Treatment of gvhd

Abstract

The invention relates to treatment of graft versus host disease (GVHD) using compounds that inhibit ROCK2. In preferred aspects, the present invention provides methods for the treatment of GVHD, including chronic GVHD (cGVHD) using compounds having the formulae I-XXV, as set forth herein.

We claim: 
     
         1 . A method of treating graft versus host disease (GVHD) in a subject, which comprises administering to the subject an effective amount of a rho kinase inhibitor, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the disease treated is chronic graft versus host disease (cGVHD). 
     
     
         3 . The method of  claim 1 , wherein the rho kinase inhibitor or pharmaceutically acceptable salt thereof, is ROCK2 selective. 
     
     
         4 . The method of  claim 1 , wherein the rho kinase inhibitor is a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is selected from N or C—R 1 ; 
 Y is selected from N or C—R 5 ; 
 Z is selected from N or C—R 3 ; 
 R 1  is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, and (lower alkyl)-O-(lower alkyl); 
 R 2  is a group having the formula -A-R 10 ; 
 A is selected from the group consisting of a covalent bond, aryl, heteroaryl, cycloalkyl, and heterocyclyl; 
 R 10  is selected from the group consisting of H, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, and -(M) x -(CH 2 ) y —R 11 ; 
 M is selected from the group consisting of N—R 20 , CR 21 R 22 , and C═O; 
 x is 0 or 1; 
 R 20  is selected from H and C 1-5  alkyl; 
 R 21  and R 22  are independently selected from the group consisting of H, halogen, and lower alkyl, or alternatively R 21  and R 22  may be taken together with the atom to which they are attached to form a C 3-6  cycloalkyl; 
 y is 0, 1, 2, 3, 4, 5, or 6; 
 R 1  is selected from the group consisting of H, C 1-6  alkyl, optionally substituted C 3-6  cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, wherein the optional substituents are selected from the group consisting of lower alkyl, C 1-6  cycloalkyl, oxo, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, and (lower alkyl)-O-(lower alkyl); 
 alternatively R 11  is selected from the group consisting of —NR 13 R 14 , —C(═O)NR 13 R 14 , and —C(═O)R 12 , and —CO 2 R 12 ; 
 R 12  is selected from the group consisting of C 1 -C 10  alkyl, aryl, heteroaryl, —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), aralkyl, 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, oxo, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, (C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), hydroxy, cyano and C 1 -C 3  perfluoro alkyl; 
 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), aryl, aralkyl, heteroaryl, C 3 -C 6  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, oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 7  cycloalkyl, C 1 -C 6  alkoxy, (C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), hydroxy, amino, cyano and C 1 -C 3  perfluoro alkyl; 
 or R 13  and R 14  may be taken together 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, (C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), oxo, hydroxy, cyano and C 1 -C 3  perfluoro alkyl; 
 R 3  is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, and (lower alkyl)-O-(lower alkyl); 
 R 5  is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, and (lower alkyl)-O-(lower alkyl); 
 R 6  is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, and (lower alkyl)-O-(lower alkyl); 
 R 7  is selected from the group consisting of H and lower alkyl; and 
 R 8  is a nitrogen-containing heterocyclic ring system ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy. 
 
     
     
         5 . The method of  claim 1 , wherein the rho kinase inhibitor is a compound of Formula XXVI: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from the group consisting of H or C 1 -C 6  alkyl; 
         R 2  is selected from the group consisting of aryl, 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 from 1 to 3 substituents independently selected from halo and C 1 -C 6  alkyl;
 X is selected from N or CR 3 ; 
 Y is selected from N or CR 3 ; 
 Z is selected from N or CR 4 ; 
 W is selected from CR 5 ; 
 wherein X, Y, and Z are independently selected and at least one of which is N; 
 
         wherein each R 3  is 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), —NR 31 R 32 , and —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl);
 R 31  and R 32  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); 
 
         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;
 a is selected from 0 to 2; 
 b is selected from 0 to 2; 
 wherein a or b are independently selected and one of which is at least 1 
 
         A is 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, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  alkoxy, C 3 -C 7  cycloalkyl, oxo, acyl, —S—(C 1 -C 6  alkyl), OH, NH 2 , CN and C 1 -C 3  perfluroalkyl. 
       
     
     
         6 . The method of  claim 1 , wherein the rho kinase inhibitor is a compound of Formula XXXI: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from the group consisting of —O—(CH 2 ) y —CO 2 R 12 , —O—(CH 2 ) y —C(═O)NR 13 R 14 , —O—(CH 2 ) y -heteroaryl, —O—(CH 2 ) y -cycloalkyl, —O—C(═O)—(CH 2 ) y —NR 13 R 14 , —O—(CH 2 ) z —NR 13 R 14 , —NH—C(═O)—(CH 2 ) y —NR 13 R 14 , —NH—C(═O)—X—R 15 , —NH—(CH 2 ) y —NR 13 R 14 ; 
         R 12  is selected from the group consisting of C 1 -C 6  alkyl, —(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 , —(C 1 -C 6  alkyl)-O—(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 at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C 1 -C 6  alkoxy, hydroxy, amino, cyano and C 1 -C 3  perfluoro alkyl;
 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 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, OH, NH 2 , CN and C 1 -C 3  perfluoro alkyl; 
 X is selected from a covalent bond, O, NH, and C 1 -C 6  alkyl; 
 R 15  is selected from the group consisting of 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, OH, NH 2 , CN and C 1 -C 3  perfluoro alkyl; 
 or R 15  is selected from —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —(C 1 -C 6  alkyl)-NR 16 R 17 , —CO 2 R 18 , —O—(CH 2 ) x —CO 2 R 18 , and —C(═O)NR 16 R 17 ;
 R 16  and R 17  independently selected from the group consisting of H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 1 -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, OH, NH 2 , CN and C 1 -C 3  perfluoro alkyl; 
 or R 16  and R 17  may be taken together 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 18  is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6  alkyl, —(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)-O—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6  alkoxy, hydroxy, amino, cyano and C 1 -C 3  perfluoroalkyl; 
 
 x is selected from 0 to 6; 
 y is selected from 0 to 6; 
 z is selected from 2 to 6; 
 
         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; 
         R 4  is selected from —(CH 2 ) a —NR 43 R 44 , —Y—R 42 , —O—(CH 2 ) a —CO 2 R 42 , —O—(CH 2 ) a —C(═O)NR 43 R 44 , O—(CH 2 ) a -heteroaryl, —O—(CH 2 ) a -cycloalkyl, —O—C(═O)—(CH 2 ) a —NR 43 R 44 , —O—(CH 2 ) c —NR 43 R 44 , —NH—C(═O)—(CH 2 ) a —NR 43 R 44 , —NH—C(═O)—Y—R 45 , —NH—C(═O)—(CH 2 ) a —NR 43 R 44 ;
 R 42  is selected from the group consisting of C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —(C 1 -C 6  alkyl)-NR 46 R 47 , —(C 1 -C 6  alkyl)-C(═O)NR 46 R 47 , —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C 1 -C 6  alkoxy, hydroxy, amino, cyano and C 1 -C 3  perfluoro alkyl; 
 R 43  and R 44  are independently selected from the group consisting of H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 1 -C 8  alkynyl, —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —(C 1 -C 6  alkyl)-NR 46 R 47 , —(C 1 -C 6  alkyl)-C(═O)NR 46 R 47 , 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 43  and R 44  may be taken together 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; 
 Y is selected from a covalent bond, O, NH, and C 1 -C 6  alkyl; 
 R 45  is selected from the group consisting of H, aryl, —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —(C 1 -C 6  alkyl)-NR 46 R 47 , —CO 2 R 48 , —O—(CH 2 ) b —CO 2 R 48 , and —C(═O)NR 46 R 47 ,
 R 46  and R 47  independently selected from the group consisting of H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 1 -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 46  and R 47  may be taken together 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 48  is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —(C 1 -C 6  alkyl)-NR 46 R 47 , —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6  alkoxy, hydroxy, amino, cyano and C 1 -C 3  perfluoroalkyl; 
 
 a is selected from 0 to 6; 
 b is selected from 0 to 6; 
 c is selected from 2 to 6; 
 
         R 5  is selected from the group consisting of H, C 1 -C 6  alkyl, —(CH 2 ) d —C(═O)—NR 53 R 54 , —C(═O)—(CH 2 ) d —NR 53 R 54 , —C(═O)—X—R 55 , and —C(═O)—(CH 2 ) d —NR 53 R 54 ;
 R 53  and R 54  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 56 R 57 , —(C 1 -C 6  alkyl)-C(═O)NR 56 R 57 , 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 53  and R 54  may be taken together 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; 
 R 55  is selected from the group consisting of H, aryl, —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —(C 1 -C 6  alkyl)-NR 56 R 17 , —CO 2 R 8 , —O—(CH 2 ) e —CO 2 R 8 , and —C(═O)NR 56 R 17 ,
 R 56  and R 57  independently selected from the group consisting of H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 1 -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 56  and R 57  may be taken together 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 58  is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —(C 1 -C 6  alkyl)-NR 56 R 17 , —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6  alkoxy, hydroxy, amino, cyano and C 1 -C 3  perfluoroalkyl; 
 d is selected from 0 to 6; 
 e is selected from 0 to 6; 
 
 
         R 6  is selected from the group consisting of H, C 1 -C 6  alkyl, —(CH 2 ) r —C(═O)—NR 63 R 64 , —C(═O)—(CH 2 ) r —NR 63 R 64 , —C(═O)—X—R 65 , and —C(═O)—(CH 2 ) r —NR 63 R 64 ;
 R 63  and R 64  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 66 R 67 , —(C 1 -C 6  alkyl)-C(═O)NR 66 R 67 , 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 63  and R 64  may be taken together 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; 
 R 65  is selected from the group consisting of H, aryl, —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —(C 1 -C 6  alkyl)-NR 66 R 67 , —CO 2 R 68 , —O—(CH 2 ) s —CO 2 R 68 , and —C(═O)NR 66 R 67 ,
 R 66  and R 67  independently selected from the group consisting of H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 1 -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 66  and R 67  may be taken together 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 68  is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —(C 1 -C 6  alkyl)-NR 66 R 67 , —(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6  alkoxy, hydroxy, amino, cyano and C 1 -C 3  perfluoroalkyl; 
 r is selected from 0 to 6; 
 s is selected from 0 to 6; 
 
 
         n is selected from 0 to 4; 
         m is selected from 0 to 3; and 
         p is selected from 0 and 1. 
       
     
     
         7 . The method of  claim 1 , wherein the rho kinase inhibitor is a compound of Formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The method of  claim 1 , wherein the rho kinase inhibitor is administered to the subject with a second agent.