The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the PKC, Jak1, Jak2, Jak3, Tyk2, KDR, Flt-3, ROCK, CDK2, CDK4, TANK, Trk, FAK, Abl, Bcr-Abl, cMet, b-RAF, FGFR3, c-kit, PDGF-R, Syk, or Aurora kinases.
Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within cells (see, e.g., Hardie and Hanks, The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif., 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 25-300 amino acid catalytic domain. The kinases may be categorized into families by the substrate that they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids etc.). Sequence motifs have been identified that generally correspond to each of these families (see e.g., Hanks and Hunter, (1995), FASEB J. 9:576-596; Knighton et al., (1991), Science 253:407-414; Hiles et al., (1992), Cell 70:419-429; Kunz et al., (1993), Cell 73:585-596; Garcia-Bustos et al., (1994), EMBO J. 13:2352-2361).
The protein kinase C family is a group of serine/threonine kinases including at least ten related isoenzymes, including alpha, beta 1, beta 2, gamma, delta, epsilon, eta, lambda, iota, theta and zeta. The isoenzymes have been divided into three groups based on their different expression patterns and co-factor requirements. The classical PKC enzymes (cPKC), including alpha, beta 1, beta 2 and gamma isozymes require diacylglycerol (DAG), phosphatidylserine (PS) and calcium for activation. The novel PKC's (nPKC), including delta, epsilon, theta and eta isozymes, require DAG and PS but are calcium independent. The atypical PKC's (aPKC), including zeta, lambda/iota do not require calcium or DAG.
PKC isoforms have been shown to play key roles in cellular signaling, proliferation, differentiation, migration, survival, and death. In resting cells, PKCs are predominantly localized in the cytosol and are catalytically inactive due to autoinhibition by their pseudosubstrate domain. Upon cell activation, PKC isotype-specific signals trigger translocation from the cytosol to the membrane and induce conformational changes, which displace the pseudosubstrate moiety from the catalytic domain and enable PKC isotypes to phosphorylate specific protein substrates (Biochem. J. 370:361-371, 2003). Most isoforms are ubiquitously expressed, except PKCγ and PKCθ. While PKCγ is exclusively found in the brain, high protein levels of PKCθ are seen predominantly in hematopoietic cells and skeletal muscle. PKCα and PKCθ as well as PKCβ and PKCδ are functionally important for T and B cell signaling, respectively (Nat. Immunol. 5:785-790, 2004. Curr. Opin. Immunol. 16:367-373, 204. Nature. 416:860-865, 2002). PKCθ plays an essential role in T cell activation because it is the only isoform that is selectively translocated to the T cell/antigen-presenting cell contact site immediately after cell-cell interaction (Nature. 385:83-86, 1997). Furthermore, PKCθ is crucial for IL-2 production, a prerequisite for the proliferation of T cells (Eur. J. Immunol. 30:3645-3654, 2000). PKCθ-deficient mice are defective in NF-κB (Cell Mol. Immunol. 3:263-270, 2006), NFAT and AP-1 activation (Nature, 404 (96776), 402-407, 2000. Journal of Immunology 176:6004-6011, 2006) and are resistant to experimental autoimmune encephalomyelitis (J. Immunol. 176:2872-2879, 2006), collagen-induced arthritis (Journal of Immunology 177 (3), 1886-1893, 2006) and asthma (Journal of Immunology 173 (10), 6440-6447, 2004). PKCα in T cells is required for proliferation and IFN-γ production (J. Immunol. 176:6004-6011, 2006). B cells require PKCβ for proper antigen receptor function and PKCδ for the induction of tolerance (Nature. 416:860-865, 2002). Thus, PKC isoforms in T and B cells are considered attractive therapeutic targets for autoimmune diseases and transplantation (Curr. Opin. Investig. Drugs. 7:432-437, 2006).
Further, PKCε and PKCγ have been suggested to play a role in nociception and inflammatory pain (J. Pharm. Exp. Ther. Pain 110, 281-289, 2004) and PKCζ has been proposed as an intermediary in the activation of the NF-κB and IL-4/Stat6 pathway (Cell Death Differ. 13: 702, 2006). The NF-κB pathway is important for inflammatory and immune diseases, therefore a PKCζ inhibition may serve to reduce the severity of these type of diseases (Allergol. Int. 55: 245, 2006. J. Biol. Chem. 281: 24124, 2006. Arthritis Rheum. 56: 4074, 2007. J. Interferon Cytokine Res. 27: 622, 2007).
The novel compounds of this invention inhibit the activity of one or more protein kinases and are, therefore, expected to be useful in the treatment of kinase-mediated diseases.