Janus kinase inhibitors and uses thereof

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

W 1 is N, W 2 is N and W 3 is CR X , or W 1 is N, W 2 is CH, and W 3 is N;

R Y1 is a group of formula

L 3 is a bond or a linker selected from the group consisting of substituted and unsubstituted C 1-6 alkylene, substituted and unsubstituted C 2-6 alkenylene, substituted and unsubstituted C 2-6 alkynylene, substituted and unsubstituted heteroC 1-6 alkylene, substituted and unsubstituted heteroC 2-6 alkenylene, and substituted and unsubstituted heteroC 2-6 alkynylene;

G 1 is NR G1a and G 2 is N(R G2a ) 2 , OR G2a , or C(R G2a ) 2 ; or G 1 is CHR G1a and G 2 is N(R G2a ) 2 , OR G2a ;

each instance of R G1a and R G2a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or R G1a and one instance of R G2a are joined to form the group —C(R B ) 2 —C(R B ) 2 —;

represents a single or double bond;

each instance of R D1 , R D2 , and R D3 is independently hydrogen or substituted or unsubstituted alkyl;

R D4 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;

G 5 is O, S, or NR E ;

each instance of R E and R G is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;

each instance of R J1 and R J2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl;

each instance of R A and R C is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , or —OC(═O)N(R A1 ) 2 ;

each instance of R B is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , or —OC(═O)N(R A1 ) 2 ; or two R B groups attached to the same carbon atom are joined to form a ═O group;

each instance of R A1 is independently hydrogen, 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, 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 a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

a and k are each independently 0, 1, or 2, provided when k is 0, then R A is absent, and when a is 0, then R C is absent; and

each instance of R X and R Z is independently hydrogen, halogen, substituted or unsubstituted alkyl, cyclopropyl, —CN, —OR X1 , or —NHR X1 , wherein R X1 is hydrogen, substituted or unsubstituted alkyl, an oxygen protecting group when attached to an oxygen, or a nitrogen protecting group when attached to a nitrogen, or R X and R Z are joined to form a substituted or unsubstituted 5-membered heterocyclic ring, or a ring of formula:

wherein R X2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;

or R X and R E are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring, or a ring of formula:

wherein R X is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

2. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

W 1 is N, W 2 is N and W 3 is CR X , or W 1 is N, W 2 is CH, and W 3 is N;

is selected from the group consisting of:

wherein t is 2, 3, 4, 5, or 6;

R Y2 is hydrogen, substituted or unsubstituted alkyl, —C(═O)R A2 , a nitrogen protecting group if attached to a nitrogen atom, or a group of formula

R A2 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;

L 3 is a bond or a linker selected from the group consisting of substituted and unsubstituted C 1-6 alkylene, substituted and unsubstituted C 2-6 alkenylene, substituted and unsubstituted C 2-6 alkynylene, substituted and unsubstituted heteroC 1-6 alkylene, substituted and unsubstituted heteroC 2-6 alkenylene, and substituted and unsubstituted heteroC 2-6 alkynylene;

G 1 is NR G1a and G 2 is N(R G2a ) 2 , OR G2a , or C(R G2a ) 2 ; or G 1 is CHR G1a and G 2 is N(R G2a ) 2 , OR G2a ;

each instance of R G1a and R G2a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or R G1a and one instance of R G2a are joined to form the group —C(R B ) 2 —C(R B ) 2 —;

represents a single or double bond;

each instance of R D1 , R D2 , and R D3 is independently hydrogen or substituted or unsubstituted alkyl;

R D4 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;

G 5 is O, S, or NR E ;

each instance of R E and R G is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;

each instance of R J1 and R J2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl;

each instance of R A and R C is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , or —OC(═O)N(R A1 ) 2 ;

each instance of R B is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , or —OC(═O)N(R A1 ) 2 ; or two R B groups attached to the same carbon atom are joined to form a ═O group;

each instance of R A1 is independently hydrogen, 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, 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 a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

a and k are each independently 0, 1, or 2, provided when k is 0, then R A is absent, and when a is 0, then R C is absent; and

each instance of R X and R Z is independently hydrogen, halogen, substituted or unsubstituted alkyl, cyclopropyl, —CN, —OR X1 , or —NHR X1 , wherein R X1 is hydrogen, substituted or unsubstituted alkyl, an oxygen protecting group when attached to an oxygen, or a nitrogen protecting group when attached to a nitrogen, or R X and R Z are joined to form a substituted or unsubstituted 5-membered heterocyclic ring, or a ring of formula:

wherein R X2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;

or R X and R E are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring, or a ring of formula:

wherein R X2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

3. The compound of claim 1 , wherein the group

is attached meta to the point of attachment

4. The compound of claim 1 , wherein the group

is attached para to the point of attachment

5. The compound of claim 1 , wherein the ring system:

is a bicyclic ring system of formula:

wherein R X2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

6. The compound of claim 1 , wherein the ring system:

is of the formula:

7. The compound of claim 1 , wherein the ring system:

is of the formula:

8. The compound of claim 1 of the Formula:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 of the Formula:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

11. The compound of claim 2 of the Formula:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 2 of the Formula:

wherein:

each instance of R Y4 is independently hydrogen, halogen, —OR Y3 , —N(R Y3 ) 2 , —C(═O)OR Y3 , —C(═O)N(R Y3 ) 2 , provided at least one R Y4 group is not hydrogen; and

R Y3 is independently hydrogen, substituted or unsubstituted alkyl, or two R Y3 groups attached to a N atom are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring,

wherein:

each instance of R Y4 is independently hydrogen, halogen, —OR Y3 , —N(R Y3 ) 2 , —C(═O)OR Y3 , —C(═O)N(R Y3 ) 2 , provided at least one R Y4 group is not hydrogen;

R Y3 is independently hydrogen, substituted or unsubstituted alkyl, or two R Y3 groups attached to a N atom are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring. In certain embodiments, one R Y4 is halogen, —OR Y3 , —N(R Y3 ) 2 , —C(═O)OR Y3 , —C(═O)N(R Y3 ) 2 , and the other two R Y4 groups are hydrogen; and

each instance of R Y5 is independently hydrogen or —CH 3 ,

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 2 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

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

15. A method of reducing the activity of a Janus kinase (JAK) in a subject in need thereof, the method comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the activity of the Janus kinase (JAK).

16. A method of treating a condition associated with aberrant activity of a Janus kinase in a subject in need thereof, the method comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat the condition, wherein the condition is a hematological malignancy.

17. A kit comprising:

a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and

instructions for using the kit.

18. A labeled compound of Formula (I) or (II):

or a pharmaceutically acceptable salt thereof;

wherein:

Group

is selected from the group consisting of:

wherein t is 2, 3, 4, 5, or 6;

L 1 is a linking group selected from the group consisting of substituted or unsubstituted alkylene; substituted or unsubstituted alkenylene; substituted or unsubstituted alkynylene; substituted or unsubstituted heteroalkylene; substituted or unsubstituted heteroalkenylene; substituted or unsubstituted heteroalkynylene; substituted or unsubstituted heterocyclylene; substituted or unsubstituted carbocyclylene; substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene; and combinations thereof;

B is a label;

W 1 is N, W 2 is N and W 3 is CR X , or W 1 is N, W 2 is CH, and W 3 is N;

represents a single or double bond;

each instance of R D1 , R D2 , and R D3 is independently hydrogen or substituted or unsubstituted alkyl;

R D4 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;

G 5 is O, S, or NR E ;

each instance of R E and R G is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;

each instance of R J1 and R J2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl;

each instance of R A and R C is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , or —OC(═O)N(R A1 ) 2 ;

each instance of R A1 is independently hydrogen, 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, 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 a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

a and k are each independently 0, 1, or 2, provided when k is 0 then R A is absent, and when a is 0 then R C is absent; and

each instance of R X and R Z is independently hydrogen, halogen, substituted or unsubstituted alkyl, cyclopropyl, —CN, —OR X1 , or —NHR X1 , wherein R X1 is hydrogen, substituted or unsubstituted alkyl, an oxygen protecting group when attached to an oxygen, or a nitrogen protecting group when attached to a nitrogen, or R X and R Z are joined to form a substituted or unsubstituted 5-membered heterocyclic ring, or a ring of formula:

wherein R X2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;

or R X and R E are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring, or a ring of formula:

wherein R X2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

19. The labeled compound of claim 18 :

20. A pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. A kit comprising:

a compound of claim 2 , or a pharmaceutically acceptable salt thereof; and

instructions for using the kit.

22. A method of reducing the activity of a Janus kinase (JAK) in a subject in need thereof, the method comprising administering to the subject a compound of claim 2 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the activity of the Janus kinase (JAK).

23. A method of treating a condition associated with aberrant activity of a Janus kinase in a subject in need thereof, the method comprising administering to the subject a compound of claim 2 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat the condition, wherein the condition is a hematological malignancy.

24. The method of claim 16 , wherein the hematological malignancy is leukemia or lymphoma.

25. The method of claim 16 , wherein the Janus kinase is Janus kinase 3 (JAK3).

26. The method of claim 23 , wherein the hematological malignancy is leukemia or lymphoma.

27. The method of claim 23 , wherein the Janus kinase is Janus kinase 3 (JAK3).