Inhibitors of cyclin-dependent kinase 7 (cdk7)

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., 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 (e.g., CDK7), and therefore induce cellular apoptosis and/or inhibit transcription in the subject.

1 . A compound having the structural formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate,
 hydrate, tautomer, or stereoisomer thereof, wherein: 
 ring A is an optionally substituted heteroaryl ring of any one of the Formulae (i-1)-(i-6): 
 
       
         
           
           
               
               
           
         
         wherein: 
         each instance of V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 , V 9 , V 10 , V 11 , V 12 , V 13 , V 14  and V 15  is independently O, —S, N, N(R A1 ), C, or C(R A2 ); 
         each instance of R A1  is independently selected from hydrogen, deuterium, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         each instance of R A2  is independently selected from hydrogen, deuterium, halogen, —CN, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl —OR A2a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a  is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 
         any two R A1 , any two R A2 , or one R A1  and one R A2  are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring; 
         each X is independently selected from N and CH, wherein at least one X is N; 
         W is selected from N and C(R 1a ); 
         each of R 1a , if present, and R 1b  is independently selected from hydrogen, deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR B1a , —N(R B1a ) 2 , and —SR B1a , wherein each occurrence of R B1a  is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 
         R 1a  and R 1b  are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring; 
         R 2  is 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 -0-, -S-, or -N(R 7 )-; 
         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 7 )—, or —S(O) 2 —; 
         R 4  is selected from —C 1 -C 8  alkyl, —O—C 1 -C 8  alkyl, —NH 2 , —NH(C 1 -C 8  alkyl), and —N(C 1 -C 8  alkyl) 2 , wherein each alkyl in R 4  is optionally and independently substituted. 
         each R 5 , if present, is independently selected from deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR D1 , —N(R D1 ) 2 , and —SR D1 , wherein each occurrence of R D1 -is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, and optionally substituted aryl, optionally substituted heteroaryl; 
         each R 6 , if present, is independently selected from the group consisting of deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, ═O, —CN, —OR C1 , —N(R c1 ) 2 , and —SR C1 , wherein each occurrence of R C1  is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R C1  groups are joined to form an optionally substituted heterocyclic ring; or 
         two R 6  are taken together to form a first 5-7-membered optionally substituted, heterocyclyl or carbocyclyl ring fused to the ring to which the R 6  are bound, wherein two substituents on the substituted heterocyclyl or carbocyclyl ring, or one substituent on the substituted heterocyclyl or carbocyclyl ring and a third R 6  may be taken together with the atoms to which they are bound to form a second optionally substituted, heterocyclyl or carbocyclyl ring fused to the ring to the first optionally substituted, heterocyclyl or carbocyclyl ring and/or the ring to which the third R 6  is bound; 
         each R 7  is independently selected from hydrogen, and optionally substituted —C 1 -C 6  alkyl; 
         n is 0, 1, 2, 3, 4, 5 or 6; and 
         p is 0, 1, 2 or 3, 
         wherein the compound is other than 
       
       
         
           
           
               
               
           
         
       
       and stereoisomers and enantiomers thereof. 
     
     
         2 .- 22 . (canceled)