Rho kinase inhibitors
The invention relates to inhibitors of ROCK1 and/or ROCK2. Also provided are methods of treating diseases and disorders involving inhibiting ROCK1 and/or ROCK2.
1. A method for the treatment of graft-versus-host disease (GVHD) in a human subject by orally administering a therapeutically effective amount of a compound of the formula XXXI:
or a pharmaceutically acceptable salt thereof, wherein:
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 16 R 17 , —(C 1 -C 6 alkyl)-C(═O)NR 16 R 17 , aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
X is selected from a covalent bond, 0, NH, and C 1 -C 6 alkyl;
R 16 and R 17 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 16 and R 17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
n is selected from 0 to 4; and
m is selected from 0 to 3.
2. The method according to claim 1 , wherein the compound has formula XXXIV a :
or a pharmaceutically acceptable salt thereof, wherein:
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C(═O)NR 16 R 17 , aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
R 16 and R 17 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 16 and R 17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl.
3. The method according to claim 1 , wherein the compound has of the formula:
or a pharmaceutically acceptable salt thereof.