Cathepsin cysteine protease inhibitors

1. A compound of the formula:

wherein R 1 is hydrogen, C 1-6 alkyl or C 2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with halo;

R 2 is hydrogen, C 1-6 alkyl or C 2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with halo;

or R 1 and R 2 can be taken together with the carbon atom to which they are attached to form a C 3-8 cycloalkyl ring wherein said ring system is optionally substituted with C 1-6 alkyl, hydroxyalkyl or halo;

R 3 is hydrogen, C 1-6 alkyl or C 2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with C 3-6 cycloalkyl or halo;

R 4 is hydrogen, C 1-6 alkyl or C 2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with C 3-6 cycloalkyl or halo;

or R 3 and R 4 can be taken together with the carbon atom to which they are attached to form a C 3-8 cycloalkyl ring, C 5-8 cycloalkenyl ring, or five to seven membered heterocyclyl wherein said cycloalkyl, cycloalkenyl and heterocyclyl groups are optionally substituted with C 1-6 alkyl, halo, hydroxyalkyl, hydroxy, alkoxy or keto;

X is selected from the group consisting of NH, NR 6 , —NHSO 2 —, O, —C(R 7 )(R 8 )O—, —OC(R 7 )(R 8 )—, —C(R 7 )(R 8 )C(R 7 )(R 8 )O—, S, SO 2 , —C(R 7 )(R 8 )S—, —SC(R 7 )(R 8 )—, C(R 7 )(R 8 )SO 2 , SO 2 C(R 7 )(R 8 )—, —C(R 7 )(R 8 )—, —C(R 7 )(R 8 )N(R 7 )—, —N(R 7 )C(R 7 )(R 8 )—;

R 6 is C 1-6 alkyl;

or R 6 and R 4 can be taken together with any of the atoms to which they may be attached or are between them to form a 4–12 membered heterocyclyl ring system wherein said ring system, which may be monocyclic or bicyclic, is optionally substituted with C 1-6 alkyl, halo, hydroxyalkyl, hydroxy, keto, OR 7 , SR 7 or N(R 7 ) 2 ;

R 7 is hydrogen or C 1-6 alkyl;

R 8 is hydrogen or C 1-6 alkyl;

D is aryl, heteroaryl, C 3-8 cycloalkyl or heterocyclyl wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups, which may be monocyclic or bicyclic, are optionally substituted on either the carbon or the heteroatom with one to three substituents selected from hydrogen, halogen, C 1-10 alkyl, C 3-8 cycloalkyl, aryl, arylC 1-8 alkyl, amino, aminoC 1-8 alkyl, C 1-3 acylamino, C 1-3 acylamino C 1-8 alkyl, C 1-6 alkylamino, C 1-6 alkylamino C 1-8 alkyl, C 1-6 dialkylamino, C 1-6 dialkylamino-C 1-8 alkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-6 alkyl, hydroxycarbonyl, hydroxycarbonylC 1-6 alkyl, C 1-5 alkoxycarbonyl, C 1-3 alkoxycarbonyl C 1-6 alkyl, hydroxycarbonylC 1-6 alkyloxy, hydroxy, hydroxyC 1-6 alkyl, cyano, trifluoromethyl, oxo and C 1-5 alkylcarbonyloxy;

E is aryl, heteroaryl, C 3-8 cycloalkyl or heterocyclyl wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups, which may be monocyclic or bicyclic, are optionally substituted on either the carbon or the heteroatom with one to three substituents selected from hydrogen, halogen, C 1-10 alkyl, C 3-8 cycloalkyl, aryl, arylC 1-8 alkyl, amino, aminoC 1-8 alkyl, C 1-3 acylamino, C 1-3 acylamino C 1-8 alkyl, C 1-6 alkylamino, C 1-6 alkylaminoC 1-8 alkyl, C 1-6 dialkylamino, C 1-6 dialkylamino-C 1-8 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C 1-6 alkyl, C 1-5 alkoxycarbonyl, C 1-3 alkoxycarbonyl C 1-6 alkyl, hydroxycarbonyl C 1-6 alkyloxy, hydroxy, hydroxy C 1-6 alkyl, cyano, trifluoromethyl, oxo and C 1-5 alkylcarbonyloxy;

R 5 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkyloxy, halo, nitro, cyano, amino, aryl, heteroaryl, C 3-8 cycloalkyl, heterocyclyl, —C(O)OR 7 , —C(O)OSi[CH(CH 3 ) 2 ] 3 , —OR 7 , —C(O)R 7 , —R 7 C(O)R 9 , —C(O)R 9 , —C(O)N(R 7 )(R 8 ), —C(O)(R 7 )N(R 7 )(R 8 ), —SR 7 , —SR 9 , —R 7 SR 9 , —R 9 , —C(R 9 ) 3 , —C(R 7 )(R 8 )N(R 9 ) 2 , —NR 7 CONR 7 S(O) 2 R 9 , —SO 2 R 7 , —SO 2 R 9 , —SO 2 N(R 7 )(R 8 ), —SO 2 CH(R 7 )(R 8 ), —OSO 2 R 7 , —N(R 7 )C(O)NR 7 R 9 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)OR 7 , —N(R 7 )SO 2 R 7 , —C(R 7 )(R 8 )NR 7 C(R 7 )(R 8 )R 9 , —C(R 7 )(R 8 )N(R 7 )R 9 , C(R 7 )(R 8 )N(R 7 )(R 8 ), —C(R a )(R b )NR a C(R a )(R b ), —C(R a )(R b )N(R a )(R b ), —C(R a )(R b )C(R a )(R b )N(R a )(R b ), —C(O)C(R a )(R b )N(R a )(R b ), C(O)C(R a )(R b )S(R a )(R b ), C(R a )(R b )C(O)N(R a )(R b );

wherein the above R 5 groups can be optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from the group consisting of C 1-6 alkyl, aryl, halo, —OR 7 , —O(aryl), —NO 2 , —NH 2 , —NHS(O) 2 R 6 , C(R 7 )(R 8 )N(R 7 )(R 8 ), —C(R a )(R b )C(O)N(R a )(R b ), —N(R 7 )C(R 7 )(R 8 ), —NH(CH 2 ) 2 OH, —NHC(O)OR 7 , Si(CH 3 ) 3 , heterocyclyl and heteroaryl;

R 9 is selected from the group consisting of aryl, aryl(C 1-4 ) alkyl, heteroaryl, heteroaryl(C 1-4 )alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl(C 1-4 )alkyl, and heterocyclyl(C 1-4 )alkyl; and

R a is hydrogen, C 1-6 alkyl, (C 1-6 alkyl)aryl, (C 1-6 alkyl)hydroxyl, hydroxyl, halo, aryl, heteroaryl, C 3-8 cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl, C 3-8 cycloalkyl and heterocyclyl can be optionally substituted on either the carbon or the heteroatom with C 1-6 alkyl or halo;

R b is hydrogen, C 1-6 alkyl, (C 1-6 alkyl)aryl, (C 1-6 alkyl)hydroxyl, hydroxyl, halo, aryl, heteroaryl, C 3-8 cycloalkyl, heterocyclyl,wherein said alkyl, aryl, heteroaryl, C 3-8 cycloalkyl and heterocyclyl can be optionally substituted on either the carbon or the heteroatom with C 1-6 alkyl or halo;

or R a and R b can be taken together with the carbon atom to which they are attached or are between them to form a C 3-8 cycloalkyl ring or C 3-8 heterocyclyl ring wherein said 3–8 membered ring system may be optionally substituted with C 1-6 alkyl and halo;

n is independently selected from an integer from one to two;

provided that when R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-8 cycloalkyl ring, n is independently selected from zero to two;

and provided that when R 3 and R 4 are taken together with the carbon atom to which they are attached to form a C 3-8 cycloalkyl ring, n is independently selected from zero to two;

and provided that when R 4 and R 6 are taken together with the carbon atom to which they are attached to form a C 3-8 cycloalkyl ring, n is independently selected from zero to two;

and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

2. The compound of claim 1 wherein R 3 is C 1-4 alkyl, and R 4 is hydrogen; and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

3. The compound of claim 1 wherein R 1 and R 2 can be taken together with the carbon atom to which they are attached to form a C 3-8 cycloalkyl ring wherein said ring system is optionally substituted with C 1-6 alkyl, hydroxyalkyl or halo; and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

4. The compound of claim 1 wherein X is NR 6 ; R 6 and R 4 can be taken together with any of the atoms to which they may be attached or are between them to form a 4–8 membered heterocyclyl ring system wherein said ring system, which may be monocyclic or bicyclic, is optionally substituted with C 1-6 alkyl, halo, hydroxyalkyl, hydroxy, keto, OR 7 , SR 7 or N(R 7 ) 2 ; n is an integer from zero to two; and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

5. The compound of claim 4 wherein R 6 and R 4 can be taken together with any of the atoms to which they may be attached or are between them to form a 5 or 6 membered heterocyclyl ring system wherein said ring system is optionally substituted with C 1-6 alkyl, halo, hydroxyalkyl, hydroxy, keto, OR 7 , SR 7 or N(R 7 ) 2 ; and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

6. The compound of claim 5 selected from:

(4S)-1-(3-bromophenyl)-N-cyanomethyl)-4-methyl-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-(4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-L-prolinamide;

(4S)-N-(1-cyanocyclopropyl)-4-methyl-1-(4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-L-prolinamide;

(4S)-1-(1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-(4-chloro-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-N-(cyanomethyl)-1-[3-(3,3-dimethylbut-1-ynyl)phenyl]-4-methyl-L-prolinamide;

(4S)-N-(cyanomethyl)-1-[3-(3-hydroxy-3-methylbut-1-ynyl)phenyl]-4-methyl-L-prolinamide;

N-(cyanomethyl)-1-(1-phenyl-1H-tetraazol-5-yl)piperidine-2-carboxamide;

(4S)-1-(5-bromo-2-chlorophenyl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-(3-bromo-4-chlorophenyl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-(6-chloro-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

1-(5-bromo-2-chlorophenyl)-N-(cyanomethyl)piperidine-2-carboxamide;

1-(3-bromo-4-chlorophenyl)-N-(cyanomethyl)piperidine-2-carboxamide;

1-(4-chloro-1,1′-biphenyl-3-yl)-N-(cyanomethyl)piperidine-2-carboxamide;

(4S)-1-(2-chlorophenyl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-(6-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

1-(3-bromophenyl)-N-(cyanomethyl)-D-prolinamide;

(4S)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

N-(cyanomethyl)-1-(4′-piperazin-1-yl 1,1′-biphenyl-3-yl)-D-prolinamide;

1-(5-bromo-2-chlorophenyl)-N-(cyanomethyl)-D-prolinamide;

1-(3-bromo-4-chlorophenyl)-N-(cyanomethyl)-D-prolinamide;

(4S)-1-[4-chloro-4′-(hydroxymethyl)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-(2-chloro-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-{4-chloro-4′-[(dimethylamino)methyl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide;

1-(4-chloro-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-D-prolinamide;

(4S)-1-[4-chloro-4′-(methylthio)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-[4-chloro-4′-(methylsulfonyl)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-4-methyl-L-prolinamide;

N-(cyanomethyl)-1-(2-phenyl-1,3-thiazol-4-yl)-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-(2-phenyl-1,3-thiazol-4-yl)-L-prolinamide;

(4S)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-hydroxy-L-prolinamide;

(4R)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-hydroxy-L-prolinamide;

1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-oxo-L-prolinamide;

(4S)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-fluoro-L-prolinamide; (4R)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-fluoro-L-prolinamide;

1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4,4-difluoro-L-prolinamide;

(4S)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methoxy-L-prolinamide;

(4R)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methoxy-L-prolinamide;

(4S)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-(methylthio)-L-prolinamide;

(4R)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-(methylthio)-L-prolinamide;

(1R,2S,5S)-3-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1S,2S,5R)-3-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;

N-(cyanomethyl)-1-[2-(4-piperazin-1-ylphenyl)cyclopropyl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[2-(4-piperazin-1-ylphenyl)cyclopropyl]-L-prolinamide;

N-(cyanomethyl)-4,4-difluoro-1-[2-(4-piperazin-1-ylphenyl)cyclopropyl]-L-prolinamide;

(4S)-1-(1,3-benzothiazol-2-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-(1-methyl-5-piperazin-1-yl-1H-benzimidazol-2-yl)-L-prolinamide;

(4S)-1-(4-bromo-1-methyl-1H-benzimidazol-2-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-(1-naphthyl)-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-(2-naphthyl)-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-(5,6,7,8-tetrahydronaphthalen-1-yl)-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[5-methyl-2-(4-piperazin-1-ylphenyl)-1,3-thiazol-4-yl]-L-prolinamide;

N-(cyanomethyl)-1-[5-methyl-2-(4-piperazin-1-ylphenyl)-1,3-thiazol-4-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[5-methyl-2-(3-piperazin-1-ylphenyl)-1,3-thiazol-4-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-(5-methyl-2,2′-bi-1,3-thiazol-4-yl)-L-prolinamide;

(3S)-N-(cyanomethyl)-2-[5-methyl-2-(4-piperazin-1-ylphenyl)-1,3-thiazol-4-yl]-2-azabicyclo[2.2.1]heptane-3-carboxamide;

(4S)-1-{4-chloro-4′-[(methylamino)carbonyl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-(4-chloro-4′-{[(2-methoxyethyl)(methyl)amino]methyl}-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-(4-chloro-4′-propionyl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-{4-chloro-4′-[(methylsulfonyl)amino]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-[4-chloro-4′-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-{4-chloro-4′-[(methylamino)sulfonyl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-{4-chloro4′-[(1-methyl-1H-315-imidazol-3-yl)methyl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-[4-chloro-4′-(N,N-dimethylglycyl)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-[4-chloro-4′-(5-methyl-1,1-dioxido-1,2,5-thiadiazinan-2-yl)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-{4′-[1-(2-amino-2-oxoethyl)-4-hydroxypiperidin-4-yl]-4-chloro-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-(4-chloro-4′-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-{4-chloro-4′-[1-(2-hydroxyethyl)piperidin-4-yl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-{2-chloro-5-[(1E,3E)-4-({2-[(2-fluoroethyl)amino]ethyl}amino)-1-methylhexa-1,3,5-trienyl]phenyl}-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-[4-chloro-4′-(2-oxoimidazolidin-1-yl)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-1-(4-chloro-4′-{1-[(methoxycarbonyl)amino]cyclopropyl}-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide;

(4S)-N-(cyanomethyl)-4methyl-1-[4-(4-piperazin-1-ylphenyl)-1,3-thiazol-2-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[5-(4-piperazin-1-ylphenyl)-1,3-thiazol-2-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[5-(4-piperazin-1-ylphenyl)isothiazol-3-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[1-(4-piperazin-1-ylphenyl)-1H-pyrazol-3-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[1-(4-piperazin-1-ylphenyl)-1H-pyrazol-4-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[1-methyl-3-(4-piperazin-1-ylphenyl)-1H-pyrazol-5-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[5-(4-piperazin-1-ylphenyl)-1,2,4-thiadiazol-3-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[5-(4-piperazin-1-ylphenyl)-1,3,4-thiadiazol-2-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[3-(4-piperazin-1-ylphenyl)-1,2,4-thiadiazol-5-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[1-(4-piperazin-1-ylphenyl)-1H-1,2,4-triazol-3-yl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[1-methyl-3-(4-piperazin-1-ylphenyl)-1H-1,2,4-triazol-5-yl]-L-prolinamide;

1-(3-bromophenyl)-N-(cyanomethyl)-2-piperidinecarboxamide;

N-(cyanomethyl)-1-[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]-2-piperidinecarboxamide;

(2R,3S)-1-(3-bromophenyl)-N-(cyanomethyl)-3-methyl-2-piperidinecarboxamide;

1-[1,1′-biphenyl]-3-yl-N-(cyanomethyl)-2-piperidinecarboxamide;

N-(cyanomethyl)-1-[3-(2-naphthyl)phenyl]-2-piperidinecarboxamide;

N-(cyanomethyl)-1-(1-bromophenyl)piperidine-2-carboxamide;

1-{4′-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1,1′-biphenyl-4-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-[4′-(piperazin-1-yl)-1,1′-biphenyl-4-yl]-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{3′-[4-(piperidin-1-yl)piperidin-1-yl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{3′-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{4′-[4-(morpholin-4-yl)piperidin-1-yl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{3′-(piperazin-1-yl)-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{4′-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{3′-[4-(morpholin-4-yl)piperidin-1-yl)-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-(4′-trifluoromethyl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-piperidine-2-carboxamide;

1-(2′,3′difluoro-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{3′-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1,1′-biphenyl-4-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-[3′-(piperazin-1-yl)-1,1′-biphenyl-4-yl]-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{4′-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1,1′-biphenyl-2-yl}-N-(cyanomethyl)-piperidine-2R-carboxamide;

N-(cyanomethyl)-1-(3-bromophenyl)piperidine-2R-carboxamide;

1-{3′-(piperazin-1-yl)-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2R-carboxamide;

1-{3-[2-(4-morpholin-4-ylpiperazin-1-yl)thiazol-4-yl]-phenyl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{3-[2-(piperazin-1-yl)thiazol-4-yl]-phenyl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{3-[2-(4-methylhomopiperazin-1-yl)thiazol-4-yl]-phenyl}-N-(cyanomethyl)-piperidine-2-carboxamide;

N-(cyanomethyl)-1-(3-bromo-5-fluorophenyl)piperidine-2-carboxamide;

N-(cyanomethyl)-1-(3-bromo-6-fluorophenyl)piperidine-2-carboxamide;

N-(cyanomethyl)-1-(3-bromo-4-fluorophenyl)piperidine-2-carboxamide;

1-{5-fluoro-4′-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-[5-fluoro-4′-(piperazin-1-yl)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{6-fluoro-4′-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-[6-fluoro-4′-(piperazin-1-yl)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-piperidine-2-carboxamide;

N-(cyanomethyl)-1-(6-bromopyridin-2-yl)piperidine-2-carboxamide;

1-[6-(4-piperazin-1-ylphenyl)pyridin-2-yl]-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{6-[4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]pyridin-2-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{5-[4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]pyridin-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{4-fluoro-[4′-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

1-[4-fluoro-4′-(piperazin-1-yl)-1,1′-biphenyl-3-yl]-N-(cyanomethyl)-piperidine-2-carboxamide;

1-{5-[4-(piperazin-1-yl)phenyl]pyridin-3-yl}-N-(cyanomethyl)-piperidine-2-carboxamide;

and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

7. The compound of claim 5 wherein D is aryl, heteroaryl, C 3-8 cycloalkyl or heterocyclyl wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups, which may be monocyclic or bicyclic, are optionally substituted on either the carbon or the heteroatom with one to three substituents selected from C 1-6 alkyl, halo, —OR 7 , haloalkyl, haloalkyloxy, cyano, amino, oxo, methylenedioxy, and nitro; and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

8. The compound of claim 5 wherein E is aryl, heteroaryl, C 3-8 cycloalkyl or heterocyclyl wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups, which may be monocyclic or bicyclic, are optionally substituted on either the carbon or the heteroatom with one to three substituents selected from C 1-6 alkyl, halo, —OR 7 , haloalkyl, haloalkyloxy, cyano, amino, oxo, methylenedioxy, and nitro; and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

9. The compound of claim 1 wherein X is NH;

D is an optionally substituted 5-membered ring heteroaryl wherein said heteroaryl can be substituted on either the carbon or the heteroatom with the group consisting of C 1-6 alkyl and halo;

E is selected from optionally substituted aryl, heteroaryl, C 3-8 cycloalkyl and heterocyclyl wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl can be substituted with C 1-6 alkyl and halo;

and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

10. The compound of claim 9 selected from:

N1-(cyanomethyl)-N2-{4-[4-(4-methylpiperazin-1-yl)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-piperazin-1-ylphenyl)isothiazol-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[(dimethylamino)methyl]phenyl}thien-3-yl)-L-leucinamide;

N1(cyanomethyl)-N2-[4-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(morpholin-4-ylmethyl)phenyl]thien-3-yl}-L-leucinamide;

N2-(4-{4-[(benzylamino)methyl]phenyl}thien-3-yl)-N1-(cyanomethyl)-L-leucinamide;

N2-[4-(4-tert-butylphenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-isopropylphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[3-(4-piperazin-1-ylphenyl)isoxazol-4-yl]leucinamide;

N1-(cyanomethyl)-N2-[3-(4-piperazin-1-ylphenyl)isoxazol-4-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[3-(4-piperazin-1-ylphenyl)isoxazol-4-yl]-D-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[2-(dimethylamino)ethyl]phenyl}thien-3-yl)-L-leucinamide;

N1-(1-cyanocyclopropyl)-N2-[3-(4-piperazin-1-ylphenyl)isoxazol-4-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{3-[4-(4-isopropylpiperazin-1-yl)phenyl]isoxazol-4-yl}-L-leucinamide;

N2-[4-(3-bromo-4-piperazin-1-ylphenyl)-3-methylisothiazol-5-yl]-N1-(cyanomethyl)leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(4-isopropylpiperazin-1-yl)phenyl]isothiazol-3-yl}-L-leucinamide;

N2-[4-(3-bromo-4-piperazin-1-ylphenyl)isothiazol-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N2-[4-(4-bromophenyl)isothiazol-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(1-phenyl-1H-tetraazol-5-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-(1-phenyl-1H-tetraazol-5-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-iodophenyl)-3-methylisothiazol-5-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-(3-methyl-4-phenylisothiazol-5-yl)-L-leucinamide;

N2-[4-(1,1′-biphenyl-4-yl)-3-methylisothiazol-5-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-piperazin-1-ylphenyl)isothiazol-5-yl]leucinamide;

N1-(cyanomethyl)-N2-[3-methyl-4-(4-pyridin-3-ylphenyl)isothiazol-5-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[3-methyl-4-(4-pyridin-4-ylphenyl)isothiazol-5-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{3-methyl-4-[4-(1-trityl-1H-imidazol-5-yl)phenyl]isothiazol-5-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(1H-imidazol-5-yl)phenyl]-3-methylisothiazol-5-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{3-methyl-4-[4-(1-trityl-1H-imidazol-2-yl)phenyl]isothiazol-5-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-hydroxyphenyl)-3-methylisothiazol-5-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{3-methyl-4-[4-(1-oxidopyridin-4-yl)phenyl]isothiazol-5-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(2-piperazin-1-ylpyridin-5-yl)isothiazol-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-piperazin-1-yl-2-(trifluoromethyl)phenyl]isothiazol-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(1,4-diazepan-1-yl)phenyl]isothiazol-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(3,5-dimethylpiperazin-1-yl)phenyl]isothiazol-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(N,N-dimethylglycyl)phenyl]isothiazol-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[(2,6-dimethylpiperidin-1-yl)acetyl]phenyl}isothiazol-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(N,N-dimethylglycyl)phenyl]-3-methylisothiazol-5-yl}-L-leucinamide;

N2-{4-[4-(1-amino-1-methylethyl)phenyl]isothiazol-3-yl}-N1-(cyanomethyl)-L-leucinamide;

N2-[4-(4-acetylphenyl)-3-methylisothiazol-5-yl]-N1-(cyanomethyl)-L-leucinamide;

N2-(4-{4-[(tert-butylamino)sulfonyl]phenyl}-3-methylisothiazol-5-yl)-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-{3-methyl-4-[4-(piperazin-1-ylsulfonyl)phenyl]isothiazol-5-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{3-methyl-4-[4-(methylsulfonyl)phenyl]isothiazol-5-yl}-L-leucinamide;

N2-{4-[4-(aminosulfonyl)phenyl]-3-methylisothiazol-5-yl}-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(2-fluoro-4-piperazin-1-ylphenyl)-3-methylisothiazol-5-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-fluoro-4-piperazin-1-ylphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[3-(hydroxymethyl)phenyl]thien-3-yl}-L-leucinamide;

N2-(2-bromo-4-{3-[(dimethylamino)methyl]phenyl}thien-3-yl)-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{3-[(dimethylamino)methyl]phenyl}thien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[3-fluoro-4-(hydroxymethyl)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(4-hydroxypiperidin-4-yl)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[(dimethylamino)methyl]-3-fluorophenyl}thien-3-yl)-L-leucinamide;

4-(4-{4-[1-(Cyanomethyl-carbamoyl)-3-methyl-butylamino]-thiophen-3-yl}-2-fluoro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester;

N1-(cyanomethyl)-N2-{4-[3-fluoro-4-(piperazin-1-ylmethyl)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(pyrrolidin-1-ylmethyl)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-[3-methyl-4-(4-piperazin-1-ylphenyl)isothiazol-5-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(4-isopropylpiperazin-1-yl)phenyl]-3-methylisothiazol-5-yl}-L-leucinamide;

6-{5-[1-(Cyanomethyl-carbamoyl)-3-methyl-butylamino]-3-methyl-isothiazol-4-yl}-napthalene-2-carboxylic acid methyl ester;

N1-(cyanomethyl)-N2-(3-methyl-4-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl}isothiazol-5-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-{3-methyl-4-[4-(4-propylpiperazin-1-yl)phenyl]isothiazol-5-yl}-L-leucinamide;

N2-{4-[4-(4-acetylpiperazin-1-yl)phenyl]-3-methylisothiazol-5-yl}-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(3-methyl-4-{4-[4-(methylsulfonyl)piperazin-1-yl]phenyl}isothiazol-5-yl)-L-leucinamide;

N2-{4-[4-(4-tert-butylpiperazin-1-yl)phenyl]-3-methylisothiazol-5-yl}-N1-(cyanomethyl)-L-leucinamide;

N2-(cyanomethyl)-N2-(4-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl}-3-methylisothiazol-5-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[6-(hydroxymethyl)-2-naphthyl]-3-methylisothiazol-5-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-3-methylisothiazol-5-yl)-L-leucinamide

N1-(cyanomethyl)-N2-{4-[4-(4-cyclopropylpiperazin-1-yl)phenyl]-3-methylisothiazol-5-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-3-methylisothiazol-5-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[4-(2-fluoroethyl)piperazin-1-yl]phenyl}-3-methylisothiazol-5-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{6-[(dimethylamino)methyl]-2-naphthyl}-3-methylisothiazol-5-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-{3-methyl-4-[6-(pyrrolidin-1-ylmethyl)-2-naphthyl]isothiazol-5-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[4-(2-hydroxypropyl)piperazin-1-yl]phenyl}-3-methylisothiazol-5-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl}-3-methylisothiazol-5-yl)-L-leucinamide;

N2-(4-{4-[4-(2-anilino-2-oxoethyl)piperazin-1-yl]phenyl}-3-methylisothiazol-5-yl)-N1-(cyanomethyl)-L-leucinamide;

N2-(4-{4-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-3-methylisothiazol-5-yl)-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-{3-methyl-4-[4-(4-methylmorpholin-2-yl)phenyl]isothiazol-5-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-[3-methyl-4-(4-morpholin-4-ylphenyl)isothiazol-5-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-(4-phenylthien-3-yl)-L-leucinamide;

N1-(1-cyanocyclopropyl)-N2-[4-(4-piperazin-1-ylphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[1-methyl-4-(4-piperazin-1-ylphenyl)-1H-pyrazol-3-yl]leucinamide;

N1-(cyanomethyl)-N2-[3-methyl-4-(4-piperazin-1-ylphenyl)isothiazol-5-yl]leucinamide;

N1-(cyanomethyl)-N2-[4-(4-piperazin-1-ylphenyl)-1,2,5-oxadiazol-3-yl]leucinamide;

N1-(cyanomethyl)-N2-[4-(4-piperazin-1-ylphenyl)-1H-pyrazol-3-yl]leucinamide;

N1-(cyanomethyl)-N2-[3-methyl-4-(4-piperazin-1-ylphenyl)isoxazol-5-yl]leucinamide;

N1-(cyanomethyl)-N2-[5-methyl-4-(4-piperazin-1-ylphenyl)isoxazol-3-yl]leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[(methylamino)methyl]phenyl}thien-3-yl)-L-leucinamide;

N2-(4-{4-[(tert-butylamino)methyl]phenyl}thien-3-y])-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[1-(methylamino)ethyl]phenyl}thien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[(isopropylamino)methyl]phenyl}thien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-{[(cyclopropylmethyl)amino]methyl}phenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-(4-{4-[1-(isopropylamino)ethyl]phenyl}thien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}phenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-{[(3-pyrrolidin-1-ylpropyl)amino]methyl}phenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(1H-imidazol-1-ylmethyl)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(6-piperazin-1-ylpyridin-3-yl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(trifluoromethyl)phenyl]thien-3-yl}-L-leucinamide;

N2-[4-(3-bromophenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(1-naphthyl)thien-3-yl]-L-leucinamide;

N2-(5-acetyl-2,3′-bithien-4′-yl)-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(5-methyl-2,3′-bithien-4′-yl)-L-leucinamide;

N2-[4-(4-chlorophenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-fluorophenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(2-methylphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-vinylphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-ethoxyphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(1H-indol-5-yl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-fluoro-2-methylphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(1H-pyrrol-2-yl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-methylphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-(4-pyridin-3-ylthien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-methoxyphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(5-fluoro-2-methylphenyl)thien-3-yl]-L-leucinamide;

N2-(3,3′-bithien-4-yl)-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3,5-dichlorophenyl)thien-3-yl]-L-leucinamide;

N2-{4-[3-(acetylamino)phenyl]thien-3-yl}-N1-(cyanomethyl)-L-leucinamide;

N2-[4-(4-bromophenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-fluoro-3-(trifluoromethyl)phenyl]thien-3-yl}-L-leucinamide;

N2-[4-(1-benzofuran-2-yl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(2-formylphenyl)thien-3-yl]-L-leucinamide;

N2-[4-(3-chlorophenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(2,4-dichlorophenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(trifluoromethyl)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[3-(trifluoromethyl)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-fluorophenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(2-methoxyphenyl)thien-3-yl]-L-leucinamide;

N2-{4-[3,5-bis(trifluoromethyl)phenyl]thien-3-yl}-N1-(cyanomethyl)-L-leucinamide;

N2-[4-(3-chloro-4-fluorophenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[2-(trifluoromethyl)phenyl]thien-3-yl}-Leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(methylthio)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-fluoro-4-methoxyphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3,4-dichlorophenyl)thien-3-yl]-L-leucinamide;

N2-[4-(1,3-benzodioxol-5-yl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3,4-dimethoxyphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3,4,5-trimethoxyphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-formyl-2-furyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-isopropoxyphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(2,3-dimethoxyphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(trifluoromethoxy)phenyl]thien-3-yl}-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[4-(hydroxymethyl)phenyl]thien-3-yl}-L-leucinamide;

N2-[4-(1,1′-biphenyl-3-yl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-cyanophenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(1H-indol-5-yl)thien-3-yl]-L-leucinamide;

N2-[4-(5-chloro-2-methoxyphenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(2,5-dimethoxyphenyl)thien-3-yl]-L-leucinamide;

N2-[4-(4-chloro-3-fluorophenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3,5-dimethylisoxazol-4-yl)thien-3-yl]-L-leucinamide;

N2-[4-(4-acetylphenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-methylphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-(4-pyrimdin-5-ylthien-3-yl)-L-leucinamide

N1-(cyanomethyl)-N2-[4-(3-nitrophenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-(4-phenylthien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-methoxyphenyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-{4-[2-(hydroxymethyl)phenyl]thien-3-yl}-L-leucinamide;

N2-[4-(3-aminophenyl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(4-pyridin-4-ylthien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(4-cyanophenyl)thien-3-yl]-L-leucinamide;

N2-[4-(1-benzothien-3-yl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(4-quinolin-5-ylthien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-(4-quinolin-8-ylthien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(1H-pyrazol-3-yl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(5-fluoro-2-methoxyphenyl)thien-3-yl]-L-leucinamide;

N2-[4-(1-benzothien-7-yl)thien-3-yl]-N1-(cyanomethyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(4-quinolin-6-ylthien-3-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-oxo-3-phenylpropanoyl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(3-phenylisoxazol-5-yl)thien-3-yl]-L-leucinamide;

N1-(cyanomethyl)-N2-[4-(2-naphthyl)thien-3-yl]-L-leucinamide;

N-(cyanomethyl)-2-[(5,5-dimethyl-2-oxo-4-phenyl-2,5-dihydro-3-furanyl)amino]-4-methylpentanamide;

(2S)-N-(cyanomethyl)-4-methyl-2-({4-[4-(1-piperazinyl)phenyl]-3-thienyl}amino)pentanamide;

and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

11. The compound of claim 1 wherein X is S, and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

12. The compound of claim 11 selected from:

2-{[4′-(aminomethyl)-1,1′-biphenyl-4-yl]thio}-N-(cyanomethyl)-4-methylpentanamide;

2-(1,1′-biphenyl-4-ylthio)-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-2-{[4′-(ydroxymethyl)-1,1′-biphenyl-4-yl]thio}-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-[(4′-piperidin-1-yl-1,1′-biphenyl-4-yl)thio]pentanamide;

2-({4′-[(benzylamino)methyl]-1,1′-biphenyl-4-yl}thio)-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-2-({4′-[(cyclopropylamino)methyl]-1,1′-biphenyl-4-yl}thio)-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-[(4′-{[(1-methylpiperidin-4-yl)amino]methyl}-1,1′-biphenyl-4-yl)thio]pentanamide;

N-(cyanomethyl)-2-({4′-[(dicyclobutylamino)methyl)-1,1′-biphenyl-4-yl}thio)-4-methylpentanamide;

N-(cyanomethyl)-2-({4′-[(dicyclopentylamino)methyl]-1,1′-biphenyl-4-yl}thio)-4-methylpentanamide;

N-(cyanomethyl)-2-({4′-[(cyclopentylamino)methyl]-1,1′-biphenyl-4-yl}thio)-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-[(4-piperazin-1-ylphenyl)thio]pentanamide;

N-(cyanomethyl)-2-[(3′,5′-difluoro-1,1′-biphenyl-4-yl)thio]-4-methylpentanamide;

2-{[4-(5-chlorothien-2-yl)phenyl]thio}-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]thio}pentanamide;

N-(cyanomethyl)-4-methyl-2-[(3′-methyl-1,1′-biphenyl-4-yl)thio]pentanamide;

N-(cyanomethyl)-4-methyl-2-[(4-quinolin-5-ylphenyl)thio]pentanamide;

2-{[4-(1-benzothien-3-yl)phenyl]thio}-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-[(4-quinolin-8-ylphenyl)thio]pentanamide;

2-[(4′-cyano-1,1′-biphenyl-4-yl)thio]-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-{[4-(1H-pyrazol-3-yl)phenyl]thio}pentanamide;

N-(cyanomethyl)-2-[(5′-fluoro-2′-methoxy-1,1′-biphenyl-4-yl)thio]4-methylpentanamide;

2-{[4-(1-benzothien-7-yl)phenyl]thio}-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-[(4-quinolin-6-ylphenyl)thio]pentanamide;

N-(cyanomethyl)-2-[(3′-fluoro-4′-piperazin-1-yl-1,1′-biphenyl-4-yl)thio]-4-methylpentanamide;

N-(cyanomethyl)-2-{[4′-(4-ethylpiperazin-1-yl)-1,1′-biphenyl-4-yl]thio}-4-methylpentanamide;

N-(cyanomethyl)-2-[(3′-ethyl-4′-piperazin-1-yl-1,1′-biphenyl-4-yl)thio]-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-[(4-{2-[(4-propylpiperazin-1-yl)carbonyl]-1H-indol-5-yl}phenyl)thio]pentanamide;

N-(cyanomethyl)-4-methyl-2-[(4-{2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-5-yl}phenyl)thio]pentanamide;

N-(cyanomethyl)-4-methyl-2-({4-[2-(piperazin-1-ylcarbonyl)-1H-indol-5-yl]phenyl}thio)pentanamide;

N-(cyanomethyl)-2-{[4′-(4-methoxypiperidin-4-yl)-1,1′-biphenyl-4-yl]thiol}-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-{[4-(2-piperazin-1-ylpyrimidin-5-yl)phenyl]thio}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-piperazin-1-yl-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl)thio}pentanamide;

N-(cyanomethyl)-1-{[4′-(4-ethylpiperazin-1-yl)-1,1′-biphenyl-4-yl]thio}cyclohexanecarboxamide;

N-(cyanomethyl)-2-{[4′-(2,6-dimethylpiperazin-1-yl)-1,1′-biphenyl-4-yl]thio}-4-methylpentanamide;

N-(cyanomethyl)-2-({4-[5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-2-yl]phenyl}thio)-4-methylpentanamide;

2-[(4′-acetyl-1,1′-biphenyl-4-yl)thio]-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-3-(1-methylcyclopropyl)-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)thio]propanamide;

N-(cyanomethyl)-2-{[4-(1H-imidazol-4-yl)phenyl]thio}-4-methylpentanamide;

(2R)-N-(cyanomethyl)-4-methyl-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)thio]pentanamide;

(2S)-N-(cyanomethyl)-4-methyl-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)thio]pentanamide;

N-(cyanomethyl)-1-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)thio]cyclohexanecarboxamide;

N-(cyanomethyl)-4-methyl-2-[(4′-{[2-(trimethylsilyl)ethyl]sulfonyl}-1,1′-biphenyl-4-yl)thio]pentanamide;

2-{[4-(4-chlorophenyl)-1,2,3-thiadiazol-5-yl]thio}-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)thio]pentanamide;

2-[(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)thio]-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-[(5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]sulfanyl}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-2-yl]sulfanyl}pentanamide;

1-[(2-bromophenyl)sulfanyl]-N-(cyanomethyl)cyclohexanecarboxamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]sulfanyl}pentanamide;

1-[(3-bromophenyl)sulfanyl]-N-(cyanomethyl)cyclohexanecarboxamide;

N-(cyanomethyl)-1-{[4′-(1-piperazinyl)[1,1′-biphenyl]-2-yl]sulfanyl}cyclohexanecarboxamide;

N-(cyanomethyl)-1-{[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]sulfanyl}cyclohexanecarboxamide; and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

13. The compound of claim 1 selected from:

N-(cyanomethyl)-4-methyl-2-[(4-piperazin-1-ylbenzyl)thio]pentanamide;

N-(cyanomethyl)-4-methyl-2-{[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]thio}pentanamide;

(2S)-N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]amino}pentanamide;

(2S)-N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]amino}pentanamide;

1-(3-bromoanilino)-N-(cyanomethyl)cyclohexanecarboxamide;

(2S)-N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-2-yl]amino}pentanamide;

(2S)-N-(cyanomethyl)-4-methyl-2-({4′-[2-(4-methyl-1-piperazinyl)-1,3-thiazol-4-yl][1,1′-biphenyl]-3-yl}amino)pentanamide;

(2S)-N-(cyanomethyl)methyl-2-({4′-[2-(4-methyl-1-piperazinyl)-1,3-thiazol-4-yl][1,1′-biphenyl]-2-yl}amino)pentanamide;

N-(cyanomethyl)-4-methyl-2-({3-[4-(1-piperazinyl)phenyl]-2-pyridinyl}oxy)pentanamide;

(2S)-N-(cyanomethyl)-4-methyl-2-({5-[4-(1-piperazinyl)phenyl]-2-pyridinyl}amino)pentanamide;

2-([1,1′-biphenyl]-4-ylmethoxy)-N-(cyanomethyl)-4-methylpentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]sulfonyl}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]sulfonyl}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-2-yl]sulfonyl}pentanamide;

N-(cyanomethyl)-4-methyl-2-({5-[4-(1-piperazinyl)phenyl]-2-pyrinidinyl}amino)pentanamide;

N-(cyanomethyl)-1-{[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]amino}cyclohexanecarboxamide;

triisopropylsilyl 4-[3′-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)[1,1′-biphenyl]-4-yl]-1-piperazinecarboxylate;

triisopropylsilyl 4-[4′-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)[1,1′-biphenyl]-4-yl]-1-piperazinecarboxylate;

N-(cyanomethyl)-1-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]amino}cyclohexanecarboxamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]oxy}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)(1,1′-biphenyl]-4-yl]oxy}pentanamide;

N-(cyanomethyl)-1-{[4′-(1-piperazinyl)[1,1′-biphenyl]-2-yl]amino}cyclohexanecarboxamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-2-yl]oxy}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-2-yl]methyl}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]methyl}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]methyl}pentanamide;

(2S)-N-(cyanomethyl)-4-methyl-2-({2-methyl-3-oxo-5-[4-(1-piperazinyl)phenyl]-2,3-dihydro-4-pyridazinyl}amino)pentanamide;

(2S)-N-(cyanomethyl)-4-methyl-2-({[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]methyl}amino)pentanamide;

(2S)-N-(cyanomethyl)-4-methyl-2-({[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]methyl}amino)pentanamide;

tert-butyl 4-{3′-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)methyl][1,1′-biphenyl]-4-yl}-1-piperazinecarboxylate;

tert-butyl 4-{4′-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)methyl][1,1′-biphenyl]-4-yl}-1-piperazinecarboxylate;

tert-butyl 4-{2′-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)methyl][1,1′-biphenyl]-4-yl}-1-piperazinecarboxylate;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-2-yl]methoxy}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]methoxy}pentanamide;

N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]methoxy}pentanamide;

[(3S)-3-isobutyl-2-oxo-2,3-dihydroimidazo[2,1-a]thieno[3,4-c]isoquinolin-1(11bH)-yl]acetonitrile;

[(3S)-3-isobutyl-2-oxo-2,3-dihydrofuro[3,2-c]imidazo[1,2-a]thieno[3,4-e]pyridin-1(10bH)-yl]acetonitrile;

N1-(cyanomethyl)-N2-(2,2,3,3-tetrafluoro-1-phenylcyclopropyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(3,3,4,4-tetrafluoro-1-phenylcyclopentyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(2,2-difluoro-5-phenylcyclopentyl)-L-leucinamide;

N1-(cyanomethyl)-N2-(2,2-difluoro-2,3-dihydro-1H-inden-1-yl)-L-leucinamide;

N1-(cyanomethyl)-N2-{1-[4-(N,N-dimethylglycyl)phenyl]cyclopropyl}-L-leucinamide;

1-{4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-phenoxy}-cyclohexanecarboxylic acid cyanomethyl-amide;

2-(biphenyl-3-yloxy)-4-methyl-pentanoic cyanomethyl-amide;

2-(biphenyl-4-yloxy)-4-methyl-pentanoic cyanomethyl-amide;

and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

14. N 1 -(cyanomethyl)-N 2 -[3-methyl-4-(4-piperazin-1-ylphenyl)isothiazol-5-yl]-L-leucinamide and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

15. N 1 -(cyanomethyl)-N 2 -(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-3-methylisothiazol-5-yl)-L-leucinamide and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

16. (4S)-1-{4-chloro-4′-[(dimethylamino)methyl]-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

17. (4S)-1-(4-chloro-4′-piperazin-1-y]-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

18. N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]sulfanyl}pentanamide and the pharmaceutically acceptable salts and N-oxide derivatives thereof.

19. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition made by combining a compound according to claim 1 and a pharmaceutically acceptable carrier.

21. A process for making a pharmaceutical composition comprising combining a compound according to claim 1 and a pharmaceutically acceptable carrier.

22. A method of inhibiting cathepsin activity in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to claim 1 .

23. The method according to claim 11 wherein the cathepsin activity is Cathepsin K activity.

24. A method of treating or preventing bone loss in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to claim 1 .

25. A method of treating or preventing osteoporosis in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to claim 1 .

26. A method of treating cathepsin dependent conditions in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to claim 1 .

27. A pharmaceutical composition comprising a compound of claim 1 and another agent selected from: an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, or an osteoblast anabolic agent, and the pharmaceutically acceptable salts and mixtures thereof.

28. A method of treating osteoporosis comprising a compound of claim 1 and another agent selected from: an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, or an osteoblast anabolic agent, and the pharmaceutically acceptable salts and mixtures thereof.

29. A method of treating bone loss comprising a compound of claim 1 and another agent selected from: an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, or an osteoblast anabolic agent, and the pharmaceutically acceptable salts and mixtures thereof.