Kinase inhibitors

Abstract

Methods of inhibiting kinases using kinase inhibitors having olefin moieties are disclosed.

1 . A method of inhibiting a protein kinase, said method comprising contacting said protein kinase with an effective amount of a reversible kinase inhibitor and allowing said reversible kinase inhibitor to reversibly bind to an active site cysteine residue, thereby inhibiting said protein kinase,
 wherein said reversible kinase inhibitor has the structure of Formula (I):   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is substituted or unsubstituted heteroaryl; 
         L 1  is a bond, —C(O)—, —C(O)N(L 3 R 2 )—, —C(O)O—, —S(O) n —, —O—, —N(L 3 R 2 )—, 
         —P(O)(OL 3 R 2 )O—, —SO 2 N(L 3 R 2 )—, —P(O)(NL 3 R 2 )N—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
         n is 0, 1 or 2; 
         L 3  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
         R 2  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
         -L 2 -E is: 
         —W—X(L 4 R 3 ) z L 5 R 4  wherein:
 W is —C(O)— or —S(O) 2 —; 
 z is 0 or 1; 
 X is O or N, wherein if X is O, then z is 0; 
 R 3  and R 4  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3  and R 4  are joined together with X to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
 L 4  and L 5  are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; or 
 
         (b) a ring of formula 
       
       
         
           
           
               
               
           
         
       
       where ring A is substituted or unsubstituted heteroaryl;
 wherein said reversible kinase inhibitor measurably dissociates from said protein kinase when said protein kinase is not denatured, partially denatured, or fully denatured; and 
 wherein if L 1  is a bond and R 1  is (3-(4-amino-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol)-6-yl, then -L 2 -E is not —C(O)NH 2 . 
 
     
     
         2 . The method according to  claim 1 , wherein said reversible kinase inhibitor has the formula: 
       
         
           
           
               
               
           
         
         wherein:
 W is —C(O)— or —S(O) 2 —; 
 z is 0 or 1; 
 X is 0 or N, wherein if X is 0, then z is 0; 
 R 3  and R 4  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R 3  and R 4  are optionally joined together with X to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
 R 1  is a substituted 6,5 fused ring heteroaryl, a substituted 5,6 fused ring heteroaryl, a substituted 5,5 fused ring heteroaryl, or a substituted 6,6 fused ring heteroaryl; 
 L 2 , L 4  and L 5  are independently is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and 
 wherein if L 1  is a bond and R 1  is (3-(4-amino-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol)-6-yl, then at least one of R 3  and R 4  are is not hydrogen. 
 
       
     
     
         3 . (canceled) 
     
     
         4 . The method according to  claim 1 , wherein said reversible kinase inhibitor has the formula: 
       
         
           
           
               
               
           
         
         wherein the ring A is five-membered R 31 -substituted or unsubstituted heteroaryl or six-membered R 31 -substituted or unsubstituted heteroaryl; wherein: 
         R 31  is hydrogen, halogen, —CN, —OH, —COOH, —CF 3 , R 33 -substituted or unsubstituted alkyl, R 33 -substituted or unsubstituted heteroalkyl, R 33 -substituted or unsubstituted cycloalkyl, R 33 -substituted or unsubstituted heterocycloalkyl, R 33 -substituted or unsubstituted aryl, or 
         R 33 -substituted or unsubstituted heteroaryl wherein; R 33  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , R 34 -substituted or unsubstituted alkyl, R 34 -substituted or unsubstituted heteroalkyl, R 34 -substituted or unsubstituted cycloalkyl, R 34 -substituted or unsubstituted heterocycloalkyl, R 34 -substituted or unsubstituted aryl, or R 34 -substituted or unsubstituted heteroaryl wherein; 
         R 34  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , R 35 -substituted or unsubstituted alkyl, R 35 -substituted or unsubstituted heteroalkyl, R 35 -substituted or unsubstituted cycloalkyl, R 35 -substituted or unsubstituted heterocycloalkyl, R 35 -substituted or unsubstituted aryl, or R 35 -substituted or unsubstituted heteroaryl wherein; 
         R 35  is independently halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 
       
     
     
         5 . The method according to  claim 1 , wherein said reversible kinase inhibitor has the formula: 
       
         
           
           
               
               
           
         
         wherein
 ring A is a substituted or unsubstituted heteroaryl. 
 
       
     
     
         6 .- 9 . (canceled) 
     
     
         10 . The method according to  claim 2 ,
 wherein
 R 4  is hydrogen, R 23A -substituted or unsubstituted alkyl, R 23A -substituted or unsubstituted heteroalkyl, R 23A -substituted or unsubstituted cycloalkyl, R 23A -substituted or unsubstituted heterocycloalkyl, R 23A -substituted or unsubstituted aryl, or R 23A -substituted or unsubstituted heteroaryl wherein; 
 R 23A  is hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , R 24A -substituted or unsubstituted alkyl, R 24A -substituted or unsubstituted heteroalkyl, R 24A -substituted or unsubstituted cycloalkyl, R 24A -substituted or unsubstituted heterocycloalkyl, R 24A -substituted or unsubstituted aryl, R 24A -substituted or unsubstituted heteroaryl, or -L 7A -R 24B  wherein; 
 L 7A  is independently —O—, —C(O)—, —C(O)NH—, —S(O) y′ —, or —S(O) y′ NH—; 
 y′ is 0, 1, or 2; 
 R 24B  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , R 24A -substituted or unsubstituted alkyl, R 24A -substituted or unsubstituted heteroalkyl, R 24A -substituted or unsubstituted cycloalkyl, R 24A -substituted or unsubstituted heterocycloalkyl, R 24A -substituted or unsubstituted aryl, R 24A -substituted or unsubstituted heteroaryl wherein; 
 R 24A  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , R 25A -substituted or unsubstituted alkyl, R 25A -substituted or unsubstituted heteroalkyl, R 25A -substituted or unsubstituted cycloalkyl, R 25A -substituted or unsubstituted heterocycloalkyl, R 25A -substituted or unsubstituted aryl, or R 25A -substituted or unsubstituted heteroaryl wherein; 
 R 25A  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , R 26A -substituted or unsubstituted alkyl, R 26A -substituted or unsubstituted heteroalkyl, R 26A -substituted or unsubstituted cycloalkyl, R 26A -substituted or unsubstituted heterocycloalkyl, R 26A -substituted or unsubstituted aryl, or R 26A -substituted or unsubstituted heteroaryl wherein; 
 R 26A  is independently halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 
   
     
     
         11 .- 14 . (canceled) 
     
     
         15 . The method according to  claim 2 ,
 wherein
 R 1  is R 7 -substituted or unsubstituted heterocycloalkyl, R 7 -substituted or unsubstituted aryl, or R 7 -substituted or unsubstituted heteroaryl R 7 -substituted 6,5 fused ring heteroaryl, R 7 -substituted 5,6 fused ring heteroaryl, R 7 -substituted 5,5 fused ring heteroaryl, or R 7 -substituted 6,6 fused ring heteroaryl; 
 L 1 , L 4  and L 5  are independently a bond; 
 R 7  is independently —NH 2 , R 8 -substituted or unsubstituted alkyl, R 8 -substituted or unsubstituted aryl, R 8 -substituted or unsubstituted heteroaryl, or -L 4 -R 7A  wherein; 
 L 4  is —C(O)—; 
 R 7A  is independently R 8 -substituted or unsubstituted alkyl, R 8 -substituted or unsubstituted aryl, R 8 -substituted or unsubstituted heteroaryl wherein; 
 R 8  is independently —OH or R 9 -substituted or unsubstituted alkyl; 
 R 4  is hydrogen or R 15 -substituted or unsubstituted alkyl; 
 R 3  is hydrogen or R 23 -substituted or unsubstituted alkyl; or 
 R 3  and R 4  are optionally joined together with X to form a 4-7 membered heterocycloalkyl; 
 R 9  is independently hydrogen, halogen, —CN, —OH, —NH z , —COOH, R 10 -substituted or unsubstituted alkyl, R 10 -substituted or unsubstituted heteroalkyl, R 10 -substituted or unsubstituted cycloalkyl, R 10 -substituted or unsubstituted heterocycloalkyl, R 10 -substituted or unsubstituted aryl, or R 10 -substituted or unsubstituted heteroaryl; 
 R 10  is independently halogen, —CN, —OH, —NH 7 , —COOH, —CF a , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; 
 R 15  is independently hydro en, halogen, —CN, —OH, —NH 2 , —COOH R 16 -substituted or unsubstituted alkyl, R 16 -substituted or unsubstituted heteroalkyl, R 16 -substituted or unsubstituted cycloalkyl, R 16 -substituted or unsubstituted heterocycloalkyl, R 16 -substituted or unsubstituted aryl, R 16 -substituted or unsubstituted heteroaryl, or -L 7 -R 15A  wherein: 
 L′ is —O—, —C(O)—, —C(O)NH—, —S(O) Y , or —S(O) y NH—. 
 y is 0, 1, or 2; 
 R 15A  is hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, R 16 -substituted or unsubstituted alkyl, R 16 -substituted or unsubstituted heteroalkyl, R 16 -substituted or unsubstituted cycloalkyl, R 16 -substituted or unsubstituted heterocycloalkyl, R 16 -substituted or unsubstituted aryl, R 16 -substituted or unsubstituted heteroaryl wherein; 
 R 16  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , R 17 -substituted or unsubstituted alkyl, R 17 -substituted or unsubstituted heteroalkyl, R 17 -substituted or unsubstituted cycloalkyl, R 17 -substituted or unsubstituted heterocycloalkyl, R 17 -substituted or unsubstituted aryl, or R 17 -substituted or unsubstituted heteroaryl wherein; 
 R 17  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, R 18 -substituted or unsubstituted alkyl, R 18 -substituted or unsubstituted heteroalkyl, R 18 -substituted or unsubstituted cycloalkyl, R 18 -substituted or unsubstituted heterocycloalkyl, R 18 -substituted or unsubstituted aryl, or R 18 -substituted or unsubstituted heteroaryl wherein; 
 R 18  is independently halo en —CN, —OH, —NH 2 , —COOH, —CF 3 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; 
 R 23  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, R 24 -substituted or unsubstituted alkyl, R 24 -substituted or unsubstituted heteroalkyl, R 24 -substituted or unsubstituted cycloalkyl, R 24 -substituted or unsubstituted heterocycloalkyl, R 24 -substituted or unsubstituted aryl, R 24 -substituted or unsubstituted heteroaryl, or -L 8 -R 23A′  wherein; 
 L 8  is —O—, —C(O)—, —C(O)NH—, 
 p is 0, 1, or 2; 
 R 23A′  is hydrogen halogen —CN, —OH, —NH 2 , —COOH, —CF 3 , R 24 -substituted or unsubstituted alkyl, R 24 -substituted or unsubstituted heteroalkyl, R 24 -substituted or unsubstituted cycloalkyl, R 24 -substituted or unsubstituted heterocycloalkyl, R 24 -substituted or unsubstituted aryl, R 24 -substituted or unsubstituted heteroaryl wherein; 
 R 24  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , R 25 -substituted or unsubstituted alkyl, R 25 -substituted or unsubstituted heteroalkyl, R 25 -substituted or unsubstituted cycloalkyl, R 25 -substituted or unsubstituted heterocycloalkyl, R 25 -substituted or unsubstituted aryl, or R 25 -substituted or unsubstituted heteroaryl wherein; 
 R 25  is independently hydrogen, halogen, —CN, —OH, —NH 2 , —COOH, —CF 3 , R 26 -substituted or unsubstituted alkyl, R 26 -substituted or unsubstituted heteroalkyl, R 26 -substituted or unsubstituted cycloalkyl, R 26 -substituted or unsubstituted heterocycloalkyl, R 26 -substituted or unsubstituted aryl, or R 26 -substituted or unsubstituted heteroaryl wherein 
 R 26  is independently halogen, —CN, —OH, —NH 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 
   
     
     
         16 . The method according to  claim 15 , wherein R 8  is independently —OH or unsubstituted alkyl. 
     
     
         17 . The method according to  claim 15 , wherein X is N. 
     
     
         18 .- 22 . (canceled) 
     
     
         23 . The method according to  claim 1 , wherein said protein kinase is Rsk, Nek, Mekk1, MSK1 or Plk. 
     
     
         24 . A method of treating a disease associated with kinase activity in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound having the structure of Formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is substituted or unsubstituted heteroaryl; 
         L 1  is a bond, —C(O)N(L 3 R 2 )—, —C(O)O—, —S(O) n —, —O—, —S—, —N(L 3 R 2 )—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
 n is 0, 1 or 2; 
 L 3  is independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
 R 2  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 -L 2 -E is: 
 (a) —W—X(L 4 R 3 ) z L 5 R 4  wherein:
 W is —C(O)— or —S(O)2—; 
 z is 0 or 1; 
 X is O or N, wherein if X is O, then z is 0; 
 
 R 3  and R 4  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3  and R 4  are joined together with X to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
 L 4  and L 5  are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; or 
 (b) a ring of formula 
 
       
       
         
           
           
               
               
           
         
       
       where ring A is substituted or unsubstituted heteroaryl;
 wherein if L 1  is a bond and R 1  is (3-(4-amino-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol)-6-yl, then at least one of R 2  and R 3  is not hydrogen. 
 
     
     
         25 . The method according to  claim 24 , wherein said disease or disorder is cancer, autoimmune, HIV infection or inflammation. 
     
     
         26 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein
 W is —C(O)— or —S(O) 2 —; 
 z is 0 or 1; 
 X is O or N, wherein if X is O, then z is 0; 
 R 1  is a substituted 6,5 fused ring heteroaryl, a substituted 5,6 fused ring heteroaryl, a substituted 5,5 fused ring heteroaryl, or a substituted 6,6 fused ring heteroaryl; 
 R 3  and R 4  are independently hydrogen, unsubstituted alkyl, alkyl substituted with one or two hydroxy or di-(unsubstituted alkylamino, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl, wherein R 3  and R 4  are optionally joined together with X to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
 L 1 , L 4  and L 5  are independently a bond, unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and 
 wherein if L 1  is a bond and R 1  is (3-(4-amino-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol)-6-yl, then at least one of R 3  and R 4  are not hydrogen. 
 
       
     
     
         27 . The compound of  claim 26  wherein X is N. 
     
     
         28 .- 34 . (canceled) 
     
     
         35 . The compound according to  claim 27  wherein
 R 1  is R 7 -substituted 6,5 fused ring heteroaryl, or R 7 -substituted 5,6 fused ring heteroaryl; 
 R 7  is independently —NH 2 , R 8 -substituted or unsubstituted alkyl, R 8 -substituted or unsubstituted aryl; and 
 R 8  is independently —OH or unsubstituted alkyl. 
 
     
     
         36 . The compound according to  claim 35 , wherein R 1  is R 7 -substituted indazolyl, or R 7 -substituted 7H-pyrrolo[2,3-d]pyrimidinyl. 
     
     
         37 . The compound according to  claim 36 , wherein R 3  and R 4  are hydrogen. 
     
     
         38 . The compound according to  claim 36 ,
 wherein
 R 3  is unsubstituted alkyl; and 
 R 4  is hydrogen. 
   
     
     
         39 . (canceled) 
     
     
         40 . The compound according to  claim 36 , wherein R 3  and R 4  join with N to form R 23 -substituted or unsubstituted pyrrolidinyl. 
     
     
         41 .- 43 . (canceled) 
     
     
         44 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is a substituted 6,5 fused ring heteroaryl, a substituted 5,6 fused ring heteroaryl, a substituted 5,5 fused ring heteroaryl, or a substituted 6,6 fused ring heteroaryl; 
         L 1  is a bond, unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
         the ring A is a substituted or unsubstituted heteroaryl. 
       
     
     
         45 . The compound according to  claim 26 , having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         46 . The compound according to  claim 44 , having the structure 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         47 . A pharmaceutical composition comprising a compound of any of the  claim 26 ,  27 ,  35 ,  36 - 38 ,  40 ,  44 , or  45  or a pharmaceutically acceptable excipient.