Urea derivatives and uses thereof

1. A method of treating an ocular disease in a subject in need thereof, comprising:

administering to the subject a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

X A is C;

X B is N;

X C is CH, N, or NH;

X D is CH, N, or NH, with the proviso that when X A is C and X C is CH, X D is not N;

each instance of R A is independently hydrogen, halogen, substituted or unsubstituted 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 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 instances of R A are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R A1 is independently hydrogen, substituted or unsubstituted 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, 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 instances of R A1 are joined to form substituted or unsubstituted heterocyclyl;

Ring Z is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R B is independently hydrogen, halogen, substituted or unsubstituted 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 B1 , —N(R B1 ) 2 , —SR B1 , —OCN, —SCN, —C(═NR B1 )R B1 , —C(═NR B1 )OR B1 , —C(═NR B1 )N(R B1 ) 2 , —C(═O)R B1 , —C(═O)OR B1 , —C(═O) N(R B1 ) 2 , —NO 2 , —NR B1 C(═O)R B1 , —NR B1 C(═O)OR B1 , —NR B1 C(═O) N(R B1 ) 2 , —OC(═O)R B1 , —OC(═O)OR B1 , or —OC(═O)N(R B1 ) 2 , or two instances of R B are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R B1 is independently hydrogen, substituted or unsubstituted 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, 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 instances of R B1 are joined to form substituted or unsubstituted heterocyclyl;

R C is substituted or unsubstituted alkyl, a nitrogen protecting group, or of the formula:

Ring C is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R C1 is independently hydrogen, halogen, substituted or unsubstituted 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 C1a , —N(R C1a ) 2 , —SR C1a , —CN, —SCN, —C(═NR C1a )R C1a , —C(═NR C1a )OR C1a , —C(═NR C1a )N(R C1a ) 2 , —C(═O)R C1a , —C(═O)OR C1a , —C(═O)N(R C1a ) 2 , —NO 2 , —NR C1a C(═O)R C1a , —NR C1a C(═O)OR C1a , —NR C1a C(═O)N(R C1a ) 2 , —OC(═O)R C1a , —OC(═O)OR C1a , —OC(═O) N(R C1a ) 2 , or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R C1 are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R C1a is independently hydrogen, substituted or unsubstituted 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, 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 instances of R C1a are joined to form substituted or unsubstituted heterocyclyl;

R D is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;

R E is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;

a is 0, 1, 2, or 3;

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

c is 0, 1, 2, 3, 4, or 5.

2. A method of treating an ocular disease in a subject in need thereof, comprising:

administering to the subject a therapeutically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof;

wherein Ring Z is selected from the group consisting of:

wherein each instance of R A is independently hydrogen, halogen, substituted or unsubstituted 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 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 instances of R A are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted 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, 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 instances of R A1 are joined to form substituted or unsubstituted heterocyclyl;

wherein each instance of R B is independently hydrogen, halogen, substituted or unsubstituted 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 B1 , —N(R B1 ) 2 , —SR B1 , —CN, —SCN, —C(═NR B1 )R B1 , —C(═NR B1 )OR B1 , —C(═NR B1 )N(R B1 ) 2 , —C(═O)R B1 , —C(═O)OR B1 , —C(═O)N(R B1 ) 2 , —NO 2 , —NR B1 C(═O)R B1 , —NR B1 C(═O)OR B1 , —NR B1 C(═O) N(R B1 ) 2 , —OC(═O)R B1 , —OC(═O)OR B1 , or —OC(═O) N(R B1 ) 2 , or two instances of R B are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

wherein each instance of R B1 is independently hydrogen, substituted or unsubstituted 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, 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 instances of R B1 are joined to form substituted or unsubstituted heterocyclyl;

wherein R C is substituted or unsubstituted alkyl, a nitrogen protecting group, or of the formula:

wherein Ring C is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

wherein each instance of R C1 is independently hydrogen, halogen, substituted or unsubstituted 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 C1a , —N(R C1a ) 2 , —SR C1a , —CN, —SCN, —C(═NR C1a )R C1a , —C(═NR C1a )OR C1a , —C(═NR C1a ) N(R C1a ) 2 , —C(═O)R C1a , —C(═O)OR C1a , —C(═O)N(R C1a ) 2 , —NO 2 , —NR C1a C(═O)R C1a , —NR C1a C(═O)OR C1a , —NR C1a C(═O)N(R C1a ) 2 , —OC(═O)R C1a , —OC(═O)OR C1a , —OC(═O)N(R C1a ) 2 , or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R C1 are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

wherein each instance of R C1a is independently hydrogen, substituted or unsubstituted 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, 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 instances of R C1a are joined to form substituted or unsubstituted heterocyclyl;

wherein a is 0, 1, 2, or 3;

wherein b is 0, 1, 2, 3, or 4; and

wherein c is 0, 1, 2, 3, 4, or 5.

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

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein at least one instance of R A is halogen or substituted or unsubstituted C 1-6 alkyl, —O—, —N(R A3 )—, C(═O)—N(R A3 )—, —S(═O)—N(R A3 )—, —S(═O) 2 —N(R A3 )—, —N(R A3 )—C(═O)—, —N(R A3 )—S(═O)—, or —N(R A3 )—S(═O) 2 —.

6. The method of claim 1 , wherein at least one instance of R A is of the formula:

wherein:

L A is a bond, —C(═O)—N(R A3 )—, —N(R A3 )—, —N(R A3 )—C(═O)—, —N(R A3 )—S(═O)—, —N(R A3 )—S(═O) 2 —, —N(R A3 )—C(═O)—N(R A3 )—, —N(R A3 )—S(═O)—N(R A3 )—, —N(R A3 )—S(═O) 2 —N(R A3 )—, —O—, —S—, —S(═O)—N(R A3 )—, —S(═O) 2 —N(R A3 )—;

L B is a bond, —C(═O)—, —S(═O)—, or —S(═O) 2 —;

Ring A is substituted or unsubstituted, 4- to 7-membered, monocyclic heterocyclyl, or substituted or unsubstituted, 7- to 10-membered, spiro bicyclic heterocyclyl, wherein one or two atoms in the heterocyclic ring are independently selected from the group consisting of oxygen and nitrogen;

each instance of R A2 is independently hydrogen, halogen, substituted or unsubstituted alkyl, —OR A2a , —N(R A2a ) 2 , Oxo, or a nitrogen protecting group when attached to a nitrogen atom;

each instance of R A2a is independently hydrogen, substituted or unsubstituted alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of R A2a are joined to form substituted or unsubstituted heterocyclyl;

R A3 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;

d is 0, 1, 2, 3, 4, or 5; and

e is 0, 1, 2, or 3.

7. The method of claim 6 , wherein L B is a bond, —C(═O)—, or —S(═O)— or —S(═O) 2 —.

8. The method of claim 6 , wherein Ring A is substituted or unsubstituted 4- to 7-membered, monocyclic heterocyclyl, wherein one or two atoms in the heterocyclic ring are independently oxygen or nitrogen.

9. The method of claim 6 , wherein Ring A is substituted or unsubstituted oxetanyl, substituted pyrrolidinyl or substituted piperidinyl, unsubstituted pyrrolidinyl or unsubstituted piperidinyl.

10. The method of claim 6 , wherein Ring A is of the formula

11. The method of claim 6 , wherein Ring A is substituted or unsubstituted, 7- to 10-membered, spiro bicyclic heterocyclyl, wherein two atoms in the heterocyclic ring are independently selected from the group consisting of oxygen and nitrogen.

12. The method of claim 6 , wherein at least one instance of R A2 is —N(R A2a ) 2 , oxo, or substituted or unsubstituted alkyl.

13. The method of claim 6 , wherein R A3 is hydrogen.

14. The method of claim 6 , wherein a is 0 or 1.

15. The method of claim 6 , wherein at least one instance of R B is halogen, substituted or unsubstituted C 1-6 alkyl, or —OR B1 .

16. The method of claim 6 , wherein two instances of R B are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

17. The method of claim 1 , wherein two instances of R B are joined to form substituted or unsubstituted phenyl.

18. The method of claim 6 , wherein two instances of R B are joined to form substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the ring of the heteroaryl is independently selected from the group consisting of nitrogen, oxygen, and sulfur.

19. The method of claim 6 , wherein b is 0, 1 or 2.

20. The method of claim 6 , wherein R C is substituted or unsubstituted C 1-6 alkyl, unsubstituted t-butyl, or of the formula:

21. The method of claim 20 , wherein Ring C is substituted or unsubstituted, 3-7 membered, monocyclic carbocyclyl, unsubstituted cyclopropyl, substituted or unsubstituted 6- to 14-membered aryl, substituted or unsubstituted phenyl.

22. The method of claim 20 , wherein Ring C is of the formula:

23. The method of claim 20 , wherein Ring C is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring is independently selected from the group consisting of nitrogen, oxygen, and sulfur, or substituted or unsubstituted, 8- or 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring is independently selected from the group consisting of nitrogen, oxygen, and sulfur.

24. The method of claim 1 , wherein R C is of the formula:

25. The method of claim 20 , wherein at least one instance of R C1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR C1a , or —N(R C1a ) 2 , or two instances of R C1 are joined to form substituted or unsubstituted heterocyclyl.

26. The method of claim 20 , wherein at least one instance of R C1 is hydrogen, halogen, or unsubstituted C 1-6 alkyl.

27. The method of claim 20 , wherein c is 0, 1, 2, or 3.

28. The method of claim 1 , wherein R D and R E are individually, or both, hydrogen.

29. The method of claim 2 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

30. The method of claim 1 , wherein the ocular disease is macular degeneration, glaucoma, diabetic retinopathy, retinoblastoma, edema, diabetic macular edema, retinal vein occlusion, or corneal neovascularization.

31. The method of claim 1 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered topically to the eye.