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 - 74 . (canceled) 
     
     
         75 . A compound of Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 e5 is an integer from 1 to 5; 
 X′ is —O—, —NH—, or —S—; 
 R 2A  and R 2B  are independently hydrogen, or unsubstituted alkyl; 
 R 3  is independently 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; or 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; 
 L 2  is-substituted or unsubstituted heterocycloalkylene; 
 L 3  is a bond; 
 E is an 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, 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, 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         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 , —NHC═(P)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 13  is independently hydrogen, methyl, ethyl, —CN, or —NO 2 ; 
         m and v are independently 1 or 2; 
         n is an integer from 0 to 4; and 
         X is —Cl, —Br, —I, or —F. 
       
     
     
         76 . (canceled) 
     
     
         77 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein L 2  is or unsubstituted heterocycloalkylene. 
     
     
         78 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein L 2  is monocyclic 4, 5, or 6-membered heterocycloalkylene. 
     
     
         79 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein L 2  is unsubstituted piperazino or unsubstituted piperidino. 
     
     
         80 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein L 2  is bicyclic fused heterocycloalkylene. 
     
     
         81 . (canceled) 
     
     
         82 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein E is an unsubstituted vinyl sulfone moiety, a substituted or unsubstituted vinyl sulfonamide moiety, or a substituted or unsubstituted acrylamide moiety. 
     
     
         83 . The compound or pharmaceutically acceptable salt of  claim 75 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         84 . A method of treating pancreatic cancer, colorectal cancer, or lung cancer in a subject in need thereof, the method 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 75 .   
     
     
         85 - 114 . (canceled) 
     
     
         115 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein E is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         116 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein E is 
       
         
           
           
               
               
           
         
       
     
     
         117 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein E is an 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, 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, or substituted or unsubstituted propargylamide moiety. 
     
     
         118 . The compound or pharmaceutically acceptable salt of  claim 77 , wherein E is an unsubstituted vinyl sulfone moiety, substituted or unsubstituted vinyl sulfonamide moiety, or substituted or unsubstituted acrylamide moiety. 
     
     
         119 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein R 3  is methyl, —Cl, —NH 2 , —I, —CCH, —CH 2 CH 2 OH, —OCH 2 CCH, —CF 3 , —OCH 3 , —OH, —CH 2 CH 3 , —NHS(O) 2 CH 3 , —CH 2 NH 2 , —Br, isoxazolyl, —NHC(O)OC(CH 3 ) 3 , p-chlorophenyl, thiophenyl, —F, pyrazolyl, —CH 2 OH, —C(O)NHCH 2 CH 2 OH, —OCH 2 CH 2 OH, —S(O) 2 NH 2 , tetrazolyl, —CHCH 3 OH, —C(O)CH 3 , —C(O)H, —OCH 3 , —C(O)OH, —C(O)OCH 3 , —C(O)NH 2 , —N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHC(O)CH 3 , pyrrolidinyl, —OCH 2 CH 2 NH 2 , —C(O)N(CH 3 ) 2 , —NHCH 3 , —NHC(O)CH 3 , —CN, or —C(O)OCH 3 . 
     
     
         120 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein R 3  is halogen, —CX 3 , —CN, —NR 7 R 8 , —OR 10 , —OCX 3 , —OCHX 2 , substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. 
     
     
         121 . The compound or pharmaceutically acceptable salt of  claim 75 , wherein L 2  is 
       
         
           
           
               
               
           
         
       
     
     
         122 . The compound of  claim 75 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         123 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of  claim 75 . 
     
     
         124 . A method of treating pancreatic cancer, colorectal cancer, or lung cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of  claim 75 . 
     
     
         125 . A method of modulating a K-Ras protein, the method comprising contacting the K-Ras protein with an effective amount of the compound of  claim 75 . 
     
     
         126 . A K-Ras protein covalently bound to the compound of  claim 75 , wherein the compound is covalently bound to a cysteine residue of the K-Ras protein.