Rho kinase inhibitors
View Patent ↗The invention provides novel inhibitors of ROCK1 and/or ROCK2. Also provided are methods of treating diseases and disorders involving inhibiting ROCK1 and/or ROCK2. The present invention includes pharmaceutical compositions comprising the compounds of the invention and a pharmaceutically acceptable carrier and/or diluents. The present invention includes compositions comprising a substantially pure compound of the invention and a pharmaceutically acceptable salt, steroisomer, or hydrate thereof: and a pharmaceutically acceptable excipient and/or diluents.
1. A compound having the formula II:
wherein
R 2 is selected from the group consisting of indazol-5-yl, cyclohexylpyridine, phenylpyridine, 4-(1H-pyrazol-4-yl)phenyl, 1H-pyrrolo[2,3-b]pyridine, pyridine, isoquinoline, quinoline, and 1,3-thiazolyl pyridine;
R 4 and R 5 are independently selected from the group consisting of H, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 6 alkoxy, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 41 R 42 , —(CH 2 ) x NR 41 R 42 and —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
R 41 and R 42 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 41 and R 42 may be taken together to form a three to twelve membered cycloalkyl or heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
x is selected from 0 to 6;
or R 4 and R 5 may be taken together to form a three to twelve membered heterocyclic or aromatic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
each R 6 is independently selected from the group consisting of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, oxo, acyl, —S—(C 1 -C 6 alkyl), OH, NH 2 , CN and C 1 -C 3 perfluroalkyl; and
d is selected from 0 to 3.
2. The compound of claim 1 , having the formula III:
R 4 and R 5 are independently selected from the group consisting of H, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 6 alkoxy, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 41 R 42 , —(CH 2 ) x NR 41 R 42 and —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl;
R 41 and R 42 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 41 and R 42 may be taken together to form a three to twelve membered cycloalkyl or heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
x is selected from 0 to 6;
or R 4 and R 5 may be taken together to form a three to twelve membered heterocyclic or aromatic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
each R 6 is independently selected from the group consisting of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, oxo, acyl, —S—(C 1 -C 6 alkyl), OH, NH 2 , CN and C 1 -C 3 perfluroalkyl; and
d is selected from 0 to 3.
3. The compound of claim 1 , wherein R 2 is selected from:
4. The compound of claim 1 , wherein R 4 and R 5 are taken together to form a five-membered ring.
5. The compound of claim 1 , having the chemical name:
N-(2-(5-Methoxyisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine,
N-(2-(Isoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine,
N-(5-Fluoro-2-(5-methoxyisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine,
N-(5-Chloro-2-(5-methoxyisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine,
N-(2-(5-Methoxyisoindolin-2-yl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine,
N-(2-(5-Methoxyisoindolin-2-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine,
N-(2-(5-Fluoroisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine,
N-(2-(5-Chloroisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine,
N-(2-(5-(Methoxymethyl)isoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine, or
N-(2-(4-Methoxyisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine.
6. The compound of claim 1 , having the chemical name:
N-(2-(5-Methoxyisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine.
7. The compound of claim 1 , having the chemical name:
N-(4-(1H-pyrazol-4-yl)phenyl)-2-(5-methoxyisoindolin-2-yl)pyrimidin-4-amine, or
2-(5-Methoxyisoindolin-2-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine.
8. The compound of claim 1 , having the chemical name:
N-(6-(5-Methoxyisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine, or
N-(6-(5-Methoxyisoindolin-2-yl)-2-methylpyrimidin-4-yl)-1H-indazol-5-amine.