USRE50776EActiveUtilityPatentIndex 62
Inhibitors of cyclin-dependent kinases
Est. expiryMar 27, 2035(~8.7 yrs left)· nominal 20-yr term from priority
C07K 14/4738C07D 487/04C07D 473/34A61P 43/00A61K 45/06C07D 473/16
62
PatentIndex Score
0
Cited by
1,207
References
38
Claims
Abstract
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (III):
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 , —OR 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 selected from the group consisting of an amide, a carbamate, and a sulfonamide 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;
each of R 3 and R 4 is independently hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl;
L 1 is a bond, or —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 of the formula:
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 R L3a is 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 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted heterocyclyl.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of the formula:
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally substituted C 1 -C 6 alkyl.
7 . The compound of claim 1 , wherein the compound is of the formula:
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.
8 . The compound of claim 1 , wherein the compound is of the formula:
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.
9 . The compound of claim 1 , wherein the compound is of the formula:
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.
10 . The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted phenyl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted cyclohexyl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —NR L1 —.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —NR L2 (C═O)—.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is absent.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted phenyl.
17. 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.
18. 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, 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.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of Formula (i-1):
20. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
22. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 1b is —CH 2 CH 2 OH and b1 is 1.
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NR a R b .
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —NR L1 —CH 2 —.
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted piperidinyl.
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of the formula:
27. The compound of claim 1 , wherein the compound is of the formula:
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.
28. The compound of claim 1 , wherein the compound is of the formula:
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.
29. The compound of claim 1 , wherein the compound is of the formula:
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.
30. The compound of claim 1 , wherein the compound is of the formula:
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.
31. The compound of claim 1 , wherein the compound is of the formula:
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.
32. The compound of claim 1 , wherein the compound is of the formula:
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.
33. The compound of claim 1 , wherein the compound is of the formula:
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.
34. The compound of claim 1 , wherein the compound is of the formula:
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.
35. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
38. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.Cited by (0)
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