Compounds for the modulation of myc activity

Abstract

The present invention provides novel compounds of Formula (I) and Formula (II) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases, e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases in a subject.

1 . A compound of structural formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
 Y is selected from O, S and N(R 3a ); 
 Z is selected from CH(N(R 5 )(R 6 )), C(R 4 )(N(R 5 )(R 6 )), N(R 1 ), N(R 1 ), and N + (R 1 ) 2 ; 
 R 1  is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, (C 0 -C 6  alkylene)-carbocyclyl, (C 1 -C 6  heteroalkylene)-carbocyclyl, (C 0 -C 6  alkylene)-heterocyclyl, (C 1 -C 6  heteroalkylene)-heterocyclyl, (C 0 -C 6  alkylene)-aryl, (C 1 -C 6  heteroalkylene)-aryl, (C 0 -C 6  alkylene)-heteroaryl, (C 1 -C 6  heteroalkylene)-heteroaryl, CH 2 C(O)OR 7 , CH 2 C(O)N(R 10 )(R 11 ), and CH 2 CH 2 N(R 10 )(R 11 ), wherein: 
 R 10  is hydrogen or C 1 -C 4  alkyl; 
 R 11  is selected from hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, (C 0 -C 4  alkylene)-carbocyclyl, (C 0 -C 4  alkylene)-heterocyclyl, (C 0 -C 4  alkylene)-aryl, (C 0 -C 4  alkylene)-heteroaryl, (C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl), (C 1 -C 4  alkyl)-N—(C 1 -C 4  alkyl) 2 , (C 1 -C 4  alkyl)-NH—(C 1 -C 4  alkyl), C(O)—(C 1 -C 4  alkyl), and C(O)—O—(C 1 -C 4  alkyl), or 
 R 10  and R 11  are taken together with the nitrogen atom to which they are commonly bound to form a 4-11 membered heterocyclyl or heteroaryl; and any alkyl, alkylene, heteroalkyl, heteroalkylene, heterocyclyl, heteroaryl, aryl or carbocyclyl portion of R 1  is optionally substituted; 
 R 2  is selected from C(R 2a )(R 2b )(R 2c ), carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein any carbocyclyl, aryl, heterocyclyl and heteroaryl is optionally substituted; 
 R 2a  is selected from hydrogen, halogen, —CN, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl and C 1 -C 4  haloalkyl, wherein any alkyl, heteroalkyl or haloalkyl is optionally substituted; 
 each of R 2b  and R 2c  is independently selected from hydrogen, halogen, —CN, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C(O)(C 1 -C 6  alkyl), C(O)(C 1 -C 6  heteroalkyl), C(O)O(C 1 -C 6  alkyl), C(O)O(C 1 -C 6  heteroalkyl), C(O)N(R 3a )(R 3b ), (C 0 -C 6  alkylene)-carbocyclyl, (C 1 -C 6  heteroalkylene)-carbocyclyl, (C 0 -C 6  alkylene)-heterocyclyl, (C 1 -C 6  heteroalkylene)-heterocyclyl, (C 0 -C 6  alkylene)-aryl, (C 1 -C 6  heteroalkylene)-aryl, (C 0 -C 6  alkylene)-heteroaryl, (C 1 -C 6  heteroalkylene)-heteroaryl, and —CH 2 —NR 17 —(CH 2 ) 0-1 —(CH 2 CH 2 O) 3-20 —CH 2 CH 2 —R 20 , wherein: 
 R 20  is selected from —C(O)OH, —C(O)CH 3 , —C(O)CH 2 CH 3 , —NH 2 , —CH 2 NH 2 , —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 ; 
 R 3a  is selected from hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  heteroalkyl, each of which is optionally substituted; 
 R 3b  is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, —S(O) 2 —C 1 -C 6  alkyl, —C(O)—C 1 -C 6  alkyl, —C(O)-aryl, and heterocyclyl, wherein any alkyl, aryl or heterocyclyl portion of R 3b  is optionally and independently substituted; and 
 wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 2b  and R 2c  is optionally and independently substituted; 
 each R 4  is independently selected from halogen, —CN, C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, N(R 3a )(R 3b ), C(O)(C 1 -C 6  alkyl), C(O)(C 1 -C 6  heteroalkyl), C(O)O(C 1 -C 6  alkyl), C(O)N(R 3a )(R 3b ) (C 0 -C 6  alkylene)-carbocyclyl, (C 1 -C 6  heteroalkylene)-carbocyclyl, (C 0 -C 6  alkylene)-heterocyclyl, (C 1 -C 6  heteroalkylene)-heterocyclyl, (C 0 -C 6  alkylene)-aryl, (C 1 -C 6  heteroalkylene)-aryl, (C 0 -C 6  alkylene)-heteroaryl, and (C 1 -C 6  heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 4  is optionally and independently substituted; or 
 two R 4  are taken together to the carbon ring atom or carbon ring atoms to which they are bound to form a carbocyclic ring that is fused, bridged, or spirofused to the ring comprising Z; 
 each of R 5  and R 6  is independently selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C(O)(C 1 -C 6  alkyl), C(O)O(C 1 -C 6  alkyl), (C 0 -C 6  alkylene)-carbocyclyl, (C 1 -C 6  heteroalkylene)-carbocyclyl, (C 0 -C 6  alkylene)-heterocyclyl, (C 1 -C 6  heteroalkylene)-heterocyclyl, (C 0 -C 6  alkylene)-aryl, (C 1 -C 6  heteroalkylene)-aryl, (C 0 -C 6  alkylene)-heteroaryl, and (C 1 -C 6  heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of each of R 5  and R 6  is optionally and independently substituted; or 
 R 5  and R 6  are taken together with the nitrogen atom to which they are commonly bound to form an optionally substituted heterocyclyl; 
 each R 7  is independently selected from halogen, —CN, —OH, —S(O) 2 —C 1 -C 6  alkyl, —S—C 1 -C 6  alkyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  heteroalkyl, N(R 3a )(R 3b ), C(O)(C 1 -C 6  alkyl), C(O)O(C 1 -C 6  alkyl), (C 0 -C 6  alkylene)-carbocyclyl, (C 1 -C 6  heteroalkylene)-carbocyclyl, (C 0 -C 6  alkylene)-heterocyclyl, (C 1 -C 6  heteroalkylene)-heterocyclyl, (C 0 -C 6  alkylene)-aryl, (C 1 -C 6  heteroalkylene)-aryl, (C 0 -C 6  alkylene)-heteroaryl, and (C 1 -C 6  heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 7  is optionally and independently substituted; or 
 two R 7  are taken together with the ring carbon atoms to which they are bound to form a heterocyclyl fused to rest of the compound; 
 n is 0, 1 or 2; 
 m is 0, 1 or 2; 
 n+m=1, 2 or 3; 
 o is 0, 1, 2, 3 or 4; and 
 p is 0, 1, 2, 3, 4, 5 or 6, wherein 
 when Z is N(R 1 ), R 2  is —C(R 2a )(R 2b )[C(R 9a )(R 9b )] 1-7 —N(R 17 )(R 8 ), wherein 
 each of R 17  and R 8  is independently selected from hydrogen, optionally substituted C 1 -C 4  alkyl, (C 1 -C 4  alkylene)-heterocyclyl, (C 1 -C 4  alkylene)-heteroaryl, carbocyclyl, C 1 -C 6  heteroalkyl, —(CH 2 CH 2 O) 3-20 —CH 2 CH 2 R 20 , and (C 1 -C 4  alkylene)-aryl; or 
 R 17  and R 8  are taken together with the nitrogen atom to which they are commonly bound to form a heterocyclyl or a heteroaryl, wherein any alkyl, alkylene, heteroalkyl, carbocyclyl, heterocyclyl, heteroaryl or aryl portion of R 8  or R 17  is optionally substituted; 
 each R 9a  and each R 9b  is independently selected from hydrogen, halogen, —CN, C 1 -C 8  alkyl, (C 0 -C 6  alkylene)-carbocyclyl, (C 1 -C 6  heteroalkylene)-carbocyclyl, (C 0 -C 6  alkylene)-heterocyclyl, (C 1 -C 6  heteroalkylene)-heterocyclyl, (C 0 -C 6  alkylene)-aryl, (C 1 -C 6  heteroalkylene)-aryl, (C 0 -C 6  alkylene)-heteroaryl, and (C 1 -C 6  heteroalkylene)-heteroaryl, and any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 9a  or R 9b  is optionally and independently substituted; or 
 any R 9a  is optionally taken together with R 2b  or any R 9b  and the carbon atom or carbon atoms to which they are respectively bound and including any intervening atoms forms an optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl; or 
 any R 9a  is additionally and optionally taken together with R 17  and the atoms to which they are respectively bound and including any intervening atoms forms an optionally substituted heterocyclyl or heteroaryl; and 
 
       the compound is other than 
       
         
           
           
               
               
           
         
       
     
     
         2 .- 40 . (canceled)