Heteroaryl Compounds, Compositions Thereof, And
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(19) TZZ ZZ_T (11) EP 2 090 577 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 471/04 (2006.01) C07D 487/04 (2006.01) 05.04.2017 Bulletin 2017/14 C07D 498/04 (2006.01) A61K 31/4985 (2006.01) A61P 35/00 (2006.01) (21) Application number: 09006829.7 (22) Date of filing: 18.10.2007 (54) Heteroaryl compounds, compositions thereof, and their use as protein kinase inhibitors Heteroarylverbindungen, diese enthaltende Zusammensetzungen und deren Verwendung als Proteinkinaseinhibitoren Composés héteroaryliques, compositions les contenant et leur utilisation en tant qu’inhibiteurs de protein kinases (84) Designated Contracting States: • Harris, Roy Leonard lll AT BE BG CH CY CZ DE DK EE ES FI FR GB GR San Diego HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE CA 92109 (US) SI SK TR • Shevlin, Graziella Isabel Designated Extension States: San Diego AL BA HR MK RS CA 92129 (US) • Huang, Dehua (30) Priority: 19.10.2006 US 853166 P San Diego CA 92130 (US) (43) Date of publication of application: • Schwarz, Kimberley Lyn 19.08.2009 Bulletin 2009/34 San Diego CA 92117 (US) (62) Document number(s) of the earlier application(s) in • Packard, Garrick K. accordance with Art. 76 EPC: San Diego 07861467.4 / 2 078 016 CA 92121 (US) • Parnes, Jason Simon (73) Proprietor: Signal Pharmaceuticals, LLC San Diego San Diego, CA 92121 (US) CA 92130 (US) • Papa, Patrick William (72) Inventors: Carlsbad • Mortensen, Deborah Sue CA 92008 (US) San Diego • Tehrani, Lida Radnia CA 92117 (US) San Diego • Mederos, Maria Mercedes Delgado CA 92131 (US) San Diego • Perrin-Ninkovic, Sophie CA 92126 (US) Carlsbad • Sapienza, John Joseph CA 92010 (US) Chula Vista • Riggs, Jennifer R. CA 91913 (US) Cardiff • Albers, Ronald J. CA 92007 (US) San Diego CA 92111 (US) • Lee, Brandon G Encinitas, CA 92024 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 090 577 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 090 577 B1 (74) Representative: Savic, Bojan et al • SINGH B ET AL: "Novel cAMP PDE III inhibitors: Jones Day imidazo[4,5-b]pyridin-2(3H)-ones and Rechtsanwälte Attorneys-at-Law Patentanwälte thiazolo[4,5-b]pyridin-2(3H)-ones and their Prinzregentenstraße 11 analogs."JOURNAL OF MEDICINAL CHEMISTRY 80538 München (DE) 21 JAN 1994, vol. 37, no. 2, 21 January 1994 (1994-01-21), pages 248-254, XP002536652 ISSN: (56) References cited: 0022-2623 WO-A-2006/036883 WO-A1-2006/091737 • KAZAOKA KAZUNORI ET AL: "Synthesis of WO-A1-2006/108103 WO-A2-02/48152 6-substituted 9-benzyl-8-hydroxypurines with WO-A2-2004/085409 WO-A2-2008/016669 potential interferon-inducing activity." US-A- 3 567 725 US-A- 4 963 561 CHEMICAL & PHARMACEUTICAL BULLETIN MAY 2003, vol. 51, no. 5, May 2003 (2003-05), • KILLDAY K B ET AL: "Microxine, a new cdc2 pages 608-611, XP002536653 ISSN: 0009-2363 kinase inhibitor from the Australian marine sponge Microxina species." JOURNAL OF Remarks: NATURAL PRODUCTS APR 2001, vol. 64, no. 4, Thefile contains technical information submitted after April 2001 (2001-04), pages 525-526, the application was filed and not included in this XP002536650 ISSN: 0163-3864 specification • JONES J H ET AL: "6-Substituted 5-chloro-1,3-dihydro-2H-imidazo(4,5-b)pyra zin-2-ones with hypotensive activity." JOURNAL OF MEDICINAL CHEMISTRY MAY 1973, vol. 16, no. 5, May 1973 (1973-05), pages 537-542, XP002536651 ISSN: 0022-2623 2 EP 2 090 577 B1 Description [0001] This application claims the benefit of U.S. provisional application no. 60/853,166, filed October 19, 2006. 5 1. FIELD [0002] Provided herein are certain heteroaryl compounds, compositions comprising an effective amount of one or more suchcompounds and such compounds for usein methods for treatingor preventingcancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway. 10 2. BACKGROUND [0003] The connection between abnormal protein phosphorylation and the cause or consequence of diseases has been known for over 20 years. Accordingly, protein kinases have become a very important group of drug targets. See 15 Cohen, Nature, 1:309-315 (2002). Various protein kinase inhibitors have been used clinically in the treatment of a wide variety of diseases, such as cancer and chronic inflammatory diseases, including diabetes and stroke. See Cohen, Eur. J. Biochem., 268:5001-5010 (2001). [0004] The protein kinases are a large and diverse family of enzymes that catalyze protein phosphorylation and play a critical role in cellular signaling. Protein kinases may exert positive or negative regulatory effects, depending upon 20 their target protein. Protein kinases are involved in specific signaling pathways which regulate cell functions such as, but not limited to, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. Malfunctions of cellular signaling have been associated with many diseases, the most characterized of which include cancer and diabetes. The regulation of signal transduction by cytokines and the association of signal molecules with protooncogenes and tumor suppressor genes have been well documented. Similarly, the connection between diabetes 25 and related conditions, and deregulated levels of protein kinases, has been demonstrated.See e.g., Sridhar et al. Pharmaceutical Research, 17(11):1345-1353 (2000). Viral infections and the conditions related thereto have also been associated with the regulation of protein kinases. Park et al. Cell 101 (7): 777-787 (2000). [0005] Protein kinases can be divided into broad groups based upon the identity of the amino acid(s) that they target (serine/threonine, tyrosine, lysine, and histidine). For example, tyrosine kinases include receptor tyrosine kinases (RTKs), 30 such as growth factors and non-receptor tyrosine kinases, such as the src kinase family. There are also dual-specific protein kinases that target both tyrosine and serine/threonine, such as cyclin dependent kinases (CDKs) and mitogen- activated protein kinases (MAPKs). [0006] Protein kinase C (PKC) is a family of serine/threonine kinases that play a pivotal role in cellular signal trans- duction. Irie et al., 2005, The Chemical Record 5:185-195. PKC isozymes are involved in tumor promotion, as well as 35 other diverse biological events and, accordingly, are attractive targets for cancer therapy and other disorders. Id. One such PKC isozyme which is activated by tumor promoters is PKC θ. PKC isozymes are also expressed in epithelial cells of the gastrointestinal tract, especially the intestine. Farhadi et al., 2006, J. Pharm. Exp. Ther. 316:1-7. Accordingly, agents which modulate PCK acitivity are thought to be useful as therapeutics for gastrointestinal disorders such as cancer and inflammatory bowel disease. 40 [0007] mTOR (mammalian target of rapamycin), which is also called FRAP, RAFTI or SEPT), is a 2549-amino acid Ser/Thr protein kinase, which has been shown to be one of the most critical proteins in the PI3K/Akt pathway that regulatescell growthand proliferation. Georgakis and Younes, 2006, ExpertRev. Anticancer Ther.6(1):131-140. Because PI3K and Akt are involved in the regulation of several cellular functions, there may be toxicities associated with inhibiting these kinases, making inhibition of mTOR the more promising approach.Id. Three mTOR inhibitors are currently in 45 clinical trials for the treatment of cancer. These are CCI-779 (renal cancer, breast cancer, mantle cell lymphoma, gliob- lastoma multiforme and metastatic melanoma), RAD001 (refractory solid tumors, advanced hematologic tumors, GIST and advanced non-small cell lung cancer) and AP23573 (solid tumors, hematologic malignancy and sarcoma). Id. The pre-clinical success of these compounds demonstrates the usefulness of mTOR inhibitors in the treatment of cancer and the need for additional compounds with mTOR inhibitory activity. 50 [0008] Because protein kinases regulate nearly every cellular process, including metabolism, cell proliferation, cell differentiation, and cell survival, they are attractive targets for therapeutic intervention for various disease states. For example, cell-cycle control and angiogenesis, in which protein kinases play a pivotal role are cellular processes associated with numerous disease conditions such as but not limited to cancer, inflammatory diseases, abnormal angiogenesis and diseases related thereto, atherosclerosis, macular degeneration, diabetes, obesity, and pain. 55 [0009] Protein kinases have become attractive targets for the treatment of cancers. Fabbro et al., Pharmacology & Therapeutics 93:79-98 (2002). It has been proposed that the involvement of protein kinases in the development of human malignancies may occur by: (1) genomic rearrangements (e.g., BCR-ABL in chronic myelogenous leukemia), (2) muta- tions leading to constitutively active kinase activity, such as acute myelogenous leukemia and gastrointestinal tumors, 3 EP 2 090 577 B1 (3) deregulation of kinase activity by activation of oncogenes or loss of tumor suppressor functions, such as in cancers with oncogenic RAS, (4) deregulation of kinase activity by over-expression, as in the case of EGFR and (5) ectopic expression of growth factors that can contribute to the development and maintenance of the neoplastic phenotype. Fabbro et al., Pharmacology & Therapeutics 93:79-98 (2002). 5 [0010] WO 2008/016669 describes certain chemical entities that modulate skeletal myosin, skeletal actin, skeletal tropomyosin, skeletal troponin C, skeletal troponin I, skeletal troponin T, and skeletal muscle, and skeletal sarcomere. WO 2006/036883 describes substituted 1,3-dihydro-imidazo[4,5-b]pyrazin-2-ones that function as protein kinase inhib- itors.