Indole-type inhibitors of p38 kinase

Abstract

Compounds that inhibit p38-α kinase are those wherein a bicyclic aromatic system is coupled through a saturated ring to an aryl group.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
         and the pharmaceutically acceptable salts thereof wherein:  
         Ar is an aryl group substituted with 0-5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof and wherein two of said optional substituents on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members;  
         X is an aliphatic monocyclic or aliphatic polycyclic moiety optionally comprising one or more hetero ring atoms wherein the cyclic moiety may be optionally substituted with one or more noninterfering substituents and where said optional substituents may constitute a ring fused to X;  
         L 1  is CO, SO 2 , alkylene (1-4C), or CH 2 NHCO;  
         L 2  is alkylene (1-4C) or alkenylene (2-4C) optionally substituted with one or two moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , and R 3 Si, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof and wherein two substituents on L 2  can be joined to form a non-aromatic saturated or unsaturated ring that includes 0-3 heteroatoms which are O, S and/or N and which contains 3 to 8 members or said two substituents can be joined to form a carbonyl moiety or an oxime, oximeether, oximeester or ketal of said carbonyl moiety;  
         with the proviso that —X— is not:  
         
           
             
             
                 
                 
             
           
         
         wherein Z a  is CR or N wherein R is hydrogen or a noninterfering substituent; each R a  is independently a noninterfering substituent; and each of 1 and k is 0-3; and m is 0-4;  
         n is 0-3;  
         each R 1  is independently halo, alkyl, OCOR, OR, NRCOR, SR, or NR 2 , wherein R is hydrogen, alkyl or aryl or heteroforms thereof;  
         
           
             
             
                 
                 
             
           
         
         represents a single or double bond;  
         one Z 2  is CA or CR 2 A; the other Z 2  is CR 3 , CR 3   2 , NR 4  or N; and each R 2 , R 3  and R 4  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof and two of R 2  and/or R 3  on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members, or an oxime, oximeether, oximeester or ketal thereof;  
         Z 3  is NR 5  or O; where R 5  is H or is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, or is SOR, SO 2 R, RCO, COOR, alkyl-COR, SO 3 R, CONR 2 , SO 2 NR 2 , CN, CF 3 , NR 2 , OR, alkyl-SR, alkyl-SOR, alkyl-SO 2 R, alkyl-OCOR, alkyl-COOR, alkyl-CN, alkyl-CONR 2 , or R 3 Si, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof;  
         A is -W i -COX j Y, where Y is selected from COR 6 , tetrazole, 1,2,3-triazole, 1,2,4-triazole, and imidazole, each of W and X is substituted or unsubstituted alkylene or alkenylene, each of 2-6 Å; each of i and j is independently 0 or 1; and R 6  is H, or is straight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, each optionally substituted with halo, alkyl, SR, SOR, SO 2 R, SO 2 NR 2 , OR, NR 2 , OCOR, NRCOR, NRCONR 2 , NRSO 2 R, NRSO 2 NR 2 , OCONR 2 , CN, COOR, CONR 2 , COR, or R 3 Si wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof, or  
         wherein R 6  is OR, NR 2 , SR, NRCONR 2 , OCONR 2 , or NRSO 2 NR 2 , wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof and wherein two R attached to the same atom may form a 3-8 member carbocyclic or heterocyclic ring and wherein said ring may further be substituted by alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with halo, SR, OR, NR 2 , OCOR, NRCOR, NRCONR 2 , NRSO 2 R, NRSO 2 NR 2 , OCONR 2 , or R 3 Si wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof wherein two R attached to the same atom may form a 3-8 member ring, optionally substituted as above defined.  
       
     
     
         2 . The compound of  claim 1  wherein Y is COR 6 .  
     
     
         3 . The compound of  claim 2  wherein Y is tetrazole; 1,2,3-triazole; 1,2,4-triazole; or imidazole.  
     
     
         4 . The compound of  claim 1  wherein each of i and j is 0.  
     
     
         5 . The compound of  claim 1  wherein j is 0.  
     
     
         6 . The compound of  claim 1  wherein Z 3  is NR 5 .  
     
     
         7 . The compound of  claim 1  wherein R 5  is H, or is optionally substituted alkyl or acyl.  
     
     
         8 . The compound of  claim 1  wherein R 2  and R 3  are independently selected from halo, OR and alkyl.  
     
     
         9 . The compound of  claim 1  wherein L 1  is CH 2  or CO and L 2  is CH 2  or CHOH.  
     
     
         10 . The compound of  claim 9  wherein L 1  is CO.  
     
     
         11 . The compound of  claim 1  wherein L 2  and/or L 1  is unsubstituted alkylene.  
     
     
         12 . The compound of  claim 1  wherein L 2  and/or L 1  is unsubstituted methylene, or methylene substituted with alkyl.  
     
     
         13 . The compound of  claim 1  wherein Ar is optionally substituted phenyl.  
     
     
         14 . The compound of  claim 13  wherein said optional substitution is by halo, OR, or alkyl.  
     
     
         15 . The compound of  claim 14  wherein said phenyl is unsubstituted or has a single substituent.  
     
     
         16 . The compound of  claim 1  wherein R 1  is halo or alkoxy.  
     
     
         17 . The compound of  claim 16  wherein n is 0, 1 or 2.  
     
     
         18 . The compound of  claim 1  wherein L 1  is coupled to the α ring at the 4-, 5- or 6-position.  
     
     
         19 . The compound of  claim 1  wherein Z 2  at position 3 is CA or CHA.  
     
     
         20 . The compound of  claim 19  wherein the Z 2  at position 2 is CR 3  or CR 3   2 .  
     
     
         21 . The compound of  claim 20  wherein R 3  is hydrogen, or is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl and two of R 1  can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members.  
     
     
         22 . The compound of  claim 21  wherein each R 3  is selected from the group consisting of H, alkyl, acyl, aryl, arylalkyl, heteroaryl, halo, OR, NR 2 , SR, NRCOR, RCO, COOR, and CN, wherein each R is independently H, alkyl or aryl.  
     
     
         23 . The compound of  claim 19  wherein Z 2  at position 2 is N or NR 4 .  
     
     
         24 . The compound of  claim 23  wherein R 4  is H, or alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, or is SOR, SO 2 R, RCO, COOR, alkyl-COR, SO 3 R, CONR 2 , SO 2 NR 2 , CN, CF 3 , or R 3 Si wherein each R is independently H, alkyl, alkenyl or aryl.  
     
     
         25 . The compound of  claim 1  wherein  
       
         
           
           
               
               
           
         
       
       represents a double bond.  
     
     
         26 . The compound of  claim 1  wherein the portion of the compound represented by L 2 -X-L 1  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         wherein, in each of structures (I) to (IV):  
         one or more of the ring carbon atoms not bound to L 2  or L 1  may be optionally replaced with NR 4 , where R 4  is as defined in  claim 1;  or is represented by CR 2   2 , where R 2  is as defined in  claim 1  but at least one R 2  is other than H; and/or  
         one or both of the ring carbon atoms bound to L 2  and L 1  may be independently replaced by CR 2  where R 2  is as defined in  claim 1 , but is other than H; and/or  
         one or both of the ring carbon atoms bound to L 2  and L 1  may be replaced by N.  
       
     
     
         27 . The compound of  claim 26  wherein R 2  and R 3  are independently selected from halo, OR and alkyl.  
     
     
         28 . The compound of  claim 26  wherein L 2 -X-L 1  is structure II and n and p are both 1, or n and p are both 2, or one of n and p is 1 and the other is 2.  
     
     
         29 . The compound of  claim 26  wherein L 2 -X-L 1  is structure (IV) and n and p are both 2.  
     
     
         30 . The compound of  claim 26  wherein the ring carbon bonded to L 1  is replaced with N; or the ring carbon bonded to L 2  is replaced with N; or both of said ring carbons are replaced with N.  
     
     
         31 . The compound of  claim 26  wherein the ring carbon bonded to L 2  is replaced with nitrogen and the ring atom bonded to L 1  is carbon.  
     
     
         32 . The compound of  claim 26  wherein L 2  is methylene and -L 1 - is —CH 2 —NH—CO— such that the portion of the compound represented by L 2 -X-L 1 - consists of CH 2 —X—CH 2 —NH—CO—.  
     
     
         33 . The compound of  claim 26  wherein L 2 -X-L 1  is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         34 . The compound of  claim 26  wherein the compound is:  
       
         
           
           
               
               
           
         
       
     
     
         35 . A pharmaceutical composition which composition comprises a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         36 . A method to treat rheumatoid arthritis, which comprises administering to a subject in need of such treatment a compound of  claim 1  or a pharmaceutical composition thereof.