Heterotricyclic Metalloprotease Inhibitors

Abstract

The present invention relates generally to azatriocyclic containing pharmaceutical agents, and in particular, to azatricyclic metalloprotease inhibiting compounds. More particularly, the present invention provides a new class of azatricyclic MMP-3, MMP-8 and/or MMP-13 inhibiting compounds, that exhibit an increased potency and selectivity in relation to currently known MMP-13, MMP-8 and MMP-3 inhibitors.

1 . A compound having Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl, 
 wherein R 1  is optionally substituted one or more times, or 
 wherein R 1  is optionally substituted by one R 16  group and optionally substituted by one or more R 9  groups; 
 R 2  is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R 1  and R 2  when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O) x , or NR 50  and which is optionally substituted one or more times; 
 R 4  in each occurrence is independently selected from R 10 , hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF 3 , (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) x R 10 , (C 0 -C 6 )-alkyl-OC(O)R 10 , (C 0 -C 6 )-alkyl-OC(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═NR 10 NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═NR 11 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)OR 10 , (C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 SO 2 R 11 , (C 0 -C 6 )-alkyl-C(O)—NR 11 —CN, O—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , S(O) x —(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O) x —(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 —(C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —C(O)R 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)OR 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)—NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y R 10 , O—(C 0 -C 6 )-alkyl-aryl and O—(C 0 -C 6 )-alkyl-heteroaryl, 
 wherein each R 4  group is optionally substituted one or more times, or 
 wherein each R 4  group is optionally substituted by one or more R 14  groups, or 
 wherein optionally two R 4  groups, when taken together with the nitrogen or carbon to which they are attached complete a 3- to 8-membered saturated ring or multicyclic ring or unsaturated ring containing carbon atoms and optionally containing one or more heteroatom independently selected from O, S(O) x , N, or NR 50  and which is optionally substituted one or more times, or 
 optionally two R 4  groups together at one saturated carbon atom form ═O, ═S, ═NR 10  or ═NOR 10 ; 
 R 5  is independently selected from hydrogen, alkyl, C(O)NR 10 R 11 , aryl, arylalkyl, SO 2 NR 10 R 11  and C(O)OR 10  wherein alkyl, aryl and arylalkyl are optionally substituted one or more times; 
 R 8  is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R 10  and NR 10 R 11  wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted one or more times; 
 R 9  in each occurrence is independently selected from R 10 , hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF 2 , CF 3 , OR 10 , SR 10 , COOR 10 , CH(CH 3 )CO 2 H, (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-P(O) 2 OH, (C 0 -C 6 )-alkyl-S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) x R 10 , (C 0 -C 6 )-alkyl-OC(O)R 10 , (C 0 -C 6 )-alkyl-OC(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═NR 10 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═NR 11 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)OR 10 , (C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 SO 2 R 11 , C(O)NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, C(O)NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, S(O) 2 NR 10 -alkyl, S(O) 2 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 —(C 0 -C 6 )-alkyl-heteroaryl, (C 0 -C 6 )-alkyl-C(O)—NR 11 —CN, O—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , S(O) x —(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O) x —(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 —(C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —C(O)R 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)OR 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)—NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y R 11 , O—(C 0 -C 6 )-alkyl-aryl and O—(C 0 -C 6 )-alkyl-heteroaryl, 
 wherein each R 9  group is optionally substituted, or 
 wherein each R 9  group is optionally substituted by one or more R 14  groups; 
 R 19  and R 11  in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R 10  and R 11  when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O) x , or NR 50  and which is optionally substituted one or more times; 
 R 14  is independently selected from hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times. 
 R 16  is selected from cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (ii): 
 
     
       
         
         
             
             
         
       
     
     wherein cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl are optionally substituted one or more times;
 R 17  is selected from R 1 , R 4  and R 21 ; 
 R 21  is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and 
 wherein R 21  is optionally substituted one or more times, or wherein R 21  is optionally substituted by one or more R 9  groups; 
 R 30  is selected from alkyl and (C 0 -C 6 )-alkyl-aryl, wherein alkyl and aryl are optionally substituted; 
 R 50  in each occurrence is independently selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R 80 , C(O)NR 80 R 81 , SO 2 R 80  and SO 2 NR 80 R 81 , wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times; 
 R 80  and R 81  in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or 
 R 80  and R 81  when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O) x , —NH, and —N(alkyl) and which is optionally substituted one or more times; 
 E is selected from a bond, CR 10 R 11 , O, NR 5 , S, S═O, S(═O) 2 , C(═O), N(R 10 )(C═O), (C═O)N(R 10 )N(R 10 )S(═O) 2 , S(═O) 2 N(R 10 ), C═N—OR 11 , —C(R 10 R 11 )C(R 10 R 11 , CH 2 —W 1 — and 
 
     
       
         
         
             
             
         
       
       L a  is independently selected from CR 9  and N; 
       L b  is independently selected from C and N with the proviso, that both L b  are not N, and that the bond between L b  and L b  is optionally a double bond only if both L b  are C; 
       L c  is selected from a single bond or an acyclic, straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 10 carbon atoms, optionally containing 1 to 3 groups independently selected from —S—, —O—, NR 10 —, —NR 10 CO—, —CONR 10 —, —S(O) x —, —SO 2 NR 10 —, —NR 10 SO 2 —, NR 10 SO 2 NR 10 —, —NR 10 CONR 10 —, —NR 10 C(O)O—, which replace a corresponding number of non-adjacent carbon atoms, and wherein the hydrocarbon chain is optionally substituted one or more times; 
       Q is a 4- to 8-membered ring selected from cycloalkyl, heterocycloalkyl or a 5- or 6-membered ring selected from aryl and heteroaryl, 
       wherein Q is optionally substituted one or more times, or 
       wherein Q is optionally substituted one or more times with R 4 , or 
       wherein Q is fused via two of its adjacent atoms, which are selected from N and C with a further cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl and heteroaryl system, which is optionally independently substituted one or more times; 
       U is selected from)C(R 5 R 10 , NR 5 , O, S, S═O and S(═O) 2 ; 
       W 1  is selected from O, NR 5 , S, S═O, S(═O) 2 , N(R 10 )(C═O), N(R 10 )S(═O) 2  and S(═O) 2 N(R 10 ); 
       X is selected from a bond and (CR 10 R 11 ) w E(CR 10 R 11 ) w ; 
       X 1  is independently selected from O, S, NR 10 , N—CN, NCOR 10 , N—NO 2 , or N—SO 2 R 10 ; 
       g and h are independently selected from 0-2; 
       w is selected from 0-4; 
       x is selected from 0 to 2; 
       y is selected from 1 and 2; 
       the dotted line optionally represents a double bond; and 
       N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof. 
     
   
   
       2 . A compound according to  claim 1 , wherein Q is phenyl or thiophene that is fused via two of its adjacent atoms with a further cycloalkyl, heterocycloalkyl, bicycloalkyl, hetero-bicycloalkyl, aryl and heteroaryl system, which is optionally independently substituted one or more times. 
   
   
       3 . A compound according to  claim 2 , wherein L a  is N. 
   
   
       4 . A compound according to  claim 2 , wherein:
 L a  is N; and   L b  is C.   
   
   
       5 . A compound according to  claim 1 , selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       6 . A compound according to  claim 5 , wherein R 8  is H. 
   
   
       7 . A compound according to  claim 5 , wherein R 17  is selected from 
     
       
         
         
             
             
         
       
     
     wherein:
 R 6  is selected from R 9 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OR 10 , CH(CH 3 )CO 2 H, (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-P(O) 2 OH, (C 0 -C 6 )-alkyl-S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 11 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) x R 10 , (C 0 -C 6 )-alkyl-OC(O)R 10 , (C 0 -C 6 )-alkyl-OC(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═NR 10 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═NR 11 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)OR 10 , (C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 SO 2 R 11 , C(O)NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, C(O)NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, S(O) 2 NR 10 -alkyl, S(O) 2 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 —(C 0 -C 6 )-alkyl-heteroaryl, (C 0 -C 6 )-alkyl-C(O)—NR 11 —CN, O—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , S(O) x —(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O) x —(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 —(C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —C(O)R 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)OR 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)—NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y R 11 , O—(C 0 -C 6 )-alkyl-aryl and O—(C 0 -C 6 )-alkyl-heteroaryl, wherein each R 6  group is optionally substituted by one or more R 14  groups; 
 R 9  is independently selected from hydrogen, alkyl, halo, CHF 2 , CF 3 , OR 10 , NR 10 R 11 , NO 2 , and CN, wherein alkyl is optionally substituted one or more times. 
 
   
   
       8 . A compound according to  claim 5 , wherein R 1  is selected from: 
     
       
         
         
             
             
         
       
       wherein: 
       R 18  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10  COR 11 , NR 10 SO 2 NR 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11  and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl are optionally substituted one or more times; 
       R 25  is selected from hydrogen, alkyl, cycloalkyl, C(O)NR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times; 
       B 1  is selected from NR 10 , O and S; 
       D 2 , G 2 , L 2 , M 2  and T 2  are independently selected from CR 18  and N; and 
       Z is a 5- to 8-membered ring selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted one or more times. 
     
   
   
       9 . The compound according to  claim 6 , wherein R 1  is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       10 . A compound according to  claim 5 , wherein R 1  is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein: 
       R 12  and R 13  are independently selected from hydrogen, alkyl and halo, wherein alkyl is optionally substituted one or more times, or optionally R 12  and R 13  together form ═O, ═S, ═NR 10  or ═NOR 10 ; 
       R 18  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11  and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times; 
       R 19  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11  and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R 19  groups together at one carbon atom form ═O, ═S, ═NR 10  or ═NOR 10 ; 
       R 25  is selected from hydrogen, alkyl, cycloalkyl, C(O)NR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times; 
       J and K are independently selected from CR 10 R 18 , NR 10 , O and S(O) x ; 
       A 1  is selected from NR 10 , O and S(O) x ; and 
       D 2 , G 2 , J 2 , L 2 , M 2  and T 2  are independently selected from CR 18  and N. 
     
   
   
       11 . A compound according to  claim 6 , wherein R 1  is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       12 . A compound according to  claim 5 , wherein R 1  is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein: 
       R 18  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11 , and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times; 
       R 19  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11  and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R 19  groups together at one carbon atom form ═O, ═S, ═NR 10  or ═NOR 10 ; 
       R 25  is selected from hydrogen, alkyl, cycloalkyl, CONR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; 
       L 2 , M 2 , and T 2  are independently selected from CR 18  and N; 
       D 3 , G 3 , L 3 , M 3 , and T 3  are independently selected from N, CR 18 , (i) and (ii) 
     
     
       
         
         
             
             
         
       
       with the proviso that one of L 3 , M 3 , T 3 , D 3 , and G 3  is (i) or (ii); 
       B 1  is selected from the group consisting of NR 10 , O and S(O) x ; and 
       Q 2  is a 5- to 8-membered ring selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is optionally substituted one or more times with R 19 . 
     
   
   
       13 . A compound according to  claim 6 , wherein R 1  is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       14 . A compound according to  claim 6 , wherein R 1  is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       15 . A compound according to  claim 6 , wherein R 1  is selected from: 
     
       
         
         
             
             
         
       
     
   
   
       16 . A compound according to  claim 1 , having the structure: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       or N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof. 
     
   
   
       17 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1 . 
   
   
       18 . A method of treating a metalloprotease mediated disease, comprising administering to a subject in need of such treatment an effective amount of a compound according to  claim 1 . 
   
   
       19 . The method according to  claim 18 , wherein the disease is selected from rheumatoid arthritis, osteoarthritis, inflammation, atherosclerosis and multiple sclerosis. 
   
   
       20 . A pharmaceutical composition comprising:
 A) an effective amount of a compound selected from: a compound according to  claim 1 ;   B) a pharmaceutically acceptable carrier; and   C) a drug, agent or therapeutic selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.