Pyrrolidine derivatives applicable as catepsin derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) such as below, or to their pharmaceutically acceptable salts, wherein R1 means H, C1-8alkyl morpholinyl, haloC1-8alkylamino, C1-8alkyloxadiazolyl, hydroxyl, halopyrrolidinyl, azetidinyl, C1-8alkylamino, amino, cyano C1-8alkylamino, halophenylC1-8alkylamino or cyanoC3-8cycloalkylamino; R2, R3, R4, R5 and R6 independently mean H, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkyloxy, halogen, hydroxyl, cyanopyrazinyloxy, halogen, hydroxyl, cyanopyrazinyloxy, pyrazolyl, C1-8alkylpyrazolyl, imidazolyl, benzimidazolyl, 6-oxo-6H-piridazinyl, C1-8alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-C1-8alkylpiperazinyl, piperidinyl, difluoropyrrolidinyl, phenylimidazolyl, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, difluoropiperidinyl, haloC1-8alkylpiperidinyl, piperidinylC1-8alkoxy, oxetanyloxy, C1-8alkylpyrazolyl, halopyridinyl, C1-8alkylpyridinyl, C3-8cycloalkyl, C3-8 cycloalkylC1-8alkyl, halophanyl, C1-8alkylcarbonylamino-C3-8-cycloalkyl-C1-8alkyl, haloC1-8alkylpiperazinyl, C1-8alkylamino, C1-8alkoxy-C1-8alkylpiperazinyl, C3-8cycloalkylpiperazinyl, hexahydropyrrolo[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, C1-8alkylimidazolyl, azetidinyl, C3-8cycloalkylpiperazinyl, C1-8alkylimidazolyl, C1-8alkoxy C1-8alkoxy, imidazo[4,5-c]pyridinyl, C1-8alkylpiperazinyl, hexahydro-pyrrolo[1,2-a]pyrazinyl, haloazetidinyl, pyrimidinyl and C2-8alkenyloxy; A1 means -CH2-, carbonyl, -C(O)O- or is absence; A2 means N, CR7; A3 means N, CR8; A4 means N, CR9; R7 means H, C1-8alkyl, haloC1-8alkyl, halogen, hydroxyl, haloC1-8alkylaminocarbonyl; halophenylC1-8alkylaminocarbonyl, phenyl-C3-8-cycloalkylaminocarbonyl, haloC1-8alkylphenylC1-8alkylaminocarbonyl, halophenylC3-8 cycloalkylaminocarbonyl, halophenylC3-8cycloalkylC1-8alkylaminocarbonyl; R8 means H, C1-8alkyl, haloC1-8alkyl, halogen or hydroxyl; or R7 and R8 together with a carbon atom they are attached to, form C3-8cycloalkyl or substituted pyrrolidine, wherein substituted pyrrolidine represents pyrrolidine, N-substituted haloC1-8alkyl or formyl; R9 means H, C1-8alkyl, haloC1-8alkyl, halogen or nitro; or R8 and R9 together with a carbon atom they are attached to, form C3-8cycloalkyl; or its pharmaceutically acceptable salt

EFFECT: compounds inhibit the enzyme catepsin that enables using them in pharmaceutical compositions.

27 cl, 8 dwg, 1 tbl, 88 ex

 

The present invention relates to organic compounds useful for the treatment and/or prophylaxis of a mammal, specifically, to compounds that are preferential inhibitors of cysteinate of cathepsin, in particular, cysteinate of cathepsin S or L.

In particular, the invention relates to the compound of formula (I)

R1represents hydrogen, alkyl, morpholinyl, haloalkylthio, alkyloxyaryl, hydroxyl, haloperidol, azetidine, alkylamino, amino, cyanoacetamide, halogenalkynes or cyanocobalamine;

R2, R3, R4, R5and R6independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen, hydroxyl, cyanopyridine, pyrazolyl, alkylperoxyl, imidazolyl, benzimidazolyl, 6-oxo-6H-pyridazinyl, alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-alkylpiperazine, piperidine, differerential, phenylimidazoline, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, deltocephalinae, haloalkaliphilic, piperidinyloxy, oceanlake, alkylperoxyl, haloperidol, alkylpyridine, cycloalkyl, cycloalkenyl, halophenol, , Halaal�of represenla, alkylamino, alkoxycarbonyl, cycloalkylcarbonyl, hexahydropyrazino[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-silt, alkylimidazole, azetidine, cycloalkylcarbonyl, alkylimidazole, alkoxyalkane, imidazo[4,5-C]pyridinyl, alkylpiperazine, hexahydro-imidazo[1,2-a]pyrazinyl, galazutdinov, pyrimidinyl and alkenylacyl;

And1represents-CH2-, carbonyl, -C(O)O - or absent;

And2represents nitrogen or CR7;

And3represents nitrogen or CR8;

And4represents nitrogen or CR9;

R7represents hydrogen, alkyl, haloalkyl, halogen, hydroxyl, haloaluminate; halogenlithiumcarbeniod, phenylcyclohexylamine, gloucestershireheadlines, halogenlithiumcarbeniod or ;

R8represents hydrogen, alkyl, haloalkyl, halogen or hydroxyl;

or R7and R8together with the carbon atom to which they are attached, form cycloalkyl or substituted pyrrolidinyl where substituted pyrrolidinyl is pyrrolidinyl, N-substituted haloalkyl or formyl;

R9represents hydrogen, alkyl, haloalkyl, halogen or nitro; and

or R8and R9together with the atom �of geroda, to which they are attached, form cycloalkyl;

or its pharmaceutically acceptable salt.

Compounds of the invention are preferential inhibitors of cysteinate of cathepsin (Cat), in particular, cathepsin S or cathepsin L, and therefore useful in the treatment of metabolic disorders such as diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, cardiovascular complications in chronic kidney disease, glomerulonephritis, age-related macular degeneration, diabetic nephropathy and diabetic retinopathy. In addition, immunopositive diseases such as rheumatoid arthritis, Crohn's disease, multiple sclerosis, Sjogren's syndrome, lupus erythematous, neuropathic pain, diabetes type I, asthma and allergies, and skin immune disease, diseases are appropriate for treatment with an inhibitor of cathepsin S. the Objects of the present invention are compounds of formula (I) and their aforementioned salts are essentially, and their use as therapeutically active substances, a method of manufacturing such compounds, intermediates, pharmaceutical compositions, drugs containing these compounds, their pharmaceutically acceptable salts, the application of the said compounds and salts for the prophylaxis� and/or treatment of diseases, especially in the treatment or prophylaxis of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, cardiovascular complications in chronic kidney disease and diabetic nephropathy, and the application of the said compounds and salts for the manufacture of drugs for the treatment or prophylaxis of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, cardiovascular complications in chronic kidney disease and diabetic nephropathy.

Mammalian cathepsins are cysteine protease-type involved in key stages of biological and pathological processes. Cathepsins are considered manageable drug targets, because it is possible to inhibit the enzymatic activity with small molecules, and therefore of interest in the pharmaceutical industry (Bromme, D. (2001), 'Papain-like cysteine proteases', Curr Protoc Protein Sci Chapter 21, Unit 21 2; Roberts, R. (2005), 'Lysosomal cysteine proteases: structure, function and inhibition of cathepsins', Drug News Perspect, 18 (10), 605-14).

Cathepsin S markedly expressed in antigen presenting cells like macrophages and dendritic cells, and smooth muscle cells (Hsing, L. C. and Rudensky, A. Y. (2005), 'The lysosomal cysteine proteases in MHC class II antigen presentation', Immunol Rev, 207, 229-41; Rudensky, A. and Beers, C. (2006), 'Lysosomal cysteine proteases and antigen presentation', Ernst Schering Res Found Workshop, (56), 81-95). In �about cathepsin S only weakly expressed in normal arterial tissue, strong increased expression is observed in atherosclerotic arteries (Liu, J., et al. (2006), 'Increased serum cathepsin S in patients with atherosclerosis and diabetes', Atherosclerosis, 186 (2), 411-9; Sukhova, G. K., et al. (1998), 'Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells', J Clin Invest, 102 (3), 576-83).

Preclinical studies indicate that the function of cathepsin S is decisive for atherosclerosis, since mice with a deficiency in cathepsin S, have reduced the phenotype of atherosclerosis in the verification of suitable mouse models. In mice lacking LDL-Rec, observed a reduced accumulation of lipids, destruction of elastin fibers and chronic arterial inflammation. In mice lacking APO-E, a significant decrease in cases of acute ruptures of plaques. When chronic renal failure is caused in mice lacking KaS/In APO-E, there is a strong reduction of accelerated calcification over anti-atherosclerotic activity in arteries and heart valves (Aikawa, E., et al. (2009), 'Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease', Circulation, 119 (13), 1785-94; de Nooijer, R., et al. (2009), 'Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis', Arterioscler Thromb Vase Biol, 29 (2), 188-94; Rodgers, K. J., et al. (2006), 'Destabilizing role of cathepsin S in murine atherosclerotic plaques', Arterioscler Thromb Vase Biol, 26 (4), 851-6; Sukhova et al. (2003), 'Deficiency of cathepsin reduces atherosclerosis in LDL receptor-deficient mice', J Clin Invest, 111 (6), 897-906). This indicates that the potential inhibitor of cathepsin S will stabilize the atherosclerotic plaque, reducing the destruction of the extracellular matrix, reducing Pro-inflammatory state and reducing the accelerated calcification and its clinical manifestations.

These phenotypes described in atherosclerotic models, are consistent with the known cellular functions of cathepsin S. first, cathepsin S involved in the destruction of extracellular matrix that stabilizes the plaque. In particular, cathepsin S has a strong latinalicious activity and can show her at neutral pH, a feature that distinguishes cathepsin S from all the others in vitro. Secondly, cathepsin S is the main protease involved in the processing of antigen, in particular, the cleavage of the invariant chain in antigen presenting cells, which leads to reduced contribution of T cells in chronic inflammation of the atherosclerotic tissue. Increased inflammation leads to further oxidative and proteolytic damage to the tissues and then the violation of plaques (Cheng, X. W., et al. (2004), 'Increased expression of elastolytic cysteine proteases, cathepsins S and K, in the neointima of balloon-injured rat carotid arteries', Am J Pathol, 164 (1), 243-51; Driessen, S., et al. (1999), 'Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells', J Cell Biol, 147 (4), 775-90; Rudensky, A. and Beers, C. (2006), 'Lysosomal cystene proteases and antigen presentation', Ernst Schering Res Found Workshop, (56), 81-95).

Anti-inflammatory and antibactericidal properties of the inhibitor Cat S also make it an important target for chronic obstructive lung disease (Williams, A. S., et al. (2009), 'Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation', Pulm Pharmacol Ther, 22 (1), 27-32). In addition, because of its extracellular functions in the destruction of the matrix by inhibition of cathepsin S will affect neointima formation and angiogenesis (Burns-Kurtis, C. L., et al. (2004), 'Cathepsin S expression is up-regulated following balloon angioplasty in the hypercholesterolemic rabbit', Cardiovasc Res, 62 (3), 610-20;

Cheng, X. W., et al. (2004), 'Increased expression of elastolytic cysteine proteases, cathepsins S and K, in the neointima of balloon-injured rat carotid arteries', Am J Pathol, 164 (1), 243-51; Shi, G. P., et al. (2003), 'Deficiency of the cysteine protease cathepsin S impairs microvessel growth', Circ Res, 92 (5), 493-500; Wang, V., et al. (2006), 'Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors', J Biol Chem, 281 (9), 6020-9). Therefore, the inhibitor of cathepsin S can be useful in a number of different painful conditions.

Cathepsin S also plays a role in the reduction of tumor development and the penetration of tumor cells, as described by Roberta E. Burden in Clin Cancer Res 2009: 15(19). In addition, cathepsin S nephrectomized knockout mice showed a significant decrease in artery calcification compared with refractometrology wild type mice. This indicates that the inhibition of cathepsin S may have a beneficial influence on the reduction of cardiovascular complications in patients with chronic kidney disease (Elena Aikawa, Circulation, 2009, 1785-1794).

Cathepsin L shows a broader expression profile than cathepsin S, and there are also data that support a role for cathepsin L in atherosclerosis, such as a mouse, lacking LDLrec & Cat L, show reduced atherosclerotic phenotype (Kitamoto, S., et al. (2007), 'Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice', Circulation, 115 (15), 2065-75). In addition, it is assumed that the cut L is involved in metabolic syndrome, as it regulates lipogenesis and glucose tolerance in peripheral tissues. Described that renal failure of cathepsin L regulates the function of podocyte, proteoliticeski transforming dynamin and, thus, proteinuria (Sever, S., et al. (2007), 'Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease', J Clin Invest, 117 (8), 2095-104).

Tissue remodeling, destruction of the extracellular matrix, the generation of active neuropeptides and their role in antigen presentation in thymic epithelial cells are the cellular functions described for cathepsin L (Funkelstein et al. 2008; Rudensky and Beers 2006).

In the present description the term "alkyl", alone or in combination, means a straight or branched alkyl group from 1 to 8 carbon atoms, preferably unbranched or branched alkyl group from 1 to 6 carbon atoms and particularly preferably ner�svetlanna or branched alkyl group from 1 to 4 carbon atoms. Examples of unbranched and branched C1-C8-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentile, isomeric sexily, isomeric Gately and isomeric octile, preferably methyl, ethyl, propyl, isopropyl, isobutyl and tert-butyl.

The term "cycloalkyl", alone or in combination, means cycloalkyl ring of 3 to 8 carbon atoms and preferably cycloalkyl ring of 3 to 6 carbon atoms. Examples C3-C8-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferred cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclopropyl and cyclobutyl especially preferred. Dihydro most preferred.

The term "alkoxy", alone or in combination, means a group of the formula alkyl-O-in which the term "alkyl" has the above given value, such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, Deut-butoxy and tert-butoxy, preferably methoxy, ethoxy, propoxy and isopropoxy.

The term "cycloalkane", alone or in combination, means a group of the formula cycloalkyl-O-in which the term "cycloalkyl" is above this value, such as cyclobutylamine, cyclopentyloxy or cyclohexyloxy.

The term "dryer�loksi", separately or in combination, means a phenyl-O - group.

The term "hydroxy", alone or in combination, means a-O - group.

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

The terms "haloalkyl", "halachically and haloalkoxy", alone or in combination, denotes an alkyl group, cycloalkyl group and alkoxy group substituted by at least one halogen, preferably substituted with one to five Halogens, preferably one to three Halogens. Foralkyl represents an alkyl group, substituted by at least one fluorine atom, preferably substituted with one to five fluorine atoms, preferably one to three Halogens. Preferred haloalkyl represent trifluoromethyl, trifluoroethyl and cryptochromes.

The terms "Galiani", "haloperidol", "haloperidol" and "galazutdinov", alone or in combination, represent a phenyl group, pyrrolidinyl group, pyridinyl group and azetidinol group, substituted by at least one halogen, preferably substituted with one to three Halogens.

The terms "hydroxyl" and "hydroxy", alone or in combination, refer to-IT group.

The term "carbonyl", alone or in combination, about�means-C(O)- group.

The term "carboxy", alone or in combination, denotes a-COOH group.

The term "amino", alone or in combination, signifies a primary amino group (-NH2), a secondary amino group (-NH-) or tertiary amino (-N-).

The term "formyl", alone or in combination, refers to the group HC(O)-.

The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are neither biologically or otherwise undesirable. Salt get with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 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, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, N-acetylcysteine. In addition, these salts can be obtained in the form of merger of inorganic bases or organic bases of the free acid. Salts derived from near�anceschi grounds include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine resin. The compound of formula (I) may also be in the form zwitterions. Especially preferred pharmaceutically acceptable salts of compounds of formula (I) are salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

If one of the starting materials or compounds of formula (I) contains one or more than one functional group that is unstable or reactive under the reaction conditions of one or more than one stage of the reaction, suitable protective groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 3rdEd., 1999, Wiley, New York) can be entered before the decisive stage of the applied methods, well known in the art. Such protective groups can be removed at a later stage of the synthesis �when using standard methods, described in the literature. Examples of protective groups are tert-butoxy carbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylmethyl carbamate (TEOS), carbobenzoxy (Cbz) and p-methoxybenzenesulfonyl (Moz).

The compound of formula (I) can contain several asymmetric centers and can be in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemate, mixtures of diastereomers, diastereoisomers racemate or mixture diastereoisomeric of racemates.

The term 'asymmetric carbon atom means a carbon atom with four different substituents. Pursuant to rule Kahn-Ingold-Prelog asymmetric carbon atom can be "R" or "S" configuration.

The invention relates in particular to the compound of formula (I), where

R1represents hydrogen, alkyl, morpholinyl, haloalkylthio, alkyloxyaryl, hydroxyl, haloperidol, azetidine, alkylamino, amino, cyanoacetamide, halogenalkynes or cyanocobalamine;

R2, R3, R4, R5and R6independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen, hydroxyl, cyanopyridine, pyrazolyl, alkylperoxyl, imidazolyl, benzimidazolyl, 6-oxo-6H-pyridazinyl, alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-alkylpiperazine�Nile, piperidinyl, differerential, phenylimidazoline, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, deltocephalinae, haloalkaliphilic, piperidinyloxy, oceanlake, alkylperoxyl, haloperidol, alkylpyridine, cycloalkyl, cycloalkenyl, halophenol, , haloalkaliphilic, alkylamino, alkoxycarbonyl, cycloalkylcarbonyl, hexahydropyrazino[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-silt, alkylimidazole, azetidine, cycloalkylcarbonyl, alkylimidazole, alkoxyalkane, imidazo[4,5-C]pyridinyl, alkylpiperazine, hexahydro-imidazo[1,2-a]pyrazinyl, galazutdinov, pyrimidinyl and alkenylacyl;

And1represents-CH2-, carbonyl, -C(O)O - or absent;

And2represents nitrogen or CR7;

And3represents nitrogen or CR8;

And4represents nitrogen or CR9;

R7represents hydrogen, alkyl, haloalkyl, halogen or hydroxyl;

R8represents hydrogen, alkyl, haloalkyl, halogen or hydroxyl;

or R7and R8together with the carbon atom to which they are attached, form cycloalkyl;

R9represents hydrogen, alkyl, g�loukil or halogen;

or R8and R9together with the carbon atom to which they are attached, form cycloalkyl; or its pharmaceutically acceptable salt.

In the definition of R1alkyl represents, for example, methyl or ethyl. In the definition of R1haloalkaline represents, for example, triptoreline or triptoreline. In the definition of R1alkyloxyaryl represents, for example, dimethyloctadecyl. In the definition of R1haloperidol represents, for example, differerential. In the definition of R1alkylamino represents, for example, ethylamino, propylamino or dimethylamino. In the definition of R1cyanoaniline represents, for example, cyanomethylene. In the definition of R1halogenalkynes represents, for example, performativity. In the definition of R1cyanocobalamine represents, for example, cyanocobalamin.

The invention also relates to a compound of formula (I), where R1represents hydrogen, methyl, ethyl, morpholinyl, triptoreline, triptoreline, dimethyloxalate, hydroxyl, differerential, azetidine, ethylamino, propylamino, dimethylamino, amino, cyanomethylene, performanceline or cyanocobalamin.

A particular compound of the invention is a compound of Fort�uly (I), where R1represents hydrogen or amino.

Another specific compound of the invention is a compound of formula (I), where R2, R3, R4, R5and R6independently selected from hydrogen, halogen, hydroxyl, haloalkyl, cyanopyridine, alkylpiperazine, hexahydro-imidazo[1,2-a]pyrazinyl, haloalkoxy, pyrazolyl, cycloalkylcarbonyl, imidazolyl and alkoxyalkane.

Further particular compound of the invention is a compound of formula (I), where R2and R6independently selected from hydrogen, halogen and haloalkyl.

The compound of formula (I) where one of R2and R6represents a halogen or haloalkyl, and the other represents hydrogen, is another particular embodiment of the invention.

The compound of formula (I) where one of R2and R6represents chlorine or trifluoromethyl, and the other represents hydrogen, is another particular embodiment of the invention.

Still another particular connection according to the invention is a compound of formula (I), where R3and R5independently selected from hydrogen, halogen and haloalkyl.

In addition, a particular compound of the invention is a compound of formula (I), where R3and R5independently selected from hydrogen, chlorine and trifloromethyl.

In addition, a special connection invented�Yu is also the compound of formula (I), where both R3and R5represent hydrogen.

The compound of formula (I), where R4represents hydrogen, hydroxyl, halogen, cyanopyridine, alkylpiperazine, hexahydropyrazino[1,2-a]pyrazinyl, haloalkoxy, pyrazolyl, cycloalkylcarbonyl, imidazolyl or alkoxyalkane is a special embodiment of the invention.

In addition, the compound of formula (I), where R4represents hydrogen, halogen, alkylpiperazine, hexahydropyrazino[1,2-a]pyrazinyl, haloalkoxy, pyrazolyl, cycloalkylcarbonyl or alkoxyalkane is another particular embodiment of the invention.

In addition, the compound of formula (I), where R4represents hydrogen, halogen, methylpiperazine, tert-butylpiperazine, hexahydropyrazino[1,2-a]pyrazinyl, triptoreline, tricorporate, pyrazolyl, cyclopropylmethyl or methoxyethoxy is still another particular embodiment of the invention.

In particular, the invention also relates to a compound of formula (I), where A1is absent or represents a carbonyl.

In particular, the invention further relates to the compound of formula (I), where A2is a CR7.

Furthermore, the invention especially relates to compounds of formula (I), where A3is a CR8.

When R7and R8together with the atom at�of Lerida, to which they are attached, form cycloalkyl, special cycloalkyl is cyclopentyl.

The compound of formula (I), where A4represents a nitrogen, an additional special subject invention.

The compound of formula (I), where R7represents hydrogen, is another particular object of the invention.

The compound of formula (I), where R8represents hydrogen, alkyl or haloalkyl is also another particular subject of the invention.

In particular, the invention also relates to a compound of formula (I), where R8represents trifluoromethyl.

In particular, the invention also relates to a compound of formula (I), where R9represents hydrogen.

When R8and R9together with the carbon atom to which they are attached, form cycloalkyl, special cycloalkyl is cyclopentyl.

Particular compounds of formula (I) can be selected from:

6-[(2S,4S)-4-(2-Chloro-benzolsulfonat)-2-(morpholine-4-carbonyl)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile;

Methyl ester of (2S,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;

6-[3-(4-Hydroxy-benzolsulfonat)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile;

6-[3-({4-[(6-Cyanopyridine-2-yl)oxy]phenyl}sulfonyl)pyrrolidin-1-yl]pyrazine-2-carbonitrile;

(2S,4S)-4-(2-Chloro-bansilal�o'neill)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;

(2,2,2-Cryptor-ethyl)-amide (2S,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;

The ethyl ester of (2R,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;

6-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyridine-2-carbonitrile;

6-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile;

6-[(2R,4S)-4-(2-Chloro-benzolsulfonat)-2-(morpholine-4-carbonyl)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile;

(2,2,2-Cryptor-ethyl)-amide (2R,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;

4-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

4-[(2R,4S)-4-(2-Chloro-benzolsulfonat)-2-(5-methyl-[1,3,4]oxidiazol-2-yl)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

4-[(S)-3-(2-Trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

4-[(2R,4S)-2-Gidroximetil-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

4-Methyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

5-Trifluoromethyl-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

5-Fluoro-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

5-Hydroxy-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

2-[(2R,4S)-2-Morpholine-4-ylmethyl-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-4-carbonitrile;

4-[(2R,4S)-2-(3,3-Debtor-pyrrolidin-1-ylmethyl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

4-[(S)-3-(2,3-Dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

4-[(R)-3-(2-Bromo-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

4-[(S)-3-(3-Trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

(2,2,2-Cryptor-ethyl)-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

4-[(2S,4S)-2-(Azetidin-1-carbonyl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

((S)-2,2,2-Cryptor-1-methyl-ethyl)-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

The diethylamide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

(2S,4S)-1-(2-Cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

Amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

Ethylamide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

Cyanomethyl-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-cryptomate�-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

4-[(2S,4S)-2-(3,3-Debtor-pyrrolidin-1-carbonyl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

4-Fluoro-benzylamine (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

(1-Cyano-cyclopropyl)-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

Isopropylamine (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

4-[(S)-3-(2-Trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-6,7-dihydro-5H-cyclopentadienide-2-carbonitrile;

5-Methyl-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

4-Trifluoromethyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

Amide (S)-1-(2-cyano-6-trifluoromethyl-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

4-[(S)-3-(2-Chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-{(S)-3-[2-Chloro-4-(4-methyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-{(S)-3-[4-(4-tert-Butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trif�ormetal-pyrimidine-2-carbonitrile;

4-{(S)-3-[2-Chloro-4-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-[(S)-3-(2-Chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-{(3)-3-[2-Chloro-4-(4-cyclopropyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-{(3)-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-[(S)-3-(2-Chloro-4-imidazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-{(3)-3-[2-Chloro-4-(2-methoxy-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

(2,2,2-Cryptor-ethyl)-amide 4-[(S)-3-(2-chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-2-cyano-pyrimidine-5-carboxylic acid;

(2,2,2-Cryptor-ethyl)-amide 4-{(S)-3-[4-(4-tert-butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid;

(2,2,2-Cryptor-ethyl)-amide 4-{(3)-3-[2-chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid;

(2,2,2-Cryptor-ethyl)-amide 4-{(S)-3-[2-chloro-4-(4-cyclopropyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid;

(2,2,2-Cryptor-ethyl)-amide 4-[(S)-3-(2-chloro-4-imidazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-2-cyano-pyrimidine-5-carbon� acid;

[2-(4-Chloro-phenyl)-propyl]-amide 4-{(S)-3-[4-(4-tert-butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid;

4-{(3)-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-(2,2,2-Cryptor-ethyl)-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine-2-carbonitrile;

4-[(3)-3-(2-Chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-(2,2,2-Cryptor-ethyl)-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine-2-carbonitrile;

4-[(S)-3-(2-Chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-formyl-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine-2-carbonitrile;

6-[(S)-3-((3)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyridine-2-carbonitrile; compound with formic acid;

6-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile; compound with formic acid;

2-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-4-carbonitrile; compound with formic acid;

6-[3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-3-nitro-pyridin-2-carbonitrile, with formic acid;

(S)-6-(3-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidin-1-yl)picolinate;

(S)-2-(3-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile;

(S)-6-(3-(2-(Trifluoromethyl)phenylsulfonyl)PI�Raiden-1-yl)pyrazine-2-carbonitrile;

6-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-pyrazine-2-carbonitrile;

2-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-pyrimidine-4-carbonitrile;

6-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-pyridine-2-carbonitrile;

6-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-3-nitro-pyridin-2-carbonitrile;

(S)-6-(3-(2-Chloro-4-perpenicular)pyrrolidin-1-yl)picolinate;

(S)-2-(3-(2-Chloro-4-perpenicular)pyrrolidin-1-yl)pyrimidine-4-carbonitrile;

(S)-6-(3-(2-Chloro-4-perpenicular)pyrrolidin-1-yl)pyrazine-2-carbonitrile;

(S)-2-(3-(2-Chloro-4-(4-methylpiperazin-1-yl)phenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile;

(S)-6-(3-(2-Chloro-4-(4-methylpiperazin-1-yl)phenylsulfonyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile;

(2-Phenyl-cyclopropyl)-amide 2-cyano-4-((S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;

[2-(4-Chloro-phenyl)-propyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;

4-Trifluoromethyl-benzylamino 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;

4-Trifluoromethyl-benzylamino 2-cyano-4-[(S)-3-(2,3-dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimid�n-5-carboxylic acid;

[1-(4-Fluoro-phenyl)-cyclopropyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;

[1-(4-Fluoro-phenyl)-cyclopropyl]-amide 2-cyano-4-[(S)-3-(2,3-dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;

(2,2,2-Cryptor-ethyl)-amide 2-cyano-4-[(5)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;

(2,2,2-Cryptor-ethyl)-amide 2-cyano-4-[(3)-3-(2,3-dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;

[2-(4-Chloro-phenyl)-propyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;

[2-(4-Chloro-phenyl)-propyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid and

[1-(4-Chloro-phenyl)-cyclopropylmethyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid.

In addition, particular compounds of formula (I) can be selected from:

4-Trifluoromethyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;

Amide (S)-1-(2-cyano-6-trifluoromethyl-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;

4-{(3)-3-[2-Chloro-4-(4-methyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-{(3)-3-[4-(4-tert-Butyl-piperazine-1-and�)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-{(3)-3-[2-Chloro-4-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-[(S)-3-(2-Chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-{(S)-3-[2-Chloro-4-(4-cyclopropyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;

4-{(3)-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile and

4-{(3)-3-[2-Chloro-4-(2-methoxy-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile.

Compounds of the present invention can be obtained, for example, during the General methods of synthesis described below.

The following diagrams and in the description of R1-R6and And1to And4have, unless otherwise indicated, the values of R1-R6and And1-And4as defined above.

Abbreviations:

ACN: Acetonitrile;

THIEF: Benzotriazolyl N-oxy-Tris(dimethylamino)-phosphonium hexaflurophosphate;

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

CDI: 1,1'-Carbonyldiimidazole;

DABCO: 1,4-Diazabicyclo[2.2.2]octane;

Was held: dichloro methane;

DIPEA: Diisopropylethylamine;

DMA: N,N-Dimethylacetamide;

�IPA: N,N-Dimethylformamide;

EDCl: N-(3-Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride;

Fmoc: 9-Fluorenylmethyl carbamate

HATU: O-(7-Asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate;

NOT: 1-hydroxy-benzotriazole;

LiHMDS: Bis(trimethylsilyl)amide, lithium;

MSRWA: 3-Chlormadinone acid;

Mes-Cl: Methylchloride;

Na2SO4: Sodium sulphate;

NMP = N-Methylpyrrolidinone;

Nos-Cl: 3-Nitrobenzenesulfonate;

PyBOP: Benzotriazole-1-yl-oxtriphylline hexaflurophosphate;

Tea: Triethylamine;

TBAF: Tetrabutylammonium fluoride;

TBTU: O-(Benzotriazole-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate;

Theos: 2-Trimethylsilylmethyl carbamate

TFA: Trifluoroacetic acid; and

THF: Tetrahydrofuran;

Tos-Cl: Toluene-4-sulphonylchloride.

Scheme 1

Figure 1: R = methyl, ethyl or tert-butyl; R' = methyl, trifluoromethyl, 3-nitrophenyl or 4-methylphenyl; R10 = CN, -SMe, or Cl; PG = Protective group, e.g. Boc, Fmoc, Cbz or TEOS; R11 and R12 are independently selected from hydrogen, alkyl, haloalkylthio, hydroxyalkyl, alkylamino, amino, cyanoacetamide, halogenalkynes and cyanocobalamine; or R11 and R12 together with the nitrogen atom to which they are attached, form morpholinyl, haloperidol or azetidine.

Corresponding orthogonally protected derivative of 4-hydroxy-Proline, such as 1-�RET-butyl ester 2-methyl ester (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid, interacts with sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or triftormetilfullerenov anhydride, in the presence of base, such as tea, DIPEA, pyridine, etc., which gives compound 2. The reaction of 2 with thiols in the presence of an appropriate base, such as NaH, LiHMDS, DIPEA, teas, etc., gives compounds of type 3. Oxidation of the obtained thioether is performed under the influence of appropriate oxidizing agent, such as N2O2, Oxon, MSRA, etc., giving compound 4. Saponification of the ester is carried out using LiOH, NaOH in the case of R = methyl, ethyl; where R = Boc can be used TFA or HCl or other suitable acid that will give compound 5. Amide binding performed in the presence of one of the various amide binding reagents, such as BOP-Cl, TBTU, THIEF, PyBop, HATU, CDI, EDCl/HOBT, DIC/HOBT; DCC/HOBT, ammonium bicarbonate and di-tert-butyl-dicarbonate, etc., which gives the corresponding amide 6. The protective group PG is removed, in the case of Boc as protecting groups with TFA, HCl or formic acid in an appropriate solvent, such as THF, dioxane, CH2Cl2etc., which gives compound 7. In the case of PG = Fmoc is used for splitting the piperidine. In the case of PG = Cbz, you can use HBr in acetic acid or catalytic hydrogenation. In the case of PG = theos can be used TBAF for splitting, giving compound 7. The reaction of compounds 7 with Pro�svodnymi of chloropyridine, chloropyrimidine and chloropyrazine in the presence of an appropriate base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, etc., gives compounds 8. In the case of R10 = CN they are the end connections. In the case of R10 = Cl 8 connection communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, in the presence of an appropriate base such as DABCO, pyridine, tea, DIPEA that gives the final compounds 9. In the case of R10 = S-Me compound 8 is oxidized to the corresponding methylsulfone 10, for example with H2O2, axonom, MSRA, etc. At the end of the connection 10 interact with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, which gives the final compounds 11. Alternatively, compound 4 can be converted to compound 12 in the cleavage of the protective group PG. The protective group PG is removed, in the case of Boc as protecting groups with TFA, HCl or formic acid in an appropriate solvent, such as THF, dioxane, CH2Cl2etc., which gives compound 7. In the case of PG = Fmoc is used for splitting a piperidine, in the case of PG = Cbz, you can use HBr in acetic acid or catalytic hydrogenation. In the case of PG = theos can be used TBAF for splitting, which gives compound 12. The reaction of compounds 12 with derivatives of chloropyridine, harpie�Idina and chloropyrazine in the presence of an appropriate base, such as teas, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, etc., gives compounds 13. Saponification of the ester 13 is carried out using LiOH, NaOH in the case of R = methyl, ethyl; where R = Boc can be used TFA or HCl or other suitable acid. Subsequent amide linking is performed in the presence of one of the various amide binding reagents, such as BOP-Cl, TBTU, THIEF, PyBop, HATU, CDl, EDCl/HOBT, DIC/HOBT; DCC/HOBT, ammonium bicarbonate and di-tert-butyl-dicarbonate, etc., which gives the corresponding amide 14. In the case of R10 = Cl compound 14 communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, in the presence of a suitable base such as DABCO, pyridine, tea, DIPEA that gives the final compounds 11. In the case of R10 = S-Me connection 14 is oxidized to the corresponding methylsulfone 10, for example with H2O2, axonom, MSRA, etc. At the end of the connection 10 interact with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, which gives the final compounds 11.

Scheme 2

Figure 2: PG = protective group, e.g. Boc, Fmoc, Cbz or TEOS; R' = methyl, trifluoromethyl, 3-nitrophenyl or 4-methylphenyl; R10 = CN, -SMe or Cl.

Corresponding protected derivative of 3-hydroxy-pyrrolidino, such as tert-butyl ether (R)-3-hydroxy-pyrrolidin-1-carboxylic acid, inter�actuat with sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or triftormetilfullerenov anhydride, in the presence of base, such as tea, DIPEA, pyridine, etc., which gives compound 2. The reaction of 2 with thiols in the presence of an appropriate base, such as NaH, LiHMDS, DIPEA, teas, etc., gives compounds of type 3. Oxidation of the obtained thioether is performed under the influence of the respective oxidizer, such as H2O2, Oxon, MSRA, etc., giving compound 4. The protective group PG is removed, in the case of Boc as protecting groups with TFA, HCl or formic acid in an appropriate solvent, such as THF, dioxane, CH2Cl2etc., which gives compound 5. In the case of PG = Fmoc is used for splitting a piperidine, in the case of PG = Cbz, you can use HBr in acetic acid or catalytic hydrogenation. In the case of PG = theos can be used TBAF for splitting, which gives compound 5. The reaction of compounds 5 with derivatives of chloropyridine, chloropyrimidine and chloropyrazine in the presence of an appropriate base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, etc., gives compounds 6. In the case of R10 = CN they are the end connections. In the case of R10 = Cl compound 6 communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide in the presence of an appropriate base such as DABCO, �of iridin, Teas, DIPEA that gives the final compound 7. In the case of R10 = S-Me compound 6 is oxidized to the corresponding methylsulfone 8, for example with H2O2, axonom, MSRA, etc. At the end of the connection 8 communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, which gives the final compounds 9.

Figure 3

Figure 3: R = methyl, ethyl or tert-butyl; R' = methyl, trifluoromethyl, 3-nitrophenyl or 4-methylphenyl; R10 = CN or Cl; PG = Protective group, e.g. Boc, Fmoc, Cbz or theos.

Corresponding orthogonally protected derivative of 4-hydroxy-Proline, such as 1-tert-butyl ester 2-methyl ester (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid, interacts with sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or triftormetilfullerenov anhydride, in the presence of base, such as tea, DIPEA, pyridine, etc., which gives compound 2. The reaction of 2 with thiols in the presence of an appropriate base, such as NaH, LiHMDS, DIPEA, teas, etc., gives compounds of type 3. Oxidation of the obtained thioether is performed under the influence of the respective oxidizer, such as H2O2, Oxon, MSRA, etc., giving compound 4. The reaction of esters 4 with hydrazine hydrate gives compound 5. For the education of proizvodi�x 1,3,4-oxadiazole 6 hydrazides 5 is condensed with acetic anhydride in the presence of hexachlorethane and derivative Fofana, such as, for example, triphenylphosphine, tricyclohexylphosphine. The protective group PG is removed, in the case of Boc as protecting groups with TFA, HCl or formic acid in an appropriate solvent, such as THF, dioxane, CH2Cl2etc., which gives compound 7. In the case of PG = Fmoc cleavage piperidine is used; if PG = Cbz, you can use HBr in acetic acid or catalytic hydrogenation. In the case of PG = theos can be used TBAF for splitting, giving compound 7. The reaction of compounds with derivatives of 7 chloropyridine, chloropyrimidine and chloropyrazine in the presence of an appropriate base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, etc., gives compounds 8. In the case of R10 = CN they are the end connections. In the case of R10 = Cl 8 connection communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, in the presence of an appropriate base such as DABCO, pyridine, tea, DIPEA that gives the final compounds 9.

Scheme 4

Scheme 4: PG = Protective group, e.g. Boc, Fmoc or Cbz; PG1 = Protective group, for example textilemachinery, trimethylsilyl, tert-butyldimethylsilyl or triphenylsilanol; R' = methyl, trifluoromethyl, 3-nitrophenyl or 4-methylphenyl; LG = for example Cl or Br; R10 = CN, -SMe, or Cl; R11 and R12 are independent� selected from hydrogen, of alkyl, haloalkylthio, hydroxyalkyl, alkylamino, amino, cyanoacetamide, halogenalkynes and cyanocobalamine; or R11 and R12 together with the nitrogen atom to which they are attached, form morpholinyl, haloperidol, piperazinyl, alkylpiperazine or azetidine.

Corresponding protected derivative of 4-hydroxy-2-gidroximetil-pyrrolidino, such as tert-butyl ester (2R,4R)-4-hydroxy-2-gidroximetil-pyrrolidin-1-carboxylic acid, interacts with similiarites, such as taxidermically, trimethylchlorosilane or tert-butyldimethylchlorosilane, in the presence of imidazole, which gives the compound 1. Connection 1 then interacts with sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or triftormetilfullerenov anhydride, in the presence of base, such as tea, DIPEA, pyridine, etc., which gives compound 2. The reaction of 2 with thiols in the presence of an appropriate base, such as NaH, LiHMDS, DIPEA, teas, etc., gives compounds of type 3. Oxidation of the obtained thioether is performed under the influence of the respective oxidizer, such as H2O2, Oxon, MSRA, etc., giving compound 4. The cleavage of PG1 is performed under the influence of a source of fluoride, such as TBAF, KF, etc., which gives compound 5. Alcohol 5 then interacts with sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or triftormetilfullerenov Angi�Reid, in the presence of base, such as tea, DIPEA, pyridine, etc., which gives compound 6. Nucleophilic substitution of sulfonates of compounds 6 with amines R11-NH-R12 gives compound 7. The protective group PG is removed, in the case of Boc as protecting groups with TFA, HCl or formic acid in an appropriate solvent, such as THF, dioxane, CH2Cl2etc., giving compound 8. In the case of PG = Fmoc cleavage piperidine is used; if PG = Cbz, you can use HBr in acetic acid or catalytic hydrogenation. The reaction of compounds 8 with derivatives of chloropyridine, chloropyrimidine and chloropyrazine in the presence of an appropriate base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, CS2CO3and KF, NaF and CsF, etc., gives compounds 9. In the case of R10 = CN they are the end connections. In the case of R10 = Cl compound 9 communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, in the presence of an appropriate base such as DABCO, pyridine, tea, DIPEA that gives the final compound 10. In the case of R10 = S-Me compound 9 is oxidized to the corresponding methylsulfone 11, for example with H2O2, axonom, MSRA, etc. At the end of the compound (11) communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, which gives the final compound 12.

Scheme 5

Figure 5: PG = Protective group, e.g. Boc, Fmoc or Cbz; R10 = CN, -SMe, or Cl; PG1 = Protective group, for example textilemachinery, trimethylsilyl, tert-butyldimethylsilyl or triphenylsilanol; R' = methyl, trifluoromethyl, 3-nitrophenyl or 4-methylphenyl; LG = for example Cl or Br.

Corresponding protected derivative of 4-hydroxy-2-gidroximetil-pyrrolidino, such as tert-butyl ester (2R,4R)-4-hydroxy-2-gidroximetil-pyrrolidin-1-carboxylic acid, interacts with similiarites, such as taxidermically, trimethylchlorosilane or tert-butyldimethylchlorosilane, in the presence of imidazole, which gives the compound 1. Connection 1 then interacts with sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or triftormetilfullerenov anhydride, in the presence of base, such as tea, DIPEA, pyridine, etc., which gives compound 2. The reaction of 2 with thiols in the presence of an appropriate base, such as NaH, LiHMDS, DIPEA, teas, etc., gives compounds of type 3. Oxidation of the obtained thioether is performed under the influence of the respective oxidizer, such as H2O2, Oxon, MSRA, etc., giving compound 4. Cleavage of PG and PG1 is performed under the influence of acid, such as TFA, HCl, methanesulfonic acid, HBr in acetic acid, etc., which gives compound 5. The reaction of compounds 5 with derivatives of chloropyridine, chloropyrimidine and chloropyrazine in when�outstay proper reason, such as teas, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, etc., gives compounds 6. In the case of R10 = CN they are the end connections. In the case of R10 = Cl compound 6 communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, in the presence of an appropriate base such as DABCO, pyridine, tea, DIPEA that gives the final compound 7. In the case of R10 = -S-Me compound 6 is oxidized to the corresponding methylsulfone 8, for example with N2O2, axonom, MSRA, etc. At the end of the connection 8 communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, which gives the final compounds 9.

Scheme 6

Figure 6: R' is as defined above; PG = Protective group, e.g. Boc, Fmoc, Cbz or TEOS; X = N or O (R10 is absent for About);

R15 represents a leaving group such as F, Cl, Br or I; R15 = F, Cl, Br or I; LG = H, IN(OH)2B(OR')2or 4,4,5,5-pentamethyl-[1,3,2]dioxaborolane; R' = Me or Et; catalyst = example salts of copper or palladium with or without a ligand, are well known in the art; R4 is as defined above, except hydrogen.

Corresponding protected derivative of 3-hydroxy-pyrrolidino, such as tert-butyl ether (R)-3-hydroxy-pyrrolidin-1-carboxylic acid, the interaction�match with sulphonylchloride, such as Mes-Cl, Nos-Cl, Tos-Cl or triftormetilfullerenov anhydride, in the presence of base, such as tea, DIPEA, pyridine, etc., which gives compound 2. The reaction of 2 with thiols in the presence of an appropriate base, such as NaH, LiHMDS, DIPEA, teas, etc., gives compounds of type 3. Oxidation of the obtained thioether is performed under the influence of the respective oxidizer, such as H2O2, Oxon, MSRA, etc., giving compound 4. The protective group PG is removed, in the case of Boc as protecting groups with TFA, HCl or formic acid in an appropriate solvent, such as THF, dioxane, CH2Cl2etc., which gives compound 5. In the case of PG = Fmoc cleavage piperidine is used; if PG = Cbz, you can use HBr in acetic acid or catalytic hydrogenation. In the case of PG = theos can be used TBAF for splitting, which gives compound 5. The reaction of compounds 5 with derivatives of chloropyridine, chloropyrimidine and chloropyrazine in the presence of an appropriate base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, etc., gives compounds 6. In the case of R10 = CN these compounds directly interact with amines or alcohols, or derivatives Bronevoy acid R4-LG in the presence of base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs 2CO3and KF, NaF and CsF, or in the presence of base, as described above, and a catalyst, which gives the connection 11. In the case of R10 = Cl compound 6 communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, in the presence of an appropriate base such as DABCO, pyridine, tea, DIPEA that gives compound 7. Compound 7 interact with amines or alcohols, or derivatives Bronevoy acid R4-LG in the presence of base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, or in the presence of base, as described above, and a catalyst that provides the end-connections 11. In the case of R10 = S-Me compound 6 is oxidized to the corresponding methylsulfone 8, for example with N2O2, axonom, MSRA, etc. At the end of the connection 8 communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, which gives compound 9. Connection 9 interact with amines or alcohols, or derivatives Bronevoy acid R4-LG in the presence of base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, or in the presence of base, as described above, and a catalyst that provides the end-connections 10. Alternatively, in the case of R10 = S-Me connection 6 interact with amines or alcohols, or derivatives Bronevoy acid R4-L in the presence of base, such as teas, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, or in the presence of base, as described above, and a catalyst that gives compound 12. The connection 12 is oxidized to the corresponding methylsulfone 13, for example with H2O2, axonom, MSRA, etc. At the end of the connection 13 communicate with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, which gives the final compound 14.

Scheme 7

Figure 7: R15 is a leaving group such as F, Cl, Br or I; R15 = F, Cl, Br or I; LG = H, IN(OH)2, B(OR")2or 4,4,5,5-pentamethyl-[1,3,2]dioxaborolane; catalyst = example salts of copper or palladium with or without a ligand, are well known in the art; R4 is as defined above, except hydrogen.

2,4-Dichloro-pyrimidine-5-carbonylchloride 1 interacts in the presence of a suitable base, such as tea, DIPEA, pyridine, etc., with an amine R1-NH2in an appropriate solvent, such as THF, DMF, ACN, dichloro methane, etc., which gives the corresponding amide 2. After that 2 react with a derivative of pyrrolidine 3 (synthesis of 3 described above) in the presence of a suitable base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, etc., which gives compound 4. Connect 4 inter�actuat with a source of cyanide, such as NaCN, KCN or tetrabutylammonium cyanide, in the presence of an appropriate base such as DABCO, pyridine, tea, DIPEA that gives the final compound 5. Connection 5 interact with amines or alcohols, or derivatives Bronevoy acid R4-LG in the presence of base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, or in the presence of base, as described above, and the catalyst that gives the final compounds 6.

Scheme 8

Figure 8: PG: protective group as defined in scheme 1; R15 represents a leaving group such as F, Cl, Br or I; R15 = F, Cl, Br or I; LG = H, IN(OH)2, B(OR")2or 4,4,5,5-pentamethyl-[1,3,2]dioxaborolane; catalyst = example salts of copper or palladium with or without a ligand, are well known in the art; R4 is as defined above, except hydrogen. X = triflic, tosylate, brasilit, nosrat, mesilate, Cl, Br, I, IT (in the case of carboxylic acids).

Derived pyrrolidine 1 (synthesis described above) is reacted with amines or alcohols, or derivatives Bronevoy acid R4-LG in the presence of base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF, NaF and CsF, or in the presence of base, as described above, and a catalyst that gives compound 2. Protection�second group PG is removed, in the case of Boc as protecting groups with TFA, HCl or formic acid in an appropriate solvent, such as THF, dioxane, CH2Cl2etc., which gives compound 3. In the case of PG = Fmoc is used for splitting the piperidine. In the case of PG = Cbz, you can use HBr in acetic acid or catalytic hydrogenation. In the case of PG = theos can be used TBAF for cleavage, which gives compound 3. After this connection 3 communicates with a protected 2,4-dichloro-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine in the presence of a suitable base, such as tea, DIPEA, pyridine, Na2CO3, K2CO3Ca2CO3and KF, NaF and CsF, etc., which gives compound 4. The protective group PG is removed, in the case of Boc as protecting groups with TFA, HCl or formic acid in an appropriate solvent, such as THF, dioxane, CH2Cl2etc., which gives compound 5. In the case of PG = Fmoc is used for splitting the piperidine. In the case of PG = Cbz, you can use HBr in acetic acid or catalytic hydrogenation. In the case of PG = theos can be used TBAF for cleavage, which gives compound 5. Compound 5 is then interacts with alkylating or allereie agents R1-X in the course of the processes known in the art, that gives compound 6. Compound 6 reacted with a source of cyanide, such as NaCN, KCN or tet�of butylamine cyanide, in the presence of an appropriate base such as DABCO, pyridine, tea, DIPEA that gives the final compound 7.

The invention also relates to a method of obtaining compounds of formula (I), which comprises one of the following steps according to which:

(a) is subjected to the interaction of the compound of formula (A)

in the presence of base and a compound of formula (In)

;

(b) is subjected to the interaction of the compound of formula (C)

in the presence of a source of cyanide and base;

where And1-And4and R1-R6are as defined above, and where R10represents chlorine, fluorine or methyl-sulfonyl.

At the stage of (a) the base is, for example teas, DIPEA, pyridine, Na2CO3, K2CO3, Cs2CO3and KF or NaF and CsF.

At the stage (b) the source of cyanide is, for example, NaCN, KCN, potassium ferrocyanide, tetraethylammonium cyanide or tetrabutylammonium cyanide.

At the stage (b) the base is, for example, DABCO, pyridine, lutidine, tea or DIPEA, Na2CO3, K2CO3, Cs2CO3and KF or NaF and CsF.

In addition, the invention relates to the compound of formula (I) for use as therapeutically active substances.

The invention also relates�I to the compound of formula (I) for use as therapeutically active substances for the treatment or prophylaxis of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, cardiovascular complications in chronic kidney disease, diabetic nephropathy, diabetic retinopathy or age-related degeneration of the macula, particularly atherosclerosis, cancer, cardiovascular complications in chronic kidney disease, age-related macular degeneration, diabetic nephropathy or diabetic retinopathy.

Compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be entered internally, namely, oral (e.g., in the form of pills, tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, effective may also be parenteral, such as intramuscular or intravenously (e.g. in the form of injection solutions).

Manufacture of tablets, tablets, coated tablets, dragees and hard gelatin capsules may include the treatment of compounds of formula (I) and their pharmaceutically acceptable salts with pharmaceutically inert, inorganic or organic adjuvants. As such adjuvants d�I pills dragees and hard gelatin capsules can be used lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc.

Suitable adjuvants for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols, etc.

Suitable adjuvants for the production of solutions and syrups are e.g. water, polyols, sucrose, invert sugar, glucose etc.

Suitable adjuvants for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.

Suitable adjuvants for suppositories are, for example natural or solidified oils, waxes, fats, semi-solid or liquid polyols, etc.

In addition, the pharmaceutical preparations can contain preservatives, soljubilizatory that increase the viscosity of substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigent, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a therapeutically inert carrier.

The invention also relates to the use of a compound of formula (I) �La the manufacture of drugs for the treatment or prophylaxis of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, cardiovascular complications in chronic kidney disease, diabetic nephropathy, diabetic retinopathy or age-related degeneration of the macula, particularly atherosclerosis, cancer, cardiovascular complications in chronic kidney disease, age-related macular degeneration, diabetic nephropathy or diabetic retinopathy.

The compound of formula (I), manufactured according to the method of the invention is a subject invention.

The invention also relates to a method of treatment or prophylaxis of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, cardiovascular complications in chronic kidney disease, diabetic nephropathy, diabetic retinopathy or age-related degeneration of the macula, particularly atherosclerosis, cancer, cardiovascular complications in chronic kidney disease, age-related macular degeneration, diabetic nephropathy or diabetic retinopathy, according to which it is administered an effective amount of a compound of formula (I).

The invention will now be illustrated by the following examples, not limiting it.

Examples

Example 1

6-[(2S,4S)-4-(2-Chloro-benzolsulfonat)-2-(morpholine-4-carbonyl)-pyrrolidin-1-yl]-pyrazine-2-carb�nitrile

A) 1-tert-Butyl ester 2-methyl ester (2S,4R)-4-(3-nitro-benzolsulfonat)-pyrrolidin-1,2-dicarboxylic acid

1-tert-Butyl ester 2-methyl ester (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid (5.0 g) was dissolved in was held (50 ml) and 3-nitrobenzenesulfonamide (4.8 g) was added. This solution was cooled to 5°C and carefully added tea (8,52 ml). The reaction mixture was stirred at 25°C for 18 hours. Then the reaction mixture was extracted with 0.1 n aqueous HCl (50 ml) and aqueous Na2CO3(50 ml), and brine (50 ml). The organic layer was dried over Na2SO4, filtered and evaporated to dryness, which gave a light brown amorphous solid (9,05 g). MS: m/z = to 431.4 [M+H]+.

B) 1-tert-Butyl ester 2-methyl ester (2S,4S)-4-(2-chloro-phenylsulfanyl)-pyrrolidine-1,2-dicarboxylic acid

Example 1A (3.0 g) was dissolved in ACN (30 ml). 2-Chlorothiophenol (3.0 g) and tea (2,91 ml) was added to the reaction mixture. The reaction mixture was stirred under heating to reflux for 18 hours. Then the reaction mixture was quenched with water (20 ml) and was extracted with ethyl acetate (200 ml) and brine (30 ml). The organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified using �lash chromatography (silica gel; ethyl acetate/n-heptane), giving a colorless oil (2,07 g; 79.9 percent). MS: m/z = 372,0 [M+H]+.

C) 1-tert-Butyl ester 2-methyl ester (2S,4S)-4-(2-chloro-benzolsulfonat)-pyrrolidin-1,2-dicarboxylic acid

Example 1B (of 2.06 g) was dissolved in was held (25 ml) and cooled to 0°C. was Slowly added MSRA (2,87 g) and the reaction mixture was warmed to 25°C. the Reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was diluted was held (50 ml) and extracted three times with an aqueous solution of Na2CO3(50 ml) and brine (50 ml). The organic layers were dried over Na2SO4, filtered and evaporated (peroxide test was negative) to dryness, which gave a light brown oil (of 2.06 g; 92%). MS: m/z = 404,0 [M+H]+.

(D) 1-tert-Butyl ether (2S,4S)-4-(2-chloro-benzolsulfonat)-pyrrolidin-1,2-dicarboxylic acid

Example 1C (1.0 g) was dissolved in THF/water (7.5 ml/2.5 ml). To this stirred solution was added LiOH (65 mg) and the reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and was extracted with 1 n aqueous HCl solution (10 ml) and brine. The organic layers were dried over Na2SO4, filtered and evaporated to dryness, which gave a colorless oil (1.16 g, 120%, crude product). MS: m/z = 390,3 [M+H]+; 388,2 [M-N] .

(E) tert-Butyl ether (2S,4S)-4-(2-chloro-benzolsulfonat)-2-(morpholine-4-carbonyl)-pyrrolidin-1-carboxylic acid

Example 1D (1.1 g) was dissolved in ACN (15 ml) was added EDCl (703 mg), NOWT (562 mg) and DIPEA (0,62 ml). The reaction mixture was stirred for 1 hour at 25°C. After which was added morpholine (0,32 ml) and the reaction mixture was stirred at 25°C for 18 hours. Thereafter, the reaction mixture was diluted with ethyl acetate (50 ml), was extracted with 1 n aqueous HCl (20 ml), an aqueous solution of Na2CO3(20 ml) and brine (20 ml). The organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude substance was purified using flash chromatography (20 g of silica gel; ethyl acetate/n-heptane) which gave a white foam shade (0,57 g; 44%). MS: m/z = 459,1 [M+H]+.

(F) [(2S,4S)-4-(2-Chloro-benzolsulfonat)-pyrrolidin-2-yl]-morpholine-4-yl-methanon

Example 1E (0,57 g) was dissolved in was held (3.5 ml) and added TFA (2.5 ml). The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was diluted was held (3.5 ml) and was extracted with an aqueous solution of Na2CO3(10 ml) and brine (10 ml). The organic layers were dried over Na2SO4, filtered and evaporated to dryness, giving a white solid (0,43 g; 96%). MS: m/z = 359,1 [M+H]+.

G) 6-[(2S,4S)-4-(2-Chloro-benzo�sulfonyl)-2-(morpholine-4-carbonyl)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile (Specified in the header connection)

Example 1F (60 mg), 6-cyano-2-chloropyrazine (26 mg), KF (1 mg) and tea (0.07 ml) were combined in a microwave vial and was dissolved in ACN (2 ml). The reaction mixture was stirred in the microwave at 130°C for 1 hour. The reaction mixture was filtered and purified using preparative HPLC, which gave a solid white shade (9 mg; 12%). MS: m/z = 462,3 [M+H]+.

Example 2

Methyl ester (2S,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid

A) Methyl ester of (2S,4S)-4-(2-chloro-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 1C (100 mg) was dissolved in was held (1.5 ml) and added TFA (0.75 ml). The reaction mixture was stirred at 25°C for 18 hours. Thereafter, the reaction mixture was held was diluted (10 ml) and was extracted with an aqueous solution of Na2CO3(10 ml) and brine (10 ml). The organic layers were dried over Na2SO4, filtered and evaporated to dryness, giving a solid substance of white color (71 mg; 95%). MS: m/z = 304,3 [M+H]+.

B) Methyl ester of (2S,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid

Specified in the title compound was obtained in analogy to example 1G, based on the Example 2A (71 mg), which gave brown, pink�th solid (9 mg; 10%). MS: m/z=407,1 [M+H]+.

Example 3

6-[3-(4-Hydroxy-benzolsulfonat)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 1G, based on CAS 371240-19-6, which gave a light brown waxy solid (19 mg; 11%). MS: m/z = 331,3 [M+H]+.

Example 4

6-[3-({4-[(6-Cyanopyridine-2-yl)oxy]phenyl}sulfonyl)pyrrolidin-1-yl]pyrazine-2-carbonitrile

Specified in the title compound was obtained as a side product during the synthesis of example 3, which gave a light brown solid (38 mg; 25%). MS: m/z = 434,2 [M+H]+.

Example 5

(2S,4S)-4-(2-Chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylate lithium

Example 2 (77 mg) was dissolved in THF (1.5 ml) and added LiOH hydrate (10 mg). The reaction mixture was stirred at 25°C for 1 hour. Then added water (0.05 ml) and the mixture was stirred for 0.5 hours at 25°C. the Reaction mixture was evaporated to dryness, which gave specified in the title compound as a light brown solid (83 mg; 100%). MS: m/z = 390,9 [M-N]-.

Example 6

(2,2,2-Cryptor-ethyl)-amide (2S,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid

Example 5 (81 mg) was dissolved in DMF (2.0 ml) was added EDCl (58 mg), NOWT (47 mg) and DIPEA (0.05 ml) at 25°C. the Reaction mixture was stirred at 25°C for 2 hours. After which was added 2,2,2-triptorelin (30 mg) and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was filtered and purified using preparative HPLC, which gave a light brown solid (29 mg; 30%). MS: m/z = 474,1 [M+H]+.

Example 7

Ethyl ester of (2R,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid

Example 7 was obtained by analogy with the methods described for examples 1 and 2, on the basis of 1-tert-butyl ester 2-ethyl ester (2R,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid, which gave a solid substance of white color. MS: m/z = 421,1 [M+H]+.

Example 8

6-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyridine-2-carbonitril

Example 8 was obtained by analogy with the methods described for examples 1 and 2, based on tert-butyl ether (R)-3-hydroxy-pyrrolidin-1-carboxylic acid using tert-butyl ether (R)-3-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid that gave a light brown solid. MS: m/z = 348,1 [M+H]+.

Example 9

6-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrazine-2-car�amitril

Example 9 was obtained by analogy with the methods described for examples 1 and 2, based on tert-butyl ether (R)-3-hydroxy-pyrrolidin-1-carboxylic acid using tert-butyl ether (R)-3-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid that gave a brown amorphous solid. MS: m/z = to 349.1 [M+H]+.

Example 10

6-[(2R,4S)-4-(2-Chloro-benzolsulfonat)-2-(morpholine-4-carbonyl)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile

Example 10 was obtained by analogy with the methods described for example 1, on the basis of 1-tert-butyl ester 2-ethyl ester (2R,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid, giving a brown solid. MS: m/z = 462,2 [M+H]+.

Example 11

(2,2,2-Cryptor-ethyl)-amide (2R,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid

Example 10 was obtained by analogy with the methods described for example 6, on the basis of 1-tert-butyl ester 2-ethyl ester (2R,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid, giving a brown solid. MS: m/z = 474,2 [M+H]+.

Example 12

4-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Example 12 was obtained by analogy with the methods,�Izanami for example 1 based on tert-butyl ether (R)-3-hydroxy-pyrrolidin-1-carboxylic acid using tert-butyl ether (R)-3-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid except the last two reaction steps:

A) 2-Chloro-4-[(S)-3-(2-chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine

TFA salt of (S)-3-(2-chloro-benzolsulfonat)-pyrrolidine (250 mg) was dissolved in ACN (3.0 ml). To the solution was added 2,4-dichloropyrimidine (155 mg), Thea (0,39 ml) and KF (4 mg). The reaction mixture was stirred at 150°C in microwave oven for 2 hours. The reaction mixture was evaporated to dryness and purified using preparative HPLC, which gave 2-chloro-4-[(S)-3-(2-chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine (91 mg, 36%) as a light yellow solid. MS: m/z = 358,0 [M+H]+.

B) 4-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Example 12A (50 mg) was dissolved in DMSO/water (1.3 ml/0.2 ml). To the solution was added DABCO (31 mg) and KCN (18 mg). The reaction mixture was stirred at 80°C for 4 hours. Then the reaction mixture was stirred at temprature environment for 18 hours. Then the reaction mixture was again heated at 80°C for 3 hours. The reaction mixture was filtered, evaporated to dryness and purified using preparative HPLC, which gave specified in the header Conn�kit (30 mg, 63%) in the form of a solid substance of white color. MS: m/z = to 349.1 [M+H]+.

Example 13

4-[(2R,4S)-4-(2-Chloro-benzolsulfonat)-2-(5-methyl-[1,3,4]oxidiazol-2-yl)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

A) 1-tert-Butyl ester 2-ethyl ester (2R,4S)-4-(2-chloro-benzolsulfonat)-pyrrolidin-1,2-dicarboxylic acid

Example 13A was obtained in analogy to example 1C, on the basis of 1-tert-butyl ester 2-ethyl ester (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid, which gave a solid substance of white color. MS: m/z = 418,2; 362,0; 318,1 [M+H]+.

B) tert-Butyl ester (2R,4S)-4-(2-chloro-benzolsulfonat)-2-hydrazinophenyl-pyrrolidin-1-carboxylic acid

Example 13A (271 mg) was dissolved in ethanol (2.5 ml). Was added hydrazine hydrate (97 mg) and the reaction mixture was heated to reflux in 10 for three days. Then the mixture was evaporated to dryness, which gave a light yellow foam (250 mg; 95%). MS: m/z = 304,1; 348,0; 404,2 [M+H]+.

C) tert-Butyl ester (2R,4S)-4-(2-chloro-benzolsulfonat)-2-(5-methyl-[1,3,4]oxidiazol-2-yl)-pyrrolidin-1-carboxylic acid

Example 13C (250 mg) was dissolved in acetonitrile (3.5 ml) and added acetic anhydride (79 mg) and DIPEA (0,74 ml). The reaction mixture was stirred for 3 hours at 25°C. After e�CSOs were added triphenylphosphine (649 mg) and hexachlorethane (337 mg). The reaction mixture was stirred for 18 hours at 25°C. the Reaction mixture was evaporated to dryness, dissolved in ethyl acetate (20 ml), was extracted with water (10 ml) and brine (10 ml). The organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude substance was purified using flash chromatography using silica gel (20 g column) and ethyl acetate: n-heptane(0:1→1:0), which gave specified in the title compound as a light yellow solid (164 mg; 62%). MS: m/z = 428,1; 328,3 [M+H]+.

D) 2-[(2R,4S)-4-(2-Chloro-benzolsulfonat)-pyrrolidin-2-yl]-5-methyl-[1,3,4]oxidiazol

Example 13C (164 mg) was dissolved in dichloromethane(1.5 ml) and then was added TFA (1.5 ml). The reaction mixture was stirred for 2 hours at 25°C, evaporated to dryness, dissolved in dichloromethane and extracted with an aqueous solution of Na2CO3and saline solution. The organic layers were dried over Na2SO4, filtered and evaporated to dryness, which gave a light brown solid (30 mg; 24%). MS: m/z = to 328.2 [M+H]+.

(E) 2-Chloro-4-[(2R,4S)-4-(2-chloro-benzolsulfonat)-2-(5-methyl-[1,3,4]oxidiazol-2-yl)-pyrrolidin-1-yl]-pyrimidine

Specified in the title compound was obtained from 13D in analogy to example 12A, which gave a yellow solid (29 mg; 72%). MS: m/z = 440,1 [M+H]+.

Specified in the title compound was obtained from example 13E by analogy with example 12, which gave a solid white shade (8 mg; 22%). MS: m/z = 431,1 [M+H]+.

Example 14

4-[(S)-3-(2-Trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Example 14 was obtained in analogy to example 12, which gave specified in the title compound as a colorless amorphous solid (113 mg; 70%) MS: m/z = 383,1 [M+H]+.

Example 15

4-[(2R,4S)-2-Gidroximetil-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

A) tert-Butyl ester (2R,4R)-2-[dimethyl-(1,1,2-trimethyl-propyl)-silyloxy]-4-hydroxy-pyrrolidin-1-carboxylic acid

tert-Butyl ester (2R,4R)-4-hydroxy-2-gidroximetil-pyrrolidin-1-carboxylic acid (3.8 g) was dissolved in DMF (25 ml). Dropwise was added imidazole (1,79 g) and taxidermically (3,75 g) at 0°C. then the reaction mixture was warmed to 25°C. the Reaction mixture was then stirred at 25°C for additional 3 hours. The reaction mixture was then diluted with n-hexane (50 ml) and was extracted with aqueous citric acid solution (10%, 50 ml) and brine (50 ml). The organic layers were dried over Na2SO4that was filtered vypaivali dry, which gave a light brown oil (5,94 g; 94%). MS: m/z = 360,3; 260,2 [M+H]+.

B) tert-Butyl ester (2R,4R)-2-[dimethyl-(1,1,2-trimethyl-propyl)-silyloxy]-4-(3-nitro-benzolsulfonat)-pyrrolidin-1-carboxylic acid

Specified in the title compound was obtained from example 15A (5,94 g) by analogy with the method described for example 1A, which gave a brown oil (9.3 g; 99%) MS: m/z = 545,3; 489,3; 445,4 [M+H]+.

C) tert-Butyl ester (2R,4S)-2-[dimethyl-(1,1,2-trimethyl-propyl)-silyloxy]-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-carboxylic acid

Example 15C was obtained from example 15B (9.3 g), by analogy with the methods described for examples 1B and 1C, which gave specified in the title compound as light yellow solids (stage 2, 7.4 g; total yield 73%) MS: m/z = 552,4; 496,2; 542,2 [M+H]+.

(D) [(2R,4S)-4-(2-Trifluoromethyl-benzolsulfonat)-pyrrolidin-2-yl]-methanol

Example 15C (2 g) was dissolved in dichloromethane (15 ml). TFA (10 ml) was added and the reaction mixture was stirred for 18 hours at 25°C. the Reaction mixture was diluted with dichloromethane (25 ml) and was extracted with an aqueous solution of Na2CO3and saline solution. The organic layers were dried over Na2SO4, filtered and evaporated to dryness, giving a white oil about�tenka (654 mg; 58%). MS: m/z = 310,2 [M+H]+.

E) 4-[(2R,4S)-2-Gidroximetil-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained from example 15D (250 mg) in analogy to the methods described for examples 12A and 12B, which gave a light yellow solid substance (step 2, 47 mg; total yield 35%) MS: m/z = 413,2 [M+H]+.

Example 16

4-Methyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 12, which gave a colorless amorphous solid (72 mg; 61%) MS: m/z = 397,1 [M+H]+.

Example 17

5-Trifluoromethyl-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 12, which gave a brown powder (48 mg; 25%) MS: m/z = 451,1 [M+H]+.

Example 18

5-Fluoro-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 12, which gave a light brown gum (22 mg; 28%) MS: m/z = 401,1 [M+H]+.

Example 19

5-GI�Roxy-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained as a side product during the synthesis of example 18 (22 mg; 28%) MS: m/z = 399,1 [M+H]+.

Example 20

4-[(2R,4S)-2-Morpholine-4-ylmethyl-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

A) tert-Butyl ester (2R,4S)-2-gidroximetil-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-carboxylic acid

Example 15C (5.4 g) was dissolved in THF (55 ml) and added hydrate TBAF (3.7 g). The reaction mixture was stirred at 25°C for 4 hours. Thereafter, the reaction mixture was evaporated to dryness and purified using flash chromatography (200 g silica gel, ethyl acetate/n-heptane; 0:1→1:0), which gave specified in the title compound as a light yellow oil (2.85 g; 71%) MS: m/z = 410,2; 354,2; 310,2 [M+H]+.

B) tert-Butyl ester (2R,4S)-2-methanesulfonylaminoethyl-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-carboxylic acid

Example 20A (800 mg) was dissolved in acetonitrile (8 ml). Added DIPEA (0.4 ml) and methanesulfonamide (of 0.18 ml). The reaction mixture was stirred at 25°C for 18 hours. Then the reaction mixture was diluted with ethyl acetate (50 ml) and was extracted with aqueous solution of HCl (0,1 n; 10 ml), an aqueous solution of Na2CO3(10 ml) and brine (10 �l). The organic layers were dried over Na2SO4, filtered and evaporated to dryness, which gave a light brown oil (977 mg; 100%). MS: m/z = 388,1; 432,2 [M+H]+.

C) tert-Butyl ester (2R,4S)-2-morpholine-4-ylmethyl-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-carboxylic acid

Example 20B (488 mg) was dissolved in acetonitrile (5 ml). Added DIPEA (0.2 ml) and morpholine (0.98 ml). The reaction mixture was stirred at 25°C for 18 hours. Then the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was evaporated to dryness and purified using flash chromatography (20 g silica gel, ethyl acetate/n-heptane; 0:1→1:0), which gave specified in the title compound as a light red solid (254 mg; 53%) MS: m/z = 479,1; 423,2 [M+H]+.

D) 4-[(2R,4S)-2-Morpholine-4-ylmethyl-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained from example 20C (254 mg) in analogy to methods described for example 12, which gave a white solid (21 mg; 50%) MS: m/z = 482,1 [M+H]+.

Example 21

2-[(2R,4S)-2-Morpholine-4-ylmethyl-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-4-carbonitrile

Specified in the title compound was obtained as a byproduct during SYN�ESA of example 20, which gave a white solid (4 mg; 30%) MS: m/z = 482,2 [M+H]+.

Example 22

4-[(2R,4S)-2-(3,3-Debtor-pyrrolidin-1-ylmethyl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 20, which gave a white solid (15 mg; 46%) MS: m/z = to 502.1 [M+H]+.

Example 23

4-[(S)-3-(2,3-Dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 12, which gave a solid white shade (25 mg; 28%) MS: m/z = 383,1 [M+H]+.

Example 24

4-[(R)-3-(2-Bromo-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 12, which gave a yellow solid (77 mg; 44%) MS: m/z = 393,1 [M+H]+.

Example 25

4-[(S)-3-(3-Trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 12, which gave a viscous oil white tint (77 mg; 44%) MS: m/z=383,2 [M+H]+.

Example 26

(2,2,2-Cryptor-ethyl)-amide (2S,4S)-1-(2-qi�but-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

A) Methyl ester of (2S,4S)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 26A was obtained by analogy with example 2A, which gave a colorless oil (2,07 g; 85%) MS: m/z = 338,2 [M+H]+.

B) Methyl ester of (2S,4S)-1-(2-chloro-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 26A (2,07 g) was dissolved in acetonitrile (10 ml). 2,6-Dichloropyrimidine (1.01 g), Thea (2,57 ml) and KF (36 mg) was added to the mixture in a sealed tube. The mixture was heated in a microwave oven at 150°C for 1.5 hours. The reaction mixture was evaporated to dryness and purified using flash chromatography (50 g silica gel, ethyl acetate/n-heptane; 0:1→1:0), which gave a light brown solid (660 mg; 24%) MS: m/z = of 450.1 [M+H]+.

C) (2S,4S)-1-(2-Chloro-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylate lithium

Example 26B (580 mg) was dissolved in THF/water (4.5 ml/1.0 ml). Dehydrate lithium hydroxide (60 mg) was added to the solution. The resulting suspension was stirred at 25°C for 2.5 hours. Was then added water (1 ml) and the resulting solution was stirred for an additional 3.5 hours. After this was added to a solution of additional lithium hydroxide dihydrate (11 mg) and the mixture was stirred in tech�of 18 hours at 25°C. The reaction mixture was then evaporated to dryness, which gave 590 mg (104%) of salt. Example 26C used without further purification in the next stages. MS: m/z = 436,2 [M+H]+.

(D) (2,2,2-Cryptor-ethyl)-amide (2S,4S)-1-(2-chloro-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 26C (147. mg) was dissolved in acetonitrile (2.0 ml). To the mixture were added DIPEA (0,17 ml), HATU (77 mg) and EDCl (96 mg). After 30 minutes, was added 2,2,2-triptoreline hydrochloride (68 mg). The mixture was stirred for 18 hours at 25°C. Then the reaction mixture was evaporated to dryness, dissolved in ethyl acetate (20 ml) and was extracted with an aqueous solution of Na2CO3(10%; 10 ml) and aqueous HCl solution (0,1 n; 10 ml), and brine (10 ml). The organic layers were dried over Na2SO4and was filtered, and evaporated to dryness, which gave a light brown oil (93 mg; 54%). MS: m/z = 517,2 [M+H]+.

(E) (2,2,2-Cryptor-ethyl)-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 26D (93 mg) was dissolved in DMSO (1.7 ml) was added DABCO (40 mg) and KCN (23 mg). Was then added water (0.3 ml) and the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was filtered and purified using preparative HPLC, which gave specified in the title compound in the form�e white solid (22 mg; 24%). MS: m/z = 508,2 [M+H]+.

Example 27

4-[(2S,4S)-2-(Azetidin-1-carbonyl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Example 27 was obtained in analogy to methods described for example 26, which gave specified in the title compound as a light brown oil (26 mg; 27%). MS: m/z = 466,3 [M+H]+.

Example 28

((S)-2,2,2-Cryptor-1-methyl-ethyl)-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 28 was obtained by analogy with the methods described for example 26, which gave specified in the title compound as a yellow solid (18 mg; 15%). MS: m/z = 522,2 [M+H]+.

Example 29

Diethylamide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 29 was obtained in analogy to methods described for example 26, which gave specified in the title compound as a light yellow solid (14 mg; 17%). MS: m/z = 482,3 [M+H]+.

Example 30

(2S,4S)-1-(2-Cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 30 was obtained from example 26B (80 mg) using the method described for example 26E, giving you provide during account creation�e in the title compound as a yellow amorphous solid (11 mg; 15%). MS: m/z = 427,1 [M+H]+.

Example 31

Amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

(A) Amide (2S,4S)-1-(2-chloro-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 26C (75 mg) was dissolved in acetonitrile (2.0 ml) was added di-tert-butyl-dicarbonate (48 mg). Then was added pyridine (0.01 ml) and ammonium bicarbonate (17 mg). The reaction mixture is then stirred for 3 days at 25°C. After which was added ammonium bicarbonate (8 mg) and di-tert-butyl-dicarbonate (24 mg). The reaction mixture was stirred under heating to reflux for 18 hours. Then was added ammonium bicarbonate (17 mg) and di-tert-butyl-dicarbonate (48 mg) and the reaction mixture was heated to reflux for an additional 18 hours. Thereafter, the reaction mixture was diluted with ethyl acetate (20 ml) and was extracted with aqueous Na2CO3(10%; 10 ml) and brine (10 ml). The organic layers were dried over Na2SO4, filtered and evaporated to dryness, giving an example 31A in the form of a light brown oil (56 mg, 76%) which was used without further purification. MS: m/z = 435,3 [M+H]+.

In) Amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzols�were radioactive)-pyrrolidin-2-carboxylic acid

Example 31B was obtained by analogy with the method described for example 26E, which gave specified in the title compound in a solid white shade (13 mg; 24%). MS: m/z = to 426.2 [M+H]+.

Example 32

Ethylamide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 32 was obtained by analogy with the methods described for example 26, which gave specified in the title compound as a light yellow amorphous substance (13 mg; 27%). MS: m/z = 454,2 [M+H]+.

Example 33

Cyanomethyl-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 33 was obtained by analogy with the methods described for example 26, which gave specified in the title compound in a solid white shade (23 mg; 43%). MS: m/z = 465,1 [M+H]+.

Example 34

4-[(2S,4S)-2-(3,3-Debtor-pyrrolidin-1-carbonyl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Example 34 was obtained by analogy with the methods described for example 26, which gave specified in the title compound as a light yellow amorphous substance (25 mg; 29%). MS: m/z = 516,4 [M+H]+.

Example 35

4-Fluoro-benzylamine (2S,4S)-1-(2-C�ANO-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 35 was obtained by analogy with the methods described for example 26, which gave specified in the title compound as a light yellow solid (19 mg; 22%). MS: m/z = 534,2 [M+H]+.

Example 36

(1-Cyano-cyclopropyl)-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 36 was obtained by analogy with the methods described for example 26, which gave specified in the title compound as a white solid (20 mg; 27%). MS: m/z = to 491.2 [M+H]+.

Example 37

Isopropylated (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 32 was obtained by analogy with the methods described for example 26, which gave specified in the title compound in a solid white shade (7 mg; 27%). MS: m/z = 468,2 [M+H]+.

Example 38

4-[(S)-3-(2-Trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-6,7-dihydro-5H-cyclopentadienide-2-carbonitril

Specified in the title compound was obtained in analogy to methods described for example 12, which gave a light yellow solid (17 mg; 7%) MS: m/z = 423,2 [M+H]+.

Example 39

5-Methyl-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrole�in-1-yl]-pyrimidine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 12, which gave a brown solid (13 mg; 26%) MS: m/z = 397,2 [M+H]+.

Example 40

4-Trifluoromethyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

A) 2-Methylsulfanyl-4-trifluoromethyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine

(S)-3-(2-Trifluoromethyl-benzolsulfonat)-pyrrolidine (500 mg) was dissolved in acetonitrile (3.5 ml) in a microwave vial. 4-Chloro-2-(methylsulfanyl)-6-(trifluoromethyl)pyrimidine (450 mg), tea (0.75 ml) and KF (10 mg) was added. The reaction mixture was irradiated in a microwave oven at 150°C for 1.5 hours. The reaction mixture was evaporated to dryness and purified using flash chromatography (50 g silica gel, ethyl acetate/n-heptane: 0:1→1:0), which gave a light yellow oil (790 mg; 94%) MS: m/z = 472,2 [M+H]+.

B) 2-Methanesulfonyl-4-trifluoromethyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine

Example 40A (790 mg) was dissolved in dichloromethane (10 ml) and cooled to 0°C. and Then carefully added MSRWA hydrate (496 mg). The reaction mixture was stirred at 25°C for 2 hours. Then the reaction mixture was diluted with dichloromethane (20 ml) and extra�grown with an aqueous solution of Na 2CO3(10%, 10 ml) and brine (10 ml). The organic layers were dried over Na2SO4, filtered and evaporated to dryness, giving a yellow oil (930 mg; 110%), which was used for next step without purification. MS: m/z = 504,1 [M+H]+.

C) 4-Trifluoromethyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile

Example 40B (930 mg) was dissolved in DMSO/water (5.0 ml/1.0 ml) was added NaCN (91 mg). The reaction mixture was stirred at 25°C for 18 hours. Then the reaction mixture was diluted with ethyl acetate (20 ml) and was extracted with water (10 ml) and brine (10 ml). The organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified using flash chromatography (50 g of silica gel; ethyl acetate/n-heptane: 0:1→1:0), which gave a white foam (264 mg; 32%). MS: m/z = 451,2 [M+H]+.

Example 41

Amide (S)-1-(2-cyano-6-trifluoromethyl-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid

Example 41 was obtained by analogy with the methods described for examples 31A and 40, which gave a white solid (81 mg; 24%). Epimerization amide residue occurred at the last stage of synthesis. MS: m/z = 494,1 [M+H]+.

Example 42

4-[(S)-3-(2-Chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-6-cryptomate�-pyrimidine-2-carbonitrile

Example 42 was obtained by analogy with the methods described for example 40, which gave a yellow solid (50 mg; 45%). MS: m/z = 435,3 [M+H]+.

Example 43

4-{(S)-3-[2-Chloro-4-(4-methyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile

Example 42 (50 mg) was dissolved in acetonitrile (2.0 ml). DIPEA (0.04 ml) and 1-methylpiperazine (0.03 ml) was added. The reaction mixture was stirred at 25°C for 4 hours. Then was added 1-methylpiperazine (0.04 ml) and the mixture was stirred at 25°C for 24 hours. The reaction mixture was then purified using preparative HPLC, which gave specified in the title compound in a solid white shade (33 mg; 56%). MS: m/z = 515,4 [M+H]+.

Example 44

4-{(S)-3-[4-(4-tert-Butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile; compound with formic acid

Example 44 was obtained by analogy with the methods described for example 43, which gave a light brown foam (87 mg; 63%). MS: m/z = 557,3 [M+H]+.

Example 45

4-[(S)-3-((3)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile; compound with formic acid

Example 45 semi�Ali by analogy with the methods, described for example 43, which gave a light brown solid (71 mg; 53%). MS: m/z = 541,4 [M+H]+.

Example 46

4-{(S)-3-[2-Chloro-4-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile

Example 42 (100 mg) was dissolved in DMA (2 ml). Was added cesium carbonate (150 mg) and (S)-tripolitana (52 mg). The reaction mixture was stirred in the microwave for 30 minutes at 80°C. the Reaction mixture was purified using preparative HPLC, which gave a colorless solid (27 mg; 22%). MS: m/z = 529,1 [M+H]+.

Example 47

4-[(S)-3-(2-Chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile

Example 47 was obtained by analogy with the methods described for example 46, which gave a colorless solid (21 mg; 21%). MS: m/z = 483,1 [M+H]+.

Example 48

4-{(S)-3-[2-Chloro-4-(4-cyclopropyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile

Example 48 was obtained by analogy with the methods described for example 43, which gave a white solid (14 mg; 11%). MS: m/z = 541,4 [M+H]+.

Example 49

4-{(S)-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile

Example 49 was obtained by analogy with the methods described for example 46, which gave a white solid (14 mg; 12%). MS: m/z = 515,3 [M+H]+.

Example 50

4-[(S)-3-(2-Chloro-4-imidazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile

Example 50 was obtained by analogy with the methods described for example 46, except that the mixture was heated for 3 days at 80°C. this gave a colorless solid (51 mg; 46%). MS: m/z = 483,1 [M+H]+.

Example 51

4-{(S)-3-[2-Chloro-4-(2-methoxy-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile

A) 4-{(S)-3-[2-Chloro-4-(2-methoxy-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-2-methylsulfanyl-6-trifluoromethyl-pyrimidine

4-[(S)-3-(2-Chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-2-methylsulfanyl-6-trifluoromethyl-pyrimidine (intermediate compound of example 42; 300 mg) was dissolved in DMF (5.0 ml). Added Cs2CO3(429 mg) and 2-methoxy-ethanol (0.10 ml). The reaction mixture was stirred for 24 hours at 25°C. then the reaction mixture was diluted with ethyl acetate (20 ml) and was extracted with water (10 ml). The organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude substance was purified using flash chromatography (50 g with�of leakages; ethyl acetate/n-heptane), giving a colorless waxy solid (170 mg; 50%) MS: m/z = 512,2 [M+H]+.

B) 4-{(S)-3-[2-Chloro-4-(2-methoxy-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-2-methanesulfonyl-6-trifluoromethyl-pyrimidine

Example V received by analogy with the methods described for example 40B, which gave a white foam (158 mg; 87%). MS: m/z = 544,2 [M+H]+.

C) 4-{(S)-3-[2-Chloro-4-(2-methoxy-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 40 ° C, which gave a light brown waxy solid (82 mg; 61%). MS: m/z = 491,1 [M+H]+.

Example 52

(2,2,2-Cryptor-ethyl)-amide 4-[(S)-3-(2-chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-2-cyano-pyrimidine-5-carboxylic acid

A) Synthesis of (2,2,2-Cryptor-ethyl)-amide of 2,4-dichloro-pyrimidine-5-carboxylic acid

2,4-Dichloropyrimidine-5-carbonylchloride (1 g, 5 mmol) was dissolved in CH2Cl2(20 ml), 2,2,2-triptorelin (515 mg, 5 mmol) and triethylamine (1.31 ml, 9 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was purified using flash chromatography gave a white solid (780 mg, 60%). MS: m/z= 271,9 [M-N] -.

B) tert-Butyl ether (R)-3-(3-nitro-benzolsulfonat)-pyrrolidin-1-carboxylic acid

(R)-(-)-N-BOC-3-pyrrolidinone (25 g, 134 mmol) was dissolved in CH2Cl2(250 ml) and Nos-Cl (of 31.36 g, 142 mmol) was added. The solution was cooled to 0°C and tea (of 55.5 ml, 401 mmol) slowly and carefully added through the dropping funnel. The ice bath was removed and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was extracted with 10% aqueous solution of Na2CO3and 0.1 N. aqueous solution of HCl. The organic layers were dried over Na2SO4, filtered and evaporated to dryness, which gave a dark brown oil (39,8 g, 80%). MS: m/z = 373,1 [M+H]+.

C) tert-Butyl ether (S)-3-(2-chloro-4-fluoro-phenylsulfanyl)-pyrrolidin-1-carboxylic acid

Example 52) (39,8 g, 107 mmol) was dissolved in propionitrile (500 ml), 2-chloro-4-portifino (26,07 g, 160 mmol) was added. Then carefully added tea (29.6 ml). The reaction mixture was stirred under heating to reflux over night. The reaction mixture was diluted with AcOEt and extracted with aqueous solutions of 10% Na2CO3and 0.1 n HCl. The organic layers were dried over Na2SO4, filtered and evaporated. The reaction mixture was purified using flash chromatography, which gave a light yellow oil (31,8 g, 90%). MS: m/z = 26,0 [M+H-tBu] +.

D) tert-Butyl ether (S)-3-(2-chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-carboxylic acid

Example 52C) (31,8 g, 96 mmol) was dissolved in CH2Cl2(200 ml) at 25°C and cautiously portionwise added MSRA (24.8 g, 201 mmol). The reaction mixture was stirred at 25°C during the night. The reaction mixture was extracted with an aqueous 10% Na2CO3and 0.1 n HCl and a saturated aqueous solution of Na2S2O3. The organic layers were dried over Na2SO4Na2SO3within 2 hours, filtered and evaporated, which gave a colorless oil (34.3 g, 98%). MS: m/z = 308,4 [M+H-tBu]+.

(E) (S)-3-(2-Chloro-4-fluoro-benzolsulfonat)-pyrrolidin

Example 52D) (6.0 g, 16 mmol) was dissolved in formic acid (160 ml) and stirred at 25°C for 4 hours. The reaction mixture was carefully adjusted with cold aqueous 10% Na2CO3-solution (1600 ml) to pH 8 and was extracted with CH2Cl2. The aqueous layer was washed three times with CH2Cl2, the combined organic layers were dried over Na2SO4, filtered and evaporated, which gave a light brown waxy solid (4.26 g, 98%). MS: m/z = 264,1 [M+H]+.

F) (2,2,2-Cryptor-ethyl)-amide 2-chloro-4-[(S)-3-(2-chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Example 52A) (200 mg; 2 mmol) was dissolved in ACN (20 ml) was added example E) (614 mg, 2 mmol) and DIPEA (400 μl, 2 mmol). The reaction mixture was stirred at 25°C during the night. The reaction mixture was purified using flash chromatography. MS: m/z = 501,1 [M+H]+.

(G) (2,2,2-Cryptor-ethyl)-amide 4-[(S)-3-(2-chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-2-cyano-pyrimidine-5-carboxylic acid

Example 52F) (180 mg) was dissolved in DMSO (1.7 ml) was added DABCO (81 mg) and KCN (47 mg), and water (0.3 ml). The reaction mixture was stirred at 80°C for 1 hour. The mixture was purified using preparative HPLC, which gave an orange solid (43 mg, 24%). MS: m/z = 492,1 [M+H]+.

Example 53

(2,2,2-Cryptor-ethyl)-amide 4-{(S)-3-[4-(4-tert-butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid

Example 52G) (40 mg) was dissolved in ACN (2.0 ml), was added DIPEA (0.03 ml, 2 equiv.) and N-tert-butylpiperazine (23 mg, 2 equiv.). The reaction mixture was stirred for 24 hours at 25°C. the Reaction mixture was purified using preparative HPLC, which gave a brown solid (18 mg, 36%). MS: m/z = 614,1 [M+H]+.

Example 54

(2,2,2-Cryptor-ethyl)-amide 4-{(S)-3-[2-chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid

PR�measures 52G) (43 mg) was dissolved in DMF (1 ml), added Cs2CO3(56 mg, 2 equiv.) and 2,2,2-triptoreline (0.01 ml, 2 equiv.). The reaction mixture was stirred for 24 hours at 25°C. the Reaction mixture was purified using preparative HPLC, which gave a solid substance of white color (24 mg, 49%). MS: m/z = 572,1 [M+H]+.

Example 55

(2,2,2-Cryptor-ethyl)-amide 4-{(S)-3-[2-chloro-4-(4-cyclopropyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid

Example 52G) (43 mg) was dissolved in ACN (1.0 ml), was added DIPEA (0.06 ml, 4 equiv.) and 1-cyclopropylamine dihydrochloride (34 mg, 2 equiv.). The reaction mixture was stirred for 24 hours at 25°C. After which was added an additional DIPEA (0.03 ml, 2 equiv.) and 1-cyclopropylamine dihydrochloride (34 mg, 2 equiv.). The reaction mixture was stirred for additional 24 hours at 25°C. was Then added extra DIPEA (0.03 ml, 2 equiv.) and 1-cyclopropylamine dihydrochloride (34 mg, 2 equiv.). The reaction mixture was stirred for an additional 48 hours at 25°C. the Reaction mixture was purified using preparative HPLC, which gave a light yellow solid (18 mg, 35%). MS: m/z = 598,2 [M+H]+.

Example 56

(2,2,2-Cryptor-ethyl)-amide 4-[(S)-3-(2-chloro-4-imidazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-2-cyano-pyrimidine-5-carboxylic acid

�reamer 52G) (43 mg) was dissolved in ACN (1.0 ml), added DIPEA (0.03 ml, 2 equiv.) and imidazole (12 mg, 2 equiv.). The reaction mixture was stirred for 24 hours at 80°C. Then was added imidazole (12 mg, 2 equiv.). The reaction mixture was stirred for additional 24 hours at 80°C. then was added imidazole (12 mg, 2 equiv.). The reaction mixture was stirred for an additional 48 hours at 80°C. the Reaction mixture was purified using preparative HPLC, which gave a light yellow solid (16 mg, 34%). MS: m/z = 540,3 M+H]+.

Example 57

[2-(4-Chloro-phenyl)-propyl]-amide 4-{(S)-3-[4-(4-tert-butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid

(A) [2-(4-Chloro-phenyl)-propyl]-amide 4-[(S)-3-(2-chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-2-cyano-pyrimidine-5-carboxylic acid

Example 57A) was obtained by analogy with the methods described for example 52, which gave specified in the title compound as a light yellow oil (100 mg, 25%). MS: m/z = 562,1 [M+H]+.

B) [2-(4-Chloro-phenyl)-propyl]-amide 4-{(S)-3-[4-(4-tert-butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid

Example 57V) was obtained by analogy with the methods described for example 52, which gave specified in zag�lowke compound as a light yellow solid (25 mg, 44%). MS: m/z = 686,3 [M+H]+.

Example 58

4-{(S)-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-(2,2,2-Cryptor-ethyl)-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine-2-carbonitrile

A) tert-Butyl ether (S)-3-[2-chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-carboxylic acid

Example 52D) (1.2 g) was dissolved in DMF (20 ml) was added Cs2CO3(2.15 g, 2 equiv.) and 2,2,2-triptoreline (0,47 ml). The reaction mixture was stirred for 48 hours at 25°C. the Reaction mixture was purified using flash chromatography, which gave a colorless oil (1.28 g, 87%). MS: m/z = 369,9 [M+H-OtBu]+.

B) (S)-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin

Specified in the title compound was obtained in analogy to example E), which gave a light brown oil (910 mg, 92%). MS: m/z = 344,1 [M+H]+.

C) tert-Butyl ether 2-chloro-4-{(S)-3-[2-chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-5,7-dihydro-imidazo[3,4-d]pyrimidine-6-carboxylic acid

tert-Butyl 2,4-dichloro-5H-imidazo[3,4-d]-pyrimidine-6(7H)-carboxylate (500 mg) was dissolved in ACN (20 ml), was added DIPEA (0,59 ml) and example 58W) (652 mg, 1.1 equiv.). The reaction mixture was stirred for 3 hours at 25°C. the Reaction mixture was purified using flash chromatogr�IFE, which gave a white solid (510 mg, 50%). MS: m/z = 597,3 [M+H]+.

D) 2-Chloro-4-{(S)-3-[2-chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine

Example S) (510 mg) was dissolved in CH2Cl2(5 ml) and added TFA (1,31 ml). The reaction mixture was stirred 2 hours at 25°C. the Reaction mixture was extracted with saturated aqueous Na2CO3-solution and CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and evaporated, which gave a white solid (350 mg, 82%). MS: m/z = 497,1 [M+H]+.

(E) 2-Chloro-4-{(S)-3-[2-chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-(2,2,2-Cryptor-ethyl)-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine

Example 58D) (175 mg) was dissolved in CH2Cl2(3 ml), to the above suspension was added 2,2,2-trifluoroethyl triftormetilfullerenov (82 mg, 4 equiv.) and DIPEA (0,12 ml). The mixture was stirred at 25°C for 24 hours. Then the reaction mixture was heated at 40°C for 18 hours. After which was added 2,2,2-trifluoroethyl triftormetilfullerenov (82 mg, 4 equiv.) and DIPEA (0,12 ml) and the reaction mixture was heated at 40°C for 24 hours. Then additional 2,2,2-trifluoroethyl triftormetilfullerenov (164 mg, 8 equiv.) was added and the reaction mixture was heated at 40°C in �of Directors for three days. The reaction mixture was purified using flash chromatography, which gave a white foam (142 mg, 70%). MS: m/z = 579,1 [M+H]+.

F) 4-{(S)-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-(2,2,2-Cryptor-ethyl)-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine-2-carbonitrile

Specified in the title compound was synthesized according to the methods described for example 52G), which gave a light brown solid (56 mg, 40%). MS: m/z = 570,3 [M+H]+.

Example 59

Specified in the title compound was obtained by analogy with the methods described for examples 58B)-(F), which gave a brown foam (34 mg, 39%). MS: m/z = 538,2 [M+H]+except for stage (A):

A) tert-Butyl ether (S)-3-(2-chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-carboxylic acid

Example 52D) (1 g) was dissolved in DMA (7.5 ml) at 25°C. was Added pyrazole (374 mg, 2 equiv.) and Cs2CO3(1.8 g, 2 equiv.). The reaction mixture was stirred in the microwave at 100°C for 60 minutes. The reaction mixture was diluted with AcOEt (10 ml) and was extracted with water. The organic layers were dried over Na2SO4, filtered and evaporated to dryness. The reaction mixture was purified using flash chromatography, which gave a white foam (610 mg, 54%). MS: m/z = 356,1 [M+H-tBu]+.

Example 60

4-[(S)-3-(2-Chloro-4-pyrazol-1-albenzaalbenza)-pyrrolidin-1-yl]-6-formyl-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine-2-carbonitrile

Specified in the title compound was obtained by analogy with the methods described for examples 58B) to (F) and 59A), which gave a brown foam (34 mg, 39%). MS: m/z = 538,2 [M+H]+except in stage (E):

(E) 2-Chloro-4-[(S)-3-(2-chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-5,7-dihydro-imidazo[3,4-d]pyrimidine-6-carbaldehyde

Methylcyclopropane-carboxylic acid (60 mg) was dissolved in CH2Cl2(5 ml) and 3 drops of DMF. Then slowly added oxalicacid (177 mg, 2.6 equiv.). The reaction mixture was stirred for 2 hours at 25°C. the Reaction mixture was evaporated and dissolved CH2Cl2(2 ml). Was then added example 60D) (215 mg) and tea (109 mg, 2 equiv.) and stirred for 24 hours at 25°C. the Reaction mixture was purified using preparative HPLC, which gave specified in the title compound as the sole by-product in the form of a dark brown foam (62 mg, 21%). MS: m/z = 520,1 [M+H]+.

Example 61

6-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyridine-2-carbonitrile; compound with formic acid

A) tert-Butyl ether (S)-3-((S)-2-chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-carboxylic acid

In 50 ml of Crewe�ladonnas flask (S)-tert-butyl 3-(2-chloro-4-perpenicular)-pyrrolidin-1-carboxylate, example 52D), (2 g, 5.5 mmol, 1 equiv.) combined with acetonitrile (20 ml) gave a light yellow solution. Was added (S)-octahedral[1,2-a]pyrazine (1.04 g, 8.25 mmol, 1.5 equiv.) and DIPEA (1.42 g, 1.92 ml, 11.0 mmol, 2 equiv.). The reaction mixture was stirred for 15 hours. The reaction mixture was heated to 60°C and stirred for 5 hours. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into EtOAc (25 ml) and was extracted with aqueous 10% Na2CO3(2×20 ml) and brine. The organic layers were dried over Na2SO4and concentrated in vacuo, giving a colorless viscous oil (2.48 g, 96%).

B) (S)-2-[3-Chloro-4-((S)-pyrrolidin-3-sulfonyl)-phenyl]-octahydro-imidazo[1,2-a]pyrazine

In a 100 ml round-bottom flask (S)-tert-butyl 3-(2-chloro-4-((S)-hexahydropyrazino[1,2-a]pyrazine-2(1H)-yl)phenylsulfonyl)pyrrolidin-1-carboxylate, example 61A), (2,58 g, 5,49 mmol, 1.0 equiv.) was combined with dichloromethane (20 ml), which gave a light brown solution. Was added TFA (10.4 g, 7 ml of 90.9 mmol, 16.6 per equiv.). The reaction mixture was stirred for 16 hours. The crude reaction mixture was concentrated in vacuo with toluene and used without further purification, which gave a brown liquid containing toluene (35% purity, 5.7 g of crude matter, yield 98%).

C) 6-[(S)-3-((8)-2-Chloro-4-hexahydro-pyrrole,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyridine-2-carbonitril; compound with formic acid

A 5 ml microwave vial (S)-2-(3-chloro-4-((S)-pyrrolidin-3-ylsulphonyl)phenyl)-octahedral[1,2-a]pyrazine, example V), (0.2 g, 189 mmol) were combined with acetonitrile (2 ml), which gave a light brown solution. Added 6-chloropicolinic (34,1 mg, 246 μmol, 1.3 equiv.) and triethylamine (95,7 mg, 132 μl, 946 mmol, 5 equiv.). The reaction mixture was heated to 160°C and stirred for 30 minutes in a microwave oven. The crude substance was purified using preparative HPLC, which gave a brown solid (42 mg, 43%). MS: m/z = 472,3 [M+H]+.

Example 62

6-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile; compound with formic acid

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C), which gave a light brown solid (55 mg, 40%). MS: m/z = 473,3 [M+H]+.

Example 63

2-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-4-carbonitrile; compound with formic acid

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C), which gave a light brown solid (55 mg, 40%). M�: m/z = 473,3 [M+H] +.

Example 64

6-[3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-3-nitro-pyridin-2-carbonitril, with formic acid

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C), which gave a light brown solid (55 mg, 40%). MS: m/z = 517,3 [M+H]+.

Example 65

(S)-6-(3-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidin-1-yl)picolinate

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C) and example 12, giving a yellow solid (88 mg, 32%). MS: m/z = 382,0861 [M+H]+.

Example 66

(S)-2-(3-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C) and example 12, which gave a yellow gum (220 mg, 80%). MS: m/z = 383,0821 [M+H]+.

Example 67

(S)-6-(3-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C) and example 12, which gave a yellow resin (90 mg, 33%). MS: m/z = 383,0813 [M+H]+.

Example 68

6-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-p�perazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-pyrazine-2-carbonitrile

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C), which gave a light brown gum (24 mg, 20%). MS: m/z = to 491.2 [M+H]+.

Example 69

2-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-pyrimidine-4-carbonitrile

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C), which gave a light brown resin (60 mg, 49%). MS: m/z = to 491.2 [M+H]+.

Example 70

6-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-pyridine-2-carbonitril

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C), which gave a light brown gum (14 mg, 12%). MS: m/z = 490,3 [M+H]+.

Example 71

6-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-3-nitro-pyridin-2-carbonitril

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C), which gave a yellow solid (45 mg, 34%). MS: m/z = to 535.3 [M+H]+.

Example 72

(S)-6-(3-(2-Chloro-4-perpenicular)pyrrolidin-1-yl)picolinate

Specified in the header connection�s was obtained by analogy with the methods, described for examples 61A-C), on the basis of intermediate compounds E), which gave a light brown solid (4 mg, 1%). MS: m/z = 366,0496 [M+H]+.

Example 73

(S)-2-(3-(2-Chloro-4-perpenicular)pyrrolidin-1-yl)pyrimidine-4-carbonitrile

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C), on the basis of intermediate compounds E), which gave a yellow solid (60 mg, 14%). MS: m/z = 367,0441 [M+H]+.

Example 74

(S)-6-(3-(2-Chloro-4-perpenicular)pyrrolidin-1-yl)pyrazine-2-carbonitrile

Specified in the title compound was obtained by analogy with the methods described for examples 61A-C), on the basis of intermediate compounds E), which gave a brown oil (63 mg, 13%). MS: m/z = 367,0413 [M+H]+.

Example 75

(S)-2-(3-(2-Chloro-4-(4-methylpiperazin-1-yl)phenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile

A 10 ml round-bottomed flask (S)-2-(3-(2-chloro-4-perpenicular)pyrrolidin-1-yl)pyrimidine-4-carbonitrile (example 73) (50 mg, 136 μmol, 1 equiv.) combined with acetonitrile (4 ml) gave a light yellow solution. Was added 1-methylpiperazine (20.7 mg, 22,9 µl, 204 mmol, 1.5 equiv.) and DIPEA (35.2 mg, 47.6 per µl, 273 mmol, 2 equiv.). The reaction mixture was heated to 60°C and was stirred for 0 hours. Then was added 1-methylpiperazine (0.7 equiv.) and DIPEA (1 equiv.). The reaction mixture was stirred at 60°C for 5 hours. Then added an extra 1-methylpiperazin (1 equiv.) and DIPEA (1.2 equiv.). The reaction mixture was stirred at 60°C for 16 hours. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 5% aqueous solution of Na2CO3and was extracted with EtOAc (3×10 ml). The organic layers were combined and washed with saturated aqueous NaCl solution (1x). The organic layers were dried over Na2SO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 10 g, CH2Cl2/MeOH 98/2) gave a light yellow foam (42 mg, 69%). MS: m/z = 447,1409 [M+H]+.

Example 76

(S)-6-(3-(2-Chloro-4-(4-methylpiperazin-1-yl)phenylsulfonyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile

Specified in the title compound was obtained in analogy to methods described for example 75, which gave a light yellow foam (40 mg, 56%). MS: m/z = 447,1412 [M+H]+.

Example 77

(2-Phenyl-cyclopropyl)-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Specified in the title compound was obtained by analogy with the methods described for examples 52 and example 12, dava�about light yellow foam (536 mg, 70%) as a mixture of diastereomers [1:1]. MS: m/z = 542,4 [M+H]+.

Example 78

[2-(4-Chloro-phenyl)-propyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Specified in the title compound was obtained by analogy with the methods described for examples 52 and example 12, which gave a white foam (315 mg, 57%) as a mixture of diastereomers [1:1]. MS: m/z = to 578.2 [M+H]+.

Example 79

4-Trifluoromethyl-benzylamine 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Specified in the title compound was obtained by analogy with the methods described for examples 52 and example 12, giving a white solid (13 mg, 38%). MS: m/z = 584,2 [M+H]+.

Example 80

4-Trifluoromethyl-benzylamine 2-cyano-4-[(S)-3-(2,3-dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Specified in the title compound was obtained by analogy with the methods described for examples 52 and example 12, giving a white solid (15 mg, 29%). MS: m/z = 584,2 [M+H]+.

Example 81

[1-(4-Fluoro-phenyl)-cyclopropyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Specified in the header soy�the errors obtained by analogy with the methods, described for examples 52 and example 12, giving a white solid (18 mg, 44%). MS: m/z = 560,2 [M+H]+.

Example 82

[1-(4-Fluoro-phenyl)-cyclopropyl]-amide 2-cyano-4-[(S)-3-(2,3-dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Specified in the title compound was obtained by analogy with the methods described for examples 52 and example 12, giving a white solid (16 mg, 24%). MS: m/z = 560,1 [M+H]+.

Example 83

(2,2,2-Cryptor-ethyl)-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Specified in the title compound was obtained by analogy with the methods described for examples 52 and example 12, giving a white solid (10 mg, 42%). MS: m/z = 508,1 [M+H]+.

Example 84

(2,2,2-Cryptor-ethyl)-amide 2-cyano-4-[(S)-3-(2,3-dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Specified in the title compound was obtained by analogy with the methods described for examples 52 and example 12, giving a white solid (16 mg, 25%). MS: m/z = 508,0 [M+H]+.

Example 85

[2-(4-Chloro-phenyl)-propyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid (compound a)

p> Specified in the title compound was obtained as a pure enantiomer after purification of example 78 using chiral HPLC, which gave a light brown solid (132 mg, 60%). MS: m/z = to 578.2 [M+H]+.

Example 86

[2-(4-Chloro-phenyl)-propyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid (Compound In)

Specified in the title compound was obtained as a pure enantiomer after purification of example 78 using chiral HPLC, which gave a light brown solid (32 mg, 15%). MS: m/z = to 578.2 [M+H]+.

Example 87

[1-(4-Chloro-phenyl)-cyclopropylmethyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid

Specified in the title compound was obtained by analogy with the methods described for examples 52 and example 12, giving a white solid (239 mg, 66%). MS: m/z = 590,3 [M+H]+.

94

Example 88

Analysis of inhibition of the enzyme cathepsin

Enzymatic activity is measured by observing the increase in fluorescence intensity caused by the cleavage of a peptide substrate containing a fluorophore, the emission of which is extinguished in the native peptide.

Analytical buffer: 100 mm potassium phosphate pH 6.5, EDTA-Na, 5 mm, Triton X-100 0.001% OR DTT mm.

Enzyme� (all with 1 nm): cathepsin S, Cat K, Cat B, Cat L human and mouse.

The substrate (20 μm): Z-Val-Val-Arg-AMC, with the exception of the Cat, which uses Z-Leu-Arg-AMC (both from Bachem).

Ζ = Benzyloxycarbonyl.

AMC = 7-Amino-4-methyl-coumarin.

RTI = Dithiotreitol.

Final volume: 100 µl.

Excitation 360 nm, emission 465 nm.

The enzyme is added to the solutions of compounds in 96-well microplates, and the reaction begins with the substrate. Fluorescence is measured for 20 minutes, during this time, there is a linear increase in the absence of inhibitor. IR50calculated by standard methods.

The inhibition of Cat S man, Cat's mouse, Cat K human K Cat mouse, Cat To human, Cat mouse, Cat L man and Cat L mouse was measured separately. The results obtained for the Cat's humans for representative compounds of the invention are presented in the following table:

In the above analysis of the compounds according to the invention have an IC50which is between 0.00001 and 100 μm, preferably between 0.00001 and 50 microns, more preferably between 0.00001 and 20 microns.

An example of a

The compound of formula (I) can be used during the method, known essentially as an active ingredient for the manufacture of tablets available composition:

On a tablet

td align="left"> Active ingredient
200 mg
Microcrystalline cellulose155 mg
Corn starch25 mg
Talc25 mg
Hydroxypropyl methylcellulose20 mg
425 mg

The example In the

The compound of formula (I) can be used during the method, known essentially as an active ingredient for the manufacture of capsules available composition:

Per capsule

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)

where
R1represents hydrogen, C1-8the alkyl morpholinyl, Galos1-8Alki�amino, With1-8alkyloxyaryl, hydroxyl, haloperidol, azetidine, S1-8alkylamino, amino, cyano C1-8alkylamino, halophenols1-8alkylamino or cyanos3-8cyclooctylamino;
R2, R3, R4, R5and R6independently selected from hydrogen, C1-8of alkyl, Galos1-8of alkyl, hydroxys1-8alkyl, C1-8alkoxy, Galos1-8alkyloxy, halogen, hydroxyl, cyanopyridine, pyrazolyl, S1-8alkylperoxyl, imidazolyl, benzimidazolyl, 6-oxo-6H-pyridazinyl, S1-8alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-C1-8alkylpiperazine, piperidine, differerential, phenylimidazoline, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, deltocephalinae, Galos1-8alkylpiperidines, piperidinyl1-8alkoxy, oceanlake, S1-8alkylperoxyl, haloperidol, S1-8alkylpyridine, S3-8cycloalkyl, S3-8cycloalkyl1-8of alkyl, halophenol, S1-8alkylcarboxylic-C3-8-cycloalkyl-C1-8of alkyl, Galos1-8alkylpiperazine, S1-8alkylamino, S1-8alkoxy-C1-8alkylpiperazine, S3-8cycloalkylcarbonyl, hexahydropyrazino[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-silt, C1-8and�eliminatoria, azetidine, S3-8cycloalkylcarbonyl, S1-8alkylimidazole, S1-8alkoxy With1-8alkoxy, imidazo[4,5-C]pyridinyl, S1-8alkylpiperazine, hexahydro-imidazo[1,2-a]pyrazinyl, galazutdinov, pyrimidinyl and C2-8alkenylacyl;
And1represents-CH2-, carbonyl, -C(O)O - or absent;
And2represents nitrogen or CR7;
And3represents nitrogen or CR8;
And4represents nitrogen or CR9;
R7represents hydrogen, C1-8alkyl, halo, C1-8alkyl, halogen, hydroxyl, Galos1-8alkylaminocarbonyl; halophenols1-8alkylaminocarbonyl, phenyl-C3-8-cycloalkylcarbonyl, Galos1-8ALKYLPHENOLS1-8alkylaminocarbonyl, halophenols3-8cycloalkylcarbonyl or halophenols3-8cycloalkyl1-8alkylaminocarbonyl;
R8represents hydrogen, C1-8alkyl, Galos1-8alkyl, halogen or hydroxyl;
or R7and R8together with the carbon atom to which they are attached to form C3-8cycloalkyl or substituted pyrrolidin where substituted pyrrolidin is pyrrolidine, N-substituted Galos1-8the alkyl or formyl;
R9represents hydrogen, C1-8alkyl, Galos1-8alkyl, halogen or nitro;
Il� R 8and R9together with the carbon atom to which they are attached to form C3-8cycloalkyl;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where
R7represents hydrogen, C1-8alkyl, Galos1-8alkyl, halogen or hydroxyl;
R8represents hydrogen, C1-8alkyl, Galos1-8alkyl, halogen or hydroxyl;
or R7and R8together with the carbon atom to which they are attached to form C3-8cycloalkyl;
R9represents hydrogen, C1-8alkyl, Galos1-8alkyl or halogen;
or R8and R9together with the carbon atom to which they are attached to form C3-8cycloalkyl.

3. The compound according to claim 1, where R1represents hydrogen or amino.

4. The compound according to claim 1, where R2, R3, R4, R5and R6independently selected from hydrogen, halogen, hydroxyl, Galos1-8of alkyl, cyanopyridine, S1-8alkylpiperazine, hexahydro-imidazo[1,2-a]pyrazinyl, Galos1-8alkyloxy, pyrazolyl, S3-8cycloalkylcarbonyl, imidazolyl and C1-8alkoxyl1-8alkoxy.

5. The compound according to claim 1, where R2and R6independently selected from hydrogen, halogen free and Galos1-8of alkyl.

6. The compound of claim 1, wherein one of R2and R6represents a halogen �whether Galos 1-8alkyl and the other represents hydrogen.

7. The compound of claim 1, wherein one of R2and R6represents chlorine or trifluoromethyl, and the other represents hydrogen.

8. The compound according to claim 1, where R3and R5independently selected from hydrogen, halogen free and Galos1-8of alkyl.

9. The compound according to claim 1, where R3and R5independently selected from hydrogen, chlorine and trifloromethyl.

10. The compound of claim 1, wherein both of R3and R5represent hydrogen.

11. The compound according to claim 1, where R4represents hydrogen, hydroxyl, halogen, cyanopyridine, S1-8alkylpiperazine, hexahydropyrazino[1,2-a]pyrazinyl, Galos1-8alkoxy, pyrazolyl, S3-8cycloalkylcarbonyl, imidazolyl or C1-8alkoxyl1-8alkoxy.

12. The compound according to claim 1, where R4represents hydrogen, halogen, C1-8alkylpiperazine, hexahydropyrazino[1,2-a]pyrazinyl, Galos1-8alkoxy, pyrazolyl, S3-8cycloalkylcarbonyl or C1-8alkoxy With1-8alkoxy.

13. The compound according to claim 1, where R4represents hydrogen, halogen, methylpiperazine, tert-butylpiperazine, hexahydropyrazino[1,2-a]pyrazinyl, triptoreline, tricorporate, pyrazolyl, cyclopropylmethyl or methoxyethoxy.

14. The compound according to claim 1, where where A1missing or repre�ulation of a carbonyl.

15. The compound according to claim 1, where A2is a CR7.

16. The compound according to claim 1, where A3is a CR8.

17. The compound according to claim 1, where A4represents nitrogen.

18. The compound according to claim 1, where R7represents hydrogen.

19. The compound according to claim 1, where R8represents hydrogen, C1-8alkyl or Galos1-8alkyl.

20. The compound according to claim 1, where R8represents trifluoromethyl.

21. The compound according to claim 1, where R9represents hydrogen.

22. The compound according to claim 1, selected from:
6-[(2S,4S)-4-(2-Chloro-benzolsulfonat)-2-(morpholine-4-carbonyl)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile;
Methyl ester of (2S,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;
6-[3-(4-Hydroxy-benzolsulfonat)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile;
6-[3-({4-[(6-Cyanopyridine-2-yl)oxy]phenyl}sulfonyl)pyrrolidin-1-yl]pyrazine-2-carbonitrile;
(2S,4S)-4-(2-Chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;
(2,2,2-Cryptor-ethyl)-amide (2S,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;
The ethyl ester of (2R,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;
6-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyridine-2-carbonitrile;
6-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-�l]-pyrazine-2-carbonitrile;
6-[(2R,4S)-4-(2-Chloro-benzolsulfonat)-2-(morpholine-4-carbonyl)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile;
(2,2,2-Cryptor-ethyl)-amide (2R,4S)-4-(2-chloro-benzolsulfonat)-1-(6-cyano-pyrazine-2-yl)-pyrrolidin-2-carboxylic acid;
4-[(S)-3-(2-Chloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
4-[(2R,4S)-4-(2-Chloro-benzolsulfonat)-2-(5-methyl-[1,3,4]oxidiazol-2-yl)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
4-[(S)-3-(2-Trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
4-[(2R,4S)-2-Gidroximetil-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
4-Methyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
5-Trifluoromethyl-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
5-Fluoro-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
5-Hydroxy-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
4-[(2R,4S)-2-Morpholine-4-ylmethyl-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
2-[(2R,4S)-2-Morpholine-4-ylmethyl-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-4-carbonitrile;
4-[(2R,4S)-2-(3,3-Debtor-pyrrolidin-1-ylmethyl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
4-[(S)-3-(2,3-Dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrim�DIN-2-carbonitrile;
4-[(R)-3-(2-Bromo-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
4-[(S)-3-(3-Trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
(2,2,2-Cryptor-ethyl)-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
4-[(2S,4S)-2-(Azetidin-1-carbonyl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
((S)-2,2,2-Cryptor-1-methyl-ethyl)-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
The diethylamide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
(2S,4S)-1-(2-Cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
Amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
Ethylamide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
Cyanomethyl-amide (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
4-[(2S,4S)-2-(3,3-Debtor-pyrrolidin-1-carbonyl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
4-Fluoro-benzylamine (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
(1-Cyano-cyclopropyl)-amide (2S,4S-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
Isopropylamine (2S,4S)-1-(2-cyano-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
4-[(S)-3-(2-Trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-6,7-dihydro-5H-cyclopentadienide-2-carbonitrile;
5-Methyl-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
4-Trifluoromethyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
Amide (S)-1-(2-cyano-6-trifluoromethyl-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
4-[(S)-3-(2-Chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{(S)-3-[2-Chloro-4-(4-methyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{(S)-3-[4-(4-tert-Butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{(S)-3-[2-Chloro-4-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-[(S)-3-(2-Chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{(S)-3-[2-Chloro-4-(4-cyclopropyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{()-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-[(S)-3-(2-Chloro-4-imidazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{(S)-3-[2-Chloro-4-(2-methoxy-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
(2,2,2-Cryptor-ethyl)-amide 4-[(S)-3-(2-chloro-4-fluoro-benzolsulfonat)-pyrrolidin-1-yl]-2-cyano-pyrimidine-5-carboxylic acid;
(2,2,2-Cryptor-ethyl)-amide 4-{(S)-3-[4-(4-tert-butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid;
(2,2,2-Cryptor-ethyl)-amide 4-{(S)-3-[2-chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid;
(2,2,2-Cryptor-ethyl)-amide 4-{(S)-3-[2-chloro-4-(4-temporaril-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid;
(2,2,2-Cryptor-ethyl)-amide 4-[(S)-3-(2-chloro-4-imidazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-2-cyano-pyrimidine-5-carboxylic acid;
[2-(4-Chloro-phenyl)-propyl]-amide 4-{(S)-3-[4-(4-tert-butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-2-cyano-pyrimidine-5-carboxylic acid;
4-{(S)-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-(2,2,2-Cryptor-ethyl)-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine-2-carbonitrile;
4-[(S)-3-(2-Chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-(2,2,2-Cryptor-ethyl)-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine-2-carbonitrile;
4-[(S)-3-(2-Chloro-4-pyrazol-1-yl-benzolsulfonat)-p�Raiden-1-yl]-6-formyl-6,7-dihydro-5H-imidazo[3,4-d]pyrimidine-2-carbonitrile;
6-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyridine-2-carbonitrile; compound with formic acid;
6-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyrazine-2-carbonitrile; compound with formic acid;
2-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-4-carbonitrile; compound with formic acid;
6-[3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-3-nitro-pyridin-2-carbonitrile, with formic acid;
(S)-6-(3-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidin-1-yl)picolinate;
(S)-2-(3-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile;
(S)-6-(3-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile;
6-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-pyrazine-2-carbonitrile;
2-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-pyrimidine-4-carbonitrile;
6-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-pyridine-2-carbonitrile;
6-((S)-3-{2-Chloro-4-[4-(2-methoxy-ethyl)-piperazine-1-yl]-benzolsulfonat}-pyrrolidin-1-yl)-3-nitro-pyridin-2-carbonitrile;
(S)-6-(3-(2-Chloro-4-perpenicular)pyrrolidin-1-yl)picolinate;
(S)-2-(3-(2-Chlorine-forfinishing)pyrrolidin-1-yl)pyrimidine-4-carbonitrile;
(S)-6-(3-(2-Chloro-4-perpenicular)pyrrolidin-1-yl)pyrazine-2-carbonitrile;
(S)-2-(3-(2-Chloro-4-(4-methylpiperazin-1-yl)phenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile;
(S)-6-(3-(2-Chloro-4-(4-methylpiperazin-1-yl)phenylsulfonyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile;
(2-Phenyl-cyclopropyl)-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;
[2-(4-Chloro-phenyl)-propyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;
4-Trifluoromethyl-benzylamino 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;
4-Trifluoromethyl-benzylamino 2-cyano-4-[(S)-3-(2,3-dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;
[1-(4-Fluoro-phenyl)-cyclopropyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;
[1-(4-Fluoro-phenyl)-cyclopropyl]-amide 2-cyano-4-[(S)-3-(2,3-dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;
(2,2,2-Cryptor-ethyl)-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;
(2,2,2-Cryptor-ethyl)-amide 2-cyano-4-[(S)-3-(2,3-dichloro-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid;
[2-(4-Chloro-phenyl)-propyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrol�DIN-1-yl]-pyrimidine-5-carboxylic acid;
[2-(4-Chloro-phenyl)-propyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid and
[1-(4-Chloro-phenyl)-cyclopropylmethyl]-amide 2-cyano-4-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-5-carboxylic acid.

23. The compound according to claim 1, selected from:
4-Trifluoromethyl-6-[(S)-3-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-1-yl]-pyrimidine-2-carbonitrile;
Amide (S)-1-(2-cyano-6-trifluoromethyl-pyrimidine-4-yl)-4-(2-trifluoromethyl-benzolsulfonat)-pyrrolidin-2-carboxylic acid;
4-{(S)-3-[2-Chloro-4-(4-methyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{(S)-3-[4-(4-tert-Butyl-piperazine-1-yl)-2-chloro-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-[(S)-3-((S)-2-Chloro-4-hexahydro-imidazo[1,2-a]pyrazine-2-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{(S)-3-[2-Chloro-4-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-[(S)-3-(2-Chloro-4-pyrazol-1-yl-benzolsulfonat)-pyrrolidin-1-yl]-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{(S)-3-[2-Hor-4-(4-cyclopropyl-piperazine-1-yl)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile;
4-{(S)-3-[2-Chloro-4-(2,2,2-Cryptor-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile and 4-{(S)-3-[2-Chloro-4-(2-methoxy-ethoxy)-benzolsulfonat]-pyrrolidin-1-yl}-6-trifluoromethyl-pyrimidine-2-carbonitrile.

24. The compound according to any one of claims.1-23 for use as inhibiting the enzyme cathepsin substances.

25. A pharmaceutical composition inhibiting the enzyme cathepsin, comprising a compound according to any one of claims.1-23 and a therapeutically inert carrier.

26. Use of a compound according to any one of claims.1-23 for the manufacture of drugs that inhibit the enzyme cathepsin.

27. A method of inhibiting the enzyme cathepsin, according to which it is administered an effective amount of a compound according to any one of claims.1-23.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel hetericyclic compounds of general formula or to its tautometric form, or to its pharmaceutically acceptable salt, where 1-2 of X1, X2, X3, X4, X5, X6 is selected from N, and the remaining ones represent C, X7 is selected from N or CH; each of X8, X9, X10 and X11 is independently selected from N or CH on condition that fragment can simultaneously contain one or two nitrogen atoms; R1, R2, R3 and R4 are selected from H, 6-memberedaryl, CF3, halogen; R5, R6, R7 represent C1-alkyl on condition that X9, X10 or X11 in this case respectively equals C; "A" can represent simple bond or bridging ethyne moiety; Y can represent simple bond or is independently selected from methylene or ethylene bridging moieties; moiety Z is independently selected from no-substituted or substituted in nitrogen atom heterocycloalkyl or is non-substituted or substituted cycloalkyl on condition that N (nitrogen) equals C (carbon): , where R9 is selected from CH2OH, CON(R15, R16), where R15, R16 can independently represent H, C1-alkyl, Het represents N, n=1, n1=3; R8 is selected from H, C1-6-alkyl, C1-alkylcarbonyl, derivetives of arylacetic acid of general structure: , where methylheteroaryls of general structure: , where derivatives of alkylsulphonyls of general structure where R14=Alk, with Alk representing C1-alkyl, or to 2-methylamino-1-{3-[6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyridin-2-ylmethyl]-1-oxa-8-azaspiro]4.5]decan-8-yl}-ethanol dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dimethylamine dihydrochloride. Invention also relates to pharmaceutical composition based on claimed compound and to method of Haspin kinase inhibition.

EFFECT: obtained are novel compounds, possessing useful biological properties.

5 cl, 7 tbl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azoloazine salts of compounds of a fluoroquinolone line of formulae 4a-c , 5a-c , 7a-b and 8a-b , possessing antibacterial and antiviral properties. The claimed compounds can be applied for the creation of a medication for the emergency prevention and treatment of infections, caused by pathogens of both the bacterial and viral origin, including especially dangerous ones. In general formulae 4 and 5 R=CH3, R1=C2H5; R=H, R1=C2H5; R=C2H5, R1=cyclo-C3H7, in formulae 7 and 8 R=H (7a, 8a); R=CH3 (7b, 8b).

EFFECT: increased efficiency of the compound application.

8 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formulas R1 represents substituted phenyl, substituted or unsubstituted heterocyclyl, which represents an aromatic cycloalkyl containing 6 to 10 atoms in the cycle and wherein one to two carbon atoms in the cycle are independently substituted by N, wherein the above substitutes are specified in C1-8alkyl, triazolyl, halogen, aminocarbonyl, cyano or hydroxyalkyl; R2 represents H, substituted or unsubstituted C1-8alkyl, substituted C3-6cycloalkyl, unsubstituted heterocyclyl, which represents non-aromatic cycloalkyl containing 5 to 6 atoms in the cycle and wherein one to two carbon atoms in the cycle are independently substituted by N or O; unsubstituted heteroyclylalkyl, wherein heterocyclyl represents non-aromatic cycloalkyl containing 5 to 6 atoms in the cycle and wherein one to two carbon atoms in the cycle are independently substituted by N and O; substituted or unsubstituted phenylalkyl or substituted or unsubstituted C3-6cycloalkylalkyl, wherein the above substitutes are specified in C1-4alkyl, CF3, OR and NR2, wherein R represents H or C1-4alkyl; each R3 and R4 independently represents H, unsubstituted C1-8 alkyl, or R3 and R4 together with the atom to which they are attached form C3-6cycloalkyl; or R2 and one of R3 and R4 together with the atom to which they are attached form substituted or unsubstituted heterocyclyl containing 5 to 6 atoms in the cycle and which can contain additional heteroatom specified in O; wherein the substitutes are specified in -C(O)CH2OCH3, -CH2CH2OCH3, OCH3 or CH3.

EFFECT: invention refers to compounds of formula

and ,

a based pharmaceutical composition and to a method of treating or preventing cancer, immunological conditions, diabetes, obesity, neurological disturbances and age-related diseases, a method for mTOR kinase inhibition in a cell, a method of treating or preventing the condition, which can be treated or prevented by mTOR kinase metabolic path inhibition.

53 cl, 1 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a chemical compound of formula wherein R=benzyl and to an antituberculous therapeutic agent representing a composition of imidazo[1,2-b][1,2,4,5]tetrazine derivative of formula I, wherein R=benzyl, isopropyl or phenyl and the known antituberculous preparation pyrazinamide with the ingredients in mole ratio 1:1.

EFFECT: there are prepared new antituberculous therapeutic agents.

2 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining cyclic guanidine, which can be applied in coating compositions, in particular in electrically precipitated coating compositions. Method includes reaction of (i) cyanamide, (ii) polyamine and (iii) weak acid with 5.0<pKa<13.5. Invention also relates to method of obtaining polymer resin and method of obtaining cyclic guanidine, containing 6-membered ring.

EFFECT: claimed method makes it possible to reduce amount of wastes in production of cyclic guanidines.

18 cl, 1 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula (I), which possesses phosphodiesterase 10 inhibitory activity. In formula (I), R1 represents hydrogen, halogen or lower alkyl; the ring A represents optionally substituted 6-10-merous monocyclic or bicyclic heteroaryl containing 1 to 3 nitrogen atoms as heteroatoms, or a group containing a cycloaliphatic 6-merous ring condensed with the above heteroaryl, which is specified in 6-merous cycloalkane and aliphatic 6-merous heterocyclic ring containing an oxygen atom; the ring B represents optionally substituted 4-6-merous monocyclic nitrogen-containing group, which can additionally contain an oxygen atom or a 3-6-merous monocyclic hydrocarbonic group, which can be optionally saturated; R3 represents hydrogen; lower alkyl optionally substituted by a substitute specified in lower alkoxy; or lower cycloalky. The R2,Y radicals, as well as substitutes of the rings A and B are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compound, to a method of treating or preventing schizophrenia, anxiety disorders, drug addiction, disorders with a symptom of cognition deficiency, affective disorder or mood episode, each of which is mediated by phosphodiesterase 10 activity.

20 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formula , fragment A is specified in a group consisting of , or , R1, R3, R4 and R5 mean hydrogen or alkyl; each of R4a and R5a represents hydrogen; G1 represents aryl or heteroaryl, which can by unsubstituted or substituted by 1, 2, 3, 4 or 5 substitutes specified in a group consisting of alkyl, halogen, cyano, -OR1b, -S(O)R2b, -C(O)R1b, -C(O)OR1b, -OC(O)N(Rb)(R3b), -(CR4bR5b)m-OR1b, -C(OH)[(CR4bR5b)m-R4b]2, and halogenalkyl; G2 means cycloalkyl, cycloalkenyl or heterocycle unsubstituted or substituted by 1, 2, 3, 4 or 5 substitutes specified in a group consisting of alkyl; Rb represents hydrogen or alkyl; R1b and R3b represents hydrogen, alkyl or halogenalkyl; R2b represents alkyl; R4b and R5b represents hydrogen, halogen, alkyl or halogenalkyl; m represents 1, 2, 3, 4 or 5; R2 is specified in a group consisting of hydrogen, alkyl, -(CR4aR5a)m-G1 and -S(O)2R6, R6 represents G1, X1 means N or CR9; X2 means N or CR10; X3 means CR11; X4 means N or CR12; provided one fragment of X1, X2 or X4 can represent N; each of R9, R10, R11, R12, R13 and R14 independently represents hydrogen, alkyl, alkenyl, halogen, -G1, -G2, -OR1a, -C(O)G3, -C(O)OR1a, -C(O)N(Rb)(R3a), -N(Rb)(R3a), -(CR4aR5a)m-G1, -CR4a=CR5a-G1, -(CR4aR5a)m-G2, -CR6a=C(R7a)2, halogenalkyl and fragment ; R1a and R3a represents hydrogen, alkyl, haloalkyl, G1, -(CR4aR5a)m-G1, G2 or -(CR4aR5a)m-G2; R6a is alkyl or halogenalkyl; R7a represents hydrogen, alkyl or helogenalkyl; G3 represents heterocycle attached to an adjoining carbonyl fragment through a nitrogen atom being a part of heterocycle; or R10 and R11 or R13 and R14 together with carbon atoms which they are attached to, form unsubstituted phenyl or cycloalkyl; Y1 means NR17, CR18R19, C(O), S(O)n or O; Y2 means NR20, CR18R19 or C(O); Y3 means NR17, CR18R19 or C(O); or Y1 and Y2 together represent CR18=CR19, n means 2; R17 represents hydrogen; R18 and R19 represents hydrogen; and R20 is specified in a group consisting of hydrogen, alkyl and -S(O)n-G1.

EFFECT: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts possessing the properties of a 5-HT2C and/or 5-HT6 receptor modulator, to a based pharmaceutical composition and to methods for preparing them.

33 cl, 7 tbl, 20 dwg, 278 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclic indolysincarboxamides and azaindolysincarboxamides of formulas Ia and Ib:

presented below, wherein the values of R, Ra, R10, R20, R30, R40, Y, n, p and q are specified in cl. 1 of formula. What is described is a method for preparing them.

EFFECT: compounds exhibit rennin-inhibitory activity that enables using them in the pharmaceutical composition and for treating hypertension.

11 cl, 4 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula Ia, their stereoisomers or pharmaceutically acceptable salts, inhibiting JAK kinase activity. Compounds can be applied in treatment of inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis, in treatment of autoimmune diseases, such as lupus, multiple sclerosis, neurodegenerative diseases, such as Alzheimer's disease, etc. In formula Ia R1 represents H; R2 represents -OR4, -NR3R4- or -NR3S(O)2R4; R3 represents H or C1-C6alkyl, where said alkyl is optionally substituted with ORa; R4 represents H, C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atoms as heteroatoms, or -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R8 and said aryl, cycloalkyl and heteroaryl are optionally substituted with group R9; or R3 and R4, taken together with nitrogen atom, which they are bound to, form C3heterocyclyl, containing 1 nitrogen atom as heteroatom, optionally substituted with group R13; Z represents -NR5R6; R5 represents H; R6 represents H, C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains oxygen atom as heteroatom, -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected fromoxygen, nitrogen and sulphur, as heteroatoms, -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R10, and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with group R11; R7 represents H; R8 and R10 each independently represents halogen or ORa; R9 independently represents -CN, -CF3, halogen, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa, -O[C(Ra)2]1-3O-, C1-C3alkyl, optionally substituted with F, -(C0-C5alkyl)(C3-C6cycloalkyl), optionally substituted with group oxo or F, -(C0-C5alkyl)C3-C6heterocyclyl, where heterocyclyl contains 1-2 heteroatoms, selected from atoms of oxygen and nitrogen, and where heterocyclyl is optionally substituted with halogen or C1-C3alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogen, or -(C0-C5alkyl)C4-C5heteroaryl, where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected from atom of oxygen, nitrogen and sulphur as heteroatoms, and where heteroaryl is optionally substituted with or C1-C3alkyl; R10 independently represents halogen or ORa. Other values of radicals are given in the invention formula.

EFFECT: obtaining pharmaceutically acceptable salts, inhibiting JAK kinase activity.

15 cl, 4 tbl, 452 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein A represents 1,2,4-oxadiazol or 1,3,4-oxadiazol (of formula , or Ia), wherein star signs show a bond, which binds to a pyridine group of formula (I); R1 represents 3-pentyl, 3-methylbut-1-yl, cyclopentyl or cyclohexyl; R2 represents a methoxy group; R3 represents 2,3-dihidroxypropoxy group, -OCH2-CH(OH)-CH2-NHCO-CH2OH, -OCH2-CH(OH)-CH2N(CH3)-CO-CH2OH, -NHSO2CH3 or -NHSO2CH2CH3; and R4 represents ethyl or chlorine; or its pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition possessing S1P1/EDG1 receptor agonist activity, containing an effective amount of the compound of formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

EFFECT: pyridine-4-yl derivatives for preventing or treating diseases or disorders associated with the activated immune system.

26 cl, 4 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, in particular to method of obtaining 3-hetaryl-1,5,3-dithiazepinanes of general formula (1) , where ; ; ; ; ; ; ; ; , consisting in the following: N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine is subjected to interaction with hetarylamine [2-pyridinamine, 3-pyridinamine, 5-bromo-2-pyridinamine, 5-methyl-2-pyridinamine, 4-pyridinylmethylamine, 5-nitro-1,3-thiazol-2-amine, 6-nitro-1,3-benzothiazol-2-amine, 2-91h-indol-3-yl)-1-ethanamone, 5-methyl-1H-pyrazol-3-amine] in presence of catalyst CuCl2 in molar ratio N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:hetarylamine: CuCl2=10:10:(0.3-0.7) at temperature 55-65°C and atmospheric pressure in chloroform as solvent for 50-80 minutes.

EFFECT: elaborated is method of obtaining 3-hetaryl-1,5,3-dithiazepinanes, which can be applied as biologically active substances.

1 tbl, 1 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel indole and benzomorpholine derivatives of a formula (I) or its pharmaceutically acceptable salt, where R1 represents C1-6-alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 represents halogeno; R3 represents hydrogen; n equals 2, X represents -CH2CH2-O or -CH=CH-; Y represents -O- or -CR4(OH)-; R4 represents hydrogen or C1-3 alkyl. Invention also relates to a pharmaceutical composition based on formula (I) compound and a method of treatment or prevention of the said pathological states.

EFFECT: obtained are novel compounds, which are positive allosteric modulators of matabotropic subtype 2 receptors (mGluR2), which are useful for treatment or prevention of neurological and psychiatric disorders, associated with glutamate dysfunction, and diseases, involving metabotropic subtype 2 receptors GluR2.

22 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of nucleoside derivatives - 1,2,5-oxadiazoles of general structural formula I where R1 and R2 are selected from phenylsulphonyl, substituted with one or more halogen atoms, nitro groups, carboxy groups, alkyl halides, CH3, OCH3, OCF3; X is selected from N or N→O; or R1 and R2 form a group, where R', R", R'" and R'''' are independently selected from hydrogen; halogens; nitro groups, hydroxy group, carboxy group, CH3; CH2Br; OCH3; phenylsulphonyl; phenylthio group; or the following groups: R' and R" can also be merged into one of the following common rings for inhibiting human immunodeficiency virus (HIV) replication. The invention also relates to a pharmaceutical composition based on compounds of formula I and a method of inhibiting HIV-1 subtypes A and B integrase, including forms which are resistant to raltegravir.

EFFECT: detecting novel activity in compounds of formula I, which can be used in medicine as HIV replication inhibitors.

3 cl, 5 tbl, 4 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

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

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

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-[2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]methanesulphonamide and N-[6-(1-isopropoxyethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H- quinazolin-3-yl] methanesulphonamide, having antagonistic activity on the AMPA receptor. The invention also relates to a pharmaceutical composition.

EFFECT: use of said compounds to produce drugs for treating AMPA mediated conditions and primarily for treating epilepsy or schizophrenia.

6 cl, 81 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a chemical compound of formula wherein R=benzyl and to an antituberculous therapeutic agent representing a composition of imidazo[1,2-b][1,2,4,5]tetrazine derivative of formula I, wherein R=benzyl, isopropyl or phenyl and the known antituberculous preparation pyrazinamide with the ingredients in mole ratio 1:1.

EFFECT: there are prepared new antituberculous therapeutic agents.

2 cl, 2 tbl, 6 ex

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