Method for treating diseases associated with alterations in cellular integrity using Rho kinase inhibitor compounds

1. A method of treating diabetic nephropathy; the method comprises the steps of first identifying a subject suffering from diabetic nephropathy, then administering to the subject an effective amount of a compound of Formula II to treat diabetic nephropathy;

wherein:

Q is (CR 4 R 5 ) n3 ;

n 1 is 1;

n 2 is 1;

n 3 is 1, 2, or 3;

R 2 is R 2 -2:

Ar is a monocyclic aryl or bicyclic aryl;

X is from 1 to 3 substituents on Ar, and each is independently selected from the group consisting of OR 8 , NR 8 R 9 , SR 8 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , CONR 8 R 9 , NR 8 C(═O)R 9 , NR 8 C(═O)OR 9 , OC(═O)NR 8 R 9 , and NR 8 C(═O)NR 9 R 10 ;

R 3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl, optionally substituted;

R 4 and R 5 are H;

R 8 -R 10 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle; optionally substituted by one or more halogen or heteroatom-containing substituents selected from the group consisting of OR 11 , NR 11 R 12 , NO 2 , SR 11 , SOR 11 , SO 2 R 11 , SO 2 NR 11 R 12 , NR 11 SO 2 R 12 , OCF 3 , CONR 11 R 12 , NR 11 C(═O)R 12 , NR 11 C(═O)OR 12 , OC(═O)NR 11 R 12 , and NR 11 C(═O)NR 12 R 13 ;

R 11 -R 13 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle;

with the proviso that if X is acyclic and is connected to Ar by an oxygen or nitrogen atom, then X contains at least one additional oxygen, nitrogen or sulfur atom.

2. The method according to claim 1 , wherein Ar is 3-substituted phenyl; 4-substituted phenyl; 3,4-disubstituted phenyl; or 2,3-disubstituted phenyl.

3. The method according to claim 1 , wherein said compound is Compound 2.026, which is (R)—N-(1-(4-(methylthio)benzyl)pyrrolidin-3-yl)isoquinolin-5-amine; Compound 2.038, which is (R)—N-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide; Compound 2.039, which is (R)-2-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol; Compound 2.040, which is (R)-2-(3-(3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)acetamide; Compound 2.041, which is (R)—N-(3(3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)ethanesulfonamide; or Compound 2.044, which is (R)-2-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)acetic acid.

4. The method of claim 1 , wherein Ar is phenyl.

5. The method of claim 1 , wherein Q is CH 2 .

6. The method of claim 4 , wherein X is OR 8 , or NR 8 SO 2 R 9 .

7. The method of claim 6 , wherein R 8 is H, alkyl, arylalkyl, cycloalkylalkyl, optionally substituted with OR 11 , NR 11 SO 2 R 12 , or CONR 11 R 12 .

8. A method of treating diabetic nephropathy; the method comprises the steps of first identifying a subject suffering from diabetic nephropathy, then administering to the subject an effective amount of

Compound 2.038, which is (R)—N-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide, to treat diabetic nephropathy.

9. The method of claim 1 , wherein said compound is Compound 2.039, which is (R)-2-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol.