Pyrazole derivatives - p38 MAP kinase inhibitors

Abstract

The present invention relates to certain pyrazole derivatives 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 hydrogen or acyl;  
 R 2  is hydrogen or alkyl;  
 A is an aryl or heteroaryl ring;  
 B is an aryl or heteroaryl ring;  
 R 3  is selected from the group consisting of: 
 (a) amino, alkylamino or dialkylamino;  
 (b) acylamino;  
 (c) optionally substituted heterocyclyl;  
 (d) optionally substituted aryl or heteroaryl;  
 (e) heteroalkyl;  
 (f) heteroalkenyl;  
 (g) heteroalkynyl;  
 (h) heteroalkoxy;  
 (i) heteroalkylamino;  
 (j) optionally substituted heterocyclylalkyl;  
 (k) optionally substituted heterocyclylalkenyl;  
 (l) optionally substituted heterocyclylalkynyl;  
 (m) optionally substituted heterocyclylalkoxy, cyclyloxy or heterocyclyloxy;  
 (n) optionally substituted heterocyclylalkylamino;  
 (o) optionally substituted heterocyclylalkylcarbonyl;  
 (p) heteroalkylcarbonyl;  
 (q) —NHSO 2 R 6  where R 6  is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;  
 (r) —NHSO 2 NR 7 R 8  where R 7  and R 8  are, independently of each other, hydrogen, alkyl or heteroalkyl;  
 (s) —Y-(alkylene)-R 9  where: 
 Y is a single bond, —O—, —NH— or —S(O) n — where n is an integer from 0 to 2); and  
 R 9  is cyano, optionally substituted heteroaryl, —COOH, —COR 10 , —COOR 11 , —CONR 12 R 13 , —SO 2 R 14 , —SO 2 NR 15 R 16 , —NHSO 2 R 17  or —NHSO 2 NR 18 R 19 , where R 10  is alkyl or optionally substituted heterocycle, R 11  is alkyl, and R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18  and R 19  are, independently of each other, hydrogen, alkyl or heteroalkyl;  
 
 (t) —C(═NR 20 )(NR 21 R 22 ) where R 20 , R 21  and R 22  independently represent hydrogen, alkyl or hydroxy, or R 20  and R 21  together are —(CH 2 ) n — where n is 2 or 3 and R 22  is hydrogen or alkyl;  
 (u) —NHC(X)NR 23 R 24  where X is —O— or —S—, and R 23  and R 24  are, independently of each other, hydrogen, alkyl or heteroalkyl;  
 (v) —CONR 25 R 26  where R 25  and R 26  independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R 25  and R 26  together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;  
 (w) —S(O) n R 27  where n is an integer from 0 to 2, and R 27  is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or —NR 28 R 29  where R 28  and R 29are, independently of each other, hydrogen, alkyl or heteroalkyl;  
 (x) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;  
 (y) arylaminoalkylene or heteroarylaminoalkylene;  
 (z) Z-alkylene-NR 30 R 31  or Z-alkylene-OR 32  where Z is —NH—, —N(lower alkyl)- or —O—, and R 30 , R 31  and R 32  are independently of each other, hydrogen, alkyl or heteroalkyl;  
 (aa) —OC(O)-alkylene-CO 2 H or —OC(O)—NR′R″ (where R′ and R″ are independently hydrogen or alkyl); and  
 (bb) heteroarylalkenylene or heteroarylalkynylene;  
 
 R 4  is selected from the group consisting of: 
 (a) hydrogen;  
 (b) halo;  
 (c) alkyl;  
 (d) alkoxy; and  
 (e) hydroxy;  
 
 R 5  is selected from the group consisting of: 
 (a) hydrogen;  
 (b) halo;  
 (c) alkyl;  
 (d) haloalkyl;  
 (e) thioalkyl;  
 (f) hydroxy;  
 (g) amino;  
 (h) alkylamino;  
 (i) dialkylamino;  
 (j) heteroalkyl;  
 (k) optionally substituted heterocycle;  
 (l) optionally substituted heterocyclylalkyl;  
 (m) optionally substituted heterocyclylalkoxy;  
 (n) alkylsulfonyl;  
 (o) aminosulfonyl, mono-alkylaminosulfonyl or di-alkylaminosulfonyl;  
 (p) heteroalkoxy; and  
 (q) carboxy;  
 
 R 6  is selected from the group consisting of: (a) hydrogen; (b) halo; (c) alkyl; and (d) alkoxy;  
 prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound of  claim 1  wherein R 3  is: 
 (a) optionally substituted heterocyclyl;  
 (b) aryl or heteroaryl both optionally substituted with a substituent selected from halo, alkyl, amino, alkoxy, carboxy, lower alkoxy carbonyl, SO 2 R′ (where R′ is alkyl) or SO 2 NHR′R″ (where R′ and R″ are independently hydrogen or alkyl);  
 (c) heteroalkyl;  
 (d) heteroalkenyl;  
 (e) heteroalkylamino;  
 (f) heteroalkoxy;  
 (g) optionally substituted heterocyclylalkyl or heterocyclyloxy;  
 (h) optionally substituted heterocyclylalkenyl;  
 (i) optionally substituted heterocyclylalkynyl;  
 (j) optionally substituted heterocyclylalkoxy;  
 (k) optionally substituted heterocyclylalkylamino;  
 (l) optionally substituted heterocyclylalkylcarbonyl;  
 (k) —Y-(alkylene)-R 9  where Y is a single bond, —O— or —NH— and R 9  is optionally substituted heteroaryl, —CONR 12 R 13 , SO 2 R 14 , —SO 2 NR 15 R 16  —NHSO 2 R 17 or —NHSO 2 NR 18 R 19  where R 12 , R 13 , R 14 , R 15 , R 16  R 17 , R 18  and R 19  are independently of each other hydrogen, alkyl or heteroalkyl;  
 (1) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;  
 (m) arylaminoalkylene or heteroarylaminoalkylene; or  
 (n) Z-alkylene-NR 30 R 31  where Z is —NH—, —N(alkyl)- or —O—, and R 30  and R 31  are independently of each other, hydrogen, alkyl or heteroalkyl.  
 
     
     
         3 . The compound of  claim 2  wherein R 1  and R 2  are hydrogen; and B is phenyl.  
     
     
         4 . The compound of  claim 3  wherein A is phenyl.  
     
     
         5 . The compound of  claim 4  wherein R 4  is hydrogen; and R 5  is halo or alkyl.  
     
     
         6 . The compound of  claim 5  wherein R 5  is chloro, fluoro or methyl; and R 6  is hydrogen, chloro, fluoro, methyl or methoxy.  
     
     
         7 . The compound of  claim 5 , wherein R 3  is optionally substituted heteroaryl.  
     
     
         8 . The compound of  claim 7 , wherein R 3  is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxidopyridin-2-yl, N-oxidopyridin-3-yl, N-oxidopyridin-4-yl or pyridon-2-yl, all optionally substituted.  
     
     
         9 . The compound of  claim 8 , wherein R 3  is at the 3-position.  
     
     
         10 . The compound of  claim 9 , wherein R 5  is 4-F and R 6  is hydrogen.  
     
     
         11 . The compound of  claim 9 , wherein R 5  is 2-Me and R 6  is hydrogen.  
     
     
         12 . The compound of  claim 5 , wherein R 3  is optionally substituted phenyl.  
     
     
         13 . The compound of  claim 12 , wherein R 3  is 3-sulfamoylphenyl, 3-methylsulfonylphenyl, 3-carboxyphenyl or 3-ethoxycarbonylphenyl.  
     
     
         14 . The compound of  claim 13 , wherein R 3  is at the 3-position.  
     
     
         15 . The compound of  claim 14 , wherein R 5  is 4-F and R 6  is hydrogen.  
     
     
         16 . The compound of  claim 5 , wherein R 3  is: 
 (a) heteroalkyl;    (b) heteroalkoxy;    (c) heteroalkylamino;    (d) optionally substituted heterocyclylalkyl;    (e) optionally substituted heterocyclylalkoxy;    (f) optionally substituted heterocyclylalkylamino;    (g) —Y-(alkylene)-R 9  where Y is a single bond, —O— or —NH— and R 9  is optionally substituted heteroaryl, —CONR 12 R 13 , SO 2 R 14 , —SO 2 NR 15 R 16  —NHSO 2 R 17  or —NHSO 2 NR 18 R 19  where R 12 , R 13 , R 14 , R 15 , R 16  R 17 , R 18  and R 19  are independently of each other hydrogen, alkyl or heteroalkyl; or    (h) Z-alkylene-NR 30 R 31  where Z is —NH—, —N(alkyl)- or —O—, and R 30  and R 31  are independently of each other, hydrogen, alkyl or heteroalkyl.    
     
     
         17 . The compound of  claim 16 , wherein R 3  is heteroalkyl.  
     
     
         18 . The compound of  claim 17 , wherein R 3  is at the 3-position and is selected from the group consisting of 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 2-dimethylaminoethylamino, 3-dimethylaminopropylamino, hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methyl-1-butyl or 3-hydroxybutyl.  
     
     
         19 . The compound of  claim 18 , wherein R 5  is 2-F and R 6  is 4-F.  
     
     
         20 . The compound of  claim 18 , wherein R 5  is 4-F and R 6  is hydrogen.  
     
     
         21 . The compound of  claim 18 , wherein R 5  is 2-Me and R 6  is hydrogen.  
     
     
         22 . The compound of  claim 16 , wherein R 3  is heteroalkoxy or heteroalkylamino.  
     
     
         23 . The compound of  claim 22 , wherein R 3  is at the 3-position and is selected from the group consisting of 3-dimethylaminopropoxy, 2-dimethylaminoethoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 2-dimethylaminoethylamino and 3-dimethylaminopropylamino.  
     
     
         24 . The compound of  claim 23  wherein R 5  is 4-F or 2-Me and R 6  is hydrogen.  
     
     
         25 . The compound of  claim 16 , wherein R 3  is optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy or optionally substituted heterocyclylalkylamino.  
     
     
         26 . The compound of  claim 25 , wherein R 3  is at the 3-position and is selected from the group consisting of 3-(morpholin-4-yl)propoxy, 2-(morpholin-4-yl)ethoxy, 2-(2-oxo-pyrrolidin-1-yl)ethoxy, 3-(morpholin-4-yl)propyl, 2-(morpholin4-yl)ethyl, 4-(morpholin-4-yl)butyl, 3-(morpholin-4-yl)propylamino, 2-(morpholin-4-yl)ethylamino, 4-hydroxypiperidinylmethyl, 2-(S,S-dioxo-thiamorpholin-4-yl)ethyl, 3-(S,S-dioxo-thiamorpholin -4-yl)propyl and N-methylpiperazinylmethyl.  
     
     
         27 . The compound of  claim 26  wherein R 5  is 4-F or 2-Me and R 6  is hydrogen.  
     
     
         28 . The compound of  claim 16  wherein R 3  is —Y-(alkylene)-R 9  where Y is a single bond, —O— or —NH— and R 9  is optionally substituted heteroaryl, —CONR 12 R 13 , SO 2 R 14 , —SO 2 NR 15 R 16  —NHSO 2 R 17  or —NHSO 2 NR 18 R 19  where R 12 , R 13 , R 14 , R 15 , R 16  R 17 , R 18  and R 19  are independently of each other hydrogen, alkyl or heteroalkyl.  
     
     
         29 . The compound of  claim 28 , wherein Y is a single bond and R 9  is SO 2 R 14  or —SO 2 NR 15 R 16 .  
     
     
         30 . The compound of  claim 29  wherein R 3  is methylsulfonylethyl or sulfamoylethyl.  
     
     
         31 . The compound of  claim 30  wherein R 5  is 4-F or 2-Me and R 6  is hydrogen.  
     
     
         32 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         33 . 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 .  
     
     
         34 . The method of  claim 33  wherein the disease is an inflammatory disease.  
     
     
         35 . The method of  claim 34  wherein the disease is arthritis.  
     
     
         36 . A process for preparing a compound of Formula (I) selected from compounds of  claim 1 , which process comprises: 
 (i) reacting a 2-keto-3-phenylaminoacrylonitrile of Formula 1:                          with a hydrazine of Formula 2:                          where R 3 , R 4  R 5  and R 6  are as defined in  claim 1  to provide a compound of Formula (I) where R 1  is hydrogen; or    (ii) reacting a 2-keto-3-phenylaminoacrylonitrile of formula 3:                          where Z is either hydroxy, nitro or halo group and R 4  are as defined in  claim 1  with a hydrazine of formula 2 to provide a compound of formula 4:                          followed by conversion of the Z group to the desired R 3  group to provide a compound of Formula (I) where R 1  is hydrogen;    (iii) optionally modifying any of the R 1  , R 3 , R 4 , R 5  or R 6  groups;    (iv) optionally converting the compound of Formula (1) prepared in Steps (i), (ii) or (iii) above, to the corresponding acid addition salt by treatment with an acid;    (v) optionally converting the compound of Formula (I) prepared in Steps (i), (ii) or (iii) above, to the corresponding free base by treatment with a base; and    (vi) optionally separating a mixture of stereoisomers of a compound of Formula (I) prepared in Steps (i)-(v) above, to give a single stereoisomer.    
     
     
         37 . A process for preparing a compound of Formula (I) selected from compounds of  claim 1 , which process comprises reacting a compound of Formula 5:  
       
         
           
           
               
               
           
         
       
       where L is a leaving group under organometallic displacement reaction conditions with an organometallic reagent of formula  
       
         
           
           
               
               
           
         
       
       where M is a metallic moiety to provide a compound of Formula (I) where R 1  is hydrogen; 
 (ii) optionally modifying any of the R 1 , R 3 , R 4 , R 5  or R 6  groups;  
 (iii) optionally converting the compound of Formula (I) prepared in Steps (i) or (ii) above, to the corresponding acid addition salt by treatment with an acid;  
 (iv) optionally converting the compound of Formula (I) prepared in Steps (i) or (ii) above, to the corresponding free base by treatment with a base; and  
 (v) optionally separating a mixture of stereoisomers of a compound of Formula (I) prepared in Steps (i) or (iv) above, to give a single stereoisomer.