Beta disubstituted metalloprotease inhibitors

Abstract

Disclosed are compounds which are inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the compounds have a structure according to the following Formula (I): where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , G and Z have the meanings described in the specification. This invention also includes optical isomers, diastereomers and enantiomers of Formula I, and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof. Also described are pharmaceutical compositions comprising these compounds, and methods of treating metalloprotease-related maladies using the compounds or the pharmaceutical compositions.

What is claimed is:  
     
         1 . A compound having a structure according to Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein: 
 (A) R 1  is selected from —OH and —NHOH;  
 (B) R 2  is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and halogen;  
 (C) R 3  is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;  
 (D) R 4  is —(CR 7 R 7′ ) k —X—(CR 8 R 8′ ) l -E-A where: 
 (1) k is from 0 to about 4;  
 (2) l is from 0 to about 4;  
 (3) each of R 7 , R 7′ , R 8 , and R 8′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl;  
 (4) X is selected from —O—, —S—, —S(O)—, —S(O 2 )—, —N(R 9 )—, —N(COR 9 )—, N(CO 2 R 9 )—, —N(CONR 9 R 9′ )—, and —N(SO 2 R 9 )—, where (i) each R 9  and R 9′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R 9  and R 9′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;  
 (5) E is selected from a covalent bond, —O—, —S—, —S(O)—, —S(O 2 )—, —N(R 10 )—, —N(COR 10 )—, —N(CO 2 R 10 )—, —N(CONR 10 R 10′ )—, and —N(SO 2 R 10 )—, where (i) each R 10  and R 10′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R 10  and R 10′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; provided that when l=0, E is a covalent bond; and  
 (6) (a) A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or  
  (b) A, together with R 7 , R 7′ , R 8 , R 8′ , R 9 , R 9′ , R 10 , or R 10′ , join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;  
 
 (E) R 5  is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;  
 (F) R 6  is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl; provided that when k>0, R 6  is —OH and when k=0, R 6  is not —OH;  
 (G) G is selected from —S—, —O—, —N(R 11 )—, —C(R 11 )═C(R 11′ )—, —N═C(R 11 )—, and —N═N—, where each R 11  and R 11′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;  
 (H) Z is selected from: 
 (1) cycloalkyl and heterocycloalkyl;  
 (2) -L-(CR 12 R 12′ )a—R 13  where: 
 (a) a is from 0 to about 4;  
 (b) L is selected from —C≡C—, —CH═CH—, —N═N—, —O—, —S— and —SO 2 —;  
 (c) each R 12  and R 12′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; and  
 (d) R 13  is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; and, if L is —C≡C— or —CH═CH—, then R 13  may also be selected from —CON(R 14 R 14′ ) where (i) R 14  and R 14′  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R 14  and R 14′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;  
 
 (3) —NR 15 R 15′  where: 
 (a) R 15  and R 15′  each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and —C(O)-Q-(CR 16 R 16′ ) b —R 17  where: 
 (i) b is from 0 to about 4;  
 (ii) Q is selected from a covalent bond and —N(R 18 )—; and  
 (iii) each R 16  and R 16′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; each R 17  and R 18  is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or R 17  and R 18 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; or R 15  and R 18 , together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 2 to 3 are heteroatoms; or  
 
 (b) R 15  and R 15′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; and  
 
 (4)  
                     
  where: 
 (a) E′ and M′ are independently selected from —CH— and —N—;  
 (b) L′ is selected from —S—, —O—, —N(R 20 )—, —C(R 20 )═C(R 20′ )—, N═C(R 20 )—, and —N═N—, where each R 20  and R 20′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;  
 (c) c is from 0 to about 4;  
 (d) each R 19  and R 19′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy;  
 (e) A′ is selected from a covalent bond, —O—, —SO d —, —C(O)—, —C(O)N(R 21 )—, —N(R 21 )—, and —N(R 21 )C(O)—; where d is from 0 to 2 and R 21  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; and  
 (f) G′ is —(CR 22 R 22′ ) e —R 23  where e is from 0 to about 4; each R 22  and R 22′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; and R 23  is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or R 21  and R 23 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms; or R 20  and R 23 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;  
 or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.  
 
 
 
     
     
         2 . The compound according to  claim 1  wherein R 1  is —OH.  
     
     
         3 . The compound according to  claim 1  wherein R 2 , R 3  and R 5  are independently selected from hydrogen, lower alkyl, arylalkyl and heteroarylalkyl.  
     
     
         4 . The compound according to  claim 3  wherein k=0 and R 6  is aryl or lower alkyl.  
     
     
         5 . The compound according to  claim 4  wherein X is selected from O, S, —N(SO 2 R 10 )—, —N(COR 10 )— and N(CO 2 R 10 )—, where R 10  is lower alkyl or aryl.  
     
     
         6 . The compound according to  claim 5  wherein X is —S—.  
     
     
         7 . The compound according to  claim 6  wherein l=0, 1 or 2; E is selected from a covalent bond, —O— and —S—; and A is selected from lower alkyl, aryl, and heteroaryl.  
     
     
         8 . The compound according to  claim 3  wherein R 6  is —OH.  
     
     
         9 . The compound according to  claim 8  wherein k=1, 2 or 3.  
     
     
         10 . The compound according to  claim 9  wherein X is selected from —O—, —S—, —N(SO 2 R 9 )—, —N(COR 9 )—, and —N(CO 2 R 9 )—, where R 9  is lower alkyl or aryl.  
     
     
         11 . The compound according to  claim 10  wherein X is selected from —O— and —S—.  
     
     
         12 . The compound according to  claim 11  wherein l=0, 1 or 2; E is selected from a covalent bond, —O—, —S—, —N(COR 10 )—, —N(CO 2 R 10 )—, —N(CONR 10 R 10′ )—and —N(SO 2 R 10 )—; and A is selected from lower alkyl, aryl, and heteroaryl.  
     
     
         13 . The compound according to  claim 12  wherein E is selected from a covalent bond, —O— and —S—.  
     
     
         14 . The compound of  claim 3  wherein G is selected from —S— and —CH═CH—.  
     
     
         15 . The compound of  claim 14  wherein Z is selected from -L-(CR 12 R 12′ ) a R 13 ; —NR 15 R 15′ ; and  
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 15  wherein Z is -L-(CR 12 R 12′ ) a R 3  where L is selected from —C≡C—, —C═C— and —N═N—; a is 0; and R 13  is selected from aryl, heteroaryl, heterocycloalkyl and cycloalkyl.  
     
     
         17 . The compound of  claim 15  wherein Z is —NR 15 R 15′  where R 15  is hydrogen and R 15′  is —C(O)-Q-(CR 16 R 16′ ) b —R 17  where Q is a covalent bond and b is 0.  
     
     
         18 . The compound of  claim 17  wherein R 17  is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.  
     
     
         19 . The compound of  claim 15  wherein Z is  
       
         
           
           
               
               
           
         
       
       where E′ and M′ are both —CH—; c is 0; L′ is —C(R 20 )═C(R 20′ )— and R 20  and G′ join to form an optionally substituted 5-membered ring containing from 0 to 2 ring heteroatoms.  
     
     
         20 . The compound of  claim 15  wherein Z is  
       
         
           
           
               
               
           
         
       
       and wherein E′ and M′ are both —CH—; c is 0; and L′ is —HC═CH—.  
     
     
         21 . The compound of  claim 15  wherein c=0 and A′ is selected from covalent bond, —O— and —S—.  
     
     
         22 . The compound of  claim 15  wherein G′ is —(CR 22 R 22′ ) e —R 23  where e is 0 and R 23  is selected from alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl.  
     
     
         23 . A compound having a structure according to Formula (II)  
       
         
           
           
               
               
           
         
       
       wherein 
 (A) R 6  is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl;  
 (B) X is selected from —O—, —S—, —S(O)—, —S(O 2 )—, —N(R 9 )—, —N(COR 9 )—, —N(CO 2 R 9 )—, —N(CONR 9 R 9′ )—, and —N(SO 2 R 9 )—, where (i) each R 9  and R 9′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R 9  and R 9′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;  
 (C) l is from 0 to about 4;  
 (D) E is selected from a covalent bond, —O—, —S—, —S(O)—, —S(O 2 )—, —N(R 10 )—, —N(COR 10 )—, —N(CO 2 R 10 )—, —N(CONR 10 R 10′ )—, and —N(SO 2 R 10 )—, where (i) each R 10  and R 10′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R 10  and R 10′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; provided that when l=0, E is a covalent bond;  
 (E) A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;  
 (F) G is selected from —S—, —O—, —N(R 11 )—, —C(R 11 )═C(R 11′ )—, —N═C(R 11 )—, and N═N—, where each R 11  and R 11′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and  
 (G) Z is selected from: 
 (1) cycloalkyl and heterocycloalkyl;  
 (2) -L-(CR 12 R 2′ )a—R 13  where: 
 (a) a is from 0 to about 4;  
 (b) L is selected from —C≡C—, —CH═CH—, —N═N—, —O—, —S— and —SO 2 —;  
 (c) each R 12  and R 12′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; and  
 (d) R 13  is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; and, if L is —C≡C— or —CH═CH—, then R 13  may also be selected from —CON(R 14 R 14′ ) where (i) R 14  and R 14′  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R 14  and R 14′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;  
 
 (3) —NR 15 R 15′  where: 
 (a) R 15  and R 15′  each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and —C(O)-Q-(CR 16 R 16′ ) b —R 17  where: 
 (i) b is from 0 to about 4;  
 (ii) Q is selected from a covalent bond and —N(R 18 )—; and  
 (iii) each R 16  and R 16′  is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; R 17  and R 18  (i) each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R 17  and R 18 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; or R 15  and R 18 , together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 2 to 3 are heteroatoms; or  
 
 (b) R 15  and R 15′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; and  
 
 (4)  
                     
  where: 
 (a) E′ and M′ are independently selected from —CH— and —N—;  
 (b) L′ is selected from —S—, —O—, —N(R 20 )—, —C(R 20 )═C(R 20′ )—, N═C(R 20 )—, and —N═N—, where each R 20  and R 20′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;  
 (c) c is from 0 to about 4;  
 (d) each R 19  and R 19′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy;  
 (e) A′ is selected from a covalent bond, —O—, —SO d —, —C(O)—, —C(O)N(R 21 )—, —N(R 21 )—, and —N(R 21 )C(O)—; where d is from 0 to 2 and R 21  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; and  
 (f) G′ is —(CR 22 R 22′ ) e —R 23  where e is from 0 to about 4; each R 22  and R 22′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; and R 23  is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or R 21  and R 23 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms; or R 20  and R 23 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;  
 or an optical isomer, diastereomer or enantiomer for Formula (II), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.  
 
 
 
     
     
         24 . A compound having a structure according to Formula (III)  
       
         
           
           
               
               
           
         
       
       wherein 
 (A) k is from 0 to about 4;  
 (B) X is selected from —O—, —S—, —S(O)—, —S(O 2 )—, —N(R 9 )—, —N(COR 9 )—, —N(CO 2 R 9 )—, N(CONR 9 R 9′ )—, and —N(SO 2 R 9 )—, where (i) each R 9  and R 9′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R 9  and R 9′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;  
 (C) l is from 0 to about 4;  
 (D) E is selected from a covalent bond, —O—, —S—, —S(O)—, —S(O 2 )—, —N(R 10 )—, —N(COR 10 )—, —N(CO 2 R 10 )—, —N(CONR 10 R 10′ )—, and —N(SO 2 R 10 )—, where (i) each R 10  and R 10′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R 10  and R 10′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; provided that when l=0, E is a covalent bond;  
 (E) A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;  
 (F) G is selected from —S—, —O—, —N(R 11 )—, —C(R 11 )═C(R 11′ )—, —N═C(R 11 )—, and —N═N—, where each R 11  and R 11′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and  
 (G) Z is selected from: 
 (1) cycloalkyl and heterocycloalkyl;  
 (2) -L-(CR 12 R 12′ )a—R 13  where: 
 (a) a is from 0 to about 4;  
 (b) L is selected from —C≡C—, —CH═CH—, —N═N—, —O—, —S— and —SO 2 —;  
 (c) each R 12  and R 12′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; and  
 (d) R 13  is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; and, if L is —C≡C— or —CH═CH—, then R 13  may also be selected from —CON(R 14 R 14′ ) where (i) R 14  and R 14′  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R 14  and R 14′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;  
 
 (3) —NR 15 R 15′  where: 
 (a) R 15  and R 15′  each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and —C(O)-Q-(CR 16 R 16′ ) b —R 17  where: 
 (i) b is from 0 to about 4;  
 (ii) Q is selected from a covalent bond and —N(R 18 )—; and  
 (iii) each R 16  and R 16′  is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; R 17  and R 18  (i) each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R 17  and R 18 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; or R 15  and R 18 , together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 2 to 3 are heteroatoms; or  
 
 (b) R 15  and R 15′ , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; and  
 
 (4)  
                     
  where: 
 (a) E′ and M′ are independently selected from —CH— and —N—;  
 (b) L′ is selected from —S—, —O—, —N(R 20 )—, —C(R 20 )═C(R 20′ )—, —N═C(R 20 )—, and —N═N—, where each R 20  and R 20′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;  
 (c) c is from 0 to about 4;  
 (d) each R 19  and R 19′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy;  
 (e) A′ is selected from a covalent bond, —O—, —SO d —, —C(O)—, —C(O)N(R 21 )—, —N(R 21 )—, and —N(R 21 )C(O)—; where d is from 0 to 2 and R 21  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; and  
 (f) G′ is —(CR 22 R 22′ ) e —R 23  where e is from 0 to about 4; each R 22  and R 22′ , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; and R 23  is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or R 21  and R 23 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms; or R 20  and R 23 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;  
 or an optical isomer, diastereomer or enantiomer for Formula (m), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.  
 
 
 
     
     
         25 . A compound selected from the group consisting of: 
 (2R,3S)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propionic acid,    (2R,3S)-2-(4′-Methylsulfanyl-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propionic acid,    (2R,3S)-3-Benzothiazol-2-yl-3-methoxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-propionic acid,    (2S,3R)-3-Ethylsulfanyl-2-(4′-fluoro-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-3-Ethylsulfanyl-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-methylsulfanyl-3-phenyl-propionic acid    (2S,3R)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-phenysulfanyl-propionic acid,    (2S,3R)-2-(4′-Bromo-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyridin-3-ylsulfanyl)-propionic acid,    (2S,3R)-2-(4′-Bromo-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyrimidin-2-ylsulfanyl)-propionic acid,    (2S,3R)-3-(4-Fluoro-phenylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-(thiazol-2-ylsulfanyl)-propionic acid,    (2S,3R)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-(1-methyl-1H-imidazol-2-ylsulfanyl)-3-phenyl-propionic acid,    (2S,3R)-2-(4′-Chloro-biphenyl-4-sulfonylamino)-3-(oxazol-2-ylsulfanyl)-3-phenyl-propionic acid,    (2S,3R)-2-(4′-Methylsulfanyl-biphenyl-4-sulfonylamino)-3-(1-methyl-1H-[1,2,4]triazol-3-ylsulfanyl)-3-phenyl-propionic acid,    (2S,3R)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-(1-methyl-1H-[1,2,4]triazol-3-ylsulfanyl)-3-phenyl-propionic acid,    (2S,3R)-2-[Benzyl-(4′-methoxy-biphenyl-4-sulfonyl)-amino]-3-phenyl-3-phenylsulfanyl-propionic acid,    (2S,3R)-3-Benzylsulfanyl-2-(biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-3-Benzylsulfanyl-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-2-(Biphenyl-4-sulfonylamino)-3-phenethylsulfanyl-3-phenyl-propionic acid,    (2S,3R)-3-(4-Methyl-benzylsulfanyl)-3-phenyl-2-(4′-trifluoromethyl-biphenyl-4-sulfonylamino)-propionic acid,    (2S,3R)-3-(4-Methoxy-benzylsulfanyl)-2-(4′-methyl-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-3-(4-Fluoro-benzylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-3-(2,4-Difluoro-benzylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-2-(4′-Methylsulfanyl-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyridin-4-ylmethylsulfanyl)-propionic acid,    (2S,3R)-2-[(4′-Methoxy-biphenyl-4-sulfonyl)-methyl-amino]-3-phenyl-3-(pyridin-3-ylmethylsulfanyl)-propionic acid,    (2S,3R)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyridin-2-ylmethylsulfanyl)-propionic acid,    (2S,3R)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-(5-methyl-oxazol-2-ylmethylsulfanyl)-3-phenyl-propionic acid,    (2S,3R)-3-(Benzothiazol-2-ylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-3-(2-Acetylamino-ethylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-3-[2-(Methanesulfonyl-pyridin-3-yl-amino)-ethylsulfanyl]-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-2-(4′-Bromo-biphenyl-4-sulfonylamino)-3-[2-(methanesulfonyl-pyridin-3-yl-amino)-ethylsulfanyl]-3-phenyl-propionic acid,    (2S,3R)-3-(2-Benzyloxy-ethylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2S,3R)-2-(4′-Bromo-biphenyl-4-sulfonylamino)-3-(2-phenoxy-ethylsulfanyl)-3-phenyl-propionic acid,    (2S,3R)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-(2-phenoxy-ethylsulfanyl)-3-phenyl-propionic acid,    (2S,3R)-3-[2-(4-Fluoro-phenoxy)-ethylsulfanyl]-3-phenyl-2-(4′-trifluoromethyl-biphenyl-4-sulfonylamino)-propionic acid,    (2S,3R)-3-Ethylsulfanyl-2-[5-(4-methoxy-phenyl)-thiophene-2-sulfonylamino]-3-phenyl-propionic acid,    (2S,3R)-3-Ethylsulfanyl-2-[4-(4-methoxy-phenylethynyl)-benzenesulfonylamino]-3-phenyl-propionic acid,    (2S,3R)-3-Ethylsulfanyl-2-[4-(4-methoxy-benzoylamino)-benzenesulfonylamino]-3-phenyl-propionic acid,    (2R,3S)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-methylsulfanyl-3-phenyl-propionic acid,    (2R,3S)-3-Ethylsulfanyl-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2R,3S)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-phenylsulfanyl-propionic acid,    (2R,3S)-3-Benzylsulfanyl-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,    (2R,3S)-4-Benzyloxy-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butyric acid,    (2R,3S)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-4-phenoxy-butyric acid    (2R,3S)-4-Benzyloxy-2-(biphenyl-4-sulfonylamino)-3-hydroxy-butyric acid,    (2R,3R)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-5-phenoxy-pentanoic acid,    (2R,3R)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-5-(pyridin-3-yloxy)-pentanoic acid,    (2R,3S)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-4-(thiazol-2-ylsulfanyl)-butyric acid,    (2R,3S)-4-(4-Fluoro-benzylsulfanyl)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butyric acid,    (2R,3S)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-butyric acid,    (2R,3R)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-6-(1-methyl-1H-imidazol-2-ylsulfanyl)-hexanoic acid,    (2R,3S)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-4-(1-methyl-1H-imidazol-2-yloxy)-butyric acid,    (2R,3R)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-5-(1-methyl-1H-[1,2,4]triazol-3-ylsulfanyl)-pentanoic acid,    (2R,3S)-4-(Benzooxazol-2-ylsulfanyl)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butyric acid,    (2R,3R)-5-(Benzooxazol-2-ylsulfanyl)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-pentanoic acid,    (2R,3R)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-6-phenoxy-hexanoic acid,    (2R,3S)-4-(3,3-Dimethyl-butoxy)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butyric acid,    (2R,3S)-3-Hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-4-(3-methyl-butoxy)-butyric acid,    (2R,3S)-3-Hydroxy-4-(2-isopropoxy-ethoxy)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butyric acid,    (2R,3S)-3-Hydroxy-4-(2-isopropoxy-ethoxy)-2-(4′-methylsulfanyl-biphenyl-4-sulfonylamino)-butyric acid,    (2R,3R)-5-tert-Butoxycarbonylamino-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-pentanoic acid,    (2R,3R)-6-tert-Butoxycarbonylamino-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-hexanoic acid,    (2R,3R)-5-tert-Butoxycarbonylamino-3-hydroxy-2-(4-methoxy-benzenesulfonylamino)-pentanoic acid,    (2R,3R)-2-(4-Butoxy-benzenesulfonylamino)-5-tert-butoxycarbonylamino-3-hydroxy-pentanoic acid    (2R,3R)-3-Hydroxy-4-(methanesulfonyl-phenyl-amino)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butyric acid,    (2R,3R)-3-Hydroxy-5-(methanesulfonyl-pyridin-3-yl-amino)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-pentanoic acid, and    (2R,3R)-4-(2-tert-Butoxycarbonylamino-ethoxy)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butyric acid.    
     
     
         26 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 1;  and    (b) a pharmaceutically-acceptable carrier.    
     
     
         27 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 23;  and    (b) a pharmaceutically-acceptable carrier.    
     
     
         28 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 24;  and    (b) a pharmaceutically-acceptable carrier.    
     
     
         29 . A method for treating a disease associated with unwanted metalloprotease activity in a mammalian subject, the method comprising administering to said subject a safe and effective amount of a compound of  claim 1 .  
     
     
         30 . A method for treating a disease associated with unwanted metalloprotease activity in a mammalian subject, the method comprising administering to said subject a safe and effective amount of a compound of  claim 23 .  
     
     
         31 . A method for treating a disease associated with unwanted metalloprotease activity in a mammalian subject, the method comprising administering to said subject a safe and effective amount of a compound of  claim 24 .  
     
     
         32 . A method for treating a disorder modulated by metalloproteases, wherein the disorder is chosen from the group consisting of arthritis, cancer, cardiovascular disorders, skin disorders, ocular disorders, inflammation and gum disease, the method comprising administering to a mammal in need of such treatment a safe and effective amount of a metalloprotease inhibitor according to  claim 1 .  
     
     
         33 . The method for treating a disorder according to  claim 32 , wherein the disorder is arthritis, and is chosen from the group consisting of osteoarthritis and rheumatoid arthritis.  
     
     
         34 . The method for treating a disorder according to  claim 32 , wherein the disorder is cancer, and the treatment prevents or arrests tumor growth and metastasis.  
     
     
         35 . The method for the treating a disorder according to  claim 32 , wherein the disorder is a cardiovascular disorder chosen from the group consisting of dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis, and aortic aneurysm.  
     
     
         36 . The method for the treating a disorder according to  claim 32 , wherein the disorder is an ocular disorder, and is chosen from the group consisting of corneal ulceration, lack of corneal healing, macular degeneration, retinopathy, and pterygium.  
     
     
         37 . The method for treating a disorder according to  claim 32 , wherein the disorder is gum disease, and is chosen from the group consisting of periodontal disease and gingivitis.  
     
     
         38 . The method for treating a disorder according to  claim 32 , wherein the disorder is a skin a disorder chosen from the group consisting of wrinkle repair and prevention, U.V. skin damage, epidermolysis bullosa, psoriasis, sclerodema, atopic dermatitis, and scarring.  
     
     
         39 . A method for treating inflammatory conditions according to  claim 32 , wherein said inflammatory condition is chosen from the group consisting of inflammatory bowel disease, Crohn's Disease, ulcerative colitis, pancreatitis, diverticulitis, acne inflammation, bronchitis, arthritis, asthma.  
     
     
         40 . A method of treating multiple sclerosis, comprising administering to a mammal in need of such treatment, a safe and effective amount of a metalloprotease inhibitor according to  claim 1 .  
     
     
         41 . A method for preventing the loosening of prosthetic devices chosen from the group consisting of joint replacements and dental prosthesis, the method comprising administering to a mammal in need of such treatment, a safe and effective amount of a metalloprotease inhibitor according to  claim 1 .  
     
     
         42 . A method for treating musculoskeletal disease or cachexia comprising administering to a mammal in need of such treatment, a safe and effective amount of a metalloprotease inhibitor according to  claim 1.