Substituted indazolyl(indolyl)maleimide derivatives as kinase inhibitors

• US 20050004201A1
• Filed: 06/01/2004
• Published: 01/06/2005
• Est. Priority Date: 06/13/2003
• Status: Active Grant

• Current Assignee: Janssen Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceuticals, Inc. (Johnson & Johnson)
• Inventors: Ye, Hong, Maryanoff, Bruce E., Zhang, Han-Cheng
• Granted Patent: US 7,439,363 B2
• Time in Patent Office: Days
• US Class Current: 514/406
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings

Abstract

The present invention is directed to novel indazolyl-substituted pyrroline compounds of Formula (I):
R² is selected from the group consisting of —C_1-8alkyl-Z, —C_2-8alkenyl-Z and —C_2-8alkynyl-Z; wherein the —C_1-8alkyl-Z, —C_2-8alkenyl-Z and —C_2-8alkynyl-Z and Z is a 5 to 6 member aromatic monocyclic heteroaryl ring having from 2 to 4 heteroatoms. These compounds are useful as kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.

Claims

1. The compounds of Formula (I)

2. The compound of claim 1 wherein R¹ is independently selected from the group consisting of:

hydrogen,

C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl and C_3-8 cycloalkyl {wherein alkyl, alkenyl, alkynyl and C_3-8 cycloalkyl are optionally substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-OH, —

O—

(C_1-4)alkyl-O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-NH₂, —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-N[(C_1-4)alkyl]₂, —

O—

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-SO₂—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-SO₂—

NH₂, —

O—

(C_1-4)alkyl-SO₂—

NH—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-SO₂—

N[(C_1-4)alkyl]₂, —

O—

C(O)H, —

O—

C(O)—

(C_1-4)alkyl, —

O—

C(O)—

NH₂, —

O—

C(O)—

NH—

(C_1-4)alkyl, —

O—

C(O)—

N[(C_1-4)alkyl]₂, —

O—

(C_1-4)alkyl-C(O)H, —

O—

(C_1-4)alkyl-C(O)—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-CO₂H, —

O—

(C_1-4)alkyl-C(O)—

O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-C(O)—

NH₂, —

O—

(C_1-4)alkyl-C(O)—

NH—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-C(O)—

N[(C_1-4)alkyl]₂, —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SH, —

S—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-OH, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-NH₂, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-N[(C_1-4)alkyl]₂, —

S—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-OH, —

(C_1-4)alkyl-O—

(C_1-4)alkyl, —

(C_1-4)alkyl-NH₂, —

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

(C_1-4)alkyl-N[(C_1-4)alkyl]₂, —

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

C(O)C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂, —

C(N)—

NH₂, aryl and aryl(C_1-4)alkyl (wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C_1-4alkyl, C_1-4alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and C_1-4alkyl), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl and nitro)), cyano, (halo)_1-3, hydroxy, nitro, oxo, heterocyclyl, aryl and heteroaryl (wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and C_1-4alkyl), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl and nitro)},

—

C(O)—

(C_1-4)alkyl, —

C(O)-aryl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

O-aryl, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

NH-aryl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂-aryl,

heterocyclyl, aryl and heteroaryl {wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SH, —

S—

(C_1-4)alkyl, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), amino-(C_1-4)alkyl-(wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, nitro, aryl, —

(C_1-4)alkyl-aryl, heteroaryl and —

(C_1-4)alkyl-heteroaryl}.

3. The compound of claim 1 wherein R¹ is selected from the group consisting of:

hydrogen,

C_1-4alkyl, C_2-4alkenyl (wherein alkyl is substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-OH, —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

O—

C(O)—

(C_1-4)alkyl, —

C(O)H, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, —

(C_1-4)alkyl-OH, —

C(O)—

O—

(C_1-4)alkyl and aryl(C_1-4)alkyl), hydroxy, heterocyclyl, aryl and heteroaryl (wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C_1-4alkyl and halo)},

aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, aryl and heteroaryl).

4. The compound of claim 1 wherein R¹ is selected from the group consisting of:

hydrogen,

C_1-4alkyl, C_2-4alkenyl (wherein alkyl is substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), hydroxy, heterocyclyl, aryl and heteroaryl (wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C_1-4alkyl and halo)},

aryl and heteroaryl {wherein aryl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, aryl and heteroaryl).

5. The compound of claim 1 wherein R¹ is selected from the group consisting of:

hydrogen,

C_1-4alkyl, C_2-3alkenyl {wherein alkyl is substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), hydroxy, pyrrolidinyl, morpholinyl, piperazinyl (wherein piperazinyl is optionally substituted with methyl), phenyl, naphthalenyl, benzo[b]thienyl and quinolinyl (wherein phenyl and benzo[b]thienyl are optionally substituted with one to two chloro substituents)},

phenyl, naphthalenyl, furyl, thienyl, pyridinyl, pyrimidinyl, benzo[b]thienyl, quinolinyl and isoquinolinyl (wherein phenyl, naphthalenyl and pyridinyl are optionally substituted with one to two substituents independently selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, halo and hydroxy; and

, wherein phenyl is optionally substituted with one substituent selected from the group consisting of phenyl and thienyl).

6. The compound of claim 1 wherein R² is selected from the group consisting of —

C_1-4alkyl-Z, —

C_2-4alkenyl-Z and —

C_2-4alkynyl-Z;

wherein the —

C_1-4alkyl, —

C_2-4alkenyl and —

C_2-4alkynyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4)alkylamino, C_1-4alkyl, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy and hydroxy(C_1-4)alkyl.

7. The compound of claim 1 wherein R² is selected from the group consisting of —

C_1-4alkyl-Z;

wherein the —

C_1-4alkyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4)alkylamino, C_1-4alkyl, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy and hydroxy(C_1-4)alkyl.

8. The compound of claim 1 wherein Z is selected from the group consisting of pyrazine, pyrimidine, imidazol, pyridazine, triazine, furazan, isoxazole, isothiazole, thiazole, isothiazole, triazole, oxatriazole and tetrazole.

9. The compound of claim 1 wherein Z is selected from the group consisting of imidazol, triazole, oxatriazole and tetrazole.

10. The compound of claim 1 wherein Z is selected from the group consisting of oxatriazole and tetrazole.

11. The compound of claim 1 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SH, —

S—

(C_1-4)alkyl, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), amino-(C_1-4)alkyl-(wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, nitro, aryl, —

(C_1-4)alkyl-aryl, heteroaryl and —

(C_1-4)alkyl-heteroaryl.

12. The compound of claim 1 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, cyano and halogen.

13. The compound of claim 1 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, methyl, methoxy, cyano and chloro.

14. The compound of claim 1 wherein R⁵ is1 to 2 substituents attached to a carbon or nitrogen atom of Z and each substitute is independently selected from the group consisting of hydrogen, —

C_1-4alkyl, —

C_2-4alkenyl, —

C_2-4alkynyl, —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH(C_1-4alkyl), —

C(O)—

N(C_1-4)alkyl)₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH(C_1-4alkyl), —

SO₂—

N(C_1-4alkyl)₂, —

(C_1-4)alkyl-NH₂, —

(C_1-4)alkyl-NH(C_1-4alkyl), —

(C_1-4)alkyl-N(C_1-4alkyl)₂, —

(C_1-4)alkyl-(halo)_1-3, —

(C_1-4)alkyl-OH, -aryl, —

(C_1-4)alkyl-aryl, heteroaryl and —

(C_1-4)alkyl-heteroaryl;

with the proviso that, when R⁵ is attached to a carbon atom, R⁵ is further selected from the group consisting of —

C_1-4alkoxy, —

(C_1-4)alkoxy-(halo)_1-3, —

SH, —

S—

(C_1-4)alkyl, —

N—

R⁶, cyano, halo, hydroxy, and nitro.

15. The compound of claim 1 wherein R⁵ is1 to 2 substituents attached to a carbon or nitrogen atom of Z and each substitute is independently selected from the group consisting of —

C_1-4alkyl, —

C_2-4alkenyl, —

(C_1-4)alkyl-NH₂, —

(C_1-4)alkyl-NH(C_1-4alkyl), —

(C_1-4)alkyl-N(C_1-4alkyl)₂, —

(C_1-4)alkyl-(halo)_1-3, —

(C_1-4)alkyl-OH, —

(C_1-4)alkyl-aryl, heteroaryl and —

(C_1-4)alkyl-heteroaryl;

with the proviso that, when R⁵ is attached to a carbon atom, R⁵ is further selected from the group consisting of —

C_1-4alkoxy, —

(C_1-4)alkoxy-(halo)_1-3, —

S—

(C_1-4)alkyl, —

N—

R⁶, halo, and hydroxy.

16. The compound of claim 1 wherein R⁵ is selected from the group consisting of —

C_1-4alkyl

17. The compound of claim 1 wherein the compound of Formula (I) is a compound selected from Formula (Ia):

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

19. A method for preparing a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

20. A method for treating or ameliorating a kinase mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.

21. The method of claim 20 wherein the disorder is mediated by selective inhibition of a kinase selected from the group consisting of protein kinase C and glycogen synthase kinase-3.

22. The method of claim 21 wherein the kinase is selected from the group consisting of protein kinase C α

, protein kinase C, protein kinase C γ and

glycogen synthase kinase-3β

.

23. The method of claim 22 wherein the disorder is mediated by dual inhibition of at least two kinases selected from the group consisting of protein kinase C and glycogen synthase kinase-3.

24. The method of claim 23 wherein at least two kinases are selected from the group consisting of protein kinase C α

, protein kinase C β

-I, protein kinase C β

-Il, protein kinase C γ and

glycogen synthase kinase-3β

.

25. The method of claim 20 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 300 mg/kg/day.

26. The method of claim 20 wherein the kinase mediated disorder is selected from the group consisting of cardiovascular diseases, diabetes, diabetes-associated disorders, inflammatory diseases, immunological disorders, dermatological disorders, oncological disorders and CNS disorders.

27. The method of claim 26 wherein cardiovascular diseases are selected from the group consisting of acute stroke, heart failure, cardiovascular ischemia, thrombosis, atherosclerosis, hypertension, restenosis, retinopathy of prematurity and age-related macular degeneration.

28. The method of claim 26 wherein diabetes is selected from the group consisting of insulin dependent diabetes and Type II non-insulin dependent diabetes mellitus.

29. The method of claim 26 wherein diabetes-associated disorders are selected from the group consisting of impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy and neuropathy.

30. The method of claim 26 wherein inflammatory diseases are selected from the group consisting of vascular permeability, inflammation, asthma, rheumatoid arthritis and osteoarthritis.

31. The method of claim 26 wherein immunological disorders are selected from the group consisting of transplant tissue rejection, HIV-1 and PKC modulated immunological disorders.

32. The method of claim 26 wherein dermatological disorders are selected from the group consisting of psoriasis, hair loss and baldness.

33. The method of claim 26 wherein oncological disorders are selected from the group consisting of cancer or tumor growth, proliferative angiopathy, and angiogenesis.

34. The method of claim 26 wherein central nervous system disorders are selected from the group consisting of chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative conditions, dementia, Alzheimer'"'"'s disease, mood disorders, schizophrenia, manic depression and neurotraumatic, cognitive decline and ischemia-related diseases (as a result of head trauma or transient ischemic stroke).

35. The method of claim 20 further comprising a method for use for a compound of claim 1 as an adjunct to chemotherapy and radiation therapy.

36. The method of claim 20 further comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 20.

37. The method of claim 36 wherein the therapeutically effective amount of a pharmaceutical composition of claim 20 is from about 0.001 mg/kg/day to about 300 mg/kg/day.

38. A method of treating or ameliorating a disorder selected from the group consisting of diabetes-associated disorders, dermatological disorders, oncological disorders and central nervous system disorders comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I):

39. The method of claim 38 wherein diabetes-associated disorders are selected from the group consisting of impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy and neuropathy.

40. The method of claim 38 wherein dermatological disorders are selected from the group consisting of psoriasis, hair loss and baldness.

41. The method of claim 38 wherein oncological disorders are selected from the group consisting of cancer or tumor growth, proliferative angiopathy, and angiogenesis.

42. The method of claim 38 wherein central nervous system disorders are selected from the group consisting of chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative conditions, dementia, Alzheimer'"'"'s disease, mood disorders, schizophrenia, manic depression and neurotraumatic, cognitive decline and ischemia-related diseases (as a result of head trauma or transient ischemic stroke).