Piperidine/piperazine-type inhibitors of p38 kinase

Abstract

Piperazine compounds and methods for treating conditions mediated by p38-α kinase are disclosed.

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
       or the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein:  
       Ar 1  is an aryl group substituted with 0-5 non-interfering 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, alkyl-OOCR, 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;  
       L 1  is CO, CHOH or CH 2 ;  
       L is alkylene (1-4C) or alkenylene (1-4C) optionally substituted with a moiety 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, alkyl-OOCR, 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 substituents on L 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;  
       each R 1  is independently 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, alkyl-OOCR, 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 4  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 R 4  is ═O or an oxime, oximeether, oximeester or ketal thereof;  
       m is 0-4;  
       Ar 2  comprises an optionally substituted monocyclic or polycyclic aromatic nucleus, wherein said aromatic nucleus consists of carbocyclic or heterocyclic ring selected from (i) a five-membered heterocyclic or carbocyclic ring; (ii) a six-membered carbocyclic or heterocyclic ring; (iii) a five-membered carbocyclic or heterocyclic ring fused to another five-membered carbocyclic or heterocyclic ring; (iv) a six-membered carbocyclic or heterocyclic ring fused to another six-membered carbocyclic or heterocyclic ring; and (v) a five-membered heterocyclic or carbocyclic ring fused to a six-membered carbocyclic or heterocyclic ring;  
       Z is COXjCOR 3 , wherein j is 0 or 1; and  
       wherein R 3  is H, or is straight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, each optionally substituted with halo, alkyl, heteroalkyl, 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 the heteroatom-containing forms thereof, or wherein R 3  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 the heteroatom-containing forms 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 the heteroatom-containing forms thereof wherein two R attached to the same atom may form a 3-8 member ring, optionally substituted as above defined; and  
       X, if present, is CR 2  where R is as defined above;  
       with the proviso that the portion of the compound represented by Ar 2 -Z is not  
       
         
           
           
               
               
           
         
       
       wherein   represents a single or double bond; n is 0-3; one Z 2  is CA or CRA and the other is CR, CR 2 , NR or N; A is —W i —COX j Y wherein Y is COR or an isostere thereof, each of W and X is a spacer of 2-6 Å, and each of i and j is independently 0 or 1; Z 3  is NR or O; and each R is independently hydrogen or a noninterfering substituent.  
     
   
   
       2 . The compound of  claim 1  wherein Ar 2  is selected from:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein G is CR 2 , NR, O or S; and  
       H is N or CR  
       wherein R is hydrogen or a noninterfering substituent.  
     
   
   
       3 . The compound of  claim 1  wherein L 1  is CO.  
   
   
       4 . The compound of  claim 1  wherein L 2  is unsubstituted alkylene.  
   
   
       5 . The compound of  claim 1  wherein L 2  is unsubstituted methylene, methylene substituted with alkyl, or —CH═.  
   
   
       6 . The compound of  claim 1  wherein Ar 1  is optionally substituted phenyl.  
   
   
       7 . The compound of  claim 6  wherein said optional substitution is by halo, OR, or alkyl.  
   
   
       8 . The compound of  claim 7  wherein said phenyl has a single substituent which is fluoro.  
   
   
       9 . The compound of  claim 1  wherein each R 1  is halo, OR, or alkyl.  
   
   
       10 . The compound of  claim 9  wherein m is 0, 1, or 2.  
   
   
       11 . The compound of  claim 10  wherein m is 2 and both R 1  are alkyl.  
   
   
       12 . The compound of  claim 1  wherein each of the optional substituents on Ar 2 , when bonded to a ring carbon atom, is selected from the group consisting of: 
 hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl and 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 , R 3 Si, and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof;    and wherein two of the optional substituents can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members.    
   
   
       13 . The compound of  claim 12  wherein the optional substituents are independently selected from the group consisting of H, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, halo, OR, NR 2 , SR, NRCOR, alkyl-OOCR, RCO, COOR, and CN, wherein each R is independently H, alkyl, or aryl or heteroforms thereof.  
   
   
       14 . The compound of  claim 1  wherein the optional substituents on Ar 2 , when bonded to a nitrogen ring atom, are selected from the group consisting of 
 H, or alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl;    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 or heteroforms thereof.    
   
   
       15 . A pharmaceutical composition which composition comprises a therapeutically effective amount of a compound of  claim 1  and at least one pharmaceutically acceptable excipient.  
   
   
       16 . A method to treat multiple sclerosis, IBD, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, other arthritic conditions, sepsis, endotoxic shock, asthma, adult respiratory distress syndrome, reperfusion injury, psoriasis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, a bone resorption disease, graft-versus-host reaction, Crohn's Disease, ulcerative colitis, or pyresis comprising administering to a subject in need of such treatment a compound of  claim 1  or a pharmaceutical composition thereof.