HK1261759B - Novel pyrrolidine derivatives - Google Patents

Description

New pyrrolidine derivatives

The present invention relates to organic compounds useful for the treatment and/or prevention of diseases in mammals, and in particular to compounds that are preferential inhibitors of the cysteine proteases cathepsins, in particular the cysteine protease cathepsin S.

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

in

^R1 is hydrogen, alkyl, haloalkyl, halogen or triazolyl; and

R ^is (halo)(oxy)pyridinyl, (alkyl)(oxy)pyridinyl, (alkyl)(haloalkyl)pyrazolyl, haloalkoxyphenyl, alkoxyphenyl, cycloalkyloxyphenyl, cycloalkyloxy, alkyltetrazolyl, triazolyl, alkyltriazolyl, dialkyltriazolyl, halotriazolyl, haloalkylpyrazolyl, formylphenyl, aminopyrimidinyl, cyanophenyl, (alkoxy)(dihalo)phenyl, hydroxyalkylphenyl, benzo[1,3]dioxolyl, dialkylthiazolyl, alkylthiazolyl, alkoxypyrimidinyl, dialkylisoxazolyl, or (halo)(haloalkyl)triazolyl;

or a pharmaceutically acceptable salt or ester thereof.

The compounds of the present invention are preferential inhibitors of the cysteine proteases cathepsins (Cat), particularly cathepsin S, and are therefore useful in treating metabolic diseases such as diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, and diabetic nephropathy. In addition, immune-mediated diseases such as rheumatoid arthritis, multiple sclerosis, Sjorgen's syndrome, lupus erythematosus, neuropathic pain, type I diabetes, asthma, and skin-related immune diseases are suitable diseases for treatment with cathepsin S inhibitors.

The present invention relates to compounds of formula (I) and their salts as such, as well as their use as therapeutically active substances, methods for preparing said compounds, intermediates, pharmaceutical compositions, and medicaments containing said compounds and their pharmaceutically acceptable salts, the use of said compounds and salts for preventing and/or treating diseases, in particular for treating or preventing diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, and diabetic nephropathy, as well as the use of said compounds and salts in the preparation of medicaments for treating or preventing diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, and diabetic nephropathy.

Mammalian cathepsins are cysteine proteases that participate in key steps of biological and pathological events. Cathepsins are considered to be tractable drug targets because their enzymatic activity can be inhibited with small molecules and are therefore of great 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).

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

Preclinical data suggest that cathepsin S function is crucial for atherosclerosis, as cathepsin S-deficient mice have a reduced atherosclerotic phenotype when tested in appropriate mouse models. In LDL-Rec-deficient mice, reduced lipid accumulation, elastin fiber breakdown, and chronic arterial inflammation were reported. In APO E-deficient mice, a significant reduction in acute plaque rupture events was reported. When chronic renal disease is introduced into CatS/In APO-E deficient mice, a strong reduction of accelerated calcification can be seen in addition to the antiatherogenic activity in arteries and heart valves (Aikawa, E., et al. (2009), 'Arterial and aortic valve calcification abolished by elastolyticcathepsin 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, K.J., et al. (2006), 'Destabilizing role ofcathepsin S in murine atherosclerotic plaques', Arterioscler Thromb Vasc Biol, 26(4), 851-6; Sukhova, G.K., et al. (2003), 'Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice', J Clin Invest, 111(6), 897-906). This suggests that potential inhibitors of cathepsin S may stabilize atherosclerotic plaques by reducing extracellular matrix breakdown, reducing the proinflammatory state, and reducing accelerated calcification and its subsequent clinical manifestations.

These phenotypes described in atherosclerosis models are consistent with the known cellular functions of cathepsin S. First, cathepsin S is involved in the degradation of the extracellular matrix that stabilizes plaques. In particular, cathepsin S possesses potent elastin-lytic activity and can function at neutral pH, features that distinguish cathepsin S from all other cathepsins. Second, cathepsin S is the primary protease involved in antigen processing, particularly the cleavage of invariant chains in antigen-presenting cells, leading to a reduced contribution of T cells to the chronic inflammation of atherosclerotic tissue. Increased inflammation leads to further oxidative and proteolytic tissue damage and subsequent 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 antielastinolytic properties of Cat S inhibitors make them a major target for chronic obstructive pulmonary disease (Williams, A.S., et al. (2009), 'Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation', Pulm Pharmacol Ther, 22(1), 27-32). Furthermore, due to its extracellular function in matrix degradation, inhibition of cathepsin S will affect neointima formation and angiogenesis (Burns-Kurtis, C.L., et al. (2004), 'Cathepsin Sexpression is up-regulated following balloon angioplasty in the hypercholesterolemic rabbit', Cardiovasc Res, 62(3), 610-20; Cheng, X.W., et al. (2004), 'Increased expression of elastolytic cysteine proteases, cathepsins S and K, in the neointima of balloon-injured rat carotid arteries', Am J Surg Med 2003, 11(5): 101-102. J Pathol, 164(1), 243-51; Shi, G.P., et al. (2003), 'Deficiency of the cysteine protease cathepsin S impairs microvessel growth', Circ Res, 92(5), 493-500; Wang, B., et al. (2006), 'Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors', J Biol Chem, 281(9), 6020-9). Therefore, inhibitors of cathepsin S may be useful in several different disease settings.

As described by Roberta E. Burden in Clin Cancer Res 2009; 15(19), cathepsin S also plays a role in reducing tumor growth and tumor cell invasion. In addition, nephrectomized cathepsin S knockout mice showed a significant reduction in arterial calcification compared to nephrectomized wild-type mice. This suggests that inhibition of cathepsin S may have a beneficial effect on reducing cardiovascular events in patients with chronic kidney disease (Elena Aikawa, Circulation, 2009, 1785-1794).

In the present specification, the term "alkyl", alone or in combination, means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, in particular a straight-chain or branched alkyl group having 1 to 6 carbon atoms and more particularly a straight-chain 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, tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, in particular methyl, ethyl, propyl, butyl and pentyl, more particularly methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl and isopentyl. A particular example of an alkyl group is methyl.

The term "cycloalkyl", alone or in combination, means a cycloalkyl ring having 3 to 8 carbon atoms, in particular a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. A particular example of "cycloalkyl" is cyclopropyl.

The term "oxy", alone or in combination, signifies an -O- group.

As an exception, "(oxy)pyridinyl" refers to py+-O-, where py represents pyridine.

The term "alkoxy", used alone or in combination, denotes a radical of the formula alkyl-O-, wherein the term "alkyl" has the meaning given previously, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Particular "alkoxy" radicals are methoxy and ethoxy, in particular methoxy.

The term "cycloalkyloxy", used alone or in combination, denotes a radical of the formula cycloalkyl-O- wherein the term "cycloalkyl" has the previously given significance. A particular cycloalkyloxy radical is cyclopropyloxy.

The term "halogen" or "halo", alone or in combination, means fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine, more in particular fluorine and chlorine. The term "halo" in combination with another group means that the group is substituted by at least one halogen, in particular by one to five halogens, especially one to four halogens, i.e. one, two, three or four halogens. Particular "halogen" is chlorine.

The term "haloalkyl", used alone or in combination, means an alkyl group substituted by at least one halogen, in particular by one to five halogens, especially one to three halogens. Particular "haloalkyl" are trifluoromethyl and difluoromethyl, in particular trifluoromethyl.

The term "haloalkoxy", used alone or in combination, denotes an alkoxy group substituted by at least one halogen, particularly by one to five halogens, especially one to three halogens. Particular "haloalkoxy" is trifluoromethoxy.

The term "hydroxy", alone or in combination, signifies a -OH group.

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

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

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

The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness and properties of free alkali or free acid, which are not undesirable biologically or otherwise. Salt is formed by following acid: inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acid, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition, these salts can be prepared by adding inorganic base or organic base in the free acid. Salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. Compounds of formula (I) may also exist in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

"Pharmaceutically acceptable esters" means that compounds of formula (I) can be derivatized at functional groups to provide derivatives that can be converted back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl ester, methylthiomethyl ester, and pivaloyloxymethyl ester. In addition, similar to metabolically labile esters, any physiologically acceptable equivalents of compounds of formula (I) that are capable of producing the parent compound of formula (I) in vivo are within the scope of the present invention.

If a starting material or compound of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (such as those described in "Protective Groups in Organic Chemistry", TW Greene and PGM Wuts, ^3rd Ed., 1999, Wiley, New York) can be introduced before the key steps using methods well known in the art. These protecting groups can be removed in the later stages of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butyloxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), benzyloxycarbonyl (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

The compounds of formula (I) may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, mixtures of diastereomers, racemates of diastereomers or mixtures of racemates of diastereomers.

The term "asymmetric carbon atom" refers to a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog convention, an asymmetric carbon atom can be in the "R" or "S" configuration.

The present invention further relates to:

A compound of formula (I), wherein R ¹ is alkyl, haloalkyl or halogen;

A compound of formula (I), wherein R ¹ is methyl, trifluoromethyl or chloro;

A compound of formula (I) wherein R ² is (alkyl)(haloalkyl)pyrazolyl, alkyltetrazolyl, triazolyl, alkyltriazolyl, dialkyltriazolyl, halotriazolyl, haloalkylpyrazolyl, dialkylthiazolyl, alkylthiazolyl or dialkylisoxazolyl;

A compound of formula (I) wherein R ² is (methyl)(trifluoromethyl)pyrazolyl, methyltetrazolyl, triazolyl, methyltriazolyl, dimethyltriazolyl, chlorotriazolyl, trifluoromethylpyrazolyl, difluoromethylpyrazolyl, dimethylthiazolyl, methylthiazolyl or dimethylisoxazolyl;

The present invention further relates to compounds of formula (I) selected from the group consisting of:

(2S,4R)-4-[4-(2-Chloro-1-oxy-pyridin-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(2-Methyl-1-oxy-pyridin-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(2'-Trifluoromethoxy-3-trifluoromethyl-biphenyl-4-sulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(2'-ethoxy-3-trifluoromethyl-biphenyl-4-sulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(2'-Cyclopropyloxy-3-trifluoromethyl-biphenyl-4-sulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(4-Cyclobutoxy-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(2-chloro-4-(5-methyl-2H-tetrazol-2-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(5-methyl-1H-tetrazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2,4-bis(1H-1,2,4-triazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(2H-1,2,3-triazol-2-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(1H-1,2,3-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(3-chloro-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methyl-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-(trifluoromethoxy)biphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-cyclobutoxyphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(3-methyl-2'-(trifluoromethoxy)biphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-[4-(5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(3-Methyl-[1,2,4]triazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(3-Methyl-[1,2,4]triazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(4-(1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

(2S,4R)-4-[4-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-formyl-3-methylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-[4-(3-Chloro-[1,2,4]triazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(5-methyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methyl-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(4-(1H-1,2,3-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-formylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-ethoxybiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(4-(2-aminopyrimidin-5-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-ethoxy-3-methylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2'-cyano-3-methylbiphenyl-4-ylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-ethoxy-4',5'-difluoro-3-methylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-(hydroxymethyl)biphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(4-(2-aminopyrimidin-5-yl)-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-[4-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-1-(1-Trifluoromethyl-cyclopropanecarbonyl)-4-[2-trifluoromethyl-4-(4-trifluoromethyl-pyrazol-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(5-Methyl-tetrazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(2,4-Dimethyl-thiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2,4-dimethylthiazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2-methylthiazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2-methoxypyrimidin-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(4-[1,2,3]triazol-2-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(4-[1,2,3]triazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-[4-(1-Difluoromethyl-1H-pyrazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(5-Methyl-tetrazol-2-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-1-(1-Trifluoromethyl-cyclopropanecarbonyl)-4-[2-trifluoromethyl-4-(3-trifluoromethyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-(hydroxymethyl)-3-methylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2,4-dimethylthiazol-5-yl)-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methyl-4-(2-methylthiazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2-methoxypyrimidin-5-yl)-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-[4-(2-Methyl-thiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(3,5-dimethylisoxazol-4-yl)-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(4-Tetrazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2R,4R)-4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-[4-(1-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide; and

(2S,4R)-4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide.

The present invention particularly relates to compounds of formula (I) selected from the group consisting of:

(2S,4R)-4-[4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(2-chloro-4-(5-methyl-2H-tetrazol-2-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(5-methyl-1H-tetrazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(2H-1,2,3-triazol-2-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(1H-1,2,3-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(3-chloro-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(2-chloro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methyl-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-[4-(5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(3-Methyl-[1,2,4]triazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(3-Methyl-[1,2,4]triazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(4-(1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-[4-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(3-Chloro-[1,2,4]triazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(5-methyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methyl-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-(1-Trifluoromethyl-cyclopropanecarbonyl)-4-[2-trifluoromethyl-4-(4-trifluoromethyl-pyrazol-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(5-Methyl-tetrazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(2,4-Dimethyl-thiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(2-chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(4-[1,2,3]triazol-2-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(4-[1,2,3]triazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(1-Difluoromethyl-1H-pyrazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-[4-(5-Methyl-tetrazol-2-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-1-(1-Trifluoromethyl-cyclopropanecarbonyl)-4-[2-trifluoromethyl-4-(3-trifluoromethyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2,4-dimethylthiazol-5-yl)-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methyl-4-(2-methylthiazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-[4-(2-Methyl-thiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(3,5-dimethylisoxazol-4-yl)-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-(4-Tetrazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide;

(2S,4R)-4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

(2R,4R)-4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide; and

(2S,4R)-4-[4-(1-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide.

The present invention particularly relates to a compound of formula (I), which is (2S,4R)-4-[4-(5-methyl-tetrazol-2-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide.

The present invention uses the following abbreviations.

AcOEt: ethyl acetate;

ACN: acetonitrile;

boc: tert-butyloxycarbonyl

BOP: benzotriazolyl-N-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate;

BOP-Cl: bis-(2-oxo-3-oxazolidinyl)-phosphinyl chloride;

Cbz: benzyloxycarbonyl

CDI: 1,1’-carbonyldiimidazole;

DCM: dichloromethane;

DIEA: diisopropylethylamine;

DMAP: 4-dimethylaminopyridine;

DMF: N,N-dimethylformamide;

EDCI: N-(3-dimethylaminopropyl)-N’-ethyl-carbodiimide hydrochloride;

EtOAc: ethyl acetate;

Fmoc:9-fluorenylmethoxycarbonyl

h: hour;

HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate;

HOBT: 1-hydroxybenzotriazole;

Hunig's base: ethyldiisopropylamine;

mCPBA or MCPBA: meta-chloroperbenzoic acid;

MeOH: methanol;

Mes-Cl: methanesulfonyl chloride;

min: minute;

Na ₂ SO ₄ : sodium sulfate;

Nos-Cl: 3-nitrobenzenesulfonyl chloride;

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium;

PyBOP: benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate;

TBTU: O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate;

THF: tetrahydrofuran;

TFA: trifluoroacetic acid; and

Tos-Cl: toluene-4-sulfonyl chloride.

Compounds of formula (I) can be prepared by known methods or according to the methods described in Schemes 1 and 2 below.

Process 1

Definitions: a) Acid: for example methanesulfonic acid, benzenesulfonic acid, ^{trifluoromethanesulfonic} acid, HCl, HBr, sulfuric acid, TFA, formic acid; b) X: OH, Cl, O-SO2- _LG1 ; c) ^LG1 : a leaving group such as phenyl, methyl, ethyl, 3-nitrophenyl, 4-methylphenyl, 4-bromophenyl, trifluoromethyl; d) ^LG2 : F, Cl, Br, I, B(OH) ₂ , B( ^OR3 ) ₂ ; e) ^R1 as defined above; f) ^R3 : methyl, ethyl or two ^R3 together with the oxygen and boron atoms to which they are attached form a ring, for example 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane; g) Oxidation: oxidation with one of the oxidants known in the art, for example hydrogen peroxide or a metal complex of hydrogen peroxide, oxone or mCPBA; h) ^R2 as defined above; i) ^LG3 :H, B(OH) ₂ , B(OR ³ ) ₂ , Br or I.

Boc-protected compound 1 is deprotected with an appropriate acid such as TFA, HCl, formic acid, sulfuric acid, etc. to give salt 2 after crystallization. Salt 2 is reacted with 1-trifluoromethyl-cyclopropanecarboxylic acid in the presence of a base such as triethylamine, Hunig's base, or N-methylmorpholine and an appropriate amide coupling agent such as HATU, PyBop, TBTU, CDI, EDCI, BOP, or Bop-Cl to give amide 3. Alternatively, 2 is reacted with 1-trifluoromethyl-cyclopropanecarboxylic acid in the presence of, for example, oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosgene, or triphosgene to give amide 3. Ring opening of lactam 3 with 1-amino-cyclopropanecarbonitrile or a salt thereof, such as the hydrochloride salt, in the presence of an appropriate base such as Hunig's base, triethylamine, sodium 2-ethylhexanoate, pyridine, or lutidine at elevated temperatures of 30°C to 80°C gives alcohol 4. Alcohol 4 is reacted with a sulfonyl chloride derivative such as methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride or an acid anhydride such as trifluoromethanesulfonic anhydride to provide compound 5. Sulfonate 5 is reacted with thiophenol 5b in the presence _{of a} suitable base such as Hunig's base, triethylamine, pyridine, _lutidine , _Na2CO3 , _K2CO3 or _Cs2CO3 to provide _thioether 6. Subsequent oxidation of thioether 6 with a peroxide source such as hydrogen peroxide, mCPBA, _oxone or a metal complex of _hydrogen peroxide such as _MoO2Cl2 / _{H2O2 or NaxWyOz / H2O2} system provides sulfone 7. Compound 7 can be directly reacted with _a heterocyclic compound in the presence of a base such as Hunig's base, triethylamine, pyridine, _lutidine , _Na2CO3 , _K2CO3 or _Cs2CO3 in an _SNAr manner, or reacted with a boronic acid or its ester through a Suzuki reaction using a metal catalyst and a base known in the art such as Pd( _PPh3 ) ₄ , _Pd2 (dba _{) 3} or a Pd source with a phosphine ligand to give the final compound 8.

Process 2

Definitions: a) R ¹ as defined above; b) R ³ : methyl, chlorine.

Oxidation of pyridine derivatives to the corresponding N-oxides can be accomplished using oxidizing agents such as hydrogen peroxide, mCPBA or oxone.

Therefore, the present invention also relates to a process for preparing a compound of formula (I), comprising:

(a) Reaction of a compound of formula (A) in the presence of a compound of formula R2- ^LG2

wherein R ¹ and R 2 are as defined in any one of claims 1 to 6, and wherein LG ¹ is F, Cl, Br, I, B(OH) ₂ or B(OR ³ ) ₂ , LG ² is H, B(OH) ₂ , B(OR ³ ) ₂ , Br or I, and each R ³ is independently selected from methyl, ethyl, and two R ³ together with the oxygen and boron atoms to which they are attached form an organoboron ring; or

(b) In the presence of an oxidizing agent, the compound of formula (B) is reacted

wherein R ¹ is as defined in any one of claims 1 to 6, and R ⁴ is halogen or alkyl.

Examples of oxidizing agents are eg hydrogen peroxide, mCPBA or oxone.

4,4,5,5-Tetramethyl-1,3,2-dioxaborolane is an example of an organoboron ring.

The present invention also relates to compounds of formula (I) prepared according to the above process.

Another embodiment of the present invention provides a pharmaceutical composition or medicine containing the compounds of this invention and a treatment inert carrier, diluent or excipient, and methods for preparing said composition and medicine using the compounds of this invention. In one example, the compound of formula (I) can be prepared in a galenic dosage form by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient under application dose and concentration) at a suitable pH and required purity at ambient temperature. The pH of the preparation depends primarily on the concentration of the specific use and compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of delivery of the active agent, the method of administration, the administration regimen, and other factors known to the physician.

The compounds of this invention can be used by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and if necessary, for local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. The compounds of this invention can be used especially by intravitreal administration.

The compounds of the present invention can be administered in any convenient administration form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. These compositions may contain conventional components of pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

Typical formulations are prepared by mixing the compounds of the invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-shielding agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents and other known additives that can provide an elegant presentation of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or facilitate the preparation of the pharmaceutical product (i.e., the drug).

Therefore, the present invention also relates to:

Compounds of formula (I) for use as therapeutically active substances;

A pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier;

Use of a compound of formula (I) in the preparation of a medicament for treating or preventing diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, diabetic nephropathy, diabetic 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 cardiovascular events in chronic kidney disease, diabetic nephropathy, diabetic retinopathy or age-related macular degeneration; and

A method for treating or preventing diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, diabetic nephropathy, diabetic retinopathy or age-related macular degeneration, comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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

Example

Example 1

(2S,4R)-4-[4-(2-Chloro-1-oxy-pyridin-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

In a 10 mL round-bottom flask, CAS 1252637-43-6 (0.05 g, 78.7 μmol, Eq: 1.00) was mixed with dichloromethane (1 mL) to give a colorless solution. 3-Chloroperoxybenzoic acid (20.4 mg, 118 μmol, Eq: 3 x 1.5 each after 24, 48, and 72 hours) was added. The reaction mixture was heated to 22°C and stirred for a total of 168 hours. The crude material was purified by preparative HPLC to yield the title compound as a colorless amorphous solid (25 mg; 50%). m/z = 651.2 [M+H] ⁺ .

Example 2

(2S,4R)-4-[4-(2-Methyl-1-oxy-pyridin-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

In a 10 mL round-bottom flask, CAS 1252637-46-9 (50 mg, 81.4 μmol, Eq: 1.00) was mixed with dichloromethane (1 mL) to give a colorless solution. mCPBA (21.1 mg, 122 μmol, Eq: 1.5) was added. The reaction mixture was heated to 22°C and stirred for a total of 20 h. The crude material was purified by preparative HPLC to yield the title compound as a colorless amorphous solid (40 mg; 78%). m/z = 631.3 [M+H] ⁺ .

Example 3

(2S,4R)-4-[4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

a)(1S,4S)-3-oxo-2-oxa-5-azonia cation-bicyclo[2.2.1]heptane methanesulfonate

Dissolve (1S,4S)-3-oxo-2-oxa-5-aza-bicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester (100.0 g, 469 mmol) in ethyl acetate (970 mL), and add methanesulfonic acid (43.5 mL, 659 mmol) at 45°C. Stir the mixture at 45°C for 16 h. Cool the suspension to room temperature, filter, and wash the precipitate with ethyl acetate (240 mL) and dry in vacuo to yield the title compound as a white crystalline solid (94.2 g, 96%). m/z = 113 [MH] ^- .

b) (1S,4S)-5-(1-Trifluoromethyl-cyclopropanecarbonyl)-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-one

1-Trifluoromethyl-cyclopropanecarboxylic acid (167.0 g, 1084 mmol) was suspended in toluene (500 mL), followed by the addition of dimethylformamide (3.6 mL, 47 mmol). The mixture was cooled to 2°C (ice bath), and a solution of oxalyl chloride (90 mL, 1037 mmol) in toluene (167 mL) was added dropwise over 25 minutes. The mixture was then stirred for an additional 30 minutes, followed by 4 hours at room temperature. It was then cooled again to 0°C (dry ice/methanol bath), and (1S,4S)-3-oxo-2-oxa-5-azonia-bicyclo[2.2.1]heptane methanesulfonate (200 g, 956 mmol), tetrahydrofuran (330 mL), and triethylamine (500 mL, 3.59 mol) were slowly added, maintaining the reaction temperature below 5°C. The reaction became highly exothermic, especially after the addition of 50% triethylamine, and effective cooling was necessary. The mixture was stirred at room temperature for 20 h. It was then poured into an aqueous citric acid solution (10% aqueous solution, 1.6 L) and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic extracts were washed with 20 ml of brine (500 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product (245 g, brown oil) was dissolved in dichloromethane (330 mL), followed by addition of ethyl acetate (130 mL) and heptane (660 mL), and the dichloromethane was carefully distilled off in vacuo. The product began to crystallize. The suspension was cooled to 2 ° C (ice bath) and stirred for 1 h, then filtered. The precipitate was washed with ethyl acetate/heptane 1:9 (v/v, 300 mL) and dried in vacuo to give the title compound as a light brown powder (219 g, 92%). ^1H NMR (CDCl3, 400 MHz): d 1.17-1.25 (m, 1H), 1.30 (dd, J = 5.3 Hz, 8.3 Hz, 1H), 1.37-1.46 (m, 2H), 2.13 and 2.37 (AB, JAB = 10.7 Hz, each 1H), 3.63 and 3.73 (AB, JAB = 12.1 Hz, each 1H), 4.99 (s, 1H), 5.21 (s, 1H).

c) (2S,4S)-4-Hydroxy-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

(1S,4S)-5-(1-trifluoromethyl-cyclopropanecarbonyl)-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-one (220 g, 883 mmol), 1-amino-cyclopropanecarbonitrile hydrochloride (140 g, 1.18 mol), and sodium 2-ethylhexanoate (97%, 230 g, 1.34 mol) were dissolved in water (1.32 L). The mixture was stirred at 53°C for 20 h. After cooling to room temperature, tetrahydrofuran (880 mL) was added and the mixture was acidified by the addition of concentrated hydrochloric acid (37% m/m, 47 mL), followed by sodium chloride (440 g). After extraction with ethyl acetate (1 x 1.4 L, 3 x 550 mL), the combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The product began to crystallize upon addition of seed crystals at a volume of approximately 1.5 L. The volume of the suspension was further reduced to approximately 500 mL and cooled to 2°C (ice bath). After stirring for 60 min, the crystals were filtered, washed with ethyl acetate/heptane 1:1 (v/v, 600 mL) and heptane (300 mL), and dried in vacuo to afford the title compound as off-white crystals (255.0 g, 87%). ^1H NMR (CDCl3, 400 MHz): d 1.18-1.29 (m, 4H), 1.30-1.42 (m, 2H), 1.50-1.59 (m, 2H), 2.17-2.26 (m, 1H), 2.29 (d, J = 14.5 Hz, 1H), 3.73 and 3.96 (ABX, JAB = 11.8 Hz, JAX = 4.3 Hz, JBX = 0 Hz, each 1H), 4.43-4.53 (m, 2H), 4.81 (brd, J = 8.3 Hz, 1H), 7.73 (s, 1H).

d) Benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester

(2S,4S)-4-Hydroxy-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (100.0 g, 301.8 mmol) was dissolved in tetrahydrofuran (500 mL). The mixture was cooled to 2°C (ice bath), and benzenesulfonyl chloride (99%, 48 mL, 370.5 mmol), 4-(dimethylamino)pyridine (98%, 2.0 g, 16.0 mmol), and triethylamine (75.0 mL, 539 mmol) were added. The mixture was then stirred for 15 minutes. The reaction mixture was warmed to room temperature and stirred for 20 hours. After cooling to 2°C (ice bath), water (150 mL) and methanol (350 mL) were added. The tetrahydrofuran (approximately 500 mL) was carefully distilled off in vacuo, and water (500 mL) was slowly added. After the addition of 300 mL of water, crystallization was induced by seeding. The resulting suspension was stirred at 2°C (ice bath) for 30 min and filtered. The solid was washed with methanol/water 1:2 (v/v, 300 mL) and heptane (300 mL) and dried in vacuo to afford the title compound as off-white crystals (140.8 g, 99%). ^1H NMR (CDCl3, 400 MHz): d 1.06-1.27 (m, 4H), 1.28-1.41 (m, 2H), 1.44-1.54 (m, 2H), 2.26 (ddd, J = 5.9 Hz, 9.4 Hz, 14.2 Hz, 1H), 2.59 (ddd, J = 3.8 Hz, 3.8 Hz, 14.2 Hz, 1H), 3.90 and 4.03 (ABX, JAB = 12.5 Hz, JAX = 4.0 Hz, JBX = 5.2 Hz, each 1H), 4.57 (br d,J＝5.1Hz,1H),5.02-5.09(m,1H),7.08(br s,1H),7.61(t,J＝7.8Hz,2H),7.71(t,J＝7.5Hz,1H),7.95(d,J＝7.2Hz,2H).

e)(2S,4R)-4-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 3d (7.03 g, 14.9 mmol, Eq: 1.00) was dissolved in propionitrile (80 mL) and 4-bromo-2-trifluoromethyl-benzenethiol (CAS 1208075-10-8, CAS 1208075-10-8, CAS 1208075-10-8, CAS 1208075-10-8, CAS 1208075-10-8 (5.75 g, 22.4 mmol, Eq: 1.50) was added. Triethylamine (3.02 g, 4.16 mL, 29.8 mmol, Eq: 2.00) was then carefully added, and the reaction mixture was stirred at reflux for 18 h. The reaction mixture was extracted with 10% _{aqueous Na₂CO₃} /AcOEt. The organic layer was dried over _Na₂SO₄ , _filtered , and evaporated. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 50% EtOAc in heptane) to afford the title compound as a white foam (8.14 g; 96%). m/z = 571.9/570.1 [M+H] ⁺ .(Br isotope)

f)(2S,4R)-4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 3e) (8.14 g, 14.3 mmol, Eq: 1.00) was dissolved in dichloromethane (50 mL) and mCPBA (5.17 g, 30.0 mmol, Eq: 2.10) was carefully added portionwise. The reaction mixture was stirred at 25°C overnight. The reaction mixture was extracted with 10% _{aqueous Na2CO3} and saturated _{aqueous Na2S2O3} . The organic layer was dried _{over Na2SO4} and _Na2SO3 for 2 _h , filtered, and evaporated (be careful _of peroxides!) to give the title compound as a white foam (8.6 g; 100%). m/z = 602.0/604.0 [M+H] ⁺ . (Br isotope)

g) (2S,4R)-4-[4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 3f (500 mg, 830 μmol, Eq: 1.00), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (275 mg, 996 μmol, Eq: 1.20), and triphenylphosphine (43.5 mg, 166 μmol, Eq: 0.20) were dissolved in 1,2-dimethoxyethane (6 mL). Pd(OAc) _₂ (18.6 mg, 83.0 μmol, Eq: 0.10) and 2M _{aqueous Na₂CO₃} solution (1.5 mL) were added to the solution. The reaction mixture was stirred at 60°C for 8 h. The reaction mixture was poured into 0.1M aqueous HCl (100 mL) and extracted with DCM. The aqueous layer was washed with DCM (3 x 50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 80% EtOAc in heptane) to afford the title compound as a light yellow foam (410 mg; 74%). m/z = 670.1169 [MH] ⁻ .

Example 4

(2S,4R)-4-(2'-Trifluoromethoxy-3-trifluoromethyl-biphenyl-4-sulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 3f (50 mg, 83.0 μmol, Eq: 1.00), 2-(trifluoromethoxy)phenylboronic acid (20.5 mg, 99.6 μmol, Eq: 1.20), and triphenylphosphine (4.35 mg, 16.6 μmol, Eq: 0.20) were dissolved in 1,2-dimethoxyethane (1 mL). Pd(OAc) _₂ (1.86 mg, 8.3 μmol, Eq: 0.10) and 2M _{aqueous Na₂CO₃} (250 μl) were added to the solution and stirred at 50°C for 8 h. The crude material was filtered and purified by preparative HPLC to give the title compound as a white solid (41 mg; 72%). m/z = 684.0 [M+H] ^⁺ .

Example 5

(2S,4R)-4-(2'-Ethoxy-3-trifluoromethyl-biphenyl-4-sulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 5 was prepared in a manner similar to Example 4 using Example 3f) and 2-ethoxyphenylboronic acid as starting materials to give the title compound as a white solid (40 mg; 75%). m/z = 644.1 [M+H] ⁺ .

Example 6

(2S,4R)-4-(2'-Cyclopropyloxy-3-trifluoromethyl-biphenyl-4-sulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 6 was prepared in a manner similar to Example 4 using Example 3f) and 2-cyclopropyloxyphenylboronic acid as starting materials to give the title compound as a white solid (39 mg; 72%). m/z = 656.3 [M+H] ⁺ .

Example 7

(2S,4R)-4-(4-Cyclobutoxy-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

a)(2S,4R)-4-(4-Fluoro-2-trifluoromethyl-phenylsulfanyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

In a 250 mL four-necked flask, Example 3d) (7 g, 14.8 mmol, Eq: 1.00) and 4-fluoro-2-trifluoromethyl-benzenethiol (CAS 1208077-00-2) (4.08 g, 20.8 mmol, Eq: 1.40) were mixed with propionitrile (70 mL) to give a yellow solution. Triethylamine (5.38 mL, Eq: 2.60) was added at 22°C. The reaction mixture was heated to 110°C and stirred for 3 h. The reaction mixture was poured into ethyl acetate (300 mL) and extracted with 10% _{aqueous Na2CO3} (2 x 100 mL). The aqueous layer was back-extracted with EtOAc (2 x 250 mL). The organic layers were combined and washed with saturated aqueous NaCl (1 x 75 mL). The organic layer was dried _{over Na2SO4} and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 20% to 70% EtOAc in heptane) to afford the title compound as a colorless foam (6.83 g; 90%). m/z = 510.0 [M+H] ⁺ .

b) (2S,4R)-4-(4-Fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

In a 250 mL round-bottom flask, Example 7a (5.85 g, 11.5 mmol, Eq: 1.00) was mixed with dichloromethane (80 mL) to give a white suspension. 3-Chloroperoxybenzoic acid (5.15 g, 29.9 mmol, Eq: 2.60) was added. The reaction mixture was stirred at 22°C for 48 h. 3-Chloroperoxybenzoic acid (991 mg, 5.74 mmol, Eq: 0.5) was then added, and the reaction mixture was stirred for an additional 72 h. The reaction mixture was poured into 200 mL of dichloromethane and extracted with 10% _{aqueous Na₂CO₃} (3 x 150 mL). The aqueous layer was back-extracted with dichloromethane (3 x 150 mL). The organic layers were combined, washed with saturated _Na2S2O3 -aqueous solution (4 _x 100 mL) -> (peroxide test ₎ , brine (1 x 100 mL), _dried over _Na2SO4 and concentrated in vacuo to give the title compound as a white solid (6.36 g; 100%). m/z = 542.3 [M+H] ⁺ . m/z = 540.3 [MH] ^- .

c) (2S,4R)-4-(4-Cyclobutoxy-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

In a 10 mL round-bottom flask, Example 7b (100.0 mg, 185 μmol, Eq: 1.00) was combined with DMA (1.5 mL) to give a light yellow solution. Cesium carbonate (72.2 mg, 222 μmol, Eq: 1.20) and cyclobutanol (20.0 mg, 21.7 μl, 277 μmol, Eq: 1.5) were added. The reaction mixture was stirred at 25°C for 18 h. Then, additional cyclobutanol (13.3 mg, 14.5 μl, 185 μmol, Eq: 1.00) was added, and the reaction mixture was stirred at 25°C for 18 h. The crude material was purified by preparative HPLC to give the title compound as an amorphous colorless solid (31 mg; 28%). m/z = 592.3 [MH] ^- .

Example 8

(2S,4R)-4-(2-chloro-4-(5-methyl-2H-tetrazol-2-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

a)(2S,4R)-4-(2-Chloro-4-fluoro-phenylsulfanyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 8a) was prepared in a manner similar to Example 7a) using Example 3d) and 2-chloro-4-fluoro-benzenethiol as starting materials to give the title compound as a colorless gum (6.35 g; 96%). m/z = 476.1 [M+H] ⁺ .

b) (2S,4R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 8b) was prepared by a method similar to Example 7b) using Example 8a) as the starting material to obtain the title compound as a white foam (6.55 g; 97%). m/z = 508.3 [M+H] ⁺ .

c) (2S,4R)-4-(2-chloro-4-(5-methyl-2H-tetrazol-2-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

In a 10 mL round-bottom flask, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 8b)) (400 mg, 788 μmol, Eq: 1.00) was mixed with DMA (5 mL) to give a colorless solution. 5-Methyl-1H-tetrazole (132 mg, 1.58 mmol, Eq: 2.00) and cesium carbonate (513 mg, 1.58 mmol, Eq: 2.00) were added. The reaction mixture was heated to 80°C and stirred for 3 h. 5-Methyl-1H-tetrazole (13.2 mg, 0.158 mmol, Eq: 0.20) was then added, and the mixture was stirred at 80°C for an additional 2 h. The reaction mixture was poured into water and extracted with EtOAc (2x). The organic layers were combined and washed with saturated aqueous _NaHCO₃ (1x), water (3x), and brine (1x). The organic layer was dried _{over Na₂SO₄} and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, heptane/AcOEt 2/1, 1/1, 1/2, 1/3) to afford the title compound as a light brown foam (183 mg; 41%). m/z = 572.2 [M+H] ^⁺ .

Example 9

(2S,4R)-4-(2-chloro-4-(5-methyl-1H-tetrazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 9 was obtained as a regioisomer during the synthesis of Example 8 as a white foam (198 mg; 44%). m/z = 572.2 [M+H] ⁺ .

Example 10

(2S,4R)-4-(2-chloro-4-(1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

In a 10 mL round-bottom flask, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 8b)) (400 mg, 788 μmol, Eq: 1.00) was mixed with DMA (5 mL) to give a colorless solution. 1H-1,2,4-triazole (111 mg, 1.58 mmol, Eq: 2.00) and cesium carbonate (513 mg, 1.58 mmol, Eq: 2.00) were added. The reaction mixture was heated to 80°C and stirred for 3 h. The reaction mixture was poured into water and extracted with EtOAc (2x). The organic layers were combined and washed with saturated aqueous _NaHCO₃ (1x), water (3x), and brine (1x). The organic layer was dried _{over Na₂SO₄} and concentrated in vacuo. The crude material was purified twice by flash chromatography (silica gel, 20 g, DCM/MeOH 98/2, 19/1) and (silica gel, 20 g, heptane/AcOEt 1/2, 1/3, 1/4) to afford the title compound as a white foam (264 mg; 60%). m/z = 557.1 [M+H] ⁺ .

Example 11

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2,4-bis(1H-1,2,4-triazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 11 was obtained as a by-product during the synthesis of Example 10 as a white solid (34 mg; 7%). m/z = 590.1 [M+H] ⁺ .

Example 12

(2S,4R)-4-(2-chloro-4-(2H-1,2,3-triazol-2-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 12 was prepared in a manner similar to Example 10 using (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropane-carbonyl)pyrrolidine-2-carboxamide (Example 8b)) and 1H-1,2,3-triazole as starting materials to give the title compound as an off-white solid (189 mg; 43%). m/z = 557.1 [M+H] ⁺ .

Example 13

(2S,4R)-4-(2-chloro-4-(1H-1,2,3-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 13 was obtained as a regioisomer during the synthesis of Example 12 as an off-white solid (170 mg; 39%). m/z = 557.1 [M+H] ⁺ .

Example 14

(2S,4R)-4-(2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 14 was prepared in a manner similar to Example 10 using (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropane-carbonyl)pyrrolidine-2-carboxamide (Example 8b)) and 3-methyl-1H-1,2,4-triazole as starting materials. The reaction mixture was stirred at 22°C for 16 h to give the title compound as a white foam (212 mg; 47%). m/z = 571.2 [M+H] ⁺ .

Example 15

(2S,4R)-4-(2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 15 was prepared in a manner similar to Example 10 using (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropane-carbonyl)pyrrolidine-2-carboxamide (Example 8b)) and 3,5-dimethyl-1H-1,2,4-triazole as starting materials. The reaction mixture was stirred at 22°C for 16 h to give the title compound as a white foam (400 mg; 76%). m/z = 585.2 [M+H] ⁺ .

Example 16

(2S,4R)-4-(2-chloro-4-(3-chloro-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 16 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropane-carbonyl)pyrrolidine-2-carboxamide (Example 8b)) and 3-chloro-1H-1,2,4-triazole. The reaction mixture was stirred at 22°C for 16 h to give the title compound as a white foam (432 mg; 81%). m/z = 591.2 [M+H] ⁺ .

Example 17

(2S,4R)-4-(2-chloro-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 17 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropane-carbonyl)pyrrolidine-2-carboxamide (Example 8b)) and 3-(trifluoromethyl)-1H-pyrazole. The reaction mixture was stirred at 22°C for 16 h to give the title compound as a white foam (419 mg; 76%). m/z = 624.1 [M+H] ⁺ .

Example 18

(2S,4R)-4-(2-chloro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 18 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropane-carbonyl)pyrrolidine-2-carboxamide (Example 8b)) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole. The reaction mixture was stirred at 22°C for 16 h to give the title compound as a white foam (411 mg; 73%). m/z = 638.1 [M+H] ⁺ .

Example 19

(2S,4R)-N-(1-Cyanocyclopropyl)-4-(2-methyl-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

a)(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluoro-2-methylphenylthio)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 3, step e) using 4-fluoro-2-methylthiophenol and obtained as a light brown gum (3.47 g, 97%). m/z = 456.4 [M+H] ⁺ .

b) (2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluoro-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 3, step f) from (2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluoro-2-methylphenylthio)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 19a) and obtained as a white foam (2.84 g, 76%). m/z = 487.1202 [M ⁺ ].

c) (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methyl-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluoro-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 19b, 70 mg, 144 μmol), 3-(trifluoromethyl)-1H-pyrazole (39.1 mg, 287 μmol) and cesium carbonate (93.6 mg, 287 μmol) were mixed with N,N-dimethylacetamide (1.00 mL) in a sealed tube to give a white suspension. The reaction was stirred at ambient temperature over the weekend. After filtration, the title compound was isolated from the reaction mixture by preparative HPLC (Zorbax C18 21.2 x 50 mm; flow rate: 20 mL/min; gradient: acetonitrile/water (+0.1% formic acid) = (95%-5% to 5%-95%) in 7.5 min; collected by 254 nm detector; 28.8 mg, 33.2%). m/z = 604.14 [M+H ⁺ ].

Example 20

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-(trifluoromethoxy)biphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

a)(2S,4R)-4-(4-bromophenylthio)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 3, step e) using 4-bromothiophenol and obtained as a colorless foam (952 mg, 95%). m/z = 502.1/504.0 [M+H] ⁺ .

b) (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared from (2S,4R)-4-(4-bromophenylthio)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20a) in a manner similar to Example 3, step f) and obtained as a white powder (918 mg, 91%). m/z = 532.0/534.0 [MH] ^- .

c) (2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-(trifluoromethoxy)biphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

To a solution of (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b, 321 mg, 0.6 mmol) and 2-(trifluoromethoxy)phenylboronic acid (185 mg, 900 μmol) in dioxane (6 mL) and 2M aqueous sodium carbonate solution (1.5 mL, 3.00 mmol) was added 1,1'-bis(diphenylphosphino)-ferrocene-palladium(II) dichloride dichloromethane complex (24.5 mg, 30.0 μmol) with stirring under a nitrogen atmosphere. The reaction was heated to 85°C overnight. After cooling, water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using heptane:ethyl acetate (9:1 to 1:4) as eluent. The crude product was stirred with heptane/diethyl ether, filtered, and dried to give the title compound as a white powder (272.4 mg, 74%). m/z = 614.1 [MH] ^- .

Example 21

(2S,4R)-4-(2-chloro-4-cyclobutoxyphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 21 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropane-carbonyl)pyrrolidine-2-carboxamide (Example 8b)) and cyclobutanol. The reaction mixture was stirred at 22°C for 16 h to give the title compound as a white foam (166 mg; 60%). m/z = 560.2 [M+H] ⁺ .

Example 22

(2S,4R)-N-(1-cyanocyclopropyl)-4-(3-methyl-2'-(trifluoromethoxy)biphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

a)(2S,4R)-4-(4-bromo-2-methylphenylthio)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner similar to Example 3, step e) using 4-bromobenzenethiol and obtained as a colorless oil (1087 mg, 89%). m/z = 516.1/518.3 [M+H] ⁺ .

b) (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 3, step f) from (2S,4R)-4-(4-bromo-2-methylphenylthio)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22a) and 2-(trifluoromethoxy)phenylboronic acid and obtained as a colorless waxy solid (1.05 g, 93%). m/z = 550.2/548.2 [M+H] ⁺ .

c) (2S,4R)-N-(1-cyanocyclopropyl)-4-(3-methyl-2'-(trifluoromethoxy)biphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 20, step c) from (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22a) and obtained as an off-white foam (179 mg, 57%). m/z = 630.3 [M+H] ⁺ .

Example 23

(2S,4R)-4-[4-(5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 23 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (Example 7b)) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole. The reaction mixture was stirred at 22°C for 72 hours to give the title compound as a colorless foam (104 mg; 84%). m/z = 672.1325 [M+H] ⁺ .

Example 24

(2S,4R)-4-[4-(3-Methyl-[1,2,4]triazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 24 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (Example 7b)) and 3-methyl-1H-1,2,4-triazole. The reaction mixture was stirred at 22°C for 72 hours to give the title compound as a colorless amorphous solid (26 mg; 23%). m/z = 605.1390 [M+H] ⁺ .

Example 25

(2S,4R)-4-[4-(3-Methyl-[1,2,4]triazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 25 was obtained as a regioisomer during the synthesis of Example 24 to afford the title compound as a colorless amorphous solid (1.5 mg; 1.3%). m/z = 605.1398 [M+H] ⁺ .

Example 26

(2S,4R)-4-(4-(1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 26 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (Example 7b)) and 1H-1,2,4-triazole. The reaction mixture was stirred at 22°C for 4 h to give the title compound as a colorless amorphous solid (68 mg; 31%). m/z = 589.1110 [M+H] ⁺ .

Example 27

(2S,4R)-4-[4-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 27 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (Example 7b)) and 3,5-dimethyl-1H-1,2,4-triazole. The reaction mixture was stirred at 22°C for 4 h to give the title compound as a colorless foam (122 mg; 53%). m/z = 619.1553 [M+H] ⁺ .

Example 28

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in analogy to Example 20, step c) from (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole and obtained as a white solid after purification on preparative HPLC (31 mg, 8%). m/z = 602.2 [MH] ^- .

Example 29

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-formyl-3-methylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 20, step c) from (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22b) and 2-formylphenylboronic acid and obtained as a white solid (146 mg, 51%). m/z = 574.2 [M+H] ⁺ .

Example 30

(2S,4R)-4-[4-(3-Chloro-[1,2,4]triazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 30 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (Example 7b)) and 3-chloro-1H-1,2,4-triazole. The reaction mixture was stirred at 22°C for 4 hours to give the title compound as a colorless foam (135 mg; 59%). m/z = 623.0708 [M+H] ⁺ .

Example 31

(2S,4R)-N-(1-Cyanocyclopropyl)-4-(4-(5-methyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 31 was obtained as a regioisomer during the synthesis of Example 24 to afford the title compound as a colorless amorphous solid (26 mg; 23%). m/z = 605.1397 [M+H] ⁺ .

Example 32

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methyl-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 20, step c) from (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22b) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole and obtained as an off-white solid after purification on preparative HPLC (16 mg, 5%). m/z = 618.3 [M+H] ⁺ .

Example 33

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

a)(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluorophenylthio)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in analogy to Example 3, step e) using 4-fluorobenzenethiol and obtained as an off-white foam (2.72 g, 72%). m/z = 442.2 [M+H ⁺ ].

b) (2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluorophenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 3, step f) from (2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluorophenylthio)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 33a) and obtained as a white foam (840 mg, 29%). m/z = 474.11 [M+H ⁺ ].

c) (2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Under argon, (2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluorophenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 33, Step b, 0.1 g, 211 μmol) was mixed with N,N-dimethylacetamide (2.00 mL) to give a colorless suspension. 3,5-Dimethyl-1H-1,2,4-triazole (41.0 mg, 422 μmol) and cesium carbonate (138 mg, 422 μmol) were added. The reaction mixture was stirred at ambient temperature over the weekend. The crude material was purified by preparative HPLC (Zorbax Eclipse XDB-C18; 21,2x50 mm; flow rate: 25 mL/min; gradient: acetonitrile/water (+0.1% formic acid) = (95%-5% to 5%-95%) in 6 min; collection by 254 nm detector) to afford the title compound as a colorless viscous oil (13.2 mg, 11.4%). m/z = 551.17 [M+H ⁺ ].

Example 34

(2S,4R)-4-(4-(1H-1,2,3-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in analogy to Example 33 using 1H-1,2,3-triazole in step c) and obtained as a colorless viscous oil (2.5 mg, 2.83%). m/z = 523.13 [M+H ⁺ ]).

Example 35

(2S,4R)-N-(1-Cyanocyclopropyl)-4-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was obtained as a white solid in a manner analogous to Example 33 using 3-(trifluoromethyl)-1H-pyrazole in step c) (38.2 mg, 38.3%). m/z = 590.13 [M+H ⁺ ].

Example 36

(2S,4R)-N-(1-Cyanocyclopropyl)-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in analogy to Example 33 using 5-methyl-3-(trifluoromethyl)-1H-pyrazole in step c) and obtained as a white solid (22.1 mg, 21.7%). m/z = 604.14 [M+H ⁺ ]).

Example 37

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-formylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner similar to Example 20, step c) from (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b) and 2-formylphenylboronic acid and obtained as a white powder (57.6 mg, 52%). m/z = 558.2 [MH] ^- .

Example 38

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-ethoxybiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner similar to Example 20, step c) from (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b) and 2-ethoxyphenylboronic acid and obtained as a pink powder (86.1 mg, 75%). m/z = 574.2 [MH] ^- .

Example 39

(2S,4R)-4-(4-(2-aminopyrimidin-5-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in analogy to Example 20, step c) from (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b) and 2-aminopyrimidin-5-ylboronic acid and obtained as a white powder (72 mg, 66%). m/z = 547.2 [MH ⁻ ].

Example 40

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-ethoxy-3-methylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 20, step c) from (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22b) and 2-ethoxyphenylboronic acid and obtained as an off-white solid (255 mg, 87%). m/z = 590.4 [M+H] ⁺ .

Example 41

(2S,4R)-4-(2'-Cyano-3-methylbiphenyl-4-ylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 20, step c) from (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22b) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and obtained as an off-white solid after purification on preparative HPLC (43.2 mg, 12%). m/z = 571.2 [M+H] ⁺ .

Example 42

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-ethoxy-4',5'-difluoro-3-methylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 20, step c) from (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22b) and 2-ethoxy-4,5-difluorophenylboronic acid and obtained as an off-white solid after purification on preparative HPLC (235.5 mg, 75%). m/z = 626.3 [M+H] ⁺ .

Example 43

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-(hydroxymethyl)biphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

To a solution of (2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-formylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 37, 35.6 mg, 63.6 μmol) in methanol (1 mL) was added sodium borohydride (2.41 mg, 63.6 μmol) with stirring under a nitrogen atmosphere. The reaction was stirred at room temperature overnight. Water was added, and the reaction was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was stirred with heptane for 15 minutes, filtered, and dried to give the title compound as a white powder (26.4 mg, 74%). m/z = 560.2 [MH] ^- .

Example 44

(2S,4R)-4-(4-(2-aminopyrimidin-5-yl)-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared analogously to Example 20, step c) from (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22b) and 2-aminopyrimidin-5-ylboronic acid and obtained as an off-white solid after purification on preparative HPLC (78.8 mg, 70%). m/z = 563.4 [M+H] ⁺ .

Example 45

(2S,4R)-4-[4-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 3f (100 mg, 166 μmol, Eq: 1.00) and 2,2-difluorobenzo[d][1,3]dioxol-5-ylboronic acid (50.3 mg, 249 μmol, Eq: 1.50) were dissolved in _dioxane (2 mL). A 2M aqueous _Na₂CO₃ solution (415 μl, 830 μmol, Eq: 5.00) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride dichloromethane complex (6.78 mg, 8.3 μmol, Eq: 0.05) were added to the solution and stirred at 85°C for 13 h. The crude material was filtered and purified by preparative HPLC to yield the title compound as a light yellow foam (83 mg; 74%). m/z = 680.2 [M+H] ^⁺ .

Example 46

(2S,4R)-1-(1-Trifluoromethyl-cyclopropanecarbonyl)-4-[2-trifluoromethyl-4-(4-trifluoromethyl-pyrazol-1-yl)-phenylsulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 46 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (Example 7b)) and 4-(trifluoromethyl)-1H-pyrazole. The reaction mixture was stirred at 22°C for 24 hours to give the title compound as a colorless foam (75 mg; 62%). m/z = 657.1103 [M+H] ⁺ .

Example 47

(2S,4R)-4-[4-(5-Methyl-tetrazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 47 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (Example 7b)) and 5-methyl-1H-tetrazole. The reaction mixture was stirred at 22°C for 24 hours to give the title compound as a colorless amorphous solid (63 mg; 28%). m/z = 605.1289 [M+H] ⁺ .

Example 48

(2S,4R)-4-[4-(2,4-Dimethyl-thiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

In a 5 mL microwave tube, Example 3f (100 mg, 166 μmol, Eq: 1.00), potassium acetate (24.4 mg, 249 μmol, Eq: 1.50) and tetrakis(triphenylphosphine)palladium(0) (9.59 mg, 8.3 μmol, Eq: 0.05) were dissolved in DMA (1 mL). 2,4-Dimethylthiazole (94.0 mg, 89.0 μl, 830 μmol, Eq: 5.00) was then added. The tube was sealed and the mixture was stirred in a microwave oven at 170°C for 30 min. 2,4-Dimethylthiazole (94.0 mg, 89.0 μl, 830 μmol, Eq: 5.00) was then added to the reaction mixture. The reaction mixture was heated in a microwave oven at 170°C for 30 min. The reaction mixture was then poured into EtOAc (15 mL) and extracted with 0.1 M aqueous HCl (20 mL). The aqueous layer was back-extracted with EtOAc (2 _x 15 mL). The organic layers were combined, then dried over _Na₂SO₄ , filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 60% EtOAc in DCM). The crude material was further purified by preparative HPLC to yield the title compound as a colorless solid (11 mg; 10%). m/z = 635.1210 [M+H] ^⁺ .

Example 49

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2,4-dimethylthiazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 49 was prepared similarly to Example 48 using (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b) and 2,4-dimethylthiazole as starting materials. After purification on preparative HPLC, the title compound (44 mg, 39%) was obtained as a white powder. m/z = 565.2 [MH] ^- .

Example 50

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2-methylthiazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 50 was prepared similarly to Example 48 using (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b) and 2-methylthiazole as starting materials. After purification on preparative HPLC, the title compound (42 mg, 38%) was obtained as a white powder. m/z = 551.3 [MH] ^- .

Example 51

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2-methoxypyrimidin-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner similar to Example 20, step c) from (2S,4R)-4-(4-bromo-phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b) and 2-methoxypyrimidin-5-ylboronic acid and obtained as a white powder (67.2 mg, 60%). m/z = 562.1 [MH] ^- .

Example 52

(2S,4R)-4-(2-chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 52 was obtained as a regioisomer during the synthesis of Example 14 to give the title compound as a white solid (69 mg; 15%). m/z = 571.2 [M+H] ⁺ .

Example 53

(2S,4R)-4-(4-[1,2,3]triazol-2-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 53 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (Example 7b)) and 1H-1,2,3-triazole. The reaction mixture was stirred at 22°C for 24 hours to give the title compound as a colorless foam (89 mg; 41%). m/z = 590.1175 [M+H] ⁺ .

Example 54

(2S,4R)-4-(4-[1,2,3]triazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 54 was prepared as a regioisomer during the synthesis of Example 53 to give the title compound as a colorless foam (38 mg; 36%). m/z = 590.1175 [M+H] ⁺ .

Example 55

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 55 was prepared similarly to Example 48 using (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b) and 3,5-dimethylisoxazole as starting materials. After purification on preparative HPLC, the title compound (10 mg, 9%) was obtained as a colorless solid. m/z = 549.2 [MH] ^- .

Example 56

(2S,4R)-4-[4-(1-Difluoromethyl-1H-pyrazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 3f (100 mg, 166 μmol, Eq: 1.00) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (60.8 mg, 249 μmol, Eq: 1.50) were dissolved in dioxane (2 mL). A 2M _{aqueous Na₂CO₃} solution (415 μl, 830 μmol, Eq: 5.00) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (6.78 mg, 8.3 μmol, Eq: 0.05) were added to the solution, and the mixture was stirred at 85°C for 14 h. The crude product was filtered and purified by preparative HPLC. The material was then purified by flash chromatography (silica gel, 4 g, 0% to 66% EtOAc in heptane) to afford the title compound as a light yellow foam (90 mg; 85%). m/z = 638.1113 [MH] ⁻ .

Example 57

(2S,4R)-4-[4-(5-Methyl-tetrazol-2-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 57 was obtained as a regioisomer during the synthesis of Example 47 to give the title compound as a colorless amorphous solid (34 mg; 15%). m/z = 604.2 [MH] ⁻ .

Example 58

(2S,4R)-1-(1-Trifluoromethyl-cyclopropanecarbonyl)-4-[2-trifluoromethyl-4-(3-trifluoromethyl-1H-pyrazol-4-yl)-phenylsulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 58 was prepared in a manner similar to Example 56 using Example 3f) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole as starting materials to provide the title compound as a white solid (6.0 mg; 5.5%). m/z = 658.5 [M+H] ⁺ .

Example 59

(2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-(hydroxymethyl)-3-methylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 59 was prepared similarly to Example 43 using (2S,4R)-N-(1-cyanocyclopropyl)-4-(2'-formyl-3-methylbiphenyl-4-ylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 29) as the starting material. After purification by preparative HPLC, the title compound (36.1 mg, 45%) was obtained as an off-white solid. m/z = 574.2 [MH] ^- .

Example 60

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2,4-dimethylthiazol-5-yl)-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 60 was prepared similarly to Example 48 using (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22b) and 2,4-dimethylthiazole as starting materials. After purification by preparative HPLC, the title compound (44.9 mg, 39%) was obtained as an off-white solid. m/z = 581.2 [M+H] ⁺ .

Example 61

(2S,4R)-N-(1-Cyanocyclopropyl)-4-(2-methyl-4-(2-methylthiazol-5-yl)phenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 61 was prepared similarly to Example 48 using (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22b) and 2-methylthiazole as starting materials. After purification by preparative HPLC, the title compound (55.9 mg, 49%) was obtained as an off-white solid. m/z = 567.2 [M+H] ⁺ .

Example 62

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(2-methoxypyrimidin-5-yl)-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 20, step c) from (2S,4R)-4-(4-bromo-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 22b) and 2-methoxypyrimidin-5-ylboronic acid and obtained as a light brown solid (72 mg, 62%). m/z = 578.2 [M+H ⁺ ].

Example 63

(2S,4R)-4-[4-(2-Methyl-thiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

In a 5 mL microwave tube, Example 3f (100 mg, 166 μmol, Eq: 1.00), potassium acetate (24.4 mg, 249 μmol, Eq: 1.50) and tetrakis(triphenylphosphine)palladium(0) (9.59 mg, 8.3 μmol, Eq: 0.05) were mixed with DMA (1 mL). 2-Methylthiazole (82.3 mg, 74.2 μl, 830 μmol, Eq: 5.00) was added. The tube was sealed and the mixture was stirred at 160° C. in a microwave oven for 30 minutes. The reaction mixture was poured into EtOAc (15 mL) and extracted with 0.1 M aqueous HCl (1 x 20 mL). The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 60% EtOAc in DCM) to afford the title compound as an off-white solid (8 mg; 8%). m/z = 621.1064 [M+H] ⁺ .

Example 64

(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-(3,5-dimethylisoxazol-4-yl)-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Example 64 was prepared similarly to Example 48 using (2S,4R)-4-(4-bromophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 20b) and 3,5-dimethylisoxazole as starting materials. After purification by preparative HPLC, the title compound was obtained as an off-white solid (28.5 mg, 25%). m/z = 565.3 [M+H] ⁺ .

Example 65

(2S,4R)-4-(4-Tetrazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 65 was prepared in a manner similar to Example 10 starting from (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (Example 7b)) and 1H-tetrazole. The reaction mixture was stirred at 22°C for 48 hours to give the title compound as an amorphous colorless solid (29 mg; 13%). m/z = 591.113 [M+H] ⁺ .

Example 66

(2S,4R)-4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Under argon, (2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluoro-2-methylphenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 19, Step b, 0.2 g, 410 μmol) was mixed with N,N-dimethylacetamide (8.00 mL) to give a colorless suspension. 3-Chloro-1H-1,2,4-triazole (86.7 mg, 821 μmol) and cesium carbonate (267 mg, 821 μmol) were added. The reaction mixture was stirred for 5 days and then heated to 140°C in a microwave oven for 30 min. The reaction mixture was then poured into water (40 mL) and extracted with ethyl acetate (2 x 40 mL). The crude material was purified by preparative HPLC and obtained as a light yellow viscous oil (12 mg, 5.1%). m/z = 571.11 [M+H ⁺ ].

Example 67

(2R,4R)-4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-2-methylphenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

The title compound was obtained as a by-product in the preparation of Example 66 and was obtained as a light yellow viscous oil (13.9 mg, 5.9%, stereochemistry assigned by NOESY-NMR). m/z = 571.1137 [M+H ⁺ ].

Example 68

(2S,4R)-4-[4-(1-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Example 68 was prepared in a manner similar to Example 56 using Example 3f) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole as starting materials to give the title compound as a white foam (167 mg; 75%). m/z = 689.1581 [M+NH ₄ ] ⁺ .

Example 69

(2S,4R)-4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

Under argon, (2S,4R)-N-(1-cyanocyclopropyl)-4-(4-fluorophenylsulfonyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (Example 33, step b, 0.3 g, 634 μmol) was mixed with N,N-dimethylacetamide (12 mL) to give a colorless suspension. 3-Chloro-1H-1,2,4-triazole (134 mg, 1.27 mmol) and cesium carbonate (413 mg, 1.27 mmol, Eq: 2) were added. The reaction mixture was stirred at ambient temperature over the weekend and then heated to 140°C in a microwave oven for 30 min. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The crude material was purified by preparative HPLC to give the title compound as a colorless viscous oil (93.9 mg, 26.6%). m/z = 557.09 [M+H ⁺ ].

Example 70

Cathepsin inhibition assay

Enzyme activity is measured by observing the increase in fluorescence intensity caused by cleavage of a peptide substrate containing a fluorophore whose emission is quenched in the intact peptide.

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

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

Substrates (20 μM): Z-Val-Val-Arg-AMC, except for Cat K where Z-Leu-Arg-AMC was used (all from Bachem).

Z = benzyloxycarbonyl.

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

DTT=dithiothreitol.

Final volume: 100 μL.

Excitation 360nm, emission 465nm.

The enzyme was added to the substance dilution in a 96-well microtiter plate and the reaction was initiated with substrate. Fluorescence emission was measured over 20 minutes, during which a linear increase was observed in the absence of inhibitor. _IC50 was calculated by standard methods.

Inhibition was measured for human Cat S, mouse Cat S, human Cat K, human Cat B, human Cat L, and mouse Cat L. The results obtained for human Cat S are expressed in μM in the table below for representative compounds of the invention.

The compounds of the present invention are preferential inhibitors of cathepsin-S relative to cathepsin-L, K and B.

In the aforementioned assay, compounds according to the invention have an _IC50 for CatS between 0.00001 and 100 μM, in particular between 0.00001 and 50 μM, more in particular between 0.00001 and 20 μM. Specific compounds of the invention have an _IC50 below 0.09 μM in the aforementioned assay.

Example A

Film-coated tablets containing the following ingredients can be prepared in a conventional manner:

core: Compound of formula (I) 10.0mg 200.0mg microcrystalline cellulose 23.5mg 43.5mg Lactose hydrate 60.0mg 70.0mg Povidone K30 12.5mg 15.0mg Sodium starch glycolate 12.5mg 17.0mg magnesium stearate 1.5mg 4.5mg (Core Heavy) 120.0mg 350.0mg Film coating: Hydroxypropyl methylcellulose 3.5mg 7.0mg Polyethylene glycol 6000 0.8mg 1.6mg talc 1.3mg 2.6mg Iron oxide (yellow) 0.8mg 1.6mg Titanium dioxide 0.8mg 1.6mg

The active ingredient is sieved and mixed with microcrystalline cellulose, and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to yield cores of 120 or 350 mg, respectively. The cores are sprayed with an aqueous solution/suspension of the film coating described above.

Example B

Capsules containing the following ingredients can be prepared in a conventional manner:

Compound of formula (I) 25.0mg lactose 150.0mg corn starch 20.0mg talc 5.0mg

The ingredients were sieved and mixed and filled into size 2 capsules.

Example C

The injection solution may have the following composition:

Compound of formula (I) 3.0mg polyethylene glycol 400 150.0mg Acetic acid Adjust to pH 5.0 Aqueous solution for injection Add to 1.0ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by adding acetic acid. The volume is adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Claims (3)

1. (2S,4R)-4-[4-(5-methyl-tetrazole-2-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical composition comprising the compound according to claim 1 and a therapeutically inert carrier. 3. Use of the compound according to claim 1 in the preparation of a medicament for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral artery disease, cancer, reduction of cardiovascular events in chronic kidney disease, diabetic nephropathy, diabetic retinopathy, or age-related macular degeneration.