MXPA05013655A

MXPA05013655A - Substituted indazolyl(indolyl)maleimide derivatives as kinase inhibitors

Info

Publication number: MXPA05013655A
Application number: MXPA/A/2005/013655A
Authority: MX
Inventors: Hancheng Zhang; Hong Ye; Bruce E Maryanoff
Original assignee: Bruce E Maryanoff; Hong Ye; Hancheng Zhang
Priority date: 2003-06-13
Filing date: 2005-12-13
Publication date: 2006-10-17

Abstract

The present invention is directed to novel indazolyl-substituted pyrroline compounds of Formula (I):Formula (I), R2 is selected from the group consisting of -C1-8alkyl-Z, -C2-8alkenyl-Z and -C2-8alkynyl-Z;wherein the -C1-8alkyl-Z, -C2-8alkenyl-Z and -C2-8alkynyl-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.

Description

DERIVATIVES OF INZZOLILDNDOLLDMALEIMIPA SUBSTITUTED AS KINASE INHIBITORS This application claims the benefit of the provisional patent application serial number 60 / 478,516 filed on June 13, 2003 incorporated herein by reference in the present invention.

FIELD OF THE INVENTION This invention is directed to certain novel compounds, methods for producing them, and methods for treating or improving a kinase or dual kinase mediated disorder. More particularly, this invention is directed to substituted pyrroline compounds with useful indazolyl as selective inhibitors of kinase or dual-kinase, methods for producing such compounds and methods for treatment or amelioration of a condition mediated by kinase or dual kinase disorder.

BACKGROUND OF THE INVENTION U.S. Patent 5,057,614 to Davis, et.al., discloses pyrrolo substituted compounds of formula I: wherein R 1 signifies hydrogen, alkyl, aryl (limited to phenyl), aralkyl (limited to phenylalkyl), alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylsulfonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalquilo, isotiocianatoalquilo, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalquiltioalquilo, arylthioalkyl or carboxyalkylthioalkyl or a group of the formula - (CHzjrt-W-Hßt, - { CH2)? T-C (= V) -Z, (a) ib) (o) wherein Het means a heterocyclyl group, W means NH, S or a bond, T means NH or S, V means O, S, NH, NNO2, NCN OR CHNO2, Z means alkylthio, amino, monoalkylamino or dialkylamino, lm means 1-imidazolyl, Ar means aryl, and n is set to 2-6; R2 is hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl; R3 means a carbocyclic or heterocyclic aromatic group; R4, R5, R6 and R7 each independently represents hydrogen, halogen, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulphonyl; and one of X and Y means O and the other means O, S, (H, OH) or (H, H); with the proviso that R1 has a meaning other than hydrogen when R2 means hydrogen, R3 means 3-indolyl or 6-hydroxy-3-indolyl, R4, R5 and R7 each means hydrogen, R6 means hydrogen or hydroxy and X e And both signify O and when R2 signifies hydrogen, R3 signifies 3-indolyl, R4, R5, R6 and R7 each signifies hydrogen, X signifies (H, H) and Y signifies O; as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids, as therapeutically active substances for use in the control or prevention of inflammatory, immunological, bronchopulmonary and cardiovascular disorders. The novel compounds of the present invention are structurally different from those described by Davis Patent 5,057,614. In particular, Davis Patent 5,057,614 discloses pyrrole substituted indolyl compounds of formula I which may be further substituted at the R 3 position with a carbocyclic or heterocyclic aromatic group. The carbocyclic aromatic group denoted by R3 can be a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group, for example phenyl or naphthyl, which may be substituted or unsubstituted, for example, with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Unlike the compounds of the present invention, examples of the carbocyclic aromatic groups denoted in Davis' 614 patent by R3 are phenyl, 2-, 3-, or 4-chlorophenyl, 3-bromophenyl, 2- or 3- methylphenyl, 2,5-dimethylphenyl, 4-methoxyphenyl, 2- or 3-trifluoromethylphenyl, 2-, 3-, or 4-nitrophenyl, 3-, or 4-aminophenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl and 1-, or 2-naphthyl. The heterocyclic aromatic group denoted by R3 may be a 5- or 6-membered heterocyclic aromatic group in which it may optionally carry a fused benzene ring and which may be substituted or unsubstituted, for example, with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, mono- or dialkylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Unlike the compounds of the present invention, the examples of heterocyclic aromatic groups denoted in Davis' 614 patent by R3 are 2-, or 3-thienyl, 3-benzothienyl, 1-methyl-2-pyrroline, 1-benzimidazolyl , 3-indolyl, 1- or 2-methyl-3-undolyl, 1-methoxymethyl-3-indolyl, 1- (1-methoxyethyl) -3-indolyl, 1- (2-hydroxypropyl) -3-indolyl, - (4-hydroxybutyl) -3-indolyl, 1- [1- (2-hydroxyethylthio) ethyl] -3-indolyl, 1- [1- (2-mercaptoethylthio) ethyl] -3-indolyl, 1- (1 - phenylthioethyl) -3-indolyl, 1 - [1 - (carboxymethylthio) ethyl] -3-indolyl and 1-benzyl-3-indolyl. U.S. Patent 5,721,245 to Davis, et. al., describes substituted 4- [3-indolyl] -1H-pyrrolone compounds of formula I: wherein R is hydrogen or hydroxy, R1 and R2 taken together are a group of the formula - (CH2) n- and R7 is hydrogen or R1 and R7 taken together are a group of the formula - (CH2) n- and R2 is hydrogen; R3 is an aromatic aryl or heterocyclic group; R4, R5 and R6 each independently are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl; R8 is a group of the formula - (CH2) P-R9 or - (CH2) q-R10; R9 is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl; R10 is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, alkoxycarbonylamino, aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy, a 5- or 6-membered saturated heterocyclic containing nitrogen bound via the nitrogen atom or a group of the formula -UC (V) -W; U is S or NH; V is NH, NN02, NCN, CHN02; W is amino, monoalkylamino or dialkylamino; one of X and Y is O and the other is O or (H, H); Z is CH or N; m, p and q are, independently, an integer from 0 to d, and n is an integer from 1 to d, with the proviso that q and m are, independently, 2 to d when Z is N; as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of the basic compounds of formula I with acids, as active therapeutic substances for use in the control or prevention of inflammatory, immunological, bronchopulmonary and cardiovascular disorders. The novel compounds of the present invention are structurally different from those described by the Davis patent 6,721, 246. In particular, the Davis patent 6,721, 246 discloses 4- [3-indolyl] -1H-pyrrolone compounds of formula I which may be further substituted at the R3 position with an aromatic aryl or heterocyclic group. The term "aryl", alone or in combination denotes a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group, for example, phenyl or naphthyl, which may be substituted or unsubstituted, for example, with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Unlike the compounds of the present invention, examples of such aryl groups in the Davis' 245 patent are phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-methylphenyl, 3-methylphenyl, 2,5-dimethylphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl, 1-naphthyl, 2-naphthyl and the like. The term "aromatic heterocyclic" means a d- or 6-membered heterocyclic aromatic group which may optionally carry a fused benzene ring and which may be substituted or unsubstituted, for example, with one or more, preferably one to three , substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Unlike the compounds of the present invention, examples of such heterocyclic groups in the Davis' 245 patent are 2-thienyl, 3-thienyl, 3-benzothienyl, 3-benzofuranyl, 2-pyrrolyl, 3-indolyl and the like which may be unsubstituted or substituted in the manner indicated. The saturated 5- or 6-membered nitrogen-containing heterocyclic linked via the nitrogen atom may contain an additional nitrogen or oxygen or sulfur atom, examples of said heterocycles are pyrrolidino, piperidino, piperazino, morpholino and thiomorpholino. U.S. Patent 6,624,949 to Heath, Jr., et. al., describes bis-indolmaleimide derivatives of the formula: wherein W is -O-, -S-, -SO-, -S02-, -CO-, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl-, -aryl (CH2) mO- , -heterocycle-, -heterocycle- (CH2) mO-, -cyclic- fused-, -cyclic-fused- (CH2) mO-, -NR3-, -NOR3-, -CONH- or -NHCO-; X and Y are independently C1-C4 alkylene, substituted alkylene, or together, X, Y and W combine to form (CH2) n-AA-; R1 is independently hydrogen, halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, NR4R5 or -NHCOalkyl (C1-C4); R2 is hydrogen, CH3CO-, NH2 or hydroxy; R3 is hydrogen, (CH2) maryl, CrC4 alkyl, -COO (C4 alkyl), -CONR4R5, -C (C = NH) NH2, -SO (C4 alkyl), -S? 2 (NR4R5 ) or -S-2 (C 1 -C 4 alkyl); R 4 and 5 are independently hydrogen, C 1 -C 4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are attached to form a 5 or 6 membered saturated or unsaturated ring; AA is an amino acid residue; m is independently 0, 1, 2 or 3; and n is independently 2, 3, 4 or d as inhibitors of protein kinase C (PKC) and as selective inhibitors of PKCβ-1 and PKCβ-11.

Patent application WO 00/06664 discloses disubstituted maleimide compounds of formula (I): wherein R 1 represents hydrogen or alkyl; R2 represents aryl, cycloalkyl or a heterocycle; R3, R5, R6, R7 and R8 each represent hydrogen, halogen, hydroxy, amino, alkyl or alkoxy; and R 4 is W, or R 4 and R 3 or R 4 and R 5 can together form a ring substituted by W therein; wherein W represents - (CH2) r (Y) m- (CH2) n-Z as inhibitors of PKCβ. Patent application WO 00/21927 describes 3-amino-4-arimaleimide compounds having the formula (I): or a pharmaceutically acceptable derivative thereof, wherein: R is hydrogen, alkyl, aryl or aralkyl; R1 is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl; R2 is substituted or unsubstituted aryl or substituted or unsubstituted heterocyclyl; R3 is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or aralkyl wherein the aryl portion is substituted or unsubstituted; or, R1 and R3 together with the nitrogen to which they are attached form a particular or fused, optionally substituted, saturated or unsaturated heterocyclic ring and a method for the treatment of conditions associated with a need for inhibition of GSK-3, such as diabetes, dementias such as Alzheimer's disease and manic depression. The indazolyl-substituted pyrroline compounds of the present invention have not been described to date. Accordingly, it is an object of the present invention to provide indazolyl-substituted pyrroline compounds useful as a kinase or dual kinase inhibitor (in particular, a kinase selected from protein kinase C or glycogen synthase kinase-3; , more particularly, a kinase selected from protein kinase C a, protein kinase C β (for example protein kinase Cβ-I and protein kinase Cβ-ll), protein kinase Cβ or glycogen synthase kinase-3β), methods for its production and methods for the treatment or improvement of a kinase or dual kinase mediated disorder.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to pyrroline compounds substituted with indazolyl of formula (I) Formula (I) wherein R1 is selected from the group consisting of: hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-s alkynyl and C3-8 cycloalkyl. { wherein alkyl, alkenyl, alkynyl and C3-8 cycloalkyl are optionally substituted with one to two substituents independently selected from the group consisting of -O-alkyl of (d.8), -O-alkyl of (d.8) ) -OH, -O-alkyl (C? 8) -0-alkyl (C? 8), -O-alkyl (C 1-8) -NH2, -O-alkyl (C? .8) ) -NH-(C 1-8) alkyl, -O-alkyl of (d 8) -N [(C 1. 8) alkyl] 2, -O-alkyl of (d 8) -S-alkyl of (C? .8), -O-alkyl of (d.8) -S02-alkyl of (d.8), -O-alkyl of (d.8) -S02-NH2, -O-alkyl of (ds) -S02-NH-alkyl of (d.8), -O-alkyl of (d.8) -S02- N [alkyl of (d.8)] 2, -0-C (0) H, -OC (0) -alkyl of (C? 8), -0-C (0) -NH2, -0 -C (0) -NH-alkyl of (d.8), -OC (O) -N [alkyl of (d.8)] 2, -O-alkyl of (C1.8) -C (O ) H, -O-alkyl of (d.8) -C (0) -alkyl of (d.8), -O-alkyl of (C? 8) -C02H, -O-alkyl of (C? 8) -C (0) -0-alkyl of (C? 8), -O-alkyl of (C? -8) -C (0) -NH2, -O-alkyl of (d.8) -C (0) -NH-alkyl (C? -8), -O-alkyl (d-8) -C (0) -N [(C1-C8) alkyl] 2, -C (0) H, -C (0) -alkyl of (C? 8), -C02H, -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl (Ci-s), -C (0) -N [(d-8) alkyl] 2, -SH, -S-alkyl (C? -8), - S- (C? -8) -S-alkyl of (C? -8), -S-alkyl of (d.8) -0-alkyl of (C? -8), -S-alkyl of ( C? 8) -0-alkyl of (C? .d); -OH, -S-alkyl of (d_8) -0-alkyl of (C1.8) -NH2, -S-alkyl of (d.8) -0-alkyl of (C? 8) -NH- alkyl (Ci-β), -S-alkyl of (C 8) -O-alkyl of (d 8) -N [alkyl of (d 8)] 2, -S-alkyl of (C 1) -8) -NH-alkyl of (Ci. 8), -S02-alkyl of (d.8), -S02-NH2, -S02-NH-alkyl of (d.8), -S02-N [ (C? 8)] 2 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, d-β alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -alkyl ( C.8) -OH, -alkyl of (d.8) -0-alkyl of (C? -8), -alkyl of (C? -8) -NH2, -alkyl of (C? .8) -NH -alkyl of (d-8), -alkyl of (C? -8) -N [(C? 8) alkyl] 2, -alkyl of (C? -s) -S-alkyl of (C? 8), -C (0) -alkyl of (d.8), -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (0) -NH-alkyl of (C? -8), -C (0) -N [alkyl of (d.8)] 2, -S02-alkyl of (C? .8), -S02-NH2, -S02-NH-alkyl of (dd), -S02-N [(C? 8)] 2, -C (N) -NH2, aryl and arylalkyl (Ci-β) alkyl (wherein the aryl is optionally substituted with one at substituents independently selected from the group consisting of halogen, C? -8 alkyl, C8-alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and C? _8 alkyl), cyano , halo, halo (halo)? -3alkyl of (C? 8), (halo)? 3alkoxy of (C? .8), hydroxy, hydroxyalkyl of (C? .8) and nitro)), cyano, (halo) ? 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 1-8 alkyl, d alkoxy. 8, amino (substituted with two substituents selected from the group consisting of hydrogen and C 1-8 alkyl), cyano, halo, (halo) β 3 alkyl of (C _ 8), (halo) β 3 alkoxy of ( C? 8), hydroxy, hydroxyalkyl of (C? 8) and nitro)} , -C (0) -alkyl of (d.8), -C (0) -aryl, -C (0) -0-alkyl of (d.8), -C (0) -0-aryl, - C (0) -NH-alkyl (ds), -C (0) -NH-aryl, -C (0) -N [(d-β) alkyl] 2, -S02-alkyl (d-β) ), -S? 2-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 C1-8 alkyl, C2.8 alkenyl, C2-alkynyl, C ?8 alkoxy, - C (0) H, -C (O) -alkyl of (C? 8), -C02H, -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl of (d.8), -C (0) -N [(C? -8)] 2, -SH, -S-alkyl of (d.8), -S02-alkyl of (C? 8), -S02-NH2, -S02-NH-alkyl of (C? .8), -S02-N [alkyl of (C? -8)] 2, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkyl) NH2, -C (0) -alkyl of (d.8), -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (0) -NH-alkyl of (C? 8), -C (O) -N [(C? 8)] 2 alkyl, -S02-alkyl of (d.8), -S02-NH2, -S02-NH-alkyl of (d.8), -SO2-N [(C -s)] 2 alkyl and -C (NH) -NH2), amino-alkyl of (d.8) - (wherein the amino is substituted with two sust The compounds are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2. alkenyl, C 2-8 alkynyl, -alkyl (C 1 -s) -NH 2, -C (0) -alkyl (d. 8), -C (0) -0-alkyl of (d.8), -C (0) -NH2l -C (0) -NH-alkyl of (d.8), -C (O) -N [ alkyl of (d.8)] 2, -S02-alkyl of (C? -8), -S02-NH2, -S02-NH-alkyl of (Ci-8), -S02-N [alkyl of (C? .8)] 2 and -C (NH) -NH2), cyano, halo, (halo ^ alkyl of (Ci-s) -, (halo ^ (C? -8) - alkoxy, hydroxy, hydroxyalkyl of (C) ? -8), nitro, aryl, -alkyl (C? -8) -aryl, heteroaryl, and (C -8) -heteroaryl alkyl; R.sup.2 is selected from the group consisting of -alkyl Ci-s-Z, -C2-8-Z alkenyl and C2-s-Z alkynyl; wherein the -alkyl of d-8, -C2-8alkenyl and C2.8alkynyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, C1- alkylamino 4, dialkylamino of (C 1-4). C 1-4 alkyl, C 1-4 alkoxy, (halo)? -3 alkyl of (C 1-4), (halo ^ (C 1-4) alkoxy and hydroxyalkyl of (C 1-); Z is a monocyclic heteroaryl ring of gives 6 members having 2 to 4 heteroatoms containing at least one carbon atom and at least one nitrogen atom, wherein Z is optionally substituted with R 5, R 5 is 1 to 2 substituents attached to a carbon or nitrogen atom of Z and each substituent is independently selected from the group consisting of hydrogen, -C 8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -C (0) H, -C (0 ) -Alkyl of (C1-8), -CO2H, -C (0) -0-alkyl of (C1-8), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH (d-β alkyl), -C (0) -Nalkyl of (C? -8)) 2, -S02-alkyl of (d-8), -S02-NH2, -S02-NH (alkyl) d-8), -S02-N (C? -8 alkyl) 2, -alkyl of (C? -8) -NH2, -alkyl of (C? .8) -NH (C? -8 alkyl) , -alkyl of (C? -s) -N (C? -8) alkyl 2, -alkyl of (C? -8) - (halo)? -3, -alkyl of (Ci-8) -OH, -aryl, -alkyl (C? -8) -aryl, heteroaryl or and - (C? -8) -heteroaryl alkyl; with the proviso that, when R5 is attached to a carbon atom, R5 is further selected from the group consisting of -alkoxy of C? .8, -alkoxy of (C? -8) - (halo) 1- 3, -SH, -S-alkyl (Ci-s), -N-R6, cyano, halo, hydroxy, and nitro; R6 is 1 to 2 substituents independently selected from the group consisting of hydrogen, -D-β alkyl, -C2-8alkenyl, -C2.8alkynyl, -C3.8cycloalkyl, -C (0) H, -C (0) -alkyl of (C? 8), -C (O) -O-alkyl of (C? -8), -C (0) -NH2, -C (0) -NH ( C 1-8 alkyl), -C (0) -N (C 1 -8 alkyl) 2, -S0 2 -alkyl (C 1 -8), -S 0 2 -NH 2, -S 0 2 -NH (C1-6 alkyl) 8), -S02-N (C? 8 alkyl) 2, -C (N) -NH2, -C (N) -NH (C? .8 alkyl) and -C (N) -N (alkyl) from C 1.8) 2; R3 and R4 are independently selected from the group consisting of hydrogen, C? -8 alkyl, C2.8 alkenyl, C2.8 alkynyl, d-β alkoxy, -C (0) H, -C ( 0) -alkyl of (C? 8), -C02H, -C (0) -0-alkyl of (C? -8), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl of (C? 8), -C (0) -N [alkyl of (d. Β)] 2, -SH, -S-alkyl of (d.8), -S02- alkyl of (d.8), -S02-NH2 | -S02-NH- (Ci-d) alkyl, -S02-N [(C? S)] 2 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C-alkyl? .8, C2-8 alkenyl, C2.s alkynyl, -alkyl of (d.8) ~ NH2, -C (0) -alkyl of (C? .8), -C (0) -0-alkyl of (C? .8), -C (0) -NH2, -C (0) -NH-alkyl of (d.8), -C (0) -N [alkyl of (d.8)] 2, -S02- (C? -8) alkyl, -S02-NH2, -S02-NH- (C? -8) alkyl, -S02-N [(C? .8) alkyl] 2 and -C ( NH) -NH2), aminoalkyl of (C? -8) - (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C? -8 alkyl, C2.8 alkenyl, C2.8 alkynyl, -alkyl of (d.8) -NH2, -C (0) -alkyl of ( C .8), -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (O) -NH-alkyl of (d-8), -C (0) -N [(C? 8)] 2 alkyl, -S02-alkyl of (d-β), -S02-NH2l -S02-NH- (C1-8) alkyl, -S02-N [alkyl of ( C1.8)] 2 and -C (NH) -NH2), cyano, halo, (halo) -3alkyl of (d-β) -, (halo) -3alkoxy of (C .d) -, hydroxy, hydroxyalkyl of (C? 8), nitro, aryl, -alkyl of (C? -s) -aryl, heteroaryl and -alkyl of (C? 8) -heteroaryl; and pharmaceutically acceptable salts thereof. The present invention is directed to indazolyl substituted pyrroline compounds useful as a selective inhibitor to kinase or dual kinase; in particular, a kinase selected from protein kinase C or glycogen synthase kinase-3; and, more particularly, a kinase selected for protein kinase C a, protein kinase C ß (e.g., protein kinase C ßl and protein kinase C ß-ll), protein kinase C? or glycogen synthase kinase-3β. The present invention is also directed to methods for producing the present pyrroline compounds substituted with indazolyl and pharmaceutical compositions and medicaments thereof. The present invention is further directed to methods for the treatment or amelioration of a kinase or dual kinase mediated disorder. In particular, the method of the present invention is directed to the treatment or amelioration of a kinase or dual kinase mediated disorder such as, but it is not limited to, cardiovascular diseases, diabetes, disorders associated with diabetes, inflammatory diseases, immunological disorders, dermatological disorders, oncological disorders and CNS disorders.

DETAILED DESCRIPTION OF THE INVENTION Preferred embodiments of the present invention include compounds of formula (I) wherein, R 1 is selected from the group consisting of: hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and cycloalkyl C3-s. { wherein alkyl, alkenyl, alkynyl and the C3-8 cycloalkyl are optionally substituted with one to two substituents independently selected from the group consisting of O-alkyl of (d-), -O-alkyl of (d.4) -OH, -O-alkyl of (d- -O-alkyl of (CM), -O-alkyl of (C? ^) - NH2, -O-alkyl of (Ci ^ -NH-alkyl of (C1.4 ), -O-alkyl of (C? 4) -N [(C 1.) Alkyl] 2, -O-alkyl of (C? ^) -S- (C 1-4) alkyl, -O-alkyl of (C? ^) - S02-(C1-4) alkyl, -O-alkyl of (d.) -S02-NH2, -O-alkyl of (C? -4) -S02-NH-alkyl of ( C1-4), -O-alkyl of (C) -S02-N [alkyl of (C ^)] 2, -0-C (0) H, -0-C (0) -alkyl of (C1.4 ), -0-C (0) -NH2, -0-C (0) -NH-alkyl of (d.4), -0-C (0) -N [(C? 4) alkyl] 2 , -O-alkyl of (C? -4) -C (0) H, -O-alkyl of (C? -4) -C (0) -alkyl of (C?), -O-alkyl of (d. 4) -C02H, -O-alkyl of (d.4) -C (0) -0-alkyl of (Ci ^), -O-alkyl of (C? 4) -C (O) -NH2 , -O-(C1-) alkyl-C (O) -NH- (C1-) alkyl, -O-alkyl (d-4) -C (0) -N [alkyl of (C? )] 2, -C (0) H, -C (0) -alkyl of (d) .4), -C02H, -C (0) -0-alkyl of (CM), -C (O) -NH2, -C (NH) -NH2, -C (O) -NH- (C1-) alkyl 4), -C (0) -N [alkyl of (d-4) .2, -SH, -S-alkyl of (CM), -S-alkyl of (CM) -S-alkyl of (C1-4) ), -S- (C? -4) -0-alkyl of (CM). -S-alkyl of (d-) -0-alkyl of (C? -4) -OH, -S-alkyl of (C? -4) -0-alkyl of (C? -4) -NH2, -S -alkyl of (C? -4) -0-alkyl of (C1-4) -NH-alkyl of (C1.4), -S-alkyl of (C? ^) -O-alkyl of (d-4) -N [(C)] 2 alkyl, -S-alkyl of (d.4) -NH-alkyl of (CM), -S02- (C1-4) alkyl, -S02-NH2, - S02-NH-alkyl (d-4), -S02-N [(d.)] 2 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C-alkyl, C2-alkenyl -4, C 2-4 alkynyl, -alkyl of (CMJ-OH, -alkyl of (C 1-4) -0-alkyl of (C 1-4), -alkyl of (C? ^) -NH 2, -alkyl of (C? ^) - NH- (1-4C) alkyl, - (C? ^) - N ([C? -4) _2 alkyl, - (C? -4) -S-alkyl What is (C1.4), -C (0) -acyl (CM), -C (0) -0- (C1-4) alkyl, -C (0) -NH2, -C (0) -NH-alkyl (CM), -C (0) -N [alkyl of (d.4)] 2, -S02-alkyl of (CM), -S02-NH2, -SO2-NH-alkyl of (CM) ), S02-N [(C) alkyl], -C (N) -NH2, aryl and (C1.4) arylalkyl (wherein the aryl is optionally its is substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and C 1-4 alkyl ), cyano, halo, (halo) ?. 3alquilo of (CH), (halo) ?. 3alcoxi of (CM), hydroxy, hydroxyalkyl (C1-4) alkyl and nitro)), cyano, (halo) - 3 , hydroxy, nitro, oxo, heterocililo, aryl and heteroaryl (wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one to three independently selected from the group substituents consisting of alkyl of CM alkoxy, d-4, amino (substituted with two substituents selected from the group consisting of hydrogen and alkyl of d-), cyano, halo, (halo) - 3alquilo of (CM), (halo) -3alcox¡ of (CM), hydroxy, hydroxyalkyl ( CM) and nitro)} , -C (0) -alkyl of (CM), -C (0) -aryl, -C (0) -0-alkyl of (CM), -C (0) -0-aryl, -C (0) -NH-alkyl (CM), -C (0) -NH-aryl, -C (0) -N [alkyl (CM)] 2, -S02-alkyl (CM), -S02-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 CM alkyl, C2-4 alkenyl, C2-4 alkynyl, d-, -C (0) H alkoxy, -C (O) -alkyl of (CM), -C02H, -C (0) -0-alkyl (CM), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl of (CM), -C (0) -N [alkyl of (CM)], - SH, -S-alkyl of (CM), -S02-alkyl of (CM), -S02-NH2, -S02-NH-alkyl of (CM), -S02-N [alkyl of (C? -4)] 2, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C-alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -alkyl of (d.) -NH 2, -C (0) -alkyl of (C1.4), -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (0) -NH-alkyl of (CM), -C (O) -N [(CM) alkyl] 2, -S02-alkyl of (CM), -S02-NH2, -S02-NH-alkyl of (C1. 4), -S? 2-N [alkyl of (d-) 4) k and -C (NH) -NH2), amino-alkyl of (CM) - (wherein the amino is substituted with two substituents independently selected from the group consisting of hydrogen, CM alkyl, C2-4 alkenyl , C2-4 alkynyl, -alkyl of (d.4) -NH2, -C (0) -alkyl of (d-4), -C (0) -0-alkyl of (CM) , -C (O) -NH2l -C (0) -NH-alkyl of (CM), -C (O) - N-akalkyl of (Cμ) k, -S02-alkyl of (CM), -S02-NH2, - S02-NH-alkyl of (d. 4), -S02-N [(CM) alkyl] 2 and -C (NH) -NH2), cyano, halo, (halo)? 3alkyl of (d .4), (halo)? 3alcoxy (CM), hydroxy, hydroxyalkyl of (CM), nitro, aryl, -alkyl of (CM) -aryl, heteroaryl and -alkyl of (CM) -heteroaryl} . More preferably, R1 is selected from the group consisting of: hydrogen, CM alkyl, C2.4 alkenyl. { wherein the alkyl is substituted with one to two substituents independently selected from the group consisting of -O-alkyl of (CM), -O-alkyl of (CM) -OH, -O-alkyl of (C? -4 ) -NH-alkyl (CM), -0-C (0) -alkyl (CM), -C (0) H, -C02H, -C (0) -0-alkyl (CM), amino ( substituted with two substituents independently selected from the group consisting of hydrogen, alkyl of CM, -alkyl of (CM) -OH, -C (0) -0-alkyl of (CM) and arylalkyl of (CM), hydroxy, heterocyclyl, aryl, and heteroaryl (wherein the heterocyclyl, aryl, and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C.sub.5 V alkyl), aryl, and heteroaryl. and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of CM alkyl, CM alkoxy, -C02H, -C (0) -0-alkyl of (CM), -C (0) - NH2, -C (NH) -N H2, -C (0) -NH-alkyl (CM), -C (0) -N [alkyl of (d.4)] 2, amino (substituted with two substituents independently selected from the group consisting of hydrogen and d-) alkyl, cyano, halo, (halo) - | .3alkyl of (CM), (halo) - ?. 3alcoxy of (CM), hydroxy, hydroxyalkyl of (CM), aryl and heteroaryl} . Preferred embodiments of the present invention include compounds of formula (I) wherein, R 1 is selected from the group consisting of hydrogen, C 1 -4 alkyl, C 2-4 alkenyl. { wherein alkyl is substituted with one to two substituents independently selected from the group consisting of -O-alkyl of (d.4) -NH-alkyl of (d.4), amino (substituted with two substituents independently selected from of the group consisting of hydrogen and CM 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 d. alkyl) and halo)} , aryl and heteroaryl. { wherein aryl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of CM alkyl, CM alkoxy, -C02H, -C (0) -0-alkyl of (CM), -C ( 0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl (CM), -C (0) -N [(C? 4)] 2 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and alkyl of CM), cyano, halo, (ha! o)? 3 alkyl of (CM), (halo)? 3 alkoxy of (CM), hydroxy, hydroxyalkyl of (CM), aryl and heteroaryl} . More preferably, R1 is selected from the group consisting of hydrogen, CM alkyl, C2.3 alkenyl. { wherein the alkyl is substituted with one to two substituents independently selected from the group consisting of -O-alkyl (CM) -NH-alkyl (CM), amino (substituted with two substituents independently selected from the group that consists of hydrogen and alkyl of CM), 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 chlorine 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 CM alkyl , CM alkoxy, halo and hydroxy; and, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of phenyl and thienyl).

To clarify the subject, when R2 is alkynyl-Z, the bond (s) unsaturated in the alkynyl will not be directly associated with a nitrogen atom in Z or the indazolyl of formula I. Preferred embodiments of the present invention include formula (I) wherein, R2 is selected from the group consisting of: -alkyl of (Cμ) -Z, -alkenyl of C2 ^ -Z and -alkynyl of C2-4-Z; wherein the-C, C2-4alkenyl and C2-4alkynyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, alkylamino of CM, dialkylamino of (C1-4), C-alkyl, CM-alkoxy, (halo) -3-alkyl of (CM), (halo) -3-alkoxy of (d-) and hydroxyalkyl of (CM) - More preferably, R2 is selected from starting from the group consisting of: -alkyl of (C) -Z wherein the -alkyl of CM is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, alkylamino of CM, dialkylamino of (CM), CM alkyl, CM alkoxy, (halo) β 3 alkyl of (CM), (halo) β 3 alkoxy of (CM) and hydroxyalkyl of (d-4). Preferred embodiments of the present invention include compounds of formula I wherein Z is a monocyclic 6-membered heteroaryl ring having from 2 to 4 heteroatoms containing at least one carbon atom and at least one nitrogen atom selected from group consisting of pyrazine, pyrimidine, imidazole, pyridazine, triazine, furazane, isoxazole, isothiazole, thiazole, isothiazole, triazole, oxatriazole and tetrazole. More preferably Z is selected from the group consisting of imidazole, triazole, oxatriazole and tetrazole. More preferably Z is selected from the group consisting of oxatriazole and tetrazole. Preferred embodiments of the present invention include compounds of formula I wherein R5 is 1 to 2 substituents attached to a carbon or nitrogen Z atom and each substituent is independently selected from the group consisting of hydrogen, -alkyl CM , -C2-4alkenyl, -C2-4alkynyl, -C (0) H, -C (0) -alkyl (CM), -C02H, -C (0) -0-alkyl (CM) , -C (0) -NH2, -C (NH) -NH2, -C (0) -NH (CM alkyl), -C (0) -Nalkyl of (d-4) 2, -S02-alkyl of (CM), -S02-NH2, -S02-NH2 (C alquilo alkyl), -S02-N (CM alkyl) 2, -alkyl of (CM) -NH2, -alkyl of (C? -4) -NH (CM alkyl), -alkyl of (CM) -N (alkyl of CM) 2, -alkyl of (d-4) - (halo)? -3, -alkyl of (CM) -OH, -aryl, - alkyl (CM) -aryl, heteroaryl and -alkyl (CM) -heteroaryl; with the proviso that, when R5 is attached to a carbon atom, R5 is further selected from the group consisting of -alkoxy of CM, -alkoxy of (CM) - (halo)? 3, -SH, - S-alkyl (CM), -N-R6, cyano, halo, hydroxy, and nitro. More preferably R5 is 1 to 2 substituents attached to a carbon or nitrogen atom of Z and each substituent is independently selected from the group consisting of -CM alkyl, -C2-4 alkenyl, -alkyl (CM) -NH2, -alkyl of (CM) -NH (alkyl of CM), -alkyl of (CM) -N (alkyl of Cμ) 2, -alkyl of (C?) - (halo)? 3, -alkyl of (Ci- 4) -OH, -alkyl (CM) -aryl, heteroaryl and -alkyl (CM) -heteroaryl; with the proviso that, when R5 is attached to a carbon atom, R5 is further selected from the group consisting of -alkoxy of CM, -alkoxy of (CM) - (halo). (CM), -N-R6, halo, and hydroxy. More preferably Rd is -alkyl of (CM) - Preferred embodiments of the present invention include compounds of formula I wherein R6 is 1 to 2 substituents independently selected from the group consisting of hydrogen, -alkyl of CM, -alkenyl of C2-4, -C2-4alkynyl, -C3-4alkyl, -C (0) H, -C (0) -alkyl (CM), -C (0) -0-alkyl (CM) , -C (0) -NH2, -C (0) -NH (alkyl of CM), -C (0) -N (alkyl of Cμ) 2, -S02-alkyl of (CM), -S02- NH2, -S02-NH (alkyl of CM), -S02-N (alkyl of d.4) 2, -C (N) -NH2, -C (N) -NH (alkyl of CM) and -C (N) -N (alkyl of Cμ) 2. Preferred embodiments of the present invention include compounds of formula (I) wherein, R3 and R4 are independently selected from the group consisting of hydrogen, CM alkyl, C2-4 alkenyl, C2-4 alkynyl, alkoxy CM, -C (0) H, -C (0) -alkyl of (CM), -C02H, -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (NH ) -NH2, -C (0) -NH-alkyl (CM), -C (0) -N [(Cι) alkyl] 2, -SH, -S-alkyl (CM), -S02-alkyl of (CM), -S02-NH2, -S02-NH-alkyl of (CM), -S02-N [(d.)] alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C2-4alkenyl, C2-4alkenyl, C2-4alkynyl, -alkyl (CM) -NH2, -C (0) -alkyl (C1-4), -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (0) -NH-alkyl of (CM), -C (0) -N [(C1-4) alkyl] 2, -S02-alkyl of (CM), -S02-NH2, -S02-NH-alkyl of (CL 4), -S02-N [alkyl of (Cμ)] 2 and -C (NH) -NH 2), cyano, halo, (halo) ? ^ (4) alkyl, (halo)? 3alkoxy of (C1.4), hydroxy, hydroxy (d-4) alkyl, nitro, aryl, (C 4 -4) alkylaryl, heteroaryl, and (CM) -heteroaryl alkyl. More preferably, R3 and R4 are independently selected from the group consisting of hydrogen, CM alkyl, CM alkoxy, cyano, and halogen. More preferably, R3 and R4 are independently selected from the group consisting of hydrogen, methyl, methoxy, cyano and chloro. Exemplified compounds of formula (I) include compounds selected from formula (la) (N1 and N2 for the substituent R2 indicates that R2 is attached to the N1 or N2 position of the indazole ring, respectively): and pharmaceutically acceptable salts thereof. The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms approved by the FDA (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1977, January, 66 (1), p1) include acid / anionic salts or basic / cationic pharmaceutically acceptable Acidic / pharmaceutically acceptable anionic salts include, and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisilate, estolate, esylate, fumarate, glycetate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate and triethyodide. The pharmaceutically acceptable basic / cationic salts include, and are not limited to, aluminum, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, megiumine, potassium, procaine, sodium and zinc. However, other salts may be useful in the preparation of compounds according to this invention or their pharmaceutically acceptable salts. Organic or inorganic acids also include, and are not limited to, hydroiodic acid, perchloric acid, sulfuric acid, phosphoric acid, propionic acid, glycolic acid, methanesulfonic acid, hydroxyethane sulfonic acid, oxalic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexansuiphamic acid, saccharinic acid or trifluoroacetic acid. The present invention includes within its scope prodrugs of the compounds of this invention. In general, said prodrugs will be functional derivatives of the compounds which are easily converted in vivo to the required compound. Therefore, in the methods of treatment of the present invention, the term "administration" should encompass the treatment of the various disorders described with the specifically described compound or with a compound of which it may not be specifically described, but which converts the compound specified in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Desiqn of Prodrugs", ed. H. Bundgaard, Elsevier, 1986. Where the compounds according to this invention have at least one chiral center, these may exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in the form of racemic or individual enantiomers by standard techniques known to those skilled in the art, for example, by enantiospecific synthesis or resolution, diastereomeric pair formation by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by the formation of diastereomeric esters or amides, followed by separation chromatography and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column. It should be understood that all isomers and mixtures thereof are encompassed within the scope of the present invention. During any of the methods for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the participating molecules. This can be achieved by conventional group protection methods, such as those described in Protective Groups in Organic Chemistry. ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. Wuts, Protective Groups in Organic Svnthesis. John Wiley & Sons, 1991. The protecting groups can be removed in a convenient subsequent step using methods known in the art. In addition, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (eg, hydrates) or common organic solvents and said solvates are also intended to be encompassed within the scope of this invention. Unless otherwise specified, the term "alkyl" refers to a straight or branched saturated chain consisting of only 1-8 carbon atoms substituted with hydrogen; preferably, 1-6 carbon atoms substituted with hydrogen; and, more preferably, 1-4 carbon atoms substituted with hydrogen. The term "alkenyl" refers to a straight or branched partially unsaturated chain consisting of only 2-8 carbon atoms substituted with hydrogen containing at least one double bond. The term "alkynyl" refers to a straight or branched partially unsaturated chain consisting of only 2-8 carbon atoms substituted with hydrogen containing at least one triple bond. The term "alkoxy" refers to -O-alkyl, wherein the alkyl is as defined above. The term "hydroxyalkyl" refers to radicals wherein the alkyl chain ends with a hydroxy radical of the formula HO-alkyl, wherein the alkyl is as defined above. The alkyl, alkenyl and alkynyl chains are optionally substituted within the alkyl chain or at a terminal carbon atom. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic alkyl ring consisting of 3-8 carbon atoms substituted with hydrogen or a saturated or partially unsaturated bicyclic ring consisting of 9 or 10 carbon atoms substituted with hydrogen. Examples include, and are not limited to, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "heterocyclyl" as used in the present invention refers to a saturated or unsaturated unsaturated or substituted monocyclic three to seven membered monocyclic ring system consisting of carbon atoms and from one to three selected heteroatoms. from N, O or S, or a bicyclic ring system of eight to eleven saturated or partially saturated stable which consists of carbon atoms and from one to four heteroatoms selected from N, O, or S. In any of the monocyclic or bicyclic rings the nitrogen or sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may be optionally quatemized. Saturated or partially unsaturated rings having five to six members are preferred, of which at least one member is a N, O or S atom and which optionally contains an additional N, O or S atom; saturated or partially unsaturated bicyclic rings having from nine to ten members of which at least one member is a N, O or S atom and which optionally contains one or two additional N, O or S atoms; wherein said bicyclic rings of nine to ten members may have an aromatic ring and a non-aromatic ring. In another embodiment of this invention the previously defined heterocyclyl has as the additional heteroatom N, wherein at least two nitrogen atoms are adjacent. Examples include, and are not limited to, pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolidinyl, piperidinyl, morpholinyl or piperazinyl. The term "aryl" refers to an aromatic monocyclic ring containing carbon and hydrogen, such as a carbon ring containing 6 carbon atoms with hydrogen atoms substituted therein, an aromatic bicyclic ring system containing 10 carbon atoms with hydrogen substituted therein or aromatic tricyclic ring system containing 14 carbon atoms with hydrogen atoms substituted therein. Also included within the scope of the definition of aryl are the bicyclic and tricyclic ring systems (containing carbon and hydrogen) wherein only one of the rings is aromatic such as tetrahydronaphthalene and indane. The hydrogen atoms on the monocyclic, bicyclic and tricyclic rings can be replaced with other groups or substituents as indicated. Examples include, and are not limited to, phenyl, naphthalenyl or anthracenyl. The term "heteroaryl" as used in the present invention represents a stable unsubstituted or substituted five or six membered monocyclic heteroaromatic ring system or a nine- or ten-membered unsubstituted or substituted bicyclic heteroaromatic ring system and ring systems stable tricyclics of twelve to fourteen unsubstituted or substituted members which consist of carbon atoms and one to four heteroatoms selected from N, O or S, and wherein the nitrogen heteroatom of any of these heteroaryls may optionally be oxidized , or it can be optionally quatemized. Preferred heteroaryls are monocyclic aromatic rings containing five members of which at least one member is an N, O or S atom and which optionally contains one, two or three additional N atoms; an aromatic monocyclic ring having six members of which one, two or three members are N atoms; an aromatic bicyclic ring having nine members of which at least one member is an atom of N, O or S and which optionally contains one, two or three additional N atoms; an aromatic bicyclic ring having ten members of any one, two, three or four members are N atoms; or, an aromatic tricyclic ring system containing 13 members of which at least one member is an N, O or S atom and which optionally contains one, two or three additional N atoms. In another embodiment of this invention, the previously defined heteroaryls have the additional N hetero atom, wherein at least four nitrogen atoms are adjacent. Examples include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolium, thiazolyl, imidazolyl, triazolyl, oxatriazole, tetrazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazine, indolyl, indazolyl, benzo ( b) thienyl, quinolinyl, isoquinolinyl or quinazolinyl. Whenever the term "alkyl" or "aryl" or any of its prefix roots appears in a name of a substituent (eg, aralkyl, aikylamino) it should be construed as including those limitations given above for "alkyl" and " aril. " The numbers of carbon atoms designed (eg, d-Cß) should refer independently to the number of carbon atoms in an alkyl or cycloalkyl portion or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. Using standard naming rules throughout this description, the terminal portion of the designated side chain is initially described followed by functionality adjacent to the point of attachment. Thus, for example, a substituent "phenylalkylamido (Ci-CβJ-alkyl (Cr C6)" refers to a group of the formula: - a junction point of the substituent can also be indicated by a dotted line to imply a junction point (s), followed by the adjacent functionality and ending with the terminal functionality such as, for example, __- aiquilo de (C? - 6) -C (0) NH-alkyl of (d.6) -phenyl. It is intended that the definition of any substituent or variable in a particular location in a molecule be independent of its definitions elsewhere in the molecule. It is understood that substituents and substitution patterns in the compounds of this invention can be selected by one skilled in the art to provide compounds that are chemically stable and that can be easily synthesized by techniques known in the art as well as those methods set forth above in the present invention. One embodiment of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Illustrative of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for the manufacture of a pharmaceutical composition comprising the mixture of any of the above-described compounds and a pharmaceutically acceptable carrier. Further illustrative of the present invention are pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.

As used in the present invention, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the ingredients specified in the specified amounts. The compounds of the present invention are selective kinase or dual kinase inhibitors useful in a method for the treatment or amelioration of a kinase or dual kinase mediated disorder. In particular, the kinase is selected from protein kinase C or glycogen synthase kinase-3. More particularly, the kinase is selected from protein kinase C a, protein kinase Cß-ll, protein kinase C? or glycogen synthase kinase-3β.

Isoforms of Protein kinase C It is known that protein kinase C plays a key role in the transduction of the intracellular signal (cell-cell signaling), gene expression and in the control of cell differentiation and growth. The PKC family is composed of twelve isoforms that are further classified into 3 subfamilies: the classic calcium-dependent PKC alpha (a) isoforms, the beta-I (ß-l), beta-ll (ß-ll) and gamma isoforms ( ?); the independent PKC sophomores of calcium delta (d), epsilon (e), eta (?), theta (?) and mu (μ); and, the atypical PKC isoforms zeta (?), lambda (?) and ota (i).

Certain disease states tend to be associated with an elevation of the particular isoforms of PKC. The PKC isoforms exhibit a distinct tissue distribution, subcellular localization and cofactor-dependent activation. For example, the ß and β-sofmas of PKC are selectively induced in vascular cells stimulated with agonists such as vascular endothelial growth factor (VEGF) (P. Xia, et al., J. Clin. Invest., 1996, 98, 2018) and have been implicated in cell growth, differentiation, and vascular permeability (H. Ishii, et al., J. Mol. Med., 1998, 76, 21). The elevated blood glucose levels found in diabetes produce a specific isoform elevation of the ß-ll isoform in vascular tissues (Inoguchi, et al., Proc. Nati, Acad. Sci. USA, 1992, 89, 11059-11065 ). An elevation associated with diabetes of the β isoform in human platelets has been related to its altered response to agonists (Bastar III, E. J. and Lu, J., Diabetes, 1993, 42, (Suppl 1) 97A). It has been shown that the human vitamin D receptor is selectively phosphorylated by PKCß. This phosphorylation has been associated with alterations in the functioning of the receptor (Hsieh, et al., Proc. Nati, Acad. Sci. USA, 1991, 88, 9315-9319).; Hsieh, et al., J. Biol. Chem., 1993, 268, 15118-15126). In addition, the work has shown that the ß-ll isoform is responsible for the proliferation of the erythroleukemia cell while the isoform a participates in the megakaryocyte differentiation in these same cells (Murray, et al., J. Biol. Chem. , 1993, 268, 15847-16863).

Cardiovascular diseases The activity of PKC plays an important role in cardiovascular diseases. The increased activity of PKC in the vasculature has been shown to cause increased vasoconstriction and hypertension (Bilder, G.E., et al., J. Pharmacol. Exp. Ther., 1990, 252, 626-630). PKC inhibitors block the proliferation of smooth muscle cells induced by agonists (Matsumoto, H. and Sasaqui, Y., Biochem, Biophys, Res. Commun., 1989, 168, 106-109). PKC β activates events that lead to the induction of Egr-1 (early growth factor-1) and growth factor under hypoxic conditions (as part of the pathway mediated by oxygen deprivation to activate the events that procoagulation) (Yan , SF, et al., J. Biol. Chem., 2000, 276, 16, 11921-11928). PKC β is suggested as a mediator for the production of PAI-1 (plasminogen activator inhibitor-1) and is implicated in the development of thrombosis and atherosclerosis (Ren, S, et al., Am. J. Physio ., 2000, 278, (4, Pt. 1), E656-E662). PKC inhibitors are useful in the treatment of cardiovascular ischemia and improvement of cardiac function after ischemia (Muid, RE, et al., FEBS Lett., 1990, 293, 169-172; Sonoqui, H. et al. , Kokyu-To Junkan, 1989, 37, 669-674). Elevated levels of PKC have been correlated with an increased response in platelet function to agonists (Bastar III, E. J. and Lu, J., Diabetes, 1993, 42, (Suppl 1) 97A). PKC has been implicated in the biochemical pathway in the modulation of vascular micropermeability by platelet activating factor (FAP) (Kobayashi, et al., Amer. Phys. Soo, 1994, H1214-H1220). PKC inhibitors affect platelet aggregation induced by the agonist (Toullec, D., et al., J. Biol. Chem., 1991, 266, 15771-15781). Accordingly, PKC inhibitors can be indicated for use in the treatment of cardiovascular disease, ischemia, thrombotic conditions, atherosclerosis and restenosis.

Diabetes Excessive activity of PKC has been associated with defects in insulin signaling and therefore in insulin resistance observed in type II diabetes (Karasik, A., et al., J. Biol. Chem. ., 1990, 265, 10226-10231; Chen, K.S., et al., Trans. Assoc. Am. Physicians, 1991, 104, 206-212; Chin, J. E., et al., J. Biol. Chem., 1993, 268, 6338-6347).

Disorders associated with diabetes Studies have shown an increase in the activity of PKC in tissues known to be susceptible to diabetic complications when exposed to hyperglycemic conditions (Lee, T-S., Et al., J. Clin. Invest., 1989, 83, 90-94; Lee, T-S., Et al., Proc. Nati Acad. Sci. USA, 1989, 86, 5141-5145; Craven, P. A. and DeRubertis, F. R., J. Clin. Invest., 1989, 87, 1667-1675; Wolf, B.A., et al., J. Clin. Invest., 1991, 87, 31-38; Tesfamariam, B., et al., J. Clin. Invest., 1991, 87, 1643-1648). For example, activation of the PKC-ß-ll isoform plays an important role in diabetic vascular complications such as retinopathy (Ishii, H., et al., Science, 1996, 272, 728-731) and PKC ß has been involved in the development of cardiac hypertrophy associated with heart failure (X. Gu, et al., Circ Res., 1994, 75, 926; RH Strasser, et al., Circulation, 1996, 94, 1561). The overexpression of PKC ßll cardiac in transgenic mice causes cardiomyopathy involving hypertrophy, fibrosis and decreased left ventricular function (H. Wakasaqui, et al., Proc Nati, Acad Sci. USA, 1997, 94, 9320).

Inflammatory diseases PKC inhibitors block inflammatory responses such as the oxidative burst of the neutrophil, the down-regulation of CD3 in T lymphocytes and the phlebol-induced foot edema (Twoemy, B., et al., Biochem. Biophys. Res. Commun., 1990, 171, 1087-1092; Mulqueen, MJ, et al., Agents Actions, 1992, 37, 86-89). PKC β plays an essential role in the degranulation of mast cells derived from the bone marrow, thus affecting the cellular capacity to produce IL-6 (interleukin-6) (Nechushtan, H., et al., Blood, 2000 (March), 95, 5, 1752-1757). PKC plays a role in improving the growth of the ASM cell (smooth muscle of the airways) in rat models with two potential risks for asthma: hyperresponsiveness to contractile agonists and growth stimuli (Ren, S, et al. , Am. J. Physio, 2000, 278, (4, Pt. 1), E656-E662). The overexpression of PKC β-1 increases an increase in endothelial permeability, suggesting an important function in the regulation of the endothelial barrier (Nagpala, PG, et al., J. Cell Physiol., 1996, 2, 249-dd ). PKC ß mediates the activation of neutrophil NADPH oxidase by PMA and by stimulation of Fc? in neutrophils (Dekker, L.V., et al., Biochem. J., 2000, 347, 286-289). Therefore, PKC inhibitors can be indicated for use in the treatment of inflammation and asthma.

Immunological disorders PKC can be used in the treatment or improvement of certain immunological disorders. Although one study suggests that the inhibition of HCMV (human cytomegalovirus) does not correlate with the inhibition of PKC (Slater, MJ, et al., Biorg. & Med. Chem., 1999,7, 1067-1074), another study showed that the transduction pathway of the PKC signal interacts in a synergistic manner with the cAMP-dependent PKA pathway to activate or increase HIV-1 transcription and viral replication and was eliminated with a PKC inhibitor (Rabbi , MF, et al., Virology, 1998 (June 5), 245, 2, 267-69). Therefore, an immunological disorder can be treated or improved as a function of the response of the underlying pathway affected for PKC over or under regulation. Deficiency in PKC ß can result in an immunodeficiency characterized by altered immune humoral responses and a reduced response of the B cell, similar to X-linked immunodeficiency in mice, playing an important role in the transduction of the signal mediated by the antigen receptor (Leitges, M., et al., Science (Wash., D. C), 1996, 273, 5276, 788-789). Consequently, the rejection of transplanted tissue can be improved or prevented by suppressing the immune response using an inhibitor to PKC β.

Dermatological disorders The abnormal activity of PKC has been associated with dermatological disorders characterized by an abnormal proliferation of keratinocytes, such as psoriasis (Hom, F., et al., J. Invest, Dermatol., 1987, 88, 220- 222; Raynaud, F. and Evain-Brion, D., Br. J. Dermatol., 1991, 124, 542-546). It has been shown that inhibitors of PKC inhibit keratinocyte proliferation in a dose-dependent manner (Hegemann, L., et al., Arch. Dermatol Res., 1991, 283, 456-460, Bollag, WB, et al. , J. Invest, Dermatol., 1993, 100, 240-246).

Oncological disorders The activity of PKC has been associated with cell growth, tumor promotion and cancer (Rotenberg, SA and Weinstein, IB, Biochem.M. Aspects Sel.Cancer, 1991, 1, 25-73; Ahmad, et al. , Molecular Pharmacology, 1993, 43, 858-862); it is known that inhibitors of PKC are effective in the prevention of tumor growth in animals (Meyer, T., et al., Int. J. Cancer, 1989, 43, 851-856; Aquinagaka, S., et al. , Cancer Res., 1991, 51, 4888-4892). The expression of PKC ß-1 and ß-2 in differentiated cells of colon carcinoma HD3 blocked their differentiation, allowing them to proliferate in response to basic FGF (fibroblast growth factor) in a similar way to undifferentiated cells, increasing their rate of growth and activating various MBP (myelin basic proteins) kinases, including p57 MAP (mitogen-activated protein) cinase (Sauma, S., et al., Cell Growth Differ., 1996, 7, 5, 687-94). The inhibitors of PKC a, which have an additive therapeutic effect in combination with other anti-cancer agents, inhibited the growth of leukemia lymphocytic cells (Konig, A., et al., Blood, 1997, 90, 10, Suppl. 1 Pt. 2). PKC inhibitors improved MMC-induced apoptosis (Mitomycin-C) in a time-dependent manner in the gastric cancer cell line, indicating their potential use as agents for apoptosis induced by chemotherapy (Danso, D., et al., Proc. Am. Assoc. Cancer Res., 1997, 38, 88 Meet., 92). Therefore, PKC inhibitors can be indicated for use in cell enhancement and tumor growth, in the treatment or improvement of cancers (such as leukemia or colon cancer) and as adjuncts for chemotherapy. PKC a (through enhanced cell migration) can mediate some proangiogenic effects of PKC activation while PKC d can direct the anti-angiogenic effects of general activation of PKC (by inhibiting cell growth and proliferation) in capillary endothelial cells, thereby regulating endothelial proliferation and angiogenesis (Harrington, EO, et al., J. Biol. Chem., 1997, 272, 11, 7390-7397). PKC inhibitors inhibit cell growth and induce apoptosis in human glioblastoma cell lines, inhibiting the growth of human astrocytoma xenografts and acting as radiation sensitisers in glioblastoma cell lines (Begemann, M., et al. ., Anticancer Res. (Greece), 1998 (July-August), 18, 4A, 2276-82). PKC inhibitors, in combination with other anti-cancer agents, are radiation and chemosensitizers useful in cancer therapy (Teicher, BA, et al., Proc, Am. Assoc. Cancer Res., 1998, 39, 89 Meet. , 384). Inhibitors of PKC β (by blocking MAP kinase signal transduction pathways for VEGF (vascular endothelial growth factor) and bFGF (basic fibrinogen growth factor) in endothelial cells), in a combination regimen with other anti-cancer agents, has an anti-angiogenic and anti-tumor effect in a T98G glioblastoma multiforme xenograft model of human (Teicher, BA, et al., Clinical Cancer Research, 2001 (March), 7, 634-640) . Accordingly, PKC inhibitors may be indicated for use in the improvement of angiogenesis and in the treatment or improvement of cancers (such as breast, brain, kidney, bladder, ovarian or colon cancers) and as adjuncts to chemotherapy and radiation therapy.

Central nervous system disorders The activity of PKC plays a central role in the functioning of the central nervous system (CNS) (Huang, K. P., Trends Neurosci., 1989, 12, 425-432) and PKC has been implicated in the disease of Alzheimer (Shimohama, S., et al., Neurology, 1993, 43, 1407-1413) and inhibitors have been shown to arrest the damage seen in focal and central ischemic brain injury and cerebral edema (Hara, H. , et al., J. Cereb Blood Flow Metab., 1990, 10, 646-653; Shibata, S., et al., Brain Res., 1992, 594, 290-294). Accordingly, PKC inhibitors can be indicated for use in the treatment of Alzheimer's disease and in the treatment of neurotraumatic and ischemic-related diseases. The long-term increase in the expression of the receptor to PKC? (as a component of the second messenger system of phosphoinositol) and the expression of the muscarinic acetylcholine receptor in rat model with bright amygdala has been associated with epilepsy, serving as a basis for the state of permanent hyperexcitability of the rat (Beldhuis, HJA, et al., Neuroscience, 1993, 56, 4, 965-73). Therefore, PKC inhibitors can be indicated for use in the treatment of epilepsy. Subcellular changes in the content of PKC isozymes? and PKC ß-ll for animals in an in-vivo model of thermal hyperalgesia suggests that peripheral nerve injury contributes to the development of persistent pain (Miletic, V., et al., Neurosci, Lett., 2000, 288, 3, 199-202). Mice lacking PKC? they exhibit normal responses to acute pain stimuli, but usually can not develop a neuropathic pain syndrome after partial sectioning of sciatic nerves (Chen, C, et al., Science (Wash., D.C.), 1997, 278, 5336 , 279-283). Therefore the modulation of PKC can be indicated for use in the treatment of chronic pain and neuropathic pain.

It has been demonstrated that PKC has a role in the pathology of conditions such as, but not limited to, cardiovascular diseases, diabetes, disorders associated with diabetes, inflammatory diseases, immunological disorders, dermatological disorders, oncological disorders and nervous system disorders. central.

Glycogen synthase kinase-3 Glycogen synthase kinase-3 (GSK-3) is a serine / threonine protein kinase composed of two isoforms (and ß) which are encoded by different genes. GSK-3 is one of several protein kinases which phosphorylate glycogen synthase (GS) (Embi, et al., Eur. J. Biochem, 1980, 107, 519-527). The isoforms a and ß have a monomeric structure of 49 and 47kD respectively and both are found in mammalian cells. Both isoforms phosphorylate muscle glycogen synthase (Cross, et al., Biochemical Journal, 1994, 303, 21-26) and these two isoforms show good homology between species (GSK-3a from human and rabbit are 96% identical).

Diabetes Type II diabetes (or non-insulin dependent Diabetes Mellitus, NIDDM) is a multifactorial disease. Hyperglycemia is due to insulin resistance in the liver, muscle and other tissues coupled with inadequate or defective insulin secretion from pancreatic islets. In skeletal muscle it is the main site for taking glucose stimulated by insulin and in this tissue the glucose is removed from the circulation either by being metabolized through glycolysis and the TCA (tricarboxylic acid) cycle or stored as glycogen. The deposition of glycogen in muscle plays the most important role in glucose homeostasis and subjects with type II diabetes have a defective storage of glycogen in muscle. The stimulation of glycogen synthesis by insulin in skeletal muscle results from the dephosphorylation and activation of glycogen synthase (Villar-Palasi C. and Lamer J., Biochim. Biophys. Acta, 1960, 39, 171-173, Parker P.J., et al., Eur. J. Biochem., 1983, 130, 227-234, and Cohen P., Biochem. Soc. Trans., 1993, 21, 555-567). The phosphorylation and dephosphorylation of GS are mediated by specific kinases and phosphatases. GSK-3 is responsible for the phosphorylation and deactivation of GS, while protein phosphatase 1 bound to glycogen (PP1G) dephosphorylates and activates GS. Insulin inactivates GSK-3 and activates PP1G (Srivastava A.K. and Pandey S.K., Mol.and Cellular Biochem., 1998, 182, 135-141).

Studies suggest that an increase in GSK-3 activity may be important in muscle with type II diabetes (Chen, et al., Diabetes, 1994, 43, 1234-1241). The overexpression of GSK-3β and constitutively activates the mutants GSK-3β (S9A, S9e) in HEK-293 cells resulted in the suppression of glycogen synthase activity (EIdar-Finkelman, et al., PNAS, 1996 , 93, 10228-10233) and the overexpression of GSK-3β in CHO cells, which express both the insulin receptor and the insulin receptor 1 substrate (IRS-1) resulted in an alteration of the action of the insulin (EIdar-Finkelman and Krebs, PNAS, 1997, 94, 9660-9664). Recent evidence has emerged of the participation of elevated GSK-3 activity and the development of insulin resistance and type II diabetes in adipose tissue from studies that have been conducted in mice with diabetes and in C57BL mice / 6J prone to obesity (EIdar-Finkelman, et al., Diabetes, 1999, 48, 1662-1666).

Dermatological disorders The finding that transient stabilization of β-catenin may play a role in hair development (Gat, et al., Cell, 1998, 95, 605-614) suggests that GSK-3 inhibitors also They can be used in the treatment of baldness.

Inflammatory diseases Studies on fibroblasts from mice that have been eliminated with GSK-3ß indicate that the inhibition of GSK-3 may be useful in the treatment of inflammatory disorders or diseases through the negative regulation of the activity of NFkB (Hoeflich KP, et al., Nature, 2000, 406, 86-90).

Central nervous system disorders In addition to the modulation of glycogen synthase activity, GSK-3 also plays an important role in CNS disorders. Inhibitors of GSK-3 may be valuable as neuroprotectants in the treatment of acute stroke and other neurotraumatic lesions (Pap and Cooper, J. Biol. Chem., 1998, 273, 19929-19932). It has been shown that lithium, an inhibitor of GSK-3 at low mM, protects granular neurons of the cerebellum from death (D'Mello, et al., Exp. Cell Res., 1994, 211, 332-338) and chronic treatment with lithium has demonstrated efficiency in the stroke model due to occlusion of the middle cerebral artery in rodents (Nonaka and Chuang, Neuroreport, 1998, 9 (9), 2081-2084). Tau and β-catenin, two substrates known in vivo for GSK-3, are of direct relevance in the consideration of additional aspects of the value of GSK-3 inhibitors in relation to the treatment of chronic neurodegenerative conditions. Tau hyperphosphorylation is an early event in neurodegenerative conditions such as Alzheimer's disease and it has been postulated that it promotes the disassembly of microtubules. It has been reported that lithium reduces the phosphorylation of tau, promotes the binding of tau to microtubules and promotes the disassembly of microtubules through the direct and reversible inhibition of GSK-3 (Hong M. et al. J. Biol. Chem., 1997, 272 (40), 25326-32). Β-catenin is phosphorylated by GSK-3 as part of a tripartite complex of axin protein that results in the degradation of β-catenin (Ikeda, et al., EM80 J., 1998, 17, 1371-1384) . The inhibition of GSK-3 activity is involved in the stabilization of catenin and therefore promotes the transcriptional activity of β-catenin-LEF-1 / TCF (Eastman, Grosschedl, Curr Opin Cell Cell, 1999, 11, 233). Studies have also suggested that GSK-3 inhibitors may be valuable in the treatment of schizophrenia (Cotter D., et al., Neuroreport, 1998, 9, 1379-1383, Lijam N., et al., Cell, 1997, 90, 895-906) and manic depression (Manji, et al., J. Clin. Psychiatry, 1999, 60, (Suppl 2) 27-39 for review). Accordingly, the compounds that have been found useful as GSK-3 inhibitors may have additional therapeutic utility in the treatment of diabetes, dermatological disorders, inflammatory diseases and central nervous system disorders. Modalities of the method of the present invention include a method for the treatment or amelioration of a dual kinase or kinase mediated disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the present compound or pharmaceutical composition. of the same. The amount Therapeutically effective of the compounds of formula (I) exemplified in said method is from about 0.001 mg / kg / day to about 300 mg / kg / day. The embodiments of the present invention include the use of a compound of formula (I) for the preparation of a medicament for the treatment or amelioration of a dual kinase or kinase mediated disorder in a subject in need thereof. In accordance with the methods of the present invention, a single compound of the present invention or a pharmaceutical composition thereof can be administered separately at different times during the course of therapy or concurrently in divided or particular combination forms. Therefore, it is understood that the present invention encompasses all such simultaneous or alternate treatment regimens and the term "administration" should be construed accordingly. The embodiments of the present method include a compound or pharmaceutical composition thereof co-administered advantageously in combination with other agents for the treatment or amelioration of a disorder mediated by a dual kinase or kinase. For example, in the treatment of diabetes, especially type II diabetes, a compound of formula (I) or pharmaceutical composition thereof can be used in combination with other agents, especially insulin or antidiabetic agents including, but not limited to, insulin secretagogues (such as sulfonylureas), insulin sensitizers including, but not limited to, insulin sensitizers such as glitazone (such as thiazolidinediones) or biguanides or glucosidase inhibitors. The combination product comprises the co-administration of a compound of formula (1) or pharmaceutical composition thereof and an additional agent for treatment or amelioration of a dual kinase or kinase mediated disorder, the sequential administration of a compound of formula (I) ) or pharmaceutical composition thereof and an additional agent for the treatment or amelioration of a dual kinase or kinase mediated disorder, administration of a pharmaceutical composition containing a compound of formula (I) or pharmaceutical composition thereof and an additional agent for the treatment or improvement of a dual kinase or kinase mediated disorder or essentially the simultaneous administration of a separate pharmaceutical composition containing a compound of formula (I) or pharmaceutical compositions thereof and a separate pharmaceutical composition containing an additional agent for the treatment or improvement of a disorder mediated by kinase or dual kinase. The term "subject" as used in the present invention refers to an animal, preferably a mammal, more preferably a human, which has been the objective of treatment, observation or experiment. The term "therapeutically effective amount" as used in the present invention means that amount of the active compound or pharmaceutical agent that induces the biological or medicinal response in a tissue, animal or human system, which is to be studied by a researcher, veterinarian, doctor, or other clinician, which includes relief of the symptoms of the disease or disorder to be treated. The ubiquitous nature of the PKC and GSK isoforms and their important roles in physiology provide an incentive to produce highly selective inhibitors of PKC and GSK. Given the evidence demonstrating the binding of certain isoforms to disease states, it is reasonable to assume that inhibitor compounds that are selective to one or two isoforms of PKC or to an isoform of GSK relative to other isoforms of PKC and GSK and other protein kinases they are superior therapeutic agents. These compounds must demonstrate greater efficiency and lower toxicity by virtue of their specificity. Accordingly, it will be appreciated by one skilled in the art that a compound of formula (I) is therapeutically effective for certain kinase or dual kinase mediated disorders on modulation of the disorder by selective inhibition of the kinase or dual kinase. The utility of a compound of formula (I) as a selective inhibitor to the kinase or dual kinase can be determined in accordance with the methods described in the present invention and the scope of said use includes the use of one or more disorders mediated by kinase or by dual kinase. Thus, the term "kinase or dual kinase mediated disorders" as used in the present invention, includes, and is not limited to, cardiovascular diseases, diabetes, disorders associated with diabetes, inflammatory diseases, immunological disorders, dermatological disorders, Oncology and CNS disorders. Cardiovascular diseases include, and are not limited to, acute stroke, heart failure, cardiovascular ischemia, thrombosis, atherosclerosis, hypertension, restenosis, retinopathy of prematurity or age-related macular degeneration. Diabetes includes insulin-dependent diabetes or type II non-insulin-dependent diabetes mellitus. Disorders associated with diabetes include, and are not limited to, impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy, or neuropathy. Inflammatory diseases include, and are not limited to, vascular permeability, inflammation, asthma, rheumatoid arthritis or osteoarthritis. Immune disorders include, and are not limited to, rejection of transplanted tissue, HIV-1 or immune disorders treated or improved by modulation of PKC. Dermatological disorders include, and are not limited to, psoriasis, hair loss or baldness. Oncological disorders include, and are not limited to, cancers or tumor growth (such as breast, brain, kidney, bladder, ovarian or colon cancer or leukemia), proliferative angiopathy and angiogenesis; and includes the use of the compounds of formula (I) as an adjunct to chemotherapy and radiation therapy. CNS disorders include, and are not limited to, chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative conditions (such as dementia or Alzheimer's disease), mood disorders (such as schizophrenia), manic or neurotraumatic depression, decreased cognitive and diseases related to ischemia. { as a result of trauma to the head (from acute ischemic stroke, injury or surgery) or transient ischemic stroke (from coronary bypass surgery or other transient ischemic conditions)} . In another embodiment of a method of treating or ameliorating a disorder selected from the group consisting of disorders associated with diabetes, dermatological disorders, oncological disorders and central nervous system disorders comprising administration to a subject in need of treatment of a therapeutically effective amount of a compound of formula (I): Formula (I) wherein R 1 is selected from the group consisting of: hydrogen, Ci-s alkyl, C 2-8 alkenyl, C 2-8 alkynyl and C 3-8 cycloalkyl. { wherein alkyl, alkenyl, alkynyl and C3.8 cycloalkyl are optionally substituted with one to two substituents independently selected from the group consisting of -O-alkyl (C? 8), -O-alkyl (C? _8) ) -OH, -O-alkyl of (d.8) -0-alkyl of (C? 8), -O-alkyl of (Ci. 8) -NH2, -O-alkyl of (C? .8) -NH-alkyl of (C? 8), -O-alkyl of (d.8) -N [alkyl of (d.8)] 2, -O-alkyl of (d.8) -S -alkyl of (C? 8), -O-alkyl of (d.8) -S02-alkyl of (C? -8), -O-alkyl of (C? -8) -S02-NH2, -O -alkyl of (C? 8) -S02-NH-alkyl (C? 8), -O-alkyl of (d.8) -S02-N [(C? -8) alkyl] 2 , -0-C (0) H, -OC (0) -alkyl of (C? .8), -0-C (0) -NH2, -0-C (0) -NH-alkyl of ( C? 8), -OC (O) -N-C (8) alkyl] -2, -O-alkyl of (d.8) -C (0) H, -O-alkyl of (C? 8) -C (0) -alkyl of (C? _8), -O-alkyl of (C? -8) -C02H, -O-alkyl of (d.8) -C (0) -0-alkyl of (C? -8), O-alkyl of (C?. 8) -C (0) -NH2, -O-alkyl of (C1-8) -C (0) -NH-alkyl of (C? -8) ), -O- (C1-8) alkyl-C (0) -N [alkyl (d-8)] 2, -C (0) H, -C (0) -alkyl of (C1-8), -C02H, -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (NH) -NH2, -C (0) - NH-alkyl of (d-β), -C (0) -N [alkyl of (C ?.8)] 2, -SH, -S-alkyl of (d.8), -S-alkyl of (C) .8) -S-alkyl of (C? 8), -S-alkyl of (C? 8) -0-alkyl of (C? .8), -S-alkyl of (C? -s) -O-alkyl (C? 8) -OH, -S-alkyl (d.8) -0-alkyl of (C? .8) -NH2, -S-alkyl (C? -d) ) -O-alkyl (C? -8) -NH-alkyl (C? -8), -S-alkyl (C.8) -O-alkyl of (d.8) -N [alkyl of ( C?. 8)] 2, -S-alkyl of (C .8) -NH-alkyl of (C ?. 8), -S02-alkyl of (d-8), -S02-NH2, -S02-NH-alkyl of (C .8), -S02-N [alkyl of (C? .8)] 2, amino ( substituted with two substituents independently selected from the group consisting of hydrogen, C2.8 alkyl alkenyl, C2.8 aikinyl, (C 1-8) -OH alkyl, (C? 8) alkyl -0- (C-8) alkyl, -C (8) -NH 2 -alkyl, (d 8) -NH-alkyl (C 8), -alkyl (C 8) -N- [Alkyl of (C? 8)] 2, -alkyl of (C? 8) -S-alkyl of (d.8), -C (0) -alkyl of (C -8) , -C (0) -0-alkyl of (C? 8), -C (0) -NH2, -C (0) -NH-alkyl of (C? _8), -C (0) -N [ alkyl of (d.8)] 2, -S02-alkyl of (C? 8), -S02-NH2, -S02-NH-alkyl of (C? -8), -SO2-N [alkyl of (d .8)] 2, -C (N) -NH2, aryl and arylalkyl of (C? -8) (wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, Ci-β, C?-8 alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and C? -8 alkyl), cyano, halo, (halo)? 3alkyl of (C? .8), (halo)? 3alkoxy of (C? .8), hydroxy, hydroxyalkyl of (C -8) and nitro)), cyano, (halo)? -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 which consists of C -8 alkyl, d-β alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and C? 8 alkyl), cyano, halo, (halo) .3alkyl of ( d-ß), (halo)? _ 3alcoxy of (C? -8), hydroxy, hydroxyalkyl of (C? .8) and nitro)} , -C (0) -alkyl of (d.8), -C (0) -aryl, -C (0) -0-alkyl of (C? 8), -C (0) -0-aryl, -C (0) -NH-alkyl of (C? -8), -C (0) -NH-aryl, -C (0) -N [alkyl of (C? -8)] 2, -S02 -alkyl (C1-8), -S02-aryl, aryl and heterocyclyl. { wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C8 alkyl, C2-alkenyl, C2-8 alkynyl, alkoxy of d.8, -C (0 ) H, -C (0) -alkyl of (C1-8), -C02H, -C (0) -0-alkyl of (C? 8), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl of (C? 8), -C (0) -N [alkyl of (d.8)] 2, -SH, -S-alkyl of (d.8) ), -S02-alkyl of (d.8), -S02-NH2, -S02-NH-alkyio of (d.8), -S02-N [(C? 8) alkyl] 2, amino (substituted with two substituents independently selected from the group consisting of hydrogen, d-β alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -alkyl of (d 8) -NH 2, -C ( 0) -alkyl of (C? 8), -C (0) -0-alkyl of (C? -β), -C (0) -NH 2, -C (0) -NH-alkyl of ( C? 8), -C (0) -N [(C? 8)] 2 alkyl, -S02-alkyl (C? 8), -S02-NH2, -S02-NH-alkyl ( d.8), -S02-N [(C?-8) alkyl] 2 and -C (NH) -NH2), amino-alkylamino (C_d) - (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, d-β alkyl, d-β alkenyl, d-β alkynyl, -alkyl of (C ?.8) -NH2, -C (0) -alkyl of ( C? -8), -C (0) -0-alkyl of (C? -8), -C (O) -NH2, -C (0) -NH-alkyl of (d.8), -C ( 0) -N [alkyl of (C?. D)] 2, -S02-alkyl of (d.8), -SO2-NH2, -S02-NH-alkyio of (C? -8), -S02-N [(d8) alkyl] 2 and -C (NH) -NH2), cyano, halo, (halo)? 3alkyl of (C? 8) -, (halo)? 3alkoxy of (d-8) ) -, hydroxy, hydroxyalkyl of (C? -8), nitro, aryl, -alkyl (C?. d) -aryl, heteroaryl and (C. 8) -heteroaryl alkyl}; R 2 is selected from the group consisting of-C?-8-Z alkyl, C 2-8 -alkenyl and C 8 -Z alkynyl; wherein the -C.sub.8.alkyl-C2.8alkenyl and C -8alkynyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, aikylamino of CM, CM dialkylamino, CM alkyl, CM alkoxy, (halo) 3 3 alkyl of (CM), (halo) - 3-alkoxy of (CM) and hydroxyalkyl of (CM); Z is a 5-6 membered monocyclic heteroaryl ring having 2 to 4 heteroatoms containing at least one carbon atom and at least one nitrogen atom; wherein Z is optionally substituted with R5; R5 is 1 to 2 substituents attached to a carbon or nitrogen Z atom and each substituent is independently selected from the group consisting of hydrogen, -C 8 alkyl, C 2-8 alkenyl, C2.8, -C (0) H, -C (0) -alkyl of (C1-8), -C02H, -C (0) -0-alkyl of (C? -8), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH (C? -8 alkyl), -C (0) -Nalkyl of (C -8)) 2, -SO2-alkyl (C) ? -8), -S02-NH2, -SO2-NH (C? -8 alkyl), -S02-N (C? -8 alkyl) 2, -alkyl of (C? -8) -NH2, - (C? -8) -NH alkyl (C? -8 alkyl), -alkyl of (C? -d) -N (C8 alkyl) 2, -alkyl of (C? .8) - ( halo) 3, -alkyl of (Ci-β) -OH, -aryl, -alkyl of (C? 8) -aryl, heteroaryl and -alkyl of (C?. 8) -heteroaryl; with the proviso that, when R5 is attached to a carbon atom, R5 is further selected from the group consisting of -C1.8alkoxy, -alkoxy of (C? -d) - (halo) ?. , -SH, -S-alkyl of (C -s), -N-R6, cyano, halo, hydroxy, and nitro; R6 is 1 to 2 substituents independently selected from the group consisting of hydrogen, - d-β alkyl, -C2-d alkenyl, C2.8alkynyl, -C3.8 cycloalkyl, -C (0) H, -C (0) -alkyl of (d.8), -C (O) -O-alkyl of (d.8), -C (0) -NH2, -C (0) -NH (alkyl of C? 8), -C (0) -N (C? -8 alkyl) 2, -S02-alkyl (C? 8), -S02-NH2, -S02-NH (C? 8), -S02-N (C 1-8 alkyl) 2, -C (N) -NH 2, -C (N) -NH (C 1 .dome.) And -C (N) -N ( R3 and R4 are independently selected from the group consisting of hydrogen, C? 8 alkyl, C2-8 alkenyl, C2-8 alkynyl, d8 alkoxy, -C (0) H, -C ( 0) -alkyl of (C? 8), -C02H, -C (0) -0-aikyl of (d.8), -C (0) -NH2, -C (NH) -NH2, -C ( 0) -NH-alkyl of (C? 8), -C (0) -N [alkyl of (d. 8)] 2, -SH, -S-alkyl of (d.8), -S02-alkyl of (C? 8), -S02-NH2, -S02-NH-alkyl (C .8), -S02-N [(C? 8)] 2 alkyl, amino (substituted with two independently selected substituents from the group consisting of hydrogen, d-β alkyl, ds alkenyl, ds alkynyl, -dialkyl (d.8) -NH2, -C (0) -alkyl (C? 8), - C (O) -0-alkyl of (d.8), -C (0) -NH2, -C (0) -NH-alkyl of (C? -8), -C (0) -N [alkyl of (C? 8)] 2, -S02-alkyl of (d.8), -S02-NH2, -S02-NH-alkyl of (C? -8), -S02-N [(C? d)] 2 and -C (NH) -NH2), amino (C8) alkyl- (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C.sub.8.8, C2-β alkenyl, d-β alkynyl, -alkyl of (d.8) -NH2, -C (0) -alkyl of (C? .8), -C (0) -0-alkyl of (C? -8), -C (0) -NH2, -C (0) -NH-alkyl of (C? .8), -C (0) -N [alkyl of (d-) 8)] 2, -S02-alkyl of (d.8), -S02-NH2, -S02-NH-alkyl of (d.8), -S02-N [alkyl of (C? .8)] 2 and -C (NH) -NH2), cyano, halo, (halo) 1-3 alkyl (C? -8) -, (halo)? 3alkoxy of (C? -8) -, hydroxy, hydroxyalkyl of (C-) 8), nitro, aryl, -alkyl of (C? 8) -aryl, heteroaryl and -alkyl of (C -8) -heteroaryl; and pharmaceutically acceptable salts thereof. A compound can be administered to a subject in need of such treatment by any conventional route of administration including, but not limited to, oral, nasal, sublingual, ocular, transdermal, rectal, vaginal and parenteral (e.g., subcutaneous, intramuscular, intradermal, intravoid, etc.). To prepare the pharmaceutical compositions of this invention, one or more compounds of formula (I) or salts thereof as the active ingredient, is intimately mixed with a pharmaceutical carrier in accordance with the techniques for forming conventional pharmaceutical compounds, said carrier can take a variety of forms depending on the form of preparation desired for administration (for example oral or parenteral). Pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable vehicles can be found in The handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Methods for the formulation of pharmaceutical compositions have been described in numerous publications in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Extended, Volumes 1-3, edited by Lieberman, et al.; Pharmaceutical Dosage Forms: Parenteral Medications. Volumes 1-2, edited by Avis, et al .; and Pharmaceutical Dosaqe Forms: Disperse Systems, Volumes 1-2, edited by Lieberman, et al .; published by Marcel Dekker, Inc. In the preparation of a pharmaceutical composition of the present invention in liquid dosage form for oral, topical and parenteral administration, any of the usual pharmaceutical media or excipients may be employed. Therefore, for liquid dosage forms, such as suspensions (for example colloids, emulsions and dispersions) and solutions, suitable carriers and additives include but are not limited to pharmaceutically acceptable wetting agents, dispersants, condensing agents, thickeners, agents for pH control (for example pH regulators), osmotic agents, coloring agents, flavorings, fragrances, preservatives (for example to control microbial growth, etc.) and a liquid vehicle can be employed. Not all of the components listed above will be required for each liquid dosage form. In solid oral preparations such as, for example, powders, granules, capsules, caplets, gel capsules, pills and tablets (each including formulations for immediate release, progressive release and sustained release), suitable carriers and additives include but are not limit diluents, granulating agents, lubricants, binder, glidants, disintegrating agents and the like. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which cases solid pharmaceutical carriers are obviously employed. If desired, the tablets may be sugar coated, gelatin coated, film coated or enteric coated by standard techniques. The pharmaceutical compositions in the present invention will contain, per dosage unit, for example, tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to administer an effective dose as described above. The pharmaceutical compositions in the present invention will contain, per unit dose unit, for example, tablet, capsule, powder, injection, suppository, teaspoon and the like, from about 0.001 mg to about 300 mg (preferably about 0.01). mg to about 100 mg, and, more preferably, from about 0.1 mg to about 30 mg) and can be provided at a dose of about 0.001 mg / kg / day to about 300 mg / kg / day (preferably, about 0.01 mg / kg / day to approximately 100 mg / kg / day, and, more preferably, from approximately 0.1 mg / kg / day to approximately 30 mg / kg / day). Preferably, in the method for treating or ameliorating a kinase or dual kinase mediated disorder described in the present invention and using any of the compounds as defined in the present invention, the dosage form will contain a pharmaceutically acceptable carrier containing between approximately 0.01 mg and 100 mg; and, more preferably, between about 5 mg and 50 mg of the compound; and, it can be constituted in any suitable form for the selected administration mode. However, the doses may vary depending on the requirements of the subjects, the severity of the condition to be treated and the compound to be used. The use of any daily dose administration or post-periodic dose can be employed. Preferably these compositions are in the form of unit doses such as tablets, pills, capsules, powders, granules, tablets, sterile parenteral solutions or suspensions, measured aerosols or liquid sprays, drops, ampoules, self-injection devices or suppositories for administration by oral methods. , intranasal, sublingual, intraocular, transdermal, parenteral, rectal, vaginal, for inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for administration once a week or once a month; for example, an insoluble salt of the active compound, such as the decanoate salt, can be adapted to provide a reservoir preparation for intramuscular injection. For the preparation of solid pharmaceutical compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example conventional tabletting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, anti-adherents and glidants. Suitable diluents include, but are not limited to, starch (eg, corn, wheat, or potato starch, which can be hydrolyzed), lactose (granulated, spray-dried or anhydrous), sucrose, sucrose-based diluents. (sugar for confectionery, sucrose plus about 7 to 10 weight percent invert sugar, sucrose plus about 3 weight percent modified dextrins, sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 percent by weight of corn starch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (for example AVICEL ™ microcrystalline cellulose available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, lactate calcium trihydrate and the like. Suitable binders and adhesives include, but are not limited to, acacia gum, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics (e.g., methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like) water-soluble binder or binders that can be present (for example alginic acid and salts thereof, magnesium aluminum silicate, hydroxyethylcellulose (for example TYLOSE ™ available from Hoechst Celanese), polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates and pregelatinized starch) and the like. Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycollates, pregelatinized starches, resins (magnesium aluminum silicate), celluloses (such as cross-linked sodium carboxymethylcellulose and microcrystalline cellulose), alginates , pregelatinized starches (for example corn starch, etc.), gums (for example agar, guar, carob, karaya, pectin and gum tragacanth), cross-linked polyvinylpyrrolidone and the like. Suitable and non-stick lubricants include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc, waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, oleate sodium, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate and the like. Suitable glidants include, but are not limited to, talc, corn starch, silica (e.g. CAB-O-SIL ™ silica available from Cabot, SYLOID ™ silica available from WR Grace / Davison and AEROSIL ™ silica available from Degussa) and the like. The sweeteners and flavors can be added to the chewable solid dosage forms to improve the taste of the oral dosage form. Additionally, colorants and coatings may be added or applied to the second dosage form for ease of drug identification or for aesthetic purposes. These vehicles are formulated with the active pharmaceutical ingredient to provide an accurate, appropriate dose of the pharmaceutical active ingredient with a therapeutic release profile. Generally these vehicles are mixed with the pharmaceutical active ingredient to form a preformulation composition containing a homogeneous mixture of the pharmaceutical active ingredient of the present invention, or a pharmaceutically acceptable salt thereof. Generally the preformulation will be formed by one of three common methods: (a) wet granulation, (b) dry granulation and (c) dry mixing. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed homogeneously throughout the composition so that the composition can be easily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 mg to about 600 mg of the active ingredient of the present invention. Tablets or pills containing the novel compositions can also be formulated into fast multilayer tablets to provide a sustained release product or to provide dual release products. For example, a dual-release tablet or pill may comprise an internal dose component and an external dose component, the latter having the form of a cover over the first. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allows the internal component to pass intact into the duodenum or to have a delayed release. A variety of materials can be used for said coatings or enteric layers, said materials include numerous polymeric materials such as shellac, cellulose acetate (for example cellulose acetate phthalate), polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, copolymers of methacrylate and ethylacrylate, methacrylate and copolymers of methyl methacrylate and the like. Tablets for sustained release can also be made by film coating or wet granulation using slightly soluble or insoluble substances in solution (which for wet granulation act as binding agents) or low melting point solids to molten forms (which in a wet granulation can incorporate the active ingredient). These materials include natural and synthetic polymers, waxes, hydrogenated oils, fatty acids and alcohols (for example, beeswax, carnauba wax, cetylalcohol, cetilestearylalcohol and the like), the fatty acid esters of metal soaps and other acceptable materials that can be used for granulation, coating, entrapment or others limits the solubility of an active ingredient to achieve a prolonged or sustained release product. The liquid forms in which the novel compositions of the present invention can be incorporated for oral administration or by injection include, but are not limited to, aqueous solutions, flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils, such as such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable suspending agents for aqueous suspensions include synthetic and natural gums such as acacia, agar, alginate (for example propylene alginate, sodium alginate and the like), guar, karaya, carob, pectin, tragacanth and xanthan gum, cellulosics such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose and combinations thereof, synthetic polymers such as polyvinylpyrrolidone, carbomer (for example carboxypolymethylene) and polyethylene glycol; resins such as bentonite, hectorite, attapulgite or sepiolite; and other pharmaceutically acceptable suspending agents such as lecithin, gelatin or the like. Suitable surfactants include but are not limited to sodium docusate, sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxamer 188, polyoxamer 235, and combinations thereof. . The suitable agent for decondensation or dispersion includes pharmaceutical grade lecithins. The suitable condensation agent includes but is not limited to simple neutral electrolytes (for example sodium chloride, potassium, chloride and the like), highly charged insoluble polymers and polyelectrolyte species, divalent or trivalent water-soluble ions (e.g. calcium, alum or sulphates, citrates and phosphates (which can be used together in formulations as pH regulators and agents for condensation.) Suitable preservatives include but are not limited to parabens (e.g., methyl, ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternary ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate, phenylethanol and the like There are many liquid vehicles that can be used in pharmaceutical liquid dosage forms, however, the vehicle Liquid that is used in particular dosage forms must be compatible with the agent (s) for suspension. Nonpolar liquids such as fatty esters and oily liquid carriers are preferably used with suspending agents such as low HLB surfactants (hydrophilic-lipophilic balance), stearalkonium hectorite, water-insoluble resins, water-insoluble films that form polymers and Similar. Conversely, polar liquids such as water, alcohols, polyols and glycols are preferably used with suspending agents such as high HLB surfactants, resins, silicates, gums, water soluble cellulosics, water soluble polymers and the like. For parenteral administration, sterile suspensions and solutions are desired. Liquid forms useful for parenteral administration include sterile solutions, emulsions and suspensions. Isotonic preparations are employed which generally contain suitable preservatives when intravenous administration is desired. In addition, the compounds of the present invention can be administered in an intranasal dosage form via topical use of suitable intranasal vehicles or via transdermal skin patches, the composition of which is well known to those skilled in the art. To be administered in the form of a transdermal delivery system, the administration of a therapeutic dose will, of course, continue more than intermittently throughout the dosage regimen. The compounds of the present invention can also be administered in the form of systems for liposome administration, such as small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles and the like. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, phosphatidylcholines and the like. The compounds of the present invention can also be administered by the use of monoclonal antibodies as individual vehicles to which the molecules of the compound are coupled. The compounds of the present invention can also be coupled with soluble polymers as vehicles for drug targeting. Such polymers may include, but are not limited to, polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxy ethyl aspartamide phenol, or polyethylene polylysine oxide substituted with palmitoyl residue. In addition, the compounds of the present invention can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug., for example, to homopolymers and copolymers (which mean polymers containing two or more chemically distinguishable repeating units) of lactide (which include lactic acid d-, I- and meso-lactide), glycolide (including glycolic acid), e-caprolactone , p-dioxanone (1,4-dioxan-2-one), trimethylene carbonate (1,3-dioxan-2-one), alkyl derivatives of trimethylene carbonate, d-valerolactone, butyrolactone,? -butyrotactone, and -decatactone, hydroxybutyrate, hydroxyvalerate, 1,4-dioxepan-2-one (including its 1, 5,8,12-tetraoxacyclotetradecane-7,14-dione), 1,5-dioxepan-2-one, 6, 6-dimethyl-1,4-dioxan-2-one, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphiphmatic copolymers of hydrogels and mixtures thereof. The compounds of this invention can be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art which is required to treat or ameliorate a kinase or dual kinase mediated disorder for a subject that needs the same; in particular, when it is required to treat or ameliorate a kinase mediated disorder by selective inhibition of a kinase selected from protein kinase C or glycogen synthase kinase-3; and, when it is required to treat or ameliorate a kinase-mediated disorder by the dual inhibition of at least two kinases selected from protein kinase C and glycogen synthase kinase-3; and, more particularly, when it is required to treat or ameliorate a kinase mediated disorder by selective inhibition of a kinase selected from protein kinase C a, protein kinase Cß-I, protein kinase Cß-ll, protein kinase C? or glycogen synthase kinase-3β; and, when it is required to treat or ameliorate a kinase mediated disorder by the dual inhibition of at least two kinases selected from protein kinase Ca, protein kinase Cß-1, protein kinase Cß-ll, protein kinase C? or glycogen synthase kinase-3β. The daily dose of a pharmaceutical composition of the present invention can vary in a wide range from about 0.7 mg to about 21,000 mg per 70 kilogram (kg) of human adult per day; preferably in the range of about 7 mg to about 7,000 mg per adult human per day; and, more preferably, in the range of about 7 mg to about 2,100 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the An active ingredient for the symptomatic adjustment of the dose to the subject to be treated. A therapeutically effective amount of the drug is ordinarily supplied at a dose level of about 0.001 mg / kg to about 300 mg / kg of body weight per day. Preferably, the range is from about 0.1 mg / kg to about 100 mg / kg of body weight per day; and, more preferably, from about 0.1 mg / kg to about 30 mg / kg of body weight per day. Advantageously, the compounds of the present invention can be administered in a particular daily dose or the total daily dose can be administered in divided doses of two, three or four times a day. The optimal doses to be administered can be easily determined by those skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation and the progress of the disease condition. In addition, the factors associated with the particular subject to be treated, including the subject's age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level.

The abbreviations used in the present specification, particularly in the schemes and examples, are the following: ATP = adenosine triphosphate BSA = bovine serum albumin DCM = dichloromethane DMF = NN-dimethylformamide DMSO = dimethylsulfoxide EGTA = ethylenebis (oxyethylene-nitrile) tetraacetic acid Co h = hour HEPES = 4- (2-hydroxyethyl) -1-piperazine-ethanesulfonic acid min = minute rt = room temperature TCA = trichloroacetic acid THF = tetrahydrofuran TFA trifluoroacetic acid TMSCHN2 = trimethylsilyldiazomethane General Synthetic Methods Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and are illustrated more particularly in the schemes below. Since the schemes are an illustration, the invention should not be considered as limited by the chemical reactions and conditions expressed. The preparation of the various initial materials used in the schemes is within the capabilities of those skilled in the art. The following schemes describe the general synthetic methods by means of which the intermediates and target compounds of the present invention can be prepared. Additional representative compounds of the present invention can be synthesized using the intermediates prepared according to the schemes and other materials, compounds and reagents known to those skilled in the art. In scheme AA, the substituted indole compound AA1 was arylated with an appropriate substituted aryl or heteroaryl halide and a base such as cesium or potassium carbonate and copper oxide in a dipolar aprotic solvent such as DMF to yield compound AA2. Compound AA2 was acylated with oxalyl chloride in an aprotic solvent such as diethyl ether or DCM and stopped with sodium methoxide to obtain an intermediate glyoxyl ester compound AA3. b Ra1sCeI, (CBuG> OR ilo or heteroaryl Another intermediate compound AA5 was prepared from compound AA1 via acylation with oxalyl chloride followed by treatment with sodium methoxide to obtain the glyoxal ester compound AA4 which was then alkylated with a suitable alkylating agent under basic conditions.

The substituted 3-indazoleacetic acid compound AA7 was prepared from the aldehyde compound AA6 by reaction with malonic acid and ammonium formate followed by reductive cycling under basic conditions (B. Mylari, et al., J. Med. Chem., 1992, 36, 21dd). The AA7 acid compound was coupled with ammonium hydroxide in an aprotic solvent such as DCM or acetonitrile using a dehydrating agent similar to dicyclohexylocarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) to yield the amide compound AA8, which was treated with an agent suitable alkylator AA9 in the presence of a base such as sodium hydride to obtain the indazole compound AA10 as a mixture of the N1-alkylated (major) and N2-alkyl (minor) products.

The ester compound AA3 or AA5 can be reacted with the amide compound AA10 by stirring in an aprotic solvent such as THF with ice bath for cooling and a base, such as potassium tert-butoxide or sodium hydride, to yield the compound AA11. Compound AA11 was converted to its AA12 mesylate by treatment with methanesulfonic anhydride. Treatment of AA12 with a heteroaryl containing NH in the presence of a base yielded the white compound AA13. The N1-alkylated (major) and N2-alkylated (minor) products can be separated by chromatography.

The indazole amide compound AA15 was prepared via alkylation of AA8 with an alkylating agent containing heteroaryl AA14 in the presence of a base, such as potassium carbonate or sodium hydride. The AA15 amide can be reacted with the ester compound AA3 or AA5 in an aprotic solvent such as THF with ice bath for cooling and a base, such as potassium tert-butoxide or potassium hydride, to give AA16.

R > 2 - ~ heteroarylalkyl, etc.

AA16 Specific synthetic methods The specific compounds which are representative of this invention were prepared by the following examples and reaction sequences; The examples and diagrams illustrating the reaction sequences are given by way of illustration, to aid in the understanding of the invention and are not to be construed as limiting in any way the invention set forth in the claims which follow below. The illustrated intermediates can also be used in subsequent examples to produce additional compounds of the present invention. No attempts have been made to optimize the yields obtained in any of the reactions. A person skilled in the art could know how to increase said yields through variations in the routine in the reaction times, temperatures, solvents and / or reagents. All chemicals were obtained from commercial suppliers and used without further purification. The 1H and 13C NMR spectra were recorded on a Bruker AC 300B spectrometer (300 MHz proton) or a Bruker AM-400 (400 MHz proton) with Me4Si as an internal standard (s = singlet, d = doublet, t = triplet, br = broad). APCl-MS and ES-MS were recorded on a VG Platform II mass spectrometer; Methane was used for chemical ionization, unless otherwise mentioned. Accurate mass measurements were obtained by using a VG ZAB 2-SE spectrometer in FAB mode. TLC was carried out with Whatman 250-Rm silica gel plates. The preparative TLC was carried out with GF Analtech 1000-μm silica gel plates. Flash column chromatography was carried out with silica gel for flash column (40-63 μm) and column chromatography was carried out with standard silica gel. The CLAR separations were carried out in three Waters PrepPak® cartridges (25 x 100 mm, Bondapak® C18, 15-20 μm, 125 A) connected in series; the detection was at 254 nm in a Waters 486 UV detector. The analytical HPLC was carried out on a Supelcosil ABZ + PLUS column (5 cm x 2.1 mm), with detection at 264 nm in a Hewlett Packard 1100 UV detector. The microanalysis was carried out by Robertson Microlit Laboratories, Inc.

Representative names similar to Chemical Abstracts Service (CAS) Index for the compounds of the present invention were derived using the software program for naming SOFTWARE ACD / LABS Index Ñame Pro Version 4.5 provided by Advanced Chemistry Development, Inc., Toronto, Ontario, Canada.

EXAMPLE 1 3- (5-Chloro-1-methyl-1 H-indol-3-yn-4-r (3-imidazol-1-yl-propyl) -1 H -ndazol-3-pyrrolidone -2.5-dione (compound 1) Pyridine (1024 g, 12.96 mmol) and methanesulfonic anhydride (1.3 g, 7.4 d millimoles) were added to compound 1a (1.62 g, 3.7 mmol, preparation described in WO 02/46183) in THF (60 mL). The mixture was stirred at 50 ° C for 3 hours, and then cooled to room temperature. Another portion of THF (10 mL) was added, followed by 1 N HCl (10 mL). The mixture was stirred for another 15 minutes, then extracted with EtOAc several times. The combined EtOAc layers were washed once with 1 N HCl (10 mL), water (2 x 20 mL) and saturated NaCl (20 mL), then dried (Na 2 SO 4) and evaporated in vacuo to obtain compound 1 b (1.6 g, 84%) as a reddish solid. ES-MS m / z 513 (MH +). 75% NaH (3.74 mg, 0.117 mmol) was added to the mixture of Imidazole (7.96 mg, 0.117 millimoles) in DMF (5 mL) at 0 ° C. The mixture was heated to reflux for 30 minutes. Then the solution was cooled to room temperature. Compound 1b (50 mg, 0.0975 mmol) in DMF (1 mL) was added dropwise. The mixture was heated at 80 ° C for 1 hour, and then stirred at room temperature overnight. The solvent was evaporated in vacuo to a dark oil. The oil was purified by Gilson to obtain compound 1 (5.3 mg) as a TFA salt. 1 H NMR (CD 3 OD) d 8.93 (s, 1 H), 8.1 d (s, 1 H), 7.62 (d, J = 8.5 Hz, 1 H), 7.56 (s, 1 H), 7.48 (s, 1 H), 7.36 (m, 3H), 6.96 (m, 2H), 6.06 (d, J = 1.9 Hz, 1H), 4.52 (t, J = 6.2 Hz, 2H), 4.14 (t, J = 6.6 Hz, 2H), 3 88 (s, 3H), 2.45 (t, J = 6.3 Hz, 2H). ES-MS m / z 485 (MH +).

EXAMPLE 2 3- (5-Chloro-1-methyl-1 H-indol-3-yl) -4-p- (3-M, 2,3-triazol-1-yl-propyl) -1 H-indazole-3- ill-Pyrrol-2,5-dione (compound 2) 75% NaH (3 mg, 0.093 mmol) was added to the mixture of trizol (5 mg, 0.072 mmol) in DMF (4 mL) at 0 ° C. The mixture was heated to reflux for 30 minutes. Then the solution was cooled to room temperature. Compound 1 b (20 mg, 0.03 mmol) in DMF (1 mL) was added dropwise. The mixture was heated at 80 ° C for 1 hour, and then stirred at room temperature overnight. The CCF showed that it still contained some initial material. The mixture was heated at 90 ° C overnight. The solvent was evaporated in vacuo to a dark oil. The oil was purified by preparative TLC to obtain compound 2 (3 mg) as an orange solid. 1 H NMR (CDCl 3) d 8.08 (s, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.64 (s, 1 H), 7.43 (m, 3 H), 7.17 (m, 2 H), 7.01 (dd) , J = 1.9, 8.7 Hz, 1H), 6.12 (d, J = 1.8 Hz, 1 H), 4.31 (t, J = 6.2 Hz, 2H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 ( s, 3H), 2.40 (m, 2H). ES-MS m / z 486 (MH +).

EXAMPLE 3 3- (5-Chloro-1-methyl-1 H-indol-3-yl) -4-n- (3-tetrazol-2-yl-propyl) -1 H -indazol-3 > inpyrrol-2.5-dione v 3- (5-Chloro-1-methyl-1H-indol-3-yl) -4-n- (3-tetrazol-1-yl-propy) -1H-indazole-3 N-pyrrole-2,5-dione (compound 3 and compound 4) A solution of 3% tetrazole in CH 3 CN (10.15 mL, 3.4 mmol) was diluted with DMF (10 mL), potassium carbonate (0.47 g, 3.4 mmol) was added and the mixture was heated at 90 ° C for 2 hours. The mixture was cooled to room temperature. Compound 1b (350 mg, 0.68 mmol) in DMF (5 mL) was added dropwise. The mixture was heated at 80 ° C overnight. The solvent was evaporated. Water (10 mL) was added, and then the mixture was extracted with EtOAc (3 x 60 mL). The organic layers were combined, washed with H20 and brine, then dried (Na2SO4) and evaporated in vacuo to a dark oil. The oil was purified by flash column chromatography (96: 4: 0.4; DCM: MeOH: NH4OH) to obtain compound 3 (60 mg) and compound 4 (34 mg). Compound 3: 1 H NMR (CDCl 3) d 8.63 (s, 1 H), 8.09 (s, 1 H), 7.7 d (d, J = 8.3 Hz, 1 H), 7.44 (m, 2 H), 7.19 (m, 2 H), 7.01 (dd, J = 2.0, 8.7 Hz, 1H), 6.06 (d, J = 1.9 Hz, 1H), 4.49 (t, J = 6.5 Hz, 2H), 4.42 (t, J = 6.5 Hz, 2H), 3.87 (s, 3H), 2.43 (m, 2H). ES-MS m / z 487 (MH +). Compound 4: H NMR (CDCl 3) d 8.36 (s, 1H), 8.07 (s, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.44 (m, 2H), 7.20 (m, 1H), 7.15 (d, J = 8.7 Hz, 1 H), 6.99 (dd, J = 2.0, 8.7 Hz, 1 H), 6.12 (d, J = 1.9 Hz, 1 H), 4.25 (t, J = 5.9 Hz, 2H ), 4.07 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H), 2.38 (m, 2H). ES-MS m / z 487 (MH +).

Using the procedure of Example 1 and the appropriate reagents and starting materials known to those skilled in the art, other compounds of the present invention can be prepared including, but not limited to: EXAMPLE 4 3-f 1 -Naphthalen-2-yl-1 H-indol-3-yl-p - (3-tetrazol-2-yl-propyl) -1 H -indazol-3-ffl-pyrrole-2.5 -dione and 3-f 1 -Naphthalen-2-yl-1 H -indol-3-yl) -4-p -3-tetrazol-1-yl-propyl) -1H-indazol-3-inpyrrole-2,5 -dione (compound 5 and compound 6) Within a solution of 4a (95 mg, 0.185 mmol) in THF (10 mL) was added methanesulfonic anhydride (48.4 mg, 0.278 mmol) and pyridine (44 mg, 0.5dd mmol). The mixture was heated at d0 ° C for 3 hours.

Then it was cooled to room temperature. Another portion of THF (5 mL) was added, followed by 1 N HCl (2 mL). The mixture was stirred for another 16 minutes, and then extracted with EtOAc several times. The combined EtOAc layers were washed once with 1 N HCl (10 mL), water (2 x 20 mL) and saturated NaCl (20 mL), then dried (Na 2 SO) and concentrated to yield a red solid (0.11 g). as 4b. A solution of 3% tetrazole in CH 3 CN (7 mL, 2.4 mmol) was diluted with DMF (10 mL), potassium carbonate (0.5 g, 3.6 mmol) was added and the mixture was heated at 90 ° C for 2 hours. The mixture was cooled to room temperature. Compound 4b (110 mg, 0.19 mmol) in DMF (10 mL) was added dropwise. The mixture was heated at 80 ° C overnight. The solvent was evaporated. Water (10 mL) was added, and then the mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with H20 and brine, then dried (Na2SO4) and evaporated in vacuo to a dark oil. The oil was purified by preparative TLC to obtain compound 5 (10 mg) and compound 6 (10 mg). Compound d 1 H NMR (CDCl 3) d 8.49 (s, 1 H), 8.37 (s, 1 H), 8.02 (m, 2 H), 7.94 (m, 3 H), 7.68 (dd, J = 2.1, 8.7 Hz, 1 H ), 7.60 (m, 2H), 7.64 (m, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1 H), 6.77 (t, J = 7.2 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1 H), 4.38 (t, J = 6.3 Hz, 2H), 4.32 (t, J = 6.6 Hz, 2H), 2.34 (t, J = 6.5 Hz, 2H ). ES-MS m / z 565 (MH +). Compound 6 1 H NMR (CDCl 3) d 8.36 (s, 1 H), 8. 32 (s, 1 H), 8.02 (d, J = 8.6 Hz, 1 H), 7.91 (m, 4 H), 7.89 (m, 3H), 7.47 (m, 3H), 7.26 (t, J = 7.0 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 4.19 (t, J = 5.8 Hz, 2H), 3.90 (t, J = 6.3 Hz, 2H), 2.31 (m, 2H). ES-MS m / z 565 (MH +).

Compound 5 Compound s EXAMPLE 5 3-1-Pyridin-3-yl-1 H-indol-3-yl) -4-ri - (3-tetrazol-2-yl-propyl) -1 H -indazol-3-yl -pyrrole-2,5-dione and 3- (1-pyridin-3-yl-1 H-indol-3-i0-4-H -f 3-tetrazol-1-yl-propiQ-1H-indazol-3-in- pyrrole-2,5-dione (compound 7 and compound 8) Within a solution of 5a (100 mg, 0.22 mmol) in THE (5 mL) was added methanesulfonic anhydride (77 mg, 0.44 mmol) and pyridine (62.2 mg, 0.66 mmol). The mixture was heated at 50 ° C for 3 hours. Then it was cooled to room temperature. Another portion of THF (d mL) was added, followed by 1 N HCl (2 mL). The mixture was stirred for another 16 minutes, and then extracted with EtOAc several times. The combined EtOAc layers were washed once with 1 N HCl (10 mL), water (2 x 20 mL) and saturated NaCl (20 mL), then dried (Na 2 SO 4) and concentrated to yield a red solid (0.11 g). ) as db. A solution of 3% tetrazole in CH 3 CN (7 mL, 2.4 mmol) was diluted with DMF (10 mL), potassium carbonate (0.5 g, 3.6 mmol) was added and the mixture was heated at 90 ° C for 2 hours. The mixture was cooled to room temperature. Compound 5b (110 mg, 0.2 mmol) in DMF (10 mL) was added dropwise. The mixture was heated at 80 ° C overnight. The solvent was evaporated. Water (10 mL) was added, and then the mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with H20 and brine, then dried (Na2SO) and evaporated in vacuo to a dark oil. The oil was purified by flash column chromatography (from 100% DCM to DCM: MeOH: NH 4 OH; 97: 3: 0.3) to obtain compound 7 (32 mg) and compound 8 (27 mg). Compound 7 1 H NMR (CDCl 3) d 8.92 (s, 1 H), 8.70 (s, 1 H), 8.60 (s, 1 H), 8.26 (s, 1 H), 7.92 (dd, J = 3.2, 8.2 Hz, 2 H ), 7.52 (m, 1 H), 7.42 (m, 3H), 7.25 (m, 1 H), 7.06 (t, J = 7.6 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.43 (d, J = 8.1 Hz, 1 H), 4.37 (t, J = 6.3 Hz, 2H), 4.30 (t, J = 6.6 Hz, 2H), 2.32 (m, 2H). ES-MS m / z 516 (MH +).

Compound 8 1 H NMR (CDCl 3) d 8.85 (d, J = 2.4 Hz, 1 H), 8.70 (dd, J = 1.4, 4.7 Hz, 1 H), 8.41 (s, 1 H), 8.20 (s, 1 H), 7.91 (m, 1 H), 7.85 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 4.8, 8.0 Hz, 1H), 7.45 (m, 2H), 7.35 (d, J = 8.3 Hz, 1 H), 7.23 (dd, J = 6.8, 8.3 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1 H), 6.54 (d, J = 8.1 Hz, 1 H), 4.19 (t, J = 5.8 Hz, 2H), 3.96 (t, J = 6.2 Hz, 2H), 2.31 (m, 2H). ES-MS m / z 616 (MH +). 5a 5b Compound 7 Compound 8 EXAMPLE 6 3- (5-Chloro-1-methyl-1 H-indol-3-yl) -4- (1-f2- (1 H-tetrazol-5-yl) -etip-1 H-indazole-3- il) -pyrrole-2,5-dione (compound 11) To a solution of 6a (880 mg, 6.6 mmol) in anhydrous CH2Cl2 (60 mL) was added tritylchloride (1.84 g, 6.6 mmol), 1 N NaOH (6.9 mL, 6.9 mmol) and catalytic tetrabutylammonium bromide. The organic mixture was stirred vigorously at room temperature overnight. Then water was added followed by extraction with CH2Cl2. The organic layers were combined, washed with H2O (2x20 mL), saturated NaHC3 (2d mL) and brine (2d mL). They were dried (Na2SO4) and concentrated to yield 6b as a white solid (2.27 g, 92%). 1 H NMR (CDCl 3) d 7.31 (m, 9 H), 7.09 (m, 6 H), 3.91 (t, J = 7.1 Hz, 2 H), 3.40 (t, J = 7.0 Hz, 2 H); MS (ES) m / z: 375 (MH +). To a solution of 6c (957 mg, 5.47 mmol) in anhydrous DMF (50 mL) was added K2C03 (3.78 g, 27.35 mmol) and 6b under N2. The reaction mixture was heated at 110 ° C for 4 hours. The CCF showed that it still contained portions of the initial material 6c, but not of 6b. Therefore, more 6b (1 g, 2.67 mmol) was added and the mixture was heated at 110 ° C overnight. Water was added and the solution was extracted with EtOAc (3 times). The organic layers were combined, washed with water, brine, dried ((Na 2 SO 4) and concentrated to a brown oil.The oil was purified by flash column chromatography (from 100% DCM to DCM: MeOH : NH4OH; 97: 3: 0.3) to obtain compound 6d (0.6 g, 21%) as a light yellow solid.1H NMR (DMSO-d6) d 7.75 (d, J = 8.1, 1 H), 7.51 (s) , 1 H), 7.33 (m, 9H), 7.20 (m, 1H), 7.02 (m, 2H), 6.81 (m, 5H), 4.74 (t, J = 6.3 Hz, 2H), 3.68 (s, 2H) ), 3.45 (m, 2H); MS (ES) m / z: 636 (MH +). A mixture of compound 6d (100 mg, 0.196 mmol) and compound 6e (94.7 mg, 0.27 mmol) in 4 mL of anhydrous THF was stirred under nitrogen and cooled in an ice bath while being treated dropwise with 1.0 mL of 1N potassium t-butoxide in THF. The mixture was stirred for 30 minutes in an ice bath then at room temperature for another 30 minutes. Then ethyl acetate (150 mL) and H20 (10 mL) were added. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to yield an unpurified product which was purified by flash chromatography on silica gel (CH2Cl2 / MeOH / NH4OH, 97: 3 : 0.3) to yield 22.3 mg of compound 6f as a red solid. 1 H NMR (CDCl 3) d 8.01 (s, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.30 (m, 12 H), 7.10 (m, 2 H), 7.04 (dd, J = 1.9, 8.7 Hz, 1 H), 6.98 (m, 5H), 6.32 (d, J = 1.8 Hz, 1H), 4.75 (t, J = 7.4 Hz, 2H), 3.75 (s, 3H), 3.40 (t, J = 7.4 Hz , 2H). ES-MS m / z 715 (MH +). Compound 6f (22.3 mg, 0.03 mmol) in CH2Cl2 (5 mL) was cooled in an ice bath. TFA (0.5 mL) was added dropwise. Then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by flash chromatography (from 100% DCM to DCM: MeOH: 94: 6) to obtain compound 11 (13 mg, 92%). 1 H NMR (DMSO-de) d 8.24 (s, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.50 (d, J = 8.7 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.11 (m, 2H), 6.22 (d, J = 2. 0 Hz, 1 H), 4.77 (t, J = 7. 5 Hz, 2H), 3.90 (s, 3H), 3.34 (m, 2H). ES-MS m / z 473 (MH +).

Compound 11 EXAMPLE 7 3- (5-Chloro-1-pyridin-3-yl-1 H-indol-3-H) -4-. { 1 -I2- (1 H-tetrazol-5-yl) -ethyl] -1 H-indazol-3-yl (compound 12) A compound of 5-chloroindole 7a (6.0 g, 0.026 moles) in CH2Cl2 (40 mL) was cooled in a bath with ice and treated dropwise with oxalyl chloride (6.66 g, 0.052 mol) while stirring under argon. The resulting yellow colored wash solution was stirred at room temperature for 1 hour, then at 30 ° C overnight. Some yellow solids were formed, filtered and washed with CH2Cl2. The solid was dried under vacuum and again subjected to anhydrous methanol (100 mL) and heated at 45 ° C for 3 hours. The solid was filtered and dried to yield compound 7b (7.94 g, 86%) as an HCl salt. The solid was neutralized by treatment with saturated NaHCO3, extraction with ethyl acetate, dried (Na2S4) and concentrated in vacuo to yield compound 7b as a free base. 1 H NMR (CDCl 3) d 8.86 (s, 1 H), 8.79 (m, 1 H), 8.61 (s, 1 H), 8. 62 (s, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 7.67 (m, 1 H), 7.34 (m, 2H), 3.98 (s, 3H). ES-MS m / z 31d (MH +). A mixture of compound 6d (160 mg, 0.292 mmol) and compound 7f (142 mg, 0.41 mmol) in 5 mL of anhydrous THF was stirred under nitrogen and cooled in an ice bath while being treated dropwise with 1.5 mL of 1 N potassium t-butoxide in THF. The mixture was stirred for 1 hour in an ice bath then at room temperature for another 2 hours.

Then ethyl acetate (1.50 mL) and H20 (10 mL) were added. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to yield an unpurified product which was purified by flash chromatography on silica gel (CH2Cl2 / MeOH / NH4OH, 97: 3 0.3) to yield 20 mg (6%) of compound 7c as a red solid. Compound 7c (18 mg, 0.023 mmol) in CH2Cl (5 mL) was cooled in an ice bath. TFA (O.d mL) was added dropwise. Then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by flash chromatography (from 100% DCM to DCM: MeOH; 94: 6) to obtain compound 12 (5.2 mg, 42%). 1 H NMR (CD30D) d 8.85 (s, 1 H), 8.66 (s, 1 H), 8.31 (s, 1 H), 8.11 (d, J = 7.8 Hz, 1 H), 7.65 (m, 3 H), 7.42 ( m, 2H), 7.11 (m, 2H), 6.30 (s, 1 H), 4.73 (m, 2H), 3.30 (m, 2H). ES-MS m / z 536 (MH +). 7a 7b Compound 12 EXAMPLE 8 As a specific embodiment of an oral composition, 100 mg of compound 14 was formulated with enough finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O gel hard capsule.

EXAMPLES OF BIOLOGICAL EXPERIMENTS The utility of the compounds for treating kinase or dual kinase mediated disorders (in particular, kinases selected from protein kinase C and glycogen synthase kinase-3; and, more particularly, kinases selected from protein kinase Ca, protein kinase C ß-ll, protein kinase C and glycogen synthase kinase-3β) was determined using the following procedures.

EXAMPLE 9 Assay based on Protein kinase C in histone The compounds were evaluated for selectivity to PKC using histone III as the substrate. The isoforms of PKC a, -II or y were added to the reaction mixture containing 20 mM HEPES, (pH 7.4), 940 μM CaCl2, 10 mM MgCl2, 1 mM EGTA. 100 μg / mL of phosphatidylserine, 20 μg / mL of diacylglycerol, ATP30 μM, 1 μCi (33P) ATP and 200 μg / mL of histone III. The reaction was incubated for 10 minutes at 30 ° C. The reactions were terminated by precipitation with TCA and placed in droplets on Whatman P81 filters. The filters were washed in 75 mM phosphoric acid and the radioactivity was quantified by liquid scintillation counting. Table 1 shows the biological activity in the histone-based assay as Ido (M) values for representative compounds of the present invention.

TABLE 1 EXAMPLE 10 Glycogen synthase kinase-3 assay The compounds were evaluated for their ability to inhibit the recombinant rabbit protein GSK-3p using the following protocol. The test compound was added to a reaction mixture containing protein phosphatase-2 (PPI-2) inhibitor (Calbiochem) (45 ng), rabbit GSK-3p protein (New England Biolabs) (0.7d units) and 33P -ATP (1 μCi) in 60 mM Tris-HCl (pH 8.0), 10 mM MgCl 2, 0.1% BSA, 1 mM DTT and 100 LM sodium vanadate. The mixture was reacted for 90 minutes at 30 ° C to allow phosphorylation of the PPI-2 protein and then the protein in the reaction was precipitated using 10% TCA. The precipitated protein was collected on filter plates (MultiScreen-DV / Millipore), which were subsequently washed. Finally, the radioactivity was quantified using a TopCount scintillation counter (Packard). The inhibitory compounds of GSK-3 resulted in PPI-2 less phosphorylated and therefore a lower radioactive signal was observed in the precipitated protein. Staurosporine or Valproate, known inhibitors of GSK-3ß, were used as a positive control for selection. Table 2 shows the biological activity in the GSK-3p assay as IC 50 (M) values for representative compounds of the present invention.

TABLE 2 GSK-3B Activity Assay (IC50 uM) The results from the foregoing experiments indicate that a compound of the present invention could be expected to be useful in the treatment or amelioration of a kinase or dual kinase mediated disorder.

Although the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all customary variations, adaptations and / or modifications as presented in the scope of the following claims. and its equivalents.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - The compounds of formula (I) Formula (I) wherein R 1 is selected from the group consisting of: hydrogen, C 2. 8 alkyl C 2 -d alkenyl, C 2-8 alkynyl and C 3-8 cycloalkyl. { wherein alkyl, alkenyl, alkynyl and C3.8 cycloalkyl are optionally substituted with one to two substituents independently selected from the group consisting of -O-alkyl of (C? .8), -O-alkyl of (C? .8) -OH, -O-alkyl (C? 8) -0-alkyl (C? -8), -O-alkyl (C? -8) -NH2, -O-alkyl (d) .8) -NH-alkyl (d-β), -O-alkyl of (d ^ -Nalkyl of (C? 8)] 2, -O-alkyl of (C? 8) -S-alkyl of (d-8), -O-alkyl (C? -8) -S02-alkyl (C -8), -0-alkyl (d.8) -S02-NH2, -O-alkyl (d) .8) -S02-NH- (C? -8) alkyl, -0-alkyl of (d.8) -S02-N [(C? .8) alkyl] 2, -0-C (0) H, -0-C (0) -alkyl of (C? 8), -0-C (0) -NH2, -0-C (O) -NH-alkyl of (Cw), -0-C ( 0) -N [alkyl of (d.8)] 2, -0-alkyl of (d.8) -C (0) H, -O-alkyl of (d.8) -C (0) -alkyl of (C? 8), -O-(C 1-8) -CO 2 H alkyl, -O-alkyl of (C? 8) -C (O) -O-alkyl of (dd), O-alkyl of ( d. 8) -C (0) -NH2, -O-alkyl (C? -8) -C (0) -NH-alkyl (C? 8), -O-alkyl (C? 8) - C (0) -N [alkyl of (d.8)] 2, -C (0) H, -C (0) -alkyl of (d.8), -C02H, -C (0) -0-alkyl of (C? 8), -C (0) -NH 2, -C (NH) -NH 2, -C (0) -NH-alkyl of (C? -8), -C (O) -N [(C? 8)] 2 alkyl, -SH, -S-alkyl of (d.8), -S-alkyl of (d.8) -S-alkyl of (C? -8), -S -alkyl of (C? 8) -0-alkyl of (C? 8), -S-alkyl of (C? 8) -0-alkyl of (d_8) -OH, -S-alkyl of (d) .8) -0-alkyl of (C? -8) -NH2, -S-alkyl of (C? 8) -0-alkyl of (C? .8) -NH-alkyl of (C? .8) , -S-alkyl (C?. 8) -0-C 1-8 alkyl-N [(C? 8)] 2 alkyl, -S-alkyl (C? .8) -NH- alkyl of (C .8), -S02-alkyl of (d.8), -S02-NH2, -S02-NH-alkyl of (d.8), -S02-N [alkyl of (d.8)] 2, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8 alkyl, C2.s alkenyl, C2.8 alkynyl, -alkyl of (C? -s) -OH, - (C? -8) -0-alkyl (C -8) alkyl, -alkyl of (d-8) -NH2, -alkyl of (C? -8) -NH-alkyl or of (C? -8), -alkyl of (C? _8) -N- [(C? 8)] 2 alkyl, -alkyl of (C?. 8) -S-alkyl of (C? 8), -C (0) -alkyl of (Ci-8), -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (0) -NH-alkyl Of (Ci-ß), -C (O) -N [(C? D)] 2 alkyl, -S02-alkyl of (dd), -S02-NH2, -S02-NH-alkyl of ( d-8), -S02-N [(C? -8)] 2, -C (N) -NH2, aryl and arylalkyl of (C? .8) (wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, d-β alkyl, C?-8 alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and d-β alkyl), cyano, Halo, (halo)? - 3alkyl of (C? .8), (halo)? 3alkoxy of (C? .8), hydroxy, hydroxy ((Ci-β) and nitro), cyano, (halo ^ -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 or consisting of C? 8 alkyl, C? 8 alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and dd alkyl), cyano, halo, (halo)? - 3 alkyl of (Ci-d), (halo)? 3alkoxy of (d.8), hydroxy, hydroxyalkyl of (C? .8) and nitro)} , -C (0) -alkyl of (d.8), -C (0) -aryl, -C (0) -0-alkyl of (Ci-β), -C (0) -0-aryl, - C (0) -NH-alkyl of (d.8), -C (0) -NH-aryl, -C (0) -N [alkyl of (d.8)] 2, -S02-alkyl of (C) .8), -S02-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 d-β alkyl, C2.8 alkenyl, C2-8 alkynyl, d-8 alkoxy, -C (0) H, -C (O) -alkyl of (d-8), -C02H, -C (0) -0-alkyl of (C? -8), -C (0) -NH2, -C ( NH) -NH2, -C (0) -NH-alkyl (C? -8), -C (0) -N [alkyl of (d.8)] 2, -SH, -S-alkyl of (C? 8), -S02-alkyl of (d.8), -S02-NH2, -S02-NH-alkyl of (Ci-β), -S02-N [alkyl of ( C? -ß)] 2, amino (substituted with two substituents independently selected from the group consisting of hydrogen, Ci-d alkyl, d-β alkenyl, C2-β alkynyl, -Calkyl (C? 8) - H2, -C (0) -alkyl of (Ci-8), -C (0) -0-alkyl of (C? 8), -C (0) -NH2, -C (0) - NH-Alkyl of (Cw), -C (O) -N-alkyl (C? -8)] 2, -S02-alkyl of (d-8), -S02-NH2, -S02-NH-alkyl of (d) 8), -S02-N [(C? D)] 2 alkyl and -C (NH) -NH2), amino-alkyl of (d.8) - (wherein amino is substituted with two independently selected substituents) from the group consisting of hydrogen, C? -8 alkyl, C2-d alkenyl, d-β alkynyl, (C? .8) -NH2 alkyl, -C (0) -alkyl (Ci) 8), -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (0) -NH-alkyl of (d.8), -C (O) - N [(C. 8) alkyl] 2, -S02-alkyl of (C? 8), -S02-NH2, -S02-NH-alkyl of (C? 8), -S02-N [ (C? .8)] 2 and -C (NH) -NH2), cia no, halo, (halo) .3alkyl of (Ci. 8) -, (halo) - 3-alkoxy of (C? 8) -, hydroxy, hydroxyalkyl of (C- | 8), nitro, aryl, - (C?. 8) -aryl alkyl, heteroaryl and - (C? -d) -heteroaryl alkyl}; R2 is selected from the group consisting of -Ci-d-Z alkyl, -D-β-Z alkenyl and C2.8-Z alkynyl; wherein the -C 8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, alkylamino of CM , dialkylamino of CM, alkyl of CM, alkoxy of CM, (halo)? 3alkyl of (CM), (halo)? - 3alkoxy of (CM) and hydroxyalkyl of (CM); Z is a 5-6 membered monocyclic heteroaryl ring having 2 to 4 heteroatoms containing at least one carbon atom and at least one nitrogen atom; wherein Z is optionally substituted with R5; R5 is 1 to 2 substituents attached to a carbon or nitrogen Z atom and each substituent is independently selected from the group consisting of hydrogen, -C 8 alkyl, C 2-8 alkenyl, C2-8, -C (0) H, -C (0) -alkyl of (C1-8), -C02H, -C (0) -0-alkyl of (d-8), -C (0) - NH2, -C (NH) -NH2, -C (0) -NH (C -8 alkyl), -C (0) -Nalkyl of (C1-8)) 2, -S02-alkyl of (C? 8), -S02-NH2, -S02-NH (alkyl), -S02-N (C? -d) alkyl 2, -alkyl of (C? -8) -NH2, -alkyl of (C? -8) -NH (C? _8 alkyl), -alkyl of (C? -g) -N (C? -8) alkyl 2, -alkyl of (C? -8) - (halo)? -3 , -alkyl of (d-ß) -OH, -aryl, -alkyl of (C? -8) -aryl, heteroaryl and -alkyl of (C?. 8) -heteroaryl; with the proviso that, when R5 is attached to a carbon atom, R5 is further selected from the group consisting of -alkoxy of C? .8l -alkoxy of (C? -8) - (halo)? -3 , -SH, -S-alkyl of (C? .8), -N-R6, cyano, halo, hydroxy, and nitro; R6 is 2 substituents independently selected from the group consisting of hydrogen, -C 8 alkyl, C2-d alkenyl, C2.8 alkynyl, C3.8 cycloalkyl, -C (0) H , -C (0) -alkyl of (C? 8), -C (0) -0-alkyl of (C? _8), -C (0) -NH2, -C (0) -NH (alkyl) C (-8), -C (0) -N (C-8 alkyl) 2, -S02-alkyl (C? d), -S02-NH2, -S02-NH (alkyl) Ci-d), -S02-N (alkyl of d_8) 2, -C (N) -NH2, -C (N) -NH (alkyl of d_8) and -C (N) -N (alkyl of d.8) )2; R3 and R4 are independently selected from the group consisting of hydrogen, C? 8 alkyl, C2.8 alkenyl, C2.8 alkynyl, C?. 8 alkoxy, -C (0) H, -C (0) -alkyl of (d.8), -C02H, -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (NH) -NH2, -C ( 0) -NH-alkyl of (d-8), -C (0) -N [alkyl of (d.8)] 2, -SH, -S-alkyl of (d.8), -S02-alkyl of (C? 8), -S02-NH2, -S02-NH-alkyl of (d.8), -S02-N [(C? 8)] 2 alkyl, amino (substituted with two substituents independently selected from from the group consisting of hydrogen, Ci-β alkyl, d-β alkenyl, d-β alkynyl, (dd) -NH 2 alkyl, -C (0) -alkyl of (d.8), - C (0) -0-alkyl of (C? .d), -C (0) -NH2, -C (0) -NH-alkyl of (d.8), -C (0) -N [alkyl of (d.8)] 2, -S02-alkyl of (C? 8), -S02-NH2, -S02-NH-alkyl of (d-8), -S02-N [alkyl of (d.8) 2 and -C (NH) -NH2), aminoalkyl of (Cis) - (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, ilo of C? 8, alkenyl of ds, alkynyl of C2-8, -alkyl of (d-8) -NH2, -C (0) -alkyl of (d.8), -C (0) -0- alkyl of (d.8), -C (0) -NH2, -C (0) -NH-alkyl of (ds), -C (0) -N [alkyl of (C? -8)] 2, - S02-alkyl (C? -8), -S02-NH2, -S02-NH-alkyl of (d.8), -S02-N [alkyl of (d_d)] 2 and -C (NH) -NH2) , cyano, halo, (halo)? 3alkyl of (C? 8) -, (halo)? 3alkoxy of (da) -, hydroxy, hydroxyalkyl of (C? .8), nitro, aryl, -alkyl (C? -d) -aryl, heteroaryl and (C -8) -heteroaryl-alkyl; and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1, further characterized in that R1 is independently selected from the group consisting of: hydrogen, CM alkyl, C2-4 alkenyl, C2_4 alkynyl, and C3-8 cycloalkyl. { wherein alkyl, alkenyl, alkynyl and C3.8 cycloalkyl are optionally substituted with one to two substituents independently selected from the group consisting of -O-alkyl of (CM), -O-alkyl of (CM) -OH, -O-alkyl of (CM) -O-alkyl of (CM), -O-alkyl of (C? -4) -NH2, -O-alkyl of (CM) ) -NH- (C 1-4) alkyl, -O-alkyl (d-4) -N [(Cι) alkyl) J 2, -O-alkyl (CM) -S-alkyl (CM), - O-C1-4 alkyl-S02-alkyl of (d-4), -O-alkyl of (CM) -S02-NH2, -O-alkyl of (C? _4) -S02-NH-alkyl of (CM), -O-alkyl of (CM) -S02-N [(C 1-4) alkyl] 2, -0-C (0) H, -0-C (0) -alkyl of (d) .4), -0-C (0) -NH2, -0-C (0) -NH-alkyl of (C1.4), -0-C (0) -N [alkyl of (d.4)] l -O-alkyl of (d.4) -C (0) H, -0-alkyl of (d.) -C (O) -alkyl of (CM), -O-alkyl of (C1-4) - CO2H, -O-alkyl of (C? -) -C (0) -0-alkyl of (d-4), -O-alkyl of (CM) -C (0) -NH2, -O-alkyl of ( C? ^) - C (0) -NH-alkyl of (d.4), -O-alkyl of (d-4) -C (0) -N [(C? -4) alkyl] 2, - C (0) H, -C (0) -alkyl of (C1.4), -C02H, -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl of (CM), -C (0) -N [(Cι) alkyl] 2, -SH, -S-alkyl of (CM), -S-alkyl of (C?) -S-alkyl of (CM), -S-alkyl of (Cμ) -O-alkyl of (CM), -S-alkyl uilo of (CM) -O-alkyl of (CM) -OH, -S-alkyl of (d. 4) -0-alkyl of (CM) -NH2, -S-(C1-4) alkyl-0-alkyl of (CM) -NH-alkyl of (CM), -S-alkyl of (d ^ -O) -alkyl (CM) -N [(Cι) alkyl] 2, -S-alkyl (CM) -NH-alkyl (CM), -S02-alkyl (CM), -S02-NH2, -S02 -NH-alkyl of (d.4), -S02-N [(C 1 .4)] 2 alkyl, amine (substituted with two substituents independently selected from the group consisting of hydrogen, alkyl of CM, alkenyl of C2-, C2- alkynyl, -alkyl of (CM) -OH, -alkyl of (CM) -O-alkyl of (CM), -alkyl of (C -4) -NH2, -alkyl of (C? 4) -NH-alkyl of (CM), -alkyl of (CM) -N [alkyl of (d-)] 2, -alkyl of (Cμ) -S-alkyl of (CM), -C (0) - alkyl of (C), -C (0) -0-alkyl of (CM), -C (O) -NH2, -C (0) -NH-alkyl of (C1.4), -C (0) ) -N [(C) alkyl] 2, -S02-alkyl (CM), -SO2-NH2, -S02-NH-alkyl (CM), -S02-N [alkyl (CM)] 2, -C (N) -NH2, aryl and arylalkyl (CM) (wherein aryl is optionally substituted with one to three substituents independently selected from the a group consisting of halogen, C-alkyl, C-alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and alkyl of CM), cyano, halo, (halo) -3alkyl of (CM), (halo)? 3alkoxy of (CM), hydroxy, hydroxyalkyl of (CM) and nitro)), cyano, (halo)? 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 CM alkyl, CM alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and (CM) alkyl, cyano, halo, (halo) β3 alkyl of (CM), (halo) β 3 alkoxy of (CM), hydroxy, hydroxyalkyl of (C 1-4) and nitro)} , -C (0) -alkyl of (d.4), -C (0) -aryl, -C (0) -0-alkyl of (d-4), -C (O) -O-aryl, - C (0) -NH-alkyl of (CM), -C (0) -NH-aryl, -C (0) -N [alkyl of (Cμ)] 2, -S? 2-alkyl of (CM), -S02-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 CM alkyl, C2-4 alkenyl, C2- alkynyl, C, -C (0) H alkoxy, -C (0) -alkyl of (CM), -C02H, -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl of (d.4), -C (0) -N [alkyl of (CM)] 2, -SH, -S-alkyl of (CM), -S02-alkyl of (CM), -S02 -NH2, -S02-NH-alkyl of (CM), -S02- [N [(C) alkyl]] 2, amino (substituted with two substituents independently selected from the group consisting of hydrogen, alkyl of CM, alkenyl of C2-4, C2-4 alkynyl, -alkyl of (Cμ) -NH2, -C (0) -alkyl of (d.4), -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (0) -NH-alkyl (CM), -C (0) -N [(Cι) alkyl] 2, -S02-alkyl (CM), -S02-NH 2, -S02-NH-alkyl of (d-4), -S02-N [(C) alkyl] 2 and -C (NH) -NH2), amino-alkyl of (CM) - (wherein amino is replaced with two substituents independently from the group consisting of hydrogen, C, alkyl, C2-4 alkenyl, C2-4 alkynyl, -alkyl (Cμ) -NH2, -C (0) -alkyl (CM), -C (0) -0-alkyl (CM) ), -C (0) -NH2, -C (0) -NH- (CM) alkyl, -C (0) -N [(Cι) alkyl] 2, -S02-alkyl (CM), - S02-NH2, -S02-NH-alkyl of (d.4), -S02-N [alkyl of (Cμ)] 2 and -C (NH) -NH2), cyano, halo, (halo) -3alkyl of (CM), (halo)? 3 alkoxy of (CM), hydroxy, hydroxyalkyl of (d-4), nitro, aryl, -alkyl of (CM) -aryl, heteroaryl and -alkyl of (CM) -heteroaryl} .
3. The compound according to claim 1, further characterized in that R1 is selected from the group consisting of: hydrogen, CM alkyl, C2.4 alkenyl. { wherein alkyl is substituted with one to two substituents independently selected from the group consisting of -O-alkyl of (CM), -O-alkyl of (CM) -OH, -O-alkyl of (C? -4) -NH-alkyl (CM), -OC (O) -alkyl (CM), -C (O) H, -C02H, -C (0) -0-alkyl (CM), amino (substituted with two substituents independently selected from the group consisting of hydrogen, d-4 alkyl, -alkyl of (d.4) -OH, -C (0) -0-alkyl of (C -4) and arylalkyl of (CM) ), 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 CM alkyl and halo)} , aryl and heteroaryl. { wherein aryl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of C1.4 alkyl, CM alkoxy, -CO2H, -C (0) -0-alkyl of (CM), - C (0) -NH2I -C (NH) -NH2, -C (0) -NH-alkyl (CM), -C (0) -N [(CM) alkyl] 2, amino (substituted with two substituents independently selected from the group consisting of hydrogen and alkyl of CM), cyano, halo, (halo) β 3 alkyl of (CM), (halo) -. 3 alkoxy of (CM), hydroxy, hydroxyalkyl of ( d.4), aryl and heteroaryl} .
4. The compound according to claim 1, further characterized in that R1 is selected from the group consisting of: hydrogen, CM alkyl, C2-4 alkenyl. { wherein alkyl is substituted with one to two substituents independently selected from the group consisting of -O-alkyl (CM) -NH-alkyl (CM), amino (substituted with two substituents independently selected from the group consisting of of hydrogen and alkyl of d.4), 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 CM alkyl) and halo)} , aryl and heteroaryl. { wherein aryl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of CM alkyl, d-, -C02H alkoxy, -C (0) -0-alkyl (C? 4) , -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl (CM), -C (0) -N [(C1.4) 2 alkyl, amino ( substituted with two substituents independently selected from the group consisting of hydrogen and C) alkyl, cyano, halo, (halo ^ -3 alkyl of (CM), (halo) - | .3 alkoxy of (CM), hydroxy, hydroxyalkyl of (d-4), aryl and heteroaryl. The compound according to claim 1, further characterized in that R 1 is selected from the group consisting of: hydrogen, C 1 -C 2 alkyl, C 2 alkenyl -3., Wherein alkyl is substituted with one to two substituents independently selected from the group consisting of -O-alkyl (CM) -NH-alkyl (CM), amino (substituted with two independently selected substituents from the group consisting of hydrogen and C 1-4 alkyl), hydroxy, pyrrolidinyl, morpholinyl, piperazinyl (wherein piperazinyl is optionally substituted with methyl), phenyl, naphthalenyl, benzo [b] thienyl and quinolinyl (wherein phenyl and benzo [b] thienyl is 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 CM alkyl , CM alkoxy, halo and hydroxy; and, wherein phenyl is optionally substituted with a substituent selected from the group consisting of phenyl and thienyl). 6. The compound according to claim 1, further characterized in that R2 is selected from the group consisting of -alkyl of (C? -4) -Z, -alkenyl of d-4-Z and -alkynyl of d -4-Z; wherein the -C1_4alkyl, -C2_4alkenyl and C2_4alkynyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, alkylamino of CM, dialkylamino of (CM), alkyl of CM, alkoxy of CM, (halo) β 3 alkyl of (CM), (halo) -3 alkoxy of (CM) and hydroxyalkyl of (CM) - 7.- The compound in accordance with claim 1, further characterized in that R2 is selected from the group consisting of -Calkyl -Zalkyl; wherein the -CM alkyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, C-alkylamino, dialkylamino of (CM), CM alkyl, C-alkoxy, (haio) ^ -alkyl of (CM), (halo)? -3 alkoxy of (CM) and hydroxyalkyl of (d.4) 8. The compound according to claim 1, further characterized in that Z is selected from the group 9. The compound according to claim 1, further characterized in that Z is selected from the group consisting of pyrazine, pyrimidine, imidazole, pyridazine, triazine, furazan, isoxazole, isothiazole, thiazole, triazole, oxatriazole and tetrazole. consists of imidazole, triazole, oxatriazole and tetrazole 10. The compound according to claim 1, further characterized in that Z is selected from the group consisting of oxatriazole and tetrazole 11. The compound according to claim 1 , caracter further curly because R3 and R4 are independently selected from the group consisting of hydrogen, CM alkyl, C2.4 alkenyl, d-4 alkynyl, CM alkoxy, -C (0) H, -C (0) -alkyl of (CM), -C02H, -C (O) -O-alkyl of (CM), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl of (CM), -C (O) -N-chloro (Cμ)] 2, -SH, -S-alkyl (CM), -S02-alkyl (CM), -S02-NH2, -S02-NH-alkyl of (CM), -S02-N [(CM)] 2 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, CM alkyl, C 2-4 alkenyl, C 2-4 alkynyl , -alkyl of (CM) -NH2, -C (0) -alkyl of (CM), -C (0) -0-aikyl of (CM), -C (O) -NH2, -C (0) - NH-alkyl of (CM), -C (0) -N [alkyl of (Cμ)] 2, -S02-alkyl of (CM), -S02-NH2, -S02-NH-alkyl of (CM), - S02-N [(C 1-4) alkyl] 2 and -C (NH) -NH 2), amino-alkyl (d-4) - (wherein amino is substituted with two substituents independently selected from the group consisting hydrogen, alkyl of C, C2-4 alkenyl, C2-4 alkynyl, -alkyl of (C? -4) -NH2, -C (O) -alkyl of (C1-4), -C (O) -O-alkyl of (CM), -C (O) -NH2, -C (0) -NH-alkyl of (CM), -C (0) -N [alkyl of (Cμ)] 2, -S02-alkyl of (CM), -S02-NH2, -S02-NH-alkyl (CM), -S02-N [(C1-) alkyl] 2 and -C (NH) -NH2), cyano, halo, (halo) ? -3 alkyl (CM), (halo)? 3alkoxy of (CM), hydroxy, hydroxyalkyl of (d-4), nitro, aryl, -alkyl of (CM) -aryl, heteroaryl and -alkyl of (CM) -heteroaryl. 12. The compound according to claim 1, further characterized in that R3 and R4 are independently selected from the group consisting of hydrogen, CM alkyl, d-alkoxy. ) cyano and halogen. 13. The compound according to claim 1, further characterized in that R3 and R4 are independently selected from the group consisting of hydrogen, methyl, methoxy, cyano and chloro 14. The compound according to claim 1, further characterized in that R5 is 1 to 2 substituents attached to a carbon or nitrogen atom of Z and each substituent is independently selected from the group consisting of hydrogen, -alkyl of CM, -annyl of C2.4, -alkynyl of C2-4, -C (0) H, -C (0) -alkyl of (CM), -C02H, -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH (alkyl of CM), -C (0) Nalkyl of (Cμ)) 2, -S02-alkyl of (CM) , -S02-NH2, -S02-NH (C1-4 alkyl), -S? 2-N (alkyl of d.4) 2, -alkyl of (CM) -NH2, -alkyl of (C -4) -NH (alkyl of CM), -alkyl of (CM) -N (C? -) alkyl 2, -alkyl of (C? -4) - (halo)? 3, -alkyl of (CM) -OH, -aryl, -alkyl of (CM) -aryl, -alkyl of (Ci-4) -aryl, heteroaryl and -alkyl of (CM) -heteroaryl; with the proviso that, when Rd is attached to a carbon atom, R5 is further selected from the group consisting of -alkoxy of CM, -alkoxy of (d-4) - (halo)? -3, -SH , -S-alkyl (CM), -N-R6, cyano, halo, hydroxy, and nitro. 15. The compound according to claim 1, further characterized in that R5 is 1 to 2 substituents attached to a carbon or nitrogen atom of Z and each substituent is independently selected from the group consisting of-CM alkyl, -C 2-4 alkenyl, -alkyl of (d.) -NH 2, -alkyl of (CM) -NH (alkyl of CM), -alkyl of (d.4) -N (alkyl of d.) 2, - (C? -4) - (halo)? 3 alkyl, -Ci-4alkyl-OH, -alkyl (CM) -aryl, heteroaryl, and (C? -4) -heteroaryl-alkyl; with the proviso that, when R5 is attached to a carbon atom, R5 is further selected from the group consisting of -alkoxy of CM, -alkoxy of (CM) - (halo)? 3, -S-alkyl of (CM), -N-R6, halo, and hydroxy. 16. The compound according to claim 1, further characterized in that R5 is selected from the group consisting of -alkyl of C. 17. The compound according to claim 1, further characterized in that the compound of formula (I) is a compound selected from formula (Ia): Formula (la) wherein R > 1, D R2, R D3 and R are dependently selected from the group consisting of; formula 18. - A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier. 19. The use of a compound as defined in claim 1, for preparing a medicament for the treatment or amelioration of a kinase mediated disorder in a subject. 20. The use claimed in claim 19, wherein the disorder is mediated by the selective inhibition of a kinase selected from the group consisting of protein kinase C and glycogen synthase kinase-3. 21- The use claimed in claim 20, wherein the kinase is selected from the group consisting of protein kinase C a, protein kinase C, protein kinase C? and glycogen synthase kinase-3β. 22. The use claimed in claim 21, wherein the disorder is mediated by the dual inhibition of at least two kinases selected from the group consisting of protein kinase C and glycogen synthase kinase-3. 23. The use claimed in claim 22, wherein at least two kinases are selected from the group consisting of protein kinase C a, protein kinase C ß-l, protein kinase C ß-ll, protein kinase C ? and glycogen synthase kinase-3β. 24. The use claimed in claim 19, wherein the medicament comprises the compound as defined in claim 1 in an amount of about 0.001 mg / kg / day to about 300 mg / kg / day. 25. The use claimed in claim 19, wherein the kinase-mediated disorder is selected from the group consisting of cardiovascular diseases, diabetes, disorders associated with diabetes, inflammatory diseases, immunological disorders, dermatological disorders., oncological disorders and CNS disorders. 26. The use claimed in claim 25, wherein the cardiovascular diseases are selected from the group consisting of acute stroke, heart failure, cardiovascular ischemia, thrombosis, atherosclerosis, hypertension, restenosis, retinopathy of prematurity and degeneration. Macular disease related to age. 27. The use claimed in claim 25, wherein the diabetes is selected from the group consisting of insulin-dependent diabetes and type II non-insulin-dependent diabetes mellitus. 28. The use claimed in claim 25, wherein the disorders associated with diabetes are selected from the group consisting of impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy and neuropathy. 29. The use claimed in claim 25, wherein the inflammatory diseases are selected from the group consisting of vascular permeability, inflammation, asthma, rheumatoid arthritis and osteoarthritis. 30. - The use claimed in claim 25, wherein the immunological disorders are selected from the group consisting of rejection of transplanted tissue, HIV-1 and immune disorders modulated by PKC. 31. The use claimed in claim 25, wherein the dermatological disorders are selected from the group consisting of psoriasis, hair loss and baldness. 32. The use claimed in claim 25, wherein the oncological disorders are selected from the group consisting of cancer or tumor growth, proliferative angiopathy, and angiogenesis. 33. The use claimed in claim 25, wherein the disorders of the central nervous system are selected from the group consisting of chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative conditions, dementia, Alzheimer's disease, disorders of the mood, schizophrenia, manic and neurotraumatic depression, cognitive decline and diseases related to ischemia (as a result of trauma to the head or of a transient ischemic cerebrovascular event). 34. The use claimed in claim 19, wherein the drug is an adjunct to chemotherapy and radiation therapy. 35.- The use of a compound of formula (I): Formula (I) wherein R1 is selected from the group consisting of: hydrogen, C? -8 alkyl, C2-d alkenyl, C2-b alkynyl and C3-b cycloalkyl. { wherein alkyl, alkenyl, alkynyl and C3-8 cycloalkyl are optionally substituted with one to two substituents independently selected from the group consisting of -O-alkyl (C? -8), -O-alkyl (C-? 8) -OH, -O-alkyl of (C? 8) -0-alkyl of (d-8), -O-alkyl of (C? -8) -NH2, -O-alkyl of (C? - 8) -NH-alkyl of (C? 8), -O-alkyl of (d-8) -N [(C? -8)] 2 alkyl, -O-alkyl of (C-8) ) -S-alkyl (C? -8), -O-alkyl (C 1-8) -S02-alkyl (d-8), -O-alkyl (dd) -S02-NH2, -O- alkyl (d_d) -S02-NH-alkylene of (d-8), -O-alkyl of (C? -8) -S02-N [alkyl of (C? -8)] 2, - OC (O) H, -OC (O) -alkyl of (d.8), -0-C (0) -NH2, -0-C (0) -NH-alkyl of (C? _8), -0 -C (0) -N [(d-8) alkyl] 2, -0-alkyl of (C? -8) -C (0) H, -O-alkyl of (C1.8) -C (0) ) -alkyl of (C1-8), -O-alkyl of (C? -8) -C02H, -O-alkyl of (C? .8) -C (0) -0-alkyl of (Ci-β) , -O-alkyl of (Ci. 8) -C (0) -NH2, -O-alkyl of (dd) -C (0) -NH-alkyl of (d.8), -O-alkyl of (d) 8) -C (0) -N [(C?-D)] 2 alkyl, -C (0) H, -C (0) -a alkyl of (C?. d), -C02H, -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (NH) -NH2, -C (0) - NH-alkyl of (ds), -C (O) -N-alkyl of (C .8)] 2, -SH, -S-alkyl of (C 1-8), -S-alkyl of (C? -8) - S- (CIB) alkyl, -S- (C? 8) -0-alkyl of (C? 8), -S-(C? 8) -0-alkyl of (C?. C? -d) -OH, -S-alkyl (C? 8) -O-alkyl (C? _8) -NH2, -S-alkyl (d_8) -0- (C? -8) alkyl ) -NH-alkyl (Ci-s), -S-alkyl (C? S) -0-alkyl (C-d) -N-alkyl (C? 8)] 2, -S-alkyl (d.8) -NH-alkyl of (C? 8), -S02-alkyl of (d-β), -S02-NH2, -S02-NH-alkyl of (C? -8), - S02-N [(d8)] 2 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, d-8 alkyl, C2.d alkenyl, C2.8 alkynyl, - (d.8) -OH alkyl, (C? 8) -0-alkyl (C? -8) alkyl, -alkyl (C? -d) -NH2, -alkyl (C? d) -NH-alkyl of (C? _d), -alkyl of (C -8) -N [alkyl of (C? 8)] 2, -alkyl of (d.8) -S-alkyl of (d) -8), -C (0) -alkyl of (Ci. ß), -C (0) -0-alkyl of (d.8), -C (0) -NH2, -C (0) -NH-alkyl of (C? 8), -C (O) - N-chloroyl of (d.8)] 2, -S02-alkyl of (C? 8), -S02-NH2, -S02-NH-alkyl of (Ci. 8), -S02-N [alkyl of (C-) 8)] 2, - C (N) -NH2, aryl and arylalkyl of (C? .8) (wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C? .8, C? -8 alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and C? -8 alkyl), cyano, halo, halo (halo)? -3alkyl of (d.8), (halo)? 3alkoxy of (d.8), hydroxy, hydroxyalkyl of (C -8) and nitro)), cyano, (halo)? .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.sub.8-8 alkoxy alkyl. , amino (substituted with two substituents selected from the group consisting of hydrogen and C? -8 alkyl), cyano, halo, (halo)? _ 3a! quilo of (C1.3), (halo)? 3alkoxy (C? -8), hydroxy, hydroxyalkyl of (C? -8) and nitro)} , -C (0) -alkyl of (d.8), -C (0) -aryl, -C (0) -0-alkyl of (C? 8), -C (0) -0-aryl, -C (0) -NH-alkyl of (C? 8), -C (0) -NH-aryl, -C (0) -N [alkyl of (d.8)] 2, -S02-alkyl of (d.8), -S02-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 Ci-β alkyl, C2.8 alkenyl, C2.8 alkynyl, C ?8 alkoxyalkoxy, - C (0) H, -C (O) -alkyl of (Ci-d), -C02H, -C (0) -0-alkyl of (C? .8), -C (0) -NH2, -C (NH) -NH 2, - (O) -NH-alkyl (d-β), -C (0) -N [(C 1-8 alkyl]] 2, -SH, -S-alkyl (CM) , -S02- (C? -8) alkyl, -S02-NH2, -S02-NH-alkyl (CM), -S02-N [(C? -8)] 2, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, (C 1-8) -NH 2 alkyl, -C (0) -alkyl ( C? -8), -C (O) -O-alkyl (CM), -C (O) -NH2, -C (O) -NH-alkyl (CM), -C (O) -N [ alkyl of (d-β) 2, -S02-alkyl of (CM), -S02-NH2, -S02-NH- (C1-8) alkyl, -S02-N [alkyl of (CM)] 2 V -C (NH) -NH2), amino-alkyl of (C? 8) - (wherein amino is substituted with two substituy is independently selected from the group consisting of hydrogen, C? -8 alkyl, C2.8 alkenyl, C2-8 alkynyl, -alkyl of (d-β) -NH2l -C (0) -alkyl of ( CM), -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (0) -NH-alkyl of (CM), -C (0) -N [alkyl] of (C? 8)] 2, -S02-alkyl of (CM), -S02-NH2, -S02-NH-alkyl of (CM), -S02-N [alkyl of (C? -8) ] 2 and -C (NH) -NH 2), cyano, halo, (halo) β-3-alkyl of (CM) -, - (halo) β-3-alkoxy of (C?-8) -, hydroxy, hydroxyaikyl of (d) -8), nitro, aryl, (C. 8) -aryl, heteroaryl, and (C 1 -d) -heteroaryl alkyl}; R2 is selected from the group consisting of-C-Z alkyl, -C2.-Z alkenyl, and d-β-Z-alkynyl; wherein the -C 8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl is optionally substituted with one to two substituents independently selected from the group consisting of halo, hydroxy, amino, C-alkylamino. , dialkylamino of CM, alkyl of CM, alkoxy of CM, (halo)? -3alkyl of (CM), (halo) Malkoxy of (CM) and hydroxyalkyl of (C1.4); Z is a 5-6 membered monocyclic heteroaryl ring having 2 to 4 heteroatoms containing at least one carbon atom and at least one nitrogen atom; wherein Z is optionally substituted with R5; R5 is 1 to 2 substituents attached to a carbon or nitrogen atom of Z and each substituent is independently selected from the group consisting of hydrogen, -D-8 alkyl, -C2-8 alkenyl, -C2 alkynyl -8, -C (O) H, -C (0) -alkyl of (CM), -C02H, -C (0) -0-alkyl of (CM), -C (0) -NH2I -C (NH ) -NH2, -C (0) -NH (alkyl of CM), -C (0) -Nalkyl of (d.8)) 2, -S02-alkyl of (d. 8), -SO2-NH2, - S02-NH (CM alkyl), -S02-N (d-β alkyl) 2, -alkyl of (C? -d) -NH2, -alkyl of (C? .8) -NH (CM alkyl) , -alkyl of (C? -8) -N (C? 8 alkyl) 2, -alkyl of (d.8) - (halo)? -3, -alkyl of (d.8) -OH, - aryl, - (d-β) -aryl alkyl, heteroaryl and - (C 8) -heteroaryl alkyl; with the proviso that, when R5 is attached to a carbon atom, R5 is additionally selected from the group consisting of -d-βalkoxy, -alkoxy of (d.8) - (halo)? -3, -SH, -S-alkyl of (C? .8), -N-R6, cyano, halo, hydroxy, and nitro; R6 is 1 to 2 substituents independently selected from the group consisting of hydrogen, -C 8 alkyl, 8-alkenyl, d-β-alkynyl, C 3-8 cycloalkyl, -C (0 ) H, -C (0) -alkyl of (CM), -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (0) -NH (alkyl of CM), -C (0) -N (alkyl of d.8) 2, -S02-alkyl of (CM), -S02-NH2, -S02-NH (alkyl of CM), -S02-N (alkyl) or of C1 -8) 2, -C (N) -NH2, -C (N) -NH (CM alkyl) and -C (N) -N (C1-8 alkyl) 2; R3 and R4 are independently selected from the group consisting of hydrogen, d8 alkyl, C2-8 alkenyl, C2.8 alkynyl, d-β alkoxy, -C (0) H, -C (0 ) -alkyl of (CM), -C02H, -C (0) -0-alkyl of (CM), -C (0) -NH2, -C (NH) -NH2, -C (0) -NH-alkyl of (CM), -C (0) -N [alkyl of (d.8)] 2, -SH, -S-alkyl of (CM), -S02-alkyl of (CM), -S02-NH2, - S02-NH-alkyl (CM), -S02-N [(d_3)] 2 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C? β, alkynyl of -8, -alkyl of (d-β) -NH 2, -C (0) -alkyl of (CM), -C (0) -0-alkyl of (CM), -C (0) - NH2, -C (0) -NH-alkyl of (CM), -C (0) -N [(C1-C8) alkyl] 2, -S02-alkyl of (CM), -S02-NH2, -S02 -NH-alkyl (CM), -S02-N [(C [beta] 8 alkyl]] and -C (NH) -NH2), (C [beta] -) aminoalkyl (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, d-β alkyl, alke nyl of d-β, alkynyl of d-β, -alkyl of (d-β) -NH 2, -C (0) -alkyl of (CM), -C (0) -0-alkyl of (CM), - C (0) -NH2, -C (0) -NH-alkyl (CM), -C (0) -N [(C? -8)] 2 alkyl, -S02-alkyl (CM), - S02-NH2, -S02-NH-alkylated from (CM), -S02-N [alkyl from (CM)] 2 and -C (NH) -NH2), cyano, halo, (halo)? -3alkyl from ( d.8) -, (halo)? - 3-alkoxy of (C? -8) -, hydroxy, hydroxyalkyl of (C? -8), nitro, aryl, - (C? -8) -aryl alkyl, heteroaryl and - (C? -8) -heteroaryl alkyl; and pharmaceutically acceptable salts thereof, for the preparation of a medicament for the treatment or amelioration of a disorder selected from the group consisting of disorders associated with diabetes, dermatological disorders, oncological disorders and central nervous system disorders in a subject . 36. The use claimed in claim 35, wherein the disorders associated with diabetes are selected from the group consisting of impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy and neuropathy. 37. The use claimed in claim 35, wherein the dermatological disorders are selected from the group consisting of psoriasis, hair loss and baldness. 38.- The use claimed in claim 35, wherein the oncological disorders are selected from the group consisting of cancer or tumor growth, proliferative angiopathy, and angiogenesis. 39.- The use claimed in claim 35, wherein the disorders of the central nervous system are selected from the group consisting of chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative conditions, dtia, Alzheimer's disease, disorders of the mood, schizophrenia, manic and neurotraumatic depression, cognitive decline and diseases related to ischemia (as a result of trauma to the head or transient ischemic cerebrovascular event).