Inhibitors of cyclin-dependent kinases

1. A compound of Formula-(I) (I-a) or (I-b):

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, or a nitrogen protecting group when attached to nitrogen, or an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur; or Ra 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 5 is 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 protection 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—, —N RL3a —, —N RL3a 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 —C RL3b ═C RL3b —, cis-CR L3b ═C RL3b —, —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 —N RL3a 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 , and —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; and provided that the compound is not

2. The compound of claim 1 , wherein the compound is of Formula (I-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.

3. The compound of claim 2 , wherein the compound is of Formula (I-1-a):

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein the compound is of Formula (I-1-a-i):

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 , wherein the compound is of Formula (I-1-b):

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , wherein the compound is of Formula (I-1-b-i):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5 , wherein the compound is of Formula (I-1-b-ii):

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 , wherein the compound is of Formula (I-1-c):

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein the compound is of Formula (I-1-c-i):

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein the compound is of Formula (I-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.

11. The compound of claim 10 , wherein the compound is of Formula (I-2-a):

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 10 , wherein the compound is of Formula (I-2-a-i):

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 10 , wherein the compound is of Formula (I-2-b):

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 , wherein the compound is of Formula (I-2-b-i):

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 13 , wherein the compound is of Formula (I-2-b-ii):

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is of Formula (I-3):

or a pharmaceutically acceptable salt thereof, wherein

each instance of R 1c 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

c1 is 0 or an integer between 1 and 6, inclusive.

17. The compound of claim 16 , wherein the compound is of Formula (I-3-a):

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 16 , wherein the compound is of Formula (I-3-a-1):

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 16 , wherein the compound is of Formula (I-3-b):

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 16 , wherein the compound is of Formula (I-3-b-i):

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. 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.

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —NH— or —NH—CH 2 —.

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is:

wherein each ring atom of Ring A is optionally substituted.

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is:

wherein each ring atom of Ring A is optionally substituted.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is:

wherein in L 1 is attached to a carbon atom of Ring A, and each carbon atom of Ring A is optionally substituted.

27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —(C═O)— or —NH(C═O)—.

28. The compound of claim 27 , or a pharmaceutically acceptable salt thereof, wherein Ring B is:

wherein each ring atom of Ring B is optionally substituted.

29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond, and Ring B is absent.

30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NR a R b .

31. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R a is optionally substituted carbocyclyl.

32. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

33. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted carbocyclyl.

34. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 3 is a bond, —NR L3a —, —(CH 2 ) 1-4 —N RL3a —, or —N RL3a —CH 2 ) 1-4 —; and Y is O.

35. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:

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.