Aryl cyclopropyl-amino-isoquinolinyl amide compounds
Provided herein are arylcyclopropyl amino-isoquinoline amide compounds. In particular, the disclosure provides compounds that affect the function of kinases in a cell and that are useful as therapeutic agents or with therapeutic agents. The compounds of the disclosure are useful in the treatment of a variety of diseases and conditions including eye diseases such as glaucoma, cardiovascular diseases, diseases characterized by abnormal growth, such as cancers, and inflammatory diseases. The disclosure further provides compositions containing isoquinoline amide compounds.
1. A compound of Formula (X):
or a pharmaceutically acceptable salt thereof,
wherein,
R 1 is H, —C 1-6 alkyl, —C 1-6 haloalkyl, aryl, heteroaryl, —(C 1-6 alkyl)-pyridinyl, —(C 1-6 alkyl)-N(R 3 )R 4 , —(C 1-6 alkyl)-heterocyclyl or heterocycloalkyl;
R 2 is H, —C 1-6 alkyl, —C 1-6 haloalkyl, aryl, heteroaryl, —(C 1-6 alkyl)-pyridinyl, —(C 1-6 alkyl)-N(R 3 )R 4 , —(C 1-6 alkyl)-heterocyclyl or heterocycloalkyl;
or R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclyl;
R 3 is H, C 1-6 alkyl or —C 1-6 haloalkyl;
R 4 is H, C 1-6 alkyl or —C 1-6 haloalkyl;
X is H, C 1-6 alkyl, —C 1-6 haloalkyl, halogen or hydroxyl;
Y is H, C 1-6 alkyl, —C 1-6 haloalkyl, halogen or hydroxyl; and
Z is H, C 1-6 alkyl, —C 1-6 haloalkyl, halogen or hydroxyl.
2. The compound of claim 1 , wherein the compound of Formula (X) is:
a compound of Formula (XI):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XII):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XIII):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XIV):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XV):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XVI):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XVII):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XVIII):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XIX):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XX):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XXI):
or a pharmaceutically acceptable salt thereof;
a compound of Formula (XXII):
or a pharmaceutically acceptable salt thereof; or
a compound of Formula (XXIII):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 1 is H or —C 1-6 alkyl.
4. The compound of claim 1 , wherein R 2 is phenyl, pyridinyl, —(C 1-6 alkyl)-pyridinyl, —(C 1-6 alkyl)-N(R 3 )R 4 , —(C 1-6 alkyl)-heterocyclyl or heterocycloalkyl.
5. The compound of claim 1 , wherein R 2 is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.
6. The compound of claim 1 , wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclyl containing six ring atoms.
7. The compound of claim 1 , wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclyl containing six ring atoms, wherein one or two of the ring atoms are, independently, O, S or N.
8. The compound of claim 1 , wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclyl containing six ring atoms, wherein one or two of the ring atoms are N.
9. The compound of claim 1 , wherein R 3 and R 4 are H, or R 3 and R 4 are, independently, C 1-6 alkyl.
10. The compound of claim 1 , wherein:
X is C 1-6 alkyl, halogen or hydroxyl; and
Y and Z are H.
11. The compound of claim 1 , wherein X is C 1-6 alkyl, halogen or hydroxyl.
12. The compound of claim 1 , wherein X, Y, and Z are each, independently, methyl, ethyl, CF 3 , CHF 2 or CH 2 F.
13. The compound of claim 1 , wherein X is halogen.
14. The compound of claim 1 , wherein Z is H or F.
15. A compound, selected from:
or a pharmaceutically acceptable salt thereof.
16. A composition, comprising the compound of claim 1 .
17. A pharmaceutical composition, comprising the composition of claim 16 and a pharmaceutically acceptable carrier.
18. A method of treating an ocular disorder in a subject in need thereof, comprising administering to the subject the compound of claim 1 .
19. The method of claim 18 , 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.
20. A method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject the compound of claim 1 .
21. A method of modulating kinase activity in a cell, comprising contacting the cell with a compound of claim 1 .
22. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
23. A composition, comprising the compound of claim 15 .
24. A pharmaceutical composition, comprising the composition of claim 23 and a pharmaceutically acceptable carrier.
25. A method of treating an ocular disorder in a subject in need thereof, comprising administering to the subject the compound of claim 15 .
26. The method of claim 25 , 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.
27. A method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject the compound of claim 15 .
28. A method of modulating kinase activity in a cell, comprising contacting the cell with a compound of claim 15 .