US2009312312A1PendingUtilityA1
Heterobicyclic Metalloprotease Inhibitors

Assignee: ALANTOS PHARM HOLDINGPriority: May 20, 2005Filed: Feb 12, 2009Published: Dec 17, 2009
Est. expiryMay 20, 2025(expired)· nominal 20-yr term from priority
Inventors:Christoph Steeneck Christian Gege Frank Richter Heiko Kroth Matthias Hochgürtel Michael Essers Joshua J. Van Veldhuizen Bert Nolte Brian Gallagher Tim Feuerstein Matthias Schneider Torsten Arndt Hongbo Deng Ralf Biesinger Xinyuan Wu Harald Bluhm Irving Sucholeiki Arthur G. Taveras
A61P 9/14A61P 9/10A61P 3/10A61P 31/22A61P 35/00A61P 39/02A61P 37/08A61P 9/08A61P 43/00A61P 33/06A61P 7/00A61P 9/00A61P 31/12A61P 9/12A61P 37/06A61P 7/02A61P 9/04A61P 31/18A61P 3/02A61P 25/16A61P 27/02A61P 25/28A61P 25/14A61P 25/02A61P 29/00A61P 31/04A61P 25/08A61P 25/00A61P 27/16A61P 25/18A61P 11/00A61P 19/02A61P 1/02A61P 1/04A61P 19/10A61P 1/18C07D 487/04A61P 17/02A61P 11/14A61P 13/02A61P 17/10A61P 13/12A61P 15/06A61P 21/00A61P 17/00A61P 11/06A61P 1/16A61P 17/06A61P 17/04A61P 19/06
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Claims
Abstract

The present invention relates generally to amide group containing pharmaceutical agents, and in particular, to amide containing heterobicyclic metalloprotease inhibitor compounds. More particularly, the present invention provides a new class of heterobicyclic MMP-13 inhibiting and MMP-3 inhibiting compounds, that exhibit an increased potency in relation to currently known MMP-13 and MMP-3 inhibitors.
Claims

exact text as granted — not AI-modified
1 - 173 . (canceled) 
   
   
       174 . A compound having the structure: 
     
       
         
         
             
             
         
       
       R 51  is independently selected from the group consisting of hydrogen, and alkyl, 
       R 1  in each occurrence is independently selected from the group consisting of hydrogen, alkyl, trifluoroalkyl, 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, or
 wherein R 1  is optionally substituted by one R 16  group and optionally substituted by one or more R 9  groups; 
 wherein optionally two hydrogen atoms on the same atom of one or more R 1  groups are replaced with ═O; 
 R 4  in each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, halo, and 
 R 5  in each occurrence is independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4 alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
 R 9  in each occurrence is independently selected from the group consisting of 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 10 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) n —(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O) n —(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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, or
 wherein each R 9  group is optionally substituted by one or more R 14  groups; 
 R 10  and R 11  in each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
 R 14  is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkyl are optionally substituted one or more times by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(H)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
 R 16  is selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4 alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl;
 R 23  is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, and fluoroalkyl; 
 R 30  is selected from the group consisting of alkyl and (C 0 -C 6 )-alkyl-aryl, wherein alkyl and aryl are optionally substituted by a substituent selected from halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxyl, —COOH, alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, NH 2 —CO—, (R 10 )(R 11 )N—CO— wherein R 10  or R 11  are as defined below, except that at least one of R 10  or R 11  is not hydrogen, amino, heterocyclo, mono- or dialkylamino and thiol; 
 R 50  in each occurrence is independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
 R 80  and R 81  in each occurrence are independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4 alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4 alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
 E is selected from the group consisting of 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 
 
     
       
         
         
             
             
         
       
       W is a 5- or 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R 4 ; 
       aryl is an aromatic group containing 1 or 2 rings and 6 to 12 ring carbon atoms; 
       heteroaryl is an aromatic 5- or 6-membered monocyclic or bicyclic ring having 5 to 10 atoms, in which one or more of the atoms in the ring are selected from nitrogen, oxygen or sulfur; 
       heterocycloalkyl is a 5- or 6-membered saturated monocyclic or multicyclic ring system of 3 to 10 carbon atoms, in which one or more of the carbon atoms in the ring system are selected from nitrogen, oxygen and sulfur; 
       heterocyclyl is a 5- or 6-membered saturated monocyclic or multicyclic ring system of 3 to 10 carbon atoms, in which one or more of the carbon atoms in the ring system are selected from nitrogen, oxygen and sulfur; 
       arylalkyl an aryl bonded through an alkyl; 
       heteroarylalkyl is a heteroaryl bonded through an alkyl; 
       heterocyclylalkyl is a heterocyclyl bonded through an alkyl; 
       U is selected from the group consisting of C(R 5 R 10 ), NR 5 , O, S, S═O and S(═O) 2 ; 
       W 1  is selected from the group consisting of 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 the group consisting of a bond and (CR 10 R 11 ) w E(CR 10 R 11 ) w ; 
       g and h are independently selected from 0-2; 
       w is independently selected from 0-4; 
       x is selected from 0 to 2; 
       y is selected from 1 and 2; or 
       pharmaceutically acceptable salts, racemic mixtures or stereoisomers thereof. 
     
   
   
       175 . The compound of  claim 174 , wherein at least one R 1  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein:
 R 6  is independently selected from the group consisting of R 9 , alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, 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 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) n 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 the group consisting of 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 by a substituent selected from halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxyl, —COOH, alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, NH 2 —CO—, (R 10 )(R 11 )N—CO— wherein R 10  or R 11  are as defined below, except that at least one of R 10  or R 11  is not hydrogen, amino, heterocyclo, mono- or dialkylamino and thiol; 
 R 25  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CO 2 R 10 , C(O)NR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
 B 1  is selected from the group consisting of NR 10 , O and S(O) x ; 
 D 4 , G 4 , L 4 , M 4 , and T 4  are independently selected from CR 6  and N; and 
 Z is a 5- to 8-membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, or a 5- to 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
 R 19  is independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), substituted one or more times by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl. 
 
   
   
       176 . The compound of  claim 175 , wherein at least one R 1  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       177 . The compound of  claim 176 , wherein:
 R 6  is selected from the group consisting of hydrogen, halo, CN, OH, CH 2 OH, CF 3 , CHF 2 , OCF 3 , OCHF 2 , COCH 3 , SO 2 CH 3 , SO 2 CF 3 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , NH 2 , NHCOCH 3 , N(COCH 3 ) 2 , NHCONH 2 , NHSO 2 CH 3 , alkoxy, alkyl, CO 2 H,   
     
       
         
         
             
             
         
       
       wherein 
       R 9  is independently selected from the group consisting of hydrogen, fluoro, chloro, CH 3 , CF 3 , CHF 2 , OCF 3 , and OCHF 2 ; 
       R 25  is selected from the group consisting of hydrogen, CH 3 , COOCH 3 , COOH, and CONH 2 . 
     
   
   
       178 . The compound of  claim 174 , wherein at least one R 1  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein: 
       R 12  and R 13  are independently selected from the group consisting of hydrogen, alkyl and halo, wherein alkyl is optionally substituted one or more times by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4 alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, or optionally R 12  and R 13  together form ═O, ═S or ═NR 10 ; 
       R 18  is independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, or optionally two R 19  groups together at one carbon atom form ═O, ═S or ═NR 10 ; 
       R 25  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CO 2 R 10 , C(O)NR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
       J and K are independently selected from the group consisting of CR 10 R 18 , NR 10 , O and S(O) x ; 
       A 1  is selected from the group consisting of 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 the group consisting of CR 18  and N. 
     
   
   
       179 . The compound of  claim 178 , wherein at least one R 1  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       180 . The compound of  claim 174 , wherein one R 1  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein: 
       R 18  is independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
       R 19  is independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, or optionally two R 19  groups together at one carbon atom form ═O, ═S or ═NR 10 ; 
       R 25  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CONR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4 alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
       L 2 , M 2 , and T 2  are independently selected from the group consisting of CR 18  and N; 
       D 3 , G 3 , L 3 , M 3 , and T 3  are independently selected from N, CR 18 , (i), or (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 the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is optionally substituted one or more times with R 19 . 
     
   
   
       181 . The compound of  claim 180 , wherein one R 1  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       182 . The compound of  claim 181 , wherein one R 1  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       183 . The compound of  claim 174 , wherein said compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       184 . A compound according to  claim 174  selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       185 . A pharmaceutical composition comprising a compound of  claim 174  and a pharmaceutically acceptable carrier. 
   
   
       186 . A pharmaceutical composition comprising:
 a) a compound according to  claim 174 ;   b) a pharmaceutically acceptable carrier; and   c) a member selected from the group consisting of: (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.   
   
   
       187 . A compound having the structure: 
     
       
         
         
             
             
         
       
       R 51  is independently selected from the group consisting of hydrogen, and alkyl; 
       R 1  in each occurrence is independently selected from the group consisting of hydrogen alkyl, 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 alkyl, 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
       R 4  in each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, halo, haloalkyl, and CF 3 ; 
       R 10  and R 11  in each occurrence are independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
       R 14  is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl. 
       R 23  is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, and fluoroalkyl; 
       R 50  in each occurrence is independently selected from the group consisting of 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, heteroaryl, C(O)R 80 , C(O)NR 80 R 81 , SO 2 R 80  and SO 2 NR 80 R 81  are optionally substituted by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4 alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
       R 80  and R 81  in each occurrence are independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
       aryl is an aromatic group containing 1 or 2 rings and 6 to 12 ring carbon atoms; 
       heteroaryl is an aromatic 5- or 6-membered monocyclic or bicyclic ring having 5 to 10 atoms, in which one or more of the atoms in the ring are selected from nitrogen, oxygen or sulfur; 
       heterocycloalkyl is a 5- or 6-membered saturated monocyclic or multicyclic ring system of 3 to 10 carbon atoms, in which one or more of the carbon atoms in the ring system are selected from nitrogen, oxygen and sulfur; 
       heterocyclyl is a 5- or 6-membered saturated monocyclic or multicyclic ring system of 3 to 10 carbon atoms, in which one or more of the carbon atoms in the ring system are selected from nitrogen, oxygen and sulfur; 
       arylalkyl an aryl bonded through an alkyl; 
       heteroarylalkyl is a heteroaryl bonded through an alkyl; 
       heterocyclylalkyl is a heterocyclyl bonded through an alkyl; 
       W is a 5- or 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R 4 ; 
       x is selected from 0 to 2; 
       y is selected from 1 and 2; or 
       pharmaceutically-acceptable salts, racemic mixtures or stereoisomers thereof. 
     
   
   
       188 . The compound of  claim 187 , wherein at least one R 1  is selected from: 
     
       
         
         
             
             
         
       
       R 6  is selected from the group consisting of hydrogen, halo, CN, OH, CH 2 OH, CF 3 , CHF 2 , OCF 3 , OCHF 2 , COCH 3 , SO 2 CH 3 , SO 2 CF 3 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , NH 2 , NHCOCH 3 , N(COCH 3 ) 2 , NHCONH 2 , NHSO 2 CH 3 , alkoxy, alkyl, CO 2 H, 
     
     
       
         
         
             
             
         
       
       R 9  is independently selected from the group consisting of hydrogen, fluoro, chloro, CH 3 , CF 3 , CHF 2 , OCF 3 , and OCHF 2 ; and 
       R 25  is selected from the group consisting of hydrogen, CH 3 , COOMe, COOH, and CONH 2 . 
     
   
   
       189 . The compound of  claim 187 , wherein at least one R 1  is selected from: 
     
       
         
         
             
             
         
       
       wherein: 
       R 12  and R 13  are independently selected from the group consisting of hydrogen, alkyl and halo, wherein alkyl is optionally substituted one or more times by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, or optionally R 12  and R 13  together form ═O, ═S or ═NR 10 ; 
       R 18  is independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
       R 19  is independently selected from the group consisting of 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 by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl, or optionally two R 19  groups together at one carbon atom form ═O, ═S or ═NR 10 ; 
       R 25  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, C(O)NR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times by a substituent selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, CF 3 , halo, OH, O—(C 1 -C 4  alkyl), OCH 2 F, OCHF 2 , OCF 3 , ONO 2 , OC(O)—(C 1 -C 4  alkyl), OC(O)—(C 1 -C 4  alkyl), OC(O)NH—(C 1 -C 4  alkyl), OC(O)N(C 1 -C 4  alkyl) 2 , OC(S)NH—(C 1 -C 4  alkyl), OC(S)N(C 1 -C 4  alkyl) 2 , SH, S—(C 1 -C 4  alkyl), S(O)—(C 1 -C 4  alkyl), S(O) 2 —(C 1 -C 4  alkyl), SC(O)—(C 1 -C 4  alkyl), SC(O)O—(C 1 -C 4  alkyl), NH 2 , N(H)—(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , N(H)C(O)—(C 1 -C 4  alkyl), N(CH 3 )C(O)—(C 1 -C 4  alkyl), N(H)C(O)—CF 3 , N(CH 3 )C(O)—CF 3 , N(H)C(S)—(C 1 -C 4  alkyl), N(CH 3 )C(S)—(C 1 -C 4  alkyl), N(H)S(O) 2 —(C 1 -C 4  alkyl), N(H)C(O)NH 2 , N(H)C(O)NH—(C 1 -C 4  alkyl), N(CH 3 )C(O)NH—(C 1 -C 4  alkyl), N(H)C(O)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 , N(H)S(O) 2 NH 2 ), N(H)S(O) 2 NH—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl), N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 , N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 , N(H)C(O)O—(C 1 -C 4  alkyl), N(CH 3 )C(O)O—(C 1 -C 4  alkyl), N(H)S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl), N(CH 3 )C(S)NH—(C 1 -C 4  alkyl), N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 , N(CH 3 )C(S)O—(C 1 -C 4  alkyl), N(H)C(S)NH 2 , NO 2 , CO 2 H, CO 2 —(C 1 -C 4  alkyl), C(O)N(H)OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )OH, C(O)N(CH 3 )O—(C 1 -C 4  alkyl), C(O)N(H)—(C 1 -C 4  alkyl), C(O)N(C 1 -C 4  alkyl) 2 , C(S)N(H)—(C 1 -C 4  alkyl), C(S)N(C 1 -C 4  alkyl) 2 , C(NH)N(H)—(C 1 -C 4  alkyl), C(NH)N(C 1 -C 4  alkyl) 2 , C(NCH 3 )N(H)—(C 1 -C 4  alkyl), C(NCH 3 )N(C 1 -C 4  alkyl) 2 , C(O)—(C 1 -C 4  alkyl), C(NH)—(C 1 -C 4  alkyl), C(NCH 3 )—(C 1 -C 4  alkyl), C(NOH)—(C 1 -C 4  alkyl), C(NOCH 3 )—(C 1 -C 4  alkyl), CN, CHO, CH 2 OH, CH 2 O—(C 1 -C 4  alkyl), CH 2 NH 2 , CH 2 N(H)—(C 1 -C 4  alkyl), CH 2 N(C 1 -C 4  alkyl) 2 , aryl, heteroaryl, cycloalkyl and heterocyclyl; 
       J and K are independently selected from the group consisting of CR 10 R 18 , NR 10 , O and S(O) x ; 
       A 1  is selected from the group consisting of NR 10 , O and S; and 
       D 2 , G 2 , L 2 , M 2  and T 2  are independently selected from the group consisting of CR 18  and N. 
     
   
   
       190 . The compound of  claim 187 , wherein at least one R 1  is selected from:
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