Mapk inhibitors

Abstract

The present invention relates to certain novel substituted thiophene compounds and the finding that they display useful efficacy in the inhibition of the p38α MAPK enzyme. This provides for use of the compounds in various treatment methodologies related to MAPK inhibition, including the treatment of inflammation.

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein, R 1  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkanoyl, carboalkoxy, acyloxy, aryl, aroyl, heteroaryl, heteroaroyl, heterocyclyl, heterocycloyl, cycloalkyl, O-alkyl and O-aryl, O-heteroaryl, amino and amido, all of which groups may be substituted or unsubstituted; 
         R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl and heteroaryl, all of which may be substituted or unsubstituted; and 
         R 3  and R 4  are independently selected from the group consisting of aryl, heteroaryl, heterocyclyl and cycloalkyl, all of which groups may be substituted or unsubstituted. 
       
     
     
         2 . The compound of  claim 1  wherein R 1  is selected from the group consisting of C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 2 -C 12  alkanoyl, C 5 -C 7  aryl, C 5 -C 7  aroyl, C 5 -C 7  heteroaryl, C 5 -C 7  heteroaroyl, C 5 -C 7  heterocyclyl, C 5 -C 7  heterocycloyl and C 5 -C 7  cycloalkyl, all of which groups may be substituted or unsubstituted. 
     
     
         3 . The compound of  claim 1  wherein R 1  is selected from the group consisting of C 2 -C 6  alkynyl, C 2 -C 6  alkanoyl, C 5 -C 6  aryl, C 5 -C 6  aroyl, C5-C 6  heteroaryl, C 5 -C 6  heteroaroyl, C 5 -C 6  heterocyclyl and C 5 -C 6  heterocycloyl, all of which groups may be substituted or unsubstituted. 
     
     
         4 . The compound of  claim 1  wherein R 2  is selected from the group consisting of hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 5 -C 7  aryl and alkyl-C 5 -C 7  aryl, all of which may be substituted or unsubstituted. 
     
     
         5 . The compound of  claim 1  wherein R 2  is hydrogen. 
     
     
         6 . The compound of  claim 1  wherein R 3  is selected from the group consisting of C 5 -C 7  heteroaryl and C 5 -C 7  heterocyclyl, each of which groups may be substituted or unsubstituted. 
     
     
         7 . The compound of  claim 1  wherein R 3  is selected from the group consisting of C 6  nitrogen heteroaryl and C 6  nitrogen heterocycyl, each of which groups may be substituted or unsubstituted. 
     
     
         8 . The compound of  claim 1  wherein R 3  is selected from the group consisting of pyridyl, piperidyl, pyrazyl, pyrimidyl and pyridazyl, each of which groups may be substituted or unsubstituted. 
     
     
         9 . The compound of  claim 1  wherein R 4  is substituted or unsubstituted C 5 -C 7  aryl or C 5 -C 7  heteroaryl. 
     
     
         10 . The compound of  claim 1  wherein R 4  is substituted or unsubstituted phenyl. 
     
     
         11 . The compound of  claim 1  wherein R 4  is phenyl substituted with a substituent selected from the group consisting of halo, haloalkyl, hydroxy and nitro. 
     
     
         12 . The compound of  claim 1  wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as described in  claim 1 ; 
         Het is selected from the group consisting of C 5 -C 7  heteroaryl and C 5 -C 7  heterocyclyl, each of which groups may be substituted or unsubstituted; and 
         R 5 , R 5 ′, R 6 , R 6 ′ and R 7  are independently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy and nitro. 
       
     
     
         13 . The compound of  claim 1  wherein the compound is a compound of formula (III), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 6 , R 6 ′ and R 7  are defined in  claim 12 . 
       
     
     
         14 . The compound of  claim 1  wherein the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein, Ar 1  and Ar 2  are independently substituted or unsubstituted aryl or heteroaryl, A is selected from oxygen, sulphur or nitrogen, n is 1 or 2, m is 0 to 6, R 1  is as described in  claim 1 , 
         R 11  is selected from the group consisting of hydroxy, amino, C 1 -C 6  alkyl, phenyl, furan, morpholine, piperazine and N-phthalimide; 
         R 12  is selected from the group consisting of hydrogen, alkylphenyl and hydroxyalkyl phenyl wherein the phenyl ring may be substituted with R 13 ; 
         R 13 , when present, is selected from the group consisting of halo, amino, hydroxy, haloalkyl, C 1 -C 6  alkyl and C 1 -C 6  alkanoyl; and 
       
       each incidence of R 14  is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, amino and aminoalkyl. 
     
     
         15 . The compound of  claim 1  wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
         17 . A method of treating a patient suffering from a disease, disorder or condition responsive to MAPK inhibition including the step of administering an effective amount of a compound according to  claim 1 , or a pharmaceutically effective salt thereof, or the pharmaceutical composition according to  claim 16 , to the patient. 
     
     
         18 . The method of  claim 17  wherein the disease, disorder or condition is inflammation. 
     
     
         19 . The method of  claim 17  wherein the disease, disorder or condition is selected from the group consisting of arthritis, inflammatory bowel disease, asthma, psoriasis, myocardial injury, stroke, cancer, Alzheimer's disease, HIV, COPD, multiple myeloma, myelodysplastic syndrome, acute respiratory distress syndrome, coronary heart disease, acute coronary syndrome, major depressive disorder, dental pain, artherosclerosis, neuropathic pain and inflammation associated with any one or more of these diseases, disorders or conditions. 
     
     
         20 . The method of  claim 17  wherein the patient is a human. 
     
     
         21 . A complex of a compound according to  claim 1 , or a pharmaceutically effective salt thereof, with a p38 MAPK enzyme.