Protein kinase C inhibitors and uses thereof

1. A compound having the formula (I):

wherein

R 1 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)OR 1a , —S(O)R 1b , and —S(O) 2 R 1c ; wherein each of R 1a , R 1b , and R 1c is independently hydrogen, alkyl or phenyl-alkyl;

R a , R b , R c and R d independently are selected from hydrogen and alkyl;

m is an integer from one to five;

p is an integer from zero to six;

R 2 is selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, substituted alkyl, substituted alkoxy, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, and trihalomethyl;

X 1 , X 2 , and X 3 are CR 5 or one of X 1 , X 2 , and X 3 is N and rest are CR 5 ;

R 5 is selected from hydrogen, halogen, alkyl and substituted alkyl;

R 3 and R 4 are, for each occurrence, independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 3 and R 4 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic 4 to 8-membered ring;

n is an integer from one to three;

Z 1 , Z 2 , and Z 3 are selected from CR 6 R 6a , N, O, and S;

Z 4 and Z 5 are selected from N, C, and CR 6 ;

R 6 is selected from hydrogen, halogen, alkyl and substituted alkyl;

R 6a is selected from hydrogen, halogen, alkyl and substituted alkyl or is absent to satisfy valence requirements; and

the dashed lines represent a single bond or double bond;

or a salt or stereoisomer thereof.

2. The compound of claim 1 , wherein R a , R b , R c , and R d are lower alkyl.

3. The compound of claim 1 , wherein R 1 is selected from hydrogen and alkyl.

4. The compound of claim 1 , wherein m is an integer selected from one and two.

5. The compound of claim 1 , wherein p is an integer selected from zero and one.

6. The compound of claim 1 , wherein R 2 is selected from hydroxy, alkyl, alkoxy, cyano, halogen, nitro, and trihalomethyl.

7. The compound of claim 1 , wherein R 2 is halogen.

8. The compound of claim 1 , wherein X 1 , X 2 , and X 3 are CH.

9. The compound of claim 1 , wherein one of X 1 , X 2 , and X 3 is N and rest are CH.

10. The compound of claim 1 , wherein n is one.

11. The compound of claim 1 , wherein n is two.

12. The compound of claim 1 , R 3 and R 4 are, for each occurrence, independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, halogen, hydroxyl, and nitro.

13. The compound of claim 1 , R 3 and R 4 are, for each occurrence, independently selected from hydrogen, alkyl, and halogen.

14. The compound of claim 1 , wherein Z 1 , Z 2 , and Z 3 are independently selected from CR 6 and N, wherein R 6 is selected from hydrogen, halogen, alkyl and substituted alkyl.

15. The compound of claim 1 , wherein Z 1 , Z 2 , and Z 3 are each N.

16. The compound of claim 1 , wherein Z 1 , Z 2 , and Z 3 are each CH.

17. The compound of claim 1 , wherein Z 4 is N.

18. The compound of claim 1 , wherein Z 4 is C.

19. The compound of claim 1 , wherein Z 5 is N.

20. The compound of claim 1 , wherein Z 5 is C.

21. A compound selected from

N2-(4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-8-yl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-8-yl)-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(4,4-difluoro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(4,4-difluoro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(4,4-dimethyl-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(4,4-dimethyl-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(5,5-dimethyl-5H-benzo[e]tetrazolo[1,5-c][1,3]oxazin-9-yl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(5,5-dimethyl-5H-benzo[e]tetrazolo[1,5-c][1,3]oxazin-9-yl)-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(8,9-dihydrospiro[benzo[b]tetrazolo[1,5-d][1,4]oxazine-4,1′-cyclobutane]-8-yl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(8,9-dihydrospiro[benzo[b]tetrazolo[1,5-d][1,4]oxazine-4,1′-cyclobutane]-8-yl)-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine;

5-fluoro-N2-(4-methyl-8,9-dihydro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine;

5-fluoro-N2-(4-methyl-8,9-dihydro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine;

N2-(4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-((1,2,2,5,5-pentamethylpyrrolidin-3-yl)methyl)pyrimidine-2,4-diamine;

N2-(4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-((2,2,5,5-tetramethylpyrrolidin-3-yl)methyl)pyrimidine-2,4-diamine;

N2-(4,4-dimethyl-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-((1,2,2,5,5-pentamethylpyrrolidin-3-yl)methyl)pyrimidine-2,4-diamine;

N2-(4,4-dimethyl-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-((2,2,5,5-tetramethylpyrrolidin-3-yl)methyl)pyrimidine-2,4-diamine;

N2-(4,4-dimethyl-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N4-(((3S)-2,2,5-trimethylpyrrolidin-3-yl)methyl)pyrimidine-2,4-diamine; and

N2-(4,4-dimethyl-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-yl)-5-fluoro-N-4-(((3R)-2,2,5-trimethylpyrrolidin-3-yl)methyl)pyrimidine-2,4-diamine;

or a salt or stereoisomer thereof.

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

23. A method of inhibiting a protein kinase C (PKC) activity in a biological sample or a patient, which method comprises contacting the biological sample or administering to the patient a compound of claim 1 .

24. The method of claim 23 , wherein the inhibition of PKC results in treatment of a disease or disorder that is mediated or sustained through the activity of a PKC activity.

25. The method of claim 24 , wherein the disease or disorder is associated with activation of T cells.

26. The method of claim 24 , wherein the disease or disorder is an inflammatory disease.

27. The method of claim 24 , wherein the disease or disorder is an autoimmune disease.

28. The method of claim 24 , wherein the disease or disorder is an ocular disease or disorder involving inflammatory and/or neovascular events.

29. A method for treating a cell proliferative disorder mediated by protein Kinase C, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

30. The method of claim 29 , further comprising administering an effective amount of a Syk kinase inhibitory compound to the subject.

31. A method of preparing a compound of formula (I):

wherein

R 1 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)OR 1a , —S(O)R 1b , and —S(O) 2 R 1c ; wherein each of R 1a , R 1b , and R 1c is independently hydrogen, alkyl or phenyl-alkyl;

R a , R b , R c and R d independently are selected from hydrogen and alkyl;

m is an integer from one to five;

p is an integer from zero to six;

R 2 is selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, substituted alkyl, substituted alkoxy, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, and trihalomethyl;

X 1 , X 2 , and X 3 are CR 5 or one of X 1 , X 2 , and X 3 is N and rest are CR 5 ;

R 5 is selected from hydrogen, halogen, alkyl and substituted alkyl;

R 3 and R 4 are, for each occurrence, independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 3 and R 4 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic 4 to 8-membered ring;

n is an integer from one to three;

Z 1 , Z 2 , and Z 3 are selected from CR 6 R 6a , N, O, and S;

Z 4 and Z 5 are selected from N, C, and CR 6 ;

R 6 is selected from hydrogen, halogen, alkyl and substituted alkyl;

R 6a is selected from hydrogen, halogen, alkyl and substituted alkyl or is absent to satisfy valence requirements; and

the dashed lines represent a single bond or double bond;

or a salt or stereoisomer thereof;

the method comprising:

contacting a compound of formula:

 with a compound of formula

 wherein LG 1 is a leaving group.