Urea derivatives and uses thereof
The present invention provides novel compounds of any one of Formulae (I)-(III), and pharmaceutical compositions thereof. Also provided are particles (e.g., nanoparticles) comprising compounds of Formula (I)-(III) and pharmaceutical compositions thereof that are mucus penetrating. The invention also provides methods and kits for using the inventive compounds, and pharmaceutical compositions thereof, for treating and/or preventing diseases associated with abnormal or pathological angiogenesis and/or aberrant signaling of a growth factor (e.g., vascular endothelial growth factor (VEGF)), such as proliferative diseases (e.g., cancers, benign neoplasms, inflammatory diseases, autoimmune diseases) and ocular diseases (e.g., macular degeneration, glaucoma, diabetic retinopathy, retinoblastoma, edema, uveitis, dry eye, blepharitis, and post-surgical inflammation) in a subject in need 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 C is CH, or N;
X D is CH, or 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 RA 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 RB 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;
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;
wherein if X C is CH, X D is N, Z is phenyl, R A , R B , R D , and R E are all H, and R C is of the formula:
Ring C is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, 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;
wherein the ocular disease is a macular degeneration, glaucoma, diabetic retinopathy, retinoblastoma, edema, diabetic macular edema, retinal vein occlusion, or corneal neovascularization.
2. The method of claim 1 , wherein Rina Z is:
3. The method of claim 1 , wherein Ring Z is:
4. The method of claim 1 , wherein Ring Z is:
5. The method of claim 1 , wherein Ring Z is:
6. The method of claim 1 , wherein Ring Z is:
7. The method of claim 1 , wherein X C is N.
8. The method of claim 1 , wherein X D is N.
9. The method of claim 1 , wherein a is 0 or 1.
10. The method of claim 1 , wherein a is 0.
11. The method of claim 1 , wherein R D is H or C 1-6 alkyl.
12. The method of claim 1 , wherein R D is H.
13. The method of claim 1 , wherein R E is H.
14. The method of claim 1 , wherein R C is optionally substituted phenyl.
15. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the macular degeneration is an age related macular degeneration.
20. The method of claim 1 , wherein the compound, pharmaceutically acceptable salt, or pharmaceutical composition containing the compound is administered topically to the eye.”