Ras inhibitors and uses thereof

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof,

wherein:

each of R 1 and R 2 is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group, or R 1 and R 2 are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;

L is a bond, optionally substituted C 1-6 alkylene, —O—, —S—, or —NR N —;

Y 1 is —O—, —NR N —, or —C(R C ) 2 —;

each instance of Y 2 is independently —O—, —S—, —NR N —, or —C(R C ) 2 —;

each instance of V is independently —C(═O)—, —S(═O) 2 —, or

each instance of X is independently hydrogen, —OR O , or —NR N1 R N2 ;

each instance of R N , R N1 , and R N2 is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; or R N1 and R N2 are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;

each instance of R O is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or an oxygen protecting group;

each instance of R C is independently hydrogen, halogen, or optionally substituted alkyl;

n is 1, 2, or 3; and

R D is of the formula:

wherein:

each instance of R D1 is independently hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO 2 , —OR D1a , —N(R D1a ) 2 , —SR D1a , —CH 2 OR D1a , —CH 2 N(R D1a ) 2 , —CH 2 SR D1a , —C(═O)R D1a , —C(═O)OR D1a , —C(═O)SR D1a , —C(═O)N(R D1a ) 2 , —C(═S)R D1a , —C(═S)OR D1a , —C(═S)SR D1a , —C(═S)N(R D1a ) 2 , —C(═NR D1a )R D1a , —C(═NR D1a )OR D1a , —C(═NR D1a )SR D1a , or —C(═NR D1a )N(R D1a ) 2 , wherein each occurrence of R D1a is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R D1a groups are joined to form an substituted or unsubstituted heterocyclic ring;

each instance of R D2 is independently hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO 2 , —OR D2a , —N(R D2a ) 2 , —SR D2a , —CH 2 OR D2a , —CH 2 N(R D2a ) 2 , —CH 2 SR D2a , —C(═O)R D2a , —C(═O)OR D2a , —C(═O)SR D2a , —C(═O)N(R D2a ) 2 , —C(═S)R D2a , —C(═S)OR D2a , —C(═S)SR D2a , —C(═S)N(R D2a ) 2 , —C(═NR D2a )R D2a , —C(═NR D2a )OR D2a , —C(═NR D2a )SR D2a , and —C(═NR D2a )N(R D2a ) 2 , wherein each occurrence of R D2a is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or two R D2a groups are joined to form an substituted or unsubstituted heterocyclic ring;

each instance of R D3 is independently hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR D3a , —N(R D3a ) 2 , —SR D3a , —CH 2 OR D3a , —CH 2 N(R D3a ) 2 , —CH 2 SR D3a , —C(═O)R D3a , —C(═O)OR D3a , —C(═O)SR D3a , —C(═O)N(R D3a ) 2 , —C(═S)OR D3a , —C(═S)SR D3a , —C(═S)N(R D3a ) 2 , —C(═NR D3a )R D3a , —C(═NR D3a )OR D3a , —C(═NR D3a )SR D3a , or —C(═NR D3a )N(R D3a ) 2 wherein each occurrence of R D3a is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R D3a groups are joined to form an substituted or unsubstituted heterocyclic ring;

optionally R D1 and R D3 , or R D2 and R D3 , or R D1 and R D2 are joined to form an substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;

R D4 is a leaving group selected from the group consisting of —Br, —Cl, —I, and —OS(═O) w R D4a , wherein w is 1 or 2, and R D4a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of X 1 is independently a bond, —C(═O)—, —S(═O) 2 —, NR D5 , optionally substituted alkylene, or optionally substituted heteroarylene, wherein R D5 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;

each instance of Y is independently O, S, or NR D6 , wherein R D6 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group; and

each instance of z and z 1 is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is of Formula (I-b1):

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is of Formula (I-c1) or (I-c2):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is of Formula (I-c2-1):

or a pharmaceutically acceptable salt thereof,

wherein:

R 3 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aralkyl, or optionally substituted carbocyclyl; and

R 3 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, or optionally substituted aralkyl.

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

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein the compound is of Formula (I-d1) or (I-d2):

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound is of Formula (I- or (I-e2):

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is of Formula (I-f1):

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —(CH 2 ) m —, wherein m is 1, 2, 3, 4, 5, or 6.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are taken together with their intervening atoms to form a heterocyclic ring of the formula

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R D is

17. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 is hydrogen.

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

21. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

represents a single bond or a double bond;

each of R 1 and R 2 is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group, or R 1 and R 2 are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;

L is a bond, optionally substituted C 1-6 alkylene, —O—, —S—, or —NR N —;

each instance of G 1 and G 2 is independently —O—, —S—, —NR N —, or —C(R C ) 2 —;

each instance of R N is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

each instance of R C is independently hydrogen, halogen, or optionally substituted alkyl; and

R D is of the formula:

wherein:

each instance of R D1 is independently hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO 2 , —OR D1 a, —N(R D1 a) 2 , —SR D1a , —CH 2 OR D1a , —CH 2 N(R D1a ) 2 , —CH 2 SR D1a , —C(═O)R D1a , —C(═O)OR D1a , —C(═O)SR D1a , —C(═O)N(R D1a ) 2 , —C(═S)OR D1a , —C(═S)SR D1a , —C(═S)N(R D1a ) 2 , —C(═NR D1a )R D1a , —C(═NR D1a )OR D1a , —C(═NR D1a )SR D1a , or —C(═NR D1a )N(R D1a ) 2 , wherein each occurrence of R D1a is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R D1a groups are joined to form an substituted or unsubstituted heterocyclic ring;

each instance of R D2 is independently hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO 2 , —OR D2a , —N(R D2a ) 2 , —SR D2a , —CH 2 OR D2a , —CH 2 N(R D2a ) 2 , —CH 2 SR D2a , —C(═O)R D2a , —C(═O)OR D2a , —C(═O)SR D2a , —C(═O)N(R D2a ) 2 , —C(═S)R D2a , —C(═S)OR D2a , —C(═S)SR D2a , —C(═S)N(R D2a ) 2 , —C(═NR D2a )R D2a , —C(═NR D2a )OR D2a , —C(═NR D2a )SR D2a , and —C(═NR D2a )N(R D2a ) 2 , wherein each occurrence of R D2a is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or two R D2a groups are joined to form an substituted or unsubstituted heterocyclic ring;

each instance of R D3 is independently hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR D3a , —N(R D3a ) 2 , —SR D3a , —CH 2 OR D3a , —CH 2 N(R D3a ) 2 , —CH 2 SR D3a , —C(═O)R D3a , —C(═O)OR D3a , —C(═O)SR D3a , —C(═O)N(R D3a ) 2 , —C(═S)R D3a , —C(═S)OR D3a , —C(═S)SR D3a , —C(═S)N(R D3a ) 2 , —C(═NR D3a )R D3a , —C(═NR D3a )OR D3a , —C(═NR D3a )SR D3a , or —C(═NR D3a )N(R D3a ) 2 wherein each occurrence of R D3a is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R D3a groups are joined to form an substituted or unsubstituted heterocyclic ring;

optionally R D1 and R D3 , or R D2 and R D3 , or R D1 and R D2 are joined to form an substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;

R D4 is a leaving group selected from the group consisting of —Br, —Cl, —I, and —OS(═O) w R D4a , wherein w is 1 or 2, and R D4a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of X 1 is independently a bond, —C(═O)—, —S(═O) 2 —, NR D5 , optionally substituted alkylene, or optionally substituted heteroarylene, wherein R D5 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;

each instance of Y is independently O, S, or NR D6 , wherein R D6 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group; and

each instance of z and z 1 is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.

22. The compound of claim 21 , wherein the compound is of Formula (II-a):

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 21 , wherein the compound is of Formula (II-a1):

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 21 , wherein the compound is of Formula (II-a2):

or a pharmaceutically acceptable salt thereof, wherein each instance of R N is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group.

25. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein L is —(CH 2 ) m —, wherein m is 1, 2, 3, 4, 5, or 6.

26. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are taken together with their intervening atoms to form a heterocyclic ring of the formula

27. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R D is

28. The compound of claim 21 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a compound of claim 21 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

30. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 is hydrogen.

31. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R D is:

32. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising a compound of claim 32 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

34. A method of treating a proliferative disease in a subject, the method comprising:

administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

35. A method of inhibiting Ras activity in a biological sample, the method comprising:

contacting the biological sample with a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

36. A method of inhibiting cell growth in a biological sample or subject, the method comprising:

administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

37. A method of inducing apoptosis of a cell in a subject or biological sample, the method comprising:

administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

38. A method of treating a proliferative disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 32 , or a pharmaceutically acceptable salt thereof.

39. A method of treating a proliferative disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 21 , or a pharmaceutically acceptable salt thereof.