p38 MAP kinase inhibitors

Abstract

The present invention relates to compounds of Formula (I) that are p-38 MAP kinase inhibitors, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.

What is claimed:  
     
         1 . A compound selected from the group of compounds represented by Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is heteroaryl;  
 - - - represents a bond between either B and CR 1  or Q and CR 1  such that: 
 (i) when - - - is between Q and —CR 1 — then: 
 B is nitrogen;  
 R 2  is aryl; and  
 Q is —CR— wherein: 
 R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, nitro, cyano, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, —OR 5  (where R 5  is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —COOR 7  (where R 7  is hydrogen or alkyl) or —CONR′R″ (where R′ and R″ independently represent hydrogen, alkyl or heteroalkyl); and  
 
 
 (ii) when - - - is between B and —CR 1 —then: 
 B is carbon;  
 R 2  is aryl or heteroaryl; and  
 Q is —NR 4 —, —O—, or —S— wherein: 
 R 4  is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, —OR 5  (where R 5  is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —SO 2 R″ (where R″ is alkyl, amino, monosubstituted amino or disubstituted amino), —CONR′R″ (where R′ and R″ independently represent hydrogen, alkyl or heteroalkyl), -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein:  
 
 Z is cyano; 
 —COOR 7  where R 7  is hydrogen or alkyl;  
 —CONR 8 R 9  where R 8  is hydrogen or alkyl, R 9  is alkoxy or -(alkylene)-COOR 7 , or R 8  and R 9  together with the nitrogen atom to which they are attached form a heterocycle;  
 —C(═NR 10 )(NR 11 R 12 ) where R 10 , R 11  and R 12  independently represent hydrogen or alkyl, or R 10  and R 11  together are —(CH 2 ) n — where n is 2 or 3 and R 12  is hydrogen or alkyl; or  
 —COR 13  where R 13  is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and  
                     
 is a group represented by formula (S), (T), (U), (V) or (W);  
                     
 where:  
 
 
 
 R 6  is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, —COOR 14 , -(alkylene)-COOR 14 (where R 14  is hydrogen or alkyl), —CONR 15 R 16  (where R 15  and R 16  independently represent hydrogen or alkyl, or R 15  and R 16  together with the nitrogen atom to which they are attached form a heterocycle), —S(O) n R 17  (where n is an integer from 0 to 2 and R 17  is alkyl, amino, monosubstituted amino or disubstituted amino), —OR 18  (where R 18  is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —NRC(O)R″ [where R is hydrogen, alkyl or hydroxyalkyl and R″ is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)], —NRSO 2 R″ [where R is hydrogen or alkyl and R″ is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)]; and R 3  is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylthio, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, —OR 19  (where R 19  is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —COOR 20  (where R 20  is hydrogen or alkyl), —CONR 21 R 22  (where R 21  and R 22  independently represent hydrogen, alkyl or heteroalkyl, or R 21  and R 22  together with the nitrogen atom to which they are attached form a heterocycle), —S(O) n R 23  (where n is an integer from 0 to 2 and R 23  is alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted amino), -(alkylene)-Z″ or -(alkylene)-CO-(alkylene)-Z″ wherein: 
 Z″ is cyano; 
 —COOR 24  where R 24  is hydrogen or alkyl;  
 —CONR 25 R 26  where R 25  and R 26  independently represent hydrogen or alkyl, or R 25  and R 26  together with the nitrogen atom to which they are attached form a heterocycle;  
 —C(═NR 27 )(NR 28 R 29 ) where R 27 , R 28  and R 29  independently represent hydrogen or alkyl, or R 27  and R 28  together are —(CH 2 ) n — where n is 2 or 3 and R 29  is hydrogen or alkyl; or  
 —COR 30  where R 30  is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and  
 their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that both R 3  and R 6  are not either amino, monosubstituted amino or disubstituted amino.  
 
 
 
     
     
         2 . The compound of  claim 1  wherein, - - - is between B and —CR 1 —, and  
       
         
           
           
               
               
           
         
       
       is a group represented by formula (S), (V) or (W).  
     
     
         3 . The compound of  claim 2  wherein, R 2  is an aryl ring.  
     
     
         4 . The compound of  claim 3  wherein:  
       
         
           
           
               
               
           
         
       
       is a group represented by formula (S); 
 Q is —NR 4 —;  
 R 3 is at the 7-position; and  
 R 6  is hydrogen, alkyl, alkoxy or halo.  
 
     
     
         5 . The compound of  claim 4  wherein, R 3  is hydrogen, alkyl, halo or heteroalkyl.  
     
     
         6 . The compound of  claim 5  wherein, R 1  is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, —NRR′ (where R and R′ are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), —NR a C(O) R b  [where R a  is hydrogen or alkyl and R b  is hydrogen, alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)], —NRSO 2 R″ [where R is hydrogen or alkyl and R″ is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)] or -OR (where R is alkyl or heteroalkyl).  
     
     
         7 . The compound of  claim 6  wherein, R 2  is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or —OR where R is alkyl.  
     
     
         8 . The compound of  claim 7  wherein, R 4  is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Zwherein: 
 Z is —COOR 7  where R 7  is alkyl;  
 —CONR 8 R 9  where R 8  is hydrogen or alkyl, R 9  is alkoxy or -(alkylene)-COOR 7 , or R 8  and R 9  together with the nitrogen atom to which they are attached form a heterocycle; or  
 —C(═NR 10 )(NR 11 R 12 ) where R 10 , R 11  and R 12  independently represent hydrogen or alkyl, or R 10  and R 11  together are —(CH 2 ) n — where n is 2 or 3 and R 12  is hydrogen or alkyl.  
 
     
     
         9 . The compound of  claim 8  wherein: 
 R 3  is hydrogen, methyl, chloro, fluoro, 2-hydroxyethyl, 2-aminoethyl or 2-dimethylaminoethyl; and  
 R 6  is hydrogen, methyl, methoxy, fluoro or chloro.  
 
     
     
         10 . The compound of  claim 9  wherein: 
 R 1  is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonyl-amino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy;  
 R 2  is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; and  
 R 3  and R 6  are hydrogen.  
 
     
     
         11 . The compound of  claim 10  wherein, R 4  is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl)ethyl, or 3-(piperazin-1-yl)propyl.  
     
     
         12 . The compound of  claim 11  wherein: 
 R 1  is 2-(2-hydroxyethylamino)-4-pyridyl;  
 R 2 is 4-fluorophenyl; and  
 R 4  is hydrogen; namely, 3-(4-fluorophenyl)-2-[2-(2-hydroxyethylamino)-pryidin-4-yl]-1H-pyrrolo-[3,2-b]pyridine.  
 
     
     
         13 . The compound of  claim 11  wherein: 
 R 1  is 4-pyridyl;  
 R 2  is 4-fluorophenyl; and  
 R 4  is 2-(morpholin-4-yl)ethyl;  
 namely, 3-(4-fluorophenyl)-1-[2-(morpholin-4-yl)ethyl]-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine.  
 
     
     
         14 . The compound of  claim 3  wherein:  
       
         
           
           
               
               
           
         
       
       is a group represented by formula (S); 
 Q is —O—; and  
 R 6  is hydrogen, alkyl, alkoxy or halo.  
 
     
     
         15 . The compound of  claim 14  wherein, R 3  is at the 7-position and is hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, halo, —OR 19  (where R 19  is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -(alkylene)-Z″ or -(alkylene)-CO-(alkylene)-Z″ wherein: 
 Z″ is —COOR 24  where R 24  is alkyl; 
 —CONR 25 R 26  where R 25  and R 26  independently represent hydrogen or alkyl or R 25  and R 26  together with the nitrogen atom to which they are attached form a heterocycle; or  
 —C(═NR 27 )(NR 28 R 29 ) where R 27 , R and R 29  independently represent hydrogen or alkyl, or R 27  and R 28  together are —(CH 2 ) n — where n is 2 or 3 and R 29  is hydrogen or alkyl.  
 
 
     
     
         16 . The compound of  claim 15  wherein, R 1  is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, —NRR′ (where R and R′ are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), —NR a C(O) R b  [where R a  is hydrogen or alkyl and R b  is hydrogen, alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)], —NRSO 2 R″ [where R is hydrogen or alkyl and R″ is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —S(O) n R″ (where n is 0 to 2 and R′ is alkyl)] or —OR (where R is alkyl or heteroalkyl).  
     
     
         17 . The compound of  claim 16  wherein: 
 R 2  is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or —OR where R is alkyl;  
 R 3  is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxy-propoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-(morpholin-4-yl)ethoxy, 3-(morpholin-4-yl)propoxy, 2-(piperidin-1-yl)ethoxy, 3-(piperidin-1-yl)propoxy, 2-(piperazin-1-yl)ethoxy or 3-(piperazin-1-yl)propoxy; and  
 R 6  is hydrogen, methyl, methoxy, fluoro or chloro.  
 
     
     
         18 . The compound of  claim 17  wherein: 
 R 1  is a 4-pyridyl ring optionally substituted with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; and  
 R 3  and R 6  are hydrogen.  
 
     
     
         19 . The compound of  claim 18  wherein R 2  is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy.  
     
     
         20 . The compound of  claim 3  wherein:  
       
         
           
           
               
               
           
         
       
       is a group represented by formula (W); and 
 R 6  is hydrogen, alkyl, halo, amino, monsubstituted amino, disubstituted amino, —NRC(O)R″ [where R is hydrogen, alkyl or hydroxyalkyl and R″ is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)] or —NRSO 2 R″ [where R is hydrogen or alkyl and R″ is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)].  
 
     
     
         21 . The compound of  claim 20  wherein, Q is —NR 4 —.  
     
     
         22 . The compound of  claim 21  wherein, R 1  is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, —NRR′ (where R and R′ are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), —NR a C(O) R b   [where R a  is hydrogen or alkyl and R b  is hydrogen, alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)], —NRSO 2 R″ [where R is hydrogen or alkyl and R″ is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)] or —OR (where R is alkyl or heteroalkyl).  
     
     
         23 . The compound of  claim 22  wherein: 
 R 2  is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or —OR where R is alkyl; and  
 R 6  is at the 6-position.  
 
     
     
         24 . The compound of  claim 23  wherein, R 4  is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein: 
 Z is —COOR 7  where R 7  is alkyl; 
 —CONR 8 R 9  where R 8  is hydrogen or alkyl and R 9  is alkoxy or -(alkylene)-COOR 7 , or R 8  and R 9  together with the nitrogen atom to which they are attached form a heterocycle; or  
 —C(═NR 10 )(NR 11 R 12 ) where R 10 , R 11  and R 12  independently represent hydrogen or alkyl or R 10  and R 11  together are —(CH 2 ),— where n is 2 or 3 and R 12  is hydrogen or alkyl.  
 
 
     
     
         25 . The compound of  claim 24  wherein, R 4  is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl)ethyl, or 3-(piperazin-1-yl)propyl.  
     
     
         26 . The compound of  claim 25  wherein: 
 R 6  is selected from hydrogen, methyl, methoxy, fluoro, chloro, amino, 2-hydroxyethylamino or acetylamino; and  
 R 1  is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy.  
 
     
     
         27 . The compound of  claim 26  wherein: 
 R 2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; and  
 R 4  and R 6  are hydrogen.  
 
     
     
         28 . The compound of  claim 27  wherein: 
 R 1  is 4-pyridyl;  
 R 2  is 4-fluorophenyl; and  
 namely, 3-(4-fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine.  
 
     
     
         29 . The compound of  claim 27  wherein: 
 R 1  is 2-(2-hydroxyethylamino)-4-pyridyl;  
 R 2  is 4-fluorophenyl; and  
 namely, 3-(4-fluorophenyl)-6-[2-(2-hydroxyethylamino)pyridin-4-yl]-5H-pyrrolo[2,3-b]pyrazine.  
 
     
     
         30 . The compound of  claim 20  wherein, Q is —O—.  
     
     
         31 . The compound of  claim 30  wherein, R 1  is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, —NRR′ (where R and R′ are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), —NR a C(O) R b   [where R a  is hydrogen or alkyl and R b  is hydrogen, alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)], —NRSO 2 R″ [where R is hydrogen or alkyl and R″ is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)] or —OR (where R is alkyl or heteroalkyl).  
     
     
         32 . The compound of  claim 31  wherein, R 2  is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or —OR where R is alkyl.  
     
     
         33 . The compound of  claim 32  wherein: 
 R 1  is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; and  
 R 6  is at the 6-position and is hydrogen, methyl, methoxy, 2-hydroxyethyl-amino, fluoro or chloro.  
 
     
     
         34 . The compound of  claim 33  wherein: 
 R 2  is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; and  
 R 6  is hydrogen.  
 
     
     
         35 . The compound of  claim 3  wherein:  
       
         
           
           
               
               
           
         
       
       is a group represented by formula (S); 
 Q is —NR 4 —; and  
 R 1  is a heteroaryl ring substituted with —NRR′ (where R is hydrogen, alkyl, or heteroalkyl and R′ is heterocyclylalkyl or heteroalkyl).  
 
     
     
         36 . The compound of  claim 35  wherein, 
 R 3  is at the 7-position;  
 R 4  is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein: 
 Z is —COOR 7  where R 7  is alkyl;  
 —CONR 8 R 9  where R 8  is hydrogen or alkyl, R 9  is alkoxy or -(alkylene)-COOR 7 , or R 8  and R 9  together with the nitrogen atom to which they are attached form a heterocycle; or  
 
 —C(═NR 10 )( NR 11 R 12 ) where R 10 , R 11  and R 12  independently represent hydrogen or alkyl, or R 10  and R 11  together are —(CH 2 ) n — where n is 2 or 3 and R 12  is hydrogen or alkyl; and  
 R 6  is hydrogen, alkyl, alkoxy or halo.  
 
     
     
         37 . The compound of  claim 36  wherein: 
 R 2  is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or —OR where R is alkyl;  
 R 3  is hydrogen, alkyl, halo or heteroalkyl; and  
 R 4  is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl)ethyl, or 3-(piperazin-1-yl)propyl.  
 
     
     
         38 . The compound of  claim 37  wherein: 
 R 1  is a 4-pyridyl or 4-pyrimidinyl ring substituted with —NRR′ (where R is hydrogen, alkyl, or heteroalkyl and R′ is heterocyclylalkyl or heteroalkyl);  
 R 2  is a phenyl ring substituted with one or two substituents selected from alkyl, halo, or —OR where R is alkyl; and  
 R 3  and R 4  are hydrogen.  
 
     
     
         39 . The compound of  claim 38  wherein: 
 the —NRR′ substituent is at the 2-position of the 4-pyridyl or 4-pyrimidinyl ring and is 2-hydroxyethylamino, 2-aminoethylamino, 2-methylaminoethylamino or 2-dimethylaminoethylamino; and  
 R 2  is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy.  
 
     
     
         40 . The compound of  claim 3  wherein:  
       
         
           
           
               
               
           
         
       
       is a group represented by formula (W); 
 Q is —NR 4 —; and  
 R 1  is a heteroaryl ring substituted with —NRR′ (where R is hydrogen, alkyl, or heteroalkyl and R′ is heterocyclylalkyl or heteroalkyl).  
 
     
     
         41 . The compound of  claim 40  wherein: 
 R 6 is at the 6-position and is hydrogen, alkyl, halo, amino, monsubstituted amino, disubstituted amino, —NRC(O)R″ [where R is hydrogen, alkyl or hydroxyalkyl and R″ is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)] or —NRSO 2 R″ [where R is hydrogen or alkyl and R″ is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —S(O) n R′ (where n is 0 to 2 and R′ is alkyl)]; and  
 R 4  is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein:  
 Z is —COOR 7  where R 7  is alkyl; 
 —CONR 8 R 9  where R 8  is hydrogen or alkyl and R 9  is alkoxy or -(alkylene)-COOR 7 , or R 8  and R 9  together with the nitrogen atom to which they are attached form a heterocycle; or  
 —C(═NR 10 )(NR 11 R 12 ) where R 10 , R 11  and R 12  independently represent hydrogen or alkyl or R 10  and R 11  together are —(CH 2 ) n  where n is 2 or 3 and R 12  is hydrogen or alkyl.  
 
 
     
     
         42 . The compound of  claim 41 , wherein: 
 R 2  is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or —OR where R is alkyl;    R 4  is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl)ethyl, or 3-(piperazin-1-yl)propyl; and    R 6  is at the 6-position and is selected from hydrogen, methyl, methoxy, fluoro, chloro, amino, 2-hydroxyethylamino or acetylamino.    
     
     
         43 . The compound of  claim 42  wherein: 
 R 1  is a 4-pyridyl or 4-pyrimidinyl ring substituted with —NRR′ (where R is hydrogen, alkyl, or heteroalkyl and R′ is heterocyclylalkyl or heteroalkyl); and  
 R 2  is a phenyl ring substituted with one or two substituents selected from alkyl, halo, or —OR where R is alkyl.  
 
     
     
         44 . The compound of  claim 43  wherein: 
 the —NRR′ substituent is at the 2-position of the 4-pyridyl or 4-pyrimidinyl ring and is 2-hydroxyethylamino, 2-aminoethylamino, 2-methylaminoethylamino or 2-dimethylaminoethylamino;  
 R 2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; and  
 R 6  is hydrogen.  
 
     
     
         45 . A compound of Formula (IIa):  
       
         
           
           
               
               
           
         
       
       wherein: 
 One of Z 1  and Z 2  is nitrogen and the other is —CR 6 — wherein R 6  is hydrogen, alkyl, or alkoxy; or both Z 1  and Z 2  are nitrogen such that: 
 (a) when Z 1  or Z 2  is nitrogen and the other is —CR 6 — then: 
 (i) when Y is halo, then —Q—R is —NH—C(R 1 )═CH(R 2 ) or —N═C(CH 3 )(R 1 );  
 (ii) when Y is —C(R 2 )═C(R 1 )OX (where X is p-CH 3 C 6 H 4 SO 2 —, CH 3 SO 2 —, or CF 3 SO 2 —), then —Q—R is nitro or amino; and  
 (iii) when Y is —C(O)R 2 , then —Q—R is —NHC(O)R 1 , —OCH 2 CO 2 R, or —SCH 2 R 1  where: 
 R is alkyl;  
 R 1  is heteroaryl; and  
 R 2  is aryl or heteroaryl; and  
 
 
 (b) when Z 1  and Z 2  both are nitrogen then: 
   4  Y is halo and —Q—R is —NH—C(R 1 )═CH(R 2 ) where R 1  and R 2  are as defined above; and  
 
 
 R 3  is hydrogen, alkyl, halo, or alkoxy.  
 
     
     
         46 . A compound of Formula (IIb):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Z 4   3  is nitrogen and Z 4  is —CR 3 — wherein R 3  is hydrogen, alkyl, or alkoxy; or Z 4  is nitrogen and Z 3  is —CH—; such that:  
 (a) when Y is hydrogen, then —Q—R is —NH—N═C(R 1 )CH 2 (R 2 ); and  
 (b) when Y is —C(O)R 2 , then —Q—R is —OCH 2 CO 2 R or —SCH 2 R 1  where: 
 R is alkyl;  
 R 1  is heteroaryl; and  
 R 2  is aryl or heteroaryl; and  
 
 R 6  is hydrogen, alkyl, halo, or alkoxy.  
 
     
     
         47 . The compound of  claim 46 , wherein: 
 Z 4  is nitrogen; and    Y is hydrogen.    
     
     
         48 . The compound of  claim 47 , wherein: 
 R 1  is optionally substituted 4-pyridy; and    R 2  is optionally substituted phenyl.    
     
     
         49 . The compound of  claim 45 , wherein: 
 Z 1  is nitrogen and Z 2  is —CH—; and    —Q—R is —NH—C(R 1 )═CH(R 2 ), —N═C(CH 3 )(R 1 ), nitro, amino, or —NHC(O)R 1 .    
     
     
         50 . The compound of  claim 49 , wherein: 
 R 1  is optionally substituted 4-pyridy; and    R 2  is optionally substituted phenyl.    
     
     
         51 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         52 . A method of treatment of a disease in a mammal treatable by administration of a p38 MAP kinase inhibitor, comprising administration to the mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         53 . The method of  claim 52 , wherein the disease is an inflammatory disease.