Cathespin cysteine protease inhibitors

1. The present invention relates to compounds of the following chemical 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 one to six halo, C 3-6 cycloalkyl, —SR 5 , —SOR 5 , —SO 2 R 5 , —SO 2 CH(R a )(R b ), —OR 5 , —N(R 5 ) 2 or aryl, wherein said aryl, group is optionally substituted with one or two substitutents independently selected from the group consisting of C 1-6 alkyl, halo, hydroxyalkyl, hydroxy, alkoxy and keto;

R 2 is is hydrogen, C 1-6 alkyl or C 2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with one to six halo, C 3-6 cycloalkyl, —SR 5 , —SOR 5 ,—SO 2 R 5 , —SO 2 CH(R a )(R b ), —OR 5 , —N(R 5 ) 2 or aryl, wherein said aryl group is optionally substituted with one or two substitutents independently selected from the group consisting of C 1-6 alkyl, halo, hydroxyalkyl, hydroxy, alkoxy and keto;

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 one or two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyalkyl, haloalkyl, 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 one to six halo;

R 4 is hydrogen or C 1-6 alkyl substituted with 1-6 halo;

D is aryl, which may be monocyclic or bicyclic, is 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, haloalkyl, halo, keto, alkoxy, —SR 5 , —OR 5 , N(R 5 ) 2 , —SO 2 R 5 , and —SO 2 R a ;

E is aryl which may be monocyclic or bicyclic, is 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, haloalkyl, halo, keto, alkoxy, —SR 5 , —OR 5 , N(R 5 ) 2 , —SO 2 R 5 , and —SO 2 R a ;

Each G is independently C 1-6 alkyl, C 1-6 alkyloxy, aryl, C 3-8 cycloalkyl, —O—, NR 5 , S(O)m, or carbonyl wherein said groups are 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, halo, keto, haloalkyl, hydroxyalkyl, —OR 5 , —NHS(O) 2 R 5 , —SO m R 5 , —SO m N(R a )(R b ), —C(R a )(R b )OH, or aryl;

R 5 is hydrogen, C 1-6 alkyl, aryl, aryl(C 1-4 )alkyl, C 3-8 cycloalkyl, or C 3-8 cycloalkyl(C 1-4 )alkyl, wherein said groups can be optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, alkoxy, cyano, —NR a or —SR a or —SO m R 5 ;

R a is hydrogen or C 1-6 alkyl which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo and —OR 5 ;

R b is hydrogen or C 1-6 alkyl which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo and —OR 5 ;

m is an integer from zero to two;

n is an integer from one to three;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. 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 one or two substituents selected from the group consisting of C 1-6 alkyl and halo.

3. The compound of claim 2 wherein R 3 is C 1-6 alkyl which is optionally substituted with one to six halo.

4. The compound of claim 3 wherein R 3 is n-propyl, isobutyl, 2-fluoro-2-methylpropyl, 2-trifluoromethylpropyl, 3-fluoro-2-(2-fluoromethyl)propyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, or 2,2-dichioroethyl.

5. The compound of claim 2 wherein R 4 is difluoromethyl, 2,2-difluoroethyl, trifluoromethyl or 3,3,3,2,2-pentafluoroethyl.

6. The compound of claim 5 wherein D is phenyl.

7. The compound of claim 6 wherein E is phenyl.

8. The compound of claim 7 wherein each G is independently C 1-6 alkyl, C 3-8 cycloalkyl or SO m CH(R a )(R b ).

9. The compound of claim 1 which is: 1-[4′-[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]3-fluoro-3-methylbutyl]amino]-2,2,2-trifluoroethyl][1,1′-biphenyl]-4-yl]-cyclopropanecarboxylic acid;

N 1 -(1-cyanocyclopropyl)-N 2 -{(1S)-2,2-difluoro-1-{4′-[1-(carboxy)cyclopropyl]biphenyl-4-yl}-ethyl}-L-leucinamide;

N 1 (1-cyanocyclopropyl)-N 2 -{(1S)-2,2-difluoro-1-{4′-[1-(carboxy)cyclopropyl]biphenyl-4-yl}-ethyl}-4-fluoro-L-leucinamide;

1-[[4′-[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-methylbutyl]amino]-2,2-difluoroethyl][1,1′-biphenyl]-3-yl]methyl]-cyclobutanecarboxylic acid;

4′[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-fluoro-3-methylbutyl]amino]-2,2,2-trifluoroethyl]-α,α-dimethyl-[1,1′-biphenyl]-4-propanoic acid;

1-[4′-(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-methylbutyl]amino]-2,2,2-trifluoroethyl][1,1′-biphenyl]-4-yl]-cyclopropanecarboxylic acid;

1-[4′-(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-fluoro-3-methylbutyl]amino]-2,2,2-trifluoroethyl][1,1′-biphenyl]-3-yl]-cyclopropanecarboxylic acid;

4′-[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-fluoro-3-methylbutyl]amino]-2,2,2-trifluoroethyl]-α-methyl-[1,1′-biphenyl]-4-acetic acid;

4′-[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-fluoro-3-methylbutyl]amino]-2,2,2-trifluoroethyl]-α,α-dimethy-[1,1′-biphenyl]-4-acetic acid;

1-[4′-[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-fluoro-3-methylbutyl]amino]-2,2,2-trifluoroethyl][1,1′-biphenyl]-4-yl]-cyclopropaneacetic acid;

1-[4′-[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-methylbutyl]amino]-2,2,2-trifluoroethyl][1,1′-biphenyl]-4-yl]-cyclopropanecarboxylic acid;

1-[4′-[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]butyl]amino]-2,2,2-trifluoroethyl][1,1′-biphenyl]-4-yl]-cyclopropanecarboxylic acid;

4′-[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-fluoro-3-methylbutyl]amino]-2,2,2-trifluoroethyl]-[1,1′-biphenyl]-4-acetic acid;

N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -((1S)-2,2,2-trifluoro-1-{4′-[(1S)-1-carboxyethyl]biphenyl-4-yl}-ethyl)-L-leucinamide;

or a pharmaceutically acceptable salt or stereoisomer thereof.

10. A pharmaceutical compositon comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound of claim 1 and another agent selected from the group consisting of: an organic bisphosphonate, an estrogen receptor modulator, an estrogen receptor beta 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, a Nonsteroidal anti-inflammatory drug, a selective cyclooxygenase-2 inhibitor, an inhibitor of interleukin-1 beta, a LOX/COX inhibitor and the pharmaceutically acceptable salts and mixtures thereof.