Novel tricyclic compounds

Abstract

The invention provides compounds of Formula (I) and Formula (II) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

What is claimed: 
     
         1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein
 T is N, U is N, X is CR 3  and Y is N; or 
 T is CR 6 , U is N, X is CR 3  and Y is N; or 
 T is N, U is CR 4 , X is CR 3  and Y is N; or 
 T is CR 6 , U is CR 4 , X is CR 3  and Y is N; or 
 T is CR 6 , U is N, X is NR 3  and Y is C; or 
 T is O, U is N, X is CR 3  and Y is C; or 
 T is NR 6 , U is N, X is CR 3  and Y is C; or 
 T is CR 6 , U is CR 4 , X is NR 3  and Y is C; or 
 T is S, U is N, X is CR 3  and Y is C; or 
 T is N, U is CR 4 , X is NR 3  and Y is C; or 
 T is N, U is N, X is NR 3  and Y is C; 
 R 1 , R 2  and R 5  are each independently hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —SR a , —S(O)R a , —S(O) 2 R a , —NO 2 , —C(O)OR a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)(R b ), —C(O)R a , —C(OH)R a R b , —N(R a )S(O) 2 —R b , —S(O) 2 N(R a )(R b ), —CF 3 , —OCF 3 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 1 -C 10 )heteroaryl, optionally substituted (C 1 -C 10 ) heterocyclyl, or optionally substituted (C 6 -C 10 )aryl;
 wherein in a moiety containing —N(R a )(R b ), the nitrogen, R a  and R b  may form a ring such that —N(R a )(R b ) represents an optionally substituted (C 2 -C 10 )heterocyclyl or optionally substituted (C 1 -C 10 )heteroaryl linked through a nitrogen; 
 
 R 3  is hydrogen, an optionally substituted bridged (C 5 -C 12 )cycloalkyl, optionally substituted bridged (C 2 -C 10 )heterocyclyl, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkenyl, optionally substituted (C 6 -C 10 )aryl, optionally substituted (C 1 -C 10 )heteroaryl, optionally substituted (C 2 -C 10 )heterocyclyl; or 
 R 3  is -A-D-E-G, wherein: 
 A is a bond, —C(O)—, optionally substituted (C 1 -C 6 )alkylene, optionally substituted (C 2 -C 6 )alkenylene, optionally substituted (C 2 -C 6 )alkynylene, optionally substituted (C 3 -C 12 )cycloalkylene, optionally substituted (C 2 -C 6 )heterocyclylene, —C(O)N(R a )—R e —, —N(R a )C(O)—R e —, —O—R e —, —N(R a )—R e —, —S—R e —, —S(O) 2 —R e —, —S(O)R e —, —C(O—R a )(R b )—R e —, —S(O) 2 N(R a )—R e —, —N(R a )S(O) 2 —R e — or —N(R a )C(O)N(R b )—R e —; 
 D is an optionally substituted (C 1 -C 8 )alkylene, optionally substituted bridged (C 5 -C 12 )cycloalkylene, optionally substituted (C 3 -C 10 )cycloalkylene, optionally substituted bridged (C 5 -C 10 )cycloalkenylene, optionally substituted (C 3 -C 10 )cycloalkenylene, optionally substituted (C 6 -C 10 )arylene, optionally substituted (C 1 -C 10 )heteroarylene, optionally substituted bridged (C 2 -C 10 )heterocyclylene or an optionally substituted (C 2 -C 10 )heterocyclylene; 
 E is a bond, —R e —, —R e —C(═NCN)—R e —, —R e —C(O)—R e —, —R e —C(O)C(O)—R e —, —R e —C(O)O—R e —, —R e —C(O)C(O)N(R a )—R e —, —R e —N(R a )—C(O)C(O)—R e —, —R e —O—R e —, —R e —S(O) 2 —R e —, —R e —S(O)—R e —, —R e —S—R e —, —R e —N(R a )—R e —, ═N—R e —, —R e —N(R a )C(O)—R e —, —R e C(O)N(R a )R e —, —R e —OC(O)N(R a )—R e —, —R e —N(R a )C(O)OR e —, —R e —OC(O)—R e , —R e —OC(O)—O—R e , —R e —N(R a )C(O)N(R b )—R e —, —R e —N(R a )S(O) 2 —R e —, —R e —S(O) 2 N(R a )—R e —, or —R e —N(R a )S(O) 2 N(R a )—R e —; or 
 E is 
 
       
         
           
           
               
               
           
         
         where in all cases, E is linked to either a carbon or a nitrogen atom in D; 
         G is hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —SR a , —S(O)R a , —S(O) 2 R a , —NO 2 , —C(O)OR a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)R b , —N(R a )C(O)OR b , —OC(O)N(R a ), —N(R a )C(O)N(R b ) 2 , —C(O—R a )(R b ) 2 , —C(O)R a , —CF 3 , —OCF 3 , —N(R a )S(O) 2 R b , —S(O) 2 N(R a )(R b ), —S(O) 2 N(R a )C(O)R b , an optionally substituted —(C 1 -C 6 )alkyl, an optionally substituted —(C 2 -C 6 )alkenyl, an optionally substituted —(C 2 -C 6 )alkynyl, an optionally substituted —(C 3 -C 10 )cycloalkyl, an optionally substituted —(C 1 -C 10 )heteroaryl, an optionally substituted —(C 1 -C 10 ) heterocyclyl, an optionally substituted —(C 6 -C 10 )aryl;
 wherein in a moiety containing —N(R a )(R b ), the nitrogen, R a  and R b  may form a ring such that —N(R a )(R b ) represents an optionally substituted (C 2 -C 10 )heterocyclyl or an optionally substituted (C 1 -C 10 ) heteroaryl linked through a nitrogen; 
 
         R 4  and R 6  are each independently a hydrogen, halogen, deuterium, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , C(O)OH, C(O)OCH 3 , CN, an optionally substituted bridged (C 5 -C 12 )cycloalkyl group, optionally substituted bridged (C 2 -C 10 )heterocyclyl group, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkenyl, optionally substituted (C 6 -C 10 )aryl, optionally substituted (C 1 -C 10 )heteroaryl, optionally substituted (C 2 -C 10 )heterocyclyl or -J-L-M-Q; 
         wherein: 
         J is a bond, —C(O)—, optionally substituted (C 1 -C 6 )alkylene, optionally substituted (C 2 -C 6 )alkenylene, optionally substituted (C 2 -C 6 )alkynylene, optionally substituted (C 3 -C 12 )cycloalkylene, optionally substituted (C 2 -C 6 )heterocyclylene, —C(O)N(R a )—R e —, —N(R a )C(O)—R e —, —O—R e —, —N(R a )—R e —, —S—R e —, —S(O) 2 —R e —, —S(O)R e —, —C(O—R a )(R b )—R e —, —S(O) 2 N(R a )—R e —, —N(R a )S(O) 2 —R e — or —N(R a )C(O)N(R b )—R e —; 
         L is a bond, an optionally substituted (C 1 -C 8 )alkylene, optionally substituted bridged (C 5 -C 12 )cycloalkylene, optionally substituted (C 3 -C 10 )cycloalkylene, optionally substituted bridged (C 5 -C 10 )cycloalkenylene, optionally substituted (C 3 -C 10 )cycloalkenylene, optionally substituted (C 6 -C 10 )arylene, optionally substituted (C 1 -C 10 )heteroarylene, optionally substituted bridged (C 2 -C 10 )heterocyclylene or an optionally substituted (C 2 -C 10 )heterocyclylene; 
         M is a bond, —R e —, —R e —C(O)—R e —, —R e —C(O)C(O)—R e —, —R e —C(O)O—R e —, —R e —OC(O)—R e , —R e —C(O)C(O)N(R a )—R e —, —R e —N(R a )—C(O)C(O)—R e —, —R e —O—R e —, —R e — S(O) 2 —R e —, —R e —S(O)—R e —, —R e —S—R e —, —R e —N(R a )—R e —, —R e —N(R a )C(O)—R e —, —R e —C(O)N(R a )R e —, —R e —OC(O)N(R a )—R e —, —R e —N(R a )C(O)OR e —, —R e —N(R a )C(O)N(R b )—R e —, —R e —N(R a )S(O) 2 —R e —, or —R e —S(O) 2 N(R a )—R e —; or 
         M is 
       
       
         
           
           
               
               
           
         
       
       where in all cases, M is linked to either a carbon or a nitrogen atom in L;
 Q is hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —SR a , —S(O)R a , —S(O) 2 R a , —NO 2 , —C(O)OR a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)R b , —N(R a )C(O)OR b , —N(R a )C(O)N(R b ) 2 , —C(O—R a )(R b ) 2 , —C(O)R a , —CF 3 , —OCF 3 , —N(R a )S(O) 2 R b , —S(O) 2 N(R a )(R b ), —S(O) 2 N(R a )C(O)R b , an optionally substituted (C 1 -C 6 )alkyl, an optionally substituted (C 2 -C 6 )alkenyl, an optionally substituted (C 2 -C 6 )alkynyl, an optionally substituted (C 3 -C 10 )cycloalkyl, an optionally substituted (C 1 -C 10 )heteroaryl, an optionally substituted (C 1 -C 10 ) heterocyclyl, an optionally substituted (C 6 -C 10 )aryl;
 wherein in a moiety containing —N(R a )(R b ), the nitrogen, R a  and R b  may form a ring such that —N(R a )(R b ) represents an optionally substituted (C 2 -C 10 )heterocyclyl or an optionally substituted (C 1 -C 10 ) heteroaryl linked through a nitrogen; 
 
 R a  and R b  are each independently hydrogen, deuterium, CN, an optionally substituted (C 1 -C 10 )alkyl, an optionally substituted (C 2 -C 10 )alkenyl, an optionally substituted (C 2 -C 10 )alkynyl, an optionally substituted (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl, an optionally substituted (C 3 -C 10 )cycloalkyl, an optionally substituted (C 6 -C 10 )aryl, an optionally substituted (C 1 -C 10 )heteroaryl, an optionally substituted (C 1 -C 10 )heterocyclyl, an optionally substituted —(C 1 -C 6 )alkylene-(C 3 -C 10 )cycloalkyl, an optionally substituted —(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, an optionally substituted —(C 1 -C 6 )alkylene-(C 1 -C 10 )heteroaryl, or an optionally substituted —(C 1 -C 6 )alkylene-(C 1 -C 10 )heterocyclyl; and 
 R e  for each occurrence is independently a bond, an optionally substituted (C 1 -C 10 )alkylene, an optionally substituted (C 2 -C 10 )alkenylene, an optionally substituted (C 2 -C 10 )alkynylene, an optionally substituted —(C 1 -C 10 )alkylene-O—(C 1 -C 10 )alkylene group, an optionally substituted (C 3 -C 10 )cycloalkylene, an optionally substituted (C 6 -C 10 )arylene, an optionally substituted (C 1 -C 10 )heteroarylene, or an optionally substituted (C 1 -C 10 )heterocyclylene; 
 provided that when T is N, U is CR 4 , X is NR 3  and Y is C, R 4  is not OH; 
 provided that when T is N, U is CR 4 , X is NR 3  and Y is C, R 1  is H; 
 provided that when the compound is 
 
       
         
           
           
               
               
           
         
         R 3  is defined as above and R 6  is not linked to the pyrazole ring by a nitrogen or oxygen atom; and 
         provided that when the compound is 
       
       
         
           
           
               
               
           
         
         when R 3  is H, CH 3  or C(O)OH then R 4  is not H, —C(O)OCH 2 CH 3 , —C(O)NH-optionally substituted phenyl, —NHC(O)-optionally substituted phenyl or S(O) 2 -phenyl. 
       
     
     
         2 . The compound of  claim 1  wherein R 3  is -A-D-E-G and 
       A is a bond, optionally substituted (C 1 -C 6 )alkylene, optionally substituted (C 3 -C 12 )cycloalkylene or optionally substituted (C 2 -C 6 )heterocyclylene. 
     
     
         3 . The compound of  claim 1  wherein R 3  is -A-D-E-G and D is an optionally substituted (C 1 -C 8 )alkylene, optionally substituted (C 3 -C 10 )cycloalkylene, optionally substituted bridged (C 5 -C 10 )cycloalkenylene, optionally substituted (C 3 -C 10 )bridged heterocyclylene or optionally substituted (C 2 -C 10 )heterocyclylene. 
     
     
         4 . The compound of  claim 3  wherein D is optionally substituted (C 1 -C 6 )alkylene, optionally substituted (C 3 -C 6 )cycloalkylene, optionally substituted bicyclo[2.2.2]octany-1-yl, optionally substituted 2,5-diazabicyclo[2.2.1]heptane, optionally substituted 2,6-diazabicyclo[3.2.1]octane, optionally substituted octahydropyrrolo[3,4-c]pyrrole, optionally substituted octahydropyrrolo[3,2-b]pyridine, optionally substituted 1,4-diazepane, optionally substituted cubane, optionally substituted 1,4-dioxane-spiro[4.4]nonane, optionally substituted 2,5-diazaspiro[3.5]nonane, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrrolidine, optionally substituted tetrahydrofuran or optionally substituted tetrahydropyran. 
     
     
         5 . The compound of  claim 1  wherein R 3  is -A-D-E-G and E is a bond, —R e —, —R e —C(O)—R e —, —R e —O—R e —, —R e —S(O) 2 —R e —, —R e —N(R a )—R e —, ═N—R e —. —R e —N(R a )C(O)—R e —, —R e —N(R a )C(O)O—R e —, —R e —N(R a )C(O)N(R b )—R e —, —R e C(O)N(R a )R e —, —R e —N(R a )S(O) 2 —R e —, —R e —S(O) 2 N(R a )—R e —, —R e —N(R a )S(O) 2 N(R a )—R e —, —R e —OC(O)N(R a )—R e , —R e —C(O)O—R e , —R e —OC(O)—R e ; or 
       
         
           
           
               
               
           
         
       
       wherein
 R a  for each occurrence is independently hydrogen, CN, an optionally substituted (C 1 -C 10 )alkyl or an optionally substituted —(C 1 -C 6 )alkylene-(C 3 -C 10 )cycloalkyl; and 
 R e  for each occurrence is independently a bond, an optionally substituted (C 1 -C 10 )alkylene, an optionally substituted (C 3 -C 10 )cycloalkylene, an optionally substituted (C 6 -C 10 )arylene, an optionally substituted (C 1 -C 10 )heteroarylene, or an optionally substituted (C 1 -C 10 )heterocyclylene. 
 
     
     
         6 . The compound of  claim 1  wherein R 3  is -A-D-E-G and G is hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —S(O) 2 R a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)R b , —CF 3 , —S(O) 2 N(R a )(R b ), an optionally substituted —(C 1 -C 6 )alkyl, an optionally substituted —(C 3 -C 10 )cycloalkyl, an optionally substituted —(C 1 -C 10 )heteroaryl, an optionally substituted —(C 1 -C 10 ) heterocyclyl, or an optionally substituted —(C 6 -C 10 )aryl;
 wherein in a moiety containing —N(R a )(R b ), the nitrogen, R a  and R b  may form a ring such that —N(R a )(R b ) represents an optionally substituted (C 2 -C 10 )heterocyclyl or an optionally substituted (C 1 -C 10 ) heteroaryl linked through a nitrogen; 
 R a  is independently hydrogen, CN, an optionally substituted (C 1 -C 10 )alkyl, an optionally substituted (C 3 -C 10 )cycloalkyl, or an optionally substituted (C 6 -C 10 )aryl. 
 
     
     
         7 . The compound of  claim 6  wherein G is hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —S(O) 2 R a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)R b , —CF 3 , —S(O) 2 N(R a )(R b ), an optionally substituted —(C 1 -C 4 )alkyl, an optionally substituted —(C 3 -C 6 )cycloalkyl, optionally substituted azepanyl, optionally substituted azetidinyl, optionally substituted benzo[d]isoxazolyl, optionally substituted 4,5-dihydroisoxazolyl, optionally substituted isothiazolidinyl, optionally substituted isothiazolyl, optionally substituted isoxazolyl, optionally substituted morpholinyl, optionally substituted oxadiazolyl, optionally substituted oxazolyl, optionally substituted oxetanyl, optionally substitute phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrazinyl, optionally substituted pyrazolyl, optionally substituted pyridazinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted pyrrolyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrothiopyranyl, optionally substituted thienyl, optionally substituted thiomorpholinyl, optionally substituted 1,1-dioxo-thiomorpholinyl, optionally substituted thiazolyl or optionally substituted triazolyl. 
     
     
         8 . The compound of  claim 1  wherein R 3  is hydrogen, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 3 -C 10 )cycloalkyl, or optionally substituted (C 2 -C 10 )heterocyclyl. 
     
     
         9 . The compound of  claim 1  wherein R 6  is J-L-M-Q and J is a bond, optionally substituted (C 1 -C 6 )alkylene, or an optionally substituted (C 2 -C 6 )alkenylene. 
     
     
         10 . The compound of  claim 1  wherein R 6  is J-L-M-Q and L is a bond, or an optionally substituted (C 1 -C 8 )alkylene. 
     
     
         11 . The compound of  claim 1  wherein R 6  is J-L-M-Q and M is a bond, —R e —, —R e —C(O)—R e —, —R e —O—R e —, —R e —S(O) 2 —R e —, —R e —S(O)—R e —, —R e —S—R e —, —R e —N(R a )—R e —, —R e —N(R a )C(O)—R e —, —R e —C(O)N(R a )R e —, —R e —N(R a )C(O)N(R b )—R e —, —R e —N(R a )S(O) 2 —R e —, or —R e —S(O) 2 N(R a )—R e —; where in all cases, M is linked to either a carbon or a nitrogen atom in L. 
     
     
         12 . The compound of  claim 1  wherein R 6  is J-L-M-Q and Q is hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —SR a , —S(O)R a , —S(O) 2 R a , —NO 2 , —C(O)OR a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)R b , —N(R a )C(O)OR b , —N(R a )C(O)N(R b ) 2 , —C(O—R a )(R b ) 2 , —C(O)R a , —CF 3 , —OCF 3 , —N(R a )S(O) 2 R b , —S(O) 2 N(R a )(R b ), —S(O) 2 N(R a )C(O)R b , an optionally substituted (C 1 -C 6 )alkyl, an optionally substituted (C 3 -C 10 )cycloalkyl, an optionally substituted (C 1 -C 10 )heteroaryl, an optionally substituted (C 1 -C 10 ) heterocyclyl, an optionally substituted (C 6 -C 10 )aryl;
 wherein in a moiety containing —N(R a )(R b ), the nitrogen, R a  and R b  may form a ring such that —N(R a )(R b ) represents an optionally substituted (C 2 -C 10 )heterocyclyl or an optionally substituted (C 1 -C 10 ) heteroaryl linked through a nitrogen; 
 R a  and R b  are each independently hydrogen, deuterium, an optionally substituted (C 1 -C 6 )alkyl, an optionally substituted (C 2 -C 10 )alkenyl, an optionally substituted (C 3 -C 6 )cycloalkyl, an optionally substituted (C 6 -C 10 )aryl, an optionally substituted (C 1 -C 10 )heteroaryl, or an optionally substituted (C 1 -C 10 )heterocyclyl. 
 
     
     
         13 . The compound of  claim 1  wherein T is N, U is N, X is CR 3  and Y is N and forms a compound of Formula (Ia) 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1  wherein T is CR 6 , U is N, X is CR 3  and Y is N and forms a compound of Formula (Ib) 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1  wherein T is N, U is CR 4 , X is CR 3  and Y is N and forms a compound of Formula (Ic) 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1  wherein T is CR 6 , U is CR 4 , X is CR 3  and Y is N and forms a compound of Formula (Id) 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1  wherein T is CR 6 , U is N, X is NR 3  and Y is C and forms a compound of Formula (Ie) 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 1  wherein T is O, U is N, X is CR 3  and Y is C and forms a compound of Formula (If) 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 1  wherein T is NR 6 , U is N, X is CR 3  and Y is C and forms a compound of formula (Ig) 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1  wherein T is CR 6 , U is CR 4 , X is NR 3  and Y is C and forms a compound of formula (Ih) 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 1  wherein T is S, U is N, X is CR 3  and Y is C and forms a compound of Formula (Ii) 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 1  wherein T is N, U is CR 4 , X is NR 3  and Y is C and forms a compound of formula (Ij) 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 1  wherein T is N, U is N, X is NR 3  and Y is C and forms a compound of Formula (Ik) 
       
         
           
           
               
               
           
         
       
     
     
         24 . A compound of Formula (II) wherein the compound is 
       
         
           
           
               
               
           
         
       
       pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein
 R 1 , and R 2  are independently hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —SR a , —S(O)R a , —S(O) 2 R a , —NO 2 , —C(O)OR a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)(R b ), —C(O)R a , —C(OH)R a R b , —N(R a )S(O) 2 —R b , —S(O) 2 N(R a )(R b ), —CF 3 , —OCF 3 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 1 -C 10 )heteroaryl, optionally substituted (C 1 -C 10 ) heterocyclyl, or optionally substituted (C 6 -C 10 )aryl;
 wherein in a moiety containing —N(R a )(R b ), the nitrogen, R a  and R b  may form a ring such that —N(R a )(R b ) represents an optionally substituted (C 2 -C 10 )heterocyclyl or optionally substituted (C 1 -C 10 )heteroaryl linked through a nitrogen; 
 
 R 3  is hydrogen, an optionally substituted bridged (C 5 -C 12 )cycloalkyl, optionally substituted bridged (C 2 -C 10 )heterocyclyl, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkenyl, optionally substituted (C 6 -C 10 )aryl, optionally substituted (C 1 -C 10 )heteroaryl, optionally substituted (C 2 -C 10 )heterocyclyl; or 
 R 3  is -A-D-E-G, wherein: 
 A is a bond, —C(O)—, optionally substituted (C 1 -C 6 )alkylene, optionally substituted (C 2 -C 6 )alkenylene, optionally substituted (C 2 -C 6 )alkynylene, optionally substituted (C 3 -C 12 )cycloalkylene, optionally substituted (C 2 -C 6 )heterocyclylene, —C(O)N(R a )—R e —, —N(R a )C(O)—R e —, —O—R e —, —N(R a )—R e —, —S—R e —, —S(O) 2 —R e —, —S(O)R e —, —C(O—R a )(R b )—R e —, —S(O) 2 N(R a )—R e —, —N(R a )S(O) 2 —R e — or —N(R a )C(O)N(R b )—R e —; 
 D is an optionally substituted (C 1 -C 8 )alkylene, optionally substituted bridged (C 5 -C 12 )cycloalkylene, optionally substituted (C 3 -C 10 )cycloalkylene, optionally substituted bridged (C 5 -C 10 )cycloalkenylene, optionally substituted (C 3 -C 10 )cycloalkenylene, optionally substituted (C 6 -C 10 )arylene, optionally substituted (C 1 -C 10 )heteroarylene, optionally substituted bridged (C 2 -C 10 )heterocyclylene or an optionally substituted (C 2 -C 10 )heterocyclylene; 
 E is a bond, —R e —, —R e —C(═NCN)—R e —, —R e —C(O)—R e —, —R e —C(O)C(O)—R e —, —R e —C(O)O—R e —, —R e —C(O)C(O)N(R a )—R e —, —R e —N(R a )—C(O)C(O)—R e —, —R e —O—R e —, —R e —S(O) 2 —R e —, —R e —S(O)—R e —, —R e —S—R e —, —R e —N(R a )—R e —, ═N—R e —, —R e —N(R a )C(O)—R e —, —R e C(O)N(R a )R e —, —R e —OC(O)N(R a )—R e —, —R e —N(R a )C(O)OR e —, —R e —OC(O)—R e , —R e —OC(O)—O—R e , —R e —N(R a )C(O)N(R b )—R e —, —R e —N(R a )S(O) 2 —R e —, —R e —S(O) 2 N(R a )—R e —, or —R e —N(R a )S(O) 2 N(R a )—R e —; or 
 E is 
 
       
         
           
           
               
               
           
         
         where in all cases, E is linked to either a carbon or a nitrogen atom in D; 
         G is hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —SR a , —S(O)R a , —S(O) 2 R a , —NO 2 , —C(O)OR a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)R b , —N(R a )C(O)OR b , —OC(O)N(R a ), —N(R a )C(O)N(R b ) 2 , —C(O—R a )(R b ) 2 , —C(O)R a , —CF 3 , —OCF 3 , —N(R a )S(O) 2 R b , —S(O) 2 N(R a )(R b ), —S(O) 2 N(R a )C(O)R b , an optionally substituted —(C 1 -C 6 )alkyl, an optionally substituted —(C 2 -C 6 )alkenyl, an optionally substituted —(C 2 -C 6 )alkynyl, an optionally substituted —(C 3 -C 10 )cycloalkyl, an optionally substituted —(C 1 -C 10 )heteroaryl, an optionally substituted —(C 1 -C 10 ) heterocyclyl, an optionally substituted —(C 6 -C 10 )aryl;
 wherein in a moiety containing —N(R a )(R b ), the nitrogen, R a  and R b  may form a ring such that —N(R a )(R b ) represents an optionally substituted (C 2 -C 10 )heterocyclyl or an optionally substituted (C 1 -C 10 ) heteroaryl linked through a nitrogen; 
 
         R a  and R b  are each independently hydrogen, deuterium, CN, an optionally substituted (C 1 -C 10 )alkyl, an optionally substituted (C 2 -C 10 )alkenyl, an optionally substituted (C 2 -C 10 )alkynyl, an optionally substituted (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl, an optionally substituted (C 3 -C 10 )cycloalkyl, an optionally substituted (C 6 -C 10 )aryl, an optionally substituted (C 1 -C 10 )heteroaryl, an optionally substituted (C 1 -C 10 )heterocyclyl, an optionally substituted —(C 1 -C 6 )alkylene-(C 3 -C 10 )cycloalkyl, an optionally substituted —(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, an optionally substituted —(C 1 -C 6 )alkylene-(C 1 -C 10 )heteroaryl, or an optionally substituted —(C 1 -C 6 )alkylene-(C 1 -C 10 )heterocyclyl; and 
         R e  for each occurrence is independently a bond, an optionally substituted (C 1 -C 10 )alkylene, an optionally substituted (C 2 -C 10 )alkenylene, an optionally substituted (C 2 -C 10 )alkynylene, an optionally substituted —(C 1 -C 10 )alkylene-O—(C 1 -C 10 )alkylene group, an optionally substituted (C 3 -C 10 )cycloalkylene, an optionally substituted (C 6 -C 10 )arylene, an optionally substituted (C 1 -C 10 )heteroarylene, or an optionally substituted (C 1 -C 10 )heterocyclylene. 
       
     
     
         25 . A pharmaceutical composition comprising a compound of Formula (I) as defined in  claim 1  or Formula (II) as defined in  claim 24   
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable carrier and excipient and a second therapeutic agent selected from the group consisting of cytokine suppressive anti-inflammatory drugs, antibodies to or antagonists of other human cytokines or growth factors, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, PDGF, CTLA or their ligands including CD154, HUMIRA™, REMICADE™, SIMPONI™ (golimumab), CIMZIA™, ACTEMRA™, CDP 571, soluble p55 or p75 TNF receptors, ENBREL™, Lenercept, TNFα converting enzyme inhibitors, IL-1 inhibitors, Interleukin 11, IL-18 antagonists, IL-12 antagonists, IL-12 antibodies, soluble IL-12 receptors, IL-12 binding proteins, non-depleting anti-CD4 inhibitors FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, IL-1β converting enzyme inhibitors, T-cell signalling kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, derivatives p75TNFRIgG, sIL-1RI, sIL-1RII, sIL-6R, celecoxib, hydroxychloroquine sulfate, rofecoxib, infliximab, naproxen, valdecoxib, sulfasalazine, meloxicam, acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, anti-IL15, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists, FTY720, PKC family inhibitors, Ruboxistaurin, AEB-071, Mesopram, methotrexate, leflunomide, corticosteroids, budenoside, dexamethasone, sulfasalazine, 5-aminosalicylic acid, olsalazine, IL-1β converting enzyme inhibitors, IL-1ra, T cell signaling inhibitors, tyrosine kinase inhibitors, 6-mercaptopurines, IL-11, mesalamine, prednisone, azathioprine, mercaptopurine, infliximab, methylprednisolone sodium succinate, diphenoxylate/atrop sulfate, loperamide hydrochloride, omeprazole, folate, ciprofloxacin/dextrose-water, hydrocodone, bitartrate/apap, tetracycline hydrochloride, fluocinonide, metronidazole, thimerosal/boric acid, cholestyramine/sucrose, ciprofloxacin hydrochloride, hyoscyamine sulfate, meperidine hydrochloride, midazolam hydrochloride, oxycodone HCl/acetaminophen, promethazine hydrochloride, sodium phosphate, sulfamethoxazole/trimethoprim, polycarbophil, propoxyphene napsylate, hydrocortisone, multivitamins, balsalazide disodium, codeine phosphate/apap, colesevelam HCl, cyanocobalamin, folic acid, levofloxacin, natalizumab, interferon-gamma, methylprednisolone, azathioprine, cyclophosphamide, cyclosporine, methotrexate, 4-aminopyridine, tizanidine, interferon-β1a, AVONEX®, interferon-β1b, BETASERON®, interferon α-n3, interferon-α, interferon β1A-IF, Peginterferon α 2b, Copolymer 1, COPAXONE®, hyperbaric oxygen, intravenous immunoglobulin, cladribine, cyclosporine, FK506, mycophenolate mofetil, leflunomide, NSAIDs, corticosteroids, prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, antiinflammatory cytokines, interferon-β, IFNβ1a, IFNβ1b, copaxone, corticosteroids, caspase inhibitors, inhibitors of caspase-1, antibodies to CD40 ligand and CD80, alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, liposome encapsulated mitoxantrone, THC.CBD, cannabinoid agonists, MBP-8298, mesopram, MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists, interferon gamma antagonists, IL-4 agonists, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, methotrexate, azathioprine, minocyclin, prednisone, etanercept, rofecoxib, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, and efalizumab, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin, COX2 inhibitors, rofecoxib, valdecoxib, hydroxychloroquine, steroids, prednisolone, budenoside, dexamethasone, cytotoxics, azathioprine, cyclophosphamide, mycophenolate mofetil, inhibitors of PDE4, purine synthesis inhibitor, sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®, CTLA-4-IgG, anti-B7 family antibodies, anti-PD-1 family antibodies, anti-cytokine antibodies, fonotolizumab, anti-IFNg antibody, anti-receptor receptor antibodies, anti-IL-6 receptor antibody, antibodies to B-cell surface molecules, LJP 394, Rituximab, anti-CD20 antibody and lymphostat-B.