LV13440B - Haloalkyl containing compounds as cysteine protease inhibitors - Google Patents

Description

HALOALKYL CONTAINING COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS

Field of the Invention

The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins Β, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is also directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

State of the Art

Cysteine proteases represent a ciass of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated v/ith the normai degradation and processing of proteins. The aberrant acti vity of cysteine proteases, e.g., as a result of inereased expression or enhanced activation, hov/ever, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, inereased cathepsin S Ievels and redistribution of the enzyme are found in tumors; thus, suggesting a role for the enzyme in tumor invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteoarthritis, pneumocystis carinii, acute panereatitis, inflammatory airway disease and bone and joirtt disorders.

The prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated celis and its high collagenolytic activity suggest that the enzyme is involved in ososteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis. In addition, cathepsin K expression in the lung and its elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as vvell.

Cathepsin L is implicated in normai lysosomal proteolysis as vvell as several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer's disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Gravēs' disease, myasthenia grāvis, sysremic lupus erythemotasus, rheumatoid arthritis, neuropathic pain, and Hashimoto's thyroiditis. In addition, cathepsin S is implicated in: allergic disorders, including, but not limited to asthma; and allogeneic immune reponses, including, but not limited to, rejection of organ transplants or tissue grafts.

In vievv of the number of diseases vvherein it is recognized that an increase in cysteine protease activity contributes to the pathology and/or symptomatology of the disease, molecules vvhich inhibit the activity of this class of enzymes, in particular molecules vvhich inhibitor cathepsins Β, K, L, F, and/or S, vvili therefore be useful as therapeutic aģents.

SUMMARY OF THE INVENTION

In one aspect, this invention is directed to a compound of Formula (I):

(I) vvherein:

R¹ is hydrogen, a!kyl, haloalkyl, or alkoxyalkyl;

R² is hydrogen, alkyl, haloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cyano, or -alkylene-X-R⁹ (vvhere X is -0-, -NR¹⁰-, -CONR¹'-, -S(0)_nl-, -NR¹²C0-, -CO-, or -C(0)0vvhere nl is 0-2, and R⁹, R^lQ, R¹¹, and R¹² are independently hydrogen, alkyl, haloalkyl, cycioalkyl, cycloalkylalkyl, aryl, ara!kyl, heteroaryl, or heteroaralkyl) vvherein the aromatic or a!icyclic ring in R² is optionally substituted vvith one, tvvo, or three R^a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl, or arylsulfonyl and further vvhere the aromatic or alicyclic ring in R^a is optionally substituted vvith one or tvvo substituents independent!y selected from a!kyl, halo, alkoxy, haioa!kyl, haloalkoxy, hydroxy, amino, alkyiamino, dialkylamino, carboxy, or alkoxycarbonyl; or

R¹ and R² taken together vvith the carbon atom to vvhich both R¹ and R² are attached form (i) cycloalky!ene optionally substituted vvith one or tvvo R^b independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyI, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl, (ii) a four atom heterocyclylalkylene ring, or (iii) heterocyclyiaikylene optionally substituted vvith one to four R^c independently selected from alkyl, ha!oalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroary(, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, -S(O)_n2R¹⁴, ~alkylene-S(O)„2-R.¹⁵, -COOR¹⁶,

-alkylene-COOR¹⁷, -CONR¹⁸R¹⁹, or -alkylene-CONR²⁰R²¹ (where n2 is 0-2 and R^,4-R¹⁷, R¹⁸ and R²⁰ are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl and R¹⁹ and R²' are independently hydrogen or alkyl) vvherein the aromatic or alicyclic ring in the groups attached to cycloalkylene or heterocyclylalkylene is optionally substituted vvith one, two, or three substituents independently selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryloxycarbonyl, aikoxy, hydroxy, ha!oalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyl;

R³ is hydrogen or alkyl;

R⁴ is l-alkylcyclopentylmethyl, l-alkylcyclopentylethyl, 1 -alkylcyclohexylmethyl, 1aikylcyclohexylethyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, or-alkylene-X’R²² (vvherein X¹ is -NR²³-, -O-, -S(O)n3-, -CO-, -COO-, -OCO-, -NR²³CO-, -CONR²³-, -NR²³SO2-, -SO₂NR²³-, -NR²³COO-, -OCONR²³-, -NR²³CONR²⁴-, or-NR²³SO₂NR²⁴- vvhere R²³ and R²⁴ are independently hydrogen, alkyl, or acyl, n3 is 0-2, and R²² is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl) vvherein the alkylene chain in R⁴ is optional ly substituted vvith one to six halo and vvherein the aromatic or alicyclic ring in R⁴ is optional ly substituted vvith one, tvvo, or three R^d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl;

R⁵ is hydrogen or alkyl;

R⁶ is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or -alkylene-X²-R²⁵ (vvhere X² is-NR²⁶-, -O-, -S(O)n4-, -CO-, -COO-, OCO-, -NR²⁶CO-, -CONR²⁶-, -NR²⁶SO2-, -SO2NR²⁶-, -NR²⁶COO-, -OCONR²⁶-, -NR²⁶CONR²⁷-, or -NR²⁶SO2NR²⁷- vvhere R²⁶ and R²⁷ are independently hydrogen, alkyl, or acyl, n4 is 0-2, and R²⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) vvherein said a!kylene chain in R⁶ is optionally substituted vvith one to six halo and the aromatic or alicyclic rings in R⁶ are optionally substituted by one, tvvo, or three R^e independently selected from alky 1, halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, aryl, aralkyl, aryloxy, aralkyloxy, arylsulfonyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkyloxy, heteroarylsulfonyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, alkylsulfonyl, aminosulfonyl, or aminoalkyl and further where the aromatic or alicyclic ring in R* is optionally substituted vvith one, two or three

R^f independently selected from alkyI, alkoxy, haloalkyl, haloalkoxy, halo, hydroxy, carboxy, cyano, nitro, aryl or cycloalkyl;

R⁷ is haloalkyl optionally substituted with alkoxy or alkoxya!kyloxy; and

R⁸ is hydrogen, alkyl, alkoxyalkyl or haloalkyl; or

R⁶ and R⁸ together with the carbon atom to which they are attached form cycloalkylene or heterocyclylalkylene vvherein said cycloalkylene is optionally substituted with one to four substituents independently selected from alkyl, halo, haloalkyl, hydroxy, or alkoxy and heterocyclylalkylene is optionally substituted vvith one or tvvo substituents independently selected from alkyl, halo, haloalkyl, cycloalkyl, hydroxy, or alkoxy; or a pharmaceutical ly acceptable salt thereof.

Preferably, a compound of Formula (I) vvherein:

R¹ is hydrogen or alkyl;

R² is hydrogen, alkyl, haloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cyano, -alkylene-X-R⁹ (where X is -O-, -NR¹⁰-, -CONR¹¹-, -S(O)_nl-, -NR¹²CO-, -CO-, or -C(O)Owhere nl is 0-2, and R⁹, R¹⁰, R¹¹, and R¹² are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) vvherein the aromatic or alicyclic ring in R² is optionally substituted vvith one, tvvo, or three R^a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl, or arylsulfonyl and further v/here the aromatic or alicyclic ring in R^a is optionally substituted vvith one or tvvo substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl; or

R¹ and R² taken together vvith the carbon atom to vvhich both R¹ and R² are attached form (i) cycloalkylene optionally substituted vvith one or tvvo R^b independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl or (ii) heterocyclylalkylene optionally substituted vvith one to four R^c vvhich are independently selected from alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, -S(O)n2R¹⁴, -alkylene-S(O)n2-R¹⁵, -COOR¹⁶, -alkylene-COOR¹⁷, -CONR^l8R'⁹, or -alkylene-CONR²⁰R²¹ (vvhere n2 is 0-2 and R'⁴-R¹⁷, R¹⁸ and R²⁰ are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl and R¹⁹ and R²¹ are independently hydrogen or aiky 1) wherein the aromatic or alicyclic ring in the groups attached to cycloalkylene or heterocyclylalkylene is optionally substituted with one, two, or three substituents independently selected from alkyl, haloalky 1, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyl;

R³ is hydrogen or alkyl;

R⁴ is l-alkylcyclopentylmethyl, l-alkylcyclopentylethyl, l-alkylcyclohexylmethyi, 1alkylcyclohexylethyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, or -alkyleneX‘-R²² (vvherein X^! is -NR²³-, -O-, -8(0)^-, -CO-, -COO-, -OCO-, -NR²³CO-, -CONR²³-, -NR²³SO2-, -SO2NR²³-, -NR²³COO-, -OCONR²³-, -NR²³CONR²⁴, or-NR²³SO2NR²⁴- vvhere R²³ and R²⁴ are independently hydrogen, alky 1, or acyl, n3 is 0-2, and R²² is hydrogen, alky 1, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,Or heterocyclylalkyl) vvherein said alkylene chain in R⁴ is optionally substituted vvith one to six halo and vvherein the aromatic or alicyclic ring in R⁴ is optional ly substituted vvith one, tvvo, or three R^d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl;

R⁵ is hydrogen or alkyl;

R⁶ is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or -alkylene-X²-R²⁵ (vvherein X² is -NR²⁶-, -O-, -S(O)n4-, -CO-, -COO-, -OCO-, -NR²⁶CO-, -CONR²⁶-, -NR²⁶SO2-, -SO₂NR²⁶-, -NR²⁶COO-, -OCONR²⁶-, -NR²⁶CONR²⁷-, or -NR²⁶SO₂NR²⁷- vvhere R²⁶ and R²⁷ are independently hydrogen, alky 1, or acyl, n4 is 0-2, and R²⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) vvherein said alkylene chain in R⁶ is optionally substituted vvith one to six halo and the aromatic or alicyclic ring in R⁶ is optionally substituted vvith one, tvvo, or three R' independently selected from alkyl, halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, carboxy, or alkoxycarbonyl and further vvhere the aromatic or alicyclic rings in R^e is optionally substituted by one, tvvo or three R^f independently selected from alkyI, alkoxy, haloalkyl, haloalkoxy, halo, hydroxy, carboxy, cyano, nitro, aryl or cycloalkyl;

R⁷ is haloalky 1; and

R⁸ is hydrogen, alkyl, alkoxyalkyl or haloalkyl; or

R⁶ and R⁸ together vvith the carbon atom to vvhich they are attached form cycloalkylene or heterocyclylalkylene wherein said cycloalkylene is optionally substituted with one or two substituents independently selected from alkyl, haloalkyl, hydroxy, or alkoxy and heterocyclylalkylene is optionally substituted with one or tvvo substituents independentiy selected from alkyl, haloalkyl, hydroxy, or alkoxy; or a pharmaceutically acceptable salt thereof.

Preferably, R¹ is hydrogen or alky 1;

R² is hydrogen, alkyl, haloalkyl, carboxyalkyi, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cyano, -aIkylene-X-R⁹ (vvhere X is -0-, -NR¹⁰-, -CONR¹¹-, -S(O)_nl-, -NR^I2CO-, -CO-, or -C(O)Owhere nl is 0-2, and R⁹, R¹⁰, R¹¹, and R¹² are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) wherein the aromatic or alicyclic ring in R² is optionally substituted vvith one, tvvo, or three R^a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl, or arylsulfonyl and further vvhere the aromatic or alicyclic ring in R^a is optionally substituted vvith one or tvvo substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl; or

R¹ and R² taken together vvith the carbon atom to vvhich both R¹ and R² are attached form (i) cycloalkylene optionally substituted vvith one or tvvo R^b independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl or (ii) heterocyclylalkylene optionally substituted vvith one to four R^c vvhich are independently selected from alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaiyloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, -S^R¹⁴, -alk^ene-SiOta-R¹⁵, -COOR¹⁶, -aIkylene-COOR¹⁷, -CONR¹⁸R¹⁹, or -alkylene-CONR²⁰R²¹ (vvhere n2 is 0-2 and R¹⁴-R¹⁷, R¹⁸ and R²⁰ are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl and R¹⁹ and R²' are independently hydrogen or alkyi) vvherein the aromatic or alicyclic ring in the groups attached to cycloalkylene or heterocyclylalkylene is optionaliy substituted vvith one, two, or three substituents independentiy selected from alky 1, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acvl;

R³ is hydrogen or alky 1;

R⁴ is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, or-alkylene-X'-R²² (vvherein X¹ is -NR²³-, -O-, -S(O)ri-, -CO-, -COO-, -OCO-, -NR²³CO-, -CONR²³-, -NR²³SO2-, -SO2NR²³-, -NR²³COO-, -OCONR²³-, -NR²³CONR²⁴, or-NR^SOjNR²⁴- vvhere R²³ and R²⁴ are independently hydrogen, alkyl, or acyl, n3 is 0-2, and R²² is hydrogen, alky 1, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaraikyl, heterocyclyl, or heterocyclylalkyl) vvherein said alkylene chain in R⁴ is optionally substituted vvith one to six halo and vvherein the aromatic or alicyclic ring in R⁴ is optionally substituted vvith one, tvvo, or three R^d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl;

R⁵ is hydrogen or alky 1;

R⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or -alkylene-X²-R²⁵ (vvherein X² is -NR²⁵-, -0-, -S(0)n4-, -CO-, -COO-, -OCO-, -NR²⁵CO-, -CONR²⁵-, -NR²⁵SO2-, -SO2NR²⁵-, -NR²⁵COO-, -OCONR²⁵-, -NR²⁵CONR²⁷-, or -NR²⁵SO2NR²⁷- vvhere R²⁵ and R²⁷ are independently hydrogen, alkyl, or acyl, n4 is 0-2, and R²⁵ is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyialkyl, aryl, aralkyi, heteroaryl, or heteroaralkyl) vvherein said alkylene chain in R⁶ is optionally substituted vvith one to six halo and the aromatic or alicyclic rings in R⁵ are optionally substituted by one, tvvo, or three R^e independently selected from alkyl, halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, 0x0, cyano, nitro, acyl, aryi, aralkyl, heteroaryi, heteroaralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, carboxy, or alkoxycarbonyl and ftirther vvhere the aromatic or alicyclic rings in R^e is optionally substituted by one, tvvo or three R^f independently selected from alkyI, alkoxy, haloalkyi, haloalkoxy, halo, hydroxy, carboxy, cyano, nitro, aryl or cycioalkyi;

R⁷ is haloalkyl; and

R⁸ is hydrogen, alkyl, alkoxyalkyl or haloalkyl; or

R⁵ and R⁸ together vvith the carbon atom to vvhich they are attached form cycloalkylene or heterocyclylalkylene vvherein said cycloalkylene is optionally substituted vvith one or tvvo substituents independently selected from alky 1, haloalkyl, hydroxy, or alkoxy and heterocyclylalkylene is optionally substituted vvith one or tvvo substituents independently selected from alky 1, haloalkyl, hydroxy, or alkoxy.

In a second aspect, this invention is directed to a pharmaceutical composition comprising a compound of Formula (I), individual stereoisomers or a mixture thereof; or a pharmaceutically acceptable salt thereof in admixture vvith one or more suitable excipients.

In a third aspect, this invention is directed to a method for treating a disease in an animal mediated by cysteine proteases, in particular cathepsin S, vvhich method comprises administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), individual stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof in admixture vvith one or more suitable excipients.

In a fourth aspect, this invention is directed to processes for preparing compounds of

Formula (I) and the pharmaceutically acceptable salts thereof.

In a fifth aspect, this invention is directed to a method of treating a patient undergoing a therapy vvherein the therapy causes an immune response, preferably a deleterious immune response, in the patient comprising administering to the patient a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Preferably, the immune response is mediated by MHC ciass II molecules. The compound of this invention can be administered prior to, simultaneously, or after the therapy. Preferably, the therapy involves treatment vvith a biologic. Preferably, the therapy involves treatment vvith a small molecule.

Preferably, the biologic is a protein or an antibody, preferably a monoclonal antibody. More preferrably, the biologic is Remicade®, Refacto®, Referon-A®, Factor VIII, Factor VII, Betaseron®, Epogen®, Enbrel®, Interferon beta, Botox®, Fabrazyme®, Elspar®, Cerezyme®, Myobloc®, Aldurazyme®, Verluma®, Interferon alpha, Humira®, Aranesp®, Zevalin® or 0KT3.

Preferably, the treatment involves use of heparin, Iow molecular vveight heparin, procainamide or hydralazine.

In a sixth aspect, this invention is directed to a method of treating immune response in an animal that is caused by administration of a biologic to the animal which method comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In a seventh aspect, this invention is directed to a method of conducting a clinical trial for a biologic comprising administering to an individual participating in the clinical trial a compound of Formula (I) or a pharmaceuticalty acceptable salt thereof vvith the biologic.

In an eighth aspect, this invention is directed to a method of prophylactically treating a person undergoing treatment vvith a biologic vvith a compound of Formula (ī) or a pharmaceutical ly acceptable salt thereof to treat the immune response caused by the biologic in the person.

In a ninth aspect, this invention is directed to a method of determing the loss in the efftcacy of a biologic in an animal due to the immune response caused by the biologic comprising administering the biologic to the animal in the presence and absence of a compound of Formula (I) or a pharm aceutically acceptable salt thereof.

In a tenth aspect, this invention is directed to a method of improving efficacy of a bioiogic in an animal comprising administering the biologic to the animal vvith a compound of of

Formula (I) or a pharmaceutically acceptabie salt thereof.

In an eleventh aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptabie salt thereof for the manufacture of a medicament. Preferably, the medicament is for use in the treatment of a disease mediated by Cathepsin S.

In a tvvelfth aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptabie salt thereof for the manufacture of a medicament for combination therapy with a biologic, vvherein the compound of this invention treats the immune response caused by the biologic. Preferab!y, the compound(s) of the invention is administered prior to the administration of the biological aģent. Preferably, the compound(s) of the invention is administered concomitantly vvith the biological aģent. Preferably, the compound(s) of the invention is administered after the administration of the biological aģent.

Detailed Description of the Invention

Definitions:

Unless othervvise stated, the follovving terms used in the specification and claims are defined for the purposes of this Application and have the follovving meanings.

Alicyclic means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures e.g., cycloalkyl and heterocyclyl rings as defined herein.

Alkyl represented by itself means a straight or branched, saturated aliphatic radical containing one to six carbon atoms, unless othervvise indicated e.g., alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, /ert-butyļ and the like.

Alkylene, unless indicated othervvise, means a straight or branched, saturated aliphatic, divalent radical having the number of one to six carbon atoms, e.g., methylene (-CH₂-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), tetramethylene (-CH2CH2CH2CH2-)

2-methy!tetramethylene (-CH2CH(CH3)CH2CH₂-), pentamethylene (-CH2CH2CH2CH2CH2-), and the like.

Amino means -NH? radical. Unless indicated othervvise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, /er/-butoxycarbonyl, benzyloxycarbonyl, and the like.

Alkylamino or “dialkylamino” refers to a-NHR and -NRR’ radical respectiveiy, vvhere R and R’ are independently alkyl group as defined above e.g., methylamino, dimethylamino, and the like.

Alkoxy refers to a -OR radical vvhere R is an alky 1 group as defined above e.g., methoxy, ethoxy, and the like.

Alkoxycarbonyr refers to a -C(O)OR radical vvhere R is an alkyl group as defined above e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

Alkoxycarbonylalkyl means an -(alkylene)-C(O)OR radical vvhere R is alkyl as defined above e.g., methoxycarbonylmethyl, 2-, or 3-ethoxycarbonylmethyl, and the like.

Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted vvith at least one alkoxy group, preferably one or tvvo alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyI, 2-ethoxyethyI, and the like.

Alkoxyalkyloxy refers to a -OR radical vvhere R is alkoxyalkyl is as defined above e.g., methoxymethyloxy, methoxyethyloxy, and the like.

Alkoxyalkyloxyalkyl refers to a-(alkylene)-O-(alkylene)-OR radical vvhere R is an alkyl group as defined above, e.g., 2-methoxyethyloxymethyl, 3-methoxypropyloxyethyl, and the like.

Aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted vvith at least one, preferably one or tvvo, -NRR’ vvhere R is hydrogen, alkyl, or -COR^a vvhere R^a is alky 1, and R’ is hydrogen or a!kyl as defined above e.g., aminomethyl, methylaminoethyl, dimethylaminoethyl, l,3-diaminopropyl, acetylaminopropyl, and the like e.g., aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and the like.

Aminosulfonyl refers to a -SO?R radical vvhere R is -NRR’ vvhere R is hydrogen, alkyl, or -COR^a vvhere R^a is alkyl, and R’ is hydrogen or alkyl as defined above e.g., aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and the like.

AIkylsulfonyl refers to a -SO₂R radical vvhere R is an alky 1 group as defined above e.g., methylsulfonyl, ethylsulfonyl, and the like.

Acyl refers to a -COR radical vvhere R is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclyl as defined herein, e.g., formyl, acetyl, trifluoroacetyl, benzoyl, piperazin-l-ylcarbonyl, and the like.

Animal” includes humāns, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, svvine, deer, and the like) and non-mammals (e.g., birds, and the like).

Aromatic refers to a moiety vvherein the constituent atoms make up an unsaturated ring system, ali atoms in the ring system are sp~ hybridized and the total number of pi electrons is equal to 4n+2.

Aryl refers to a monocyclic or fused bicyclic ring assembly containing 6 to 10 ring carbon atoms vvherein each ring is aromatic e.g., phenyl or naphthyl.

Aralkyl refers to a -(alkylene)-R radical vvhere R is aryl as defined above e.g., benzyl, phenethyl, and the like.

Aryloxy refers to a -OR radical vvhere R is aryl as defined above e.g., phenoxy, and the like.

Araikyloxy refers to a -OR radical vvhere R is aralkyI as defined above e.g., benzyloxy, and the like.

Aryloxyalkyl refers to a -(alkylene)-OR radical vvhere R is aryl as defined above e.g., phenoxymethyl, 2-, or 3-phenoxymethyI, and the like

Aryloxycarbonyl refers to a -C(O)OR radical vvhere R is aryl as defined above e.g., phenyloxycarbonyl, and the like.

Arylsulfonyl refers to a-SChR radical vvhere R is an aryl group as defined above e.g., phenylsulfonyl, and the like.

“Biologic” means a therapeutic aģent originally derived from living organisms for the treatment or management of a disease. Examples include, but are not limited to, proteins (recombinant and plasma derived), monoclonal or polyclonal, humanized or murine antibodies, toxins, hormones, and the like. Biologics are currently available for the treatment of a variety of diseases such as cancer, rheumatoid arthritis, and haemophilia.

Carboxy refers to -C(O)OH radical.

Carboxyalkyl refers to a -(alkyIene)-C(O)OH radical e.g., carboxymethyl, carboxyethyl, and the like.

Cycloalkyl refers to a monovalent saturated or partially unsaturated, monocyclic ring containing three to eight ring carbon atoms e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, and the like.

Cycloalkylalkyl refers to a -(alkylene)-R radical vvhere R is cycloalkyl as defined above e.g., cyclopropylmethyl, cyclobutylethyl, cyclobutyimethyl, and the like

Cycloalkylene refers to a divalent saturated or partially unsaturated monocyclic ring containing three to eight ring carbon atoms. For example, the instance vvherein R¹ and R² together vvith the carbon atom to vvhich both R¹ and R² are attached form cycloalkylene iņcludes, but is not limited to, the follovving:

and the like.

1-Alkylcyclopentylmethyl or~ethyl and 1-Alkylcyclohexylmethyl or-ethyl means a radical having the formula:

alkyl respectively;

e.g., 1 -methylcyclopentylmethyl, l-methylcyclohexylmethyl, and the like

Disubstituted amino refers to a -NRR’ radical vvhere R is alkyI, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclyl and R’ is alky 1, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyļ, heterocyclyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, or acyl as defined herein. Representative examples inelude, but are not limited to, dimethylamino, methylphenylamino, benzylmethylamino, acetylmethylamino, and the like.

Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the side effects of such therapy.

“Deleterious immune response” means an immune response that prevents effective treatment of a patient or causes disease in a patient. As an example, dosing a patient vvith a murine antibody either as a therapy or a diagnostic aģent causes the production of human antimouse antibodies that prevent or interfere vvith subsequent treatments. The incidence of antibody formation versus pure murine monoclonals can exceed 70%. (see Khazaeli, Μ. B. etal.

J. Immunother. 1994, 15, pp 42-52; Dillman R. 0. et al. Cancer Biother. 1994, 9, pp 17-28; and Reinsberg, J. Hybridoma. 1995, 14, pp 205-208). Additional examples of knovvn aģents that suffer from deleterious immune responses are blood-clotting factors such as factor VIII. When administered to hemophilia A patients, factor Vili restores the abil ity of the blood to clot. Although factor VIII is a human protein, it stili elicits an immune response in hemophiliacs as endogenous factor Vili is not present in their blood and thus it appears as a foreign antigen to the immune system. Approximately 29-33% of new patients vvill producē antibodies that bind and neutralize the therapeutically administered factor VIII (see Lusher J. M. Semin Thromb Hemost. 2002, 28(3), pp 273-276). These neutralizing antibodies require the administration of larger amounts of factor VIII in order to maintain normai blood clotting parameters; an expensive regimen of treatment in order to inducē immune tolerance (see Briet E et al. Adv.

Exp. Med. Bio. 2001, 489, pp 89-97). Another immunogenic example is adenoviral vectors. Retroviral therapy remains experimental and is of limited utility. One reason is that the application of a therapeutic virus generates an immune response capable of blocking any subsequent administration of the same or similar virus (see Yiping Yang et al. J. ofVirology. 1995, 69, pp 2004-2015). This ensures that retroviral therapies must be based on the transient expression of a protein or the direct incorporation of virai sequence into the host genome. Directed research has identified multiple virai neutralizing epitopes recognized by host antibodies (see Hanne, Gahery-Segard et al. J. of Virology 1998. 72, pp 2388-2397) suggesting that virai modifications vvili not be sufficient to overcome this obstacle. This invention vvili enable a process whereby an adenoviral therapy vvili have utility for repeated application. Another example of an immunogenic aģent that elicits neutralizing antibodies is the well-known cosmetic aģent Botox. Botulin toxin protein, is purified from the fermentation of Clostridium botulinum. As a therapeutic aģent, it is used for muscle disorders such as cervical dystonia in addition to cosmetic application. After repeated exposure patients generate neutralizing antibodies to the toxin that results in reduced efficacy (see Birklein F. ef al. Ann Neurol. 2002, 52, pp 68-73 and Rollnik, J. D. etal. Neurol. Clin. Neurophysiol. 2001,2001(3), pp 2-4). A “deleterious immune response” also encompasses diseases caused by therapeutic aģents. A specific example of this is the immune response to therapy vvith recombinant human erythropoietin (EPO). Erythropoeitin is used to stimulate the grovvth or red celis and restore red blood celi counts in patients who have undergone chemotherapy or dialysis. A small percentage of patients develop antibodies to EPO and subsequently are unresponsive to both therapeutically administered EPO and their own endogenous EPO (see Casadevall, N. et al., NEJM. 2002, 346, pp 469-475). They contract a disorder, pure red celi aplasia, in which red blood celi production is severely diminished (see Gershon S. K. et. al. NEJM. 2002, 346, pp 1584-1586). This complication of EPO therapy is lethal if untreated. Another specific example is the murine antibody, OKT3 (a.k.a., Orthoclone) a monoclonal antibody directed tovvards CD-3 domain of activated T-cells. In clinical trials 20-40% of patients administered OKT3 producē antibodies versus the therapy. These antibodies besides neutralizing the therapy also stimulate a strong host immune reaction. The immune reaction is severe enough that patients vvith high titers of human anti-mouse antibodies are specifically restricted from taking the drug (see Orthoclone package labei). A final example is a human antibody therapeutic. Humira® is a monoclonal antibody directed against TNF and is used to treat rheumatoid arthritis patients. When taken alone -12% of patients develop neutralizing antibodies. In addition, a small percentage of patients given the drug also contract a systemic lupus erthematosus-likecondition that is an IgGmediated immune response induced by the therapeutic aģent (see Humira package label).

Another example of “deleterious immune response” is a host reaction to small molecule drugs. It is knovvn to those skilled in the art that certain Chemical structures vvill conjugate vvith host proteins to stimulate immune recognition (see lu. C. et al. 2002. Current Drug Metabolism 3, pp 367-377 and Kimber I. et al. 2002, Toxicologic Pathology 30, pp 54-58.) A substantial portion of this host reactions are lgG mediated. Specific “deleterious immune responses” that are lgG mediated and include: hemolytic anemia, Steven-Johnson syndrome and drug induced Lupus.

Four atom heterocyclylalkylene refers to a saturated divalent monocyclic radical of 4 carbon ring atoms vvherein one ofthe ring carbon atoms is replaced by a heteroatom selected from -NR- vvhere R is hydrogen, alkyl, acyl, alkylsulfonyļ aminosulfonyl, hydroxyalkyl, or alkoxyalkyl, -O-, -S-, -SO-, or -S(O)₂- Representative examples include, but are not limited to, rings such as:

, and the like.

Halo refers to fluoro, chloro, bromo or iodo.

Haloalkyl refers to alkyl as defined above substituted by one or more, preferably one to five, halo atoms, as such terms are defined in this Application. Haloalkyl includes monohaloalkyi, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like e.g. ch!oromethyl, dichloromethyļ difluoromethyļ trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyļ 2,2,2-trifluoro-l,l-dichloroethyl, and the like).

Haloalkoxy refers to a-OR radical vvhere R is haloa!kyl group as defined above e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, and the like.

Heteroaryl as a group or part of a group denotes an aromatic monocyclic or multicyclic moiety of 5 to 10 ring atoms in vvhich one or more, preferably one, tvvo, or three, of the ring atom(s) is(are) selected from nitrogen, oxygen or sulfur, the remaining ring atoms being carbon. Representative heteroaryl rings include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indo!yl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolyl, and the like.

Heteroaralkyl refers to a -(alkylene)-R radical vvhere R is heteroaryl as defined above

e.g., pyridinylmethyl, 1- or 2-furanylethyl, imidazolyimethyl, and the like.

Heteroaryloxyalkyl refers to a -(alkylene)-OR radical vvhere R is heteroaryl as defined above e.g., furanyloxymethyl, 2-, or 3-indoIyloxyethyl, and the like.

Heteroaryloxy refers to a -OR radical vvhere R is heteroaryl as defined above.

Heteroaralkyloxy refers to a -OR radical vvhere R is heteroaralkyl as defined above.

Heteroarylsulfonyl refers to a -SO2R radical vvhere R is an heteroaryl group as defined above e.g., pyridinylsulfonyl, and the like.

Heterocyclyl refers to a saturated or partially unsaturated, mono or bicyclic radical of 5 or 6 carbon ring atoms vvherein one or more, preferably one, tvvo, or three of the ring carbon atoms are replaced by a heteroatom selected from -N=, -N-, -0-, -S-, -SO-, or -S(0)2- and further vvherein one or tvvo ring atoms are optional ly replaced by a keto (-C0-) group. The heterocyclyl ring is optionaily fused to cycloalkyl, aryl or hetcroaryl ring as defined herein. Representative examples include, but are not limited to, imidazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholino-l-oxide, thiomorpholino-l,l-dioxide, tetrahydropyranyl, tetrahydrothiopyranyļ l-oxo-tetrahydrothiopyranyl, l,l-dioxotetrathiopyranyl, indolinyl, piperazinyl, piperidyI, pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like.

Heterocyclyiaikyi refers to a -(alkylene)-heterocyclyl radical as defined in this Application. Representative examples include, but are not limited to, imidazolidin-l-ylmethyl, morpholin-4-ylmethyl, thiomorpholin-4-ylmethyl, thiomorpholin-4-ylmethyI-l-oxide, indolinylethyI, piperazinylmethyl or ethyl, piperidylmethyl or ethyl, pyrrolidinylmethyl or ethyl, and the like.

Heterocyclylalkylene refers to a divalent heterocyclyl group, as defined in this Application, e.g., the instance vvherein R¹ and R² together vvith the carbon atom to vvhich both R¹ and R² are attached form heterocyclylalkylene” includes, but is not limited to, the follovving:

in vvhich R is a substituent defined in the Summary of the Invention Hydroxy means -OH radical. Unless indicated othervvise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like.

Hydroxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted vvith one or tvvo hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2hydroxyethyl, 2,3-dihydroxybutyI, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and l-(hydroxymethyI)-2-hydroxyethyl.

Hydroxyalkyloxy or hydroxyalkoxy refers to a-OR radical vvhere R is hydroxyalkyl as defined above e.g., hydroxymethoxy, hydroxyethoxy, and the like.

Isomers mean compounds of Formula (I) having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. Stereoisomers that are not mirror images of one another are termed diastereomers and stereoisomers that are nonsuperimposable mirror images are termed enantiomers or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a chiral center. A compound vvith one chiral center has tvvo enantiomeric forms of opposite chirality is termed a racemic mixture. A compound that has more than one chiral center has 2”' enantiomeric pairs, vvhere n is the number of chiral centers. Compounds vvith more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a diastereomeric mixture. When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and

S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are vvell knovvn in the art (e.g., see Advanced Organic Chemistry, 4th edition, March, Jerry, John Wiley & Sons, Nevv York, 1992). It is understood that the names and illustration used in this Application to describe compounds of Formula (I) are meant to be encompassed all possible stereoisomers.

Keto or oxo means (=0) radical.

Monosubstituted amino refers to a -NHR radical vvhere R. is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, oracyl as defined herein. Representative examples include, but are not limited to, methylamino, phenylamino, benzylamino, cycloalkylmethylamino, acetylamino, trifluoroacetyl, and the like.

Nitro means -NO₂ radical.

Optional or optionally or “may be” means that the subsequentiy described event or circumstance may or may not occur, and that the description includes instances vvhere the event or circumstance occurs and instances in vvhich it does not. For example, the phrase vvherein the aromatic ring in R^a is optionally substituted vvith one or tvvo substituents independently selected from alky 1” means that the aromatic ring may or may not be substituted vvith alkyl in order to fall vvithin the scope of the invention.

The present invention also includes 7V-oxide derivatives of a compound of Formula (I). ?/-oxide derivative mean a compound of Formula (f) in vvhich a nitrogen atom is in an oxidized State (i.e., N-»O) e.g., pyridine A-oxide, and vvhich possess the desired pharmacological activity.

Pathology of a disease means the essential nature, causes and development of the disease as vvell as the structural and functional changes that result from the disease processes.

Pharmaceutical ly acceptable means that vvhich is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor othervvise undesirable and includes that vvhich is acceptable for veterinaiy use as vvell as human pharmaceutical use.

Pharmaceutically acceptable salts means salts of compounds of Formula (I)which are pharmaceuticaliy acceptable, as defined above, and vvhich possess the desired pharmacological activity. Such salts include acid addition salts formed vvith inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or vvith organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy-ethanesulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid,

4-methylbicycIo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid,

4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laury 1 sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceuticaily acceptable salts also include base addition salts vvhich may be formed vvhen acidic protons present are capable of reacting vvith inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, A-methylgIucamineand the like.

The present invention also includes prodrugs of a compound of Formula (I). Prodrug means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula (I). For example an ester of a compound of Formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Altematively an ester of a compound of Formula (I) ontaining a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitabie esters of compounds of Formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methylsulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitabie esters of compounds of Formula (I) containing a carboxy group, are for example those described by Leinvveber, F.J. Drug Metab. Res., 1987,18, page 379. An especially useful class of esters of compounds of Formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, pp 2503-2507, and include substituted (aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates in vvhich the tvvo alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-l-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-l-yl)benzoates.

Protected derivatives means derivatives of compounds of Formula (I) in vvhich a reactive site or sites are blocked vvith protecting groups. Protected derivatives of compounds of Formula (I) are useful in the preparation of compounds of Formula (I) or in themselves may be active cathepsin S inhibitors. A comprehensive list of suitabie protecting groups can be found in

T.W. Greene, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

The expression . .vvherein said alkylene chain in R⁴ or R⁶ is optionally substituted vvith one to six halo” in the Summary of the Invention refers to the alkylene chain in -alkylene-X’R“and -alkylene-X²-R²⁵ respectively, being optionally substituted vvith halo.

The expression . .vvherein the aromatic or alicyclic ring in R², R⁴, or R⁶ is optionally substituted vvith one to three R\ R^d, or R', respective!y...” refers to ali the groups attached to R², R⁴, or R⁶ that contain an aromatic or alicyclic ring being optionally substituted vvith one to three R^a, R^d, or R^e respectivelv. The aromatic or alicyciic ring may be directly attached to R², R⁴, or R⁶ or be part of a group that is directly attached to R², R⁴, or R⁶. For example, for R⁴ it includes the aromatic or alicyclic ring in the 1 -alkylcyclopentylmethyl, l-alkylcyclopentylethyl, 1alkylcyclohexylmethyl, l-alkylcyclohexylethyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, or-alkylene-X'-R²² (vvherein X¹ is -NR²³-, -O-, -S(O)„3-, -CO-, -COO-, -OCO-, -NR²³CO-, -CONR²³-, -NR²³SO2-, -SO2NR²³-, -NR²³COO-, -OCOONR²³-, -NR²³CONR²⁴-, or-NR²³SO2NR²⁴- vvhere R²³ and R²⁴ are independently hydrogen, aikyl, or acyl, n3 is 0-2, and R²² is cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyciyl, or heterocyclyla!kyl) groups being optionally substituted vvith R^d.

Therapeutically effective amount means that amount vvhich, vvhen administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.

Treatment or treating means any administration of a compound of the present invention and includes:

(1) preventing the disease from occurring in an animal vvhich may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathoiogy and/or symptomatology).

Treatment or treating vvith respect to combination therapy i.e., use vvith a biologic means any administration of a compound of the present invention and includes:

(1) preventing the immune response from occurring in an animal vvhich may be predisposed to the immune response but does not yet experience or display the pathology or symptomatology of the immune response, (2) inhibiting the immune response in an animal that is experiencing or displaying the pathology or symptomatology of the immune response (i.e., arresting further development of the pathology and/or symptomatology), or (3) ameliorating the immune response in an animal that is experiencing or displaying the pathology or symptomatology of the immune response (i.e., reducing in degree or severity, or extent or duration, the overt manifestations of the immune response or reversing the pathology and/or symptomatology e.g., reduced binding and presentation of antigenic peptides by MHC class II molecules, reduced activation of T-cells and B-cells, reduced humoral and cell-mediated responses and, as appropriate to the particular immune response, reduced inflammation, congestion, pain, necrosis, reduced loss in the efficacy of a biologic aģent, and the like).

Preferred Embodiments

Certain compounds of Formula (I) vvithin the broadest scope and in the preferred embodiments set forth in the Summary of the Invention are preferred. For example:

A. One preferred group of compounds is that wherein R¹ and R² are hydrogen.

B. Another preferred group of compounds is that vvherein R¹ and R² together vvith the carbon atom to vvhich they are attached form cyc!oalkylene optionally substituted vvith one or tvvo R^b independently selected from alkyl, halo, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl. Preferably, R^l and R² together vvith the carbon atom to vvhich they are attached form cyclopropyiene, cyclobutylene, cyclopentylene, or cyclohexylene optionally substituted vvith groups described immediately above. More preferably, R¹ and R² together vvith the carbon atom to vvhich they are attached form cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, 3benzylcyclopentylene, 3-cyclohexyImethylcyclopentyiene, 3-cyclopentylmethylcyclopentylene,

3-phenylcyclopentylene, 3-cyclohexylcyclopentylene, 3-cyclopentylcyclopentylene, 3-pyridin-2ylmethylcyclopentylene, 3-pyridin-3-ylmethylcyclopentylene, 3-pyridin-4ylmethylcyclopentylene, 2-methylcyciopropylene, 2,3-dimethylcyclopropylene, 3benzylcyclobutylene, 3-methylcyclopentylene, 3,4-dimethylcyclopentylene, 3ethylcyclopentylene, 3-(l,l-dimethyipropyI)-cycIopentylene, 3-n-butylcyc!opentylene, 3ethoxycarbonylcyclopentylene, 3,4-diethoxycarbonyl-cyclopentylene, or 3-benzyl-4dimethylaminocyclopentylene. Most preferably, R¹ and R² together vvith the carbon atom to vvhich they are attached form cyclopropylene.

C. Yet another preferred group of compounds is that vvherein R¹ and R² together vvith the carbon atom to vvhich they are attached form heterocyclylalkylene optionally substituted vvith one to four R^c vvhich are independently selected from alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkvl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, S(O)n2R'⁴, -aIkyIene-S(O)n2-R¹⁵, -COOR¹⁶, -aIkylene-COOR¹⁷, -CONR¹⁸R’⁹, or -alkyleneCONR²⁰R²¹ (vvhere n2 is 0-2 and R^l4-R¹⁷, R¹⁸ and R²⁰ are independently hydrogen, alkyl, haloalkvl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloa!kyl, cycloalkylalkyl, or heterocyclyl and R¹⁹ and R²¹ are independently hydrogen or alkyl) vvherein the aromatic or alicyclic ring in the groups attached to heterocyclylalkylene is optionally substituted vvith one, two, or three substituents independently selected from alky 1, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyl.

Preferably, R¹ and R² together with the carbon atom to vvhich they are attached form pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiopyran-4-yl-l-oxide, tetrahydrothiopyran-4-yl-l,l-dioxide, hexahydropyrimidinyl, or hexahydropyridazinyl optionally substituted as described above. More preferably, R¹ and R² together vvith the carbon atom to vvhich they are attached form piperidin-4-yl substituted vvith one or tvvo alkyl, haloalkyl, aminoalkyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxyalkyl, heterocyclyl, heterocyclylalkyl, -alkyIene-CONR²⁰R²¹, or cycloalkyl. Most preferably, R¹ and R² together vvith the carbon atom to vvhich they are attached form piperidin-4-yl optionally substituted at the 1-position vvith methyl, ethyl, propyl, n-butyl, n-pentyl, 3dimethylaminopropyl, 4-dimetbylaminobutyl, 3-morpholin-4-ylpropyl, 3-piperidin-l -yl-propyl,

3- (4-methylpiperazin-l-yI)propyl, 3-(l-methylpiperidin-4-yl)propyi, 4-morphoIin-4-yibutyl, 2(2-methoxyethyloxy)ethyl, 4-methoxybutyl, 4-aminocarbonylbutyl, 3-aminocarbonylpropyl, morpholin-4-yl, 4-methylpiperazin-I-yI, I-ethoxycarbonyIpiperidin-4-yl, l,l-dioxotctrahydrothiopyran-4-yl, hydroxy, 2,2,2-trifluoroethyl, Zeri-butyl, l,2-dimethylpiperidin-4-yl, l,2,6-trimethylpiperidin-4-yI, l,2,2-trimethylpiperidin-4-yl, l-methyl-2-oxopiperidin-4-yl, 1methylpiperidin-3-yl, l-ieri-butoxycarbonylpiperidin-4-yl, 1-cyclohexylpiperidin-4-yl, 1cyclopropylmethyipyrrolidin-3-yI, l-benzyIpyrrolidin-3-yl, 1 -benzyloxycarbonylpym>lidin-3-yl, pyrrolidin-3-yl, l-hydroxypyrrolidin-3-yI, I-methylpyrroIidin-3-yI, l-ethypyrro!idin-3-yI, 1-npropyl orn-butylpyrrolidin-3-yl, l-cyclohexylpyrrolidin-3-yI, l-ethyl-2,2-dimethylpyrroIidin-4yl, I-propyl-2-methoxycarbonyIpiperidin-4-yi, 2-oxopyrrolidin-3-yl, l-ethyi-2-oxopyrrolidin-3yl, morpholin-4-yI, l-(l-methylpiperidin-4-ylcarbonyl)piperidin-4-yl, l-ethoxycarbonylpiperidin-4-yl, l-benzylazetidin-3-yl, tetrahydrothiopyran-4-yl-l-oxide, or tetrahydrothiopyran4- yl-l,l-dioxide. Particularly preferably, R¹ and R² together vvith the carbon atom to vvhich they are attached form piperidin~4-yl optionally substituted at the 1-position vvith methyl, ethyl, propyl, «-butyl, or 2,2,2-trifluoroethyI, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl-1 oxide, tetrahydrothiopyran-4-yl-l, 1 -dioxide, or tetrahydropyran-4-yl.

(a) Within the above preferred groups (A-C) and the more preferred groups contained therein, an even more preferred group of compounds is that vvherein:

R⁴ is aralkyl, heteroaralkyl, heterocyclylalkyl, or-alkylene-X'-R²² (vvherein X¹ is -NR²³-, -o-, -S(0)n3-, -CO-, -COO-, -OCO-, -NR²³CO-, -CONR²³-, -NR²³SO2-, -SO₂NR²³-, -NR²³COO-, -OCONR²³-, -NR²³CONR²⁴, or-NR²³SO₂NR²⁴- vvhere R²³ and R²⁴ are independently hvdrogen, alkyl, or acyl, n3 is 0-2, and R²² is hydrogen, alky 1, haloalky 1, cycloaikyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl) vvherein said alkylene chain in R⁴ is optionally substituted vvith one to six halo and vvherein the aromatic or alicyclic ring in R⁴ is optionally substituted vvith one, tvvo, or three R^d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl; and

R³ and R⁵ are hydrogen.

Preferably, R⁴ is tetrahydronaphthylmethyl, benzyl, 4-methoxybenzyl, 4dimethylaminobutyl, 2-dimethylaminocarbonylethyl, dimethylaminocarbonylmethyl, methoxycarbonylmethyl, 3,4-dichlorobenzyl, 2-chlorobenzyl, 4-ethoxybenzyl, 4-nitrobenzyl, biphen-4-ylmethyI, naphth-l-ylmethyl, naphth-2-ylmethyl, 4-chlorobenzyl, 3-chlorobenzyl, 4fluorobenzyl, 2-phenethyl, 4-hydroxybenzyl, 2-(4-hydroxyphenyl)ethyl, 2,6-difluorobenzyl, 2,2difluoro-3-phenylpropyl, 2,2-dichloro-3-phenylpropyI, (cyanomethylmethylcarbamoyl)methyl, biphenyl-3-ylmethyl, naphth-2-yl, 3-phenylpropyl, or 2,2-dimethyl-3-phenylpropyl and R³ and R⁵ are hydrogen.

Preferably, R⁴ is ethylthiomethyl, ethylsulfinylmethyl, ethylsulfonylmethyl, isopropylthiomethyl, 2-methylthioethyl, 2-methylsulfinylethyl, 2-methysulfonylethyl,

2-methylpropylsulfonylmethyl, isobutylsulfanylmethyl, Zer/-butylthiomethyi, benzenesulfonylmethyl, 2-phenylsulfanylethyI, 2-phenylsulfonylethyl, naphth-2-ylmethanesulfonyImethyl, biphenyl-2-ylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, phenylmethanesulfanylmethyl, phenylmethanesulfinylmethyl, phenylmethanesulfonylmethyl, 2-phenylmethanesulfonylethyl,

4-zerZ-butylphenylmethanesuIfonylmethyl, 2-fluorophenyl-methanesulfanylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3-fluorophenylmethane-sulfonylmethyl, 4-fluorophenylmethanesu!fonylmethyl, 2-chloropheny!methanesulfanylmethyl,

2- chlorophenyImethanesulfonylmethyI, 3-chIorophenylmethanesuIfonylmethyl,

4-chlorophenylmethanesulfonyImethyl, 2-methoxyphenylmethanesulfonylmethyl,

4-methoxyphenylmethanesulfonylmethyl, 2-tnfluoromethoxyphenyimethanesulfonylmethyl,

3- trifluoromethoxyphenylmethanesulfonyl-methyl, 4-trifluoromethoxyphenylmethanesulfonylmethyl, 2-trifluoromethylphenylmethane-suIfany.lmethyl, 2-trifluoromethylphenylmethanesulfonylmethyl, 3-trifluoromethylphenyI-methanesulfonylmethyl,

4- trifluoromethylphenylmethanesu!fbnylmethyl, 2-cyanophenyl-methanesuIfanylmethyl, 2-cyanophenylmethanesulfonylmethyl, 3-cyanophenylmethanesulfonylmethyI,

2-bromophenylmethanesulfonylmethyl, 2-nitrophenylmethanesulfanylmethyl,

2- nitrophenyImethanesulfonylmethyl, 2-methylphenylmethanesulfonylmethyl,

3- methylphenylmethanesulfonylmethyl, 4-methylphenylmethanesulfonylmethyl, 2-(4-trifluoromethoxy-benzenesulfonyI)ethyl, 2-(3-trifluoromethoxybenzenesulfonyl)-ethyl, 2-(2-trifluoromethoxy-benzenesuIfbnyl)-ethyl, 2-difluoromethoxyphenylmethanesulfonylmethyl, 3-difluoromethoxyphenylmethane-sulfonylmethyl,

4- difluoromethoxypheny!methane-sulfonylmethyl, 2-(4-dif]uoromethoxybenzenesulfonyl)ethyl,

2- (2-difluoromethoxybenzene-sulfonyl)ethyl, 2-(3-difluoromethoxybenzenesulfonyI)ethyl,

3- chloro-2-fluoropheny!methane-sulfonylmethyl, 3,5-dimethylphenylmethanesulfonylmethyl,

3.5- bis-trifluoromethyIphenyl-methanesuIfonyIrnethyI, 2,5-difluorophenyImethanesulfonylmethyl, 2,6-difluorophenylmethanesulfonylmethyl, 2,3-difluorophenylmethanesulfonylmethyl, 3,4-difluorophenylmethanesuifonylmethyl, 2,4-difluorophenylmethanesulfonylmethyl, 2,5-dichlorophenylmethanesulfonylmethyl, 3,4-dichlorophenylmethanesulfonylmethyl, 2,6-dichlorophenylmethanesulfonylmethyl, 2-fluoro-3-methylphenylmethanesulfonylmethyl, 4-fIuoro-2-trifIuoromethoxyphenylmethanesuIfonylmethyl, 2-fluoro-6-trifluoromethyl-phenylmethanesulfonylmethyl, 2-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-4-trifluoromethyIphenylmethanesulfonylmethyl, 2-fluoro-5-trifluoromethyl-phenylmethanesulfonylmethyl, 4-fluoro-3-trifluoromethyiphenylmethanesulfonylmethyl, 2'Chloro-5-trifluoromethylphenylmethane-sulfonylmethyl,

2.4.6- trifluorophenylmethane-sulfonylmethyl, 2,4,5-trifIuorophenylmethanesulfonylmethyI, 2,3,4-trifluorophenyl-methanesulfbnylmethyl, 2,3,5'trifluorophenylmethanesulfonylmethyl,

2.5.6- trifluorophenylmethanesuIfonyl-methyl, 3,4,5-trimethoxyphenylmethanesulfonylmethy], pyridin-2-ylmethanesulfonylmethyI, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, 2-(pyridin-2-ylsulfonyl)ethyl, 2-(pyridin-4-ylsulfonyI)ethyl, oxypyridin-2-ylmethanesulfonylmethyl, cyclohexylmethanesulfanylmethyl, cyclohexylsulfinylthiomethyl, cyclohexylmethanesulfonylmethyl, cyclopropylmethanesulfonylmethyl, thiophene-2-suIfonylmethyl, 5-chIorothien-2-ylmethanesulfonylmethyl, or

3.5- dimethyl-isoxazol-4-ylmethanesulfonylmethyl, preferably 2-(difluoromethoxy)phenylmethanesulfonylmethyl and R³ and R^s are hydrogen.

Preferably, R⁴ is l-ethoxycarbonylpiperidin-4-yImethyl, l-methylpiperidin-4-ylmethyl, 2-tetrahydropyran-4-ylethyl, pyrrolidin-l-ylmethyl, piperidin-1 -ylmethyl, morpholin-4ylmethyl, l-morpholin-4-ylethyl, thiomorpholin-4-y!methyl, l-oxo-thiomorpholin-4-ylmethyl, l,l-dioxothiomorpholin-4-ylmethyI, tetrahydrothiopyran-4-ylmethyl, l-oxotetrahydrothiopyran4-ylmethyl, 1, l-dioxotetrahydrothiopyran-4-ylmethyl, 1 -methylpiperazin-4-ylmethyl, benzyloxymethyl, ethoxymethyl, isopropyloxymethyl, 2-dimethylaminoethyl, 2-piperidin-l-ylethyl, 2-pyrrolidin-l-ylethyl, ter/-butyloxymethyl, imidazol-4-ylmethyl, indol-3-ylmethyl, 2pyrrolidin-l-ylcarbonylethyl, pyrrolidin-l-ylcarbony[methyl, indol-2-yImethyl, I-benzylimidazol-4-ylmethyl, 4-ethyl-4-methylpiperidin-l-yImethyl, indol-l-ylmethyl, l-methylpiperidin-2-yImethyI, 2,2,-difluoro-3-thien-2-ylmethyl, or pyridin-4-ylmethyl and R³ and R⁵ are hydrogen.

Most preferably, R⁴ is isopropy!sulfonylmethyl, cyclopropylmethanesulfonylmethyl, 2phenylsulfonylethyl, pyridin-4-ylsulfonyimethyl, pyridin-2-ylmethanesuIfonyImethyI, pyridin-3· ylmethanesulfonylmethyl, benzylsulfonylmethyl i.e., phenylmethanesulfonylmethyl, 2difluoromethoxyphenylmethanesulfonylmethyl, 2-chlorophenyl, or pyridin-4-ylmethyl; and

R³ and R⁵ are hydrogen.

(b) Within the above preferred groups (A-C) and the more preferred groups contained therein, another even more preferred group of compounds is that vvherein:

R⁴ is l-methylcyclopentylmethyl or l-methyicyclohexylmethyl; and

R³ and R⁵ are hydrogen.

(c) Wīthin the above preferred groups (A-C) and the more preferred groups contained therein, yet another even more preferred group of compounds is that vvherein:

R⁴ is heteroaralkyl optionally substituted vvith one, tvvo, or three R^d independently selected from alkyl, haioalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, oracyl. Preferably, pyrimidinylmethanesulfanylmethyl, pyrimidinylmethanesulfinylmethyl, pyrimidinylmethanesulfonylmethyl, pyrazinylmethane-sulfanylmethyl, pyrazinylmethanesulfinylmethyl, pyrazinylmethanesulfonylmethyi, pyridazinylmethanesulfanylmethyl, pyridazinylmethanesulfinylmethyl, or pyridazinylmethanesulfonylmethyl, preferably pyrazin-2-ylmethanesulfonylmethyl; and

R³ and R⁵ are hydrogen.

(1) Within the above preferred, more preferred, and even more preferred groups above i.e., A, A(a-c), B, B(a-c), C and C(a-c), and preferred groups contained therein, a particularly preferred group of compounds is that vvherein:

R⁶ is alkvl, haloa!kyl, cycloalkyl, phenyl, benzyl, naphthyl, alkylSO₂alkyl, cycloalkyISO₂alkyl, aryiSO₂alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyi, thienyl, pyrrolyl, oxazolyl, thiazoly 1, imidazolyl, pyridinyl, isoxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl, benzoisoxazolyl, benzoxazolyl or amino; vvherein the aromatic or alicyclic ring in R⁶ is optionally substituted by one, tvvo, or three R^e;

each R^e is independently alkyI, halo, hydroxy, oxo, carboxy, cyano, nitro, cycloalkyl, phenyi, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazoiyl, imidazolyl, triazolyl, tetrazolyi, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, alkoxy, -COR (vvhere R is alkyI), alkoxycarbonyl, aryloxycarbonyl vvhere the aromatic or alicyclic rings in R^e may be further optional ly substituted by one, tvvo or three R^f independently selected from alkyl, alkoxy, haloaikyl, haloalkoxy, halo, hydroxy, carboxy, cyano, nitro, aryl or cycloalkyl.

Preferably, R⁶ is methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyciopentyl, cyclohexyl, phenyl, benzyl, naphthyl, pynOlidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyi, pyridinyl, or pyrazinyl vvherein the aromatic or alicylic rings in R⁶ are optionally substituted vvith one, tvvo, or three R' independently selected from methyl, ethyl, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy, cyano, nitro, cyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyi, piperazinyl, thienyl, imidazolyl, methoxy, acetyl, or methoxycarbonyl vvherein the aromatic or alicyclic rings in R^e are further optionally substituted vvith one, tvvo, or three R^f independently selected from methyl, cyclopropyl, phenyl, methoxy, fluoro, chloro, hydroxy, or carboxy. Preferably, R⁶ is methy[.

Even more preferably, R⁶ is phenyl, naphthyl, pyrrolidinyl, piperidinyl, morphoiinyl, thiomorpholinyl, furanyl, thienyI, thiazolyl, imidazolyl, pyridinyl, or pyrazinyl vvherein the aromatic or alicyclic rings in R⁶ are optionally substituted vvith one, tvvo, or three R' independently selected from methyl, fluoro, chloro, phenyi, thienyl, methoxy, acetyl, or methoxycarbonyl. Preferably, R⁶ is phenyl, naphthyl, pyrrolidinyl, piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, or pyrazinyl vvherein the aromatic or alicyclic rings in R⁶ are optionally substituted vvith one, tvvo, or three R' independently selected from methyl, fluoro, chloro, phenyl, thienyl, methoxy, acetyl, or methoxycarbonyl. Most preferably, R⁶ is phenyl, 4methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, naphthyl, piperidin-4-yl, furanyl, thienyl, pyridin-4-yl, or pyrazinyl. Particularly preferablv, R⁶ is phenyl, 4-fluorophenyl, thiophen-2-yl, furan-2-yl, 2-hydroxyphenyl, l-methylpyrrol-2-yl, or indoI-3-yl, preferably, phenyl, 4-fluorophenyl, thiophen-2-yl, or furan-2-yl.

(2) Within the above preferred, more preferred, and even more preferred groups above i.e., A, A(a-c), B, B(a-c), C and C(a-c), and preferred groups contained therein, a particularly preferred group of compounds is that vvherein:

R⁸ is hydrogen or haloalkyl, preferably hydrogen or trifluoromethyl.

Within the above preferred, more preferred, and even more preferred groups above i.e., A, A(a-c), A(a-c)(l), A(a-c)(2), B, B(a-c), B(a-c)(l), B(a-c)(2), C, C(a-c), C(a-c)(l), C(a-c)(2), and preferred groups contained therein, a particularly preferred group of compounds is that vvherein:

R⁷ is trifluoromethyl or 2,2,2-trifluoroethvI, more preferably trifluoromethyl; and

R⁸ is hydrogen.

(3) Within the above preferred, more preferred, and even more preferred groups above i.e., A, A(a-c), B, B(a-c), C and C(a-c), another particularly preferred group of compounds is that vvherein:

R⁶ and R⁸ together vvith the carbon to which they are attached from cycloalkylene, preferably cyclopentylene, cyclopent-l-enylene, cyclohexylene, cyclohex-l-enylene.

(4) Within the above preferred, more preferred, and even more preferred groups above i.e., A, A(a-c), B, B(a-c), C and C(a-c), yet another particuiarly preferred group of compounds is that vvherein:

R⁶and R⁸ together vvith the carbon to vvhich they are attached from heterocyclylalkylene, preferably tetrahydropyran-4-yl or 3,6-dihydro-2H-pyran-4-yl.

Within the above preferred, more preferred, and even more preferred groups above i.e., A(a-c)(3), A(a-c)(4), B(a-c)(3), B(a-c)(4), C(a-c)(3), and C(a-c)(4), and preferred groups contained therein, most preferred group of compounds is that vvherein R⁷ is trifluoromethyl or 2,2,2-trifluoroethyl, more preferably trifluoromethyl.

(d) Within the above preferred and more preferred groups (A-C) and more preferred groups contained therein, another even more preferred group of compounds is that vvherein:

R⁶ is phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyi, furanyl, pyranyl, thienyl, thiazo!yl, imidazoLyl, pyridiny!, or pyrazinyl vvherein the aromatic or alicyclic rings in R³ are optionally substituted vvith one, tvvo, or three R^e independently selected from methyl, fluoro, chloro, phenyl, thienyl, methoxy, acetyl, or methoxycarbonyl. Most preferably, R⁶ is phenyl, 4~methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluoro-4chlorophenyl, naphthyl, piperidin-4-yI, furanyl, thienyl, pyridin-4-yl, or pyrazinyl.

Within the above preferred, more preferred, and even more preferred groups above i.e., Ad, Bd, and Cd, and preferred groups contained therein, a more preferred group of compounds is that vvherein R⁷ is trifluoromethyl or 2,2,2-trifluoroethyl, more preferably trifluoromethyl; and

R³, R⁵, and R⁸ are hydrogen.

(D) Yet another preferred group of compounds of Formula (I) is that vvherein:

R⁴ is -alkylene-S(O)2-R²² vvhere R²² is aralkyl, heteroaralkyl, or cycloalkylalkyl vvherein the alkylene chain in R⁴ is optionally substituted vvith one to six halo and further vvherein the aromatic or alicyclic ring in R⁴ is optionally substituted vvith one, tvvo, or three R^d independently selected from alkyl, haloaikyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl.

(i) Within this group (D), a more preferred group of compounds is that vvherein:

R¹ and R² are hydrogen or R¹ and R² together vvith the carbon atom to vvhich they are attached form cycloalkylene or heterocycloalkylene;

R³ is hydrogen;

R⁴ is -alkylene-S(O)2-R²² vvhere R²² is aralkyl, heteroaryalkyl, or cycloalkylalkyl vvherein the the aromatic or alicyctic ring in R⁴ is optionaliy substituted vvith one, tvvo, or three R^d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyL

R⁵ is hydrogen;

R⁶ is aryl, or heteroaryl vvherein the aromatic or alicyclic rings in R⁶ are optionally substituted by one, tvvo, or three R^e independently selected from alkyI, halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, carboxy, alkoxycarbonyl, arylsulfonyl, alkylsulfonyl, aminosulfonyl, or aminoalkyl;

R⁷ is haloalkyl; and

R⁸ is hydrogen.

(ii) Within this group (D), another more preferred group of compounds is that vvherein:

R¹ and R² are hydrogen or R¹ and R² together vvith the carbon atom to vvhich they are attached form cyclopropylene, preferably cyclopropylene;

R³ is hydrogen;

R⁴ is -CH2-SO2-R²² vvhere R²² is aralkyl, heteroarya!kyļ or cycloalkylalkyl vvherein the the aromatic or alicyclic ring in R⁴ is optionally substituted vvith one, tvvo, or three R^d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyl, preferably methyi, ethyl, trifluoromethyl, methoxy, ethoxy, propoxy, hydroxyl, trif!uoromethoxy, difluoromethoxy, chloro, fluoro, nitro, cyano, carboxy, methoxycarbonyl;

R⁵ is hydrogen;

R⁶ is aryl, or heteroaryl vvherein the aromatic or aiicyclic rings in R⁶ are optionally substituted by one, tvvo, or three R^e independently selected from alkyļ halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, haloalkyl, haloalkoxy, 0x0, cyano, nitro, acyl, carboxy, alkoxycarbonyl, arylsulfonyl, alkylsulfonyl, aminosuifonyl, or aminoalkyl;

R⁷ is haloalkyi; and

R⁸ is hydrogen.

With the group D, D(i) and D(ii), a more preferred group of compounds is that vvherein: (a) R¹ and R² together vvith the carbon atom to vvhich they are attached form cyclopropylene; and

R⁴ is phenylmethanesulfonylmethyl, 4-/er/-butylphenyImethanesulfonylmethyl,

2- fluorophenylmethanesulfonylmethyI, 3-fluorophenylmethanesulfonylmethyl,

4-fluorophenylmethanesulfonylmethyl, 2-chlorophenylmethanesuIfonyimethyl,

3- chlorophenylmethanesulfonylmethyl, 4-chlorophenylmethanesulfonylmethyl,

2-methoxyphenylmethanesulfonylmethyl, 4-methoxyphenylmethanesulfonyimethyl, 2-trifluoromethoxyphenylmethanesulfonylmethyl, 3-trifluoromethoxyphenylmethanesulfonylmethyl, 4-trifluorornethoxyphenylmethane-sulfonylmethyļ 2-trifluoromethylphenylmethanesulfonylmethyl, 3-trifluoromethylphenylmethanesulfonylmethyl, 4-trifluoromethylphenylmethanesulfonylmethyl, 2-cyanophenylmethanesulfonylmethyl, 3-cyanophenylmethanesulfonylmethyl, 2-bromophenyimethanesuIfonylmethyl, 2-nitrophenylmethanesulfonylmethyl,

2- methylphenylmethanesulfonylmethyl, 3-methylphenylmethanesulfonylmethyl,

4- methyIpheny!methanesulfonylmethyl, 2-difluoromethoxyphenylmethanesuIfonyImethyl,

3- difluoromethoxyphenylmethanesulfonylmethyl, 4-difluoromethoxyphenylmethanesulfonylmethyl, 3-chloro-2-fluorophenylmethane-sulfonylmethyl, 3,5-dimethylphenyl28 methanesulfonylmethyl, 3,5-bis-trifluoromethylphenyl-methanesulfonylmethyl,

2.5- difluorophenylmethanesulfonylmethyl, 2,6-difluorophenylmethanesuIfonylmethyl,

2.3- difluorophenylmethane-sulfonylmethyl, 3,4-difluorophenylmethanesulfonyImethyl,

2.4- difluorophenylmethanesuIfonylmethyļ 2,5-dichlorophenylmethanesulfonylmethyļ

3.4- dichlorophenylmethanesulfonyImethyl, 2,6-dichlorophenylmethanesulfonylmethyl, 2-fluoro-3-methylphenylmethanesulfonyl-methyļ 4-fluoro-2-trifluoromethoxyphenylmethanesulfonylmethyl, 2-fluoro-6-trifluoromethylphenylmethanesulfony!methyl,

2-fluoro-3-trifluoromethylphenyl-methanesuIfonylmethyl, 2-fluoro-4-trifluoromethyIpheny!methanesulfonylmethyl, 2-fluoro-5-trifluoromethyl-phenylmethanesulfonyimethyl,

4-fluoro-3-trifluoromethyl-phenylmethanesulfonylmethyI, 2-chloro-5-trifluoromethylphenylmethane-sulfonylrnethyl, 2_>4,6-trifluorophenylmethanesulfonylmethyl, 2,4,5«trifluorophenylmethanesulfonylmethyl, 2,3,4-trifluorophenylmethanesulfonyImethyl,

2.3.5- trifluorophenylmethanesulfonylmethyl, 2,5,6-triiluorophenylmethanesulfonyl-methyl,

3.4.5- trimethoxyphenyImethanesuIfonylmethyļ pyridin-2-ylmethanesulfonylmethyl, pyridin-3ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonyImethyI, W-oxypyndin-2-ylmethanesulfonylmethyl, 2-trifluoropyridin-6-ylmethanesulfonylmethyl, pyrazin-2-ylmethanesulfonylmethyl, cyclohexylmethanesulfonylmethyl, cyclohexylmethanesulfonylmethyl, cyclopropylmethanesulfonylmethyl, thiophene-2-sulfonylmethyl, 5-chlorothien-2-ylmethanesulfonylmethyļ or 3,5-dimethyl-isoxazol-4-ylmethanesulfonylmethyl.

With the group D, D(i), D(ii), D(i)(a) and D(ii)(a), a more preferred group of compounds is that vvherein:

R¹ and R² together vvith the carbon atom to vvhich they are attached form cyclopropy!ene;

R⁴ is phenylmethanesulfonylmethyl, 4-fluoropheny]methanesulfonylmethyl, cyclopropylmethanesulfonyimethy[, pyridin-2-ylmethanesuIfonylmethyI, 2trifluoromethyIpyridin-6-yImethanesulfonylmethyļ 2-difluoromethoxyphenylmethanesulfonylmethyi, or pyrazin-2-yImethanesulfonylmethyl;

R⁶ is furan-2-yl, indoI-3-yļ lhiophen-2-yl, l-methylpyrrol-2~yļ I -phenylsulfonylpyrrol2-yļ pyridin-2-yl, or phenyl optional ty substituted vvith one, tvvo, or three R^e independently selected from alkyl, hydroxyl, or halo. Preferably, R⁶ is furan-2-yl, indol-3-yl, thiophen-2-yļ 1methylpyrrol-2-yl, 1 -phenylsulfonylpyrrol-2-yl, pyridin-2-yl, phenyi, 2-hydroxyphenyļ 4hydroxyphenyl, 3-chloro-4-hydroxypheny!, 3-bromophcnyl, 4-fluorophenyļ 3,4-difluorophenyl, or 3,4,5-trifluorophenyl. Even more preferably, R^č is phenyl, 2-hydroxyphenyl, 4hydroxyphenyl, or4-fluorophenyi; and

R⁷ is 2,2,3,3,3-pentafluoroethyl, trifluoromethyl or difluoromethyl, preferably trifluoromethyl.

With the group D, D(i), D(ii), D(i)(a) and D(ii)(a), a more preferred group of compounds is that vvherein:

R¹ and R² together vvith the carbon atom to vvhich they are attached form cyclopropylene;

R⁴ is phenylmethanesulfony!methyl, 4-f!uorophenylmethanesulfonylmethyl, cyclopropylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonyImethyI, 2trifluoromethylpyridin-6-ylmethanesulfonylmethy], 2-difluoromethoxyphenylmethanesulfonyimethyl, or pyrazin-2-ylmethanesuIfonyimethyl;

R⁶ is furan-2-yI, indol-3-yl, thiophen-2-yl, l-methyIpyrrol-2-yl, I-phenylsulfonylpyrrol2-yI, pyridin-2-yl, or pheny! optionally substituted vvith one, tvvo, or three R^e independently selected from alkyl, hydroxyl, or halo. Preferably, R⁶ is furan-2-yl, indoI-3-yl, thiophen-2-yl, 1methylpyrrol-2-yl, l-phenylsulfonylpyrrol-2-yl, pyridin-2-yl, phenyl, 2-hydroxyphenyl, 4hydroxyphenyl, 3-chloro-4-hydroxyphenyI, 3-bromophenyl, 4-fīuorophenyl, 3,4-difluorophenyl, or 3,4,5-trifluorophenyl. Even more preferably, R⁶ is phenyl, 2-hydroxyphenyl, 4hydroxyphenyl, or 4-fluorophenyl;

R⁷ is 2,2,3,3,3-pentafluoroethyl, trifluoromethyl or difluoromethyl, preferably trifluoromethyl; and the stereochemistry at the carbon to vvhich R⁴ is attached is (R) and to vvhich R⁵ is attached is (5) vvhen R⁶ is phenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, or 4-fluorophenyl.

Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups unless stated othervvise.

Compounds of Formula (1) vvhere R³, R^s and R⁸ are hydrogen, R¹, R², R\ R⁶ and R⁷ are as defined in Table I belovv are:

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and are named as:

V-(l-cyanocyclopropyl)-3-phenylmethanesulfony!-2(J?)-(2,2,2-trifluoro-l(S)-phenylethylamino)propionamide;

jV-(4-cyano-l-ethylpiperidin-4-yl)-3-phenylmethanesulfonyl-2(/?)-(2,2,2-trifluoro-l(5)-phenylethylamino)propionamide;

jV-(4-cyano-1,1 -dioxohexahydro-1 X⁶-thiopyran-4-yl)-3-phenylmethanesulfonyl-2(7?)-(2,2,2trifluoro-1 (5)-phenyIethy lamino)-propionamide;

A^r-(l-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(/?)-(2,2,2-trifluoro-l(5)-4-hydroxyphenylethylamino)propionamide;

N-() -cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-1 (*S)-phenylethy 1amino)propionam i de;

7/-(l-cyanocycIopropyI)-3-phenylmethanesulfanyl-2(7?)-(2,2,2-trifluoro-l(RS)-furan-2-ylethylamino)propionamide;

jV-(l-cyanocyclopropyl)-3-phenylmethanesulfony]-2(/?)-(2,2,2-trifluoro-l(J?S)-furan-2-ylethylamino)propionamide;

V-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(S)-3-bromophenylethylamino)propionamide;

V-(l-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(7?)-(2,2,2-trifluoro-l(/?S)-indol-3-ylethylanuno)propionamide;

V-( 1 -cyanocyclopropyl)-3-phenylmethanesulfonyl-2(f?)-(2_J2,2-trifIuoro-1 (&S)-indoI-3-ylethylamino)propionamide;

V-(l-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(A)-(2,2,2-trifluoro-l(/?5)-thiophen-2ylethyl-amino)propionamide;

V-(l-cyanocyclopropyI)-3-phenylmethanesuIfonyl-2(7?)-(2,2,2-trifluoro-l(AS)-thiophen-2ylethyl-amino)propionamide;

/V-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(5)-4-fluorophenylethylamino)propionamide;

V-(l-cyanocyclopropyI)-3-phenylmcthanesulfonyl-2(J?)-(2,2,2-trifluoro-l(5)-methylethylamino)propionamide;

W-(l-cyanocyclopropyl)-3-phenylmethanesulfonyI-2(/?)-(2,2,2-trifIuoro-1(5)-1 -methylpyrrol-2yl-ethyiamino)propionam ide;

V-(l-cyanocycIopropyI)-3-(I-methylcyclopentyI)-2(5)-(2,2,2-tri fluoro-l(5)-thiophen-2-ylethylam ino)prop ionam ide;

V-(l-cyanocyclopropyl)-3-(l-methylcyclopentyl)-2(S)-(2,2,2-rrif]uoro-l(7?)-thiophen-2-ylethyl35 amino)propionamide;

y-(I-cyanocyclopropyi)-3-phenylmethanesulfdnyl-2(/?)-(2,2,2-trifluoro-](S)-4-flLtorophenylethylamino)propionamide;

jV-(l-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl-2(R)-(2,2,2-trifluoro-l(/iS)-phenylethylam ino)propionam ide;

/y-(l-cyanocyclopropyl)-3-pyrdin-2-ylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(S)-phenylethylamino)propionamide;

N-( 1 -cyanocyclopropy 1)-3-( 1 -methylcyclopenty 1)-2(5)-(2,2,2-trifluoro-1 (5)-2-hydroxyphenylethylamino)propionamide;

N-( 1 -cyanocyclopropy 1)-3-( 1 -methyIcyclopentyI)-2(5)-(2,2,2-trifl uoro-1 (7?)-4-hydroxyphenylethylamino)propionamide;

A-(l-cyanocycIopropyI)-3-pyridin-2-yImethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(7?)-phenylethylamino)propionamide;

fV-(l -cyanocyclopropy 1)-3-(1 -methylcyclopentyI)-2(0)-(2,2,2-trifluoro-1 (5)-4-hydroxyphenylethylamino)propionamide;

7V-(]-cyanocyclopropyl)-3-(2-chIorophenyI)-2(S)-(2,2,2-trifluoro-l(/?S)-phenylethylamino)propionamide;

_JV-(l-cyanocyclopropyl)-3-(2-chlorophenyl)-2(5)-(2,2,2-trifluoro-l(7?5)-4-fIuorophenylethylamino)-propionamide;

7V-(l-cyanocyclopropyl)-3-pyridin-2-yImethanesuIfonyI-2(/?)-(2,2,2-trifluoro-l(&S)-4fluorophenyl-ethylamino)propionamide;

A’-(l-cyanocycIopropyI)-3-phenylmethanesulfonyl-2(/?)-(2,2,2-trifluoro-l(<S)-4-hydroxyphenylethylamino)propionamide;

?/-(l-cyanocycIopropyl)-3-phenylmethanesulfanyI-2(/?)-(2,2,2-trifluoro-l(/?)-3-chloro-4hydroxyphenylethylamino)propionamide;

//-(l-cyanocyclopropyl)-3-phenylmethanesulfany!-2(R)-(2,2,2-trifluoro-l(S)-3-chloro-4hydroxyphenylethylamino)propionamide;

jV-(l-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(A)-(2,2,2-trifluoro-l(7?)-3-chIoro-4hydroxy-phenylethylamino)propionamide;

7V-(l-cyanocyclopropyl)-3-phenylmethanesuIfonyI-2(/?)-(2,2,2-trifluoro-l(5)-3-chloro-4hydroxy-phenylethylamino)propionamide;

Y-(l-cyanocyclopropyl)-3-(l-methylcycIopentyl)-2(S)-(2,2-difluoro-l(/?)-thiophen-2-ylethylamino)propionamide;

N-( 1 -cyanocyclopropyl)-3-phenylmethanesulfanyl-2(/?)-(2,2-difluoro-1 (J?S)-thiophen-2-y lethvl36 amino)propionamide;

//-(1-cyanocyclopropyI)-3-(I-methylcyclopentyl)-2(0)-(2,2,2-trifluoro-l(5)-3-fluoro-4-hydroxyphenylethylamino)propionamide;

N-( 1 -cyanocyclopropyl)-3 -phenylmethanesulfanyl-2(/?)-(2,2,2-trifluoro-1 (/ČS)-pyr idin-2-y lethy 1amino)propionamide;

//-(l-cyanocyclopropyl)-4-pyridin-2-ylsulfanyl-2(5)-(2,2,2-trifluoro-l(/lS)-4-fluorophenylethylamino)butyramide;

jV-(l-cyanocyclopropyl)-4-pyridin-2-ylsulfonyl-2(S)-(2,2,2-trifluoro-l(/?S)-4-fluorophenylethylamino)butyramide;

jV-(l-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(/?)-(2,2,2-triifluoro-l(/?5)-pyridin-2-yl' ethylamino)propionamide;

jV-(l-cyanocycIopropyl)-3-phenylmethanesulfonyl-2(/?)-(2,2-difluoro-l(/?)-thiophen-2-ylethylamino)propionamide;

//-(l-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfanyl)-2(/?)-(2,2,2-trifluorol(&S)-thiophen-2-ylethylamino)propionamide;

//-(l-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(2?)-(2,2,2-trifluorol(/?5>toiophen-2-ylethylamino)propionamide;

Ν·( I -cyanocyclopiOpyi)-3-pyridin-2~ylmethanesuIfanyl-2(/?)-(2,2,2-trifluoro-1 (5)-4-fluorophenylethylamino)propionamide;

V-( 1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(A)-(2,2,2-trifluoro-1 (S)-4-fluorophenylethylamino)propionamide;

V-(l-cyanocycIopropy!)-3-pyridin-2-ylmethanesulfanyl-2(/?)-(2,2,2-trifluoro-l(J?)-4-fluorophenylethylamino)propionamide;

//-(l-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(/?)-(2,2,2-trifluoro-l(/?)-4-fIuorophenylethylamino)propionamide;

y-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(/?)-(2,2,2-trifluoro-l(S)-thiophen-3-ylethylamino)propionamide;

JV-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfanyl-2(/?)-(2,2,2-tri fluora-l(/?5)-thiophen'2yl-ethylamino)propionamide;

//-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfonyI-2(/?)-(2,2,2-trifluoro-l(/?5)-thiophen-2yl-ethylamino)propionamide;

N-( 1 -cyanotetrahydropyran-4-yl)-3-cycIopropylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-1 (5)-4fluorophenylethylamino)propionamide;

//-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(/?)-(2,2,2-trifluoro-l(S)-3,4-difluoro37 phenylethylamino)propionamide;

7Y-(l-cyartocyclopropyl)-3-cyclopropylmethanesulfonyl-2(A)-(2,2,2-trifluoro-l (5)-1methylpyrrol-2-ylethylamino)propionamide;

7V-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(A)-(2,2,2-trifluoro-1(5)-1-oxo-lmethyl-pyrroi-2-ylethyIamino)propionamide;

N-( 1 -cyanocyclopropyl)-3-cyclopropylmethanesuIfonyl-2(A)-(2,2,2-trifluoro-1 (5)-3,4,5trifluoro-phenylethylamino)propionamide;

A-(l -cyanocyclopropyl)-3-(4-fluorophenylmethanesulfonyl)-2(/?)-(2,2,2-trifIuoro-l (5)-4- fluorophenylethylamino)propionamide;

jV-(l-cyanotetrahydrothiopyran-4-yl)-3-(4-f]uorophenylmethanesulfonyl)-2(/?)-(2,2,2-trifluorol(5)-4-fluorophenyl-ethylamino)propionamide;

N-( 1 -cyanocyclopropyl)-3-(4-fluorophenylmethanesulfonyI)-2(/?)-(2,2,2-trifluoro-1 (5)-3phenoxy-phenylethylamino)propionamide;

N-( 1 -cyano-1,1 -dioxohexahydro-1 X⁶-thiopyran-4-yl)-3 -(4-fIuorophenylmethanesulfonyl)-2(A)(2,2,2-trifluoro-l(5)-4-fluorophenylethylamino)propionamide;

2V-(l-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(R)-(2,2,2-trifluorol(A5)-l-phenylsulfonylpyrrol-2-ylethylamino)propionamide;

7Y-(l-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(A)-(2,2,2-trifluorol(5)-4-fluorophenyl-ethylamino)propionamide;

2V-(l-cyanocyclopropyl)-3-(2-trifIuoromethylpyridin-6-ylmethanesulfonyl)-2(R)-(2,2,2-trifluorol(A5)-4-fluorophenyl-ethylamino)propionamide;

/7-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(/?)-(2,2,2-trifIuoro-l(A5)-l-phenylsulfonylpyrroI-2-yl-ethylamino)propionamide;

/Y-(l-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfonyl-2(A)-(2,2,2-trifluoro-l(A)-4-fluorophenylethylamino)propionamide;

/V-(l-cyanocyclopropyI)-3-pyrazin-2-ylmethanesulfonyI-2(A)-(2,2,2-trifluoro-l(5)-4-fluorophenylethylamino)propionamide;

jV-(l-cyanotetrahydropyran-4-yl)-3-(2-difluoromethoxyphenylmethanesuIfonyl)-2(A)-(2,2,2trifluoro-l(5)-4-fluorophenylethylamino)propionamide;

N-( 1 -cyano 1,1 -dioxohexahydro-l ?Athiopyran-4-yl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(/?)-(2,2,2-trifluoro-l(5)-4-fluorophenylethylamino)propionamide; ?/-(l-cyanocyclopropyl)-3-(2-trifluoromethylpyridin-6-ylmethanesulfonyl)-2(/?)-(2,2,2-trifluorol(5)-4-fluorophenyl-ethylamino)propionamide;

V-(l-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfanyl-2(/?)-(2,2,2-trifluoro-l(J?)-4-fiuorophenylethylamino)propionamide;

V-(l-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfanyI-2(R)-(2,2,2-trifluoro-l(S)-4fluorophenyl-ethylamino)propionamide;

A-(l-cyanocyclopropyl)-3-(l-oxopyridin-2-ylmethanesulfonyl)-2(7?)-(2,2,2-trifluoro-l(S)-4fluorophenyl-ethylamino)propionamide; and

A'-(l-cyanocycIopropyl)-3-(pyridin-2-ylmethanesulfonyI)-2-(2,2,2-trifluoro-l-phenyl-ltrifluoromethylethylamino)-propionamide.

GENERAL SYNTHETIC SCHEME

Compounds of this invention can be made by the methods depicted in the reaction schemes shovvn belovv.

The starting materiāls and reaģents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods knovvn to those skilled in the art follovving procedures set forth in references such as Fieser and Fieser's Reaģents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by vvhich the compounds ofthis invention can be synthesized, and various modifications to these schemes can be made and vvili be suggested to one skilled in the art having referred to this disclosure.

The starting materiāls and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materiāls may be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about-78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C and most preferably at about room (or ambient) temperature, e.g., about 20 °C.

in the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, vvhere these are desired in the final product, to avoid their unvvanted participation in the reactions. Conventional protecting groups may be used in accordance vvith Standard practice, for examples see T.W. Greene and P. G. M. Wuts in Protective Groups in Organic Chemistrf John Wiley and Sons, 1999.

Compounds of Formula (I) vvhere R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in the Summary of the Invention and R⁸ is hydrogen can be prepared by proceeding as in the follovving Reaction Scheme 1 belovv.

Scheme 1

Reaction of a ketone of formula 1 vvhere R⁶ is as defined in the Summary ofthe Invention and R⁷ is a haloalkyl (preferably trifluoromethyl) vvith an α-amino ester of formula 2 vvhere R is a carboxy protecting group, preferably an alkyl group, preferably methyl, and R³ and R⁴ are as defined in the Summary of the Invention under reductive amination reaction conditions provide a compound of formula 3. The reaction is carried out in the presence of a suitable dehydrating aģent such as TiCU, magnesium sulfate, isopropyl trifluoroacetate, in the presence of a base such as diisopropylethylamine, pyridine, and the like and in a suitable organic solvent such as methylene chloride to give an imine. The imine is reduced vvith a suitable reducing aģent such as sodium borohydride, sodium cyanoborohydride, and the like in a suitable organic solvent such as methanol, ethanol, and the like.

Compounds of formula 1 such as 2,2,2-trifluoromethylacetophenone and 2,2,2trif!uoromethy!-4-phenylphenylethanone are commercially available. Others can be prepared by methods vvell knovvn in the art. cc-Amino esters of formula 2 of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, and lysine are commercially available. Others can be prepared by methods vvell knovvn in the art. Some such methods are described in PCT Applications Publication Nos. WO 03075836, WO 00/55144, WO 01/19816, WO 02/20485,

WO 03/029200, U.S. Provisional Application No. 60/422,337, U. S. Patent No. 6,353,017B1,

6,492,662B1, 353,017 Bl and 6,525,036B1,6,229,011B1,6,610,700, the disclosures of vvhich are incorporated herein by reference in their entirety.

Hydrolysis of the ester group provides a compound of formula 4. The hydrolysis conditions depend on the nature of the protecting group. For example, vvhen R is alky 1 the hydrolysis is carried out under aqueous basie hydrolysis reaction conditions to give the corresponding acid of formula 4. The reaction is typically carried out with cesium carbonate, lithium hydroxide, and the Iike in an aqueous alcohol such as methanol, ethanol, and the Iike.

Alternatively, compounds of formula 4 can be prepared as shovvn belovv in Method (i) belovv.

Method (i)

R³

o

Condensation of an aldehyde of formula 6 vvith an aminoethanol of formula 7, utilizing Dean Stark apparatus provides a cyclic aminal of formula 8 vvhich upon reaction vvith a Grignard reaģent of formula R⁶MgX (vvhere X is halo) or an organolithium reaģent of formula R⁶Li provides a compound of formula 9. Oxidation of 9 vvith a suitable oxidizing aģent such as Jones oxidizing reaģent or HjIOe/CrCh, and the Iike, then provides a compound of formula 4.

Compound 7 can be prepared by reducing a compound of formula 2 vvhere R is hydrogen vvith a suitable reducing aģent such as lithium aluminum hydride, and the Iike under conditions vvell knovvn in the art.

Compound 4 is then reacted vvith an α-aminoacetonitrile of formula 5 to give a compound of Formula (I). The reaction is typically carried out in the presence of a suitable coupling aģent e.g., benzotriazole-l-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP®), (9-benzotriazol-l-yl-Y,A^r)Y’,7/^l-tetramethyI-uronium hexafluorophosphate (HBTU), č>-(7-azabenzotriazol-l -yl)-l, 1,3,3-tetramethyl-uronium hexafluorophosphate (HATU), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or 1,3-dicyclohexylcarbodiimide (DCC), optionally in the presence of l-hydroxybenzotriazole (HOBT), and a base such as :V,yV-diisopropyiethylarnine, triethylamine, Y-methylmorpholine, and the Iike. The reaction is typically carried out at 20 to 30 °C, preferably at about 25 °C, and requires 2 to 24 h to complete. Suitable reaction solvents are inert organic solvents such as halogenated organic solvents (e.g., methylene chloride, chloroform, and the Iike), acetonitrile, Nffdimethylformamide, ethereal solvents such as tetrahydrofuran, dioxane, and the Iike.

Altematively, the above coupling step can be carried out by first converting 4 into an active acid derivative such as succinimide ester and then reacting it vvith an amine of formula 5. The reaction typica!ly requires 2 to 3 h to complete. The conditions utilized in this reaction depend on the nature of the active acid derivative. For example, if it is an acid chloride derivative of 4, the reaction is carried out in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, pyridine, and the like). Suitable reaction solvents are polar organic solvents such as acetonitrile, zV^V-dimethylformamide, dichloromethane, or any suitable mixtures thereof.

The above method can also be used to prepared compounds of Formula (I) vvhere R⁸ is other than hydrogen utilizing the procedure described in method (i) above, by substituting R⁶COH vvith a ketone of formula R⁶R⁷CO and then treating the resulting cyclic aminal vvith R⁸Li/R⁸MgX, follovved by oxidation to give the free acid. The free acid is then condensed vvith 5 under conditions described above to give compound (I).

It vvill be apparent to a person skilled in the art, that compounds of Formula (I) can also be prepared by first condensing 5 vvith the iV-protected amino acid of formula 2 vvhere R is hydrogen follovved by removal of the amino protecting group and reacting the free amino compound vvith a compound of formula 1 as described in Scheme 1 above. Suitable amino acid protecting groups and reaction conditions for putting them on and removing them can be found in Greene, T.W.; and Wuts, P. G. M.; Protecting Groups in Organic Synthesis', John Wiley & Sons, Inc. 1999.

AIternatively, a compound of Formula (I) can be prepared as iliustrated and described in Scheme 2 belovv.

Scheme 2

R⁷ R³ R⁴

JL.

Reaction of a compound of formula 7 vvhere R³ and R⁴ are as defined in the Summary of the Invention and PG is a suitable oxygen protecting group vvith a hemiacetal of formula 10 vvhere R⁷ is as defined in the Summary of the Invention provides an imine compound of of formula 11. Treatment of 11 vvith an organic lithium compound of formula R⁶Li vvhere R⁶ is as defined in the Summary of the Invention provides compound 12. Removal of the oxygen protecting group, follovved by oxidation of the resulting alcohol 9 provides a compound of formula 4 vvhich is then converted to a compound of Formula (I) as described in Scheme 1 above. Suitable oxygen protecting groups and reaction conditions for putting them on and removing them can be found in Greene, T. W.; and Wuts, P. G. M.; Protecting Groups in Organic Synthesis; John Wiley & Sons, lnc. 1999.

Altematively, a compound of Formula (I) where R⁶ is aryl or heteroaryl can be prepared as illustrated and described in Scheme 3 belovv.

Scheme 3

R³ R⁴ oh r’AoCHj + nh₂ ^x^Y°^R.

HO

R⁷ q3 &4

Λ

R⁷ p3 fl ļf BF₃.Et₂O ^R fļ ļf r⁶h

O

-- (I)

Reaction of a compound of formula 2 vvhere R is alky 1 and R³ and R⁴ are as defined in the Summary of the Invention vvith a hemiacetal compound of formula 10 vvhere R⁷ is as defined in the Summary of the Invention provides a 2-(l-hydroxymethylamino)acetate compound of formula 13. The reaction is carried out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid and in an aromatic hydrocarbon solvent such as toluene, benzene, and the like.

Treatment of 13 vvith a compound of formula 14 vvhich is an aryl or heteroaryl ring under Friedel-Crafts reaction conditions provides a compound of formula 3 vvhich is then converted to a compound of Formula (I) as described above.

Altematively, a compound of Formula (I) can be prepared as illustrated and described in Scheme 4 belovv.

Scheme 4 r6 ,LG R⁸

R⁵ 0 R¹ R²

X . πν-Χ-ν-Χ.

’ R' 20 ^CN

R⁴ R³

R^S 0 _R1r2 r71 Λ H CN ^R R⁸R⁴ R^{3 H} (1)

Reaction of a compound of formula 15 vvhere LG is a suitable leaving group such as trifluoromethansulfonate, and the like, and R⁶, R⁷, and R⁸ are as defined in Summary of the Invention vvith a compound of formula 16 vvhere R'-R⁵ are as defined in the Summary of the Invention provides a compound of Formula (I). The reaction is carried out in a suitable organic solvent, including but not limited to, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, and the like, or mixtures thereof and optionally in the presence of an organic or inorganic base. Preferably, the organic base is triethylamine, pyridine, JV-methylmorpholine, collidine, diisopropylethylamine, and the like. Preferably, the inorganic base is cesium carbonate, sodium carbonate, sodium bicarbonate, and the like. The reaction is optionally carried out in the presence of a drying aģent such as molecular sieves. Preferably, the reaction is carried out at room temperature.

Compounds of formula 15 can be prepared by methods vvell knovvn in the art. For example, a compound of formula 15 vvhere R⁶ is phenyl or 4-fluorophenyI, R⁷ is trifluoromethyl, and R⁸ is hydrogen can be readily prepared from commercially available 2,2,2trifluoroacetophenone or 2,2,2,4’-tetrafluoroacetophenone respectiveIy, by reducing the keto group to an alcoholic group by suitable reducing aģent such as sodium borohydride, lithium aluminum hydride, and the like. The solvent used depends on the type of reducing aģent. For example, vvhen sodium borohydride is used the reaction is carried out in an alcoholic organic solvent such as methanol, ethanol, and the like. When lithium aluminum hydride is used the reaction is carried out in an ethereal solvent such as tetrahydrafuran, and the like. Reaction of 2,2,2-trifluoro-l-phenylethanol or 2,2,2-trifluoro-l-(4-fluorophenyl)ethanoI vvith triflic anhydride provides the desired compound. Optically enriched compound of formula 15 can be obtained by reduction of the corresponding halogenated acetophenone vvith a suitable reducing aģent such as catecholborane or BH3-DMS complex in the presence of a suitable catalyst such as (S) or (7?)-CBS catalyst or (S) or (Λ)-α,α -diphenyI-2-pyrrolidine-methanol in the presence of BBN to provide chiral alcohol vvhich is then converted to compound (a) as described above. Compounds of formula 16 can be prepared by reacting a compound of formula 2 vvhere R is hydrogen vvith a compound of formula 5 as described in Scheme 1 above.

Alternatively, the compound of Formula (I) can be prepared as illustrated and described in Scheme 5 belovv.

Scheme 5 ·5ό

OR

R^z R³ 17

R⁷ p»3 piz p*KV^R'

R⁸ R⁵ 0 optional ?’ V ?’ ^r;^r4 V ^r6/^N'ļf^0H -~ R“7^N'3f'^{X 4 H}2^N CN W

R⁸ R^s 0 R⁸ R⁵ 0 ₅

20 activated acid deriv.

Reaction of a compound of formula 15 vvhere LG is a suitable leaving group such as trifluoromethansulfonate, and the like, and R⁶, R⁷, and R⁸ are as defined in Summary of the Invention vvith a compound of formula 17 vvhere R⁵ is as defined in the Summary of the Invention, preferably hydrogen, R³ is as defined in the Summary of the Invention, R^z is R⁴ as defined in the Summary of the Invention or -(alkylene)-X^l-Z vvhere X¹ is as defined in the Summary of the Invention and Z is a protecting group e.g., trityl, and the like, and R’ is hydrogen or a suitable carboxy protecting group such as alkyl, and the like, under the reaction conditions described in Scheme 4 above, provides a compound of formula 18. Other suitable carboxy protecting and Z protecting groups and reaction conditions for putting them on and removing them can be found in Greene, T.W.; and Wuts, P. G. M.; Protecting Groups in Organic Synthesis\ John Wiley & Sons, Inc. 1999, the disclosure of vvhich is incorporated herein by reference in its entirety.

A compound of formula 18 vvhere R^z is -(alkyIene)-X'-Z can be converted to a corresponding compound of formula 18 vvhere R⁴ is -(alkylene)-X'-R²² vvhere R²² is as defined in the Summary of the invention by methods vvell knovvn in the art. For example, a compound of formula 18 vvhere X¹ is -S(0)_nr vvhere n3 is 0-2 and R^z is trityl protecting group can be easily converted to a corresponding compound of formula 18 vvhere R^z is R⁴ vvhere R⁴ is -(alkylene)-S(O)n3-R²² vvhere R²² is alky 1, cycloalkylalkyl, heterocyclylalkyl, aralkyl or heteroaralkyl by removing the trityl group and reacting the resulting thiol group vvith suitable alkylating aģent of the formula R²²LG vvhere LG is a leaving group such as halo, tosylate, mesylate, triflate, and the like, in the presence of a base and optionally oxidizing the sulfur atom to sulfoxide or sulfone vvith an oxidizing aģent such as ΟΧΟΝΕ®, and the like.

Similarly, other compounds of formula 18 vvhere R^z is R⁴ vvhere R⁴ is -(alkylene)-X^l-R²² vvhere X¹ is-NR²³-, -0-, -S(O)„3-, -CO-, -COO-, -OCO-, -NR²³CO-, -CONR²³-, -NR²³SO2-, SO₂NR²³-, -NR²³COO-, -OCOONR²³-, -NR²³CONR²⁴-, or-NR²³SO₂NR²⁴- vvhere R²², R²³ and

R²⁴ are as defined in the Summary of the Invention can be prepared from commercially available compound of formula 17 such as lysine, glutamic acid, aspartic acid, serine, and homoserine by methods vvell knovvn in the art. Some snch methods are described in US Patent No. 6,136,844 the disclosure of vvhich is incorporated herein by reference in its entirety.

Compounds of formula 17 are either commerciaily available or they can be prepared by methods vvell knovvn in the art. For example, alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, and lysine are commercially available. Others can be prepared by methods vvell knovvn in the art. Some such methods are described in PCT Applications Publication Nos. WO 03/075836, WO 00/55144, WO 01/19816, WO 02/20485, WO 03/029200,

U.S. Provisional Application No. 60/422,337, U. S. Patent No. 6,353,017B1, 6,492,662B1, 353,017 Bl and 6,525,036B 1, 6,229,011B1, 6,610,700, the disclosures of vvhich are incorporated herein by reference in their entirety.

Removal of the carboxy protecting group from a compound of formula 18 vvhere R’ is a protecting group provides a compound of formula 19. The conditions used to remove the carboxy protecting group depend on the nature of the carboxy protecting group. For example, if R’ is alky 1, it is removed under basie hydrolysis reaction conditions utilizing aqueous base such as aqueous lithium hydroxide, sodium hydroxide, and the like in an alcoholic solvent such as methanol, ethanol, and the like.

Compound 19 is then converted to an activated acid derivative 20 (X is a leaving group) and vvhich upon reaction vvith an aminoacetonitrile compound of formula 5 provides a compound of Formula (I). The activated acid derivative can be prepared and then reacted vvith compound 5 in a stepvvise manner or the acid derivative can be generated in situ in the presence of compound 5. For example, if the activated acid is acid halide it is first prepared by reacting 19 vvith a halogenating aģent such as thionyl chloride, oxalyl, chloride and the like and then reacted vvith compound 5. Alternatively, the activated acid derivative is generated in situ by reacting compound 19 and 5 in the presence ofa suitable coupling aģent e.g., benzotriazole-l-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP®), O-benzotriazol-1 -yl-jV,//,X',7/’-tetramethyl-uronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-l-yi)-l, 1,3,3-tetramethyl-uronium hexafluorophosphate (HATU), l-(3-dimethy!aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC), an the like, optionally in the presence of l-hydroxybenzotriazole (HOBT), and in the presence of a base such as 77,7/-diisopropylethylamine, triethylamine, Nmethylmorpholine, and the like. Suitable reaction solvents are inert organic solvents such as halogenated organic solvents (e.g., methylene chloride, chloroform, and the like), acetonitrile, W,/V-dimethy(formamide, ethereal solvents such as tetrahydrofuran, dioxane, and the like.

Altematively, the activated acid can be reacted vvith CR’R²(NH2)CONH2 vvhere R¹ and R² are as deseribed in the Summary of the Invention, follovved by conversion of the -CONH₂ group to the cyano group by methods vvell knovvn in the art.

Altematively, the compound of Formula (I) can be prepared as illustrated and deseribed in Scheme 6 belovv.

Scheme 6

R^{7 r3} r⁴ r8 p5 optional ?' ί-⁴

R⁸ r5

Reaction of a compound of formula 15 vvhere LG is a suitable leaving group such as trifluoromethansulfonate, and the like, and R^s, R⁷, and R⁸ are as defined in Summary of the Invention vvith a compound of formula 21 vvhere R²-R⁸ are as defined in the Summary of the Invention and R” is a suitable hydroxyl protecting group such as trialkylsilyl, and the like, under the reaction conditions deseribed in Scheme 4 above, provides a compound of formula 22. Suitable hydroxy protecting groups and reaction conditions for putting them on and removing them can be found in Greene, T.W.; and Wuts, P. G. M.; Protecting Groups in Organic Synthesis; John Wiley & Sons, Inc. 1999. Compounds of formula 21 can be prepared from corresponding natūrai and unnatural amino acids by methods vvell knovvn in the art. Some such procedures are deseribed in PCT Application Publication No. WO 03/075836, the disclosure of vvhich is incorporated herein by reference in its entirety.

Compound 22 vvhere R” is a hydroxy protecting group is then converted to a corresponding compound of formula 23 vvhere R” is hydrogen by removal of the hydroxyl protecting group. Suitable reaction conditions for removing hydroxy protecting group can be found in Greene, T.W.; and Wuts, P. G. M.; Protecting Groups in Organic Synthesis·, John Wiley & Sons, Inc. 1999.

Compounds 22 vvhere R” is hydrogen and 23 are then converted to a compound of formula 24 utilizing a suitable oxidizing aģent such as Jones oxidizing reaģent, HsIOs/CrOj, and the like. Compound 24 is then converted to a compound of Formula (I) as deseribed above.

A compound of Formula (I) can be converted to other compounds Of Formula (I). For example:

A compound of Formula (1) vvhere R⁶ is an aromatic ring substituted vvith halo can be reacted vvith appropriated boronic acid under palladium catalyzed Suzuki coupling reaction conditions to provide a correspond compound of Formula (I) vvhere R⁶ is further substituted vvith an aryl or heteroaryl ring.

A compound of Formula (I) containing a hydroxy group may be prepared by dealkylation/benzylation of an alkoxy/benzyloxy substituent; those containing an acid group, by hydrolysis of an ester group; and those containing a cyano, by displacement of a bromine atom on the corresponding compounds of Formula (I). A compound of Formula (I) containing a halo group such as chloro can be converted to a corresponding compound of Formula (I) containing an methylthio by treating it vvith sodium thiomethoxide. The methylthio group can be oxidized to methylsulfonyl using a suitable oxidizing aģent such as ΟΧΟΝΕ®. A compound of Formula (I) containing a cyano group can be converted to a corresponding carboxy containing compound by hydrolysis of the cyano group. The carboxy group, in tum, can be converted to an ester group.

A compound of Formula (I) can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound vvith a pharmaceutically acceptable inorganic or organic acid. Altematively, a pharmaceutically acceptable base addition salt of a compound of Formula (T) can be prepared by reacting the free acid form of the compound vvith a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceuticaily acceptable salts of compounds of Formula (1) are set forth in the definitions section of this Application. Altematively, the salt forms of the compounds of Formula (I) can be prepared using salts of the starting materiāls or intermediates.

The free acid or free base forms of the compounds of Formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula (I) in an acid addition salt form can be converted to the corresponding free base by treating vvith a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of Formula (I) in a base addition salt form can be converted to the corresponding free acid by treating vvith a suitable acid (e.g., hydrochloric acid, etc).

The JV-oxides of compounds of Formula (I) can be prepared by methods known to those ofordinary skill in the art. For example, A-oxides can be prepared by treating an unoxidized form of the compound of Formula (I) vvith an oxidizing aģent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, /weA3-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0°C. Alternatively, the /V-oxides of the compounds of Formula (I) can be prepared from the V-oxide of an appropriate starting material.

Compounds of Formula (I) in unoxidized form can be prepared from iV-oxides of compounds of Formula (I) by treating vvith a reducing aģent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.

Prodrug derivatives of the compounds of Formula (I) can be prepared by methods knovvn to those of ordinary skill in the art (e.g., for further details see Saulnier et a/.(1994), Bioorganic and Medicīnai Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula (I) vvith a suitable carbamylating aģent (e.g., l,l-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of Formula (I) can be made by means knovvn to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3^rt edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may be convenientiy prepared or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

Compounds of Formula (I) can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound vvith an optically active resolving aģent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula (I), dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along vvith the resolving aģent, by any practical means that vvould not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean

Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Rešolutions, John Wiley & Sons, Inc. (1981).

Preparation of Biological Aģents

In practicing this invention several processes for the generation or purification of biological aģents are used. Methods for preparing the biologics are well knovvn in the art as discussed belovv.

Monoclonal antibodies are prepared using Standard techniques, vvell knovvn in the art, such as by the method of Kohler and Milstein, Nature 1975,256:495, or a modification thereof, such as described by Buck et al. 1982, In Vitro 18:377. Typically, a mouse or rat is immunized vvith the MenB PS derivative conjugated to a protein carrier, boosted and the spleen (and optionally several large lymph nodēs) removed and dissociated into single celis. If desired, the spleen celis may be screened (after removal of non-specificalļy adherent celis) by applying a celi suspension to a plate or vvell coated vvith the antigen. B-cells, expressing membrane-bound immunoglobulin specific for the antigen, vvili bind to the plate, and vvili not be rinsed away vvith the rest of the suspension. Resulting B-cells, or ali dissociated spleen celis, are then induced to fuse vvith myeloma celis to form hybridomas. Representative murine myeloma lines for use in the hybridizations include those available from the American Type Culture Collection (ATCC).

Chimeric antibodies composed of human and non-human amino acid sequences may be formed from the mouse monoclonal antibody molecules to reduce their immunogenicity in humāns (Winter et al. Nature 1991 349:293; Lobuglio et al. Proc. Nat. Acad. Sci. USA 1989 86:4220; Shavv et al. J. Immunol. 1987 138:4534; and Brovvn et al. Cancer Res. 1987 47:3577; Riechmann et al. Nature 1988 332:323; Verhoeyen et al. Science 1988 239:1534; and Jones et al. Nature 1986 321:522; EP Publication No.519,596, published Dec. 23,1992; and U.K. Patent Publication No. GB 2,276,169, published Sep. 21, 1994).

Antibody molecule fragments, e.g., F(ab').sub.2, FV, and sFv molecules, that are capable of exhibiting immunological binding properties ofthe parent monoclonal antibody molecule can be produced using knovvn techniques. Inbar et al. Proc. Nat. Acad. Sci. USA 1972 69:2659; Hochman et al. Biochem. 1976 15:2706; Ehrlich et al. Biochem. 1980 19:4091; Huston et al. Proc. Nat. Acad Sci. USA 1988 85(16):5879; and U.S. Pat. Nos. 5,091,513 and 5,132,405, and U.S. Pat. No. 4,946,778.

In the alternative, a phage-display system can be used to expand the monoclonal antibody molecule populations in vitro. Saiki, et al. Nature 1986 324:163; Scharf et al. Science 1986 233:1076; U.S. Pat. Nos. 4,683,195 and 4,683,202; Yang et al. J. Mol. Biol. 1995 254:392;

Barbas, III et al. Methods: Comp. Meth Enzymol. 1995 8:94; Barbas, III et al. Proc. Nati. Acad. Sci. USA 1991 88:7978.

The coding sequences for the heavy and light chain portions of the Fab molecules selected from the phage display library can be isolated or synthesized, and cloned into any suitable vector or replicon for expression. Any suitable expression system can be used, including, for example, bacterial, yeasq insect, amphibian and mammalian systems. Expression systems in bacteria include those described in Chang et al. Nature 1978 275:615, Goeddel et al. Nature 1979 281:544, Goeddel et al. Nucleic Acids Res. 1980 8:4057, European Application No. EP 36,776, U.S. Pat. No. 4,551,433, deBoer et al. Proc. Nati. Acad. Sci. USA 1983 80:21 25, and Siebenlist et al. Celi 1980 20:269.

Expression systems in yeast include those described in Hinnen et al. Proc. Nati. Acad. Sci. USA 1978 75:1929, Ito et al. J. Bacterial. 1983 153:163, Kurtz etal. Mol. Celi. Biol. 1986 6:142, Kunze et al. J. Basic Microbiol. 1985 25:141, Gleeson et al. J. Gen. Microbiol. 1986 132:3459, Roggenkamp et al. Mol. Gen. Genet. 1986 202:302, Das et al. J. Bacterial. 1984 158:1165, De Louvencourt et al. J. Bacteriol. 1983 154:737, Van den Berg et al.

Bio/Technology 1990 8:135, Kunze et al. J. Basic Microbiol. 1985 25:141, Cregg et al. Mol. Celi. Biol. 1985 5:3376, U.S. Pat. Nos. 4,837,148 and 4,929,555, Beach et al. Nature 1981 300:706, Davidovv et al. Curr. Genet. 1985 10:380, Gaillardin et al. Curr. Genet. 1985 10:49, Ballance etal. Biochem. Biophys. Res. Commun. 1983 112:284-289, Tilbum et al. Gene 1983 26:205-221, Yelton et al. Proc. Nati. Acad. Sci. USA 1984 8T.1470-I474, Kelly et al. EMBOJ. 1985 4:475479; European Application No. EP 244,234, and International Publication No. WO 91/00357.

Expression of heterologous genes in insects can be accomplished as described in U.S. Pat. No. 4,745,051, European Application Nos. EP 127,839 and EP 155,476, Vlak et al. J. Gen. Virol. 1988 69:765-776, Miller et al. Ann. Rev. Microbiol. 1988 42:177, Carbonell et al. Gene 1988 73:409, Maeda et al. Nature 1985 315:592-594, Lebacq-Verheyden etal. Mol. Celi. Biol. 1988 8:3129, Smith et al. Proc. Nati. Acad. Sci. USA 1985 82:8404, Miyajima et al. Gene 1987 58:273, and Martin et al. DNA 1988 7:99. Numerous baculoviral strains and variants and corresponding permissive insect host celis from hosts are described in Luckow et al. Bio/Technology 1988 6:47-55, Miller et al. GENETIC ENGINEERING, Setlow, J. K. et al. eds., Vol. 8, Plenum Publishing, pp. 1986 277-279, and Maeda et al. Nature 1985 315:592-594.

Mammalian expression can be accomplished as described in Dijkema et al. EMBOJ. 1985 4:761, Gorman et al. Proc. Nati. Acad. Sci. USA 1982 79:6777, Boshart et al. Celi 1985 41:521, and U.S. Pat. No. 4,399,216. Other features of mammalian expression can be facilitated as described in Ham et al. Meth. Enz. 1979 58:44, Bames et al. Anal. Biochem. 1980 102:255, U.S. Pat. Nos. 4,767,704,4,657,866,4,927,762, 4,560,655 and Reissued U.S. Pat. No. RE 30,985, and in International Publication Nos. WO 90/103430, WO 87/00195.

The production of recombinant adenoviral vectors are described in U.S. Pat. No. 6,485,958.

Botulinum toxin type A can be obtained by establishing and grovving cultures of Clostridium botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance vvith knovvn procedures.

Any of the above-described protein production methods can be used to provide the biologic that vvould benefit from the present invention.

Pharmacology and Utility

The compounds of the invention are selective inhibitors of cysteine proteases such as cathepsin S, Κ, B, and/or F, and in particular cathepsin S, and accordingly are useful for treating diseases in vvhich cysteine protease activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in treating autoimmune disorders, including, but not limited to, juvenile onset diabetes, psoriasis, multiple sclerosis, pemphigus vulgaris, Gravēs' disease, myasthenia grāvis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis, allergic disorders, including, but not limited to, asthma, allogeneic immune responses, including, but not limited to, organ transplants or tissue grafts and endometriosis.

Cathepsin S is also implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g., emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities and cardiovascular disease such as plaque rupture and atheroma. Cathepsin S is implicated in fibril formation and, therefore, inhibitors of cathepsins S are of use in treatment of systemic amyloidosis.

The cysteine protease inhibitory acti vīties of the compounds of Formula (I) can be determined by methods knovvn to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by tēst compounds are knovvn. Typically, the assay measures protease-induced hydrolysis of a peptide-based substrate. Details of assays for measuring protease inhibitory activity are set forth in Biological Examples 1-5, infra.

Administration and Pharmaceutical Compositions

In general, compounds of Formula (I) vvill be administered in therapeutically effective amounts via any of the usual and acceptable modes knovvn in the art, either singly or in combination vvith one or more therapeutic aģents. A therapeutically effective amount may vary vvidely depending on the severity of the disease, the age and reiative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula (I) may range from about 10 micrograms per kilogram body vveight (pg/kg) per day to about 100 milligram per kilogram body vveight (mg/kg) per day, typically from about 100 pg/kg/day to about 10 mg/kg/day. Therefore, a therapeutically effective amount for an 80 kg human patient may range from about 1 mg/day to about 8 g/day, typically from about 1 mg/day to about 800 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personai knovvledge and the disclosure of this Application, vvill be able to ascertain a therapeutically effective amount of a compound of Formula (I) for treating a given disease.

The compounds of Formula (I) can be administered as pharmaceutical compositions by one of the follovving routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pilis, capsules, semisolids, povvders, sustained release formulations, Solutions, suspensions, elixirs, aerosols, or any other appropriate čomposition and are comprised of, in general, a compound of Formula (I) in combination vvith at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, I iquid, semisolid or, in the case of an aerosol čomposition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from vvater, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like). Preferred liquid carriers, particularly for injectable Solutions, include vvater, saline, aqueous dextrose and glycols.

The amount of a compound of Formula (I) in the čomposition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors knovvn to those of skill in the art of pharmaceutical Sciences. In general, a čomposition of a compound ofFormula (I) for treating a given disease vvill comprise from 0.01%w to 10%w, preferably 0.3%vv to l%w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum vvhen relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula (I) are described in Example 1 belovv.

Examples

The present invention is further exemplified, but not limited by, the follovving examples that illustrate the preparation of compounds of Formula (I) (Examples) and intermediates (References) according to the invention.

Example A

Synthesis of 2(RS)-benzyloxycarbonylamino-4(7tS)-(2-methoxyphenyl)pentanoic acid

To <i,/-2-methoxy-a-methylbenzyl alcohol (0.5 g, 3.29 mmol) vvas added 48% aq. HBr (2 mL) and the reaction mixture vvas stirred rapidly for 1.5 h. The reaction mixture vvas diluted vvith hexane (30 mL), vvashed vvith vvater, dried vvith MgSCL, filtered, and evaporated under vacuum. The crude d,l-2-methoxy-a-methylbenzyI bromide vvas added to a solution of tributyltin hydride (0.67 mL, 2.49 mmol), Z-dehydroalanine methyl ester (0.25 g, 1.06 mmol), and 2,2’-azobisisobutyronitrile (15 mg, 0.09 mmol) in benzene (5 mL). The reaction mixture vvas heated at 80 °C under a nitrogen atmosphere for 5 h. Benzene vvas removed under vacuum and the residue vvas dissolved in methanol (20 mL). 2N KOH (5 mL) vvas added and the mixture vvas rapīdly stirred at room temperature over night. Methanol vvas removed under vacuum and the residue vvas diluted vvith vvater (20 mL). The aqueous solution vvas vvashed vvith ether to remove the tin by products. The aqueous layer vvas acidified vvith 6 N HCI (aq.) and the product vvas extracted vvith ethyl acetate. The combined organic layers vvere vvashed vvith brine, dried vvith MgSOi, filtered, and evaporated under vacuum to give 2-benzyloxy-carbonylamino4-(2-methoxyphenyl)pentanoic acid (190 mg, 0.53 mmol) as a mixture of diastereomers in sufficiently pure form to be used vvithout further purification. MS: (Μ*+H) 358, (Μ*-H) 356. Follovving the procedure deseribed above, and utilizing appropriate starting materiāls the follovving amino acids vvere prepared:

2-benzyloxy-carbonylamino-4-(2-methoxyphenyl)hexanoic acid; 2-benzyloxy-carbonylamino-4-(4-fluorophenyl)pentanoic acid; 2-benzyloxy-carbonylamino-4-(4-chlorophenyl)pentanoic acid; 2-benzyloxy-carbonylamino-4-(4-methoxyphenyl)pentanoic acid; 2-benzyloxy-carbonyIamino-4-(2-trifluoromethylphenyl)pentanoic acid; 2-benzyloxy-carbonylamino-4-(3-trifluoromethylphenyl)pentanoic acid; 2-benzyloxy-carbonylamino-4-(napth-1 -yi)pentanoic acid; 2-benzyloxy-carbonylamino-4-(2,6-dimethylphenyl)pentanoic acid; 2-benzyIoxy-carbonylamino-4-(2,4-difluorophenyl)pentanoic acid; 2-benzyloxy-carbonylamino-4-(2,4-dimethylphenyl)pentanoic acid; 2-benzyIoxy-carbonylamino-4-(2,5-dimethylphenyl)pentanoic acid; and 2-benzyloxy-carbonylamino-4-(2,4-dichlorophenyl)pentanoic acid.

The benzyloxycarbonyl group can be removed as deseribed in Example B belovv to give the corresponding free amino acid.

Example B

Synthesis of 2(S)-2,6-difluorophenylalanine

F

H₂N COOH

Step 1

N-(BenzyIoxycarbonyi)-a-phosphonoglycine trimethyl ester (Aldrich No. 37,635-3; 6.7 g, 20 mmol) and l,8-diazabicycio[5,4,0]undec-7-ene (Aldrich No. 13, 900-9; 3.3 mL, 22 mmol) vvere dissolved in methylene chloride (11 mL) and stirred at room temperature for 15 min, and then cooled to < -30 °C. A solution of 2,6-difluorobenzaldehyde (1.9 mL, 20 mmol) in methylene chloride (25 mL) vvas added to the reaction mixture dropvvise over 20 min. The reaction mixture vvas stirred for another 20 min, and then allovved to vvarm up to room temperature for 30 min. The reaction mixturewas then poured into ethyl ether (300 mL) and vvashed vvith 1 N HCI, brine and dried over MgSCL. Rotary evaporation gavē crude 2benzyloxycarbony!amino-3-(2,6-difluorophenyl)acrylic acid methyl ester vvhich vvas purified by chromatography on a Medium Pressure Liquid Column (MPLC) eluting vvith 20% ethyI acetate/ 80% hexane to give pure product (5 g, 72% yiel<Ļ liquid).

Step 2

A mixture of 2-benzyloxycarbonylamino-3-(2,6-difluorophenyl)acrylic acid methyl ester (14.4 mmoi), and catalyst, (+)-1,2-bis-[(25, 55)2, 5-diethylphopholano]benzene (cyclooctadiene)rhodium (1) trifluoromethanesulfonate (Strem. Chemical No. 45-0151; 104 mg, 0.14mmol) was dissolved in ethanol (150 mL). Hydrogenation vvas performed at 50 psi H_? at room temperature over 2 days. The solvent vvas then removed by rotary evaporation to give 2(5)-benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid methyl ester.

Step 3

2(5)-Benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid methyl ester (5 g,

14.4 mmol) vvas dissolved in methanol (60 mL) and cooled on ice. 1 N NaOH (22 mL, 22 mmol) was added dropvvise over 15 min. The reaction mixture vvas removed from cooling bath and stirring vvas continued at room temperature for 4 h. The solvent vvas then removed by rotary evaporation and the residue vvas treated vvith vvater (100 mL) and then vvith 1 N HCI to adjust the pH to 4. The product vvas extracted vvith ethyl acetate (300 mL, 200 mL). Evaporation of the solvent and crystallization of the residue from methylene chloride/hexane gavē 2(5)benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid (4.6 g, 13.7 mmoi, 94% yield). Step 4

2(5)-BenzyIoxycarbonylamino-3-(2,6-difluorophenyl)propionic acid vvas hydrogenated at 50 psi in ethanol (25 mL) in the presence of 5% palladium on activated carbon (600 mg) for 24 h. The catalyst vvas removed by filtration through Celite® and the solvent evaporated to give a residue vvhich vvas crystalized from ethyl ether to give 2(5)-2,6-difluorophenylaIanine (2.2 g, mmol, 80% yield). 'H NMR (DMSO-d₆): δ 7.28 (m, IH), 7.0 (t, J= 7.6 Hz, 2H), 2.77 (m, 2H). MS: 202.2 (M+l), 199.7(M-1).

Example C

Synthesis of 2(7?5)-amino-4-methyl-4-phenylpentanoic acid

H₂N COOH

Step 1

4-Methyl-4-phenyl-l-pentene vvas prepared by reacting 2-phenyl-2-propanol vvith 3(trimethylsilyl)propene by the method of Celia, J. Org. Chem.. 1982, 47, 2125-2130.

Step 2

4-MethyI-4-phenyI-l-pentene vvas ozonolyzed at -78 °C in dichloromethane follovved by dimethyl sulfide quenching to give crude product vvhich vvas purified by silica gel chromatography to give 3-methyl-3-phenylbutanal vvhich vvas then converted to the title compound by proceeding as described in PCT application publication No. WO 2004/052921, Referenc C, on page 68 of the application.

Example D

Synthesis of 2(5)-benzyloxycarbonylamino-3-pyrazol-l -ylpropionic acid

The title compound vvas prepared by treating S-benzyloxycarbonylserine-3-lactone vvith pyrazole in acetonitrile at 60 °C for 16 h (see J. Am. Chem. Soc., 1985,107, 7105-7109).

Follovving the procedure described above, but substituting pyrazole vvith 1,2,4-triazole and 1,2,3-triazole provided 2(5)-benzyloxycarbonylamino-3-[1.2.4]-triazol-l-ylpropionic acid and 2(5)-benzyloxycarbonylamino-3-[1.2.3]-triazol-l-ylpropionic acid respectively.

Example E

Synthesis of 2(S)-(/er/-butoxycarbonyl)amino-3-thiazol-2-ylpropionic acid

H

To 2-/er/-butoxycarbonylamino-3-thiazol-2-ylpropionic acid methyl ester (500 mg, 1.75 mmol) in a mixture of acetonitrile (6 mL) and 0.2 M aqueous NaHCOj (12 mL) vvas added

Alcalase (2.4 L, 0.08 mL), and the solution vvas stirred vigorously at room temperature for about

2.5 h. The reaction mixture vvas then evaporated at 30 °C to remove acetonitrile, and the aqueous residue vvas vvashed vvith ether. The aqueous phase vvas acidified vvith 6N HCI to pH 3 and the soiution vvas extracted vvith ethyl acetate, The combined organic layers vvere then dried and evaporated to yield 2(S)-/erf-butoxycarbony!amino-3-thiazol-2-ylpropionic acid (204 mg).

Reference F

Synthesis of 4-amino-4-cyano-l-ethylpiperidine H2N_.CN

N

A mixture of l-ethyl-4-piperidone (13.2 mL, 100 mmol), ammonium chloride (21.4 g, 400 mmol), sodium cyanide (19.6 g, 400 mmol) and vvater (550 mL) vvas stirred at room temperature for 48 h. The pH of the reaction mixture vvas adjusted to 10.1 and the product vvas extracted vvith ethyI acetate. The organic extracts vvere vvashed vvith brine and dried over magnesium sulfate. Rotary evaporation of the soivent gavē a mixture of 4-amino-4-cyano-lethylpiperidine and 4-hydroxy-4-cyano-l-ethylpiperidine (7.67 g). This mixture of products vvas treated vvith 7M ammonia in methanol (20 mL) and allovved to stand at room temperature for 24 h. The methanol and excess ammonia vvere removed in vacuo and the residue vvas cooled to give 4-amino-4-cyano-l-ethylpiperidine as a crystalline solid (7.762 g).

Reference G

Synthesis of 2(S)-benzyloxycarbonylamino-3-(l-methylcyclopentyl)propionic acid

Step 1

1-Methylcyclopentanol (20 g, 0.2 mol) vvas added to hydrobromic acid (40 mL) at room temperature. After stirring for 1 h, the soiution vvas extracted vvith hexane and the hexane vvas vvashed vvith brine and dried vvith magnesium sulfate. After concentration of the organic layer,

20.5 g of l-methylcyclopentyl bromide vvas obtained.

Step 2

Tributyltin hydride (37.8 g, 130 mmol) vvas added at reflux to a 500 mL of flask charged vvith benzene (200 mL) vvas added Z-dehydro-Ala methyl ester (15 g, 64 mmol), 1methylcyclopentyl bromide (20.5 g) and AIBN (1.9 g). After 2 h, the solvent vvas removed and the residue vvas purified by column chromatograph to yield 2-benzyloxycarbonylamino-3-(lmethylcyclopentyl)propionic acid methyl ester (7.9 g).

Step 3

2-BenzyIoxycarbonylamino-3-(l-tnethylcyclopentyI)propionic acid methyl ester (7.6 g,

23.8 mmol) vvas dissolved in a mixture of acetonitrile (82 mL) and 0.2 M aqueous NaHCO₃ (158 mL) and Alcalase 2.4L (1.1 mL) vvas added and the reaction mixture vvas stirred vigorously for 8 h. The reaction mixture vvas then evaporated at 30 °C to remove acetonitrile, and the aqueous residue vvas vvashed vvith ether. The ethereal layer vvas concentrated to yield (J?)-2benzyIoxycarbonylamino-3-(l-methylcyclopentyl)propionic acid methyl ester (1.9 g). The aqueous phase vvas filtered vvith Celite®, the pH vvas adjusted to 3 vvith 6N HCI, and the solution vvas extracted vvith ethylacetate. The ethyl acetate layer vvas dried and evaporated to yield 2(S)benzyloxycarbonylamino-3-(l-methyicyclopentyl)propionic acid (1.4 g).

Reference H

Synthesis of trifluoromethanesulfonic acid 2,2,2-trifluoro-l-(4-fluorophenyI)ethyI ester

Step 1

To a stirred solution of 2,2,2,4’-tetrafIuoroacetophone (10 g, 52.1 mmol) in methanol (50 mL) vvas added NaBfL (0.98 g, 26.5 mmol) at 0° C. After stirring at 25° C for 2 h, the reaction mixture vvas quenched by adding IN HCI (100 mL) and then extracted vvith ethyI ether. The ether extract vvas vvashed vvith brine, dried vvith MgSO₄, and concentrated to give 2,2,2-trifluorol-(4-fluorophenyl)ethanol (11.32 g) vvhich vvas used in next step vvithout further purificaiton. Step 2

NaH (640 mg, 16mmol, 60% in mineral oil) vvas vvashed tvvice vvith hexane (20 mL) and then suspended in dried diethyl ether (20 mL). A solution of 2,2,2-trifluoro-l-(4-fluoropheny!)ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) vvas added at 0°C. After stirring for 2 h at room temperature, a solution of trif!uoromethanesulfony! chloride (1.68 g, 10 mmol) in diethyl ether (10 mL) vvas added. After 2 h, the reaction mixture vvas quenched by adding a solution of NaHCO₃ and the product vvas extracted vvith diethyl ether. The extracts were vvashed vvith brine and dried, and the solvent vvas removed to yield trifluoromethanesulfonic acid 2,2,2-trifIuoro-l-(4-fluorophenyl)ethyl ester (3.3 g).

Proceeding as described in Example H above, trifluoromethanesulfonic acid 2,2,2trifluoro-l-phenylethyl ester vvas prepared.

Reference I

Synthesis of 2,2,2-trifluoro-l (R) -(4-fluorophenyI)ethanol

ĢF₃

ΌΗ

To a -78 °C toluene (25 mL)/dichloromethane (25 mL) solution of 2,2,2,4’tetrafluoroacetophenone (2.5 g, 13.01 mmol) and IM S-CBS catalyst (1.3 mL, 1.3 mmol) vvas added freshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture vvas maintained at -78 °C for 16 h at vvhich time 4N HCI (5 mL in dioxane) vvas added and the reaction mixture vvas allovved to vvarm to room temperature. The reaction mixture vvas diluted vvith ethyl acetate and vvashed vvith a saturated brine solution. The organic laver vvas dried over magnesium sulfate, filtered and concentrated to provide a solid. The solid vvas suspended in hexanes and filtered off. The hexanes filtrate containing the desired product vvas concentrated and the residue subjected to fiash chromatography (10 hexanes: 1 ethylacetate) to provide the title compound as colorless oil (2.2g, 87% yield). The ratio of enantiomers vvas determined to be 95:5 by chiral HPLC (Chiralcel OD column, 95 hexanes: 5 isopropanol mobile phase. Ret. time major product 6.757 min. Ret. time minor isomer 8.274 min.).

Reference J

Synthesis of 2(R)-3-cyclopropylmethylsulfanyl-2-(2,2,2-trifluoro-l(A5)-phenylethylamino)propan-l -ol

S

OH

Li V 1J44U

Step 1

An ice vvater bath cooled solution of L-cysteine in IN sodium hydroxide (740 mL) and dioxane (740 mL) vvas treated vvith bromomethylcyciopropane (50 g, 370 mmol). The reaction mixture vvas allovved to vvarm to room temperature and stirred for 16 h. Dioxane vvas removed under reduced pressure and the resulting aqueous solution was adjusted to pH 6 vvith 6N HCI and placed in a refrigerator for 20 h. The product vvas collected by vacuum filtration, vvashed vvith hexanes and lyophilized to give 2(/?)-amino-3-cycIopropyimethylsulfanyIpropionic acid (57.28 g) as a vvhite solid.

Step 2

To an ice vvater cooled solution of lithium aluminum hydride (200 mLof l.G-M) vvas added solid 2(7?)-amino-3-cyclopropylmethylsuIfanylpropionic acid. The addition vvas done by tapping in portions through a funnel in such a manner as to control hydrogen gas evolution.

The ice bath vvas removed, and the reaction mixture vvas heated at reflux for 16 h. The reaction mixture vvas removed from heat and cooled in an ice vvater bath. Diethyl ether (110 mL) vvas added, follovved by dropvvise addition of vvater (5 mL), 15% aqueous sodium hydroxide (5 mL), and vvater (15 mL). After stirring in the ice vvater bath for 1.5 h, the reaction mixture vvas filtered. The filtrate vvas dried over anhydrous sodium sulfate, and concentrated to give 2(7?)amino-3-cyclopropylmethylsulfanyI-propan-l-ol (14.9 g).

Step 3

To a stirred solution of 2(7?)-amino-3-cyclopropylmethylsulfanylpropan-l-ol (80.5 mg, 0.5 mmol) in anhydrous THF (3 mL) vvere added activated 4A molecular sieves (250 mg) and Nmethylmorpholine (51 mg, 0.5 mmol). After stirring for lOmin, trifluoromethanesulfonic acid 2,2,2-trifluoro-l -phenylethyl ester (190.5 mg, 0.5 mmol) vvas added and the reaction vvas stined at room temperature for 2 days. The reaction mixture vvas filtered and the filtrate vvas concentrated. The residue vvas purified by flash column chromatography to afford the desired mixture of diastereomers of 2(7?)-3-cyclopropylmethyl-sulfanyl-2-(2,2,2-trifluoro-l(7?5)phenylethylamino)-propan-l-ol. LC-MS: 318.3(M-1), 320.8(M+l).

Reference K

Synthesis of l-aminocyclopropanecarbonitrile hydrochloride

H_ZN CN

Δ HCI

Step 1

A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) vvas stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture vvas filtered to remove the precipitated ammonium chloride and the filtrate vvas evaporated to dryness in vacuo. The resulting residue vvas dissolved in ether (400 mL) vvashed vvith vvater (200 mL) and brine. After drying over magnesium sulfate the solution vvas evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g).

Step 2

A solution of sodium hydroxide (91 g, 2.275 mol) in vvater (91 mL) in a 2L flask vvas cooled on ice under nitrogen and then treated vvith benzyl triethyi ammonium chloride (2.0 g, 0.0088 mol, Aldrich ) and (benzhydrylideneamino)acetonitrile (47.89 g) in toluene (100 mL).

1,2-Dibromoethane (23 mL, 122.4 mmol, Aldrich) vvas then added dropvvise over 25 min, to the reaction mixture vvith mechanical stirring and cooling to maintain the internai temperature near +10 °C. The reaction mixture vvas then stirred vigorously for 24 h at room temperature and then poured into ice vvater and extracted vvith toluene. The combined extracts vvere vvashed vvith brine and then treated vvith MgSO4 and Norite. After fīltering, toluene vvas removed by rotary evaporation to give an oil (67 g). The residue vvas dissolved in boiling hexane (400 mL), treated vvith Norite and filtered hot and allovved to cool. A dark oil separated and vvhich vvas removed by pipet (~2 mL). Scratching induced crystallization in the remaining solution vvhich vvas cooled on ice for 2 h. Light yellow crystals vvere collected by filtration and vvashed vvith cold hexane to give l-(benzhydrylideneamino)cyclopropanecarbonitrile (30.56 g).

Step 3

A mixture of l-(benzhydrylideneamino)cyclopropanecarbonitrile (30.56 g, 0.124 mol) in concentrated HCI (12 mL) in vvater (100 mL) and ether (100 mL) vvas stirred at room temperature for 15 h. The ether layer vvas discarded and the aqueous Iayer vvas vvashed vvith ether. The aqueous layer vvas then freeze dried to give the title compound as a tan povvder (13.51 g).

Reference L

Synthesis of 2(R)-amino-3-[2-(difluoromethoxy)phenylmethanesulfanyl]propionic acid

H₂

o

A solution of L-cysteine (5.1 g, 42.2 mmol) in 2N NaOH (42.2 mL) vvas cooled in an ice vvater bath. Neat 1 -bromomethyl-2-difluoromethoxybenzene (10 g, 42.2 mmol) vvas added and the reaction mixture vvas allovved to stir and vvarm to room temperature over 4 h. The reaction mixture vvas cooled in an ice bath and the pH vvas adjusted 6 using 3N HCI, then IN HCI vvhen the vvhite precipitate that formed became too thick to allovv stirring. The precipitates vvere collected by vacuum filtration, vvashed vvith hexanes and dried by lyophilization to give the title compound (11.14 g) as a vvhite solid.

Reference M

Synthesis of 4-amino-l-(2,2,2-trifluoroethyI)piperidine-4-carbonitrile hydrochloride H₂N .CN .HCI cf₃

Step 1

In a solution of l,4-dioxa-8-aza-spiro[4.5]decane (14.3 g, 100 mmol) in CH2CI2 (200 mL) vvas added Et₃N (15.2 g, 150 mmol), DMAP (30 mg) and trifloroacetic acid anhydride (25.2 g, 150 mmol) at 0 °C, then allovved to warm-up to room temperature and stirred for 12 h. The reaction mixture vvas quenched vvith vvater and vvashed vvith IN HCI and brine, dried vvith MgSO₄. Removal ofthe solvent, yielded l-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2,2,2trifluoroethanone (35 g). The crude product vvas used in the next reaction.

Step 2

In the solution of l-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2,2,2-trifluoroethanone (20 g, 83.7 mmol) in THF, borane-methyl sulfide complex (83.7 mL, 2M solution in THF ) vvas added at 0 °C. After refluxing the reaction mixture for 12 h, the reaction vvas cooled and quenched vvith MeOH. After removal of THF, the residue vvas extracted vvith ethy I acetate and vvashed vvith brine, dried vvith MgSO₄ and concentrated to give 8-(2,2,2-trifluoroethyl)-l,4-dioxa-8-azaspiro[4.5]decane (19 g) vvas obtained.

Step 3

8-(2,2,2-Trifluoroethyl)-l,4-dioxa-8-aza-spiro[4.5]decane (3.7g, 16mmol) was added to a solution of 5% HCI (45 mL) and acetone (8 mL). After refluxing for 12h, the solvent vvas removed to give crude 1 -(2,2,2-trifluoroethyl)piperidin-4-one hydrochloride vvhich vvas used in the next reaction.

Step 4

A solution of ammonium chloride (3.2 g, 60 mmol) and potassium cyanide (2.94 g, 60 mmol) vvas prepared in vvater (25 mL) and l-(2,2,2-trifluoroethyl)-piperidin-4-one hydrochloride (3.5 g, 15 mmol) vvas added and the reaction mixture vvas stirred for 2 days. The solution vvas then brought to ρΗ 11 vvith sodium carbonate and the reaction mixture vvas extracted vvith ethyl acetate. After drying over Na₂SO4, the solvent vvas removed to yield a mixture of 4-hydroxy-l(2,2,2-trifluoroethyl)piperidine-4-carbonitrile and 4-amino-l -(2,2,2-trifluoroethyl)piperidine-4carbonitrile. This mixture vvas then treated vvith 7N ammonia solution in MeOH for 12 h at room temperature. After removal of the solvent, the residue vvas dissolved in ethyl ether and treated vvith 4N HCI solution in dioxane. The solīds vvere filtered and dried under vacuum, to yield 4-amino-l-(2,2,2-trifluoroethyl)piperidine-4-carbonitrile hydrochloride (2.5 g).

Example 1

Synthesis ofjV-(l-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(RS)thiophen-2-yl-ethylamino)propionamide

Step 1

To a cold (0°C), stirred solution of 2(/?)-amino-3-phenylmethanesulfanylpropionic acid (commercially available) (4.01 g, 19.0 mmol) in methanol (100 mL) vvas introduced HCI gas for 15 min and the reaction mixture vvas sealed and stirring vvas continued at rt overnight. The solvent vvas then evaporated under vacuum to give methyl 2(7?)-amino-3-phenylmethanesulfanylpropionate HCI in quantitative yield (4.98 g).

Step 2

A mixture of methyl 2(/?)-amino-3-phenylmethanesulfanylpropionate HCI salt (4.95 g,

18.9 mmol) and trifiuoroacetaldehyde methyl hemiacetal (3.12 g, 24.0 mmol) containingp64 toluenesulfonic acid (0.19 g) in benzene (60 mL) vvas stirred at rt ovemight. The reaction mixture vvas diluted vvith ethyl acetate (100 mL), vvashed vvith 100% sodium bicarbonate, and then vvater. The organic phase vvas dried (MgSOJ and the solvent was removed under reduced pressure to give methyl 3-phenylmethanesulfanyl-2(/?)-(2,2,2-trifluoro-l(/?S)hydroxyethylamino)-propionate as a mixture of diastereomers in about 3 : 2 ratio. This crude material vvas used for the next step vvithout purification.

Step 3

To a cold (0 °C) stirred mixture of methyl 3-phenylmethanesulfanyI-2(/?)-(2,2,2trifluoro-l(7?S)-hydroxyethylamino)propionate (524 mg,l .65 mmol) and thiophene (415 mg, 4.95 mmol) in dichlomethane (3 mL) vvas added BF₃.Et₂O (0.25 mL, 1.98 mmol) dropvvise via a micro syringe and the reaction mixture vvas allovved to vvarm to rt over 1 h. After being stirred at rt for additional 4 h, the reaction mixture vvas quenched by addition of about 0.2 mL methanol. The reaction mixture vvas stirred for 5 min, diluted vvith dichloromethane, and partitioned vvith vvater. The combined organic extracts vvere dried (MgSO₄), concentrated under reduced pressure, and the residue vvas purified by flash chromatography on silica gel (eluted vvith l: 6 EtOAc/ hexanes) to yield methyl 3-phenylmethanesulfanyl-2(K)-(2,2,2-trifluorol(/?S)-thiophen-2-yl-ethylamino)propionate (200 mg) as a mixture of diastereomers in a 3: 2 ratio.

Step 4

To a stirred solution of the methyl 3-phenylmethanesuIfanyl-2(/?)-(2,2,2-trifluoro-l(J?S)thiophen-2-yl-ethylamino)-propionate (200 mg, 0.514 mmol) in methanol (3 mL) at room temperature vvas added aqueous IN KOH solution (0.77 mL). After being stirred ovemight, the reaction mixture vvas concentrated, diluted vvith vvater (5 mL), acidified vvith IN HCI (pH = ca. 3), and then extracted vvith ethyl acetate. The combined organic layers vvere dried over MgSO₄, and concentrated to give 3-phenyImethanesuIfanyl-2(/?)-(2,2,2-trifIuoro-l(/?S)-thiophen-2-ylethylamino)-propionic acid (191 mg) vvhich vvas used directly vvithout further purification.

Step 5

To a solution of 3-phenylmethanesulfanyl-2(/?)-(2,2,2-trifluoro-l(/?S)-thiophen-2-ylethylamino)propionic acid (190 mg, 0.52 mmol), l-aminocyclopropanecarbonitrile HCI salt (92 mg, 0.78 mmol) in DMF (3 mL) at rt vvas added HATU (237 mg, 0.624 mmol), follovved by diisopropylethylamine (0.45 mL, 2.6 mmol). After being stirred at rt ovemight, the reaction mixture vvas concentrated under reduced pressure and then partitioned betvveen ethvl acetate and brine. The combined organic extracts vvere dried (MgSO₄), concentrated under reduced pressure, and the residue vvas purified by flash chromatography on silica gel (eluted vvith 1: 2 EtOAc/ hexanes) to yield 3-phenylmethanesulfanyl-A-(l-cyanocyclopropyl)-2(/?)-(2,2,2-trifluoro-l(7?S)thiophen-2-yIethy!amino)-propionamide (164 mg) as a mixture of diastereomers in a 3: 2 ratio. 'H NMR for a major isomer (400 MHz, CDClj): δ 7.8-6.95(9H, m) 4.39(1 H, q), 3.78(2H, s), 3.35(1H, s), 2.82(2H, m), 1.65-1,01(4H, m). MS: 440.1(M+l).

Step 6

A solution of ΟΧΟΝΕ® (290 mg, 0.47 mmol) in vvater (1.5 mL) vvas added to a solution of 3-phenylmethanesulfanyI-A-(I -cyanocyclopropyl)-2(7?)-(2,2,2-tri fiuoro-1 (7?S)-thiophen-2ylethylamino)propionamide (159 mg, 0.362 mmol) in methanol (3 mL). The reaction mixture vvas stirred at rt for 4h and then removed the solvent under reduced pressure. The residue obtained vvas partitioned betvveen ethy 1 acetate and brine. The combined organic extracts vvere dried (MgSO₄), concentrated under reduced pressure. The crude vvas purified by passing through a short pad of a Celite® to give the title compound as a mixture of diastereomers in a 3: 2 ratio.

’H NMR (400 MHz, CDCb): δ 7.57(1H, s), 7.40-7.25 (6H, m), 7.00 (IH, d), 6.89 (IH, t), 4.58 (IH, q), 4.48-4.19 (2H, m), 3.69 (lH,m), 3.30(lH, dd), 3.09 (IH, dd),1.45-0.79 (4H, m). MS: 472.5(M+1).

Proceeding as described above, the follovving compounds were prepared: jV-(l-cyanocyclopropyl)-3-pheny[methanesulfony!-2(7?)-(2,2,2-trifluoro-l(7?S)-furan-2yl-ethylamino)propionamide as a mixture of diastereomers in a 3: 2 ratio. ^!H NMR (400 MHz, DMSO-d6): δ 9.01(1 H, s), 7.63(1H, s), 7.39(5H, m), 6.60-6.40(2¾ m), 4.58(2H, m), 4.45(1H, m), 3.69(1H, m), 3.80-3.05(3H, m), 3.09(lH, dd),1.45-0.79(4H, m). MS: 456.0 (M+l).

A-(l-cyanocyclopropyI)-3-phenylmethanesulfonyl-2(7?)-[2,2,2-trifluoro-l(5)-(l-methyll//-pyrrol-2-yl)ethylamino]propionamide.

’H NMR (400 MHz, CDCb): δ 7.50-7.35(6H, m), 6.56(1H, m), 6.06(1 H, m), 4.45(2H, m), 4.22(1H, q), 3.73(1H, dd), 3.33(1H, dd), 3.04(lH, dd), 1.55-1.00(4H, m). MS: 469.2 (M+l).

N-( 1 -cyanocyclopropyl)-3-pheny lmethanesulfonyl-2(A)-[2,2,2-trifluoro-1 (6)-(4hydroxy-pheny!)ethylamino]propionamide.

^lH NMR (400 MHz, DMSO-d₆): δ 9.60(1 H, s), 9.02(lH, s), 7.40 (5H, m), 7.I8(2H, m), 6.73(2H, m), 4.7O(1H, d), 4.5O(1H, d), 4.21(m, IH), 3.69(1H, m), 3.45-3.09(3H, m), 1.400.60(4H, m). MS: 482.1(M+1).

N-(l -cyanocyclopropyI)-3-phenylmethanesulfonyl-2(/?)-[2,2,2-trifluoro-l (2?S)-( 1Hindol-3-yl)ethylamino]propionamide as a mixture of diastereomers in a 5: 4 ratio.

'HMR (400 MHz, CDCb): δ 8.40 (s, IH), 7.60-7.0(10H, m), 4.58(1H, m), 4.384.05(2H, m), 3.62(1H, m), 3.80-2.95(4H, m),1.40-0.69(4H, m). MS: 505.4(M+l).

jV-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(7Z)-(2,2,2-trifluoro-l(J?S)-lphenylsulfonylpyrrol-2-ylethylamino)propionamide (using commercially available 1phenylsulfonylpyrrole). MS: 559.3 (M+l).

A^r-(l-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(7?)-(2,2,2trifluoro-l(/iS)-l-phenylsulfonylpyrrol-2-yIethylamino)propionamide. MS: 661.6 (M+l).

M(1 -cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(7?)'(2,2,2-trifluoro-l (S)-l methylpyrrol-2-ylethylamino)propionamide. MS: 432.9 (M+l).

77-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(7?S)thiophen-2-yl-ethylamino)propionamide. MS: 436.2 (M+l).

jV-(l-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(/?)-(2,2,2trifluoro-l(.RS)-thiophen-2-ylethylamino)propionamide. MS: 538.2 (M+l)

V-(l-cyanocyclopropyl)-3-(l-methylcyclopentyl)-2(.S)-(2,2,2-trifluoro-l(S)-3-fluoro-4hydroxyphenylethylamino)propionamide. MS: 428.1 (M+l).

M-( 1 -cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1 (S)-3-chloro-4hydroxyphenylethylamino)propionamide. MS: 516.3 (M+l).

V-( 1-cyanocyclopropyl)-3-( 1-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-1 (S)-4-hydroxyphenylethylamino)propionamide. MS: 410.2 (M+l).

M(l-cyanocyclopropyl)-3-(l-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-I(5)-2-hydroxyphenylethylamino)propionamide. MS: 410.2 (M+l).

7V-(l-cyanocyclopropyI)-3-(l-methylcyclopenty 1)-2(5)-(2,2,2-trifIuoro-I(/?)-thiophen-2yl-ethylamino)propionamide. MS: 400.2 (M+l).

V-(I-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(5)methylethylamino)propionamide. MS: 404.1 (M+l).

A^r-(I-cyanocyclopropyl)-3-phenyImethanesulfanyl-2(7?)-(2,2,2-trifluoro-l(S)-4-hydroxyphenylethylamino)propionamide. MS: 450.2 (M+l).

N-( 1 -cyanocyclopropyl)-3-phenylmethanesulfanyl-2(7?)-(2,2,2-trifluoro-1 (&S)-furan-2ylethylamino)propionamide. MS: 424.0 (M+l).

jV-(l-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(J?)-(2,2,2-trifluoro-l(AS)-indol-3yl-ethylamino)propionamide. MS:473.4 (M+l).

jV-(l-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(7?)-(2,2,2-trifluoro-l(7?5)-thiophen2-ylethyl-amino)propionamide. MS: 440.1 (M+l).

V-(l-cyanocyclopropyl)-3-phenylmethanesulfonyI-2(7?)-(2,2,2-trif]uoro-l(AS)-thiophen2-ylethylamino)propionamide. MS: 472.5 (M+l).

V-(l-cyanocyclopropyl)-3-(l-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-l(S)-thiophen-267 ylethylamino)propionamide. MS: 422.4 (M+23).

JV-(l-cyanocyclopropyl)-3-(l-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-l(R)-4-hydroxyphenylethylamino)propionamide. MS: 410.2 (M+l).

A^r-(l-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(R)-(2,2,2-trifluoro-l(R)-3-chloro-4hydroxyphenylethylamino)propionamide. MS: 484.2 (M+l).

N-( 1 -cyanocyclopropyI)-3-phenylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1 (S)-3-chloro-4hydroxy-phenylethylamino)propionamide. MS: 484.2 (M+l).

,V-(l-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-l(/?)-3-chloro-4hydroxyphenylethylamino)propionamide. MS: 516.3 (M+l).

Y-(l-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfanyl)-2(R)-(2,2,2trifluoro-l(R5)-thiophen-2-ylethylamino)propionamide. MS: 506.3 (M+l).

y-(l-cyanocyclopropyI)-3-cyclopropylmethanesulfanyl-2(7?)-(2,2,2-trifluoro-l(R5)thiophen-2-yl-ethylamino)propionamide. MS: 404.1 (M+l).

//-( 1 -cyanocyclopropyi)-3-cyclopropylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-1 (5)-1 -oxol-methylpyirol-2-ylethylamino)propionamide. MS: 449.2 (M+l).

Proceeding as described above but substituting trifluoroacetaldehyde methyl hemiaceta! vvith difluoroacetaldehyde ethyl acetal and 2(/?)-amino-3-phenylmethanesulfanylpropionic acid vvith 2(S)-benzyloxycarbonylamino-3-(l-methylcyclopentyl)propionic acid provided jV-(lcyanocyclopropyl)-3-(l-methylcyclopentyl)-2(S)-(2,2-difluoro-l(R)-thiophen-2-yIethylamino)propionamide. ’HNMR (DMSO-ds): δ 8.80 (IH, s), 7.56 (IH, dd), 7.08 (IH, m), 7.03 (IH, m), 6.07 (IH, dt), 4.15 (IH, m), 3.23 (IH, m), 1.50 (12H, m), 0.95 (2H, m), 0.94 (3H, s).

Proceeding as described above but substituting trifluoroacetaldehyde methyl hemiacetal vvith difluoroacetaldehyde ethyl acetal provided Y-(l-cyanocyclopropyl)-3phenylmethanesulfanyl-2(R)-(2,2-difluoro-l(7?5)-thiophen-2-yl-ethylamino)propionamide. ’HNMR (DMSO-d₆): δ 8.92-8.88 (IH, s), 7.61-7.55 (IH, d), 7.30 (5H, m), 7.10 (2H, m), 6.11 (IH, dt), 4.35-4.20 (IH, m), 3.30-3.20 (IH, m), 2.88-2.81 (IH, m), 2.64 (IH, m), 2.58 (2H, m), 1.52-145 (2H, m), 1.16 (IH, m), 1.00 (IH, m). LC/MS: M+l: 422.2.

jV-(l-cyanocyclopropyI)-3-phenylmethanesulfanyl-2(R)-(2,2-difluoro-l(R5)-thiophen-2yl-ethylamino)propionamide vvas oxidized as described above and 2V-(l-cyanocyc!opropyl)-3phenyImethanesulfanyI-2(7?)-(2,2-difluoro-l(R)-thiophen-2-yl-ethylamino)propionamide. ’HNMR: δ9.01-9.04 (IH, s), 7.62-7.56 (IH, dd), 7.40 (5H, m), 7.14 (IH, m), 7.09-7.05 (IH, m), 6.18 (IH, dt), 4.73 (IH, m), 4.55 (IH, m), 4.40-4.25 (IH, m), 3.40-3.25 (IH, m), 3.40 (3H, m),

3.20 (1H, m) 1.50 (2H, m), 1.10 (2H, m). LC/MS, M+l: 454.1.

Example 2

Synthesis of7/-(l-cyanocyclopropyl)-3-cycIopropylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(5)phenylethylamino)propionamide

CN

Step 1

An ice vvater bath cooled solution of L-cysteine in IN sodium hydroxide (740 mL) and dioxane (740 mL) vvas treated vvith bromomethyicyclopropane (50 g, 370 mmol). The reaction mixture vvas allovved to vvarm to room temperature and stirred for 16 h. Dioxane vvas removed under reduced pressure and the resulting aqueous solution vvas adjusted to pH 6 vvith 6N HCI and placed in a reffigerator for 20 h. The product vvas collected by vacuum filtration, vvashed vvith hexanes and lyophilized to give 2(7?)-amino-3-cyclopropylrnethylsulfanylpropionic acid (57.28 g) as a vvhite solid.

Step 2

To an ice vvater cooled solution of lithium aluminum hydride (200 mL of 1.0 M) vvas added solid 2(/?)-amino-3-cycIopropyImethyIsu!fanyIpropionic acid. The addition vvas done by tapping in portions through a funnel in such a manner as to control hydrogen gas evolution.

The ice bath vvas removed, and the reaction mixture vvas heated at reflux for 16 h. The reaction mixture vvas removed from heat and cooled in an ice vvater bath. Diethyl ether (110 mL) vvas added, follovved by dropvvise addition of vvater (5 mL), 15% aqueous sodium hydroxide (5 mL), and vvater (15 mL). After stirring in the ice vvater bath for 1.5 h, the reaction mixture vvas filtered. The filtrate vvas dried over anhydrous sodium sulfate, and concentrated to give 2(7?)amino-3-cyclopropylmethylsulfanyl-propan-l-ol (14.9 g).

Step 3

A solution of 2(7?)-amino-3-cyclopropyimethyisuifanylpropan-!-oi (14.9 g, 93 mmol), Zert-butyldimethylchlorosilane (15.4 g, 102 mmol), 4-(77,77-dimethylamino)pyridine (182 mg, 1.49 mmol) and triethylamine (20.7 mL, 149 mmol) in dichloromethane (190 mL) vvas stirred at room temperature for 3.5 h. Saturated ammonium chloride (300 mL) vvas added and the layers vvere separated. The aqueous Iayer vvas extracted with dichloromethane and the combined organic layers vvere vvashed vvith brine, dried over anhydrous sodium sulfate, and concentrated to give 1 -(/eri-butyldimethylsilanyIoxy)-2(7?)-cyclopropylmethylsulfanylmethylethylamine (24.06 g).

Step 4

A mixture of l-(terf-butyldimethylsilanyloxy)-2(/?)-cyclopropylmethylsulfanylmethylethylamine (24 g, 87.5 mmol), trifluoroacetaldehyde methyl hemiacetal (11.4 g, 87.5 mmol) and toluene (90 mL) vvas heated at reflux vvith Dean Stark trapping of vvater for 22 h. The reaction mixture vvas concentrated and chromatographed on silica gel using 9:1 hexanes:ethyl acetate to give [l-(tert-butyIdimethyIsilanyloxy)-2(/?)cyclopropylmethylsulfanylmethylethyl]-(2,2,2-trifIuoro-ethylidene)amine (22.5 g) as a pale tan oil.

Step 5

To a solution of phenyllithium (6 mL of 1.8 M solution in di-n-butyl ether, 10.8 mmol) and anhydrous tetrahydrofuran (19.5 mL) cooled in a dry ice acetone bath vvas added butyldimethylsilanyloxy)-2(A)-cyclopropylmethylsulfanylmethylethyl]-(2,2,2trifluoroethylidene)-amine (3.55 g, 10.0 mmol) in anhydrous tetrahydrofuran (4.9 mL) dropvvise. The reaction mixture vvas then transferred to an acetonitrile dry ice bath and allovved to stir for

2.5 h. It vvas then ķept in a freezer for 12 h. The reaction mixture vvas poured into ice and saturated ammonium chloride and vvas extracted vvith ethyl acetate. The organic layer vvas dried over anhydrous sodium sulfate, concentrated to give [l-(ierz-butyldimethylsilanyloxymethyl)2(/?)-cyclopropylmethyl-sulfanylethyl]-(2,2,2-trifluoro-l(S)-phenylethyI)amine and [l-(/er/butyldimethylsilanyloxymethyl)-2(7?)-cyclopropylmethyl-sulfanylethyl]-(2,2,2-trifluoro-l(A)phenylethyl)amine (5.65 g) as a approx. 2:1 mixture vvhich vvas used in the next step vvithout further purification.

Step 6

To an ice vvater bath cooled anhydrous tetrahydrofuran solution (25 mL) of[l-(/e/7butyIdimethyIsilanyloxymethyl)-2(/?)-cyclopropylmethyl-sulfanyIethyl]-(2,2,2-trifIuoro-l(5)pheny!ethyl)amine and [1 -(/erz-butyldimethylsilanyloxymethyl)-2(7?)-cyclopropylmethylsulfanylethyl]-(2,2,2-trifIuoro-l(A)-phenyiethyl)amine vvas added tetrabutylammonium fluoride (10 mL of 1.0 M) in tetrahydrofuran dropvvise. The reaction mixture vvas placed in a 4°C freezer for 16 h and then poured into cold saturated ammonium chloride and vvas extracted vvith ethyl acetate. The organic layer vvas vvashed vvith vvater and brine, dried over anhydrous sodium sulfate and concentrated to a liquid product that vvas further purified by silica gel chromatography using 4:1 hexanes:ethyl acetate eluent to give a mixture of3-cyclopropylmethyIsulfanyI-2(/?)-(2,2,2-trifluoro-l(5)-phenylethyIamino)propan-l-ol and 3cyclopropylmethylsulfanyl-2(7?)-(2,2,2-trifluoro-l(7?)-phenylethylamino)propan-l-oI (1.91 g) as a pale yellow oil.

Step 7

To an ice vvater bath cooled solution of 3-cyclopropylmethylsulfanyl-2(/?)-(2,2,2trifluoro-15-phenylethylamino)propan-l-ol and 3-cyclopropylmethylsulfanyl-2(7?)-(2,2,2trifluoro-l(7?)-phenylethylamino)propan-l-ol (1.75 g, 5.5 mmol) in anhydrous acetonitrile (26 mL) vvas added HsIOs/CrOj (26.3 mL of 0.41M) in acetonitrile [Note: HsIOe (11.4 g, 50 mmol), C1O3 (23 mg) and anhydrous acetonitrile (114 mL) vvere stirred at room temperature for 3 h before use]. The cooling bath vvas removed and the reaction mixture vvas stirred for 4 h. An additional oxidant solution (5 mL) vvas added and the reaction mixture vvas stirred an additional 0.5 h. Saturated aqueous KH2PO4 (50 mL) vvas added and the reaction mixture vvas extracted vvith ethyl acetate. The combined organic layers vvere vvashed vvith 1:1 vvater: brine, then 1:1 dilute NaHSOj, brine, dried over anhydrous sodium sulfate, and concentrated. The crude product vvas dissolved in saturated sodium bicarbonate vvashed vvith diethyl ether. This diethyl ether layer contained some unreacted alcohol starting material. The aqueous layer vvas pH adjusted to 4.3 vvith 6N HCI and extracted vvith ethyl acetate. The organic Iayers vvere dried over anhydrous sodium sulfate, concentrated to give a mixture of 3-cyclopropylmethanesuIfonyl-2(J?)-(2,2,2-trifluoro-l(5)-phenylethylamino)-propionic acid and 3-cyclopropyimethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(J?)-phenylethylamino)-propionic acid (150 mg).

Step 8

A solution of 3-cyclopropylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(S)phenylethy!amino)-propionic acid and 3-cyclopropylmethanesulfonyI-2(/č)-(2,2,2-trifluoro-l(/?)phenylethylamino)-propionic acid (140 mg, 0.38 mmol), I-aminocyc!opropanecarbonitrile hydrochloride (45 mg, 0.38 mmol) HATU (173 mg, 0.4 6mmol) and Y-methylmorpholine (100 pL, 0.91 mmol) in anhydrous DMF (0.75 mL) vvas stirred at room temperature for 16 h. The reaction mixture vvas partitioned betvveen ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer vvith extracted again vvith ethyi acetate. The combined ethyl acetate layers vvere vvashed vvith brine, dried over anhydrous sodium sulfate, and concentrated. The crude product vvas purified by silica gel chromatography using 1:1 hexanes: ethyl acetate to give a fraction that vvas further purified by crystallization from diethyl ether and hexanes to give jV-(l-cyanocyclopropyI)-3-cyclopropyl-methanesulfonyl-2(/?)-(2,2,2-trifluoro-l(5)phenylethylamino)propionamide (6.77 mg).

CDCIj, 400MHz. δ 7.59 (IH, br s), 7.44 (3H, m), 7.39 (2H m), 4.38 (IH, q, J=6.8Hz), 3.68 (IH, m), 3.64 (IH, dd, J=14.0Hz, 6.4Hz), 3.39 (IH, dd, J=14.4Hz, 4.0Hz), 3.03 (2H, d, J=7.2Hz), 1.57 (2H, m), 1.21 (3H, m), 0.79 (2H, m), 0.49 (2H, m).

Proceeding as described above, but using commercially available 2(/?)-amino-3benzylsulfanylpropan-l -ol, 7/-(1 -cyanocyclopropyl)-3-phenylmethanesulfonyI-2(/?)-(2,2,2trifluoro-l(5)-phenylethylamino)propionamide vvas prepared. MS: 466.2 (M+l); 488.1 (M+23);

464.1 (M-l).

Proceeding as described above, but substituting l-aminocyclopropanecarbonitrile hydrochloride vvith 4-amino-4-cyano-l-ethylpiperidine hydrochloride salt and 2(7?)-amino-3cyclopropylmethylsulfanyl-propan-l-ol vvith 2(7?)-amino-3-benzylsulfanylpropan-l-ol provided yV-(4-cyano-l-ethylpiperidin-4-yl)-3-cyclopropylphenylmethanesulfonyl-2(/?)-(2,2,2-trifluorol(5)-phenylethylamino)propionamide.

Proceeding as described in Example 2 above but substituting l-aminocyclopropanecarbonitrile vvith l-aminotetrahydrothiopyran-4-ylcarbonitrile (prepared as described in J. Med. Chem., 1978, 1070 or PCT application publication No. WO 01/19816 as described on page 141, Example 2 substituting tetrahydropyran-4-one vvith tetrahydrothiopyran-4-one) and 2(Ā)-amino3-cyclopropyImethylsulfanylpropan-l-ol vvith 2(7?)-amino-3-benzylsulfanylpropan-l-ol provided /V-(4-cyanotetrahydrothiopyran-4-yl)-3-phenylmethanesulfanyl-2(/?)-(2,2,2-trifluoro-l(5)phenylethylamino)-propionamide vvhich upon oxidation as provided in Example 3 belovv provided Y-(4-cyano-l-hexahydro-lX⁶-thiopyran-4-yl)-3-phenylmethanesulfonyl-2(7?)-(2,2,2trifluoro-l(5)-phenylethylamino)-propionamide. MS: 526.3 (M+l); 548.1 (M+23); 524.2 (M-l).

JV-( 1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(Ā)-(2,2,2-trifluoro-1 (5)-3bromophenylethylamino)propionamide. MS: 508 (M+l).

7/-(l-cyanocyclopropyI)-3-phenylmethanesulfonyl-2(/?)-(2,2,2-trifluoro-1 (5)-4fluorophenylethylamino)propionamide. MS: 484.0 (M+l)

N-( 1 -cyanocyclopropy I)-3-cyclopropylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-1(5)thiophen-3-ylethylamino)propionamide. MS: 435.9 (M+l) jV-(l-cyanotetrahydropyran-4-yl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluorol(5)-4-fluoropheny!ethylamino)propionamide. MS: 492.0 (M+l)

7/-(1 -cyanocyclopropyl)-3-(4-fluorophenylmethanesulfonyl)-2(/?)-(2,2,2-trifluoro-1(5)-4fluorophenylethylamino)propionamide. MS: 502.2 (M+l)

7/-(1-cyanotetrahydrothiopyran-4-yl)-3-(4-fluorophenylmethanesulfonyl)-2(/?)-(2,2,2trifluoro-l(5)-4-fluorophenyl-ethylamino)propionamide. MS: 562.1 (M+l)

V-( 1 -cyanocyclopropyl)-3-(4-fluorophenylmethanesulfonyl)-2(/?)-(2,2,2-trifluoro-1 (S)-3phenoxyphenylethylamino)propionamide. MS: 476.1 (M+l)

N-( 1 -cyano-1,1 -dioxohexahydro-1 X⁶-thiopyran-4-y l)-3 -(4fluorophenylmethanesulfonyl)-2(/?)-(2,2,2-trifluoro-l(5)-4fluorophenylethylamino)propionamide. MS: 494.2 (M+l)

Example 3

Synthesis of V-(4-cy ano-1,1 -dioxohexahydro-1 X⁶-thiopyran-4-y l)-3 cyclopropyImethanesulfonyl-2(/?)-(2,2,2-trifluoro-l(5^-phenylethylamino)propionamide

A solution of V-(4-cyanotetrahydrothiopyran-4-yl)-3-cyclopropyImethanesulfanyl-2(/?)(2,2,2-trifluoro-l(S)-phenylethylamino)-propionamide (0.131 mmol) in methanol (3 mL) vvas treated vvith a solution of ΟΧΟΝΕ® (245 mg) in vvater (3 mL) and stirred for 30 h at room temperature. The reaction mixture vvas extracted vvith diethyl ether and the organic layer vvas vvashed vvith brine, dried over anhydrous sodium sulfate, and concentrated. The crude product vvas purified by silica gel chromatography using 50% ethyl acetate in hexane to 100% ethyl acetate gradient as eluent to give the title compound (9 mg) after trituration vvith diethy 1 ether. M+l = 558.4; M+23 = 580.7; M-l = 556.4.

Example 4

Synthesis ofV-(l-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(/?)-(2,2,2-trifluoro-l(S)4-fluorophenylethylamino)propionamide

Step 1

To a solution of (Boc-Cys-OH)₂ (20 g, 45.4 mmol) and P(CH₂CH₂COOH)₃.HC1 (15.61 g, 54.47 mmol) in DMF (162 mL) vvas added 5N KOH (109 mL) slowly over 20 min. After stiring overnight, 2-picolylchloride hydrochloride (22.34 g, 136.2 mmol) vvas added in one portion and the reaction mixture vvas stirred at room temperature for 2.5h. The pH of the solution vvas adjusted to 3 vvith 10N HCI and the product vvas extracted vvith methylene chloride. The combined organic extract vvas vvashed vvith sat. NaHCO₃, dried over MgSO₄, filtered and concentrated to give 2(R)-iV-/er/-butoxycarbony!amino-3-(pyridin-2-y!methylsulfanyl)propionic acid vvhich vvas crystallized from methylene chloride and hexane mixture to give pure product (13.70 g) as a vvhite solid.

Step 2

2(7?)-A^r-/er/-Butoxycarbonylamino-3-(pyridin-2-ylmethylsulfanyl)propionic acid (3.12 g, 10 mmol) vvas dissolved in mixture of methanol (10 mL) and benzene (10 mL). Trimethylsilyldiazomethane (10 mL, 2.0M solution in hexane, 20 mM) was added slowly. After 1 h, the solvent vvas removed to give methyl 2(7?)-yV-/er/-butoxycarbonylamino-3-(pyridtn-2ylmethylsulfanyl)-propionate as a yellow oil.

Step 3

Methyl 2(A)-/V-ierf-butoxycarbonylamino-3-(pyridin-2-ylmethylsulfanyl)-propionate vvas dissolved in dioxane and 3 equiv. of 4M HCI in dioxane vvas added. After stirring at room temperature for 3 h, the solvent vvas removed under reduced pressure to give methyl 2(7?)amino-3'(pyridin-2-yImethylsuIfanyl)propionate hydrochloride as a hygroscopic solid.

Step 4

To a mixture of methyl 2(7?)-amino-3-(pyridin-2-ylmethyIsulfanyl)-propionate hydrochloride (1.31 g, 5 mmol), 2,2,2-trifluoro-l-(4-fluorophenyl)ethanone (0.875 g), DIPEA (2.39 g, 18.5 mmol), in dichloromethane (20 mL) vvas added titanium tetrachloride (4.65 mmol) dropvvise over 5 min. After stirring for 3 h at ambient temperature, additional titanium tetrachloride (0.3 mmol) vvas added. After an additional hour of stirring, NaCNBH₄ (0.973 g,

15.5 mmol) vvas added in methanol (10 mL). After lh, the reaction mixture vvas diluted vvith ethy 1 acetate (200 mL) and poured onto magnesium sulfate. After filtration and concentration, the residue vvas purified by fiash chromatography to afford methyl 3-(pyridin-2-y 1methylsulfanyl)-2(R)-[2,2,2-trifluoro-I(AS)-(4-fluorophenyl)ethylamino]-propionate (640 mg, 1.59 mmol).

Step 5

To a solution of methyl 3-(pyridin-2-ylmethylsulfanyl)-2(7?)-[2,2,2-trifluoro-l(7?5)-(4fluorophenyl)ethylamino]propionate (0.64 g, 1.59 mmol) in methanol (9 mL) vvas added IN sodium hydroxide (4.77 mL). The resulting solution vvas stirred for 2 h at ambient temperature and then methanol vvas removed in vacuo. The residue vvas portioned betvveen vvater and ethyl acetate. The aqueous layer vvas extracted tvvice more vvith ethyl acetate and the combined organic layers vvere dried over magnesium sulfate. Removal of the solvents provided 3(pyridin-2-ylmethyIsulfanyl)-2(/?)-[2,2,2-trifluoro-l(/ŽS)-(4-fluorophenyl)ethylamino]propionic acid (0.410 g, 1.06 mmol) as a vvhite solid vvhich vvas a mixture of diastereomers. 3-(Pyridin-2ylmethylsu!fanyl)-2(7?)-[2,2,2-trifluoro-l(AS)-(4-fluorophenyl)ethylamino]propionic acid vvas converted to of yV-(!-cyano-cyclopropyl)-3-(pyridin-2-ylmethylsulfanyl)-2(7?)-[2,2,2-trifluorol(RS)-(4-fIuorophenyl)-ethylamino]propionamide by proceeding as described in Example 2, Step 8 above. 2V-(l-Cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl-2(/J)-(2,2,2-trifluorol(S)-4-fluorophenyl-ethylamino)propionamide (95 mg) vvas obtained from the diasteriomeric mixture by flash chromatography and vvas converted to the title compound (50 mg) by proceeding as described in Example 1, Step 6 above.

NMR (CDClj): 1.16(q, 2H), 1.54(q, 2H), 3.5O(dd, 2H), 3.72(dd, IH), 3.80(b, IH), 4.37(q, IH), 4.57(d, IH), 4.75(d, IH), 7.13(t, 2H), 7.41(t, 2H), 7.47(t, IH), 7.56(d, IH), 7.69(s, IH), 7.90(t, 1H), 8.67(d, IH). MS: 507.0 (M+23), 484.9 (M+l), 483.2 (M-1).

Proceeding as described in Example 4 above, follovving compounds of the invention vvere prepared.

N-( 1 -cyanocyclopropyl)-3-pyridin-2-y lmethanesulfanyl-2(7?)-(2,2,2-trtfluoro-1 (7?S)phenylethylamino)propionamide. MS: 467 (M+l).

/V-(l-cyanocyciopropyl)-3-pyrdin-2-ylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(5)phenylethyl-amino)propionamide. MS: 467 (M+l).

V-(l -cyanocyclopropy])-3-pyridin-2-ylmethanesulfonyl-2(/?)-(2,2,2-trifIuoro-1 (7?)phenylethylamino)propionamide. MS: 467 (M+l).

N-( I-cyanocyclopropy l)-3-pyridin-2-ylmethanesulfonyl-2(/?)-(2,2,2-trifluorO'l (AS)-4fluorophenylethylamino)propionamide. MS: 485 (M+I).

A^r-(l-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(/?)-(2,2,2-trifluoro-l(/?.S)-pyridin-2ylethyl-amino)propionamide. MS: 437 (M+l).

jV-(l-cyanocyclopropyl)-4-pyridin-2-ylsulfanyl-2(7?)-(2,2,2-trifluoro-l(^y)-4-fluorophenylethylamino)butyramide. MS: 453 (M+l).

N-(l-cyanocyclopropyl)-4-pyridin-2-ylsulfonyl-2(j?)-(2,2,2-trifluoro-l(AS)-4-fluorophenylethylamino)butyramide. MS: 485 (M+l).

jV-(l-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(7?)-(2,2,2-triifluoro-l(7?5)-pyridin2-y!-ethy!amino)propionamide. MS: 467 (M+l).

rV-(l-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl-2(7?)-(2,2,2-trifluoro-l(S)-4fluoro-phenylethylamino)propionamide. MS: 453 (M+l).

Z/-(l-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl-2(7?)-(2,2,2-trifluoro-l(7?)-4fluoro-phenylethylamino)propionamide. MS: 453 (M+l).

A^r-(l-cyanocyclopropy!)-3-pyridin-2-ylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(R)-4fluoro-phenylethylamino)propionamide. MS: 485 (M+l).

N-(l -cyanocyc!opropyl)-3-( 1 -oxopyridin-2-ylmethanesulfonyl)-2(/?)-(2,2,2-trifluorol(5)-4-fluorophenylethylamino)propionamide. MS: 501 (M+l); 499 (M-l).

Example 5

Synthesis of N-( 1 -cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfanyl)-2(7?)-(2,2,2-trifluorol(/?S)-phenylethylammo)propionarnide

Slēp 1

2(/?)-terr-Butoxycarbonylamino-3-(pyridin-2-ylmethylsuIfanyI)propionic acid (1.644 g,

5.3 mmol) vvas dissolved in DMF, l-aminocyclopropanecarbonitrile hydrochloride (747 mg, 6.3 mmol), HATU (2.4 g, 6.3 mmol) and Y-methylmorpholine (2.3 mL, 21.2 mmol) vvere added and the reaction mixture vvas stirred at room temperature for 4 h. Saturated NaHCO₃ solution and ethyl acetate vvere added after stirring for 20 min at room temperature, aqueous Iayer vvas extracted by ethy 1 acetate. Combined organic layers vvas dried by MgSCL and removed under the reduced pressure. Purified by flash column (ethyl acetate) provided [l-(l-cyanocyclopropylcarbamoyI)-2(7?)-(pyridin-2-ylmethylsulfanyl)ethyl]carbamic acid ter/-butyl ester (1.28 g).

Step 2 [l-(l-Cyanocyclopropylcarbamoyl)-2(R)-(pyridin-2-ylmethylsulfanyl)ethyl]-carbamic acid ierz-butyl ester (1.28 g, 3.4 mmol) vvas dissolved in THF, methanesulfonic acid ( 0.65 mL, 10 mmol) vvas added and the reaction mixture vvas stirred ovemight at room temperature. Water (1 mL) and solid NaHCO₃ vvere added until no bubbles vvere observed. The product vvas extracted vvith ethyl acetate. The organic layer vvas dried vvith MgSC>4 and removed under the reduced pressure to get 2(A)-amino-2V-(l-cyanocyclopropyl)-3-(pyridin-2-ylmethylsulfanyl)propionamide as an oil (100% yield).

Step 3

To a stirred solution of 2(7?)-amino-V-(l-cyanocyclopropyl)-3-(pyridin-2-yimethylsulfanyl)propionamide (110 mg, 0.4 mmol) in anhydrous THF (2 mL) vvere added activated 4A molecular sieves (250 mg) and V-methylmorpholine (40 mg, 0.4 mmol). After 10 min, trifluoromethanesulfonic acid 2,2,2-trifiuoro-l-phenyIethyl ester (152 mg, 0.4 mmol) vvas added and the reaction mixture vvas stirred at room temperature for 2 days. The reaction mixture vvas filtered and the filtrate vvas concentrated and the residue vvas purified by flash column chromatography to afford a mixture ofJV-(l-cyanocyclopropyl)-3-(pyridin-2-ylmethylsulfanyl)2(7?)-(2,2,2-trifluoro-l(7?)-phenylethylamino)propionamide andY-(l-cyanocyclopropyl)-3(pyridin-2-ylmethylsulfanyl)-2(7?)-(2,2,2-trifluoro-l(S)-phenylethylamino)propionamide (65 mg). LC-MS: 433.3 (M-1), 435.1 (M+l), 457.1 (M+Na).

Example 6

Synthesis ofA^r-(l-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(7?)-[2,2,2trifluoro-1 (5}-(4-fluorophenyl)ethylamino]propionamide

Step I

A dried 50 mL of flask vvas charged sodium hydride, 60% dispersion in mineral oil (624 mg, 15.6 mmol) under N₂ and then vvashed vvith dried hexane (20 mL) tvvice. Dried ethyl ether (10 mL) vvas added and a solution of 2,2,2-trifluoro-l(7?5)-(4-fluorophenyl)ethanol (90% ee) (2.5 g, 12.89 mmol) in ethyl ether (10 mL) vvas added at 0 °C. After completion of addition, the reaction mixture vvas allovved to vvarm up to room temperature and stirred for lh. A solution of trifluoromethanesulfonyi chloride (3.28 g, 19.5 mmol) in ethyl ether (10 mL) vvas added at 0 °C. After completion of addition, the reaction vvas allovved to vvarm up to room temperature and stirred for lh. The solvent vvas removed under rot-vap and diluted vvith hexane (150 mL) and vvashed vvith a saturated NaHCOj n and brine. After drying vvith MgSO₄, the organic solvent vvas removed to give trifluoro-methanesulfonic acid 2,2,2-trifluoro-l(2?5)-(4-fluorophenyI)ethyl ester (3.15 g) (90% ee) as a colorless oil vvhich vvas used in the next step vvithout further purification.

Step 2

Into a stirred suspension of 2(/?)-amino-3-(2-difluoromethoxyphenylmethanesulfariyl)propionic acid (277 mg, 1 mmol) in DCM (3 mL) vvas added DIPEA (323 mg, 2.5 mmol) and trifluoromethanesulfonic acid 2,2,2-trif!uoro-l(R5)-(4-fluorophenyI)ethyl ester (489 mg, 1.5 mmol) (90% ee) at 25 ^ŪC. After 12 h, HPLC shovved diastereomeric mixture of tvvo major products 3-(2-difluoromethoxyphenylmethanesulfany!)-2(/?)-[2,2,2-trifluoro-1(^5)-(4fluorophenyl)ethylamino]-propionic acid and l(&S)-(4-fluorophenyI)-2,2,2-trifluoroethane 3-(2difluoromethoxy-phenylmethanesulfanyl)-2(R)-[2,2,2-trifluoro-l(R5)-(4-fluorophenyl)ethylamino]propionate (t= 4.177, t= 4.852). The reaction mixture vvas diluted vvith ethyl ether (150mL) and vvashed vvith IN HCI solution and brine. After drying vvith MgSO₄, the solvent vvas removed and the residue vvas purified by prep-HPLC to give 3-(2-dif1uoromethoxyphenylmethanesulfany I)-2(jR)-[2,2,2-trif!uoro-1 (&S)-(4-fluorophenyl)ethy laminoļpropionic acid (178 mg) and l(ftS')-(4-fluoropheny!)-2,2,2-trifluoroethane 3-(2-difluoromethoxyphenylmethanesu!fanyl)-2(/?)-[2,2,2-trifluoro-l(ftS)-(4-fluorophenyl)-ethylaminoJpropionate (203 mg)

Step 3

To a solution of l(AS)-(4-fluorophenyI)-2,2,2-trifluoroethane 3-(2-difluoromethoxyphenylmethanesuIfanyl)-2(R)-[2,2,2-trifluoro-l(AS)-(4-fIuorophenyl)ethylamino]propionate in THF (2mL) and MeOH (1 mL) vvas added IN solution of LiOH (1 mL) at 25 °C. After 30 min, the solvent was removed and the residue vvas diluted vvith vvater (10 mL) and extracted vvith hexane to remove alcohol. The vvater phase vvas acidified by IN HCI to pH=l-2 and extracted vvith ethyl ether (120 mL). After drying vvith MgSO₄, the solvent vvas removed under rot-vap, to give 3-(2-difluoromethoxy-phenylmethanesulfanyl)-2(R)-(2,2,2-trifluoro-l(7?S)-(4fluorophenyi)ethylamino]-propionic acid.

Step 4

In to a stirred solution of 3-(2-difluoromethoxyphenylmethanesuifanyI)-2(/?)-[2,2,2trifluoro-l(7?5)-(4-fluorophenyl)ethylamino]propionic acid (153 mg, 0.338 mmol) in MeOH (10 mL) vvas added a solution of ΟΧΟΝΕ® (314 mg, 0.51 mmol) in vvater (10 mL) at room temperature. After stirringfor 30min, the methanol vvas removed and extracted vvith ethy 1 acetate (100 mL), then vvashed vvith brine and dried vvith MgSO₄. Removal of the solvent gavē 3-(2difluoromethoxy-phenylmethanesu[fonyl)-2(/?)-[2,2,2-trifluoro-l(R5)-(4-fluorophenyl)ethyl78 aminojpropionic acid (157 mg).

Step 5

To a solution of3-(2-difluoromethoxyphenyImethanesuffonyI)-2(R)-[2,2,2-trifluorol(RS)-(4-fluorophenyl)ethylamino]propionic acid (157 mg, 0.325 mmol) in DMF (5 mL) vvas added l-aminocyclopropanecarbonitrile hydrochloride (46.4 mg, 0.39 mmol), HATU (186.3 mg, 0.49 mmol) and DIPEA (63.2 mg, 0.49 mmol). After lh, the reaction mixture was extracted vvith ethyl acetate (100 mL) and washed vvith satured NaHCCh and brine. After driying vvith MgSC>4, the solvent was removed and the residue vvas purified by column chromatograph yield the title compound (125 mg).

HNMR (CDC1₃): 7.69(IH, s), 7.5-7(8H, m), 6.5(1H, t, J=58.8Hz), 4.47(2H, dd), 4.25(1H, dd), 3.65-3.6(lH, m), 3.45-3.35(lH, m), 3.3-3.1(lH, m), 1.2-1.1(2H, m), 1.01-0.9(2H, m). LC-MS: 548(M-1), 550.1(M+1), 572(M+Na).

Example 7

Synthesis of JV-(4-cyano-1, l-dioxohexahydro-l X⁶-thiopyran-4-yl)-3-(2-difluoromethoxyphenylmethanesulfonyl-2(7?)-(2,2,2-trifluoro-l(5)-4-fluorophenylethylamino)propionamide

Proceeding as described in Example 6, Step 5 above, but substituting Iaminocyclopropane-carbonitrile hydrochloride vvith 4-amino-4-cyanotetrahydrothiopyran provided V-(4-cyano-tetrahydrothiopyran-4-yl)-3-(2-difluoromethoxyphenylmethanesulfanyl2(/?)-(2,2,2-trifluoro-l(RS)-4-fluorophenylethylamino)propionamide vvhich vvas converted to N(4-cyanotetrahydrothiopyran-4-yl)-3-(2-difluoromethoxyphenylmethanesulfonyl-2(/?)-(2,2,2trifluoro-l(ftS)-4-fluorophenyI-ethylamino)propionamide as described in Example 3 above. The title compound vvas isolated via column chromatography.

HNMR (CDCh): 7.69(1 H, s), 7.5-7(8H, m), 6.5(1H, t,J=74Hz), 4.6(2H,dd), 4.2(1H,

d), 3.8(1H, m), 3.5-2.8(4H, m), 2.7-1.9(3H, m), 1.8-l.4(2H, m), 1.2-1.1(2H, m). LC-MS: 640.2(M-l), 641.8(M+1)

Example 8

Synthesis of/V-(4-cyanotetrahydropyran-4-yl)-3-(2-difluoromethoxyphenylmethanesulfonyl2(7?)-(2,2,2-trifluoro-1 (S)-4-fluorophenylethylamino)propionamide

Proceeding as described in Example 6, Step 5 above, but substituting 1aminocyclopropane-carbonitrile hydrochloride vvith 4-amino-4-cyanotetrahydropyran (prepared as described in PCT application publication No. WO 01/19816, page 141, Example 2) provided N-(4-cyanotetrahydropyran-4-yl)-3-(2-difluoromethoxyphenylmethanesulfanyl-2(7?)-(2,2,2trifluoro-l(AS)-4-fluorophenylethylamino)propionamide vvhich vvas converted to N-(4cyanotetrahydropyran-4-yl)-3-(2-difluoromethoxyphenylmethanesuIfonyl-2(7?)-(2,2,2-trifluorol(&S')-4-fluorophenylethylamino)propionamide as described in Example 3 above. The title compound vvas isolated via column chromatography.

HNMR (CDCb): 7.69(1 H, s), 7.5-7(8H, m), 6.6(1H, t, J=73.6Hz), 4.63(2H, dd), 4.38(1H, m), 4-3.2(8H, m), 2.3-2.1(2H, dd), l.8-1.5(2H, m). LC-MS: 592.2(M-1), 593.8(M+1), 615.7(M+Na).

Example 9

Synthesis of 2V-(1 -cyanocyclopropyl)-3-(6-trifluoromethylpyridin-2-ylmethanesulfonyl)-2(2?)(2,2,2-trifluoro-l (S)-phenylethylamino)propionamide

Step I

6-Trifluoromethylpyridine-2-carboxylic acid vvas prepared as described in (Schlosser, M and Marull, M. Eur. J. Org. Chem. 2003, 1569-1575.

Step 2

To a suspension of 6-trifluoromethylpyridine-2-carboxylic acid (2.53 g, 13,2 mmol) in THF (50 mL) cooled to -5 °C was added triethylamine (1.84 mL, 13.2 mmol) followed by addition of ethyl chloroformate (1.26 mL, 13.2 mmol) and the reaction mixture vvas stirred for 30 min at 0 °C. Lithium borohydride (718 mg, 33 mmol) was added in portions, maintaining the temperature below -5 °C. After the addition vvas complete, the reaction vvas allovved to vvarm to room temperature and stirred for 1 h. Temperature vvas lowered to -5 °C and methanol (10 mL) was added followed by addition of aqueous sodium hydroxide (10 mL, 10 %). After the addition of ethyl acetate (50 mL) and vvater (40 mL), dilute hydrochloric acid vvas added to obtain pH = 5.0. After washing aqueous layer thoroughly vvith ethyl acetate the combined organic extracts were dried over MgSO₄ and concentrated. Purification by flash column (30% EtOAc-Hexane) gavē (6-trifluoromethylpyridin-2-yl)methanol (760 mg) as an oil.

Step 3 (6-Trifluoromethylpyridin-2-yl)methanol (760 mg, 4.3 mmol) vvas dissolved in CH2CI2 and thionyl chloride vvas added slovvly at room temperature. The reaction mixture vvas stirred at room temperature for 4 h. Solvent vvas removed under the reduced pressure, the pH vvas adjusted to 5, and the product vvas extracted vvith EtOAc. Purification by flash column ( 5% EtOAc-Hexane) gavē 2-chloromethyl-6-trifluoromethylpyridine (200 mg) as a vvhite solid.

Step 4

2(J?)-jV-rerr-butoxycarbonylamino-3-(pyridin-2-ylmethyIsulfanyl)propionic acid vvas prepared as described in Example 4, Step 1.

Step 5

2(/?)-zer/-Butoxycarbonylamino-3-(6-trifluoromethylpyridin-2-ylmethylsulfanyl)propionic acid (760 mg, 2 mmol) vvas dissolved in DMF and l-aminocyclopropanecarbonitrile hydrochloride (284 mg, 2.4 mmol), HATU (912 mg, 2.4 mmol) and jV-methylmorpholine (0.9 mL, 8 mmol) vvere added. After stirring for 4 h at room temperature, saturated NaHCO₃ solution and ethyl acetate vvere added and stirring vvas continued for an additional 20 min. The reaction mixture vvas extracted vvith ethyl acetate and the combined organic layer vvas dried by MgSO₄, filtered, and concentrated under reduced pressure. Purification by flash column (100 % CH2CI2) gavē [1 -(1 -cyano-cyclopropylcarbamoyl)-2(J?)-(6-trifluoromethylpyridin-2ylmethylsulfanyl)ethyl]carbamic acid fer/-butyl ester (340 mg) as an oil.

Step 6 [l-(l-Cyanocyclopropylcarbamoyl)-2(7?)-(6-trifluoromethylpyridinT2-ylmethylsulfanyl)ethyl]-carbamic acid reri-butyl ester (340 mg) was dissolved in THF and 3 eq. of methanesulfonic acid vvas added. After stirring overnight, vvater (1 mL) vvas added and solid NaHCCb vvas added until no bubbles vvere observed. The reaction mixture vvas extracted vvith ethyl acetate. The organic Iayer vvas dried vvith MgSO₄, filtered and concentrated under the reduced pressure to get 2(R)-amino-?/-(l-cyanocyclopropyl)-3-(6-trifluoromethylpyridin-2ylmethylsulfanyl)propionamide as an oil.

Step 7

2(/?)-Amino-W-(l-cyanocycIopropyl)-3-(6-trifluoromethylpyridin-2-ylmethylsulfanyl)propionamide (86 mg, 0.25 mmol), NMM (0.054 mL, 0.5 mmol) and molecular sieves vvere added in THF. After 5 min, trifluoromethanesulfonic acid 2,2,2-trifluoro-l-(4fluorophenyl)ethyl ester (122 mg, 0.37 mmol) vvas added at room temperature. The reaction mixture vvas stirred at room temperature overnight. Solvent vvas removed under the reduced pressure and jV-(l-cyanocyclo-propyl)-2(7?)-[2,2,2-trifluoro-l(/?S)-(4-fluorophenyl)ethylamino]3-(6-trifluoromethylpyridin-2-ylmethyl-sulfanyl)propionamide vvas purified by flash column ( 30 % EtOAc-Hexane) to get (40 mg) of pure product as an oil. LC-MS: 521 (M+l), 543 ( M+23), 519 (M-1). This vvas converted to Y-(l-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-l(RS)(4-fluorophenyl)ethylamino]-3-(6-trifluoromethylpyridin-2-ylmethyl-suIfonyl)propionamide compound as described in Example 3 above. Tvvo diastereomers are separated by flash column (1% MeOH-CH₂Cl₂) to give the title compound.

NMR (DMSO-de): O.74(1H, m), O.970H, m), 1.33(2H, m), 3.270H, m), 3.45(2H, m), 3.72(1H, m), 4.39(1H, m), 4.93(2H, m), 7.19(2H, t), 7.42(2H, m), 7.77(1H, d), 7.920H, d), 8.15(1H, t), 9.O10H, s). LC-MS: 553(M+1), 575( M+23), 551 (M-1).

Example 10

Synthesis of A-(l-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-l(S)4-fluorophenylethylamino)propionamide and jV-(l-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfonyl-2(/?)-(2,2,2-trifluoro-l(/?)-4-fluorophenylethylamino)propionamide

cf₃ ^indFm

Λ⁵

J-0

H Λ

Step 1

A mixture of 2-methylpyrazine (7.0 g, 74.4 mmol), 77-chlorosuccinamide (12.6 g, 94.4 mmol), and benzoyl peroxide (0.1 g, 0.41 mmol) in carbon tetrachloride (200 mL) vvas heated to reflux for 16 h. The resulting dark heterogeneous solution vvas filtered, the filtrate concentrated, and the residue purified by flash chromatography (EtOAC/hexanes) to give 2-chIoromethylpyrazine.

Step 2 (Boc-NH-Cys-OH)₂ (1.04 g, 2.35 mmol) vvas dissolved in DMF (8.5 mL) and after adding tris (2-carboxyethyl) phosphine hydrochloride (0.81 g, 2.82 mmol) the resulting slight suspension was stirred for 10 min. 5N KOH (5.65 ml) vvas added dropvvise over a 20 min period (slight exotherm noticed) and the resulting solution vvas stirred for 6 h at ambient temperature.

A solution of 2-chloromethylpyrazine (1.16 g, 7.07 mmol) in DMF (2 mL) vvas added and the reaction mixture vvas allovved to stir ovemight. The pH vvas adjusted to 4 vvith IN HCI and the product vvas extracted vvith ethy 1 acetate. The combined organic layers vvere vvashed vvith brine and dried over MgSO4. After concentration, the crude 2(7?)-ier/-butoxycarbonylamino-3(pyrazin-2-y!methanesulfonyl)-propionic acid (1.42 g, 4.53 mmol) vvas used in the next step.

Step 3

2(7?)-/er/-Butoxycarbonylamino-3-(pyrazin-2-ylmethanesulfonyl)propionic acid (1.42 g, 4.53 mmol) vvas dissolved in mixture of MeOH (10 mL) and toluene (33 mL) and Me₂SiCHN₂ (2.0 M solution in hexanes, 3.06 ml) vvas added dropvvise over 10 min. After stirring the reaction mixture ovemight, the solvent vvas removed and the resulting residure vvas purified by flash chromatography vvith EtOAc/hexanes as eluent to afford methyl 2(R)-tertbutoxycarbonylamino-3-(pyrazin-2-ylmethanesulfonyl)propionate (0.755 g).

Step 4

Methyl 2(/?)-ierf-butoxycarbonylamino-3-(pyrazin-2-yImethanesuIfonyI)propionate vvas dissolved in THF (5 mL) and a solution of HCI/dioxane (4.0M, 2.9 mL) vvas added. After stirring for 48 h, the solvent vvas removed in vacuo and the residue vvas precipitated vvith diethyl ether and dried under vacuum to give methyl 2(/?)-amino-3-(pyrazin-2ylmethanesulfonyl)propionate vvhich vvas converted to the title compounds utilizing the procedure deseribed in Example 4 above.

N-( l-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfony!-2(/?)-(2,2,2-trif]uoro-l (5)-4fluorophenylethylamino)propionamide. ’H NMR (400 MHz, DMSO) 9.1 (s, 1 H), 8.75 (d, 6.5 Hz, 1H), 7.48 (m, 2 H), 7.27 (m, 2 H), 4.92 (m, 2 H), 4.42 (m, 2 H), 3.80 (m, 1 H), 3.90 (dd, 4.5,

11.2 Hz, 2 H), 3.45 (m, 2H), 1.40 (m, 2 Η), 1.05 (m, 1 H), 0.87 (m, 1 H). MS: 484.0 (M-l).

N-( 1 -cyanocyclopropy l)-3-pyrazin-2-ylmethane-sulfonyl-2(7?)-(2,2,2-trifluoro-1 (R)-483 fluorophenylethylamino)propionamide. 'H NMR (400 MHz, DMSO) 9.05 (s, 1 H), 8.75 (d, 6.5 Hz,

IH), 7.55 (m, 2 H), 7.32 (m, 2 H), 4.95 (dd, 2 H), 4,45 (m, 2 H), 3.80 (m,lH), 3.45 (m, 2H) 0,951.40 (m,4H). MS: 484.0 Μ - l).

/y-(l-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfanyl-2(7?)-(2,2,2-trifluoro-l (/2)-4fluorophenyl-ethylamino)propionamide. MS: 454 (M+l).

/Y-(l-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfanyl-2(/2)-(2,2,2-trifluoro-l(S)-4fluorophenyl-ethylamino)propionamide. MS: 454 (M+l).

Example 11

Synthesis of yV-(l-cyanocyc!opropyl)-3-(pyridin-2-ylmetlianesulfonyl)-2-(2,2,2-trifluoro-lphenyl-l-trifluoromethylethylamino)propionamide

Step 1

Potassium hydride (1.05 g, 26.2 mmol) vvas suspended in ethyl ether (100 mL) and cooled in and ice vvater bath. l,l,l,3,3,3-Hexafluoro-2-phenylpropan-2-ol (4.0 g, 16.4 mmol) in ethyl ether (20 mL) vvas added over a 5 min and the solution vvas stirred for an hour. Triflic anhydride (4.62 g, 16.4 mmol) vvas added neat over 5 min and the reaction mixture vvas allovved to vvarm to ambient temperature ovemight. The reaction mixture vvas quenched vvith vvater and diluted vvith ether (300 mL). The organic layer vvas vvashed vvith saturated sodium bicarbonate and brine and dried over magnesium sulfate to give trifluoromethanesulfonic acid 2,2,2trifluoro-l-pheny!-l -trifluoromethyl-ethyl ester

Step 2

2(/?)-Amino-jV-(l-cyanocyclopropyI)-3-(pyridin-2-yImethylsulfanyl)propionamide and trifluoromethanesulfonic acid 2,2,2-trifluoro-I-phenyl-l-trifluoromethyl-ethyl ester vvere converted to /V-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethylsulfanyl)-2(R)-(2,2,2-trifIuoro-Iphenyl-l-trifluoromethylethylamino)propionamide utilizing the procedure described in reference J, step 3 above.

Step 3

A^r-(l-Cyanocyclopropy!)-3-(pyridin-2-ylmethylsulfanyl)-2(/?)-(2,2,2-trifluoro-l-phenyll-trifluoromethylethylamino)propionamide vvas oxidized to the title compound utilizing a procedure outlined in Example 1, step 5 above.

Example 12

Synthesis of A'-(l-cyanocyclopropyl)-3-cyclopropylmethanesuIfonyI-2(Λ)-(2,2,2-trifluoro-l(S)4-fluoropheny lethy lam ino)propionam ide

Step 1

A solution of 2(/?)-amino-3-cyclopropylmethylsulfanylpropan-l-ol (3.2g, 20.0mmol), prepared as described in Example 2, Steps 1 and 2 above, and trifluoroacetaldehyde methyl hemiacetal (2.6 g, 20.0 mmol) in toluene (20 mL) vvas heated at reflux vvith Dean Stark trapping of vvater for 24 h. The reaction mixture vvas concentrated to give 4cyclopropylmethylsulfanylmethyl-2-trifluoromethyloxazolidine (4.18 g) as a pale yellow oil. Step 2

Part Α: A solution of 4-cyclopropylmethylsulfanylmethyl-2-trifluoromethyloxazolidine (4.18 g, 17.0mmol) in anhydrous tetrahydrofuran (34 mL) vvas cooled in an ice vvater bath and treated vvith chlorotrimethylsilane (2.58 mL, 20.4 mmol) and lithium bis(trimethylsilyl)amide (20.4mL of 1.0M solution in tetrahydrofuran). The reaction mixture vvas allovved to stir under ice bath cooling for 30 minūtes and then at room temperature for 1 hour.

Part Β: A solution of 4-fluorobromobenzene (5.6mL, 51mmol) in anhydrous tetrahydrofuran (100 mL) vvas cooled to -78°C, treated vvith rc-butyl lithium (31.9mL of 1.6M solution in hexanes, and allovved to stir for 15 min. The solution from Part A vvas transferred by cannula to this reaction mixture at -78°C over 10 min. Stirring at -78°C for 2 h vvas follovved by addition of HCI (34 mL IN), then the reaction mixture vvas allovved to vvarm to room temperature. Potassium hydroxide (9 mL of 25% solution in vvater) vvas added, but the resulting mixture appeared to have the trimethylsily 1 ether protecting group stili intact. Therefore, the mixture vvas acidified vvith more IN HCI (20 mL) before it vvas extracted vvith ethyl acetate.

The combined organic layers vvere dried over anhydrous sodium sulfate, concentrated, and chromatographed using an 8:1 to 5:1 gradient of hexane:ethyl acetate to give 3cyclopropylmethylsulfanyl-2(/?)-[2,2,2-trif1uoro-1(S)-(4-fluoro-phenyl)-ethylamino]propan-l-ol (2.36 g) and 3-cyclopropylmethylsulfanyl-2(7?)-[2,2,2-trifluoro-l(/?)-(485 fluorophenyl)ethylamino]propan-l-ol (370 mg).

Step 3

Solutions of 0.41M periodic acid in dry acetonitrile and 0.02M chromium trioxide in dry acetonitrile were prepared 3 hours ahead, vvith stirring at room temperature. Periodic acid solution (36.5 mL) was chilled in an ice/acetone bath and treated first vvith chromium trioxide solution (3.6 mL), then a solution of 3-cyclopropylmethylsulfanyl-2(R)-[2,2,2-trifluoro-15-(4fluorophenyl)-ethylamino]propan-l -ol in acetonitrile (18 mL). The reaction was monitored by reverse phase HPLC and portions of the chromium trioxide solution vvere added (2 mL at 2 h reaction time, 2 mL at 4 h reaction time). After 1 more hour reaction time, the reaction vvas found to be complete by HPLC analysis. Isopropanol (50 mL) vvas added. The reaction mixture vvas allovved to vvarm to room temperature and then vvas concentrated. The resulting solids vvere partitioned betvveen ethyI acetate (30 mL) and saturated aqueous KH₂PO₄ (30 mL). The aqueous layer vvas extracted vvith ethyl acetate and the combined organic layers vvere vvashed vvith brine and dried over anhydrous sodium sulfate. Removal of solvent gavē 3cycIopropylmethylsuIfonyl-2(R)-[2,2,2-trif!uoro-I(S)-(4-fIuorophenyl)ethylamino]propionic acid (0.82 g ) as an amber oil vvhich vvas converted to the title compounds as described in Example 2, step 8 above.

NMR (CDCb, 400MHz): δ 7.61 (IH, br s), 7.42 (2H, dd, 7=8.4hz, 5.6Hz), 7.15 (2H, t, 7=8.8Hz), 4.41 (IH, q, 7=7.2Hz), 3.68 (IH, m), 3.62 (IH, dd, 7=14.4Hz, 6.4Hz), 3.41 (IH, dd, 7=14.4Hz, 4.0Hz), 3.06 (2H, d, 7=6.8Hz), 1.60 (2H, m), 1.24 (3H, m), 0.81 (2H, m), 0.48 (2H, m). MS: 448.3 (M+l). M+l = 429.9; M+23 = 451.9; M-l = 428.0.

jV-(l-cyanocyclopropyI)-3-cyclopropylmethanesulfonyI-2(R)-(2,2,2-trifluoro-l (5)-3,4difluorophenylethyiamino)propionamide. MS: 466.1 (M+l).

77-(l-cyanocyclopropy!)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-l(S)-3,4,5trifluoro-phenylethylamino)propionamide. MS: 484.0 (M+l).

Example 13

Synthesis of N-(l-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-l(5)methylethylamino)propionamide

To a cold (0°C), stirred mixture of 3-phenylmethanesulfanyl-2(/?)- (2,2,2-trifluoro-1 (/?S)hydroxyethylamino)propionic acid methyl ester (162 mg, 0.5 mmol) prepared as described in Example 1 above, in dichlomethane (2 mL) was added 2.0M solution of trimethylaluminum in toluene dropvvise via a microsyringe and the reaction mixture vvas allovved to vvarm to rt over 2 h. After stirring at rt for 2 h, the reaction vvas quenched vvith vvater, and extracted vvith dichloromethane. The combined organic extracts vvere dried (MgSOJ, concentrated under reduced pressure, and the residue vvas purified by flash chromatography on silica gel (eluted vvith 1: 6 EtOAc/ hexanes) to yield the title compound (55 mg) as a mixture of diastereomers in a 8: 2 ratio. MS: 404.1 (M+l).

Example 14

Synthesis ofjV-(4-cyanocyclopropyl)-3-(4-fluorophenylmethanesulfonyl)-2(/?)-(2,2,2-trifluorol(5)-4-fluorophenylethylamino)propionamide ,SO₂

N, .CN

Step 1

L-cysteine (15.97 g) vvas dissolved in a mixture of 1.0M aqueous sodium hydroxide (265 mL) and l,4-dioxane (265 mL). 4-F!uorobenzylbromide (24.85 g) vvas added dropvvise over 30 min. After stirring overnight, dioxane vvas removed and the pH ofthe residual aqueous solution vvas adjusted to pH~6 vvith 3M hydrochloric acid. A vvhite precipitate began to form immediately upon addition of the acid and additional vvater (150 mL) vvas added to aid stirring ofthe thick suspension. The reaction mixture vvas cooled to 0 °C for 1 h and the precipitates vvere collected by filtration and vvashed vvith cold vvater, Et₂O, and hexane, and dried under high vacuum to give 2(/?)-amino-3-(4-fluorobenzylsulfanyl)-propionic acid (28.68 g) as a vvhite solid. Step 2

A 1000 mL 3-neck round bottom flask fitted vvith a mechanical stirrer, reflux condenser, addition port, and nitrogen inlet vvas charged vvith a 1.0 M solution of lithium aluminum hydride (200 mL) in THF and anhydrous THF (200 mL). The solution vvas cooled in an ice/vvater bath and 2(A)-amino-3-(4-fluorobenzylsuIfanyl)-propionic acid (24.08 g) vvas added vvith rapid stirring in small portions over 15 min. The ice bath vvas removed and the reaction mixture vvas heated to reflux ovemight. After cooling the reaction mixture to room temperature, saturated aqueous potassium carbonate (50 mL) vvas added dropvvise over 1 h. The solids vvere filtered off and the filter cake vvas vvashed vvith THF. The combined filtrate vvas dried over anhydrous MgSCL and concentrated to give 2(2?)-amino-3-(4-fluorobenzylsulfanyl)-propan-l-ol (16.16 g) as a pale amber resin.

Step 3

2(7?)-Amino-3-(4-fluorobenzy[suIfanyl)propan-l-ol (16.15 g), 4-dimethylaminopyridine (554 mg), and triethylamine (16.7 mL) vvere vveighed into a 1000 mL round bottom flask fitted vvith a stir bar, 250 mL addition funnel, septum, and nitrogen inlet. Methylene chloride (150 mL) vvas added to give a clear pale amber solution. A solution of /ert-butyldimethylsilyl chloride (12.54 g) in CH₂C1₂ (100 mL) vvas added dropvvise over 40 min. After stirring overnight, the reaction mixture vvas poured into vvater and the organic phase vvas separated, dried over anhydrous MgSC>4 and removed the solvent on rotavap to give 2-(tertbutyIdimethyIsilanyIoxy)-l(7?)-(4-fluoro-benzylsulfanylmethyl)ethylamine (25.92 g) as a clear yellow oil.

Step 4

2(ieri-ButyldimethylsiIanyloxy)'I(/?)-(4-fIuorobenzylsulfanylmethyl)ethylamine (25.92

g) and trifluoroacetaldehyde methyl hemiacetal [10.78 g, Avocado, 95% technical grade] vvere vveighed into a 1000 mL round bottom flask fitted vvith a Dean-Stark trap vvith condenser. Toluene (500 mL) vvas added and the reaction mixture vvas refluxed the reaction under anhydrous conditions ovemight. The solvent vvas removed and the residue vvas purified by flash chromatography on silica gel using 9:1 hexane:EtOAc eluent to obtain [2-(ter(buty]dimethylsilanyloxy)-l(/?)-(4-fIuorobenzylsuIfanylmethyl)ethyl]-(2,2,2-trifluoromethylethylidine)amine (21.25 g) as a clear yellow liquid.

Step 5

A solution of 4-fluoro-l-bromopyridine (1.88 g) vvas vveighed into an oven-dried 100 mL flask fitted vvith a stir bar, septum, and nitrogen inlet in anhydrous THF (20 mL) vvas cooled to 78°. n-Butyllithium in hexanes (4.2 mL of a 2.5M solution) vvas added dropvvise and the reaction mixture vvas stirred the reaction at -78° for 30 min. A solution of[2-(/eributyldimethyl-silanyloxy)-l(7?)-(4-fluorobenzyisulfanylmethyl)ethyl]-(2,2,2-trifluoromethylethylidine)amine in anhydrous THF (13.7 mL of a 0.366M solution) vvas added dropvvise over 15 min. After stirring at -78° 2 h, the reaction mixture vvas poured into a vigorously stirred mixture of 250 mL vvater, 250 mL crushed ice, 25 mL saturated aqueous ΝΗ4Ο, and 250 mL

EtOAc. The organic layer vvas separated and the aqueous phase vvas extracted vvith EtOAc. The combined extracts vvere vvashed vvith brine and dried over MgSO₄. The solvent vvas removed and the residue vvas dissolved in THF (20 mL) and and stirred in an ice/vvater bath. Tetrabutylammonium fluoride (5.25 mL of a 1.0M solution in THF) vvas added dropvvise over 15 min. After stirring for 2 h in in ice bath, the reaction mixture vvas poured into a vigorously stirred mixture of 250 mL vvater, 250 mL crushed ice, 25 mL saturated aqueous ammonium chloride and 250 mL EtOAc and allovved to stand ovemight. The organic layer vvas separated, vvashed vvith brine, and dried over MgSO₄. After concentration, the residue vvas purified by flash chromatography on 250 cm³ silica gel using 5% Et₂O/CH2Cl2 eluent to obtain 3-(4fluorobenzylsulfanyl)-2(A)-[2,2,2-trifluoro-l(5)-(4-fiuorophenyl)ethylamino]-propan-l-ol (822 mg) as a clear yellovv resin.

Step 6

A 500 mL round bottom flask vvas charged vvith 10.2 mL of a stock solution of 25 mg chromium(VI) oxide in 25 mL HPLC grade acetonitrile containing 0.75% v/v vvater and 46 mL of a stock solution of 10.0 g periodic acid in 100 mL HPLC grade acetonitrile containing 0.75% v/v vvater. HPLC grade acetonitrile (50 mL, 0.001% H₂O) and HPLC grade acetonitrile (50 mL) containing 0.75% v/v vvater) vvere added and the solution vvas cooled in an ice/vvater bath. A solution of 3-(4-fluorobenzylsulfanyl)-2(A)-[2,2,2-trifluoro-l(S)-(4-fIuorophenyI)ethyIamino]propan-l-ol (530 mg) in HPLC grade acetonitrile (8.2 mL containing 0.001% H2O) vvas added over 30 min, maintaining the temperature belovv 5°. After stirring at 0 °C for 3 h, the reaction mixture vvas quenched vvith 2-propanol (10 mL) and stirred 30 min at 0 °C. Phosphate buffer 50 mL of 0.40M pH 4) vvas added and the flask vvas removed from the ice bath and the organic solvent vvas removed on a rotary evaporator at 20°. The aqueous mixture vvas stirred vvith EtOAc and sufficient vvater to dissolve the solids. The organic phase vvas separated, dried over anhydrous MgSO₄, and removed to obtain 3-(4-fluorophenylmethanesulfonyl)-2(A)-[2,2,2trifluoro-l(5)-(4-fluorophenyl)-ethyIamino]propionic acid (489 mg) as an amber resin.

Step 7

3-(4-Fluorophenylmethanesulfonyl)-2(A)-[2,2,2-tri fluoro-1 (S)-(4-fluorophenyl)ethylamino]propionic acid (76 mg) and l-aminocyclopropanecarbonitrile hydrochloride (23 mg) vvere vveighed into a 4 mL vial fitted vvith a stir bar and cap. DMF (600 pL) vvas added and the reaction mixture vvas irred to obtain a clear amber solution. Diisopropylethylamine (105 pL) and £>-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (83 mg) vvere added and the vial vvas flushed vvith nitrogen and sealed vvith the cap. After 2 h, the reaction mixture vvas diltuted vvith 15 mL EtOAc and vvashed vvith 1.0M aqueous KHSO₄, vvater, saturated aqueous NaHCO₃₎ and brine, and dried over anhydrous MgSO₄.. The solvent vvas removed and the residue vvas purified the residue by flash chromatography on 22 cm³ silica gel using 3:1 CH₂Cl₂:EtOAc eluent to give the title compound (44 mg) as a vvhite solid.

Example 15

Synthesis of N-(4-cyano-1,1 -dioxohexahydro-lX⁶'thiopyran-4~yI)-3-(4-fluorophenylmethanesulfonyl)-2(7?)-(2,2,2-trifluoro-l(0)-4-fluorophenylethylamino)propionamide

o₂

Step 1

3-(4-Fluorophenylmethanesulfonyl)-2(7?)-[2,2,2-trifluoro-l(5)-(4-fluorophenyl)ethylamino]propionic acid (146 mg) and 4-aminotetrahydrothiopyran-4-carbonitrile (104 mg) vvere vveighed into a 4 mL vial fitted with a stir bar and cap and DMF (2 mL) vvas added to give a dark amber solution. Diisopropylamine (0.23 mL) and <?-(7-azabenzotriazol-l-yl)-l,1,3,3tetramethyluronium hexafluorophosphate (271 mg) vvere added and the vial vvasflushed the vial vvith nitrogen and sealed vvith the cap. After 1 h, the reaction mixture vvas diluted vvith a 9:1 mixture of CH₂Cl₂:EtOAc (40 mL)) and vvashed vvith 1.0M aqueous KHSO₄, vvater, a 1:1 H₂O:saturated aqueous NaHCO₃, and brine and dried over anhydrous MgSO₄. After concentration, the residue vvas purified by flash chromatography on 20 cm³ silica gel using 9:1 CHCl₃:EtOAc eluent to give theN-(4-cyanotetrahydrothiopyran-4-yl)-3-(4fluoropheny! methanesu lfonyl)-2(7?)-(2,2,2-trifl uoro-1 (5)-4-fluorophenyl ethylamino)propionamide (30 mg) as a beige solid.

Step 2 /V-(4-cyanotetrahydrothiopyran-4-yl)-3-(4-fluorophenylmethanesulfonyl)-2(7?)-(2,2,2trifluoro-l(S)-4-fluorophenylethylamino)propionamide (24 mg) vvas vveighed into a 25 mL pear flask fitted vvith a stir bar and vented cap. Methanol (4.75 mL) vvas added and the reaction mixture vvas stirred at 50°C to obtain a clear colorless solution. ΟΧΟΝΕ® (0.43 mL of a 0.30M aqueous solution) vvas added. A vvhite precipitate formed. After 2 h, methanol vvas removed on a rotary evaporator and the residue vvas partitioned betvveen 10 mL vvater and 10 mL dichloromethane. The organic phase was separated, vvashed vvith vvater and brine and dried over anhydrous MgSO* and concentrated to give the title compound (16 mg) as awhite solid.

Example 16

Synthesis of Y-(4-cyanocyclopropyl)-3-(4-fluorophenylmethanesuIfonyI)-2(/?)-(2,2,2-trifluoro1 (S)-3-phenoxyphenylethylamino)propionamide

Step 1

3-Phenoxybromobenzene (552 mg, purchased from Apollo Scientific) vvas vveighed into an oven-dried 20 mL vial fitted vvith a stir bar, septum, and nitrogen inlet and anhydrous THF (8 mL) vvas added and stirred to obtain a clear colorless solution. The reaction mixture vvas cooled to -78° and n-butyllithium in hexanes (0.84 mL of a 2.5M solution) vvas added dropvvise. After 30 min, [2-(iert-butyIdimethyIsilanyIoxy)-1 (R)-(4-fluorobenzyIsulfanylmethyl)ethyl]-(2,2,2trifluoromethylethylidine (2.75 mL of a 0.366M solution in anhydrous THF) vvas added dropvvise over 15 min. After 2 h, the reaction mixture vvas poured into a vigorously stirred mixture of 50 mL vvater, 50 mL crushed ice, 5 mL saturated aqueous NH4CI, and 25 mL EtOAc. The organic layre vvas separated and vvashed vvith brine and dried over MgSOi. After concentration the residue vvas dissolved in 10 mL anhydrous THF and stirred in an ice/vvater bath. A l.OAfsolution oftetrabutylammonium fluoride (1.10 mL) in THF vvas added dropvvise over 15 min. After 2 h of stirring in an ice bath, the reaction mixture vvas poured into a vigorously stirred mixture of 50 mL vvater, 50 mL crushed ice, 5 mL saturated aqueous ammonium chloride and 50 mL EtOAc and allovved to stand ovemight. The organic layer vvas separated and vvashed vvith brine and dried over MgSO,». After concentrated the residue vvas purified by flash chromatography on 70 cm³ silica gel using 5% EtjO/CnTCL eluent to obtain 3(4-fluorobenzylsulfanyl)-2(/?)-[2,2,2-trifluoro-l(5)-(3-phenoxyphenyl)ethylamino]propan-l-ol (237 mg) as a clear colorless resin vvhich vvas converted to the title compound by follovving the procedure described in Example 14, Steps 6 and 7 above.

Example 17

Synthesis of A-(4-cyanocyclopropy l)-3-(2-chloropheny 1)-2(5)-(2,2,2-trifluoro-l (RS)-3phenylethylamino)propionamide

Step 1

2(5)-Amino-3-(2-chiorophenyl)propionic acid (1 g, commercially available) vvas dissolved in methanol (10 mL) and HCI gas vvas bubbled through the solution for 5 min. The reaction mixture vvas stirred at room temperature for 3 h and the solvent vvas evaporated using the rotavap to get 2(S)-amino-3-(2-chlorophenyl)propionic acid methyl ester hydrochloride (1.2

g)·

Step 2

2,2,2-Trifluorol-phenylethanone (305 mg, 1.75 mmol) and 2(5)-amino-3-(2chlorophenyl)-propionic acid methyl ester hydrochioride (500 mg, 1.75mmol) vvere dissolved in DCM (10 mL). N, A-Diisopropylethylamine (1.2 mL, 7mmol) vvas added follovved by the addition IM solution ofTiCL in DCM (1.75 mL, 1.75mmol) and the reaction mixture vvas stirred for 18 h at room temperature. TiCl+ (0.9 mL, 0.9mmol) vvas added again and the solution vvas stirred at room temperature for 3 h. NaCNBH₃ (330 mg, 5.25 mmol) in MeOH (5 mL) vvas added and after stirring for 2 h, IN NaOH solution (5 mL) vvas added. After 30min, the suspension vvas filtered through celeite and the filtrate vvas extraced vvith ethylacetate. The organic layer vvas vvashed vvith brine and dried over MgSO₄. The solvent vvas evaporated to get methyl 3-(2-chlorophenyl)-2(S)-(2,2,2-trifluoro-l (7?<S)-phenylethylamino)propionate (600 mg) as a yellow solid vvhich vvas used as such for the next step.

Step3

Methyl 3-(2-chlorophenyl)-2(5)-(2,2,2-trifluoro-l(Ā5)-phenylethylamino)-propionate vvas dissolved in a mixture of MeOH (2 mL) and THE (5 mL) and IN NaOH (4 mL) vvas added and the reaction mixture vvas stirred at room temperature for 4 h. The solvent vvas evaporated using a rotavap and the pH vvas adjusted to 6 using IN HCI. The precipitated yellow solid vvas filtered and dried to give 3-(2-chlorophenyl)-2(5)-(2,2,2-trifluoro-l(/?5)-phenylethylamino)propionic acid (500 mg).

Step 4

3-(2-chlorophenyl)-2(5)-(2,2,2-trifluoro-l(7?5)-phenylethylamino)propionic acid (100 mg, 0.3 mmol) vvas dissolved in DMF (1 mL) and HATU (133 mg, 0.35 mmol), NMM (96 μΐ, 0.87mmol) and l-aminocyČlopropylcarbonitrile (41.3 mg, 0.35mmol) vvere added and the solution vvas stirred at room temperature for 4 h. The solution vvas diluted vvith ethylacetate (10 mL) and vvas vvashed vvith vvater, saturated solution of sodium bicarbonate, and brine. The organic layer vvas dried over MgSO₄ and the solvent vvas evaporated and the crude vvas purified by HPLC to give title compound (40 mg) as sticky solid. LCMS: 420.2(M-l)‘^!, 422.2(M+l)^+l.

Proceeding as described in Example 17 above, but substituting 2,2,2-trifluorol-phenylethanone vvith 2,2,2-trifluorol-(4-fluoropheny!)ethanone provided jV-(4-cyanocyclopropy!)-3-(2chlorophenyl)-2(5)-[2,2,2-trifluoro-1 (&S)-3-(4-fluorophenyl)ethylamino]propionamide LCMS: 438.3(M-l)’’,440.2(M+l)⁺¹.

Example 18

77-( 1 -cyanocycIopropyl)-3-cyciopropylmethanesuifonyl-2(J?)-(2,2,2-trifluoro-1 (5)-4fluorophenylethylamino)propionamide

Step 1

To a slurry of S-trityl-L-cysteine (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 mL/g AA) at room temperature vvas added diisopropylethylamine (9.32 mL, 53.48 mmol) follovved by a solution of trifluoromethanesulfonic acid 2,2,2-trifluoro-l(7?5)-phenyIethyl ester (5.32 g, 16.04 mmol) (major enantiomer (5), 90 ee) in dichloromethane (15 mL) via syringe ali at once. After 19 h, the reaction mixture vvas concentrated on the rotovap to give an oil. Diethyl ether vvas added and the solution vvas vvashed vvith IN HCI and brine. The organic layer vvas dried over MgSO₄, filtered, and concentrated. Flash chromatography of the residue vvith 2 hexanes/l ethyl acetate/.25% acetic acid as the eluent provided 2(/?)-[2,2,2-trifIuoro-l(/?5)-(4fluorophenyl)ethylamino]-3-tritylsulfanyl-propionic acid (6 g) (major diastereomer (7?,5), 90 de) as an oil/foam.

Step 2

Into a stirred solution of 2(7?)-[2,2,2-trifluoro-l(7?5)-(4-fluorophenyl)ethylamino]-3tritylsulfanylpropionic acid (1.93 g, 3.58 mmol) in dichloromethane (5 mL) vvas added trifluoroacetic acid (489 mg, 4.29 mmol) and triethylsilane (498.9 mg, 4.29 mmol) at room temperature. After 16 h, the reaction vvas completed and the solvent vvas removed under vacuum. The residue vvas dissolved in IN NaOH solution (15 mL) and extracted vvith hexane to remove the by products. To the aqueous solution, vvas added cyclopropylmethane bromide (482.9 mL, 3.58 mmol) in dioxane (15 mL) at room temperature. After 16 h, the organic solvent was removed under vacuum and the aqueous layer vvas acidified vvith IN HCI, then extracted vvith ethyl ether (150 mL). The organic layer vvas vvashed vvith brine, dried vvith MgSO4, and concentrated to give 2(7?)-[2,2,2-trifluoro-l(7?S)-(4-fluorophenyl)ethylamino]-3-cyclopropylmethanesulfanylpropionic acid (1.32 g).

Step 3

To a solution of 2(J?)-[2,2,2-trifluoro-l(ftS)-(4-fluorophenyI)ethylamino]-3-cyclopropylmethanesulfanylpropionic acid (1.32 g) in DMF (10 mL) vvas added l-aminocyclopropanecarbonitrile HCI salt (428.4 mg, 3.6 mg), HATU (1.64 g, 4.32 mmol), and DĪPEA (1.39 g, 10.8 mmol) at room temperature. After 2 h, the reaction mixture vvas diluted vvith ethyl ether (150 mL) and vvashed vvith saturated NaHCCL and brine, dried over MgSO₄, and concentrated to provide 77-(l-cyanocycIopropyI)-3-cyclopropyl-methanesulfanyl-2(7?)-(2,2,2-trifluoro-l(7?5)-4fluorophenyl-ethylamino)propionamide (1.03 g). LC-MS; 414.1 (M-l), 416.2(M+1), 438.1(M+Na).

Step 4

To a solution of 77-(1-cyanocycIopropyl)-3-cyclopropylmethanesulfanyl-2(7?)-(2,2,2trifIuoro-l(7iS)-4-fluorophenylethylamino)propionamide (1.03 g) in MeOH (10 mL) vvas added a solution of ΟΧΟΝΕ® (2.29 g, 3.72 mmol) in vvater (10 mL) at room temperature. After 2h, the organics vvere removed under vacumn and the product vvas extracted into ethyl acetate (150 mL). The combined organic extracts vvere vvashed vvith brine, dried over MgSO₄₎ and concentrated to yield a vvhite solid product (1.1 g). The solid vvas crystallized from a hot mixture of ethyl acetate (10 mL) and hexane (10 mL), to yield the title compound (622 mg) as a vvhite crystalline product.

H-NMR(CDC1₃): δ 8.56(1H, s, NH), 8.35-8.25(2H, m), 8.1 -8(2H, m), 5.26(1H, ab), 4.654.55(1H, m), 4.46(1H, ab), 4.25(1H, ab), 4(2H, d), 2.48-2.4(3H, m), 2.12-2(3H, m), 1.7-1.6(2H, m), 1.4-1,3(2H, m). LC-MS: 446(M-1), 448(M+1), 470.3(M+Na).

Biological Examples

Examp!e 1 Cathepsin B Assay

Solutions of tēst compounds in varying concentrations vvere prepared in 10 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: JVJV-bis(2hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMoles in 25 pL of assay buffer) vvas added to the dilutions. The assay Solutions vvere mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room temperature. Z-FR-AMC (20 nMoles in 25 pL of assay buffer) vvas added to the assay Solutions and hydrolysis vvas follovved spectrophotometrically at (λ 460 nm) for 5 min. Apparent inhibition constants (K,·) vvere calculated from the enzyme progress curves using Standard mathematical models.

Compounds of the invention vvere tested by the above-described assay and observed to exhibit cathepsin B inhibitory activity.

Example 2 Cathepsin K Assay

Solutions of tēst compounds in varying concentrations vvere prepared in 10 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μι, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25 pL of assay buffer) vvas added to the dilutions. The assay Solutions vvere mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room temperature. Z-Phe-ArgAMC (4 nMoles in 25 pL of assay buffer) vvas added to the assay Solutions and hydrolysis vvas follovved spectrophotometrically at (λ 460 nm) for 5 min. Apparent inhibition constants (K,) vvere calculated from the enzyme progress curves using Standard mathematical models.

Compounds of the invention vvere tested by the above-described assay and observed to exhibit cathepsin K inhibitory activity.

Example 3 Cathepsin L Assay

Solutions of tēst compounds in varying concentrations vvere prepared in 10 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25 pL of assay buffer) vvas added to the dilutions. The assay Solutions vvere mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room temperature. Z-Phe-Arg-AMC (1 nMoles in 25 pL of assay buffer) vvas added to the assay Solutions and hydrolysis vvas follovved spectrophotometrically at (λ 460 nm) for 5 min. Apparent inhibition constants (K,) vvere calculated from the enzyme progress curves using Standard mathematical models.

Compounds of the invention vvere tested by the above-described assay and observed to exhibit cathepsin L inhibitory activity.

Example 4 Cathepsin S Assay

Solutions of tēst compounds in varying concentrations vvere prepared in 10 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM); β-mercaptoethanol, 2.5 mM; and BSA, 0.00%. Human cathepsin S (0.05 pMoles in 25 pL of assay buffer) vvas added to the dilutions. The assay Solutions vvere mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room temperature. Z-Val-Val-Arg-AMC (4 nMoles in 25 pL of assay buffer containing 10% DMSO) vvas added to the assay Solutions and hydrolysis vvas follovved spectrophotometrically (at λ 460 nm) for 5 min. Apparent inhibition constants (K,) vvere calculated from the enzyme progress curves using Standard mathematical models.

Compounds of the invention vvere tested by the above-described assay and observed to exhibit cathepsin S inhibitory activity of less than lOOnm.

Example 5 Cathepsin F Assay

Solutions of tēst compounds in varying concentrations vvere prepared in 10 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (_PH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM); DTT, 2.5 mM; and BSA, 0.01%. Human cathepsin F (0.1 pMoles in 25 pL of assay buffer) vvas added to the dilutions. The assay Solutions vvere mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room temperature. Z-Phe-Arg-AMC (2 nMoles in 25 pL of assay buffer containing 10% DMSO) vvas added to the assay Solutions and hydrolysis vvas follovved spectrophotometrically (at λ 460 nm) for 5 min. Apparent inhibition constants (K,) vvere calculated from the enzyme progress curves using Standard mathematical models.

Compounds of the invention vvere tested by the above-described assay and observed to exhibit cathepsin F inhibitory activity.

Example 1

Representative pharmaceutical formulations Containing a Compound of Formula (I) ORAL FORMULATION

Compound of Formula (I)	10-100 mg
Citric Acid Monohydrate	105 mg
Sodium Hydroxide	18 mg
Flavoring
Water	q.s. to 100 mL
INTRAVENOUS FORMULATION
Compound of Formula (I)	0.1-10 mg
Dextrose Monohydrate	q.s. to make isotonic
Citric Acid Monohydrate	1.05 mg
Sodium Hydroxide	0.18 mg
Water for Injection	q.s. to 1.0 mL
TABLET FORMULATION
Compound of Formula (I)	1%
Microcrystalline Cellulose	73%
Stearic Acid	25%
Colloidal Silica	1%

The foregoing invention has been described in some detail by way of iIlustration and example, for purposes of clarity and understanding. It vvill be obvious to one of skill in the art that changes and modifications may be practiced vvithin the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not vvith reference to the above description, but should instead be determined vvith reference to the follovving appended claims, along vvith the full scope of equivalents to vvhich such claims are entitled.

Claims (34)

1. Izgudrojuma formula

   1. Savienojums ar formulu (I):

   kurā:

   R¹ ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa vai alkoksialkilgrupa; ir ūdeņraža i

   karboksialkilgrupa, cikloalkilalkilgrupa, heteroaralkilgrupa,

   R‘ atoms, alkilgrupa, halogēnalkilgrupa, alkoksikarbonilalkilgrupa, cikloalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heterocikliska grupa, heterociklilalkilgrupa, ciāngrupa, vai alkilēngrupa-X-R⁹ (kur X ir -0-, -NR¹⁰-, -CONR¹¹-, -S(O)ni-, -NR¹²CO-, -CO- vai -C(O)O-, kur n1 ir 0-2, un R⁹, R¹⁰, R¹¹ un R¹², neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa vai heteroaralkilgrupa), kur aromātiski vai alicikliski cikli R² grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^a, kas neatkarīgi ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, karboksilgrupa, alkoksikarbonilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa, nitrogrupa, ariloksigrupa, benziloksigrupa, acilgrupa vai ariisulfonilgrupa un papildus aromātiski vai alicikliski cikli R^a grupā ir neobligāti aizvietoti ar vienu vai diviem aizvietotājiem, kas ir izvēlēti no rindas: alkilgrupa, halogēna atoms, alkoksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, hidroksilgrupa, aminogrupa, alkilaminogrupa, dialkilaminogrupa, karboksilgrupa vai alkoksikarbonilgrupa; vai

   R¹ un R² ir savienoti kopā ar oglekļa atomu, pie kā abi R¹ un R² ir pievienoti, veidojot:

   (i) cikloalkilēngrupu, neobligāti aizvietotu ar vienu vai diviem R^b, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, alkilaminogrupa, dialkilaminogrupa, arilgrupa, aralkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, heteroarilgrupa, heteroaralkilgrupa, alkoksikarbonilgrupa vai ariloksikarbonilgrupa, (ii) četru atomu heterociklilalkilēnciklu, vai (iii) heterociklilalkilēngrupu, neobligāti aizvietotu ar 1-4 R^c, kas, neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, hidroksilgrupa, hidroksialkilgrupa, alkoksialkilgrupa, alkoksialkiloksialkilgrupa, ariloksialkilgrupa, heteroariloksialkilgrupa, aminoalkilgrupa, acilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa, heterociklilalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, -S(O)_n2R¹⁴, -alkilēngrupa-S(O)n2-R¹⁵. -COOR¹⁶, -alkilēngrupa-COOR¹⁷, -CONR¹⁸R¹⁹ vai -alkilēngrupa-CONR²⁰R²¹ (kur n2 ir 0-2, un R¹⁴-R¹⁷, R¹⁸ un R²⁰, neatkarīgi viens no otra, ir izvēlēti no rindas: ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, cikloalkilgrupa, cikloalkilalkil• grupa vai heterocikliska grupa un R¹⁹ un R²¹, neatkarīgi viens no otra, ir ūdeņraža atoms vai alkilgrupa), kur aromātiski vai alicikliski cikli grupās, kas ir pievienotas pie cikloalkiiēngrupas vai heterocikloalkilēngrupas ir neobligāti aizvietoti ar vienu, diviem vai trim aizvietotājiem, kas neatkarīgi ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, aralkilgrupa, ariloksikarbonilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, karboksilgrupa, alkoksikarbonilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa vai acilgrupa;

   R³ ir ūdeņraža atoms vai alkilgrupa;

   R⁴ ir 1 -alkilciklopentilmetilgrupa, 1 -alkilciklopentiletilgrupa, 1-alkilcikloheksilmetilgrupa, 1 -alkilcikloheksiletilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterociklilalkilgrupa vai -alkilēngrupa-X¹-R²² (kur X¹ ir -NR-, -0-, -S(O)n3-, -CO-, -COO-, -OCO-, -NR²³CO-, -CONR²³-, -NR²³SO2-, -SO₂NR²³-, -NR²³COO-, -OCONR²³-, -NR²³CONR²⁴- vai -NR²³SO₂NR²⁴-, kur R²³ un R²⁴, neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa vai acilgrupa, n3 ir 0-2, un R²² ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa vai heterociklilalkilgrupa), kur alkilēngrupas ķēde R⁴ aizvietotājā ir neobligāti aizvietota ar 1-6 halogēna atomiem un kur aromātiski vai alicikliski cikli R⁴ grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^d, kas, neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, nitrogrupa, ciāngrupa, karboksilgrupa, alkoksikarbonilgrupa, arilgrupa, heteroarilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, aralkilgrupa, heteroaralkilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa vai acilgrupa;

   R⁵ ir ūdeņraža atoms vai alkilgrupa;

   R⁶ ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa, vai alkilēngrupa-X²-R²⁵ (kur X² ir -NR²⁶-, -O-, -S(O)n4-, -CO-, -COO-, -OCO-, -NR²⁶CO-, -CONR²⁶-, -NR²⁶SO2-, -SO₂NR²⁶-, -NR²⁶COO-, -OCONR²⁶-,

   -NR²⁶CONR²⁷- vai -NR²⁶SO₂NR²⁷-, kur R²⁶ un R²⁷, neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa vai acilgrupa, n4 ir 0-2, un R²⁵ ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, heterocikliska grupa, heterociklilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa vai heteroaralkilgrupa), kur minētā alkilēngrupas ķēde R⁶ aizvietotājā ir neobligāti aizvietota ar

   1-6 halogēna atomiem un kur aromātiski vai alicikliski cikli R⁶ grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^e, kas, neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, hidroksilgrupa, hidroksialkilgrupa, hidroksialkoksigrupa, alkoksigrupa, alkoksialkilgrupa, alkoksialkiloksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, oksogrupa, ciāngrupa, nitrogrupa, acilgrupa, arilgrupa, aralkilgrupa, ariloksigrupa, aralkiloksigrupa, arilsulfonilgrupa, heteroarilgrupa, heteroaralkilgrupa, heteroariloksigrupa, heteroaralkiloksigrupa, heteroarilsulfonilgrupa, heterocikliska grupa, heterociklilalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, karboksilgrupa, alkoksikarbonilgrupa, alkilsulfonilgrupa, aminosulfonilgrupa vai aminoalkilgrupa un papildus aromātiski vai alicikliski cikli R^e grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^f, kas neatkarīgi ir izvēlēti no rindas: alkilgrupa, alkoksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, halogēna atoms, hidroksilgrupa, karboksil-grupa, ciāngrupa, nitrogrupa, arilgrupa vai cikloalkilgrupa;

   R⁷ ir halogēnalkilgrupa, neobligāti aizvietota ar alkoksigrupu vai alkoksialkiloksigrupu; un

   R⁸ ir ūdeņraža atoms, alkilgrupa, alkoksialkilgrupa vai halogēnalkilgrupa; vai

   R⁶ un R⁸ ir savienoti kopā ar oglekļa atomu, pie kā tie ir pievienoti, veidojot cikloalkilēngrupu vai heterociklilalkilēngrupu, kur minētā cikloalkilēngrupa ir neobligāti aizvietota ar 1-4 aizvietotājiem, kas, neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, halogēnalkilgrupa, hidroksilgrupa vai alkoksigrupa un heterociklilalkilēngrupa ir neobligāti aizvietota ar 1 vai 2 aizvietotājiem, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, halogēnalkilgrupa, cikloalkilgrupa, hidroksilgrupa vai alkoksigrupa; vai tā farmaceitiski pieņemama sāls.
2. 2. Savienojums ar formulu (I):

   kurā:

   R¹ ir ūdeņraža atoms vai alkilgrupa;

   R² ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, karboksialkilgrupa, alkoksikarbonilalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa, heterociklilalkilgrupa, ciāngrupa, vai alkilēngrupa-X-R⁹ (kur X ir -0-, -NR¹⁰-, -CONR¹¹-, -S(0)m-, -NR¹²CO-, -CO- vai -C(O)O-, kur n1 ir 0-2, un R⁹, R¹⁰, R¹¹ un R¹², neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa vai heteroaralkilgrupa), kur aromātiski vai alicikliski cikli R² grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^a, kas neatkarīgi ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, karboksilgrupa, alkoksikarbonilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa, nitrogrupa, ariloksigrupa, benziloksigrupa, acilgrupa vai arilsulfonilgrupa un papildus aromātiski vai alicikliski cikli R^a grupā ir neobligāti aizvietoti ar vienu vai diviem aizvietotājiem, kas ir izvēlēti no rindas: alkilgrupa, halogēna atoms, alkoksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, hidroksilgrupa, aminogrupa, alkilaminogrupa, dialkiiaminogrupa, karboksilgrupa vai alkoksikarbonilgrupa; vai

   R¹ un R² ir savienoti kopā ar oglekļa atomu, pie kā R¹ un R² ir pievienoti, veidojot:

   (i) cikloalkilēngrupu, neobligāti aizvietotu ar vienu vai diviem R^b, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, alkilaminogrupa, dialkiiaminogrupa, arilgrupa, aralkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, heteroarilgrupa, heteroaralkilgrupa, alkoksikarbonilgrupa vai ariloksikarbonilgrupa, vai (ii) heterociklilalkilēngrupu, neobligāti aizvietotu ar 1-4 R^c, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, hidroksilgrupa, hidroksialkilgrupa, alkoksialkilgrupa, alkoksialkiloksialkilgrupa, ariloksialkilgrupa, heteroariloksialkilgrupa, aminoalkilgrupa, acilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa, heterociklilalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, -S(O)n2R¹⁴, -alkilēngrupa-S(O)n2-R¹⁵, -COOR¹⁸, -alkilēngrupa-COOR¹⁷, -CONR¹⁸R¹⁹ vai -alkilēngrupa-CONR²⁰R²¹ (kur n2 ir 0-2, un R¹⁴-R¹⁷, R¹⁸ un R²⁰, neatkarīgi viens no otra, ir izvēlēti no rindas: ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa vai heterocikliska grupa un R¹⁹ un R²¹, neatkarīgi viens no otra, ir ūdeņraža atoms vai alkilgrupa), kur aromātiski vai alicikliski cikli grupās, kas ir pievienotas pie cikloalkilēngrupas vai heterocikloalkilēngrupas ir neobligāti aizvietoti ar vienu, diviem vai trim aizvietotājiem, kas neatkarīgi ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, karboksilgrupa, alkoksikarbonilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa vai acilgrupa;

   R³ ir ūdeņraža atoms vai alkilgrupa;

   R⁴ ir arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterociklilalkilgrupa vai -alkilēngrupa-X-R²² (kur X¹ ir -NR²³-, -O-, -S(O)n3-, -co-, -coo-, -oco-, -nr²³co-, -conr²³-, -nr²³so2-, -SO₂NR²³-, -NR²³COO-, -OCONR²³-, -NR²³CONR²⁴- vai -NR²³SO₂NR²⁴-, kur R²³ un R²⁴, neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa vai acilgrupa, n3 ir 0-2, un R²² ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa vai heterociklilalkilgrupa), kur minētā alkilēngrupas ķēde R⁴ aizvietotājā ir neobligāti aizvietota ar 1-6 halogēna atomiem un kur aromātiski vai alicikliski cikli R⁴ grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^d,.kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, nitrogrupa, ciāngrupa, karboksilgrupa, alkoksikarbonilgrupa, arilgrupa, heteroarilgrupa, cikloalkilgrupa, cikloaikilalkilgrupa, aralkilgrupa, heteroaralkilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa vai acilgrupa;

   R⁵ ir ūdeņraža atoms vai alkilgrupa;

   R⁶ ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa, vai alkilēngrupa-X²-R²⁵ (kur X² ir -NR²⁶-, -0-, -S(O)n4-, -CO-, -COO-, -OCO-, -NR²⁶CO-, -CONR²⁶-, -NR²⁶SO2-, -SO₂NR²⁶-, -NR²⁶COO-, -OCONR²⁶-, -NR²⁶CONR²⁷- vai -NR²⁶SO₂NR²⁷-, kur R²⁶ un R²⁷, neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa vai acilgrupa, n4 ir 0-2, un R²⁵ ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloaikilalkilgrupa, heterocikliska grupa, heterociklilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa vai heteroaralkilgrupa), kur minētā alkilēngrupas ķēde R⁶ aizvietotājā ir neobligāti aizvietota ar 1-6 halogēna atomiem un aromātiski vai alicikliski cikli R⁶ grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R®, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, hidroksilgrupa, alkoksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, oksogrupa, ciāngrupa, nitrogrupa, acilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa, cikloalkilgrupa, cikloaikilalkilgrupa, karboksilgrupa vai alkoksikarbonilgrupa, un papildus aromātiski vai alicikliski cikli R® grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^f, kas ir izvēlēti no rindas: alkilgrupa, alkoksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, halogēna atoms, hidroksilgrupa, karboksilgrupa, ciāngrupa, nitrogrupa, arilgrupa vai cikloalkilgrupa;

   R⁷ ir halogēnalkilgrupa; un

   R⁸ ir ūdeņraža atoms, alkilgrupa, alkoksialkilgrupa vai halogēnalkilgrupa; vai

   R⁶ un R⁸ ir savienoti kopā ar oglekļa atomu pie kā tie ir pievienoti, veidojot cikloalkilēngrupu vai heterociklilalkilēngrupu, kur minētā cikloalkilēngrupa ir neobligāti aizvietota ar 1 vai 2 aizvietotājiem, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, hidroksilgrupa vai alkoksigrupa un heterociklilalkilēngrupa ir neobligāti aizvietota ar 1 vai 2 aizvietotājiem, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, hidroksilgrupa vai alkoksigrupa; vai tā farmaceitiski pieņemama sāls.
3. 3. Savienojums pēc 2. punkta, kur R¹ un R² ir ūdeņraža atoms.
4. 4. Savienojums pēc 2. punkta, kur R¹ un R² ir savienoti kopā ar oglekļa atomu pie kā tie ir pievienoti, veidojot cikloalkilēngrupu, neobligāti aizvietotu ar vienu vai diviem R^b, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, dialkilaminogrupa, arilgrupa, aralkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, heteroarilgrupa, heteroaralkilgrupa, alkoksikarbonilgrupa vai ariloksikarbonilgrupa.
5. 5. Savienojums pēc 2. punkta, kur R¹ un R² ir savienoti kopā ar oglekļa atomu, pie kā tie ir pievienoti, veidojot ciklopropilēngrupu.
6. 6. Savienojums pēc 2. punkta, kur R¹ un R² ir savienoti kopā ar oglekļa atomu, pie kā tie ir pievienoti, veidojot heterocikloalkilēngrupu.
7. 7. Savienojums pēc 2. punkta, kur R¹ un R² ir savienoti kopā ar oglekļa atomu, pie kā tie ir pievienoti, veidojot pirolidinilgrupu, piperidin-4ilgrupu, aizvietotu 1. pozīcijā ar metilgrupu, etiigrupu, propilgrupu, nbutilgrupu vai 2,2,2-trifluoretilgrupu, tetrahidropiranilgrupu, tetrahidrotiopiranilgrupu, tetrahidrotiopiran-4-il-1-oksīda grupu vai tetrahidropiran-4il-1,1-dioksīda grupu.
8. 8. Savienojums pēc jebkura no 2., 4. vai 5. punkta, kur:

   R⁴ ir aralkilgrupa, heteroaralkilgrupa, heterociklilalkilgrupa vai

   -aikilēngrupa-X¹-R²² (kur X¹ ir -NR²³-, -0-, -S(0)_n3-, -CO-, -COO-,

   -OCO-, -NR²³CO-, -CONR²³-, -NR²³SO₂-, -SO₂NR²³-, -NR²³COO-,

   -OCONR²³-, -NR²³CONR²⁴- vai -NR²³SO₂NR²⁴-, kur R²³ un R²⁴, neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa vai acilgrupa, n3 ir 0-2, un R²² ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa vai heterociklilalkilgrupa), kur minētā alkilēngrupas ķēde R⁴ aizvietotājā ir neobligāti aizvietota ar 1-6 halogēna atomiem un kur papildus aromātiski vai alicikliski cikli R⁴ grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^d, kas, neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, nitrogrupa, ciāngrupa, karboksilgrupa, alkoksikarbonilgrupa, arilgrupa, heteroarilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, aralkilgrupa, heteroaralkilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa vai acilgrupa;

   R³ un R⁵ ir ūdeņraža atoms.

   i ⁹
9. 9. Savienojums pēc 6. vai 7. punkta, kur:

   R⁴ ir aralkilgrupa, heteroaralkilgrupa, heterociklilalkilgrupa vai

   -alkilēngrupa-X¹-R²² (kur X¹ ir -NR²³-, -0-, -S(0)_n3-, -CO-, -COO-,

   -OCO-, -NR²³CO-, -CONR²³-, -NR²³SO₂-, -SO₂NR²³-, -NR²³COO-,

   -OCONR²³-, -NR²³CONR²⁴- vai -NR²³SO₂NR²⁴-, kur R²³ un R²⁴, neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa vai acilgrupa, n4 ir 0-2, un R²² ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa vai heterociklilalkilgrupa), kur minētā alkilēngrupas ķēde R⁴ aizvietotājā ir neobligāti aizvietota ar 1-6 halogēna atomiem un kur papildus aromātiski vai alicikliski cikli R⁴ grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^d, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, nitrogrupa, ciāngrupa, karboksilgrupa, alkoksikarbonilgrupa, arilgrupa, heteroarilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, aralkilgrupa, heteroaralkilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa vai acilgrupa;

   R³ un R⁵ ir ūdeņraža atoms.
10. 10. Savienojums pēc jebkura no 2., 4. vai 5. punkta, kur:

    R⁴ ir etiltiometilgrupa, etilsulfinilmetilgrupa, etilsulfonilmetilgrupa, izopropiltiometilgrupa, 2-metiltioetilgrupa, 2-metilsulfiniletilgrupa, 2metilsulfoniletilgrupa, 2-metilpropilsulfonilmetilgrupa, izobutilsulfanilmetilgrupa, t-butiltiometilgrupa, benzolsulfonilmetilgrupa, 2fenilsulfaniletilgrupa, 2-fenilsulfoniletilgrupa, naft-2-ilmetan-sulfonilmetilgrupa, bifenil-2-ilmetansulfonilmetilgrupa, bifenil-4-ilmetansulfonilmetilgrupa, fenilmetansulfanilmetilgrupa, fenilmetansulfinilmetilgrupa, fenilmetansulfonilmetilgrupa, 2-fenilmetansulfoniletilgrupa, 4-t-butilfenilmetansulfonilmetilgrupa, 2-fluorfenilmetansulfanilmetilgrupa, 2-fluorfenilmetansulfonilmetilgrupa, 3-fluorfenilmetansulfonilmetilgrupa, 4-fluorfenilmetansulfonilmetilgrupa, 2-hlorfenilmetansulfanilmetilgrupa, 2-hlorfenilmetansulfonilmetilgrupa, 3hlorfenilmetansulfonilmetilgrupa, 4-hlorfenilmetansulfonilmetilgrupa,

    2-metoksifenilmetansulfonilmetilgrupa, 4-metoksifenilmetansulfonilmetilgrupa, 2-trifluormetoksifenilmetansulfonilmetilgrupa, 3-trifluormetoksifenilmetansulfonilmetilgrupa, 4-trifluormetoksifenilmetansulfonilmetilgrupa, 2-trifluormetilfenilmetansulfanilmetilgrupa, 2trifluormetilfenilmetansulfonilmetilgrupa, 3-trifluormetilfenilmetansulfonilmetilgrupa, 4-trifluormetilfenilmetansulfonilmetilgrupa, 2ciānfenilmetansulfanilmetilgrupa, 2-ciānfenilmetansulfonilmetilgrupa, 3-ciānfenilmetansulfonilmetilgrupa, 2-bromfenilmetansulfonilmetilgrupa, 2-nitrofenilmetansulfanilmetilgrupa, 2-nitrofenilmetansuifonilmetilgrupa, 2-metilfenilmetansulfonilmetilgrupa, 3-metilfenilmetansulfonilmetilgrupa, 4-metilfenilmetansulfonilmetilgrupa, 2-(4trifluormetoksibenzolsulfonil)etilgrupa, 2-(3-trifluormetoksibenzolsulfonil)etilgrupa, 2-(2-trifluormetoksibenzolsulfonil)etilgrupa, 2difluormetoksifenilmetansulfonilmetilgrupa, 3-difluormetoksifenilmetansulfonilmetilgrupa, 4-difluormetoksifenilmetansulfonilmetilgrupa, 2-(4-difIuormetoksibenzolsulfonil)etilgrupa, 2-(2difluormetoksibenzolsulfonil)etilgrupa, 2-(3-difluormetoksibenzolsulfonil)etilgrupa, 3-hlor-2-fluorfenilmetansulfonilmetilgrupa, 3,5dimetilfenilmetansulfonilmetilgrupa, 3,5-bis-trifluormetilfenilmetansulfonilmetilgrupa, 2,5-difluorfenilmetansulfoniimetilgrupa, 2,6difluorfenilmetansulfonilmetilgrupa, 2,3-difluorfenilmetansulfonilmetilgrupa, 3,4-difluorfenilmetansulfonilmetilgrupa, 2,4-difluorfenilmetansulfonilmetilgrupa, 2,5-dihlorfenilmetansulfonilmetilgrupa,

    3,4-dihlorfenilmetansulfonilmetilgrupa, 2,6-dihlorfenilmetansulfonilmetilgrupa, 2-fluor-3-metilfenilmetansulfonilmetilgrupa, 4-fluor-2trifluormetoksifenilmetansuifonilmetilgrupa, 2-fluor-6-trifluormetilfenilmetansulfoniimetilgrupa, 2-fluor-3-trifluormetilfenilmetansulfonilmetiigrupa, 2-fluor-4-trifluormetilfenilmetansulfonilmetilgrupa, 2fluor-5-trifluormetilfenilmetansulfonilmetilgrupa, 4-fluor-3-trifluormetilfenilmetansulfonilmetilgrupa, 2-hlor-5-trifluormetilfenilmetansulfonilmetilgrupa, 2,4,6-trifluorfenilmetansulfonilmetilgrupa, 2,4,5trifluorfenilmetansulfonilmetilgrupa, 2,3,4-trifluorfenilmetansulfonilmetilgrupa, 2,3,5-trifluorfenilmetansulfonilmetilgrupa, 2,5,6-trifluorfenilmetansulfonilmetilgrupa, 3,4,5-trimetoksifenilmetansulfonil8 metilgrupa, piridin-2-ilmetansulfonilmetilgrupa, piridin-3-ilmetansulfonilmetilgrupa, piridin-4-ilmetansulfonilmetilgrupa, 2-(piridin-2ilsulfonil)etilgrupa, 2-(piridin-4-ilsulfonil)etilgrupa, oksipiridin-2ilmetansulfonilmetilgrupa, cikoheksilmetansulfanilmetilgrupa, cikoheksilsulfiniltiometilgrupa, cikoheksilmetansulfonilmetilgrupa, cikoheksilmetansulfonilmetilgrupa, cikopropilmetansulfonilmetilgrupa, tiofen-2-sulfonilmetilgrupa, 5-hlortien-2-ilmetansulfonilmetilgrupa vai 3,5-dimetilizoksazol-4-ilmetansulfonilmetilgrupa;

    un R³ un R⁵ ir ūdeņraža atoms.
11. 11. Savienojums pēc 7. punkta, kur:

    R⁴ ir etiltiometilgrupa, etilsulfinilmetilgrupa, etilsulfonilmetilgrupa, izopropiltiometilgrupa, 2-metiltioetilgrupa, 2-metilsulfiniletilgrupa, 2metilsulfoniletilgrupa, 2-metilpropilsulfonilmetilgrupa, izobutilsulfanilmetilgrupa, t-butiltiometilgrupa, benzolsulfonilmetilgrupa, 2fenilsulfaniletilgrupa, 2-fenilsulfoniletilgrupa, naft-2-ilmetansulfonilmetilgrupa, bifenil-2-ilmetansulfonilmetilgrupa, bifenil-4ilmetansulfonilmetilgrupa, fenilmetansulfanilmetilgrupa, fenilmetansulfinilmetilgrupa, fenilmetansulfonilmetilgrupa, 2-fenilmetansulfoniletilgrupa, 4-t-butilfenilmetansulfonilmetilgrupa, 2-fluorfenilmetansulfanilmetilgrupa, 2-fluorfenilmetansulfonilmetilgrupa, 3-fluorfenilmetansulfonilmetilgrupa, 4-fluorfenilmetansulfonilmetilgrupa, 2-hlorfenilmetansulfanilmetilgrupa, 2-hlorfenilmetansulfonilmetilgrupa, 3hlorfenilmetansulfonilmetilgrupa, 4-hlorfenilmetansulfonilmetilgrupa,

    2-metoksifenilmetansulfonilmetilgrupa, 4-metoksifenilmetansulfonilmetilgrupa, 2-trifluormetoksifenilmetansulfonilmetilgrupa, 3-trifluormetoksifenilmetansulfonilmetilgrupa, 4-trifluormetoksifenilmetansulfonilmetilgrupa, 2-trifluormetilfenilmetansulfanilmetilgrupa, 2trifluormetilfenilmetansulfonilmetilgrupa, 3-trifluormetilfenilmetansulfonilmetilgrupa, 4-trifluormetilfenilmetansulfonilmetilgrupa, 2ciānfenilmetansulfanilmetilgrupa, 2-ciānfenilmetansulfonilmetilgrupa, 3-ciānfenilmetansulfonilmetilgrupa, 2-bromfenilmetansulfonilmetilgrupa, 2-nitrofenilmetansulfanilmetilgrupa, 2-nitrofenilmetansulfonilmetilgrupa, 2-metilfenilmetansulfonilmetilgrupa, 3-metilfenilmetansulfonilmetilgrupa, 4-metilfenilmetansulfonilmetilgrupa, 2-(4trifluormetoksibenzolsulfonil)etilgrupa, 2-(3-trifluormetoksibenzolsulfonil)etilgrupa, 2-(2-trifluormetoksibenzolsulfonil)etilgrupa, 2difluormetoksifenilmetansulfonilmetilgrupa, 3-difluormetoksifenilmetansulfonilmetilgrupa, 4-difluormetoksifenilmetansulfonilmetilgrupa, 2-(4-difluormetoksibenzolsulfonil)etilgrupa, 2-(2difluormetoksibenzolsulfonil)etilgrupa, 2-(3-difluormetoksibenzolsulfoniljetilgrupa, 3-hlor-2-fluorfenilmetansulfonilmetilgrupa, 3,5dimetilfenilmetansulfonilmetilgrupa, 3,5-bis-trifluormetilfenilmetansulfonilmetilgrupa, 2,5-difluorfenilmetansulfonilmetilgrupa, 2,6difluorfenilmetansulfonilmetilgrupa, 2,3-difluorfenilmetansulfonilmetilgrupa, 3,4-difluorfenilmetansulfonilmetilgrupa, 2,4-difluorfenilmetansulfonilmetilgrupa, 2,5-dihlorfenilmetansulfonilmetilgrupa,

    3,4-dihlorfenilmetansulfonilmetilgrupa, 2,6-dihlorfenilmetansulfonilmetilgrupa, 2-fluor-3-metilfenilmetansulfonilmetilgrupa, 4-fluor-2trifluormetoksifenilmetansulfonilmetilgrupa, 2-fluor-6-trifluormetilfenilmetansulfonilmetilgrupa, 2-fluor-3-trifluormetilfenilmetansulfonilmetilgrupa, 2-fluor-4-trifluormetilfenilmetansulfonilmetilgrupa, 2LV 13440 fluor-5-trifluormetilfenilmetansulfonilmetilgrupa, 4-fluor-3-trifluormetilfenilmetansulfonilmetilgrupa, 2-hlor-5-trifluormetilfenilmetansulfonilmetilgrupa, 2,4,6-trifluorfenilmetansulfonilmetilgrupa, 2,4,5trifluorfenilmetansulfonilmetilgrupa, 2,3,4-trifluorfenilmetansulfonilmetilgrupa, 2,3,5-trifluorfenilmetansulfonilmetilgrupa, 2,5,6-trifluorfenilmetansulfonilmetilgrupa, 3,4,5-trimetoksifenilmetansulfonilmetilgrupa, piridin-2-ilmetansulfonilmetilgrupa, piridin-3-ilmetansulfonilmetilgrupa, piridin-4-ilmetansulfonilmetilgrupa, 2-(piridin-2ilsulfonil)etilgrupa, 2-(piridin-4-ilsulfonil)etilgrupa, oksipiridin-2ilmetansulfonilmetilgrupa, cikoheksilmetansulfanilmetilgrupa, cikoheksilsulfiniltiometilgrupa, cikoheksilmetansulfonilmetilgrupa, cikoheksilmetansulfonilmetilgrupa, cikopropiimetansulfonilmetilgrupa, tiofen-2-sulfonilmetilgrupa, 5-hlortien-2-ilmetansulfonilmetilgrupa vai 3,5-dimetilizoksazol-4-ilmetansulfonilmetilgrupa;

    un R³ un R⁵ ir ūdeņraža atoms.

    i
12. 12. Savienojums pēc 10. vai 11. punkta, kur:

    R⁶ ir alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, fenilgrupa, benzilgrupa, naftilgrupa, alkil-SO2-alkilgrupa, cikloafkil-SC>2alkilgrupa, aril-SO2-alkilgrupa, pirolidinilgrupa, piperidinilgrupa, morfolinilgrupa, tiomorfolinilgrupa, piperazinilgrupa, indolinilgrupa, piranilgrupa, tiopiraniigrupa, furanilgrupa, tienilgrupa, pirolilgrupa, oksazolilgrupa, tiazolilgrupa, imidazolilgrupa, piridinilgrupa, izoksazolilgrupa, pirimidinilgrupa, piraziniigrupa, piridazinilgrupa, indolilgrupa, hinolinilgrupa, benzofuranilgrupa, benztienilgrupa, benzimidazolil-grupa, benztiazolilgrupa, benzizoksazolilgrupa, benzoksazolilgrupa vai aminogrupa; kur aromātiski vai alicikliski cikli R⁶ aizvietotājā ir neobligāti aizvietoti ar vienu, diviem vai trim R^e;

    katrs R^e ir neatkarīgi alkilgrupa, halogēna atoms, hidroksilgrupa, oksogrupa, karboksilgrupa, ciāngrupa, nitrogrupa, cikloalkilgrupa, fenilgrupa, naftilgrupa, pirolidinilgrupa, piperidinilgrupa, morfolinilgrupa, tiomorfolinilgrupa, piperazinilgrupa, furanilgrupa, tienilgrupa, oksazolilgrupa, tiazolilgrupa, imidazolilgrupa, triazolilgrupa, tetrazolilgrupa, piridinilgrupa, pirimidinilgrupa, piraziniigrupa, indolilgrupa, benzofuranilgrupa, benztienilgrupa, benzimidazolilgrupa, benztiazolilgrupa, benzoksazolilgrupa, hinolinilgrupa, izohinolinilgrupa, hinazoiinilgrupa, hinoksalinilgrupa, alkoksigrupa, -COR (kur R ir alkilgrupa), alkoksikarbonilgrupa, ariloksikarbonilgrupa, kur aromātiski vai alicikliski cikli R^e aizvietotājā ir papildus neobligāti aizvietoti ar vienu, diviem vai trim R^f, kas ir neatkarīgi izvēlēts no rindas: alkilgrupa, alkoksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, halogēna atoms, hidroksilgrupa, karboksilgrupa, ciāngrupa, nitrogrupa, arilgrupa vai cikloalkilgrupa.
13. 13. Savienojums pēc 10. vai 11. punkta, kur:

    R⁶ ir metilgrupa, etilgrupa, izopropilgrupa, trifluormetilgrupa, ciklopropilgrupa, ciklopentilgrupa, cikloheksilgrupa, fenilgrupa, benzilgrupa, naftilgrupa, pirolidinilgrupa, piperidinilgrupa, morfolinilgrupa, tiomorfolinilgrupa, piperazinilgrupa, furanilgrupa, tienilgrupa, tiazolilgrupa, imidazolilgrupa, piridinilgrupa vai pirazinilgrupa, kur aromātiski vai alicikliski cikli R³ aizvietotājā ir neobligāti aizvietoti ar vienu, diviem vai trim R^e, kas ir netkarīgi izvēlēts no rindas: metilgrupa, etilgrupa, fluora.atoms, hlora atoms, broma atoms, joda atoms, hidroksilgrupa, oksogrupa, karboksilgrupa, ciāngrupa, nitrogrupa, ciklopropilgrupa, fenilgrupa, pirolidinilgrupa, piperidinilgrupa, morfolinilgrupa, tiomorfolinilgrupa, piperazinilgrupa, tienilgrupa, imidazolilgrupa, metoksigrupa, acetilgrupa vai metoksikarbonilgrupa, kur aromātiski vai alicikliski cikli R^e aizvietotājā ir papildus neobligāti aizvietoti ar vienu, diviem vai trim R^f, kas ir neatkarīgi izvēlēts no rindas: metilgrupa, ciklopropilgrupa, fenilgrupa, metoksigrupa, fluora atoms, hlora atoms, hidroksilgrupa vai karboksilgrupa.
14. 14. Savienojums pēc 10. vai 11. punkta, kur:

    R⁶ ir metilgrupa, etilgrupa, izopropilgrupa, trifluormetilgrupa, ciklopropilgrupa, ciklopentilgrupa, cikloheksilgrupa, fenilgrupa, benzilgrupa, naftilgrupa, pirolidinilgrupa, piperidinilgrupa, morfolinilgrupa, tiomorfolinilgrupa, piperazinilgrupa, furanilgrupa, tienilgrupa, tiazolilgrupa, imidazolilgrupa, piridinilgrupa vai pirazinilgrupa, kur aromātiski vai alicikliski cikli R³ aizvietotājā ir neobligāti aizvietoti ar vienu, diviem vai trim R^e, kas ir netkarīgi izvēlēts no rindas: metilgrupa, etilgrupa, fluora atoms, hlora atoms, broma atoms, joda atoms, hidroksilgrupa, oksogrupa, karboksilgrupa, ciāngrupa, nitrogrupa, ciklopropilgrupa, fenilgrupa, pirolidinilgrupa, piperidinilgrupa, piperazinilgrupa, tienilgrupa, imidazolilgrupa, metoksigrupa, acetilgrupa vai metoksikarboniigrupa, kur aromātiski vai alicikliski cikli R^e aizvietotājā ir papildus neobligāti aizvietoti ar vienu, diviem vai trim R^f, kas ir neatkarīgi izvēlēts no rindas: metilgrupa, ciklopropilgrupa, fenilgrupa, metoksigrupa, fluora atoms, hlora atoms, hidroksilgrupa vai karboksilgrupa.
15. 15. Savienojums pēc 10. vai 11. punkta, kur:

    R⁶ ir fenilgrupa, 4-metoksifenilgrupa, 4-hlorfenilgrupa, 4fluorfenilgrupa, 2-fluorfenilgrupa, 2-fluor-4-hlorfenilgrupa, naftilgrupa, piperidin-4-ilgrupa, morfolinil-4-ilgrupa, furanilgrupa, tienilgrupa, piridin-4-ilgrupa vai pirazinilgrupa un R⁸ ir ūdeņraža atoms vai halogēnalkilgrupa.
16. 16. Savienojums pēc 15. punkta, kur R⁷ ir trifluormetilgrupa un R⁸ ir ūdeņraža atoms.

    J
17. 17. Savienojums pēc 2. punkta, kur:

    R⁶ un R⁸ kopā ar oglekļa atomu, pie kā tie ir pievienoti, veido cikloalkilēngrupu.
18. 18. Savienojums pēc 2. punkta, kur:

    R⁶ un R⁸ kopā ar oglekļa atomu, pie kā tie ir pievienoti, veido heterocikloalkilēngrupu.
19. 19. Savienojums pēc 2. punkta, kur:

    R¹ un R² kopā ar oglekļa atomu, pie kā tie ir pievienoti, veido ciklopropilēngrupu;

    R³ un R⁵ ir ūdeņraža atoms;

    R⁴ ir izopropiisulfonilmetilgrupa, ciklopropilmetilsulfonilmetilgrupa, 2fenilsulfoniletilgrupa, piridin-4-ilsulfonilmetilgrupa, piridin-2ilmetilsulfonilmetilgrupa, piridin-3-ilsulfonilmetllgrupa, fenilmetansulfonilmetilgrupa, 2-(difluormetoksi)benzilsulfonilmetilgrupa, 2hlorfenilgrupa vai piridin-4-ilmetilgrupa;

    R⁶ ir feniigrupa, 4-metoksifenilgrupa, 4-hlorfenilgrupa, 4fluorfenilgrupa, 2-fluorfenilgrupa, 2-fluor-4-hlorfenilgrupa, naftiigrupa, piperidin-4-ilgrupa, furanilgrupa, tienilgrupa, piridin-4ilgrupa vai pirazinilgrupa; un

    R⁸ ir ūdeņraža atoms vai halogēnalkilgrupa.
20. 20. Savienojums ar formulu (I):

    cn (i) kurā:

    R¹ ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa vai alkoksialkilgrupa;

    R² ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, karboksialkilgrupa, alkoksikarbonilalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, ariigrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliskā grupa, heterociklilalkilgrupa, ciānarupa, vai alkilēngrupa-X-R⁹ (kur X ir -O-, -NR¹⁰-, -CONR¹*-, -S(O)_ni-, -NR¹²CO-, -CO- vai -C(O)O-, kur n1 ir 0-2, un R⁹, R¹⁰, R¹¹ un R¹², neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, ariigrupa, aralkilgrupa, heteroarilgrupa vai heteroaralkilgrupa), kur aromātiski vai alicikliski cikli R² grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^a, kas neatkarīgi ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, karboksilgrupa, alkoksikarbonilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa, nitrogrupa, ariloksigrupa, benziloksigrupa, acilgrupa vai arilsulfonilgrupa un papildus aromātiski vai alicikliski cikli R^a grupā ir neobligāti aizvietoti ar vienu vai diviem aizvietotājiem, kas ir izvēlēti no rindas: alkilgrupa, halogēna atoms, alkoksigrupa, halogēnalkiigrupa, halogēnalkoksigrupa, hidroksilgrupa, aminogrupa, alkilaminogrupa, dialkilaminogrupa, karboksilgrupa vai alkoksikarbonilgrupa; vai

    R¹ un R² ir savienoti kopā ar oglekļa atomu, pie kā R¹ un R² ir pievienoti, veidojot:

    (i) cikloalkilēngrupu, neobligāti aizvietotu ar vienu vai diviem R^b, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, alkilaminogrupa, dialkilaminogrupa, ariigrupa, aralkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, heteroarilgrupa, heteroaralkilgrupa, alkoksikarbonilgrupa vai ariloksikarbonilgrupa, (ii) četru atomu heterociklilalkilēnciklu, vai (iii) heterociklilalkilēngrupu, neobligāti aizvietotu ar 1-4 R^c, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, hidroksilgrupa, hidroksialkilgrupa, alkoksialkilgrupa, alkoksialkiloksialkilgrupa, ariloksialkilgrupa, heteroariloksialkilgrupa, aminoalkilgrupa, acilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa, heterociklilalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, -S(O)_n2R^u, -alkilēngrupa-S(O)n2-R¹⁵, -COOR¹⁶, -alkilēngrupa-COOR¹⁷, -CONR¹⁸R¹⁹ vai -alkilēngrupa-CONR²⁰R²¹ (kur n2 ir 0-2, un R¹⁴-R¹⁷, R¹⁸ un R²⁰, neatkarīgi viens no otra, ir izvēlēti no rindas: ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa vai heterocikliska grupa un R¹⁹ un R²¹, neatkarīgi viens no otra, ir ūdeņraža atoms vai alkilgrupa), kur aromātiski vai alicikliski cikli grupās, kas ir pievienotas pie cikloalkilēngrupas vai heterocikloalkilēngrupas ir neobligāti aizvietoti ar vienu, diviem vai trim aizvietotājiem, kas, neatkarīgi ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, aralkilgrupa, ariloksikarbonilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, karboksilgrupa, alkoksikarbonilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa vai acilgrupa;

    R³ ir ūdeņraža atoms vai alkilgrupa;

    R⁴ ir -alki!ēngrupa-SO2-R²², kur R²² ir arilgrupa, aralkilgrupa, heteroarilgrupa, heteroarilalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, kur alkilēngrupas ķēde R⁴ aizvietotājā ir neobligāti aizvietota ar 1-6 halogēna atomiem un kur aromātiski vai alicikliski cikli R⁴ grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^d, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, nitrogrupa, ciāngrupa, karboksilgrupa, ’ alkoksikarbonilgrupa, arilgrupa, heteroarilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, aralkilgrupa, heteroaralkilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa vai acilgrupa;

    R⁵ ir ūdeņraža atoms vai alkilgrupa;

    R⁶ ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikliska grupa, vai alkilēngrupa-X²-R²⁵ (kur X² ir -NR²⁶-, -0-, S(O)n4-, -CO-, -COO-, -OCO-, -NR²⁶CO-,

    -CONR²⁶-, -NR²⁶SO₂-, -SO₂NR²⁶-, -NR²⁶COO-, -OCONR²⁶-,

    -NR²⁶CONR²⁷- vai -NR²⁶SO₂NR²⁷-, kur R²⁶ un R²⁷, neatkarīgi viens no otra, ir ūdeņraža atoms, alkilgrupa vai acilgrupa, n4 ir 0-2, un R²⁵ ir ūdeņraža atoms, alkilgrupa, halogēnalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, heterocikliska grupa, heterociklilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa vai heteroaralkilgrupa), kur minētā alkilēngrupas ķēde R⁶ aizvietotājā ir neobligāti aizvietota ar

    1-6 halogēna atomiem un aromātiski vai alicikliski cikli R⁶ grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^e, kas, neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, hidroksilgrupa, hidroksialkilgrupa, hidroksialkoksigrupa, alkoksigrupa, alkoksialkilgrupa, alkoksialkiloksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, oksogrupa, ciāngrupa, nitrogrupa, acilgrupa, arilgrupa, aralkilgrupa, ariloksigrupa, aralkiloksigrupa, arilsulfonilgrupa, heteroarilgrupa, heteroaralkilgrupa, heteroariloksigrupa, heteroaralkiloksigrupa, heteroarilsulfonilgrupa, heterocikliska grupa, heterociklilalkilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, karboksilgrupa, alkoksikarbonilgrupa, alkilsulfonilgrupa, aminosulfonilgrupa vai aminoalkilgrupa un papildus aromātiski vai alicikliski cikli R^e grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^f, kas ir izvēlēti no rindas: alkilgrupa, alkoksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, halogēna atoms, hidroksilgrupa, karboksilgrupa, ciāngrupa, nitrogrupa, arilgrupa vai cikloalkilgrupa;

    R⁷ ir halogēnalkilgrupa, neobligāti aizvietota ar alkoksigrupu vai alkoksialkiloksigrupu; un

    R⁸ ir ūdeņraža atoms, alkilgrupa, alkoksialkilgrupa vai halogēnalkilgrupa; vai

    R⁶ un R⁸ ir savienoti kopā ar oglekļa atomu, pie kā tie ir pievienoti, veidojot cikloalkilēngrupu vai heterociklilalkilēngrupu, kur minētā cikloalkilēngrupa ir neobligāti aizvietota ar 1-4 aizvietotājiem, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, hidroksilgrupa vai alkoksigrupa un heterociklilalkilēngrupa ir neobligāti aizvietota ar 1 vai 2 aizvietotājiem, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, halogēnalkilgrupa, cikloalkilgrupa, hidroksilgrupa vai alkoksigrupa; vai tā farmaceitiski pieņemama sāls.
21. 21. Savienojums pēc 20. punkta, kurā:

    R¹ un R² ir ūdeņraža atoms vai R¹ un R² kopā ar oglekļa atomu, pie kā tie ir pievienoti, veido cikloalkilēngrupu;

    R³ ir ūdeņraža atoms;

    R⁴ ir -CH2-SO2-R^{21 22}, kur R²² ir arilgrupa, aralkilgrupa, heteroarilgrupa, heteroarilalkilgrupa, cikloalkilgrupa vai cikloalkilalkilgrupa, kur aromātiski vai alicikliski cikli R⁴ grupā ir neobligāti aizvietoti ar vienu, diviem vai trim R^d, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēnalkilgrupa, alkoksigrupa, hidroksilgrupa, halogēnalkoksigrupa, halogēna atoms, nitrogrupa, ciāngrupa, karboksilgrupa, alkoksikarbonilgrupa, aminogrupa, monoaizvietota aminogrupa, diaizvietota aminogrupa vai acilgrupa;

    R⁵ ir ūdeņraža atoms;

    R⁶ ir arilgrupa vai heteroarilgrupa, neobligāti aizvietota ar vienu, diviem vai trim R^e, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, halogēna atoms, hidroksilgrupa, hidroksialkilgrupa, hidroksialkoksigrupa, alkoksigrupa, alkoksialkilgrupa, alkoksialkiloksigrupa, halogēnalkilgrupa, halogēnalkoksigrupa, oksogrupa, ciāngrupa, nitrogrupa, acilgrupa, karboksilgrupa, alkoksikarbonilgrupa, arilsulfonilgrupa, alkilsulfonilgrupa, aminosulfonilgrupa vai aminoalkilgrupa;

    R⁷ ir halogēnalkilgrupa;

    R⁸ ir ūdeņraža atoms.
22. 22. Savienojums pēc 21. punkta, kurā:

    R¹ un R² kopā ar oglekļa atomu, pie kā tie ir pievienoti, veido ciklopropilēngrupu;

    R⁴ ir benzolsulfonilmetilgrupa, naft-2-ilmetansulfonilmetilgrupa, fenilmetansulfanilmetilgrupa, fenilmetansulfonilmetilgrupa, 2fenilmetansulfoniletilgrupa, 4-t-butilfenilmetansulfonilmetilgrupa, 2fluorfenilmetansulfonilmetilgrupa, 3-fIuorfenilmetansulfonilmetilgrupa, 4-fluorfenilmetansulfonilmetilgrupa, 2-hlorfenilmetansulfonilmetilgrupa, 3-hiorfenilmetansulfonilmetilgrupa, 4-hlorfenilmetansulfonilmetilgrupa, 2-metoksifenilmetansulfonilmetilgrupa, 4metoksifenilmetansulfonilmetilgrupa, 2-trifluormetoksifenilmetansulfonilmetilgrupa, 3-trifluormetoksifenilmetansulfonilmetilgrupa, 4trifluormetoksifenilmetansulfonilmetilgrupa, 2-trifluormetilfenilmetansulfonilmetilgrupa, 3-trifluormetilfenilmetansulfonilmetilgrupa, 4trifluormetilfenilmetansulfonilmetilgrupa, 2-ciānfenilmetansulfonilmetilgrupa, 3-ciānfenilmetansulfonilmetilgrupa, 2-bromfenilmetansulfonilmetilgrupa, 2-nitrofenilmetansulfonilmetilgrupa, 2-metilfenilmetansulfonilmetilgrupa, 3-metilfenilmetansulfonilmetilgrupa, 4metilfenilmetansulfonilmetilgrupa, 2-difluormetoksifenilmetansulfonilmetilgrupa, 3-difluormetoksifenilmetansulfonilmetilgrupa, 4difluormetoksifenilmetansulfonilmetilgrupa, 3-hlor-2-fluorfenilmetansulfonilmetilgrupa, 3,5-dimetilfenilmetansulfonilmetilgrupa, 3,5-bistrifluormetilfenilmetansulfonilmetilgrupa, 2,5-difluorfenilmetansulfonilmetilgrupa, 2,6-difluorfenilmetansulfonilmetilgrupa, 2,3difluorfenilmetansulfonilmetilgrupa, 3,4-difIuorfenilmetansulfonilmetilgrupa, 2,4-difIuorfenilmetansulfonilmetilgrupa, 2,5-dihlorfenilmetansulfonilmetilgrupa, 3,4-dihlorfenilmetansulfonilmetilgrupa, 2,6dihlorfenilmetansulfonilmetilgrupa, 2-fluor-3-metilfenilmetansulfonilmetilgrupa, 4-fluor-2-trifluormetoksifenilmetansulfonilmetilgrupa, 2fluor-6-trifluormetilfenilmetansulfonilmetilgrupa, 2-fluor-3trifluormetilfenilmetansulfonilmetilgrupa, 2-fluor-4-trifluormetilfenilmetansulfonilmetilgrupa, 2-fļuor-5-trifluormetilfenilmetansulfonilmetilgrupa, 4-fluor-3-trifluormetilfenilmetansulfonilmetilgrupa, 2-hlor5-trifluormetilfenilmetansulfonilmetilgrupa, 2,4,6-trifluorfenilmetansulfonilmetilgrupa, 2,4,5-trifluorfenilmetansulfonilmetilgrupa, 2,3,4trifluorfenilmetansulfonilmetilgrupa, 2,3,5-trifluorfenilmetansulfonilmetilgrupa, 2,5,6-trifluorfenilmetansulfonilmetilgrupa, 3,4,5trimetoksifenilmetansulfonilmetilgrupa, piridin-2-ilmetansulfonilmetilgrupa, piridin-3-ilmetansulfonilmetilgrupa, piridin-4-ilmetansulfonilmetilgrupa, N-oksipiridin-2-ilmetansulfonilmetilgrupa, 2trifluorpiridin-6-ilmetansulfonilmetilgrupa, pirazin-2-ilmetansulfonilmetilgrupa, cikloheksilmetansulfonilmetilgrupa; ciklopropilmetansulfonilmetilgrupa, tiofen-2-sulfonilmetilgrupa, 5-hlortien-2ilmetansulfonilmetilgrupa vai 3,5-dimetilizoksazol-4ilmetansulfonilmetilgrupa.
23. 23. Savienojums pēc 22. punkta, kurā:

    R⁴ ir fenilmetansulfonilmetilgrupa, 4-fluorfenilmetansulfonilmetilgrupa, ciklopropilmetansulfonilmetilgrupa, piridin-2-ilmetansulfonilmetilgrupa, 2-trifluormetilpiridin-6-ilmetansulfonilmetilgrupa, 2trifluormetoksifenilmetansulfonilmetilgrupa vai pirazin-2ilmetansulfonilmetilgrupa;

    R⁶ ir furan-2-ilgrupa, indol-3-ilgrupa, tiofen-2-ilgrupa, 1 -metilpirol-2ilgrupa, 1-fenilsulfonilpirol-2-ilgrupa, piridin-2-ilgrupa vai fenilgrupa, neobligāti aizvietota ar vienu, diviem vai trim R^e, kas neatkarīgi viens no otra, ir izvēlēti no rindas: alkilgrupa, hidroksilgrupa vai halogēna atoms.
24. 24. Savienojums pēc 22. punkta, kurā:

    R⁴ ir fenilmetansulfonilmetilgrupa, 4-fluorfenilmetansulfonilmetilgrupa, ciklopropilmetansulfonilmetilgrupa, piridin-2-ilmetansulfonilmetilgrupa, 2-trifluormetilpiridin-6-ilmetansulfonilmetilgrupa, 2trifluormetoksifenilmetansulfonilmetilgrupa vai pirazin-2ilmetansulfonilmetilgrupa;

    R⁶ ir fenilgrupa, 2-hidroksifenilgrupa, 4-hidroksifenilgrupa, 3-hlor-4hidroksifenilgrupa, 3-bromfenilgrupa, 4-fluorfenilgrupa, 3,4difluorfenilgrupa vai 3,4,5-trifluorfenilgrupa; un

    R⁷ ir trifluormetilgrupa vai difluormetilgrupa.
25. 25. Savienojums, kas ir izvēlēts no rindas:

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(S)feniletilamino)propionamīds;

    N-(4-ciān-1-etilpiperidin-4-il)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(S)feniletilamino)propionamīds;

    N-(4-ciān-1,1 -dioksoheksahidro-1 λ⁶-ίίορϊΓ3η-4-ίΙ)-3-ίβηϋι·ηβί3η3υΙίοηίΙ-2^)(2,2,2-trifluor-1(S)-feniletilamino)propionamīds;

    N-(1 -ciānciklopropil)-3-fenilmetānsulfanil-2(R)-(2,2,2-trifluor-1 (S)-4hidroksifeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetānsulfonil-2(R)-(2,2,2-trifluor-1(S)feniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfanil-2(R)-(2,2,2-trifluor-1(RS)-furan-2iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(RS)-furan-2iletilaminojpropionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetānsulfonil-2(R)-(2,2,2-trifluor-1(S)-3bromfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfanil-2(R)-(2,2,2-trifluor-1(RS)-indol-3iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(RS)-indol-3iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfanil-2(R)-(2,2,2-trifluor-1(RS)-tuofen2-iletilamino)propionamīds;

    N-(1 -ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1 (RS)-tiofen-2iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetānsulfanil-2(R)-(2,2,2-trifluor-1(S)-4fluorfeniietilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(S)-metiletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfanil-2(R)-(2,2,2-trifIuor-1(S)-1metilpirol-2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(1-metilciklopentil)-2(S)-(2,2,2-trifluor-1(S)-tiofen-2iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(1-metilciklopentil)-2(S)-(2,2,2-trifluor-1(R)-tiofen-2iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(S)-4fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-piridin-2-ilmetānsulfanil-2(R)-(2,2,2-trifluor-1(RS)feniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-piridin-2-ilmetānsulfonil-2(R)-(2,2,2-trifluor-1(S)feniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(1-metilciklopentil)-2(S)-(2,2,2-trifluor-1(S)-2hidroksifeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(1-metilciklopentil)-2(S)-(2,2,2-trifluor-1(R)-4hidroksifeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-piridin-2-ilmetansulfonil-2(R)-(2,2,2-trifluor-1(R)feniletilamino)propionamTds;

    N-(1-ciānciklopropil)-3-(1-metilciklopentil)-2(S)-(2,2,2-trifluor-1 (S)-4hidroksifeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(2-hlorfenil)-2(S)-(2,2,2-trifluor-1(RS)feniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(2-hlorfenil)-2(S)-(2,2,2-trifluor-1(RS)-4fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-piridin-2-ilmetānsulfonil-2(R)-(2,2,2-trifluor-1(RS)-4fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(S)-4hidroksifeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfanil-2(R)-(2,2,2-trifluor-1(R)-3-hlor-4hidroksifeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfanil-2(R)-(2,2,2-trifluor-1(S)-3-hlor-4hidroksifeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(R)-3-hlor-4hidroksifeniletilamino)propionamTds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(S)-3-hlor-4hidroksifeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(1-metilciklopentil)-2(S)-(2,2-difluor-1(R)-tiofen-2iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfanil-2(R)-(2,2-difluor-1(RS)-tiofen-2iletilamino)propionamīds;

    N-(1 -ciān ciklo propil )-3-( 1 -metilciklopentil )-2(S )-(2,2,2-trifluor-1 (S)-3-fluor-4hidroksifeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfanil-2(R)-(2,2,2-trifluor-1(RS)-piridin2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-4-piridin-2-ilsulfanil-2(S)-(2,2,2-trifIuor-1 (RS)-4fluorfeniletilamino)butiramīds;

    N-(1-ciānciklopropil)-4-piridin-2-ilsulfonil-2(S)-(2,2,2-trifluor-1(RS)-4fluorfeniletilamino)butiramīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2,2-trifluor-1(RS)-piridin2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-fenilmetānsulfonil-2(R)-(2,2-difluor-1(R)-tiofen-2iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(2-difluormetoksifenilmetānsulfanil)-2(R)-(2,2,2trifluor-1(RS)-tiofen-2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(2-difluormetoksifenilmetānsulfonil)-2(R)-(2,2,2trifluor-1(RS)-tiofen-2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-piridin-2-ilmetansulfanil-2(R)-(2,2,2-trifluor-1(S)-4fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-piridin-2-ilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)-4fluorfeniletilamino)propionamīds;

    N-(1 -ciānciklopropil)-3-piridin-2-ilmetansulfanil-2(R)-(2,2,2-trifluor-1 (R)-4fluorfeniletilamino)propionamīds;

    N-(1 -ciānciklopropil)-3-piridin-2-ilmetansulfonil-2(R)-(2,2,2-trifluor-1 (R)-4fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropi1metansulfonil-2(R)-(2,2,2-trifluor-1(S)tiofen-3-iletilamino)propionamTds;

    N-(1-ciānciklopropil)-3-ciklopropilmetansulfanil-2(R)-(2,2,2-trifluor-1(RS)tiofen-2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetansulfonil-2(R)-(2,2,2-trifluor-1(RS)tiofen-2-iletilamino)propionamīds;

    N-(1-ciāntetrahidropiran-4-il)-3-ciklopropilmetansulfonil-2(R)-(2,2,2-tnfluor1(S)-4-fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)-3,4difluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)-1metil-pirol-2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)-1okso-1-metilpirol-2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)3,4,5-trifluorfeniletilamino)propionamīds;

    N-(1-ciānciktopropil)-3-(4-fluorfenilmetansulfonil)-2(R)-(2,2,2-trifluor-1(S)-4fluorfeniletilamino)propionamTds;

    N-(1-ciāntetrahidropiran-4-il)-3-(4-fluorfenilmetansulfonil)-2(R)-(2,2,2trifluor-1(S)-4-fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(4-fluorfenilmetansulfonil)-2(R)-(2,2,2-trifluor-1(S)-3fenoksifeniletilamino)propionamīds;

    N-(1-ciān-1,1-dioksoheksahidro-1X⁶-tiopiran-4-il)-3-(4-fluorfenilmetansulfonil)-2(R)-(2,2,2-trifluor-1(S)-4-fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(2-difluormetoksifenilmetansulfonil)-2(R)-(2,2,2trifluor-1(RS)-1-fenilsulfonilpirol-2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(2-difluormetoksifenilmetansulfonil)-2(R)-(2,2,2trifluor-1(S)-4-fluorfeniletilamino)propionamīds;

    N-(1 -ciānciklopropil)-3-(2-trifluormetilpiridin-6-ilmetansulfonil)-2(R)-(2,2,2trifluor-1(RS)-4-fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetansulfonil-2(R)-(2,2,2-trifluor-1(RS)-1fenilsulfonilpirol-2-iletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-pirazin-2-ilmetansulfonil-2(R)-(2,2,2-trifluor-1(R)-4fluorfeniletilamino)propionamīds;

    N-(1 -ciānciklopropil)-3-pirazin-2-ilmetansulfonil-2(R)-(2,2,2-trifluor-1 (S)-4fluorfeniletilamino)propionamTds;

    N-(1-ciāntetrahidropiran-4-il)-3-(2-difluormetoksifenilmetansulfonil)-2(R)(2,2,2-trifluor-1(S)-4-fluorfeniletilamino)propionamīds;

    N-(1 -ciān-1,1 -dioksoheksahidro-1 λ⁶-tiopίran-4-il)-3-(2-difluormetoksifenilmetansulfonil)-2(R)-(2,2,2-trifluor-1(S)-4-fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(2-trifluormetilpiridin-6-ilmetansulfonil)-2(R)-(2,2,2trifluor-1(S)-4-fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-pirazin-2-ilmetansulfanil-2(R)-(2,2,2-trifluor-1(R)-4fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-pirazin-2-ilmetansulfanil-2(R)-(2,2,2-trifluor-1(S)-4fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(1 -oksopiridin-2-ilmetansulfonil)-2(R)-(2,2,2-trifluol· 1 (S)-4-fluorfeniletilamino)propionamīds; un

    N-( 1 -ciā nci klopro pil)-3-(pirid i η-2-il metansu Ifonil )-2-(2,2,2-trifIuor-1 -fenil-1 trifluormetiletilamino)propionamīds; vai tā farmaceitiski pieņemama sāls.
26. 26. Savienojums, kas ir izvēlēts no rindas:

    N-(1-ciānciklopropil)-3-cikiopropilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)feniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-ciklopropilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)-4fluorfeniletilamino)propionamīds;

    N-(1 -ciānciklopropil)-3-piridin-2-ilmetansu!fonil-2(R)-(2,2,2-trifIuor-1 (S)feniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-piridin-2-ilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)-4fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(2-trifluormetilpiridin-6-ilmetansulfonil)-2(R)-(2,2,2trifluor-1(S)-4-fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-(2-trifluormetiipiridin-6-ilmetansuifonil)-2(R)-(2,2,2trifluor-1(S)-feniletilamino)propionamīds;

    N-(1-ciāncikiopropii)-3-ciklopropilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)-3,4difluorfeniletilamino)propionamīds;

    N-(1 -ciānciklopropil)-3-(4-fluorfenilmetansulfonil)-2(R)-(2,2,2-trifluor-1 (S)-4fluorfeniletilamino)propionamīds;

    N-(1-ciānciklopropil)-3-pirazin-2-ilmetansulfonil-2(R)-(2,2,2-trifluor-1(R)-4fluorfeniletilamino)propionamīds; un

    N-(1-ciānciklopropil)-3-pirazin-2-ilmetansulfonil-2(R)-(2,2,2-trifluor-1(S)-4fluorfeniletilamino)propionamīds; vai tā farmaceitiski pieņemama sāls.
27. 27. Farmaceitiska kompozīcija, kas ietver savienojumu pēc jebkura no 1. līdz 24. punktam maisījumā ar vienu vai vairākām pieņemamām palīgvielām.
28. 28. Farmaceitiska kompozīcija, kas ietver savienojumu pēc 25. punkta maisījumā ar vienu vai vairākām pieņemamām palīgvielām.
29. 29. Farmaceitiska kompozīcija, kas ietver savienojumu pēc 26. punkta maisījumā ar vienu vai vairākām pieņemamām palīgvielām.
30. 30. Savienojuma pēc 1. punkta maisījumā ar vienu vai vairākām pieņemamām palīgvielām pielietojums ārstnieciskā līdzekļa izgatavošanai Katepsīna S izraisītu slimību ārstēšanai dzīvniekiem.
31. 31. Savienojuma pēc 25. punkta maisījumā ar vienu vai vairākām pieņemamām palīgvielām pielietojums ārstnieciskā līdzekļa izgatavošanai Katepsīna S izraisītu slimību ārstēšanai dzīvniekiem.
32. 32. Savienojuma pēc 26. punkta maisījumā ar vienu vai vairākām pieņemamām palīgvielām pielietojums ārstnieciskā līdzekļa izgatavošanai Katepsīna S izraisītu slimību ārstēšanai dzīvniekiem.
33. 33. Ārstnieciskais līdzeklis pēc 31. vai 32. punkta, kur slimība ir reimatoīdais artrīts, multiplā skleroze, smagā miastēnija, psoriāze, vienkāršais pemfiguss, Greivsa slimība, smagā miastēnija, sistēmiskā sarkanā vilkēde, astma, sāpes un ateroskleroze.
34. 34. Savienojuma pēc 1. punkta pielietojums ārstnieciskā līdzekļa izgatavošanai terapijai pakļauto pacientu ārstēšanai, kur terapija izraisa imūno atbildi pacientos.