Antiinflammation agents

Abstract

Compounds, compositions and methods that are useful in the treatment of inflammatory, immunoregulatory, metabolic and cell proliferative conditions or diseases are provided herein. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in inflammation, metabolism and cell proliferation. The subject compounds contain fused carbocyclic or heterocyclic rings.

1 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 W and X are independently selected from the group consisting of N and CH;  
 Y is selected from the group consisting of O, S and N(R); 
 wherein R is selected from the group consisting of H, CN, NO 2 , (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )alkenyl and (C 2 -C 10 )alkynyl;  
 
 Z is selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl and NR 2 R 3 ;  
 R 1 , R 2  and R 3  are independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 1 -C 10 )heteroalkyl (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, aryl(C 1 -C 4 )heteroalkyl, heteroaryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )heteroalkyl and perfluoro(C 1 -C 6 )alkyl; and wherein when Z is NR 2 R 3 , R 2  and R 3  can be combined to form a 5- to 7-membered heterocyclyl ring;  
 R 4  is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkyl-alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl;  
 A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated; and  
 B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF 3 , CF 3 O, (C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, cyano, nitro, sulfonamido, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxamido and (C 1 -C 6 )heteroalkoxy.  
 
   
   
       2 . A compound of  claim 1 , wherein W is N and X is CH.  
   
   
       3 . A compound of  claim 1 , wherein W is N and X is N.  
   
   
       4 . A compound of  claim 1 , wherein W is CH and X is N.  
   
   
       5 . A compound of  claim 1 , wherein W is CH and X is CH.  
   
   
       6 . A compound of  claim 2 , wherein Y is selected from the group consisting of O and S.  
   
   
       7 . A compound of  claim 2 , wherein Y is O.  
   
   
       8 . A compound of  claim 2 , wherein Y is S.  
   
   
       9 . A compound of  claim 2 , wherein Z is NR 2 R 3 .  
   
   
       10 . A compound of  claim 6 , wherein R 4  is H.  
   
   
       11 . A compound of  claim 1 , wherein A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       12 . A compound of  claim 1 , wherein A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein 
 R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, halogen, CF 3 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl, cyano, nitro, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl (C 1 -C 6 )alkyl, CONH 2 , CO—NH—(C 1 -C 6 )alkyl, CO—N[(C 1 -C 6 )alkyl] 2 , SO 2 NH 2 , SO 2 NH—(C 1 -C 6 )alkyl, SO 2 N—[(C 1 -C 6 )alkyl] 2  and (C 1 -C 6 )heteroalkoxy; or two adjacent R groups selected from R 5 , R 6 , R 7  and R 8 , can be linked together to form a new 5- or 6-membered carbocyclic or heterocyclic ring.  
 
   
   
       13 . A compound of  claim 12 , wherein W is N; X is CH; Y is O or S; and A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       14 . A compound of  claim 1 , wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.  
   
   
       15 . A compound of  claim 1 , wherein B contains a nitrogen atom at the point of attachment of B to the remainder of the molecule.  
   
   
       16 . A compound of  claim 1 , wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl, 1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.  
   
   
       17 . A compound of  claim 1 , wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.  
   
   
       18 . A compound of  claim 13 , wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.  
   
   
       19 . A compound of  claim 13 , wherein B contains a nitrogen atom at the point of attachment of B to the remainder of the molecule.  
   
   
       20 . A compound of  claim 13 , wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl, 1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.  
   
   
       21 . A compound of  claim 13 , wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.  
   
   
       22 . A compound of  claim 1 , wherein W is N; X is CH; Y is O or S; Z is H, CH 3 , NH 2  or NHCH 3 ; R 1  is H, (C 1 -C 6 )alkyl, (C 1 -C 10 )heteroalkyl, (C 4 -C 10 )cycloheteroalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, aryl(C 1 -C 4 )alkyl, aryl(C 1 -C 4 )heteroalkyl, heteroaryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )heteroalkyl, or perfluoro(C 1 -C 6 )alkyl; R 4  is H; A represents  
     
       
         
         
             
             
         
       
       wherein R 6  and R 7  are independently selected from the group consisting of H, halogen, CF 3 , CF 3 O, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )heteroalkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl and cyano; and B is a five-membered aromatic ring system containing at least one nitrogen atom.  
     
   
   
       23 . A compound of  claim 22 , wherein Y is S.  
   
   
       24 . A compound of  claim 22 , wherein Z is NR 2 R 3 .  
   
   
       25 . A compound of  claim 22 , wherein Z is NH 2 .  
   
   
       26 . A compound of  claim 22 , wherein R 1  is (C 1 -C 6 )alkyl, (C 1 -C 6 )heteroalkyl or (C 3 -C 10 )cycloheteroalkyl-alkyl.  
   
   
       27 . A compound of  claim 22 , wherein B is a five-membered aromatic ring system containing 1-2 nitrogen atoms and 0-1 sulfur atoms.  
   
   
       28 . A compound of  claim 27 , wherein B is unsubstituted or substituted by (C 1 -C 3 )alkyl, CF 3 , cyano, or halogen.  
   
   
       29 . A compound of  claim 22 , wherein Z is NH 2 ; R 6  is selected from the group consisting of H, halogen, CF 3 , CF 3 O, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 1 -C 4 )heteroalkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl and cyano, wherein the alkyl, alkenyl and heteroalkyl groups optionally bear additional substituents selected from cyano, carboxamido,(C 1 -C 3 )alkylsulfonyl or (C 1 -C 3 )alkoxy; and R 7  is selected from the group consisting of H, halogen, CF 3 , CF 3 O, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )heteroalkyl and cyano.  
   
   
       30 . A compound of  claim 29 , wherein R 6  is selected from the group consisting of CH 2 (CH 2 ) m CN, CH 2 (CH 2 ) n SO 2 CH 3  and CH 2 (CH 2 ) n OCH 3 , wherein the subscript n is an integer from 0 to 2.  
   
   
       31 . A compound of  claim 29 , wherein R 6  is  
     
       
         
         
             
             
         
       
     
   
   
       32 . A compound of  claim 29 , wherein R 7  is selected from H, halogen, CF 3  and (C 1 -C 4 )alkyl.  
   
   
       33 . A compound of  claim 29 , wherein R 7  is methyl.  
   
   
       34 . A compound of  claim 1 , having the formula:  
     
       
         
         
             
             
         
       
     
     wherein Y is O, S or N—CN; W′ is N(CH 3 ), N(CF 3 ), N(CH 2 CH 3 ), O or S; the subscripts n and n′ are independently integers from 0 to 3; R 7  is H, halogen, CF 3 , CF 3 O, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )heteroalkyl or cyano; R 9  is CN, CONH 2 , CO—NH—(C 1 -C 6 )alkyl, CO—N[(C 1 -C 6 )alkyl] 2 , CO—NH—(C 1 -C 6 )heteroalkyl, CO—N[(C 1 -C 6 )heteroalkyl] 2 , S(O) n″ -(C 1 -C 6 )alkyl, S(O) n″ -(C 1 -C 6 )heteroalkyl, heteroaryl, (C 1 -C 6 )alkoxy or (C 3 -C 6 )cycloheteroalkyl, wherein each n″ is independently an integer of 0 to 2; R 1  is NH 2 , NH—(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , NH—(C 1 -C 6 )heteroalkyl, N[(C 1 -C 6 )heteroalkyl] 2 , (C 1 -C 6 )heteroalkyl, S(O) n″ -(C 1 -C 6 )alkyl, S(O) n″ -(C 1 -C 6 )heteroalkyl, aryl, heteroaryl, O—(C 1 -C 6 )alkyl, O—(C 1 -C 6 )heteroalkyl or (C 3 -C 8 )cycloheteroalkyl; and R 11  is H, CF 3 , NH 2 , NH—(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , halogen or (C 1 -C 3 )alkyl.  
   
   
       35 . A compound of  claim 34 , wherein Y is O or S; W′ is N—CH 3 ; n is 2; n′ is 1-3; R 9  is cyano, CONH 2 , SO 2 -(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 3 -C 6 )cycloheteroalkyl; R 10  is NH—(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , NH—(C 1 -C 6 )heteroalkyl, N[(C 1 -C 6 )heteroalkyl] 2 , O—(C 1 -C 6 )alkyl, O—(C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy or (C 3 -C 8 )cycloheteroalkyl; and R 11  is H.  
   
   
       36 . A compound of  claim 22 , wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.  
   
   
       37 . A compound of  claim 22 , wherein B contains a nitrogen atom at the point of attachment of B to the remainder of the molecule.  
   
   
       38 . A compound of  claim 22 , wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.  
   
   
       39 . A compound of  claim 22 , wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl, 1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.  
   
   
       40 . A compound of  claim 1 , wherein Y is S; Z is NH 2  and R 1  is (C 1 -C 6 )alkyl.  
   
   
       41 . A compound of  claim 40 , wherein R 1  is methyl.  
   
   
       42 . A compound of  claim 1 , wherein said compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       43 . A composition comprising a pharmaceutically acceptable excipient and a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 W and X are independently selected from the group consisting of N and CH;  
 Y is selected from the group consisting of O, S and N(R); 
 wherein R is selected from the group consisting of H, CN, NO 2 , (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )alkenyl and (C 2 -C 10 )alkynyl;  
 
 Z is selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl and NR 2 R 3 ;  
 R 1 , R 2  and R 3  are independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 2 -C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 4 )heteroalkyl, heteroaryl(C 2 -C 4 )alkyl, heteroaryl(C 2 -C 4 )heteroalkyl and perfluoro(C 1 -C 6 )alkyl; and wherein when Z is NR 2 R 3 , R 2  and R 3  can be combined to form a 5- to 7-membered ring; and wherein when Y is N(R), R and R 1  are optionally combined to form a 5- to 7-membered ring;  
 R 4  is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkyl-alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl;  
 A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated; and  
 B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF 3 , CF 3 O, (C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, cyano, nitro, sulfonamido, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 2 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxamido and (C 1 -C 6 )heteroalkoxy.  
 
   
   
       44 . A composition in accordance with  claim 43 , wherein W is N and X is CH.  
   
   
       45 . A composition in accordance with  claim 43 , wherein W is N and X is N.  
   
   
       46 . A composition in accordance with  claim 43 , wherein W is CH and X is N.  
   
   
       47 . A composition in accordance with  claim 43 , wherein W is CH and X is CH.  
   
   
       48 . A composition in accordance with  claim 43 , wherein Y is selected from the group consisting of O and S.  
   
   
       49 . A composition in accordance  claim 43 , wherein Y is O.  
   
   
       50 . A composition in accordance  claim 43 , wherein Y is S.  
   
   
       51 . A composition in accordance  claim 43 , wherein Z is NR 2 R 3 .  
   
   
       52 . A composition in accordance with  claim 48 , wherein R 4  is H.  
   
   
       53 . A composition in accordance with  claim 43 , wherein A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       54 . A composition in accordance with  claim 43 , wherein A is selected from the group consisting of.  
     
       
         
         
             
             
         
       
     
     wherein 
 R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, halogen, CF 3 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl, cyano, nitro, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 2 -C 6 )alkoxycarbonyl, (C 3 -C 6 )alkoxycarbonylalkyl, CONH 2 , CO—NH—(C 1 -C 6 )alkyl, CO—N[(C 1 -C 6 )alkyl] 2 , SO 2 NH 2 , SO 2 NH—(C 1 -C 6 )alkyl, SO 2 N—[(C 1 -C 6 )alkyl] 2  and (C 1 -C 6 )heteroalkoxy; or two adjacent R groups can be linked together to form a new 5- or 6-membered carbocyclic or heterocyclic ring.  
 
   
   
       55 . A composition in accordance with  claim 43 , wherein W is N; X is CH; Y is O or S; and A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       56 . A composition in accordance with  claim 43 , wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.  
   
   
       57 . A composition in accordance with  claim 43 , wherein B contains a nitrogen atom at the point of attachment of B to the remainder of the molecule.  
   
   
       58 . A composition in accordance with  claim 43 , wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl, 1-methyl-1,3,4-triazolyl, and 4 methyl-1,2,4-triazol-3-yl.  
   
   
       59 . A composition in accordance with  claim 43 , wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.  
   
   
       60 . A composition in accordance with  claim 55 , wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.  
   
   
       61 . A composition in accordance with  claim 55 , wherein B contains a nitrogen atom at the point of attachment of B to the remainder of the molecule.  
   
   
       62 . A composition in accordance with  claim 55 , wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl, 1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.  
   
   
       63 . A composition in accordance with  claim 55 , wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.  
   
   
       64 . A method for treating an inflammatory, metabolic or malignant condition, said method comprising administering to a subject in need of such treatment, an effective amount of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 W and X are independently selected from the group consisting of N and CH;  
 Y is selected from the group consisting of O, S and N(R); 
 wherein R is selected from the group consisting of H, CN, NO 2 , (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )alkenyl and (C 2 -C 10 )alkynyl;  
 
 Z is selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl and NR 2 R 3 ;  
 R 1 , R 2  and R 3  are independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 2 -C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 4 )heteroalkyl, heteroaryl(C 2 -C 4 )alkyl, heteroaryl(C 2 -C 4 )heteroalkyl and perfluoro(C 1 -C 6 )alkyl; and wherein when Z is NR 2 R 3 , R 2  and R 3  can be combined to form a 5- to 7-membered ring; and wherein when Y is N(R), R and R 1  are optionally combined to form a 5- to 7-membered ring;  
 R 4  is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkyl-alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl;  
 A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated; and  
 B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF 3 , CF 3 O, (C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, cyano, nitro, sulfonamido, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 2 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxamido and (C 1 -C 6 )heteroalkoxy.  
 
   
   
       65 . A method in accordance with  claim 64 , wherein W is N and X is CH.  
   
   
       66 . A method in accordance with  claim 64 , wherein W is N and X is N.  
   
   
       67 . A method in accordance with  claim 64 , wherein W is CH and X is N.  
   
   
       68 . A method in accordance with  claim 64 , wherein W is CH and X is CH.  
   
   
       69 . A method in accordance with  claim 65 , wherein Y is selected from the group consisting of O and S.  
   
   
       70 . A method in accordance with  claim 65 , wherein Y is O.  
   
   
       71 . A method in accordance with  claim 65 , wherein Y is S.  
   
   
       72 . A method in accordance with  claim 65 , wherein Z is NR 2 R 3 .  
   
   
       73 . A method in accordance with  claim 69 , wherein R 4  is H.  
   
   
       74 . A method in accordance with  claim 64 , wherein A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       75 . A method in accordance with  claim 64 , wherein A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein 
 R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, halogen, CF 3 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloaklyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl, cyano, nitro, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 2 -C 6 )alkoxycarbonyl, (C 3 -C 6 )alkoxycarbonylalkyl, CONH 2 , CO—NH—(C 1 -C 6 )alkyl, CO—N[(C 1 -C 6 )alkyl] 2 , SO 2 NH 2 , SO 2 NH—(C 1 -C 6 )alkyl, SO 2 N—[(C 1 -C 6 )alkyl] 2  and (C 1 -C 6 )heteroalkoxy; or two adjacent R groups can be linked together to form a new 5- or 6-membered carbocyclic or heterocyclic ring.  
 
   
   
       76 . A method in accordance with  claim 64 , wherein W is N; X is CH; Y is O or S; and A is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       77 . A method in accordance with  claim 64 , wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.  
   
   
       78 . A method in accordance with  claim 64 , wherein B contains a nitrogen atom at the point of attachment of B to the remainder of the molecule.  
   
   
       79 . A method in accordance with  claim 64 , wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl, 1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.  
   
   
       80 . A method in accordance with  claim 64 , wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.  
   
   
       81 . A method in accordance with  claim 76 , wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.  
   
   
       82 . A method in accordance with  claim 76 , wherein B contains a nitrogen atom at the point of attachment of B to the remainder of the molecule.  
   
   
       83 . A method in accordance with  claim 76 , wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl, 1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.  
   
   
       84 . A method in accordance with  claim 76 , wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.  
   
   
       85 . A method in accordance with  claim 64 , wherein said compound is administered orally.  
   
   
       86 . A method in accordance with  claim 64 , wherein said compound is administered topically.  
   
   
       87 . A method in accordance with  claim 64 , wherein said compound is administered intravenously or intramuscularly.  
   
   
       88 . A method in accordance with  claim 64 , wherein said compound is administered in combination with a second therapeutic agent, said second therapeutic agent being a member selected from the group consisting of prednisone, dexamethasone, beclomethasone, methylprednisone, betamethasone, hydrocortisone, methotrexate, cyclosporin, rapamycin, tacrolimus, antihistamine drugs, TNF antibodies, IL-1 antibodies, soluble TNF receptors, soluble IL-1 receptors, TNF or IL-1 receptor antagonists, non-steroidal antiinflammatory agents, COX-2 inhibitors, antidiabetic agents, and anticancer agents.  
   
   
       89 . A method in accordance with  claim 88 , wherein said administering is sequential.  
   
   
       90 . A method in accordance with  claim 64 , wherein said inflammatory, metabolic or malignant condition is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, psoriasis, cancer, diabetes and septic shock.  
   
   
       91 . A method for treating a condition or disorder mediated by IKK, comprising 
 administering to a subject in need thereof a therapeutically effective amount of a compound having the formula:                          wherein    W and X are independently selected from the group consisting of N and CH;    Y is selected from the group consisting of O, S and N(R);    wherein R is selected from the group consisting of H, CN, NO 2 , (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )alkenyl and (C 2 -C 10 )alkynyl;    Z is selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl and NR 2 R 3 ;    R 1 , R 2  and R 3  are independently selected from the group consisting of H. (C 1 -C 10 )alkyl, (C 3 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, aryl(C 1 -C 4 )heteroalkyl, heteroaryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )heteroalkyl and perfluoro(C 1 -C 6 )alkyl; and wherein when Z is NR 2 R 3 , R 2  and R 3  can be combined to form a 5- to 7-membered heterocyclyl ring;    R 4  is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkyl-alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl;    A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated; and    B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF 3 , CF 3 O, (C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 - 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, cyano, nitro, sulfonamido, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxycarbonyl, (C 1 -6)alkoxycarbonyl(C 1 -C 6 )alkyl, carboxamido and (C 1 -C 6 )heteroalkoxy.    
   
   
       92 . A method for modulating IKK, comprising contacting a cell with a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 W and X are independently selected from the group consisting of N and CH;  
 Y is selected from the group consisting of O, S and N(R); 
 wherein R is selected from the group consisting of H, CN, NO 2 , (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )alkenyl and (C 2 -C 10 )alkynyl;  
 
 Z is selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl and NR 2 R 3 ;  
 R 1 , R 2  and R 3  are independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, aryl(C 1 -C 4 )heteroalkyl, heteroaryl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )heteroalkyl and perfluoro(C 1 -C 6 )alkyl; and wherein when Z is NR 2 R 3 , R 2  and R 3  can be combined to form a 5- to 7-membered heterocyclyl ring;  
 R 4  is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkyl-alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl;  
 A is a substituted or in substituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated; and  
 B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF 3 , CF 3 O, (C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, cyano, nitro, sulfonamido, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxamido and (C 1 -C 6 )heteroalkoxy.  
 
   
   
       93 . The method of  claim 92 , wherein said compound is an IKK inhibitor.  
   
   
       94 . The method of  claim 92 , wherein said compound is an IKK activator.  
   
   
       95 . A method for the preparation of antiinflammation agents comprising contacting a precursor compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 W and X are independently selected from the group consisting of N and CH;  
 R 4  is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkyl-alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl;  
 A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated; and  
 B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF 3 , CF 3 O, (C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, cyano, nitro, sulfonamido, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 2 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxamido and (C 1 -C 6 )heteroalkoxy  
 with a compound having the formula:  
                     
 wherein  
 Y is selected from the group consisting of O, S and N(R); 
 wherein R is selected from the group consisting of H, CN, NO 2 , (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )alkenyl and (C 2 -C 10 )alkynyl;  
 
 Z is selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl and NR 2 R 3 ;  
 R 1 , R 2  and R 3  are independently selected .from the group consisting of H, (C 1 -C 10 )alkyl, (C 3 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 2 -C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 4 )heteroalkyl, heteroaryl(C 2 -C 4 )alkyl, heteroaryl(C 2 -C 4 )heteroalkyl and perfluoro(C 1 -C 6 )alkyl; and wherein when Z is NR 2 R 3 , R 2  and R 3  can be combined to form a 5- to 7-membered ring; and wherein when Y is N(R), R and R 1  are optionally combined to form a 5- to 7-membered ring;  
 under conditions sufficient to produce compounds having the formula:  
                     
 wherein each of A, B, R 1 , R 4 , W, X, Y and Z have the meanings provided above.  
 
   
   
       96 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 W and X are independently selected from the group consisting of N and CH;  
 R 4  is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkyl-alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl;  
 A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated; and  
 B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF 3 , CF 3 O, (C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 3 -C 10 )cycloalkyl, (C 4 -C 10 )cycloalkyl-alkyl, (C 3 -C 10 )cycloheteroalkyl, cyano, nitro, sulfonamido, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 2 -C 6 )alkoxycarbonyl, (C 2 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxamido and (C 1 -C 6 )heteroalkoxy.  
 
   
   
       97 . A compound of  claim 96 , wherein R 4  is hydrogen.  
   
   
       98 . A compound of  claim 96 , wherein R 4  is hydrogen, Y is O or S, and Z is NR 2 R 3 .  
   
   
       99 . A compound of  claim 96 , wherein R 4  is hydrogen, Y is O or S, Z is NR 2 R 3 , and B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.  
   
   
       100 . A compound of  claim 96 , B contains a nitrogen atom at the point of attachment of B to the remainder of the molecule.  
   
   
       101 . A compound of  claim 99 , wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl, 1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.