Heteroaromatic compounds useful for the treatment of prolferative diseases

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 a kinase, such as a cyclin-dependent kinase (CDK) (e.g., cyclin-dependent kinase 7 (CDK7)), and therefore, in duce 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 —O—, —S—, or —N(R 6 )—; 
         each instance of R 3 , 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 C1 , —N(R C1 ) 2 , and —SR C1 , wherein each occurrence of R C1  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 
         two R 3  groups bound to the same ring carbon atom are taken together to form ═O, or 
         two R 3  groups bound to the same or different ring carbon atoms are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring; 
         R 4  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 other than a methylene unit bound to a nitrogen atom is optionally and independently replaced with —O—, —S—, —N(R 6 )—, or —S(═O) 2 —, and 
 two substituents on either the same or adjacent carbon atoms in the alkylene, alkenylene or alkynylene are taken together to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
 
         each R 6  is independently selected from hydrogen, and —C 1 -C 6  alkyl; 
         R 7  is any one of the Formulae (ii-1)-(ii-20): 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
         L 3  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—, 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; 
         R E1  is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 , —Si(R E1a ) 3 , and —SR E1a , wherein each occurrence of R E1a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E1a  groups are joined to form an optionally substituted heterocyclic ring; 
         R E2  is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N(R E2a ) 2 , and —SR E2a , wherein each occurrence of R E2a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E2a  groups are joined to form an optionally substituted heterocyclic ring; 
         R E3  is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E3a  groups are joined to form an optionally substituted heterocyclic ring; 
         optionally 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; 
         R E5  is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E5a , —CH 2 N(R E5a ) 2 , —CH 2 SR E5a , —OR E5a , —N(R E5a ) 2 , and —SR E5a , wherein each occurrence of R E5a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E5a  groups are joined to form an optionally substituted heterocyclic ring; Y is O, S, or NR E6 , wherein R E6  is hydrogen, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
         a is 1 or 2; 
         z is 0, 1, 2, 3, 4, 5, or 6; 
         each instance of R 8 , 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, or 
         two R 8  groups are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring; 
         m is 0, 1, 2, 3 or 4; and 
         n is 0, 1, 2, 3, 4, 5 or 6. 
       
     
     
         2 . The compound of  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein each of R 1a  is chloro. 
     
     
         4 . The compound of  claim 1 , wherein R 1b  is hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein W is C(R 1a ). 
     
     
         6 . The compound of  claim 1 , wherein each X is N. 
     
     
         7 . The compound of  claim 1 , wherein R 2  is selected from —NH and —NH—CH 2 -**, wherein “**” represents a portion of R 2  bound to piperidin-1,3-diyl. 
     
     
         8 . The compound of  claim 1 , wherein n is 0. 
     
     
         9 . The compound of  claim 1 , wherein R 4  is —C(O)—,  †† —C(O)—NH—, or —CH 2 , wherein “††” represents a portion of R 4  bound to piperidin-1,3-diyl. 
     
     
         10 . The compound of  claim 1 , wherein each R 6  is hydrogen. 
     
     
         11 . The compound of  claim 1 , wherein R 7  is located para or meta to R 4 . 
     
     
         12 . The compound of  claim 11 , wherein R 7  is located para to R 4 . 
     
     
         13 . The compound of  claim 11 , wherein R 7  is located meta to R 4 . 
     
     
         14 . The compound of  claim 11 , wherein R 7  is 4-dimethylaminobut-2-enamido. 
     
     
         15 . The compound of  claim 1 , wherein m is 0 or 1. 
     
     
         16 . The compound of  claim 1 , wherein R 8  is optionally substituted alkyl. 
     
     
         17 . The compound of  claim 16 , wherein R is methyl. 
     
     
         18 . The compound of  claim 1 , selected from any one of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and isotopically labeled derivatives of the foregoing. 
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         20 . A method of treating a subject suffering from a disease or condition associated with aberrant activity of a cyclin-dependent kinase (CDK) comprising the step of administering to the subject in need thereof a composition of  claim 19 . 
     
     
         21 . The method of  claim 20 , wherein the CDK is CDK7. 
     
     
         22 . The method of  claim 20 , wherein the disease or condition is selected from cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease, or an infectious disease. 
     
     
         23 . The method of  claim 20 , wherein the subject is a mammal. 
     
     
         24 . The method of  claim 20 , wherein the disease is cancer. 
     
     
         25 . The method of  claim 24 , wherein the cancer is selected from a blood cancer, melanoma, a bone cancer, a breast cancer, a brain cancer, or a lung cancer. 
     
     
         26 . The method of  claim 25 , wherein the cancer is a blood cancer selected from chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), lymphoma, and multiple myeloma. 
     
     
         27 . The method of  claim 25 , wherein the disease is a bone cancer selected from osteosarcoma and Ewing's sarcoma. 
     
     
         28 . The method of  claim 25 , wherein the disease is triple-negative breast cancer (TNBC). 
     
     
         29 . The method of  claim 25 , wherein the disease is neuroblastoma. 
     
     
         30 . The method of  claim 25 , wherein the disease is small cell lung cancer (SCLC). 
     
     
         31 . The method of  claim 20 , comprising the additional step of administering to the subject in need thereof one or more additional agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressant agents, and pain-relieving agents. 
     
     
         32 . The method of  claim 24 , comprising the additional step of administering to the subject in need thereof one or more additional agents independently selected from a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, and a DNA damage inducer.