Compositions and methods for treating cancer

Abstract

K-Ras is the most frequently mutated oncogene in human cancer. Disclosed herein are compositions and methods for modulating K-Ras and treating cancer.

1 . A compound having the formula:
   R 1 -L 1 -L 2 -L 3 -E   wherein,   R 1  is a Switch 2-Binding Pocket binding moiety;   L 1  is a bond or a divalent radical chemical linker;   L 2  is a bond or a divalent radical chemical linker;   L 3  is a bond or a divalent radical chemical linker;   E is an electrophilic chemical moiety capable of forming a covalent bond with a K-Ras cysteine residue or a K-Ras aspartate residue.   
     
     
         2 . The compound of  claim 1 , wherein R 1  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. 
     
     
         3 .- 6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein R 1  is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein, 
         R 3  is independently hydrogen, oxo, 
       
       halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , 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; Two adjacent R 3  substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two R 3  substituents bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
 R 7 , R 8 , R 9 , and R 10  are independently hydrogen, 
 
       halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
 m and v are independently 1 or 2; 
 n is independently an integer from 0 to 4; 
 X is independently —Cl, —Br, —I, or —F; 
 e2 is independently an integer from 0 to 2; 
 e3 is independently an integer from 0 to 3; 
 e4 is independently an integer from 0 to 4; 
 e5 is independently an integer from 0 to 5; 
 e6 is independently an integer from 0 to 6; 
 e7 is independently an integer from 0 to 7. 
 
     
     
         8 . The compound of  claim 1 , wherein R 1  is R 3 -substituted pyridinyl, R 3 -substituted pyrimidinyl, R 3 -substituted thiophenyl, R 3 -substituted furanyl, R 3 -substituted indolyl, R 3 -substituted benzoxadiazolyl, R 3 -substituted benzodioxolyl, R 3 -substituted benzodioxanyl, R 3 -substituted thianaphthanyl, R 3 -substituted pyrrolopyridinyl, R 3 -substituted indazolyl, R 3 -substituted quinolinyl, R 3 -substituted quinoxalinyl, R 3 -substituted pyridopyrazinyl, R 3 -substituted quinazolinonyl, R 3 -substituted benzoisoxazolyl, R 3 -substituted imidazopyridinyl, R 3 -substituted benzofuranyl, R 3 -substituted benzothiophenyl, R 3 -substituted phenyl, R 3 -substituted naphthyl, R 3 -substituted biphenyl, R 3 -substituted pyrrolyl, R 3 -substituted pyrazolyl, R 3 -substituted imidazolyl, R 3 -substituted pyrazinyl, R 3 -substituted oxazolyl, R 3 -substituted isoxazolyl, R 3 -substituted thiazolyl, R 3 -substituted furylthienyl, R 3 -substituted pyridyl, R 3 -substituted pyrimidyl, R 3 -substituted benzothiazolyl, R 3 -substituted purinyl, R 3 -substituted benzimidazolyl, R 3 -substituted isoquinolyl, R 3 -substituted thiadiazolyl, R 3 -substituted oxadiazolyl, R 3 -substituted pyrrolyl, R 3 -substituted diazolyl, R 3 -substituted triazolyl, R 3 -substituted tetrazolyl, R 3 -substituted benzothiadiazolyl, R 3 -substituted isothiazolyl, R 3 -substituted pyrazolopyrimidinyl, R 3 -substituted pyrrolopyrimidinyl, R 3 -substituted benzotriazolyl, or R 3 -substituted quinolyl;
 R 3  is independently hydrogen, oxo,   
       halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , 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; Two adjacent R 3  substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two R 3  substituents bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
 R 7 , R 8 , R 9 , and R 10  are independently hydrogen, 
 
       halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCHF 2 , 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  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
 m and v are independently 1 or 2; 
 n is independently an integer from 0 to 4; 
 X is independently —Cl, —Br, —I, or —F. 
 
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein
 L 1 , L 2  and L 3  are independently a bond, —NR 2C —, —O—, —S—, —C(O)—, —S(O)—, —S(O) 2 —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; or a substituted or unsubstituted spirocyclic linker;   R 2C  is independently hydrogen, oxo,   
       halogen, —CX c   3 , —CN, —SO 2 Cl, —SO n3 R 10c , —SO v3 NR 7c R 8c , —NHNH 2 , —ONR 7c R 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7c R 8c , —N(O) m3 , —NR 7c R 8c , —C(O)R 9c , —C(O)—OR 9c , —C(O)NR 7c R 8c , —OR 10c , —NR 7c SO 2 R 10c , —NR 7c C═(O)R 9c , —NR 7c C(O)—OR 9c , —NR 7c OR 9c , —OCX c   3 , —OCHX c   2 , 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; Two adjacent R 2C  substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Two R 2C  substituents bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
 R 7c , R 8c , R 9c  and R 10c  are independently hydrogen, 
 
       halogen, —CF 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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 7c  and R 8c  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
 m1, m3, v1, and v3 are independently an integer from 1 to 2; 
 n1 and n3 are independently an integer from 0 to 4; 
 X c  is independently —Cl, —Br, —I, or —F. 
 
     
     
         11 . The compound of  claim 1 , wherein
 L 1 , L 2  and L 3  are independently —CR 2A R 2B —,   
       
         
           
           
               
               
           
         
         R 2A  and R 2B  are independently hydrogen, oxo, 
       
       halogen, —CX a   3 , —CN, —SO 2 Cl, —SO n1 R 10a , —SO v1 NR 7a R 8a , —NHNH 2 , —ONR 7a R 8a , —NHC═(O)NHNH 2 , —NHC═(O)NR 7a R 8a , —N(O) m1 , —NR 7a R 8a , —C(O)R 9a , —C(O)—OR 9a , —C(O)NR 7a R 8a , —OR 10a , —NR 7a SO 2 R 10a , —NR 7a C═(O)R 9a , —NR 7a C(O)—OR 9a , —NR 7a OR 9a , —OCX a   3 , —OCHX a   2 , 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 2A  and R 2B  substituent bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
 R 2C  is independently hydrogen, oxo, 
 
       halogen, —CX c   3 , —CN, —SO 2 Cl, —SO n3 R 10c , —SO v3 NR 7c R 8c , —NHNH 2 , —ONR 7c R 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7c R 8c , —N(O) m3 , —NR 7c R 8c , —C(O)R 9c , —C(O)—OR 9c , —C(O)NR 7c R 8c , —OR 10c , —NR 7c SO 2 R 10c , —NR 7c C═(O)R 9c , —NR 7c C(O)—OR 9c , —NR 7c OR 9c , —OCHX c   2 , 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 7a , R 8a , R 9a  and R 10a  are independently hydrogen, 
 
       halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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 7a  and R 8a  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
 R 7c , R 8c , R 9c  and R 10c  are independently hydrogen, 
 
       halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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 7c  and R 8c  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
 z is independently an integer from 0 to 10; 
 m1, m3, v1, and v3 are independently an integer from 1 to 2; 
 n1 and n3 are independently an integer from 0 to 4; 
 X a  and X c  are independently —Cl, —Br, —I, or —F. 
 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . The compound of  claim 1 , wherein E comprises 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 13  is independently hydrogen, oxo, halogen, —CX b   3 , —CN, —SO 2 Cl, —SO r R 17 , —SO p NR 14 R 15 , NHNH 2 , —ONR 14 R 15 , —NHC═(O)NHNH 2 , 
       
       —NHC═(O)NR 14 R 15 , —N(O) q , —NR 14 R 15 , —C(O)R 16 , —C(O)—OR 16 , —C(O)NR 14 R 15 , —OR 17 , —NR 14 SO 2 R 17 , —NR 14 C═(O)R 16 , —NR 14 C(O)—OR 16 , —NR 14 OR 16 , —OCX b   3 , —OCHX b   2 , 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; Two adjacent R 13  substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Two R 13  substituents bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
 R 14 , R 15 , R 16 , and R 17  are independently hydrogen, 
 
       halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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 14  and R 15  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
 p is independently 1 or 2; 
 q is independently an integer from 1 to 2; 
 r is independently an integer from 0 to 4; 
 X b  is independently —Cl, —Br, —I, or —F. 
 
     
     
         16 . The compound of  claim 1 , wherein E comprises a substituted or unsubstituted vinyl sulfone moiety, substituted or unsubstituted vinyl sulfonamide moiety, substituted or unsubstituted fluoro(C 1 -C 4 )alkylketone moiety, substituted or unsubstituted chloro(C 1 -C 4 )alkylketone moiety, substituted or unsubstituted acrylamide moiety, substituted or unsubstituted disulfide moiety, substituted or unsubstituted thiol moiety, substituted or unsubstituted phosphonate moiety, substituted or unsubstituted aldehyde moiety, substituted or unsubstituted enone moiety, substituted or unsubstituted diazomethylketone moiety, substituted or unsubstituted diazomethylamide moiety, substituted or unsubstituted cyanocyclopropyl carboxamide moiety, substituted or unsubstituted epoxide moiety, substituted or unsubstituted epoxyketone moiety, substituted or unsubstituted epoxyamide moiety, substituted or unsubstituted aryl aldehyde moiety, substituted or unsubstituted aryl dialdehyde moiety, substituted or unsubstituted dialdehyde moiety, substituted or unsubstituted nitrogen mustard moiety, substituted or unsubstituted propargyl moiety, substituted or unsubstituted propargylamide moiety. 
     
     
         17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of  claim 1 . 
     
     
         19 . A method of treating a disease in a patient in need of such treatment, said method comprising administering a therapeutically effective amount of a compound of  claim 1  to said patient. 
     
     
         20 . The method of  claim 19 , wherein said disease is cancer. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . A method of modulating the activity of a K-Ras protein, said method comprising contacting said K-Ras protein with an effective amount of a compound of  claim 1 . 
     
     
         25 .- 37 . (canceled) 
     
     
         38 . A K-Ras protein covalently bound to a compound of  claim 1 , wherein said compound is covalently bound to a cysteine residue of said K-Ras protein. 
     
     
         39 .- 46 . (canceled) 
     
     
         47 . A K-Ras protein covalently bound to a compound of  claim 1 , wherein said compound is covalently bound to an aspartate residue of said K-Ras protein. 
     
     
         48 .- 64 . (canceled) 
     
     
         65 . A method of selectively modulating a Ras protein, said method comprising contacting said Ras protein with a compound which contacts at least one amino acid residue forming a Switch 2 binding pocket of said Ras protein, wherein said at least one amino acid residue is selected from valine-7, valine-9, glycine-10, proline-34, threonine-58, glycine-60, glutamine-61, glutamate-62, glutamate-63, arginine-68, tyrosine-71, methionine-72, tyrosine-96, glutamine-99 and isoleucine-100 of said Ras protein, and wherein said compound covalently reacts with an amino acid residue of said Ras protein. 
     
     
         66 .- 73 . (canceled) 
     
     
         74 . A compound having molecular dimensions compatible with the shape of a K-Ras Switch 2 binding pocket wherein the compound, when present in an aqueous solution comprising 200 μM of the compound and 4 μM K-Ras, covalently binds to at least 50% of K-Ras proteins present in solution after 24 hours. 
     
     
         75 . A compound of Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 e5 is an integer from 0 to 5; 
 X′ is —O—, —NH—, or —S—; 
 R 2A  and R 2B  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; R 2A  and R 2B  substituent bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; 
 R 3  is independently hydrogen, oxo, halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , 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  is independently R 2C -substituted or unsubstituted cycloalkylene, R 2C -substituted or unsubstituted heterocycloalkylene, R 2C -substituted or unsubstituted arylene, R 2C -substituted or unsubstituted heteroarylene, or R 2C -substituted or unsubstituted spirocyclic linker; 
 L 3  is independently R 2C -substituted or unsubstituted cycloalkylene, R 2C -substituted or unsubstituted heterocycloalkylene, R 2C -substituted or unsubstituted arylene, R 2C -substituted or unsubstituted heteroarylene, or R 2C -substituted or unsubstituted spirocyclic linker; 
 E is an electrophilic chemical moiety capable of forming a covalent bond with a cysteine or aspartate residue; 
 R 2C  is independently hydrogen, oxo, 
 
       halogen, —CX c   3 , —CN, —SO 2 Cl, —SO n3 R 10c , —SO v3 NR 7c R 8c , —NHNH 2 , —ONR 7c R 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7c R 8c , —N(O) m3 , —NR 7c R 8c , —C(O)R 9c , —C(O)NR 7c R 8c , —OR 10c , —NR 7c SO 2 R 10c , —NR 7c C═(O)R 9c , —NR 7c C(O)—OR 9c , —NR 7c OR 9c , —OCX c   3 , —OCHX c   2 , 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; two adjacent R 2C  substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R 2C  substituents bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
 R 7 , R 8 , R 9 , and R 10  are independently hydrogen, 
 
       halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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 7a , R 8a , R 9a  and R 10a  are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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 7a  and R 8a  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 
 R 7c , R 8c , R 9c  and R 10c  are independently hydrogen, 
 
       halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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;
 m, m1, m3, v, v1, and v3 are independently 1 or 2; 
 n, n1, and n3 are independently an integer from 0 to 4; 
 X, X a  and X c  are independently —Cl, —Br, —I, or —F. 
 
     
     
         76 . The compound of  claim 75 , wherein E comprises a substituted or unsubstituted vinyl sulfone moiety, substituted or unsubstituted vinyl sulfonamide moiety, substituted or unsubstituted peroxide moiety, substituted or unsubstituted fluoro(C 1 -C 4 )alkylketone moiety, substituted or unsubstituted chloro(C 1 -C 4 )alkylketone moiety, substituted or unsubstituted acrylamide moiety, substituted or unsubstituted disulfide moiety, substituted or unsubstituted thiol moiety, substituted or unsubstituted phosphonate moiety, substituted or unsubstituted aldehyde moiety, substituted or unsubstituted enone moiety, substituted or unsubstituted diazomethylketone moiety, substituted or unsubstituted diazomethylamide moiety, substituted or unsubstituted cyanocyclopropyl carboxamide moiety, substituted or unsubstituted epoxide moiety, substituted or unsubstituted epoxyketone moiety, substituted or unsubstituted epoxyamide moiety, substituted or unsubstituted aryl aldehyde moiety, substituted or unsubstituted aryl dialdehyde moiety, substituted or unsubstituted dialdehyde moiety, substituted or unsubstituted nitrogen mustard moiety, substituted or unsubstituted propargyl moiety, substituted or unsubstituted propargylamide moiety. 
     
     
         77 .- 83 . (canceled) 
     
     
         84 . A method of treating a disorder in a subject in need thereof, comprising:
 a. determining the presence or absence of a K-Ras mutation in a malignant or neoplastic cell isolated from the subject; and   b. if a K-Ras mutation is determined to be present in the subject, administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of  claim 1 .   
     
     
         85 . (canceled) 
     
     
         86 . (canceled) 
     
     
         87 . A method of treating cancer in a human subject in need thereof, comprising administering to said subject at least one compound or pharmaceutically acceptable salt of  claim 1 , wherein said subject has a K-Ras mutation. 
     
     
         88 . (canceled) 
     
     
         89 . (canceled) 
     
     
         90 . The compound, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein said compound modulates the binding of GDP or GTP to a K-Ras protein. 
     
     
         91 .- 114 . (canceled)