the reaction mixture was carefully set equal to 8 and extragear the Vali with the help of CH 2Cl2. The aqueous layer 3 times washed with CH2Cl2combined organic layers were dried over Na2SO4was filtered and evaporated and obtained the desired compound (53 mg; 79%) as a pale yellow foam substance. MS (IER): m/z = 521,1 [M+H]+.

Example 418

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-Chlorobenzyl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-Chlorobenzyl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with (4-chlorbenzyl)-hydrazine (registration number CAS 25198-45-2) and got the desired compound as an orange oil. MS (IER): m/z = 508,0 [M+H]+.

b) (2S,4R)-4-(2-Chlorobenzenesulfonyl)-1-[2-(4-Chlorobenzyl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-Chlorobenzyl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without D. the additional purification. MS (IER): m/z = 494,1 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-Chlorobenzyl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-Chlorobenzyl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound after purification using preparative HPLC as a yellow oil. MS (IER): m/z = 558,1 [M+H]+.

Example 419

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-pyrimidine-4-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, methyl ester (2S,4R)-4-(4-bromo-2-trifloromethyl)-pyrrolidin-2-carboxylic acid (example 18) were introduced in the reaction with tert-butylacetoacetate and got the desired compound as a brown oil.

b) Methyl ester of (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 308d, methyl is fir (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson (registration number CAS 19172-47-5) and cyclobutanecarbonitrile (registration No. CAS 158001-21-9) and got the desired compound as a brown oil. MS (IER): m/z = 549,8 [M+H]+.

c) (2S,4R)-4-(4-Bromo-2-trifloromethyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a brown solid, which was used in the next stage without additional purification. MS (IER): m/z = 538,1 [M+H]+.

d) (2S,4R)-4-(4-Bromo-2-(trifluoromethyl)phenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide

According to the method similar to that described in example 237, (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a brown foam substance. MS (IER): m/z = 602,1 [M+H]+.

e) 4-((3R,5S)-5-(1-Cyanocyclohexane)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)pyrrolidin-3-ylsulphonyl)-3-(trifluoromethyl)phenylboronic acid

A solution of (2S,4R)-4-(4-bromo-2-(trifluoromethyl)phenylsulfonyl)--(1-cyanocyclohexyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (40 mg, 66.6 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) cases (33.8 mg, 133 μmol; registration number CAS 73183-34-3), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)chloride with dichloromethane composition of 1:1 (10,9 mg, 13.3 mmol) and potassium acetate (32.7 mg, 333 μmol) in DMSO (0.8 ml) was heated at 80°C for 20 hours, the Reaction mixture was cooled to ambient temperature and poured into 20 ml of a mixture of 0.1 G. of HCl/ice/brine and was extracted with iPrOAc (2×25 ml). The combined organic layers were washed with a mixture of 0.1 G. of HCl/ice/brine (3×), the mixture of water with ice/brine (3×), dried over sodium sulfate and filtered. The solvent is evaporated under reduced pressure and obtained the crude desired compound (66 mg; quantitative yield) which was used in the next stage of the reaction without additional purification. MS (IER): m/z = 566,2 [M+H]+.

f) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-pyrimidine-4-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid

The complex [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)chloride with dichloromethane composition of 1:1 (6,23 mg, 7.62 mmol) in an argon atmosphere was added to a solution of 4-((3R,5S)-5-(1-cyanocyclohexane)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)pyrrolidin-3-ylsulphonyl)-3-(trifluoromethyl)phenylboronic acid (to 43.1 mg, 76.2 mmol), 4-bromopyrimidine (15.3 mg, 91.5 mmol; registration number CAS 3162-56-3) and sodium carbonate (to 21.8 mg, 206 μmol) in DMF (1.5 ml) and water (125 ml). The reaction mixture was stirred at 80°C for 1.75 h, cooled to ambient temperature, poured into 100 ml of a mixture of a saturated solution of sodium bicarbonate/ice and was extracted with iPrOAc (2×25 ml). The combined organic layers were washed with a mixture of water with ice/brine 1/1 (2×), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and obtained dark oil (50 mg) which was purified using preparative HPLC (MeCN/water) and obtained the desired compound (16 mg, 27 mmol; 35%) as a yellow foam substance. MS (IER): m/z = 600,3 [M+H]+.

Example 420

(2S,4R)-N-(1-Cyanocyclohexyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)-4-(4-(1-methyl-1H-pyrazole-5-yl)-2-(trifluoromethyl)phenylsulfonyl)pyrrolidin-2-carboxamide

The complex [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)chloride with dichloromethane composition of 1:1 (5,44 mg, 6,66 mmol) in an argon atmosphere was added to a solution of (2S,4R)-4-(4-bromo-2-(trifluoromethyl)phenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (40 mg, 66.6 mmol; compound of example 419d), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16.6 mg, 79.9 mmol, registration number CAS 847818-74-0) and sodium carbonate (19.1 mg, 180 μmol) in DMF (2 ml) and water (109 μl). The mixture was stirred at 80°C during the 3.5 h, was cooled to ambient temperature, poured into a mixture of saturated solution of sodium bicarbonate (20 ml)/ice (20 ml) and was extracted with iPrOAc (2×25 ml). The combined organic layers were washed with a mixture of water with ice/brine (2×), dried over sodium sulfate and filtered. The solvent was removed in vacuum and received a dark oil (48 mg) which was purified using preparative HPLC (MeCN/water) and obtained the desired compound (24 mg, 30 mmol; 45%) as a light brown oil. MS (IER): m/z = 602,2 [M+H]+.

Example 421

(1-Cyanocyclohexyl)-amide (R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-(2,2,2-triptoreline)-acetyl]-pyrrolidin-2-carboxylic acid

The compound of example 417 (44 mg, 84,4 of µmol, 1.00 equiv.) was dissolved in THF (1 ml). Added Diisopropylamine (9,39 mg, 13,2 μl, 92,8 of μmol, 1.1 EQ.) and 2,2,2-triftoratsetilatsetonom (21,5 mg of 13.4 μl, 92,8 of μmol, 1.1 EQ.). The reaction mixture was stirred at 25°C for 48 hours the Crude substance was purified by means of preparative HPLC. and received 8 mg (16%) of white foam substance. MS (IER): m/z = 603,1 [M+H]+.

Example 422

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(3-cryptomaterial-1-yl)-acetyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 215, the application of the compound of example 42 in the form of the free base (100 mg) as a starting substance and received 111 mg (74%) of light brown foam substance. MS (IER): m/z = 530,1 [M+H]+.

Example 423

(1-Cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

a) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-cyclopropanesulfonyl-1,2-dicarboxylic acid

According to the method similar to that described in example 409b, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-mercaptopyrimidine-1,2-dicarboxylic acid (example a) were introduced in the reaction with cyclopropanemethylamine (registration number CAS 7051-34-5) and got the desired compound in the form of colorless liquid. MS (IER): m/z = 316,2 [M+H]+.

b) 1-Tert-butyl ether,2-methyl ester (2S,4R)-4-cyclopropanesulfonyl-1,2-dicarboxylic acid

According to the method similar to that described in example C, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-cyclopropanesulfonyl-1,2-dicarboxylic acid was oxidized using MJPBK and got the desired compound as a white solid.

c) 1-Tert-butyl ester (2S,4R)-4-cyclopropanesulfonyl-1,2-dicarboxylic acid

According to the method similar to that described in example I, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-cyclopropanesulfonyl-1,2-dicarboxylic acid omilami in the presence of lithium hydroxide and got the desired connection is tion in the form of a white solid. MS (IER): m/z = 333,6 [M+H]+.

(d) Tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-cyclopropanesulfonyl-1-carboxylic acid

According to the method similar to that described in example 237, 1-tert-butyl ester (2S,4R)-4-cyclopropanesulfonyl-1,2-dicarboxylic acid was introduced into the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired connection. MS (IER): m/z = 399,6 [M+H]+.

e) (1-Cyanocyclohexyl)-nitrilotriacetate (2S,4R)-4-cyclopropanesulfonyl-2-carboxylic acid

According to the method similar to that described in example 409f, tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-cyclopropanesulfonyl-1-carboxylic acid were processed triperoxonane acid in dichloromethane and got the desired compound, which was used in the next stage without additional purification. MS: m/z = 299,2 [M+H]+.

f) (1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (1-cyanocyclohexyl)-nitrilotriacetate (2S,4R)-4-cyclopropanesulfonyl-2-carboxylic acid were introduced into a reaction with 1-trifluoromethyl-cyclopropanecarbonyl acid (registration number CAS 277756-46-) in the presence of HATU and DIEA and got the desired compound as a yellow solid. MS (IER): m/z = 434,6 [M+H]+.

Example 424

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-cyclopropanesulfonyl-2-carboxylic acid

According to the method similar to that described in example 237, (1-cyanocyclohexyl)-nitrilotriacetate (2S,4R)-4-cyclopropanesulfonyl-2-carboxylic acid (example I) were introduced in the reaction with 1-(4-chlorophenyl)-cyclopropanecarboxylic acid (registration number CAS 72934-37-3) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 476,0 [M+H]+.

Example 425

(2S,4R)-4-(2-Chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-(4-forfinal)-cyclopropanecarbonyl)pyrrolidin-2-carboxamide

The desired compound was obtained analogously to receive in example 215 using the compound of example 42 in the form of the free base (100 mg) as a starting substance and received 141 mg (97%) of white solids. MS (IER): m/z = 512,3 [M+H]+.

Example 426

(28,4 R)-1-(1-(4-Bromophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide

The desired compound was obtained analogously to receive in example 425 and received 91 mg (56%) of a white foam substance. MS (IER): m/z = 578,0 [M+H]+.

Example 427

(2S,4R)--(2-Chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-(4-(trifluoromethyl)phenyl)cyclopropanecarbonyl)pyrrolidin-2-carboxamide

The desired compound was obtained analogously to receive in example 425 and received 127 mg (79%) of light yellow solid. MS (IER): m/z = 566,2 [M+H]+.

Example 428

(2S,4R)-1-(1-(3-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide

The desired compound was obtained analogously to receive in example 425 and received 113 mg (75%) of light yellow solid. MS (IER): m/z = 532,1 [M+H]+.

Example 429

(2S,4R)-4-(2-Chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-(3-(trifluoromethyl)phenyl)cyclopropanecarbonyl)pyrrolidin-2-carboxamide

The desired compound was obtained analogously to receive in example 425 and got 148 mg (92%) of light yellow solid. MS (IER): m/z = 566,2 [M+H]+.

Example 430

(2S,4R)-1-(2-(4-Chlorophenyl)propanol)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide [epimer 1:12]

The desired compound was obtained analogously to receive in example 425, and received 15 mg (10,2%) of white solids. MS (IER): m/z = 522,2 [M+H]+.

Example 431

(2S,4R)-1-(2-(4-Chlorophenyl)propanol)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide [epimer 4:1]

The desired compound was obtained similarly to what auchenia in example 425 and received 72 mg (49%) of white solids. MS (IER): m/z = 522,2 [M+H]+.

Example 432

(2S,4R)-1-(2-(4-Chlorophenyl)-3-methylbutanoyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide [epimer 1:1]

The desired compound was obtained analogously to receive in example 425, and received 100 mg (64,4%) of light yellow solid. MS (IER): m/z = 548,2 [M+H]+.

Example 433

Tert-butyl 4-(4-chlorophenyl)-4-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclohexane)pyrrolidin-1-carbonyl)piperidine-1-carboxylate

The desired compound was obtained analogously to receive in example 425, and received 21 mg (11%) of nearly white solid. MS (IER): m/z = 619,2 [M+H]+.

Example 434

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-morpholine-4-ylacetic]-pyrrolidin-2-carboxylic acid [epimer 4:3]

The desired compound was obtained analogously to receive in example 425, and received 16 mg (10%) of nearly white solid. MS (IER): m/z = to $ 591.1 [M+H]+.

Example 435

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-morpholine-4-ylacetic]-pyrrolidin-2-carboxylic acid [epimer 1:2]

The desired compound was obtained analogously to receive in example 425, and received 75 mg (45%) of nearly white solid. MS (IER): m/z= to $ 591.1 [M+H] +.

Example 436

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-morpholine-4-ylacetic]-pyrrolidin-2-carboxylic acid [1 epimer]

The desired compound was obtained analogously to receive in example 425 and obtained 41 mg (25%) of nearly white solid. MS (IER): m/z = to $ 591.1 [M+H]+.

Example 437

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(3,4-dichlorophenyl)-2,2-divercity]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 425 and received 98 mg (60%) of nearly white solid. MS (IER): m/z = 576,0 [M+H]+.

Example 438

(2S,4R)-4-(2-Chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-p-tooltipcontent)pyrrolidin-2-carboxamide

The desired compound was obtained analogously to receive in example 425 and received 141 mg (97%) of white solids. MS (IER): m/z = 512,3 [M+H]+.

Example 439

(2S,4R)-1-(1-(4-Chloro-2-forfinal)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide

The desired compound was obtained analogously to receive in example 425 and got 92 mg (59%) of nearly white solid. MS (IER): m/z = 550,2 [M+H]+.

Example 440

(1-Cyanocyclohexyl)-amide (2S,4R)-4-methane is sulfonyl-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (1-cyanocyclohexyl)-nitrilotriacetate (2S,4R)-4-methanesulfonamide-2-carboxylic acid (example 409f) were introduced in the reaction with 1-trifluoromethyl-cyclopropanecarbonyl acid (registration number CAS 277756-46-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = 394,2 [M+H]+.

Example 441

(2S,4R,5S)-5-(4-Tert-butylphenyl)-N-(1-cyanocyclohexyl)-4-(phenylsulfonyl)-2-(2-(phenylsulfonyl)ethyl)pyrrolidin-2-carboxamide

a) (E)-Ethyl-2-(4-tert-butylbenzylamine)acetate

To a suspension of the hydrochloride of the ethyl ester of glycine (2.4 g, 17 mmole; registration number CAS 623-33-6) and dihydrate magnesium sulfate (4.8 g) in dichloromethane (25 ml) was added triethylamine (2.4 ml). The mixture was stirred at ambient temperature for 1 h, then was added tert-butylbenzaldehyde (2.5 g, 15.4 mmole; registration number CAS 939-97-9) and the reaction mixture was stirred at ambient temperature for 18 hours the Mixture was washed with water (2×100 ml) and brine (100 ml). The aqueous layer was extracted with dichloromethane (200 ml). The combined extracts were dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and obtained the desired compound (3,41 g, 15.3 mmole; 90%) as a yellow liquid, the cat heaven was pure enough for use in the next stage of the reaction. MS (IER): m/z = 248,3 [M+H]+.

b) ethyl ester of 4-benzazolyl-2-(2-benzosulfimide)-5-(4-tert-butylphenyl)-pyrrolidin-2-carboxylic acid

With stirring to a solution of (E)-ethyl-2-(4-tert-butylbenzylamine)acetate (226 mg, 914 mmol) in THF (5 ml) in an argon atmosphere was added lithium bromide (119 mg, of 1.37 mmole), triethylamine (191 μl, of 1.37 mmole) and phenylenesulfonyl (154 mg, 914 mmol; registration number CAS 5535-48-8). The mixture was stirred at ambient temperature for 20 hours was Added iPrOAc (50 ml) and ice water (40 ml) and the layers were separated. The organic layer was washed with brine (40 ml), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and were awarded a yellow oil, which was purified by column chromatography (silica gel, iPrOAc/n-heptane) and obtained the desired compound (37 mg, 64 μmol; 7%) as a colourless oil. MS (IER): m/z = 584,2 [M+H]+.

c) 4-Benzazolyl-2-(2-benzosulfimide)-5-(4-tert-butylphenyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 4-benzazolyl-2-(2-benzosulfimide)-5-(4-tert-butylphenyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow solid, which was used in the next stage without additional purification. MS (IER): m/z = 56,2 [M+H] +.

d) (2S,4R,5S)-5-(4-Tert-butylphenyl)-N-(1-cyanocyclohexyl)-4-(phenylsulfonyl)-2-(2-(phenylsulfonyl)ethyl)pyrrolidin-2-carboxamide

According to the method similar to that described in example 237, 4-benzazolyl-2-(2-benzosulfimide)-5-(4-tert-butylphenyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and after purification using preparative HPLC was obtained a mixture of the desired compound and its enantiomer in the form of a yellow oil. MS (IER): m/z = 620,2 [M+H]+.

Example 442

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2,2-divercity]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 425 and received 84 mg (55%) of white foam substance. MS (IER): m/z = 540,2 [M-N]-.

Example 443

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(2,4-dichlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 425, and received 36 mg (23%) of nearly white solid. MS (IER): m/z = 566,0 [M-N]-.

Example 444

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chloro-3-forfinal)-acetyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 425 and received 96 mg (65%) of nearly white solid. MS (IER): m/z = 522,1 [M-N]-.

Example 445

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid

a) Triptorelin methyl ester (2S,4R)-4-cyclopropanesulfonyl-2-carboxylic acid

According to the method similar to that described in example 409f, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-cyclopropanesulfonyl-1,2-dicarboxylic acid (example C) were introduced in the reaction with triperoxonane acid and was obtained the desired compound as a yellow liquid.

b) Methyl ester of (2S,4R)-4-cyclopropanesulfonyl-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, triptorelin methyl ester (2S,4R)-4-cyclopropanesulfonyl-2-carboxylic acid were introduced into a reaction with tert-butylacetoacetate in the presence of triethylamine and got the desired compound as a brown solid. MS (IER): m/z = 332,2 [M+H]+.

c) Methyl ester of (2S,4R)-4-cyclopropanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example h, methyl ester (2S,4R)-4-cyclopropylmethyl sulfonyl-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson and got the desired compound as a brown solid. MS (IER): m/z = 348,4 [M+H]+.

d) Methyl ester of (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid were introduced into a reaction with benzoylhydrazone (registration number CAS 555-96-4) and got the desired compound as a brown solid. MS (IER): m/z = 418,2 [M+H]+.

e) (2S,4R)-1-(2-Benzyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 404,2 [M+H]+.

f) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in Pris is accordance HATU, DIEA and got the desired compound as a brown solid. MS (IER): m/z = 468,0 [M+H]+.

Example 446

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chloro-3-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 425 and got 92 mg (59%) of light yellow solid. MS (IER): m/z = 548,1 [M-N]-.

Example 447

(1-Cyanocyclohexyl)-amide 4-benzazolyl-5-(4-tert-butylphenyl)-pyrrolidin-2-carboxylic acid

a) Ethyl ester of 5-(4-tert-butylphenyl)-4-(phenylsulfonyl)pyrrolidin-2-carboxylic acid

With stirring to a solution of (E)-ethyl-2-(4-tert-butylbenzylamine)acetate (226 mg, 914 micromole; compound of example a) in THF (5 ml) in an argon atmosphere was added lithium bromide (119 mg, of 1.37 mmole), triethylamine (191 μl, of 1.37 mmole) and phenylenesulfonyl (154 mg, 914 mmol; registration number CAS 5535-48-8). The mixture was stirred at ambient temperature for 20 hours was Added iPrOAc (50 ml) and ice water (40 ml) and the layers were separated. The organic layer was washed with brine (40 ml), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and were awarded a yellow oil, which was purified by column chromatography (silica gel, iPrOAc/n-heptane), and obtained the desired compound (56 mg, 73 μmol; 8%) as a colourless solid in the society. MS (IER): m/z = 416,2 [M+H]+.

b) 5-(4-Tert-butylphenyl)-4-(phenylsulfonyl)pyrrolidin-2-carboxylic acid

According to the method similar to that described in example e, ethyl ester 5-(4-tert-butylphenyl)-4-(phenylsulfonyl)pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a colourless solid, which was used in the next stage without additional purification. MS (IER): m/z = 388,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide 4-benzazolyl-5-(4-tert-butylphenyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, 5-(4-tert-butylphenyl)-4-(phenylsulfonyl)pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow foam substance. MS (IER): m/z = 452,2 [M+H]+.

Example 448

(1-Cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

a) Triptorelin methyl ester (2S,4R)-4-methanesulfonamide-2-carboxylic acid

According to the method similar to that described in example 409f, 1-tert-butyl ether,2-methyl ester (2S,4R)-4-methanesulfonanilide-1,2-dicarboxylic acid (example C) were introduced in the reaction with referencesee acid and was obtained the desired compound as a brown solid.

b) Methyl ester of (2S,4R)-4-methanesulfonyl-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192f, triptorelin methyl ester (2S,4R)-4-methanesulfonamide-2-carboxylic acid were introduced into a reaction with tert-butylacetoacetate in the presence of triethylamine and got the desired connection. MS (IER): m/z = 292,2 [M+H]+.

c) Methyl ester of (2S,4R)-4-methanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example h, methyl ester (2S,4R)-4-methanesulfonyl-1-(3-oxobutyryl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with the reagent Lawesson and got the desired compound as a brown solid. MS (IER): m/z = 308,4 [M+H]+.

d) Methyl ester of (2S,4R)-4-methanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-methanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-(2-phenylethyl)hydrazine (registration number CAS 51-71-8) and got the desired compound as a brown solid. MS (IER): m/z = 392,6 [M+H]+.

e) (2S,4R)-4-Methanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-m is canalphones-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 378,0 [M+H]+.

f) (1-Cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-methanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = TP 442.6 [M+H]+.

Example 449

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-methanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with benzoylhydrazone (registration number CAS 555-96-4) and got the desired connection. MS (IER): m/z = 378,5 [M+H]+.

b) (2S,4R)-1-(2-Benzyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-methane is sulfanilamide-2-carboxylic acid omilami in the presence of lithium hydroxide and got the desired connection, which was used in the next stage without additional purification. MS (IER): m/z = 364,3 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a brown solid. MS (IER): m/z = 428,2 [M+H]+.

Example 450

Tert-butyl ester (2S,4R)-4-(2-allyloxymethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

a) Synthesis of 1-tert-butyl ether,2-methyl ester (2S,4R)-4-(2-permentantly)-pyrrolidine-1,2-dicarboxylic acid

The desired compound was obtained in accordance with the methods described in example 120 a-C), and got to 8.1 g (92%) of a colorless resin. MS (IER): m/z = 388,1 [M+H]+.

b) Synthesis of 1-tert-butyl ether,2-ethyl ester (2S,4R)-4-(2-allyloxymethyl)-pyrrolidine-1,2-dicarboxylic acid

In a round bottom flask with a volume of 50 ml sodium hydride, 60% dispersion in mineral oil (434 mg, 10.8 mmole, 1.4 EQ.), combined with DMF (20,00 ml) and got a white suspension. Was slowly added about the-2-EN-1-ol (630 mg, 739 μl, 10.8 mmole, 1.4 EQ.) (caution: the formation of gas and heat!). Light yellow liquid suspension was added to a solution of compound of example 450A) (3 g, 7,74 mmole, 1.00 EQ.) in DMF (10 ml). The reaction mixture was heated at 50°C and stirred for 1.5 hours the Crude reaction mixture was evaporated, then the residue was added 150 ml of AcOEt (150 ml) and water (40 ml). Watched the transesterification of ethyl ether (according to LC/MS). The aqueous layer was extracted with EtOAc (3×150 ml). The organic layers were combined and washed with brine. The organic layers were dried over Na2SO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 25 to 60% EtOAc in hexano) and obtained the desired compound (1.3 g; 38%) as colorless resinous substance. MS (IER): m/z = 440,2 [M+H]+, 340,1 [M+H-Boc]+.

c) Synthesis of 1-tert-butyl ester (2S,4R)-4-(2-allyloxymethyl)-pyrrolidine-1,2-dicarboxylic acid

In a round bottom flask with a volume of 25 ml of the compound of example 450b) (1.48 g, 3,37 mmole, 1.00 EQ.), combined with tetrahydrofuran (8 ml) and received a colorless solution. Was added lithium hydroxide (129 mg, 5,39 mmole, 1.6 EQ.) in water (4,00 ml). The reaction mixture was stirred for 5 hours, the pH Value of the reaction mixture brought to = 2-3 0,5 N. aqueous solution of HCl and was extracted with EtOAc (2×25 ml). The aqueous layer was extracted with the aid of the rd EtOAc (3×25 ml). The organic layers were combined and washed with brine. The organic layers were dried over Na2SO4and concentrated in vacuum and obtained the desired compound (1,36 g; 98%) as a colourless foam substance. MS (IER): m/z = 410,1 [M-N]-.

d) Synthesis of tert-butyl ester (2S,4R)-4-(2-allyloxymethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid

In a round bottom flask with a volume of 25 ml of the compound of example 450S) (1,363 g of 3.31 mmole, 1.00 EQ.), combined with acetonitrile (15 ml) and received a colorless solution. Added HATU (2,52 g, 6,63 mmole, 2.0 EQ.) and DIPEA (856 mg, of 1.16 ml, 6,63 mmole, 2.0 EQ.). The color of the solution became yellow. Was added 1-aminocyclohexanecarboxylic (471 mg, 3,98 mmole, 1.2 EQ.) and was stirred at ambient temperature for 6 hours, the Reaction mixture was evaporated to dryness and purified using flash chromatography and was obtained the desired compound (1.26 g; 80%) as a colourless foam substance. MS (IER): m/z = 476,1 [M+H]+.

Example 451

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(1-hydroxymethylpropane)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 211 using connection with registration number CAS 49640-66-6 in as the starting material and the floor is made of 25 mg (19%) of light yellow solid. MS (IER): m/z = 584,1 [M+H]+.

Example 452

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-hydroxymethylpropane)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 425 using connection with registration number CAS 49640-66-6 as the initial substance and received 59 mg (51%) of nearly white foam substance. MS (IER): m/z = 452,1 [M+H]+.

Example 453

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-allyloxymethyl)-pyrrolidin-2-carboxylic acid

In a round bottom flask with a volume of 10 ml was combined compound of example 450 (0.6 g, of 1.26 mmole, 1.00 EQ.) and formic acid (1,74 g of 1.45 ml of 37.9 mmole, 30 EQ.) and received light yellow solution. The reaction mixture was heated at 22°C and was stirred for 18 hours ice 10% aqueous solution of Na2CO3(2 ml), the pH value of the reaction mixture was carefully set equal to 8 and was extracted with EtOAc (1×35 ml). The aqueous layer was extracted with EtOAc (2×30 ml). The combined organic layers were washed with brine, dried over Na2SO4was filtered and evaporated and obtained the desired compound (460 mg; 97%) as a colourless foam substance. MS (IER): m/z = 376,1 [M+H]+.

Example 454

(1-Cyanocyclohexyl)-amide (2S,4R)-4-cyclopropyl econsultancy-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-cyclopropanesulfonyl-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, triptorelin methyl ester (2S,4R)-4-cyclopropanesulfonyl-2-carboxylic acid (example a) were introduced in the reaction with 1-methyl-cyclopropanecarbonyl acid (registration number CAS 6914-76-7) in the presence of HATU and DIEA and got the desired connection. MS (IER): m/z = 330,0 [M+H]+.

b) (2S,4R)-4-Cyclopropanesulfonyl-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound, which was used in the next stage without additional purification.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-cyclopropanesulfonyl-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired connection in the de white solid. MS (IER): m/z = 380,0 [M+H]+.

Example 455

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[(R)-2-allylamino-2-(4-chlorophenyl)-acetyl]-4-(2-allyloxymethyl)-pyrrolidin-2-carboxylic acid

a) Synthesis of methyl ester of (R)-allylamino-(4-chlorophenyl)-acetic acid

In a round bottom flask with a volume of 25 ml (R)-methyl-2-amino-2-(4-chlorophenyl)acetylhydrolase (1,000 g, 4,24 mmole, 1.00 EQ.) and 3-bromoprop-1-ene (564 mg, 394 μl, 4,66 mmole, 1.1 EQ.) combined with dichloromethane (10.0 ml) and received light yellow solution. The reaction mixture was heated at 22°C and was stirred for 1 h, the Reaction mixture was stirred at 25°C for 18 hours the Crude reaction mixture was concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 40 g, from 25 to 60% EtOAc in hexano) and obtained the desired compound (331 mg; 33%) as a yellow oil. MS (IER): m/z = 376,1 [M+H]+.

b) Synthesis of (R)-allylamino-(4-chlorophenyl)-acetic acid

In a round bottom flask with a volume of 25 ml of the compound of example a) (0.33 g, to 1.38 mmole, 1.00 EQ.) combined with tetrahydrofuran (1.6 ml) and received a yellow solution. Was added lithium hydroxide (52,8 mg, 2.2 mmole, 1.6 EQ.) in water (0.8 ml). The reaction mixture was stirred for 2 hours, the pH value of the reaction mixture brought to = 2-3 0,5 N. aqueous solution of HCl and was extracted with EtOAc (2×25 ml). The aqueous layer was extrage is ovali with EtOAc (3×25 ml). The organic layers were combined and washed with brine. The organic layers were dried over Na2SO4and concentrated in vacuum. The aqueous layer was concentrated in vacuum and obtained the desired compound (300 mg; 97%) as a white solid. MS (IER): m/z = 226,2 [M+H]+.

c) Synthesis of (1-cyanocyclohexyl)-amide (2S,4R)-1-[(R)-2-allylamino-2-(4-chlorophenyl)-acetyl]-4-(2-allyloxymethyl)-pyrrolidin-2-carboxylic acid

In a round bottom flask with a volume of 10 ml of the compound of example 453 (83,2 mg, 222 μmol, 1.00 EQ.) combined with DMF (1,00 ml) and received light yellow solution. Added HATU (169 mg, 443 μmol, 2.0 EQ.) and DIPEA systems (57.3 mg, 77,4 µl, 443 μmol, 2.0 EQ.). The color of the solution became yellow. Added the compound of example 455b) (65,0 mg, 288 μmol, 1.3 EQ.) and 2.0 EQ. DIPEA (77,4 µl, 443 μmol) and stirred at 25°C for 0.5 H. the Crude substance was purified by means of preparative HPLC and was obtained the desired compound (60 mg; 46%) as a pale yellow foam substance. MS (IER): m/z = 583,2 [M+H]+.

Example 456

(2S,4R)-4-(2-Chloro-4-(3,3-diversecity-1-yl)phenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide

According to the method similar to that described in example 389, (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic what Islami (example 385b) were introduced in the reaction with 3,3-diversityconservation (registration number CAS 288315-03-7) in acetonitrile at 90°C for 48 h, and was obtained the desired compound in the form of almost white foam substance. MS (IER): m/z = 579,3 [M+H]+.

Example 457

(2S,4R)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)-4-(phenylsulfonyl)pyrrolidin-2-carboxamide

a) (1S,4S)-5-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-2-oxa-5-azabicyclo[2.2.1]heptane-3-one

1-(4-Chlorophenyl)cyclopropanecarbonyl acid (8,58 g) and dimethylformamide (136 mg) suspended in toluene (20 ml). The mixture was cooled to room temperature and then for 10 min was added dropwise a solution of oxalicacid (the 5.25 g) in toluene (6,7 ml). The reaction mixture was stirred at 0°C for 30 min and at room temperature for 3 hours At 0-5°C. to the reaction mixture was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-3-inmeasurement (registration No. CAS: 769167-53-5; 8 g) and tetrahydrofuran (13,2 ml) and then dropwise added triethylamine (14.5 g). The mixture was stirred at 22°C for 16 h was Added an aqueous solution of citric acid (10%, 30 ml) and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated in vacuum. The crude mixture was led from a mixture of dichloromethane, ethyl acetate and heptane was obtained 10.6 g (95%) of the desired compound as a white solid. MS (IER): m/z = 292,07 [M+H]+.

b) (2S,4S)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-N-(1-zionazi sapropel)-4-hydroxypyrrolidine-2-carboxamide

A mixture of (1S,4S)-5-(1-(4-chlorophenyl)cyclopropanecarbonyl)-2-oxa-5-azabicyclo[2.2.1]heptane-3-one (example a; 10,578 g), 1-aminocyclohexanecarboxylic (5,94 g), 2-ethylhexanoate sodium (9,44 g) in water (54 ml) was stirred at 52-54°C for 20 hours, the Reaction mixture was diluted with 36 ml of tetrahydrofuran. Added concentrated hydrochloric acid (1.9 ml) and sodium chloride (18,09 g). The reaction mixture was stirred for 15 min, then was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The crude mixture was led from a mixture of ethyl acetate and heptane and received 11,94 g (88%) of the desired compound as a white solid. MS (IER): m/z = 374,12 [M+H]+.

c) (3S,5S)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-5-(1-cyanocyclohexane)pyrrolidin-3-albenzaalbenza

To a solution of (2S,4S)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)-4-hydroxypyrrolidine-2-carboxamide (example 457b; 5 g) in tetrahydrofuran (22 ml) at 0-5°C for 5 min was added benzosulphochloride (2,89 g, 2.1 ml, 16.2 mmole, 1,21 equiv.) dimethylaminopyridine (88,7 mg) and triethylamine (2,41 g). The mixture was stirred at 0-5°C for 15 min, then at 22°C for 22 h At 0-5°C was added water (6,7 ml) and methanol (15.6 ml) and the mixture was concentrated in vacuum and the obtained resin. This resin prom the Vali with methanol and was dried in vacuum and received 6,82 g (99%) of the desired compound as a light brown foam substance. MS (IER): m/z = 531,15 [M+NH4]+.

d) (2S,4R)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)-4-(phenylthio)pyrrolidin-2-carboxamide

To a suspension of (3S,5S)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-5-(1-cyanocyclohexane)pyrrolidin-3-albenzaalbenza (example 457; 200 mg) and potassium carbonate (134 mg) in dimethylacetamide (1 ml) at room temperature was added tetrahydrofuran (1.2 ml) and sensation (50,7 mg). The reaction mixture was stirred at 22°C for 20 h, then poured into water and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified via chromatography on silica gel and got the desired compound as a colourless oil (184 mg; 89%). MS (IER): m/z = 466,13 [M+H]+.

e) (2S,4R)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)-4-(phenylsulfonyl)pyrrolidin-2-carboxamide

To a suspension oxone (873 mg) in methanol (0.7 ml) and water (0.2 ml) at 10-15°C for 45 min, the solution was added (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)-4-(phenylthio)pyrrolidine-2-carboxamide (example 457d, 147 mg) in methanol (0.5 ml). The mixture was stirred at 22°C for 20 hours, the Reaction mixture was filtered and the residue was washed with methanol. Was added water (2 ml) and the filtrate was concentrated in vacuo (50°C, 150-80 m the ar). The aqueous layer was extracted with methyl tert-butyl ether and the combined organic layers were washed with an aqueous solution of sodium metabisulfite (10% wt./wt.), aqueous solution of potassium bicarbonate (1M) and brine then dried over sodium sulfate and filtered through a layer of silica gel. Layer washed with methyl tert-butyl ether, the filtrate was concentrated in vacuo and obtained 42 mg (30%) of the desired compound as a white solid. MS (IER): m/z = 498,12 [M+H]+.

Example 458

(2S,4R)-4-(Benzylmethyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide

a) (2S,4R)-4-(Benzylthio)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide

The desired compound was obtained analogously to receive in example 457d) using (3S,5S)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-5-(1-cyanocyclohexane)pyrrolidin-3-albenzaalbenza (example 457, stage 3; 200 mg) and phenylmethanol (57 mg) and received 109 mg (53%) of white solids. MS (IER): m/z = 480,15 [M-N]-.

b) (2S,4R)-4-(Benzylmethyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide

The desired compound was obtained analogously to receive in example I) using (2S,4R)-4-(benzylthio)-1-(1-(4-chlorophenyl)cyclopropane the Nile)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide (example 458, stage 1; 96 mg) was obtained 50 mg (55%) of a white resin. MS (IER): m/z = 512,14 [M+H]+.

Example 459

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-itfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 425 and received 112 mg (64%) of white solids. MS (IER): m/z = 624,1 [M+H]+.

Example 460

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(2,4-dichloro-5-methoxyphenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained as a side product during the synthesis of the compound of example 461 and received 22 mg (11%) of white solids. MS (IER): m/z = 596,2 [M+H]+.

Example 461

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(2,4-dichloro-5-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

a) Synthesis of 1-(2,4-dichloro-5-forfinal)-cyclopropanecarbonitrile

2-(2,4-Dichloro-5-forfinal)acetonitrile (1 g, 4.9 mmole, 1.00 EQ.) was dissolved in toluene (4 ml). To the resulting suspension was added 1,2-dibromoethane (1,38 g, 634 μl, of 7.35 mmole, 1.50 equiv.) an aqueous solution of NaOH (or 4.31 ml, 12.5 M; 53,9 mmole, 11,0 EQ.) and tetrabutyrate ammonium (348 mg, 1,08 mmole, 0.22 equiv.) and vigorously stirred at RT for 4 h, the Reaction mixture RA is balali water and was extracted with AcOEt. The organic solution washed with 1 N. aqueous solution of HCl, then brine, dried over Na2SO4, filtered and evaporated to dryness. The crude substance was purified using flash chromatography (silica gel, 50 g, from 0 to 50% EtOAc in heptane) and received the compound of example a) (1.13 g; 100%) as an almost white solid.1H-NMR (CDCl3, 250 MHz) δ [ppm million]: 7,51 (1 proton, d, 6,7 Hz); 7,16 (1, proton, d; a 8.9 Hz); of 1.76 and 1.80 (2 protons, m); 1,31-1,36 (2 protons, m)

b) Synthesis of 1-(2,4-dichloro-5-forfinal)-cyclopropanecarbonyl acid and 1-(2,4-dichloro-5-methoxyphenyl)-cyclopropanecarboxylic acid (mixture 1:1)

1-(2,4-Dichloro-5-forfinal)cyclopropanecarbonitrile (1.13 g, 4,91 mmole, 1.00 EQ.) was dissolved in methanol (2.5 ml). Added 9 N. aqueous solution of NaOH (10 ml, 90,0 mmole, 18,3 EQ.) and the reaction mixture was stirred for 3 h at 25°C. the Reaction mixture was acidified using 2 N. aqueous solution of HCl and was extracted with CH2Cl2. The organic layers were dried over Na2SO4, was filtered and was concentrated in vacuum and got a 1:1 mixture of the desired compounds.

F-derivative:1H-NMR (CDCl3, 250 MHz) δ [ppm million]: of 11.15 (broad, 1 proton); 7,43 (1 proton, d, 6,86 Hz); 7,10 (d; 1 proton, 9,29 Hz); 1,78-1,82 (2 protons, m); 1,23-1,29 (2 protons, m)

methoxypropane:1H-NMR (CDCl3, 250 MHz) δ [ppm million]: of 11.15 (broad, 1 proton); 7,38 (1 proton, s); 6,85 (s, 1 proton); 3,88 (s, 3 protons); 1,78-1,82 (2 CR the tone, m); 1,23-1,29 (2 protons, m)

(C) (1-Cyanocyclohexyl)-amide 2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(2,4-dichloro-5-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 425, using a mixture obtained in example 461b), as the initial substance and received 42 mg (21%) of white solids. MS (IER): m/z = 586,0 [M+H]+.

Example 462

(1-Cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-methanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with 4-(trifluoromethyl)phenylhydrazine (registration number CAS 368-90-1) and got the desired connection. MS (IER): m/z = 432,0 [M+H]+.

b) (2S,4R)-4-Methanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and got the desired connection, the cat is itself used in the next stage without additional purification. MS (IER): m/z = 418,4 [M+H]+.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = 482,4 [M+H]+.

Example 463

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-methanesulfonamide-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-methanesulfonamide-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-methanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with (2-chloropyridin-4-yl)-hydrazine (registration number CAS 700811-29-6) and got the desired connection.

b) (2S,4R)-1-[2-(2-Chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-methanesulfonamide-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-methanesulfonyl irreligion-2-carboxylic acid omilami in the presence of lithium hydroxide and got the desired connection, which was used in the next stage without additional purification.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-methanesulfonamide-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-methanesulfonamide-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = 449.6 M. [M+H]+.

Example 464

(2S,4R)-4-(2-Chloro-4-(3,3-diversecity-1-yl)phenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide

a) (2S,4R)-Methyl-4-(2-chloro-4-perpenicular)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate

According to the method similar to that described in example h, (2S,4R)-methyl-4-(2-chloro-4-perpenicular)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate (example 375b) were introduced in the reaction with the reagent Lawesson (registration number CAS 19172-47-5) and got the desired compound as an orange foam substance. MS (IER): m/z = 421,9 [M+H]+.

b) Methyl ester of (2S,4R)-4-(2-chloro-4-perpenicular)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid

For the determination of the e, similar to that described in example 192h, (2S,4R)-methyl-4-(2-chloro-4-perpenicular)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate was introduced in the reaction with (tetrahydropyran-4-yl)-hydrazinecarboxamide (registration number CAS 116312-69-7) and got the desired compound as a yellow solid. MS (IER): m/z = 486,2 [M+H]+.

c) (2S,4R)-4-(2-Chloro-4-perpenicular)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chloro-4-perpenicular)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow foam substance that is used in the next stage without additional purification. MS (IER): m/z = 472,1 [M+H]+.

d) (2S,4R)-4-(2-Chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide

According to the method similar to that described in example 237, (2S,4R)-4-(2-chloro-4-perpenicular)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (EEC) m/z = 536,1 [M+H] +.

e) (2S,4R)-4-(2-Chloro-4-(3,3-diversecity-1-yl)phenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide

According to the method similar to that described in example 389, (2S,4R)-4-(2-chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamid introduced into reaction with 3,3-diversityconservation (registration number CAS 288315-03-7) in acetonitrile at 90°C for 48 h, and was obtained the desired compound in the form of almost white foam substance. MS (IER): m/z = 609,2 [M+H]+.

Example 465

(2S,4R)-4-(2-Chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide

a) Methyl ester of (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, (2S,4R)-methyl-4-(2-chlorophenylsulfonyl)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate (example C) were introduced in the reaction with (tetrahydro-2H-thiopyran-4-yl)hydrazine-2,2,2-trifurcation (registration number CAS 693287-87-5) and got the desired compound as a yellow foam substance. MS (IER): m/z = Ozenmunaygas given KZT 484.1 ecological [M+H]+.

b) (2S,4R)-4-(2-Chlorophenylsulfonyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carb is a new acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound in the form of a brown liquid, which was used in the next stage without additional purification. MS (IER): m/z = 470,0 [M+H]+.

c) (2S,4R)-4-(2-Chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of almost white foam substance. MS (IER): m/z = 534,1 [M+H]+.

Example 466

(1-Cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-methanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic key is lots (example C) were introduced in the reaction with 2,2,2-cryptgetkeyparam (registration number CAS 5042-30-8) and got the desired connection. MS (IER): m/z = 370,4 [M+H]+.

b) (2S,4R)-4-Methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound, which was used in the next stage without additional purification. MS (IER): m/z = 356,3 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = 420,0 [M+H]+.

Example 467

(1-Cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with 2,2,2-cryptgetkeyparam (registration number CAS 5042-30-8) and got the desired compound as a brown solid. MS (IER): m/z = 409,9 [M+H]+.

b) (2S,4R)-4-Cyclopropanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 396,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow solid. MS (IER): m/z = 460,0 [M+H]+.

Example 468

(1 Ciani chlorophil)-amide (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-cyclopropanesulfonyl-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with (2-chloropyridin-4-yl)-hydrazine (registration number CAS 700811-29-6) and got the desired compound as a brown solid. MS (IER): m/z = 439,4 [M+H]+.

b) (2S,4R)-1-[2-(2-Chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-cyclopropanesulfonyl-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-cyclopropanesulfonyl-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 425,0 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-cyclopropanesulfonyl-2-carboxylic acid were introduced into a reaction with 1-amino what chlorobenzotrichloride (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow solid. MS (IER): m/z = 489,0 [M+H]+.

Example 469

(1-Cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with 4-(trifluoromethyl)phenylhydrazine (registration number CAS 368-90-1) and got the desired compound as a brown solid. MS (IER): m/z = 472,6 [M+H]+.

b) (2S,4R)-4-Cyclopropanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 458,0 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrole the h-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = 522,0 [M+H]+.

Example 470

(1-Cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-cyclopropanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with 1-(2-phenylethyl)hydrazine (registration number CAS 51-71-8) and got the desired compound as a brown solid. MS (IER): m/z = 432,6 [M+H]+.

b) (2S,4R)-4-Cyclopropanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of hydroxide litei received the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 417,6 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-cyclopropanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = 482,7 [M+H]+.

Example 471

(1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid

a) Methyl ester of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid

According to the method similar to that described in example 192h, methyl ester (2S,4R)-4-cyclopropanesulfonyl-1-(3-occationally)-pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with cyclobutylamine (registration number CAS 742673-64-9) and got the desired compound as a brown solid. MS (IER): m/z = 382,2 [M+H]+.

b) (2S,4R)-1-(2-Cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic to the slot

According to the method similar to that described in example I, methyl ester (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a nearly white solid, which was used in the next stage without additional purification. MS (IER): m/z = 367,2 [M+H]+.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = 381,8 [M+H]+.

Example 472

(1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-does not depend-1-yl)-cyclopropanecarbonyl]-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (4-does not depend-1-yl)-acetic acid

To a solution of 2-(naphthalene-1-yl)acetic acid (2 g) in acetic acid (10 ml) at room temperature was added bromine (1.7 g). The mixture was stirred at 80°C for 2 h, then was allowed to cool to room tempera is URS during the weekend (when mixing the formed crystals). The reaction mixture was diluted with water and the crystals were filtered off, washed with water and dried and received 2.5 g of the crude mixture containing (4-does not depend-1-yl)-acetic acid as a light brown solid. To a solution of this solid (2.5 g) dimethylaminopyridine (86,4 mg) and triethylamine (787 mg) in dichloromethane (20 ml) at 0°C was added methylchloroform (668 mg). The reaction mixture was stirred for 6 h at room temperature. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous solution of sodium bicarbonate, hydrochloric acid (0.1 N.) and brine, then dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified via chromatography on silica gel and then further purified using preparative chiral HPLC on a Reprosil Chiral-NR and got the desired compound as a white solid (669 mg; 23%). MS (IER): m/z = 278 [M+H]+.

b) 1-(4-does not depend-1-yl)-cyclopropanecarbonyl acid

To a solution of methyl ester (4-does not depend-1-yl)-acetic acid (example a), 687 mg) in tetrahydrofuran (13 ml) and hexamethylphosphoramide (1.3 ml) at -78°C for 5 min, the solution was added diisopropylamide lithium (2M, 2,71 ml) in a mixture tetrahydrofuran/heptane/ethylbenzene. Quickly added 1,2-dibromoethane (695 mg) and the reaction mixture paramashiva and at room temperature for 3 hours The reaction mixture was concentrated in vacuo and the residue was subjected to distribution between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuum and got the crude mixture containing methyl ester 4-bromo-2-(4-does not depend-1-yl)-butyric acid. This crude substance was dissolved in tetrahydrofuran (13 ml) at room temperature was added potassium carbonate (692 mg). The mixture was stirred at room temperature for 36 h, concentrated in vacuo and subjected distribution between ethyl acetate and hydrochloric acid (0.1 N.). The aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated in vacuo. The crude mixture was concentrated to dryness and purified via chromatography on silica gel and got the desired compound as a colourless oil (215 mg; 30%). MS (IER): m/z = 290 [M-N]-.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-does not depend-1-yl)-cyclopropanecarbonyl]-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 15 (112 mg) and 1-(4-does not depend - 1-yl)-cyclopropanecarboxylic acid (example 472b) and the floor is made of 95 mg (53%) of colorless semisolid substances. MS (IER): m/z = 627,1 [M+H]+.

Example 473

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorphenoxy)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

a) 3-(4-Chlorphenoxy)-dihydrofuran-2-he

The cesium fluoride (7.6 g) was added to a solution of 4-chlorophenol (1.29 g) in dimethylformamide (35 ml) and the mixture was stirred at 100°C for 5 minutes was Added 3-bradykinin-2(3H)-he (3.3 grams) and the reaction mixture was heated at 120°C for 1.5 h, the Reaction mixture was poured into water and was extracted with EtOAc. The aqueous layer was extracted with ethyl acetate. The organic layers were washed with water, dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified via chromatography on silica gel and got the desired compound as a colourless oil (1,17 g; 55%). MS (IER): m/z = 212 [M]+.

b) Methyl ester of 2-(4-chlorophenoxy)-4-hydroxybutiric acid

3-(4-Chlorphenoxy)dihydrofuran-2(3H)-he (example a), 1,136 g), iodine (30.0 mg) and methanol (28,9 ml) was stirred at 65°C for 24 h the Reaction mixture was concentrated in vacuum. The excess iodine was removed by adding an aqueous solution of sodium sulfite (10% wt./wt., 15 ml). The mixture was extracted with ethyl acetate. The organic layers were washed with brine (10 ml), dried over sodium sulfate and filtered. The crude mixture koncentrirane and dryness and purified via chromatography on silica gel and got the desired compound as a colourless oil (433 mg; 33%). MS (IER): m/z = 244 [M]+.

c) Methyl ester of 2-(4-chlorophenoxy)-4-(toluene-4-sulfonyloxy)-butyric acid

To a solution of methyl ester of 2-(4-chlorophenoxy)-4-hydroxybutiric acid (example 473b), 0,225 g) in dichloromethane (1,88 ml) at room temperature was added triethylamine (116 mg) and 4-methylbenzol-1-sulphonylchloride (177 mg). The mixture was stirred at 22°C for 48 hours the Reaction mixture was subjected to distribution between water and ethyl acetate. The phases were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and filtered. The crude mixture was concentrated to dryness and purified via chromatography on silica gel and got the desired compound as a colourless oil (169 mg; 46%). MS (IER): m/z = 419 [M+NH4]+.

d) Methyl ester of 1-(4-chlorphenoxy)-cyclopropanecarbonyl acid

A suspension of sodium hydride in oil (55% wt./wt., of 36.4 mg) at room temperature was added to a solution of methyl ester of 2-(4-chlorophenoxy)-4-(toluene-4-sulfonyloxy)-butyric acid (example 473 (C), 145 mg) in 1,2-dimethoxyethane of 2.27 ml). The mixture was stirred at 22°C for 48 hours the Reaction mixture was filtered and the solid washed with ethyl acetate. To the filtrate was added water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate is filtered. The crude mixture was concentrated to dryness and purified via chromatography on silica gel and got the desired compound as a colourless oil (56 mg; 68%). MS (IER): m/z = 226 [M]+.

e) 1-(4-Chlorphenoxy)-cyclopropanecarbonyl acid in the form of a lithium salt

A mixture of methyl ester 1-(4-chlorphenoxy)-cyclopropanecarboxylic acid (example 473d), 51 mg) and monohydrate of lithium hydroxide (15.1 mg) in tetrahydrofuran (0.6 ml), water (0.3 ml) and Meon (0.2 ml) was stirred at 22°C for 2 h, the Reaction mixture was concentrated in vacuo and obtained the desired compound as a colorless oil (49 mg; 99%). MS (IER): m/z = 211,6 [M-N]-.

f) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorphenoxy)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

The desired compound was obtained analogously to receive in example 239 using the compound of example 42 (75 mg) and 1-(4-chlorphenoxy)-cyclopropanecarbonyl acid in the form of a lithium salt (example 473 stage 5) and 31 mg (30%) of a white solid. MS (IER): m/z = 549,5 [M+H]+.

Example 474

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(3-phenylpropyl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(3-phenylpropyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid

what about the method, similar to that described in example 192h, (2S,4R)-methyl-4-(2-chlorophenylsulfonyl)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate (example C) were introduced in the reaction with 1-(3-phenylpropyl)hydrazine (registration number CAS 3381-02-0) and got the desired compound as a yellow oil. MS (IER): m/z = 502,1 [M+H]+.

b) (2S,4R)-4-(2-Chlorophenylsulfonyl)-1-(3-methyl-1-(3-phenylpropyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(3-phenylpropyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a colourless oil, which was used in the next stage without additional purification. MS (IER): m/z = 486,2 [M-N]-.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(3-phenylpropyl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(3-phenylpropyl)-1H-pyrazole-5-yl)pyrrolidin-2-carbonum was introduced in the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of almost white semi-liquid substances. MS (IER): m/z = 552,2 [M+H]+.

Example 475

Formate 4-(2-{5-[(2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cenotillo OpenCalais)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-ethyl)-morpholine-4-FL

a) Methyl ester of (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, (2S,4R)-methyl-4-(2-chlorophenylsulfonyl)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate (example C) were introduced in the reaction with 4-(2-hydrazinophenyl)morpholine (registration number CAS 2154-24-7) and got the desired compound as a yellow oil. MS (IER): m/z = 497,3 [M+H]+.

b) (2S,4R)-4-(2-Chlorophenylsulfonyl)-1-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a brown oil, which was used in the next stage without additional purification. MS (IER): m/z = 483,4 [M+H]+.

c) Formate 4-(2-{5-[(2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-ethyl)-morpholine-4-FL

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in presets is under HATU, DIEA and after purification using preparative HPLC using formic acid as solyent received the desired compound as a colourless oil. MS (IER): m/z = 545,2 [M-N]-.

Example 476

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(3-methyl-3H-imidazol-4-ylmethyl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) (2S,4R)-Methyl-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylate

According to the method similar to that described in example 192h, (2S,4R)-methyl-4-(2-chlorophenylsulfonyl)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate (example C) were introduced in the reaction with 5-(hydrosilylation)-1-methyl-1H-imidazole (registration number CAS 887592-51-0) and got the desired compound as a yellow oil. MS (IER): m/z = 478,1 [M+H]+.

b) (2S,4R)-4-(2-Chlorophenylsulfonyl)-1-(3-methyl-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylate lithium

According to the method similar to that described in example e, (2S,4R)-methyl-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylate omilami in the presence of lithium hydroxide and obtained the desired compound as a brown solid, which was used in the next stage without additional purification. MS (IER): m/z = 462,1 [M-N]-.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(3-methyl-3H-imidazol-4-ylmethyl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method analogion the th described in example 237, (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylate lithium was introduced into the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as an orange solid. MS (IER): m/z = 528,2 [M+H]+.

Example 477

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, (2S,4R)-methyl-4-(2-chlorophenylsulfonyl)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate (example C) were introduced in the reaction with cyclohexanedimethanol (registration number CAS 24214-73-1) and got the desired compound as an orange oil. MS (IER): m/z = 466,2 [M+H]+.

b) (2S,4R)-4-(2-Chlorobenzenesulfonyl)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z = 450,0 [M-N]-.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = 516,3 [M+H]+.

Example 478

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, (2S,4R)-methyl-4-(2-chlorophenylsulfonyl)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate (example C) were introduced in the reaction with (tetrahydropyran-4-yl)hydrazinecarboxamide (registration number CAS 194543-22-1) and got the desired compound as an orange oil. MS (IER): m/z = 468,1 [M+H]+.

b) (2S,4R)-4-(2-Chlorobenzenesulfonyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in the ore e, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z = 453,8 [M+H]+.

(C) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a yellow oil. MS (IER): m/z = 518,2 [M+H]+.

Example 479

(2S,4R)-4-[(2-Chlorophenyl)sulfonyl]-N-(1-cyanocyclohexyl)-1-[1-(1,1-dissidocerida-2H-thiopyran-4-yl)-3-methyl-1H-pyrazole-5-yl]-L-prolinamide

It chilled with ice to a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (20 mg, 37.4 mmol; compound of example s) in dichloromethane (0.4 ml) was added MJPBK (of 5.45 mg, 77.9 mmol). The mixture was stirred at ambient temperature for 20 hours Extra is niteline added MJPBK (of 5.45 mg, 77.9 mmol). The reaction mixture was stirred for 48 h at ambient temperature. Added MJPBK (of 5.45 mg, 77.9 mmol) and the reaction mixture was stirred for 3 days at ambient temperature, poured into 25 ml of an aqueous solution of sodium sulfite and extracted with dichloromethane (2×50 ml). The organic layers were washed with saturated aqueous solution of sodium bicarbonate (3×15 ml). The combined organic layers were washed with brine (2×25 ml), dried over sodium sulfate and filtered. The solvent was removed in vacuum and received 15 mg of colorless oil. The crude substance was purified using preparative thin-layer chromatography (silica gel, dichloromethane/Meon) and obtained the desired compound (2 mg, 3.4 mmol; 9%) as a colourless oil. MS (IER): m/z = 518,2 [M+H]+.

Example 480

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 392, (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid (example 385b) were introduced in the reaction with 2,2,2-triptoreline (registration number CAS 75-89-8 99) and got the desired compound as a colourless solid. MS (IER): m/z = 586,0 [M+H] +.

Example 481

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 389, (2S,4R)-4-(2-chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (example 464d) were introduced in the reaction with 1-tert-butylpiperazine (registration number CAS 38216-72-7) and got the desired compound as a colourless oil. MS (IER): m/z = 658,4 [M+H]+.

Example 482

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 392, (2S,4R)-4-(2-chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (example 464d) were introduced in the reaction with 2,2,2-triptoreline (registration number CAS 75-89-899) and got the desired compound after purification using preparative chiral HPLC as a colorless oil. MS (IER): m/z = 616,1 [M+H]+.

Example 483

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(3,3-diversecity-1-yl)-benzazolyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-CT is about acid

a) Methyl ester of (2S,4R)-4-(2-chloro-4-perpenicular)-1-(3-methyl-1-phenethyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 192h, (2S,4R)-methyl-4-(2-chloro-4-perpenicular)-1-(3-oxobutanoic)pyrrolidin-2-carboxylate (example a) were introduced in the reaction with 2-penicillinresistant (registration number CAS 56-51-4) and got the desired compound as a yellow oil. MS (IER): m/z = 506,1 [M+H]+.

b) (2S,4R)-4-(2-Chloro-4-perpenicular)-1-(3-methyl-1-phenethyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chloro-4-perpenicular)-1-(3-methyl-1-phenethyl - 1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow foam substance that is used in the next stage without additional purification. MS (IER): m/z = 492,1 [M+H]+.

c) (2S,4R)-4-(2-Chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-phenethyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide

According to the method similar to that described in example 237, (2S,4R)-4-(2-chloro-4-perpenicular)-1-(3-methyl-1-phenethyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and D is EA and got the desired compound in the form of almost white foam substance. MS (IER): m/z = 556,2 [M+H]+.

d) (1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(3,3-diversecity-1-yl)-benzazolyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 389, (2S,4R)-4-(2-chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-phenethyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamid introduced into reaction with 3,3-diversityconservation (registration number CAS 288315-03-7) in acetonitrile at 90°C for 48 h, and was obtained the desired compound in the form of almost white foam substance. MS (IER): m/z = 629,2 [M+H]+.

Example 484

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 392, (2S,4R)-4-(2-chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-phenethyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (example C) were introduced in the reaction with 2,2,2-triptoreline (registration number CAS 75-89-899) and got the desired compound as a colourless oil. MS (IER): m/z = 636,2 [M+H]+.

Example 485

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

By the method similar to opican the th in example 392, (2S,4R)-4-(2-chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-phenethyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (example C) were introduced in the reaction with 1-tert-butylpiperazine (registration number CAS 38216-72-7) and got the desired compound as a colourless oil. MS (IER): m/z = 678,3 [M+H]+.

Example 486

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-pyrrolidin-2-carboxylic acid

a) Methyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid (example a) were introduced in the reaction with 3,5-dichloro-[1,2,4]thiadiazole (registration number CAS 2254-88-8) swinging the reactor at 55°C for 48 h, and was obtained the desired compound as a red oil. MS (IER): m/z = 422,0 [M+H]+.

b) (2S,4R)-4-(2-Chlorobenzenesulfonyl)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example I, methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-pyrrolidin-2-carboxylic acid omilami in the presence of lithium hydroxide and obtained the desired compound as a yellow oil, which was used in the next stage without additional purification. MS (IER): m/z= 406,0 [M-N] -.

c) (1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-pyrrolidin-2-carboxylic acid were introduced into a reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound as a white solid. MS (IER): m/z = 472.0 M. [M+H]+.

Example 487

(1-Cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 392, (2S,4R)-4-(2-chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (example 464d) were introduced in the reaction with 2,2,2-triptoreline (registration number CAS 75-89-899) and got the desired compound after purification using preparative chiral HPLC as a colorless oil. MS (IER): m/z = 616,1 [M+H]+.

Example 488

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-methoxyethoxy)-benzazolyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described is Oh in example 392, (2S,4R)-4-(2-chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (example 464d) were introduced in the reaction with 2-methoxyethanol (registration number CAS 109-86-4) and got the desired compound as a colourless oil. MS (IER): m/z = 592,2 [M+H]+.

Example 489

(1-Cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-methoxyethoxy)-benzazolyl]-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 392, (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid (example 385b) were introduced in the reaction with 2-methoxyethanol (registration number CAS 109-86-4) and got the desired compound as a colourless oil. MS (IER): m/z = 562,2 [M+H]+.

Example 490

(1-Cyanocyclohexyl)-amide 2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 416, (2S,4R)-4-(2-chloro-4-perpenicular)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide (example 464d) were introduced in the reaction with pyrazole (registration number CAS 288-11-9) and got the desired compound in the form of colourless what about the oil. MS (IER): m/z = 584,2 [M+H]+.

Example 491

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 392, (1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid (example 385b) were introduced in the reaction with pyrazole (registration number CAS 288-11-9) and got the desired compound as a colourless oil. MS (IER): m/z = 554,3 [M+H]+.

Example 492

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid

According to the method similar to that described in example 237, (2S,4R)-4-(2-chloro-4-perpenicular)-1-(3-methyl-1-phenethyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid (example 484b) were introduced in the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of almost white foam substance. MS (IER): m/z = 556,2 [M+H]+.

Example 493

(1-Cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid

According to the technique, anal is the same as described in example 237, (2S,4R)-4-(2-chloro-4-perpenicular)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxylic acid (example C) were introduced in the reaction with 1-aminocyclohexanecarboxylic (registration number CAS 127946-77-4) in the presence of HATU and DIEA and got the desired compound in the form of an almost white solid. MS (IER): m/z = 536,1 [M+H]+.

Example 494

Study of the inhibition of the enzyme cathepsin.

Enzymatic activity was determined by the increase in fluorescence intensity caused by the cleavage of the peptide substrate containing the fluorophore, the emission of which extinguished the intact peptide.

The buffer for the study: 100 mm potassium phosphate pH 6.5, Na salt of ethylenediaminetetraacetic acid, 5 mm, Triton X-100 0,001%, 5 mm DDT.

Enzymes (all 1 nm): human and mouse cathepsin S, Cat, Cat, Cat L. Substrate (20 μm): Z-Val-Val-Arg-AMC, except for the Cat, for which the use of Z-Leu-Arg-AMC (both produced by the company Bachem).

Z = benzyloxycarbonyl.

AMC = 7-amino-4-methylcoumarin.

Final volume: 100 μl.

The wavelength of excitation 360 nm, the wavelength of emission of 465 nm.

The enzyme was added to the diluted compounds in 96-well tablets for micrometrology and the reaction was started with the substrate. The emitted fluorescence was measured for 20 min and during this time, in the absence of inhibitor, there is a linear increase in intensity. C 50calculated by standard methods. The results, expressed in microns, is presented in the table below.

According to the study of the compounds proposed in the present invention are characterized by the values of the IC50for cathepsin S, equal from 0.00001 to 100 μm, preferably from 0.00001 to 50 μm, more preferably from 0.00001 to 20 microns.

According to the study of the compounds proposed in the present invention are characterized by the values of the IC50for cathepsin L, is equal to from 0.00001 to 200 microns, preferably from 0.00001 to 100 μm, more preferably from 0.00001 to 80 microns.

ExampleCathepsin SCathepsin LExampleCathepsin SCathepsin L
IC50IC50IC50IC50
10,015252480,0005554,675
20,043525 2490,00025525,81
30,011252500,0003471,55
40,005216,52510,000291,25
50,00089,77332520,0017525
60,0385252530,00111,3825
70,0027252540,000832,265
80,0007252550,0056550
90,0006252560,0026 45,725
100,0007252570,00019548,21
110,03252580,0001958,04
120,01842,232590,0001979,525
130,0465252600,00024516,545
140,0032252610,01227,04
150,00454,9252620,0044of 28.72
160,0132252630,00033
17to 0.032252640,000495scored 8.38
180,003330,292650,001352,05
190,0013252660,001322,14
200,001252670,00237,81
210,000840,792680,0023547,32
220,0005252690,001675,07
230,0009252700,00039525
240,0026252710,0017585,59
250,0023252720,000617,1
260,0028252730,000290,00806
270,0022252740,0009359,135
280,0015252750,000382,685
290,000839,862760,0003929,4325
300,003252770,000140,445
31 0,002252780,0000032,75

ExampleCathepsin SCathepsin LExampleCathepsin SCathepsin L
IC50IC50IC50IC50
320,005252790,000021,31
330,6752252800,024546,54
340,7656252810,000280,145
354,0976252820,000240,27
360,00051,2752830,000120,024
371,03252840,000070,463333
380,005252850,0002272,6
390,002250,212860,01550
400,005241,412870,0001753,165
410,0312252880,000083,48
420,0059,432890,00038535,095
43 0,0022252900,000131,6
440,1515252910,01466750
450,3783252920,0001574,13
460,2078252930,000181,4
470,00142940,0003537,835
480,235252950,000030,925
490,00186,922960,0001231,183333
500,0044 8,772970,000081,336667
510,026252980,000221,58
520,014252990,000171,176667
530,0052253000,00088550,74
540,215,343010,000121,535
550,0148253020,000030,575
560,0427253030,00003of 1.485
570,014316,97670,0004450,805
580,001627,363050,01966750
590,001812,1553060,00055564,47
600,000512,793070,00020552,125
610,001222,4653080,00074525
620,001221,0253090,036525

ExampleCathepsin SCathepsin LExampleCathepsin SCathepsin L
IC 50IC50IC50IC50
630,1253100,000260,22
640,109253110,0001550,745
650,0006253120,000195
660,0006253130,000461,39
67is 0.0002253140,000371,68
680,0003253150,000392,5
690,000425 3160,00035,236667
700,001625,1753170,0228225
710,0005253180,00043711,32333
720,0008253190,00143340,82333
730,0127253200,080525
740,0066253210,06833325
750,00086,78673220,000328,48333
760,00148,8323 0,000444,816667
77is 0.00028,25333240,00009
780,0185253250,00008
790,001429,7153260,00018
800,00089,77333270,000175
810,00326,0353280,000160,13
820,00876,83290,000115
830,030562,153300,00008
840,055253310,000181,055
850,0094253320,0001950,58
860,023of 14.573330,0019around 7.985
870,03754,71673340,7825
880,275253350,00048425
890,11253360,00033
900,0845253370,0016513,04
910,12253380,37525
920,04161,723390,062525
930,9655253400,00097526,405

ExampleCathepsin SCathepsin LExampleCathepsin SCathepsin L
IC50IC50IC50IC50
940,94539,9853410,1525
950,0076253420,00008 0,0495
960,002631,54333430,09933325
970,002422,793440,0005425
980,001115,67673450,00091570,28
990,0026253460,0001010,0285
1000,0077253470,0008550,06
1010,0067253480,000170,051
1020,0036253490,000030,22
1030,001625350of 0.000060,26
104is 0.0002253510,019525
1050,0003253520,000257,225
1060,0004253530,0009913,475
1070,02516,643540,00017525
1080,005847,7053552,4525
1090,012725356of 0.0000631,77
110 0,0605253570,017525
1110,0007253580,000525
1120,0008253590,000671,05
1133,135253600,0001851,1825
1143,505253610,000020,995
1150,0483,473620,3825
1160,0355253630,001510,775
1170,086525 3640,29525
1180,0009253650,2425
1190,0071253660,00032725
1200,0028253670,00156725
1210,004123,6953680,000210,266667
1220,009423,8153690,000070,026333
1232,61253700,000070,021667
124of 0.012525 3710,000080,026333

ExampleCathepsin SCathepsin LExampleCathepsin SCathepsin L
IC50IC50IC50IC50
125of € 0.195253720,000080,044333
1261,25253730,000080,042667
1270,0025,9953740,000070,050333
1280,0014the 17.33750,00029lower than the 5.37
1290,008/td> 20,423760,0006571,756667
1300,0024253770,000240,293333
1310,000933,933780,00010,2
1320,003834,9553790,001752,71
1330,000923,363800,000050,13
1340,0062253810,0002950,1015
1350,00033,153820,000040,068
1360,0022 12,5653830,01419,995
1370,001253840,000050,1
1380,003428,63850,000546,46
1390,0078253860,001754,025
1400,005924,533870,006752,455
1410,0006of 3.463880,0004835,61
1420,00032,48389is 0.0002of 8.06
1430,004328,075 3900,000830,12
1440,009728,20333910,0002216,74
1450,000611,7553920,0009125
1460,006425,53673930,0037525
1470,000413,6443940,0029525
1480,016253950,15525
1490,00078,10333960,0016557,46
1500,001727,9367397 0,0004357,2
1510,0058253980,00055518,805
1520,002230,833990,00098>25
1530,002543,984000,003325
1540,00186,634010,000461,076667
1550,00258,324020,001425

177
ExampleCathepsin SCathepsin LExampleCathepsin SCathepsin L
IC50 IC50IC50IC50
1560,00044,3954030,00049
1570,00044,4054040,000405
1580,12254050,00093525
1592,605254060,00425
1600,006254070,038525
1610,00046,0654080,04225
1620,023525409 2,5325
1630,00032,624100,004829,71
1640,0008254110,0005250,55
1650,1097254120,002750,785
1660,0006254130,000311,095
1670,001417,4454140,000295the 5.45
1680,00068,79754150,00021511,67
1690,00047,5854160,000338 21,415
1700,00118,384170,002450,0555
1710,007254180,0041,62
1720,00048,934190,00041516,885
1730,005927,334200,00039514,05
1740,003341,51334210,01154,955
1750,0004915,87334220,001854,36
1760,0009835,8254231,4725
0,000295,83334240,4125
1780,00016being 0.0364250,000260,335
1790,0004217,63334260,000470,045
1800,0004721,374270,000510,095
1810,003716,47334280,0004150,335
1820,0097254290,0003650,46
1830,000449,66824300,000822,59
184 to 0.032254310,0008750,13
1850,0032254320,0005950,115
1860,0034254330,001950,945

ExampleCathepsin SCathepsin LExampleCathepsin SCathepsin L
IC50IC50IC50IC50
1870,0463254340,00123,44
1880,006416,724350,0005350,525
1890,665254360,000480,109
1900,00155,15674370,001450,335
1910,107254380,000520,13
1920,000543,744390,0008950,0295
193is 0.000228,544407,47525
1940,000416,5854410,085525
1950,0036254420,0006150,24
196 0,000341,394430,0006050,022
1970,000919,02334440,0008950,26
1980,027254450,72525
1990,00057,744460,0002750,0215
2000,0467254476,1325
2010,003425448of 8.3725
2020,00010,60644910,4725
2030,0008 was 9.334500,67525
2040,205254510,0007586,375
205is 0.000271,994520,0011687,925
206is 0.0002254530,84525
2070,0003254541,66525
2080,0008254550,07725
209is 0.0002254560,0007253,995
2100,00042545 34,015460,53
2110,000363,86245861,855
2120,0003254590,0005050,0065
2130,00047,96674600,005850,0525
2140,0005of 11.264610,0009850,0225
215is 0.00020,0224629,495>25
216is 0.00020,2854635,13>25
2170,000713,9567464 0,001153,02

ExampleCathepsin SCathepsin LExampleCathepsin SCathepsin L
IC50IC50IC50IC50
2180,000414,55334650,003052,74
2190,000312,644668,695% at 25 ám
2200,000417,84672,0895% at 25 ám
2210,13254680,506596% at 25 ám
2220,0012 18,59674690,8497% at 25 ám
2230,00010,0454702,79594% at 25 ám
224is 0.000214713,6996% at 25 ám
2250,001218,28472
2260,000613,554730,07to 4.41
2270,000615,57334740,00241,54
2280,000915,3767475
2290,01466723,8833 4760,00664,76
2300,01533314,834770,00060,3185
2310,0005>254780,0031to 3.67
2320,0002112,764790,00324of 3.07
2330,00046521,0954800,001055,365
2340,001567254810,00061,275
2350,000950,554820,0007652,71
2360,2425 4830,001340,521
2370,000168254840,003311,547
2380,0000520,824850,00090,275
2390,000080,0844860,0008521,95
2400,000090,59487
2410,0003331,824880,00253,88
2420,004751,434890,000513,538
2430,00045512,275490 0,000944,33
2440,003155,94910,0006555,285
2450,00016839,165492
2460,0002450,185493
2470,0003853,44

Example

The compound of formula (I) can be used in known manner as an active ingredient for the preparation of tablets of the following composition:

For one pill

The active ingredient200 mg
Microcrystalline cellulose155 mg
Corn starch25 mg
Talc 25 mg
The hypromellose20 mg
425 mg

The example In

The compound of formula (I) can be used in known manner as an active ingredient for the preparation of capsules of the following composition:

For one capsule

The active ingredient100.0 mg
Corn starch20.0 mg
Lactose95,0 mg
Talc4.5 mg
Magnesium stearate0.5 mg
220,0 mg

1. The compound of formula (I)

in which
R1denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cycloalkyl, cycloalkenyl, alkylsilanes, halogenallylacetic, phenylcyclohexyl, halogenosilanes, phenylalanyl, halogennitroalkane, alkoxycarbonylmethyl, cyanoacrylates, halogenfrei, pyridinylmethyl, aminocyclohexanol, amino shall urbanistically, halogensilberemulsionen, alkylphenolethoxylates, bis(halogenfree)alkyl, phenylcyclohexyl, alkylresorcinols, halogennitroalkane, halogenerator, aftercollege, halogenbenzonitriles, benzo[1,3]dioxole, naftiliaki, halogen-1H-indazole, galogenangidridy, (halogenfree)(alkoxycarbonyl)alkyl, alkylresorcinols, halogenopyrimidines, (halogenfree)(amino)alkyl, (halogenfree)(halogenosilanes)alkyl, halogenallylacetic, (halogenfree)(alkoxycarbonylmethyl), (halogenfree)(morpholinyl)alkyl, halogenanlagen, alkylresorcinols, hydroxyalkyloxy, (halogenfree)(alkanolamine)alkyl, alkoxycarbonylmethyl, gamogenetically, galopenforceskyblogcom, vinyltetrahydrofuran or R11;
A denotes-CH2-, -CH2CH2-, carbonyl, -C(O)O-, -SO2- or is absent;
R2denotes hydrogen, alkyl, halogenated, cycloalkyl, phenyl, phenylalkyl or phenylsulfonyl;
or A, R1and R2together form-CH2CH2-, -CH2CF2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-; -CH2CH2OCH2- or-CH2CH2CH(CN)-;
R3denotes alkyl, hydroxyalkyl, cycloalkyl, phenyl, phenylalkyl alsamixergui phenyl, where the substituted phenyl is a phenyl containing from 1 to 3 substituents independently selected from the group comprising alkyl, halogenated, hydroxyalkyl, alkoxygroup, halogenaryloxy, halogen, pyrazolyl, alkylphenolic, imidazolyl, benzoimidazolyl, 6-oxo-6H-pyridazinyl, alkyl-6-oxo-6H-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, ecomorphology, oxopyridine, 2-oxo-2H-pyrazinyl, ceftobiprole, galogenangidridy, piperidinecarboxylate, acetamidoxime, alkylphenolic, halogenopyrimidines, alkylpyridine, cycloalkyl, cycloalkenyl, halogenfree, alkylarylsulphonates, halogenatedbiphenyls, alkylamino, alkoxycarbonyl, cycloalkylcarbonyl, hexahydropyrazino[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, alkylimidazole, azetidine, cycloalkylcarbonyl, alkylimidazole, alkoxyalkyl, imidazo[4,5-c]pyridinyl, alkylpiperazine, hexahydropyrazino[1,2-a]pyrazinyl, halogenations, pyrimidinyl and alkenylacyl;
R4denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cycloalkyl, cycloalkylation, phenyl, alkylphenyl, halogenfree, fenoxaprop or halogenerator;br/> R5and R6independently selected from the group comprising hydrogen, alkyl, cycloalkyl, alkyloxy, hydroxyalkyl, halogenated, halogenaryloxy, phenyl and phenylalkylamine;
or R5and R6together with the carbon atom to which they are attached, form cycloalkyl, pyrrolidinyl or piperidinyl; and
R11denotes phenyl, substituted phenyl, tetrahydropyranyl, pyridinyl, alkylpyridine, galgenlieder, oxetanyl, alkyloxyaryl, pyrrolidinyl, alkylpyridine, pyrimidinyl, halogensilberemulsionen, alkylpiperidines, naphthyl, biphenyl, halogenated-[1,3,4]thiadiazolyl, alkoxycarbonylmethyl, halogen-[1,2,4]thiadiazolyl, pyrazolyl or substituted pyrazolyl, where the substituted phenyl and substituted pyrazolyl represent phenyl and pyrazolyl, each of which contains from 1 to 3 substituents independently selected from the group comprising alkyl, halogen, halogenated, alkoxygroup, alkoxycarbonyl, halogenfree, halogenopyrimidines, oxopiperidine, a nitrogroup, thiazolyl, halogenosilanes, alkylphenyl, phenyl, alkylpyridine, tetrahydropyranyl, pyridinyl, cycloalkyl, phenylalkyl, oxazolyl, alkoxyphenyl, chinoline, allylcarbosilane, halogenlampe, alkylsulfonyl, generalquartiermeister, piperidinyl, tiopronin, dioxathiapine, m is hollinrake and alkylimidazole;
or its pharmaceutically acceptable salt.

2. Connection on p. 1, in which
R1denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cycloalkyl, cycloalkenyl, alkylsilanes, halogenallylacetic, phenylcyclohexyl, halogenosilanes, phenylalanyl or R11;
A denotes-CH2-, -CH2CH2-, carbonyl, -C(O)O-, -SO2- or is absent;
R2denotes hydrogen, alkyl, halogenated, cycloalkyl, phenyl or phenylalkyl;
or A, R1and R2together form-CH2CH2-, -CH2CF2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- or-CH2CH2OCH2-;
R3denotes alkyl, hydroxyalkyl, cycloalkyl, phenyl or substituted phenyl, where the substituted phenyl is a phenyl containing from 1 to 3 substituents independently selected from the group comprising alkyl, halogenated, hydroxyalkyl, halogenaryloxy, halogen, pyrazolyl, imidazolyl, benzoimidazolyl, 6-oxo-6H-pyridazinyl, alkyl-6-oxo-6H-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, ecomorphology, oxopyridine, 2-oxo-2H-pyrazinyl, ceftobiprole, galogenangidridy, piperidinecarboxylate and acetamidoxime is;
R4denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cycloalkyl, cycloalkylation, phenyl, halogenfree, fenoxaprop or halogenerator;
R5and R6independently selected from the group comprising hydrogen, alkyl, cycloalkyl, alkyloxy, hydroxyalkyl, halogenated, halogenaryloxy, phenyl and phenylalkylamine;
or R5and R6together with the carbon atom to which they are attached, form cycloalkyl, pyrrolidinyl or piperidinyl; and
R11denotes phenyl, substituted phenyl, tetrahydropyranyl, pyridinyl, alkylpyridine, galgenlieder, oxetanyl, pyrrolidinyl, alkylpyridine, pyrimidinyl, halogensilberemulsionen, alkylpiperidines, pyrazolyl or substituted pyrazolyl, where the substituted phenyl and substituted pyrazolyl represent phenyl and pyrazolyl, each of which contains from 1 to 3 substituents independently selected from the group comprising alkyl, halogen, halogenated, alkoxygroup, alkoxycarbonyl, halogenfree, halogenopyrimidines, oxopiperidine and the nitro-group;
or its pharmaceutically acceptable salt.

3. Connection on p. 1, in which R1denotes hydrogen, alkyl, halogenated, alkoxygroup, alkoxyalkyl, cycloalkyl, cycloalkenyl, alkylsilanes, halogenallylacetic, FeNi is cycloalkyl, halogenosilanes, phenylalanyl or R11where R11is as defined in paragraph 1.

4. Connection on p. 1, in which R1denotes hydrogen, alkyl, foralkyl, finalforce, alkoxygroup, alkoxymethyl, alkylsilanes, divorcecare, cryptomaterial, vinylcyclopropyl, chlorophenylsulfonyl, cyclobutyl, cyclohexyl, cryptometrics, cryptomaterial or cyclopentyloxy.

5. Connection on p. 1, in which R1denotes hydrogen, methyl, ethyl, propyl, butyl, deformity, trifluoromethyl, triptorelin, pentafluoroethyl, cryptochromes, denitrifier, a methoxy group, propyloxy, butylacrylate, methoxymethyl, methylcyclopropyl, divorcecare, cryptomaterial, vinylcyclopropyl, chlorophenylsulfonyl, cyclobutyl, cyclohexyl, cryptometrics, cryptomaterial or cyclopentyloxy.

6. Connection on p. 1, in which R1represents tert-butyl, cryptomaterial, methylcyclopropyl or chlorophenylacetyl.

7. Connection on p. 1, in which A represents-CH2-, -CH2CH2-, carbonyl or absent.

8. Connection on p. 1, in which A denotes a carbonyl.

9. Connection on p. 1, in which R2denotes hydrogen or alkyl.

10. Connection on p. 1, in which R2indicates adored.

11. Connection on p. 1, in which R3denotes alkyl, hydroxyalkyl, cycloalkyl, phenyl or substituted phenyl, where the substituted phenyl is a phenyl containing from 1 to 3 substituents independently selected from the group comprising alkyl, halogenated, halogenlampe, hydroxyalkyl, halogen, pyrazolyl, imidazolyl, benzoimidazolyl, 6-oxo-6H-pyridazinyl, alkyl-6-oxo-6H-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, ecomorphology, oxopyridine, 2-oxo-2H-pyrazinyl, ceftobiprole, triftormetilfullerenov, piperidinyloxy and oceanologique.

12. Connection on p. 1, in which R3denotes alkyl, hydroxyalkyl, cycloalkyl, phenyl or substituted phenyl, where the substituted phenyl is a phenyl containing from 1 to 3 substituents independently selected from the group comprising methyl, trifluoromethyl, tripterocarpa, cryptometer, hydroxymethyl, fluorine, bromine, chlorine, pyrazolyl, imidazolyl, benzoimidazolyl, 6-oxo-6H-pyridazinyl, alkyl-6-oxo-6H-pyridazinyl, piperazinil, N-alkylpiperazine, piperidinyl, differerential, phenylimidazole, oxopyrrolidin, oxoacridine, morpholinyl, ecomorphology, oxopyridine, 2-oxo-2H-pyrazinyl, ceftobiprole, thrift methylpiperidine, piperidinyloxy and oceanologique.

13. Connection on p. 1, in which R3denotes phenyl containing 1 or 2 substituent, independently selected from the group comprising chlorine, trifluoromethyl, cryptometer, tripterocarpa and pyrazolyl.

14. Connection on p. 1, in which R3means dichlorophenyl, (chloro)(pyrazolyl)phenyl, (chloro)(triptoreline)phenyl, (chloro)(cryptochrome)phenyl, triptoreline (triptoreline)(trifluoromethyl)phenyl or chlorophenyl.

15. Connection on p. 1, in which R4denotes hydrogen.

16. Connection on p. 1, in which R5denotes hydrogen, alkyl, cycloalkyl or phenyl.

17. Connection on p. 1, in which R5denotes hydrogen, methyl, cyclopropyl or phenyl.

18. Connection on p. 1, in which R6denotes hydrogen.

19. Connection on p. 1, in which R5and R6together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl or cyclohexyl.

20. Connection on p. 1, in which R5and R6together with the carbon atom to which they are attached, form cyclopropyl.

21. Connection on p. 1, in which R11denotes phenyl, substituted phenyl, tetrahydropyranyl, pyridinyl, alkylpyridine, alkylpyridine, oxetanyl, pyrrolidinyl, alkylpyridine, pyrimidinyl, halogensilberemulsionen, the alkyl is piperidinyl, pyrazolyl or substituted pyrazolyl, where the substituted phenyl and substituted pyrazolyl represent phenyl and pyrazolyl, each of which contains from 1 to 3 substituents independently selected from the group comprising halogenated, halogen, alkoxygroup, alkoxycarbonyl, halogenlampe, halogenated, halogenfree, halogenopyrimidines, oxopiperidine and the nitro-group.

22. Connection on p. 1, in which R11denotes phenyl, substituted phenyl, tetrahydropyranyl, pyridinyl, methylpyrimidine, cryptomaterial, oxetanyl, pyrrolidinyl, methylpyrrolidinyl, pyrimidinyl, cryptomaterial, methylpiperidine, pyrazolyl or substituted pyrazolyl, where the substituted phenyl and substituted pyrazolyl represent phenyl and pyrazolyl, each of which contains from 1 to 3 substituents independently selected from the group comprising methyl, fluorine, methoxy group, methoxycarbonyl, cryptometer, trifluoromethyl, chlorophenyl, forfinal, chloropyridinyl, oxopiperidine and the nitro-group.

23. Connection on p. 1, in which R11denotes phenyl, forfinal, chlorophenyl, methoxyphenyl, ethoxycarbonylphenyl, triptoreline, nitrophenyl, tetrahydropyranyl, pyridinyl, methylpyrimidine, cryptomaterial, oxetanyl, pyrrolidinyl, methylpyrrolidinyl, pyrimidinyl, cryptomaterial, IU ipipeline, pyrazolyl, methylvinylpyridine, globaldeleteatom, chlorophenylpiperazine, performativity or oxodehydroepiandrosterone.

24. A compound selected from the group including:
cyanomethylene (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid;
cyanomethylene (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid;
cyanomethylene (2S,4R)-4-benzazolyl-1-cyclohexylpiperidine-2-carboxylic acid;
cyanomethylene (2S,4R)-4-benzazolyl-1-(2,2,2-Cryptor-1-phenylethyl)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-4-benzazolyl-1-cyclohexanecarbonitrile-2-carboxylic acid;
cyanomethylene (2S,4R)-1-benzoyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-benzylpyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-(tetrahydropyran-4-carbonyl)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-Cryptor-1-phenylethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-perbenzoic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-cyclohexanol is of IMT-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(4-perbenzoic)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(4-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2,3,3,3-pentafluoropropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-benzoyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexanecarbonitrile-2-carboxylic acid;
ethyl ester of (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
cyclopentyloxy ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
4-forfinally ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-pyridin-4-iletilenlerin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-ethylpyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-phenotypically-2-carboxylic to the slots;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclobutylmethyl-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexylpiperidine-2-carboxylic acid;
(1-cyanocyclohexyl)-methylamide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-methylpyrrolidine-2-carboxylic acid; salt with formic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-triptorelin)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2-dottorati)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-perbenzoic)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-cyclohexanecarbonitrile-2-carboxylic acid;
cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-propenylboronic-2-carboxylic acid;
cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-methoxyacetyl)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-oxetan-3-iparralde-2-carboxylic acid;
cyanomethylene (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(tetrahydropyran-4-yl)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-1-benzoyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-1-(4-perbenzoic)-4-(2-trifloromethyl)-pyrrole the h-2-carboxylic acid;
cyanomethylene (2S,4R)-1-(4-methylbenzoyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-1-(tetrahydropyran-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-1-(pyridine-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-1-(1-methylpiperidin-4-carbonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
cyclopentyloxy ester (2S,4R)-2-(cyanomethylene)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,3,3,3-pentafluoropropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-Cryptor-2-methylpropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-cryptochromes)-pyrrolidin-2-carboxylic acid;
cyanomethylene 6-benzazolyl-2,2-divorceregistration-7a-carboxylic acid;
cyanomethylene 1-benzazolyl-6,6-divorceregistration-7a-carboxylic acid;
cyanomethylene 1-benzazolyl-6,6-divorceregistration-7a-carboxylic acid;
(1 lanecyklar who drank)-amide (2S,4R)-1-acetyl-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
methyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
isopropyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2,2-TRIFLUOROACETYL)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dimethylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(cianfanelli)-carbarnoyl]-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(cyanomethylene)-carbarnoyl]-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-benzyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-pyridin-4-ylmethyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-chloro-2-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(cianfanelli)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic key is lots;
(cyanomethylene)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2,2-TRIFLUOROACETYL)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-methylpyrrolidine-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-[(centimetres)-carbarnoyl]-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexyl)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(centimetres)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,3-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (R)-4-(2-chlorobenzenesulfonyl)-1-((S)-1-metier ridin-2-carbonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-propionyl 4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-methylpiperidin-4-carbonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-methoxyethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-ethylbenzonitrile)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,6-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-hydroxymethanesulfinic)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-hydroxymethanesulfinic)-pyrrolidin-2-carboxylic acid;
methyl ester of 4-[(2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carbonyl]-benzoic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-phenyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic key is lots;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2,4-differentiality)-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(4-imidazol-1-eventality)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-differentiality)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-2-[(cyanocobalamin)-carbarnoyl]-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-imidazol-1-eventality)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-(4-bromo-2-trifloromethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-formylpyridine-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-chloro-4-piperidine-1-ylbenzyl Lionel)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4S,5R)-5-(4-forfinal)-2-isobutyl-4-methanesulfonamide-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-chloro-4-permentantly)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2R,4S,5R)-2-(1-cyanocyclohexane)-5-(4-forfinal)-2-isobutyl-4-methanesulfonamido-1-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4S,5R)-4-benzazolyl-5-(4-forfinal)-2-isobutylpyrazine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-formyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-(4-benzimidazole-1-yl-2-trifloromethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
tert-Buti is inhibiting ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(3-methyl-6-oxo-6H-pyridazin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-[2-chloro-4-(3,3-debtorprovidian-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chloro-4-piperidine-1-eventality)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(2-chloro-4-permentantly)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-benzimidazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(3,3-debtorprovidian-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid;
methyl ester of 4-[(2S,4R)-2-(cyanomethylene)-4-(2-trifloromethyl)-pyrrolidin-1-carbonyl]-benzoic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(3-methyl-6-oxo-6H-pyridazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-4-[2-chloro-4-(2-piperidine-1-ylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-Mei-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-phenylimidazol-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-oxopyrrolidin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-oxoacridine-3-yl)-2-trifloromethyl solarpanel]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(3,3-debtorprovidian-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-(morpholine-4-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(3-exmortis-4-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-oxo-2H-pyridin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-oxo-2H-pyrazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-formylpyridine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(4-imidazol-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-acetyl-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-forbindelse hanil)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperidine-1-eventality)-1-formylpyridine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-formylpyridine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-formylpyridine-2-carboxylic acid;
cyanomethylene (2S,4R)-1-phenyl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-[2-chloro-4-(4,4-deformability-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
tert-butyl ester (2S,4R)-4-[2-chloro-4-(4-triftormetilfosfinov-1-yl)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-triftormetilfosfinov-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (S,4R)-4-[2-chloro-4-(4,4-deformability-1-yl)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-triftormetilfosfinov-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4,4-deformability-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide(2S,4S)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(4-methoxyphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-morpholine-4-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-4-(2-chloro-4-morpholine-4-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-piperazine-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
cyanomethylene (2S,4R)-1-(2-nitrophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic what Islami;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-nitrophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(2-nitrophenyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-triftoratsetilatsetonom)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(2,2-divorcecelebration)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-[2-chloro-4-(oxetan-3-yloxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-x is the PR-4-(2,2,2-triptoreline)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-isobutylpyrazine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(3-methylbutyryl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(oxetan-3-yloxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-formylpyridine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(2-cryptomaterial-4-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-CT is about acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-4-(2-trifloromethyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-ethylpiperazin-1-yl)-benzazolyl]-1-(3-triptorelin-2-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-phenyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-chlorophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-forfinal)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2-oxo-1,2-dihydropyridines-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-PI is Raiden-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-cyclopropanecarbonitrile-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-cyclopropanecarbonitrile-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(oxetan-3-yloxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl) s is (2S,4R)-4-(2-trifloromethyl)-1-(3,3,3-triptocaine)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-2-(1-cyanocyclohexane)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2-dimethylpropanoyl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2-dimethylpropanoyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-phenylcyclopropanecarboxylic)-pyrrolidin-2-Carbo the OIC acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-isobutylpyrazine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3,3,3-triptocaine)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-methylbutyryl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-[4-chloro-2-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2,4-dichlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-isobutylpyrazine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3,3,3-triptocaine)-pyrrolidin-2-carboxylic acid; and
(1-cyanocyclohexyl) s is (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(3-methylbutyryl)-pyrrolidin-2-carboxylic acid.

25. A compound selected from the group including:
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2,4-dichlorobenzenesulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(2,2-dimethylpropionic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(1-triftormetilfullerenov)-PI is Raiden-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,2-dimethylpropanoyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid; and
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid.

26. A compound selected from the group including
tert-butyl ester (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2-oxo-1,2-dihydropyridines-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-chlorophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-thiazol-2-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1 cyanotic propyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2,4-differentiality)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2-methylpropan-1-sulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(1-methyl-1H-pyrazole-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(3,4-dichlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2,2-divorcecelebration)-pyrrolidin-2-carboxylic acid;
tert-butyl ether ({1-[(2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carbonyl]-cyclopropyl}-carbamino acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-cyanocyclohexane)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-chlorophenyl)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic KIS is the notes;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-chloropyridin-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-phenylcyclopropanecarboxylic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-methylpyridin-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(1-methyl-1H-pyrazole-4-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-pyridine-4-enciclopediaper)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2,2-debtor-2-phenylacetyl)-pyrrolidin-2-carboxylic acid;
4-hlorfenilovy ester (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1 zionazi sapropel)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-cyclopropyl-2-trifloromethyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2-methylpyridin-4-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-chloropyridin-4-yl)-2-trifloromethyl]-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2',4'-debtor-3-triptorelin-4-sulfonyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-benzazolyl-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2',4'-debtor-3-triptorelin-4-sulfonyl)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
tert-butyl ester (4-{2-[(2S,4R)--[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-2-(1-cyanocyclohexane)-pyrrolidin-1-yl]-2-oxoethyl}-cyclohexyl)-carbamino acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-aminocyclohexane)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromo-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-cyclopropyl-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-bromophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl) s the d (2S,4R)-1-[2-(4-acetylaminophenol)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2,2-bis-(4-chlorophenyl)-acetyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-m-tolyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-carbamoylphenoxy)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclobutanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R-)-1-[2-(4-chlorophenyl)-2-methylpropionyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4S)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-trifloromethyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-methylpropionyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclobutanecarbonyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(3,4-DIH arvanil)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-pyridine-4-enciclopediaper)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-1H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(4-vinyltetrahydrofuran-4-carbonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-{1-[4-(1-methyl-1H-pyrazole-4-yl)-phenyl]-cyclopropanecarbonyl}-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(2-methylpyridin-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-{2-chloro-4-[4-(2,2,2-triptorelin)-piperazine-1-yl]-benzazolyl}-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-dimethylaminobenzylidene)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-isopropylpiperazine-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid; (1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(3-methyloxiran-3-carbonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(4-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-{2-chloro-4-[4-(2-methoxyethyl)-piperazine-1-yl]-benzazolyl}-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-cyclopropylmethyl-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-((S)-2-chloro-4-hexahydropyrazino[1,2-a]pyrazin-2-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2,5-dimethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopentanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-phenylcyclohexanecarboxylic)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-p-tooltipcontent)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-isopropyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(4-triptoreline)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[1-(3-triptoreline)-Cyclops percarbonic]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclohexanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(biphenyl-4-sulfonyl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-pyridazin-3-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl) s is (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(4-oxazol-5-eventality)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazol-1-eventality)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-Mei-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(2-chloro-4-pyrazole-1-eventality)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-azetidin-1-yl-2-chlorobenzenesulfonyl)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-cyclopropylmethyl-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(3-chlorophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyan is cyclopropyl)-amide (2S,4R)-1-[1-(3-bromophenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-1-[2-(3-methoxyphenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-trifloromethyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-isopropylimidazole-1-yl)-benzazolyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-tert-butyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2-methoxyethoxy)-benzazolyl]-1-[1-(4-chlorphen is)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide 1-biphenyl-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide 1-naphthalene-1-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(4-bromophenyl)-[1,3]dioxolane-2-carbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-naphthalene-1-enciclopediaper)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(1-naphthalene-2-enciclopediaper)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazo[4,5-c]pyridine-1-eventality)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazo[4,5-C]pyridine-5-eventality)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-quinoline-4-yl-2H-pyrazole-3-yl)4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide 4-(2-trifloromethyl)-1-(3-triptoreline)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide 1-(2-tert-butylphenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-1-[2-(3-acetamidophenyl)-5-methyl-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide 1-(3-cyanophenyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclobutanecarbonyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide 1-(tetrahydropyran-4-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[5-cyclopropyl-(4-triptoreline)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
tert-butyl ester 4-[2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-yl]-piperidine-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropylmethyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide 1-(3-trifloromethyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-isopropylpiperazine-1-yl)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-{2-chlorine�-4-[4-(2-methoxyethyl)-piperazine-1-yl]-benzazolyl}-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-((S)-2-chloro-4-hexahydropyrazino[1,2-a]pyrazin-2-eventality)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-cyclopropylmethyl-1-yl)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid; compound with formic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-methoxybenzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chloro-4-methoxybenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (R)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (R)-4-[2-chloro-4-(2-methoxyethoxy)-benzazolyl]-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-pyrazole-1-eventality)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(6-chlorp ridin-3-yl)-cyclopropanecarbonyl]-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-imidazol-1-eventality)-1-[1-(6-chloropyridin-3-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (6R,7aS)-6-(2-chloro-4-permentantly)-1-cyano-tetrahydropyrazin-7a-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-benzo[1,3]dioxol-5-enciclopediaper)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chloro-4-permentantly)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-pyrrolidin-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-chloro-4-methoxybenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-fluoro-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-naphthalene-1-yl-[1,3]dioxolane-2-carbonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cycle is butyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-methyl-5-(tetrahydropyran-4-yl)-1H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide and (2R,4S)-1-(3-chloro-4-forfinal)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-fluoro-2-trifloromethyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-cyclobutyl-5-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-cyclopropyl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(4-methylpiperazin-1-yl)-benzazolyl]-1-(2-what kilobytes-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(3-methanesulfonyl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(3,3-diversecity-1-yl)-2-trifloromethyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-methylpiperazin-1-yl)-2-trifloromethyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
benzyl ether of 4-{5-[(2S,4R)-2-(1-cyanocyclohexane)-4-(2-trifloromethyl)-pyrrolidin-1-yl]-3-methylpyrazole-1-yl}-piperidine-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(5-methyl-2-piperidine-4-yl-2H-pyrazole-3-yl)-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-pyrimidine-2-yl-4-(2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-methanesulfonamide-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(6-chloro-1H-indazol-3-carbonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[(R)-2-(4-chlorophenyl)-2-hydrox the acetyl]-pyrrolidin-2-carboxylic acid;
tert-butyl ester [(R)-2-[(2S,4R)-4-(2-chlorobenzenesulfonyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-yl]-1-(4-chlorophenyl)-2-oxoethyl]-carbamino acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-methylthiazole-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(5-chloropyridin-2-yl)-acetyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-[4-(3,3-diversecity-1-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-(pyrazole-1-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[(R)-2-amino-2-(4-chlorophenyl)-acetyl]-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-Chlorobenzyl)-5-methyl-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-(4-pyrimidine-4-yl-2-trifloromethyl)-pyrrolidin-2-carboxylic acid;
(2S,4R)-N-(1-cyanocyclohexyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)-4-(4-(1-methyl-1H-pyrazole-5-yl)-2-(trifluoromethyl)phenylsulfonyl)pyrrolidin-2-carboxamide;
(1-cyanocyclohexyl)-amide (R)-4-(2-chlorobenzenesulfonyl)-1-[2-(chlorphenyl)-2-(2,2,2-triptoreline)-acetyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(3-cryptomaterial-1-yl)-acetyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-cyclopropanesulfonyl-2-carboxylic acid;
(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-(4-forfinal)cyclopropanecarbonyl)pyrrolidin-2-carboxamide;
(2S,4R)-1-(1-(4-bromophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;
(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-(4-(trifluoromethyl)phenyl)cyclopropanecarbonyl)pyrrolidin-2-carboxamide;
(2S,4R)-1-(1-(3-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;
(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-(3-(trifluoromethyl)phenyl)cyclopropanecarbonyl)pyrrolidin-2-carboxamide;
(2S,4R)-1-(2-(4-chlorophenyl)propanol)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;
(2S,4R)-1-(2-(4-chlorophenyl)propanol)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;
(2S,4R)-1-(2-(4-chlorophenyl)-3-methylbutanoyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;
tert-butyl 4-(4-CHL is henyl)-4-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclohexane)pyrrolidin-1-carbonyl)piperidine-1-carboxylate;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-morpholine-4-ylacetic]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-morpholine-4-ylacetic]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2-morpholine-4-ylacetic]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(3,4-dichlorophenyl)-2,2-divercity]-pyrrolidin-2-carboxylic acid;
(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-p-tooltipcontent)pyrrolidin-2-carboxamide;
(2S,4R)-1-(1-(4-chloro-2-forfinal)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;
(1-cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid;
(2S,4R,5S)-5-(4-tert-butylphenyl)-N-(1-cyanocyclohexyl)-4-(phenylsulfonyl)-2-(2-(phenylsulfonyl)ethyl)pyrrolidin-2-carboxamide;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chlorophenyl)-2,2-divercity]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(2,4-dichlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[2-(4-chloro-3-forfinal)-acetyl]-Pierre is lidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-cyclopropanesulfonyl-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chloro-3-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide 4-benzazolyl-5-(4-tert-butylphenyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid;
tert-butyl ester (2S,4R)-4-(2-allyloxymethyl)-2-(1-cyanocyclohexane)-pyrrolidin-1-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(1-hydroxymethylpropane)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(1-hydroxymethylpropane)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-allyloxymethyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(1-methylcyclopropyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[(R)-2-allylamino-2-(4-chlorophenyl)-acetyl]-4-(2-allyloxymethyl)-PI is Raiden-2-carboxylic acid;
(2S,4R)-4-(2-chloro-4-(3,3-diversecity-1-yl)phenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide;
(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)-4-(phenylsulfonyl)pyrrolidin-2-carboxamide;
(2S,4R)-4-(benzylmethyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclohexyl)pyrrolidin-2-carboxamide;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-itfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(2,4-dichloro-5-methoxyphenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(2,4-dichloro-5-forfinal)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-methanesulfonamide-2-carboxylic acid;
(2S,4R)-4-(2-chloro-4-(3,3-diversecity-1-yl)phenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide;
(2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclohexyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-5-yl)pyrrolidin-2-carboxamide;
(1-cyanocyclohexyl) s is (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(2,2,2-triptorelin)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[2-(2-chloropyridin-4-yl)-5-methyl-2H-pyrazole-3-yl]-4-cyclopropanesulfonyl-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-[5-methyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-cyclopropanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-4-methanesulfonamide-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-does not depend-1-yl)-cyclopropanecarbonyl]-4-(2-chlorobenzenesulfonyl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[1-(4-chlorphenoxy)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-4-(diphenylmethylene)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(4-bromophenylacetonitrile)-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-phenylmethanesulfonyl]-1-[1-(4-chlorophenyl)-cyclopropanecarbonyl]-pyrrolidine-2-ka is oil acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(2-cyclohexyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(4R)-4-[(2-chlorophenyl)sulfonyl]-N-(1-cyanocyclohexyl)-1-[1-(1,1-dissidocerida-2H-thiopyran-4-yl)-3-methyl-1H-pyrazole-5-yl]-L-prolinamide;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(3,3-diversecity-1-yl)-benzazolyl]-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(2-cyclobutyl-5-methyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-[5-methyl-2-(tetrahydropyran-4-yl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(3,3-diversecity-1-yl)-benzazolyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-(2,2,2-triptoreline)-benzazolyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1 lanecyklar who drank)-amide (2S,4R)-4-[4-(4-tert-butylpiperazine-1-yl)-2-chlorobenzenesulfonyl]-1-(5-methyl-2-phenethyl-2H-pyrazole-3-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-(3-chloro-[1,2,4]thiadiazole-5-yl)-pyrrolidin-2-carboxylic acid;
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(3-phenylpropyl)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid; and
(1-cyanocyclohexyl)-amide (2S,4R)-4-(2-chlorobenzenesulfonyl)-1-[5-methyl-2-(2-morpholine-4-retil)-2H-pyrazole-3-yl]-pyrrolidin-2-carboxylic acid.

27. The compound according to any one of paragraphs.1-26, which is a (1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2,2,2-triptoreline)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid.

28. The compound according to any one of paragraphs.1-26, which is a (1-cyanocyclohexyl)-amide (2S,4R)-4-[2-chloro-4-((S)-2,2,2-Cryptor-1 methylethoxy)-benzazolyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid.

29. The compound according to any one of paragraphs.1-26, which is a (1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(1-methyl-1H-pyrazole-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid.

30. The compound according to any one of paragraphs.1-26, which is a (1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-chloropyridin-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid.

31. The compound according to any one of paragraphs.1-26, which is a(1-cyanocyclohexyl)-amide (2S,4R)-4-[4-(2-methylpyridin-4-yl)-2-trifloromethyl]-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid.

32. The compound according to any one of paragraphs.1-26, which is a (1-cyanocyclohexyl)-amide (2S,4R)-4-((S)-2-chloro-4-hexahydropyrazino[1,2-a]pyrazin-2-eventality)-1-(1-triftormetilfullerenov)-pyrrolidin-2-carboxylic acid.

33. The compound according to any one of paragraphs.1-26, which is a (1-cyanocyclohexyl)-amide (2S,4R)-1-(1-methylcyclopropyl)-4-[4-(2-methylpyridin-4-yl)-2-trifloromethyl]-pyrrolidin-2-carboxylic acid.

34. The method of obtaining the compounds of formula (I) under item 1, in which R1denotes hydrogen, and A is absent, including
the reaction of the compound of formula (Ia)

in the presence of a reagent that removes the protective group of amino group;
where Y represents a protective group of amino group, and R2-R6are as defined in paragraph 1.

35. The method of obtaining the compounds of formula (I) according to any one of paragraphs.1-33, including
the reaction of compounds of formula (Ic)

in the presence of H2N-CR5R6-CN;
in which A, R1-R6are as defined in one of the paragraphs.1-23.

36. The compound according to any one of paragraphs.1-33 intended for use as therapeutically active compounds having activity as inhibitors of cathepsin.

37. Pharmaceutical composition having activity as inhibit the ditch cathepsin, containing compound according to one of paragraphs.1-33 and a therapeutically inert carrier.

38. The use of compounds according to any one of paragraphs.1-33 for the preparation of drugs, inhibiting the enzyme cathepsin.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinoxaline derivatives of general formula

,

a based pharmaceutical composition, using them as therapeutic agents, as well as to a based therapeutic agent for treating tumour diseases. In general formula I X represents: oxygen or sulphur; R1 represents hydrogen, R2/R3 represents hydrogen, R4 represents: (i) C1-C12-alkyl, (ii) saturated C3-C8-cycloalkyl, optionally substituted by C6-aryl, (iii) unsaturated C3-C8-cycloalkyl, (iv) heterocyclyl substituted by C(O)CF3, (v) C1-C6-alkyl substituted by C6-aryl, the above C6-aryl can be substituted by F, Cl, Br, I, -O-C1-C6-alkyl, C1-C6-alkyl, C6-aryl or hydroxy, (vi) C1-C6-alkyl substituted by C5-heteroaryl, (vii) C1-C8-alkylene, (viii) 1-adamantyl, (ix) C1-C6-alkyl substituted by C6-heterocyclyl containing a nitrogen atom and an oxygen atom, (x) C1-C6-alkyl substituted by C3-C6-cycloalkyl, or (xi) C1-C6-alkyl substituted by C6-heteroaryl; R5 represents hydrogen, R6 represents (i) aryl optionally substituted by C1-C6-alkyl, -O-C1-C6-alkyl, hydroxy, F, Cl, Br, I or amino, or (ii) C5-heteroaryl containing 2 nitrogen atoms optionally substituted by C1-C6-alkyl, R7 and R8 represent hydrogen.

EFFECT: producing the therapeutic agent for treating the tumour diseases.

7 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formula A1 stands for CR10R11 or S; A2 stands for CR12R13, C(=O), O, S or S(=O)2; R1 stands for C1-10-alkyl, saturated or unsaturated, branched or non-branched, non-substituted, or monosubstituted, or polysubstituted; C3-10-cycloalkyl or 5- or 6-membered heterocyclyl with the O-atom, each time saturated or unsaturated, non-substituted, or monosubstituted, or polysubstituted; C6-10-aryl or C5-10-heteroaryl with 1-3 heteroatoms, selected from N, O or S, each time non-substituted, or monosubstituted, or polysubstituted; through C1-8-alkyl or C2-8-heteroalkyl bound by the bridge bond C3-10-cycloalkyl, each time saturated, non-substituted, and the alkyl or heteroalkyl chain each time can be branched or non-branched, saturated, non-substituted; or through C1-8-alkyl, bound by the bridge bond aryl or heteroaryl, each time non-substituted, or monosubstituted, or polysubstituted, and the alkyl chain each time can be branched or non-branched, saturated or unsaturated, non-substituted, or monosubstituted, or polysubstituted; R2, R3 and R4 each time independently on each other stand for H; F; Cl; Br; I; methyl; O-C1-6-alkyl or NRaRb, and Ra and Rb together with the nitrogen atom that binds them form heterocyclyl, saturated, non-branched, non-substituted; R5, R6, R7, R8, R10, R11, R12 and R13each time independently on each other stand for H; F; Cl; Br; I; OH or C1-10-alkul; or R5 and R6 or R7 and R11 together with carbon atom(s), that bind(s) them form C3-8-cycloalkyl, each time saturated or non-saturated, non-substituted, or monosubstituted, or polysubstituted; with respective remaining substituents R5, R6, R7, R8, R10, R11, R12 and R13 having the value given above; R9 stands for C3-10-cycloalkyl, saturated, non-substituted; C6-10-aryl or 5- or 6-membered heteroaryl with heteroatom, selected from N and S, each time non-substituted or monosubstituted.

EFFECT: invention relates to substituted nicotinamides of general formula (1), to a medication based on them and their application for treating KCNQ2/3-mediated diseases.

13 cl, 3 tbl, 224 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I) , where A is selected from -C(=O)-, -S(=O)2-, and -P(=O)(R5)-, where R5 is selected from C1-6-alkyl, C1-6-alkoxy and hydroxy; B is selected from single bond, -O-, and -C(=O)-NR6-, where R6 is selected from hydrogen; D is selected from single bond, -O-, and -NR9, where R7, R8 and R9 are independently selected from hydrogen; m equals integer number 0-12 and n equals integer number 0-12, where the sum m+n equals 1-20; p equals integer number 0-2; R1 is selected from optionally substituted heteroaryl, where heteroaryl represents aromatic carbocyclic ring, where one carbon atom is substituted with heteroatom; R2 is selected from hydrogen, optionally substituted C1-12-alkyl, and substituents are selected from phenyl, morpholine, halogen and pyridine; C3-12-cycloalkyl, -[CH2CH2O]1-10-C1-6-alkyl); and R3 is selected from optionally substituted C1-12-alkyl, and substituents are selected from morpholine, phenyl, dialkylamine and C3-12-cycloalkyl, optionally substituted with halogen aryl; or R2 and R3 together with adjacent atoms form optionally substituted with alkylcarbonyl or alkyl N-containing heterocyclic or heteroaromatic ring; each of R4 and R4* independently represents hydrogen; and their pharmaceutically acceptable salts, as well as to application of said compounds for treatment of diseases/states, induced by increased level of nicotinamide phosphoribosyltransferase (NAmPRTase).

EFFECT: obtaining novel compounds.

21 cl, 1 dwg, 2 tbl, 83 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to piridazine derivatives of formula II

,

in which radicals and symbols have determinations, given in the invention formula, or to their pharmaceutically acceptable salts.

EFFECT: compounds of formula II demonstrate inhibiting effect with respect to proteinkinases such as c-met, ron, or ALK, or chimeric proteins, and can be useful for treatment of disorders, associated with abnormal activity of proteinkinases, such as cancer.

7 cl, 1 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula