Methods and compositions useful in treating cancer and reducing wnt mediated effects in a cell

Abstract

Provided herein are novel compounds, pharmaceutical compositions for use, inter alia, in methods of reducing Wnt-mediated effects and treating cancer.

What is claimed is: 
     
         1 . A method of reducing a Wnt-mediated effect on a cell, said method comprising contacting said cell with an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  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; 
         R 2  is hydrogen, halogen, —CN, —CF 3 , 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 3  is halogen, —CN, —CF 3 , 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 independently halogen, —CN, —CF 3 , —NR 4A —C(O)R 4B , —NR 4A —C(O)—OR 4B , —C(O)NR 4A R 4B , —NR 4A S(O) 2 R 4B , —S(O) 2 N(R 4A )(R 4B ), —SR 4A , —S(O)R 4B , —S(O) 2 R 4B , —NR 4A R 4B , —OR 4A , —C(O)R 4B , 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 4A  and R 4B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         w is an integer from 0 to 4; and 
         L 1  is —NH—C(O)— or —C(O)—NH—. 
       
     
     
         2 . The method of  claim 1 , wherein said Wnt-mediated effect is an increase in degradation of Pygopus, an increase in degradation of non-oncogenic beta-Catenin, a decrease in degradation of Axin, a decrease in activity of Myc, a decrease in activity of CD44, a decrease in activity of Axin2, a decrease in activity of Bcl-9, or a decrease in activity of cyclin D. 
     
     
         3 . The method of  claim 1 , wherein R 1  is a substituted or unsubstituted heteroaryl or a substituted or unsubstituted phenyl. 
     
     
         4 . The method of  claim 1 , wherein R 1  is a substituted or unsubstituted thiazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted 4,5-dihydro-1H-benzoindazolyl or substituted or unsubstituted pyrazolyl. 
     
     
         5 . The method of  claim 1 , wherein R 2  is hydrogen or unsubstituted alkyl. 
     
     
         6 . The method of  claim 5 , wherein R 3  is substituted or unsubstituted phenyl. 
     
     
         7 . The method of  claim 1 , wherein R 2  and R 3  are joined together to form a substituted or unsubstituted heteroaryl. 
     
     
         8 . The method of  claim 7 , wherein R 2  and R 3  are joined together to form a substituted or unsubstituted indolin-1-yl or a substituted or unsubstituted tetrahydroquinolinyl. 
     
     
         9 . A method of treating cancer in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound, or pharmaceutically acceptable salt thereof, having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  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; 
         R 2  is hydrogen, halogen, —CN, —CF 3 , 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 3  is halogen, —CN, —CF 3 , 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 independently halogen, —CN, —CF 3 , —NR 4A —C(O)R 4B , —NR 4A —C(O)—OR 4B , —C(O)NR 4A R 4B , —NR 4A S(O) 2 R 4B , —S(O) 2 N(R 4A )(R 4B ), —SR 4A , —S(O)R 4B , —S(O) 2 R 4B , —NR 4A R 4B , —OR 4A , —C(O)R 4B , 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 4A  and R 4B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         w is an integer from 0 to 4; and 
         L 1  is —NH—C(O)— or —C(O)—NH—. 
       
     
     
         10 . The method of  claim 9 , wherein said cancer is colon cancer, breast cancer, gastric cancer, brain cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, melanoma, pancreatic cancer or prostate cancer. 
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
         L 1  is NH—C(O)— or C(O)—NH—; 
         R 2  is hydrogen, halogen, —CN, —CF 3 , 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 4  is independently halogen, —CN, —CF 3 , —NR 4A —C(O)R 4B , —NR 4A —C(O)—OR 4B , —C(O)NR 4A R 4B , —NR 4A S(O) 2 R 4B , —S(O) 2 N(R 4A )(R 4B ), —SR 4A , —S(O)R 4B , —S(O) 2 R 4B , —NR 4A R 4B , —OR 4A , —C(O)R 4B , 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  is hydrogen, halogen, —CN, —CF 3 , —NR 5A —C(O)R 5B , —NR 5A —C(O)—OR 5B , —C(O)NR 5A R 5B , —NR 5A S(O) 2 R 5B , —S(O) 2 N(R 5A )(R 5B ), —SR 5A , —S(O)R 5B , —S(O) 2 R 5B , —NR 5A R 5B , —OR 5A , —C(O)R 5B , 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 6  is independently halogen, —CN, —CF 3 , —NR 6A —C(O)R 6B , —NR 6A —C(O)—OR 6B , —C(O)NR 6A R 6B , —NR 6A S(O) 2 R 6B , —S(O) 2 N(R 6A )(R 6B ), —SR 6A , —S(O)R 6B , —S(O) 2 R 6B , —NR 6A R 6B , —OR 6A , —C(O)R 6B , 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 4A , R 4B , R 5A , R 5B , R 6A  and R 6B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         z is an integer from 0 to 4; and 
         w is an integer from 0 to 4. 
       
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein R 2  and R 5  are not joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 
     
     
         15 . The pharmaceutical composition of  claim 11 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R 7  is hydrogen, halogen, —CN, —CF 3 , —NR 7A —C(O)R 7B , —NR 7A —C(O)—OR 7B , —C(O)NR 7A R 7B , —NR 7A S(O) 2 R 7B , —S(O) 2 N(R 7A )(R 7B ), —SR 7A , —S(O)R 7B , —S(O) 2 R 7B , —NR 7A R 7B , —OR 7A , —C(O)R 7B , 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 8  is hydrogen, halogen, CN, —NR 8A —C(O)R 8B , —NR 8A —C(O)—OR 8B , —C(O)NR 8A R 8B , —NR 8A S(O) 2 R 8B , —S(O) 2 N(R 8A )(R 8B ), —SR 8A , —S(O)R 8B , —S(O) 2 R 8B , —NR 8A R 8B , —OR 8A , —C(O)R 8B , 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 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 7A , R 7B , R 8A  and R 8B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
       
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The pharmaceutical composition of  claim 15 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The pharmaceutical composition of  claim 15 , wherein R 2  and R 5  are not joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 
     
     
         19 . The pharmaceutical composition of  claim 15 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         X 1  and X 2  are independently carbon or nitrogen; 
         R 9  is independently halogen, —CN, —CF 3 , —NR 9A —C(O)R 9B , —NR 9A —C(O)—OR 9B , —C(O)NR 9A R 9B , —NR 9A S(O) 2 R 9B , —S(O) 2 N(R 9A )(R 9B ), —SR 9A , —S(O)R 9B , —S(O) 2 R 9B , —NR 9A R 9B , —OR 9A , —C(O)R 9B , 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 
         R 9A  and R 9B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
         u is an integer from 0 to 5. 
       
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The pharmaceutical composition of  claim 19 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The pharmaceutical composition of  claim 19 , wherein R 2  and R 5  are not joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 
     
     
         23 . The pharmaceutical composition of  claim 11 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R 10  is hydrogen, halogen, —CN, —CF 3 , —NR 10A —C(O)R 10B , —NR 10A —C(O)—OR 10B , —C(O)NR 10A R 10B , —NR 10A S(O) 2 R 10B , —S(O) 2 N(R 10A )(R 10B ), —SR 10A , —S(O)R 10B , —S(O) 2 R 10B , —NR 10A R 10B , —OR 10A , —C(O)R 10B , 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 11  is hydrogen, halogen, —CN, —CF 3 , —NR 11A —C(O)R 11B , —NR 11A  C(O)—OR 11B , —C(O)NR 11A R 11B , —NR 11A S(O) 2 R 11B , —S(O) 2 N(R 11A )(R 11B ), —SR 11A , —S(O)R 11B , —S(O) 2 R 11B , —NR 11A R 11B , —OR 11A , —C(O)R 11B , 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 10  and R 11  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
         R 12  is hydrogen, halogen, —CN, —CF 3 , —NR 12A —C(O)R 12B , —NR 12A —C(O)—OR 12B , —C(O)NR 12A R 2B , —NR 12A S(O) 2 R 12B , —S(O) 2 N(R 12A )(R 12B ), —SR 12A , —S(O)R 12B , —S(O) 2 R 12B , —NR 12A R 12B , —OR 12A , —C(O)R 12B , 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 
         R 10A , R 10B , R 11A , R 11B , R 12A  and R 12B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
       
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The pharmaceutical composition of  claim 23 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The pharmaceutical composition of  claim 23 , wherein R 2  and R 5  are not joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 
     
     
         27 . The pharmaceutical composition of  claim 11 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R 13  is independently halogen, —CN, —CF 3 , —NR 13A —C(O)R 13B , —NR 13A —C(O)—OR 13B , —C(O)NR 13A R 13B , —NR 13A S(O) 2 R 13B , —S(O) 2 N(R 13A )(R 13B ), —SR 13A , —S(O)R 13B , —S(O) 2 R 13B , —NR 13A R 13B , —OR 13A , —C(O)R 13B , 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 13A  and R 13B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
         m is an integer from 0 to 5. 
       
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         30 . The pharmaceutical composition of  claim 27 , wherein R 2  and R 5  are not joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 
     
     
         31 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         L 1  is —NH—C(O)— or —C(O)—NH—; 
         R 2  is hydrogen, halogen, —CN, —CF 3 , 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 4  is independently halogen, —CN, —CF 3 , —NR 4A —C(O)R 4B , —NR 4A —C(O)—OR 4B , —C(O)NR 4A R 4B , —NR 4A S(O) 2 R 4B , —S(O) 2 N(R 4A )(R 4B ), —SR 4A , —S(O)R 4B , —S(O) 2 R 4B , —NR 4A R 4B , —OR 4A , —C(O)R 4B , 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  is hydrogen, halogen, —CN, —CF 3 , —NR 5A —C(O)R 5B , —NR 5A —C(O)—OR 5B , —C(O)NR 5A R 5B , —NR 5A S(O) 2 R 5B , —S(O) 2 N(R 5A )(R 5B ), —SR 5A , —S(O)R 5B , —S(O) 2 R 5B , —NR 5A R 5B , —OR 5A , —C(O)R 5B , 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 5  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
         R 6  is independently halogen, —CN, —CF 3 , —NR 6A —C(O)R 6B , —NR 6A —C(O)—OR 6B , —C(O)NR 6A R 6B , —NR 6A S(O) 2 R 6B , —S(O) 2 N(R 6A )(R 6B ), —SR 6A , —S(O)R 6B , —S(O) 2 R 6B , —NR 6A R 6B , —OR 6A , —C(O)R 6B , 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 8  is hydrogen, halogen, CN, —NR 8A —C(O)R 8B , —NR 8A —C(O)—OR 8B , —C(O)NR 8A R 8B , —NR 8A S(O) 2 R 8B , —S(O) 2 N(R 8A )(R 8B ), —SR 8A , —S(O)R 8B , —S(O) 2 R 8B , —NR 8A R 8B , —OR 8A , —C(O)R 8B , 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 9  is independently halogen, —CN, —CF 3 , —NR 9A —C(O)R 9B , —NR 9A —C(O)—OR 9B , —C(O)NR 9A R 9B , —NR 9A S(O) 2 R 9B , —S(O) 2 N(R 9A )(R 9B ), —SR 9A , —S(O)R 9B , —S(O) 2 R 9B , —NR 9A R 9B , —OR 9A , —C(O)R 9B , 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 4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 8A , R 8B , R 9A  and R 9B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         z is an integer from 0 to 4; 
         w is an integer from 0 to 4; and 
         u is an integer from 0 to 5. 
       
     
     
         32 . The compound of  claim 31 , wherein said compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         33 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         L 1  is —NH—C(O)— or —C(O)—NH—; 
         R 4  is independently halogen, —CN, —CF 3 , —NR 4A —C(O)R 4B , —NR 4A —C(O)—OR 4B , —C(O)NR 4A R 4B , —NR 4A S(O) 2 R 4B , —S(O) 2 N(R 4A )(R 4B ), —SR 4A , —S(O)R 4B , —S(O) 2 R 4B , —NR 4A R 4B , —OR 4A , —C(O)R 4B , 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 6  is independently halogen, —CN, —CF 3 , —NR 6A —C(O)R 6B , —NR 6A —C(O)—OR 6B , —C(O)NR 6A R 6B , —NR 6A S(O) 2 R 6B , —S(O) 2 N(R 6A )(R 6B ), —SR 6A , —S(O)R 6B , —S(O) 2 R 6B , —NR 6A R 6B , —OR 6A , —C(O)R 6B , 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 8  is hydrogen, halogen, CN, —NR 8A —C(O)R 8B , —NR 8A —C(O)—OR 8B , —C(O)NR 8A R 8B , —NR 8A S(O) 2 R 8B , —S(O) 2 N(R 8A )(R 8B ), —SR 8A , —S(O)R 8B , —S(O) 2 R 8B , —NR 8A R 8B , —OR 8A , —C(O)R 8B , 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 9  is independently halogen, —CN, —CF 3 , —NR 9A —C(O)R 9B , —NR 9A —C(O)—OR 9B , —C(O)NR 9A R 9B , —NR 9A S(O) 2 R 9B , —S(O) 2 N(R 9A )(R 9B ), —SR 9A , —S(O)R 9B , —S(O) 2 R 9B , —NR 9A R 9B , —OR 9A , —C(O)R 9B , 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 4A , R 4B , R 6A , R 6B , R 8A , R 8B , R 9A  and R 9B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         z is an integer from 0 to 4; and 
         w is an integer from 0 to 4. 
         u is an integer from 0 to 5. 
       
     
     
         34 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         L 1  is —NH—C(O)— or —C(O)—NH—; 
         R 2  is hydrogen, halogen, —CN, —CF 3 , 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 4  is independently halogen, —CN, —CF 3 , —NR 4A —C(O)R 4B , —NR 4A —C(O)—OR 4B , —C(O)NR 4A R 4B , —NR 4A S(O) 2 R 4B , —S(O) 2 N(R 4A )(R 4B ), —SR 4A , —S(O)R 4B , —S(O) 2 R 4B , —NR 4A R 4B , —OR 4A , —C(O)R 4B , 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  is hydrogen, halogen, —CN, —CF 3 , —NR 5A —C(O)R 5B , —NR 5A —C(O)—OR 5B , —C(O)NR 5A R 5B , —NR 5A S(O) 2 R 5B , —S(O) 2 N(R 5A )(R 5B ), —SR 5A , —S(O)R 5B , —S(O) 2 R 5B , —NR 5A R 5B , —OR 5A , —C(O)R 5B , 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 6  is independently halogen, —CN, —CF 3 , —NR 6A —C(O)R 6B , —NR 6A —C(O)—OR 6B , —C(O)NR 6A R 6B , —NR 6A S(O) 2 R 6B , —S(O) 2 N(R 6A )(R 6B ), —SR 6A , —S(O)R 6B , —S(O) 2 R 6B , —NR 6A R 6B , —OR 6A , —C(O)R 6B , 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 8  is hydrogen, halogen, CN, —NR 8A —C(O)R 8B , —NR 8A —C(O)—OR 8B , —C(O)NR 8A R 8B , —NR 8A S(O) 2 R 8B , —S(O) 2 N(R 8A )(R 8B ), —SR 8A , —S(O)R 8B , —S(O) 2 R 8B , —NR 8A R 8B , —OR 8A , —C(O)R 8B , 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 9  is independently halogen, —CN, —CF 3 , —NR 9A —C(O)R 9B , —NR 9A —C(O)—OR 9B , —C(O)NR 9A R 9B , —NR 9A S(O) 2 R 9B , —S(O) 2 N(R 9A )(R 9B ), —SR 9A , —S(O)R 9B , —S(O) 2 R 9B , —NR 9A R 9B , —OR 9A , —C(O)R 9B , 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 4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 8A , R 8B , R 9A  and R 9B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         z is an integer from 0 to 4; and 
         w is an integer from 0 to 4. 
         u is an integer from 0 to 5. 
       
     
     
         35 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         L 1  is —NH—C(O)— or —C(O)—NH—; 
         R 4  is independently halogen, —CN, —CF 3 , —NR 4A —C(O)R 4B , —NR 4A —C(O)—OR 4B , —C(O)NR 4A R 4B , —NR 4A S(O) 2 R 4B , —S(O) 2 N(R 4A )(R 4B ), —SR 4A , —S(O)R 4B , —S(O) 2 R 4B , —NR 4A R 4B , —OR 4A , —C(O)R 4B , 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 6  is independently halogen, —CN, —CF 3 , —NR 6A —C(O)R 6B , —NR 6A —C(O)—OR 6B , —C(O)NR 6A R 6B , —NR 6A S(O) 2 R 6B , —S(O) 2 N(R 6A )(R 6B ), —SR 6A , —S(O)R 6B , —S(O) 2 R 6B , —NR 6A R 6B , —OR 6A , —C(O)R 6B , 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 13  is independently halogen, —CN, —CF 3 , —NR 13A —C(O)R 13B , —NR 13A —C(O)—OR 13B , —C(O)NR 13A R 13B , —NR 13A S(O) 2 R 13B , —S(O) 2 N(R 13A )(R 13B ), —SR 13A , —S(O)R 13B , —S(O) 2 R 13B , —NR 13A R 13B , —OR 13A , —C(O)R 13B , 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 4A , R 4B , R 6A , R 6B , R 13A  and R 13B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
         m is an integer from 0 to 5. 
         z is an integer from 0 to 4; and 
         w is an integer from 0 to 4. 
       
     
     
         36 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R 2  is hydrogen, halogen, —CN, —CF 3 , 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 4  is independently halogen, —CN, —CF 3 , —NR 4A —C(O)R 4B , —NR 4A —C(O)—OR 4B , —C(O)NR 4A R 4B , —NR 4A S(O) 2 R 4B , —S(O) 2 N(R 4A )(R 4B ), —SR 4A , —S(O)R 4B , —S(O) 2 R 4B , —NR 4A R 4B , —OR 4A , —C(O)R 4B , 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  is hydrogen, halogen, —CN, —CF 3 , —NR 5A —C(O)R 5B , —NR 5A —C(O)—OR 5B , —C(O)NR 5A R 5B , —NR 5A S(O) 2 R 5B , —S(O) 2 N(R 5A )(R 5B ), —SR 5A , —S(O)R 5B , —S(O) 2 R 5B , —NR 5A R 5B , —OR 5A , —C(O)R 5B , 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 5  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
         R 6  is independently halogen, —CN, —CF 3 , —NR 6A —C(O)R 6B , —NR 6A —C(O)—OR 6B , —C(O)NR 6A R 6B , —NR 6A S(O) 2 R 6B , —S(O) 2 N(R 6A )(R 6B ), —SR 6A , —S(O)R 6B , —S(O) 2 R 6B , —NR 6A R 6B , —OR 6A , —C(O)R 6B , 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 10  is hydrogen, halogen, —CN, —CF 3 , —NR 10A —C(O)R 10B , —NR 10A —C(O)—OR 10B , —C(O)NR 10A R 10B , —NR 10A S(O) 2 R 10B , —S(O) 2 N(R 10A )(R 10B ), —SR 10A , —S(O)R 10B , —S(O) 2 R 10B , —NR 10A R 10B , —OR 10A , —C(O)R 10B , 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 11  is hydrogen, halogen, —CN, —CF 3 , —NR 11A —C(O)R 11B , —NR 11A —C(O)—OR 11B , —C(O)NR 11A R 11B , —NR 11A S(O) 2 R 11B , —S(O) 2 N(R 11A )(R 11B ), —SR 11A , —S(O)R 11B , —S(O) 2 R 11B , —NR 11A R 11B , —OR 11A , —C(O)R 11B , 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 12  is hydrogen, halogen, —CN, —CF 3 , —NR 12A —C(O)R 12B , —NR 12A —C(O)—OR 12B , —C(O)NR 12A R 12B , —NR 12A S(O) 2 R 12B , —S(O) 2 N(R 12A )(R 12B ), —SR 12A , —S(O)R 12B , —S(O) 2 R 12B , —NR 12A R 12B , —OR 12A , —C(O)R 12B , 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 4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 10A , R 10B , R 11A , R 11B , R 12A  and R 12B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         z is an integer from 0 to 4; and 
         w is an integer from 0 to 4. 
       
     
     
         37 . The compound of  claim 36 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R 14  is independently halogen, —CN, —CF 3 , —NR 14A —C(O)R 14B , —NR 14A —C(O)—OR 14B , —C(O)NR 14A R 14B , —NR 14A S(O) 2 R 14B , —S(O) 2 N(R 14A )(R 14B ), —SR 14A , —S(O)R 14B , —S(O) 2 R 14B , —NR 14A R 14B , —OR 14A , —C(O)R 14B , 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 
         R 14A  and R 14B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
         q is an integer from 0 to 5. 
       
     
     
         38 . The compound of  claim 37 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         39 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         L 1  is NH—C(O)— or C(O)—NH—; 
         R 2  is hydrogen, halogen, —CN, —CF 3 , 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 4  is independently halogen, —CN, —CF 3 , —NR 4A —C(O)R 4B , —NR 4A —C(O)—OR 4B , —C(O)NR 4A R 4B , —NR 4A S(O) 2 R 4B , —S(O) 2 N(R 4A )(R 4B ), —SR 4A , —S(O)R 4B , —S(O) 2 R 4B , —NR 4A R 4B , —OR 4A , —C(O)R 4B , 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  is hydrogen, halogen, —CN, —CF 3 , —NR 5A —C(O)R 5B , —NR 5A —C(O)—OR 5B , —C(O)NR 5A R 5B , —NR 5A S(O) 2 R 5B , —S(O) 2 N(R 5A )(R 5B ), —SR 5A , —S(O)R 5B , —S(O) 2 R 5B , —NR 5A R 5B , —OR 5A , —C(O)R 5B , 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 6  is independently halogen, —CN, —CF 3 , —NR 6A —C(O)R 6B , —NR 6A —C(O)—OR 6B , —C(O)NR 6A R 6B , —NR 6A S(O) 2 R 6B , —S(O) 2 N(R 6A )(R 6B ), —SR 6A , —S(O)R 6B , —S(O) 2 R 6B , —NR 6A R 6B , —OR 6A , —C(O)R 6B , 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 15  is independently halogen, —CN, —CF 3 , —NR 15A —C(O)R 15B , —NR 15A —C(O)—OR 15B , —C(O)NR 15A R 15B , —NR 15A S(O) 2 R 15B , —S(O) 2 N(R 15A )(R 15B ), —SR 15A , —S(O)R 15B , —S(O) 2 R 15B , —NR 15A R 15B , —OR 15A , —C(O)R 15B , 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 4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 15A  and R 15B  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         z is an integer from 0 to 4; 
         w is an integer from 0 to 4; and 
         t is an integer from 0 to 4.