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 (IVa): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 
         wherein:
 R b  and R c  are each C 1 -C 6  alkyl; 
 W is —NR b R c , wherein R b  is hydrogen and R c  is optionally substituted C 1 -C 6  alkyl; 
 R 2  is a bond; 
 Q is a bond; 
 R 3  is —C(O)— or —CH 2 —; 
 Z is an unsubstituted, monocyclic aryl; and 
 R 4  is Formula (ii-1): 
 
       
       
         
           
           
               
               
           
         
       
       wherein L 3  is —N(R 6 )—, wherein R 6  is hydrogen, Y is O, and each of R E1 , R E2 , and R E3  is hydrogen or optionally substituted alkyl. 
     
     
         49 . The compound of  claim 48 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
 R b  and R c  are each methyl;   W is —NR b R c , wherein R b  is hydrogen and R c  is optionally substituted C 2  alkyl;   R 3  is —C(O)—; and   R 4  is —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2  or —NH—C(O)—CH═CH 2 .   
     
     
         50 . The compound of  claim 49 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
 R 1  is —NR b R c , wherein R b  is hydrogen and R c  is a C 2  alkyl substituted with phenyl and with —N(R ∘ ) 2 , wherein each R ∘  is methyl; and   R 4  is —NH—C(O)—CH═CH 2 .   
     
     
         51 . The compound of  claim 50 , or the pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Z is 
       
         
           
           
               
               
           
         
       
       wherein “1” represents a portion of Z bound to R 3 , “2” represents a portion of Z bound to R 4 , and m is zero (0). 
     
     
         52 . The compound of  claim 51 , wherein Z is 
       
         
           
           
               
               
           
         
       
     
     
         53 . The compound of  claim 50  in the form of the pharmaceutically acceptable salt. 
     
     
         54 . A pharmaceutical composition comprising the compound of  claim 50 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient. 
     
     
         55 . The pharmaceutical composition of  claim 54 , wherein the composition comprises a pharmaceutically acceptable salt of the compound of  claim 50 . 
     
     
         56 . The pharmaceutical composition of  claim 54 , wherein the composition is formulated for oral administration. 
     
     
         57 . The pharmaceutical composition of  claim 54 , 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 54 , 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 50 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer 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 54 , wherein the compound of  claim 48  or the pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer 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 blood cancer, melanoma, a bone cancer, a breast cancer, a brain cancer, a lung cancer, or ovarian 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).