Inhibitors of c-Jun-N-terminal kinase (JNK)

1. A method of treating a proliferative disease comprising administering to a subject in need thereof an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a 6-membered monocyclic heteroaryl ring or a bicyclic heteroaryl ring; each instance of R A is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A1 ) 2 , and —SR A1 , wherein each occurrence of R A1 is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1 groups are joined to form an optionally substituted heterocyclic ring; and m is 0, 1, 2, 3, or 4; or

Ring A is a heteroaryl ring, and m is 0;

Ring B is a group of the formula:

R B1 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B1a , —N(R B1a ) 2 , and —SR B1a , wherein each occurrence of R B1a is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R B1a groups are joined to form an optionally substituted heterocyclic ring;

W B is N or CR B2 , wherein R B2 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B2a , —N(R B2a ) 2 , and —SR B2a , wherein each occurrence of R B2a is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R B2a groups are joined to form an optionally substituted heterocyclic ring;

optionally wherein R B1 and R B2 are joined to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl;

L 1 is a bond directly attaching Ring A to Ring B;

represents a single bond;

X is —NR X —, wherein R X is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;

L 2 is —NR L2a C(═O)— or —C(═O)NR L2a —, wherein R L2a is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;

each instance of R C is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR C1 , —N(R C1 ) 2 , and —SR C1 , wherein each occurrence of R C1 is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R C1 groups are joined to form an optionally substituted heterocyclic ring;

n is 0, 1, 2, 3, or 4;

each instance of R D is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR D1 , —N(R D1 ) 2 , and —SR D1 , wherein each occurrence of R D1 is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R D1 groups are joined to form an optionally substituted heterocyclic ring;

p is 0, 1, 2, 3, or 4; and

R E is a group of the formula:

wherein:

L 3 is a bond, —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—, —OC(R L3b ) 2 —, —C(R L3b ) 2 O—, —NR L3a C(R L3b ) 2 —, —C(R L3b ) 2 NR L3a —, —SC(R L3b ) 2 —, —C(R L3b ) 2 S—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, —NR L3a S(═O) 2 —, or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —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) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein each instance of R L3a is independently hydrogen, C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and 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 C 1-4 hydrocarbon chain;

R E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 , and —SR E1a , wherein each occurrence of R E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E1a groups are joined to form an optionally substituted heterocyclic ring;

R E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N(R E2a ) 2 , and —SR E2a , wherein each occurrence of R E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E2a groups are joined to form an optionally substituted heterocyclic ring;

R E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E3a groups are joined to form an optionally substituted heterocyclic ring;

optionally wherein 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;

each instance of Y is independently O, S, or NR E5 , wherein each instance of R E5 is independently hydrogen, C 1-6 alkyl, or a nitrogen protecting group;

a is 1 or 2; and

z is 0, 1, 2, 3, 4, 5, or 6.

2. The method of claim 1 , wherein Ring A is of the formula:

3. The method of claim 1 , wherein Ring A is of the formula:

4. The method of claim 1 , wherein Ring A is of the formula:

5. The method of claim 1 , wherein R A is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and m is 1.

6. The method of claim 1 , wherein W B is CR B2 .

7. The method of claim 1 , wherein each of R B1 and R B2 is independently hydrogen, halogen, or optionally substituted alkyl.

8. The method of claim 1 , wherein R B1 and R B2 are joined to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl.

9. The method of claim 1 , wherein Ring B is of the formula:

wherein:

each instance of R B3 is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B3a , —N(R B3a ) 2 , and —SR B3a , wherein each occurrence of R B3a is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R B3a groups are joined to form an optionally substituted heterocyclic ring; and

q is 0, 1, 2, or 3.

10. The method of claim 1 , wherein X is —NH—.

11. The method of claim 1 , wherein R C is optionally substituted alkyl; and n is 1.

12. The method of claim 1 , wherein L 2 is —NHC(═O)—.

13. The method of claim 1 , wherein L 2 is —C(═O)NH—.

14. The method of claim 1 , wherein R D is halogen or optionally substituted alkyl; and p is 1.

15. The method of claim 1 , wherein R E is a group of formula:

16. The method of claim 15 , wherein R E3 is hydrogen or —CH 2 N(R E3a ) 2 .

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

21. The method of claim 1 , wherein the proliferative disease is cancer.

22. The method of claim 1 , wherein the proliferative disease is skin cancer.

23. The method of claim 1 , wherein the proliferative disease is lung cancer.

24. The method of claim 1 , wherein the proliferative disease is bone cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, kidney cancer, liver cancer, or pancreatic cancer.

25. The method of claim 1 , wherein the proliferative disease is leukemia or lymphoma.

26. The method of claim 1 , wherein the proliferative disease is a benign neoplasm.

27. The method of claim 1 , wherein the proliferative disease is an inflammatory disease.

28. The method of claim 1 , wherein the proliferative disease is rheumatoid arthritis.

29. The method of claim 1 , wherein the proliferative disease is inflammatory bowel disease.

30. The method of claim 1 , wherein the proliferative disease is an autoimmune disease.

31. A method of treating a proliferative disease comprising administering to a subject in need thereof an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof.

32. The method of claim 31 , wherein the proliferative disease is cancer or an inflammatory disease.