Aryl cyclopropyl-amino-isoquinolinyl amide compounds
Provided herein are amino isoquinolinyl amide and sulfonamide compounds that affect the function of kinases and other proteins in a cell and that are useful as therapeutic agents. In particular, these compounds are useful in the treatment of eye diseases such as glaucoma and retinal diseases, as anti-inflammatory agents, for the treatment of cardiovascular diseases, and for diseases characterized by abnormal growth, such as cancers.
1. A method of treating an ocular disorder 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
R 1 is H, halo, —CN, —C 1-6 alkyl, —C 1-6 alkoxyl, —C 1-6 haloalkyl, —C 1-6 haloalkoxyl;
R 2 is H or halo;
X is —(C 1-5 heteroaryl)-R 3 ; and
R 3 is —C 2-6 heterocyclyl, or —C 1-6 heteroalkyl.
2. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (II):
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (III):
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein R 1 is H, halo, —CN, —C 1-3 alkyl, —C 1-3 alkoxyl, —C 1-3 haloalkyl, —C 1-3 haloalkoxyl.
5. The method of claim 1 , wherein R 1 is H, Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CF 3 , or —OCF 3 .
6. The method of claim 1 , wherein R 1 is Cl, —ON, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CF 3 , or —OCF 3 .
7. The method of claim 1 , wherein R 2 is F, Cl, Br, or I.
8. The method of claim 1 , wherein R 2 is H or F.
9. The method of claim 1 , wherein X is —(—C 3-5 heteroaryl)-R 3 .
10. The method of claim 1 , wherein X is
11. The method of claim 1 , wherein R 3 is —C 2-6 heterocyclyl.
12. The method of claim 1 , wherein R 3 is —C 3-5 heterocycloalkyl or —C 1-4 heteroalkyl.
13. The method of claim 1 , wherein R 3 is
14. The method of claim 1 , wherein
R 1 is H, Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , or —OCF 3 ;
R 2 is H or F;
X is
R 3 is
15. The method of claim 1 , wherein
R 1 is Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CF 3 , or —OCF 3 ;
R 2 is H or F;
X is
and
R 3 is
16. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the ocular disorder is glaucoma, an inflammatory eye disease, a neurodegenerative eye disease, diabetic eye disease, wet age-related macular degeneration, or dry age-related macular degeneration.
18. The method of claim 1 , wherein the compound is administered topically to an eye of the subject.
19. The method of claim 1 , wherein the compound is administered topically to an eyelid of the subject.
20. A method of reducing intraocular pressure 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
R 1 is H, halo, —CN, —C 1-6 alkyl, —C 1-6 alkoxyl, —C 1-6 haloalkyl, —C 1-6 haloalkoxyl;
R 2 is H or halo;
X is —(C 1-5 heteroaryl)-R 3 ; and
R 3 is —C 2-6 heterocyclyl, or —C 1-6 heteroalkyl.
21. The method of claim 20 , wherein the compound is administered topically to an eye of the subject.
22. The method of claim 20 , wherein the compound is administered topically to an eyelid of the subject.
23. The method of claim 20 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
24. A method of modulating kinase activity in a cell, comprising contacting the cell with an effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein
R 1 is H, halo, —CN, —C 1-6 alkyl, —C 1-6 alkoxyl, —C 1-6 haloalkyl, —C 1-6 haloalkoxyl;
R 2 is H or halo;
X is —(C 1-5 heteroaryl)-R 3 ; and
R 3 is —C 2-6 heterocyclyl, or —C 1-6 heteroalkyl.
25. The method of claim 24 , wherein the cell is in a subject.
26. The method of claim 24 , wherein the cell is in a human subject.
27. The method of claim 24 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.