Macrocyclic therapeutic agents, methods of manufacture, and methods of treatment

Abstract

The instant invention describes macrocyclic compounds having therapeutic activity, and the mechanism and methods of treating disorders such as autoimmune diseases, inflammation, and cancer, tumors and cell proliferation related disorders.

1 . A compound of formula 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
       
       wherein
 X is S or O; 
 each Y is independently H or optionally substituted alkyl; 
 Each R is independently alkyl optionally substituted with OH, OMe, SH, SMe, optionally substituted phenyl, NH 2 , NH-alkyl, or N(alkyl)(alkyl); or each R is independently the side chain of a naturally-occurring or non-natural amino acid; 
 or wherein each Y and R and the adjacent atoms attached to them (nitrogen and carbon, respectively) can combine to form a heterocyclic ring; 
 R 1  is optionally substituted alkyl; 
 R 2  is H or optionally substituted alkyl; and 
 R 3  is H, optionally substituted alkyl, or —C(O)alkyl. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof; according to formula 3: 
       
         
           
           
               
               
           
         
       
       wherein:
 each n is independently 0, 1, 2, 3, or 4; and 
 each R 5  is independently OH, SH, thioalkoxy, alkoxy, halo, NH 2 , NH-alkyl, or N(alkyl)(alkyl). 
 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, of any of formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein the variables are as defined in  claim 1 . 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is S. 
     
     
         5 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, according to formula 15: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein the variables are as defined in  claim 1 . 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, that is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 .- 18 . (canceled) 
     
     
         19 . A method of treating a subject suffering from or susceptible to a cell proliferation related disorder or disease, comprising administering to said subject an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, such that said subject is treated for said disorder. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 19 , wherein the disorder is cancer, solid tumor, an angiogenesis disorder, or metastatic tumor. 
     
     
         22 .- 37 . (canceled) 
     
     
         38 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         39 . (canceled) 
     
     
         40 . A process to prepare a compound formula 17: 
       
         
           
           
               
               
           
         
       
       wherein the process comprises the step of reacting a compound of formula 18, 
       
         
           
           
               
               
           
         
       
       with a compound of formula 19, 
       
         
           
           
               
               
           
         
       
       to afford a compound of formula 20, 
       
         
           
           
               
               
           
         
         wherein 
         each X is independently S or O; 
         each Ri is optionally substituted alkyl; 
         each R 2  is H; 
         each R 3  is independently H, optionally substituted alkyl, or —C(O)alkyl; 
         each R 6  is independently H, optionally substituted alkyl, or —C(O)alkyl; 
         each R 7  and R 8  are independently H or optionally substituted alkyl; and 
         each R 9  is independently H, optionally substituted alkyl, or optionally substituted aralkyl. 
       
     
     
         41 .- 57 . (canceled) 
     
     
         58 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is alkyl. 
     
     
         59 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is methyl. 
     
     
         60 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is H. 
     
     
         61 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is alkyl; and R 2  is H. 
     
     
         62 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is methyl; and R 2  is H. 
     
     
         63 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         64 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, according to Formula 32b: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein R 1  is optionally substituted alkyl; 
         R 2  is H or optionally substituted alkyl; 
         R 3  is H; and 
         each R 6  is independently H or methyl. 
       
     
     
         65 . The compound of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein R 1  is alkyl. 
     
     
         66 . The compound of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein R 1  is methyl. 
     
     
         67 . The compound of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein R 1  is alkyl; and R 2  is H.