MXPA00004375A - Dipeptide nitriles - Google Patents

Abstract

N-terminal substituted dipeptide nitriles as defined are useful as inhibitors of cysteine cathepsins, e.g. cathepsins B, K, L and S, and can be used for the treatment of cysteine cathepsin dependent diseases and conditions, including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization). Particular dipeptide nitriles are compounds of formula (I), or physiologically-acceptable and -cleavable esters or salts thereof, wherein:the symbols are as defined. In particular it has been found that by appropriate choice of groups R, R2, R3, R4, R5, X1, Y and L, the relative selectivity of the compounds as inhibitors of the various cysteine cathepsin types, e.g. cathepsins B, K, L and S, may be altered, e.g. to obtain inhibitors which selectively inhibit a particular cathepsin type or combination of cathepsin types.

Description

DIPEPTIDE NITRILE This invention relates to inhibitors of cysteinoproteases, in particular to inhibitors of the dipeptide nitrilocatepsin, and to their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsins are involved. Cysteincatepsins, for example, cathepsins B, K, L and S, are a class of lysosomal enzymes that are involved in different disorders, including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including rupture and destabilization of the atherosclerotic plaque), autoimmune diseases, respiratory diseases, infectious diseases, and immunologically mediated diseases (including transplant rejection). In accordance with the invention, it has been discovered that dipeptide nitriles are particularly useful as inhibitors of cysteincatepsin, and can be used for the treatment of the aforementioned cysteincatepsin-dependent conditions. Accordingly, the present invention provides an N-terminally-substituted dipeptide nitrile, ie, a dipeptide wherein the C-terminal carboxyl group of the dipeptide is replaced by a nitrile group (-C = N), and in wherein the N-terminal nitrogen atom is substituted by means of a peptide or pseudopeptide bond, which optionally further comprises a -methylene-heteroatom- linker, or an additional heteroatom, directly by aryl, lower alkyl, lower alkenyl, alkynyl lower or heterocyclyl, or a physiologically acceptable and dissociable ester or a salt thereof, for use as a pharmaceutical. The invention further provides a pharmaceutical composition comprising an N-terminally-substituted dipeptide nitrile as defined above, as an active ingredient. The invention also provides a method for the treatment of a patient suffering from, or susceptible to, a disease or medical condition wherein a cathepsin is involved, which comprises administering an effective amount of an N-terminal dipeptide nitrile. replaced as defined above, to the patient. The invention further includes the use of an N-terminally-substituted dipeptide nitrile as defined above, for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition wherein a cathepsin is involved.

The dipeptide nitrile of the invention conveniently comprises -amino acid residues, including amino acid residues, both natural and non-natural. Here, the "natural amino acid residues" denote the 20 amino acids that can be obtained by translating the RNA according to the genetic code or the corresponding nitriles thereof, as appropriate. "Non-natural amino acid residues" are the -amino acids that have -substituents different from those found in the "natural amino acid residues". The preferred amino acid residues, such as the C-terminal amino acid residue of the dipeptide nitrile, are the nitriles of trifophant, 2-benzyloxymethyl-2-aminoacetic acid, 2,2-dimethyl-2-aminoacetic acid, 2-butyl acid. -2-aminoacetic acid, methionine, leucine, lysine, alanine, phenylalanine, and glycine, and derivatives thereof, for example, as described hereinafter. Preferred amino acid residues as the N-terminal amino acid residue of the dipeptide nitrile are 1-amino-cyclohexanecarboxylic acid, 1-aminocycloheptanecarboxylic acid, phenylalanine, histidine, tryptophan and leucine, and their derivatives, for example, as describe later in the present. The substituent of aryl, lower alkyl, lower alkenyl, lower alkynyl or heterocyclyl (hereinafter referred to as R) is attached to the N-terminal nitrogen atom of the dipeptide via a peptide bond, that is, as R-C (0) -NH-, or by means of a pseudopeptide bond. Suitable pseudopeptide bonds include sulfur instead of oxygen, and sulfur and phosphorus instead of carbon, for example, as RC (S) -NH-, RS (0) -NH-, RS (0) 2-NH- or RP (0) 2-NH, and analogs thereof. Additionally, the peptide or pseudopeptide bond between the R substituent and the N-terminal nitrogen atom may comprise an additional heteroatom, for example, as R-Het-C (O) -NH, or a -methylene-heteroatom linker , for example, as R-Het-CH2-C (0) -NH- or R-CH2-Het-C (O) -NH-, where Het is a heteroatom selected from O, N or S, and pseudopeptide containing alternatives thereof, for example, as defined above. When the bond between the aryl substituent and the N-terminal nitrogen atom comprises a -methylene-heteroatom linker-, the methylene group and the heteroatom may be optionally further substituted, for example, as described hereinafter. The substituent R may be further substituted, for example, by up to 3 substituents selected from halogen, hydroxyl, amino, nitro, optionally substituted alkyl of 1 to 4 carbon atoms (eg, alkyl substituted by hydroxyl, alkyloxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, aryl or heterocyclyl), alkoxy of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, CN, trifluoromethyl, trifluoromethoxy, aryl, for example, phenyl (for example, phenyl substituted by CN, CF3, halogen, 0CH3), aryloxy, for example, phenoxy (for example, phenoxy substituted by CN, CF3, halogen, 0CH3), benzyloxy or a heterocyclic residue. The invention also provides novel dipeptide nitriles. Accordingly, the invention provides a compound of Formula I, or a physiologically acceptable and dissociable ester, or a salt thereof: wherein: R is optionally substituted (aryl, lower alkyl, lower alkenyl, lower alkynyl, or heterocyclyl); R2 and R3 are independently hydrogen, or are optionally substituted [lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl) -lower alkyl]; or R2 and R3 together represent lower alkylene, optionally interrupted by O, S or NR6, to form a ring with the carbon atom to which they are attached, wherein R6 is hydrogen, lower alkyl or arylalkyl; or any of R2 or R3 is linked by lower alkylene to the adjacent nitrogen to form a ring; R4 and R5 are independently H, or are optionally substituted (lower alkyl, arylalkyl), -C (0) 0R7, or -C (0) NR7R8, wherein: R7 is optionally substituted (lower alkyl, aryl, arylalkyl, cycloalkyl, bicycloalkyl or heterocyclyl), and R8 is H, or is optionally substituted (lower alkyl, aryl, arylalkyl, cycloalkyl, bicycloalkyl or heterocyclyl), or R4 and R5 together represent lower alkylene, optionally interrupted by 0, S or NR6, to form a ring with the carbon atom to which they are attached, wherein R6 is hydrogen, lower alkyl, or arylalkyl, or R4 is H or optionally substituted lower alkyl, and Rs is a substituent of the formula -X2- ( Y1) n- (Ar) pQZ, where: Yj. is O, S, SO, S02, N (R6) S02, N-R6, S02NR6, CONR6 or NR6CO; n is zero or one; P is zero or one; X2 is lower alkylene; or when n is zero, X2 is also alkylene of 2 to 7 carbon atoms interrupted by 0, S, SO, S02, NRS, S02NRS, C0NR6 or NR6C0; wherein R6 is hydrogen, lower alkyl or arylalkyl; Ar is arylene; Z is hydroxyl, acyloxy, carboxyl, esterified carboxyl, amidated carboxyl, aminosulfonyl, (lower alkyl or arylalkyl) aminosulfonyl, or (lower alkyl or arylalkyl) sulfonylaminocarbonyl; or Z is tetrazolyl, triazolyl or imidazolyl; Q is a direct bond, lower alkylene, lower YX-alkylene, or alkylene of 2 to 7 carbon atoms interrupted by Y17-X, is -C (0) -, -C (S) -, -S (0) - , -S (0) 2-, -P (0) () R6) -, wherein R6 is as defined above; And it's oxygen or sulfur; L is -Het-, -Het -CH2- or -CH2-Het- optionally substituted, wherein Het is a heteroatom selected from O, N or S, and x is zero or one; and aryl, in the above definitions, represents carbocyclic or heterocyclic aryl, to be used as a pharmaceutical; a pharmaceutical composition comprising a compound of formula I as defined above as an active ingredient; a method for treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin is involved, which comprises administering an effective amount of a compound of formula I to the patient as defined above; and the use of a compound of formula I, as defined above, in the preparation of a medicament for the therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin is involved. The invention also provides novel dipeptide nitriles. According to the invention there is further provided a compound of formula I as defined above. with the understanding that when R is lower alkyl, is not substituted by aryl, one of R4 or R5 is a substituent of the formula -X2- (Yx) n- (Ar) pQZ, with the understanding that when x is 1 , L is -O-, or any of R4 or R5 is a substituent of the formula -X2- (Yx) n- (Ar) pQZ, or R is not an unsubstituted phenyl, with the understanding that when R2 R_ R * H, x is zero, and Xx is -C (0) -, R3 is not H, -CH3 / -CH (CH3) 2, -CH2-CH2- (CH3) 2, -CH2-COOH, or -CH2- COO-CH2-CH3, when R is unsubstituted phenyl, R3 is not H, -CH (CH3) 2, or -CH2-CH2 (CH3) 2, when R is 4-aminophenyl or 4-nitrophenyl, R3 is not H, when R is 3-aminophenyl, 3-nitrophenyl, 2-chloropyridin-4-yl, or vinyl or R, it is not -CH2-CH2-S-CH3, when R is pyridin-3-yl or 2-chloropyridin-4-yl , with the understanding that, when R2 = R3 = R4 = H, x is zero, and Xx is -C (O) -, and R is phenyl, R, is not -CH (CH3) 2, in the understanding of that, when R3 R, H, R5 is CH2-CH2-COOH, x is zero, and Xx is -C (O) -, R2 does not form a heterocyclic ring with the adjacent nitrogen atom, and with the understanding that when R2 = R3 = R4 = Rs = H, x is zero, and Xx is -S02-, R is not 4-methylphenyl. In the formula IR, R2, R3, R4, Rs and L may be further substituted by one or more, for example, up to 3 substituents independently selected from lower alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, -CN, - halogen, -OH, -N02, -NR9RX0, -X3-R7, lower alkyl-X3-R8, lower alkyl substituted by halogen, wherein R7 and R8 are as defined above, X3 is -O-, -S-, -NR8-, -C (O) -, -C (S) -, -S (O) -, - S (0) 2-, -C (0) 0-, -C (S) 0-, - C (0) NR8-, wherein R8 is as defined above, R9 and R10 are independently as defined above for R8, or -X4-R8, where X4 is -C (O) -, -C (S) -, -S (O) -, -S (0) 2-, - C (0) 0-, -C (S) 0-, -C (0) NR6-, where R6 and R7 are as defined previously, or R9 and R10, together with N, form a heteroaryl group, or a saturated or unsaturated heterocycloalkyl group, optionally containing one or more additional heteroatoms selected from O, N or S. The compounds of Formula I exhibit valuable pharmacological properties in mammals, in particular as inhibitors of cysteincatepsin. In accordance with the present invention, it has been discovered that, by appropriate choice of the groups R, R2, R3, R4, R5, Xx, Y and L, the relative selectivity of the compounds as inhibitors of the different types can be altered of cysteinecatepsin, for example, cathepsins B, K, L, and S, for example, to obtain inhibitors that selectively inhibit a particular type of cathepsin, or a combination of cathepsin types. In a first aspect, the invention provides a compound of the Formula II, or a physiologically acceptable and dissociable ester or a salt thereof. wherein: R 20 is optionally substituted (aryl, arylalkyl, lower alkenyl, lower alkynyl, heterocyclyl, or heterocyclylalkyl); R22 is H, or optionally substituted lower alkyl, and R23 is optionally substituted (lower alkyl, lower arylalkyl, or lower cycloalkylalkyl), or R-22 and &23; together with the carbon atom to which they are attached, form a optionally substituted group (cycloalkyl group or heterocycloalkyl group); R24 and R25 are independently H, or are optionally substituted (lower alkyl, or lower aryalkyl), -C (0) OR7, or -C (0) NR7R8, wherein R7 and R8 are as defined above, or R-2 and K-25 together with the carbon atom to which they are attached form an optionally substituted group (cycloalkyl group or heterocycloalkyl group); Xx is as defined above; And it's oxygen or sulfur; L 'is optionally substituted (-Het-CH2- or -CH2- Het-), where Het is a heteroatom selected from O, N or S, and x is 1 or 0, with the understanding that, when x is one, L is -CH2- 0- and Xx is -C (0) -, R20 is not unsubstituted phenyl, on the understanding that, when R22 = R24 = R25 = H, x is zero, and Xx is -C ( 0) -, R23 is not H, -CH3, -CH (CH3) 2, -CH2-CH2- (CH3) 2, -CH2-COOH, or -CH2-C00-CH2-CH3, when R20 is unsubstituted phenyl, R23 is not H, -CH (CH3) 2, or -CH2-CH2 (CH3) 2), when R20 is 4-aminophenyl or 4-nitrophenyl, R23 is not H when R20 is 3-aminophenyl, 3-nitrophenyl, 2 -chloropyridin-4-yl, or vinyl, or R23 is not -CH2-CH2-S-CH3 when R20 is pyridin-3-yl or 2-chloropyridin-4-yl, in the understanding that, when R22 = R23 = R24 = H, x is zero, and Xx is -C (0) - and R20 is phenyl, R25 is not -CH (CH3) 2, with the understanding that, when R23 = R24 = H, R2S is -CH2-CH2 -C00H, x is zero, and Xx is -C (0) -, R22 does not form a heterocyclic ring with the nitro atom adjacent, and with the understanding that, when R22 = R23 = R24 = R25 = H, x is zero, and Xx is -S02-, R20 is not 4-methylphenyl. The compounds of Formula II are normally inhibitors of cathepsins K, L or S, especially selective inhibitors of cathepsin K or cathepsin L or cathepsin S, or in some cases, inhibitors of, for example, cathepsins L and S. Substituents of the compounds of Formula II have the following preferred meanings. Preferred compounds of Formula II comprise compounds having preferred substituents, alone or in any combination. Preferably, when R20 comprises aryl, the aryl is optionally substituted (phenyl, naphthylenyl, phenanthrenyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzothienyl and benzofuranyl). Preferably, R22 is hydrogen. Preferably R23 is optionally substituted (lower alkyl, lower arylalkyl, or lower cycloalkylalkyl), or R23 and R22, together with the carbon atom with which they are attached, form a cycloalkyl group of 5 to 8 carbon atoms, especially of 6 or 7 carbon atoms. More preferably, R23 is -CH2-CH (CH3) 2, or optionally substituted benzyl, cyclohexylmethyl, naphthalenylmethyl, indolylmethyl, benzothienylmethyl or benzofuranylmethyl, or R23 and R22, together with the carbon atom to which they are attached, form a ring of cyclohexane. Preferred meanings for R24 and R25 are: R24 and R25 are both H or -CH3, or R24 is H, and R2S is arylalkyl, lower alkyl, both optionally substituted by up to 3 substituents selected from amino, halogen (e.g. , fluorine, or preferably chlorine), or S-CH 3, or 2 and 25 / together with the carbon atom to which they are attached, form a cycloalkyl ring of 3 to 7 carbon atoms. More preferably, R24 is H and R25 is optionally substituted (-CH2-phenyl, -CH2-indolyl, - (CH2) 2-S-CH3, -CH2-CH (CH3) 2, - (CH2) 4- NH2 or - (CH2) 3-CH3), or even more preferably, R4 and R5 are both -CH3, or especially R4 and Rs are both -CH3, or especially R4 and R5 are both H. Preferably, -Xx- is -CO)-. Preferably Y is = 0. Preferably any x is 0, or when x is 1, L '-CH2-0-, -NH-CH2-, -0-CH2- or -S-CH2.

In particular embodiments, the invention provides a compound of Formula II ', or a physiologically acceptable and dissociable ester or a salt thereof: wherein: R20 'is optionally substituted (aryl of 6 to 18 carbon atoms, or heteroaryl of 4 to 18 carbon atoms); R22 'is H, or optionally substituted alkyl of 1 to 8 carbon atoms, and R23' is optionally substituted (alkyl of 2 to 8 carbon atoms, or aralkyl of 7 to 14 carbon atoms), or R22 'and R23' / together with the carbon atom to which they are attached, form an optionally substituted group (cycloalkyl group of 3 to 8 carbon atoms, or heterocycloalkyl group of 4 to 7 carbon atoms); R, and R25 'are independently H, or are optionally substituted (alkyl of 1 to 8 carbon atoms, aralkyl of 7 to 14 carbon atoms, or heteroaralkyl of 5 to 15 carbon atoms), -C (0) 0Rs' , or -C (0) NR6 'R7', wherein: R6 'is optionally substituted (alkyl of 1 to 8 carbon atoms, aralkyl of 7 to 14 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocycloalkyl of 4 to 7 carbon atoms, heteroaralkyl of 5 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, or heteroaryl of 4 to 14 carbon atoms), and R7 'is H, or is optionally substituted (alkyl of 1 to 4 carbon atoms). to 8 carbon atoms, aralkyl of 7 to 14 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocycloalkyl of 4 to 7 carbon atoms, heteroaralkyl of 5 to 14 carbon atoms, aryl of 6 to 14 carbon atoms , or heteroaryl of 4 to 14 carbon atoms), or R2 'and R25' together with the carbon atom to which they are attached, an optionally substituted group (cycloalkyl group of 3 to 8 carbon atoms, or heterocycloalkyl group of 4 to 7 carbon atoms); Xx is -C (0) -, -C (S) -, -S (O) -, -S (0) 2-, -P (0) (OR6 ') - wherein R6' is as defined above; And it's oxygen or sulfur; L1 is optionally substituted (-Het-CH2- or -CH2-Het-), where Het is a heteroatom selected from O, N or S, and x is 1 or 0, with the understanding that when x is one, L 'is -CH2-0-, and Xj. is -C (O) -, R20 'is not unsubstituted phenyl, with the understanding that when R22' = R24 '= R25' = H, x is zero, and Xx is -C (O) -, R23 'not is H, -CH3, -CH (CH3) 2, -CH2-CH2- (CH3) 2, -CH2-COOH, or -CH2-COO-CH2-CH3, when R20 'is unsubstituted phenyl, R23' is not H , -CH (CH3) 2, or -CH2-CH2- (CH3) 2, when R20 'is 4-aminophenyl or 4-nitrophenyl, R23' is not H, when R20 'is 3-aminophenyl, 3-nitrophenyl, 2-chloropyridin-4-yl, or vinyl, or R23 'is not -CH2-CH2-S-CH3, when R20 'is pyridin-3-yl, or 2-chloropyridin-4-yl, on the understanding that, when R22' = R23 '= R24' = H, x is zero and Xx is -C (O) - and R20 'is phenyl,, is not -CH (CH3): with the understanding that when R23' = R24 '= H, R25' is -CH2-CH2-COOH, x is zero, and Xx is -C (O ) -, R20 'does not form a heterocyclic ring with the adjacent nitrogen atom, and on the understanding that, when R22' = R23 '= R24' = R25 '= H, x is zero, and Xx is -S02-, R20 'is not 4-methylphenyl. The compounds of Formula II1 are typically selective inhibitors of cathepsin K. In a further aspect, the invention provides a compound of Formula III: wherein: R30 is an acyl group derived from an organic, carbonic, carbamic or sulfonic carboxylic acid; R32 and R33 are independently hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl, or bicycloalkyl) -lower alkyl; or R32 and R33 together represent lower alkylene, to form a ring together with the carbon atom to which they are attached; R34 is hydrogen or lower alkyl; X2, Yx, Ar, Q, Z, n and p are as defined above; - and pharmaceutically acceptable salts and esters thereof for use as a pharmaceutical. In preferred embodiments, the invention further provides a compound of formula III as defined above, wherein R 30 is an acyl group derived from an organic carboxylic, carbamic or sulfonic acid. The compounds of Formula III are normally selective inhibitors of cathepsin B and / or L. Particular embodiments refer to compounds of Formula III, wherein R 30, R 32, R 33, R 34, Q, Z and n are as defined above.; and where: (a) p is one; (b) Yx is O, S, SO, S02, N (R6) S02 or N-R6; and (c) X2 is lower alkylene; or when n is zero, X2 is also alkylene of 2 to 7 carbon atoms interrupted by O, SO, S02 or NR6; wherein N6 is as defined above, and pharmaceutically acceptable salts thereof. Other particular embodiments refer to compounds of Formula III wherein: R30, R32, R33, R34, R35, Ar, Z and Q have the meaning defined above; and wherein: (a) p is one, n is zero, and X2 is lower alkylene or alkylene of 2 to 7 carbon atoms interrupted by O, S, SO, S02NR6, NR6S02, S02NR6, CONR6 or NR6CO; or (b) p is one, n is one, X2 is lower alkylene, and Yx is O, S, SO, S02, N (R6) S02 or NR6, S02NR6, CONR6, NR6CO; or (c) p is one, n is zero and X 2 is lower alkylene; or (d) p is one, n is zero and X 2 is alkylene of 2 to 7 carbon atoms interrupted by O, S, SO, S02, or NR6, S02NR6, C0NR6, or NR6C0; or (e) p is zero, n is one, X2 is lower alkylene, and Yx is O, S, SO, S02, N (R6) S02 or NR6, S02NR6, CONR6, or NRsCO; or (f) p is zero, n is zero and X2 is alkylene of 2 to 7 carbon atoms interrupted by O, S, SO, S02 or NR6, S02NR6, C0NR6 or NR6C0; and pharmaceutically acceptable salts thereof. Preferred compounds of Formula III are those wherein Z is carboxyl, or carboxyl derivative as a pharmaceutically acceptable ester. A particular embodiment of the invention relates to the compounds of Formula III, wherein n is zero, in particular those of Formula III ': wherein: R30, X2, Ar, Q, and p are as defined above; and wherein: R33 'is carbocyclic or heterocyclic lower arylalkyl; Z 'is hydroxyl, acyloxy, carboxyl, carboxyl derivative as a pharmaceutically acceptable ester or an amide, or 5-tetrazolyl; and pharmaceutically acceptable salts thereof. In a specific embodiment of the compounds of the Formula III ', R30 is acyl derivative of carboxylic acid; R33 'is carbocyclic or heterocyclic lower arylalkyl; X2 is alkylene of 1 to 5 carbon atoms, or X2 is alkylene of 2 to 4 carbon atoms interrupted by O or S; p is one; Ar is carbocyclic arylene; Q is a direct bond or alkylene of 1 to 4 carbon atoms; and Z is carboxyl or carboxyl derivative as a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof. In a more specific embodiment of the compounds of Formula III 'R30 is aroyl, R33' is carbocyclic arylmethyl; X2 is alkylene of 3 carbon atoms; or X is alkylene of 2 carbon atoms interrupted by O; p is one; Ar is phenylene; Q is a direct link; and Z is carboxyl; and pharmaceutically acceptable salts thereof. A further particular embodiment of the invention relates to compounds of Formula III, wherein n is one, in particular those of Formula III ": where: R3o 33 '/? i Ar, Y z' are as defined above; X2 'is lower alkylene; Q 'is a direct bond or lower alkylene; and pharmaceutically acceptable salts thereof. A specific embodiment of the invention relates to compounds of Formula III ", wherein R 30 is an acyl derivative of carboxylic acid, R 33 'is a carbocyclic or heterocyclic lower alkyl aryl, X 2' is alkylene of 1 to 4 carbon atoms; Y x is O or S: Ar is carbocyclic arylene, Q 'is a direct bond or alkylene of 1 to 4 carbon atoms, and Z' is carboxyl or carboxyl derivative as a pharmaceutically acceptable ester, and pharmaceutically acceptable salts thereof. Specific to the invention relates to compounds of Formula III ", wherein R30 is aroyl, R33 'is carbocyclic arylmethyl; X2 is alkylene of 2 carbon atoms, - Yx is O; Ar is phenylene; Q 'is a direct link; and Z 'is carboxyl, and pharmaceutically acceptable salts thereof. A still further aspect of the invention relates to a compound of Formula IV: wherein: R40 is substituted phenyl or heterocyclic aryl, (mono- or di-carbocyclic or heterocyclic aryl) -lower alkyl or lower alkenyl, or heterocyclyl; R42 is hydrogen or lower alkyl, - R43 is "carbocyclic or heterocyclic" lower arylalkyl; R44 and R4S are independently hydrogen or lower alkyl; or R44 and R5 combined represent lower alkylene; and pharmaceutically acceptable salts and esters thereof. Preferred are compounds of Formula IV, wherein R40 is morpholino, substituted phenyl or heterocyclic aryl; R2 is hydrogen; R43 is carbocyclic or heterocyclic lower arylalkyl; R44 and R45 are hydrogen or lower alkyl; or R44 and R45 combined represent ethylene, to form a cyclopropyl ring. Particularly preferred are the compounds of the Formula IV, wherein R40 is pyrazolyl or pyrazolyl substituted by 1,3-lower alkyl; R42 is hydrogen; R43 is arylalkyl of 1 to 4 carbocyclic or heterocyclic carbon atoms; and R44 and R45 are hydrogen; or R44 and R4S combined are ethylene. The compounds of Formula IV are normally selective inhibitors of cathepsin L and / or S. The compounds of Formulas I, II, III and IV, depending on the nature of the substituents, possess one or more asymmetric carbon atoms. The resulting diastereomers and enantiomers are encompassed by the present invention. However, preferably, for example, for pharmaceutical use according to the invention, the compounds of Formulas I, II, III and IV are provided in a pure or substantially pure epimeric form, for example, compositions wherein the compounds are present in a form comprising at least 90 percent, for example, preferably at least 95 percent of a single epimer (i.e., comprising less than 10 percent, for example, preferably less than 5 percent of other epimeric forms). Preferred compounds of Formula I are those in which the asymmetric carbon atom with which R2 and / or R3 are attached, corresponds to that of an L-amino acid precursor, and the asymmetric carbon atom with which the cyano group also corresponds to that of an L-amino acid, has generally assigned the configuration (S). Preferred compounds of Formula I, wherein R3 and R4 represent hydrogen, may be represented by Formulas V, V and V ", which correspond to the preferred compounds of Formulas II, III and IV, respectively. Particularly preferred embodiments, the invention provides a compound of Formulas V, V or V ": R'2.0 -L'- -X; NH EN V R '3.3 H T R30'-NH-C-CONH-C C = N v' H X-Y? -Ar-0-Z R O '43 H T O NH G CO NH C C = N V "- A H R' 4.5 wherein the symbols are as defined above, and physiologically acceptable and dissociable esters or salts thereof. The compounds of Formulas I, II, II ', III, III', III ", IV, V, V and V" as defined above, are hereinafter referred to as the Compounds of the Invention. The general definitions used herein have the following meaning within the scope of the invention, unless otherwise specified. The term "lower" referred to above and subsequently herein in relation to radicals or organic compounds, respectively, defines those branched or unbranched with up to and including 7, preferably up to and including 4, and conveniently one or two carbon atoms. carbon. A lower alkyl group is branched or unbranched, and contains from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. Lower alkyl represents, for example, methyl, ethyl, propyl, butyl, isopropyl or isobutyl. Lower alkenyl represents straight or branched chain alkenyl of 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms, for example, as vinyl, propenyl, isopropenyl, butenyl, isobutenyl or butadienyl. Lower alkynyl represents straight or branched chain alkynyl of 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms, for example, as acetylenyl, propynyl, isopropynyl, butynyl or isobutynyl. Lower alkyl, lower alkenyl and lower alkynyl can be substituted by up to 3 substituents selected from lower alkoxy, aryl, hydroxyl, halogen, cyano, or trifluoromethyl. Lower alkylene represents straight or branched chain alkylene of 1 to 7 carbon atoms, and preferably represents straight chain alkylene of 1 to 4 carbon atoms, for example, a methylene, ethylene, propylene or butylene chain, or that chain of methylene, ethylene, propylene or butylene mono-substituted by alkyl of 1 to 3 carbon atoms (conveniently methyl), or di-substituted on the same or different carbon atoms by alkyl of 1 to 3 carbon atoms (conveniently methyl) , the total number of carbon atoms up to and including 7. A lower alkoxy group (or alkyloxy) preferably contains from 1 to 4 carbon atoms, conveniently from 1 to 3 carbon atoms, and represents, for example, ethoxy, propoxyl, isopropoxyl, or more conveniently methoxy. Halogen (halo) preferably represents chlorine or fluorine, but can also be bromine or iodine. An acyl group, as represented by R30, is preferably derived from an organic carbonic acid, an organic carboxylic acid, a carbamic acid or an organic sulfonic acid. Acyl deriving from a carboxylic acid represents, for example, carbocyclic or heterocyclic aroyl, cycloalkylcarbonyl, (oxa or thia) -cycloalkylcarbonyl, lower alkanoyl, (lower alkoxy, hydroxyl or acyloxy) -low alkanoyl, (lower alkanoyl, or lower alkanoyl substituted by lower alkoxy, hydroxy or acyloxy) - (mono- or di-carbocyclic or heterocyclic), or biaroyl. Carbocyclic aroyl represents, for example, benzoyl, substituted benzoyl, by one to three substituents independently selected from, for example, halogen, trifluoromethyl, lower alkyl, lower alkoxy, hydroxyl, methylenedioxyl, nitro, lower-dialkylamino, cyano, or carbocyclic aroyl represents, for example, 1- or 2-naphthol. A heterocyclic heteroaryl represents, for example, 2-, 3-or 4-pyridylcarbonyl (such as nicotinoyl), furoyl, thienoyl, oxazoloyl, isoxazoloyl, quinoxaloyl, each optionally substituted, for example, by halogen, lower alkyl, lower alkoxy or nitro . (Oxa or tia) -cycloalkylcarbonyl is, for example, tetrahydrofuranoyl or tetrahydrothienoyl. Diaryl (carbocyclic or heterocyclic) -lower alkanoyl is, for example, diphenylacetyl or dipyridylacetyl. Lower arylalkanoyl (substituted by lower alkoxy, hydroxy or acyloxy) is, for example, phenyl- (2-alkoxy-hydroxy or acyloxy) -acetyl. Biaroyl is, for example, 2-, 3- or 4-biphenylcarbonyl. Acyl derived from an organic carbonic acid is, for example, alkoxycarbonyl, especially lower alkoxycarbonyl, which is unsubstituted or substituted by carbocyclic or heterocyclic aryl, or is cycloalkoxycarbonyl, especially cycloalkyloxycarbonyl of 3 to 7 carbon atoms, which is unsubstituted or substituted by lower alkyl. Acyl derived from a carbamic acid is, for example, aminocarbonyl which is optionally substituted on the nitrogen by one or two of lower alkyl, carbocyclic or heterocyclic lower arylalkyl, carbocyclic aryl or heterocyclic, or by lower alkylene, or lower alkylene interrupted by O or S Acyl deriving from an organic sulphonic acid represents, for example, lower alkylsulfonyl, lower sulfonyl, carbocyclic or heterocyclic arylsulfonyl, carbocyclic aryl or heterocyclic alkylsulfonyl lower sulfonyl, wherein aryl is, for example, phenyl, naphthyl or thienyl, being optionally substituted, for example, by lower alkyl, lower alkoxy, halogen, nitro, trifluoromethyl, carboxyl or lower alkoxycarbonyl. Aryl represents carbocyclic or heterocyclic aryl. Carbocyclic aryl represents monocyclic, bicyclic or tricyclic aryl, for example, phenyl or phenyl mono-, di- or tri-substituted by one, two or three radicals selected from lower alkyl, lower alkoxy, aryl, hydroxyl, halogen, cyano, trifluoromethyl, lower alkylenedioxy, and oxyalkylene of 2 to 3 carbon atoms; or 1- or 2 -naphthyl; or 1- or 2-phenanthrenyl. Lower alkylenedioxyl is a divalent substituent attached to two adjacent carbon atoms of phenyl, for example, methylenedioxyl or ethylenedioxyl. Oxyalkylene of 2 to 3 carbon atoms is also a divalent substituent attached to two adjacent carbon atoms of phenyl, for example, oxyethylene or oxypropylene.

An example for oxyalkylenephenyl of 2 to 3 carbon atoms is 2,3-dihydrobenzofuran-5-yl. As the carbocyclic aryl is preferred naphthyl, phenyl or phenyl monosubstituted by lower alkoxy, phenyl, halogen, lower alkyl, or trifluoromethyl, especially phenyl, or phenyl monosubstituted by lower alkoxy, halogen or trifluoromethyl, and in particular phenyl. Examples of substituted phenyl groups as R are, for example, 4-chlorophen-1-yl, 3,4-dichlorophen-1-yl, 4-methoxyphen-1-yl, 4-methylphen-1-yl, 4- aminomethylphen-1-yl, 4-methoxyethylaminomethylphen-1-yl, 4-hydroxyethylaminomethylphen-1-yl, 4-hydroxyethyl- (methyl) -aminomethylphen-1-yl, 3-aminomethylphen-1-yl, 4-N-acetylaminomethylphen- l -yl, 4-aminophen-1-yl, 3-aminophen-1-yl, 2-aminophen-1-yl, 4-phenyl-1-yl, 4- (imidazol-1-yl) -phenyl- 1-yl, 4- (imidazol-1-ylmethyl) -phen-1-yl, 4- (morpholin-1-yl) -phen-1-yl, 4- (morpholin-1-ylmethyl) -phen-1- ilo, 4- (2-methoxyethylamino-methyl) -phen-1-yl and 4- (pyrrolidin-1-ylmethyl) -phen-1-yl, 4- (2-thiophenyl) -phen-1-yl, 4- (3-thiophenyl) -phen-1-yl, 4- (4-methylpipera-zen-1-yl) -phen-1-yl, and 4- (piperidinyl) -phenyl, and 4- (pyridinyl) -phenyl optionally substituted in the heterocyclic ring. Heterocyclic aryl represents monocyclic or bicyclic heteroaryl, for example, pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any substituted radical, especially mono- or di-substituted, for example, by lower alkyl, nitro, or halogen. Pyridyl represents 2-, 3- or 4-pyridyl, conveniently 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl. Quinolinyl preferably represents 2-, 3- or 4-quinolinyl. Isoquinolinyl preferably represents 1-, 3- or 4-isoquinolinyl. Benzopyranyl, benzothiopyranyl are preferably 3-benzopyranyl or 3-benzothiopyranyl, respectively. Thiazolyl preferably represents 2- or 4-thiazolyl, suitably 4-thiazolyl. Triazolyl is preferably 1-, 2- or 5- (1, 2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl. Preferably, heterocyclic aryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any substituted radical, especially mono- or di-substituted, by lower alkyl or halogen; and in particular pyridyl.

Arylene (Ar in Formula III) is an aryl linking group, wherein aryl is heterocyclic or carbocyclic aryl, preferably monocyclic as defined above. A heterocyclic aryl linking group is, for example, (but not limited to), 1,3-pyrazolyl, 2,4- or 2,5-pyridyl, or 1,4-imidazolyl, wherein the groups illustrated in Formula III are attached to the ring in the indicated positions. A carbocyclic aryl linking group is, for example, (but is not limited to), optionally substituted phenyl, wherein the two groups illustrated in Formula I are ortho, meta or para-linked. Biaryl can be carbocyclic biaryl, preferably, for example, biphenyl, ie 2-, 3- or 4-biphenyl, conveniently 4-biphenyl, each optionally substituted, for example, by lower alkyl, lower alkoxy, halogen, trifluoromethyl or cyano, or carbocyclic heterocyclic biaryl, preferably, for example, thienylphenyl, pyrrolylphenyl and pyrazolylphenyl. Cycloalkyl represents a saturated cyclic hydrocarbon optionally substituted by lower alkyl containing from 3 to 10 carbon atoms of the ring, and is conveniently cyclopentyl, cyclohexyl, cycloheptyl or cyclo-octyl optionally substituted by lower alkyl.

Bicycloalkyl is, for example, norbornyl. Heterocyclyl represents a saturated cyclic hydrocarbon containing one or more, preferably 1 or 2, heteroatoms selected from O, N or S, and from 3 to 10, preferably from 5 to 8 ring atoms; for example, tetrahydro-furanyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholino. Lower arylalkyl preferably represents (carbocyclic aryl or heterocyclic aryl) -lower alkyl. Carbocyclic aryl-lower alkyl preferably represents straight or branched chain 1 to 4 carbon arylalkyl, wherein carbocyclic aryl has the meaning defined above, for example, benzyl or phenyl- (ethyl, propyl or butyl), each unsubstituted or substituted on the phenyl ring as defined under carbocyclic aryl above, conveniently optionally substituted benzyl, for example, substituted benzyl, or phenylalkyl lower. Heterocyclic-lower alkyl aryl preferably represents arylalkyl of 1 to 4 straight-chain or branched heterocyclic carbon atoms, wherein heterocyclic aryl has the meaning defined above, for example 2-, 3- or 4-pyridylmethyl, or (2- , 3- or 4-pyridyl) - (ethyl, propyl or butyl); or 2- or 3-thienylmethyl, or (2- or 3-thienyl) - (ethyl, propyl or butyl); 2-, 3- or 4-quinolinylmethyl, or (2-, 3- or 4-quinolinyl) - (ethyl, propyl or butyl); or 2- or 4-thiazolylmethyl, or (2- or 4-thiazolyl) - (ethyl, propyl or butyl). Lower cycloalkylalkyl represents, for example (cyclopentyl or cyclohexyl) - (methyl or ethyl). Biarylalkyl lower represents, for example, 4-biphenylyl- (methyl or ethyl). Acyl, as in acyloxy, is derived from an organic carboxylic acid, a carbonic acid, or a carbamic acid. Acyl represents, for example, lower alkanoyl, carbocyclic aryl-lower alkanoyl, lower alkoxy-carbonyl, aroyl, lower dialkyl-aminocarbonyl, or lower dialkyl-lower aminoalkanoyl. Preferably, acyl is lower alkanoyl. Lower alkanoyl represents, for example, alkanoyl of 1 to 7 carbon atoms, including formyl, and is preferably alkanoyl of 2 to 4 carbon atoms, such as acetyl or propionyl. Aroyl represents, for example, benzoyl. or benzoyl mono- or di-substituted by one or two radicals selected from lower alkyl, lower alkoxy, halogen, cyano and trifluoromethyl; or 1- or 2-naphthoyl; and also, for example, pyridylcarbonyl. Lower alkoxycarbonyl-carbonyl preferably represents alkoxycarbonyl of 1 to 4 carbon atoms, for example, ethoxycarbonyl. Esterified carboxy is carboxyl derivative as a pharmaceutically acceptable ester, for example, lower alkoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl. Amidocarboxyl is carboxyl derivative as a pharmaceutically acceptable amide, for example, aminocarbonyl, mono- or di-alkylaminocarbonyl lower. The pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, ie, cationic salts, such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as salts of ammonium, such as ammonium, trimethyl ammonium, diethyl ammonium, and tris- (hydroxymethyl) -methyl ammonium salts. In a similar manner, acid addition salts, such as mineral acids, organic carboxylic acids and organic sulphonic acids are also possible, for example, hydrochloric acid, methanesulfonic acid, maleic acid, in the understanding that a basic group, such as pyridyl, is part of the structure. The compounds of the invention exhibit valuable pharmacological properties in mammals, and are particularly useful as inhibitors of cysteincatepsin. The inhibitory effects of cathepsin of the compound of the invention can be determined in vi tro, by measuring the inhibition, for example, of the recombinant human cathepsins B, K, L and S. The regulator used in the cathepsin B, L and S assays , is a 0.1 M phosphate regulator, with a pH of 5.8, which contains EDTA (1.33 mM), DTT (2.7 mM) and Brij (0.03 percent). The in vi tro tests are carried out as follows: (a) For cathepsin B: To a microtiter well, 100 microliters of a 20 M solution of the inhibitor is added to the assay regulator, followed by 50 microliters of a 6.4 mM solution of Z-Arg-Arg-AMC substrate (Peptides International) in the assay regulator. After mixing, 50 microliters of a 0.544 nM solution of recombinant human cathepsin B is added to the assay buffer in the well, yielding a final inhibitor concentration of 10 M. The enzyme activity is determined by measuring the fluorescence of the aminomethylcoumarin released at 440 nM. , using a 380 nM excitation, at 20 minutes. The percentage of enzymatic inhibition is determined by a comparison of this activity with that of a solution containing no inhibitor. The compounds are subsequently subjected to a dose response curve analysis to determine the IC 50 values. (b) For cathepsin K: In assay, it is carried out in 96-well microtiter plates at room temperature, using recombinant human cathepsin K. Inhibition of cathepsin K is tested at a constant concentration of enzyme (0.16 nM) and substrate (54 mM Z-Phe-Arg-MCA - Peptide Institute Inc. Osaka, Japan) in 100 mM sodium phosphate buffer, pH of 7.0, containing 2 mM dithioerythritol, 20 mM Tween 80, and 1 mM EDTA. Cathepsin K is pre-incubated with the inhibitors for 30 minutes, and the reaction is initiated by the addition of the substrate. After 30 minutes of incubation, the reaction is stopped by the addition of E-64 (2 mM), and the fluorescence intensity is read on a multi-well plate reader at the excitation and emission wavelengths of 360 and 460 nanometers, respectively. (c) For cathepsin L: Recombinant human cathepsin L is activated before being used in this assay: To 500 microliters of a 510 nM solution of cathepsin L in a 50 mM acetate buffer, pH 5.0, containing 1 mM EDTA, DTT 3 mM, and 150 mM NaCl, add 10 microliters of a 625 M solution of dextran sulfate (average molecular weight = 8000), and the resulting solution is incubated on ice for 30 minutes. Then 4 microliters of this solution is diluted in 46 microliters of assay buffer, yielding a 40 nM enzyme solution.

To perform the assay, 100 microliters of a 20 M solution of inhibitor in assay buffer is added to the microtiter well. Then 50 microliters of a 20 M solution of Z-Phe-ARg-AMC (Peptides International) are added. After mixing, 50 microliters of the activated 40 nM solution of recombinant human cathepsin L is then added to the well, yielding a final inhibitor concentration of 10 M. The enzyme activity is determined by measuring the fluorescence of the aminomethylcoumarin released at 440 nM, using an excitation of 380 nM of 20 minutes. The percentage of enzymatic inhibition is determined by a comparison of this activity with that of a solution containing no inhibitor. The compounds are subsequently subjected to a dose response curve analysis to determine the IC 50 values. (d) For cathepsin S: To a microtiter well, 100 microliters of a 20 M solution of inhibitor is added to the assay regulator. Then 50 microliters of a 700 M solution of Z-Val-Val-Arg-AMC substrate (Peptides International) is added. After mixing, 50 microliters of a 5.2 nM solution of recombinant human cathepsin S in assay buffer is then added to the well, yielding a final inhibitor concentration of 10 M. Enzyme activity is determined by measuring the fluorescence of the aminomethylcoumarin released at 440 nM, using an excitation of 380 nM for 200 minutes. The percentage of enzymatic inhibition is determined by a comparison of this activity with that of a solution containing no inhibitor. The compounds are subsequently subjected to a dose response curve analysis to determine the IC 50 values.

In view of their activity as inhibitors of cysteine cathepsin enzymes, the Compounds of the Invention are particularly useful in mammals as agents for the treatment and prophylaxis of diseases and medical conditions involving high levels of cathepsins. These diseases include diseases that involve infection by organisms, such as Pneumocystis carinii, Trypsanoma cruzi, Trypsanoma brucei, Cri thidia fusiculata, as well as parasitic diseases, such as schistosomiasis and malaria, tumors (tumor invasion and tumor metastasis), and other diseases, such as metachromatic leukodystrophy, muscular dystrophy, amyotrophy and similar diseases. Cathepsins, in particular K, have been implicated in diseases of excessive bone loss, and therefore, the Compounds of the Invention can be used for the treatment and prophylaxis of these diseases, including osteoporosis, gingival diseases, such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, for example, tumor-induced hypercalcemia and metabolic bone disease. Also, the Compounds of the Invention can be used for the treatment or prophylaxis of diseases of excessive cartilage or matrix degradation, including osteoarthritis and rheumatoid arthritis, as well as certain neoplastic diseases that involve the expression of high levels of proteolytic enzymes and degradation. of matrix. The Compounds of the Invention are also indicated to prevent or treat coronary artery disease, atherosclerosis (including rupture and destabilization of atherosclerotic plaque), autoimmune diseases, respiratory diseases, and immunologically mediated diseases (including transplant rejection). The Compounds of the Invention, in particular the selective cathepsin K inhibitor compounds, are particularly indicated for preventing or treating osteoporosis of different genesis (eg, juvenile, menopausal, post-menopausal, post-traumatic, caused by aging or by therapy with corticosteroids, or inactivity). The beneficial effects are evaluated in pharmacological tests in vi tro and in vivo, generally known in the art, and as illustrated herein. The aforementioned properties can be demonstrated in in vi tro and in vivo tests, conveniently using mammals, for example rats, mice, dogs or isolated organs and tissues, as well as enzymatic preparations of mammals, either natural or prepared by, for example , recombinant technology. The Compounds of the Invention may be applied in the form of solutions, for example, preferably aqueous solutions or suspensions, and in vivo, either enterally or parenterally, in an orally convenient manner, for example, as a suspension or in an aqueous solution, or as a solid capsule formulation. The in vi tro dosage can be of concentrations between approximately 10"5 molar and 10" 9 molar. The in vivo dosage may be, depending on the route of administration, between about 0.1 and 100 milligrams / kilogram. The anti-arthritic efficacy of the compounds of the invention for the treatment of rheumatoid arthritis can be determined using models such as, or similar to, the adjuvant arthritis rat model, as described above (RE Esser, et al., J. Rheumatology , 1993, 20, 1176). The efficacy of the compounds of the invention for the treatment of West Osteoarthritis can be determined using models such as, or similar to, the rabbit partial lateral meniscectomy model, as described previously (Colombo et al., Arth. Rheum. 26, 875-886). The efficacy of the compounds in the model can be quantified using histological rating methods, as described previously (O'Byrne et al., Inflamm Res 1995, 44, S117-S118). The efficacy of the compounds of the invention for the treatment of osteoporosis can be determined using an animal model, such as the ovariectomized rat, or other similar species where the test compounds are administered to the animal, and the presence of markers is measured of bone resorption in urine or serum (e.g., as described in Osteoporos Int (1997) 7: 539-543). The compounds of the invention are prepared by: (a) converting an amide of Formula VI: R. X.-NH-CC-CONH-C-CONH, R, Rc VI wherein R, R2, R3, R4 and Rs have the previously defined meaning for the compounds of Formula I, in a nitrile of Formula I; or condensing a compound of Formula VII: R < NH2-C-C: N Vil R? wherein R 4 and R 5 have the meaning defined hereinbefore, with an acid of Formula VIII: wherein R, R2 and R3 have the meaning defined above; or with a reactive derivative thereof; or (c) condensing a compound of the Formula la: R, R, H2N-C-CONH-C-CE = N (the) wherein R2, R3, R4 and R5 have the meaning defined hereinbefore, with an acid corresponding to the group R- [L] X-XX-, or with a reactive derivative thereof; and in the above processes, if required, temporarily protect any reactive groups that interfere, and then isolate the resulting compound of the invention; and if desired, converting any resulting compound to another compound of the invention; and / or if desired, converting a resulting compound into a salt, or a salt resulting in the free acid or base, or in another salt.

Appropriate protecting groups are used for the starting compounds and the intermediates, for example, as described hereinafter, in the Examples. The conversion of primary amides of Formula V to the nitriles of Formula I, according to process (a), can be carried out according to methods well known in the art for the dehydration of a primary amide in a nitrile, for example, with thionyl chloride in the presence of a base. A preferred process involves treatment with oxalyl chloride and pyridine in dimethylformamide, at or below room temperature, as illustrated in the examples. The starting materials of Formula VI can be prepared by the condensation of an amino acid amide of Formula IX: R. IX NH2-C-CONH2 R. wherein R4 and Rs have the meaning defined above, with an acid of Formula VIII, in a protected form, as appropriate. The condensation can be carried out according to methods well known in the art, for example, by the reaction of a mixed anhydride or an acyl halide of the acid of Formula VIII, for example, the acid chloride, with an amide of amino acid of Formula IX, in an inert solvent, such as methylene chloride, in the presence of a base, such as an amine such as triethylamine or pyridine. The acylation of an acid of Formula VIII with an amino acid amide of Formula IX can also be carried out in the presence of a condensing agent, such as N- (3-dimethylaminopropyl) -N'-ethyl-carbodiimide, optionally in the presence of, for example, hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole, and a base, such as N-methylmorpholine. The amino acid amides of Formula IX are known or can be prepared according to the methodology known in the art, and illustrated herein. Alternative procedures and conditions can be used; for example, as described in the Examples. The compounds of the invention are obtained in the free form, or as a salt thereof, if salt-forming groups are present. The acidic compounds of the invention can be converted into metal salts with pharmaceutically acceptable bases, for example, an aqueous alkali metal hydroxide, conveniently in the presence of an etheric or alcoholic solvent, such as lower alkanol. The resulting salts can be converted into the free compounds by their treatment with acids. These or other salts can also be used for the purification of the obtained compounds. The ammonium salts are obtained by reaction with the appropriate amine, for example, diethylamine, and the like. Compounds of the Invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example, sulfuric acid, a phosphoric or halohydric acid, or with organic carboxylic acids, such as alkanocarboxylic acids (of 1 to 4 carbon atoms), which, for example, they are unsubstituted or substituted by halogen, for example, ac acid, such as saturated or unsaturated dicarboxylic acids, for example, oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example, glycolic, lactic, malic acid , tartaric, or citric, such as amino acids, for example, aspartic or glutamic acid, or with organic sulfonic acids, such as alkylsulfonic acids (of 1 to 4 carbon atoms) (for example, methanesulfonic acid), or arylsulfonic acids, which they are unsubstituted or substituted (for example, by halogen). Preferred are salts formed with hydrochloric acid, methanesulfonic acid, and maleic acid. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred in this context, a corresponding salt is also intended, provided it is possible or appropriate according to the circumstances. The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The pharmaceutical compositions according to the invention are those suitable for enteral administration, such as oral or rectal, transdermal, local, and parenteral, to mammals, including man, to inhibit the activity of cathepsin, and for the treatment of dependent disorders. of cathepsin, in particular inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis, and comprise an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers. More particularly, the pharmaceutical compositions comprise an effective cathepsin inhibiting amount of a compound of the invention. The pharmaceutically active Compounds of the Invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof, as a whole or in admixture with excipients or vehicles suitable for enteral or parenteral application. Preferred are gelatin capsules and tablets comprising the active ingredient together with: a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt, and / or polyethylene glycol; for tablets also c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired d) disintegrants, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbers, colorants, flavors and sweeteners. The injectable compositions are preferably aqueous isotonic solutions or suspensions, and the suppositories are conveniently prepared from emulsions or fat suspensions. These compositions can be sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating the osmotic pressure, and / or pH regulators. In addition, they may also contain other therapeutically valuable substances. These compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain from about 0.1 to 75 percent, preferably from about 1 to 50 percent, of the active ingredient. The tablets may be film coated or enteric coated according to methods known in the art. Formulations suitable for transdermal application include an effective amount of a compound of the invention with a carrier. Convenient carriers include pharmacologically acceptable absorbable solvents to assist passage through the skin of the host. For example, the transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with vehicles, optionally a speed control barrier for applying the compound of the host skin at a controlled rate and previously determined for a prolonged period of time, and elements to secure the device to the skin. Transdermal matrix formulations can also be used. Formulations suitable for local application, for example, to the skin and to the eyes, are preferably aqueous solutions, ointments, creams or gels well known in the art. These may contain solubilizers, stabilizers, tonicity improving agents, pH regulators and preservatives. The pharmaceutical formulations contain an effective cathepsin inhibiting amount of a Compound of the Invention as defined above, either alone or in combination with another therapeutic agent. In conjunction with another active ingredient, a Compound of the Invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration, or together in the same pharmaceutical formulation. The dosage of the active compound administered depends on the species of warm-blooded animal (mammal), the body weight, the age and the individual condition, and the manner of administration. A unit dosage for oral administration to a mammal of about 50 to 70 kilograms may contain between about 5 and 500 milligrams of the active ingredient. The present invention also relates to methods for using the Compounds of the Invention and their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in mammals, to inhibit cathepsins, such as cathepsin B, K, L and / or S, and the treatment of cathepsin-dependent conditions, such as cathepsin B, K, L and / or S dependent conditions, described herein, eg, inflammation, osteoporosis, rheumatoid arthritis, and osteoarthritis. In a particular manner, the present invention relates to a method for selectively inhibiting cathepsin activity in a mammal, which comprises administering to a mammal in need, an effective cathepsin inhibiting amount of a Compound of the Invention. More specifically, it relates to a method for the treatment of rheumatoid arthritis, osteoarthritis, and inflammation (and other diseases identified above) in mammals, which comprises administering to a mammal in need, a correspondingly effective amount of a Compound of the invention. The following examples are intended to illustrate the invention, and should not be construed as limitations thereon. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are carried out under reduced pressure, preferably between about 15 and 100 mm Hg (= 20-133 mbar). The structure of the final products, intermediates, and starting materials are confirmed by conventional analytical methods, for example, microanalysis and spectroscopic characteristics (e.g., MS, IR, NMR). The abbreviations used are those conventional in the art.

EXAMPLES Example 1: Preparation of Indol-4-yl-C (O) -Leu-Gly (CN) of Formula X F oc-Leu-Gly (CN) 9.H. [1- (Cyanomethyl-carbamoyl) -3-methyl-butyl] -carbamic acid-fluoren-9-yl ester. Fmoc-Leucine (0.27 mmol) and aminoacetonitrile hydrochloride (32.4 mmol) are dissolved in dimethylformamide (300 milliliters), and they are cooled with ice-salt. HOBt (32.4 mmol) and WSCD (32.4 mmol) are added, and the reaction mixture is stirred at 4-25 ° C overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with saturated sodium bicarbonate, 1N hydrochloric acid and brine, dried over magnesium sulfate, and the solvent is evaporated. Chromatography on silica gel using normal hexane / ethyl acetate = 1 / L (volume / volume) gives the product in 90 percent yield. P.f. 173-175 ° C, Rf = 0.68 (chloroform: methanol: acetic acid = 90: 10: 1).

B. H-Leu-Gly (CN) 2-amino-4-methyl-pentanoic acid cyanomethylamide Fmoc-Leu-Gly (CN) (18 mmol) is dissolved in 20 percent piperidine in dimethylformamide (36 milliliters). The reaction mixture is stirred at room temperature for 60 minutes. After evaporation of the solvent, and chromatography on silica gel using normal hexane, normal hexane / ethyl acetate = 1/1, and 10 percent methanol in chloroform, the product is obtained in 93 percent yield . Oil, Rf = 0.73 (normal propanol: water: ethyl acetate: ammonia = 5: 1: 2: 1).

C. Indol-5-yl-C (0) -Leu-Gly (CN) Indole-5-ylcarboxylic acid (1.0 equivalent) and H-Leu-Gly (CN) (1.2 equivalents) are dissolved in dimethylformamide, and cooled with ice-salt. HOBt (1.2 equivalents) and WSCD (1.2 equivalents) are added, and the reaction mixture is stirred at 4-25 ° C overnight. After ethyl acetate is added to the reaction mixture, the organic layer is washed with saturated sodium bicarbonate, 1N hydrochloric acid, and brine, dried over magnesium sulfate, and evaporated. Chromatography on silica gel gives the title product in a 70 percent yield. P.f. 201-204 ° C, Rf = 0.39 (normal hexane: AcOEt = 1: 2).

Example 2: 5-Amino-quinoline-2-carboxylic acid [1- (cyanomethyl-carbamoyl) -3-methylbutyl] -amide 5-Nitro-quinoline [1- (cyanomethyl-carbamoyl) -3-methylbutyl] -amide -2-carboxylic acid (0.35 mmol) is dissolved in tetrahydrofuran (10 milliliters) and methanol (10 milliliters) at room temperature. Aqueous Na2SO4 * (7 mmol) is added to the solution, and the reaction mixture is refluxed for 90 minutes. The crude product is isolated by filtration, and purified by chromatography on silica gel using 2 percent methanol in chloroform. The product is obtained in a yield of 33 percent. P.f. 190-194 ° C, Rf = 0.60 (normal hexane: ethyl acetate = 1.5). *ACE. Kende et al., Tetrahedron Lett., 25, 923-926, (1984).

Example 3: p-Acetamidomethylbenzo l-Leu-Gly (CN) p-aminomethylbenzoyl-Leu-Gl (CN) is dissolved (see Example 14 below) (0.33 millimoles) and acetic acid (3.3 millimoles) in dimethylformamide (10 milliliters), and cooled in an ice bath. HOBt (0.4 mmol) and WSCD are added (0.4 mmol), and the reaction mixture is stirred at 4-25 ° C overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with saturated sodium bicarbonate, 1N hydrochloric acid, and brine, dried over magnesium sulfate and evaporated. Diethyl ether is added to the residue to give a precipitate, which is collected by filtration, and again precipitated from ethyl acetate with diethylether to give the product in 32 percent yield. P.f. 176-184.5 ° C, Rf = 0.24 (chloroform: methanol = 9: 1).

By repeating the procedures described in the preceding Examples, using appropriate starting materials and conditions, the following compounds of Formula XI are obtained, as identified in Table 1 below.

Table 1 Example 31:. { l- [(cyano-dimethyl-methyl) -carbamoyl] cyclohexyl amide of indole-2-carboxylic acid A. Fmoc-1-aminocyclohexanecarboxylic acid The title compound is prepared from 1-cyclohexanecarboxylic acid (7 mmol), Fmoc-CI (7.7 mmol) and NaOH (14 mmol) in the usual manner in 18 percent yield . Rf = 0.17 (normal hexane: ethyl acetate = 1: 2).

B. Boc-2-aminoisobutylene acid amide 28% aqueous ammonia (66 mmol) is added to the mixed anhydride (prepared from 22 millimoles of Boc-2-aminobutyric acid and 22 millimoles of isobutyl chloroformate) customary procedures), at -20 ° C. The reaction mixture is stirred at 4-25 ° C overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with saturated sodium bicarbonate, 1N hydrochloric acid and brine, dried over magnesium sulfate, and evaporated. The crude product is purified by chromatography on silica gel using normal hexane / ethyl acetate = 1/1, and normal hexane / ethyl acetate = 1/2, to give the product in a 31 percent yield. P.f. 168-177.5 ° C, Rf = 0.41 (chloroform: methanol = 9: 1).

C. 2-aminobutyric acid amide hydrochloride Boc-2-aminoisobutyric acid amide is dissolved in 4N hydrochloride in dioxane. The reaction mixture is stirred at room temperature for 60 minutes. Diethyl ether is added to the solution to give a white precipitate, which is collected in a 91 percent yield by filtration. The crude product is used for the next coupling without further purification. Rf = 0.28 (n-PrOH: H20: ethyl acetate: NH3 = 5: 1: 2: 1).

Fmoc-1-amino-cyclohexanecarboxylic acid (1-carbamoyl-l-methyl-ethyl) amide Fmoc-1-aminocyclohexanecarboxylic acid (2.2 mmol) and 2-aminobutyric acid amide hydrochloride (2.2 mmol) in dimethylformamide are dissolved. (30 milliliters), and cooled with ice-salt. HOBt (2.6 mmol) and WSCD (2.6 mmol) are added, and the reaction mixture is stirred at 4-25 ° C overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with saturated sodium bicarbonate, 1N hydrochloric acid, and brine, dried over magnesium sulfate, and evaporated. The crude product is purified by chromatography on silica gel using normal hexane / ethyl acetate = 1/4, and normal hexane / ethyl acetate = 1/6, to give the product in a quantitative yield. P.f. 177.5-178.5 ° C, Rf = 0.24 (normal hexane: ethyl acetate = 1: 5).

E. (Cmo-dimethyl-methyl) amide of Fmoc-1-amino-cyclohexanecarboxylic acid Thionyl chloride (2.6 mmol) is added to the solution of Fmoc-1- (1-carbamoyl-1-methyl-ethyl) amide amino-cyclohexanecarboxylic acid (0.86 mmol) in dimethylformamide (10 milliliters) at 4 ° C. The reaction mixture is stirred at 4 ° C for 2 hours, ethyl acetate and a saturated solution of sodium bicarbonate are added, and the organic layer is washed with brine, dried over magnesium sulfate, and evaporated. The crude product is purified by chromatography on silica gel using normal hexane / ethyl acetate = 3/1, to give the product in a quantitative yield. Rf = 0.57 (normal hexane: ethyl acetate = 1: 1). 1-Amino-cyclohexanecarboxylic acid (cyano-dimethyl-methyl) amide (cyano-dimethyl-methyl) amide of the acid Fmoc-1-amino-cyclohexanecarboxylic acid (2.1 mmol) in 20 percent piperidine in dimethylformamide (6.3 milliliters). The reaction mixture is stirred at room temperature for 60 minutes. After evaporation of the solvent, the crude product is purified by chromatography on silica gel using normal hexane, normal hexane / ethyl acetate = 1/1, and 10% methanol in chloroform, to give the product in a yield of 31 percent, oil, Rf = 0.84 (normal propanol: water: ethyl acetate: ammonia) 5: 1: 2: 1).

G. { l- [(cyano-dimethyl-methyl) -carbayl] -cyclohexyl} amide of indole-2-carboxylic acid 2-indole-carboxylic acid (0.51 mmol), and 1-amino-cyclohexanecarboxylic acid (cyano-dimethyl-methyl) amide (0.61 mmol) in dimethylformamide (15 milliliters) are dissolved, and cool in an ice bath. HOBt (0.61 millimoles) and WSCD are added. HCl (0.61 mmol), and the reaction mixture is stirred at 4-25 ° C overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with saturated sodium bicarbonate, 1N hydrochloric acid and brine, dried over magnesium sulfate, and evaporated. The crude product is purified by chromatography on silica using normal hexane / ethyl acetate = 4/1, and normal hexane / ethyl acetate = 2/1, to give the product in a 71 percent yield.

P.f. 200-202 ° C, Rf = 0.55 (normal hexane: ethyl acetate = 1: 1).

Example 32: Synthesis of naphthalene-2-carboxylic acid [1- (cyanomethyl-carbamoyl) -2-methyl-butyl] -amide A. 2-tert-butyloxyl-carbonylamino-3-methyl-pentanoic acid cyanomethylamide The N-terbutyloxy-carbonyl-isoleucine hemihydrate (3 grams, 12.5 mmol), HOBt (3.71 grams, 27.5 mmol, 2.2 equivalents), and hydrochloride are dissolved. of aminoacetonitrile (1.27 grams, 13.7 millimoles, 1.1 equivalents), in dimethylformamide (36 milliliters), and WSCD (2.5 milliliters, 13.7 millimoles, 1.1 equivalents) is added. After stirring for 1 hour at room temperature, a 4 percent sodium bicarbonate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate and dilute hydrochloric acid, dried over magnesium sulfate, and evaporated, to give the product in a quantitative yield. P.f. 125-133.5 ° C, Rf = 0.44 (hexane: ethyl acetate = 1: 1).

B. 2-Amino-3-methyl-pentanoic acid cyanomethylamide hydrochloride 2-tert-butyloxy-carbonylamino-3-methyl-pentanoic acid cyanomethylamide (2 grams, 7.4 mmol) is dissolved in 4N hydrochloride in dioxane (10 milliliters). After 15 minutes at room temperature, the solvent is evaporated to give the product in a quantitative yield. The crude product is used for the next step without further purification. Rf (free amine) = 0.33 (ethyl acetate: methanol = 10: 1).

Naphthalene-2-carboxylic acid [1- (cyanomethyl-carbamoyl) -2-methyl-butyl] -amide 2-naphthoyl chloride (255 milligrams, 1.34 millimoles, 1.1 equivalents) is added to the solution of cyanomethylamide hydrochloride of the 2-amino-3-methyl-pentanoic acid (250 milligrams, 1.22 millimoles), and triethylamine (0.42 milliliters, 3.04 millimoles, 2.5 equivalents) in 5 milliliters of dichloromethane. After 1 hour at room temperature, 1 N hydrochloric acid is added, and the reaction mixture is extracted with ethyl acetate. The organic layer is washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and evaporated. Chromatography on silica gel (hexane / ethyl acetate 10/1 to 5/1, followed by ethyl acetate) gives the product in a yield of 97 percent (381 milligrams).

P.f. 203.5-207 ° C, Rf = 0.44 (hexanes: ethyl acetate = l: l) Example 33: Synthesis of naphthalene-2-carboxylic acid [1- (l-cyano-3-methyl-butylcarbamoyl) -2-methyl-butyl] -amide A. N- (Naphthalene-2-carbonyl) -isoleucine Methylester Methyl ester hydrochloride of L-isoleucine (2.0 grams, 11.0 mmol) and triethylamine (3.1 milliliters, 22.0 mmol, 2 equivalents) are dissolved in dichloromethane (40 milliliters). The solution is cooled in an ice bath, and 2-naphthoyl chloride (2.1 grams, 11.0 mmol, 1 equivalent) is added. The reaction mixture is allowed to warm to room temperature, and after 1 hour, 1 N hydrochloric acid is added. The mixture is extracted with ethyl acetate, the organic layer is washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and evaporated, to give the product in 98 percent yield. Rf = 0.50 (hexanes: ethyl acetate = 2: 1).

B. N- (naphthalene-2-carbonyl) -isoleucine N- (naphthalene-2-carbonyl) -isoleucine methyl ester (3.14 grams, 10.5 mmol) is stirred in a mixture of methanol (35 milliliters), and 1 N aqueous sodium hydroxide (16.8 milliliters, 1.6 equivalents). After 3 hours at room temperature, the mixture is heated for 1 hour at 40 ° C. 1N hydrochloric acid and brine are added, and the mixture is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, and evaporated to give the product in a quantitative (partially epimerized) yield. Rf = 0.32 (hexane: ethyl acetate = 1: 2).

C. (S) -l-cyano-3-methyl-butylamine hydrochloride (S) -N-tert butyloxy-carbonyl-l-cyano-3-methyl-butylamine (CAS 115654-59-6) (3.7 grams, 17.4 mmol) in 4N hydrogen chloride in dioxane (20 milliliters). After 15 minutes at room temperature, the solvent is evaporated, the residue is taken up in diethyl ether, the solid is filtered and dried under vacuum, to give the product in an 81 percent yield. Rf (free amine) = 0.34 (hexane: ethyl acetate = 1: 1).

Naphthalene-2-carboxylic acid [1- (1-cyano-3-methyl-butylcarbamo-1-l) -2-methyl-butyl] -amide. N- (naphthalene-2-carbonyl) -isoleucine (250 milligrams, 0.87 mmol), (S) -l-cyano-3-methyl-butylamine (143 milligrams, 0.96 millimoles, 1.1 equivalents), and HOBt (260 milligrams, 1.93 millimoles, 2.2 equivalents) in dimethylformamide (5 milliliters), and WSCD (0.17 milliliters, 0.96 millimoles, 1.1 equivalents) is added. After stirring for 1 hour at room temperature, a 4 percent sodium bicarbonate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate and dilute hydrochloric acid, dried over magnesium sulfate, and evaporated. Chromatography on silica gel (hexane / ethyl acetate, 2/1) gives the product in a 68 percent yield (mixture of epimers). Rf = 0.43 (hexanes: ethyl acetate = 2: 1).

Example 34: Synthesis of naphthalene-2-carboxylic acid [1- (l-cyano-3-methyl-butylcarba-moxl) -methyl-butyl] -amide A. N- (naph alen-2-carbonyl-leucine) The title compound is prepared in an analogous manner, to give N- (naphthalene-2-carbonyl) -isoleucine (see above) in a 98 percent yield, starting from from leucine methyl ester Rf = 0.34 (hexanes: ethyl acetate = 1: 1).

B. Naphthalene-2-carboxylic acid [1- (1-cyano-3-methyl-butylcarbamoyl) -3-methyl-butyl] -amide. N- (naphthalene-2-carbonyl) -leucine (250 milligrams, 0.88 mmol. ), (S) -l-cyano-3-methyl-butylamine (143 milligrams, 0.96 millimoles, 1.1 equivalents), and HOBt (260 milligrams, 1.93 millimoles, 2.2 equivalents) in dimethylformamide (5 milliliters), and WSCD (0.18 milliliters, 0.97 millimoles, 1.1 equivalents) is added. After stirring for 1 hour at room temperature, a 4 percent sodium bicarbonate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate and dilute hydrochloric acid, dried over magnesium sulfate, and evaporated. Chromatography on silica gel (hexane / ethyl acetate, 2/1) gives the product in a yield of 79 percent (mixture of epimers). Rf = 0.44 (hexane: ethyl acetate = 2: 1).

Example 35: { l- [l-cyano-2- (lH-indol-3-yl) ethylcarbamoyl] -3-methyl-butyl} Naph alen-2-carboxylic acid amide The title compound is prepared in a manner analogous to the compound of Example 22. N- (naphthalene-2-carbonyl) -leucine and l-cyano-2- (lH-indole) are reacted -3-yl) -ethylamine (CAS 169545-97-5) by the same procedure as for naphthalene-2-carboxylic acid [1- (l-cyano-3-methyl-butylcarbamoyl) -3-methylbutyl] -amide for give the product in a yield of 36 percent after chromatography on silica gel (hexane / ethyl acetate l / l (mixture of epimers) Rf = 0.59 (hexane: ethyl acetate = 11).

Example 36: Naphthalene-2-carboxylic acid [1- (1-cyano-l-methyl-ethylcarbamoyl) -3-methylbutyl] -amide N-tert-butyloxy-carbonyl-1-cyano-1-methyl-ethyl-amine Boc-2-aminoisobutyric acid amide (4.58 grams, 22.6 millimoles) and triethylamine (7 milliliters, 50 millimoles, 2.2 equivalents) are dissolved in tetrahydrofuran (100 milliliters), and trifluoroacetic anhydride is added. (3.5 milliliters, 25 milliliters, 1.1 equivalents) at 0 ° C. The reaction mixture is stirred at 0 ° C for 1 hour. The mixture is concentrated and water is added. The organic layer is extracted with ethyl acetate, washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel using normal hexane / ethyl acetate = 20 μl, 10/1, 5/1 and 1/1, to give the product in a yield of 74 percent. Rf = 0.45 (normal hexane / ethyl acetate = 3 / L).

B. 1-Cyano-l-methyl-ethylamine HCl hydrochloride. H2N and '^ .C N-tert-butyloxy-carbonyl-l-cyano-1-methyl-ethylamine (3.09 grams, 16.8 mmol) is dissolved in dioxane (15 milliliters), and 4N-dioxane hydrochloric acid (25 milliliters) is added at 0 ° C. The reaction mixture is stirred at 0 ° C for 1.5 hours, then at room temperature for 1 hour. The mixture is concentrated, and diethyl ether is added. The resulting white precipitate is washed with diethyl ether, and dried to give the product in 83 percent yield. The crude product is used for the next coupling without further purification. Rf = 0.66 (n-PrOH / H20 / ethyl acetate / NH3 = 5 / l / 2 / l).

Naphthalene-2-carboxylic acid [1- (1-cyano-l-methyl-ethylcarbamoyl) -3-methylbutyl] -amide N- (naphthalen-2 -carbonyl) -leucine (279 milligrams, 0.98 millimoles), 1-cyano-1-methyl-ethylamine hydrochloride (137 milligrams, 1.14 millimoles, 1.2 equivalents), and HOBt (297 milligrams, 2.20 are dissolved. millimoles, 2.2 equivalents) in dimethylformamide (5 milliliters), and WSCD (0.2 milliliters, 1.09 millimoles, 1.1 equivalents) is added at -10 ° C. After stirring for 1.5 hours at -10 ° C, a 5 percent sodium bicarbonate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and evaporated. Chromatography on silica gel (normal hexane / ethyl acetate = 20 μl, 10/1, 5/1, 3/1 and 1 μl) gives the product in a yield of 8.7 percent (mixture of enantiomers). Rf = 0.54 (normal hexane / ethyl acetate = 1 / l).

Example 37: naphthalene-2-carboxylic acid [1- (l-cyano-4-phenyl-propylcarbamoyl) -3-methylbutyl] -amide Amide of Boc ~ 2-amino-4-phenyl-buty ric acid, Boc-Hph-CO-STH2 28% aqueous ammonia (34 mmol) is added to the mixed anhydride (prepared from 16.8 millimoles of Boc-homophenylalanine and 17.0 millimoles of isobutyl chloroformate as usual) at -10 ° C. The reaction mixture is stirred at room temperature for 4.5 hours. The mixture is concentrated, washed with saturated sodium bicarbonate, 1N hydrochloric acid, and brine, dried over sodium sulfate and evaporated to give the product in a quantitative yield. The crude product is used for the next reaction without further purification. Rf = 0.60 (chloroform / methanol = 10 / l). Then, the title compound is prepared: in a manner analogous to steps A, B and C of Example 36. Rf = 0.81 (normal hexane / ethyl acetate = 1/1). Example 38: naphthalene-2-carboxylic acid [1- (l-cyano-4-phenyl-propylcarbamoyl) -cyclohexyl] -amide A [naphthalene-2-carboxylic acid [(1-meoxycarbonyl) -cyclohexyl] -amide] Dissolve 1-amino-cyclohexanecarboxylic acid methyl ester hydrochloride (1 gram, 5.2 mmol) and triethylamine (1.44 milliliters, 10.3 mmol, 2 equivalents) in dichloromethane (15 milliliters) and add 2-naphthoyl chloride (1 gram, 5.2 millimoles, 1 equivalent) at 0 ° C. The reaction mixture is stirred at 0-25 ° C for 2 hours, and 1N hydrochloric acid is added. The mixture is extracted with ethyl acetate, the organic layer is washed with a saturated solution of sodium bicarbonate, dried over sodium sulphate and evaporated. Chromatography on silica gel (normal hexane / ethyl acetate = 10l /, 5/1, 3/1 and 1 / L) gives the product in 93 percent yield. Rf = 0.30 (normal hexane / ethyl acetate) 3/1).

B. N- (2-naphthoyl) -1-amino-cyclohexanecarboxylic acid Starting from [(1-methoxycarbonyl) -cyclohexyl] amide of naphthalene-2-carboxylic acid, the product is prepared in a manner analogous to N-naphthalene-2-carbonyl) -isoleucine in a quantitative yield. It is used for the next coupling without further purification. Rf = 0.60 (chloroform / methanol = 10 / l).

Naphthalene-2-carboxylic acid [1- (l-cyano-4-phenyl-propylcarbamoyl) -cyclohexyl] -amide N- (2-naphthoyl) -1-amino-cyclohexane-carboxylic acid (67 milligrams, 0.22 millimole), 1-cyano-3-phenylpropylamine hydrochloride (47 milligrams, 0.24 millimole, 1.1 equiv.), And HOAt (65) are dissolved. milligrams, 0.48 millimole, 2.2 equivalents) in dimethylformamide (2 milliliters), and added WSCD (0.044 milliliters, 0.24 millimoles, 1.1 equivalents) at -10 ° C. After stirring at 0-25 ° C overnight, a 5 percent sodium bicarbonate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated. Chromatography on silica gel (chloroform / acetone = 200 μl and 100/1) gives the product in a 63 percent yield. Rf = 0.73 (chloroform / acetone = 9 / l).

Example 39: l- H [1- (Cyanomethyl-carbamoyl) -cyclohexyl] amide. -indole-5-carboxylic acid 1-Amino-cyclohexanecarboxylic acid cyanomethylamide (136 milligrams, 0.50 millimole), indole-5-carboxylic acid (80 milligrams, 0.50 millimole, 1.0 equivalent), and HOBt (74 milligrams, 0.55 millimole, 1.1 equivalents) in dimethylformamide (5 milliliters), and WSCD (0.10 milliliters), 0.55 millimoles, 1.1 equivalents) is added. After stirring for 20 hours at room temperature, a 4 percent sodium bicarbonate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate, dried over magnesium sulfate, and evaporated. Chromatography on silica gel (hexanes / ethyl acetate 2/1, and then ethyl acetate) gives the product in a 20 percent yield. Rf = 0.31 (hexanes / ethyl acetate = 3 / L).

Example 40 Synthesis of N- [cyanomethyl-carbamoyl] -cyclohexyl] -imidazol-1-ylmethyl-benzamide A. Boc-1-aminocyclohexanecarboxylic acid The title compound is prepared from 1-cyclohexanecarboxylic acid (140 mmol), Boc20 (154 millimoles), and Na2CO3 (140 millimoles) in 200 milliliters of dioxane and 100 milliliters of water, by conventional methods. P.f. 157-161 ° C; Rf = 0.23 (CH2Cl2 / MeOH = 95: 5.

B. (1- (Cyanomethyl-carbamoyl) amide of Boc-1-amino-cyclohexanecarboxylic acid Boc-1-aminocyclohexanecarboxylic acid (40 millimoles), HOBt (40 millimoles) and WSCD (42 millimoles) in dimethylformamide (75 milliliters) are dissolved and stirred for 15 minutes at room temperature, 2-aminoacetonitrile hydrochloride (40 mmol) and triethylamine (40 mmol) in dimethylformamide (25 milliliters) are suspended and added to the reaction mixture, which is stirred at room temperature. C. After the evaporation of the solvent, the residue is extracted with ethyl acetate, the extract is washed with water, 10% citric acid, brine, sodium bicarbonate, brine and dried over magnesium sulfate. The residue is suspended in diethyl ether and the solid is filtered and dried (in vacuo) to obtain 7.35 grams of a white powder with mp 160-162 ° C, Rf = 0.28 (normal hexane: ethyl acetate = l: l).

C. 1-Aminocyclohexanecarboxylic acid (1- (cyanomethyl-carbamoyl) amide hydrochloride HCl in diethylether (3-4N, 50 milliliters) is added to the solution of Boc-1- (1- (cyanomethyl-carbamoyl) amide amino-cyclohexanecarboxylic acid (33 mmol) in tetrahydrofuran (50 milliliters) at room temperature, and stirred overnight.The reaction mixture is cooled with an ice bath at 0-4 ° C, and the solid is filtered and washed with diethyl ether The white crystals are dried (vacuum), Mp 205-209 ° C, Rf = 0.45 (CH 2 Cl 2 / MeOH = 9.1).

D. N- [1- (Cyanomethyl-carbamoyl) -cyclohexyl] -4-bromomethyl-benzamide 4-Bromoethyl-benzoic acid (2.3 mmol) is suspended in CH2C12 (7 milliliters), and cooled to 0-5 °. C. Chloramine (2.3 mmol) is added, and the mixture is stirred for 45 minutes at 0-5 ° C. Add 1-amino-cyclohexanecarboxylic acid (1- (cyanomethyl-carbamoyl) amide hydrochloride (2.3 mmol), and N-ethyldi-isopropylamine (4.6 mmol) in CH2C12 (7 milliliters) at a low temperature. The reaction mixture is diluted with CH2C12 (40 milliliters), washed with water, dried over magnesium sulphate and evaporated. The crude product is purified by chromatography on silica using CH2Cl2 / MeOH = 97: 3. The fractions containing the pure product are collected and evaporated, the residue is suspended in diethylether, and the solid is evaporated. It is obtained a white powder with a mp of 194-196 ° C, Rf = 0.38 (CH2Cl2 / MeOH = 95: 5).

E. N- [1-cyanomethyl-carbamoyl) -cyclohexyl] -4-imidazol-1-ylmethyl-benzamide N- [1-cyanomethyl-carbamoyl] -cyclohexyl] -4-bromomethyl-benzamide (0.34 mmol) in tetrahydrofuran is dissolved. (2 milliliters), and sodium imidazole (0.41 mmol) is added, and the reaction mixture is stirred at room temperature overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated. The residue is suspended in diethyl ether, and the solid is filtered. The crude product is purified by chromatography on silica using CH 2 Cl 2 / MeOH = 9: 1. Fractions containing the pure product are collected and evaporated. The residue is suspended in diethyl ether, and the solid is filtered. A white powder with a m.p. from 194-196 ° C, Rf = 0.28 (CH2Cl2 / MeOH = 9: 1).

By repeating the procedure described above in Example 40, using appropriate starting materials and reaction conditions, the following compounds of Formula XII are obtained, as identified in Table 2 below.

Table 2 Example 68: Synthesis of N- (l- I "(cyano-dimethyl-methyl) -carbamoyl] -3-methyl-butyl) -4-imidazol-1-ylmethyl-benzamide A. Acid terbutilter. { l- [Cyano-dimethyl-methyl) -carbamoyl] -3-methyl-butyl} -carbamic Boc-Leu-OH (62 mmol), HOBt (62 mmol), and WSCD (62 mmol) in dimethylformamide (150 milliliters) are dissolved, and stirred for 15 minutes at room temperature. Suspend 2-amino-2-methylpropionamide hydrochloride (62 mmol) and triethylamine (62 mmol) in dimethylformamide (25 milliliters), and add to the reaction mixture, which is stirred at 25 ° C overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, 10 percent citric acid, brine, sodium bicarbonate, brine, and dried over magnesium sulfate and evaporated. The residue is suspended in diethyl ether, and the solid is filtered and dried (vacuum). 14.78 grams of a white powder with a m.p. of 182-184 ° C, Rf = 0.39 (CH2Cl2 / MeOH = 9: 1).

B. Terbutiléster of acid. { l- [(cyano-dimethyl-methyl) -carbamoyl] -3-methyl-butyl} -carbamic acid terbutiléster is dissolved. { l- [(cyano-dimethyl-methyl) -carbamoyl] -3-methyl-butyl} -carbamic (47 millimoles) in tetrahydrofuran (150 milliliters) and cooled to -10 ° C. Trifluoroacetic acid anhydride (56 mmol) and triethylamine (94 mmol) are added at -10 ° C, and the stirred mixture is slowly heated to 0 ° C for 2 hours. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and evaporated. The residue is suspended in diethyl ether / pentane, and the solid is filtered and dried (vacuum). 9.93 grams of a white powder with a m.p. 166-168 ° C, Rf = 0.55 (normal hexane: ethyl acetate = 1: 1).

C. (Cyan-dimethyl-methyl) amide of 2-amino-4-methyl-pentanoic acid The terbutil ester of the acid is dissolved. { l- [Cyano-dimethyl-methyl) -carbamoyl] -3-methyl-butyl} -carbamic (19 mmol) in ethyl acetate containing HCl (3-4N, free of water), and the mixture is stirred at room temperature overnight. After evaporation of the solvent, the product is purified by chromatography on silica using CH2Cl2 / MeOH = 9: 1. The fractions containing the pure product are collected and evaporated. 2.3 grams of a yellowish oil are obtained, Rf = 0.36 (CH2Cl2 / MeOH = 9: 1) D. N-. { l- [(cyano-dimethyl-methyl) -carbamoyl] -3-methylbutyl} -4-bromomethyl-benzamide 4-Bromomethylbenzoic acid (4.1 mmol), HOBt (4.1 mmol) and WSCD.HCl (4.1 mmol) in dimethylformamide (7 milliliters) are dissolved and stirred for 10 minutes. 2-Amino-4-methyl-pentanoic acid (cyano-dimethyl-methyl) amide (4.1 mmol) in dimethylformamide (3 milliliters) is added, and the reaction mixture is stirred at room temperature overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, 10 percent citric acid, brine, sodium bicarbonate, brine and dried over magnesium sulfate, and evaporated. The crude product is suspended in diethyl ether, and the solid is filtered and dried (in vacuo). A white powder with a m.p. 185-187 ° C, Rf = 0.43 (normal hexane: ethyl acetate = 1: 1).

IN-. { l- [(cyano-dimethyl-methyl) -carbamoyl] -3-methylbutyl} -4-imidazol-1-ylmethyl-benzamide N- is dissolved. { l- [(cyano-dimethyl-methyl) -carbamoyl] -3-methyl-butyl} -4-bromomethyl-benzamide (0.18 mmol) in tetrahydrofuran (1 milliliter), and sodium imidazole (0.41 mmol) is added, and the reaction mixture is stirred at room temperature overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated. An oil with an Rf = 0.44 (CH2Cl2 / MeOH = 9.1) is obtained.

By repeating the procedure described above in Example 68, using appropriate starting materials and conditions, the following compounds of Formula XIII are obtained, as identified in Table 3 below.

Table 3 Example 72 N- [1- (Cyanomethyl-carbamoyl) -3-methyl-butyl] -4- (2-pyrrolidin-1-yl-ethylsulfane) -benzamide A. 4- (2-Chloroethylsulfanyl) -benzoic acid 4-mercaptobenzoic acid (65 millimoles) and l-bromo-2-chloroethane (71 millimoles) are dissolved in acetone (120 milliliters), and powdered potassium carbonate ( 71 millimoles). The mixture is heated to 40 ° C, and stirred for 7 hours. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, and dried over sodium sulfate and evaporated. The crude product is suspended in diethyl ether, and the solid is filtered and dried (in vacuo). 7.8 grams of a white powder with a m.p. 142-144 ° C, Rf = 0.37 (methylene chloride / methanol = 9 / L).

B. 4- (2-Chloroethylsulfanyl) -benzoyl-Leu-Gly (CN) 4- (2-Chloroethylsulfanyl) -benzoic acid (18.5 mmol), HOBt (18.5 mmol) and WSCD are dissolved. HCl (19.4 mmol) in dimethylformamide (50 milliliters), and stirred for 15 minutes. H-Leu-Gly (CN) (18.5 mmol) is added, and the reaction mixture is stirred at room temperature overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, 10 percent citric acid, brine, sodium bicarbonate, brine, and dried over magnesium sulfate. After evaporation of the solvent with the crude product, it is purified by chromatography on silica using CH 2 Cl 2 / MeOH = 95: 5. The fractions containing the pure product are collected and evaporated. The product is suspended in diethyl ether, and the solid is filtered and dried (vacuum). 3.15 grams of a yellowish powder with a m.p. 108-110 ° C, Rf = 0.33 (normal hexane: ethyl acetate = 1: 1).

C. N- [1- (Cyanomethyl-carbamoyl) -3-methyl-butyl] -4- (2-pi-rrolidin-1-yl-ethylsulfanyl) -benzamide. 4- (2-Chloroethylsulfanyl) -benzoyl-Leu is dissolved. -Gly (CN) (1.36 mmol) in dimethylformamide (2 milliliters), and pyrrolidine (3 mmol) is added. The reaction mixture is stirred for 8 hours at room temperature, then a catalytic amount of potassium iodide is added, and again it is stirred at 50 ° C overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, and dried over magnesium sulfate and evaporated. The raw material is applied to a column of silica gel. Elution with CH2Cl2 / MeOH = 93: 7 gives the product in a yield of 24 percent, Rf = 0.12 (CH2Cl2 / MeOH = 95: 5).

Example 73: Synthesis of N- [1- (Cyanomethyl-carbamoyl) -3-methyl-butyl] -4- (2-pyrrolidin-1-yl-ethylsulfonyl) -benzamide A. 4- (2-Chloroethylsulfonyl) -benzoic acid 4- (2-Chloroethylsulfanyl) -benzoic acid (18.4 mmol) is suspended in methylene chloride (60 milliliters), and cooled to -10 ° C. M-Chloroperbenzoic acid (38.6 mmol) in methylene chloride (60 milliliters) is added dropwise, and the mixture is stirred for hours at -10 ° C. The mixture is diluted in methylene chloride (100 milliliters), and a 5 percent solution of sodium thiosulfate in water is added, and the mixture is stirred vigorously. The mixture is extracted, washed with water, and dried over sodium sulfate, and evaporated. The crude product is recrystallized from ethyl acetate, and the solid is filtered and dried (vacuum). 2.19 grams of a pale powder with a m.p. of 142-144 ° C, Rf = 0.37 (CH2Cl2 / MeOH = 9: 1).

B. 4- (2-Chloroethylsulfonyl) -benzoyl-Leu-Gly (CN) 4- (2-Chloroethylsulfonyl) -benzoic acid is dissolved (8.8 millimoles), HOBt (8.8 millimoles) and WSCD. HCl (8.8 mmol) in dimethylformamide (25 milliliters), and stirred for 15 minutes. H-Leu-Gly (CN) (18.5 mmol) is added, and the reaction mixture is stirred at room temperature overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, 10 percent citric acid, brine, sodium bicarbonate, brine and dried over magnesium sulfate. After evaporation of the solvent, the crude product is purified by chromatography on silica using CH2Cl2 / MeOH = 95: 5. The fractions containing the pure product are collected and evaporated. The product is suspended in diethyl ether, and the solid is filtered and dried (vacuum). 0.3 grams of a white powder are obtained, Rf = 0.25 (CH2Cl2 / MeOH = 95: 5).

C. N- [1- (Cyanomethyl-carbamoyl) -3-methyl-butyl] -4- (2-pi-rrolidin-1-yl-ethylsulfonyl) -benzamide. 4- (2-Chloroethylsulfonyl) -benzoyl-Leu is dissolved. -Gly (CN) (0.4 mmol) in pyrrolidine (1 milliliter). The reaction mixture is stirred for 1.5 hours at room temperature. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and evaporated. The raw material is applied to a column of silica gel. Elution with CH2Cl2 / MeOH = 95: 5 gives the product in a yield of 43 percent, Rf = 0.30 (CH2Cl2 / MeOH = 95: 5).

Example 74: Synthesis of N- [1- (l-cyano-3-methyl-butyl-carbamoyl) -3-methyl-butyl] -4-imidazol-l-ylmethyl-benzamide A. Boc-Leu-Leu-NH2 Boc-Leu-Leu-OH (Bachem, 43.6 millimoles) is dissolved in tetrahydrofuran (250 milliliters), and N-methylmorpholine (43.6 millimoles) is added. The mixture is cooled to -20 ° C, and isobutyl chloroformate (43.6 millimoles) is added dropwise. The mixture is stirred for 10 minutes, and then a 25 percent aqueous solution of ammonia (52.3 mmol) is added at -20 ° C. The mixture is stirred for 3 hours at -20 ° C to -10 ° C. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, and dried over magnesium sulfate, and evaporated.

The crude product is suspended in diethyl ether, and the solid is filtered and dried (in vacuo). 14.2 grams of a white powder with a m.p. from 155-156 ° C, Rf = 0.5 (CH2Cl2 / MeOH = 9: 1).

B. Boc-Leu-Le (CN) Boc-Leu-Leu-NH2 (41 mmol) is suspended in tetrahydrofuran (200 milliliters) and triethylamine (83 mmol), and trifluoroacetic anhydride (41 mmol) is added to -5 ° C. The mixture is stirred for 2 hours at -5 ° C. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, and dried over magnesium sulfate and evaporated. A yellowish oil with Rf = 0.59 is obtained (normal hexane: ethyl acetate = 2.1), and deprotected without further purification (step C).

C. H-Leu-Leu (CN) Dissolve Boc-Leu-Leu (CN) (41 mmol) in tetrahydrofuran (50 milliliters) and add HCl in diethyl ether (50 milliliters, 3-4N, water-free) at room temperature, and the mixture is stirred overnight. After evaporation of the solvent, the residue is dissolved in methanol, and ammonia in methanol (40 milliliters, 3-4N, free of water) is added, and the solid material is filtered. The filtrate is evaporated, and the crude product is purified by chromatography on silica using CH2Cl2 / MeOH = 95: 5. Fractions containing the pure product are collected and evaporated. 5.07 grams of a yellowish oil with Rf = 0.43 (CH2Cl2 / MeOH = 9: 1) are obtained.

D. 4-Bromomethylbenzoyl-Leu-Leu (CN) 4-Bromomethylbenzoic acid (6.67 millimoles), HOBt (6.67 millimoles) and WSCD are dissolved. HCl (7.0 mmol) in dimethylformamide (15 milliliters), and stirred for 15 minutes. H-Leu-Leu (CN) (6.67 mmol) is added, and the reaction mixture is stirred for 2.5 hours at room temperature. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, 10 percent citric acid, brine, sodium bicarbonate, brine and dried over magnesium sulfate. After evaporation of the solvent, the crude product is purified by chromatography on silica using CH2Cl2 / MeOH = 97.3. The fractions containing the pure product are collected and evaporated. 1.74 grams of a yellowish oil are obtained with a Rf = 0.59 (CH2Cl2 / MeOH = 95: 5).

? N- [l-cyano-3-methyl-butylcarbamoyl) -3-methyl-butyl] -4-imidazol-1-ylmethyl-benzamide. 4-Bromomethyl-Leu-Leu (CN) (1.23 mmol) is dissolved in tetrahydrofuran (5). milliliters) and sodium imidazole (1.48 mmol) is added, and the reaction mixture is stirred at room temperature overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on silica using CH2Cl2 / MeOH = 95: 5. The fractions containing the pure product are collected and evaporated. The product is suspended in diethyl ether, and the solid is filtered and dried (vacuum). A white powder with a m.p. 100-103 ° C, Rf = 0.36 (CH2Cl2 / MeOH = 9: 1).

By repeating the procedure described above in Example 74, using appropriate starting materials and conditions, the following compounds of Formula XIV are obtained as identified in Table 4 below.

Example 78: [1- (2-Benzyloxy-l-cyano-ethylcarbamoyl) -3-methyl-butyl] -carbamic acid benzyl ester A. 3-Benzyloxy-2- (2-benzyloxycarbonylamino-methyl-pentanoylamino) -propionic acid To a suspension of 0.975 grams of H-Ser (OBzl) -OH in 5 milliliters of methylene chloride, 1.52 milliliters of trimethylchlorosilane are added. After ten minutes at room temperature, 0.98 milliliters of N, N-diisopropylethylamine and 1.81 grams of N-hydroxysuccinimide-benzyloxy-leucine ester are added. The reaction mixture is stirred for 2 hours at room temperature, and diluted with ethyl acetate. The ethyl acetate is washed once with a saturated NH 4 Cl solution, and once with H 2 O, then dried over sodium sulfate, the solvent is removed and the residue is crystallized from diethyl ether. ^ -NMR (CDC13, ppm): 7.30 (m, 10H), 6.83 (d, 1H), 5.32 (d, 1H), 5.10 (s, 2H), 4.71 (m, 1H), 4.50 (s, 2H) , 4.28 (m, 1H), 3.92 (m, 1H), 3.67 (m, 1H), 1.46-1.79 (m, 3H), 0.92 (d, 6H).

B. [1- (2-Benzyloxy-l-carbamoyl-ethylcarbamoyl) -3-methyl-butyl] -carbamic acid benzyl ester To a solution of 0.980 grams of 3-benzyloxy-2- (2-benzyloxycarbonylamino-4-methyl) acid pentanoylamino) -propionic, and 0.25 milliliters of N-methylmorpholine in 12 milliliters of tetrahydrofuran, 0.3 milliliters of isobutyl chloroformate are added dropwise at -15 ° C. The reaction mixture is stirred at -15 ° C for 10 minutes, then 4 milliliters of aqueous NH 3 (25 percent) are added dropwise over a period of 5 minutes. The reaction mixture is stirred for an additional 15 minutes, and diluted with ethyl acetate. The ethyl acetate is washed once with a saturated solution of NH 4 Cl, and once with H 2 O, then it is dried with sodium sulfate, the solvent is removed and the residue is triturated with diethyl ether. ^ -RM (CDC13, ppm): 7.38 (m, 10H), 6.87 (d, 1H), 6.60 (m, (br.), 1H), 5.41 (m (br.), 1H), 5.12 (d, 1H), 5.08 (s, 2H), 4.50 (d, 2H), 4.20-3.92 (m, 2H), 3.50 (m, 1H), 1.70 - 1.41 (m, 3H), 0.90 (d, 6H).

C. [1- (2-Benzyloxy-l-cyano-ethylcarbamoyl) -3-methyl-butyl] -carbamic acid benzyl ester 0.3 milliliters of trifluoroacetic acid anhydride are added dropwise to a solution of 0.9 grams of acid benzyl ester [ 1- (2-benzyloxy-1-carbamoyl-ethylcarbamoyl) -3-methyl-ethyl] -α-arabic acid and 0.6 milliliter of triethylamine in 15 milliliters of tetrahydrofuran at -5 ° C. The reaction mixture is stirred at -5 ° C for 3 hours, and then for 12 hours at room temperature. The reaction mixture is then poured into H20, and the aqueous layer is extracted three times with ethyl acetate. The combined organic layers are washed once with H20, once with brine, then dried over sodium sulfate, the solvent is removed, and the residue is crystallized from diethylether / hexane, P.f. 126-127 ° C.

The following compounds of Formula XV, as identified in the following Table 5, are prepared in a manner analogous to the compound of Example 78.

Example 86: 2 - [2-Chloro-f-enyla-mino) -acetylamino] -4-methyl-pentanoic acid cyanomethylamide (4-Chloro-phenylamino) -acetic acid (0.5 grams) and H-Leu-Gl (CN). HCl (0.55 grams) are dissolved in dimethylformamide (4 milliliters). HOBt (0.44 grams), WSCD are added. HCl (0.54 grams), triethylamine (0.37 milliliters), and the reaction mixture is stirred for 18 hours. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with 10 percent citric acid, brine, sodium bicarbonate, brine, and dried over magnesium sulfate, and evaporated. The crude product is formed in a paste in diethyl ether, and the solid is filtered and dried (in vacuo), yielding a white powder with a m.p. of 131-134 ° C.

By repeating the procedure described above in Example 86, using appropriate starting materials and conditions, the following compounds of Formula XVI are obtained, as identified in Table 6 below.

Table 6 Example No. | R * | pf. (° C) I Rf (solvent) By repeating the procedures described in the previous examples, using appropriate starting materials and reaction conditions, the following compounds of Formula XVII are obtained, as identified in Table 7 below. or The compounds of Examples 1 to 153 are typically cathepsin K selective inhibitors, and in general have ICs for the inhibition of human cathepsin K, from about 100 to about 1 nM or less, for example, about 0.5 nM. Representative compounds, for example, as described in the Examples above, typically have IC50s for the inhibition of Cathepsin K, on the scale from less than 1 to about 100 nM, and IC50s for the inhibition of Cathepsin K, which are at least from 10 to approximately 1000 times lower than its ICsos for the inhibition of Cathepsin L and Cathepsin S, for example, when tested in the tests described above. The cathepsin K selective compounds of the invention are particularly indicated for preventing or treating osteoporosis of different genesis (eg, juvenile, menopausal, post-menopausal, post-traumatic, caused by aging, or by corticosteroid therapy, or inactivity). By repeating the procedures described in the above Examples, using appropriate starting materials and reaction conditions, the following compounds of the Formula XVII are obtained, as identified immediately in Tables 8, 9 and 10.

Table 8 Ry *? L- is cyclopropyl, that is, Rz is ethylene, and makes a cyclopropyl ring with the carbon atom to which it is attached.

The compounds of Table 8 are typically selective inhibitors for cathepsin S, and typically have ICs for the inhibition of cathepsin S on the scale of about 100 to about 10 nM.

Table 9 eleven The compounds of Table 9 are typically selective inhibitors for cathepsin L, which have ICs for the inhibition of cathepsin S, which are preferably in the range of about 100 to about 1 nM.

Table 10 The compounds of Table 10 are cathepsin L and cathepsin S inhibitors, which have IC50s for the inhibition of cathepsin L on the scale of about 100 to about 50 nM, and IC50s for the inhibition of cathepsin S on the scale of about 50 to approximately 10 nM.

Example 302: Synthesis of N- [2- [3-methoxy-carbonyl) -phenyl) -methoxy] -1 (S) -cyanomethyl] -3-methyl-N- (2,2-diphenylacetyl) -L-phenyl- alaninamide A. O- [[3- (methoxycarbonyl) -phenyl] methyl] -N- (terbutoxicar-bonyl) -L-serine To a solution of N- (terbutoxy-carbonyl) -L-serine (16.1 grams, 78.46 millimoles) in dimethylformamide (90 milliliters) at -15 ° C, sodium hydride (6.9 grams, 60 percent in mineral oil, 172.6 millimoles) is added in portions with vigorous stirring for 0.5 hours. After all of the sodium hydride is added, the mixture is stirred for an additional 10 minutes at 0 ° C, and then at room temperature for 30 minutes. The solution is again cooled to 0 ° C, and a solution of methyl 3-bromomethylbenzoate (19.77 grams, 86.30 mmol) in dimethylformamide (90 milliliters) is added dropwise over 15 minutes. Then the mixture is heated at room temperature for 16 hours. The dimethylformamide is then evaporated (high vacuum, <40 ° C), and the residue is diluted with cold water (200 milliliters), and acidified to a pH of 4-5 with 1 N HCl. The resulting mixture is extracted with EtOAc (4 x 150 milliliters). The combined extracts are washed with 0.1 N HCl (2 x 300 milliliters) and brine (2 x 300 milliliters), dried over MgSO4, and evaporated, to give a yellowish syrup. Chromatography (silica, 5 percent MeOH / CH2Cl2) produces 0 - [[3- (methoxycarbonyl) -phenyl] methyl] -N- (terbutoxy-carbonyl) -L-serine as a yellowish oil.

B. O- [[3- (methoxycarbonyl) -phenyl] methyl] -N- (terbutoxycarbonyl) -L-serinamide A solution of O- [[3- (methoxycarbonyl) -phenyl] methyl] -N- (terbutoxy -carbonyl) -L-serine (3.0 grams, 8.50 millimoles), and N-methylmorpholine (2.8 milliliters, 2.58 grams, 25.5 millimoles) in CH2C12 (50 milliliters), is cooled to -10 ° C, and chloroformate is added by drip of isobutyl (1.1 milliliters, 1.16 grams, 8.5 millimoles) for 10 minutes. After stirring for 15 minutes, ammonia gas is bubbled into the solution at a moderately vigorous rate for 15 minutes. Then the solution is heated at room temperature for 30 minutes. The CH2C12 is evaporated, and the residue is dissolved in EtOAc (50 milliliters). This solution is then extracted with 1 N HCl (2 x 50 milliliters), saturated NaHCO 3 (50 milliliters), water (50 milliliters) and brine (50 milliliters), dried over MgSO 4, and evaporated. Chromatography (silica, 75 percent EtOAc / hexane) yields 0 - [[3- (methoxycarbonyl) -phenyl] methyl] -N- (terbutoxy-carbonyl) -L-serinamide as a thick oil.

C. O- [[3- (methoxycarbonyl) -phenyl] methyl] -L-serinamide.HCl To a solution of O- [[3- (methoxycarbonyl) -phenyl] methyl] -N- (terbutoxy-carbonyl) -L -serinamide (2.4 grams, 6.82 mmol) in EtOAc (50 milliliters) at 0 ° C, HCl gas is bubbled at a moderately vigorous rate for 5 minutes, during which time, a batch of white precipitate is observed. The mixture is warmed to room temperature for 30 minutes, after which time the EtOAc is removed, yielding 0- [[3- (methoxy-carbonyl) -phenyl] methyl] -L-serinamide.HCl as a white solid.

D. 3 -methyl-N- (2,2-diphenylacetyl) -L-phenylalanine To a solution of 3-methyl-L-phenylalanine (1.8 grams, 10.06 millimoles) and Na2CO3 (3.2 grams, 30.18 millimoles) in water (150 milliliters), add a solution of diphenylacetyl chloride (2.32 grams, 10.06 millimoles) in tetrahydrofuran (150 milliliters), and the resulting solution is vigorously stirred at room temperature overnight. The tetrahydrofuran is then evaporated, and the aqueous layer is diluted with 6 percent aqueous Na2CO3 (100 milliliters), and washed with Et20 (3 x 150 milliliters). The aqueous layer is then acidified to a pH of 1 with concentrated HCl, and the resulting slurry is extracted with EtOAc (3 x 100 milliliters). The organic phase is then washed with water (2 x 100 milliliters) and brine (1 x 100 milliliters), dried over MgSO 4 and evaporated, to give 3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanine. , as a white solid.

E. N- [3-methyl-N-. { 2, 2-diphenylacetyl) -L-phenylalanyl] -0- [[3-methoxycarbonyl) phenyl] methyl] -L-serinamide To a solution of 3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanine ( 1.0 gram, 2.68 mmol) and 0 - [[3-methoxycarbonyl) phenyl] methyl] -L-serinamide. HCl (0.774 grams, 2.68 millimoles), 1-hydroxybenzotriazole hydrate (0.452 grams, 2.95 millimoles), and N-methylmorpholine (1.18 milliliters, 1.085 grams, 10.72 millimoles) in CH2C12 (50 milliliters), is added 1- (3 -dimethylaminopropyl) -3-ethylcarbodi-imide.HCl (0.771 grams, 4.02 mmol) in one portion, and the mixture is stirred at room temperature for 16 hours. The solution is then washed with 1 N HCl (100 milliliters), saturated aqueous NaHCO3 (1 x 50 milliliters), water (1 x 50 milliliters) and brine (1 x 50 milliliters), dried over MgSO4, and evaporated. The residual solid is triturated with hot methanol to give N- [3-methyl-N- (2,2-diphenylacetyl) -L-phenylalanyl] -O- [[3- (methoxycarbonyl) phenyl] methyl] -L-serinamide as a white solid.

F. N- (2- [3- (methoxy-carbonyl) -phenyl) -methoxy] -1 (S) -cia-noethyl] -3-methyl-N - (2,2-diphenylacetyl) -L-phenyl- alaninamide Oxalyl chloride (0.057 milliliter, 0.084 gram, 0.66 millimole) is added dropwise to dimethylformamide (10 milliliters), and the resulting solution is cooled to 0 ° C. After the solution becomes clear, pyridine (0.11 milliliters, 0.10 grams, 1.31 millimoles) is added, followed by N- [3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanyl] -O- [ [3-methoxy-carbonyl) -phenyl] methyl] -L-serinamide (0.20 grams, 0.329 mmol), in one portion. The yellow reaction solution is stirred at 0 ° C for 1.5 hours, after which time, it is diluted with EtOAc (50 milliliters), and washed with saturated NaHCO 3 (1 x 50 milliliters), saturated LiCl (1 x 50 milliliters). , it is dried over MgSO4 and evaporated. The residue is passed through chromatography (silica, 80 percent EtOAc / hexane) to give N- [2- [(3- (methoxy-carbonyl) -phenyl) -methoxy] -1 (S) -cianoethyl] -3- methyl-N- (2, 2-diphenylacetyl) -L-phenyl-alaninamide as a white solid, having the following structure: Example 303: Synthesis of N- [2- [(3-carboxyphenyl) methoxy] -1 (S) -cyanoethyl] -3-methyl-N- (diphenylacetyl) -L-phenylalaninamide A solution of N- [2- [( 3-methoxycarbonyl) phenyl) methoxy] -1 (S) -cyanoethyl] -3-methyl-N - (2,2-diphenylacetyl) -L-phenylalaninamide (0.34 grams, 0.58 mmol) in pinacolone (20 milliliters), degass with nitrogen bubbling for 10 minutes. Then lithium iodide (0.78 grams, 5.80 mmol) is added, and the solution is refluxed in the dark for 24 hours, after which time it is cooled to room temperature, eluted with ethyl acetate (50 milliliters), and it is washed with 5 percent aqueous sodium thiosulfate (2 x 50 milliliters), water (1 x 50 milliliters) and brine (1 x 50 milliliters). The organic layer is then dried over MgSO 4, evaporated, and the residue is chromatographed (silica, 3% MeOH / CH 2 Cl 2 / 0.05 percent acetic acid) to give a clear crystal, which is crystallized with a mixture. of EtOAc / hexane (1:50), to give N- [2- [(3-carboxyphenyl) methoxy] -1 (S) -cyanoethyl] -3-methyl-N- (diphenylacetyl) -L-phenylalaninamide as a solid white, mp 160-162 ° C.

Example 304: N- [2- [(3- (Allyloxycarbonyl) -phenyl) methoxy] -1 (S) -cyanoethyl] -3-methyl-N- (N-morpholinocarbonyl) -L-phenylalaninamide A. 3-Methyl-N- (terbutoxy-carbonyl) -L-phenylalanine To a suspension of 3-methyl-L-phenylalanine (2.7 grams, 15 mmol) in 85 milliliters of 10 percent triethylamine / methanol, is added Terbutyl dicarbonate (6.5 grams, 30 mmol), and the solution is refluxed for 2.5 hours. After cooling, the methanol and triethylamine are evaporated, and the residue is diluted with Et20 (250 milliliters), and extracted with saturated Na2CO3 (2 x 75 milliliters). The combined aqueous layers are again washed with Et20 (250 milliliters), and then acidified with concentrated HCl to pH = 2-3. The resulting mixture is then extracted with EtOAc (3 x 75 milliliters), and washed with water and brine, dried over MgSO 4, and evaporated to give 3-methyl-N- (terbutoxy-carbonyl) -L-phenylalanine as a transparent oil.

B. Allyl 3- (chloromethyl) -benzoate A solution of 3- (chloromethyl) -benzoic acid (50.0 grams, 0.293 moles), potassium carbonate (48.61 grams, 0.352 moles), and allyl bromide (50.7 milliliters, 0.586) moles) in acetone (500 milliliters), refluxed for 2 hours, after which time, the solution is cooled to room temperature, and filtered through celite. The filtrate is evaporated, and the residue is chromatographed (silica, 5 percent EtOAc / hexane) to give allyl 3- (chloromethyl) -benzoate as a clear oil.

C. Allyl 3- (iodomethyl) -benzoate A solution of allyl 3- (chloromethyl) -benzoate (54.5 grams, 0.259 mmol), and sodium iodide (46.56 grams, 0.311 moles) in acetone (500 milliliters), stir at room temperature for 6.5 hours, after which time the mixture is filtered. The filtrate is evaporated and the residue is dissolved in diethyl ether (500 milliliters), then washed with water (1 x 200 milliliters), with a 5 percent sodium sulfite solution (1 x 200 milliliters), and brine (1 x 200 milliliters), dried over magnesium sulfate, and evaporated to give allyl 3- (iodomethyl) -benzoate as a white solid, which is used directly. D. O- E [3-allyloxycarbonyl) -phenyl] methyl] -N- (terbutoxy-carbonyl) -L-serine. Sodium hydride (19.4 grams, 60 percent in mineral oil, 484.4 mmol) is washed with dry hexanes. (2 x 30 milliliters), to remove the mineral oil, and then suspended in anhydrous dimethylformamide (330 milliliters). To this suspension, a solution of N-butoxycarbonyl-L-serine (45.2 grams, 220.2 mmol) in dimethylformamide (110 milliliters) is added dropwise at 0 ° C with vigorous stirring. The mixture is stirred for an additional 5 minutes at 0 ° C, and then at room temperature for 30 minutes. The solution is again cooled to 0 ° C, and a solution of allyl 3-iodomethylbenzoate (66.6 grams, 220.2 mmol) in dimethylformamide (110 milliliters) is added dropwise over 15 minutes. The mixture is then heated at room temperature for 30 minutes. The reaction mixture is poured into ice water (2.2 liters) and acidified to a pH of 2 with 1 N HCl (270 milliliters). The mixture is extracted with ether (1 x 600 milliliters, then 3 x 300 milliliters), and the combined ether extracts are then washed with water (5 x 200 milliliters), and then dried (MgSO 4), and evaporated in vacuo. to give 0 - [[3- (allyloxycarbonyl) -phenyl] methyl] -N- (terbutoxycarbonyl) -L-serine as a yellowish oil, which is used as is in the next step. E. O- [[3- (allyloxycarbonyl) phenyl] methyl] -N- (terbutoxy-carbonyl) -L-serinamide A solution of O- [[3- (allyloxycarbonyl) phenyl] methyl] -N- (terbutoxy-carbonyl) ) -L-serine (79.2 grams, 209 millimoles) and N-methylmorpholine (68.9 milliliters, 63.4 grams, 627 millimoles) in CH2C12 (800 milliliters), is cooled to -10 ° C, and isobutyl chloroformate is added dropwise ( 32.5 milliliters, 34.2 grams, 251 millimoles) for 10 minutes. After stirring for 15 minutes, ammonia gas is bubbled into the solution at a moderately vigorous rate for 15 minutes at -10 ° C. The solution is then heated to room temperature, and stirred for 30 minutes. The reaction mixture is cooled to 0 ° C, and 1 N HCl (800 milliliters) is added. The organic phase is washed with 1 N HCl (2 x 700 milliliters), then washed with saturated NaHCO 3 (700 milliliters), then dried (MgSO 4), and evaporated in vacuo to give 0 - [[3- (allyloxycarbonyl) phenyl] methyl] -N- (terbutoxy-carbonyl) -L-serinamide as a thick oil, which is used as it is in the next step.

F. O- [[3- (allyloxycarbonyl) phenyl] methyl] -L-serinamide.HCl To a solution of 0 - [[3- (allyloxycarbonyl) phenyl] methyl] -N- (terbutoxy-carbonyl) -L -serinamide (69 grams, 182.5 millimoles) in EtOAc (1000 milliliters) at 0 ° C, HCl gas was slowly bubbled for 1 hour, during which time a white precipitate was observed. The mixture is heated at room temperature for 30 minutes, after which time the EtOAc is removed by evaporation. The resulting residue is triturated with ether (500 milliliters) with vigorous stirring for 30 minutes. The precipitate is collected by vacuum filtration, washed with ether (2 x 100 milliliters), and then air dried to give 0 - [[3- (allyloxycarbonyl) phenyl] methyl] -L-serinamide.HCl as a solid free-flowing white.

G. N- [3-methyl-N- (terbutoxy-carbonyl) -L-phenylalanyl] -O- [[3-allyloxycarbonyl) -phenyl] -methyl-L-serinamide To a solution of O- [[3- ( allyloxycarbonyl) phenyl] methyl] -L-serinamide. HCl (2.92 grams, 10.46 millimoles), 3-methyl-N- (terbutoxy-carbonyl) -L-phenylalanine (3.29 grams, 10.46 millimoles), 1-hydroxybenzotriazole (1.92 grams, 12.55 millimoles), and N-methylmorpholine (4.6 milliliters) , 4.23 grams, 41.84 millimoles) in CH2C12 (120 milliliters), 1- (3-dimethylaminopropyl) -3-ethylcarbodi-imide.HCl (3.01 grams, 15.69 millimoles) is added in one portion. The solution is stirred for 16 hours, then washed with 1 N HCl (100 milliliters), saturated aqueous NaHCO3 (1 x 50 milliliters), water (1 x 50 milliliters) and brine (1 x 50 milliliters), dried over MgSO4. , and it evaporates. The residual solid is triturated with hot methanol to give N- [3-methyl-N- (terbutoxy-carbonyl) -L-phenylalanyl] -O- [[3- (allyloxycarbonyl) -phenyl] methyl] -L-serinamide as a solid white.

H. N- [2- [3- (Allyloxycarbonyl) -phenyl) methoxy] -1 (S) -cyanoe-tyl] -3-methyl-N- (terbutoxycarbonyl) -L-phenylalaninamide Oxalyl chloride is added dropwise ( 1.79 milliliters, 2.6 grams, 20.48 millimoles) to dimethylformamide (30 milliliters), and the resulting solution is cooled to 0 ° C. After the solution becomes clear, pyridine (3.31 milliliters, 3.24 grams, 40.96 millimoles) is added, followed by N- [3-methyl-N- (terbutoxy-carbonyl) -L-phenylalanyl] -0 [[3- (allyloxycarbonyl) phenyl] methyl] -L-serinamide (5.52 grams, 10.24 mmol), in one portion. The yellow reaction solution is stirred at 0 ° C for 1.5 hours, after which time it is diluted with EtOAc (50 milliliters), and washed with saturated NaHCO 3 (1 x 50 milliliters), saturated LiCl (1 x 50 milliliters), it is dried over MgSO4, and evaporated. The residue is passed through chromatography (silica, 40 percent EtOAc / hexane) to give N- [2- [(3-allyloxycarbonyl) -phenyl) methoxy] -1 (S) -cyanoethyl] -3-methyl-N- (terbutoxycarbonyl) -L-phenylalaninamide as a white solid.

I. N- [2- [(3-Allyloxycarbonyl) -phenyl) methoxy] -1 (S) -cyanoethyl] -3-methyl-L-phenylalaninamide A solution of N- [2- [(3-allyloxycarbonyl) -phenyl) ) -methoxy] -1 (S) -cianoethyl] -3-methyl-N- (terbutoxy-carbonyl) -L-phenylalaninamide (3.18 grams, 6.10 mmol) in 96 percent formic acid (40 milliliters), is stirred at room temperature for 5.5 hours. The formic acid is evaporated (high vacuum, 25 ° C), and the residue is taken up in water (50 milliliters), and basified with saturated NaHCO 3 (100 milliliters). The resulting mixture is extracted with EtOAc (3 x 50 milliliters), and then washed with water (2 x 100 milliliters) and brine (1 x 100 milliliters), dried over MgSO 4, and evaporated to give N- [2- [(3-Allyloxycarbonyl) -phenyl) methoxy] -1 (S) -cyanoethyl] -3-methyl-L-phenylalaninamide as a clear, thick oil.

J. N- [2- [(3-Allyloxycarbonyl) -phenyl) methoxy] -1 (S) -cyanoe-tyl] -3-methyl-N- (N-morpholinocarbonyl) -L-phenylalaninamide To a solution of N- [2- [(3-allyloxycarbonyl) -phenyl) methoxy] -1 (S) -cyanoethyl] -3-methyl-L-phenylalaninamide.HCl (0.29 grams, 0.69 mmol), and N-methylmorpholine (0.23 milliliters, 0.21 grams) , 2.07 millimoles) in CH2C12 (10 milliliters), morpholinecarbonyl chloride (0.21 grams, 0.23 milliliters, 2.065 millimoles) is added in one portion, and the solution is stirred at room temperature for 16 hours. The solution is then diluted with additional CH2C12 (40 milliliters), and washed with 1 N HCl (50 milliliters), saturated aqueous NaHCO3 (1 x 50 milliliters), water (1 x 50 milliliters) and brine (1 x 50 milliliters). , it is dried over MgSO4, and evaporated. The residue is chromatographed (silica, 80 percent EtOAc / hexane) to give N- [2- [(3-allyloxycarbonyl) -phenyl) -methoxy] -1 (S) -cyanoethyl] -3-methyl-N - (N-morpholinecarbo-nyl) -L-phenylalaninamide as a clear oil. The corresponding 3-carboxyphenylmethoxy compound is prepared as follows: To a solution of N- [2- [(3- (allyloxycarbonyl) -phenyl) methoxy] -1 (S) -cyanoethyl] -3-methyl-N- (N -morpholinocarbonyl) -L-phenylalaninamide (see Example 3, 0.2 grams, 0.375 mmol) in anhydrous tetrahydrofuran (20 milliliters), morpholine (0.327 milliliters, 0.326 grams, 3.75 millimoles) is added, followed by Pd (PPh3) 4 ( 0.043 grams, 0.0375 millimoles). The solution is stirred at room temperature for 3 hours, after which time the tetrahydrofuran is evaporated. The residue is taken up in EtOAc (100 milliliters), and washed with 1 N HCl (100 milliliters), saturated aqueous NaHCO 3 (1 x 50 milliliters), water (1 x 50 milliliters), and brine (1 x 50 milliliters), it is dried over MgSO4, and evaporated. The residue is passed through chromatography (silica, 3% MeOH / CH2Cl2 / 0.05 percent acetic acid), to give a clear crystal, which is crystallized with a mixture of EtOAc / hexane (1:50), to give N- [2- [(3-carboxyphenyl) -methoxy] -1 (S) -cyanoethyl] -3-methyl-Noc- (N-morpholinocarbonyl) -L-phenylalaninamide as a white solid, mp 100 ° C (decomposition).

Example 305: Synthesis of N- [3- (3-methoxycarbonyl) -phenoxy-1-cyanopropyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide A. 3- (2-bromoethoxy) - Methyl benzoate A solution of methyl 3-hydroxybenzoate (5.0 grams, 32.86 millimoles), 1,2-dibromoethane (11.3 milliliters, 131.44 millimoles), and potassium carbonate (5.45 grams, 39.43 millimoles) in dimethylformamide (100 milliliters), reflux for 16 hours, after which time, the solution is cooled, concentrated in vacuo, and chromatographed to give methyl 3- (2-bromoethoxy) -benzoate, as a yellow oil.

B. Methyl 3- (2-iodoethoxy) -benzoate A solution of methyl 3- (2-bromoethoxy) -benzoate (2.4 grams, 9.26 millimoles), and sodium iodide (2.78 grams, 18.52 millimoles) in acetone (50 milliliters), it is refluxed for 2 hours. Then the resulting mixture is filtered and concentrated. The residue is diluted with EtOAc (100 milliliters), washed with 5 percent Na 2 SO 3 (50 milliliters), water (2 x 50 milliliters) and brine (50 milliliters), dried over MgSO 4, and evaporated to give 3 - Methyl (2-iodoethoxy) -benzoate, as a yellow oil, which is used directly. 2- (diphenylmethyleneamino) -4- [(3-methoxycarbonyl) -phenoxy] -butyronitrile To a solution of sodium hexamethyldisilazide (8.82 milliliters of a 1.0 M solution, 8.82 mmol) in 90 milliliters of tetrahydrofuran at -78 ° C, add to a solution of N- (diphenylmethylene) aminoacetonitrile (1.90 grams, 8.65 mmol) in tetrahydrofuran (30 milliliters), by means of a syringe. After stirring for 30 minutes at -78 ° C, a solution of methyl 3- (2-iodoethoxy) -benzoate (2.7 grams, 8.82 mmol) in tetrahydrofuran (20 milliliters) is added to the reaction solution by means of a syringe Then the solution is warmed to room temperature, and it is left stirring for 3 hours. The mixture is then quenched with saturated NH4C1 (50 milliliters), and the aqueous layer is extracted with EtOAc (3 x 50 milliliters). The combined organic layers are washed with water (1 x 50 milliliters) and brine (1 x 50 milliliters), and passed by chromatography (silica, 12.5 percent EtOAc / hexane), to give 2- (diphenylmethyleneamino) -4- [(3-methoxycarbonyl) -phenoxy] -butyronitrile, as a clear oil. D. 2-amino-4- [3- (methoxycarbonyl) -phenoxy] -butyronitrile The 2- (diphenylmethyleneamino) -4- [(3-methoxycarbonyl) -phenoxy] -butyronitrile (3.7 grams, 6.78 mmol) is vigorously stirred during 16 hours in a biphasic mixture of 1 N HCl (7.5 milliliters) and Et20 (90 milliliters). The ether layer is removed, and the aqueous layer is washed with Et20 (3 x 50 milliliters), basified to a pH of 8 with 1 N NaOH, and extracted with EtOAc (3 x 50 milliliters). The combined organic layers are then washed with brine (1 x 50 milliliters), dried over MgSO 4, and evaporated to give 2-amino-4- [3- (methoxycarbonyl) -phenoxy] -butyronitrile, as a clear oil.

E. N- [3- (3- (methoxycarbonyl) -phenoxy-1-cyanopropyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide To a solution of 2-amino-4- [3 - (methoxycarbonyl) -phenoxy] -butyronitrile (0.5 grams, 2.13 millimoles), 3-methyl-N- (2,2-diphenylacetyl) -L-phenylalanine (see Example 1, 0.80 grams, 2.13 millimoles) and di-isopropylethylamine (1.1 milliliters, 6.39 millimoles) in CH2C12 (15 milliliters), benzotriazole-1-yloxy-tris- (pyrrolidino) -phosphonium hexafluorophosphate (PyBop, 1.22 grams, 2.34 millimoles) is added in one portion after stirring for 1.5 hours, add an additional portion of PyBop (0.61 grams, 1.2 mmol), and the solution is stirred overnight.The reaction mixture is washed with 1 N HCl (50 milliliters), saturated aqueous NaHCO 3 (1 x 50 milliliters) , water (1 x 50 milliliters), and brine (1 x 50 milliliters), dried over MgSO 4, and evaporated The residue is passed through chromatography (silica, 50 percent EtOAc / hexane), to give N- [ 3- (3- (methoxycarbonyl ) -phenoxy) -1-cyanopropyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide as a white solid, m.p. 152 -153 ° C.

The corresponding carboxyphenoxy compound is prepared as follows: To a solution of N- [3- (3- (methoxycarbonyl) -phenoxy) -1-cyanopropyl] -3-methyl-Nx- (2, 2-diphenylacetyl) -L-phenylalaninamide ( 0.16g, 0.272 mmol) in tetrahydrofuran (3ml) is added a solution of LiOH H20 (22mg, 0.544 mmol) in water (1.5ml). The reaction is stirred for 1 hour, after which time, tetrahydrofuran is evaporated. The residue is ocidified with 1N HCl and extracted with EtO A6 (3x3Oml). The aqueous layer is washed with brine (30ml), dried over MgSO 4, evaporated and chromatographed (5% MeOH, 0.05% AcOH, CH 2 C 12) to give N- [3- (3-carboxyphenoxy) -l-cyanopropyl ] -3-methyl-Nx- (2,2-diphenylacetyl) -L-phenylalaninamide, as a white solid pf 169-170 ° C.

Example 306: Synthesis of N- [2- [(5-methoxycarbonyl) -fur-2-yl) methoxy] -1 (S) -cyanoethyl] -3-methyl-N- (2,2-diphenylacetyl) -L- phenylalaninamide A. 5- (bromomethyl) -2-furoate To a solution of 5-methylfurfural (5.0 grams, 45.5 millimoles) in CH2C12 (100 milliliters), powdered N-bromosuccinimide (17.8 grams, 100 millimoles) is added, and the solution It undergoes sun lamp irradiation. After 15 minutes, the solution begins to have a vigorous reflux, and then settles down after another 2 to 3 minutes. After an additional 10 minutes, the dark mixture is cooled to room temperature, and MeOH (30 milliliters) is added. After 10 minutes, the solution is evaporated, and the residue is diluted with Et20, and washed with saturated NaHCO3 (50 milliliters), water (50 milliliters), and brine (50 milliliters), dried over MgSO4, and evaporated. . The residue is chromatographed (silica, 15 percent EtOAc / hexane) to give methyl 5- (bromomethyl) -2-furoate, as a yellowish oil.

B. O- [[(5-methoxycarbonyl) -fur-2-yl] -methyl] -N- (terbuto-xi-carbonyl) -L-serine To a solution of N- (terbutoxy-carbonyl) -L-serine (2.5 grams, 12.3 millimoles) in dimethylformamide (50 milliliters) at -15 ° C, sodium hydride (1.22 grams, 60 percent in mineral oil, 30.7 millimoles) is added in portions with vigorous stirring for 0.5 hours. After all of the sodium hydride is added, the mixture is stirred for an additional 10 minutes at 0 ° C, and then at room temperature for 30 minutes. The solution is again cooled to 0 ° C, and a solution of methyl 5- (bromomethyl) -2-furoate (2.5 grams, 12.3 mmol) in dimethylformamide (10 milliliters) is added dropwise over 2 minutes. The mixture is then heated at room temperature for 16 hours, and the residue is quenched with 10 percent NaH2P04 (100 milliliters), and acidified to a pH of 3 with 1N HCl. 10 percent LiCl is added (30 milliliters) to the solution, and the resulting mixture is extracted with EtOAc (3 x 50 milliliters). The combined extracts are washed with brine (50 milliliters), dried over MgSO4, and evaporated to give a yellowish syrup. This residue is taken up in Et20 (50 milliliters), and extracted with saturated NaHCO3 (2 x 50 milliliters). The aqueous layer is acidified with concentrated HCl, and extracted with Et20 (2 x 50 milliliters), dried (MgSO4), and evaporated. Chromatography (silica, 5 percent MeOH / CH2Cl2) produces O - [[(5-methoxycarbonyl) -fur-2-yl] -methyl] -N. (terbutoxicarbonil) -L-serine as a yellowish oil.

C. O- [[(5-methoxycarbonyl) -fur-2-yl] -methyl] -N- (terbutoxy-carbonyl) -L-serinamide A solution of 0 - [[(5-methoxycarbonyl) -fur-2- il] -methyl] -N- (terbutoxy-carbonyl) -L-serine (0.79 grams, 2.1 mmol) and N-methylmorpholine (0.46 milliliters, 4.2 mmol) in CH2C12 (50 milliliters), cooled to -10 ° C, and isobutyl chloroformate (0.27 milliliters, 2.1 mmol) was added dropwise over 10 minutes. After stirring for 15 minutes, ammonia gas is bubbled into the solution at a moderately vigorous rate for 15 minutes. Then the solution is heated at room temperature for 30 minutes. The CH2C12 is evaporated *, and the residue is dissolved in EtOAc (50 milliliters). This solution is then extracted with 1 N HCl (2 x 50 milliliters), Saturated NaHC03 (50 milliliters), water (50 milliliters), and brine (50 milliliters), dried over MgSO4, and evaporated, to give O- [[(5-methoxycarbonyl) -fur-2-yl] -methyl] ] -N - (terbutoxy-carbonyl) -L-serinamide as a chestnut solid. D. O- [[(5-methoxycarbonyl) -fur-2-yl] -methyl-L-serineamide.HCl To a solution of O - [[(5-methoxycarbonyl) -fur-2-yl] -methyl] ] -N- (terbutoxycarbonyl) -L-serinamide (0.52 grams, 1.58 millimoles) in EtOAc (50 milliliters) at 0 ° C, HCl gas is bubbled at a moderately vigorous rate for 1 minute, during which time, a batch of white precipitate is observed. The mixture is stirred at 0 ° C for 10 minutes, after which time, the ethyl acetate is removed, yielding O- [[(5-methoxycarbonyl) -fur-2-yl] -methyl] -L-serinamide. HCl as a yellowish solid.

E. N- [3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanyl] -O- [[5-methoxycarbonyl) -fur-2-yl] -methyl] -L-serinamide To a solution of 3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanine (0.40 grams, 1.5 mmol), O - [[(5-methoxycarbonyl) -fur-2-yl] methyl] -L-serinamide. HCl (0.54 grams, 1.5 mmol), 1-hydroxybenzotriazole hydrate (0.2 grams, 1.5 mmol) and N-methylmorpholine (0.66 milliliters), 6.0 mmol) in CH2C12 (30 milliliters), is added 1- (3-dimethylaminopropyl) 3-ethylcarbodi-imide HCl (0.43 grams, 2.3 mmol) in one portion, and the mixture is stirred at room temperature for 16 hours. The solution is then washed with 1 N HCl (100 milliliters), saturated aqueous NaHCO 3 (1 x 50 milliliters), water (1 x 50 milliliters), and brine (1 x 50 milliliters), dried over MgSO 4, and evaporated. The residual solid is triturated from ether, to give N- [3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanyl] -O- [[5- (methoxycarbonyl) -fur-2-yl]] -methyl] -L-serinamide as a light yellow solid.

F. N- [2- [5-methoxycarbonyl) -fur-2-yl) -methoxy] -1 (S) -cyanoethyl] -3-methyl-N- (2,2-diphenylacetyl) -L-phenylalaninamide It is added drip oxalyl chloride (0.046 milliliters, 0.36 millimoles) to dimethylformamide (5 milliliters), and the resulting solution is cooled to 0 ° C. After the solution remains clear, pyridine (0.032 milliliters, 0.40 millimoles) is added, followed by N- [3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanyl] -O- [[5-methoxycarbonyl] ) -fur-2-yl] -methyl-L-serinamide (0.20 grams, 0.33 mmol), in one portion. The yellow reaction solution is stirred at 0 ° C for 1.5 hours, after which time it is diluted with EtOAc (50 milliliters), and washed with saturated NaHCO 3 (1 x 50 milliliters), saturated LiCl (1 x 50 milliliters), dried over MgSO 4, and evaporated. The residue is passed through chromatography (silica, 40 percent EtOAc / hexane) to give N- [2 - [(5-methoxycarbonyl) -fur-2-yl) -methoxy] -1 (S) -cianoethyl] -3 -methyl-N- (2,2-diphenylacetyl) -L-phenylalaninamide as a white solid.

Example 307: Synthesis of N- [2- [(3-methoxycarbonyl) phenyl) -thiomethoxy] -1 (S) -cyanoethyl] -3-methyl-N- (2,2-diphenylacetyl) -L-phenylalaninamide A. N- [3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanyl] -S-trityl-L-cysteinamide To a solution of 3-methyl-N- (2, 2-diphenylacetyl-L- phenylalanine (see Example 1, 1.0 grams, 2.68 millimoles), 1-hydroxybenzotriazole hydrate (0.41 grams, 2.68 millimoles) and N-methylmorpholine (0.74 milliliters, 6.69 millimoles) in CH2C12 (80 milliliters), 1- ( 3-dimethylaminopropyl) -3-ethylcarbodi-imide.HCl (0.77 grams, 4.02 mmol) in one portion After stirring for 30 minutes at room temperature, S-trityl-L-cysteinamide (0.97 grams, 2.68 mmol) was added to the solution in one portion, and the solution is stirred for 16 hours.The solution is evaporated, and the residue is partitioned between water (80 milliliters) and ethyl acetate (80 milliliters) .The aqueous layer is washed with EtOAc (2 x 80 milliliters), and the combined organic layers are then washed with 1 N HCl (100 milliliters), saturated aqueous NaHCO 3 (1 x 50 milliliters), water (1 x 50 milliliters), and brine (1 x 50 milliliter). s), dried over MgSO4, and evaporated. The residue is triturated with Et20 / hexane (1: 1), to give N- [3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanyl] -S-trityl-L-cysteinamide as a white solid.

B, N- [3-methyl-N- (2,2-diphenylacetyl) -L-phenylalanyl] -L-cysteinamide To a solution of N- [3-methyl-N- (2, 2-diphenylacetyl) -L- phenylalanyl] -S-trityl-L-cysteinamide (0.68 grams, 0.95 mmol) in CH2C12 (20 milliliters), triethylsilane (0.30 milliliters, 1.9 millimoles) is added in one portion, followed by the trickle-drop addition of trifluoroacetic acid ( 10 milliliters). The yellow solution is stirred at room temperature for 1 hour, after which time the solvent is evaporated, and the residue is suspended in water (30 milliliters), filtered, and the collected solid is washed with water and ether (100 milliliters of water). each), and dried in vacuo, to give N- [3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanyl] -L-cysteinamide, as a white solid.

C. N- [3-methyl-N- (2,2-diphenylacetyl) -L-phenylalanyl] -S- [[3-methoxycarbonyl) phenyl] methyl] -L-cysteinamide A solution of N- [3-methyl- N- (2, 2-diphenylacetyl) -L-phenylalanyl] -L-cysteinamide (0.72 grams, 1.51 mmol), methyl 3-bromomethyl) -benzoate (0.35 grams, 1.41 mmol), and di-isopropylethylamine (0.27 milliliters, 1.53 mmol) is stirred at room temperature overnight. The solvent is evaporated, and the residue is treated with 1 N HCl (50 milliliters), and filtered to collect a white solid, which is washed with water and Et20 (100 milliliters each). Vacuum drying yields N- [3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanyl] -S- [[3-methoxycarbonyl) phenyl) methyl] -L-cysteinemide as a white solid.

D. N- [2- [(3-methoxycarbonyl) phenyl) thiomethoxy] -1 (S) -cia-noethyl] -3-methyl-N- (2,2-diphenylacetyl) -L-phenylalaninamide. Chloride is added dropwise. of oxalyl (0.29 mmol, 2.90 mmol) to dimethylformamide (20 milliliters), and the resulting solution is cooled to 0 ° C. After the solution becomes clear, pyridine (0.54 mmole, 5.8 mmole) is added, followed by N- [3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanyl] -S- [[3 - (methoxycarbonyl) -phenyl] -methyl] -L-cysteinamide (0.90 grams, 1.51 mmol), in one portion. The yellow reaction solution is stirred at 0 ° C for 1.5 hours, after which time it is diluted with EtOAc (50 milliliters), and washed with saturated NaHCO 3 (1 x 50 milliliters), saturated LiCl (1 x 50 milliliters), dried over MgSO 4, and evaporated. The residue is passed through chromatography (silica, 33 percent EtOAc / hexane) to give N- [2 - [(3-methoxycarbonyl) phenyl) thiomethoxy] -1 (S) -cianoethyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide as a white solid.

Example 308: N- [2- [(3-carboxyphenyl) methansulfinyl] -1 (S) -cyanoethyl] -3-methyl-N- (2,2-diphenylacetyl-L-phenylalaninamide To a solution of N- [2- [(3-carboxyphenyl) thiomethoxy] -1- (S) -cyanoethyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide (89 milligrams, 0.15 mmol) in acetone (5 milliliters), add a solution of potassium peroxymonosulfate (Oxone®, 0.11 grams, 0.18 millimoles) in water (5 milliliters) at 0 ° C, and the solution is stirred at 0 ° C for 40 minutes, 5% NaHS04 is added (10 milliliters), and the cloudy suspension is filtered.The solid is washed with water (50 milliliters), dried under vacuum, and then recrystallized (CH2C12, Et20) to give the product of N- [2 - [(3-carboxyphenyl) methansulfinyl] -1 (S) -cyanoethyl] -3-methyl-N- (2,2-diphenylacetyl-L-phenylalaninamide, as a white solid, mp 170-171 ° C.

Example 309: N- [4- (3-methoxycarbonyl-lH-pyrazol-1-yl) -1 (S) -cyanobutyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide A. (S) -5-hydroxy-2- (terbutoxy-carbonylamino) -terthoxy-pentanoate To a solution of N- (terbutoxy-carbonyl) -L-glutamic acid terbutilyester (6.0 grams, 19.78 mmol), and trimethylamine ( 2.83 milliliters, 20.27 millimoles) in tetrahydrofuran at -10 ° C, ethyl chloroformate (1.94 millimoles, 20.27 millimoles) is added dropwise, by means of a syringe, and the solution is stirred at -10 ° C for 30 minutes. The solution is filtered to remove the precipitate, and the filtrate is added to a solution of NaBH 4 (2.3 grams, 60.86 millimoles) in tetrahydrofuran (40 milliliters) and water (50 milliliters). This solution is then stirred for 4 hours, after which time the solution is acidified with 1 N HCl to pH = 5, and the tetrahydrofuran is evaporated. The aqueous residue is extracted with EtOAc (3 x 200 milliliters), and the organic layers are then washed with 1 N NaOH (2 x 300 milliliters), water (300 milliliters), and brine (300 milliliters), dried over MgSO4, and evaporate. Chromatography (silica, 20 percent EtOAc / hexane) produces (S) -5-hydroxy-2- (terbutoxy-carbonylamino) -terthoxybutyrate as a thick oil.

B. (S) -5-Iodo-2- (terbutoxycarbonylamino) -terthoxybutyrateto a solution of (S) -5-hydroxy-2- (terbutoxycarbonylamino) -terthoxybutyrate (5.79 grams), 20.0 mmol), triphenylphosphine (8.13 grams, 31.0 mmol) and imidazole (2.04 grams, 30.0 mmol) in CH2C12 (200 milliliters) at room temperature, iodine (6.35 grams, 25.0 milliliters) was added, in portions, for 30 minutes . Then the mixture is stirred for 16 hours at room temperature. Methanol (20 milliliters) is added to the solution, which is then stirred for an additional 1 hour. The solvent is evaporated, and the residue is purified by chromatography (silica, 33 percent EtOAc / hexane) to give tert-butyl (S) -5-iodo-2- (terbutoxy-carbonylamino) -pentanoate as a clear oil.

C. N-hydroxysuccinimide-ester of 3-methyl-N- (2,2-diphenylacetyl) -L-phenylalanine A solution of 3-methyl-N- (2,2-diphenylacetyl) -L-phenylalanine (see Example 1, 10.93 grams, 2.5 millimoles) in dioxane (50 milliliters) at 0 ° C, is added to N-hydroxysuccinimide (0.29 grams, 2.5 millimoles) in one portion, followed by a DCC solution (0.52 grams, 2.5 millimoles) in dioxane (10 milliliters), which is added by dripping for 10 minutes. The cloudy mixture is warmed to room temperature overnight, after which time it is again cooled to 0 ° C, and filtered. The filtrate is evaporated to give 3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanine N-hydroxysuccinimide ester as a white solid.

D. (S) -5- (3-methoxycarbonyl-lH-pyrazol-1-yl) -2- (terbutoxy-carbonylamino) -terthoxy-pentanoate To a solution of methyl IH-pyrazole-3-carboxylate (Synth. Comm., 25, 1995, 761) (0.98 grams, 7.74 millimoles) in dimethylformamide (20 milliliters) at 0 ° C, NaH is added (suspension at 60 percent, 0.31 grams, 7.74 millimoles) in portions, for 10 minutes. After stirring for an additional 10 minutes, a solution of tert-butyl (S) -5-iodo-2- (terbutoxy-carbonylamino) -pentanoate (2.78 grams, 9.29 mmol) in dimethylformamide (20 milliliters) is added over 2 minutes, and The solution is heated at room temperature for 16 hours. The solvent is evaporated (high vacuum), the residue is treated with water (50 milliliters), and the aqueous layer is extracted with EtOAc (3 x 80 milliliters). The combined organic layers are washed with water (2 x 200 milliliters) and brine (100 milliliters), dried over MgSO4, and evaporated. Chromatography (silica, 25 percent EtOAc / hexane) produces the two regioisomeric products in a ratio of about 2: 1. The minor product, which is determined to be the desired product, (S) -5- (3-methoxycarbonyl-1H-pyrazol-1-yl) -2- (terbutoxy-carbonylamino) -terthoxybutyrate, is isolated as an oil thick transparent.

E. (S) -5- (-3-methoxycarbonyl-lH-pyrazol-1-yl) -2-aminopentanoic acid. HCl To a solution of (S) -5- (-3-methoxycarbonyl-1H-pyrazole-1 -il) -2- (terbutoxy-carbonylamino) -terthobutyl pentanoate (0.84 grams, 0.21 millimoles in CH2C12 (20 milliliters) at 0 ° C, HCl gas is bubbled in for 30 minutes, then the solution is heated to room temperature environment for 30 minutes The evaporation of the solvent produces (S) -5- (3-methoxycarbonyl-1H-pyrazol-1-yl) -2-aminopentanoic acid.HCl as a gray-white solid.

F. N- [4- (3-methoxyphenyl-lH-pyrazol-1-yl) -1 (S) -carboxibuyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide A Solution of (S) -5- (-3-methoxycarbonyl-1H-pyrazol-1-yl) -2-aminopentanoic acid HCl (0.67 grams, 2.13 mmol) in 10 milliliters of water, a solution of NaHCO3 ( 0.72 grams, 8.53 millimoles) in water (10 milliliters). After the bubbling is complete, a solution of N-hydroxysuccinimide-ester of 3-methyl-Noc- (2,2-diphenylacetyl) -L-phenylalanine (0.67 grams, 2.13 mmol) in 20 milliliters of dioxane is added dropwise. 10 minutes, and the solution is stirred at room temperature for 16 hours. Then the solvent evaporates, and the residue is diluted with water (50 milliliters), and adjusted to a pH = 4 with 1 N HCl. The aqueous layer is extracted with EtOAc (3 x 80 milliliters), and the combined extracts are washed with brine (2 x 100 milliliters), dried over MgSO4, evaporate, and triturate from Et20 to give N- [4- (3-methoxycarbonyl-1H-pyrazol-1-yl) -1 (S) -carboxybutyl] -3-methyl-Noc- (2, 2-diphenylacetyl) -L-phenylalanine, which is carried out directly.

G. N- [4- (3-methoxycarbonyl-lH-pyrazol-1-yl) -1 (S) -amino-carbonyl) -butyl] -3-methyl-N - (2,2 -diphenylacetyl) -L- phenylalaninamide A solution of N- [4- (3-methoxycarbonyl-1H-pyrazol-1-yl) -1 (S) -carboxybutyl] -3-methyl-Noc- (2, 2-diphenylacetyl) -L-phenylalaninamide (0.3 grams, 0.5 millimoles), and N-methylmorpholine (0.17 milliliters), 1.5 mmol) in CH2C12 (50 milliliters), cooled to -10 ° C, and isobutyl chloroformate (0.065 milliliters, 0.5 mmol) was added dropwise during 10 minutes. After stirring for 15 minutes, ammonia gas is bubbled into the solution at a moderately vigorous rate for 15 minutes. Then the solution is heated at room temperature for 30 minutes. The CH2C12 is evaporated, the residue is treated with water (30 milliliters). The suspension is adjusted to pH = 7 with 1 N HCl, and filtered. The solid is washed with water (50 milliliters), and dried in vacuo to give N- [4- (3-methoxycarbonyl-1H-pyrazol-1-yl) -1 (S) - (aminocarbonyl) -butyl] -3 -methyl-N - (2,2-diphenylacetyl) -L-phenylalaninamide.

H. N- [4- (3-methoxycarbonyl-lH-pyrazol-1-yl) -1 (S) -cyano-butyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide It is added drip oxalyl chloride (0.082 milliliters, 0.94 millimoles) to dimethylformamide (20 milliliters), and the resulting solution is cooled to 0 ° C. After the solution becomes clear, pyridine (0.15 milliliters, 1.88 millimoles) is added, followed by N- [4- (3-methoxycarbonyl-1H-pyrazol-1-yl) -1 (S) - (aminocarbonyl) butyl] -3-methyl-N- (2, 2-diphenyl-acetyl) -L-phenylalaninamide (0.28 grams, 0.47 mmol), in one portion. The yellow reaction solution is stirred at 0 ° C for 1.5 hours, after which time it is diluted with EtOAc (50 milliliters), and washed with saturated NaHCO 3 (1 x 50 milliliters), saturated LiCl (1 x 50 milliliters), it is dried over MgSO4, and evaporated. The residue is passed through chromatography (silica, 66 percent EtOAc / hexane) to give N- [4- (3-methoxycarbonyl-1H-pyrazol-1-yl) -1 (S) -cyanobutyl] -3-methyl- N - (2,2-diphenylacetyl) -L-phenylalaninamide as a white solid.

Example 310: N- [4- (3-methoxycarbonyl-phenyl) -1 (S) -cyanobutyl] 3-methyl-N- (2,2-diphenylacetyl) -L-phenylalaninamide A. N- (terbutoxy-carbonyl) - (S) -propargylglycinamide To a solution of N- (terbutoxy-carbonyl) - (S) -propargylglycine (2.44 grams, 11.45 millimoles) in CH2C12 (50 milliliters), N is added -methylmorpholine (3.78 milliliters, 34.4 millimoles) in one portion. The solution is then cooled to -10 ° C, and isobutyl chloroformate is added dropwise for 5 minutes. After stirring for 15 minutes, ammonia gas is bubbled into the reaction mixture at a moderately vigorous rate for 15 minutes. Then the resulting milky suspension is heated at room temperature for 2 hours, and the mixture is washed with 1 N HCl (2 x 25 milliliters), aqueous NaHCO 3 (25 milliliters), and brine (25 milliliters), and then dried over MgSO 4. . Evaporation of the solvent, followed by chromatography (silica, 65 percent EtOAc / hexane), produces N- (terbutoxy-carbonyl) - (S) -propargylglycinamide, as a clear oil.

B. (S) -2- (terbutoxy-carbonylamino) -5- (3-carbomethoxyphenyl) -4-pentynoic acid amide A solution of N- (terbutoxy-carbonyl) - (S) -propargylglycinamide (1.15 grams, 5.33 millimoles ), Methyl 3-bromobenzoate (1.15 grams, 5.33 millimoles), and Cu (I) I (0.042 grams, 0.214 millimoles) in triethylamine (25 milliliters), is deoxygenated with N2 bubbling for 2 to 3 minutes. Then bis (triphenylphosphine) palladium dichloride (0.075 grams, 0.11 mmol) is added in one portion, and the mixture is refluxed for 3 hours, after which time the solvent evaporates. The residue is then taken up in EtOAc (10 milliliters), and then washed with 1 N HCl (40 milliliters), and brine (30 milliliters), and then dried over MgSO4. The residue is passed through chromatography (silica, 80 percent EtOAc / hexane) to give (S) -2- (terbutoxy-carbonylamino) -5- (3-carbethoxyphenyl) -4-pentynoic acid amide, as a yellow solid Clear.

C. (S) -2-Butoxycarbonylamino-4- (3-carbomethoxyphenyl) pentane A To a solution of (S) -2- (terbutoxy-carbonylamino) -5- (3-carbethoxy-phenyl) -4-pentanoic acid amide ( 1.11 grams, 3.22 mmol) in 1: 1 ethanol / tetrahydrofuran (50 milliliters), 10% Pd / C (0.5 grams) is added, and the mixture is hydrogenated at 1 atmosphere for 1.5 hours. The mixture is filtered through celite, and evaporated to give (S) -2-butoxycarbonylamino-4- (3-carbomethoxyphenyl) -pentanamide, as a clear oil.

E. (S) -2-amino-4- (3-carbomethoxy-phenyl) -pentanamide.HCl To a solution of (S) -2- (terbutoxy-carbonyl-amino) -5- (3-carbomethoxyphenyl) -pentanamide (1.22) grams, 3.5 mmol) in EtOAc (75 mmol) at 0 ° C, HCl gas is bubbled at a moderately vigorous rate, for 5 minutes. Then the solution is heated at room temperature for 30 minutes. Evaporation of the solvent produces (S) -2-amino-4- (3-carbomethoxyphenyl) -pentanamide salt. HCl as a light yellow solid.

F. N- [4- (3-methoxycarbonyl-phenyl) -1 (S) - (aminocarbonyl) butyl] -3-methyl-Na- (2, 2-diphenylacetyl) -L-phenylalaninamide To a solution of (S) -2-amino-5- (3-carbomethoxyphenyl) -pentanamide.HCl (0.30 grams, 0.80 mmol), of 3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalanine (0.23 grams, 0.80 millimoles), 1-hydroxybenzotriazole hydrate (0.135 grams, 0.89 millimoles), and N-methylmorpholine (0.35 milliliters, 3.2 millimoles) in CH2C12 (25 milliliters), is added 1- (3-dimethylaminopropyl) - 3-ethylcarbodi-imide HCl (0.23 grams, 1.2 mmol) in one portion, and the mixture is stirred at room temperature for 16 hours. The solution is then washed with 1 N HCl (100 milliliters), saturated aqueous NaHCO 3 (1 x 50 milliliters), water (1 x 50 milliliters), and brine (1 x 50 milliliters), dried MgSO4, and evaporate. The residual solid is triturated with ether to give N- [4- (3-methoxycarbonyl-phenyl) -1 (S) - (aminocarbonyl) -butyl] -3-methyl-Na- (2, 2-diphenylacetyl) -L- phenylalaninamide as a light yellow solid.

G. N- [4- (3-methoxycarbonyl-phenyl) -1 (S) -cyanobutyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide. Oxalyl chloride (0.12 milliliter) is added dropwise. , 1.39 mmol) to dimethylformamide (10 milliliters), and the resulting solution is cooled to 0 ° C. After the solution is clear, pyridine is added (0.22 milliliters, 2.78 mmol), followed by N- [4- (3-methoxycarbonylphenyl) -1 (S) - (aminocarbonyl) butyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide ( 0.42 grams, 0.70 millimoles), in one portion. The yellow reaction solution is stirred at 0 ° C for 1.5 hours, after which time it is diluted with EtOAc (50 milliliters), and washed with a saturated aqueous solution of NaHCO 3 (1 x 50 milliliters), a saturated aqueous solution of LiCl (1 x 50 milliliters), dried over MgSO4, and evaporate. The residue is chromatographed to give N- [4- (3-methoxycarbonyl-phenyl) -1 (S) -cyanobutyl] -3-methyl-N- (2, 2-diphenylacetyl) -L-phenylalaninamide, as a solid yellow. By repeating the procedure described above in Examples 302 to 310, using appropriate starting materials and conditions, the following compounds of Formula XVIII are obtained as identified in Table 11 below. 00 CD CD CD OR CN - W The compounds of Examples 302 to 419 are selective inhibitors of cathepsin B, which have IC50s for the inhibition of cathepsin B, in the cathepsin B assay in vi tro described above, which is normally in the range of about 5 nM to about 1000 nM. Illustrating the invention, the IC 50 in the cathepsin B in vitro assay is about 5 nM for the compound of Example 303. In view of its properties as selective and broad base inhibitors of cathepsin L, S and / or B, the Compounds of the Invention described above in Examples 154 to 419 can be used for the treatment or prophylaxis of diseases or medical conditions mediated by cathepsin L, S or B; for example, as described hereinabove.

Example 420: Preparation of 1,000 capsules, each containing 25 milligrams of a Compound of the Invention, using the following ingredients: Compound of the Invention: 25.00 grams Lactose: 192.00 grams Modified starch: 80.00 grams Magnesium stearate: 3.00 grams Procedure: All powders are passed through a mesh with 0.6 mm openings. The drug substance is then placed in a suitable mixer, and first mixed with the magnesium stearate, then with the lactose and the starch until homogeneous. Number 2 hard gelatin capsules are filled with 300 milligrams of the mixture each, using a capsule filling machine.

Claims (15)

1. A dipeptide nitrile, wherein the C-terminal carboxyl group of the dipeptide is replaced by a nitrile group (-C = N), and wherein the N-terminal nitrogen atom is substituted by means of a peptide or pseudopeptide bond, which optionally further comprises a -methylene-heteroatom- linker, or an additional heteroatom, directly by aryl, lower alkyl, lower alkenyl, lower alkynyl, or heterocyclyl, or a physiologically acceptable and dissociable ester or a salt thereof, to be used as a pharmaceutical product.

2. A compound of Formula I, or a physiologically acceptable and dissociable ester, or a salt thereof: wherein: R is optionally substituted (aryl, lower alkyl, lower alkenyl, lower alkynyl, or heterocyclyl); R2 and R3 are independently hydrogen, or are optionally substituted [lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl) -lower alkyl]; or R2 and R3 together represent lower alkylene, optionally interrupted by O, S or NRS, to form a ring with the carbon atom to which they are attached, wherein R6 is hydrogen, lower alkyl or arylalkyl; or any of R2 or R3 is linked by lower alkylene to the adjacent nitrogen to form a ring; R4 and R5 are independently H, or are optionally substituted (lower alkyl, arylalkyl), -C (0) 0R7, or -C (0) NR7R8, wherein: R7 is optionally substituted (lower alkyl, aryl, arylalkyl, cycloalkyl, bicycloalkyl or heterocyclyl), and R8 is H, or is optionally substituted (lower alkyl, aryl, arylalkyl, cycloalkyl, bicycloalkyl or heterocyclyl), or R4 and Rs together represent lower alkylene, optionally interrupted by O, S or NR6, to form a ring with the carbon atom to which they are attached, wherein R6 is hydrogen, lower alkyl, or arylalkyl, or R4 is H or optionally substituted lower alkyl, and R5 is a substituent of the formula -X2- ( Y1) n- (Ar) pQZ, where: Yx is 0, S, SO, S02, N (R6) S02, N-Rs, S02NR6, C0NR6 or NR6C0; n is zero or one; P is zero or one; X22 is lower alkylene; or when n is zero, X2 is also alkylene of 2 to 7 carbon atoms interrupted by O, S, SO, S02, NR6, S02NR6, CONR6 or NR6CO; wherein R6 is hydrogen, lower alkyl or arylalkyl; Ar is arylene; Z is hydroxyl, acyloxy, carboxyl, esterified carboxyl, amidated carboxyl, aminosulfonyl, (lower alkyl or arylalkyl) aminosulfonyl, or (lower alkyl or arylalkyl) sulfonylaminocarbonyl; or Z is tetrazolyl, triazolyl or imidazolyl; Q is a direct bond, lower alkylene, lower Y x -alkylene, or alkylene of 2 to 7 carbon atoms interrupted by Y x; X1 is -C (O) -, -C (S) -, -S (0) -, -S (0) 2-, -P (0) (OR6) -, wherein R6 is as defined above; And it's oxygen or sulfur; L is -Het, -, -Het-CH2- or -CH2-Het- optionally substituted, wherein Het is a heteroatom selected from O, N or S, and x is zero or one; and aryl, in the above definitions, represents carbocyclic or heterocyclic aryl, to be used as a pharmaceutical product; a pharmaceutical composition comprising a compound of formula I as defined above, as an active ingredient; a method for the treatment of a patient suffering from, or susceptible to, a disease or medical condition wherein a cathepsin is involved, which comprises administering an effective amount of a compound of the formula I as defined above, patient; or the use of a compound of the formula I as defined above, for the preparation of a medicament for the therapeutic or prophylactic treatment of a disease or medical condition in which a cathepsin is involved.

3. A compound of the formula I as defined in claim 2, with the understanding that when R is lower alkyl, is not substituted by aryl, one of R4 or R5 is a substituent of the formula -X2- (Y1) n- (Ar) pQZ, with the understanding that when x is one, L is -0-, or -CH2-0- and Xx is -C (0) -, either of R4 or R5 is a substituent of the formula -X2- (Y:?.) n- (Ar) pQZ , or R is not an unsubstituted phenyl, with the understanding that when R2 = R4 = Rs = H, x is zero, and Xx is -C (O) -, R, is not H, -CH3, -CH (CH3 ) 2, -CH2-CH2- (CH3) -CH2 COOH, or -CH2-COO-CH2-CH3, when R is unsubstituted phenyl, R3 is not H, -CH (CH3) 2, or -CH2-CH2 (CH3) 2, when R is 4-aminophenyl or 4-nitrophenyl , R, is not H, when R is 3-aminophenyl, nitrophenyl, 2-chloropyridin-4-yl, or vinyl or R, is not -CH2-CH2-S-CH3, when R is pyridin-3-yl or -chloropyridin-4-yl, with the understanding that, when R2 = R3 = R4 = H, x is zero, and Xx is -C (0) -, and R is phenyl, Rs is not -CH (CH3) 2 , with the understanding that, when R3 = R4 = H, R5 is -CH2-CH2-C00H, x is zero, and Xx is -C (0) -, R2 does not form a heterocyclic ring with the adjacent nitrogen atom, and with the understanding that when R2 = R3 = R4 = R5 = H, x is zero, and Xx is -S02-, R is not 4-methylphenyl.

4. A compound according to claim 3, of Formula II, or a physiologically acceptable and dissociable ester or a salt thereof: wherein: R 20 is optionally substituted (aryl, arylalkyl, lower alkenyl, lower alkynyl, heterocyclyl, or heterocyclylalkyl); R22 is H, or optionally substituted lower alkyl, and R23 is optionally substituted (lower alkyl, lower arylalkyl, or lower cycloalkylalkyl), or R22 and R23, together with the carbon atom with which they are attached, form an optionally substituted group ( cycloalkyl group or heterocycloalkyl group); R24 and R25 are independently H, or are optionally substituted (lower alkyl, or lower aryalkyl), -C (0) 0R7, or -C (0) NR7R8, wherein R7 and R8 are as defined above, or R-2 and R-25 together with the carbon atom with which they are attached form an optionally substituted group (cycloalkyl group or heterocycloalkyl group); Xx is as defined in claim 2; And it's oxygen or sulfur; L 'is optionally substituted (-Het-CH2- or -CH2-Het-), where Het is a heteroatom selected from O, N or S, and x is 1 or 0, with the understanding that, when x is one, L is -CH2- R20 is not unsubstituted phenyl, on the understanding that, when R22 = R24 = R25 = H, x is zero, and X is -C (0) -, R23 is not H, -CH3 / -CH (CH3) 2 / -CH2-CH- (CH3) 2, -CH2-COOH, or -CH2-COO-CH2-CH3, when R20 is unsubstituted phenyl, R23 is not H, -CH (CH3) 2, or -CH2-CH (CH3) 2), when R20 is 4-aminofenyl or 4-nitrophenyl, R23 is not H when R20 is 3-aminofenyl, 3-nitrophenyl, 2-chloropyridin-4-yl, or vinyl , or R23 is not -CH2-CH2-S-CH3 when R20 is pyridin-3-yl or 2-chloropyridin-4-yl, in the understanding that, when R22 = R23 = R24 = H, x is zero, and Xx is -C (0) - and R20 is phenyl, R25 is not -CH (CH3) 2, with the understanding that, when R23 = R24 = H, R25 is -CH2-CH2-COOH, x is zero, and Xx is -C (O) -, R22 does not form a heterocyclic ring with the adjacent nitrogen atom, and in the understanding that, when R22 = R23 = R24 = R25 = H, x is zero, and Xx is -S02-, R .220 is not 4-methylphenyl.

5. A compound according to claim 3, of Formula II ', or a physiologically acceptable and dissociable ester or a salt thereof: wherein: R20 'is optionally substituted (aryl of 6 to 18 carbon atoms, or heteroaryl of 4 to 18 carbon atoms); R22 'is H, or optionally substituted alkyl of 1 to 8 carbon atoms, and R23' is optionally substituted (alkyl of 2 to 8 carbon atoms, or aralkyl of 7 to 14 carbon atoms), or R22 'and R23' together with the carbon atom to which they are attached, form an optionally substituted group (cycloalkyl group of 3 to 8 carbon atoms, or heterocycloalkyl group of 4 to 7 carbon atoms); R24 'and R2S' are independently H, or are optionally substituted (alkyl of 1 to 8 carbon atoms, aralkyl of 7 to 14 carbon atoms, or heteroaralkyl of 5 to 15 carbon atoms), -C (0) OR6 ' , or -C (O) NR6 'R7', wherein: R6 'is optionally substituted (alkyl of 1 to 8 carbon atoms, aralkyl of 7 to 14 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocycloalkyl of 4 to 7 carbon atoms, heteroaralkyl of 5 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, or heteroaryl of 4 to 14 carbon atoms), and R7 'is H, or is optionally substituted (alkyl of 1 to 8 carbon atoms, aralkyl of 7 to 14 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocycloalkyl of 4 to 7 carbon atoms, heteroaralkyl of 5 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, or heteroaryl of 4 to 14 carbon atoms), or R24 'and R2S', together with the carbon atom with which they are attached, form an optionally substituted group (cycloalkyl group of 3 to 8 carbon atoms, or heterocycloalkyl group of 4 to 7 carbon atoms). carbon); X1 is -C (O) -, -C (S) -, -S (O) -, -S (0) 2-, -P (0) (OR6 ') - wherein R6' is as defined above; And it's oxygen or sulfur; L 'is optionally substituted (-Het-CH2- or -CH2- Het-), where Het is a heteroatom selected from O, N or S, and x is 1 or 0, with the understanding that when x is one , L 'is -CH2- R20' is not unsubstituted phenyl, with the understanding that, when R22 '= R24' = R25 '= H, x is zero, and Xx is -C (0) -, R23' is not H, -CH3, -CH (CH3) 2, -CH2-CH- (CH3) 2, -CH2-COOH, -CH2-C00-CH2-CH3, when R20 'is unsubstituted phenyl, R23' is not H, - CH (CH3) 2, or -CH2-CH- (CH3) 2, when R20 'is 4-aminophenyl or 4-nitrophenyl, R23' is not H, when R20 'is 3-aminophenyl, 3-nitrophenyl, 2- chloropyridin-4-yl, or vinyl, or R23 'is not -CH2-CH2-S-CH3, when R20' is pyridin-3-yl, or 2-chloropyridin-4-yl, on the understanding that, when R22 '= R23' = R24 '= H, x is zero and Xx is -C (O) - and R20' is phenyl, R25 'is not -CH (CH3) 2, with the understanding that when R23' = R24 ' = H, R25 'is -CH2-CH2-C00H, x is zero, and X? is -C (0) -, R20 'does not form a heterocyclic ring with the adjacent nitrogen atom, and on the understanding that, when R22' = R23 '= R24' = R2S '= H, x is zero, and Xx be -S02-, R20 'is not 4-methylphenyl.

6. A compound according to claim 2, of Formula III: wherein: R30 is an acyl group derived from an organic, carbonic, carbamic or sulfonic carboxylic acid; R-32 and K.33 are independently hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl, or bicycloalkyl) -lower alkyl; or R32 and R33 together represent lower alkylene, to form a ring together with the carbon atom to which they are attached; R34 is hydrogen or lower alkyl; X2, Yx, Ar, Q, Z, n and p are as defined in claim 2; and pharmaceutically acceptable salts and esters thereof, for use as a pharmaceutical product.

7. A compound of formula III as defined in claim 6, wherein R30 is an acyl group derived from an organic carboxylic, carbamic, or sulfonic acid, and pharmaceutically acceptable salts and esters thereof.

8. A compound according to claim 7, wherein: (a) p is one; (b) Y-. is O, S, SO, S02, N (R6) S02 or N-Rs; and (c) X2 is lower alkylene; or when n is zero, X2 is also alkylene of 2 to 7 carbon atoms interrupted by O, SO, S02 or NR6; and pharmaceutically acceptable salts and esters thereof.

9. A compound according to claim 2, of Formula IV: R '40 C- NH C CO NH C C = N (IV) wherein: R40 is carbocyclic or heterocyclic aryl, (mono- or di-carbocyclic or heterocyclic aryl) -lower alkyl or lower alkenyl, or heterocyclyl; R42 is hydrogen or lower alkyl; R43 is carbocyclic or heterocyclic lower arylalkyl; R44 and R45 are independently hydrogen or lower alkyl; or K4 and R4s combined represent lower alkylene; and pharmaceutically acceptable salts and esters thereof.

10. A compound according to claim 3 of Formulas V, V or V ": R H O 43 R 40 NH c - CO T -NH 'c C = N V "1 H R 45 wherein the symbols are as defined above, and physiologically acceptable and dissociable esters or salts thereof.

11. A process for the preparation of a compound of formula I as defined in claim 2, which comprises: (a) converting an amide of Formula VI: R- -L- | X NH- wherein R, R2, R3, R4 and R5 have the meaning previously defined in claim 2 for the compounds of Formula I, in a nitrile of Formula I; or (b) condensing a compound of Formula VII: R. NH 2 -C C = N VII RE wherein R 4 and R 5 have the meaning defined in claim 1, with an acid of Formula VIII: wherein R, R2 and R3 have the meaning defined in claim 1; or with a reactive derivative thereof; or (c) condensing a compound of the Formula la: R. R, wherein R2, R3 / R4 and R5 have the meaning defined in claim 1, with an acid corresponding to the group R- [Llx-X] .-, or with a reactive derivative thereof; and in the above processes, if required, temporarily protect any reactive groups that interfere, and then isolate the resulting compound of the invention; and if desired, converting any resulting compound to another compound of the invention; and / or if desired, converting a resulting compound into a salt, or a salt resulting in the free acid or base, or in another salt.

12. A method for inhibiting cathepsin activity in a mammal, which comprises administering to a mammal in need, an effective amount of a compound of formula I as defined in claim 2.

13. A method for treatment of cathepsin-dependent conditions in a mammal, which comprises administering to a mammal in need, an effective amount of a compound of formula I, as defined in claim 2.

14. A method according to claim 13, for the treatment of inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis.

15. A cathepsin inhibitory pharmaceutical composition, which comprises a compound of the formula I as defined in claim 2, as an active ingredient.