Inhibitors of cyclin-dependent kinase 7 (cdk7)

Abstract

The present invention provides novel compounds described herein, such as 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., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

What is claimed is: 
     
         1 . A compound having the structural formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
 G is selected from: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein a hydrogen on G is replaced by a bond to R 2 , and:
 each R 1  is independently selected from hydrogen, halogen, optionally substituted C 1 -C 6  alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, OR a , NR b R c , —C(O)R a , —C(O)NR b R c , —S(O) x R a , and S(O) x NR b R c ; 
 R A6  is hydrogen, halogen, heterocyclyl, C 1 -C 6  alkyl, carbocyclyl, —OR a , —NR b R c , —C(O)R a , —C(O)NR b R c , —S(O) x R a , or —S(O) x NR b R c ; 
 R A7  is hydrogen, halogen, heterocyclyl, C 1 -C 6  alkyl, carbocyclyl, —OR a , —NR b R c , —C(O)R a , —C(O)NR b R c , —S(O) x R a , or —S(O) x NR b R c ; 
 each R a  is independently selected from hydrogen, C 1 -C 6  alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; 
 each R b  and R c  is independently selected from hydrogen and —C 1 -C 6  alkyl, or 
 R b  and R c  taken together with the atom to which they are attached form a 3-7-membered ring; 
 Y is N or CH; 
 K is bond, aryl, heteroaryl, carbocyclyl, or heterocyclyl; 
 R B1  is hydrogen or —C(O)R a ; 
 J is —NH— or —O—; 
 T is a 5-membered aryl or heteroaryl; 
 p is 0, 1, 2, 3, 4, or 5; 
 x is 0, 1, or 2; 
 R 2  is a bond, an optionally substituted C 1 -C 4  alkylene or an optionally substituted C 2 -C 4  alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, —C(O)—, or —N(R 6 )—, wherein R 6  is hydrogen or a C 1 -C 6  alkyl chain; 
 Q is selected from a bond, an optionally substituted divalent carbocyclyl, an optionally substituted divalent heterocyclyl, an optionally substituted divalent aryl, and an optionally substituted divalent heteroaryl; 
 R 3  is selected from a bond, an optionally substituted C 1 -C 4  alkylene, and an optionally substituted C 2 -C 4  alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene is optionally and independently replaced with —O—, —S—, —N(R 6 )—, —NHC(O)—, —C(O)NH—, —C(O)—, or —S(═O) 2 —; 
 each R 6  is independently selected from hydrogen, and optionally substituted —C 1 -C 6  alkyl; 
 Z is selected from a bond; a monocyclic or bicyclic aryl, carbocyclyl, heterocyclyl and heteroaryl, wherein when Z is other than a bond, Z is optionally substituted; 
 R 4  is any one of the Formulae (ii-0)-(ii-19): 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           wherein:
 L 3  is a bond, an optionally substituted C 1 -C 7  alkylene, or an optionally substituted C 2 -C 7  alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, —S(O)—, —S(O) 2 , —N— or —N(R 6 )—; 
 L 4  is a bond, an optionally substituted C 1 -C 4  alkylene, or an optionally substituted C 2 -C 4  alkenylene or alkynylene; 
 each of R E1 , R E2  and R E3  is independently selected from hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR 9 , —CH 2 N(R 9 ) 2 , —CH 2 SR 9 , —CN, —OR 9 , —N(R 9 ) 2 , and —SR 9 , wherein each occurrence of R 9  is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 
 R E1  and R E3 , or R E2  and R E3 , or R E1  and R E2  are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
 R E4  is a leaving group; 
 Y is O, S, or N(R 6 ); and 
 z is 0, 1, 2, 3, 4, 5, or 6; 
 
           when Q is phenyl, Z is other than a bond; and 
           except in the case wherein R 4  is (ii-0), no more than one of Q, R 3 , and Z is a bond. 
         
       
     
     
         2 - 47 . (canceled)