Tricyclic compounds and methods of use therefor

Abstract

The invention relates to novel compounds of Formula I: wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and subscripts m and n each has the meaning as described herein. Compounds of Formula I and pharmaceutical compositions thereof are useful in the treatment of disease and disorders in which undesired or over-activation of NF-kB signaling is observed.

We claim: 
     
         1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         wherein 
         A 1 , A 2 , A 3  and A 4  are selected from group consisting of:
 A 1 , A 2 , A 3  are each N and A 4  is C; 
 A 1  and A 2  are each N, A 3  is C(R A3 ) and A 4  is C; 
 A 1  is C, A 2  is N, A 3  is N(R N3 ) and A 4  is C; 
 A 1  is C, A 2  is N(R N2 ), A 3  is N and A 4  is C, wherein R N2  is hydrogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkyl-C(═O)— or C 1-3  haloalkyl-C(═O)—; 
 A 1  is C and one of A 2  and A 3  is N and the other is S and A 4  is C; 
 A 1  is C, A 2  is S, A 3  is C(R A3 ) and A 4  is C; 
 A 1  is C, A 2  is N, A 3  and A 4  is N; 
 A 1  is C, A 2  is N, A 3  is C(R A3 ) and A 4  is N; 
 A 1  is C, A 2  is C(R C2 ), A 3  is S and A 4  is C, wherein R C2  is hydrogen, halogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkyl-C(═O)— or C 1-3  haloalkyl-C(═O)—; and 
 A 1  is C, A 2  and A 3  and A 4  are each N; 
 A 5  and A 6  are each independently C or N; 
 
         X is O or C(R 1 ) 2 ; 
         m is an integer from 0 to 4; 
         R 1 , R 2  and R A3  and R N3  at each occurrence each is independently selected from the group consisting of hydrogen, F, —Cl, —Br, —I, —(X 1 ) 0-1 —CN, —(X 1 ) 0-1 —NO 2 , —(X 1 ) 0-1 —SF 5 , —(X 1 ) 0-1 —OH, —(X 1 ) 0-1 —NH 2 , —(X 1 ) 0-1 —N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1b )(R 1a ), —(X 1 ) 0-1 —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, —(X 1 ) 0-1 —C 1-6  alkyl, —(X 1 ) 0-1 —C 3-10  cycloalkyl, —(X 1 ) 0-1 —C 2-9  heterocycloalkyl, —(X 1 ) 0-1 -5-10 membered heteroaryl, —(X 1 ) 0-1 —6-10 membered aryl, —C(═O)(X 1 ) 1 —C 3-10  cycloalkyl, —C(═O)(X 1 ) 1 —C 2-9  heterocycloalkyl, ═O, —(X 1 ) 0-1 —C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —C(═Y 1 )NH 2 , —(X 1 ) 0-1 —C(═Y 1 )N(R 1a )(R 1b ), —(X 1 ) 0-1 —C(═Y 1 )OR 1a , —(X 1 ) 0-1 —C(═Y 1 )OH, —(X 1 ) 0-1 —N(H)C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(H), —(X 1 ) 0-1 —N(H)C(═Y 1 )OR 1a , —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )OR 1a , —(X 1 ) 0-1 —S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(H)S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(R 1b )S(O) 1-2 R 1a , —(X 1 ) 0-1 —S(O) 0-1 N(H)(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 N(R 1b )(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 NH 2 , —(X 1 ) 0-1 —S(═O)(═NR 1b )R 1a , —(X 1 ) 0-1 —C(═Y 1 )R 1a , —(X 1 ) 0-1 —C(═Y 1 )H, —(X 1 ) 0-1 —C(═NOH)R 1a , —(X 1 ) 0-1 —C(═NOR 1b )R 1a , —(X 1 ) 0-1 —NHC(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —NHC(═Y 1 )NH 2 , —(X 1 ) 0-1 —NHC(═Y 1 )N(R 1b )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(R 1a )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )NH 2 , —(X 1 ) 0-1 —OC(═Y 1 )R 1a , —(X 1 ) 0-1 —OC(═Y 1 )H, —(X 1 ) 0-1 —OC(═Y 1 )OR 1a , —(X 1 ) 0-1 —OP(═Y 1 )(OR 1a )(OR 1b ), —(X 1 )—SC(═Y 1 )OR 1a  and —(X 1 )—SC(═Y 1 )N(R 1a )(R 1b ) wherein X 1  is selected from the group consisting of C 1-4  alkylene, C 1-4  haloalkylene, C 1-4  heteroalkylene, C 2-4  alkenylene, C 2-4  alkynylene, C 1-4  alkyleneoxy, C 3-7  cycloalkylene and C 2-6  heterocycloalkylene, phenylene, 5-6 membered heteroarylene, R 1a  and R 1b  are each independently selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-4  alkyl, C 2-6  heterocycloalkyl, C 2-6  heterocycloalkyl-C 1-4  alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl-C 1-4  alkyl, C 6  aryl, C 6  aryl-C 1-4  alkyl and benzyl, or R 1a  and R 1b  when attached to the same nitrogen atom are optionally combined to form a 3 to 7 membered heterocyclic ring comprising 0-2 additional heteroatoms selected from N, O and S; Y 1  is O, NR 1d  or S wherein R 1d  is hydrogen or C 1-6  alkyl; wherein any portion of R 1 , R 2  and R A3  and R N3  substituent at each occurrence is each independently further substituted with from 0 to 4 R 1/2  substituents selected from the group consisting of F, —Cl, —Br, —I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —N(C 1-6  alkyl) 2 , —NH(C 1-6  alkyl), —CF 3 , ═O, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 3-7  cycloalkyl, C 2-6  heterocycloalkyl, —C(═O)N(H)(C 1-6 (halo)alkyl), —C(═O)N(C 1-6  (halo)alkyl) 2 , —C(═O)NH 2 , —C(═O)OC 1-6 (halo)alkyl, —C(═O)OH, —N(H)C(═O)(C 1-6 (halo)alkyl), —N(C 1-6 (halo)alkyl)C(═O)(C 1-6 (halo)alkyl), —N(H)C(═O)OC 1-6 (halo)alkyl, —N(C 1-6  (halo)alkyl)C(═O)OC 1-6 (halo)alkyl, —S(O) 1-2 C 1-6 (halo)alkyl, —N(H)S(O) 1-2 C 1-6 (halo)alkyl, —N(C 1-6  (halo)alkyl)S(O) 1-2 C 1-6 (halo)alkyl, —S(O) 0-1 N(H)(C 1-6 (halo)alkyl), —S(O) 0-1 N(C 1-6 (halo)alkyl) 2 , —S(O) 0-1 NH 2 , —C(═O)C 1-6 (halo)alkyl, —C(═O) C 3-7  cycloalkyl, —C(═NOH)C 1-6 (halo)alkyl, —C(═NOC 1-6  alkyl)C 1-6 (halo)alkyl, —NHC(═O)N(H)(C 1-6 (halo)alkyl), —NHC(═O)N(C 1-6  (halo)alkyl) 2 , —NHC(═O)NH 2 , —N(C 1-6 (halo)alkyl)C(═O)N(H)(C 1-6 (halo)alkyl), —N(C 1-6  (halo)alkyl)C(═O)NH 2 , —OC(═O)C 1-6 (halo)alkyl, —OC(═O)OC 1-6 (halo)alkyl, —OP(═O)(OC 1-6  (halo)alkyl) 2 , —SC(═O)OC 1-6 (halo)alkyl and —SC(═O)N(C 1-6 (halo)alkyl) 2 , wherein any two R 2  substituents attached to the same or different ring vertices in the B ring or a R 1  and R 2  substituents attached to different ring vertices in the B ring are optionally combined to form a 3 to 6-membered carbocyclic or heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S, wherein said 3 to 6-membered carbocyclic or heterocyclic ring is optionally substituted with 1 to 2 R 1/2  substituents; 
         R 4  and R 6  are each independently absent if attached to a nitrogen atom or selected from the group consisting of hydrogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkyl-C(═O)— or C 1-3  haloalkyl-C(═O)—, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  dialkylamino, C 1-3  alkylthio, NH 2 , OH, F, Cl, Br, I, CN and NO 2 ; 
         R 5  is selected from the group consisting of hydrogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkyl-C(═O)— or C 1-3  haloalkyl-C(═O)—, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  dialkylamino, C 1-3  alkylthio, NH 2 , OH, F, Cl, Br, I, CN and NO 2    
         R 7  at each occurrence is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 3-10  cycloalkyl, C 2-9  heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, —C(═O)R 7a , —C(═O)H, —C(═O)OR 7a  or —C(═O)NR 7a R 7b , wherein R 7a  and R 7b  at each occurrence is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  heteroalkyl, C 3-10  cycloalkyl, C 2-9  heterocycloalkyl, —(C 1-6  alkylene)-(C 3-10  cycloalkyl), —(C 1-6  alkylene)-(C 2-9  heterocycloalkyl), —(C 1-6  alkylene)-(6-membered aryl) and —(C 1-6  alkylene)-(5-6 membered heteroaryl), and wherein R 7a  and R 7b , when attached to the same nitrogen atom, are optionally combined to form a C 2-9  heterocycloalkyl further comprising 0-2 additional heteroatoms selected from N, O and S; 
         R 8  at each occurrence is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl or —CH 2 —OH; or alternatively R 7  and R 8  are combined to form a C 3-10  cycloalkyl, C 2-9  heterocycloalkyl, wherein optionally fused to said C 3-10  cycloalkyl and C 2-9  heterocycloalkyl is a 6 membered aryl, 5-6 membered heteroaryl ring or 3-6 membered heterocycloalkyl ring; and wherein the R 7  substituent, either alone or as combined with R 8 , are optionally substituted with 1 to 5 R R7/8  substitutents selected from the group consisting of F, Cl, Br, I, —OH, —NH 2 , —SH, —CF 3 , —OCF 3 , —SF 5 , —OCH 3 , C 1-6  alkyl, CD 3 , C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 3-5  cycloalkyl and C 2-5  heterocycloalkyl, ═O, —(X 7 ) 0-1 —CN, —(X 7 ) 0-1 —NO 2 , —(X 7 ) 0-1 —N 3 , —(X 7 ) 0-1 —OH, —(X 7 ) 0-1 —H, —(X 7 ) 0-1 —OR R7 , —(X 7 ) 0-1 —N(H)R R7 , —(X 7 ) 0-1 —N(H) 2 , —(X 7 ) 0-1 —N(R R7 ) 2 , —(X 7 ) 0-1 —SR R7 , —(X 7 ) 0-1 —SH, —(X 7 ) 0-1 —C(O)R R7 , —(X 7 ) 0-1 —C(O)H, —(X 7 ) 0-1 —S(O) 2 R R7 , —(X 7 ) 0-1 —S(O)R R7 , —(X 7 ) 0-1 —N(H)S(O) 2 R R7 , —(X 7 ) 0-1 —N(R R7 )S(O) 2 R R7 , —(X 7 ) 0-1 —OC(O)R R7 , —(X 7 ) 0-1 —N(H)C(O)OR R7 , —(X 7 ) 0-1 —N(R R7 )C(O)OR R7 , —(X 7 ) 0-1 —C(═O)OR R7 , —(X 7 ) 0-1 —C(═O)OH, —(X 7 ) 0-1 —C(═O)N(H)R R7 , —(X 7 ) 0-1 —C(═O)N(R R7 )R R7 , —(X 7 ) 0-1 — N(H)C(═O)R R7 , —(X 7 ) 0-1 —N(R R7 )C(═O)R R7 , —(X 7 ) 0-1 —N(H)C(═O)OR R7  and —(X 7 ) 0-1 —N(R R7 )C(═O)OR R7 , wherein X 7  is selected from the group consisting of C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, C 1-6  heteroalkylene, C 3-7  cycloalkylene and C 2-6  heterocycloalkylene, and R R7  at each occurrence is independently selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl and C 2-6  heterocycloalkyl; and the subscript n is an integer from 0 to 1. 
       
     
     
         2 . The compound of  claim 1  having Formula I-A or I-B: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein said compound having Formula I is selected from the subformula group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein A 1  and A 2  are each N, A 3  is C(R A3 ) and A 4  is C, wherein
 R A3  is optionally substituted and selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —(X 1 ) 0-1 —CN, —(X 1 ) 0-1 —NO 2 , —(X 1 ) 0-1 —SF 5 , —(X 1 ) 0-1 —OH, —(X 1 ) 0-1 —NH 2 , —(X 1 ) 0-1 —N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1b )(R 1a ), —(X 1 ) 0-1 —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, —(X 1 ) 0-1 —C 3-10  cycloalkyl, —(X 1 ) 0-1 —C 2-9  heterocycloalkyl, —(X 1 ) 0-1 -5-10 membered heteroaryl, —(X 1 ) 0-1 —6-10 membered aryl, —(X 1 ) 0-1 —C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —C(═Y 1 )NH 2 , —(X 1 ) 0-1 —C(═Y 1 )N(R 1a )(R 1b ), —(X 1 ) 0-1 —C(═Y 1 )OR 1a , —(X 1 ) 0-1 —C(═Y 1 )OH, —(X 1 ) 0-1 —N(H)C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(H), —(X 1 ) 0-1 —N(H)C(═Y 1 )OR 1a , —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )OR 1a , —(X 1 ) 0-1 —S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(H)S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(R 1b )S(O) 1-2 R 1a , —(X 1 ) 0-1 —S(O) 0-1 N(H)(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 N(R 1b )(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 NH 2 , —(X 1 ) 0-1 —S(═O)(═NR 1b )R 1a , —(X 1 ) 0-1 C(═Y 1 )R 1a , —(X 1 ) 0-1 —C(═Y 1 )H, —(X 1 ) 0-1 —C(═NOH)R 1a , —(X 1 ) 0-1 —C(═NOR 1 )R 1a , —(X 1 ) 0-1 —NHC(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —NHC(═Y 1 )NH 2 , —(X 1 ) 0-1 —NHC(═Y 1 )N(R 1b )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(R 1a )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )NH 2 , —(X 1 ) 0-1 —OC(═Y 1 )R 1a , —(X 1 ) 0-1 —OC(═Y 1 )H, —(X 1 ) 0-1 —OC(═Y 1 )OR 1a , —(X 1 ) 0-1 —OP(═Y 1 )(OR 1a )(OR 1b ), —(X 1 )—SC(═Y 1 )OR 1a  and —(X 1 )—SC(═Y 1 )N(R 1a )(R 1b );   R 2  is optionally substituted and selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —N(H)(R 1a ), —N(R 1b )(R 1a ), —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy and C 1-6  alkylthio; and m is 0 to 4.   
     
     
         5 . The compound of  claim 4 , wherein m is 0-2 and e is other than hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein A 1  and A 2  are each N, A 3  is C(R A3 ) and A 4  is C, wherein m is 0 to 4; R 2  is optionally substituted and selected from the group consisting of consisting of hydrogen, —F, —Cl, —Br, —I, —(X 1 ) 0-1 —CN, —(X 1 ) 0-1 —NO 2 , —(X 1 ) 0-1 —SF 5 , —(X 1 ) 0-1 —OH, —(X 1 ) 0-1 —NH 2 , —(X 1 ) 0-1 —N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1b )(R 1a ), —(X 1 ) 0-1 —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, —(X 1 ) 0-1 —C 3-10  cycloalkyl, —(X 1 ) 0-1 —C 2-9  heterocycloalkyl, —(X 1 ) 0-1 -5-10 membered heteroaryl, —(X 1 ) 0-1 —6-10 membered aryl, —(X 1 ) 0-1 —C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —C(═Y 1 )NH 2 , —(X 1 ) 0-1 —C(═Y 1 )N(R 1a )(R 1b ), —(X 1 ) 0-1 —C(═Y 1 )OR 1a , —(X 1 ) 0-1 —C(═Y 1 )OH, —(X 1 ) 0-1 —N(H)C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(H), —(X 1 ) 0-1 —N(H)C(═Y 1 )OR 1a , —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )OR 1a , —(X 1 ) 0-1 —S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(H)S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(R 1b )S(O) 1-2 R 1a , —(X 1 ) 0-1 —S(O) 0-1 N(H)(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 N(R 1b )(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 NH 2 , —(X 1 ) 0-1 —S(═O)(═NR 1b )R 1a , —(X 1 ) 0-1 —C(═Y 1 )R 1a , —(X 1 ) 0-1 —C(═Y 1 )H, —(X 1 ) 0-1 —C(═NOH)R 1a , —(X 1 ) 0-1 —C(═NOR 1b )R 1a , —(X 1 ) 0-1 —NHC(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —NHC(═Y 1 )NH 2 , —(X 1 ) 0-1 —NHC(═Y 1 )N(R 1b )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(R 1a )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )NH 2 , —(X 1 ) 0-1 —OC(═Y 1 )R 1a , —(X 1 ) 0-1 —OC(═Y 1 )H, —(X 1 ) 0-1 —OC(═Y 1 )OR 1a , —(X 1 ) 0-1 —OP(═Y 1 )(OR 1a )(OR 1b ), —(X 1 )—SC(═Y 1 )OR 1a  and —(X 1 )—SC(═Y 1 )N(R 1a )(R 1b ); and
 R A3  is optionally substituted and selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —N(H)(R 1a ), —N(R 1b )(R 1a ), —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy and C 1-6  alkylthio. 
 
     
     
         7 . The compound of  claim 6 , wherein m is 1-2. 
     
     
         8 . The compound of  claim 1 , wherein A 1  and A 4  are each C, A 2  is N and A 3  is N(R N3 ); wherein
 R N3  is optionally substituted and selected from the group consisting of consisting of hydrogen, —(X 1 ) 0-1 —CN, —(X 1 ) 0-1 —NO 2 , —(X 1 ) 0-1 -5F 5 , —(X 1 ) 0-1 —OH, —(X 1 ) 0-1 —NH 2 , —(X 1 ) 0-1 —N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1b )(R 1a ), —(X 1 ) 0-1 —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, —(X 1 ) 0-1 —C 3-10  cycloalkyl, —(X 1 ) 0-1 —C 2-9  heterocycloalkyl, —(X 1 ) 0-1 -5-10 membered heteroaryl, —(X 1 ) 0-1 —6-10 membered aryl, —(X 1 ) 0-1 —C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —C(═Y 1 )NH 2 , —(X 1 ) 0-1 —C(═Y 1 )N(R 1a )(R 1b ), —(X 1 ) 0-1 —C(═Y 1 )OR 1a , —(X 1 ) 0-1 —C(═Y 1 )OH, —(X 1 ) 0-1 —N(H)C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(H), —(X 1 ) 0-1 —N(H)C(═Y 1 )OR 1a , —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )OR 1a , —(X 1 ) 0-1 —S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(H)S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(R 1b )S(O) 1-2 R 1a , —(X 1 ) 0-1 —S(O) 0-1 N(H)(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 N(R 1b )(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 NH 2 , —(X 1 ) 0-1 —S(═O)(═NR 1b )R 1a , —(X 1 ) 0-1 —C(═Y 1 )R 1a , —(X 1 ) 0-1 —C(═Y 1 )H, —(X 1 ) 0-1 —C(═NOH)R 1a , —(X 1 ) 0-1 —C(═NOR 1b )R 1a , —(X 1 ) 0-1 —NHC(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —NHC(═Y 1 )NH 2 , —(X 1 ) 0-1 —NHC(═Y 1 )N(R 1b )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(R 1a )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )NH 2 , —(X 1 ) 0-1 —OC(═Y 1 )R 1a , —(X 1 ) 0-1 —OC(═Y 1 )H, —(X 1 ) 0-1 —OC(═Y 1 )OR 1a , —(X 1 ) 0-1 —OP(═Y 1 )(OR 1a )(OR 1b ), —(X 1 )—SC(═Y 1 )OR 1a  and —(X 1 )—SC(═Y 1 )N(R 1a )(R 1b );   R 2  is optionally substituted and selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —N(H)(R 1a ), —N(R 1b )(R 1a ), —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy and C 1-6  alkylthio; and m is from 0 to 4.   
     
     
         9 . The compound of  claim 8 , wherein m is 0-2 and R N3  is other than hydrogen. 
     
     
         10 . The compound of  claim 1 , wherein A 1  and A 4  are each C, A 2  is N and A 3  is N(R N3 ); wherein m is from 0 to 4; R 2  is optionally substituted and selected from the group consisting of consisting of —F, —Cl, —Br, —I, —(X 1 ) 0-1 —CN, —(X 1 ) 0-1 —NO 2 , —(X 1 ) 0-1 —SF 5 , —(X 1 ) 0-1 —OH, —(X 1 ) 0-1 —NH 2 , —(X 1 ) 0-1 —N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1b )(R 1a ), —(X 1 ) 0-1 —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, —(X 1 ) 0-1 —C 3-10  cycloalkyl, —(X 1 ) 0-1 —C 2-9  heterocycloalkyl, —(X 1 ) 0-1 -5-10 membered heteroaryl, —(X 1 ) 0-1 —6-10 membered aryl, —(X 1 ) 0-1 —C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —C(═Y 1 )NH 2 , —(X 1 ) 0-1 —C(═Y 1 )N(R 1a )(R 1b ), —(X 1 ) 0-1 —C(═Y 1 )OR 1a , —(X 1 ) 0-1 —C(═Y 1 )OH, —(X 1 ) 0-1 —N(H)C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(H), —(X 1 ) 0-1 —N(H)C(═Y 1 )OR 1a , —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )OR 1a , —(X 1 ) 0-1 —S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(H)S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(R 1b )S(O) 1-2 R 1a , —(X 1 ) 0-1 —S(O) 0-1 N(H)(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 N(R 1b )(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 NH 2 , —(X 1 ) 0-1 —S(═O)(═NR 1b )R 1a , —(X 1 ) 0-1 —C(═Y 1 )R 1a , —(X 1 ) 0-1 —C(═Y 1 )H, —(X 1 ) 0-1 —C(═NOH)R 1a , —(X 1 ) 0-1 —C(═NOR 1b )R 1a , —(X 1 ) 0-1 —NHC(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —NHC(═Y 1 )NH 2 , —(X 1 ) 0-1 —NHC(═Y 1 )N(R 1b )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(R 1a )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )NH 2 , —(X 1 ) 0-1 —OC(═Y 1 )R 1a , —(X 1 ) 0-1 —OC(═Y 1 )H, —(X 1 ) 0-1 —OC(═Y 1 )OR 1a , —(X 1 ) 0-1 —OP(═Y 1 )(OR 1a )(OR 1b ), —(X 1 )—SC(═Y 1 )OR 1a  and —(X 1 )—SC(═Y 1 )N(R 1a )(R 1b ); and
 R N3  is optionally substituted and selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —N(H)(R 1a ), —N(R 1b )(R 1a ), —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio. 
 
     
     
         11 . The compound of  claim 10 , wherein m is 1-2. 
     
     
         12 . The compound of  claim 1 , wherein in compounds of Formula I or a subformula thereof, A 1  is C, A 2  and A 4  are each N and A 3  is C(R A3 ); wherein e is optionally substituted and selected from the group consisting of consisting of hydrogen, —(X 1 ) 0-1 —CN, —(X 1 ) 0-1 —NO 2 , —(X 1 ) 0-1 —SF 5 , —(X 1 ) 0-1 —OH, —(X 1 ) 0-1 —NH 2 , —(X 1 ) 0-1 —N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1b )(R 1a ), —(X 1 ) 0-1 —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, —(X 1 ) 0-1 —C 1-6  alkyl, —(X 1 ) 0-1 —C 3-10  cycloalkyl, —(X 1 ) 0-1 —C 2-9  heterocycloalkyl, —(X 1 ) 0-1 -5-10 membered heteroaryl, —(X 1 ) 0-1 —6-10 membered aryl, —(X 1 ) 0-1 —C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —C(═Y 1 )NH 2 , —(X 1 ) 0-1 —C(═Y 1 )N(R 1a )(R 1b ), —(X 1 ) 0-1 —C(═Y 1 )OR 1a , —(X 1 ) 0-1 —C(═Y 1 )OH, —(X 1 ) 0-1 —N(H)C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(H), —(X 1 ) 0-1 —N(H)C(═Y 1 )OR 1a , —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )OR 1a , —(X 1 ) 0-1 —S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(H)S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(R 1b )S(O) 1-2 R 1a , —(X 1 ) 0-1 —S(O) 0-1 N(H)(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 N(R 1b )(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 NH 2 , —(X 1 ) 0-1 —S(═O)(═NR 1b )R 1a , —(X 1 ) 0-1 —C(═Y 1 )R 1a , —(X 1 ) 0-1 —C(═Y 1 )H, —(X 1 ) 0-1 —C(═NOH)R 1a , —(X 1 ) 0-1 —C(═NOR 1b )R 1a , —(X 1 ) 0-1 —NHC(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —NHC(═Y 1 )NH 2 , —(X 1 ) 0-1 —NHC(═Y 1 )N(R 1b )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(R 1a )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )NH 2 , —(X 1 ) 0-1 —OC(═Y 1 )R 1a , —(X 1 ) 0-1 —OC(═Y 1 )H, —(X 1 ) 0-1 —OC(═Y 1 )OR 1a , —(X 1 ) 0-1 —OP(═Y 1 )(OR 1a )(OR 1b ), —(X 1 )—SC(═Y 1 )OR 1a  and —(X 1 )—SC(═Y 1 )N(R 1a )(R 1b ). R 2  is optionally substituted and selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —N(H)(R 1a ), —N(R 1b )(R 1a ), —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy and C 1-6  alkylthio; and m is from 0 to 4. 
     
     
         13 . The compound of  claim 12 , wherein in compound of Formula I or a subformula thereof, m is 0-2 and R N3  is other than hydrogen. 
     
     
         14 . The compound of  claim 1 , wherein in compounds of Formula I or a subformula thereof, A 1  is C, A 2  and A 4  are each N and A 3  is C(R A3 ), wherein m is from 0 to 4; R 2  is optionally substituted and selected from the group consisting of consisting of —F, —Cl, —Br, —I, —(X 1 ) 0-1 —CN, —(X 1 ) 0-1 —NO 2 , —(X 1 ) 0-1 —SF 5 , —(X 1 ) 0-1 —OH, —(X 1 ) 0-1 —NH 2 , —(X 1 ) 0-1 —N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1b )(R 1a ), —(X 1 ) 0-1 —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, —(X 1 ) 0-1 —C 3-10  cycloalkyl, —(X 1 ) 0-1 —C 2-9  heterocycloalkyl, —(X 1 ) 0-1 -5-10 membered heteroaryl, —(X 1 ) 0-1 —6-10 membered aryl, —(X 1 ) 0-1 —C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —C(═Y 1 )NH 2 , —(X 1 ) 0-1 —C(═Y 1 )N(R 1a )(R 1b ), —(X 1 ) 0-1 —C(═Y 1 )OR 1a , —(X 1 ) 0-1 —C(═Y 1 )OH, —(X 1 ) 0-1 —N(H)C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(R 1a ), —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )(H), —(X 1 ) 0-1 —N(H)C(═Y 1 )OR 1a , —(X 1 ) 0-1 —N(R 1b )C(═Y 1 )OR 1a , —(X 1 ) 0-1 —S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(H)S(O) 1-2 R 1a , —(X 1 ) 0-1 —N(R 1b )S(O) 1-2 R 1a , —(X 1 ) 0-1 —S(O) 0-1 N(H)(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 N(R 1b )(R 1a ), —(X 1 ) 0-1 —S(O) 0-1 NH 2 , —(X 1 ) 0-1 —S(═O)(═NR 1b )R 1a , —(X 1 ) 0-1 —C(═Y 1 )R 1a , —(X 1 ) 0-1 —C(═Y 1 )H, —(X 1 ) 0-1 —C(═NOH)R 1a , —(X 1 ) 0-1 —C(═NOR 1b )R 1a , —(X 1 ) 0-1 —NHC(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —NHC(═Y 1 )NH 2 , —(X 1 ) 0-1 —NHC(═Y 1 )N(R 1b )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )N(R 1a )(R 1a ), —(X 1 ) 0-1 —N(R 1a )C(═Y 1 )NH 2 , —(X 1 ) 0-1 —OC(═Y 1 )R 1a , —(X 1 ) 0-1 —OC(═Y 1 )H, —(X 1 ) 0-1 —OC(═Y 1 )OR 1a , —(X 1 ) 0-1 —OP(═Y 1 )(OR 1a )(OR 1b ), —(X 1 )—SC(═Y 1 )OR 1a  and —(X 1 )—SC(═Y 1 )N(R 1a )(R 1b ). R N3  is optionally substituted and selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —N(H)(R 1a ), —N(R 1b )(R 1a ), —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio. 
     
     
         15 . The compound of  claim 14 , wherein in compound of Formula I or a subformula thereof, m is 1-2. 
     
     
         16 . The compound of  claim 1 , wherein R 7  at each occurrence is optionally substituted and independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or —C(═O)NR 7a R 7b ; and R 8  at each occurrence is independently selected from the group consisting of hydrogen C 1-6  alkyl, C 1-6  haloalkyl or —CH 2 —OH. 
     
     
         17 . The compound of  claim 16 , wherein R 7  is optionally substituted and selected from the group consisting of: furan, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, imidazole, triazole, tetrazole, thiazole, thiadiazole, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, indole, indazole, indole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrrolo[3,2-b]pyridine, 5H-pyrrolo[3,2-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, 5H-pyrrolo[2,3-b]pyrazine, benzimidazole, benzofuran and benzothiophene. 
     
     
         18 . The compound of  claim 17 , wherein R 7  is optionally substituted and selected from the group consisting of: oxazole, isoxazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, thiazole, thiazole, 1,3,4-thiadiazole, imidazole, pyrazole, triazole, pyrimidine, pyridazine, pyrazine, pyridine, 2H-1,2,3-triazole, 1H-1,2,4-triazole. 
     
     
         19 . The compound of claim of  claim 16 , wherein R 7  is optionally substituted with from 1 to 5 substituents selected from the group consisting of F, Cl, Br, —OH, C 1-6  alkyl, C 1-6  haloalkyl, —(X 7 ) 0-1 —CN, —(X 7 ) 0-1 —OH, —(X 7 ) 0-1 —H and —(X 7 ) 0-1 —OR a . 
     
     
         20 . The compound of  claim 16 , wherein R 7  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 16 , wherein R 7  is selected from the group consisting of methyl, ethyl hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, cyanomethyl, cyclopropyl, 3-hydroxycyclobut-1-yl cyclopropylmethyl, isopropyl and 1-hydroxyeth-1-yl. 
     
     
         22 . The compound of  claim 1 , wherein R 7  and R 8  are combined with the carbon atom to each is attached to form an optionally substituted C 3-10  cycloalkyl or C 2-9  heterocycloalkyl, and wherein optionally fused to said C 3-10  cycloalkyl and C 2-9  heterocycloalkyl is a 6 membered aryl or 5-6 membered heteroaryl ring. 
     
     
         23 . The compound of  claim 22 , wherein R 7  and R 8  are combined with the carbon atom in Formula I (denoted as “*C” below) to which each is attached to form a ring selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 1 , wherein n is 0. 
     
     
         25 . The compound of  claim 1 , wherein R 4 , R 5  and R 6  are each independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, methoxy, OH, F, Cl, Br, I, CN and NO 2 . 
     
     
         26 . The compound of  claim 1 , wherein m is 0 and R A3  and R N3 ′, if present, is hydrogen. 
     
     
         27 . The compound of  claim 1 , wherein m is 0 and R A3  and R N3 , if present, is selected from the group consisting of F, —Cl, —Br, —I, —(X 1 ) 0-1 —CN, —(X 1 ) 0-1 —SF 5 , —(X 1 ) 0-1 —OH, —(X 1 ) 0-1 —NH 2 , —(X 1 ) 0-1 —N(H)(R 1a ), —(X 1 ) 0-1 —N(R 1b )(R 1a ), —(X 1 ) 0-1 —CF 3 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylthio, —(X 1 ) 0-1 —C 3-10  cycloalkyl, —(X 1 ) 0-1 —C 2-9  heterocycloalkyl, —(X 1 ) 0-1 -5-10 membered heteroaryl, —(X 1 ) 0-1 —6-10 membered aryl, —(X 1 ) 0-1 —C(═Y 1 )N(H)(R 1a ), —(X 1 ) 0-1 —C(═Y 1 )NH 2 , —(X 1 ) 0-1 —C(═Y 1 )N(R 1a )(R 1b ), —(X 1 ) 0-1 —C(═Y 1 )OR 1a  and —(X 1 ) 0-1 —C(═Y 1 )OH. 
     
     
         28 . The compound of  claim 1 , wherein R 1 , R 2′  in its first occurrence, e and R N3 , each if present, is independently selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . The compound of Formula I selected from the group selected from the group on Table 1, and salts thereof. 
     
     
         30 . A pharmaceutical composition comprising a compound of  claim 1  and at least one pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         31 . The use of a compound of  claim 1  for the treatment of an inflammatory condition. 
     
     
         32 . The use of a compound of  claim 1  for the preparation of a medicament for the treatment of an inflammatory condition. 
     
     
         33 . A compound of  claim 1  for the treatment of an inflammatory condition. 
     
     
         34 . A method for the treatment of an inflammatory condition, wherein said method comprises administering an effective amount of a compound as defined in  claim 1 . 
     
     
         35 . The method of  claim 34 , wherein said inflammatory condition is selected from the group consisting of lupus, systemic lupus erythematosus, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatisis, endometriosis and transplant rejection.