Heteroaromatic compounds useful for the treatment of proliferative diseases
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, induce cellular apoptosis and/or inhibit transcription in the subject.
1. A compound having the structural formula I:
or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:
ring A is of Formula:
wherein:
R A1 is 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;
each X is independently selected from N and CH, wherein at least one X is N;
W is C(R 1a );
R 1a , if present, is 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;
R 1b is selected from hydrogen, deuterium, and halogen;
R 2 is an optionally substituted C 1 -C 4 alkylene, an optionally substituted C 2 -C 4 alkenylene, or an optionally substituted C 2 -C 4 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 )—;
R 4 is selected from a bond, an optionally substituted C 1 -C 4 alkylene, an optionally substituted C 2 -C 4 alkenylene, and an optionally substituted C 2 -C 4 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 optionally 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 of Formula (ii-1):
wherein:
L 3 is a bond, an optionally substituted C 1 -C 4 alkylene, an optionally substituted C 2 -C 4 alkenylene, or an optionally substituted C 2 -C 4 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 )—;
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;
Y is O;
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, optionally substituted aryl, and 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.
2. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein ring A is
3. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R 1a is chloro.
4. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R 1b is hydrogen.
5. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein each X is N.
6. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R 2 is selected from —NH and —NH—CH 2 —**, wherein “**” represents a portion of R 2 bound to the piperidin-1,3-diyl ring.
7. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R 4 is —C(O)—, †† —C(O)—NH—, or —CH 2 —, wherein “ †† ” represents a portion of R 4 bound to the piperidin-1,3-diyl ring.
8. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein each R 6 is hydrogen.
9. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R 7 is located para or met a to R 4 .
10. The compound of claim 9 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R 7 is 4-dimethylaminobut-2-enamido.
11. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein m is 0 or 1.
12. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R 8 is optionally substituted alkyl.
13. The compound of claim 12 , the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R 8 is methyl.
14. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer of the foregoing.
15. A pharmaceutical composition comprising a compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, and a pharmaceutically acceptable excipient.
16. The compound of claim 1 , wherein the compound is in the form of a salt or a solvate.
17. The compound of claim 16 , wherein the compound is in the form of a solvate and the solvate is a hydrate.
18. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R A1 is selected from hydrogen, deuterium, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl;
each instance of R A2 is independently selected from hydrogen, deuterium, halogen, —CN, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —OR A2a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a is independently selected from hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl;
R 1a , if present, is selected from hydrogen, deuterium, halogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —OR B1a , —N(R B1a ) 2 , and —SR B1a , wherein each occurrence of R B1a is independently selected from hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl;
R 2 is an unsubstituted C 1 -C 4 alkylene, an unsubstituted C 2 -C 4 alkenylene, or an unsubstituted C 2 -C 4 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 )—;
R 4 is selected from a bond, an unsubstituted C 1 -C 4 alkylene, an unsubstituted C 2 -C 4 alkenylene, or an unsubstituted C 2 -C 4 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 optionally taken together to form an unsubstituted carbocyclic or unsubstituted heterocyclic ring;
L 3 is a bond, an unsubstituted C 1 -C 4 alkylene, an unsubstituted C 2 -C 4 alkenylene, or an unsubstituted C 2 -C 4 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 )—;
R E1 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted 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, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl, or two R E1a groups are joined to form an unsubstituted heterocyclic ring;
R E2 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted 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, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl, or two R E2a groups are joined to form an unsubstituted heterocyclic ring;
R E3 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted 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, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl, or two R E3a groups are joined to form an unsubstituted 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 unsubstituted carbocyclic or unsubstituted heterocyclic ring;
each instance of R 8 , if present, is independently selected from deuterium, halogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —OR D1 , —N(R D1 ) 2 , and —SR m , wherein each occurrence of R D1 is independently selected from hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl, or
two R 8 groups are joined to form an unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl ring.
19. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R 7 is
20. The compound of claim 19 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein R E2a is optionally substituted alkyl.
21. The compound of claim 1 , wherein the compound is in the form of a salt.