Pyrazole compounds and methods for making and using the compounds

Abstract

Disclosed embodiments concern novel interleukin receptor associated kinases (IRAK) inhibitors and compositions comprising such inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.

We claim: 
     
         1 . A compound having a formula 
       
         
           
           
               
               
           
         
       
       or salt thereof, wherein:
 R is aliphatic, heteroaliphatic, heteroaryl, aryl, halo, amide or CN; 
 R 1  is H, aliphatic or heteroaliphatic;
 or R and R 1 , together with the atoms to which they are attached, form a heterocyclyl ring; 
 
 R 2  is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amide, heterocyclyl or araliphatic; 
 each R 3  independently is H, aliphatic, halogen, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl, alkylphosphate, or alkylphosphonate; 
 y is from 1 to 6; and 
 Het-1 is heteroaryl. 
 
     
     
         2 . A method, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         3 . The method of  claim 2 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 3 , wherein the method is a method for treating a disease or condition for which an IRAK inhibitor is indicated, comprising administering to the subject an amount of the compound effective to treat the disease or condition. 
     
     
         5 . The method of  claim 4 , wherein the disease or condition comprises an auto-immune disease, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, allergic disorder, multi-organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injury, respiratory disease, ischemic condition, bacterial infection, viral infection, immune regulatory disorder or a combination thereof. 
     
     
         6 . The method of  claim 5 , wherein the disease or condition comprises an auto-immune disease, inflammatory disorder, cardiovascular disease, cancer, ischemic condition, immune regulatory disorder or a combination thereof. 
     
     
         7 . The method of  claim 5 , wherein the disease or condition comprises an autoimmune disease, an inflammatory disorder, or both. 
     
     
         8 . The method of  claim 5 , wherein the cancer is breast cancer, lung cancer, melanoma, leukemia, large B-cell lymphoma, Waldenström's macroglobulinemia, myelodysplastic syndromes, Kaposi's sarcoma, or a combination thereof. 
     
     
         9 . The method of  claim 4 , wherein the disease or condition comprises a myelodysplastic syndrome. 
     
     
         10 . The method of  claim 3 , wherein the compound is in the form of a pharmaceutically acceptable salt. 
     
     
         11 . A method, comprising:
 a) treating a compound having a formula   
       
         
           
           
               
               
           
         
       
       with an acid compound having a formula 
       
         
           
           
               
               
           
         
       
       to form a compound having a formula 
       
         
           
           
               
               
           
         
       
       and
 b) treating the compound having a formula 
 
       
         
           
           
               
               
           
         
       
       with a pyrazolyl boronic acid or boronic ester compound to form compound having a formula 
       
         
           
           
               
               
           
         
         wherein 
         R is aliphatic, heteroaliphatic, heteroaryl, aryl, halo, amide or CN; 
         R 3  is H, aliphatic, halogen, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl, alkylphosphate, or alkylphosphonate; 
         R x  is alkyl; 
         LG is a leaving group; 
         Het-1 is heteroaryl; and 
         Het-2 is pyrazolyl. 
       
     
     
         12 . The method of  claim 11 , further comprising:
 i) treating a compound having a formula   
       
         
           
           
               
               
           
         
       
       with a compound having a formula 
       
         
           
           
               
               
           
         
       
       to form a compound having a formula 
       
         
           
           
               
               
           
         
         ii) treating the compound having a formula 
       
       
         
           
           
               
               
           
         
       
       with a first reducing agent to form an alcohol compound;
 iii) treating the alcohol compound with an alkyl halide to form a compound having a formula 
 
       
         
           
           
               
               
           
         
       
       and
 iv) treating the compound having a formula 
 
       
         
           
           
               
               
           
         
       
       with a second reducing agent to form the compound having a formula 
       
         
           
           
               
               
           
         
         wherein the first reducing agent is selected from a borohydride reagent or an aluminum hydride reagent; and 
         the second reducing agent is selected from hydrogen gas in the presence of a catalyst, a borohydride reagent, zinc metal in acetic acid, or iron powder.