MXPA03010535A - Inhibitors of src and other protein kinases - Google Patents

Abstract

The present invention provides compounds of formula I:wherein A is N or CR, and G, R1, R2, and R3 are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of Src mammalian protein kinase involved in cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.

Description

INHIBITORS OF SRC AND OTHER PROTEINS KINASES TECHNICAL FIELD OF THE INVENTION The present invention relates to the inhibitors of the c-Jun N-terminal kinases (JNK) and to the kinases belonging to the Src family of the protein kinases, especially the protein kinases Src and Lck. The kinases of the Src family are involved in cancer, immune disorders and bone disorders. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods for using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the family of mitogen-activated protein kinase (MAP), which includes kinases regulated by the extracellular signal ( ERK), the MAP kinases p38 and the c-Jun N-terminal kinases (JNK). MAP kinases (MAPKs) are activated by a variety of signals that include growth factors, cytokines, UV radiation, and stress-inducing agents. MAPKs are kinases of P03./158-VPI serine / threonine and its activation occurs by the double phosphorylation of threonine and tyrosine in the Thr-X-Tyr segment in the activation ring. MAPKs phosphorylate various substrates, including transcription factors, which, in turn, regulate the expression of specific sets of genes and, therefore, by a specific response to stimuli. One family of kinases of particular interest is the Src family of kinases. These kinases are involved in cancer, the immune system's dysfunction and bone remodeling diseases. For general reviews, see Thomas and Brugge, Annu. Rev. Cell Dev.

Biol. (1997) 13, 513; Lawrence and Niu, Pharmacol. Ther. (1998) 77, 81; Tatosyan and Mizenina, Biochemi stry (Moscow) (2000) 65, 49; Boschelli et al., Drugs of the Future 2000, 25 (7), 717, (2000). Members of the? Rc family include the following eight kinases in mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck and Blk. These are non-receptor protein kinases that fluctuate in molecular mass from 52 to 62 kD. All are characterized by a common structural organization that is comprised of six distinctive functional domains: Src homology domain 4 (SH4), a single domain, SH3 domain, SH2 domain, a catalytic domain (SH1), and a C terminal regulatory region. Tatosyan et al.

P03 / 158-VPI Biochemistry (Moscow) 65, 49-58 (2000). Based on published studies, Src kinases are considered as potential therapeutic targets for several human diseases. Mice that are deficient in Src develop osteopetrosis, or bone accumulation, due to depressed bone resorption by osteoclasts. This suggests that osteoporosis resulting from abnormally high bone resorption can be treated by inhibiting Src. Soriano et al., Cell, 69, 551 (1992) and Soriano et al., Cell, 64, 693 (1991). The suppression of arthritic bone destruction by overexpression of CSK in synoviocytes and rheumatoid osteoclasts has been achieved. Takayanagi et al., J ".Clin.Invest., 104, 137 (1999) .The CSK, or the Src C terminal kinase, phosphorylates and therefore inhibits the catalytic activity of Src. Src can prevent joint destruction that is characteristic in patients suffering from rheumatoid arthritis Boschelli et al., Drugs of the Future 2000, 25 (7), 717, (2000). reproduction of the hepatitis B virus. The virally encoded transcription factor HBx activates the Src at a step required for the propagation of the virus Klein et al., EMBO J., 18, 5019, (1999) and Klein et al., Mol. Cell. Biol., P03 / 158-VPI 17, 6427 (1997). Several studies have linked the expression of Src with cancers such as colon, breast, hepatic and pancreatic cancers, certain B-cell leukemias and lymphomas. Talamonti et al., J. Clin. Invest. 91, 53 (1993); Lutz et al., Biochem. Biophys. Res. 243, 503 (1998); Rosen et al-, J. Biol. Chem., 261, 13754 (1986); Bolen et al., Proc. Nati Acad. Sci. USA, 84, 2251 (1987); Masaki et al., Hepatology, 27, 1257 (1998); Biscardi et al., Adv. Cancer Res. , 76, 61 (1999); Lynch et al., Leuke ia, 7, 1416 (1993). In addition, antisense Src expressed in ovarian and colon tumor cells has been shown to inhibit tumor growth. Wiener et al., Clin. Cancer Res. , 5, 2164 (1999); Staley et al., Cell Growth Diff. , 8, 269 (1997). Other kinases of the Src family are also potential therapeutic targets. Lck plays a role in the signaling of T cells. Mice lacking the Lck gene have a poor ability to develop thymocytes. The function of the Lck. as a positive activator of T cell signaling suggest that Lck inhibitors may be useful for treating autoimmune diseases, such as rheumatoid arthritis. Molina et al., Nature, 357, 161 (1992). The Hck, Fgr and Lyn, have been identified as P03 / 158-VPI important mediators of integrin signaling in myeloid leukocytes. Lowell et al., J. Leukoc. Biol. , 65, 313 (1999). The inhibition of these kinase mediators may therefore be useful in treating inflammation. Boschelli et al., Druga of the Future 2000, 25 (7), 717, (2000). In the c-Jun NH terminal protein kinases, also known as JNK, three distinct genes have been identified, JNK1, JNK2, JNK3, and there are at least ten different JNK splicing isoforms, in mammalian cells [Gupta et al. ., EMBO J., 15, 2760-70 (1996)]. Members of the JNK family are activated by proinflammatory cytokines, such as tumor necrosis factor (TNFa), and interleukin-lß (IL-lß), as well as by environmental aggression, including anisomycin, irradiation UV, hypoxia and osmotic shock [Minden et al., Biochemistry et Biophys ica Acta, 1333, F85-F104 (1997)]. Substrates below the JNK include the transcription factors c-Jun, ATF-2, Elkl, p53 and a cell death domain protein (DENN) [Zhang et al., Proc. Nati Acad. Sci. USA, 95, 2586-91 (1998)]. Each isoform of the JNK binds to these substrates with different affinities, suggesting a regulation of the signaling paths by a specificity of the P03 / 158-VPI substrate of different JNK in vivo (Gupta et al-, supra). JNKs, along with other MAPKs, have also been implicated in the mediation of the cellular response to cancer, platelet aggregation induced by thrombin, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and heart disease. Therapeutic conditions related to JNK pathway activation include chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and neurodegenerative diseases. Several reports have detailed the importance of JNK activation associated with liver disease or episodes of hepatic ischemia [Nat. Genet 21, 326-9 (1999); FEBS Lett. 420, 201-4 (1997); J. Clin. Invest. 102, 1942-50 (1998); Hepatology 28, 1022-30 (1998)]. A role of JNK in cardiovascular disease, such as myocardial infarction or congestive heart failure, has also been reported, since it has been shown that JNK mediates hypertrophic responses to various forms of cardiac stress [Circ. Res. 83, 167-78 (1998); Circulation 97, 1731-7 (1998); J. Biol. Chem. 272, 28050-6 (1997); Circ. Res. 79, 162-73 (1996); Circ. Res. 78, 947-53 P03 / 158-VPI (nineteen ninety six); J. Clin. Invest. 97, 508-14 (1996)]. It has been shown that the JNK cascade also plays a role in the activation of T cells, including the activation of the IL-2 promoter. Thus, inhibitors of JNK have a potential therapeutic value in the alteration of pathological immune responses ["Immunol 162, 3176-87 (1999); Eur. J. Immunol. 28, 3867-77 (1998); J. Exp. Med. 186, 941-53 (1997); Eur. J. Immunol. 26, 989-94 (1996)]. A role of JNK activation in several cancers has also been established, suggesting the potential use of JNK inhibitors in cancer. For example, constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis [Oncogene 13, 135-42 (1996)]. The proliferative effects of bFGF and OSM on Kaposi's sarcoma cells (KS) are mediated by their activation of the JNK signaling pathway [J. Clin. Invest. 99, 1798-804 (1997)]. Other proliferative effects of other cytokines involved in KS proliferation, such as vascular endothelial growth factor (VEGF), IL-6 and TNFa, are also mediated by JNK. In addition, the regulation of the c-jun gene in transformed p210 BCR-ABL cell corresponds to the activity of the JNK, suggesting a role for JNK inhibitors.

P03 / 158-VPI in the treatment for chronic myelogenous leukemia (CML) [Blood 92, 2450-60 (1998)]. JNK1 and JNK2 are widely expressed in a variety of tissues. In contrast, JNK3 is selectively expressed in the brain and to a lesser extent in the heart and testes [Gupta et al., Supra; Mohit et al., Neuron 14, 67-78 (1995); Martin et al., Brain Res. Mol. Brain Res. 35, 47-57 (1996)]. JNK3 has been linked to neuronal apoptosis induced by cainic acid, which indicates a role of JNK in the pathogenesis of glutamate neurotoxicity. In the adult human brain, the expression of JNK3 is located in a subpopulation of the pyramidal neurons CAÍ, CA4 and the hippocampal subiculum and layers 3 and 5 of the neocortex [Mohit et al., Supra]. The CAI neurons of patients with acute hypoxia showed a strong nuclear immunoreactivity to JNK3 compared to the minimal, diffuse cytoplasmic staining of hippocampal neurons in the brain tissues of normal patients [Zhang et al., Supra]. Thus, it seems that JNK3 is involved in the hypoxic and ischemic damage of CAI neurons in the hippocampus. In addition, JNK3 is located immunochemically with vulnerable neurons in Alzheimer's disease [Mohit et al., Supra]. The breakdown of the JNK3 gene caused the resistance of the mice to cainic acid, an agonist of P03 / 158-VPI excitotoxic glutamate receptor, including the effects on seizure activity, AP-1 transcriptional activity and apoptosis of hippocampal neurons, indicating that the signaling pathway of JNK3 is a critical component in the pathogenesis of glutamate neurotoxicity [Yang et al., Nature, 389, 865-870 (1997)]. Based on these findings, J? K signaling, especially that of J? K3, has been implicated in the areas of neurodegenerative diseases activated by apoptosis, such as Alzheimer's Disease, Parkinson's Disease, ALS (Sclerosis). Amyotrophic Lateral), epilepsy and seizures, Huntington's disease, traumatic brain injuries, as well as ischemic and hemorrhagic stroke. Accordingly, there is still a great need to develop potent inhibitors of the kinase proteins J? K3, Src and Lck, which are useful in the treatment of various diseases or conditions associated with the activation of J? K3, Src and Lck.

SUMMARY OF THE INVENTION It has now been found that the compounds of this invention, and the pharmaceutically acceptable compositions thereof, are effective as inhibitors of the Src, Lck and JNK3 protein kinases. These compounds have P03 / 158-VPI the general formula I or a pharmaceutically acceptable derivative thereof, wherein A is nitrogen CH, and R1, R2, R3 and G are as described below. These compounds and the pharmaceutically acceptable compositions thereof are useful for treating or ameliorating the severity of a variety of disorders, such as cancer, autoimmune disease, osteoporosis, and inflammatory diseases.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula I: or a pharmaceutically acceptable derivative thereof, wherein: P03 / 158-VPI G is -XR or -XAr; each X is independently selected from an alkylidene chain of C? _6, wherein one or two non-adjacent methylene units of X, are independently replaced by -0-, -NR-, -S-, -C (0) -, -C (0) NR-, -NRC (O) -, -NRC (0) NR-, -SO-, -S02-, -NRS02-, -? 02NR- or -NRS02NR-; A is N or CR; each R is independently selected from hydrogen or an optionally substituted aliphatic group of C? _8, or two R groups attached to the same nitrogen are taken together with the nitrogen to form a 3-7 membered heterocyclic ring having 0-2 heteroatoms , in addition to the nitrogen attached to them, independently selected from nitrogen, oxygen or sulfur; with the proviso that when G is -N (R) 2, the two R groups are not taken together to form a ring; Ar is an optionally substituted 5-6 membered monocyclic ring, saturated, partially unsaturated or completely unsaturated, having zero to three heteroatoms independently selected from nitrogen, sulfur or oxygen, or an optionally substituted bicyclic ring of 8- 10 members, saturated, partially unsaturated, or completely unsaturated, having from zero to four heteroatoms selected in a manner P03 / 158-VPI independent of nitrogen, sulfur or oxygen; R1 is T (n) -R or T (n) -Ar; n is zero or one; T is selected from -C (0) -, -C02-, -C (0) C (0) -, -C (0) CH2C (0) -, -CONR-, -S (0) 2- or - S (0) 2NR-; R2 is selected from hydrogen, Ar, or an aliphatic group of C? _B optionally substituted with 1-3 groups independently selected from oxo, OR,? R, S02R, C (0) R, C02R, CN, N (R ) 2, = N-OR, = NN (R) 2 # = NNHC (0) R, = NNHC02R, = NNHS02R, Ar, NRC (0) N (R) 2, NRC (0) R, NRC02R, C ( 0) N (R) 2, S02N (R) 2 or NRS02N (R) 2; and R3 is selected from R or Ar. As used herein, the following definitions should apply, unless otherwise indicated. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Unless otherwise indicated, an optionally substituted group may have one substituent at each substitutable position in the group, and each substitution is independent of the other. The term "aliphatic" or "aliphatic group," as used herein, means a hydrocarbon chain of C? -CB of straight or branched chain, which is completely saturated or which contains one or more unsaturation units, P03 / 158-VPI or a monocyclic C3-C8 hydrocarbon or a bicyclic CB-Ci2 hydrocarbon, which is fully saturated or containing one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" or "cycloalkyl") , which has a single point of attachment to the reactive molecule, where any single ring in the bicyclic ring system has 3-7 members. For example, suitable aliphatic groups include, but are not limited to, linear or branched alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger portion, include linear and branched chains containing from one to twelve carbon atoms. The terms "alkenyl" and "alkynyl", used alone or as part of a larger portion, should include linear and branched chains containing from two to twelve carbon atoms. The term "heteroatom" means nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also, the term "nitrogen" includes a suitable nitrogen of a heterocyclic ring. As P03 / 158-VPI an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) ) or NR + (as in the substituted N-pyrrolidinyl). The term "aryl", used alone or as part of a larger portion as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems, having a total of five to fourteen members in the ring, wherein at least one ring in the system is aromatic and wherein each ring in the system contains from 3 to 7 members in the ring. The term "aryl" can be used interchangeably with the term "aryl ring". The term "aryl" also refers to annular heteroaryl systems as defined hereinbelow. The term "heterocycle," "heterocyclyl," or "heterocyclic," as used herein, means non-aromatic, monocyclic, bicyclic, or tricyclic, ring systems having from five to fourteen member in the ring, in which one or more members The ring is a heteroatom, where each ring in the system contains 3 to 7 members in the ring. The term "heteroaryl", used alone or as part of a larger portion, as in "heteroaralkyl" P03 / 15B-VPI or "heteroarylalkoxy", refers to monocyclic, bicyclic and tricyclic ring systems, having a total of five to fourteen members in the ring, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms; and where each ring in the system contains 3 to 7 members in the ring. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". An aryl group (including aralkyl, aralkoxy, aryloxyalkyl and the like), or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like), may contain one or more e substituents. Suitable autoantibodies at the unsaturated carbon atom of an aryl, heteroaryl, aralkyl or heteroaralkyl group are selected from halogen, -R °, -OR °, -SR °, 1,2-methylenedioxy, 1,2-ethylenedioxy, phenyl (Ph) optionally substituted with R °; -O (Ph) optionally substituted with R °; -CH2 (Ph) optionally substituted with R °, -CH2CH2 (Ph) optionally substituted with R °; -N02; -CN; -N (R °) 2; -NR ° C (0) R °; -NR ° C (0) N (R °) 2; -NR ° C02R °; -NR ° NR ° C (O) R °; -NR ° NR ° C (O) N (R °) 2; -NR ° NR ° C02R °; -C (O) C (O) R °; -C (O) CH2C (O) R °; -C02R °, -C (O) R °; -C (0) N (R °) 2; -OC (0) N (R °) 2; -S (0) 2R °; -S02N (R °) 2; -S (0) R °; -NR ° S02N (R °) 2; -NR ° S02R °; -C (= S) N (R °) 2; -C (= NH) -N (R °) 2; O - (CH2) and NHC (0) R °; where each R ° is selected from P03 / 158-VPI hydrogen, an optionally substituted C 1-6 aliphatic group, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O (Ph), or -CH 2 (Ph). The optional substituents in the aliphatic group of R ° e selected from NH2, NH (aliphatic group of C? _4), N (aliphatic group of C1_4) 2, halogen, aliphatic group of C? _4), OH, O (aliphatic group) of C? _4), N02, CN, C02H, C0 (aliphatic group of C ^), O (haloaliphatic group of C? _4), or haloaliphatic group of C? _4. An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic group or a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and of the following: = 0, = S, = NNHR * , = NN (R *) 2, = NNHC (O) R *, = NNHC02 (alkyl), = NNHS02 (alkyl) or = NR *, where each R * ae independently selects hydrogen, or an aliphatic group of C? _6 optionally substituted. The optional substituents in the aliphatic group of R * are selected from NH2, NH (aliphatic group of C1-4), N (aliphatic group of C? -4) 2, halogen, aliphatic group of C? _4, OH, 0 ( aliphatic group of C? _4), N02 CN, C02H, C02 (aliphatic group of Ci_4), O (haloaliphatic group of C? -4), or halo (aliphatic group of C? -4).

P03 / 158-VPI The optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from R +, -N (R +) 2, -C (0) R +, -C02RC (0) C (0) R +, -C (0) CH2C (0) R +, -S02R +, -S02N (R +) 2, -C (=?) N (R +) 2, -C (= NH) -N (R +)?, Or -NR + S02R +; wherein each R + is hydrogen, an optionally substituted C ?_6 aliphatic group, optionally substituted phenyl, -O (Ph) optionally substituted, -CH2 (Ph) optionally substituted, -CH2CH2 (Ph) optionally substituted, or a heteroaryl ring or 5-6 membered heterocyclic unsubstituted. Optional substituents on the aliphatic group or the phenyl ring of R * are selected from NH2, NH (aliphatic group of C? _4), N (aliphatic group of C? -) 2, halogen, aliphatic group of C? _4) , OH, 0 (aliphatic group of C? _4), N02 CN, C02H, C02 (aliphatic group of C? _4), 0 (haloaliphatic group of C? -4), or halo (aliphatic group of C? -4) . The term "alkylidene chain" refers to a linear or branched carbon chain that may be completely saturated or have one or more units of unsaturation, and which has two binding sites to the molecule's reagent. A combination of substituents or variables is permissible only if such combination results in a stable or chemically feasible compound. An eatable compound or a chemically feasible compound is one that is not substantially altered when maintaining a P03 / 158-VPI temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. It will be apparent to one of ordinary skill in the art that certain compounds of this invention can exist in the tauromeric forms, all such tauromeric forms of the compounds being within the scope of the invention. Unless indicated otherwise, the structures described herein, are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, the unique stereochemical isomers, as well as the enantiomeric and stereomeric mixtures of the present compounds, are within the scope of the invention. Unless indicated otherwise, the structures described herein are also intended to include the compounds, which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a carbon enriched by 13C or 4C, are within the scope of this invention. Such compounds are useful, for example, as analytical probes or tools in biological assays.

P03 / 158-VPI Preferred G groups of formula I are -XR and -X-Ar, where X is an alkylidene chain of C? -4, and wherein one or two non-adjacent methylene units of X are independently replaced by - S-, -SO-, -S02-, -0- or -NH-. More preferred X groups of formula I are selected from -S-, -0-, -NH-, -S02-, -NHCH2CH2NHCH2CH2-, -NHCH2CH2CH2-, -NHCH2CH2? CH2CH2-, or -NHCH2CH2-. The preferred R groups within the -X-R portion of formula I are selected from an optionally substituted C 1-6 aliphatic group, and most preferably, an optionally substituted C 4 -alkyl. Preferred substituents in the R group of -XR of formula I are selected from halo, CN, oxo, N (R °) 2, OH, 0R °, C02R °, C (0) R °, C (0) N (R °) 2, NR ° C02R °, SR °, NR °? 02R °, S02R °, NR ° C (0) R °, 0C (0) R ° or NR ° C (0) N (R °) 2, wherein each R ° group is independently selected from hydrogen or an aliphatic group of C? _4. The most preferred R groups of -XR of formula I are selected from methyl, ethyl, iopropyl, isobutyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, CH2CN, CH20H, CH2CH20CH3, CH2CH2CF3, CH2syclopropyl, CH2C (0) CH3, CH2CH2N (Me) 2, CH2CH2NHC (0) CH3, CH2CH2NHC02CH3, CH2CH2OC (0) CH3, CH2CH (NH2) C02Et, CH2C = CCH3, or CH2CH (Me) 2. Preferred Ar groups within the -X-Ar portion of formula I are selected from an aryl ring or P03 / 158-VPI an optionally substituted 5-6 membered saturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an optionally substituted 9-10 membered bicyclic aryl or heteroaryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. More preferred Ar groups within -X-Ar of formula I are optionally substituted rings selected from phenyl, pyridyl, imidazolyl, thienyl, thiazolyl, [1, 3] dioxanyl, piperidinyl, morpholinyl, pyrrolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, pyranyl , imidazolyl, benzimidazolyl, pyrrolyl, piperazinyl, thiomorpholinyl, naphthyl, oxazolyl, triazinyl, tetrazolyl, dithiolanyl, dioxalanyl, benzofuranyl, benzothienyl or indolyl. Preferred R1 groups of formula I are T (ll) -Ar. Preferred Ar groups within the R1 portion are selected from an optionally substituted aryl ring or 6-membered saturated ring, having 0-2 nitrogens, or a partially unsaturated or fully unsaturated bicyclic ring of 9-10 members optionally substituted, which has 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. The most preferred Ar groups within the R1 portion are suatituidoe rings optionally selected from phenyl, P03 / 158-VPI cyclohexyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, or indanyl. Preferred substituents on Ar of R1 of formula I are selected from R °, halogen, N02, CN, 0R °, SR °, N (R °) 2, C02R °, C (0) R °, C0N (R °) 2, phenyl, S02R °, or NR ° C (0) R °, wherein each R ° is independently selected from hydrogen or an aliphatic group of optionally substituted C? _4. The most preferred substituents on Ar of R1 of formula I are selected from methyl, ethyl, oxo, CF3, OMe, C (0) Me, C (0) phenyl, CH = CH, C02H, C (0) NH2, SMe , C02Me, fluorine, S02Me, N02, CN, chlorine, N (Me) 2, NHC (0) Me, NH2, cyanophenyl, C02Et, CH20H, CH20Me, 3-CH2C02H-phenyl, or 3-CH2CH2C02H-phenyl. Preferred R2 groups of formula I are selected from R, CH2N (R) 2, or CH2Ar, where R is hydrogen or an optionally substituted C4-4 aliphatic group, and Ar is a saturated or unsaturated 6-membered ring optionally substituted, having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. More preferred R2 groups of formula I are methyl, ethyl, CH2 (morpholin-4-yl), CH2N (Me) 2, CH2N (Et) 2, CH2N (Me) CH2C02CH3, or CH2 (? I? Eracin-1- ilo). Preferred R3 groups of formula I are selected from a 5-7 membered cyclic aliphatic ring, or from a saturated monocyclic ring, partially not P03 / 158-VPI saturated, or completely unsaturated of 6 members optionally substituted, having from zero to three heteroatoms, independently selected from nitrogen, sulfur or oxygen. More preferred R3 groups of formula I are selected from an optionally substituted cyclohexyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl or pyridazinyl ring. A preferred embodiment of this invention relates to a compound of formula I wherein G is S-R, as shown by the following general formula IA: IA or a pharmaceutically acceptable derivative thereof, wherein A, R, R1, R2 and R3 are as defined above. The preferred R, R1, R2 and R3 groups of formula IA are those described for formula I above. According to a more preferred embodiment, the present invention relates to a compound of formula HA: P03 / 158-VPI IIA or a pharmaceutically acceptable derivative thereof, wherein A, R, Ar, R2 and R3 are as defined above. Preferred Ar, R2 and R3 groups of formula IIA are those described for formula I above. Table 1 below shows the representative examples of compounds IIA, wherein A is N and Ar is an optionally substituted phenyl ring.

Table 1. Examples of the compounds of the formula IIA: P03 / 158-VPI P03 / 158-VPI P03 / 158-VPI P03 / 158-VPI P03 / 158-VPI P03 / 158-VPI Examples of compounds of Formula IIA, wherein R 2 is methyl, R 3 is phenyl, and R 1 is different from phenyl, are shown below in Table 2.

P03 / 158-VPI Table 2. Examples of the Compueatos of Formula HA: P03 / 158-VPI Representative examples of the compounds of formula HA, wherein A is CH, G is? -Me, R1 is phenyl, R3 is phenyl, and R2 is different from methyl, are shown in Table 3 below.

P03 / 158-VPI Table 3. Examples of Compound HA Another embodiment of this invention relates to a compound of formula IB or IB ': IB IB 'or a pharmaceutically acceptable derivative thereof, wherein each X is independently selected from an alkylidene chain of C? _4 and wherein one or two methylene units not adjacent to X are P03 / 158-VPI independently replaced by -S-, -S02-, -0-, or -NH-, and wherein A, R, Ar, R1, R2 and R3 are as defined above. The preferred R, Ar, R1, R2 and R3 groups, within formulas IB and IB ', are as described above for formula I. Table 4 below shows the specific examples of the compounds of formula IB and IB'.

Table 4. Examples of the IB Compounds IB-l IB-2 IB-3 IB-4 P03 / 158-VPI IB-5 IB-6 IB-7 IB-8 IB-9 IB-10 IB-11 IB-12 P03 / 158-VPI IB '-2 IB' -3 IB ' Other embodiments of this invention relate to compounds of formula I, wherein G is -NH-R (formula IC), G is -NH-Ar (formula ID), G is -OR (formula IE), G is -O -Ar (formula IF), G is -S02-R (formula 10), G is -S02-Ar (formula IH), G is -S (0) -R (formula IJ), and G is -S (0 ) -Ar (formula IK). Specific examples of these embodiments, wherein R 3 is phenyl, are shown below in Table 5.

P03 / 158-VP? Table 5 P03 / 158-VPI The compounds of this invention can be prepared in general, by methods known to those of ordinary skill in the art for analogous compounds, as illustrated by the following General Reaction Scheme and the following preparative examples.

P03 / 158-VPI Reaction Scheme I HA ia Reagents and conditions: (a) (CH3CO) 2C = C (SR) 2, 60 ° C; (b) DMF-DMA, toluene, reflux; (c) R1-NHC (= NH) NH2, MeOH, reflux Reaction Scheme I above shows a general route to prepare the present compounds, wherein R3 is pyridyl. In step (a) pyridinylhydrazine is condensed with 3- (bie-alkylsulfanylmethylene) -pentan-2, 4-dione, for example, using 3- (bia-methylsulfanyl-methylene) -pentan-2,4-dione to provide 2 (wherein R is methyl). Treatment of 2 with dimethylformamide dimethylacetal (DMF-DMA), according to step (b), provides enamine 3. Compound 3 can be cyclized with various guanidine derivatives to provide compounds of formula HA. Oxidation of an HA compound with oxone provides the corresponding sulfonyl compound of formula IG. The sulfonyl group of IG, in turn, can be displaced by several amines, P03 / 158-VPI provide IC. Alternatively, the corresponding sulfonyl group or sulfoxide group can be displaced by -? Ar, -? R, -OAr, or -OR to provide other compounds of this invention, using methods known to one of skill in the art. The activity of a compound used in this invention as an inhibitor of JNK3, Lck or Src, can be tested in vi tro, in vivo or in a cell line according to methods known in the art. The enaayoa in vi tro include assays that determine the inhibition of phosphorylation activity or ATPase activity of activated JNK3, Lck or Src. Alternative assays in vitro quantify the ability of an inhibitor to bind to JNK3, Lck or Src. The binding of the inhibitor can be measured by radiolabeling the antea inhibitor of the binding, isolating the inhibitor / JNK3 complex, inhibitor / Lck, or inhibitor /? Rc, and determining the amount of binding of the radiolabel. Alternatively, the binding of the inhibitor can be determined by running a competition experiment where the new inhibitors are incubated with JNK3, Lck or Src, bound to known radioligands. The detailed conditions for testing a compound used in this invention as an inhibitor of the JNK3, Lck or Src kinase are set out in the following Examples. According to another embodiment, the invention P03 / 158-VPI provides a composition comprising a compound of this invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the compositions of this invention is such that it is effective to detectably inhibit a cinaaa protein, particularly JNK3, Lck or Src, in a biological sample or in a patient. Preferably, the composition of this invention is formulated for administration to a patient in need of such a composition. More preferably, the composition of this invention is formulated for oral administration to a patient. The term "patient", as used herein, means an animal, preferably a mammal, and even more preferably a human. The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. The pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as P03 / 158-VPI human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salt or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, chloride sodium, zinc salt, colloidal silica, magnesium triailicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and anhydrous lanolin. The term "detectably inhibited", as used herein, means a measurable change in the activity of JNK3, Lck or Src, between a sample containing the composition and a JNK3, Lck or Src kinase, and an equivalent sample that comprises the JNK3, Lck or Src kinase, in the absence of the composition. A "pharmaceutically acceptable derivative" means any salt, ether, salt of an ester or other derivative of a non-toxic compound of this invention, which upon administration to a container, is capable of providing, either directly or indirectly, a compound of this invention or a metabolite or active inhibitory residue thereof. The pharmaceutically acceptable eals of the P03 / 158-VPI Compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glycoheptanoate, glycerophosphate, glycolate, semisulfate. , heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate , salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic acids, although by themselves are not pharmaceutically acceptable, can be used in the preparation of the salts useful as intermediates for the preparation of the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from the appropriate bases include alkali metals (eg, sodium and potassium), alkaline earth metals (eg, magnesium), ammonium salts and N + (C? _4 alkyl) 4. This invention also considers the quaternization of any groups that P03 / 158-VPI contain basic nitrogen of the compounds described herein. Dispersible or water or oil soluble products can be obtained by such quaternization. The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, naeally, buccally, vaginally or via an implanted container. The term "parenteral", as used herein, includes the techniques of subcutaneous, intravenous, intramuacular, intraarticular, intrasynovial, intraeaternal, intrathecal, intrahepatic, intrathecal, and intracranial injection or infusion. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable formae of the compositions of this invention may be aqueous or oleaginous suspensions. Eataa can be formulated according to techniques known in the art, using suitable dispersing agents or humectants, and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenterally-acceptable diluent or solvent, for example, a 1,3-butanediol solution. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and an isotonic sodium chloride solution.

P03 / 158-VPI In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be used, including synthetic mono or diglycerides. Fatty acids, such as oleic acid and its diglyceride derivatives, are useful in the preparation of injectable solutions, since they are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a diluent or dispersant of a long chain alcohol, such as carboxymethyl cellulose or similar dispersing agents, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens,? Pans and other emulsifying agents or bioavailability promoters, which are commonly used in the manufacture of solid, liquid or other pharmaceutically acceptable dosage forms, can also be used for the same purposes. of the formulation. The pharmaceutically acceptable compositions of this invention can be administered orally in any orally acceptable dosage form, including, of P03 / 15B-VPI non-exclusive way, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with the emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient, which is solid at room temperature, but liquid at the rectal temperature, and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the purpose of the treatment includes areas or organs easily accessible by the application.

P03 / 15T-VPI topical, including diseases of the eyes, skin or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs. Topical application to the lower intestinal tract may be effected in a rectal suppository formulation (see above), or in a suitable enema formulation. Topically transdermal patches can also be used. For topical applications, the pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the suspended active component dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream, containing the active components suspended or dialyzed in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl stear wax, cetearyl alcohol, 2- P03 / 158-VPI octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, sterile saline, at adjusted pH, or preferably, as solutions in isotonic saline, sterile, at adjusted pH, either with or without a condom such as benzalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated into an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention can also be administered by nasal spray or by inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulating art, and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption pters to improve bioavailability, fluorocarbons, and / or other conventional solubilizing or conducting agents. Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. The amount of the compounds of the present invention that can be combined with the materials P03 / 158-VPI carriers to produce a composition in a single dosage form, it will vary depending on the treated host, the particular mode of administration. Preferably, the compositions should be formulated so that a dose between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving compositions. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, the rate of excretion, the combination of drugs and the judgment of the attending physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend on the particular compound in the composition. Depending on the particular condition, or disease to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent this condition in monotherapy, may also be present in the compositions of this invention. As used herein, the additional therapeutic agents that are administered P03 / 158-VPI normally to treat or prevent a particular disease or condition, they are known as "appropriate for the disease, or condition being treated". For example, chemotherapeutic agents or other antiproliferative agents can be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, Gleevec ™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives. Other examples of the agents with which the compounds of this invention can also be combined include, but are not limited to, anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasazine; immunomodulatory and immunosuppressive agents talea such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclo-pofoafamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsives, ion channel blockers, riluzole, and antiparkinson agents; agents to treat cardiovascular disease, such as beta blockers, ACE inhibitors, diuretics, P03 / 158-VPI nitrates, calcium channel blockers and statins; agents for treating liver diseases, such as corticosteroids, coleetiramine, interferons and antiviral agents; agents for treating blood disorders such as corticosteroids, antileukemic agents and growth factors; agent to treat diabetes, such as inaulin, insulin analogues, alpha glucosidase inhibitors, biguanides and insulin sensitizers; and agents for treating immunodeficiency disorders such as gamma globulin. The amount of additional therapeutic agent in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the presently described compositions will vary from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. According to another embodiment, the invention relates to a method for inhibiting the activity of the JNK3, Lck or Src kinase in a biological sample, comprising the step of contacting the biological sample with a compound of this invention, or a composition that P03 / 158-VPI understand the compound. The term "biological sample", as used herein, includes, but is not limited to, cell culture or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tear or other body fluids or extracts thereof. The activity of the JNK3, Lck or Src kinase in a biological sample is useful for a variety of purposes that are known to one skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological specimens and biological assays. According to another embodiment, the invention provides a method for treating or ameliorating the severity of a disease or condition measured by JNK3, Lck or Src, in a patient, comprising the step of administering to the patient a pharmaceutically acceptable composition in accordance with the present invention. The term "JNK-mediated disease," as used herein, means any disease or other harmful condition in which JNK is known to play a role. Talea conditions include, but are not limited to, inflammatory diseases, autoimmune diseases, P03 / 158-VPI destructive bone disorders, proliferative disorders, cancer, infectious diseases, neurodegenerative diseases, allergies, reperfusion / ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, platelet aggregation induced by thrombin and associated conditions with the prostaglandin endoperoxidase sintaaa-2. Inflammatory diseases that can be treated or prevented by the compounds of this invention include, but are not limited to, acute pancreatitis, chronic pancreatitis, asthma, allergies and respiratory distress syndrome in adults. Autoimmune diseases that can be treated or prevented by the compounds of this invention include, but are not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, eacleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia. , thrombocytopenia, atopic dermatitis, active chronic hepatitis, myasthenia gravia, multiple erythroaia, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis or graft disease. Guest. Destructive bone disorders that can P03 / 158-VPI being treated or prevented by the compounds of this invention include, but are not limited to, osteoporosis, osteoarthritis and multiple bone disorders related to myeloma. Proliferative diseases that can be treated or prevented by the compounds of this invention include, but are not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HTLV-mediated tumorigenesis. 1. Angiogenic disorders that can be treated or prevented by the compounds of this invention include solid tumors, ocular neovasculization, infantile hemangiomas. Infectious diseases that can be treated or prevented by the compounds of this invention include, but are not limited to, sepsis, septic trauma, and Shigellosis. Viral diseases that can be treated or prevented by the compounds of this invention include, but are not limited to, acute hepatitic infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis. Neurodegenerative diseases that can be treated or prevented by the compounds of this invention include, but are not limited to, Alzheimer's disease, P03 / 158-VPI Parkinson's disease, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, Huntington's disease, traumatic brain injury, ischemic and hemorrhagic stroke, cerebral ischemia or neurodegenerative disease, including neurodegenerative disease triggered by apoptosis, caused by a traumatic injury, acute hypoxia, ischemia or neurotoxicity of glutamate. "JNK mediated diseases" also include iaque ia / reperfusion in stroke, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, hepatic ischemia, liver disease, congestive heart failure, pathological immune responses, such as those caused by the activation of T cells and platelet aggregation induced by thrombin. In addition, the compounds of the present invention may be capable of inhibiting the expression of inducible proinflammatory proteins. Therefore, other "JNK-mediated conditions", which can be treated by the compounds of this invention include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain caused by cancer, dental pain and pain caused by arthritis. The compounds of this invention are also P03 / 158-VPI useful as inhibitors of the cinasae of the Src family, especially Src and Lck. The term "disease mediated by Src or mediated by Lck", as used herein, means any disease or other harmful condition in which it is known that Src or Lck plays a role. Accordingly, these compounds are useful for treating diseases or conditions known to be affected by the activity of one or more family kinases? Rc. Such diseases or conditions include hypercalcemia, restenosis, osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriaeis, lupus, graft versus host disease, hypersensitivity disease mediated by cells T, Hashimoto's thyroiditis, Guillain-Barre syndrome, chronic obstructive pulmonary disorder, contact dermatitis, cancer, Paget's disease, asthma, ischemic or reperfusion injury, allergic disease, atopic dermatitis and allergic rhinitis. Diseases that are affected by Src activity, in particular, include hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis and Paget's disease. The conditions that are affected by Lck activity, in particular, include autoimmune diseases, P03 / 158-VPI allergies, rheumatoid arthritis and leukemia. A preferred embodiment relates to the method used to treat or prevent a disease mediated by JNK, selected from inflammatory diseases, autoimmune diseases, destructive bone disorders, neurodegenerative diseases, allergies, reperfusion / ischemia in stroke, heart attacks, angiogenic disorders, hypoxia organs, vascular hyperplasia, cardiac hypertrophy or platelet aggregation induced by thrombin. Another preferred embodiment relates to the method used to treat or prevent a disease mediated by Src or Lck, selected from hypercalcemia, osteoporosis, osteoarthritis or the symptomatic treatment of bone metastasis. In an alternative embodiment, the methods of this invention that utilize the compositions that do not contain an additional therapeutic agent, comprise the additional step of separately administering to the patient an additional therapeutic agent. When these additional therapeutic agents are administered separately, they can be administered to the patient before, sequentially or after administration of the compositions of this invention. The compounds of this invention or the P03 / 158-VPI Pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, atents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after an injury). However, patients who use attentive or other implantable devices run the risk of clot formation or the activation of platelets. These undesired effects can be prevented or mitigated by precoating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable coatings and the general preparation of the coated implantable devices are described in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings can be further covered, by a suitable top coating of fluorosilicon, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

P03 / 158-VPI Implantable devices coated with a compound of this invention are another embodiment of the present invention. In order that the invention described herein be understood more fully, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present invention in any way.

Synthetic Examples Example 1. 3- (Bis-? Tysulfanyl-m? Tilen) -pentan-2, 4-dione: A suspension in DMF of 2,4-pentanedione (1.0 equivalents), carbon disulfide (1.5 equivalents) and K2C03 ( 1.5 equivalents), was stirred at 0 ° C for 3 h. To the resulting suspension was added iodomethane (3.0 equivalents) at 0 ° C, and the reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. To the reaction mixture was added ethyl acetate and brine, the organic phase was washed with brine several times and dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the product was crystallized to give the title compound in 83% yield.

P03 / 158-VPI Example 2. 1- (5-Methyl-3-methylsulfanyl-l-plridin-2-yl-l-H-pyrazol-4-yl) -ethanone: A mixture of pyridin-2-yl-hydrazine (1.0 equivalent) and 3- (bis-methylsulfonyl-methylene) -pentan-2,4-dione (1.0 equivalent) was stirred at 60 ° C overnight. To the reaction mixture was added ethyl acetate and brine, the organic phase was washed with brine twice, dried over magnesium sulfate, and filtered. The organic solvent was removed under reduced pressure to provide the title compound.

Example 3 ^ _ 3-dimethylamino-l- (5-methyl-3-methylsulfyl-pyridin-2-yl-lH-pyrazol-4-yl) -propend: A toluene solution of 1- (5-methyl-3-methyl-sulphañyl-1-pyridin-2-yl-lH-pyrazol-4-yl) -ethanone (1.0 equivalents) and DMF-DMA (10.0 equivalents) was heated to reflux overnight. To the reaction mixture was added ethyl acetate and brine, the organic phase was P03 / 158-VPI washed with brine twice, dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the crude product was purified by chromatography to provide the title compound.

Example 4. N- (3-b-nycloxy-phenyl) -guanidine: A suspension in 4 N dioxane HCl of 3-benzyloxyaniline (1.0 equivalent) and cyanamide (1.0 equivalent) was stirred at 100 ° C overnight. Water and ether were added to the reaction mixture. The aqueous layer was washed with ether twice. The aqueous layer was adjusted to a pH higher than 10 with 1M NaOH, and the desired guanidine was extracted with methylene chloride, precipitated and filtered. The filter cake was N- (3-benzyloxy-phenyl) -guanidine (yield greater than 80%).

Example 5. (3-bissycloxy-phenyl) - [4- (5-methyl-3-methylsulfyl-l-pyridin-2-yl-lH-pyrazol-4-yl) -pyrimidin-2-yl] -amine ( HA-124): A methanol solution of 3-dimethylamino-1- (5- P03 / 158-VPI methyl-methyl-sulphanyl-1-pyridin-2-yl-lH-pyrazol-4-yl) -propenone (1.0 equivalent) and N- (3-benzyloxy-phenyl) -guanidine (1.0 equivalent) was refluxed overnight. Analytical HPLC indicated that the reaction was complete by 40%. To the reaction mixture was added ethyl acetate and brine. The organic phase was washed with brine twice, dried over magnesium sulfate, and filtered. The product was precipitated and filtered to provide the title compound in a 40% yield.

Example 6 ^ Phenyl hydrazinecarbodithioic acid methyl ester: To a stirred solution of phenylhydrazine (30 mmol, 1 equivalent), in dry acetonitrile (20 ml), dimethyl tritylcarbonic acid ester (30 mmol, 1 equivalent) was added, slowly at the temperature of an ice bath. The mixture was stirred for 18 hours and diluted with diethyl ether (30 ml). The resulting white solid was filtered and washed with ether and dried under nitrogen to provide the title compound.

P03 / 158-VPI Example 7 1- (5-methyl-3-methylsulfanyl-f-enyl-lH-pyrazol-4-yl) -ethanone: The N-phenylhydrazincarbodithioic acid methyl ester (1.98g, 10mmol), 3-chloro-2,4-pentanedione (1.35g, 10mmol), and diethyl iaopropylamine (2.0mL, 12mmol), in acetonitrile (10mg) were added. ml), was heated at 70 ° C for 10 hours. The mixture was diluted with ethyl acetate (30 ml) and water (30 ml). The organic layer was washed with water (30 ml). The aqueous layers were extracted again with ethyl acetate (30 ml, twice). The combined organic layers were dried with sodium sulfate and concentrated. The resulting solid was recrystallized with diethyl ether (30 ml) to give the pale yellow title compound.

Example 8. 3-Dimethylamino-1- (5-methyl-3-methylsulfanyl-phenyl-lff-pyrazol-4-yl) -propenyone: 1- (5-Methyl-3-methylsulfanyl-1-phenyl-1H-pyrazol-4-yl) -ethanone (1.2 g, 5 mmol) and the?,? - dimethylformamide P03 / 158-VPI dimethyl acetal (1.32 ml, 10 mmol), diluted in acetonitrile (2 ml) and heated at 80 ° C for 36 hours. The mixture was diluted with diethyl ether (10 ml) and hexane (20 ml), and heated briefly. The yellow solid was collected and washed with diethyl ether (5 ml).

Example 9. [4- (5-Methyl-3-methylsulfanyl-l-phenyl-lH-pyrazol-4-yl) -pyrimidin-2-yl] -phenyl-a-na (IIA-1): 3-Dimethylamino-1- (5-methyl-3-methyl-sulphanyl-1-phenyl-1H-pyrazol-4-yl) -propenone (30 mg, 0.1 mmol) and N-phenylguanidine (15 mg, 1.1 equivalents), they were suspended in acetonitrile (0.5 ml), and heated at 100 ° C for 24 hours. The mixture was diluted with methanol (2 ml) and briefly heated and cooled. The resulting solid was filtered and washed with methanol (1 ml). The aolide was dried under reduced pressure to provide the title compound. The following compounds were prepared using the procedure described in Example 9 above, except for the replacement of the N-phenylguanidine with the N-f nilguanidine suitably substituted.

P03 / 158-VPI These compounds were purified by reverse phase HPLC and characterized by NMR and LC / MS. Example 10. (4-Fluoro-phenyl) - [4- (5-methyl-3-methylsulfanyl-l-phenyl-lH-pyrazol-4-yl) -pyrimidin-2-yl] -amine (HA-9) Example 11. (4-chloro-phenyl) - [4- (5-methyl-3-methylsulfanyl-1-phenyl-1H-pyrazol-4-yl) -pyrimidin-2-yl] -amine (IIA-114) Example 12. (3-chloro-phenyl) - [4- (5-methyl-3-methylsulfanyl-l-phenyl-lff-pyrazol-4-yl) -pyrimidin-2-yl] -amine (IIA-115 ) Example 13. (4-Nitro-phenyl) - [4- (5-methyl-3-methylsulfanyl-l-phenyl-lH-pyrazol-4-yl) -pyrimidin-2-yl] -amine (IIA-116) Example 14. (3-benzyloxy-phenyl) - [4- (5-methyl-3-methyl-sulphanyl-l-phenyl-lJ-pyrazol-4-yl) -pyrimidin-2-yl] -amine (HA-117 ) Example 15. (4-benzyloxy-phenyl) - [4- (5-methyl-3-methyl-sulphanyl-1-phenyl-1H-pyrazol-4-yl) -pyrimidin-2-yl] -amine (IIA-118) Example 16. 3- [4- (5-Methyl-3-methylsulfanyl-l-phenyl-lH-pyrazol-4-yl) -pyrimidin-2-ylamino] -phenol (IIA-119) P03 / 158-VPI Src inhibition assay Compounds were evaluated as inhibitors of the human Src kinase using a radioactivity-based assay or a spectrophotometric assay.

Radioactivity-based assay The compounds were analyzed as inhibitors of the full-length recombinant human Src kinase (from Upstate Biotechnology, cat.14-117), expressed and purified from baculoviral cells. The activity of the Src kinase was verified following the incorporation of 33P of the ATP into the tyrosine of a polymeric substrate poly Glu-Tyr random, of composition, Glu: Tyr = 4: 1 (Sigma, cat.No.P-0275). The following were the final concentrations of the components of the analysis: 0.025 M HEPES, pH 7.6, 10 M MgCl 2, 2 mM DTT, 0.25 mg / ml BSA, 10 μM ATP (1-2 μCi of 33 P-ATP per reaction), poly Glu-Tyr 5 mg / ml, and 1-2 units of recombinant human Src kinase. In a typical assay, all components of the reaction, with the exception of ATP, were premixed and aliquoted into the wells of a test plate. The inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of 2.5%. The assay plate was incubated at 30 ° C for 10 minutes before starting P03 / 158-VPI the reaction with 33P-ATP. After 20 minutes of reaction, the reactions were cooled with 150 μl of 10% trichloroacetic acid (TCA), containing 20 mM Na3P04. The cooled samples were transferred to a 96-well filter plate (Whatman, UNI-Filter GF / F Fiberglass Filter, cat No. 7700-3310), installed in a vacuum manifold of a filter plate. The filter plates were washed four times with 10% TCA containing 20 mM Na3P04 and then 4 times with methanol. 200 μl of the scintillation fluid were then added to each well. The plates were sealed, and the amount of radioactivity associated with the filters was quantified in a TopCount scintillation counter. The incorporated radioactivity was plotted as a function of the concentration of the inhibitor. The data were adjusted to a kinetic model of competitive inhibition, to obtain the Ki of the compound. Βspßctrofotometry assay The ADP produced by ATP by phosphorylation catalyzed by the recombinant human src kinase of the poly Glu-Tyr substrate was quantified using a coupled enzyme assay (Fox et al., (1998) Protein Sci. 7, 2249) . In this assay, one molecule of NADH ae oxidizes NAD for each ADP molecule produced in the kinase reaction. The P03 / 158-VPI disappearance of NADH can conveniently be followed at 340 nm. The following final concentrations of the test components are: 0.025 M HEPES, pH 7.6, 10 mM MgCl 2, 2 mM DTT, 0.25 mg / ml poly Glu-Tyr and 25 nM recombinant human cinaaa. The final concentrations of the components of the enzyme system coupled are 2.5 mM phosphoenyl pyruvate, 200 μM NADH, 30 μg / ml pyruvate kinase and 10 μg / ml lactide dehydrogenase. In a typical trial, all the components of the reaction, with the exception of ATP, are premixed and aliquoted into wells of a test plate. The inhibitors dissolved in DMSO are added to the wells to give a final DMSO concentration of 2.5%. The assay plate is incubated at 30 ° C for 10 minutes before starting the reaction with 65 μM ATP. The change in absorbance at 340 nm with time, the reaction rate, is verified in a plate reader of molecular devices. Velocity data as a function of inhibitor concentration are adjusted to the competitive inhibition kinetic model to calculate Ki for the compound. Many of the present compounds tested in the Src inhibition enaayoa provided a Ki value below one micromolar.

P03 / 1S8-VPI Lck Inhibition Assay The compounds were evaluated as inhibitors of the human src kinase using a radioactivity-based assay or a spectrophotometric assay.

Assay based on radioactivity The compounds were analyzed as inhibitors of the full-length bovine thymus cell Lck kinase (from Upstate Biotechnology, cat.No. 14-106), expressed and purified from baculoviral cells. The activity of the Lck kinase was verified following the incorporation of 33P of the ATP into the tyrosine of a polymeric substrate Glu-Tyr randomized, composition, Glu: Tyr = 4: 1 (Sigma, cat .. P-0275). The following were the final concentrations of the components of the analysis: 0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg / ml BSA, 10 μM ATP (1-2 μCi of 33P-ATP per reaction), poly Glu-Tyr 5 mg / ml, and 1-2 units of recombinant human Src kinase. In a typical assay, all components of the reaction, with the exception of ATP, were premixed and aliquoted into the wells of a test plate. The inhibitors dissolved in DMSO were added to the wells to give a final DM? O concentration of 2.5%. The assay plate was incubated at 30 ° C for 10 minutes before starting the reaction with 33P-ATP. After 20 minutes of reaction, P03 / 158-VPI the reactions were cooled with 150 μl of 10% trichloroacetic acid (TCA), containing 20 mM Na3P04. The cooled samples were then transferred to a 96-well filter plate (Whatman, UNI-Filter GF / F Fiberglass Filter, cat No. 7700-3310), installed in a vacuum manifold of a filter plate. The filter plates were washed four times with 10% TCA containing 20 mM Na3P0 and then 4 times with methanol. 200 μl of the scintillation fluid were then added to each well. The plates were sealed, and the amount of radioactivity associated with the filters was quantified in a TopCount scintillation counter. The incorporated radioactivity was plotted as a function of the concentration of the inhibitor. The data were adjusted to a kinetic model of competitive inhibition, to obtain the Ki of the compound.

Spectrophotometric assay The ADP produced from ATP by the phosphorylation catalyzed by the recombinant human Lck kinase of the poly Glu-Tyr substrate was quantified using a coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay, one molecule of NADH is oxidized to NAD for each ADP molecule produced in the kinase reaction. The disappearance of NADH can be followed conveniently at 340 nm.

P03 / 158-VPI The following were the final concentrations of the components of the analysis: 0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 5 mg / ml poly Glu-Tyr, and 50 nM recombinant human Lck kinase. The final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 200 μM NADH, 30 μg / ml pyruvate kinase and 10 μg / ml lactate dehydrogenase. In a typical assay, all components of the reaction, with the exception of ATP, were premixed and aliquoted into the wells of an assay plate. The inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of 2.5%. The assay plate was incubated at 30 ° C for 10 minutes before initiating the reaction with 150 μM ATP. The change in absorbance at 340 nm over time, the rate of the reaction, was verified in a plate reader of molecular devices. Velocity data as a function of inhibitor concentration were adjusted to a kinetic model of competitive inhibition to obtain the Ki of the compound. Many of the present compounds tested in the Lck inhibition assays gave a value of K ± below one micromolar.

P03 / 158-VPI JNK inhibition assays Cloning, Expression and Purification of the JNK3 Protein A search with BLA? T of the EST database using the JNK3al cDNA published as a query, identified an EST clone (# 632588) that contains the complete coding sequence for human JNK3al. Polymerase chain reactions (PCR) are used using pfu polymerase (Strategene), to introduce the restriction sites in the cDNA for cloning into the expression vector pET-15B at the Ncol and BamHI sites. The protein is expressed in E. Coli. Due to the deficient solubility of the expressed full-length protein (Met 1-Gln 422), a truncated N-terminal protein is produced which starts at the Ser residue at position 40 (Ser 40). This truncation corresponds to Ser 2 of the JNK1 and JNK2 proteins, and is preceded by a methionine residue (start) and a glycine residue. The glycine residue is added in order to introduce an Ncol site for cloning into the expression vector. In addition, systematic terminal C truncations were performed by PCR to identify a construct that produces crystals that have diffraction qualities. Such a construct encodes the amino acid residues Ser40-Glu402 of the JNK3al and is preceded by the Met and Gly residues.P03 / 1S8-VPI The construct is prepared by PCR using the deoxyoligonucleotides: 5 'GCTCTAGAGCTCCATGGGCAGCAAAAGCAAAGTTGACAA 3' (forward primer with the start codon underlined) (SEQ ID NO: 1) and 5 'TAGCGGATCCTCATTCTGAATTCATTACTTCCTTGTA 3' (reverse primer with the stop codon underlined) ( SEQ ID NO: 2), as primers and confirmed by DNA sequencing. Control experiments indicated that the truncated JNK3 protein has equivalent kinase activity towards the myelin basic protein when activated with an upstream MKK7 kinase in vi tro. Strain BL21 (DE3) from E. Coli (Novagen) is transformed with the JNK3 expression construct and grown at 30 ° C in LB supplemented with 100 μg / ml carbenicillin in shaken flasks, until the cells were in the phase logarithmic (OD600 ~ 0.8). Isopropylthio-β D-galactosidase (IPTG) is added to the final concentration of 0.8 mM and the cells are harvested 2 hours later by centrifugation. The paste of E. Coli cells containing JNK3 is resuspended in 10 volumes / g of the lysis buffer (50 mM HEPES, pH 7.2, containing 10% glycerol (v / v), 100 mM NaCl, 2 mM DTT, 0.1 mM PM? F, 2 μg / ml Pepstatin, 1 μg / ml E-64 and Leupeptin). The cells were used on ice using a microfluidizer and centrifuged at P03 / 158-VPI 100,000 x g for 30 minutes at 4 ° C. The supernatant at 100,000 xg is diluted 1: 5 with Buffer A (20 mM HEPES, pH 7.0, 10% glycerol (v / v), 2 mM DTT), and purified by SP-Sepharose cation exchange chromatography ( Pharmacia) (column dimensions: 2.6 x 20 cm) at 4 ° C. The resin is washed with 5 column volumes of Buffer A, followed by 5 column volumes of Buffer A containing 50 mM NaCl. The bound JNK3 is eluted with a linear gradient of 7.5 column volumes of 50-300 mM NaCl. JNK3 is eluted between 150-200 mM NaCl.

Example 9. Activation of JNK3 5 mg of JNK3 is diluted to 0.5 mg / ml in 50 mM HEPES buffer, pH 7.5, containing 100 mM NaCl, 5 mM DTT, 20 mM MgCl2 and 1 mM ATP. GST-MKK7 (DD) is added at a molar ratio of 1: 2.5 of GST-MKK7: JNK3. After incubation for 30 minutes at 25 ° C, the reaction mixture is concentrated 5 times by ultrafiltration in a Centriprep-30 (Amicon, Beverly, MA), diluted to 10 ml and additional 1 mM ATP is added. This procedure is repeated three times to remove the ADP and replenish the ATP. The final ATP addition is 5 mM and the mixture is incubated overnight at 4 ° C. The activated JNK3 / GST-MKK7 (DD) reaction mixture is exchanged in 50 mM HEPES buffer, pH P03 / 158-VPI 7. 5, which contains 5 mM of DTT and 5% glycerol (weight / volume) by dialysis or ultrafiltration. The reaction mixture is adjusted with 1.1 M potassium phosphate, pH 7.5, and purified by hydrophobic interaction chromatography (at 25 ° C) using a Rainin column.

Hydropore. GST-MKK7 and inactivated JNK3 do not bind under these conditions, so that when a potassium phosphate gradient of 1.1 to 0.05 M is developed during 60 minutes at a flow rate of 1 ml / minute, the double-buffolated JNK3 is separated from the phosphorylated JNK only once. Activated JNK3 (ie, double phosphorylated JNK3) is stored at -70 ° C to 0.25-1 mg / ml.

Example 10. Analysis of inhibition of JNK The compounds are analyzed for the inhibition of JNK3, by means of a spectrophotometric coupled enzyme assay. In this assay, a fixed concentration of activated JNK3 (10 nM) is incubated with various concentrations of a potential inhibitor dissolved in DMSO for 10 minutes at 30 ° C, in a buffer containing 0.1 M HEPES buffer, pH 7.5, containing 10 mM MgCl 2, 2.5 nM phosphoenolpyruvate, 200 μM NADH, 150 μg / ml pyruvate kinase, 50 μg / ml lactate dehydrogenase and a 200 μM EGF receptor peptide. The EGF receptor peptide has the sequence KRELVEPLTPSGEAPNQALLR (SEQ ID NO: 3), and is a P03 / 158-VPI Phosphoryl acceptor in the kinase reaction catalyzed by JNK3. The reaction is initiated by the addition of 10 μM ATP and the analysis plate is inserted into the compartment of the spectrophotometer analysis plate, which is maintained at 30 ° C. The decrease in absorbance at 340 nm is verified as a function of time and the percent inhibition is determined. It was found that many of the present compounds tested in JNK3 inhibition assays inhibit JNK3. Although we have described various embodiments of this invention, it will be apparent that these basic examples can be altered to provide other embodiments, which utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention will be defined by the appended claims, rather than by the specific embodiments, which have been represented by way of example.

P03 / 158-VPI

Claims (1)

1. CLAIMS I A compound of formula I or a pharmaceutically acceptable derivative thereof, wherein: G is -XR or -XAr; each X is independently selected from an alkylidene chain of C? _6, wherein one or two non-adjacent methylene units of X, are independently replaced by -O-, -NR-, -S-, -C (O) -, -C (0) NR-, -NRC (O) -, -NRC (0) NR-, -SO-, -S02-, -NRS02-, -S02NR- or -NRS02NR-; A is N or CR; each R is independently selected from hydrogen or an optionally substituted C? _B aliphatic group, or two R groups attached to the same nitrogen are taken together with the nitrogen to form a 3-7 membered heterocyclic ring having 0-2 heteroatoms , in addition to the nitrogen bound thereto, independently selected from nitrogen, oxygen or sulfur; with the proviso that when G is -N (R) 2, the two R groups are not P03 / 158-VPI take together to form a ring; Ar is an optionally substituted 5-6 membered monocyclic ring, saturated, partially unsaturated or completely unsaturated, having zero to three heteroatoms independently selected from nitrogen, sulfur or oxygen, or an optionally substituted bicyclic ring of 8- 10 members, saturated, partially unsaturated, or completely unsaturated, having from zero to four heteroatoms independently selected from nitrogen, sulfur or oxygen; R1 is T (n, -R or T (n) -Ar; n is zero or one; T is selected from -C (0) -, -C02-, -C (0) C (0) -, -C (0) CH2C (0) -, -CONR-, -S (0) 2- or -S (0) 2NR-; R2 is selected from hydrogen, Ar, or an aliphatic group of C? _B optionally substituted with 1- 3 groups independently selected from oxo, OR, SR, S02R, C (0) R, C02R, CN, N (R) 2, = N-0R, = NN (R) 2, = NNHC (0) R, = NNHC02R, = NNHS02R, Ar, NRC (0) N (R) 2, NRC (0) R, NRC02R, C (0) N (R) 2, S02N (R) 2 or NRS02N (R) 2, and R3 is selected from R or Ar. The compound according to claim 1, wherein G is -XR or -X-Ar, wherein: each X is independently selected from P03 / 158-VPI an alkylidene chain of C? _4, wherein one or two non-adjacent methylene units of X, are independently replaced by -S-, -SO-, -S02-, -0- or -NH-; R is an optionally substituted C ?_6 aliphatic group; Ar is an aryl ring or an optionally substituted 5-6 membered saturated ring, having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 9-10 membered bicyclic aryl or heteroaryl ring, optionally substituted which has 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; and R3 is selected from a 5-7 membered cyclic aliphatic ring, or from a saturated, partially unsaturated, or completely unsaturated, 6-membered, optionally substituted monocyclic ring, having from zero to three heteroatoms, independently selected from nitrogen , sulfur or oxygen. The compound according to claim 2, wherein: R is an aliphatic group of C? _4, optionally substituted with halo, CN, oxo, N (R °) 2, OH, 0R °, C02R °, C (0) R °, C (0) N (R °) 2, NR ° C02R °, SR °, NR ° S02R °, S02R °, NR ° C (0) R °, 0C (0) R ° or NR ° C (0) N (R °) 2, where each group R ° is independently selected from hydrogen or a P03 / 158-VPI aliphatic group of C? _4; Ar is an optionally substituted ring selected from pyridyl phenyl, imidazolyl, thienyl, thiazolyl, [1, 3] dioxanyl, piperidinyl, morpholinyl, pyrrolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, pyranyl, imidazolyl, benzimidazolyl, pyrrolyl, piperazinyl, thiomorpholinyl, naphthyl, oxazolyl, triazinyl, tetrazolyl, dithiolanyl, dioxalanyl, benzofuranyl, benzothienyl or indolyl; and R3 is selected from an optionally substituted cyclohexyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl or pyridazinyl ring. 4. The compound according to claim 2, wherein: R2 is selected from R, CH2N (R) 2, or CH2Ar, wherein; each R is independently selected from hydrogen or an optionally substituted C? _4 aliphatic group, and Ar is an optionally substituted saturated or unsaturated 6-membered ring, having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 5. The compound according to claim 1, wherein: P03 / 158-VPI R1 is T (n) -R, where n is zero; and Ar is selected from an optionally substituted aryl ring or 6-membered saturated ring, having 0-2 nitrogens, or a 9-10 membered partially unsaturated or fully unsaturated bicyclic ring optionally substituted, having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 6. The compound according to claim 5, wherein: R1 is phenyl, cyclohexyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl or indanyl, wherein: R1 is optionally substituted with 1-3 groups selected from R °, halogen, N02, CN , 0R °, SR °, N (R °) 2, C02R °, C (0) R °, C0N (R °) 2, phenyl, S02R °, or NR ° C (0) R °, where each R ° are independently selected from hydrogen or an optionally substituted C? _4 aliphatic group. The compound according to claim 6, wherein R1 is optionally substituted with 1-3 groups that are independently selected from methyl, ethyl, oxo, CF3, OMe, C (0) Me, C (O) phenyl, CH = CH, C02H, C (0) NH2, SMe, C02Me, Fluorine, S02Me, N02, CN, Chlorine, N (Me) 2, NHC (0) Me, NH2, Cyanophenyl, C02Et, CH20H, CH2OMe, 3-CH2C02H -phenyl, or 3-CH2CH2C02H-phenyl. P03 / 158-VPI 8. The compound according to claim 5, wherein: R2 is selected from R, CH2N (R) 2, or CH2Ar, wherein: each R is independently selected from hydrogen or an optionally substituted C? - aliphatic group, and Ar is an optionally substituted saturated or unsaturated 6-membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 9. The compound according to claim 2, wherein the compound is selected from the following compounds: P03 / 158-VPI P03 / 158-VPI P03 / 158-VPI P03 / 158-VPI P03 / 158-VPI P03 / 158-VPI 10. The compound according to claim 5, wherein the compound is selected from the following compounds: P03 / 158-VPI P03 / 158-VPI 11. The compound according to claim 8, wherein the compound is selected from the following compounds: P03 / 158-VPI 12. The compound according to claim 2, wherein the compound is selected from the following compounds: IB-1 IB-2 P03 / 158-VPI IB-3 IB-4 IB-5 IB-6 IB-7 IB-8 IB-9 IB-10 P03 / 158-VPI IB- 11 IB- 12 IB7 -2 IB '-3 IB '-4 13. The compound according to claim 2, wherein the compound is selected from the following compounds: P03 / 158-VPI P03 / 158-VPI 14. A composition comprising a compound according to claim 1, in an amount for detectably inhibiting the activity of the JNK3, Lck or Src kinase, and a pharmaceutically acceptable carrier, adjuvant or vehicle. 15. The composition according to claim 14, further comprising an additional therapeutic agent, selected from an antiproliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating a cardiovascular disease, an agent for treating a disease of the liver, an antiviral agent, an agent for treating blood disorders, an agent for treating diabetes or an agent for treating immunodeficiency disorders. P03 / 158-VPI 16. A method for inhibiting the activity of the JNK3, Lck or Src kinase in a biological sample, comprising the step of contacting the biological sample with: a) a compound according to claim 1; or b) a composition according to claim 14. 17. A method for treating or ameliorating the severity of a disease or condition measured by JNK3, Lck or Src, in a patient, comprising the step of administering to the patient a composition according to claim 14. 18. A method to treat or lessen the severity of an inflammatory disease, autoimmune disease, destructive bone disorders, proliferative disorders, infectious diseases, neurodegenerative diseases, allergies, reperfusion / ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, platelet aggregation induced by thrombin or a condition associated with cytokines proinflammatory agents comprising the step of administering to the patient a composition according to claim 14. 19. The method according to claim 18, wherein the method is used to treat or prevent an inflammatory disease selected from acute pancreatitis, P03 / 158-VPI chronic pancreatitis, asthma, allergies or respiratory distress syndrome in adults. The method according to claim 18, wherein the method is used to treat or prevent an autoimmune disease selected from glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia , autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriaeie or graft disease. Guest. The method according to claim 18, wherein the method is used to treat or prevent destructive bone disorders selected from osteoarthritis, osteoporosis or multiple bone disorders related to myeloma. The method according to claim 18, wherein the method is used to treat or prevent proliferative diseases selected from acute myelogenous leukemia, chronic myelogenous leukemia, metatatic melanoma, Kaposi's sarcoma or multiple myeloma. 23. The method according to claim 18, wherein the method is used to treat or prevent the P03 / 158-VPI selected neurodegenerative diseases of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or neurodegenerative disease caused by a traumatic injury, hypoxia or glutamate neurotoxicity. The method according to claim 18, wherein the method is used to treat or prevent ischemia / reperfusion in heart attacks or myocardial ischemia, renal ischemia, heart attack, organ hypoxia, platelet aggregation induced by thrombin. The method according to claim 18, wherein the method is used to treat or prevent a condition associated with the activation of T cells or with pathological immune responses. 26. The method according to claim 18, wherein the method is used to treat or prevent an angiogenic disorder selected from solid tumors, ocular neovasculization or infantile hemangiomas. The method according to claim 17, wherein the disease selected from hypercalcemia, restenosis, osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, P03 / 158-VPI psoriasis, lupus, graft versus host disease, T-cell mediated hypersensitivity disease, Hashimoto's thyroiditis, Guillain-Barre syndrome, chronic obstructive pulmonary disorder, contact dermatitis, cancer, Paget's disease, asthma, ischemic or by reperfusion, allergic disease, atopic dermatitis and allergic rhinitis. The method according to claim 27, wherein the disease selected from hypercalcemia, osteoporosis, osteoarthritis, or symptomatic treatment of bone metastasis. The method according to claim 17, wherein the disease selected from autoimmune diseases, allergies, rheumatoid arthritis and leukemia. 30. The method according to claim 17, comprising the additional step of administering to the patient an additional therapeutic agent, selected from an antiproliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating a cardiovascular disease, a agent for treating a liver disease, an antiviral agent, an agent for treating blood disorders, an agent for treating diabetes or an agent for treating immunodeficiency disorders, wherein: the additional therapeutic agent is appropriate for P03 / 158-VPI the disease that is being treated; and the additional therapeutic agent is administered together with the composition as a single dosage form or separately from the composition, as part of a multiple dosage form. 31. A composition for coating an implantable device, comprising a compound according to claim 1, and a suitable carrier, for coating the implantable device. 32. An implantable device, coated with a composition according to claim 31. P03 / 158-VPI