MXPA06008543A - Silinane compounds as cysteine protease inhibitors - Google Patents

Abstract

The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, 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. The present invention is also directed to the use of these inhibitors in combination with a therapy that causes a deleterious immune response in patients receiving the therapy.

Description

SILINANE COMPOUNDS AS CISTEIN PROTEASE INHIBITORS Field of the invention. The present invention is it targets compounds which are inhibitors of cysteine proteases, in particular cathepsins B, K, L, F and S, and are therefore useful in the treatment of diseases mediated by these proteases. The present invention is also directed to pharmaceutical compositions comprising these compounds and to processes for preparing them. The present invention is also directed to the use of these inhibitors in combination with a therapy that causes a damaging immune response in patients receiving the therapy.

State of the art Cysteine proteases represent a class of peptidases characterized by the presence of a __ cysteine residue at the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. However, the aberrant activity of cysteine proteases, e.g. ex. , as a result of an increased expression or an improved activity, may have 'pathological consequences. In this regard, certain cysteine proteases are associated with numerous disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy, and others. For example, increased levels of cathepsin B and redistribution of the enzyme are found in tumors; therefore, they suggest a role for the enzyme in tumor invasion and metastasis. In addition, the aberrant activity of cathepsin B is implicated in disease states such as rheumatoid arthritis, osteoarthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease, and disorders of bones and joints.

The prominent expression of cathepsin K in osteoclasts and multinucleated cells related to the osteoclast, and its high collagenolytic activity, suggest that the enzyme is involved in bone resorption mediated by osteoclast and therefore in bone abnormalities as those that occur in osteoporosis. In addition, the expression of cathepsin K in the lung and its elastinolytic activity suggest that the enzyme also plays a role in lung disorders.

Cathepsin L is involved in normal lysosomal proteolysis as well as in several severe disease states, which include, but are not limited to, the metastasis of melanomas. Cathepsin S is implicated in Alzheimer's disease and in certain autoimmune disorders including, but not limited to, juvenile diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, and thyroiditis. Hashimoto. In addition, cathepsin S is implicated in: allergic disorders including, but not limited to, asthma and allogeneic immune responses including, but not limited to, rejection of organ transplants or tissue grafts.

Another cysteine protease, cathepsin F, has been found in macrophages and is involved in the antigen process. It is believed that cathepsin F, in stimulated macrophages of the lung and possibly in other cells that present antigens, could play a role in airway inflammation (see GP Shi et al., Exp. Med. 2000, 191, 1177).

In view of the numerous diseases in which it is recognized that an increase in the activity of the cysteine protease contributes to the pathology and / or the symptomatology of the disease, the molecules that inhibit the activity of this class of enzymes, in particular the molecules that are inhibitors of cathepsins B, K, L, F and / or S, will therefore be useful as therapeutic agents.

Detailed description of the invention. In a first aspect, the invention is directed to a compound of Formula (I): where: Q is -CO-, -S02-, -OCO-, NR4C0-, -NR4S02, or -CHR- wherein R is haloalkyl and R4 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or aralkyl; E is: (i) -C (R5) where X1 is -C (R7) (R8) R10, -CH = CHS (0) 2R10, C (R7) (R8) C (R7) (R8) 0R10, - C (R7) (R8) CH2N (R11) S02R10, -C (R7) (R8) C (0) N (R) (CH2) 20R11, -C (R7) (R8) C (O) NR ^ R11, or C (R7) (R8) C (0) N (Rn) (CHz NR ^ R11; (ii) C (R5a) (R6a) CN; wherein: R5 and R5a are independently hydrogen or alkyl; R6 and R6a are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, -alkylene-X2-R12 (where X2 is -0-, NR13- , -S (0) n? -, -CONR13-, NR13C0-, NR13C (0) 0-, -NR13CONR13-, -0C0NR13-, NR13S02-, -S02NR13-, -NR13S02NR13-, -CO-, or -0C (0) -, where it is not 0-2 and each R13 is hydrogen or alkyl and R12 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl where the aromatic or alicyclic ring in R6 and R6a is optionally substituted with one, two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl, alkylsulfonyl, or arylsulfonyl where the aromatic ring or cyclic in Ra is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl; or: R5 and R6 and R5a and R6a taken together with the carbon atom to which both of R5 and R6 and R5a and R6 are linked from: (i) cycloalkylene optionally substituted with one or two Rb, independently selected from alkyl, halo , alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl, or (ii) heterocycloalkylene optionally substituted with one to four alkyls or one or two Rc, independently selected from alkyl, haloalkyl, hydroxy , hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, -S (0) n2R14, -alkylene-S (0) n2R15, COOR16, -alkylene-COOR17, -CONR18R19 'or -alkylene ~ CONR20R21 (where n2 is 0-2, and R14-R17, R18 and R20 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl or cycloalkylalkyl, or the heterocycloalkyl and R19 and Y21 are independently hydrogen or alkyl), wherein the aromatic or alicyclic ring in the groups linked to the cycloalkylene or the heterocycloalkylene is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, benzyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, or acyl; R7 is hydrogen or alkyl; R8 is hydroxy; or R7 and R8 together form oxo; R10 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl where the aromatic or alicyclic ring in R10 is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, alkoxyalkyl , cycloalkyl, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, aryisulfonyl, heteroarylsulfonyl, aryl, aralkyl, heteroaryl, amino, monosubstituted amino, disubstituted amino, carbamoyl, or acyl, wherein the aromatic or alicyclic ring in Rd is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, or dialkylamino; and R11 is hydrogen or alkyl; or (i) a group of the formula (a): wherein: n is 0, 1 or 2; X4 is selected from -NR22-, -S-, or -O-, where R is hydrogen, alkyl, or alkoxy; and X5 is -O-, -S-, -S02- or NR23-, wherein R23 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl , cycloalkylalkyl, -S (0) 2R24, -alkylene-S (0) n3-R25, -COOR26, -alkylene-COOR27, -CONR28R29, or -alkylene-CONR30R31 (where n3 is 0-2 and R2-R27, R28 and R30 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl and R29 and R31 are independently hydrogen or alkyl), wherein the aromatic or alicyclic ring in R23 is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, and a substituent selected from aryl, aralkyl, heteroaryl, or teroaralkyl; and R5 is as defined above; R1 is hydrogen or alkyl; Rla is 1, 1-dialkylsilyano-4-ylalkylene or - (alkylene) -SiR32R33R34 where R32 is alkyl, R33 is alkyl, and R34 is alkyl, alkenyl, cycloalkylalkyl, aryl, aralkyl, heteroachalkyl, or heterocycloalkylalkyl, or R33 and R34 together with Si form a heterocycloalkylene ring containing the Si atom and from 3 to 7 carbon ring atoms, where one or two carbon ring atoms are optionally independently replaced with -NH-, -0-, -S-, -SO-, -S02-, -CO-, -CONH-, or -S02NH- and wherein the aralkyl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylene ring in Rla is optionally substituted in the ring with one, two or three Re independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl, alkylsulfonyl, or arylsulfonyl and further where the aromatic or alicyclic ring in Re is optionally replaced c on one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl; R2 is hydrogen or alkyl; R3 is alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, or -alkylene-X6-R35 [where X6 is -NR36, -0-, S (0) n4, -CO-, COO- , -0C0-, NR36CO-, CONR36-, -NR36S02-, -S02NR36-, -NR36COO-, -OCONR36, -NR36CONR37, or -NR36S02NR37- (where each R36 and R37 is independently hydrogen, alkyl, or acyl, and n4 is 0-2 ) and R35 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl] where the alkylene chain in R3 is optionally substituted with one to four halo atoms and the aromatic rings and alicyclics in R3 are optionally substituted by one, two or three Rf, independently selected from alkyl, . aminoalkyl, halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, acyloxy, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryloxy, benzyloxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, • alkylsulfinyl, alkylsulfonyl, arylthio, ariisulfonilo, arylsulfinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, oyloxy arilcarba, alkylsulfonylamino, arylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, aralkylaminosulfonyl, aminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, amino, monosubstituted amino • or disubstituted, and also wherein the aromatic and alicyclic rings in Rf are optionally substituted with one, two or three R9, wherein R9 is independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylthio, alkylsulfonyl, amino, monosubstituted amino, dialkylamino, aryl, heteroaryl, cycloalkyl, carboxy, carboxamido, or alkoxycarbonyl; or a pharmaceutically acceptable salt thereof.

Preferably, R11 is alkyl when E is' -C (R7) (R8) C (0) NR10R11.

In a second aspect, this invention is directed to a method for treating in an animal a disease mediated by cysteine proteases, in particular cathepsin S, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula (I) : where: Q is -CO-, S02-, -OCO-, -NRCO-, NRS02-, or -CHR-, where R is haloalkyl and R4 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or aralkyl; E is: (i) -C (R5) (R6) X1 where X1 is -CHO, -C (R7) (R8) CF3, -C (R7) (R8) CF2CF2R9, -C (R7) (R8) R10 , -CH = CHS (0) 2R10, C (R7) (R8) C (R7) (R8) OR10, -C (R7) (R8) CH2OR10, -C (R7) (R8) C (R7) (R8) ) R10, -C (R7) (R8) CH2N (R1: L) S02R10, -C (R7) (R8) CF2C (O) NR10R1: L, C (R7) (R8) C (O) NR10R11, -C (R7) (R8) C (O) N (R11) (CH2) 20Rn, or • C (R7) (R8) C (0) N (R11) (CH2) 2NR10RU; (ii) -C (R5) (R6a) CN; wherein: R5 and R5a are independently hydrogen or alkyl; R6 and R6a are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, -alkylene-X2-R12 (where X2 is -0-, -NR13 -, -S (0) n? -, -CONR13-, -NR13C0, - NR13C (0) 0-, NR13CONR13, -0C0NR13-, NR13S02-, S02NR13-, NR13S02NR13-, -CO-, U -0C0 (0 ) -, where neither is 0-2 and each R13 - is hydrogen or alkyl) and R12 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, where the aromatic ring or alicyclic in R6 and R6a is optionally substituted with one, two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl , alkylsulfonyl, or arylsulfonyl, where the aromatic ring Attic or alicyclic in Ra is optionally substituted with one or more substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl; or R5 and R6 and R5a and R6a taken together with the carbon atom to which both of R5 and R6 and R5 and Rd are linked from: (i) cycloalkylene optionally substituted with • one or two Rb independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl, or (ii) heterocycloalkylene optionally substituted with from one to four alkyls or one or two Rc, independently selected from alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, -S (0) n2R14, -alkylene-S (0) n2-R15, COOR16, -alkylene-COOR17, -CONR18R19, or -alkylene-CONR20R21 (where n2 is 0-2 and R14-R17, R18 and R20 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl , or heterocycloalkyl and R19 and R21 are independently hydrogen or alkyl) wherein the aromatic or alicyclic ring in the groups linked with the cycloalkylene or the heterocycloalkylene is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, benzyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, or acyl; R7 is hydrogen or alkyl; R8 is hydroxy; or R7 and R8 together form oxo; R9 is hydrogen, halo, alkyl, aralkyl or heteroaralkyl; R10 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl where the aromatic or alicyclic ring in R10 is optionally substituted with one, two or three Rd independently selected from alkyl, haloalkyl, alkoxy, alkoxyalkyl, cycloalkyl, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryl, aralkyl, heteroaryl, amino, monosubstituted amino, disubstituted amino, carbamoyl, or acyl, where the aromatic or alicyclic ring in Rd is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino or dialkylamino; and RX1 is hydrogen or alkyl; Y (iii) a group of the formula (a): •: 00 where: n is 0, 1 or 2; X4 is selected from -NR22-, -S-, or -O-, where R 'is hydrogen, alkyl or alkoxy; and X5 is -O-, -S-, -S02-, or -NR23-, wherein R23 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl , heteroaralkyl, cycloalkyl, cycloalkylalkyl, -S (0) 2R24, ~ alkylene-S (O) n3-R25, -COOR26, -alkylene-COOR27, -CONR28R29, or -alkylene-CONR30R31 (where n3 is 0-2 and R24-R27, R28 and R30 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and R29 and R31 are independently hydrogen or alkyl), where the aromatic or alicyclic ring in R23 is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl and a substituent selected from aryl, aralkyl, heteroaryl,. or heteroaralkyl; and R5 is as defined above; R1 is hydrogen or alkyl; Rla is 1, 1-dialkylsilylan-4-ylalkylene or '- (alkylene) -SiR32R33R34, where R32 is alkyl, R33 is alkyl, and R34 is alkyl, alkenyl, cycloalkylalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl or R33 and R34 together with If they form a heterocycloalkylene ring containing the Si atom and from 3 to 7 carbon ring atoms where one or two carbon ring atoms are optionally and independently replaced with -NH-, -O-, -S-, -SO-, -S02-, -CO-, -CONH-, or -S02NH- and wherein the aralkyl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylene ring in Rla is optionally substituted in the ring with one, two or three Re, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, -alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl, alkylsulfonyl or aryisulfonyl, and wherein the aromatic or alicyclic ring in Re is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy or alkoxycarbonyl.; R2 is hydrogen or alkyl; R3 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, or -alkylene-X6-R35 [where X6 is -NR36-, -0-, -S (0) n4-, -CO-, -COO-, -0C0-, NR36CO-, -CONR36-, NR36S02-, S02NR36-, -NR36COOr-, -OCONR36-, -NR36CONR37-, or -NR36S02NR37- (where each R36 and R37 is independently hydrogen , alkyl, or acyl, and n4 is 0-2) and R35 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl] where the alkylene chain in R3 is optionally substituted with one to four halo atoms and the aromatic and alicyclic rings on R3 are optionally substituted by one, two or three Rf independently selected from alkyl, aminoalkyl, halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro acyl, acyloxy, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cyc loalquilalquilo, heterocycloalkyl, heterocycloalkylalkyl, aryloxy, benzyloxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, ariisulfonilo, arylsulfinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, aralkylaminosulfonyl, aminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, amino, monosubstituted or disubstituted amino, and further, wherein the aromatic and alicyclic rings in Rf are optionally substituted with one, two or three R9 where R9 is independently selected from alkyl, halo, haloalkyl, haloalkoxy , hydroxy, nitro, cyano, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylthio, alkylsulfonyl, amino, monosubstituted amino, dialkylamino, aryl, heteroaryl, cycloalkyl, carboxy, carboxamido or alkoxycarbonyl; or a pharmaceutically acceptable salt thereof.

Preferably, the disease is juvenile diabetes, psoriasis, multiple sclerosis, pemphigus vulgaris, Grave's disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's thyroiditis, allergic disorders including, but not limited to, asthma and immune responses. Allogeneic diseases that include, but are not limited to, organ transplants or tissue grafts and endometriosis, chronic obstructive pulmonary disease (eg, emphysema, bronchiolitis, excessive elastolysis of the airways in asthma and bronchitis, neu onitis) and cardiovascular disease such as rupture of plaque and atheroma, systemic amyloidosis, Alzheimer's disease, and iatrogenic disorders.Preferably, the disease is psoriasis, iratrogenic disorders, and myasthenia gravis.

In a third aspect, this invention is directed to a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in admixture with a suitable excipient.

In a fourth aspect, this invention is directed to a method of treating a patient receiving a therapy wherein the therapy causes an immune response of the patient, which comprises administering to the patient a compound of the Formula (I) or a salt pharmaceutically acceptable thereof. Preferably, the immune response is mediated by MHC class II molecules. The compound of Formula (I) can be administered before, or simultaneously with, or after, the therapy. Preferably, the therapy involves treatment with a biological. Preferably, the therapy involves treatment with a small molecule.

Preferably, the biological is a protein, preferably an antibody, more preferably a monoclonal antibody. More preferably, the biological is Remicade®, Refacto®, Referon-A®, Factor VIII, Factor VII, Betaseron®, Epogen®, Embrel®, Inferieron beta, Botox®, Fabrazyme®, Elspar®, Cerezyme®, Myobloc®, Aldurazyme®, Verluma®, Inferieron alfa, Humira®, Aranesp®, Zevalin®, or 0KT3.

Preferably, small molecule therapy involves the use of heparin, low molecular weight heparin, procainamide or hydralazine.

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

In a sixth aspect, this invention is directed to a method for conducting a clinical test for a biological, which comprises administering, to an individual participating in the clinical trial, a compound of the Formula (I) or a pharmaceutically acceptable salt of the same, with the biological.

In a seventh aspect, this invention is directed to a method of treating prophylactically, a person being treated with a biological, with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to treat the immune response. • caused by the biological in the person.

In an eighth aspect, this invention is directed to a method for determining the loss of efficacy of a biological in an animal, due to the immune response caused by the biological, which comprises administering the biological to the animal in the presence and absence of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In a ninth aspect, this invention is directed to a method for improving the efficacy of a biological in an animal, comprising administering the biological to the animal with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. • In a tenth aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament.

In an eleventh aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for combination therapy with a biological, to treat the immune response caused for the biological.

Preferably, the cathepsin S inhibitor is administered prior to the administration of the biological agent.

Preferably, the cathepsin inhibitor £ > it is administered concomitantly with the biological agent.

Preferably, the cathepsin S inhibitor is administered after the administration of the biological agent.

Detailed description of the invention. Definitions: Unless otherwise indicated, the following terms used in the specification and in the claims are defined for the purposes of this Application, and have the following meanings: "Alicyclic" means cycloalkyl and heterocycloalkyl rings as defined herein.

"Alkyl", represented by itself, means a saturated aliphatic radical, linear or branched, containing from one to six carbon atoms, unless otherwise indicated, e.g. ex. , alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, and the like.

"Alkenyl", represented by itself, means a straight or branched aliphatic radical of two to six carbon atoms containing one or two double bonds, e.g. ex. , ethenyl, propenyl, and the like.

"Alkylene", unless otherwise indicated, means an aliphatic, straight or branched saturated divalent radical having from one to six carbon atoms, e.g. ex. , methylene (-CH2), ethylene (-CH2CH2 ~), trimethylene (-CH2CH2CH2-), tetramethylene (-CH2CH2CH2CH2-), 2-methyltetramethylene (-CH2CH2 {CH3CH2CH2-), pentamethylene (-CH2CH2CH2CH2CH2-), and the like .

"Alkylcarbamoyloxy" refers to a radical -OCONHR where R is an alkyl group as defined above, e.g. ex. , methylcarbamoyloxy, ethylcarbamoyloxy, and the like.

"Alkylsulfonylamino" refers to a radical - NHS02R where R is an alkyl group as defined above, e.g. ex. , methylsulfonylamino, ethylsulfonylamino, and the like.

"Amino" means the radical -NH2-.

"Aminosulfonyl" refers to the radical -S02NH2.

"Alkylaminosulfonyl" or "dialkylaminosulfonyl" refers respectively to a radical -S02NHR and -S02NRR ', where R and R1 are independently an alkyl group as defined above, e.g. ex. , methylaminosulfonyl, dimethylaminosulfonyl, and the like.

"Alkylamino" or "dialkylamino" refers respectively to a radical -NHR and -NRR ', where R and R' are independently an alkyl group as defined above, e.g. ex. , methylamino, dimethylamino, and the like.

"Alkoxy" refers to a radical -OR where R is an alkyl group as defined above, e.g. ex. , methoxy, ethoxy, and the like.

"Alkoxycarbonyl" refers to a radical -C (0) OR where R is an alkyl group as defined above, p. ex. , methoxycarbonyl, ethoxycarbonyl, and the like.

"Alkoxycarbonylalkyl" means a radical (alkylene) -C (0) OR where R is alkyl as defined above, e.g. ex. , methoxycarbonylalkyl, 2- or 3-ethoxycabonylpropyl, and the like.

"Alkoxycarbonylamino" refers to an -NHC (0) 0R radical wherein R is an alkyl group as defined above, • p. ex. , methoxycarbonylamino, ethoxycarbonylamino, 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 with at least one alkoxy group, preferably by one or two alkoxy groups, as defined above, p. ex. , 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

"Alkoxyalkyloxyalkyl" refers to a radical - (alkylene) -0- (alkylene) -OR where R is an alkyl group as defined above, e.g. ex. , 2-methoxyethyl-oxymethyl, 3-methoxy-propyloxyethyl, 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 with at least one, preferably one or two, -NRR ', wherein R is hydrogen, alkyl or -C0Ra where Ra is alkyl, and R 'is hydrogen or alkyl as defined above, p. ex. , aminomethyl, methylaminoethyl, dimethylaminoethyl, 1,3-diaminopropyl, acetylaminopropyl, and the like.

"Alkylthio" refers to a radical -SR where R is an alkyl group as defined above, e.g. ex. , methylthio, ethylthio, and the like.

"Alkylsulfinyl" refers to a radical -S (0) R where R where R is an alkyl group as defined above, p. ex. , methylisulfinyl, etiisulfinyl, and the like.

"Alkylsulfonyl" refers to a radical -S02R where R is an alkyl group as defined above, e.g. ex. , methylsulfonyl, ethylsulfonyl, and the like.

"Acyl" means a radical -COR where R is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkyl as defined herein, e.g. ex. , formyl, acetyl, trifluoroacetyl, benzoyl, piperazin-1-ylcarbonyl, and the like.

"Acyloxy" means a radical -OCOR where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl as defined herein, e.g. ex. , acetyloxy, trifluoroacetyloxy, benzoyloxy, piperazin-1-ylcarbonyloxy, and the like.

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

"Aromatic" means a portion in which the constituent atoms form an unsaturated ring system, all the atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n + 2"Aryl" means a fused monocyclic or bicyclic ring assembly containing from 6 to 10 carbon ring atoms unless otherwise indicated, where each ring is aromatic, e.g. ex. , phenyl or naphthyl.

"Aralkyl" means a radical - (alkylene) -R where R is aryl as defined above, p. ex. , benzyl, phenethyl and the like.

"Aryloxy" means a radical -OR where R is aryl as defined above.

"Aryloxyalkyl" means a radical (alkylene) -OR where R is aryl as defined above p. ex. , phenoxymethyl, 2-, or 3-phenoxypropyl, and the like.

"Aryloxycarbonyl" means a radical -C (0) OR where R is aryl as defined above, p. ex. , phenyloxycarbonyl and the like.

"Oryloxy arylcarba" means a radical -OC (0) NHR where R is aryl as defined above, e.g. ex. , phenylcarbamoyloxy, and the like.

"Arylthio" refers to a radical -SR where R is an aryl group as defined above, e.g. ex. , phenylthio, and the like.

"Arylsulfinyl" refers to a -SOR radical where R is an aryl group as defined above, e.g. ej '. , phenylsulfinyl and the like.

"Arylsulfonyl" refers to a radical -S02R where R is an aryl group as defined above, e.g. ex. , phenylsulfonyl and the like.

"Aryloxycarbonylamino" refers to a radical -NHC (0) OR where R is an aryl group as defined above, p. ex. , phenoxycarbonylarrd.no and the like.

"Arylsulfonylamino refers to a radical NHS02R- where R is an aryl group as defined above, e.g., phenylsulfonylamino and the like.

"Arylaminosulfonyl" means a radical -S02NHR where R is aryl as defined above, p. ex. , phenylaminosulfonyl and the like.

"Aralkylaminosulfonyl" means a radical -S02NHR where R is aralkyl as defined above, p. ex. , benzylaminosulfonyl- and the like.

"Arylaminocarbonyl" means a radical -CONHR where R is aryl as defined above, p. ex. , phenylaminocarbonyl and the like.

"Aralkylaminocarbonyl" means a radical -CONHR where R is aralkyl as defined above, p. ex. , benzylaminocarbonyl and the like.

"Biological" means a therapeutic agent 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), e.g. ex. , monoclonal or polyclonal, humanized or urea antibodies, toxins, hormones, and the like. Biologics are currently available for the treatment of a variety of diseases such as cancer, rheumatoid arthritis and hemophilia.

"Carbamoyl" or "aminocarbonyl" means a radical -C (0) NRR 'wherein R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl as herein provided, provided that an R and R1 is not hydrogen.

"Carboxi" means the radical -C (0) 0H.

"Cycloalkyl" means a monovalent saturated or partially unsaturated, monocyclic, bicyclic, fused ring assembly containing from three to eight carbon ring atoms, e.g. ex. , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and the like.

"Cycloalkylalkyl" means a radical (alkylene) -R where R is cycloalkyl as defined above, p. ex. , cyclopropylmethyl, cyclobutylethyl, cyclobutylmethyl, and the like.

"Cycloalkylene" means a saturated divalent or partially unsaturated monocyclic fused ring assembly containing from three to eight carbon atoms. For example, the case where "R5 and R6 together with the carbon atom to which both of R5 and R6 are linked form cycloalkylene", includes, but is not limited to, the following: and similar. "Disubstituted amino" means a radical -NRR1 where R is alkyl, aryl, aralkyl, heteroaryl, heteraralkyl, or heterocycloalkyl, and R 'is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl or, acilo, as defined here. Representative examples include, but are not limited to, dimethylamino, ethylphenylamino, benzylmethylamino, acetyl ethylamino, and the like. "1, 1-dialkylsilyan-4-ylalkylene" means a group having the structure shown below: where Z is alkylene and. each R is independently alkyl, as defined herein.

"Derivative" means an agent similar to the one that can be traced.

"Disease" specifically includes any unhealthy situation of an animal or part thereof and includes the unhealthy condition that may be caused by, or be incident to, the medical or veterinary therapy applied to that animal, p. ex. , the "collateral effects" of. that therapy.

"Harmful immune response" means an immune response that prevents the effective treatment of a patient or that causes disease in a patient. As an example, dosing a patient with a urid antibody either as a therapy or as a diagnostic agent causes the production of human anti-mouse antibodies that prevent or interfere with subsequent treatments. The incidence of antibody formation versus Pure murine monoclonal antibodies may exceed 70% (see Khazaeli, MB et al., J. Immunother, 1994, 15, pp. 42-52, Dillman RO et al., Cancer Biother, 1994, 9, pp. 17-28; Reinsberg, J. Hybridoma, 1995, 14, pp. 205-208). Additional examples of known agents that suffer from harmful immune responses are the blood coagulation factors, such as factor VIII. When given to patients with hemophilia, factor VIII restores the ability of blood to clot. Although factor VIII is a human protein, it still elicits an unbound response in hemophiliacs, since factor VIII is not present in its blood and therefore appears as a foreign antigen to the immune system. Approximately 29-33% of new patients will produce antibodies that agglutinate and neutralize factor VIII administered therapeutically (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 to maintain normal blood coagulation parameters; an expensive treatment regimen for inducing immune tolerance (see Briet E. et al., Adv. Exp. Med. Bio, 2001, 489, pp. 89-97). Another immunogenic example is the adenoviral vectors. Retroviral therapy remains experimental and is of limited utility. One reason is that the application of therapeutic viruses generates an immune response capable of blocking any subsequent administration of the same virus or a similar one (see Yiping Yang et al., J. of Virology, 1995, 69, pp. 2004-2015). This ensures that retroviral therapies should be based on the transient expression of a protein or on the direct incorporation of the viral sequence into the host genome. Targeted research has identified multiple viral neutralizing epitopes recognized by host antibodies (see Hanne, Gahery-Segard et al. J. of Virology 1998, 12, pp. 2388-2397), suggesting that viral modifications will not be sufficient to overcome this obstacle. This invention will allow a process by which an adenoviral therapy will be useful for repeated application. Another example of an immunogenic agent that causes neutralizing antibodies is the well-known Botox cosmetic agent. The botulinum toxin protein is purified from the fermentation of Clostridium botulinum. As a therapeutic agent, 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, which results in reduced efficacy (see Birklein F. et al., Ann Neurol, 2002, 52, pp. 68-73 and Rollnik, JD et al. Neurol, Clin Neurophysiol, 2001, 2001 (3), pp. 2-4). A "harmful immune response" also encompasses diseases caused by therapeutic agents. A specific example of this is the immune response to human recombinant erythropoietin (EPO) therapy. Erythropoietin is used to stimulate the development of red blood cells and restore the red blood cell count in patients who have undergone chemotherapy or dialysis. A small percentage of patients develop antibodies to EPO and subsequently do not respond to both EPO administered therapeutically and their own endogenous EPO (see Casadevall, N. et al., NEJM, 2002, 346, pp. 469-475). They contract a disorder, pure red cell aplasia, in which the production of red blood cells in the blood is severely diminished (see Gershon S. K. et al., 5 NEJM 2002, 346, pp. 1584-1586). This complication of EPO therapy is lethal, if not treated. Another specific example is the murine 0KT3 antibody (a.k.a., Orthoclon), a monoclonal antibody that is directed to the CD-3 domain of activated T cells. In the tests clinics, of 20-40% of patients given 0KT3 produce antibodies against the therapy. These antibodies, in addition to neutralizing the therapy, also stimulate a strong immune reaction of the host. The immune reaction is severe enough-for that patients with high doses of human anti-mouse antibodies are restricted from taking the drug (see package label of orthoclon). A final example is a therapeutic human antibody. Humira® is a monoclonal antibody directed against T? F and is used to treat patients with rheumatoid arthritis. When taken alone, -12% of patients develop neutralizing antibodies. In addition, a small percentage of patients who are given the drug also develop a condition similar to systemic lupus erythematosus, which is the . immune response mediated by the IgG induced by the therapeutic agent (see package label of Humira).

Another example of "harmful immune response" is a reaction of the host to small molecule drugs. Those skilled in the art know that certain chemical structures will be conjugated with host proteins to stimulate immune recognition (see Ju.C. et al, 2002, Current Drug Metabolism 3, pp. 367 and 377, and Kimber I. et al. 2002, Toxicologic Pathology 30, pp. 54-58). A substantial portion of these guest responses are mediated by IgG. Specific "harmful immune responses" that are mediated by IgG include: hemolytic anemia, Steven-Johnson syndrome, and drug-induced lupus.

"Halo" means fluorine, chlorine, bromine or iodine.

"Haloalkyl" means alkyl substituted by one or more, preferably by one to five "halo" atoms, such as those terms are defined in this Application. Haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like, p. ex. , chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like.

"Haloalkoxy" refers to a radical -OR where R is a haloalkyl group as defined above, e.g. ex. , trifluoromethoxy, 2, 2, 2-trifluoroethoxy, difluoromethoxy, and the like.

"Heteroaryl" means a monocyclic or multicyclic aromatic ring of 5 to 10 ring atoms in which one or more, preferably one, two or three of the ring atoms are selected from nitrogen, oxygen or sulfur, with the remaining carbon being carbon . Representative heteroaryl rings include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl. , quinazolinyl, quinoxalinyl, pyrazolyl, and the like.

"Heteroaralkyl" means a radical (alkylene) -R where R is heteroaryl as defined above, p. ex. , pyridinylmethyl, 1-, or 2-furanylethyl, imidazolylmethyl, and the like.

"Heteroaryloxyalkyl" means a radical (alkylene) -OR where R is heteroaryl as defined above, e.g. ex. , furanyloxymethyl, 2-, or 3-indolyloxyethyl, and the like.

"Heteroarylsulfonyl" refers to a radical -S02R where R is a heteroaryl group, e.g. eg, pyridinylsulfonyl, and the like.

"Heterocycloalkyl" means cycloalkyl, as defined in this Application, provided that one or more, preferably one, two or three of the indicated carbon atom (s) are (are) replaced by a heteroatom selected from -N-, -0-, -S-, -SO-, or -S (0) 2- and additionally where one or two carbon atoms are optionally replaced by -C (0) -. Representative examples include, but are not limited to, imidazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholino-1-oxide, thiomorpholino-1-dioxide, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetra thiopyranyl, indolinyl, piperazinyl, piperidyl. , pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like.

"Heterocycloalkyl" means a radical (alkylene) -heterocycloalkyl where the heterocycloalkyl is as defined in this Application. Representative examples include, but are not limited to, imidazolidin-1-ylmethyl, morpholin-4-ylmethyl, thiomorpholin-4-ylmethyl, thiomorpholin-4-ylmethyl-l-oxide, indolinylethyl, piperazinylmethyl or -ethyl, piperidylmethyl or -ethyl , pyrrolidinylmethyl or -ethyl, and the like.

"Heterocycloalkylene" means cycloalkylene, as defined in this Application, provided that one or more, preferably one or two of the atoms of the carbon member is replaced by a heteroatom selected from -N-, -O-, -S- or -S (0) 2- and optionally one or two ring atom (s) of the carbon member are (are) replaced with -C (O) -. For example, the case in which "R5 and R6 together with the carbon atom to which both R5 and R6 are linked are linked from heterocycloalkylene" includes, but is not limited to, the following: where R is a substituent defined in the Description of the Invention.

"Hydroxy" means the -OH radical.

"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 with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both in the same hydroxy group. carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3 -dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- ( hydroxymethyl) -2-hydroxyethyl.

"Isomers" means the compounds of the present invention that have identical molecular formulas but differ in the nature or binding sequence of their atoms or in the arrangement of their atoms in space. The isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are mirror images that can not overlap are called "enantiomers" or, sometimes, "optical isomers." A carbon atom bonded to four non-identical substituents is termed a "chiral center". A compound with a chiral center that has enantiomeric forms of opposite chirality is known as a "racemic mixture". A compound that has more than one chiral center has 2n_1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers, called "diastereomeric mixture". When a chiral center is present, a stereoisomer can be characterized by the absolute configuration of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents linked to the chiral center. The enantiomers are characterized by the absolute configuration of their chiral centers, and are described by the sequencing rules of R- and S- of Cahn, Ingold and Prelog.

The conventions of the stereochemical nomenclature, the methods for the determination of the stereochemistry and the separation of the stereoisomers are well known in the art (eg, see "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & amp; Sons, New York, 1992). It is understood that the names and illation used in this Application to describe the compounds of Formula (I) are intended to encompass all possible stereoisomers.

Additionally, the compounds of Formula (I) may exist as tautomers. Tautomeric forms (individual tautomers or mixtures thereof) are within the purview of this invention.

"Keto or oxo" means the radical (= 0).

"Monosubstituted amino" means a radical -NHR where R is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl or acyl, as defined herein. Representative examples include, but are not limited to, methylamino, phenylamino, benzylamino, cyclopropylmethylamino, acetylamino, trifluoroacetyl, and the like.

"Nitro" means the radical -N02.

• "Optional" or "optionally" or "may be" means that the event or circumstance described below may or may not occur, and that the description includes the cases in which the event or circumstance occurs and the cases in which not. For example, the phrase "wherein the aromatic ring Ra is optionally substituted with one or two substituents independently selected from alkyl, ...", means that the aromatic ring Ra may or may not be substituted with alkyl to fall within the competence. of the invention. Additionally, the phrase "wherein R33 and R34 together with Si form a heterocycloalkylene ring containing the Si atom and from 3 to 7 carbon atoms, where one or two carbon ring atoms are optionally and independently replaced with -NH -, -O-, -S-, -SO-, -S02-, -CO-, -CONH-, or -S02NH- and where the "ring of heterocycloalkylene in Rla is optionally substituted in the ring with one, two or three Re independently selected from alkyl, ... ", means that the hydrogen in the -NH- group in the heterocycloalkylene ring may or may not be substituted with alkyl to fall within the competence of the invention.

The present invention also includes the N oxide derivatives of the compounds of this invention. "N-oxide derivatives" means those derived from the compounds of the present invention in which the nitrogens are in an oxidized state (eg, N? O), e.g. ex. ,. N oxide of pyridine, and they possess. the desired pharmacological activity.

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

"Pharmaceutically acceptable" means that which is useful for preparing a pharmaceutical composition and is generally safe, non-toxic or undesirable either biologically or otherwise, and includes what is acceptable for veterinary use as well as for human pharmaceutical use.

"Pharmaceutically acceptable salts" means the salts of the compounds of the present invention that - are pharmaceutically acceptable, as defined above, and possess the desired pharmacological activity. These salts include the acid addition salts that are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with 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-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid , p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [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, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

The pharmaceutically acceptable salts also include the base addition salts that can be formed when the acidic protons present are capable of reacting with organic or inorganic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

The present invention also includes prodrugs of a compound of the present invention. Prodrug means a compound that is convertible in vivo, through metabolic means (eg, by hydrolysis), to a compound of the present invention. For example, an ester of a compound of the present invention containing a hydroxy group can be converted, by hydrolysis in vivo, to the parent molecule. Alternatively, an ester of a compound of the present invention containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of the compounds of the present invention containing a hydroxy group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b- hydroxynaphthates, gentisatos, isethionates, di-p-toluoyltartrates, methylsulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and kinatos Suitable esters of the compounds of the present invention which contain a carboxy group are, for example, those described by Lein Eber , FJ Drug Metab. Res., 1987, 18, p 379. An especially useful class of esters of the compounds of the present invention which contain a hydroxy group, can be formed from portions of acid selected from those described. by Bundgaard et al., J. Med. Chem., 1989, 32, pp. 2503-2507, and include the substituted (aminomethyl) -benzoates, for example, the dialkylamino-methylbenzoates in which the two gr Alkyl groups can be joined together and / or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. ex. , an alkylated nitrogen atom, more especially the (morpholino-methyl) -benzoates, p. ex. , the 3- or 4- (morpholinomethyl) -benzoates, and the (4-alkylpiperazin-1-yl) -benzoates, p. ex. , 3- or 4 - ^ (4-alkylpiperazin-1-yl) -benzoates.

"Protected derivatives" means the derivatives of the compounds of the present invention in which a reactive site or sites (2) are blocked with protecting groups. The protected derivatives of the compounds of the present invention are useful in the preparation of the compounds of the present invention or in which they themselves can be active inhibitors of cathepsin S. A list comprising the appropriate protecting groups can be found in TW Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., 1999.

"The expression in which the aromatic or alicyclic ring in R6, R6a, Ra, R10, R23, ... etc., is optionally substituted with alkyl, haloalkyl ...", includes both the aromatic ring or the acyclic ring It is directly. linked or that is part of a group that is linked to the specific group, p. ex. , R6, R6a, ... etc. For example, the expression R23 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, -S (0) 2R24, -alkylene- S (0) n23-R25, COOR26, -alkylene-COOR27, -CONR28R29, or -alkylene-CONR30R31 (where 'n3 is 0-2 and R24-R27-, R28 and R30 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl , cycloalkylalkyl, heterocycloalkyl, or • heterocycloalkylalkyl and R29 and R31 are independently hydrogen or alkyl), wherein the aromatic or alicyclic ring in R23 is optionally substituted with one, two. or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, amino, alkylamino, dialkylamino,. carboxy or alkoxycarbonyl and a substituent selected from aryl, aralkyl, heteroaryl or heteroaralkyl include aromatic and alicyclic rings such as aryl, aralkyl, cycloalkyl, and aromatic or alicyclic ring in the -alkylene-S (0) 23-R25 group, where R25 is aryl, aralkyl, cycloalkyl, ... etc.

"Therapeutically effective amount" means that amount which, when administered to an animal to treat a disease, is sufficient to effect the treatment for the disease.

"Treatment" or "treating" means means any administration of a compound of the present invention, and includes: (1) preventing the disease from occurring in an animal that may be predisposed to the disease but still does not experience or show the pathology or the - symptomatology of the disease, (2) inhibiting the disease in an animal that is experiencing or showing the pathology or the symptomatology of the patient (eg, stopping the further development of the pathology and / or the symptomatology), or (3) improve the disease in an animal that is - experiencing or showing the pathology or symptomatology of the patient (eg, reversing the pathology and / or symptomatology).

"Treatment" or "treatment" with respect to combination therapy, p. ex. , using with biological means any administration of a compound of the present invention, includes: (1) preventing the occurrence of the immune response in an animal that may be predisposed to the immune response but still does not experience or show the pathology or symptomatology of the immune response, (2) inhibiting the immune response in an animal that is experiencing or showing the pathology or symptomatology of the immune response (eg, stopping the further development of the pathology and / or symptomatology), or (3) improve the immune response in an animal that is experiencing or showing the pathology OR the symptomatology of the immune response (eg, reducing in degree or severity, or in extent or duration, the evident manifestations of the immune response or reverse the pathology and / or the symptomatology, eg, reduced agglutination and the presentation of antigenic peptides through MHC class II molecules, activation induced from T cells and B cells, humoral and reduced cell-mediated responses, and, where appropriate for the immune response in particular, reduction of inflammation, congestion, pain, necrosis, reduced loss in efficacy of the biological agent, and the like) .

Preferred representations. While the broader definition of this invention is set forth in the Description of the invention, certain compounds of the invention are preferable. For example: A. A preferable group of compounds is that wherein E is -C (R5) (R6) X1, wherein: R5 is hydrogen or alkyl; and R6 is hydrogen, alkyl, - (alkylene) -OR12 (where R 12 is hydrogen, alkyl or haloalkyl), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, wherein aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl is. optionally substituted with one, two or three R independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, or acyl. Preferably, R5 is hydrogen; R6 is alkyl, preferably ethyl or propyl, more preferably ethyl; and X1 is -CHO, -C (0) R10, -C (0) CF3, -C (O) CF2CF2R9, - CH = CHS (0) 2R10, -C (O) CF2C (O) NR10R, -C ( O) C (O) NR10R, C (0) CH2OR10, -C (0) CH2N (R11) S02R10, -C (O) C (O) N (R11) (CH2) 20R1X, - C (0) C ( 0) N (RX1) (CH2) 2NHR1: L or C (0) C (0) R10, where R10 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, where the aromatic ring in R10 is optionally substituted with Rd selected from heteroaryl, aryl, alkyl, o-alkoxyalkyl, R 11 is hydrogen or alkyl, and R 9 is halo. More preferably, X1 is -C (O) C (O) NHR11, where R11 is cycloalkyl, preferably cyclopropyl.

More preferably, E is -CHR6C (0) R10, where R6 is alkyl, preferably ethyl, propyl or butyl, more preferably ethyl, and R10 is heteroaryl optionally substituted with one or two. Rd, independently selected from alkyl, haloalkyl, alkoxy, alkoxyalkyl, cycloalkyl, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, aryl, heteroaryl, amino, monosubstituted amino, di-substituted amino, or acyl, where the aromatic or alicyclic ring in is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl ,. alkoxy, haloalkoxy, halo, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, or dialkylamino. More preferably, R10 is benzoxazol-2-yl, 4-azabenzoxazol-2-yl, 2-pyridin-3-yl- [3, 4] -oxadiazol-5-yl, 2-ethyl- [1,3, 4] -oxadiazol-5-yl, 2-isopropyl- [1,3,4] -oxadiazol-5-yl, 2-tert-butyl- [1,3,4] -oxadiazol-5-yl, 2-phenyl - [1, 3,] -oxadiazol-5-yl, 2-methoxymethyl- [1, 3, 4] -oxadiazol-5-yl, 2-furan-2-yl- [1, 3,] -pxadiazole-5 -yl, 2-thien-2-yl [1, 3, 4] -oxadiazol-5-yl, 2- (4-methoxyphenyl) - [1,3,4] -oxadiazol-5-yl, 2- (2 -methoxyphenyl) - [1, 3,4] -oxadiazol-5-yl, 2- (3-methoxyphenyl) - [1, 3, 4] -oxadiazol-5-yl, 2- (2-trifluoromethoxyphenyl) - [1 , 3,4] -oxadiazol-5-yl, 2- (3-trifluoromethoxy-phenyl) - [1,3,] -oxadiazol-5-yl, 2- (4-trifluoromethoxyphenyl) - [1, 3, 4] -oxadiazol-5-yl, 2- (4-dimethylaminophenyl) - [1,4] -oxadiazol-5-yl, piradicin-3-yl, pyrimidin-2-yl, 3-phenyl- [1, 2, 4] -oxadiazol-5-yl, 3-ethyl- [1, 2, 4] -oxadiazol-5-yl, 3-cyclopropyl- [1,2,4] -oxadiazol-5-yl, 3-thien-3 -yl- [1,2,4] -oxadiazol-5-yl, 3-pyridin-4-yl- [1, 2, 4] -oxadiazol-5-yl, 3-pyridin-2-yl- [1, 2 ,] -oxadiazol-5-yl, 5-ethyl- [1,2,4] -oxadiazol-3-yl, 5-phenyl- [1, 2, 4] -oxadiazol-3-yl, 5-thien-3 -yl- [1,2,4] -oxadiazol-3-yl, 5-trifluoromethyl- [1,2, 4] -oxadiazol-3-yl, 5-pyridin-4-yl- [1, 2, 4] -oxadiazol-3-yl, or 5-phenyloxazol-2-yl. Even more preferably, R10 is benzoxazol-2-yl, oxazolo [4, 5-b] pyridin-2-yl, 2-ethyl- [1,3,4] -oxadiazol-5-yl, 2-phenyl- [1 , 3,4] -oxadiazol-5-yl, 3-phenyl- [1,2,4] -oxadiazol-5-yl, 3-thien-3-yl- [1, 2, 4] -oxadiazol-5-yl, 3-pyridin-3-yl- [1 , 2,4] -oxadiazol-5-yl, 3-ethyl- [1, 2, 4] -oxadiazol-5-yl, 5-ethyl- [1, 2,] -oxadiazol-3-yl, or 2- methoxymethyl- [1, 3, 4] -oxadiazol-5-yl. More preferably, R10 is benzoxazol-2-yl.

B. Another preferred group of compounds is that wherein E is -C (R5) (R6) X1 where R5 and R6 taken together with the carbon atom to which both R5 and R6 are attached form cycloalkylene or heterocycloalkylene, preferably cyclopropylene, cyclopentylene, ciciohexileno, tetrahydropyran-4-yl, tertahidrotiopiran-4-yl, tetrahydrothiopyran-4-yl-l-oxide, tetrahydrothiopyran-4-yl-1, 1-dioxide, or piperidin-4-yl, where Nitrogen atom is optionally substituted with alkyl, alkoxy, or hydroxy, preferably tetrahydrothiopyran-4-yl-l, 1-dioxide, and X1 is -CHO, -C (0) R10, -C (0) CF3, -C ( O) CF2CF2R9, -CH = CHS (0) 2R10, -CYZJCFZCÍOJNR1 ^ 11, -C (O) C (O) NR ^ R11, C (0) CH2OR10, -C (0) CH2N (R11) S02R10, -C (O) C (O) N (R11) (CH2) 2ORn, -C (0) C (0) N (Ru) (CH) ^ NR11 or -C (O) C (O) R10 More preferably, X1 is -C (O) C (O) NR10R1: L, where R11 is hydrogen and R10 is cycloalkyl or benzyl Preferably, R10 is cyclopropyl and R11 It is hydrogen.

C. Another preferable group of compounds is that in which E is a group of the formula (a): wherein: n is 0, 1 or 2; X4 is -NR22-, -O- or -S-, where R22 is hydrogen, alkyl or alkoxy; X5 is -0-, -S (0) 2-, -S-, or NR23-, where R23 is selected from hydrogen, alkyl, -S (0) 2R24, -C (0) OR26, or acyl, -where R 24 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, and R 26 is hydrogen or alkyl.

Preferably X4 is -O-, n is 0 or 1 and X5 is -O-.

D. Another preferable group of compounds is that in which E is CR5aR6aCN, where R5a and R6a are hydrogen.

E. Another preferable group of compounds is that wherein E is -CR5aR6aCN, where R5a and R6a together with the carbon atom to which they are linked optionally form cycloalkylene. substituted with one or two Rb independently selected from alkyl, halo, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl or aryloxycarbonyl. Preferably, R5a and R6a together with the carbon atom to which they are attached form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, optionally substituted with the groups described immediately above. More preferably, R5a and R6a together with the carbon atom to which they are attached form cyclopropylene, cyclobutylene, cyclopentylene, or ciciohexileno, cycloheptylene, 2-metilciclopropileno, 3- bencilciclopentileno, 3-ciclohexilmetilciclopentileno, 3- ciclopentilmetilciclopentileno, 3-fenilciclopentileno, 3- ciclohexilciclopentileno, 3-ciclopentilciclopentileno, 3- pyridin-2-ilmetilciclopentileno, 3-pyridin-3- ilmetilciclopentileno, 3-pyridin-4-ilmetilciclopentileno, 2-metilciclopropileno, 2, 3-dimetilciclopropileno, 3- bencilciclobutileno, 3-metilciclopentileno, 3,4- dimetilciclopentileno, 3-etilciclopentileno, 3- (1,1- dimetipropil) -ciclopentileno, 3-n-butilciclopentileno, 3- etoxicarbonilciclopentileno, 3, 4-dietoxicarbonil- cyclopentylene, or 3-benzyl-4-dimetilaminociclopentileno. More preferably, R5 and R6a together with the carbon atom to which they are linked form cyclopropylene.

F. another preferred group of compounds is that wherein E is CR5aR6aCN where R5a and R6a together with the carbon atom to which they are attached form heterocycloalkylene optionally substituted with one to four alkyls or two Rc which are independently selected from alkyl, haloalkyl, hydroalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, -S (0) n2-R15, -COOR16, -alkylene-COOR17, -CONR18R19, or -alkylene-CONR20R21 (where n2 is 0-2 and R14-R17, R18 and R20 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl and R19 and R21 are independently hydrogen or alkyl), wherein the aromatic or acyclic ring in the groups bonded to the heterocycloalkylene is optionally substituted with one, two or • three substituents independently selected from alkyl ', haloalkyl, cycloalkyl, cycloalkylalkyl, benzyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, or acyl. Preferably, R5a and R6a together with the carbon atom to which they are linked form pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiopyran-4-yl-l-oxide, tetrahydrothiopyran-4-yl-l, 1-dioxide, hexahydropyrididinyl, or hexahydropyridazinyl optionally substituted as described above. More preferably, R5a and R6a together with the carbon atom to which they are linked form piperidin-4-yl substituted with one to three alkyls and an Rc selected from haloalkyl, aminoalkyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxyalkyl, heterocycloalkyl, heterocycloalkylalkyl, - alkylene-CONR20R21, or cycloalkyl wherein the alicyclic ring is optionally substituted with the substituents listed above. More preferably, R5a and R6a together with the carbon atom to which they are attached form piperidin-4-yl optionally substituted at the 1-position with methyl, ethyl, propyl, n-butyl, n-pentyl, 3- dimethylaminopropyl, 4- dimethylaminobutyl, 3-morpholin-4-ylpropyl, 3-piperidin-1-yl-propyl, 3- (4-methylpiperazin-1-yl) propyl, 3- (1-methylpiperidin-4-yl) propyl, 4-morpholino- 4- butyl, 2- (2-methoxyethyl-oxy) ethyl, 4-methoxybutyl, 4-aminocarbonyl butyl, 3-aminocarbonylpropyl, morpholin-4-yl, 4-methylpiperazin-1-yl, l-ethoxycarbonylpiperidin-4-yl, 1, l-dioxotetrahydrothiopyran-4-yl, hydroxy, 2,2,2-trifluoroethyl, or tert-butyl, 1,2-dimethylpiperidin-4-yl, 1,2,6-trimethylpiperidin-4-yl, 1, 2, 2 -trimethylpiperidin-4-yl, l-methyl-2-oxopiperidin-4-yl, l-methylpiperidin-3-yl, '1-tert-butoxycarbonylpiperidin-4-yl, 1-cyclohexylpiperidin-4-yl, l- cyclopropylmethylpyrrolidin-3-yl, 1-benzylpyrrolidin-3-yl, l-benzyloxycarbonylpyrrolidin-3-yl, pyrrolidin-3-yl, l-hydroxypyrrole idin-3-yl, 1-methylpyrrolidin-3-yl, l-ethylpyrrolidin-3-yl, 1-n-propyl or n-butylpyrrolidin-3-yl, l-cyclohexyl-pyrrolidin-3-yl, 1-ethyl-2, 2-dimethylpyrrolidin-4-yl, l-propyl-2-methoxycarbonylpiperidin-4-yl, 2-oxopyrrolidin-3-yl, 1-ethyl-2-oxopyrrolidin-3-yl, morpholin-4-yl, 1- (1 -methylpiperidin-4-ylcarbonyl) piperidin-4-yl, 1-ethoxycarbonylpiperidin-4-yl, l-benzylacetidin-3-yl, tetrahydrothiopyran-4-yl-l-oxide, or tetrahydrothiopyran-4-yl-1,1- dioxide. Particularly preferably, R5 and R6a together with the carbon atom to which they are attached form piperidin-4-yl substituted in the 1-position with ethyl, n- or 2-propyl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl-1 -oxide, or tetrahydrothiopyran-4-yl-l-dioxide. Even more particularly preferable, R5a and R6a together with the carbon atom to which they are linked form piperidin-4-yl substituted in the 1-position with ethyl, n- or 2-propyl or tetrahydrothiopyran-4-yl-1, 1-dioxide .

I. Within the preferable and more preferable groups above (A-F), an even more preferable group of compounds is that in which R1 and R2 are hydrogen. (i) Within these preferable, more preferable and even more preferable groups, a more preferable group of compounds is that in which Q is -CO-. (ii) Within these preferable, more preferable and even more preferable groups, another more preferable group of compounds is that in which Q is -0C0-. (iii) Within these preferable, more preferable and even more preferable groups, another even more preferable group of compounds is that in which Q is -NHCO-. (iv) Within these preferable, more preferable and even more preferable groups, another even more preferable group of compounds is that in which Q is -CH (CF3) -.

Within the preferable, more preferable and even more preferable groups - from above, a particularly preferable group of compounds is that in which: (a) Rla is - (alkylene) -SiR32R33R34 where R32 is alkyl, R33 is alkyl, and R34 is alkyl.

Preferably, R32, R33 and R34 are independently methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, or tert-butyl. More preferably, Rla is -CH2_Si (CH3) 3, -CH2-Si (2-methylpropyl) (CH3) 2, -CH2-Si (2- tert -butyl) (CH3) 2, or - (CH2) 2-Si (ethyl) (CH3) 2. Even more preferably, R1 is -CH2-Si (CH3) 3. (b) Within the preferable, more preferable and even more preferable groups above, another particularly preferable group of compounds is that in which: Rla is a group having the structure: (c) Within the preferable, more preferable and even more preferable groups above, another particularly preferable group of compounds is that in which: Rla is - (alkylene) -SiR32R33R34, where R32 is alkyl and R33 and R34 together with Si form a heterocycloalkylene ring containing an Si atom and 4 or 5 carbon ring atoms where one or two carbon ring atoms are optionally independently replaced with -NH-, -0-, -S-, -S0 -. -S02-, -CO-, -CONH-o -S02NH-. Preferably Rla is a group that has the structure: Preferably, R is a group that * has the structure: (d) Within the preferable, more preferable and even more preferable groups above, another particularly preferable group of compounds is that in which: Rla is - (alkylene) -SiR32R33R34, where R32 and R33 are alkyl and R34 is cycloalkylalkyl. Preferably, Rla is a group that has the structure: (e) Within the preferable, more preferable and even more preferable groups above, another particularly preferable group of compounds is that in which: Rla is - (alkylene) -SiR32R33R34, where R32 and R33 are alkyl and R34 is aralkyl. 'Preferably, Rla is a group that has the structure: wherein each Re is independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, or alkoxy. (f) Within the preferable, more preferable and even more preferable groups above, another particularly preferable group of compounds is that in which: Rla is - (alkylene) -SiR32R33R34, where R32 and R3a are alkyl and R34 is heteroalkyl optionally substituted with Re. Preferably, Rla is a group having the structure: (g) Within the preferable, more preferable and even more preferable groups above, another particularly preferable group of compounds is that in which: Rla is - (alkylene) -SiR32R33R34 where R32 and R33 are alkyl and R34 is aryl. Preferably, Rla is a group that has the structure: wherein each Re is independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy or alkoxy.

Within the groups of preferable, more preferable, even more preferable and particularly preferable compounds, a more particularly preferable group is that wherein R3 is alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, preferably aryl, heteroaryl, or heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with one or two of Rf.

Within the groups of preferable, more preferable, even more preferable and particularly preferable compounds, another group more particularly preferable is one in which R3 is a group selected from methyl, cyclohexylmethyl, 3-cyclohexylpropyl, 2-cyclohexylethyl, 2-cyclopentylethyl , 6-hydroxypyrid-3-yl, li-imidazol-4-yl, naphth-1-ylmethyl, 2-phenylethyl, piperazin-1-yl, piperidin-4-yl, pyrazin-2-yl, pyridin-3-yl , pyridin-4-yl, and tetrahydropyran-4-yl.

Within the groups of preferable, more preferable, even more preferable and particularly preferable compounds, another group more particularly preferable is - that in which Q is -CO- and R3 is morpholin-4-yl, piperidin-4-yl, pyrazin-2-yl, pyridin-3-yl, pyridin-4-yl or tetrahydropyran-4-yl.

Within the groups of preferable, more preferable, even more preferable and particularly preferable compounds, another group more particularly preferable is that in which Q is -CHCF3- and R3 is aryl optionally substituted with one, two or three Rf independently selected from alkyl, halo, hydroxyl, alkoxy, haloalkyl, haloalkoxy, or carboxy. Preferably, R3 is phenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl or 2,6-difluorophenyl. More preferably, R3 is phenyl, 4-fluorophenyl or 2,6-difluorophenyl.

G. Another preferable group of compounds of Formula (I) is that wherein: Rla is - (alkylene) -SiR32R33R34, where R32 is alkyl, and R34 is alkyl.

Preferably, R32, R33 and R34 are independently methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, or tert-butyl. More preferably, Rla. is -CH2-Si (CH3) 3 or -CH2-Si (2-methylpropyl) (CH3) 2. Even more preferably, Rla is -CH2-Si (CH3) 3.

Within this group, a more preferable group of compounds is that in which: Q is -C0-; and - R1 and R2 are hydrogen.

Another group of preferred compounds of Formula (I) is one in which Rla is a group having the structure: Within this group, a more preferable group of compounds is one in which: Q is -C0-; and R1 and R2 are hydrogen.

Another preferable group of compounds of Formula (I) is that in which: Rla is - (alkylene) -SiR32R33R34, where R32 is alkyl and R33 and R34 together with Si form a heterocycloalkylene ring containing a Si and 4 atom. or 5 carbon ring atoms where one or two carbon ring atoms are optionally independently replaced with -NH-, -0-, -S-, -SO-, -S02-, -CO-, -CONH or -S02NH-. Preferably, Rla is a group that has the structure: Within this group, a more preferable group of compounds is that in which: Q is -C0-; and R1 and R2 are hydrogen.

J. Another preferable group of compounds of Formula (I) is that wherein: Rla is - (alkylene) -SiR32R33R34, where R32 is alkyl and R33 and R34 together with Si form a heterocycloalkylene ring. Preferably, Rla is a group that has the structure: Within this group, a more preferable group of compounds is that in which: Q is -CO-; and R1 and R2 are hydrogen.

K. Another preferable group of compounds of Formula (I) is that wherein: Rla is - (alkylene) -SiR32R33R34, where R32 and R33 are alkyl and R34 is cycloalkylalkyl. Preferably, Rla is a group that has the structure: Within this group, a more preferable group of compounds is that in which: Q is -C0-; and R1 and R2 are hydrogen.

L. Another preferable group of compounds of Formula (I) is that wherein: Rla is - (alkylene) -SiR32R33R34, where R32 and R33 are alkyl and R34 is aralkyl. Preferably, Rla is a group that has the structure: wherein each Re is independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, or alkoxy.

Within this group, a more preferable group of compounds is one in which: Q is -C0-; and R1 and R2 are hydrogen.

M. Another preferable group of compounds of the Formula (I) is that in which: Rla is - (alkylene) -SiR32R33R34, where R32 and R33 are alkyl and R34 is heteroaralkyl optionally substituted with Re. Preferably, Rla is a group having the structure: Within this group, a more preferable group of compounds is one in which: Q is -C0-; and R1 and R2 are hydrogen.

N. Another preferable group of compounds of the Formula (I) is that in which: Rla is - (alkylene) -SiR32R33R34, where R32 and R33 are alkyl and R34 is aryl. Preferably, Rla is a group that has the structure: wherein each Re is independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy or alkoxy.

Within this group, a more preferable group of compounds is that in which: Q is -CO-; and R1 and R2 are hydrogen. within the preferable and more preferable groups above in (GN), an even more preferable group of compounds is that in which E is -CHR6C (0) R10, wherein R6 is alkyl, preferably ethyl, propyl or butyl, more preferably ethyl, and R10 is heteroaryl optionally substituted with one or two Rd independently selected from alkyl, haloalkyl, alkoxy, cycloalkyl, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, aryl, heteroaryl, amino, monosubstituted amino, disubstituted amino or acyl, where the aromatic or alicyclic ring in Rd is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, or dialkylamino, more preferably R10 is benzoxazole- 2-yl, 4-azabenzoxazol-2-yl, 2-pyridin-3-yl- [1,3,4] -oxadiazol-5-yl, 2-pyridin-4-yl- [1,3,4] - oxadiazol-5-yl, 2-ethyl- [1, 3, 4] -oxadiazol-5-yl, 2-isopropyl - [1, 3, 4] -oxadiazol-5-yl, 2-tert-butyl- [1, 3, 4] -oxadiazol-5-yl, 2-phenyl- [1,3,4] -oxadiazole-5 -yl, 2-methoxymethyl- [1,3,4] -oxadiazol-5-yl, 2-furan-2-yl- [1, 3, 4] -oxadiazol-5-yl, 2-thien-2-yl - [1, 3, 4] -oxadiazol-5-yl, 2- (4-methoxy-phenyl) - [1, 3, 4] -oxadiazol-5-yl, 2- (2-methoxyphenyl- [1, 3 , 4] -oxadiazol-5-yl, 2- (3-methoxy-phenyl) - [1, 3, 4] -oxadiazol-5-yl, 2- (2-trifluoromethoxyphenyl) - [1, 3, 4] - oxadiazol-5-yl, 2- (3-trifluoromethoxyphenyl) - [1,3,4] -oxadiazol-5-yl, 2- (4-trifluoromethoxyphenyl) - [1,4,4] -oxadiazol-5-yl, 2- (4-dimethylaminophenyl) - [1,3,4] -oxadiazol-5-yl, piradicin-3-yl, pyrimidin-2-yl, 3-phenyl- [1, 2, 4] -oxadiazole-5- ilo, 3-ethyl- [1,2,4] -oxadiazol-5-yl, 3-cyclopropyl- [1,2,4] -oxadiazol-5-yl, 3-thien-3-yl- [1, 2 , 4] -oxadiazol-5-yl, 3-pyridin-4-yl- [1, 2, 4] -oxadiazol-5-yl, 3-pyridin-2-yl- [1, 2, 4] -oxadiazole- 5-yl, 5-ethyl- [1, 2, 4] -oxadiazol-3-yl, 5-phenyl- [l, 2,4] -oxadiazol-3-yl, 5-thien-3-yl- [1 , 2,4] -oxadiazol-3-yl, 5-trifluor omethyl- [1, 2,4] -oxadiazol-3-yl, -pyridin-4-yl- [1, 2,] -oxadiazol-3-yl, or 5-phenyloxazol-2-yl. Even more preferably, R10 is benzoxazol-2-yl, oxazolo [4, 5-b] pyridin-2-yl, 2-ethyl- [1, 3, 4] -oxadiazol-5-yl, 2-phenyl- [1 , 3, 4] -oxadiazol-5-yl, 3-f-enyl- [1, 2, 4] -oxadiazol-5-yl, 3-thien-3-yl- [1, 2, 4] -oxadiazole-5 -yl, 3-pyridin-3-yl- [1, 2, 4] -oxadiazol-5-yl, 3-ethyl- [1, 2, 4] -oxadiazol-5-yl, 5-ethyl- [1, 2,4] -oxadiazol-5-yl, or 2-methoxymethyl- [1, 3, 4] -oxadiazol-5-yl.

Within the preferable and more preferable groups above (GN), another group of compounds even more preferable is that in which E is -CR5R6aCN, where R5a and R6a together with the carbon atom to which they are linked form cycloalkylene, preferably cyclopropylene .

Within the preferable and more preferable groups above (GN), another group of compounds even more preferable is that in which E is -CR5aR6aCN, where R5a and R6a together with the carbon atom to which they are linked form heterocycloalkylene, preferably R5a and R6a together with the carbon atom to which they are linked form piperidin-4-yl substituted in the 1-position with ethyl, n- or 2-propyl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl-1-oxide, or tetrahydrothiopyran-4-yl-l, 1-dioxide.

Within the preferable and more preferable groups above (G-N), another group of compounds even more preferable is one in which E is -CR6COCOR10, wherein R10 is cycloalkyl, preferably R6 is ethyl, propyl or butyl, and R10 is cyclopropyl.

Within the preferable groups, more preferable and even more preferable from above (G-N), a group of compounds particularly preferable is one in which R3 is aryl, heteroaryl or heterocycloalkyl. Preferably, R3 is morpholin-4-yl, l-ethylpiperazin-4-yl, phenyl optionally substituted with one or two substituents independently selected from halo, alkoxy, alkyl, haloalkoxy, phenyl, alkylsulfonyl, haloalkyl, heteroaryl, cyano, acyl. , hydroxyalkyl, or alkoxycarbonyl. Preferably, R3 is morpholin-4-yl, 1-ethylpiperazin-4-yl, 3'-methoxy-biphen-3-yl, 3'-iodophenyl, 3'-trifluoromethoxy-biphen-3-yl, bifen-3-yl, 2 ', 6'-dimethoxybifen-3-yl,. 4 '-methylsulfonyl-biphen-3-yl, 2'-chlorobiphen-3-yl, 2'-trifluoromethylmethylbiphen-3-yl, 3'-methylbiphen-3-yl, 3-pyridin-3-yl-phenyl, 3'-cyclobiphen-3-yl, 3'-hydroxymethylbiphen-3-yl, 4'-hydroxymethyl-biphen-3-yl, 2 '-methylbiphen-3-yl, 3'-methoxycarbonylbiphen-3-yl, or 4! - acetylbifen-3-yl.

Additionally, in the preferable representations above, numerous different preferences have been given and following any of these preferences results in a compound of this invention that is currently more preferable than a compound in which that particular preference is not followed. However, these preferences are generally independent; and following more than one of those preferences can result in a compound currently more preferable than one in which fewer preferences have been followed. 1. The compounds of Formula (I), where Q is -CO-, R1, R2 are hydrogen, E is CR5R6CR7R8R10 'where R5 is hydrogen, R7 and R8 together form oxo and R3, Rla, R6 and R10 are as defined below , They are: and they are called: { 1 (R) - [1 (S) - (benzoxazol-2-ylcarbonyl) -butylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; . { 1 (R) - [1 (S) - (benzoxazol-2-ylcarbonyl) -propylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; 27883 1H-NMR (CDC13): 7.86 (d, J = 8Hz, ÍH), 7.62 (d, J = 8 Hz, ÍH), 7.51 (dt, J = 7.2 Hz, J = 1.2 Hz, ÍH), 7.43 (dt, J = 1.2 Hz, ÍH), 6.94 (d , J = 7.2 Hz, 1H), 5.55 (m, 1H), 4.83 (d, J = 8.0 Beam, IH), 4.42 (m, 1H), 3.65 (m, 4H), 3.31 (, 4H), 2.13 ( m, 1H), 1.87 (, 1H), 1.14 (m, 2H), 0.98 (t, J = 12 Hz, 2H), 0.0 (s, 9H). LC-MS: 459.2 (M-1), 461.3 (M + 1). Exact mass: 460.21. . { 1 (R) - [1 (R) - (benzoxazol-2-ylcarbonyl) -propylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; . { 1 (R) - [1 (S) - (benzoxazol-2-ylcarbonyl) -pentyl-carbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; . { 1 (R) - [1 (S) - (5-chlorobenzoxazol-2-ylcarbonyl) -propylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; 1H-NMR (CDC13): 7.83 (d, J = 2 Hz, ÍH), 7.54 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.8 Hz, J = 2 Hz, 1H), 6.93 ( d, J = 6.4 Hz, 1H), 5.49 (, HH), 4.77 (d, J = 8 Hz, 1H), 4.41 (m, HH), 3.60 (, 4H), 3.32 (m, 4H), 2.13 ( m, HH), 1.84 (, 1H), 1.16 (m, 2H), 0.97 (t, J = 11.6 Hz, 2H), 0.98 (m, HH), 0.007 (s, 9H). LC-MS: 493.2 (M-1), 495.4 (M + 1). Exact mass: 494.18. . { 1 (S) - [1 (S) - (benzoxazol-2-ylcarbonyl) -propylcarbaoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; LCMS: 461.1 (M + 1) +1, 483.0 (M + Na) +, 459.1 (M-D "1; . { 1 (S) - [1 (S) - (benzoxazol-2-ylcarbonyl) -butylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; LCMS: 475.1 (M + 1), 497.0 (M + Na) t 473.2 (M-1) "1.

The compounds of Formula (I) wherein Q is -CO-, R1, R2 are hydrogen, E is CR5aR6aCN, where R5 and R6a are as defined below, and R3 and Rla are as defined RS 3 '-methoxybifen- -CH2Si (CH3) 3?,? - 3-yl dioxohexahydro-l6-thiopyran.-4-yl and they are called: 1- (1-cyanocyclopropylcarbamoyl) -2- (trimethyl-silanyl) ethyl] -amide of 1-acid. { R) -morpholino-4-carboxylic acid; [1- (4-cyano-l-ethylpiperidin-4-ylcarbamoyl) -2- (trimethyl-silanyl) ethyl] amide of 1- (JR) -morpholino-4-carboxylic acid; [1- (4-cyano-l, l-dioxohexahydro-l6-thiopyran-4-yl-carbamoyl) -2- (trimethylsilanyl) ethyl] amide of l- (i?) - morpholino-4-carboxylic acid; [1- . { RS) - morpholino-4-carboxylic acid (1-benzyloxymethyl-l-cyanocyclopropyl-carbamoyl) -2-trimethyl-silanylethyl] -amide; [1- . { RS) - (2-benzyloxy-l-cyano-l-methyl-ethylcarbaoyl) -2- (trimethyl-silanylethyl] -amide of morpholino-4-car-oxylic acid; [1- . { R) - 4-ethylpiperazine-1-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanyl-ethyl] -amide; [1- . { R) - 3'-methoxybiphenyl-3-carboxylic acid (1-cyano-cyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; 1H-NMR (CDC13): 7.89 (m, 1H), 7.66 (m, 2H), 7.44 (t, J = 4.4 Hz, ÍH), 7.30 (t, J = 3.6 Hz, 1H), 7.11 (d, J = 5.6 Hz, ÍH), '7.04 (t, J = 2 Hz, 1H), 6.85 (dd, J = 8.8 Hz, J = .2 Hz, ÍH), 4.55 (q, J = 8 Hz, ÍH), 3.80 (s, 3H), 1.43 (m, 3H), 1.31 (m, ÍH), 1.15 (m, 3H), 1.00 (dd, 1H), 0.00 (s, 9H). LC-MS: 434.2 (M-1), 436.3 (M + 1). Exact mass: "435.2; N- [1- (RS) - (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -3-iodobenzamide; M + H = 456.1; M-H = 454.0; exact mass = 455.06; [1- . { RS) 3 'trifluoromethoxybiphenyl-3-carboxylic acid (3-cyanocyclopropylcarbamoyl) -2-tri-ethyl-silanyl-ethyl] -amide; M + H = 490.2; M-H = 488.2; exact mass = 489.17; [1- . { RS) - biphenyl-3-carboxylic acid (1-cyanocyclopropycarbamoyl) -2-trimethylsilanylethyl] -amide; M + H = 406.3; M-H = 404.2; exact mass = 405.19; [1- . { RS) 2 '-6'-dimethoxybiphenyl-3-carboxylic acid ~ (1-cyanocyclopro? Ilcarbamoyl) -2-trimethyl-silanylethyl] amide; M + H = 466.2; M-H = 464.3; exact mass = 465.21; [1- . { RS) - (1-Cyanocyclopropylcarbamoyl) -2-tripylamino-silanylethyl] -amide of 4 '-methylsulfonylbiphenyl-3-carboxylic acid; aH-NMR (DMSO-d6): 8.91 (s, ÍH), 8.71 (d, J = 8Hz, ÍH), 8.02 (s, 5H), 7.84 (m, 2H), 7.61 (t, J = 8 Hz, 1H), 4.5 (m, 1H), 3.28 (s, 3H), 1.45 (m, 1H), 1.1 (, 4H), 0.01 (s, 9H). LC-MS: 482.2 (M-1), 484.1 (M + 1). Exact mass: 483.16; [1- . { RS) - 2'-chlorobiphenyl-3-carboxylic acid (l-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; M + H = 440.3; M-H = 438.2; Exact mass: 439.16; [1- . { RS) - (1-Cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide of 2'-trifluoromethylbiphenyl-3-carboxylic acid; M + H = 474.3; M-H = 472.3; exact mass = 473.17; [1- . { RS) - 3'-methylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; M + H = 420.5; M-H = 418.3; exact mass = 419.20; N- [1-. { RS) - (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -3-pyridin-3-ylbenzamide; M + H = 406.9; M-H = 405.3; exact mass = 406.18; [1- . { RS) - 3'-cyclobiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; 1 H-NMR (DMSO-de): 8.91 (s, ÍH), 8.69 (d, J = 8.4 Hz, ÍH), • 8.23 (s, 2H), 8.11 (d, J = 7.6 Hz, ÍH), 7.92 (m, 2H), 7.85 (.d, J = 7.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.59 (t, J = 7. 6 Hz, ÍH), 4.50 (m, ÍH), 1.45 (m, 2H), 1.19-1.00 (m, 4H.), 0.00 (s, 9H). LC-MS: 429.2 (M-1), 431.3 (M + 1). Exact mass: 430. 18; [1- . { RS) - (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide. 3 '-hydroxymethylbiphenyl-3-carboxylic acid; [1- . { RS) - (4-hydroxymethylbiphenyl) -3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl- "silanylethyl] -amide: M + Na = 458.1, M-H = 434.0, exact mass = 435.20; [1- . { RS) - 2'-methylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethylsilylethyl] -amide; M + H = 420.2; exact mass = 419.20; [1- . { RS) - 3'-methoxycarbonylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; M + H = 464.3; M-H = 462.2; exact mass = 463.18; [1- . { RS) - 4'-acetylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; ^ -NMR (DMSO-de): 8.01 (s, ÍH), 7.96 (d, J = 7.6 Hz, 2H), 7.72 (dd, J = 1.6 Hz, J = 1.6 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.5 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 4.6 (, 1H '), 2.58 (s, 3H), 1.47 (, 2H), 1.27 (m, 1H), 1.18 (, 2H), 1.03 (, ÍH), 0.00 (s, 9H). LC-MS: 446.5 (M-l), 448.5 (M + l). Exact mass: 447; [1- . { RS) - 3'-methoxybiphenyl-3-carboxylic acid (4-cyano-4-tetrahydrothiopyran-4-ylcarbamoyl) -2-trimethyl-silanylethyl] -amide; M + Na = 518.5; M-H = 494.5; exact mass = 495.20; Y [1- . { RS) - 3'-methoxybiphenyl-3-carboxylic acid (4-cyano-l, l-dioxohexahydro-l6-thiopyran-4-ylcarbamoyl) -2- (trimethylsilanyl) ethyl] amide; 1H-NMR (CDC13): -7.88 (, ÍH), 7. 85 (s, ÍH), 7.70 (d, J = 6.8 Hz, ÍH), 7.62 (d, J = 6.0 Hz, 1H), 7.45 (t, J = 6.0 Hz, ÍH), 7.30 (t, J = 6 Hz, 1H), 7. 10 (d, J = 7.2 Hz, ÍH), 7.04 (t, J = 2 Hz, HH), 6.85 (d, J = 6.8 Hz, 1H), 6.53 (d, J = 5.6 Hz, HH), 4.55 ( my h) , 3. 8 (s, 2H), 3.2 (m, 2H), 3.1 (m, ÍH), 3.0 (m, 1H), 2.8 (, ÍH), 2.65 (m, ÍH), 2.5"(, 2H), 1.33 (dd, J = 6.0 Hz, J = 11. 6 Hz, ÍH), 0.96 (dd, J = 6.4 Hz, J = 11.6 Hz, 1H), 0.80 (, 1H), 0.00 (s, 9H). LC-MS: 526.4 (M-1), 528.6 (M + 1). Exact mass: 527.20.

III. 1- [3- (benzyldimethylsilanyl) -2R- (2,2,2-trifluoro-1-phenylethylamino) propionyl] -cyclopropanecarbonitrile.

GENERAL SYNTHETIC DIAGRAM. The compounds of this invention can be made through the methods illustrated in the reaction schemes shown below.

The starting materials and reagents used to prepare these compounds are available from any of the commercial suppliers such as "Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), Or Sigma (St. Louis, Mo.), or are prepared by methods known to those skilled in the art, following established procedures in references such as Reagents for Organic Synthesis, by Fieser and Fieser, Volumes 1-17 (John Wiley and Sons, 1991); Chemistry of Coal Compounds, by Rodd, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Advanced Organic Chemistry, by March (John Wiley and Sons, 4th edition) and Comprehensive Organic Transformations by Larock (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and one skilled in the art can make, and suggest, various modifications to these schemes when referring to this description.

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

Unless otherwise specified, the reactions described herein take place at atmospheric pressure above a temperature scale of from about -78 ° C to about 150 ° C, more preferably from about 0 ° C to near of 125 ° C, and most preferably, near room temperature (room temperature), p. ex. , of about 20 ° C.

In the reactions described hereinafter, it may be necessary to protect the reactive functional groups, for example the hydroxy, amino, imino, thio or carboxy groups, when these are desired in the final product, to avoid their unwanted participation in The reactions. Conventional protection groups can be used in accordance with standard practice, for the examples, see "Protective Groups in Organic Chemistry" by TW Greene and PGM Wuts, John Wiley and Sons, 1991. The compounds of Formula (I) can be prepared through the procedures described in Schemes 1-4 below.

The compounds of Formula (I) wherein E is -C (R5) (R6) C (R7) (R8) R10, wherein R5, R6, R7, R8, R10 and other groups are as defined in the Description of the invention, can be prepared through the process illustrated and described in Scheme 1 below: Scheme 1: Reaction of a compound of Formula 1 [wherein Y is hydroxy or an activation group (eg, 2,5-dioxopyrrolidin-1-yl, succinimide, or the like), preferably hydroxy] with an aminoalcohol compound of Formula 2, wherein R7 is hydrogen and R8 is hydroxy, provides a compound of Formula (I) wherein R7 is hydrogen and R8 is hydroxy. The reaction conditions vary based on the nature of the group Y. When Y is an activation group, the reaction is carried out in the presence of a suitable base (eg, triethylamine, diisopropylethylamine, or the like) and in a solvent suitable (eg, acetonitrile, N, N-di-ethylformamide (DMF), dichloromethane, or any suitable combination thereof, or the like), at 10 to 30 ° C, preferably at about 25 ° C, and It requires 24 to 30 hours to complete. When Y is hydroxy, the reaction is carried out in the presence of a suitable binding agent (eg, benzotriazole-1-yloxytrispyrrolidinophosphonium-hexafluoro phosphate).

(PyBOP®), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), 0-benzotriazole-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTÜ), O-hexafluorophosphate - (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium (HATU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and a base is required (eg, N, N -diisopropylethylamine, triethylamine, or the like) and the reaction takes about 2 to 3 hours to complete. The compounds of Formulas 1 and 2 are commercially available, or can be prepared by methods well known in the art. For example, compound 1 wherein Q is -CO- and Y is hydroxy, can be easily prepared by reacting -an amino acid of the formula CR1Rla (COOR ') NHR2 (where R' is hydrogen or alkyl and - R1, R2 and R1) are as defined in the description of the invention) with an acylating agent of the formula R3COL, where L is a leaving group such as halo (particularly Cl or Br) or imidazolide. Suitable solvents for the reaction include polar aprotic solvents (e.g., dichloromethane, THF, dioxane and the like). When L is halo, the reaction is carried out in the presence of a non-nucleophilic organic base, e.g. ex. , triethylamine, pyridine, and the like. The acylating agents of the formula R3COL are commercially available, or they can be prepared by treating the corresponding acid with a halogenating agent such as oxalyl chloride, sulphonyl chloride, carbon tetrabromide, and the like. When R 'is alkyl, removal of the alkyl group under basic hydrolysis reaction conditions provides a corresponding compound of Formula 1, where Y is hydroxy.

Compound 1, where Q is -S02- and Y is hydroxy, can be easily prepared by reacting an amino acid of the formula CR ^ 13 (COOR ') NHR2, where R', R1, R2 and Rla are as defined above, with a sulfonyl halide of the formula R3S02L where L is halo, using the reaction conditions described in the method immediately above. Sulfonyl halides are commercially available, or can be prepared by methods such as those described in: (1) Langer, R.F .; Can. J. Chem.; 1983, 61, 1583-1592; (2) Aveta, R. ", et al., Gazetta Chimica Italiana, 1986, 116, 649-652; (3) King, JF and Hillhouse, JH, Can. J. Chem., 1976, 54, 498; (4) Szymonifka, MJ and Heck, J .. V., Tet. Lett., 1989, 30, 2869-2872.

Compound 1 where Q is -NHCO- 'and Y is hydroxy, can be easily prepared by reacting an amino acid of the formula CRxRla (COOR') NHR2, where R ', R1, R2 and Rla are as defined above, with an agent of activation such as carbonyl diimidazole / thiocarbonyl diimidazole, followed by the nucleophilic displacement of the imidazole group with a primary or secondary amine of the formula R3NH2, where R3 is as defined in the description of the invention. The reaction occurs at room temperature.

Suitable solvents include organic polar solvents (e.g., THF, dioxane and the like). Alternatively, these compounds can be prepared by reacting the CR ^ -R1 (COOR1) NHR2 with a carbamoyl halide of the formula R3NHCOL, where L is halo. The reaction is carried out in the presence of a non-nucleophilic organic base. Suitable solvents for the reaction are dichloromethane, 1,2-dichloroethane, THF or pyridine. These compounds can also be prepared by reacting the CR-R1 (COOR ') NHR2 with an isocyanate of the formula R3N = C = 0 in an aprotic organic solvent (eg, benzene, THF, DMF and the like).

Compound 1, where Q is -NHS02- and Y is hydroxy, can be easily prepared by reacting a "amino acid of the formula CRxRla (COOR ') NHR2, wherein R', R1, R2 and R1 are as defined above, with a sulfamoyl halide of the formula R3NHS02L where L is halo, using the reaction conditions described in paragraph immediately above.Sulfamoyl halides are commercially available, or can be prepared by methods such as those described in Graf, R. German Patent 931225 (1952) and Catt, JD and Matler, WL, Org. Chem., 1974, 39, 566-568.

Compound 1 where Q- is -CHR-, where R is haloalkyl and Y is hydroxy, can be easily prepared by reacting an amino acid of the formula CR 13 (COOR ') NHR 2, where R' is alkyl, by the methods described in PCT Application Publication No. WO 03/075836, which is incorporated herein by reference in its entirety.

The amino acids of the formula CR ^ -R13 (COOR ') NHR2, where R' is hydrogen or alkyl and R1, Rla and R2 are defined in the description of the invention, can be prepared by methods well known in the art. Detailed syntheses of an amino acid wherein R1 and R2 are hydrogen and Rla is 2-trimethylsilylmethyl, are given in the working examples below.

Compounds of formula 2 wherein R10 is benzoxazol-2-yl, oxazolo [4, 5-b] pyridin-2-yl, and the like, can be prepared under deprotonation reaction conditions through treatment with benzoxazole, oxazole [4] , 5-b] pyridine, 2-pyridin-3-yloxadiazole, 2-pyridin-4-yl-oxadiazole, 2-phenyloxyazole, and the like, with a Grignard reagent such as isopropylmagnesium chloride, and then reacting the reagent resulting organomagnesium with an alpha- (N-amino protected) aldehyde of the formula CR5R6 (? HPG) CHO, where PG is a suitable amino protecting group (such as tert-butyloxycarbonyl, benzyloxycarbonyl, or benzyl) to provide a compound of the formula CR6R5 (NHPG) CH (R10) OH, where R10 is benzoxazol-2-yl, oxazolo [4, 5-b] pyridin-2-yl, 2-pyridin-3-yloxadiazolyl, 2-pyridin-4-yl- oxadiazolyl, 2-phenyloxadiazolyl, and the like, after treatment with an aqueous acid or regulator. Removal of the amino protecting group then provides a compound of the formula 2, wherein R10 is benzoxazol-2-yl, oxazolo [4,5-b] pyridin-2-yl, 2-pyridin-3-yloxadiazolyl, 2- pyridin-4-yl-oxadiazolyl, 2-phenyloxadiazolyl, and the like.

The reaction of the addition is typically carried out in an ether organic solvent such as tetrahydrofuran, diethyl ether, dioxane, and the like, preferably tetrahydrofuran, at a temperature of from about -78 ° C to about 40 ° C. Preferably, the reaction is carried out at from about -10 ° C to about 40 ° C, more preferably from about -10 ° C to about 10 ° C. The reaction typically requires one hour to complete. The nucleophilic addition reaction is typically carried out from about -10 ° C to near room temperature. Compounds of the formula CR5R6 (NHPG) CHO are prepared from commercially available amino acids by methods well known in the art. Some of these methods are described in the working examples below.

The reaction conditions employed for the removal of the amino protecting group depend on the nature of the protecting group. For example, if the protective group is tert-butoxycarbonyl, it is removed under acid reaction conditions. Suitable acids are trifluoroacetic acid (TFA), hydrochloric acid, and the like. If the protecting group is benzyl or benzyloxycarbonyl, it is removed under conditions of catalytic hydrogenation. Suitable catalysts are catalysts based on palladium, platinum, rhodium, and others known in the art. Other suitable reaction conditions for its removal can be found in Greene, T. W. and Wuts, P.M., Protecting Groups in Organic Synthesis; Jonh Wiley and Sons, Inc., 1999. This reaction is carried out in an inert organic solvent: methylene chloride, tetrahydrofuran, dioxane, dimethylformamide, and the like.

Oxidation of the hydroxy group in (I), wherein "R7 is hydroxy and R8 is hydrogen, with a suitable oxidizing agent such as Dess-Martin Periodinano, in a halogenated organic solvent such as methylene chloride, chloroform, carbon tetrachloride, and the like, or in a TEMPO / bleach mixture, then provides a corresponding compound of Formula (I) wherein R7 and R8 together form oxo.

'Alternatively, the compounds of Formula (I) wherein E is -C (R5) (R6) C (R7) (R8) R10, where R7 and R8 together form oxo, R5-R8, R10 and other groups are as defined in the description of the invention, can be prepared, by the method illustrated and described in Scheme 2 below: . Scheme 2: The compounds of Formula (I) wherein E is -C (R5) (R6) C (R7) (R8) R10, and R7 and R8 together form oxo, can be prepared by reacting a compound of formula 3 with a organometallic compound of the formula R10Li. The reaction is carried out in a suitable solvent (e.g., tetrahydrofuran (THF), ether, or the like), at -80 to -70 > C, preferably at about -78 > C, and requires 30 minutes to an hour to complete. The organometallic compound of the formula R10Li is generated by treating a corresponding organ compound or a brominated derivative thereof, with n-butyl lithium or tert-butyl lithium in a suitable solvent (e.g., THF, ether or the like) at -80 to -70 > C, preferably at about -78 > C, for approximately 30 minutes to an hour.

The compounds of the formula 3 can be prepared by reacting an amino acid of the formula 4: with a compound of the formula R3QN (R2) C (R1) (Rla) C (0) Y, where Q and R3 are as defined in the description of the invention, and Y is hydroxy or an activation group (succinimide, or similar), under the conditions described in Scheme 1 above.

The compounds of formula 4 can be prepared by reacting a corresponding N-protected amino acid with N, 0-dimethylhydroxylamine hydrochloride, followed by deprotection of the amino group. The reaction with N, O-dimethylhydroxylamine is carried out in the presence of a suitable binding agent (PyBOP®, EDC, HBTU, DCC, and the like) and a base (eg, N, N-diisopropylethylamine, triethylamine, or the like) in a suitable solvent (e.g., dichloromethane, DMF, and the like), at 20 to 30 > C, preferably at about 25 > C, and it takes about 2 to 4 hours to complete. Deprotection of the amino group provides the compound 4 that is desired.

The compounds of Formula (I) wherein E is -C (R5a) (R6a) C ?, where R5a, R6a and other groups are as defined in the description of the invention, can be prepared by the process illustrated and described in Scheme 3 below: Scheme 3: The reaction of a compound of formula 1 where Y is hydroxy or succinimide ester, with an aminonitrile compound of formula 5 under the reaction conditions described in Scheme 1 above, provides a compound of Formula (I). The compounds of formula r are commercially available, or they can be prepared by methods well known in the art.

The compounds of Formula (I) wherein E is -C (R5) (R6) CH = CHS (0) 2R10, wherein R5, R6, R10 and other groups are as defined in the description of the invention, can be prepared by the procedure that is illustrated and described in Scheme 4 below: The reaction of a protected N-amino acid of formula 6 with N, O-dimethylhydroxylamine hydrochloride in the presence of (1) equivalent of triethylamine and N, N-dicyclohexylcarbodiimide forms N, O-dimethylhydroxamate (Weinreb amide) (7) , which is then reduced to the corresponding aldehyde (8) with a suitable reducing agent such as equivalents of 0.5 lithium aluminum hydride.

The condensation of (8) with a Wadsworth-Emmons (EtO) 2POCH2S02R1 reagent, where R10 is as defined in the description of the invention, provides the vinyl sulfone (10). Removal of the N-protecting group, followed by reaction of the resulting free amine with a compound of the formula 1 under the reaction conditions described above, provides a compound of the Formula (I).

The compounds of Formula (I) wherein Q is -CHR where R is haloalkyl, E and other groups are as defined in the description of the invention, can * Prepare by the procedure that is illustrated and described in Scheme 5 below: Scheme 5 The reaction of a compound of formula 11 where LG is a suitable leaving group such as trifluoromethanesulfonate, and the like, and R and R 3 are as defined in the description of the invention, with a compound of formula 12 wherein R 1, Rla and R2 are as defined in the description of the invention, and R 'is hydrogen or a suitable carboxy protecting group such as alkyl, and the like, provides a compound of formula 13. The reaction is carried out in an organic solvent suitable, 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 inorganic base. Preferably, the organic base is triethylamine, pyridine, N-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 agent such as molecular filters. Preferably, the reaction is carried out at room temperature.

The compounds of Formula II can be prepared by methods well known in the art. For example, a compound of formula 11, wherein R 6 is phenyl or 4-fluorophenyl, R is trifluoromethyl, and LG is trifluoropolyethyl sulfonate, 2,2,2-trifluoroacetophenone or 2, 2, 2 can be easily prepared from the commercially available. , 4'-tetrafluoroacetophenone, respectively, by reducing the keto group to an alcohol group with an acceptable reducing agent such as sodium borohydride, lithium aluminum hydride, and the like. The solvent used depends on the type of reducing agent. For example, when 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 ether solvent such as tetrahydrofuran, and the like. The reaction of 2,2,2-trifluoro-1-phenylethanol or 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol with triflic anhydride gives the desired compound. The optically enriched compound of formula 11 can be obtained by reduction of the corresponding halogenated acetophenone with a suitable reducing agent such as catecholborane or BH3DMS complex in the presence of a suitable catalyst such as (5) or. { R) ~ CBS or (S) -a, -diphenyl-2-pyrrolidine-methanol in the presence of BBN to provide a chiral alcohol which is then converted to compound 11 as described above.

The compounds of formula 12 can be prepared by methods well known in the art. For example, the compounds of formula 12, wherein R1 is hydrogen and Rla is - (alkylene) -SiR32R33R34, where R32 is alkyl and R33 and R34 together with Si form a heterocycloalkylene ring containing from 3 to 7 carbon atoms , or R32 and R33 are alkyl and R34 is aryl, can be prepared through the process that. is described in Smith, R. J. et al., Tetrahedron 1997, Vol. 53, No. 40, p 13695, the disclosure of which is incorporated herein by reference in its entirety. A compound of formula 12, wherein R1 is hydrogen and Rla is - (alkylene) -SiR32R33R34, where R32 and R33 are alkyl and R34 is p-heterocycloalkyl. ex. [(dimethyl) tetrahydropyran-4-ylmethylsilyl] alanine "can be prepared by reacting dichloromethylsilane with buten-3-ylmagnesium bromide followed by tetrahydropyran-4-ylmagnesium bromide to give 4- [(dimethyl) tetrahydropyran-4-ylmethylsilyl] buten- l-ene. Oxidation "from 4- [(dimethyl) tetrahydropyran-4-ylmethylsilyl] buten-l-ene would provide 3- [(dimethyl) tetrahydropyran-4-ylmethylsilyl] propionic acid which can then be converted, to 4 [(dimethyl) tetrahydropyran-4- ilmethylsilyl] alanine under the conditions described in Smith, RJ et al., Tetrahedron: Assymmetry, 2001, 157. A compound of formula 12 wherein R1 is hydrogen and Rla is 1,1-dialkylsilylan-4-ylalkylene, p. 1, 1-dimethylsilane-4-ylalanine, can be prepared by reacting 1 1, 1-dimethylsilinan-4-one commercially available with a Witting reagent, PH3P = CH (CH2) 20H, to provide 3- (1, l-dimethylsilinan-4-ylidene) propan-l-ol, which upon reduction of the double bond under hydrogenation reaction conditions, followed by oxidation, would provide 3- (1, 1-dimethylsilyan-4-ylidene) propionic acid, which can be converted to 1, 1-dimethylsilyan-4-ylalanine as described above A compound of the formula wherein R32 is alkyl and R33 and R34 together with Si form an unsaturated heterocycloalkylene ring containing from 3 to 7 carbon atoms, e.g. ex. (1-methyl-1,2,3-tetrahydrosylin-1-yl) alanine can be prepared by reacting 1,1-dichloro-1,2,3,4-tetrahydrosiline (Brook et al., Can. Chem, 1970, 818) with magnesium chloride, followed by O-protected 3-propylmagnesium bromide to form O-protected 3- (1-methyl-1, 2, 3, 4-tetrahydrosilyn-1-yl) propanol. The "Removal of the oxygen protecting group followed by oxidation of the hydroxyl group, would give 3- (l-methyl-1,2,3,4-tetrahydrosilyn-1-yl) propionic acid, which is converted to the desired compound as described above. .

A compound of the formula wherein R32 is alkyl and R33 and R34 together with the Si form an unsaturated heterocycloalkiene ring containing from 3 to 7 carbon atoms where one of the carbon atoms is replaced by a heteroatom such as oxygen, . ex. , (4-methyl- [1,4] oxasilinan-4-yl) alanine, can be prepared through the treatment of (3-PGO-propyl) -ethoxy-methyl- (2-vinyloxyethyl) silane (via a procedure analogous to described in Voronkov et al., J. Organomet, Chem., 1992, 289) with a suitable reducing agent such as lithium aluminum hydride, to give (3-PGO-propyl) -methyl- (2-vinyloxyethyl) silane which, with treatment with chloroplatinic acid (see Voronkov et al., J. Organomet, Chem., - 1992, 289), would provide 3- (4-methyl- [1,4] oxasilinan-4-yl) propanol O-protected, which can be converted to the desired compound as described above.

Removal of the carboxy protecting group from a compound of the formula 13 wherein R 'is a protecting group, provides a corresponding compound of the formula where R is hydrogen The conditions used to remove the carboxy protecting group depend on the nature of the carboxy protecting group For example, i R 'is alkyl, this is removed under basic hydrolysis reaction conditions using such an aqueous base as hydroxide 'lithium, aqueous sodium hydroxide, and the like, in an alcohol solvent such as methanol ethanol, and the like.

Compound 13 (where R 'is H), is then converted to an activated acid derivative 14 (X is a leaving group) which, upon reaction with an amine compound of the formula 15, provides a compound of the Formula ( I). The activated acid derivative 14 can be prepared and then reacted with the compound 15 in a suitable manner, or it can be generated in situ in the presence of the compound 15. For example, if the activated acid 14 is an acid halide, it is prepare first by reacting 13 (where R 'is H) with a halogenating agent such as thionyl chloride, oxalyl chloride and the like, and then reacting it with compound 15. Alternatively, the activated acid derivative 14 is generated in situ by reacting compound 13 (where R 'is H) with 15, in the presence of a suitable binding agent, e.g. ex. , benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP®), 0-benzotriazole-1-yl-N, N, N'-N'-tetramethyl-uronium hexafluorophosphate (HBTU), O- (7-azabenzotriazole hexafluorophosphate -l-yl) -1, 1, 3,3-tetramethyl-uronium (HATU), l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexyl-carbodiimide (DCC), and similar, optionally in the presence of 1-hydroxybenzotriazolate (HOBT), and in the presence of a base such as N, N-diisopropyl-ethylamine, triethylamine, N-methylmorpholine, and the like. Suitable reaction solvents are inert organic solvents such as halogenated organic solvents (e.g., methylene chloride, chloroform, and the like), acetonitrile, N, N-di-ethylformamide, ethereal solvents such as tetrahydrofuran, dioxane, and the like. .

The compounds of the Formula (I) can also be prepared by the methods described in the Publications of US and PCT applications Nos. US 2003 / 0092634A1, US 2003 / 0232863A1, US 2003/0134889, WO 02/098850, WO 03/024924, WO 00/55126, WO 03/037892, and WO 95/09838, and US Patent Nos. 6,506,733, 6,576,630, and 6,506,733, which are incorporated herein by reference in their entirety.

Additional process for preparing the compounds of the Formula (I). A compound of the present invention can be prepared as a pharmaceutically acceptable acid addition salt, by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the present invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. The inorganic and organic acids and bases, suitable for the preparation of pharmaceutically acceptable salts of the compounds of the present invention, are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of the present invention can be prepared using salts of the starting materials or intermediates.

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

The N-oxides of the compounds of the present invention can be prepared by methods known to those of ordinary skill in the art. For example, the N-oxides can be prepared by treating a non-oxidized form of the compound of the present invention with an oxidizing agent (eg, trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, urea-chloroperoxy-benzoic acid, or similar), n a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at about 0 ° C. Alternatively, the N-oxides of the compounds of the present invention can be prepared from the N-oxide of an appropriate starting material.

The compounds of the present invention in the non-oxidized form can be prepared from N-oxides of the compounds of the present invention, by treating them with a reducing agent (eg, sulfur, sulfur dioxide, triphenyl phosphine, borohydride lithium, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like), at 0 to 80 ° C.

The prodrug derivatives of the compounds of the present invention can be prepared by methods known to those of ordinary skill in the art (eg, for further details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, vol. 4, page 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivative compound of the present invention with a suitable carbamylating agent. (eg, 1, 1-acyloxyalkylcarbonchloridate, para-nitrophenyl carbonate, or the like).

The protected derivatives of the compounds of the present invention can be made by means known to those of ordinary skill in the art. A detailed description of the techniques, applicable to the creation of protection groups and their removal, can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., 1999.

The compounds of the present invention can be prepared conveniently, or formed during the process of the invention, as solvates (eg hydrates). The hydrates of the compounds of the present invention can be conveniently prepared by recrystallization from a mixture of aqueous organic solvent, using organic solvents such as dioxin, tetrahydrofuran or methanol.

The compounds of the present invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent, to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering it optically pure enantiomer. Although the resolution of the enantiomers can be performed using covalent diastomeric derivatives of the -incompounds of the present invention, dissociable complexes are preferable (eg, crystalline diastereomeric salts). Diastereomers have different physical properties (e.g. fusion, boiling points, solubilities, reactivity, etc.) and can be easily separated if one takes advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of the compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & amp;; Sons, Inc. (1981).

Preparation of biological agents. In practicing this invention, various methods are used for the generation or purification of the biological agents. The methods for preparing the biologics are well known in the art, as discussed below.

Monoclonal antibodies are prepared using standard techniques, well known in the art, such as the method of Kohier and Milstein, Nature 1975, 256: 495, or a modification thereof, as described in Buck et al., 1982, Jn Vi tro 18: 377. Typically, a mouse or a rat is immunized with the MenB PS derivative conjugated to a stimulated protein carrier and the spleen (and optionally several lymph nodes) is removed and dissociated into separate cells. If desired, spleen cells can be filtered (after removal of non-specifically adherent cells) by applying a suspension of cells to a tray or platen covered with the antigen.

The B cells, which express the immunoglobulin linked to the specific membrane for the antigen, will agglutinate to the tray and will not rinse with the rest of the suspension. The resulting B cells, or all dissociated spleen cells, are then induced to fuse with myeloma cells to form hybridomas. Representative lines of murine myeloma for use in hybridization include those available from the American Type Culture Collection (ATCC).

Chimeric antibodies composed of human and non-human amino acid sequences can be formed from mouse monoclonal antibody molecules to reduce their immunogenicity in humans (Winter et al., Nature 1991, 349: 293; Lobuglio et al., Proc. Nat. Acad Sci. USA 1989,86: 4220; Shaw et al., J: Immunol., 1987, 138: 4534; and Brown 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 in "Dec. 23, 1992; and UK Patent Publication No. GB 2,276; 169, Published on Sept. 21, 1994).

Fragments of antibody molecule, - p. ex. , F (ab '). sub.2, FV, and Fv molecules, which are capable of displaying the immunological agglutination properties of the parent monoclonal antibody molecule, can be produced using known 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. Use 1988, 85 (16): 5879; and US Patent Nos. 5,091,513 and 5,132,405, A Huston et al .; And US Patent No. 4,946,778, to Ladner et al.

In the alternative, a phage-projection system can be used to expand in vitro the monoclonal populations of antibody molecules. Saiki, et al.

Nature 1986, 324: 163; Scharf et al. Science 1986, 233: 1076; US Patent 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 projection phage library can be isolated or synthesized, and cloned into any vector or replicon suitable for expression. Any suitable expression system can be used including, for example, the bacterial, yeast, insect, amphibian and mammalian systems. The bacterial expression systems 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, US Patent No. 4,551,433, Deboer et al. Proc. Na ti. Acad. Sci. USA 1983, 80: 21-25, and Siebenlist et al. Cell 1980, 20: 269.

Yeast expression systems include those described in Hinnen et al. Proc. Nati Acad.

Sci. USA 1978, 75: 1929, Ito et al. J. Bacteriol. 1983, 153: 163, Kurtz et al. Mol. Cell. 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 Bacteriol. 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. Cell. Biol. 1985, 5: 3376, US Patent Nos. 4 / 837,148 and 4,929, 555, Beach et al. Nature 1981, 300: 706, Davidow et al. Curr. Genet 1985, 10: 380, Gaillardin et al. Curr.

Genet 1985, 10:49, Ballance et al. Biochem. Biophys. Beef.

Commun. 1983, 112: 284-289, Tilburn et al. Gene 1983, - 26: 205-221, Yelton et al. Proc. Nati Acad. Sci. USA 1984, 81: 1470-1474, Kelly et al. EMBO J. 1985, 4: 475479; European Application No. EP 244,234, and International Publication No. WO 91/00357.

The expression of heterologous genes in insects can be performed as described in US Patent No. 4,745,051, in European Applications 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 et al. Mol. Cell. Biol. 1988, 8: 3129, Smith et al. Proc. Nati Acad. Sci. USA 1985, 82: 8404, Miyaji a et al. Gene 1987, 58: 273, and Martin et al. DNA 1988, 7:99. Numerous strains and baculoviral variants and the corresponding cells of the permissive insect host are described in Luckow et al. Bio / Technology 1988, 6: 47-55, Miller et al. GENERIC ENGINEERING, Setlow, J. K. et al. Eds., Vol. 8, Plenum Publishing, pp. 1986, 277-279, and Maeda et al. Nature 1985, 315: 592-594.

Expression in mammals can be performed as described in Dijkema et al. EMBO J. 1985, 4: 761, Gorman et al. Proc. Nati Acad. Sci. USA 1982, 79: 6777, Boshart et al. Cell 1985, 41: 521, and US Patent No. 4,399,216. Other * representations of the mammalian expression can be provided as described in Ham et al. Meth. Enz. 1979, 58:44, Barnes et al., Anal. Biochem. 1980, 102: 255, US Patent Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655 and the newly sent Patent US No. RE 30,985, and in the International Publications Nos. WO90 / 103430, WO87 / 00195.

The production of recombinant adenoviral vectors is described in US Patent No. 6,485,958.

Botulinum toxin type A can be obtained by establishing and developing Clostridium botulinum cultures in a fermenter 'and then' harvesting and -Imlimiting the fermented mixture according to known procedures.

Any of the protein production methods described above can be used to provide the biological that would benefit from the present invention.

Utility. The compounds of the invention are selective inhibitors of cysteine proteases, in particular of cathepsin S, K, B and / or F, and accordingly are useful in the treatment of diseases in which the ^ cysteine protease activity contributes to the pathology and / or symptomatology of the disease. For example, the compounds of the invention are useful in the treatment of autoimmune disorders, including, but not limited to, juvenile diabetes, psoriasis, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis and Hashimoto's thyroiditis; allergic disorders, including, but not limited to, asthma; Allogeneic immune responses including, but not limited to, organ transplants and tissue grafts and endometriosis.

Cathepsin S is also implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (eg, emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonitis, and cardiovascular disease such as rupture of the plaque and atheroma. Cathepsin S is involved in fibril formation and, therefore, the compounds of Formula (I) are useful in the treatment of systemic amyloidosis.

Tests . The inhibitory activity of the cysteine protease, in particular the inhibitory activities of cathepsin S of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro tests are known to measure the activity of the protease and inhibition thereof by the test compounds.

Typically, the test measures the induced hydrolysis of the protease from a peptide-based substrate. The details of the tests to measure the. Inhibitory activity of the protease is established in Biological Examples 1-6, infra.

Administration and pharmaceutical compositions.

In general, a compound of the present invention will be administered in therapeutically effective amounts via any of the usual and accepted modes in the art, either individually or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely, depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. For example, the quantities Therapeutically effective compounds of the compounds of the present invention can be in a range of from about 10 micrograms per kilogram of body weight (μg / kg) to about 20 milligrams per kilogram of body weight (mg / kg) per day, typically from close from 100 μg / kg / day to about 10 mg / kg / day. Therefore, a therapeutically effective amount for a human patient of 80 kg ranges from about mg / day to about 1.6 g / day, typically from about 1 mg / day to about 100 mg / day. In general, someone with ordinary skill in the art, acting with confidence in their personal knowledge and in the description of this Application, will be able to ascertain a therapeutically effective amount of a compound of the present invention, to 'treat a disease Dadaist. The compounds of the present invention can be administered as pharmaceutical compositions through one of the following routes: oral, systemic (eg, transdermal, intranasal or suppository) or parenteral (eg, intramuscular, intravenous or subcutaneous). The compositions can take the form of tablets, pills, . capsules, semisolids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition and are generally comprised of a compound of the present invention in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, "they aid administration, and do not adversely affect the therapeutic benefit of the active ingredient." The excipient may be any solid, liquid or semi-solid or, in the case of an aerosol composition, the gaseous excipient that is generally available to someone with experience in The technique.

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 skimmed milk , and similar. Liquid and semi-solid carriers can be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (eg, peanut oil, soy bean oil). , mineral oil, sesame oil, and the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.

The amount of a compound of the present invention in the composition can vary widely depending on the type of formulation, the size of a "unit dose, type of excipients, and other factors known to those of skill in the pharmaceutical science art." In general, a composition of a compound of the present invention for treating a given disease will comprise from 0.01% w to 10%. % w, preferably from 0.3% w to l% w, of active ingredient, the carrier or excipients being present, preferably, the pharmaceutical composition is administered in the form of a single unit dose for continuous treatment on a unit dose form unique 'ad libitum, when symptom relief is specifically required Representative pharmaceutical formulations containing a compound of the present invention are described in the working example below.

EXAMPLES The following preparations and examples are given to enable those skilled in the art to understand and practice the invention more clearly. They should not be considered as limiting the competence of the invention, but only as illustrative and representative of it.

And synthetic materials. Reference A. Synthesis of (R) -2-amino-3-trimethylsilanyl-propionic acid.

Step 1 To a stirred solution of 3- (trimethylsilanyl) propionic acid (10 g, 68.5 mmol) in THF (100 mL) was added oxalyl chloride (8.9 mL, 102.7 mmol) and one drop of DMF at room temperature. After stirring for 2 h, the solvent and oxalyl chloride access were removed in vacuo. The product, 3-trimethylsilanylpropionyl chloride, was used in the next step without further purification.

Step 2. To a stirred solution of (S) -4-benzyl-2-oxazolidinone (12.1 g, 68.5 mmol) in THF (100 mL) was added n-BuLi (1.6 M solution in hexane, 42.8"mL, 68.5 mmol), at -75 ° C. After stirring for 30 min, 3-trimethylsilanylpropionyl chloride was added, and the reaction mixture was allowed to warm to room temperature, and then quenched with saturated NHC1, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified by silica gel column chromatography to yield (S) -4-benzyl-3- [3- (trimethyl-silanyl) propionyl] oxazolidin-2-one (16.15 g).

Step 3. Sodium acide (21.45 g, 0.33 mol) was dissolved in ethanol in water (300 ml, 1: 1) and 2,4,6-triisopropylbenzenesulfonyl chloride (30.3 g, 0.1 mol) was added at room temperature. . After stirring for 14 h, the reaction mixture was diluted with water and then extracted with ethyl ether. The organic layer was washed with brine, dried with MgSO4, and the solvent was removed in vacuo. Methanol (50 L) was added to the residue, to give 2,4,6-triisopropylbenzenesulfonyl acrylate as a white crystalline solid (27.5 g).

Step 4. In a solution of (S) -4-benzyl-3- [3- (trimethylsilanyl) propionyl] -oxazolidin-2-one (6.1 g, 20 mmol) in THF (50 ml) was added bis (trimethylsilyl) potassium amide (0.5 M solution in toluene, 44 ml, 22 mmol) at -65 ° C. After stirring for 2 h, acrylamide was added 2,4,6-triisopropylbenzenesulfonyl (7.4 g, 24 mmol) in THF (50 ml) at -75 ° C. After stirring for 20 min, acetic acid (3 g) was added and the reaction mixture was allowed to warm to room temperature. 1N hydrochloric acid (11.2 ml) was added and the product was extracted with ethyl acetate. The organic layer was collected and washed with brine, and dried with MgSO4. The organics were removed to give a residue which was purified by column chromatography with silica gel, to produce. { 2R, A S) -4-benzyl-3- [3- (trimethylsilanyl) -2-acidopropionyl] -2-one (3.2 g).

Alternate synthesis: Tetrahydrofuran (120 ml) was cooled to -70 ° C and then treated with potassium hexamethyldisilazate (0-5.

M, 80 ml). A precooled solution was added at -66 ° C of (S) -4-Benzyl-3- [3- (trimethylsilanyl) propionyl] -oxazolidin-2-one in THF (120 ml), for 15 min. A solution of 2,4,6-2,4,6-trisopropylbenzenesulfonyl acide (13.7 g) in tetrahydrofuran was added over 10 min. (120 ml). After 5 min, a solution of acetic acid was added. (9 ml) in tetrahydrofuran (10 ml) and the reaction mixture was warmed to 25 ° C. The reaction mixture was diluted with water, treated with sodium chloride and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel by leaching with mixtures of ethyl acetate-hexane gave (2J ?, 4S) -4-benzyl-3- [3- (trimethylsilanyl) -2-acidopropionyl] oxazolidin-2-one as an oil colorless (9.06 g).

Step 5. The (2i?, 4S) -4-benzyl-3- [3- (trimethylsilanyl) -2-acidopropionyl] oxazolidin-2-one was dissolved in tetrahydrofuran (400 ml) and cooled to 0 ° C., and then treated with a solution of lithium hydroxide (1.09 g), water (140 ml), and 30% hydrogen peroxide (13.3 ml), for 35 min. After 75 min, a solution of sodium hydrogen sulfite (31 g) in water (140 ml) was added over 25 min. The tetrahydrofuran was removed by rotary evaporation and the product was isolated by extraction with ethyl acetate. Purification by chromatography with silica gel by leaching with ethyl acetate-hexane then gave acid (2iR) -3-tri-ethylsilypropionic acid (4.36 g).

Step 6. The (2i?) -acid-3-trimethylsilypropionic acid (2.38 g) in methanol (120 ml) was treated with 10% Pd / C (130 mg) and hydrogenated at 48 psi for 1 h. The catalyst was removed by filtration through celite. The evaporation of the methanol then gave acid. { R) -2-amino-3-trimethyl-silanyl propionic acid (1.50 g) as a white solid. LC-MS: 159.7 (M-1); 161.7 (M + l); 184 (M + Na).

REFERENCE B. Synthesis of (J) -2-amino-3-trimethylsilanylpropionic acid hydrobromide.

MB? Step 1 (a) To a stirred solution of benzyloxycarbonyl-phosphonoglycine trimethyl ester (16.6 g, 50 mmol) in dichloromethane (50 ml) at room temperature, DBU (8.4 g, 55 mmol) was added. After stirring for 30 min, the reaction mixture was added to the next reaction mixture. (b) To a stirred solution of oxalyl chloride (9.2 g, 72 mmol) in dichloromethane (150 ml) at -78 ° C, dimethyl sulfoxide (6.4 g, 82 mmol) was added. After min, a solution of trimethylsilylmethanol (5 g, 48 mmol) in dichloromethane (30 ml) was added to the reaction mixture over 10 min. After 30 min, triethylamine (17.94 g, 177.6 mmol) was added and after 30 min the reaction mixture prepared in (a) was added at -78 ° C. After stirring for 15 min, the reaction mixture was allowed to warm to room temperature and then quenched with 1N HCl. The organics were removed in a rotoevaporator and the residue was extracted with ethyl ether. The organic layer was separated and washed, with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to yield (Z) -2-benzyloxycarbonyl-amino-3- (trimethylsilanyl) acrylic acid methyl ester (5.1 g).

Step 2. To a solution of (Z) -2-benzyloxycarbonylamino-3- (trimethylsilanyl) acrylic acid methyl ester (150 mg, 0.49 mmol) in ethyl acetate (3 mL), (+) - trifluoromethanesulfonate was added. 1, 2-bis- (2S, 5S) -2,5-diethylphospholanebenzene (cyclooctadiene) rhodium (I) (7 mg, 0.0098 mmol). The reaction mixture was stirred under a hydrogen atmosphere at 5 psi for 2 h. The ethyl acetate was removed and the residue was purified by column chromatography with silica gel, to produce methyl acid ester. { R) -2-benzyloxycarbonylamino-3- (trimethylsilanyl) -propionic (150 mg). The e.e (> 98%) was determined by analytical HPLC on chiral column (column: OD, solvent: 90% hexane, 10% isopropanol, 1 ml / min).

Step 3. To a stirred solution of methyl acid ester. { R) 2-benzyloxycarbonylamino-3- (trimethylsilanyl) -propionic acid (4.2 g, 13.6 mmol) in methanol (30 ml), 1N NaOH solution (20 ml) was added at room temperature. After stirring for 2 h, the reaction mixture was acidified with IN HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and concentrated, to give ((3) -benzyloxycarbonylamino-3- (trimethylsilanyl) -propionic acid (4).

Step 4. To a stirred flask containing (i) -2-benzyloxycarbonylamino-3- (trimethylsilanyl) -propionic acid methyl ester (4 g, 13.5 mmol). he added 33% w hydrogen bromide solution in acetic acid (10 ml). After stirring for 2 h, the access hydrogen bromide and acetic acid were removed in vacuo. Ethyl ether (40 ml) was added to the residue and after stirring for 30 min the solid was filtered, washed with ethyl ether, and dried to give hydrogen bromide of (i) -2-amino-3 acid. - (trimethylsilanyl) propionic (3.2 g). H1 NMR (DMSO-de): d 8.11 (3H, s), 3.82 (HH, t), 1.05 (2H, dd), 0.06 (9H, s). LC-MS: 160.1 (M-1); 161.8 (M + l).

REFERENCE C Synthesis of (S) -2-amino-l-benzoxazol-2-ylbutan-l-ol hydrochloride Step 1. To a solution of benzoxazole (28.6 g, 240 mmol) in toluene (150 mL), a 2M solution of isopropyl-magnesium chloride in THF (120 mL, 240 mmol) was added thereto for ca. 20 min. -4 ° C. The reddish brown mixture was stored at ca -4 ° C and was used as needed.

Step 2. To a solution of (5) -2-Boc-aminobutanol (50 g, 264 mmol) in dichloromethane (500 mL) and water (350 mL) were added, at 20 ° C, TEMPO (0.01 eq), Sodium bromide (1 eq) and sodium bicarbonate (3 eq). The reaction mixture was stirred at 0 ° C and diluted bleach (1.3 eq, 450 ml) was added over 40 min. The reaction mixture was stirred for 30 min at 0 ° C and then quenched with aqueous thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacuo to dryness, yielding (S) -2- (tert-butoxycarbonyl) -aminobutyraldehyde as a low melting solid (38.1 g).

Step 3. A solution of (S) -2- (tert-butoxycarbonyl) amino-butyraldehyde (30 g, 160 mmol) in toluene (150 ml) was added for 30 min at -5 ° C to a solution of Grignard's benzoxazole reagent (prepared as described in Step 1 above). The reaction mixture was stirred for 0.5 h at 0 ° C, then for 2.5 h at T.A. Quenching with 5% aqueous acetic acid, washing with 5% aqueous sodium carbonate, then with brine, and concentrating to dryness, gave (S) -2- (tert-butoxycarbonyl) amino-1-benzoxazole- 2-ilbutan-l-ol. The residue was diluted with toluene, and silica gel was added. The watery mixture was filtered. Toluene leaching removed non-polar impurities. Then, an 8/2 mixture of toluene and ethyl acetate deaerated the (S) -2- (tert-butoxycarbonyl) amino-1-benzoxazol-2-ylbutan-1-ol.

Step 4. To a solution of (S) -2- (tert-butoxycarbonyl) -amino-l-benzoxazol-2-ylbutan-1-ol (26.3 g, 86 mmol) in isopropanol (118 ml) at 20-25 ° C was added trimethylchlorosilane (1.4 eq) and the solution was stirred for 5 h at 50 ° C. The concentration of the reaction mixture up to 52 ml, followed by the addition of isopropyl ether (210 ml), filtration and drying under vacuum, gave (S) -2-amino-1-benzoxazol-2-ylbutan-1-ol hydrochloride salt as a gray solid (16.4 g of diastereomer mixture).

REFERENCE D. Synthesis of 2 (S) - (tert-butoxycarbonyl) amino-1-oxazolo [4,5-b] pyridin-2-yl) butan-l-ol Step 1. A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 ml) and p-toluenesulfonic acid (61 mg) was heated to 140 ° C for 8 h. Excess triethyl orthoformate was removed under vacuum and oxazolo [4, 5-b] iridine was crystallized from ethyl acetate (9 g).

Step 2. In a clean round bottom flask equipped with stirring bar, oxazolo [4,5-b] pyridine (600 mg, 5 mmol) in THF (0 ml) was placed and the reaction mixture was cooled to 0 ° C under N2 atmosphere. HE. added isopropylmagnesium chloride (2M in THF, 2.5 ml, 5 mmol). After stirring for 1 h at 0 ° C, 2 (5) - (tert-butoxycarbonyl) aminobutyraldehyde (573 mg, 3 mmol) in THF (20 ml) was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhydrous MgSO, filtered and concentrated. The crude product was purified by chromatography to yield the title compound (383 mg).

Ha NMR (DMSO-de): d 8.42 (, 1H), 8.18 (m, ÍH), 7.3 (m, ÍH), 6.8-6.6 (dd, d, ÍH, OH, diastereomer), 6.3-6.02 (d, d, 1H, NH, diastereomer), 4.82-4.5 (m, m, ÍH, diastereomer), 1.8-1.3 (, 2H), 1.2-1.05 (s, s, 9H, diastereomer), 0.89 (m, 3H). MS: 306.2 (M-1), 308.6 (M + 1).

REFERENCE E Synthesis of (s; -2-amino-l- (3-phenyl- [1,2,4] -oxadiazol-5-yl) b tan-1-ol 3-Tert-butoxycarbonylamino-2-hydroxypentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 g, -3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). mmol). Dichloromethane (10 ml) was added and then 4-methylmorpholine (1 ml) was added and the reaction mixture was stirred at room temperature for 16 h. After dilution with ethyl acetate (200 ml), the solution was washed with water (30 ml), saturated aqueous solution of? aHC03 and brine, dried with MgSO4 and evaporated in vacuo. The crude product was dissolved in pyridine (10 ml) and heated at 80 ° C for 15 h. The pyridine was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (eluent: ethyl acetate), to yield (S) -2-tert-butoxycarbonylamino-1- (3-phenyl) [1, 2, 4] oxadiazol-5-yl) butan-l-ol (290 mg, 0.83 mmol). The (S) -2-tert-butoxycarbonylamino-l- (3-phenyl [1, 2, 4] -oxadiazol-5-yl) butan-l-ol (145 mg, 0.41 mmol) was dissolved in CH2C12 (4 ml ) and TFA (4 ml) was added. After stirring for 1 h, the reaction mixture was evaporated to dryness to yield (S /) -2-amino-1- (3-phenyl- [1, 2, 4] -oxadiazol-5-yl) butan- 1-ol.

Following the procedure described above, but substituting the N-hydroxy-benzamidine with N-hydroxypropamidine was provided. { S) -2-amino-1- (3-ethyl- [1, 2, 4] -oxadiazol-5-yl) butan-1-ol.

REFERENCE F Synthesis of (S) -2-amino-1- (2-methoxymethyl [1,3,4] oxadiazol-5-yl) utan-1-ol.

Step 1. Cool to 0 ° C (S) - (+) -2-amino-1-butanol (50 g, 561 mmol) in a mixture of water and dioxane (200 ml of water and 200 ml of dioxane), and was mixed with NaOH (26.9 g, 673 mmol) and di-tert-butyl-dicarbonate (146.96 g, 673 mmol). After the addition, the mixture was allowed to warm to room temperature and stirred for 2 h. After removing the dioxane, the residue was extracted with EtOAc, then washed with brine and dried with anhydrous MgSO 4, filtered and concentrated. Without further purification, crude 1 (S) -2-Boc-imino-1-butanol (120 g) was used for the reaction in the next step.

Step 2. A solution of oxalyl chloride (40.39 g, 265 mmol) in CH2C12 (700 mL) was stirred and cooled to -60 ° C. Dimethylsulfoxide (51.7 g, 663 mmol) in CH2C12 (100 mL) was added dropwise. After 10 min, a solution of (S) -2-Boc-amino-1-butanol (50 g, 265 mmol) was added dropwise.

CH2C12 (100 mL) at -70 ° C. The reaction mixture was left - warm to -40 ° C for 10 min and then cooled again to -70 ° C. A solution of triethylamine (74.9 g, 742 mmol) in CH2C12 (100 mL) was added and the reaction mixture was allowed to warm to room temperature for 2 h. Saturated sodium dihydrogen phosphate (100 ml) was added, and then the organic layer was washed with brine and dried over MgSO4. The solvent was removed to produce (S) -2-JBoc-amino-butyraldehyde (1- formylpropyl) carbamic acid tert-butyl ester (45 g).

Step 3. A mixture of methyl methoxyacetate (52 g, 500 mmol), hydrazine hydrate (30 ml) was heated at reflux for 8 h. Hydrazine and excess water were removed under vacuum. The residue was extracted with n-butanol, dried with Na 2 SO 4. Excess n-butanol was removed, to give hydrazide (45 g).

Step 4. A mixture of the above hydrazine (45 g), triethylorthoformate (146 ml) and p-toluene sulfonic acid (€ 1 mg) was heated at 140 ° C for 8 h. The triethyloformate-. in excess it was removed to the emptiness. The product was purified by column chromatography on silica gel, to yield 2-methoxymethyl- [1, 3, 4] -oxadiazole (4.6 g).

Step 5. To a stirred solution of 2-methoxymethyl- [1, 3, 4] -oxadiazole (4.6 g, 40 mmol) in THF (100 mL) was added n-BuLi (1.6 M solution in 25.2 mL of hexane) , drip, under N2, at -78 ° C. After 1 h, MgBr.Et20 (10.4 g, 40.3 mmol) was added and the reaction mixture was allowed to warm to -45 ° C for 1 h before being treated with. { S) -2-Boc-aminobutyraldehyde (5.28 g, 28.25 mmol) in THF (20 ml). The reaction mixture was stirred for 1 h,. quenched "with NH4C1, and extracted with ethyl acetate.The organic layer was washed with brine, dried with MgSO4 and concentrated.The residue was purified by column chromatography with silica gel to produce (S) -2-Boc-amino- l- (5-methoxymethyl [1, 3, 4] -oxadiazol-2-yl) -1-butanol (500 mg).

Step 6. -2-Boc-amino-l- (5-methoxymethyl [1, 3, 4] -oxadiazol-2-yl) -1-butanol (500 g, 1.66 mmol) and CH2C12 (5 mL) were mixed, and TFA (0.5 ml) was added at room temperature. After stirring for 1 h, the solvent and excess TFA were removed in vacuo to yield TFA salt of (S) -2-amino-1- (5-methoxymethyl [1, 3, 4] -oxadiazol-2-yl. ) -1-butan-1-ol (340 mg).

REFERENCE G Synthesis of (S) -2-amino-l- (2-phenyl [1,3,4] -oxadiazol-5-yl) b tan-1-ol Step 1. A mixture of benzoic hydride (22.5 g, "165 mmol), triethylorthoformate (150 ml) and p-toluenesulfonic acid (300 mg) was heated at 120 ° C for 12 h. The excess triethyl orthoformate was removed at room temperature. vacuum and the residue was purified by column-silica gel chromatography to yield 2-phenyl- [1, 3, 4] -oxadiazole (14.5 g).

Step 2. To a stirred solution of 2-phenyl- [1, 3, 4] -oxadiazole (10 g, 68.5 mmol) in THF (100 mL) was added n-BuLi (1.6 M solution in 42.8 mL of hexane), dropwise, under N2, at -78 ° C. After 1 h, MgBr.Et20 (17.69 g, 68.5 mmol) was added and the reaction mixture was allowed to warm to -45 ° C for 1 h before being treated with. { S) -2-Boc-aminobutyraldehyde (7.8 g, 41 mmol) in THF (20 ml). The reaction mixture was stirred for 1 h, quenched with saturated NH 4 Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO 4 and concentrated. The residue was purified by silica gel column chromatography to yield 2- ((S) -2-Boc-amino-1-hydroxybutyl) -5-phenyl- [1, 3, 4] -oxadiazole (9.7 g).

Step 3. 2- ((S) -2-Boc-amino-1-hydroxybutyl) -5-phenyl- [1, 3, 4] -oxadiazole (505 mg, 1.5 mmol) and CH 2 C 2 (5 ml) were mixed. ) and TFA- (1 ml) was added at room temperature. After stirring for 1 h, the solvent and excess TFA were removed in vacuo to yield TFA salt of (S) -2-amino-1- (5-phenyl- [1, 3, 4] oxadiazole-2. -yl) -1-butanol (530 mg).

REFERENCE H Synthesis of (S) -2-amino-l-oxazolo [4,5b] pyridin-2-ylbutan-1-ol Step 1. A mixture of 2-amino-3-hydroxypyridine (25 g, 227 mmol), triethylorthoformate (75 ml) and p-toluenesulfonic acid (61 mg) was heated at 140 ° C for 8 h.

Excess triethyl orthoformate was removed in vacuo. The product was crystallized from ethyl acetate to produce oxazolo [4,5-b] pyridine (22.5 g).

Step 2. To a stirred solution of oxazolo [4, 5-b] pyridine (12 g, 100 mmol) in THF (300 mL), n-BuLi (1.6 M solution in 62.5 mL of hexane) was added, by drip, under N2, at -78 ° C. After 1 h, MgBr.Et20 (25.8, 100 mmol) was added and the reaction mixture was allowed to warm to -45 ° C for 1 h before being treated with (S) -2-Boc-amino-butyraldehyde (11.46 g, 60 mmol) in THF (50 ml). The reaction mixture was stirred for 1 h, quenched with saturated NH 4 Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with. MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give (S) -2-Boc-amino-1- (oxazolo [4, 5-b] pyridin-2-yl) -1-butanol (14.1 g).

Step 3.

(S) -2-Boc-amino-l- (oxazolo [4, 5-b] pyridin-2-yl) -1-butanol (311 mg, 1 mmol) and CH2C12 (5 mL) were mixed and TFA was added. (1 L) at room temperature. After stirring for 1 h, the solvent and excess TFA were removed in vacuo to provide TFA salt of (S) -2-amino-1-oxazolo [4,5-b] pyridin-2-yl-butan-1 -ol (355 mg).

REFERENCE I Synthesis of (S) -2-Boc-amino-l- (2-ethyl- [1,3,4] oxadiazol-5-yl) -1-butanol Step 1. A mixture of formic hydration (60 g, 1 mole), triethylorthropionate (176.26 g, 1 mole) and p-toluenesulfonic acid (250 mg) was heated at 120 ° C for 12 hours. The ethanol was removed in vacuo and the residue was distilled in vacuo to yield ethyl- [1, 3, 4] oxadiazole (24 g).

Step 2. To a stirred solution of ethyl- [1,3,4] oxadiazole (4.66 g, 48 mmol) in THF (50 mL) was added n-BuLi (1.6 M solution in 30 mL of hexane), drip, under N2, at -78 ° C. After 1 h, MgBr.Et20 (12.38 g, 48 mmol) was added and the reaction mixture was allowed to warm to -45 ° C for 1 hour before being treated with (S) -2-Boc- to inobutyraldehyde (3.2 g, 24 mmol) in THF (0 ml). The reaction mixture was stirred for 1 hour, quenched with saturated NHC1, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO 4 and concentrated. The residue was purified by column chromatography with silica gel to produce the 'title (2.13 g). XNMR (DMSO-d): 6.65-6.52 (1H, d, d, J = 9. 2 Hz, J = 9.2 Hz, NH, diastereomer), 6.14, 5.95. (1H, d, d, J = 5.6 Hz, J = 5.6 Hz, OH, diastereomer), 4.758-4.467 (HH, m, diastereomer), 3.7-3.55 (HH, m), 2.8 (2H, q), 1. 1.33 (12H, t), 1.25-1.21 (2H, m), 0.82 (3H, m). MS: 284.1 (M-1), 286 (M + 1), 308 (M + Na).

REFERENCE J Synthesis of 4-amino-4-cyano-l-ethylpiperidine 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 water (550 ml) was stirred at room temperature. environment for 48 h. The pH of the reaction mixture was adjusted to 10.1 and the product was extracted with ethyl acetate. The organic extracts were washed with brine and dried over magnesium sulfate. Rotary evaporation of the solvent gave a mixture of 4-amino-cyano-1-ethyl piperazine and 4-hydroxy-4-cyano-l-ethyl piperazine (7.67 g). This mixture of products was treated with 7 M ammonia in methanol (20 ml) and allowed to stand at room temperature for 24 h. The excess methanol and ammonia were removed in vacuo and the residue was cooled to give 4-amino-4-cyano-1-ethylpiperidine as a crystalline solid (7762 g).

REFERENCE K Synthesis of trifluoromethanesulfonic acid 2, 2, 2-trifluoro-1- (4-fluorophenyl) ethyl ester Step 1. To a stirred solution of 2,2,2,4'-tetrafluoroacetophenone (10 g, 52.1 mmol) in methanol (50 mL) was added NaBH (0.98 g, 26.5 mmol) at 0 ° C. . After stirring at 25 ° C for 2 h, the reaction mixture was quenched by adding 1N HCl (100 mL) and then extracted with ethyl ether. The ether extract was washed with brine, dried with MgSO 4, and concentrated to give 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol (11.32 g), which was used in the next step without further purification.

Step 2. NaH (640 mg, 16 mmol, 60% in mineral oil) was washed twice with hexane (20 mL) and then suspended in diethyl ether. Drying (20 mL). A solution of 2,2,2-tr'-fluoro-l- (4-fluoro-phenyl) ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) was added at 0 ° C. After stirring for 2 h at room temperature, a solution of trifluoromethanesulfonyl chloride (1.68 g, 10 mmol) in diethyl ether (10 mL) was added. After 2 h, the reaction mixture was quenched by adding a solution of NaHCO3. and the product was extracted with diethyl ether. The extracts were washed with brine and dried, and the solvent was removed to yield trifluoromethanesulfonic acid 2, 2, 2-trifluoro-1- (4-fluorophenyl) ethyl ester (3.3 g).

By proceeding as described in Example K above, 2, 2, 2-trifluoro-1-phenylethyl ester of trifluoromethanesulfonic acid was prepared.

REFERENCE Synthesis of 2, 2,2-tri luoro-l. { R) - (4-fluorophenyl) ethanol To a -78 ° C solution of toluene (25 mL) / dichloromethane (25 mL) of 2, 2, 2, 4 '-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1 M S-CBS catalyst (1.3 mL) ), 1.3 mmol) freshly distilled catecholborane (1.66 mL, 15.62 mmol) was added. The . The reaction was maintained at -78 ° C for 16 h, at which point 4N HCl (5 L in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a solid. The solid was suspended in hexanes and filtered. The hexanes filtrate containing the desired product was concentrated, and the residue subjected to flash chromatography (10 hexanes: 1 ethyl acetate) to give the title compound as a colorless oil (2.2 g, 87% yield). It was determined that the ratio of enantiomers was 95: 5 through chiral HPLC (OD Chiralcel column, 95 hexanes, 5 mobile phase isopropanol) The Ret time for the main product was 6757 min. ., for the minor isomer, was 8,274 min.

REFERENCE M Synthesis of aminocyclopropane-carbonitrile hydrochloride.

Step 1. A mixture of benzofosfenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2 L Erlenmeyer flask under nitrogen room temperature, for 2 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 L), washed with water (200 mL) and brine. After drying over magnesium sulfate, the solution was evaporated to give (benzhydrylideneamino) acetonitrile (47.89 g).

Step 2. A solution of sodium hydroxide (91 g, 2.275 mol) in water (91 mL) in a 2 L flask was cooled on ice under nitrogen and then treated with benzyl triethyl ammonium chloride (2.0 g, 0.0088). mol, Aldrich) and (benzhydrilideneamino) acetonitrile (47.89 g) in toluene (100 L). Then, 1,2-dibromoethane (23 mL, 122.4 mmol, was added dropwise over 25 minutes to the reaction mixture).

Aldrich) with mechanical agitation and cooling, to maintain the internal temperature close to + 10 ° C. Then the reaction mixture was stirred vigorously for 24 h at room temperature and then poured into ice water and extracted with toluene. The combined extracts were washed with brine and then treated with MgSO4 and Norite. After filtering, the toluene was removed by rotary evaporation to give an oil (67 g). The residue was dissolved in boiling hexane (400 mL), treated with Norite and filtered hot and allowed to cool. A dark oil was removed and removed by pipette (~ 2 L). Scraping induced crystallization in the remaining solution which was cooled on ice for 2 h. The light yellow crystals were collected by filtration and washed with cold hexane to give 1- (benzhydrylideneamino) cyclopropane-carbonitrile (30.56 g).

Step 3. A mixture of 1- (benzhydrylideneamino) cyclopropanecarbonitrile (30.56 g, 0.124 mol) in concentrated HCl (12 L) in water (100 L) and ether (100 L) was stirred at room temperature for 15 h. The ether layer was discarded and the aqueous layer was washed with ether. Then the aqueous layer was dried frozen to give the title compound as a brown powder (13.51 g).

EXAMPLE 1. Synthesis of 1- (R) -morpholine-4-carboxylic acid 1- (4-cyano-l-ethylpiperidin-4-carbamoyl) -2-trimethylsilanyl) ethyl] amide Step 1. A mixture of acid. { R) -2-amino-3-trimethylsilanylpropionic acid (0.320 g, 2 mmol) and N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) (1.85 g, 13 mmol) was heated at 70 ° C for 1 h. The reaction mixture was cooled and the excess MSTFA was removed in vacuo. Morpholinocarbonyl chloride (0.70 ml, 6 mmol) was added to the reaction mixture, which was heated at 70 ° C for 45 min and then cooled. Water and ice (25 ml) were added to. The reaction mixture was stirred until the evolution of carbon dioxide ceased. The solution was extracted with ethyl acetate to give 2- acid. { R) - [morpholine-4-carbonyl) amino] 3- (trimethyl-silanyl) propionic (0.529 g), which was used in the next step without further purification.

Step 2. To a solution of 2- acid. { R) - [morpholine-4-carbonyl) amino] 3- (trimethylsilanyl) propionic (140 mg, 0.51 mmol) in DMF (2 ml) was added 4-amino-4-cyano-l-ethylpiperidine hydrochloride salt ( 99 mg, 0.52 mmol), HATU (296 mg, 0.78 mmol) and diisopropylethylamine (198 mg, 1.53 mmol) at room temperature. After 2 h, the reaction mixture was extracted with ethyl acetate, washed with brine, and dried. After removing the solvent, the residue was purified by column chromatography with silica gel to yield the title compound (87 mg). H1? MR (DMSO-D6): d 8.24 (1H, s), 6.5 (ÍH, d, J = 8.8 Hz), 4.18 - (ÍH, m), 3.6-3.48 (4H, m), 3.35-3.2 (4H,), 2.75-2.55 (2H, M), 2.32 (2H, q, J = 7.2 Hz), 2.3-2.1 (4H,), 1.9-1.7 (2H,), 0.98 (3H, t, J = 7.2 Hz, 1.1-0.8 (2H,), 0.009 (9H, s) MS: 408.4 (Ml), .410.3 (M + 1), 432.1 (M + Na).

By proceeding as described in Example 1 above, but substituting the 4-amino-4-cyano-l-ethylpiperidine hydrochloride salt with 1-aminocyclopropanecarbonitrile, [1- (1-cyanocyclopropylcarbamoyl) -2 was provided. 1- (J?) morpholino-4-carboxylic acid (trimethylsilyl) -ethyl] amide.

H1 NM (DMS0-d6): d 8.32 (1H, s), 8.04 (1H / s), 4.2 (ÍH, dd, J = 7.2 Hz, J = 14.4 Hz), 3.64 (4H, t, J = 4.8 Hz, 3.31 (4H, m), 1.65-1.45 (2H, m), 1.25-1.15 (3H, m-), 0. 95-0.85 (HH, m), 0.008 (9H, s). MS: 337.3 (M-l), 339 (M + 1), 361.1 (M + Na).

Proceeding as described in Example 1 above, but substituting the 4-amino-4-cyano-1-ethyl-piperidine hydrochloride salt with 1-aminotetrahydro-thiopyran-4-ylcarbonitrile, [l- (4- cyanotetrahydrothiopyran-4-ylcarbamoyl) -2- (tri-ethyl silanyl) ethyl] -amide of 1-acid. { R) -morpholino-4-carboxylic acid.

LC-MS: 397. 1 (M-1); 399 1 (M + l); 421 3 (M + Na).

Proceeding as described in Example 1, step 2, above, but substituting the hydrochloride salt of 4-amino-4-cyano-l-ethylpiperidine and the acid. { R) -2-amino-3-trimethyl-silanyl propionic acid. { R) -2-benzyloxycarbonylamino-3-benzyldimethylsilanyl propionic acid (prepared as described in Reference B from dimethylbenzylsilylmethanol which was made from the dimethylbenzylsilylmethane chloride commercially available as reference (J Org. Chem., 1997, 62, 8962-8963 ), [2 (i?) - (benzyldimethylsilanyl) -1- (cyanomethylcarbamoyl) ethyl] -carbamic acid benzyl ester was given, H-NMR (CDC13): 7.4-6.9 (11H,), 6.62 (1H, H) , 5.1-5 (2H, m), 4.14-4 (3H, m), 2.1 (2H, s), 1.63 (1H, s), 1.14 (1H, dd), 0.91 (1H, dd), 0.01 (6H , d) LC-MS: 408.3 (Ml), 410.1 (M + l), 432.2 (M + Na).

Proceeding as described in Example 1, but substituting the 4-amino-4-cyano-1-ethylpiperidine hydrochloride salt with 1-aminocyclopropanecarbonitrile and the morpholinocarbonyl chloride with 4-ethylpiperazin-1-ylcarbonyl chloride, provided [1- (1-cyanocyclopropylcarbamoyl) -2- (trimethylsilanyl) ethyl] -amide of 1-acid. { R) -4-ethylpiperazine-l-carboxylic acid. LC-MS: 364.2 (M-1), 66.1 (M + 1), 388.2 (M + Na).

Proceeding as described in Example 1, step 2, above, but substituting the hydrochloride salt of 4-amino-4-cyano-l-ethylpiperidine with 2-aminoacetonitrile and the acid 2-. { R) - [morpholino-4-carbonyl) amino] -3- (trimethylsilanyl) propionic acid with (Z?) - 2 ~ benzyloxycarbonylamino-3-benzyldimethylsilanyl propionic acid, benzyl ester of acid [2. { R) - (trimethylsilyl) -1- (cyanomethyl-carbamoyl) ethyl] carbamic. LC-MS: 332.2 (M-l), 333. 9 (M + 1), 356.0 (M + Na).

EXAMPLE 2. Synthesis of 1- (4-cyano-l, l-dioxohexahydro-l6-thiopyran-4-ylcarbamoyl) -2- (trimethylsilanyl) ethyl] amide of 1- (R) -morpholino-4- acid carboxylic To a solution of 1- (4-cyanotetrahydrothio-pyran-4-ylcarbamoyl) -2- (trimethylsilanyl) ethyl] -amide of 1-acid. { R) -morpholino-4-carboxylic acid (260 mg, 0.51 mmol) in MeOH (15 mL), oxone (469 mg, 0.76 mmol) in water (15 mL) was added at room temperature. After 2 h, the MeOH was removed in vacuo and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated. The residue was purified by column chromatography with silica gel to give the title compound (47 mg). H1 NMR (DMS0-d6): d 8.39 (ÍH, s), 6.5 (1H, d ,, J = 7. 6 Hz), 4.1 (ÍH, m), 3.49 (4H, t J = 4.4 Hz), 3.4-3.1 (6H, m), 2.7-2.55 (2H, m), 2.5-2.4 (4H, m), 1.05 -0.85 (2H, m), 0. 008 (9H, s). MS: 429 2 (M-1), 431. 1 (M + l), 453. 2 (M + Na).

EXAMPLE 3 Synthesis of. { 1 (R) - [1 (S) - (benzoxazol-2-ylhydroxymethyl) -butylcarbaoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide In a solution of 2- acid. { R) -2- [(morpholino-4-carbonyl) amino] -3- (trimethylsilanyl) -propionic (140 mg, 0. 51 'mmol) in CH2C12 (5 mL), 2- (S) -amino-1-benzoxazol-2-ylpentan-1-ol (121 mg, 0.55 mmol), prepared as described in Reference C), was added, HOBt (95 mg, 0.62 mmol), EDC (148 mg, 0.77 mmol) and NMM (154 mg, 1.53 mmol), at room temperature. After 2 h, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography with silica gel, to yield the title compound (300 mg). LC-MS: 475.4 (M-1); 477.5 (M + l); 4'99.5 (M + Na) '.

EXAMPLE 4. Synthesis of. { 1 (R) - [1 (S) - (benzoxazol-2-ylcarbonyl) -butylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide To a solution of. { 1 (R) - [1 (S) - (benzoxazol-2-ylhydroxymethyl) -butylcarbaoyl] -2-trimethylsilanylethyl} crude morpholino-4-carboxylic acid amide (300 mg) of Example 3 above, in CH2C12 (5 ml), periodinane was added to Dess-Martin (324 mg, 0.76 mmol) at room temperature.

- After stirring for 1 h, Na2S2C03 ~ NaHCO3 (5 mL) was added. After another 0.5 h, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified by column chromatography on silica gel, to yield the title compound (130 mg). H1 NMR (DMSO-d6): d 8.37 (HH, d, J = 6 Hz, 8.0 (HH, d, J = 7.6 Hz), 7.9 (HH, d, J = 8.4 Hz), 7.65 (HH, d, t, J = 1.6 Hz, J = 7.2 H2), 7.55 (ÍH, d, t, J = 1.2 Hz, J = 6 Hz, 6.42 (1H, d, J = 8.8 Hz), 6.21 (1H, m), 4.26 (1H, m), 3.51 (4H,), 3.35-3.2 (4H,), 2.0-1.85 (ÍH,), 1.8-1.65 (1H, m), 1.55-1.35 (2H, ), 1-0.85 (5H, m), 0.008 (9H, s). MS: 473.3 (M-1); 475.2 (M + l); 497.3 (M + Na).

EXAMPLE 5 Synthesis of. { 1 (R) - [1 (S) - (benzoxazol-2-ylcarbonyl) -propylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide Step 1, To a solution of (Z / E) -2-benzyloxycarbonylamino-3- (trimethylsilanyl) acrylic acid methyl ester (Z / E = 3: 1, 43 g, 140.1 mmol) prepared as described in Reference B, step 1, above, in ethyl acetate (100 ml), was added trifluoromethanesulfonate of (+) - 1,2-bis- . { 2S, 5S) -2,5-diethylphospholanebenzene (cyclooctadiene) rhodium (I) (500 mg, 0.692 mmol) under nitrogen atmosphere. Hydrogen gas was introduced at 20 psi. After 2 h, the ethyl acetate was removed by rotary evaporation to yield (J?) -2-benzyloxycarbonylamino-3- (trimethylsilanyl) propionic acid methyl ester (43.8 g). The chiral HPLS analysis shows e.e > 98%. (Column: OD, solvent: 90% hexane, 10% isopropanol and flow ratio of 1 ml / min 20 psi).

Step 2. To a stirred solution of (R) -2-benzyloxycarbonylamino-3- (tri-ethylsilanyl) propionic acid methyl ester (43.8 g, 140 mmol) in methanol (300 mL) was added INN NaOH solution (170 ml, 170 mmol) at 0 ° C. After completing the addition, the reaction was allowed to warm to room temperature. After shaking. for 2 h at room temperature, HPLC showed that the reaction was complete. The methanol was removed by rotary evaporation and the residue was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO 4 and concentrated, to give crude (JR) -2-benzyloxycarbonylamino-3- (trimethylsilyl) -propionic acid (42.7 g).

Step 3 To the stirred flask containing (f?) -2-benzyloxycarbonylamino-3- (trimethylsilanyl) -propionic acid (42.7 g, 145.2 mmol), hydrogen bromide in acetic acid (33 wt%, 90 mL) was added. . After stirring for 2 h, the HPLC showed that the starting material had been consumed.

Ethyl ether (200 ml) was added and the reaction mixture was 'stirred for 30 min. The precipitated product was filtered, washed with ethyl ether and dried, to yield acid hydrogen bromide salt. { R) -2-amino-3- (trimethylsilanyl) -propionic (22.5 g). The mother liquor was collected and the solvent was removed by rotary evaporation. The residue was stirred with a mixture of the 1: 1 mixture of ethyl ether and hexane (40 ml), to give an additional 6 g of the product.

Step 4. A mixture of acid hydrobromide salt. { R) -2-amino-3- (trimethylsilyl) propionic (1.439 g, 5.95 mmol) and N-methyl-N-trimethylsilyltrifluoroacetamide (M) (5.5 mL, 29.6 mmol) was heated at 69 ° G for 55 min. The N-methyltrifluoroaceta ida and the excess M were removed by rotary evaporation and the resulting residue was treated with morpholinocarbonyl chloride (3.0 ml, 25 mmol) and stirred again at 70 ° C for 40 min. After cooling, water (30 ml) and a little ice were added to the mixture, which was stirred at room temperature until the CO 2 evolution ceased (about 30 minutes). Then the reaction mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated, to give acid (1) -2- (morpholin-4-ylcarbonyl) amino-3. Morpholine-4-carboxylic acid (trimethylsilanyl) propionic (1.76 g), which was used in the next step without further purification.

Step 5. A mixture of (R) -2- (morpholin-4-ylcarbonyl) mino-3- (trimethylsilanyl) propionic acid of morpholino-4-carboxylic acid (1.76 g), N-hydroxybenz triazole (HOBt) - (0.910 g, 5.95 mmol), (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (EDCl) (1370 g, 7. 14 mmol) and. { R) -2-amino-l-benzoxazol-2-yl-propan-l-ol • (1472 g, 7.14 mol) in methylene chloride, was cooled on ice and treated with N-methylmorpholine (0.910 ml, 8.9 mmol) . The reaction mixture was stirred at room temperature for 2 h and then poured into a solution of water (50 ml), HCl 1? (15 ml), brine (50 ml) and ice. The product was extracted with ethyl acetate and the combined organic layers were washed with saturated NaHCO3, and then with brine. The extracts were dried over magnesium sulphate and evaporated, to give. { 1 (R) - [1 (S) - (benzoxazol-2-ylhydroxymethyl) propylcarbamoyl] -2-trimethylsilanylethyl} -morpholino-4-carboxylic acid amide as a semi-solid mixture of diastomers.

Step 6. A solution of. { 1 (R) - [1 (S) - (benzoxazol-2-ylhydroxy-methyl) propylcarbamoyl] -2-trimethylsilanylethyl} - morpholino-4-carboxylic acid amide (2.476 g) in methylene chloride (33 ml), was cooled on an ice / salt bath to -2 ° C, and treated with sodium bromide (0.612 g, 6 mmol) , sodium bicarbonate (0.504 g, 6 mmol), and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (0.06 mmol). A solution of sodium hypochlorite (11 ml, 6%, 9 mmol) (the commercial laundry bleach was used as an oxidant and the amount was calculated assuming that the weight of the sodium hypochlorite was 6.5%) in water (23 ml), was then added dropwise to the reaction mixture with rapid stirring for 45 min, while maintaining the internal temperature of the reaction close to 0 ° C. After the reaction was complete (HPLC), the reaction was quenched with the addition of 10% aqueous sodium thiosulfate (10 ml). The methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, then with brine, and dried over magnesium sulfate. Evaporation of the solvent gave a brown foam (1879 g) which was dissolved in i-propyl acetate (3 ml), diluted with tert-butylmethyl ether (8 ml) and cooled in the freezer overnight. Filtration of the solid gave the title compound (1396 g).

Proceeding as described in Example 5 above but substituting the. { R) -2-amino-l-benzoxazol-2-yl-propan-1-ol with. { RS) -2-amino-1-benzoxazol-2-yl-propan-1-ol, followed by separation of the diastereomer, was provided. { 1 (R) - [1 (R) - (benzoxazol-2-ylcarbonyl) -propylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide.

H-NMR (DMS0-d6): 7.825 (1H, d), 7.57 (1H, d), 7.47 (1H, dd), 7.39 (1H, dd), 7.17 (1H, d), 5.6-5.4 (1H, ), 4.77 (1H, d), 4.5-4.4 (HH, m), 3.65-3.55 (4H,), 3.35-3.25 (4H, m), -2.15-2 (1H, m), 1.9-1.8 (HH, m) , 1.2-1.1 (2H, m), 0.94 (3H, t), 0. 01-0 (11H, m). LC-MS: '459. 3 (M-1), 461. 3 (M + 1), 483.2 (M + Na).

EXAMPLE 6 Synthesis of 3'-cyanobiphenyl-3-carboxylic acid [1- (RS) - (1-cyanocislopropylcarbamoyl) -2-trimethyl-silanylethyl] amide Step 1 A mixture of 3-iodobenzoic acid (21.73 g, 0.08-76 mol), benzene (75 ml), 2 drops of dimethylformamide, and thionyl chloride (10 ml, 0.137 mol), was heated at 82 ° C. 2 h, time in which a bubbler did not show more release of sulfur dioxide. The solvent was removed under reduced pressure to give 3-iodobenzoyl chloride. In a separate bottle, was it prepared? a solution of diethylamino malonate hydrochloride (18.3 g, 0.086 mol) in methylene chloride (100 ml), and cooled to -18 ° C. N-methylmorpholine (22 ml, 0.20 mol) was added followed by the 3-iodobenzoyl chloride prepared above, at a ratio that kept the reaction temperature below -7 ° C. The reaction mixture was allowed to warm to room temperature and then stirred for 3 h. The reaction mixture was poured into ice water and extracted with methylene chloride. The organic layers were washed with dilute HCl, aqueous sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent was removed and crystallization a. From tert-butylmethyl ether gave diethyl ester of 2- (3-iodobenzoyl-a-ino) -alonic acid (23.87 g).

Step 2 A mixture of diethyl ester of 2- (3-iodobenzoylamino) malonic acid (16.08 g, 0.0397 mol), cesium carbonate (23.2 g, 1.8 equivalents), iodomethyltrimethylsilane (10.6 ml, 1.8 equivalents) and N-methylpyrrolidinone (50 ml), was heated at 71 ° C for 6 h. The cooled reaction mixture was poured into ice water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. Flash chromatography on silica gel, leaching with ethyl acetate / hexane followed by crystallization, gave 2- (3-iodobenzoylamino) -2-trimethylsilanylmethylmalonic acid diethyl ester (8.82 g).

Step 3 A solution of diethyl ester of 2- (3-iodobenzoylamino) -2-trimethylsilanylmethylmalonic acid (8.419 g, 0.0171 mol), lithium bromide (2.19 g, 0.25 mol), dimethylformamide (25 ml) and water (0.75 ml) , was heated in a jar equipped with a bubbler at 150 ° C, for 4 h. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extracts were dried and evaporated to give ethyl ester of 2- acid. { RS) - (3-iodobenzoylamino) -3- trimethylsilanyl) propionic (6.73 g) -.

A mixture of 2- (JS) - (3-ydobenzoylamino) -3-trimethylsilanyl) propionic acid ethyl ester (6.73 g, 0.016 mol), methanol (100 ml) and 1N aqueous sodium hydroxide (40 ml) was stirred at room temperature for 1.5 h. The methanol was removed by evaporation under reduced pressure and the remaining aqueous solution was washed with ether, cooled on ice, and acidified to pH 2. The product was precipitated from the aqueous layer and collected by filtration to produce 2- acid. { RS) - (3-iodobenzoylamino) -3-trimethylsilanyl) propionic (6.25 g).

Step 5 A mixture of acid 2-. { RS) - (3-iodobenzoylamino) -3-trimethylsilanyl) propionic (4.88 g, 0.0125 mol), dimethyl formamide (25 ml), 1-amino-1-cyanocyclopropane hydrochloride (1.95 g, 0.016 mol), hexafluorophosphate-N- N- [(dimethylamino-1H-1) oxide, 2, 3-triazolo [4,5-b] pyridin-1-ylmethyl] -N-methyl-methano-amine (HATU) (5.70 g, 1.2 equivalents) and N-methylmorpholine (4.13 ml), was stirred at room temperature for 4 h. The reaction mixture was diluted with water and then extracted with ethyl acetate. The extracts were washed with dilute HCl, saturated sodium bicarbonate and brine. Drying and evaporation of the solvent gave a residue that was crystallized from t-butyl methyl ether to give N- [1-. { RS) - (1-cyano-cyclopropylcarbamoyl) -2- (trimethylsilanyl) ethyl] -3-iodobenzamide (4079 g).

Step 6 A mixture of N- [1-. { RS) - (1-cyanocyclopropylcarbamoyl) -2- (trimethylsilanyl) ethyl] -3-iodobenzamide (0.091 g, 0.0002 mol), toluene (2.5 ml), sodium carbonate 2? (0.20 ml), ethanol (0.1 ml), 3-cyanophenyl boronic acid (0.030 g, 0.0002 mol) and tetrakis (triphenylphosphine) -palladium (O) (0.015 g), was heated at 105 ° C for 14 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extracts were washed with brine and dried over magnesium sulfate. Evaporation gave 0.106 g of crude product which was chromatographed on silica gel to give [1-. { RS) - (3-cyanobiphenyl-3-carboxylic acid (1-cyano-cyclopropylcarbamoyl) -2- (trimethylsilanyl) -ethyl] -amide (0.047 g).

By proceeding as described above, but replacing the appropriate boronic acids with 3-cyanophenylboronic acid, the following analogues were prepared: [1- . { RS) - 3'-trifluoromethoxy-biphenyl-3-carboxylic acid (1-cyanocyclopropyl-carbamoyl) -2-trimethylsilanylethyl] -amide; [1- . { RS) - biphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -amide; [1- . { RS) - 2 ', 6'-dimethoxybiphenyl-3-carboxylic acid (1-cyano-cyclopropylcarbamoyl) -2-trimethylsilanylethyl] -amide; [1- . { RS) - 4'-Methylsulfonylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanyl-ethyl] -amide; [1- . { RS) - 2'-chlorobiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -amide; [1- . { RS) - 2'-trifluoromethylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; N- [1-. { RS) - (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -3-pyridin-3-ylbenzamide; [ 1- . { RS) - 3'-methylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -amide; [1- . { RS) - 3'-Hydroxymethylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -amide; [1- . { RS) - 4'-Hydroxymethylbifyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-tri-ethylsilanylethyl] -amide; [1- . { RS) - 3'-methoxycarbonylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; Y [1- . { RS) - 4'-acetylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -amide.

EXAMPLE 7 Synthesis of [1- (RS) - (4-cyano-l, l-dioxohexahydro-l6-thiopyran-4-ylcarbamoyl) -2- (trimethylsilanyl) ethyl] amide of 3'-methoxybiphenyl-3 acid -carboxylic Step 1 Proceeding as described in Example 6, step 5 above, but substituting 1-amino-1-cyanocyclopropane hydrochloride with 4-amino-tetrahydro-tertiary-4-carbonitrile, N- [1-. { RS} - (4-cyanotetrahydrothiopyran-4-ylcarbamoyl) -2- (trimethylsilanyl) -ethyl] -3-iodobenzamide.

Step 2: A mixture of N- [1-. { RS) - (4-cyanotetrahydrothiopyran-4-ylcarbamoyl) -2- (trimethylsilanyl) -ethyl] -3-iodobenzamide (0.90 g, 0.177 mmol), 3-methoxyphenylboronic acid (0.031 g, 0.20 mmol), toluene (2.5 ml) , ethanol (0.10 ml), aqueous sodium carbonate (2?, 0.20 ml) and tetrakis triphenylphosphinopalladium (0) (0.010 g), was heated at 90 ° C for 16 h and then cooled to room temperature, diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated, to give a crude product which was chromatographed on silica gel and crystallized, to give [1- (iε) - (4-cyanotetrahydrothiopyran-4-ylcarbamoyl) -2- (trimethylsilanyl) -ethyl] -amide 3'-methoxybiphenyl-3-carboxylic acid (0.040 g). The rechromatography of the impure fractions gave another 0.009 g of the product.

Step 3 A mixture of [1-. { RS) ~ (4-cyanotetrahydrothiopyran-4-ylcarbamoyl) -2- (trimethylsilanyl) -ethyl] amide of 3'- • methoxybiphenyl-3-carboxylic acid (0.047 g, 0.095 mmol) in methanol (4 ml) was cooled in ice and treated with an oxone solution (0.087 g, 1.5 equivalents) in water (1.0 ml). After 1 h of stirring at room temperature, additional oxone (0.070 g) in water (0.05 ml) was added. The reaction mixture was stirred at room temperature for 6 h and then diluted with water. The product was extracted with ethyl acetate and purified, to give the title compound (0.006 g).

EXAMPLE 8 Synthesis of [1- (R) - (4-Cyanocyclopropylsarbamoyl) -2- (trimethyl-silanyl) ethyl] 3-methoxybiphenyl-3-carboxylic acid amide Step 1 2- (i?) -amino-3- (trimethylsilanyl) propionic acid (0.424 g, 0.0020 mol) in water (5 ml), and dioxane (10 ml), was cooled on ice bath and treated with hydroxide. 2N aqueous potassium (3 ml). Then a solution of di-t-butyl dicarbonate (0.545 g, 0.0025 mol) in dioxane (2 ml) was added in portions and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was cooled in ice and then acidified with IN HCl until pH 2.8, and extraction with ethyl acetate gave 2- (i?) - tert-butoxycarbonylamino-3- (trimethylsilanyl) -propionic acid (0.558 g) .- Step 2 A mixture of 2- (i?) -tert-butoxycarbonyl-amino-3- (trimethylsilanyl) -propionic acid (0.497 g, 0.0188 mol), dimethylformamide (4 ml), HATU (0.80 g, 0.0021 mol), hydrochloride of 1-amino-1-cyanocyclopropane (0.300 g, 0.0025 mol) and N-methylmorpholine (0.44 ml), was stirred at room temperature for 16 h. The reaction mixture was diluted with HCl 0.5? and extracted with ethyl acetate. The extracts were washed with sodium bicarbonate and then brined, dried over magnesium sulfate and evaporated. Flash chromatography gave tert-butyl ester of [1-] acid. { R) - (1-cyano-cyclopropylcarbamoyl) -2- (trimethylsilanyl) -ethyl] carbamic acid (0.323 g).

Step 3 A solution of tert-butyl ester of [l- (iR) - (1-cyanocyclopropylcarbamoyl) -2- (trimethylsilyl) -ethyl] -carbamic acid (0.160 g, 0.49 mmol), methanesulfonic acid (0.20 ml) and tetrahydrofuran (3 ml), was stirred at room temperature for 48 h. The reaction mixture was diluted with aqueous sodium bicarbonate and the product was extracted with ethyl acetate. Drying and evaporation gave [1- (i?) - (1-cyanocyclopropylcarbamoyl) -2- (trimethylsilanyl) -ethyl] carbamic acid (0.090 g).

Step 4 A mixture of [l- (i?) - (l-cyanocyclopropylcarbamoyl) -2- (trimethylsilanyl) -ethyl] -carbamic acid (0.076 g, 0.337 mmol), methylene chloride (3.5 'ml), 3- acid carboxyphenyl boronic acid (0.067 g, 0.405 mmol), HATU (0.282 g, 2.2 equivalents) and N-methylmorpholine (0.081 ml), was stirred at room temperature for 18 h. The reaction mixture was poured into dilute HCl and the product was extracted with ethyl acetate, and the extracts were washed with aqueous sodium bicarbonate and brine. After drying, the solvent was removed to give benzamide N- [1-. { R) - (1-cyanocyclopropylcarbamoyl) -2- (trimethylsilanyl) -ethyl] -3-boronic acid as a white powder (0.202 g).

Step 5 A mixture of benzamide N- [1-. { R) - (1- cyanocyclopropylcarbamoyl) -2- (trimethylsilanyl) ethyl] -3-. boronic acid (0.184 g, 0.493 mmol), 3-bromoanisole (0.075 ml, 0.596 mmol), triethylamine (0.034 ml, 2.46 mmol), Pd (dppf) - (0.041 g, 0.1 equivalent) in acetonitrile (2 ml), was heated in a microwave oven at 130 ° C for • 10 min. The reaction mixture was diluted with ethyl acetate and washed with dilute HCl, aqueous sodium bicarbonate and brine. After drying over magnesium sulfate and removal of the solvent, the residue was purified by flash chromatography to give [1- (R) - (1-cyano-cyclopropylcarbamoyl) -2- (trimethylsilanyl) -ethyl] -amide 3'-acid -methoxybiphenyl-3-carboxylic acid (0.023 g).

EXAMPLE 9 Synthesis of 3- (benzyldimethylsilanyl) -27- (1-cyano-cyclopropyl) -2 (JR) - (2,2,2-trifluoro-1-phenyl-ethylamino) -propionamide Step 1 En-methyl ester of 3- (benzyldimethyl-silanyl) -2- acid. { R) -benzyloxycarbonylaminopropionic acid (1.93 g, 5 mmol) was added 30% HBr in AcOH solution (5 ml) at room temperature. After stirring for 30 ml, the reaction was diluted with toluene (50 ml) and then the solvent was removed by rotoevaporation. The residue was dissolved in ethyl acetate and washed with saturated NaHCO 3 solution in water and brine, and dried over MgSO 4. After the concentration, methyl ester of 2- acid was obtained. { R) -amino-3- (benzyldimethylsilane) propionic (1.96 g).

Step 2 In a solution of methyl ester of 2- acid. { R) -amino-3- (benzyldimethylsilanyl) propionic acid (1.96 g) in dichloro-methane (20 ml), trifluoroacetophenone (0.87 g) was added.

// J g, 5 mmol), DIPEA (2.59 g, 20 mmol) and 1 M solution of TiCl 4 in CH 2 Cl 12 (5 mL, 5 mmol) at room temperature. After stirring for 4 h, 1 M solution of TiCl4 in additional CH2C12 (3 mL) was added. After 12 h, NaBH3CN (1.28 g, 20 mmol) in MeOH (20 ml) was added. After 2 'h, the reaction was extracted with CH2C12 (150 ml) and washed with bifine and dried over MgSO4. Then the column chromatography obtained methyl ester of 3- (benzyl-dimethylsilanyl) -2 acid. { R) - (2,2, 2-trifluoro-1-phenylethylamino) -propionic (0.4 g).

Step 3 In a solution of methyl ester of 3- (benzyldimethylsilanyl) -2 acid. { R) - (2,2,2-trifluoro-1-phenylethylamino) propionic acid (0.4 g, 0.98 mmol) in a THF / MeOH mixture (10 ml / 5 ml), 1M aqueous solution of LiOH (3 ml) was added at room temperature. After stirring for 2 h, the solvent was removed by rotoevaporation, the residue was diluted with pH4 regulator and extracted with ethyl acetate (150 ml). After washing the organic layer with brine and drying over MgSO4, the solvent was removed by rotoevaporation to give 3- (benzyldimethylsilanyl) -2 acid. { R) - (2,2,2-trifluoro-l-phenylethylamino) propionic (395 mg).

Step 4 In a solution of 3- (benzyldimethylsilanyl) -2 acid. { R) -. { 2, 2, 2-trifluoro-1-phenylethylamino) propionic (395 mg, 1 mmol) in DMF (10 mL), HATU (380 mg, 1 mmol), DIPEA '(258 mg, 2 mmol) and cyclopropylammononitrile hydrochloride salt (119 mg, 1 mmol) were added at room temperature. . After 2 h, the reaction mixture was extracted with ethyl acetate (150 ml), washed with brine and dried with MgS0. After removal of the solvent, the crude was purified by column chromatography to give the title compound (229 mg).

HNMR (DMS0-d6): 8.92, 8.86 (H, s, diastereomer), 7.6-7 (10H,), 4.4-4.2 (1H, m), 3.8 (H, s), 3.5-3.4, 3.1-2.9 ( 1H, m, diastereomer), 2.65-2.5 2H,), 2.35-2.1 (2H,), 1.5-1.4 (2H, m), 1.1-0.85 (2H, m), 0.126, 0.093, 0.039, -0.001 (6H , d, diastereomer). LC-MS: 458.1 (Ml), 460.2 (M + 1), 482.3 (M + Na).

EXAMPLE 10 Synthesis of Morpholino-4-carboxylic acid [1- (RS) - (1-benzyloxymethyl-l-sianedi-cyclopropylcarbamoyl) -2-trimethyl-silanylethyl] amide Step 1 To a solution of commercially available benzyloxyacetaldehyde (1 g, 6.66 mmol) in THF (10 mL), a 1 M solution of EtMgBr in THF (6.66 mL, 6. 66 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h and then quenched with 5 ml of water and filtered through celite. The celite was washed with EtOAc and the filtrate was washed with Brine and dry over MgSO4. The organic layer was filtered and evaporated to dryness to give l-benzyloxybutan-2-ol (1 g) as a yellow oil.

Step 2 To a solution of oxalyl chloride (2.9 mL, 33.3 mmol) in dichloromethane (50 mL) at -78 ° C was added dropwise dry dimethyl sulfoxide (4.7 mL, 66.6 mmol) and the reaction mixture was stirred for 15 min. A solution of l-benzyloxybutan-2-ol (4 g, 22.2 mmol) in dichloromethane (50 ml) was added. After 1 h, triethylamine (14 ml, 99.9 mmol) was added; after 1 h the reaction mixture was warmed to room temperature. The reaction mixture was washed with water followed by brine. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated to give l-benzyloxybutan-2-one (3.9 g) as a yellow oil.

Step 3: Benzyloxypropan-2-one (4 g, 22.4 mmol, commercially available), NaCN (1.21 g, 25 mmol) and NH 4 Cl (1.34 g, 25 mmol) were mixed in a 7 N solution of NH 3 in methanol ( 13 ml, 0.12 mmol), and the reaction mixture was refluxed for 2 h. 7 N NH3 solution in additional methanol (13 ml) was added and refluxing continued. After 2 h, the reaction mixture was cooled to room temperature and was diluted with 100 ml of dichloromethane. The resulting mixture was filtered, diluted again with another 100 ml of dichloromethane and concentrated, to give 2-amino-2-benzyloxymethylbutyronitrile (4 g) as a yellow oil.

Step 4 The 2-amino-2-benzyloxymethylbutyronitrile (54.6 g, 267 mmol) was added to a solution of 2- acid. { RS) - (morpholino-4-carbonylamino) -3-trimethylsilanylpropionic acid (100 mg, 0.267 mmol) and HATU (122 mg, 0.320 mmol) in DMF (1 ml) and was followed by the addition of DIPEA (186 μl, 1068 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with 10 ml of ethyl acetate, washed with 5 ml of water and 5 ml of saturated NaHCO 3 solution and dried over MgSO 4. The solvent was evaporated and the crude mixture was purified by HPLC, to give the title compound. LCMS: 461.3 (M + 1) +1, 483.2 (M + Na) +, 459.1 (M-1) "1.

EXAMPLE 11 Synthesis of. { 1 (RS) - [(benzyloxymethylcyanomethyl-methyl) -carbamoyl] -2-trimethylsilanylethyl} amide Step 1 L-benzyloxypropan-2-one (5 g, 30 mmol, commercially available), NaCN (1.64 g, 33.5 mmol) and NH 4 Cl (1.79 g, 33.5 mmol) were mixed in a 2 M solution of NH 3 in methanol ( 60 ml, 120 mmol), and the reaction mixture was refluxed for 2 h. Another 60 ml of 2 M NH3 solution was added and refluxing was continued for another 2 h. The reaction mixture was cooled to room temperature and was diluted with 100 ml of dichloromethane. The resulting mixture was filtered, again diluted with another 100 ml of dichloromethane and concentrated, to give 2-amino-3-benzyloxy-2-methylpropionitrile (5 g) as a yellow oil which was converted to the title compound as described in Example 10 above. LCMS: 447.6 (M + 1) +1, 469.4 (M + Na) +, 445.4 (M-1) "1.

EXAMPLES Biological examples Example 1: Cathepsin B test Solutions of the test compounds were prepared in various concentrations, in 10 μL of dimethyl sulfoxide (DMSO) and then diluted in a test buffer (40 μL, comprising: N, N-bis acid ( 2-hydroxyethyl) -2-aminoethanesulfonic acid (BES), 50 mM (pH 6), polyoxyethylene sorbitan monolaurate, 0.05%, and dithiothreitol (DTT), 2.5 mM). At the dilutions, human cathepsin B (0.025 pMoles in 25 μL of test buffer) was added. The test solutions were mixed for 5-10 seconds on a vibrating tray, covered and incubated for 30 minutes at room temperature. To the test solutions were added Z-FR-AMC (20 nMoles in 25 μL of test buffer) and the hydrolysis was followed spectrophotometrically (at? 460 n) for 5 minutes. 'The constants of apparent inhibition (Ki) were calculated from the progress curves of the enzyme using standard mathematical models.

The compounds of the invention were tested with the assay described above and were shown to show inhibitory activity of cathepsin B EXAMPLE 2 Cathepsin K Test Solutions of the test compounds were prepared in various concentrations in 10 μL of dimethyl sulfoxide (DMSO) and then diluted in test buffer (40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K was added to the dilutions (0.906 pMoles in 25 μL of test buffer). The test solutions were mixed for 5-10 seconds on a vibrating tray, covered and incubated for 30 minutes at room temperature. To the test solutions was added Z-Phe-Arg-AMC (4 nMoles in 25 μL of test buffer), and hydrolysis was followed spectrophotometrically (at? 460 nm) for 5 minutes. The constants of apparent inhibition (Ki) were calculated from the progress curves of the enzyme using standard mathematical models.

The compounds of the invention were tested with the assay described above and were found to show inhibitory activity of cathepsin K.

EXAMPLE 3 Cathepsin L Test. Solutions of the test compounds were prepared in various concentrations, in 10 μL of dimethyl sulfoxide (DMSO) and then diluted in test buffer (40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 M). Human cathepsin L (0.05 pMoles in 25 μL of test buffer) was added to the dilutions. The test solutions were mixed for 5-10 seconds on a vibrating tray, covered and incubated for 30 minutes at room temperature. To the test solutions was added Z-Phe-Arg-AMC (1 nMoles in 25 μL of test buffer), and the hydrolysis was followed spectrophotometrically (at? 460 nm) for 5 minutes. The constants of apparent inhibition (Ki) were calculated from the progress curves of the enzyme using standard mathematical models.

The compounds of the invention were tested with the assay described above and were found to show inhibitory activity of cathepsin L.

Example 4 Cathepsin S Test Solutions of the test compounds were prepared in various concentrations, in 10 μL of dimethyl sulfoxide (DMSO) and then diluted in a test buffer (40 μL, comprising: MES, 50 mM (pH 6.5); EDTA, 2. 5 mM; and NaCl, 100 mM); β-mercaptoethanol, 2.5 mM; and BSA, 0. 001% Human cathepsin S (0.05 pMoles in 25 μL of test buffer) was added to the dilutions. The test solutions were mixed for 6-10 seconds on a vibrating tray, covered and incubated for 30 minutes at room temperature. To the test solutions was added Z-Val-Val-Arg-AMC (3 nMoles in 25 μL of test buffer containing 10% DMSO), and hydrolysis was followed spectrophotometrically (at Ex: 355 nm, Em: 460 nm) for 5 minutes. The constants of apparent inhibition (K) were calculated from the progress curves of the enzyme using standard mathematical models.

The compounds of the invention were tested with the above-described test and were found to show inhibitory activity of cathepsin S.

Example 5 Cathepsin F Test Solutions of the test compounds were prepared in various concentrations, in 10 μL of dimethyl sulfoxide (DMSO) and then diluted in test buffer (40 μL, 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 μL of test buffer) was added to the dilutions. The test solutions were mixed for 5-10 seconds on a vibrating tray, covered and incubated for 30 minutes at room temperature. To the test solutions was added Z-Phe-Arg-AMC (2 nMoles in 25 μL of test buffer containing 10% DMSO), and hydrolysis was followed spectrophotometrically (at? 460 nm) for 5 minutes. The constants of apparent inhibition (Ki) were calculated from the progress curves of the enzyme using standard mathematical models.

The compounds of the invention were tested with the assay described above and were found to show inhibitory activity of cathepsin F.

Example 6: In vitro accumulation test During normal antigen presentation, Iip 10 is proteolytically degraded to allow loading of a peptide fragment and the subsequent presentation of MHC-II on the surface of the antigen presented by the cells. The cleavage process is mediated by cathepsin S. Therefore, the IILO test is an in vitro measure of the ability of a compound to block cathepsin S and, by extension, the presentation of the antigen. It would be expected that a compound that causes IcipO accumulation at low concentration will block the presentation of antigens.

Method: Raji cells (4 x 106) were cultured with 2% DMSO or different concentrations of cathepsin S inhibitors in RPMI 160 medium containing 10% (v / v) FBS, 10 mM HEPES, 2 mM L- glutamine, and 1 mM sodium pyruvate, for four hours at 37 ° C under humidified C02 at 5%. After the culture period, the cells were washed with cold PBS and then the cells were used in NP-40 lysis buffer (5 mM EDTA, 1% NP-40, 150 mM NaCl, and 50 mM Tris, pH 7.6), with protease inhibitors. The determinations of the protein were made and the lysate mixtures were boiled to reduce the SDS test regulator. The proteins were separated by electrophoresis on 12% Bis-Tris NuPAGE® gels. Then the proteins were transferred to nitrocellulose membranes, and after incubation with blocking regulator (5% dry milk defatted in PBS-Tween), the spots were incubated with the primary antibody against the human peptide CD74 invariant chain (1.5 at 2 μg / ml of mouse anti-CD74 monoclonal antibody, PIN.l, Stressgen Biotechnologies). Then the spots were incubated with the secondary antibody, horseradish peroxidase IgG anti-mouse conjugated donkey, at a dilution of 1: 10,000. Immunoreactive proteins were detected by chemiluminescence reaction using Pierce Super Signal® chemi-luminescence substrate from West Pico.

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS The following are representative pharmaceutical formulations containing a compound of the present invention.

Tablet formulation The following ingredients are intimately mixed and pressed into individual labeled tablets.

Amount per Ingredient tablet, mg Compound of this invention 400 Corn starch 50 Sodium croscarmellose 25 Lactose 120 Magnesium stearate 5 Formulation for capsules. The following ingredients are intimately mixed and loaded into a hard shell gelatin capsule.

Quantity per Ingredient capsule, mg Compound of this invention 200 Corn starch 50 Lactose, dried sprinkled 148 Magnesium stearate 2 Formulation for suspension The following ingredients are mixed to form a suspension for oral administration. t Ing_red.i.ent.e Amount Compound of this invention 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propylene paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavor 0.035 ml Dyes 0.5 mg Distilled water cs to 100 ml Injectable formulation The following ingredients are mixed to form an injectable formulation.

Ingredient Amount Compound of this invention 1.2 g 0.4 M 2.0 ml buffer, sodium acetate, q.s. for suitable pH HCl (1N) or NaOH (IN) Water (distilled, sterile) q.s. to 20 ml All the ingredients above, except water, are combined and heated to 60-70 ° C with agitation. Then add a sufficient amount of water at 60 ° C with vigorous stirring to emulsify the ingredients, and then add enough water to reach 100 g.

Suppository Formulation A suppository with a total weight of 2.5 g is prepared by mixing the compound of the invention with Witepsol® H-15 (vegetable saturated fatty acid triglycerides, Riches-Nelson, Inc., New York), and has the following composition: Compound of this invention 500 mg Witepsol® H-15 balance The previous invention has been described in some detail by way of itration and example, for the - purposes of clarity and understanding. It will be obvious to one skilled in the art that changes and modifications may be practiced within the competence of the appended claims. Therefore, it is understood that the description above is intended to be itrative and not restrictive. Therefore, the - Competence of the invention should not be determined with reference to the description above, but instead be determined with reference to the following appended claims, together with the full competence of the equivalents to which these claims give entitlement. All Patents, including the Provisional Applications of the Applicant, Nos. Series, US 60 / 540,581 and 60/547, 498, filed on January 30, 2004, and on February 24, 2004, and the publications cited in this application, are they incorporate here as reference in their totalities for all purposes up to the same point as if each patent, patent application or individual publication, is denoted individually.

Claims (15)

1. Compound of Formula (I):

R2 ii) wherein: Q is -CO-, -S02-, -0C0-, NR CO-, -NR4S02, or -CHR- wherein R is haloalkyl and R4 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or aralkyl; E is: (i) C (R5) (R6) X1, where X1 is -C (R7) (R8) R10, -CH = CHS (O) 2R10, C (R7) (R8) C (R7) (R8) ) OR10, -C (R7) (R8) CH2N (R11) S02R10, C (R7) (R8) C (0) N (R1X) (CH2) 2OR1: L, -C (R7) (R8) C (O ) NR ^ R11, or C (R7) (R8) C (0) N (R11) (CH2) 2NR10R11; (ii) C (R5a) (R6a) CN; wherein: R5 and R5a are independently hydrogen or alkyl; R6 and R6a are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocyloalkylalkyl, -alkylene-X2-R12 (where X2 is -0-, NR13- , -S (0) ni-, -CONR13-, NR13CO-, NR13C (0) 0-, -NR13CONR13-, -OCONR13-, NR13S02-, -S02NR13-, -NR13S02NR13-, -CO-, or -OC ( O) -, where neither is 0-2 and each R13 is hydrogen or alkyl and R12 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl where the aromatic or alicyclic ring in R6 and R6 is optionally substituted with one, two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl, alkylsulfonyl , or arisulphonyl where the aromatic ring or Acyclic in Ra is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl; or: R5 and R6 and R5a and R6 taken together with the carbon atom to which both of R5 and R6 and R5a 'and R6a are linked form: (i) cycloalkylene optionally substituted with one or two Rb, independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl, or (ii) heterocycloalkylene optionally substituted with one to four alkyls or one or two Rc, independently selected from alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, -S (0) n2R14,. -alkylene-S (0) n2R15, COOR16, -alkylene-COOR17, -CONR18R19 'or -alkylene-CONR20R21 (where n2 is 0-2, and R1-R17, R18 and R20 are independently hydrogen, alkyl, haloalkyl,. aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl or cycloalkylalkyl, or the heterocycloalkyl and R19 and Y21 are independently hydrogen or alkyl), wherein the aromatic or alicyclic ring in the groups linked to the cycloalkylene or the heterocycloalkylene is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, benzyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, or acyl; R7 is hydrogen or alkyl; R8 is hydroxy; or R7 and R8 together form oxo; R10 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl where the aromatic or alicyclic ring in R10 is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, alkoxyalkyl , cycloalkyl, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryl, aralkyl, heteroaryl, amino, monosubstituted amino, disubstituted amino, carbamoyl, or 'acyl, where the aromatic or alicyclic ring in Rd is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, or dialkylamino; and R11 is hydrogen or alkyl; or (iii) a group of formula (a): where: n is 0, 1 or 2; X is selected from -NR-, -S-, or -O-, where R22 is hydrogen, alkyl or alkoxy; and X5 is -O-, -S-, -S02- or NR23-, wherein R23 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl , cycloalkylalkyl, S (0) 2R24, -alkylene-S (O) n3-R25, -COOR26, -alkylene-COOR27, -CONR28R29, or -alkylene-CONR30R31 (where n3 is 0-2 and R24-R27, R28 and R30 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl and R29 and R31 are independently hydrogen or alkyl), wherein the aromatic or alicyclic ring in R23 is optionally substituted with one , two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, and a substituent selected from aryl, aralkyl, heteroaryl, or heteroaralkyl; and R5 is as defined above; R1 is hydrogen or alkyl; Rla is 1,1-dialkylsilyano-4-ylalkylene or - (alkylene) -SiR32R33R34 where R32 is alkyl, R33 is alkyl, and R34 is alkyl, alkenyl, cycloalkylalkyl, aryl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl, or R33 and R34 together with Si form a heterocycloalkylene ring containing the Si atom and from 3 to 7 carbon ring atoms, where one or two carbon ring atoms are optionally independently replaced with -NH-, -0-, -S-, -SO-, -S02-, -CO-, -CONH-, or -S02NH- and wherein the aralkyl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylene ring in Rla is optionally substituted in the ring with one, two or three Re independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl, alkylsulfonyl, or arylsulfonyl and further where the aromatic or alicyclic ring in Re is optionally replaced co n one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl; R2 is hydrogen or alkyl; R3 is alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, or -alkylene-X6-R35 [where X6 is -NR36, -0-, S (0) n4, -CO-, COO- , -0C0-, NR36CO-, CONR36-, - NR36S02-, -S02NR36-, -NR36COO-, -OCONR36, -NR36C0NR37, or -NR36S02NR37- (where each R36 and R37 is independently hydrogen, alkyl, or acyl, and n4 is 0-2) and R35 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl] where the alkylene chain in R3 is optionally substituted with one to four halo atoms and the aromatic and alicyclic rings in R3 are optionally substituted by one, two or three Rf, independently selected from alkyl, aminoalkyl, halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, acyloxy, aryl, aralkyl , heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, hetero cycloalkyl, heterocycloalkylalkyl, aryloxy, benzyloxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, ariisulfonilo, arylsulfinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, aralkylaminosulfonyl, aminocarbonyl, arylcarbonyl, aralkylaminocarbonyl, amino, monosubstituted or disubstituted amino, and furthermore where the aromatic and alicyclic rings in Rf are optionally substituted with one, two or three R9, where Rg is independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylthio, alkylsulfonyl, amino, monosubstituted amino, dialkylamino, aryl, heteroaryl, cycloalkyl, carboxy, carboxamido, or alkoxycarbonyl; or a pharmaceutically acceptable salt thereof. 2. Compound of claim 1 wherein E is -CHR6C (0) R10, wherein R6 is alkyl and R10 is heteroaryl optionally substituted with one or. two Rd independently selected from alkyl, haloalkyl, alkoxy, alkoxyalkyl, cycloalkyl, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, aryl, heteroaryl, amino, monosubstituted amino, disubstituted amino or acyl, wherein the aromatic or alicyclic ring in Rd is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, or dialkylamino.

3. Compound of claim 1, wherein E is -CR5R6aCN, wherein R5a and R6a together with the carbon atom to which they are linked form cycloalkylene optionally substituted with one or two R independently selected from alkyl, halo, dialkylamino, aryl, aralkyl , cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl or aryloxycarbonyl.

4. The compound of claim 1, wherein E is -CR5aR6aCN, wherein R5a and R6a together with the carbon atom to which they are linked form cyclopropyl.

5. Compound of any of claims 2-4 wherein R1 and R2 are hydrogen and Q is -CO-.

6. Compound of any of claims 2-5 wherein Rla is - (alkylene) -SiR3R33R34, wherein R32 is alkyl, R33 is alkyl, and R34 is alkyl.

7. Compound of any of claims 2-5, wherein Rla is - (alkylene) -SiR32R33R34, wherein R32 and R33 are alkyl, and R34 is aralkyl.

8. Compound of any of claims 2-7, wherein R3 is heterocycloalkyl, aryl or heteroaryl, optionally substituted with one or two Rf.

9. Compound of any of claims 2-7, wherein R3 is morpholin-4-yl, l-ethylpiperazin-4-yl, phenyl optionally substituted with one or two substituents independently selected from halo, alkoxy, alkyl, haloalkoxy, phenyl , alkylsulfonyl, haloalkyl, heteroaryl, cyano, acyl, hydroxyalkyl, or alkoxycarbonyl.

10. Compound selected from the group consisting of:. { 1 (R) - [1 (S) - (benzoxazol-2-ylcarbonyl) -butylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; . { 1 (R) - [1 (S) - (benzoxazol-2-ylcarbonyl) -propylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; . { 1 (R) - [1 (R) - (benzoxazol-2-ylcarbonyl) -propylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; . { 1 (R) - [1 (S) - (benzoxazol-2-ylcarbonyl) -pentyl-carbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; . { 1 (R) - [1 (S) - (5-chlorobenzoxazol-2-ylcarbonyl) -propylcarbamoyl] -2-trimethylsilanylethyl} morpholino-4-carboxylic acid amide; . { 1 (S) - [1 (S) - (Benzoxazol-2-ylcarbonyl) -propylcarbamoyl] -2-trimethylsilanylethyl] -amide of morpholino-4-carboxylic acid; . (1 (R) - [1 (S) - (benzoxazol-2-ylcarbonyl) -butylcarbamoyl] -2-trimethylsilanylethylethyl} morpholino-4-carboxylic acid amide; [1- (1-cyanocyclopropylcarbamoyl) -2 1- (R) -morpholino-4-carboxylic acid (trimethyl-silyl) ethyl] amide; 1- (4-cyano-l-ethylpiperidin-4-ylcarbamoyl) -2-, (trimethyl-silanyl) ethyl] -amide of 1-acid. { R) -morpholino-4-carboxylic acid; 1- (4-cyano-l, l-dioxohexahydro-l6-thiopyran-4-yl-carbamoyl) -2- (trimethylsilanyl) ethyl] amide of 1- (i?) -morpholino-4-carboxylic acid; [1- . { RS) - morpholino-4-carboxylic acid (1-benzyloxymethyl-l-cyanocyclopropyl-carbamoyl) -2-trimethyl-silanylethyl] -amide; [1- . { RS) - [2-benzyloxy-l-cyano-1-methyl-ethylcarbamoyl] -2- (trimethyl-silanylethyl] -morpholino-4-carboxylic acid amide; [1- (RS) - (1-cyanocyclopropylcarbamoyl) -2- 4-ethylpiperazine-l-carboxylic acid trimethyl-silanyl-ethyl] - [3- ({R) - (1-cyano-cyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -3-methoxybiphenyl-3-amide carboxylic; N- [1-. { RS) - (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -3-iodobenzamide [1-. { RS) - (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanyl-ethyl] acid amide 3 'trifluoromethoxybiphenyl-3-carboxylic acid; [1- . { RS) - biphenyl-3-carboxylic acid (1-cyanocyclopropycarbamoyl) -2-trimethylsilanylethyl] -amide; . [1- (iε S) - 2'-6'-dimethoxybiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] amide; [l- (iεS) - (1-cyanocyclopropylcarbamoyl) -2'-Trimethyl-silanylethyl] -amide of 4 '-methylsulfonylbiphenyl-3-carboxylic acid; [1- (RS) - (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide of 2'-chlorobiphenyl-3-carboxylic acid [l- (iS) - (l-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide of 2'-trifluoromethyl-biphenyl-3-carboxylic acid; [1- { RS) -. {1-cyanocyclopropylcarbamoyl) - 3'-Methylbiphenyl-3-carboxylic acid 3-trimethylsilylethyl] -amide; 3-trifluoromethoxybiphenyl-3-carboxylic acid [1- (JRS) - (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; N- [l- (i? S) - (1-cyanocyclopropylcarbamoyl) -2-trimethylsilanylethyl] -3-pyridin-3-ylbenzamide; [1- (2? S) - (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl ] 3'-cyclobiphenyl-3-carboxylic acid amide; [l- (i? S) - (l-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] 3'-Hydroxymethylbiphenyl-3-carboxylic acid amide; . [1- . { RS) - 4'-Hydroxymethylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanyleethyl] -amide; [1- (RS) - (1-Cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] 2-methyl-diphenyl-3-carboxylic acid amide; [I- (iS) - (L-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide of 3 '-methoxycarbonylbiphenyl-3-carboxylic acid; [1- . { RS) - 4'-acetylbiphenyl-3-carboxylic acid (1-cyanocyclopropylcarbamoyl) -2-trimethyl-silanylethyl] -amide; [1- . { RS) - 3'-methoxybiphenyl-3-carboxylic acid (4-cyano-4-tetrahydrothiopyran-4-ylcarbamoyl) -2-trimethyl-silanylethyl] -amide; [1- (RS) - (4-cyano-l, l-dioxohexahydro-l6-thiopyran-4-ylcarbamoyl) -2- (trimethylsilanyl) ethyl] amide of 3'-methoxybiphenyl-3-carboxylic acid; and 1- [3- (benzyldimethylsilanyl) -2R- (2,2,2-trifluoro-1-phenylethylamino) propionyl] -cyclopropanecarbo-nitrile; or a pharmaceutically acceptable salt thereof.

11. Pharmaceutical composition comprising a compound of any of claims 1-10 and a pharmaceutically acceptable excipient.

12. Use of a compound of Formula (I): wherein: Q is -CO-, -S02-, -OCO-, NRCO-, -NRS02, or -CHR- wherein R is haloalkyl and R4 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or aralkyl; E is: (i) -C (R5) (R6) XX where X1 is -CHO, -C (R7) (R8) CF3, C (R7) (R8) CF2CF2R9, -C (R7) (R8) R10, -CH = CHS (O) 2R10, C (R7) (R8) C (R7) (R8) OR10, -C (R7) (R8) CH2OR10, -C (R7) (R8) C (R7) (R8) R10, -C (R7) (R8) CH2N (Ral) S02R10, -C (R7) (R8) CF2C (0) NR10R1: L, C (R7) (R8) C (O) NR10Rn, -C (R7) (R8) C (O) N (R11) (CH2) 2OR11, OR CÍR1) (R?) C (0) N (R) (CH2) 2NR10R; (ii) C (R5a) (R6a) CN; wherein: R5 and R5a are independently hydrogen or alkyl; R6 and R6a are independently selected from 'the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, -alkylene-X2-R12 (where X2 is -O-, NR13 -, -S (0) m_, -CONR13-, NR13CO-, NR13C (0) 0-, -NR13CONR13-, -OCONR13-, NR13S02-, -S02NR13-, -NR13S02NR13-, -CO-, or -OC ( O) -, where neither is 0-2 and each R13 is hydrogen or alkyl) and R12 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl where the aromatic or alicyclic ring in R6 and R6a is optionally substituted with one, two or three R independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl , alkylsulfonyl, or arylsulfonyl where the aromatic ring or acyclic in Ra is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl; or: R5 and R6 and R5a and R6a taken together with the carbon atom to which both of R5 and Re and R5a and R6a are linked form: (i) cycloalkylene optionally substituted with one or two R, independently selected from alkyl, halo , alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl or (ii) heterocycloalkylene optionally substituted with one to four alkyl or one or two Rc, independently selected from alkyl, haloalkyl, hydroxy , hydroxyalkyl, alkoxyalkyl, alcoxialquiloxialquilo, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, -S (0) n2R14, -alkylene-S (O) n2R15, COOR 16, - alkylene-COOR17, -CONR18R19 'or -alkylene-CONR20R21 (where n2 is 0-2, and R14-R17, R18 and R20 are independently hydrogen, alkyl, haloalkyl, ar yl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl or cycloalkylalkyl, or heterocycloalkyl and R19 and Y21 are independently hydrogen or alkyl) where the aromatic or alicyclic ring in the groups attached to cycloalkylene or heterocycloalkylene is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, benzyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, amino. monosubstituted, disubstituted amino, or acyl; R7 is hydrogen or alkyl; R8 is hydroxy; or R7 and R8 together form oxo; R9 is hydrogen, halo, alkyl, aralkyl or heteroaralkyl; R10 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl wherein the aromatic or alicyclic ring in R10 is optionally substituted with one, two, or three Rd independently selected • from alkyl, haloalkyl, alkoxy, alkoxyalkyl, 'cycloalkyl, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, ariisulfonilo, heteroarylsulfonyl, aryl, aralkyl, heteroaryl, amino, monosubstituted amino, disubstituted amino, carbamoyl, or acyl wherein the aromatic or alicyclic ring in R is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, or dialkylamino; and R11 is hydrogen or alkyl; or (iii) a group of formula (a): where: n is 0, 1 or 2; X4 is selected from -NR-, -S-, or -O-, where R22 is hydrogen, alkyl or alkoxy; and X5 is -O-, -S-, -S02- or NR23-, wherein R23 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl , cycloalkylalkyl, S (0) 2R24, -alkylene-S (O) n3-R25, -COOR26, -alkylene-COOR27, -CONR28R29, or -alkylene-CONR30R31 (where n3 is 0-2 and R24-R27, R28 and R30 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl and R29 and -R31 are independently hydrogen or alkyl), wherein the aromatic or alicyclic ring in R23 is optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, and a substituent selected from aryl, aralkyl, heteroaryl, oh eteroaralkyl; and R5 is as defined above; R1 is hydrogen or alkyl; Rla is 1,1-dialkylsilyanane-4-ylalkylene or. - (alkylene) -SiR32R33R34 where R32 is alkyl, R33 is alkyl, and R34 is alkyl, alkenyl, cycloalkylalkyl, aryl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl, or R33 and R34 together with Si form a heterocycloalkylene ring containing the Si and gives 3 to 7 carbon ring atoms, where one or two carbon ring atoms are optionally independently replaced with -NH-, -0-, -S-, -SO-, -S02-, -CO-, -CONH-, or -S02NH- and wherein the aralkyl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylene ring in Rla is optionally substituted in the ring with one, two or three Re independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, acyl, alkylsulfonyl, or arylsulfonyl and furthermore where the aromatic or alicyclic ring in Re is optionally substituted with one or two "-substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl; R2 is hydrogen or alkyl; R3 is alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, or -alkylene-X6-R35 [where X6 is -NR36, -0-, S (0) n4, -CO-, COO- , -OCO-, NR36C0-, CONR36-, -NR36S02-, -S02NR36-, -NR36COO-, -OCONR36, -NR36CONR37, or -NR36S02NR37- (where each R36 and R37 is independently hydrogen, alkyl, or acyl, and n4 is 0-2) and R35 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl] where the alkylene chain in R3 is optionally substituted with one to four halo atoms and the aromatic and alicyclic rings in R3 are optionally substituted by one, two "'or three Rf, independently selected from alkyl, aminoalkyl, halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, acyloxy, aryl aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, hetero cycloalkyl, heterocycloalkylalkyl, aryloxy, benzyloxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, ariisulfonilo, arylsulfinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, aralquila inosulfonilo , aminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, amino, monosubstituted amino or disubstituted amino, and further wherein the aromatic and alicyclic rings in Rf are optionally substituted with one, two or three Rg, where Rg is independently selected from alkyl, halo, haloalkyl, haloalkoxy hydroxy, nitro, cyano, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylthio, alkylsulfonyl, amino, monosubstituted amino, dialkylamino, aryl, heteroaryl, cycloalkyl, carboxy, carboxamido, or alkoxycarbonyl; or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating a disease mediated by cysteine protreases.

13. The use of claim 12, wherein the cysteine protease is cathepsin S.

14. Use of claim 13, wherein the disease is psoriasis, autoimmune disorder, allergic disorder, chronic obstructive pulmonary disease, or cardiovascular disease.

15. Use of a compound of claim 1 in the preparation of a medicament for the treatment of a disease mediated by cathepsin S.