P-38 inhibitors

Abstract

Provided are 5-membered heterocycle-based p38 kinase, including p38α and p38β kinase, inhibitors. Pharmaceutical compositions containing the compounds are also provided. Methods of use of the compounds and compositions are also provided, including methods of treatment, prevention, or amelioration of one or more symptoms of p38 kinase mediated diseases and disorders, including, but not limited to, inflammatory diseases and disorders.

1 - 109 . (canceled) 
   
   
       110 . A compound of formula (I): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable derivatives thereof, wherein:
 R 1  is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH 2  or —NR 4 R 5 ; 
 R 2  is attached to any available carbon atom of the phenyl ring A and at each occurrence is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halo, trifluoromethyl, trifluoromethoxy, —OR 4 , —CN, —NR 4 R 5 ; —S(═O)alkyl, —S(═O)aryl, —NHSO 2 -arylene-R 4 , —NHSO 2 alkyl, —CO 2 R 4 , —CONH 2 , —SO 3 H, —S(O)alkyl, —S(O)aryl, —SO 2 NHR 4 , and —NHC(═O)NHR 4 ; 
 n is 0, 1 or 2; 
 R 3  is selected from hydrogen, alkyl, —OR 4 , substituted alkyl, cycloalkyl, —CR 4 cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; 
 Y is a single bond, —C(═O)NH—, —NH(C═O)—, —NH(C═O)NH—, —SO 2 NH—, —NHSO 2 —, —C(═O)—; 
 Z is NR 4 , S or O; 
 B is a 5-membered heterocyclic ring system optionally substituted with up to two R 13 ; 
 Q is independently selected from a single bond, —O—, —S—, —NR 4 —, —S(O)—, —SO 2 —, —C(O)—, —CO(O)—, —C(O)NH—(C 0-4 alkyl)- or —CH 2 —; 
 D is a monocyclic or bicyclic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH 2  adjacent to any of the said N, O or S heteroatoms is optionally substituted with oxo (═O) or D is C 1-6 alkyl, and wherein D is optionally substituted by one to four (CR 9 R 10 ) w E groups; 
 w is an integer having a value from 0-4; 
 R 10  is selected from H, C 1 -C 4  alkylhydroxy, C 1 -C 4 alkylaryl and C 1 -C 4 alkylheteroaryl, wherein said aryl or heteroaryl group is unsubstituted or substituted with 1-3 groups independently selected from halo, NO 2 , C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloalkyl, haloalkoxy, OH, C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyl, CN, NH 2 , NR 6 R 7 , SR 6 , S(O)R 6 , SO 2 R 6 , SO 3 R 6 , SO 2 NR 6 , CO 2 H, CO 2 R 6 , and CONR 6 R 7 ; 
 E is selected from H, halogen, NO 2 , C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloalkyl, haloalkoxy, OH, OR 6 , CN, CHO, CO 2 R 6 , CONR 6 R 7 , OCOR 6 , OC(═O)OR 6 , OC(═O)NR 6 R 7 , OCH 2 CO 2 R 6 , C(═O)R 6 , NH 2 , NHR 6 , NR 6 R 7 , NR 7 C(═O)R 6 , NR 7 C(═O)OR 6 , NR 7 C(═O)C(═O)OR 6 , NR 7 C(═O)C(═O)NR 6 R 7 , NR 7 C(═O)C(═O)(C 1 -C 6 alkyl), NR 7 C(═NCN)OR 6 , NR 7 C(═O)NR 6 R 7 , NR 7 C(═NCN)NR 6 R 7 , NR 7 C(═NR 6 )NR 7 R 8 , NR 6 SO 2 NR 6 R 7 , NR 7 SO 2 R 6 , SR 6 , S(═O)R 6 , SO 2 R 6 , SO 3 R 7 , SO 2 NR 6 R 7 , NHOH, NHOR 6 , NR 6 NR 7 NR 8 , N(COR 6 )OH, N(CO 2 R 6 )OH, CONR 7 (CR 9 R 10 ) r R 6 , CO(CR 9 R 10 ) p O(CHR 9 ) q CO 2 R 6 , CO(CR 9 CR 10 ) r R 6 , CO(CR 9 R 10 ) p O(CR 9 R 10 ) p O(CHR 9 ) q CO 2 R 6 , CO(CR 9 CR 10 ) r OR 6 , CO(CR 9 R 10 ) p O(CR 9 R 10 ) q R 6 , CO(CR 6 CR 10 ) r NR 6 R 7 , OC(O)O(CR 9 R 10 ) m NR 6 R 7 , O(CO) n (CR 9 R 10 )R 6 , O(CR 9 R 10 ) m NR 6 R 7   m NR 7 C(O)(CR 9 R 10 ) r OR 6 , NR 7 C(═NC)(CR 9 R 10 ) r R 6 , NR 7 CO(CR 9 R 10 ) r NR 6 R 7 , NR 7 (CR 9 R 10 ) m OR 6 , NR 7 (CR 9 R 10 ) r CO 2 R 6 , NR 7 (CR 9 R 10 ) m NR 6 R 7 , NR 7 , NR 3 (CR 9 R 10 ) n SO 2 (CR 9 R 10 ) r CO 2 R 6 , NR 7 (CR 9 R 10 ) m NR 6 R 7 , NR 7 (CR 9 R 10 ) n SO 2 (CR 9 R 10 ) q R 6 , CONR 7 (CR 9 R 10 ) n SO 2 (CR 9 R 10 ) q R 6 , SO 2 NR 7 (CR 9 R 10 ) q R 6 , SO 2 NR 6 (CR 9 R 10 ) m OR 6 , C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylmethyl, aryl, heterocyclic optionally substituted with one or two alkyl groups, heteroaryl optionally substituted with one or two alkyl groups and alkylaryl, wherein said aryl groups are unsubstituted or substituted with 1 or 2 substituents each independently selected from R 12 ; 
 m is an integer having a value from 2-6; 
 p is an integer having a value from 1-3; 
 q is an integer having a value from 0-3; 
 r is an integer having a value from 0-6; 
 R 12  at each occurrence is independently selected from halo, NO 2 , C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloalkyl, haloalkoxy, OH, oxo, C 1 -C 4 alkoxy, OR 6 , O(CR 9 R 10 )CO 2 R 6 , O(CR 9 R 10 ) m NR 6 R 7 , O(CR 9 R 10 ) p CN, O(CR 9 R 10 ) r C(═O)NR 6 R 7 , C 1 -C 4 alkylcarbonyl, CN, NH 2 , NHR 6 , NR 6 R 7 , NR 7 (CR 9 R 10 )CO 2 R 6 , NR 7 OR 6 , NR 7 (CR 9 R 10 ) m OR 6 , NR 7 CH((CR 9 R 10 ) p OR 6 ) 2 , NR 7 C((CR 9 R 10 ) p OR 6 ) 3 , NR 7 C(═O)R 6 , NR 7 (CR 9 R 10 ) m NR 6 R 7 , NR 7 (CR 9 R 10 ) q R 6 , SR 7 , S(O)R 7 , S 2 R 7 , SO 2 NR 6 , SO 3 R 7 , CO 2 H, CO 2 R 6 , and CONR 6 R 7 ; 
 R 4  is hydrogen, lower alkyl and lower cycloalkyl; 
 R 5  is hydrogen, lower alkyl and lower cycloalkyl; 
 R 6 , R 7  and R 8  are independently selected as follows:
 i) R 6 , R 7  and R 8  are independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkyl(C 0 -C 5 alkyl)carbonyl, C 1 -C 6 alkoxycarbonyl, aryl(C 0 -C 5 alkyl)carbonyl, aryl(C 1 -C 5 alkoxy)carbonyl, heterocyclic(C 0 -C 5 alkyl)carbonyl, heterocyclic(C 1 -C 5 alkoxy)carbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C 0 -C 4 alkylaryl, C 0 -C 4 alkylheterocyclic, wherein said cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy, F, Cl, Br, haloalkyl, NO 2  and CN; or, 
 ii) R 6  and R 7 , or R 6  and R 8 , or R 7  and R 8  when both substituents are on the same nitrogen atom (as in (—NR 6 R 7 ) or (—NR 7 R 8 )), can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo(3,2,2)nonan-3yl, and 1-tetrazolyl, the said heterocycle being optionally substituted with 1-3 groups each independently selected from oxo, C 0 -C 4 alkylOH, C 0 -C 4 alkylOC 1 -C 4 alkyl, C 0 -C 4 alkylCONH 2 , C 0 -C 4 alkylCO 2 C 0 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, C 0 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 3 -C 7 cycloalkoxycarbonyl, —NHCOalkyl, aryl, heteroaryl, arylalkoxycarbonyl, heteroarylalkoxycarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl; 
 
 R 9  is hydrogen or C 1 -C 4 alkyl; and 
 R 13  is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkylalkylaminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, alkylthio, alkylaminocarbonyl or lower cycloalkyl; where the substituents on alkyl group are selected from one to four substituents selected from halo, hydroxy, alkoxy, oxo (═O), alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, CONHaryl, CONHaralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and substituted or unsubstituted heterocycles, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the substituents on aryl group are selected from one to four substituents selected from alkyl, substituted alkyl, haloalkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, hydroxyalkyl, aminoalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, cyanoalkyl, heterocyclyl, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, aminocarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, aryloxy and CONR a R b , where R a  and R b  are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonylaminoalkyl and alkylamino; or R a  and R b  together with the nitrogen on which they are substituted, form a 3-6 membered heterocyclic or heteroaryl ring; the substituent may be further substituted by hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl. 
 
   
   
       111 . The compound of  claim 110 , wherein R 1  is lower alkyl. 
   
   
       112 . The compound of  claim 110 , wherein R 3  is selected from alkyl, —OR 4 , substituted alkyl, cycloalkyl, —CR 4 cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle. 
   
   
       113 . The compound of  claim 110 , wherein R 3  is cycloalkyl, cycloalkylalkyl, alkoxyalkyl or heteroaryl. 
   
   
       114 . The compound of  claim 110 , wherein R 3  is methyl, isopropyl, ethyl, cyclopropyl, cyclopropylmethyl, methoxymethyl, oxazolyl or thiazolyl. 
   
   
       115 . The compound of  claim 110 , wherein Y is a single bond, —C(═O)NH— or —SO 2 NH. 
   
   
       116 . The compound of  claim 110 , wherein B is a thiazolyl, oxazolyl, dithiazolyl, thiadiazolyl, oxadiazolyl or triazinyl ring optionally substituted with one or two R 13 . 
   
   
       117 . The compound of  claim 110 , wherein Q is a single bond, —CO(O)—, —C(O)— or —C(O)NH—(C 0-4 alkyl)-. 
   
   
       118 . The compound of  claim 110 , wherein D is a monocyclic or bicyclic ring system optionally containing up to four heteroatoms selected from N, O, and S or D is C 1-6 alkyl and wherein D is optionally substituted by one to four (CR 9 R 10 ) w E groups. 
   
   
       119 . The compound of  claim 110 , wherein D is substituted with one to four substituents selected from halo, alkyl, nitro, alkoxy, alkoxycarbonylalkoxy, alkoxyamidoalkylamido, hydroxycarbonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, aryl, heteroaryl containing 1 to 3 heteroatoms and optionally substituted with one or two alkyl groups, and heterocyclyl containing 1 to 3 heteroatoms and optionally substituted with two or more alkyl or alkoxycarbonyl groups. 
   
   
       120 . The compound of  claim 110  that has formula (I-1): 
     
       
         
         
             
             
         
       
     
     where B is selected from 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, oxazole and thiazole. 
   
   
       121 . The compound of  claim 110  that has formula (I-2): 
     
       
         
         
             
             
         
       
     
     where X 1  is selected from O, S and optionally substituted N, where the substituent on the N when present is selected from hydrogen, alkyl, substituted alkyl, alkenyl or alkynyl and X 2  is S or O. 
   
   
       122 . The compound of  claim 110  that has formula (I-3): 
     
       
         
         
             
             
         
       
     
   
   
       123 . The compound of  claim 110  that has formula (I-5): 
     
       
         
         
             
             
         
       
     
     where n 1  is 0-5. 
   
   
       124 . The compound of  claim 110  that has formula (I-6): 
     
       
         
         
             
             
         
       
     
     where n 3  is 1-4. 
   
   
       125 . The compound of  claim 110  that has formula (I-7): 
     
       
         
         
             
             
         
       
     
     where n 2  is 0-4. 
   
   
       126 . A compound of  claim 110  selected from: 
     N-methoxy-4-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-benzamide; 
     N-methoxy-4-methyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylamino)-benzamide; 
     N-Cyclopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide; 
     3-[4-(4-Cyano-phenyl)-thiazol-2-ylamino]-N-cyclopropyl-4-methyl-benzamide; 
     N-Cyclopropyl-3-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-4-methyl-benzamide; 
     N-Cyclopropyl-3-[4-(4-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-benzamide; 
     N-Cyclopropyl-3-[4-(3-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-benzamide; 
     N-Cyclopropyl-3-[4-(2-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-benzamide; 
     N-Cyclopropyl-4-methyl-3-(5-methyl-4-phenyl-thiazol-2-ylamino)-benzamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic acid phenylamide; 
     N-Isopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide; 
     N-Ethyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide; 
     N-(2-Methoxy-ethyl)-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide; 
     [4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-phenyl]-morpholin-4-yl-methanone; 
     4-M ethyl-3-(4-phenyl-thiazol-2-ylamino)-1-thiazol-2-yl-benzamide; 
     4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-N-[1,2,4]triazol-4-yl-benzamide; 
     4-Methyl-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-3-(4-phenyl-thiazol-2-ylamino)-benzamide; 
     N-Cyclopropyl-4-methyl-3-(5-phenyl-oxazol-2-ylamino)-benzamide; 
     N-Cyclopropyl-4-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-benzamide; 
     N-Cyclopropyl-4-methyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylamino)-benzamide; 
     N-Cyclopropyl-4-methyl-3-(5-phenyl-[1,3,4]thiadiazol-2-ylamino)-benzamide; 
     N-Cyclopropyl-4-methyl-3-(3-phenyl-[1,2,4]thiadiazol-5-ylamino)-benzamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-methyl-thiazole-5-carboxylic acid benzyl ester; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-methyl-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic acid ethyl ester; 
     5-Bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic acid ethyl ester; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-nitro-phenyl)-thiazole-5-carboxylic acid ethyl ester; 
     N-Cyclopropyl-4-methyl-3-[4-(4-nitro-phenyl)-thiazol-2-ylamino]-benzamide; 
     3-[5-Bromo-4-(4-nitro-phenyl)-thiazol-2-ylamino]-N-cyclopropyl-4-methyl-benzamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-morpholin-4-yl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid methyl ester; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-phenyl-thiazole-5-carboxylic acid cyclopropylmethyl-amide; 
     4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-methoxycarbonyl-thiazol-4-yl]-phenyl}-piperidine-1-carboxylic acid methyl ester; 
     4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-(cyclopropylmethyl-carbamoyl)-thiazol-4-yl]-phenyl}piperidine-1-carboxylic acid methyl ester; 
     4-{3-[2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-5-[1,3,4]oxadiazol-2-yl-thiazol-4-yl]-phenyl}-piperidinium trifluoroacetate; 
     N-Cyclopropyl-4-methyl-3-[4-(4-nitro-phenyl)-5-[1,3,4]oxadiazol-2-yl-thiazol-2-ylamino]-benzamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 
     4-Bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-fluoro-3-methyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     4-(4-Cyanomethyl-phenyl)-2-(5-cyclo-propylcarbamoyl-2-methyl phenylamino)-thiazole-5-carboxylic acid benzylamide; 
     4-(4-Cyano-phenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-4,5-dihydro-thiazole-5-carboxylic acid benzylamide; 
     4-(2-Chloro-phenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropyl-carbamoyl-2-methyl-phenylamino)-4-(3-hydroxymethylphenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-m-tolyl-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-fluorophenyl)thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-p-tolyl-thiazole-5-carboxylic acid benzylamide; 
     4-(3-Cyanophenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazole-5-carboxylic acid benzylamide; 
     4-(5-Acetyl-thiophen-2-yl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 
     4-Benzo[1,3]dioxol-5-yl-2-(5-cyclopropylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 
     4-(5-Cyano-thiophen-2-yl)-2-(5-cycloprop-ylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     4-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazol-4-yl]benzoic acid ethyl ester; 
     3-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazol-4-yl]-benzoic acid methyl ester; 
     2-(5-Cyclopropyl-carbamoyl-2-methyl-phenylamino)-4-(4-fluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropyl-carbamoyl-2-methyl-phenylamino)-4-(2-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-hydroxymethyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     4-(3-Carbamoylphenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 
     4-(4-Carbamoyl-phenyl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-thiazole-5-carboxylic acid benzylamide; 
     4-(3-Aminomethyl-phenyl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 
     3-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-benzoic acid; 
     4-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazol-4-yl]-benzoic acid; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-o-tolyl-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2,4-difluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-methanesulfonyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-[4-(morpholine-4-carbonyl)-phenyl]-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethoxy-3-fluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-cyclopropylcarbamoyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-ethoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethylsulfanyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-fluoro-4-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-fluoro-3-methyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3,4-difluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2-fluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(1H-indol-5-yl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-methoxy-3-methyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethylcarbamoyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-hydroxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-propoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     4-[3-(3-Amino-propoxy)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 
     4-[3-(2-Amino-ethoxy)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methylphenyl-amino)-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-thiazole-5-carboxylic acid benzylamide; 
     2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-methanesulfonylamino-phenyl)-thiazole-5-carboxylic acid benzylamide; 
     4-(4-Amino-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 
     4-(3-Amino-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 
     ({3-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}methyl)-carbamic acid tert-butyl ester; 
     (2-{3-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester; 
     ({4-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl ester; 
     (2-{4-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester; 
     4-[3-(2-Amino-acetylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide ditrifluoroacetate; 
     4-[3-(3-Amino-propionylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide ditrifluoroacetate; 
     4-[4-(2-Amino-acetylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide ditrifluoroacetate; 
     2-{4-[5-benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}-ethyl-ammonium ditrifluoroacetate; 
     4-(4-Cyanomethyl-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; and 
     4-[4-(2-Amino-ethyl)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide. 
   
   
       127 . A pharmaceutical composition, comprising a compound of  claim 110  and a pharmaceutically acceptable carrier. 
   
   
       128 . A method of inhibiting p38 kinase activity, comprising administering a compound of  claim 110 . 
   
   
       129 . The method of  claim 128 , wherein the disease or disorder is selected from inflammatory disease, autoimmune disease, destructive bone disorder, proliferative disorder, angiogenic disorder, infectious disease, neurodegenerative disease and viral disease.