Benzamide inhibitors of the P2X7 receptor

Abstract

The present invention provides benzamide inhibitors of the P2X 7 receptor of the formula: wherein R 1 -R 3 are as defined herein. The compounds of the invention are useful in the treatment of IL-1 mediated disorders, including, without limitation, inflammatory diseases such as osteoarthritis and rheumatoid arthritis; allergies, asthma, COPD, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.

1 . A method of treating an IL-1 mediated disease in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I:  
       
         
           
           
               
               
           
         
         wherein R 1  is (C 1 -C 6 )alkyl, optionally substituted by (C 3 -C 10 )cycloalkyl, or (C 6 -C 10 )aryl, wherein each of said (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, or (C 6 -C 10 )aryl, are optionally substituted by one to three moieties independently selected from the group consisting of hydroxy, halogen, —CN, (C 1 -C 6 )alkyl, HO(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-NH(C═O)—, NH 2 (C═O)—, (C 1 -C 6 )alkoxy, and (C 3 -C 10 )cycloalkyl, wherein said (C 3 -C 10 )cycloalkyl is optionally substituted by one or more moieties selected from halogen, or (C 1 -C 6 )alkyl-;  
         R 2  is hydrogen, halogen, —CN, and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted by one to three moieties, independently selected from the group consisting of halo, hydroxy, amino, —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —CF 3 , CF 3 O—, (C 1 -C 6 )alkyl-NH—, [(C 1 -C 6 )alkyl] 2 -N—, (C 1 -C 6 )alkyl-S—, (C 1 -C 6 )alkyl-(S═O)—, (C 1 -C 6 )alkyl-(SO 2 )—, (C 1 -C 6 )alkyl-O—(C═O)—, formyl, (C 1 -C 6 )alkyl-(C═O)—, and (C 3 -C 6 )cycloalkyl;  
         R 3  is a nitrogen linked (C 1 -C 10 )heterocyclyl of the formula:  
         
           
             
             
                 
                 
             
           
         
         wherein R 4  and R 5  are independently selected from the group of substituents, consisting of hydrogen, halo, hydroxy, —CN, HO—(C 1 -C 6 )alkyl, and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with one to three fluoro, (C 1 -C 6 )alkoxy optionally substituted with one to three fluoro, HO 2 C—, (C 1 -C 6 )alkyl-O—(C═O)—, R 6 R 8 N(O 2 S)—, (C 1 -C 6 )alkyl-(O 2 S)—NH—, (C 1 -C 6 )alkyl-O 2 S—[(C 1 -C 6 )alkyl-N]—, R 6 R 8 N(C═O)—, R 6 R 8 N(CH 2 ) m —, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, C 6 -C 10 )aryl-O—, or (C 3 -C 8 )cycloalkyl-O—; and  
         R 7  is independently selected from the group of substituents consisting of hydrogen and (C 1 -C 6 )alkyl optionally substituted with one to three halogens, hydroxy, —CN, (C 1 -C 6 )alkoxy-, (C 2 -C 6 )alkenoxy, (C 1 -C 6 )alkyl-SO 2 —, NH 2 —, ((C 1 -C 6 )alkyl) n -N—, ((C 2 -C 6 )alkenyl) n -N—, ((C 2 -C 6 )alkynyl) n -N—, NH 2 (C═O)—, (C 1 -C 6 )alkyl-(C═O)N—, ((C 1 -C 6 )alkyl) n -N—(C═O)—, (C 2 -C 6 )alkenyl-(C═O)N—, ((C 2 -C 6 )alkenyl) n -N—(C═O)—, (C 2 -C 6 )alkynyl-(C═O)N—, ((C 2 -C 6 )alkynyl) n -N—(C═O)—, (C 1 -C 6 )alkyl-(C═O)—, (C 2 -C 6 )alkenyl-(C═O)—, (C 2 -C 6 )alkynyl-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 6 -C 10 )aryl-(C═O), (C 1 -C 6 )alkyl-(C═O)O—, (C 2 -C 6 )alkenyl-(C═O)O—, (C 2 -C 6 )alkynyl-(C═O)O—, (C 1 -C 6 )alkyl-O(C═O)—, (C 2 -C 6 )alkenyl-O—(C═O)—, (C 2 -C 6 )alkynyl-O—(C═O)—, and (C 3 -C 10 )cycloalkyl;  
         wherein R 4 , R 5  and R 7  may each be optionally substituted on any aliphatic or aromatic carbon atom by one to three moieties, independently selected from the group consisting of halo, hydroxy, amino, —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —CF 3 , CF 3 O—, (C 1 -C 6 )alkyl-NH—, [(C 1 -C 6 )alkyl] 2 -N—, (C 1 -C 6 )alkyl-S—, (C 1 -C 6 )alkyl-(S═O)—, (C 1 -C 6 )alkyl-(SO 2 )—, (C 1 -C 6 )alkyl-O—(C═O)—, formyl, (C 1 -C 6 )alkyl-(C═O)—, and (C 3 -C 6 )cycloalkyl;  
         R 6  and R 8  are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, HO—(C 2 -C 6 )alkyl and (C 3 -C 8 )cycloalkyl;  
         n is an integer from zero to two; and  
         m is an integer from one to two;  
         or a pharmaceutically acceptable salt thereof;  
         wherein said IL-1 mediated disease is selected from the group consisting of:  
         arthritis, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, acute synovitis, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, psoriasis, allergic dermatitis, hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, peripheral neuropathy, and pain.  
       
     
     
         2 . The method of  claim 1 , wherein R 2  is chloro, methyl or ethyl.  
     
     
         3 . The method of  claim 2 , wherein R 3  is a nitrogen linked (C 1 -C 10 )heterocyclyl of formula (IV):  
       
         
           
           
               
               
           
         
         R 4  is hydrogen or methyl,  
         and R 7  is selected from the group consisting of:  
         
           
             
             
                 
                 
             
           
         
       
     
     
         4 . The method of  claim 2 , wherein R 3  is a nitrogen linked (C 1 -C 10 )heterocyclyl of formula (IV), R 4  is hydrogen or methyl, and R 7  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 2 , wherein R 3  is a nitrogen linked (C 1 -C 10 )heterocyclyl of formula (IV), R 4  is hydrogen or methyl, and R 7  is  
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 2 , wherein R 3  is a nitrogen linked (C 1 -C 10 )heterocyclyl of formula (IV), R 4  is hydrogen or methyl, and R 7  is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 2 , wherein R 3  is a nitrogen linked (C 1 -C 10 )heterocyclyl of formula (IV), R 4  is hydrogen or methyl, and R 7  is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein said compound selected from the group consisting of: 
 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide;    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide;    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;    2-Chloro-5-(4-cyanomethyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide;    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;    2-Chloro-5-(4-cyanomethyl-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide;    2-Chloro-N-(1-hydroxy-3,3-dimethyl-cyclohexylmethyl)-5-(3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide;    5-(4-Carbamoylmethyl-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide;    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;    5-[4-(2-Amino-ethyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide;    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide; and    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide; or a pharmaceutically acceptable salt thereof.    
     
     
         9 . The method of  claim 1 , wherein said IL-1 mediated disease is selected from the group consisting of: arthritis, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, rheumatoid spondylitis, osteoarthritis, and gouty arthritis.  
     
     
         10 . The method of  claim 1 , wherein said IL-1 mediated disease is rheumatoid arthritis.  
     
     
         11 . The method of  claim 1 , wherein said IL-1 mediated disease is peripheral neuropathy or pain.