5-bromo-indirubins

Abstract

Disclosed herein are compositions and methods for treating cancer, FLT3-AML, and CML.

1 . A compound having formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 50  is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CH 2 COOH, —CONH 2 , —NO 2 , —SH, —OCF 3 , —OCHF 2 , or unsubstituted alkyl; 
         R 51  is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NR 51A R 51B , —COOH, —CH 2 COOH, —CONH 2 , —NO 2 , —SH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, or unsubstituted heteroalkyl; 
         R 51A  and R 51B  are independently hydrogen or unsubstituted alkyl; 
         R 52  is halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , or unsubstituted alkyl; and 
         z1 and z2 are independently 0, 1, 2, 3, 4, or 5, 
         including pharmaceutically acceptable salts thereof. 
       
     
     
         2 .- 14 . (canceled) 
     
     
         15 . A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 15 , wherein said cancer is cancer is lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, or prostate cancer. 
     
     
         18 . (canceled) 
     
     
         19 . A method of treating chronic myelogenous leukemia (CML) expressing an ABL1-kinase, said method comprising administering an effective amount of a compound of  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein said ABL1-kinase is a ABL1 mutant-kinase. 
     
     
         21 . The method of  claim 20 , wherein said ABL1 mutant-kinase is a BCR-ABL1 mutant kinase. 
     
     
         22 .- 24 . (canceled) 
     
     
         25 . A method of treating acute myeloid leukemia expressing a FLT3-kinase in a subject in need thereof, said method comprising administering an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         L is a bond or substituted or unsubstituted alkylene; 
         R 1  is hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —CN, —OH, —NH 2 , —C(O)OR 4 , —CONH 2 , —NO 2 , —SH, —NHNH 2 , —NR 2 R 3 , —OR 4 , —SR 4 , 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; 
         R 2  and R 3  are independently 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 2  and R 3  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
         R 4  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; 
         R 5  and R 6  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)OR 9 , —CONH 2 , —NO 2 , —SH, —NHNH 2 , —NR 7 R 8 , —OR 9 , —SR 9 , 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; 
         R 7  and R 8  are independently 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 7  and R 8  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
         R 9  is 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, 
         including pharmaceutically acceptable salts thereof, 
         thereby treating said acute myeloid leukemia. 
       
     
     
         26 .- 29 . (canceled) 
     
     
         30 . The method of  claim 25 , wherein R 1  is halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —CN, —OH, —NH 2 , —COOH, —C(O)OR 4 , —CONH 2 , —NO 2 , —SH, —NHNH 2 , —NR 2 R 3 , —OR 4 , —SR 4 , 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. 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 25 , wherein R 2  and R 3  are independently 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. 
     
     
         33 .- 42 . (canceled) 
     
     
         43 . A method of treating acute myeloid leukemia expressing a FLT3-kinase in a subject in need thereof, said method comprising administering an effective amount of a compound according to  claim 1 , thereby treating said acute myeloid leukemia. 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . The method of  claim 43 , wherein said FLT3-kinase is a FLT3-mutant kinase. 
     
     
         47 . The method of  claim 46 , wherein said FLT3-mutant kinase is a FLT3-TKD mutant kinase. 
     
     
         48 . The method of  claim 47 , wherein said FLT3-TKD mutant kinase comprises a mutation at an amino acid residue position corresponding to D835, I836, D839, S840, N841, or Y842 of SEQ ID NO:1. 
     
     
         49 . The method of  claim 46 , wherein said FLT3-mutant kinase comprises a FLT3-ITD mutant kinase. 
     
     
         50 .- 53 . (canceled) 
     
     
         54 . A method of modulating activity of a FLT3-kinase, said method comprising contacting a FLT3-kinase with a compound having formula: 
       
         
           
           
               
               
           
         
         wherein, 
         L is a bond or substituted or unsubstituted alkylene; 
         R 1  is hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —CN, —OH, —NH 2 , —C(O)OR 4 , —CONH 2 , —NO 2 , —SH, —NHNH 2 , —NR 2 R 3 , —OR 4 , —SR 4 , 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; 
         R 2  and R 3  are independently 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 2  and R 3  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
         R 4  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; 
         R 5  and R 6  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)OR 9 , —CONH 2 , —NO 2 , —SH, —NHNH 2 , —NR 7 R 8 , —OR 9 , —SR 9 , 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; 
         R 7  and R 8  are independently 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 7  and R 8  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
         R 9  is 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, 
         including pharmaceutically acceptable salts thereof, 
         thereby modulating said activity of said FLT3-kinase. 
       
     
     
         55 . A method of modulating activity of a FLT3-kinase,
 said method comprising contacting a FLT3-kinase with a compound according to  claim 1 , thereby modulating said activity of said FLT3-kinase.   
     
     
         56 . (canceled) 
     
     
         57 . The method of  claim 55 , wherein said FLT3-kinase is a FLT3-mutant kinase. 
     
     
         58 . The method of  claim 57 , wherein said FLT3-mutant kinase is a FLT3-TKD mutant kinase. 
     
     
         59 . The method  claim 58 , wherein said FLT3-TKD mutant kinase comprises a mutation at an amino acid residue position corresponding to D835, I836, D839, S840, N841, or Y842 of SEQ ID NO:1. 
     
     
         60 .- 61 . (canceled) 
     
     
         62 . The method of  claim 55 , wherein said method further comprises modulating STAT signaling, STAT3, STAT5, MAP kinase signaling, or AKT signaling. 
     
     
         63 . (canceled) 
     
     
         64 . (canceled) 
     
     
         65 . (canceled)