Indazolyl thiadiazolamines and related compounds for inhibition of Rho-associated protein kinase and the treatment of disease

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing; wherein:

R 1 and R 4 each represent independently for each occurrence hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyclopropyl, C 2 -C 4 alkenyl, or cyano;

R 2 and R 3 each represent independently for each occurrence hydrogen, C 1 -C 3 alkyl, cyclopropyl, or cyano;

R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, or —CO 2 R 12 ;

R 6 and R 7 each represent independently for each occurrence hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, or C 3 -C 6 cycloalkyl; or R 6 and R 7 when attached to the same nitrogen atom may be taken together with the nitrogen atom to form a 3-7 membered ring optionally substituted with 1 or 2 R 12 ;

R 8 and R 9 each represent independently for each occurrence hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), or —(C 1 -C 6 alkylene)-N(R 6 )(R 7 ); or R 8 and R 9 when attached to the same nitrogen atom may be taken together with the nitrogen atom to form a 3-7 membered ring optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxyl, cyano, hydroxyl, —CO 2 R 6 , —C(O)N(R 6 )(R 7 ), —N(R 6 )C(O)R 6 , —N(R 6 ) 2 , and —(C 1 -C 6 alkylene)-CO 2 R 6 ;

R 10 represents independently for each occurrence C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 8 )(R 9 ), —(C 1 -C 6 alkylene)-CO 2 R 6 , —(C 1 -C 6 alkylene)-(3-7 membered heterocycloalkyl), or 3-7 membered heterocycloalkyl; wherein said cycloalkyl is optionally substituted by 1 or 2 C 1 -C 6 alkyl;

R 11 represents independently for each occurrence a 5-6 membered heteroaryl or 3-7 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 occurrences of Y 1 ;

R 12 represents independently for each occurrence C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;

A 1 is a cyclic group selected from:

or dihydropyridinyl, each being optionally substituted by X 1 and 0, 1, 2, or 3 occurrences of Y 1 ;

(iii) a heteroaryl selected from the group consisting a 8-10 membered bicyclic heteroaryl, a 5-membered heteroaryl, and a 6-membered heteroaryl containing at least two ring nitrogen atoms; wherein said heteroaryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of X 1 , Y 1 , —(C 1 -C 6 alkylene)-CO 2 R 8 , —N(R 6 )(R 7 ), —O-(3-7 membered heterocyclyl), a 3-7 membered heterocycloalkyl, and C 6 aryl;

(iv) a 3-7 membered heterocycloalkyl, C 3 -C 7 cycloalkyl, or 8-10 membered bicyclic partially unsaturated heterocyclyl, each optionally substituted by oxo, C 6 aryl, X 1 , and 0, 1, 2, or 3 occurrences of Y 1 ; or

(v) aralkyl or heteroaralkyl, each being optionally substituted by a C 6 aryl, X 1 , and 0, 1, 2, or 3 occurrences of Y 1 ;

X 1 represents independently for each occurrence:

—N(R 6 )C(O)-(3-7 membered heterocyclyl), —N(R 6 )C(O)-phenyl, —N(R 6 )C(O)-aralkyl, or —N(R 6 )C(O)-heteroaralkyl; each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of Y 1 and —N(R 8 )(R 9 );

—CO 2 R 8 , —C(O)N(R 8 )(R 9 ), —C(O)R 11 , —C(O)R 12 , —C(O)-(3-7 membered heterocyclyl), —C(O)N(R 8 )(R 10 ), —N(R 6 )C(O)R 10 , —N(R 10 )C(O)R 10 , —N(R 6 )CO 2 R 10 , —N(R 8 )SO 2 R 10 , —N(R 6 )—(C 1 -C 6 alkylene)-C(O)N(R 8 )(R 9 ), —N(R 6 )—C(O)—(C 1 -C 6 hydroxyalkylene)-N(R 8 )(R 9 ), —N(R 6 )—C(O)-(2-6 membered heteroalkyl), —N(R 6 )C(O)N(R 6 )(R 7 ), or —NO 2 ;

—O—(C 1 -C 6 alkylene)-CO 2 R 8 , —OC(O)R 12 , —O—(C 1 -C 6 alkylene)-C(O)N(R 8 )(R 9 ), —O—(C 1 -C 6 alkylene)-N(R 8 )(R 9 ), —O—(C 1 -C 6 alkyl), —O-(3-7 membered heterocyclyl), —O—(C 1 -C 6 alkylene)-aryl, or —O—(C 1 -C 6 alkylene)-heteroaryl;

—SO 2 R 10 , —SO 2 N(R 8 )-heteroaryl, cyano, or —P(O)(OR 8 ) 2 ;

5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, 3-7 membered oxo-heterocycloalkyl, or 8-10 membered bicyclic heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of phenyl, and —N(R 6 )(R 7 ); or

—(C 2 -C 6 alkylene)-aryl, —(C 2 -C 6 alkylene)-heterocyclyl, or —(C 1 -C 6 alkylene)-COR 12 ;

Y 1 represents independently for each occurrence halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxyl, C 2 -C 6 alkenyl, cyano, hydroxyl, —CO 2 R 8 , —C(O)N(R 8 )(R 9 ), —N(R 6 )C(O)R 10 , —N(R 6 )C(O)N(R 6 )(R 7 ), —(C 1 -C 6 alkylene)-CO 2 R 8 , —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )(R 7 ), —(C 1 -C 6 alkylene)-N(R 6 )S(O) 2 R 12 , —(C 1 -C 6 alkylene)-S—C(O)R 12 , —S—R 12 , or 3-7 membered heterocycloalkyl; and

m is 0, 1, 2, or 3.

2. The compound of claim 1 , wherein the compound is a compound of Formula I or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein R 1 , R 2 , and R 3 are independently hydrogen.

4. The compound of claim 2 , wherein R 4 is chloro; and R 5 is hydrogen.

5. The compound of claim 4 , wherein R 6 and R 7 are independently hydrogen or C 1 -C 6 alkyl; and R 8 and R 9 each represent independently for each occurrence hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, or C 3 -C 6 cycloalkyl.

6. The compound of claim 2 , wherein A 1 is

7. The compound of claim 2 , wherein A 1 is

or A 1 is

8. The compound of claim 2 , wherein X 1 is —N(R 6 )C(O)-(3-7 membered heterocyclyl) optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of Y 1 and —N(R 8 )(R 9 ).

9. The compound of claim 2 , wherein X 1 is —N(R 6 )C(O)R 10 , —N(R 10 )C(O)R 10 , —N(R 6 )CO 2 R 10 , or —N(R 8 )SO 2 R 10 .

10. The compound of claim 6 , wherein X 1 is —N(R 6 )CO 2 R 10 .

11. The compound of claim 2 , wherein X 1 is a 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of Y 1 and phenyl.

12. The compound of claim 2 , wherein Y 1 represents independently for each occurrence halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —CO 2 R 8 , hydroxyl, or —(C 1 -C 6 alkylene)-N(R 6 )(R 7 ).

13. The compound of claim 1 , wherein the compound is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing; wherein:

R 1 , R 2 , R 3 , and R 5 are hydrogen;

R 4 is chloro or fluoro;

R 6 and R 7 each represent independently for each occurrence hydrogen or C 1 -C 3 alkyl;

R 8 and R 9 each represent independently for each occurrence hydrogen or C 1 -C 3 alkyl; or R 8 and R 9 when attached to the same nitrogen atom may be taken together with the nitrogen atom to form a 3-7 membered ring optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —CO 2 R 6 , —N(R 6 ) 2 , and hydroxyl;

R 10 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 hydroxyalkyl;

A 1 is a cyclic group selected from:

substituted by X 1 and 0, 1, 2, or 3 occurrences of Y 1 ; or

(iii) a heteroaryl selected from the group consisting of a 8-10 membered bicyclic heteroaryl, a 5-membered heteroaryl, and a 6-membered heteroaryl containing at least two ring nitrogen atoms; wherein said heteroaryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of X 1 , Y 1 , —(C 1 -C 6 alkylene)-CO 2 R 8 , —N(R 6 )(R 7 ), —O-(3-7 membered heterocyclyl), a 3-7 membered heterocycloalkyl, and C 6 aryl;

X 1 represents independently for each occurrence:

—N(R 6 )C(O)-(3-7 membered heterocyclyl) or —N(R 6 )C(O)-phenyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of Y 1 and —N(R 8 )(R 9 );

—CO 2 R 8 , —C(O)N(R 8 )(R 9 ), —N(R 6 )C(O)R 10 , —N(R 10 )C(O)R 10 , —N(R 6 )CO 2 R 10 , or —N(R 8 )SO 2 R 10 ;

—O—(C 1 -C 6 alkylene)-CO 2 R 8 , —O—(C 1 -C 6 alkylene)-C(O)N(R 8 )(R 9 ), —O—(C 1 -C 6 alkylene)-N(R 8 )(R 9 ), or —O—(C 1 -C 6 alkyl); or

5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, 3-7 membered oxo-heterocycloalkyl, or 8-10 membered bicyclic heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of Y 1 , phenyl, and —N(R 6 )(R 7 );

Y 1 represents independently for each occurrence halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —CO 2 R 8 , hydroxyl, or —(C 1 -C 6 alkylene)-N(R 6 )(R 7 ); and

m is 0, 1, 2, or 3.

14. The compound of claim 13 , wherein the compound is a compound of Formula I-A or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 , wherein R 4 is chloro.

16. The compound of claim 15 , wherein R 6 and R 7 are independently hydrogen or methyl; and R 8 and R 9 each represent independently for each occurrence hydrogen or C 1 -C 3 alkyl.

17. The compound of claim 14 , wherein A 1 is

18. The compound of claim 16 , wherein A 1 is

19. The compound of claim 14 , wherein A 1 is

20. The compound of claim 14 , wherein A 1 is

substituted by X 1 and 0, 1, 2, or 3 occurrences of Y 1 .

21. The compound of claim 17 , wherein X 1 is —N(R 6 )C(O)-(3-7 membered heterocyclyl) optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of Y 1 and —N(R 8 )(R 9 ).

22. The compound of claim 14 , wherein X 1 is —N(R 6 )C(O)R 10 , —N(R 10 )C(O)R 10 , —N(R 6 )CO 2 R 10 , or —N(R 8 )SO 2 R 10 .

23. The compound of claim 17 , wherein X 1 is —N(R 6 )CO 2 R 10 .

24. The compound of claim 17 , wherein X 1 is a 5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, 3-7 membered oxo-heterocycloalkyl, or 8-10 membered bicyclic heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of Y 1 , phenyl, and —N(R 6 )(R 7 ).

25. The compound of claim 14 , wherein m is 0.

26. A compound represented by Formula II-1:

or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing; wherein:

R 1 and R 4 each represent independently for each occurrence hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyclopropyl, or cyano;

R 2 is hydrogen, C 1 -C 3 alkyl, cyclopropyl, or cyano;

R 5 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 hydroxyalkyl;

R 6 and R 7 each represent independently for each occurrence hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; or R 6 and R 7 when attached to the same nitrogen atom may be taken together with the nitrogen atom to form a 3-7 membered ring;

R 8 and R 9 each represent independently for each occurrence hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, or —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl); or R 8 and R 9 when attached to the same nitrogen atom may be taken together with the nitrogen atom to form a 3-7 membered ring optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxyl, cyano, hydroxyl, —CO 2 R 6 , —C(O)N(R 6 )(R 7 ), —N(R 6 )C(O)R 6 , —N(R 6 ) 2 , and —(C 1 -C 6 alkylene)-CO 2 R 6 ;

R 10 represents independently for each occurrence C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxyalkyl, or —(C 1 -C 6 alkylene)-N(R 8 )(R 9 );

R 11 represents independently for each occurrence a 5-6 membered heteroaryl or 3-7 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 occurrences of Y 1 ;

A 1 is a cyclic group selected from:

(i)

(ii) a heteroaryl selected from the group consisting a 8-10 membered bicyclic heteroaryl, a 5-membered heteroaryl, and a 6-membered heteroaryl containing at least two, ring nitrogen atoms; wherein said heteroaryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of X 1 , Y 1 , —(C 1 -C 6 alkylene)-CO 2 R 8 , —N(R 6 )(R 7 ), —O-(3-7 membered heterocyclyl), and a 3-7 membered heterocycloalkyl; or

(iii) a 3-7 membered heterocycloalkyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of X 1 and Y 1 ;

X 1 represents independently for each occurrence:

—N(R 6 )C(O)-(3-7 membered heterocyclyl), —N(R 6 )C(O)-phenyl, —N(R 6 )C(O)-aralkyl, or —N(R 6 )C(O)-heteroaralkyl; each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of Y 1 and —N(R 8 )(R 9 );

—CO 2 R 8 , —C(O)N(R 8 )(R 9 ), —C(O)R 11 , —C(O)-(3-7 membered heterocyclyl), —C(O)N(R 8 )(R 10 ), —N(R 6 )C(O)R 10 , —N(R 6 )CO 2 R 10 , —N(R 8 )SO 2 R 10 , —N(R 6 )—(C 1 -C 6 alkylene)-C(O)N(R 8 )(R 9 ), —N(R 6 )—C(O)—(C 1 -C 6 hydroxyalkylene)-N(R 8 )(R 9 ), —N(R 6 )—C(O)-(2-6 membered heteroalkyl), or —NO 2 ;

—O—(C 1 -C 6 alkylene)-CO 2 R 8 , —O—(C 1 -C 6 alkylene)-C(O)N(R 8 )(R 9 ), —O—(C 1 -C 6 alkylene)-N(R 8 )(R 9 ), —O—(C 1 -C 6 alkyl), —O-(3-7 membered heterocyclyl), —O—(C 1 -C 6 alkylene)-aryl, or —O—(C 1 -C 6 alkylene)-heteroaryl;

—SO 2 R 10 , —SO 2 N(R 8 )-heteroaryl, or —P(O)(OR 8 ) 2 ;

5-membered heteroaryl optionally substituted with 1, 2, or 3 occurrences of Y 1 ; or

—(C 2 -C 6 alkylene)-aryl or —(C 2 -C 6 alkylene)-heteroaryl;

Y 1 represents independently for each occurrence halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxyl, cyano, hydroxyl, —CO 2 R 8 , —C(O)N(R 8 )(R 9 ), —N(R 6 )C(O)R 10 , —(C 1 -C 6 alkylene)-CO 2 R 8 , or —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl); and

m is 0, 1, 2, or 3.

27. A compound in any one of the following tables, wherein the compound is in solvated form, non-solvated form, or a pharmaceutically acceptable salt of any of the foregoing:

TABLE 1

No.

Compound

I-1 

I-2 

I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

TABLE 2

Compound

TABLE 3

Ex-

ample

No.

Chemical Structure

35A

35B

35C

35D

35E

35F

35G

35H

35I

35J

35K

35L

35M

35N

35O

35P

35Q

35R

35S

35T

35U

35V

35W

35X

35Y

35Z

35AA

35AB

35AC

35AD

35AE

35AF

35AG

35AH

35AI

35AJ

35AK

35AL

35AM

35AN

35AO

35AP

35AQ

35AR

35AS

35AU

35AV

35AW

35AX

35AY

35AZ

35BA

35BB

35BC

35BD

35BE

35BF

35BG

35BH

35BI

35BJ

35BK

35BL

35BM

35BN

35BO

35BP

35BQ

35BR

35BS

35BT

35BU

35BV

35BW

35BX

35BY

35BZ

35CA

35CB

35CC

35CD

35CE

35CF

35CG

35CH

35CI

35CJ

35CK

35CL

35CM

35CN

35CO

35CP

35CQ

35CR

35CS

35CT

35CU

35CV

TABLE 4

Example No.

Chemical Structure

39A

39B

39C

39D

39E

TABLE 5

Example No.

Chemical Structure

41A

41B

41C

41D

TABLE 6

Example No.

Chemical Structure

45A

TABLE 7

Example

No.

Chemical Structure

46A

46B

46C

46D

46E

46F

46G

46H

46I

46J

46K

46L

46M

46N

46O

46P

TABLE 8

Example

No.

Chemical Structure

48A

48B

48C

48D

48E

48F

48G

48H

48I

48J

48K

48L

48M

48N

48O

48P

48Q

48R

48S

48T

48U

48V

48W

48X

48Y

48Z

48AA

48AB

48AC

48AD

48AE

48AF

48AG

TABLE 9

Example No.

Chemical Structure

50A

50B*

50C

50D

50E

50F

50G

50H

TABLE 10

Example No.

Chemical Structure

52A

52B

52C

52D

52E

52F

52G

TABLE 11

Example No.

Chemical Structure

54A

54B

54C

54D

54E

TABLE 12

Example No.

Chemical Structure

56A

56B

56C

56D

56E

56F

56G

56H

TABLE 13

Example

No.

Chemical Structure

58A

58B

TABLE 13A

Example

No.

Chemical Structure

61A

61B

61C

61D

61E

61F

61G

61H

61I

61J

61K

TABLE 14

Example No.

Chemical Structure

71A

71B

71C

71D

71E

71F

71G

71H

71I

71J

71K

71L

71M

71N

71O

71P

71Q

TABLE 15

Example No.

Chemical Structure

75A

75B

75C

75D

75E

75F

75G

75H

75I

75J

75K

75L

75M

75N

75O

75P

75Q

75R

75S

75T

75U

75V

75W

TABLE 16

Compound

No.

Compound Structure

A-1

A-2

A-3

A-4

A-5

A-6

A-7

A-8

A-9

A-10

A-11

A-12

A-13

A-14

A-15

A-16

A-17

A-18

A-19

A-20

A-21

A-22

A-23

A-24

A-25

A-26

A-27

A-28

A-29

A-30

A-31

A-32

A-33

A-34

A-35

A-36

A-37

A-38

A-39

A-40

A-41

A-42

A-43

A-44

A-45

A-46

A-47

A-48

A-49

A-50

TABLE 17

Example

No.

Compound Structure

34

36

37

38

40

42

44

47

51

49

53

55

28. The compound of claim 1 , wherein the compound is at least a five-fold more potent inhibitor of Rho-associated protein kinase isoform 2 than Rho-associated protein kinase isoform 1.

29. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

30. A method of treating a Rho-associated protein kinase isoform 2 disorder selected from the group consisting of an inflammatory disorder, immune disorder, fibrotic disorder, and cardiovascular disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 to treat the disorder.

31. The method of claim 30 , wherein the disorder is scleroderma, psoriasis, nonalcoholic steatohepatitis, giant cell arteritis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, ulcerative colitis, asthma, uveitis, rheumatoid arthritis, or epidermal hyperplasia.

32. A method of inhibiting a Rho-associated protein kinase isoform 2, comprising exposing a Rho-associated protein kinase isoform 2 to a compound of claim 1 to inhibit said Rho-associated protein kinase isoform 2.