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.

1 .- 47 . (canceled) 
     
     
         48 . A compound having the structural formula (IIc) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:
 R A6  is C 1 -C 6  alkyl; 
 R A7  is C 1 -C 6  alkyl; 
 R 2  is a bond; 
 Q is an optionally substituted divalent heterocyclyl; 
 R 3  is C 1 -C 4  alkylene, wherein one or more methylene units of the alkylene is optionally and independently replaced with —O—, —S—, —N(R 6 )—, —NHC(O)—, —C(O)—, or —S(═O) 2 ; 
 Z is a monocyclic heterocyclyl; and 
 R 4  is Formula (ii-1): 
 
       
         
           
           
               
               
           
         
       
       wherein
   L 3  is a bond,   Y is O, S, or N(R 6 ), wherein R 6  is hydrogen,   R E1  is hydrogen,   R E2  is hydrogen, and   R E3  is CH 2 N(R 9 ) 2  wherein R 9  is hydrogen or unsubstituted alkyl.   
 
     
     
         49 . The compound of  claim 48 , or the pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:
 R A6  is methyl;   R A7  is a C 3  alkyl;   Q is an unsubstituted divalent piperidine;   R 3  is a C 2  alkylene, wherein one or more methylene units of the alkylene is optionally and independently replaced with —O— or —C(O)—;   Z is pyrrolidinyl;   Y is O; and   R 9  is methyl.   
     
     
         50 . The compound of  claim 49 , or the pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:
 R A7  is a branched C 3  alkyl (CH 2 (CH 3 ) 2 ); and   R 3  is a C 2  alkylene in which the first methylene unit is replaced with —O— and the second methylene unit is replaced with —C(O)—.   
     
     
         51 . The compound of  claim 48  in the form of the pharmaceutically acceptable salt. 
     
     
         52 . The compound of  claim 48 , wherein the solvate is a hydrate. 
     
     
         53 . A pharmaceutical composition comprising the compound of  claim 48 , or the pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient. 
     
     
         54 . The pharmaceutical composition of  claim 53 , wherein the composition comprises the pharmaceutically acceptable salt of the compound of  claim 48 . 
     
     
         55 . The pharmaceutical composition of  claim 53 , wherein the composition comprises a racemic mixture of stereoisomers of the compound or is optically enriched for an enantiomer of the compound. 
     
     
         56 . The pharmaceutical composition of  claim 53 , wherein the composition is formulated for oral administration. 
     
     
         57 . The pharmaceutical composition of  claim 53 , wherein the composition is formulated for intravenous administration. 
     
     
         58 . The pharmaceutical composition of  claim 57 , wherein the composition is an injectable solution or suspension and the excipient is a non-toxic, parenterally acceptable diluent or solvent. 
     
     
         59 . The pharmaceutical composition of  claim 53 , wherein the composition is packaged as a single unit dose or a plurality of single unit doses. 
     
     
         60 . A kit comprising the compound of  claim 48 , or the pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or isotopically labeled derivative thereof, and instructions for administering the compound, or the pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, to a subject having a proliferative disease. 
     
     
         61 . A method of treating a subject suffering from a proliferative disease associated with aberrant activity of cyclin-dependent kinase 7 (CDK7), the method comprising administering to the subject the pharmaceutical composition of  claim 53 , wherein the compound of  claim 48  or the pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof is provided therein in a therapeutically effective amount. 
     
     
         62 . The method of  claim 61 , wherein the proliferative disease is cancer or a benign neoplasm. 
     
     
         63 . The method of  claim 62 , wherein the cancer is a biliary cancer, a bladder cancer, a blood cancer, a bone cancer, a brain cancer, a bone cancer, a cervical cancer, a colorectal cancer, a liver cancer, a lung cancer, melanoma, an ovarian cancer, a pancreatic cancer, a prostate cancer, or a uterine cancer. 
     
     
         64 . The method of  claim 63 , wherein the blood cancer is chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myelocytic leukemia (AML), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), a lymphoma, or multiple myeloma. 
     
     
         65 . The method of  claim 63 , wherein the breast cancer is triple-negative breast cancer (TNBC). 
     
     
         66 . The method of  claim 63 , wherein the brain cancer is a glioma or medulloblastoma. 
     
     
         67 . The method of  claim 63 , wherein the lung cancer is small cell lung cancer. 
     
     
         68 . The method of  claim 61 , wherein the proliferative disease is myelodysplastic syndrome (MDS).