Inhibitors of cyclin-dependent kinase 7 (CDK7)
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. A compound having the structural formula (IIIc):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is —C(O)—;
Q is
wherein “1” represents a point of attachment to R 2 ;
R 3 is a bond, optionally substituted —CH 2 —, optionally substituted —NH—, —C(O), —N(CH 3 )—, or optionally substituted —CH(CH 3 )—;
Z is a monocyclic or bicyclic aryl, carbocyclyl, heterocyclyl, or heteroaryl, wherein Z is optionally substituted;
R 4 is
wherein L 3 is a bond, an optionally substituted C 1 -C 7 alkylene, or an optionally substituted C 2 -C 7 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, —S(O)—, —S(O) 2 , —N— or —N(R 6 )—;
Y is O, S, or N(R 6 );
each R 6 is independently selected from hydrogen and optionally substituted —C 1 -C 6 alkyl; and
each of R E1 , R E2 and R E3 is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR 9 , —CH 2 N(R 9 ) 2 , —CH 2 SR 9 , —CN, —OR 9 , —N(R 9 ) 2 , and —SR 9 , wherein each occurrence of R 9 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
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.
2. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof, or
or a pharmaceutically acceptable salt salt thereof.
3. The compound of claim 2 , wherein the compound is
or a pharmaceutically acceptable salt of either compound.
4. The compound of claim 1 , wherein Z is selected from
wherein:
“1” represents a portion of Z bound to R 3 ;
“2” represents a portion of Z bound to R 4 ;
each instance of 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, optionally substituted aryl, and optionally substituted heteroaryl;
and m is 0, 1, 2, 3 or 4.
5. The compound of claim 4 , wherein Z is selected from
6. The compound of claim 1 , wherein L 3 is selected from a bond, —NH—, —CH 2 —NH—**, —S(O) 2 —NH—**, and —NH—S(O) 2 —NH—**, wherein “**” represents a portion of L 3 bound to —C(═Y)—.
7. The compound of claim 1 , wherein R 4 is selected from: —CH 2 —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —NH—C(O)—CH═CH 2 , —C(O)—CH═CH 2 , —S(O) 2 —NH—C(O)—CH═CH 2 , and —NH—S(O) 2 —NH—C(O)—CH═CH 2 —NH—C(O)—CH═CH 2 .
8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
9. The pharmaceutical composition of claim 8 , wherein the compound is
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition of claim 9 , wherein the compound is
or a pharmaceutically acceptable salt of either compound.
11. The pharmaceutical composition of claim 8 , wherein Z is selected from
wherein:
“1” represents a portion of Z bound to R 3 ;
“2” represents a portion of Z bound to R 4 ;
each instance of 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, optionally substituted aryl, and optionally substituted heteroaryl;
and m is 0, 1, 2, 3 or 4.
12. The pharmaceutical composition of claim 8 , wherein Z is selected from
wherein:
“1” represents a portion of Z bound to R 3 ;
“2” represents a portion of Z bound to R 4 ;
each instance of 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, optionally substituted aryl, and optionally substituted heteroaryl;
and m is 0, 1, 2, 3 or 4.
13. The pharmaceutical composition of claim 8 , wherein L 3 is selected from a bond, —NH—, —CH 2 —NH—**, —S(O) 2 —NH—**, and —NH—S(O) 2 —NH—**, wherein “**” represents a portion of L 3 bound to —C(═Y)—.
14. The pharmaceutical composition of claim 8 , wherein R 4 is selected from: —CH 2 —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —NH—C(O)—CH═CH 2 , —C(O)—CH═CH 2 , —S(O) 2 —NH—C(O)—CH═CH 2 , and —NH—S(O) 2 —NH—C(O)—CH═CH 2 —NH—C(O)—CH═CH 2 .
15. A method of treating a cancer selected from triple-negative breast cancer, neuroblastoma, small cell lung cancer, ovarian cancer, acute myelogenous leukemia, and Ewing's sarcoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 5 .
16. The method of claim 15 , wherein the composition comprises
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof.
17. The method of claim 16 , wherein the composition comprises
or a pharmaceutically acceptable salt of either compound.
18. The method of claim 15 , wherein Z is selected from
wherein:
“1” represents a portion of Z bound to R 3 ;
“2” represents a portion of Z bound to R 4 ;
each instance of 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, optionally substituted aryl, and optionally substituted heteroaryl;
and m is 0, 1, 2, 3 or 4.
19. The method of claim 15 , wherein Z is selected from
wherein:
“1” represents a portion of Z bound to R 3 ;
“2” represents a portion of Z bound to R 4 ;
each instance of 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 ), 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, optionally substituted aryl, and optionally substituted heteroaryl;
and m is 0, 1, 2, 3 or 4.
20. The method of claim 15 , wherein L 3 is selected from a bond, —NH—, —CH 2 —NH—**, —S(O) 2 —NH—**, and —NH—S(O) 2 —NH—**, wherein “**” represents a portion of L 3 bound to —C(═Y)—.
21. The method of claim 15 , wherein R 4 is selected from: —CH 2 —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —NH—C(O)—CH═CH 2 , —C(O)—CH═CH 2 , —S(O) 2 —NH—C(O)—CH═CH 2 , and —NH—S(O) 2 —NH—C(O)—CH═CH 2 —NH—C(O)—CH═CH 2 .