TW201336837A - Novel azetidine derivatives - Google Patents

Abstract

The invention relates to a compound of formula (I) wherein A1, A2 and R1 to R8 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

Novel azetidine derivatives

The present invention relates to organic compounds suitable for the treatment and/or prophylaxis of mammals, and in particular to the selectivity of the cysteine protease cathepsin (specifically, the cysteine protease cathepsin S or L) Inhibitor compound.

In particular, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof:

Wherein one of A ¹ and A ² is -NR ⁹ - and the other is -CH ₂ -; R ¹ is halogen; R ² is hydrogen, halogen, alkyl or haloalkyl; R ³ is hydrogen, halogen, alkyl Or a haloalkyl group; R ⁴ and R ^{5 are} simultaneously hydrogen; or R ⁴ and R ^{5 together} with the carbon atom to which they are bonded form a cycloalkyl group; R ⁶ is hydrogen, halogen, alkyl, haloalkyl or cycloalkyl ; R ⁷ is hydrogen, halogen, alkyl, haloalkyl or cycloalkyl; R ⁸ is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, alkylpyridyl, alkyl-1H a pyrazolyl group, a phenyl group, a substituted phenyl group, a heterocyclic group or a substituted heterocyclic group, wherein the heterocyclic group is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl , imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl, wherein The substituted phenyl group is a phenyl group substituted with one to three substituents independently selected from the group consisting of alkyl, halogen, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halocycloalkyl and nitrile And its The substituted heterocyclic group is a heterocyclic group substituted with one to three substituents independently selected from the group consisting of alkyl, halogen, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halocycloalkane And nitrile; and R ⁹ is hydrogen, alkyl, haloalkyl, cycloalkyl, decyl or alkoxycarbonyl.

The compounds of the invention are selective inhibitors of the cysteine protease catalase (Cat) (specifically, cathepsin S or cathepsin L) and are therefore suitable for the treatment of metabolic diseases such as diabetes, atherosclerosis, abdomen Aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, glomerulonephritis, age-related macular degeneration, diabetic nephropathy, and diabetic retinopathy. In addition, immune-mediated diseases (such as rheumatoid arthritis, crohn's disease, multiple sclerosis, sjorgen syndrome, lupus erythematosus, neuropathic pain, type I diabetes) , asthma and allergies and skin-related immune diseases) are diseases suitable for treatment with cathepsin S inhibitors.

The object of the invention is a compound of the formula (I) and the aforementioned salts themselves and their use as therapeutically active substances; a medicament for the manufacture of such compounds, intermediates, pharmaceutical compositions, medicaments comprising such compounds, which are pharmaceutically acceptable Method of using a salt; a compound and a salt thereof for preventing and/or treating a disease, particularly for treating or preventing diabetes, atherosclerosis , abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease and use of diabetic nephropathy; and a compound and salt thereof for the treatment or prevention of diabetes, atherosclerosis, abdomen Use of drugs for aortic aneurysm, peripheral arterial disease, cancer, cardiovascular events in reducing chronic kidney disease, and diabetic nephropathy.

Mammalian cathepsins are a cysteine-type protease associated with key steps in biological and pathological events. Cathepsins are considered to be easy-to-handle drug targets because small molecules can be used to inhibit enzyme activity and are therefore of interest to 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).

The cathepsin S system is mainly expressed in antigen-presenting cells (such as macrophages and dendritic cells and smooth muscle cells). (Hsing, LC and Rudensky, AY (2005), "The lysosomal cysteine proteases in MHC class II antigen presentation", Immunol Rev, 207, 229-41; Rudensky, A. and Beers, C. (2006), "Lysosomal cysteine Protease and antigen presentation", Ernst Schering Res Found Workshop, (56), 81-95). Although cathepsin S showed only weak expression in normal arterial tissue, strong positive regulation was 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, GK 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 data suggest that the function of cathepsin S is important for atherosclerosis because when cathepsin S deficient mice are tested in a suitable mouse model, There is a reduced atherosclerotic phenotype. There have been reports of decreased fat accumulation, elastin fiber breakdown, and chronic arterial inflammation in LDL-Rec deficient mice. A significant reduction in acute plaque rupture events was reported in APO E deficient mice. When chronic kidney disease was introduced in CatS/APO-E-deficient mice, accelerated calcification was found to be significantly reduced at the highest point of anti-atherosclerotic activity of 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 Vasc Biol, 29(2), 188-94; Rodgers, KJ et al. (2006), "Destabilizing role of cathepsin S in murine atherosclerotic plaques", Arterioscler Thromb Vasc Biol, 26 ( 4), 851-6; Sukhova et al. (2003), "Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice", J Clin Invest, 111(6), 897-906). This indicates that potential inhibitors of cathepsin S will stabilize atherosclerotic plaque by reducing extracellular matrix breakdown, reducing proinflammatory conditions, and reducing accelerated calcification and subsequent clinical manifestations.

These phenotypic lines described in the atherosclerosis model are consistent with the known cellular functions of cathepsin S. First, cathepsin S is involved in the degradation of the extracellular matrix that stabilizes the plaque. In particular, cathepsin S has potent elastase-decomposing activity and can function at neutral pH, which is a feature of cathepsin S that distinguishes it from all other cathepsins. Second, cathepsin S is involved in the major proteases of antigen processing (specifically, cleavage of the invariant chain in antigen-presenting cells), which reduces the effect of T cells on chronic inflammation of atherosclerotic tissue. Promoting inflammation further leads to oxidative and proteolytic tissue damage and consequent plaque instability (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, C. 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 cysteine proteases and antigen presentation", Ernst Schering Res Found Workshop, (56) ), 81-95).

The anti-inflammatory and anti-elastase decomposition properties of Cat S inhibitors also make it a significant target for chronic obstructive pulmonary disease (Williams, AS et al. (2009), "Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation", Pulm Pharmacol Ther, 22(1), 27-32). In addition, due to its extracellular matrix degradation function, inhibition of cathepsin S will affect neointimal formation and angiogenesis (Burns-Kurtis, CL et al. (2004), "Cathepsin S expression is up-regulated following balloon angioplasty in The hypercholesterolemic rabbit", Cardiovasc Res, 62(3), 610-20; Cheng, XW 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, GP et al. (2003), "Deficiency of the cysteine protease cathepsin S impairs microvessel growth", Circ Res, 92(5), 493-500; Wang, B. et al. (2006), "Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors", J Biol Chem, 281(9), 6020-9). Cathepsin S inhibitors are therefore suitable for use in several different disease modes.

Cathepsin S also plays a role in slowing tumor growth and tumor cell invasion (as described by Roberta E. Burden in Clin Cancer Res 2009; 15 (19)). In addition, arterial calcification in nephrectomized cathepsin S knockout mice was significantly reduced compared to nephrectomized wild-type mice. This means that inhibition of cathepsin S can reduce the efforts of patients with chronic kidney disease. Tube events have a beneficial effect (Elena Aikawa, Circulation, 2009, 1785-1794).

Cathepsin L showed a broader phenotype than cathepsin S and there is also data showing the role of cathepsin L in atherosclerosis, eg, LDLrec and Cat L-deficient mice show a 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, Cat L has been shown to be associated with metabolic syndrome because it controls adipogenesis and peripheral glucose tolerance. In kidney disease, cathepsin L is described as a dynamin that regulates podocyte function and thereby causes proteinuria by protein hydrolysis (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, degradation of extracellular matrix, production of active neuropeptides, and antigen presentation in thymic epithelial cells are all cellular activities of cathepsin L (Funkelstein et al. (2008), (a) "Major role of cathepsin L for producing" The peptide hormones ACTH, β-Endorphin, and α-MSH, illustrated by protease gene knockout and expression", Journal of Biological Chemistry, 283(51), 35652-35659; (b) "Cathepsin L participates in the production of neuropeptide Y In secretory vesicles, demonstrated by protease gene knockout and expression", Journal of Neurochemistry, 106 (1), 384-391; Rudensky and Beers 2006).

As used herein, the term "alkyl", alone or in combination, denotes a straight or branched alkyl group containing from 1 to 8 carbon atoms, in particular a straight or branched alkyl group having from 1 to 6 carbon atoms and especially A linear or branched alkyl group having 1 to 4 carbon atoms. Examples of straight-chain and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and third. Butyl, isomerized pentyl, isomerized hexyl, isomerized heptyl and isomerized octyl, specifically methyl, ethyl, propyl, isopropyl, isobutyl and tert-butyl Base, more specifically methyl and ethyl.

The term "cycloalkyl", alone or in combination, denotes a cycloalkyl ring containing from 3 to 8 carbon atoms and, in particular, a cycloalkyl ring of from 3 to 6 carbon atoms. Examples of C3-C8 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Particular cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclopropyl group is specifically a cycloalkyl group.

The term "alkoxy", alone or in combination, means a group of the formula alkyl-O- (wherein the term "alkyl" is as previously defined), eg methoxy, ethoxy, n-propoxy Isopropoxy, n-butoxy, isobutoxy, second butoxy and tert-butoxy are, in particular, methoxy and tert-butoxy.

The term "oxy" refers to the -O- group, alone or in combination.

The term "halogen" or "halo", alone or in combination, means fluoro, chloro, bromo or iodo, in particular fluorine, chlorine or bromine.

The terms "haloalkyl", "halocycloalkyl" and "haloalkoxy", alone or in combination, mean substituted by at least one halogen, in particular by one to five halogens, especially one to three halogens. , cycloalkyl and alkoxy. A fluoroalkyl group is an alkyl group substituted with at least one fluorine atom, specifically one to five fluorine atoms, more specifically one to three fluorine atoms. Particular haloalkyl groups are difluoroethyl and trifluoroethyl. Particular haloalkoxy groups are trifluoroethoxy and trifluoropropoxy.

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

The term "mercapto" is used alone or in combination to mean a fluorenyl group (-CH(O)).

The term "pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness and properties of the free base or free acid which are not biologically or otherwise undesirable. The salts are composed of inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, specifically hydrochloric acid) and organic acids (such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, Malonate, Formed from succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. Further, such salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts. Salts derived from organic bases include, but are not limited to, primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and alkali ion exchange resins (eg, isopropylamine, A salt of trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyethyleneimine resin. The compounds of formula (I) may also exist in zwitterionic form. Specific pharmaceutically acceptable salts of the compounds of formula (I) are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonate.

"Pharmaceutically acceptable ester" means that the functional group of the compound of formula (I) can be derivatized to obtain a derivative which can be further converted into the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically unstable ester derivatives such as methoxymethyl ester, methylthiomethyl ester and neopentyloxymethyl ester. Furthermore, any physiologically acceptable equivalent of a compound of formula (I) which is similar to such metabolically labile esters and which produces a parent compound of formula (I) in vivo is within the scope of the invention.

If a starting material or a compound of formula (I) contains one or more functional groups which are unstable or reactive under the reaction conditions of one or more reaction steps, it may be well known in the art prior to the critical step. The method introduces a suitable protecting group (as described in TW Greene and PGM Wuts, "Protective Groups in Organic Chemistry", Third Edition, 1999, Wiley, New York). These protecting groups can be removed in subsequent synthetic stages using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbazate (Fmoc), 2-trimethyldecyl carbazate (Teoc), benzyloxycarbonyl (Cbz) and P-methoxybenzyloxycarbonyl (Moz).

The compound of formula (I) may contain several asymmetric centers and may be optically pure enantiomers, enantiomeric mixtures (eg racemates), diastereomeric mixtures, diastereomers in vitro The racemate or a mixture of diastereomeric racemates is present in the form of a mixture.

The term "asymmetric carbon atom" means a carbon atom containing four different substituents. According to the Cahn-Ingold-Prelog rule, asymmetric carbon atoms can be in the "R" or "S" configuration.

In particular, the present invention relates to the following: a compound of formula (I) wherein A ¹ is -NR ⁹ -; a compound of formula (I) wherein A ¹ is -CH ₂ -; a compound of formula (I) Wherein A ² is -NR ⁹ -; a compound of formula (I) wherein A ² is -CH ₂ -; a compound of formula (I) wherein R ¹ is chloro or bromo; a compound of formula (I) wherein R ² is hydrogen; a compound of formula (I) wherein R ³ is hydrogen or halogen; a compound of formula (I) wherein R ³ is hydrogen or fluoro; a compound of formula (I) wherein R ⁴ and R ⁵ are equivalent thereto The bonded carbon atoms together form a cyclopropyl group; a compound of formula (I) wherein R ⁶ is halogen; a compound of formula (I) wherein R ⁶ is chloro; a compound of formula (I) wherein R ⁷ is hydrogen; A compound of formula (I), wherein R ⁸ is hydrogen, halogen, alkoxy, haloalkoxy, cycloalkyl, alkylpyridyl or alkyl-1H-pyrazolyl; a compound of formula (I) wherein R ⁸ is hydrogen, halogen, alkoxy, haloalkoxy, alkylpyridyl or alkyl-1H-pyrazolyl; a compound of formula (I) wherein R ⁸ is hydrogen, fluoro, methoxy, trifluoroethyl Oxyl, trifluoropropoxy, methyl Piperidinyl, or methyl -1H- pyrazol-yl; a compound of formula (I),; of formula (I) compounds wherein R ⁹ is hydrogen, alkyl, haloalkyl, cycloalkyl, methyl acyl or an alkoxycarbonyl group Wherein R ⁹ is hydrogen, alkyl, haloalkyl or alkoxycarbonyl; a compound of formula (I) wherein R ⁹ is hydrogen or alkyl; a compound of formula (I) wherein R ⁹ is hydrogen, hydryl, ethyl, a third butoxycarbonyl or difluoroethyl; a compound of formula (I) wherein R ⁹ is hydrogen, methyl or ethyl; a compound of formula (I) wherein R ⁹ is hydrogen, alkyl, haloalkyl, A acyl or alkoxycarbonyl group; and a compound of formula (the I), wherein R ⁹ is hydrogen, methyl, ethyl, difluoroethyl, methyl acyl, methoxycarbonyl or trifluoroethyl.

The invention further relates to a compound of formula (I) selected from the group consisting of: 3-[(2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-2-(1- Cyanyl-cyclopropylamine-carbamoyl)-pyrrolidine-1-carbonyl]-3-(5-chloro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; 2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridin-2-yl)-azetidin-3-carbonyl ]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1- [3-(5-Chloro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-indole Amine; 3-(5-chloro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzene Sulfhydryl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 3-(5- Bromo-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2- (1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-[3-( 5-chloro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl ]-pyrrolidine-2- Acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-azetidin-3-carbonyl]-4 -[2-Chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-chloro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4- [2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4-[ 2-Chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 3- [(2S,4R)-4-(2-Chloro-phenylsulfonyl)-2-(1-cyano-cyclopropylaminecarbamimidyl)-pyrrolidin-1-carbonyl]-3-(5- Chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; 3-(5-bromo-3-fluoropyridin-2-yl)-3-((2S) , 4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylaminecarboxyl)pyrrolidine-1-carbonyl)azetidin-1-carboxylic acid Butyl ester; (2S,4R)-1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chlorophenylsulfonyl) -N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-aza Cyclobutane-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)-1 -[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidine 3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3 -(5-bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3-carbonyl]-4-(2-chloro-phenylsulfonyl)-pyrrolidine-2 -carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[3-(5-chloro-3-fluoro- Pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 3-(5-chloro 3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl] 2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 3-(5-bromo-3- Fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2- (1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(3-(5-chloro- 3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy)benzenesulfonyl)-N- (1-cyanocyclopropyl)pyrrolidine-2-carboxamide; 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyanide Benzyl-cyclopropylamine-mercapto)-pyrrolidin-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl Ester; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-phenylsulfonyl)-2-(1) -Cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 2-[(2S,4R)-4-(2- Chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl]-2-(5-chloro-3-fluoro-pyridine- 3-butyl)-azetidine-1-carboxylic acid tert-butyl ester; 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1 -cyano-cyclopropylaminecarbamimidyl-pyrrolidine-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid Tributyl ester; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2 S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminocarbamimidyl)-pyrrolidine-1-carbonyl]-azacyclocycle Butane-1-carboxylic acid tert-butyl ester; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro- Benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 2-(5 -Chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropan-2-yloxy) Terphenyl) phenylsulfonyl)-2-(1-cyanocyclopropylaminecarboxamido)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5- Chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropane- 3-butyloxy)benzenesulfonyl)-2-(1-cyanocyclopropylamine-methylindenyl)pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; -(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro-1 -methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidin-1-carbonyl]-azetidine-1-carboxylic acid Third butyl ester; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2, 2-Trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl]-azetidine (3S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridine- 2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-bromo- 4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrolidin-2-carboxylic acid ( 1-cyano-cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-( (S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1 -carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S, 4R )-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2, 2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrole Pyridin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azacyclocycle Butane-2-carbonyl]-4-(2-chloro-4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R )-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S)-2, 2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)- Indoleamine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4- ((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl) - decylamine; 2-(5-chloro-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridine-4- Tert-butyl benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid; -(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzenesulfonate Tertyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)- 1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridine-4 -yl)-phenylsulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R )-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridine) 4-yl)-phenylsulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; 2-(5-chloro-3-fluoropyridin-2-yl)- 2-((2S,4R)-4-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl)-2-(1-cyanocyclopropylamine) Tert-butyl pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5-bromo-3-fluoropyridin-2-yl)-2-((2S,4R) )-4-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl)-2-(1-cyanocyclopropylaminecarboxamido)pyrrolidine- 1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1- Methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; and (2S,4R)-1-[ 2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1-methyl-1H-pyrazole-4 -yl)-phenylsulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine.

In particular, the present invention relates to a compound of formula (I) selected from the group consisting of: (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3- (5-chloro-pyridin-2-yl)-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyano ring Propyl)pyrrolidine-2-carboxamide; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]- 4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo- 3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1- Cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3 -carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro -Benzenesulfonyl)-1-[3-(5-chloro-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylate Acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl) -4-(2-chloro-4-(2,2) ,2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(3-(5-chloro) 3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy)benzenesulfonyl)-N -(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2-bromo-4-fluoro-benzenesulfonyl)-1-[2-(5- Chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R) 1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)- Indoleamine; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4- ((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(( S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro-4 -((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-indole Amine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-( 2-methyl-pyridin-4-yl)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; and (2S,4R)-1-[2 -(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1-methyl-1H-pyrazole-4- () Benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine.

In particular, the invention relates additionally to a compound of formula (I) selected from the group consisting of: (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1- (2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl -ethoxyphenyl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-3 -fluoro-pyridin-2-yl)-1-carbenyl-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridine- 2-yl)-3-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonate 2-(1-cyano-cyclopropylaminocarboxamido)-pyrrolidine-1-carbonyl]- Methyl azetidine-1-carboxylate; and (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2,2- Trifluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy) -Benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine.

The compounds of formula (I) can be prepared using procedures known in the art. The following procedure can also be used to prepare the compound of formula (I).

The following abbreviations are used in this specification.

AcOEt: ethyl acetate; ACN: acetonitrile; BOP: benzotriazolyl-N-oxy-oxime (dimethylamino)-oxime; BOP-Cl: bis-(2- oxo-3 - oxazolidinyl)-phosphinium chloride; CDI: 1,1'-carbonyldiimidazole; DCM: dichloromethane; DIEA: diisopropylethylamine; DMF: N,N-dimethylformamide ;EDCI: N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride; h: hour; HATU: hexafluorophosphate O-(7-azabenzotriazole) -1-yl)-1,1,3,3-tetramethyluronium; HOBT: 1-hydroxybenzotriazole; Hunig's base: ethyl-diisopropyl-amine; KHMDS: Bis(trimethyldecyl) potassium decylamine; LDA: lithium diisopropyl guanamine; LHMDS: lithium bis(trimethyldecyl) guanamine; MeOH: ethanol; Mes-Cl: methylsulfonium chloride; : minute; Na ₂ SO ₄ : sodium sulfate; Nos-Cl: 3-nitrobenzenesulfonyl chloride; Pd ₂ (dba) ₃ : hydrazine (dibenzylideneacetone) dipalladium; PyBOP: benzotrifluorophosphate Zindol-1-yl-oxytripyrrolidinium; TBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; THF: tetrahydrofuran TFA: trifluoroacetic acid; and Tos-Cl: toluene-4-sulfonium chloride.

R ¹ -R ³ are as defined above; R is, for example, methyl, ethyl, isopropyl or benzyl; base 1 is, for example, NaOtBu, KOtBu, NaH, LiHMDS, KHMDS or LDA; base 2 is ( For example) LiOH, NaOH or KOH.

The 2-fluoropyridine derivative (for example, 1) is treated with a Boc-protected azetidine derivative 2 in the presence of a base (base 1 as defined above) to form azetidine derivative 3. Compound 3 is treated with a base (base 2 as defined above) to form the final carboxylic acid derivative 7 (in the form of the free acid or its salt).

R ¹ -R ³ are as defined above; R is, for example, methyl, ethyl, isopropyl or benzyl; base 1 is, for example, NaOtBu, KOtBu, NaH, LiHMDS, KHMDS or LDA; base 2 is ( For example) LiOH, NaOH or KOH.

The 2-fluoropyridine derivative (e.g., 1) is treated with a Boc-protected azetidine derivative 5 in the presence of a base (base 1 as defined above) to form the azetidine derivative 6. Compound 6 is treated with a base (base 2 as defined above) to form the final carboxylic acid derivative 7 (in the form of the free acid or its salt).

LG is a leaving group such as: trifluoromethanesulfonate, mesylate, tosylate, p-bromobenzenesulfonate or p-nitrobenzenesulfonate; R ⁴ -R ⁸ are as defined above; R is, for example, a methyl group, an ethyl group, an isopropyl group or a benzyl group.

The Boc-protected proline derivative 8 is reacted with a 2-chlorophenylthiol derivative in the presence of a base such as triethylamine, DIEA, 2,6-lutidine, etc. to form a thioether derivative. Matter 9. Oxidation 9 is carried out using a peroxide reagent such as H ₂ O ₂ , oxone, MCPBA to form an anthracene derivative 10. The ester is saponified to an acid using a base such as LiOH, NaOH, KOH or the like to form the corresponding carboxylic acid 11 or a salt thereof. By using 11 with 1-amino-cyclopropane-carbonitrile and a coupling agent (such as EDCI, CDI, BOP-Cl, TBTU, HATU, PyBOP, BOP, etc.) in a base (such as DIEA, triethylamine, dimethyl The reaction is carried out in the presence of pyridine or the like to effect indoleamine coupling to form indoleamine 12. Finally, the Boc-protecting group is removed by treatment of compound 12 with an acid such as TFA, HCl or formic acid in an organic solvent (eg, AcOEt, dioxane) to afford amine 13.

R ¹ -R ⁹ are as defined above; the acid is, for example, TFA, HCl or formic acid; X is a leaving group such as Cl, Br, I, triflate, mesylate, tosylate , benzenesulfonate, p-bromobenzenesulfonate or p-nitrobenzenesulfonate; R ¹⁰ is, for example, an alkyl group, a haloalkyl group or a cycloalkyl group; Y is, for example, H, an alkyl group or a haloalkyl group.

One of carboxylic acid 4 and amine 13 in a guanamine coupling agent (such as EDCI, CDI, BOP-Cl, TBTU, HATU, PyBOP, BOP, etc.) and a base (such as DIEA, triethylamine, 2,6-dimethyl The reaction is carried out in the presence of pyridine or the like to form guanamine 14. Compound 14 is deprotected to form amine 15 using an acid (e.g., TFA, formic acid, HCl) in an organic solvent (e.g., dioxane, EtOAc). The amine 15 can be alkylated using an alkylating agent R ⁹ -X (e.g., an alkyl halide, sulfonate, etc.) or by reductive amination to form the amine 16. For the latter, R ¹⁰ -C(O)-Y is an aldehyde or a ketone; R ¹⁰ is, for example, an alkyl group, a haloalkyl group or a cycloalkyl group; Y is, for example, a hydrogen, an alkyl group or a halogenated alkyl group; For example, NaBH ₄ , NaCNBH ₃ or sodium triethoxy borohydride.

R ¹ -R ⁸ are as defined above; the acid is, for example, TFA, HCl or formic acid.

Making carboxylic acid 7 and amine 13 in one of the guanamine coupling agents (such as EDCI, CDI, BOP-Cl, TBTU, HATU, PyBOP, BOP, etc.) and alkali (such as DIEA, triethylamine, lutidine, etc.) The reaction is present to form the guanamine 17. Compound 17 is deprotected using an acid (e.g., TFA, formic acid, HCl) in an organic solvent (e.g., dioxane, AcOEt) to afford amine 18.

R ¹ -R ⁷ and R ⁹ are as defined above; LG is a leaving group as defined above; R ⁸ is alkoxy or haloalkoxy; R is alkyl or haloalkyl; and the acid is, for example, TFA, HCl Or formic acid; X is a leaving group such as Cl, Br, I, triflate, mesylate, tosylate, benzenesulfonate, p-bromobenzenesulfonate or p-nitrobenzenesulfonate An acid ester; R ¹⁰ is, for example, an alkyl group, a halogenated alkyl group or a cycloalkyl group; and Y is, for example, H, an alkyl group or a halogenated alkyl group.

Compound 14 is reacted with an alcohol R-OH in the presence of a base such as Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , triethylamine, DIEA, etc. to give ether 19. Ether 19 is deprotected using an acid (e.g., TFA, formic acid, HCl) in an organic solvent (e.g., dioxane, AcOEt) to afford amine 20. The amine 20 is alkylated using an alkylating agent R ⁹ -X (e.g., a halide, sulfonate, etc.) or by reductive amination to form the amine 21. For the latter, R ¹⁰ -C(O)-Y is an aldehyde or a ketone; R ^{10 is} , for example, an alkyl group, a haloalkyl group or a cycloalkyl group; Y is, for example, a hydrogen, an alkyl group or a halogenated alkyl group; For example, NaBH ₄ , NaCNBH ₃ or sodium triethoxy borohydride.

R ¹ -R ⁷ are as defined above; LG is a leaving group as defined above; R ⁸ is alkoxy or haloalkoxy; R is alkyl or haloalkyl; and the acid is, for example, TFA, HCl or formic acid.

Compound 17 is reacted with an alcohol R-OH in the presence of a base such as Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , triethylamine, DIEA, etc. to give ether 22. The ether 22 is deprotected using an acid (e.g., TFA, formic acid, HCl) in an organic solvent (e.g., dioxane, AcOEt) to afford the amine 23.

R ¹ -R ⁷ are as defined above; LG is a leaving group such as Cl, Br, I; R ⁸ is a phenyl group, a substituted phenyl group, a heterocyclic group or a substituted heterocyclic group as defined above; R is H or methyl, or two R together with the boron atom to which it is bonded form a ring, such as 2,4,4,5,5-pentamethyl-[1,3,2]dioxaborolan Ring; acid is, for example, TFA, HCl or formic acid.

Compound 17 with The acid or ester derivative 26 is in the base (e.g., Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , KOtBu, K ₃ PO _{4 ,} etc.) and the touch for the Suzuki reaction known in the art. The reaction is carried out in the presence of a medium such as Pd(PPh ₃ ) ₄ , Pd ₂ (dba) ₃ having a phosphine ligand, or the like to form a biaryl derivative 24 . Compound 24 is deprotected using an acid such as TFA, formic acid, HCl in an organic solvent such as dioxane, AcOEt to afford amine 25.

The invention further relates to a process for the preparation of a compound of formula (I) as defined above, which comprises one of the following steps: (a) reacting a compound of formula (II) in the presence of an acid:

Wherein R ¹ to R ⁸ are as defined above, one of A ¹ and A ² is -CH ₂ - and the other is -NR ¹⁰ -, wherein R ¹⁰ is an amine protecting group; (b) a compound of formula (III) Reaction in the presence of R ⁹ -X:

Wherein A ¹ , A ² and R ¹ to R ⁹ are as defined above; or (c) reacting a compound of formula (III) as defined above in the presence of R ¹⁰ -C(O)-Y and a reducing agent, wherein A ¹ , A ² and R ¹ to R ⁹ are as defined above, R ¹⁰ is alkyl, haloalkyl or cycloalkyl and Y is hydrogen, alkyl or haloalkyl.

In step (a), the acid is, for example, TFA, HCl or formic acid.

In step (a), the amine protecting group is, for example, Boc, Fmoc, Cbz, Teoc, benzyl or Moz.

In step (c), the reducing agent is, for example, NaBH ₄ , NaCNBH ₃ or sodium triethoxy borohydride.

The compounds of formula (I) are also the objects of the invention when produced according to the above process.

The compound of the formula (I) and a pharmaceutically acceptable salt thereof can be used as a medicament (for example, in the form of a pharmaceutical preparation). Such pharmaceutical preparations may be administered orally, for example, orally (for example, in the form of lozenges, coated lozenges, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example in the form of a nasal spray) or Rectal administration (for example in the form of a suppository). However, it can also be administered parenterally (e.g., intramuscularly or intravenously (e.g., in the form of an injection)).

The compound of the formula (I) and pharmaceutically acceptable salts thereof can be treated with a pharmaceutically inert inorganic or organic adjuvant for the production of troches, coated troches, dragees and hard gelatine capsules. For example, lactose, corn starch or a derivative thereof, talc, stearic acid or a salt thereof or the like can be used as the adjuvant for the tablets, dragees and hard gelatin capsules.

Adjuvants suitable for use in soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid materials, liquid polyols and the like.

Adjuvants suitable for use in the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, and the like.

Adjuvants suitable for use in the injection are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain a preservative, a solubilizer, a viscosity increasing substance, a stabilizer, a wetting agent, an emulsifier, a sweetener, a coloring agent, a flavoring agent, a salt for changing the osmotic pressure, a buffering agent, and a masking agent. Flavor or antioxidant. They may also contain other therapeutic value Substance.

Thus, in particular, the invention also relates to the following: a compound of formula (I) for use as a therapeutically active substance; a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier; Use of a compound of formula (I) for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, diabetic nephropathy, diabetes A drug of retinopathy or age-related macular degeneration; a compound of formula (I) for use in the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of heart in chronic kidney disease Vascular events, diabetic nephropathy, diabetic retinopathy or age-related macular degeneration; and a heart for treating or preventing diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reducing chronic kidney disease a method of vascular events, diabetic nephropathy, diabetic retinopathy or age-related macular degeneration, the method comprising Compound (I) an effective amount of a formula.

The invention will be illustrated by the following examples of non-limiting features.

Instance Example 1 3-[(2S,4R)-4-(2-Chloro-4-methoxy-benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1- Carbonyl]-3-(5-chloro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

A) 3-(5-Chloro-pyridin-2-yl)-azetidine-1,3-dicarboxylic acid 1-t-butyl ester 3-methyl ester

To 5-chloro-2-fluoropyridine (0.5 g, 3.8 mmol, Eq: 1.00) and azetidine-1,3-dicarboxylic acid 1- contained in toluene (5 ml) at 0 °C A solution of the third butyl ester 3-methyl ester (818 mg, 3.8 mmol, Eq: 1.00) was added dropwise a 0.5 M toluene solution of KHMDS (7.6 ml, 3.8 mmol, Eq: 1.00) for 15 minutes. The colorless solution turned orange yellow. After stirring at 0 ° C for 45 minutes, the reaction mixture was allowed to warm to 20 ° C and stirred for 2.5 h. Saturated aqueous NH ₄ Cl (50 ml) and extracted with AcOEt (2 x 75 ml) the aqueous phase. In the combined organic phases were washed with brine and dried Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc EtOAc (EtOAc:EtOAc) m/z = 327.2 [M+H] ⁺ .

B) 1-tert-butoxycarbonyl-3-(5-chloro-pyridin-2-yl)-azetidine-3-carboxylic acid lithium

In a 10 ml round bottom flask, Example 1A) (0.21 g, 643 μmol, Eq: 1.00) and lithium hydroxide (24.6 mg, 1.03 mmol, Eq: 1.6) and tetrahydrofuran (1.8 ml) and water (1.2) Ml) combined to obtain a light yellow suspension. The reaction mixture was stirred at 22 ° C for 2 h. The crude reaction mixture was concentrated in vacuo to give a white solid (0.241 g; 100%). m/z = 311.3 [MH] ^- .

C) (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

Combine CAS No. 1252640-17-7 (0.25 g, 517 μmol, Eq: 1.00) with 4 M dioxane in hydrogen chloride (517 μl, 2.07 mmol, Eq: 4) in a 10 ml round bottom flask. A colorless solution was obtained. The reaction mixture was stirred at 22 ° C for 1.5 h. After stirring for 20 minutes, a slurry was formed. The crude reaction mixture was diluted with AcOEt (30 ml) and (20 ml) and extracted with 10% ₂ CO ₃ aq Na. The aqueous layer was back extracted with AcOEt (2 x 20 ml). The organic layers were combined, washed with brine (1×15 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give a colorless foam (202 mg; 100%). m/z = 384.3 [M+H] ⁺ .

D) 3-[(2S,4R)-4-(2-Chloro-4-methoxy-benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine- 3-carbonyl]-3-(5-chloro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

In a 10 ml round bottom flask, Example 1B) (0.165 g, 518 μmol, Eq: 1.00), HATU (394 mg, 1.04 mmol, Eq: 2) and DIPEA (134 mg, 181 μl, 1.04 mmol, Eq) : 2) Combine with acetonitrile (3 ml) to obtain a light brown solution. Example 1C) (199 mg, 518 μmol, Eq: 1.00) was added to the above solution and stirred at 20 ° C for 18 h. The crude reaction mixture was concentrated in vacuo and the residue was diluted with AcOEt (30 ml) and (25 ml) extracted with 10% Na ₂ CO ₃ solution. The aqueous layer was back-extracted with AcOEt (2 x 20 mL), washed with brine, dried over Na ₂ SO ₄ and evaporated to dry. The crude product was then purified by flash chromatography (EtOAc, 12 g, 30% to 90%EtOAc) m/z = 678.3 [M+H] ⁺ .

Example 2 (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridin-2-yl)-azetidin-3- Carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

In a 10 ml round bottom flask, Example 1D) (0.15 g, 221 μmol, Eq: 1.00) and formic acid (305 mg, 254 μl, 6.63 mmol, Eq: 30) were combined to obtain a yellow solution. The mixture was stirred at 20 ° C for 20 h. Washed with water (2 ml) and the reaction mixture was diluted, adjusted with 10% Na ₂ CO ₃ to the aqueous solution of pH = 8,, the ₂ SO ₄ and extracted twice with ₂ Cl ₂ CH, The combined organic layers were washed with brine and dried over Na Filtered and evaporated to give a pale yellow solid (0.131 g; 100%). m/z = 580.3 [M+H] ⁺ .

Example 3 (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridin-2-yl)-1-methyl-nitrogen heterocycle Butane-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

Methyl iodide (9.2 mg, 4.05 μl, 64.8 μmol, Eq: 0.75) was added to a solution of Example 2 (0.05 g, 86.4 μmol, Eq: 1.00) in MeOH (1 ml). After the addition was completed, the mixture was stirred at 80 ° C for 2 h. Additional methyl iodide (9.2 mg, 4.05 μl, 64.8 μmol, Eq: 0.75) was added and the mixture was stirred at 80 ° C for 2 h and then stirred at 20 ° C overnight. The mixture was purified by preparative HPLC to give a colourless solid (3 mg; 6%). m/z = 592.2 [M+H] ⁺ .

Example 4 3-(5-Chloro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonate Tert-butyl 2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid

The title compound was prepared starting from CAS No. 1252634-04-0 to give a colorless amorphous solid. m/z = 746.1 [M+H] ⁺ .

Example 5 3-(5-Bromo-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonate Tert-butyl 2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid

The title compound was prepared starting from 5-bromo-2-fluoro-pyridine and CAS No. 1252634-04-0 to give a yellow foam. m/z = 792.1 [M+H] ⁺ .

Example 6 (2S,4R)-1-[3-(5-chloro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2- three Fluoroethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

The title compound was prepared starting from Example 4 in a procedure analogous to Example 2 to yield a colourless waxy solid. m/z = 646.1 [M+H] ⁺ .

Example 7 (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2- Trifluoroethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

The title compound was prepared starting from Example 5 in a procedure analogous to Example 2 to yield a yellow foam. m/z = 692.0 [M+H] ⁺ .

Example 8 (2S,4R)-1-[3-(5-chloro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4- [2-Chloro-4-(2,2,2-trifluoroethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropane Amine

In a 10 ml round bottom flask, Example 6 (0.082 g, 127 μmol, Eq: 1.00), 2,2-difluoroethyl trifluoromethanesulfonate (40.7 mg, 27.0 μl, 190 μmol, Eq: 1.5) and DIEA (24.6 mg, 33.2 μl, 190 μmol, Eq: 1.5) were combined with acetonitrile (1.5 ml) to give a pale yellow solution. The reaction mixture was stirred at 22 ° C for 72 h. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography eluting elut elut elut elut elut elut elut elut %). m/z = 710.2 [M+H] ⁺ .

Example 9 (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4- [2-Chloro-4-(2,2,2-trifluoroethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

The title compound was prepared starting from Example 7 in a procedure analogous to Example 8 to yield a colorless amorphous solid. m/z = 756.1 [M+H] ⁺ .

Example 10 3-[(2S,4R)-4-(2-Chloro-phenylsulfonyl)-2-(1-cyano-cyclopropylaminocarbamimidyl)-pyrrolidine-1-carbonyl]-3-( 3-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared starting from 5-chloro-2,3-difluoropyridine and CAS No. 1252638-10-0 to give a colorless foam. m/z = 666.2 [M+H] ⁺ .

Example 11 3-(5-bromo-3-fluoropyridin-2-yl)-3-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylamine A Mercapto pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared starting from 5-bromo-2,3-difluoropyridine and CAS No. 1252638-10-0 to give a colorless foam. m/z = 712.0 [M+H] ⁺ .

Example 12 (2S,4R)-1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chlorophenylsulfonyl)-N- (1-cyanocyclopropyl)pyrrolidine-2-carboxamide

The title compound was prepared starting from Example 10, similar to the method described in Example 2, to yield a colorless foam. m/z = 566.1 [M+H] ⁺ .

Example 13 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-(2-chloro-benzenesulfonyl) -pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

The title compound was prepared starting from Example 11 to give a colorless foam, similar to the method described in Example 2. m/z = 611.9 [M+H] ⁺ .

Example 14 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-(2-chloro- Phenylsulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

Aqueous formaldehyde solution (36%; 19.1 mg, 17.5 μl, 229 μmol, Eq: 2.8) was added to Example 13 (0.05 g, 81.8 μmol, Eq: 1.00) in dichloromethane (0.5 ml) at 25 °C. ), a mixture of sodium acetate (14.8 mg, 180 μmol, Eq: 2.2) and acetic acid (10.8 mg, 10.3 μl, 180 μmol, Eq: 2.2). The mixture was stirred for 45 minutes, followed by one-time addition of sodium triethoxysulfonate (55.5 mg, 262 μmol, Eq: 3.2) at 0-5 °C. After 10 minutes the cooling bath was removed and stirring was continued for an additional 18 h at 25 °C. The reaction mixture was quenched with 0.5 M aqueous NaOH (2 mL) and stirred for 2 min. The aqueous layer was extracted with three portions of AcOEt (5 ml each). The combined organic layers were washed with brine, dried over Na ₂ CH ₄ and evaporated. The crude material was purified by preparative EtOAc (EtOAc): m/z = 626.1 [M+H] ⁺ .

Example 15 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3-carbonyl]-4-(2-chloro- Phenylsulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

The title compound was prepared starting from Example 13 to give a pale-yellow amorphous solid, similar to the method described in Example 14. m/z = 640.1 [M+H] ⁺ .

Example 16 (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[3-(5-chloro-3-fluoro-pyridin-2-yl)-1-methyl-azetidine 3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

The title compound was prepared starting from Example 12 to give a pale-yellow amorphous solid, similar to the method described in Example 14. m/z = 580.1 [M+H] ⁺ .

Example 17 3-(5-Chloro-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoroethoxy)- Phenylsulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner to that described in Example 4 to give a colorless amorphous solid. m/z = 764.3 [M+H] ⁺ .

Example 18 3-(5-Bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoroethoxy)- Phenylsulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner to that described in Example 4 to give a colorless amorphous solid. m/z = 710.1 [M+H-Boc] ⁺ .

Example 19 (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide

In a 10 mL round bottom flask, a solution of Example 18 (0.210 g, 260 μmol, Eq: 1.00) dissolved in dioxane (1.5 ml) and hydrogen chloride in 4 M dioxane (260 μl, 1.04 mmol, Eq: 4) to obtain a colorless solution. The reaction mixture was heated to 22 ° C and stirred for 18 h. The mixture and the residue was diluted in AcOEt (30 ml) and (50 ml) and extracted with 10% Na ₂ CO ₃ aq The crude reaction was concentrated in vacuo. The aqueous layer was back extracted with AcOEt (2 x 30 ml). The organic layers were combined, washed with brine and concentrated (1 x 20mL) dried over Na ₂ SO ₄ and in vacuo. The crude material was purified by preparative HPLC to give a colourless amorphous solid (0.038 g; 21%). m/z = 710.0 [M+H-Boc] ⁺ .

Example 20 (2S,4R)-1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to that described in Example 19 to yield a colorless amorphous solid. m/z = 664.1 [M+H-Boc] ⁺ .

Example 21 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl] 2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

A) 2-(5-Chloro-3-fluoro-pyridin-2-yl)-azetidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester

To 5-chloro-2,3-difluoropyridine (1.39 g, 9.29 mmol, Eq: 1.00) and azetidine-1,2-dicarboxyl in toluene (15 ml) at 0 °C A 0.5 M toluene solution of KHMDS (18.6 ml, 9.29 mmol, Eq: 1.00) was added dropwise to a solution of the acid 1-t-butyl ester 2-methyl ester (2 g, 9.29 mmol, Eq: 1.00) for 15 min. The colorless solution turned pale brown. After stirring at 0 ° C for 45 minutes, the reaction mixture was allowed to warm to 25 °C. The reaction mixture was stirred for 2.5 h. Saturated aqueous NH ₄ Cl (100 ml), and extracted with AcOEt (2x150 ml) the aqueous phase. The combined organic layers were washed with brine, dried over Na ₂ CH ₄ The crude material was purified by flash chromatography (EtOAc EtOAc (EtOAc:EtOAc) m/z = 345.2 [M+H] ⁺ .

B) 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxamide) (1)-pyrrolidin-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester [epimer 1 :1]

The title compound was prepared starting from Example 21A) and CAS No. 1252633-65-0, to afford a mixture of epimers as a colorless amorphous solid. m/z = 684.3 [M+H] ⁺ .

Example 22 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyanide Benzyl-cyclopropylamine-methylpyridyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner to that described in Example 21. The resulting mixture of epimers was purified by palmitic HPLC to obtain a single epimer as a colorless amorphous solid. m/z = 730.1 [M+H] ⁺ .

Example 23 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl] 2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

After separation of Example 21 by palm-wise HPLC, Example 23 was obtained as a single epimer, which was a single epimer of a colorless amorphous solid. m/z = 684.3 [M+H] ⁺ .

Example 24 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl] 2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

After separation of Example 21 by palm-wise HPLC, Example 24 was obtained as a single epimer, which was a single epimer of a colorless amorphous solid. m/z = 684.3 [M+H] ⁺ .

Example 25 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyanide Benzyl-cyclopropylamine-methylpyridyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

After separation of Example 22 by palm-wise HPLC, Example 25 was obtained as a single epimer, which was a single epimer of a colorless amorphous solid. m/z = 730.1 [M+H] ⁺ .

Example 26 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyanide Benzyl-cyclopropylamine-methylpyridyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

After separation of Example 22 by palm-wise HPLC, Example 26 was obtained as a single epimer, which was a single epimer of a colorless amorphous solid. m/z = 730.1 [M+H] ⁺ .

Example 27 2-(5-chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropane- 2-butyloxy)benzenesulfonyl)-2-(1-cyanocyclopropylaminecarboxyl)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

In a 25 ml round bottom flask, Example 21 (0.1 g, 146 μmol, Eq: 1.00) was combined with N,N-dimethylacetamide (1.5 ml) to give a pale yellow solution. (S)-1,1,1-Trifluoropropan-2-ol (26.7 mg, 234 μmol, Eq: 1.6) and cesium carbonate (57.1 mg, 175 μmol, Eq: 1.2) were added at 25 °C. The above solution was stirred for 24 h. Thereafter, additional (S)-1,1,1-trifluoropropan-2-ol (6.67 mg, 58.4 μmol, Eq: 0.4) was added to the reaction mixture and stirred at 25 ° C for an additional 24 h. The crude reaction mixture was concentrated, the residue was dissolved in AcOEt (100 ml) sequentially, and (25 ml) extracted with 10% Na ₂ CO ₃ with 0.5 N HCl aqueous solution (35 ml). The aqueous layer was back extracted with AcOEt (2 x 25 ml). In the combined organic layers were washed with brine and dried Na ₂ SO _4, filtered and evaporated. The crude material was then purified by flash chromatography (silica gel, 40 g, 10% to 50% EtOAc/heptane) to afford the mixture of the isomers and then purified An epimer (9 mg; 8%) which is a colorless amorphous solid. m/z = 778.3 [M+H] ⁺ .

Example 28 2-(5-chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropane- 2-butyloxy)benzenesulfonyl)-2-(1-cyanocyclopropylaminecarboxyl)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

After purification of Example 27 by palmitic HPLC, Example 28 was obtained as another epimer. m/z = 778.3 [M+H] ⁺ .

Example 29 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-azetidin-1-carboxylate Tert-butyl acid

The title compound was prepared in a similar manner to that described in Example 27. The resulting mixture of epimers was purified by palmitic HPLC to obtain a single epimer as a colorless amorphous solid. m/z = 842.1 [M+H] ⁺ .

Example 30 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl- Ethoxy)-phenylsulfonyl]-2-(1-cyano-cyclopropylamine-carbamoyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

After purification of Example 29 by palmitic HPLC, Example 30 was obtained as another epimer. m/z = 842.1 [M+H] ⁺ .

Example 31 (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine- 2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

In a 10 mL round bottom flask, Example 24 (0.034 g, 49.7 μmol, Eq: 1.00) and 4 M dioxane in hydrogen chloride (62.1 μl, 248 μmol, in dioxane (0.1 ml). Eq: 5) Combine to obtain a colorless solution. The reaction mixture was heated to 22 ° C and stirred for 18 h. Thereafter, a solution of hydrogen chloride in 4 M dioxane (62.1 μl, 248 μmol, Eq: 5) was added and the reaction mixture was stirred at 25 ° C for 24 h. Thereafter, an additional 4 M solution of hydrogen chloride in dioxane (24.8 μl, 99.3 μmol, Eq: 2) was added and the mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to give an off-white foam (0.031 g; 100%). m/z = 584.0 [M+H] ⁺ .

Example 32 (2S,4R)-4-(2-bromo-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine- 2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

The title compound was prepared from Example 26 in a procedure similar to Example 31 to yield an off white solid. m/z = 630.2 [M+H] ⁺ .

Example 33 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-azetidin-1-carboxylate Tert-butyl acid

The title compound was prepared starting from CAS No. 1252636-85-3 to give a colorless waxy solid. m/z = 824.1 [M+H] ⁺ .

Example 34 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S -2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

The title compound was prepared from Example 33 using the method described in Example 31. After evaporation, the compound was purified by preparative HPLC to give a white solid. m/z = 724.2 [M+H] ⁺ .

Example 35 (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine- 2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

The title compound was prepared from Example 23 using the method described in Example 31 to yield a colourless solid. m/z = 584.2 [M+H] ⁺ .

Example 36 (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-(2-chloro-4-fluoro- Phenylsulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

The title compound was prepared from Example 25 using the method described in Example 31 to yield a colourless solid. m/z = 630.2 [M+H] ⁺ .

Example 37 (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S -2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

The title compound was prepared from Example 27 using the method described in Example 31 to yield a colourless solid. m/z = 678.2 [M+H] ⁺ .

Example 38 (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S -2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

The title compound was prepared from Example 28 using the method described in Example 31 to yield a colourless solid. m/z = 678.2 [M+H] ⁺ .

Example 39 (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S -2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

The title compound was prepared from Example 29 using the method described in Example 31 to yield a colourless solid. m/z = 724.1 [M+H] ⁺ .

Example 40 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)- Guanamine

The title compound was prepared from Example 34 according to the procedure described in Example 14 to yield a colorless amorphous solid. m/z = 756.3 [M+H] ⁺ .

Example 41 2-(5-chloro-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzene Sulfhydryl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

A) (2S,4R)-4-(4-bromo-2-chloro-phenylthio)-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester

The CAS number 1252633-25-2 (5.3 g, 12.3 mmol, Eq: 1.00) was dissolved in propionitrile (40 ml) and 4-bromo-2-chlorobenzenethiol (3.3 g, 14.8 mmol, Eq: 1.20) was added. ). Triethylamine (2.49 g, 3.43 ml, 24.6 mmol, Eq: 2.00) was now added. The reaction mixture was stirred under reflux overnight. The reaction mixture was poured into 100 ml 10% Na ₂ CO ₃ and (2 x 100 mL) and extracted with EtOAc. , In 0.1 N HCl the organic layer was extracted with 100 ml Na ₂ SO ₄ dried, filtered and evaporated. The crude material was purified by flash chromatography (EtOAc, EtOAc (EtOAc:EtOAc) m/z = 352.1 [M+H-Boc] ⁺ .

B) (2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester

Example 41A) (4.72 g, 10.5 mmol, Eq: 1.00) was dissolved in dichloromethane (40 ml), and MCPBA (3.79 g, 22.0 mmol, Eq: 2.10) was carefully added portionwise. The reaction mixture was stirred at 25 ° C for 18 h. With 10% Na ₂ CO ₃ solution, 0.1 N HCl and saturated aqueous Na ₂ S ₂ O ₃ aqueous solution was extracted the reaction mixture. The organic layer was Na ₂ SO ₄ and dried over Na ₂ SO ₃ 2 h, filtered and carefully evaporated to give a colorless waxy solid (4.96 g; 98%). m/z = 383.9 [M+H-Boc] ⁺ .

C) (2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester

Example 41B) (4.96 g, 10.3 mmol, Eq: 1.00) was dissolved in THF (15 ml) and water (10 ml). LiOH hydrate (418 mg, 17.5 mmol, Eq: 1.70) was now added and the reaction mixture was stirred at 22 ° C for 3 h. The reaction mixture was extracted with 0.2 N aqueous HCl / dichloromethane. The organic layer was dried over Na ₂ SO _4, filtered and concentrated to a white foam (4.83 g; 100%) in vacuo. m/z = 467.9 [MH] ^- .

D) (2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carboxylic acid Tributyl ester

Example 41C) (4.83 g, 10.3 mmol, Eq: 1.00) was dissolved in acetonitrile (40 ml). HATU (7.84 g, 20.6 mmol, Eq: 2.00), DIEA (2.66 g, 3.6 ml, 20.6 mmol, Eq: 2.00) and 1-aminocyclopropane-carbonitrile hydrochloride (1.47 g, 12.4 mmol, Eq) :1.20) was added to the solution and stirred at 22 ° C for 2 h. The reaction mixture was poured into aq. EtOAc (EtOAc) The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc EtOAc EtOAc:EtOAc m/z = 531.9 [MH] ^- .

E) (2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

The title compound was prepared according to the method described in Example 2 to yield an off white solid. m/z = 434.1 [M+H] ⁺ .

F) 2-[(2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1- Carbonyl]-2-(4-chloro-2-fluoro-phenyl)-azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner to that described in Example 21 to yield a colorless foam. m/z = 746.0 [M+H] ⁺ .

G) 2-(5-Chloro-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl) -Benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

Example 41F) (0.05 g, 67.1 μmol, Eq: 1.00), 2-methylpyridine-4- contained in water (1.0 ml) and dioxane (2.5 ml) Acid pinacol ester (16.2 mg, 73.8 μmol, Eq: 1.1), tripotassium phosphate (42.7 mg, 201 μmol, Eq: 3) and 2'-(dimethylamino)-2-biphenyl-palladium chloride (II) The second norbornene phosphine complex (3.76 mg, 6.71 μmol, Eq: 0.1) was added to a 10 ml microwave vial. The vial was capped and heated in a microwave at 120 °C for 30 minutes. The crude material was purified by preparative HPLC to afford colourless foam (0.019 g; 37%). m/z = 757.4 [M+H] ⁺ .

Example 42 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzene Sulfhydryl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner to that described in Examples 21 and 41 to give a colorless amorphous solid. m/z = 803.1 [M+H] ⁺ .

Example 43 (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2- Methyl-pyridin-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

The title compound was prepared from Example 41 to give a white solid. m/z = 657.4 [M+H] ⁺ .

Example 44 (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2- Methyl-pyridin-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

The title compound was prepared from Example 42 to give a white amorphous solid, similar to the method described in Example 31. m/z = 703.3 [M+H] ⁺ .

Example 45 2-(5-Chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl) Phenylsulfonyl)-2-(1-cyanocyclopropylaminecarboxamido)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

Similar to the method of Example 41G), from Example 41F) and 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole The title compound was prepared to give a colorless foam. m/z = 746.3 [M+H] ⁺ .

Example 46 2-(5-bromo-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl) Phenylsulfonyl)-2-(1-cyanocyclopropylaminecarboxamido)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner to the methods of Examples 42 and 45 to yield a colorless foam. m/z = 746.3 [M+H] ⁺ .

Example 47 (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1- Methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

The title compound was prepared from Example 45 to give a white solid. m/z = 646.5 [M+H] ⁺ .

Example 48 (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1- Methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

The title compound was prepared from Example 46 to give a colorless foam. m/z = 692.2 [M+H] ⁺ .

Example 49 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl ]-4-[2-Chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 -cyano-cyclopropyl)-guanamine

In a 5 ml round bottom flask, Example 34 (100 mg, 138 μmol, Eq: 1.00), 2,2-difluoroethyl trifluoromethanesulfonate (51.8 mg, 34.3 μl, 242 μmol, Eq: 1.75) And Hunig's base (31.3 mg, 42.3 μl, 242 μmol, Eq: 1.75) was combined with acetonitrile (1.5 ml) to give a pale yellow solution. The reaction mixture was stirred at 25 ° C for 4 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into EtOAc (20 ml) and extracted with 10% Na ₂ CO ₃ solution (1 x 15 mL). The aqueous layer was back extracted with EtOAc (2 x 20 mL). The organic layers were combined and washed with aq. sat. NaCI (1×15 mL). The organic layer was dried over such Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut m/z = 786.0415 [MH] ^- .

Example 50 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-carboxanyl-azetidin-3-carbonyl]-4-[2-chloro 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl) - guanamine

In a 5 ml round bottom flask, Example 34 was combined with DMSO (0.5 ml) to give a colorless solution. 4-Nitrophenylcarboxylate (12.7 mg, 76.1 μmol, Eq: 1.10) was added. The reaction mixture was stirred at 25 ° C for 3 days. Thereafter, additional 4-nitrophenyl formate (3.47 mg, 20.7 μmol, Eq: 0.3) was added to the above solution and stirred for 5 days. The crude material was purified by preparative EtOAc (EtOAc:EtOAc) m/z = 752.0394 [M+H] ⁺ .

Example 51 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-azetidin-1-carboxylate Methyl ester

In a 5 ml round bottom flask, Example 34 (50 mg, 69.2 μmol, Eq: 1.00) was combined with dichloromethane (1.0 ml) to give a colorless solution. Methyl chloroformate (13.1 mg, 10.7 μl, 138 μmol, Eq: 2.00) and triethylamine (14.0 mg, 19.3 μl, 138 μmol, Eq: 2.00) were added. The reaction mixture was stirred at 25 ° C for 4 h. The crude material was purified by preparative EtOAc (EtOAc) m/z = 782.0487 [M+H] ⁺ .

Example 52 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2,2-trifluoro-ethyl)-azetidin-3 -carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine

In a 5 ml round bottom flask, Example 34 (50 mg, 69.2 μmol, Eq: 1.00) was combined with acetonitrile (1.5 ml) to give a colorless solution. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (20.1 mg, 12.5 μL, 86.5 μmol, Eq: 1.25) and Hughne base (11.2 mg, 15.1 μL, 86.5 μmol, Eq: 1.25) were added. The reaction mixture was stirred at 25 ° C for 18 h. The crude material was purified by preparative EtOAc (EtOAc) m/z = 806.0479 [M+H] ⁺ .

Example 53 Cathepsin inhibition assay

Enzyme activity was determined by observing the amount of increase in fluorescence intensity caused by cleavage of a peptide substrate containing a fluorophore that was quenched in the intact peptide.

Analytical buffer: 100 mM potassium phosphate (pH 6.5), 5 mM EDTA-Na, 0.001% Triton X-100, 5 mM DTT.

Enzymes (both 1 nM): human and mouse cathepsin S, Cat K, Cat B, Cat L.

Substrate (20 μM): Except for Z-Leu-Arg-AMC for Cat K, Z-Val-Val-Arg-AMC (both from Bachem).

Z = benzyloxycarbonyl.

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

DTT = dithiothreitol.

Final volume: 100 μL.

Excitation: 360 nm, emission: 465 nm.

The enzyme was added to the dilution in a 96-well microtiter plate and the reaction was started with the substrate. Fluorescence emission was measured for 20 minutes, during which a linear increase was observed in the absence of inhibitor. The IC ₅₀ is calculated by standard methods.

Inhibition of human Cat S, mouse Cat S, human Cat K, human Cat B, human Cat L, and mouse Cat L has been measured separately. The results for representative compounds of the invention obtained for human Cat S and L are shown in the following table in μM.

The compounds of the invention are selective inhibitors of cathepsins-S and L (relative to cathepsins-K and B).

In the foregoing assay, the compounds of the present invention _{50 pairs of} Cat S and / or L has between 0.00001 to 100 μM, preferably between 0.00001 to 50 μM, more preferably between IC 20 μM to 0.00001 in. The particular compound of the present invention in at least one of the preceding assay has less than 0.09 μM of IC _50.

Example A

The compounds of the formula (I) can be used in the form known per se as active ingredients for the manufacture of tablets having the following composition:

Instance B

The compounds of the formula (I) can be used in the form known per se as active ingredients for the manufacture of capsules having the following composition:

Claims (22)

a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, Wherein one of A ¹ and A ² is -NR ⁹ - and the other is -CH ₂ -; R ¹ is halogen; R ² is hydrogen, halogen, alkyl or haloalkyl; R ³ is hydrogen, halogen, alkyl Or a haloalkyl group; R ⁴ and R ^{5 are} simultaneously hydrogen; or R ⁴ and R ^{5 together} with the carbon atom to which they are bonded form a cycloalkyl group; R ⁶ is hydrogen, halogen, alkyl, haloalkyl or cycloalkyl; R ⁷ is hydrogen, halogen, alkyl, haloalkyl or cycloalkyl; R ⁸ is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, alkylpyridyl, alkyl-1H- Pyrazolyl, phenyl, substituted phenyl, heterocyclic or substituted heterocyclic, wherein heterocyclic is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, Imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl Substituted phenyl is phenyl substituted with one to three substituents independently selected from the group consisting of alkyl, halo, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halocycloalkyl and nitrile, And among them The heterocyclic group is a heterocyclic group substituted with one to three substituents independently selected from the group consisting of alkyl, halogen, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halocycloalkyl and Nitrile; and R ⁹ is hydrogen, alkyl, haloalkyl, cycloalkyl, decyl or alkoxycarbonyl. The compound of claim 1, wherein R ¹ is chlorine or bromine. A compound of claim 1 or 2 wherein R ² is hydrogen. A compound of claim 1 or 2 wherein R ³ is hydrogen or halogen. The compound of claim 1 or 2, wherein R ³ is hydrogen or fluoro. A compound according to claim 1 or 2, wherein R ⁴ and R ^{5 together} with the carbon atom to which they are bonded form a cyclopropyl group. A compound of claim 1 or 2 wherein R ⁶ is halogen. A compound of claim 1 or 2 wherein R ⁶ is chloro. A compound of claim 1 or 2 wherein R ⁷ is hydrogen. A compound according to claim 1 or 2, wherein R ⁸ is hydrogen, halogen, alkoxy, haloalkoxy, cycloalkyl, alkylpyridyl or alkyl-1H-pyrazolyl. A compound according to claim 1 or 2, wherein R ⁸ is hydrogen, halogen, alkoxy, haloalkoxy, alkylpyridyl or alkyl-1H-pyrazolyl. A compound according to claim 1 or 2, wherein R ⁸ is hydrogen, fluoro, methoxy, trifluoroethoxy, trifluoropropoxy, methylpyridyl or methyl-1H-pyrazolyl. A compound according to claim 1 or 2, wherein R ⁹ is hydrogen, alkyl, haloalkyl, formyl or alkoxycarbonyl. A compound according to claim 1 or 2, wherein R ⁹ is hydrogen, methyl, ethyl, difluoroethyl, decyl, methoxycarbonyl or trifluoroethyl. A compound according to claim 1 or 2 which is selected from the group consisting of: 3-[(2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-2-(1-cyano- Cyclopropylamine Mercapto)-pyrrolidine-1-carbonyl]-3-(5-chloro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-4- (2-Chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridin-2-yl)-azetidin-3-carbonyl]-pyrrolidin-2- Carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro -pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 3-(5- Chloro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2- (1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 3-(5-bromo-pyridin-2-yl) -3[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclo) Propylamine-mercapto)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-[3-(5-chloro-pyridine-2 -yl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-pyrrolidin-2- Carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-azetidin-3-carbonyl]- 4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzene Mercapto]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-chloro-pyridin-2-yl)-1- (2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonate (1), pyridin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-1-( 2,2-Difluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl ]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; 3-[(2S,4R)-4-(2-chloro-phenylsulfonyl)-2-(1- Cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-3-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid Ding Ester; 3-(5-bromo-3-fluoropyridin-2-yl)-3-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropyl) (3S,4R)-1-(3-(5-chloro-3-fluoropyridine-2-carboxylate) (a), azetidine-3-carbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S, 4R) 1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-(2-chloro-phenylsulfonyl)-pyrrolidine-2 -carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-nitrogen Heterocyclobutane-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 1-[3-(5-Bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3-carbonyl]-4-(2-chloro-phenylsulfonyl)- Pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[3-(5-chloro- 3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 3- (5-chloro-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzene Sulfhydryl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1 -carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2 -chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl] -azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl -4-(2-chloro-4-(2,2,2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; 2-[(2S,4R)-4-(2-chloro- 4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxamide) (3)-pyridyl-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; 2-(5-bromo 3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylamine Tert-butyl)-pyrrolidin-1-carbonyl]-azetidine-1-carboxylic acid; 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonate) Mercapto)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azacyclocycle Butane-1-carboxylic acid tert-butyl ester; 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylamine) Mercapto)-pyrrolidin-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; 2-(5 -Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropane Tert-butyl carbazino)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2- [(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl]-nitrogen Tert-butyl butane-1-carboxylic acid; 2-(5-chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-() (S)-1,1,1-trifluoropropan-2-yloxy)benzenesulfonate Tertyl)-2-(1-cyanocyclopropylaminemethane)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5-chloro-3- Fluoridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropan-2-yloxy)benzenesulfonate Benzyl-2-(1-cyanocyclopropylaminemethane)pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5-bromo-3-fluoro -pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)- Phenylsulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-azetidin-1-carboxylate Tert-butyl acid; (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)- Azetidine-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-bromo-4-fluoro-benzene Sulfhydryl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano- Cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-((S)-2) ,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl]-nitrogen Butane-terminated butane-1-carboxylic acid; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl ]-4-[2-Chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 -cyano-cyclopropyl)-guanamine; (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridine -2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-(2-chloro-4-fluoro-benzene Sulfhydryl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridine-2- -Azetidine-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonate (2-Silyl-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl) -azetidin-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl] - pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-nitrogen Heterocyclobutane-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrole Pyridine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)- Indoleamine; 2-(5-chloro-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl) - Benzenesulfonyl]-2-(1-cyano-cyclopropylamine-carbamoyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 2- (5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzenesulfonate Tert-butyl 2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1 -[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridine-4- -(Benzenesulfonyl)-pyrrolidinium-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-bromo-3-fluoro- Pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzenesulfonyl]-pyrrolidine-2 -carboxylic acid (1-cyano-cyclopropyl)-guanamine; 2-(5-chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro- 4-(1-Methyl-1H-pyrazol-4-yl)benzenesulfonyl)-2-(1-cyanocyclopropylaminecarbamyl) Pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5-bromo-3-fluoropyridin-2-yl)-2-((2S,4R)-4 -(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl)-2-(1-cyanocyclopropylaminemethanyl)pyrrolidine-1-carbonyl Azetidine, azetidine-1-carboxylate; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-2 -carbonyl]-4-[2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropane (2), guanamine; (2S, 4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro 4-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-ring) Propyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-aza Cyclobutane-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine 2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-carboxamidine -azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl ]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)- 4-[2-Chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropyl) Methylaminopyridyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylate; and (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridine- 2-yl)-1-(2,2,2-trifluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2, 2-Trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine. A compound according to claim 1 or 2, which is selected from the group consisting of: (2S, 4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridine) -2-yl)-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-(3-( 5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine- 2-carbamamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-(2-chloro -Benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridine- 2-yl)-1-methyl-azetidin-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl) )-decylamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3-carbonyl]-4- (2-Chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-benzenesulfonyl) 1-[3-(5-chloro-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano) -cyclopropyl)-guanamine; (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(3-(5-chloro- 3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy)benzenesulfonyl)-N- (1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2-bromo-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro 3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2, 2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)-1- [2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2- Trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2 -(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro -1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)-1-[3 -(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2 ,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1 -[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridine-4- -(Benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-chloro-3-fluoro- Pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrole Pyridine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl ]-4-[2-Chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 -cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-carboxanyl-azetidine 3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2- Carboxylic acid (1-cyano-cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminecarbamyl)-pyrrole Methyl pyridine-1-carbonyl]-azetidine-1-carboxylate; and (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1- (2,2,2-trifluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1- Methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 16, which comprises the step of: (a) reacting a compound of formula (II) in the presence of an acid: Wherein R ¹ to R ⁸ are as defined in any one of claims 1 to 14, one of A ¹ and A ² is -CH ₂ - and the other is -NR ¹⁰ -, wherein R ¹⁰ is an amine protecting group (b) reacting a compound of formula (III) in the presence of R ⁹ -X: Wherein A ¹ , A ² and R ¹ to R ⁹ are as defined in any one of claims 1 to 14; or (c) a compound of formula (III) as defined above is at R ¹⁰ -C(O)- Reaction in the presence of Y and a reducing agent, wherein A ¹ , A ² and R ¹ to R ⁹ are as defined in any one of claims 1 to 14, and R ¹⁰ is alkyl, haloalkyl or cycloalkyl and Y It is hydrogen, alkyl or haloalkyl. A compound according to claim 1 or 2, which is produced according to the method of claim 17. A compound of claim 1 or 2 for use as a therapeutically active substance. A compound according to claim 1 or 2 for use in the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, diabetic nephropathy, diabetes A therapeutically active substance for retinopathy or age-related macular degeneration. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a therapeutically inert carrier. Use of a compound according to any one of claims 1 to 16 for the preparation of a cardiovascular for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of chronic kidney disease A drug for events, diabetic nephropathy, diabetic retinopathy, or age-related macular degeneration.