Inhibitors of cyclin-dependent kinase 7 (CDK7)
The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, neuroblastoma, lung cancer), 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 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 of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
Ring A is
each instance of R A1 is independently selected from the group consisting of hydrogen and alkyl;
each instance of R A2 is independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, and heteroaryl;
Ring B is of the formula:
R B1 is selected from the group consisting of hydrogen and alkyl,
W B is CR B2 , wherein R B2 is selected from the group consisting of hydrogen, cyano, halogen, optionally substituted alkyl, carbocyclyl, and OR B2a ,
wherein R B2a is selected from the group consisting of hydrogen and alkyl;
or R B1 and R B2 are joined to form a carbocyclyl or aryl ring;
X is NR X —, wherein R X is hydrogen or C 1-6 alkyl;
L 2 is —NR L2a C(═O)— or —NR L2a S(═O) 2 —, wherein R L2a is hydrogen or C 1-6 alkyl;
each instance of R C is independently selected from the group consisting of hydrogen, halogen, and alkyl;
n is 0, 1, 2, 3, or 4;
each instance of R D is independently selected from the group consisting of hydrogen, halogen, alkyl, and —N(R D1 ) 2 ,
wherein each occurrence of R D1 is independently selected from the group consisting of hydrogen and alkyl;
p is 0, 1, 2, 3, or 4;
R E is
R E and L 2 are para or meta to each other;
L 3 is —NR L3a — or an optionally substituted C 1-4 hydrocarbon chain, wherein R L3a is hydrogen;
R E1 is selected from the group consisting of hydrogen and alkyl;
R E2 is hydrogen or alkyl;
R E3 is selected from the group consisting of hydrogen, alkyl, —CH 2 OR E3a , and —CH 2 N(R E3a ) 2 ,
wherein each occurrence of R E3a is independently selected from the group consisting of hydrogen, alkyl,
and alkynyl; and
Y is O;
wherein “substituted” within each of R B2 and L 3 , refers independently to halogen, cyano, —NO 2 , —OH, —OR aa , —N(R bb ) 2 , —SH, —SR aa ,—C(═O)R aa , —CO 2 H, —CHO, —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , —NR bb C(═O)N(R bb ) 2 , —C(═NR bb )R aa ,—C(═NR bb )N(R bb ) 2 ,—NR bb C(═NR bb )N(R bb ) 2 ;
each of R aa is independently alkyl; and
each of R bb is independently hydrogen or alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is:
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is:
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is:
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R B1 is hydrogen or methyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —NH—C(O)—, —N(CH 3 )—C(O)—, or —NH—S(O) 2 —.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R E is of Formula (ii-1):
wherein Y is O;
L 3 is —NH— or
R E1 and R E2 are each hydrogen; and
R E3 is selected from hydrogen, —CH 2 N(CH 3 )C≡CH, —CH 2 N(CH 3 ) 2 , and —CH 2 OH.
8. The compound of claim 1 , wherein the compound is of Formula (I-3):
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound is of Formula (I-5):
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein the compound is of Formula (I-7):
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
12. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R B2 is selected from hydrogen, methyl, ethyl, chloro, CF 3 , cyclopropyl, —OCH 3 , cyano, and isopropyl.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —NR L2a C(═O)—.
16. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.