Inhibitors of cyclin-dependent kinases
The present invention provides novel compounds of Formula (I), (II), or (III), 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 and/or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with 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., CDK7, CDK12, or CDK13), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.
1. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —NR a R b , —SR b , —C(═O)R b , —C(═O)OR b , or —C(═O)NR a R b , wherein each instance of R a and R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to nitrogen, an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur; or R a and R b are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
R 3 is hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl;
R 4 is halogen or optionally substituted C 1 -C 6 alkyl;
L 1 is a bond, —NR L1 —(CH 2 ) t —, —O—, or —S—;
R L1 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
t is 0 or an integer between 1 and 5, inclusive;
Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L 2 is a bond, optionally substituted C 1-4 alkylene, —C(═O)—, —NR L2 —, —C(═O)NR L2 —, —NR L2 C(═O)—, —O—, or —S—, wherein R L2 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 2 is any one of the formulae:
wherein:
L 3 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein each occurrence of R L3a is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 4 is a bond or an optionally substituted, branched or unbranched C 1-6 hydrocarbon chain;
each of R E1 , R E2 , and R E3 is independently 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 EE , —CH 2 N(R EE ) 2 , —CH 2 SR EE , —OR EE , —N(R EE ) 2 , —Si(R EE ) 3 , or —SR EE , wherein each occurrence of R EE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring;
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;
R E4 is a leaving group;
R E5 is halogen;
R E6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of Y is independently O, S, or NR E7 , wherein R E7 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
2. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
3. A kit comprising:
a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and
instructions for administering to a subject or contacting a biological sample with the compound, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A comprises an optionally substituted phenyl ring.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A comprises an optionally substituted cyclohexyl ring.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —NR L1 —.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —NR L2 (C═O)—.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is absent.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted phenyl ring.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is of Formula (n-1):
wherein:
each instance of R 1a is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;
each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and
a1 is 0 or an integer between 1 and 6, inclusive.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is of Formula (n-2):
wherein:
each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;
each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and
b1 is 0 or an integer between 1 and 6, inclusive.
12. The compound of claim 1 , wherein the compound is of Formula (II-1):
or a pharmaceutically acceptable salt thereof, wherein:
each instance of R 1a is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;
each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and
a1 is 0 or an integer between 1 and 6, inclusive.
13. The compound of claim 12 , wherein the compound is of Formula (II-1-a):
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 12 , wherein the compound is of Formula (II-1-a-i):
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 12 , wherein the compound is of Formula:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein the compound is of Formula (II-2):
or a pharmaceutically acceptable salt thereof, wherein:
each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;
each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and
b1 is 0 or an integer between 1 and 6, inclusive.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of Formula (i-1):
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:
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 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NR a R b .
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted phenyl ring.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted cyclohexyl ring.
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is absent, and L 2 is a bond.
24. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein Y is O.