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Triazole-derived kinase inhibitors and uses thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Five-membered Hetero Ring Containing At Least One Nitrogen Ring Atom (e.g., 1,2,3-triazoles, Etc.), Tetrazoles (including Hydrogenated)Triazole-derived kinase inhibitors and uses thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20050272789, Triazole-derived kinase inhibitors and uses thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application 60/287,204, filed Apr. 27, 2001, the contents of which are incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION [0002] The present invention is in the field of medicinal chemistry and relates to triazole compounds that are protein kinase inhibitors, especially inhibitors of ERK, compositions containing such compounds and methods of use. The compounds are useful for treating cancer and other diseases that are alleviated by protein kinase inhibitors. BACKGROUND OF THE INVENTION [0003] Mammalian mitogen-activated protein (MAP) kinases are serine/threonine kinases that mediate intracellular signal transduction pathways (Cobb and Goldsmith, 1995, J. Biol. Chem., 270, 14843; Davis, 1995, Mol. Reprod. Dev. 42, 459). Members of the MAP kinase family share sequence similarity and conserved structural domains, and include the ERK2 (extracellular signal regulated kinase), JNK (Jun N-terminal kinase), and p38 kinases. JNKs and p38 kinases are activated in response to the pro-inflammatory cytokines TNF-alpha and interleukin-1, and by cellular stress such as heat shock, hyperosmolarity, ultraviolet radiation, lipopolysaccharides and inhibitors of protein synthesis (Derijard et al., 1994, Cell 76, 1025; Han et al., 1994, Science 265, 808; Raingeaud et al., 1995, J. Biol. Chem. 270, 7420; Shapiro and Dinarello, 1995, Proc. Natl. Acad. Sci. USA 92, 12230). In contrast, ERKs are activated by mitogens and growth factors (Bokemeyer et al. 1996, Kidney Int. 49, 1187). [0004] ERK2 is a widely distributed protein kinase that achieves maximum activity when both Thr183 and Tyr185 are phosphorylated by the upstream MAP kinase kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylates many regulatory proteins, including the protein kinases Rsk90 (Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al., 1994, Cell 78, 1027), and transcription factors such as ATF2 (Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247), Elk-1 (Raingeaud et al. 1996), c-Fos (Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952), and c-Myc (Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2 is also a downstream target of the Ras/Raf dependent pathways (Moodie et al., 1993, Science 260, 1658) and may help relay the signals from these potentially oncogenic proteins. ERK2 has been shown to play a role in the negative growth control of breast cancer cells (Frey and Mulder, 1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breast cancer has been reported (Sivaraman et al., 1997, J. Clin. Invest. 99, 1478). Activated ERK2 has also been implicated in the proliferation of endothelin-stimulated airway smooth muscle cells, suggesting a role for this kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589). [0005] A number of compounds have been developed that purport to specifically inhibit various MAPKs. PCT publication WO 95/31451 describes pyrazole derivatives that inhibit p38. However, it is not clear whether these compounds have the appropriate pharmacological profiles to be therapeutically useful. [0006] Aryl-substituted pyrroles are known in the literature. In particular, tri-aryl pyrroles (U.S. Pat. No. 5,837,719) have been described as having glucagon antagonist activity. [0007] Heterocycle-substituted triazole compounds are known in the literature. In particular, bis([1,2,3]triazoles) (Abbasoglu et al., 1999, Indian J. Chem., Sect. B 38B, 413; Klaus, 1989, Chem. Ber. 122, 1175; Samsonov et al., 1993; Khim. Geterotsikl. Soedin. 29, 1169) and tetrazolyl-triazole (Ried and Laoutidis, 1990, Chem.-Ztg. 114, 246; Vereshchagin et al., 1984, Zh. Org. Khim. 20, 142) compounds have been described. [0008] There is a high unmet medical need to develop new therapeutic treatments that are useful in treating the various conditions associated with ERK2 activation. For many of these conditions the currently available treatment options are inadequate. [0009] Accordingly, there is great interest in new and effective inhibitors of protein kinase, including ERK2 inhibitors, which are useful in treating various conditions associated with protein kinase activation. SUMMARY OF THE INVENTION [0010] The present invention provides compounds and compositions thereof that are useful as protein kinase inhibitors, especially as inhibitors of ERK. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as antibiotics, immunomodulators or other anti-inflammatory agents, for the treatment or prophylaxis of diseases mediated by protein kinases, including ERK2. According to a preferred embodiment, the compounds of this invention are capable of binding to the active site of ERK2 and inhibiting the activity of that enzyme. [0011] It is a principal object of this invention to provide compounds that are protein kinase inhibitors represented by formula I: 2 [0012] or a pharmaceutically acceptable derivative thereof, wherein: [0013] Ht is a heterocyclic ring selected from pyrrol-3-yl, [1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, or tetrazol-5-yl, said pyrrol-3-yl having R.sup.3 and Q.sub.n-R.sup.4 substituents, and said [1,2,4]triazol-3-yl or [1,2,3]triazol-4-yl substituted by either R.sup.3 or Q.sub.n-R.sup.4; [0014] T and Q are each independently selected from --C(R.sup.7).sub.2--, --C(O)--, --C(O)C(O)--, --C(O)NR.sup.7--, --C(O)NR.sup.7NR.sup.7--, --CO.sub.2--, --OC(O)--, --NR.sup.7CO.sub.2--, --O--, --NR.sup.7C(O)NR.sup.7--, --OC(O)NR.sup.7--, --NR.sup.7NR.sup.7--, --NR.sup.7C(O)--, --S--, --SO--, --SO.sub.2--, --NR.sup.7--, --SO.sub.2NR.sup.7--, or --NR.sup.7SO.sub.2--, --NR.sup.7SO.sub.2NR.sup.7- --; [0015] m and n are each independently selected from zero or one; [0016] R.sup.2 is selected from hydrogen, CN, halogen, R, N(R.sup.7).sub.2, OR, or OH; [0017] each R.sup.3 is independently selected from R.sup.7, F, Cl, --(CH.sub.2).sub.yN (R.sup.7).sub.2, --N(R.sup.7).sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7C(O)R.sup.7, --NR.sup.7C(O)N(R.sup.7).sub.2, --C(O)N(R.sup.7).sub.2, --SO.sub.2R.sup.7, --NR.sup.7SO.sub.2R.sup.7, --C(O)R.sup.7, --C(O)OR.sup.7, CN or --SO.sub.2N(R.sup.7).sub.2; [0018] R.sup.4 is selected from --(CH.sub.2).sub.yR.sup.6, --(CH.sub.2).sub.yCH(R.sup.6).sub.2--(CH.sub.2).sub.yCH(R.sup.8)CH(R.sup.- 6).sub.2, --N(R.sup.5).sub.2, --NR.sup.5(CH.sub.2).sub.yN(R.sup.5).sub.2; [0019] each R is independently selected from an optionally substituted group selected from C.sub.1-6 aliphatic, C.sub.6-10 aryl, heteroaryl having 5-10 ring atoms, and heterocyclyl having 3-10 ring atoms; [0020] each R.sup.5 is independently selected from R, --R.sup.7, --C(O)R.sup.7, --CO.sub.2R, --C(O)N(R.sup.7).sub.2, --SO.sub.2R.sup.7, --(CH.sub.2).sub.yR.sup.6, or --(CH.sub.2).sub.yCH(R.sup.6).sub.2; Continue reading about Triazole-derived kinase inhibitors and uses thereof... 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