Inhibitors of cyclin dependent kinase 7 (cdk7)

Abstract

The present invention provides, inter alia, compounds having the structures of formulas described herein; pharmaceutically acceptable salts, solvates, hydrates, tautomers, and isotopic forms thereof; and compositions (e.g., pharmaceutical compositions and kits) containing one or more of the foregoing. Also provided are methods of administering and uses involving the compounds and/or pharmaceutical compositions for treating or preventing disease. The disease can be a proliferative disease, such as a cancer (e.g., a blood cancer (e.g., a leukemia or lymphoma), a brain cancer, a breast cancer, melanoma, multiple myeloma, or an ovarian cancer) a benign neoplasm, pathologic angiogenesis, or a fibrotic disease. While no aspect of the invention is limited by the biological events that may transpire, administering a compound or other composition described herein may selectively inhibit the aberrant expression or activity of cyclin-dependent kinase 7 (CDK7) and, thereby, induce cellular apoptosis and/or inhibit the transcription of disease-related genes in the patient (or in a biological sample).

1 . A pharmaceutical composition, wherein the composition is formulated for oral administration and comprises a pharmaceutically acceptable excipient and a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein:
 ring A is 
 
       
         
           
           
               
               
           
         
         ring B is 
       
       
         
           
           
               
               
           
         
       
       wherein each of R 2 , R 3 , R 4  and R 5  are, independently, hydrogen or —CH 3 ;
 X and Y are, independently, N or CH; 
 R 1  is hydrogen or fluoro; and 
 
       the compound is other than: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         3 .- 4 . (canceled) 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein ring B is 
       
         
           
           
               
               
           
         
       
     
     
         6 .- 7 . (canceled) 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
       
       and ring B is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein X is CH and Y is CH. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein X is N. 
     
     
         11 . A pharmaceutical composition, wherein the composition is formulated for oral administration and comprises a pharmaceutically acceptable excipient and a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein:
 ring A is 
 
       
         
           
           
               
               
           
         
       
       and
 R 1  is hydrogen or fluoro. 
 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof. 
     
     
         13 . A pharmaceutical composition, wherein the composition is formulated for oral administration and comprises a pharmaceutically acceptable excipient and a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof. 
     
     
         14 . (canceled) 
     
     
         15 . A method of treating a patient suffering from a disease associated with aberrant activity of CDK7, wherein the disease is a proliferative disease, an infectious disease, or a disease caused by or associated with expanded repeats of simple nucleotide tracts, and the method comprises a step of administering to the patient a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         16 .- 17 . (canceled) 
     
     
         18 . The method of  claim 15 , wherein the proliferative disease is a cancer or benign neoplasm. 
     
     
         19 . The method of  claim 18 , wherein the cancer is a blood cancer, a bone cancer, a brain cancer, a breast cancer, a colorectal cancer, a lung cancer, a melanoma, a neuroblastoma, an ovarian cancer, or a pancreatic cancer. 
     
     
         20 . The method of  claim 19 , wherein the blood cancer is chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), lymphoma, or multiple myeloma. 
     
     
         21 .- 25 . (canceled) 
     
     
         26 . The method of  claim 19 , wherein the blood cancer is acute myelogenous leukemia (AML). 
     
     
         27 . The method of  claim 19 , wherein the bone cancer is osteosarcoma or Ewing's sarcoma. 
     
     
         28 . The method of  claim 19 , wherein the breast cancer is triple-negative breast cancer (TNBC). 
     
     
         29 . The method of  claim 19 , wherein the cancer is a brain cancer. 
     
     
         30 . The method of  claim 19 , wherein the lung cancer is small cell lung cancer (SCLC). 
     
     
         31 . The method of  claim 19 , wherein the cancer is a colorectal cancer, a melanoma, a neuroblastoma, an ovarian cancer, or a pancreatic cancer. 
     
     
         32 . The method of  claim 15 , wherein the method further comprises a step of administering, to the patient, a therapeutically effective amount of an anti-proliferative agent, an anti-cancer agent, an immunosuppressant agent, or a pain-relieving agent.