Compounds for the modulation of myc activity

Abstract

The present invention provides novel compounds of Formula (I) 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 .- 24 . (canceled) 
     
     
         25 . A method of treating a patient who has a cancer associated with deregulated activity of c-Myc, the method comprising administering to the patient an effective amount of a compound of structural formula I: 
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of structural formula I or the pharmaceutically acceptable salt thereof, wherein:
 Y is S; 
 Z is N(R 5 ); 
 R 1  is optionally substituted heterocyclyl or optionally substituted heteroaryl; 
 R 2  is —C(R 2a )(R 2b )(R 2c ), wherein:
 R 2a  is halogen, CN, C 1 -C 4  alkyl, or C 1 -C 4  heteroalkyl, wherein any alkyl or heteroalkyl is optionally substituted; 
 each of R 2b  and R 2c  is, independently, 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), or C(O)N(R 3a )(R 3b ), 
 wherein any alkyl or heteroalkyl portion of R 2b  and R 2c  is optionally and independently substituted; 
 
 each R 3  is, independently, hydrogen, —C 1 -C 6  alkyl, or —C 1 -C 6  heteroalkyl, wherein any alkyl or heteroalkyl is optionally substituted; or 
 two R 3  bound to a common nitrogen atom are optionally taken together with the nitrogen atom to which they are commonly bound to form a 4-11 member heterocyclyl or heteroaryl; 
 each R 4  is, independently, hydrogen, halogen, —CN, C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, N(R 3 )(R 3 ), 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 3 )(R 3 ), (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, or (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; 
 R 5  is 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 8 , CH 2 C(O)N(R 10 )(R 9 ), or CH 2 CH 2 N(R 10 )(R 9 ), wherein:
 R 8  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, (C 0 -C 3  alkylene)-carbocyclyl, or (C 0 -C 3  alkylene)-heterocyclyl; 
 R 9  is hydrogen or C 1 -C 4  alkyl; and 
 R 10  is 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), or C(O)—O—(C 1 -C 4  alkyl), or 
 R 10  and R 9  are taken together with the nitrogen atom to which they are commonly bound to form a 4- to 11-membered heterocyclyl or heteroaryl; 
 
 n is 1; 
 m is 1; and 
 p is 0, 1, 2, 3, 4, 5, or 6. 
 
     
     
         26 . The method of  claim 25 , wherein, in the compound of structural formula I or the pharmaceutically acceptable salt thereof, R 5  is hydrogen. 
     
     
         27 . The method of  claim 25 , wherein, in the compound of structural formula I or the pharmaceutically acceptable salt thereof, R 1  is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2-oxo-1,2-dihydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, pyrimidin-5-yl, 2-methoxypyridin-3-yl, 5-methoxypyridin-3-yl, pyridin-3-ylaminocarbonyl, 4-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-methyl-1H-imidazol-1-yl, 1-methyl-1H-pyrazol-4-yl, 5-fluoropyridin-3-yl, phenylaminocarbonyl, piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, or morpholin-4-ylcarbonyl. 
     
     
         28 . The method of  claim 25 , wherein, in the compound of structural formula I or the pharmaceutically acceptable salt thereof, R 2  is —(CH 2 ) 2 —NH—CH(CH 3 ) 2 , —(CH 2 ) 2 —NH—(CH 2 ) 2 —OCH 3 , or —(CH 2 ) 2 —NH—CH(CH 3 )—CH 2 CH 3 . 
     
     
         29 . The method of  claim 25 , wherein, in the compound of structural formula I or the pharmaceutically acceptable salt thereof, R 3  is hydrogen and p is 0. 
     
     
         30 . The method of  claim 25 , wherein the compound of structural formula I is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         31 . The method of  claim 25 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier. 
     
     
         32 . The method of  claim 25 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 25 , wherein, in the compound of structural formula I or the pharmaceutically acceptable salt thereof, R 1  is an unsubstituted heterocyclyl or heteroaryl; R 2a  is halogen, CN, C 1 -C 4  alkyl, or C 1 -C 4  heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; each of R 2b  and R 2c  is, independently, 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), or C(O)N(R 3a )(R 3b ), wherein any alkyl or heteroalkyl portion of R 2b  and R 2c  is unsubstituted; each R 3  is, independently, hydrogen, —C 1 -C 6  alkyl, or —C 1 -C 6  heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; and/or each R 4  is, independently, hydrogen, halogen, —CN, C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, N(R 3 )(R 3 ), 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 3 )(R 3 ), (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, or (C 1 -C 6  heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 4  is unsubstituted. 
     
     
         34 . The method of  claim 25 , wherein, in the compound of structural formula I or the pharmaceutically acceptable salt thereof, R 1  is an unsubstituted heterocyclyl or heteroaryl; R 2a  is halogen, CN, C 1 -C 4  alkyl, or C 1 -C 4  heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; each of R 2b  and R 2c  is, independently, 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), or C(O)N(R 3a )(R 3b ), wherein any alkyl or heteroalkyl portion of R 2b  and R 2c  is unsubstituted; each R 3  is, independently, hydrogen, —C 1 -C 6  alkyl, or —C 1 -C 6  heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; and/or each R 4  is, independently, hydrogen, halogen, —CN, C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, N(R 3 )(R 3 ), 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 3 )(R 3 ), (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, or (C 1 -C 6  heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 4  is unsubstituted. 
     
     
         35 . The method of  claim 27 , wherein, in the compound of structural formula I or the pharmaceutically acceptable salt thereof, R 1  is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, or pyrimidin-5-yl.