MXPA05009104A

MXPA05009104A - Novel bicyclic urea derivatives useful in the treatment of cancer and other disorders.

Info

Publication number: MXPA05009104A
Application number: MXPA05009104A
Authority: MX
Inventors: Jianmei Fan
Original assignee: Bayer Pharmaceuticals Corp
Priority date: 2003-02-28
Filing date: 2004-03-01
Publication date: 2006-05-31
Also published as: EP1608639A2; JP2006519265A; WO2004078748A3; WO2004078748A2; JP5229853B2; CA2516931C; CA2516931A1

Abstract

This invention relates to novel diary) ureas, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and angiogenesis disorders, as a sole agent or in combination with cytotoxic therapies.

Description

BICYCLICAL UREA DERIVATIVES NOVEDOSA, USEFUL IN TREATMENT OF CANCER AND OTHER DISORDERS FIELD OF THE INVENTION This invention relates to novel compounds, pharmaceutical compositions containing these compounds and the use of those compounds or compositions for the treatment of hyperproliferative disorders and by angiogenesis, as a single agent or in combination with other ingredients active, for example, citotoxic therapies.

BACKGROUND OF THE INVENTION The activation of the ras signal transduction path indicates a cascade of events that have a profound impact on cell proliferation, differentiation, and transformation. Raf kinase, an effector downstream of ras, is recognized as a key mediator of these signals from cell surface receptors to the nucleus of the cell (Lowy, D. "R. Willumsen, BM Ann. Rev. Biochem 1993, 62, 851; Bos, JL Cancer Res. 1989, 49, 4682.) It has been shown to inhibit the effect of active ras by inhibiting the signaling pathway of the raf kinase by administering deactivating antibodies to the raf kinase. or by co-expressing the dominant negative raf kinase or the dominant negative MEK, the substrate of the raf kinase, leads to the reversal of transformed cells to the normal growth phenotype (see: Daum et al., Trends Biochem. Sci.- 1994, 19, 474-80, Fridman et al., J. Biol. Chem. 1994, 269, 30105-8, Kolch et al. (Nature 1991, 349, 426-28) have further indicated that the inhibition of raf expression by Antisense RNA blocks cell proliferation in oncogenes associated with n Membranes Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with the inhibition of growth of a variety of human tumor types (Monia et al., Wat. Med. 1996, 2, 668-75). Some examples of small molecule inhibitors of raf kinase activity are important agents for the treatment of cancer. (Naumann, U .; Eisenmann-Tappe, I .; Rapp, UR .Recent Results Cancer Res. 1997, 143, 237; Monia, B. P .; Johnston, J. F .; Geiger, T .; Muller, M Fabbro, D., Nature Medicine 1996, 2, 668).

To resist progressive tumor growth beyond the size of 1-2 μm3, it is recognized that tumor cells require a functional stroma, a supporting structure consisting of fibroblasts, smooth muscle cells, endothelial cells, extracellular matrix proteins. , and soluble factors (Folkman, J., Semin Oncol, 2002. 29 (6 Suppl 16), 15-8). The tumors induce the formation of stromal tissues through the secretion of soluble growth factors such as, for example, PDGF and transforming growth factor-beta (TGF-beta), which in turn stimulates the secretion of complementary factors by cells. hosts such as, for example, fibroblast growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF). These stimulatory factors induce the formation of new blood vessels, or angiogenesis that lead oxygen and nutrients to the tumor and allow it to grow and provide a route for metastasis. It is believed that some therapies aimed at inhibiting stromal formation will inhibit the growth of epithelial tumors from a wide variety of histological types. (George, D. Semin Oncol, 2001. 28 {5 Suppl 17), 27-33; Shaheen, R.M., et al. , Cancer Res, 2001. 61 (4), 1464-8; Shaheen, R.M., et al. Cancer Res, 1999. 53 (21), 5412-6). However, due to. the complex nature and multiple growth factors involved in the process of angiogenesis and tumor progression, an agent that targets a single pathway may have limited efficacy. It is desirable to provide a treatment against various key signaling pathways used by tumors to induce angiogenesis in host stroma. These include PDGF, a potent stimulator of stromal formation (Ostman, A. and CH Heldin, Adv Cancer Res, 2001, 80, 1-38), FGF, a chemoattractant and a mitogen for fibroblasts and endothelial cells, and VEGF, a powerful regulator of vascularization. PDGF is another key regulator of stromal formation that is secreted by many tumors in the form of paracrine and is thought to stimulate the growth of fibroblasts, smooth muscle and endothelial cells, stimulating stromal formation and angiogenesis. PDGF was originally identified as the product of the oncogene v-sis of the simian sarcoma virus (Heldin, C.H., et al., J Cell Sci Suppl, 1985, 3, 65-76). The growth factor is constituted by two peptide chains, named as the A or B chains that share 60% homology in their primary amino acid sequence. The chains are cross-linked disulfide to form the mature 30 kDa protein composed of either AA, BB or AB homo- or het erodimers. PDGF is found at high levels in platelets, and is expressed by endothelial cells and vascular smooth muscle cells. In addition, the production of PDGF is over-regulated under conditions of low oxygen content such as those found in poorly vascularized tumor tissue (Kourembanas, S., et al., Kidney Int, 1997, 51 (2), 438-43). . PDGF binds with high affinity to the PDGF receptor, a 124 kDa transmembrane tyrosine kinase receptor with 1106 amino acids (Heldin, CH, A. Ostman, and L. Ronnstrand, Biochim Biophys Acta, 1998. 1378 (1), 79- 113). PDGFR is found as homo- or heterodimeric chains having 30% overall homology in their amino acid sequence and 64% homology among their kinase domains (Heldin, CH, et al., Embo J, 1988, 7 (5), 1387-93). PDGFR is a member of a family of tyrosine kinase receptors with distintin kinase domains that include VEGFR2 (KDR), VEGFR3 (Flt4), c-Kit, and FLT 3. The PDGF receptor is expressed primarily in fibroblasts, cells of smooth muscle, and pericytes and to a lesser degree in neurons, mesangial renal, Leydig, and Schwann cells of the central nervous system. At the time of receptor binding, PDGF induces dimerization of the receptor and undergoes self- and trans-phosphorylation of the tyrosine residues that increase the receptor kinase activity and stimulate the uptake of effectors in the 3 'direction through the Activation of the binding domains with the SH2 protein. Various signaling molecules form complexes with activated PDGFR including the 3-kinase, phospholipase C-gamma, src and GAP (the GTPase activation protein for p21-ras) (Soskic, V., et al., Biochemistry, 1999, 38 (6), 1757-64). Through the activation of the? -3-kinase, PDGF activates the path of Rho signaling by inducing cell mobility and migration, and through the activation of GAP, induces mitogenesis through the activation of p21-ras and the MAPK signaling path. In adults, it is believed that the main function of the PDGF is. facilitate and increase the speed of healing of wounds and maintain the homeostasis of blood vessels (Baker, E.7A and D.J. Leaper, Wound Repair Regen, 2000. 8 (5), 392-8 '; Yu, J.A. Moon, and H.R. Kim, Biochem Biophys Res Commun, 2001. 282 (3), 697-700). PDGF is found at high concentrations in platelets and is a potent chemoattractant for fibroblasts, smooth muscle cells, neutrophils and macrophages. In addition to its function to heal wounds, it is known that PDGF helps maintain vascular homeostasis. During the development of new blood vessels, PDGF gathers the pericytes and smooth muscle cells that are necessary for the structural integrity of the vessels. It is thought that PDGF plays a similar role during tumor neovascularization. As part of its role in angiogenesis, PDGF controls interstitial fluid pressure, regulating vessel permeability through its regulation of the interaction between connective tissue cells and the extracellular matrix. Inhibition of PDGFR activity may decrease interstitial pressure and may facilitate the entry of cytotoxic agents into tumors by improving the anti-tumor efficacy of these agents (Pietras, K., et al. Cancer Res, 2002. 62 (19), 5476 -84; Pietras, K., et al., Cancer Res, 2001. 61 (7), 2929-34).

PDGF can stimulate tumor growth through either paracrine or autocrine stimulation of PDGFR receptors on stromal cells or tumor cells directly, or through receptor amplification or receptor activation by recombination. Over-expressed PDGF can transform human melanoma cells and keratinocytes (Forsberg, K., et al., Proc Nati Acad Sel US A., 1993. 90 (2), 393-7; Skobe, M. and NE Fusenig, Proc. Nati Acad Sel USA, 1998. 95 (3), 1050-5), two cell types that do not express PDGF receptors, probably because of the direct effect of PDGF on the formation of stromata and the induction of angi ogéne sis. This paracrine stimulation of the tumor stroma is also observed in carcinomas of the colon, lung, breast, and prostate (Bhardwaj, B., et al., Clin Cancer Res, 1996, 2 (4), 773-82; Nakanishi, K., et al., Mcd Pathol, 1997, 10 (4), 34177; Sundberg, C., et al., Am J Pathol, 1997, 151 (2), 479-92; Lindmark, G., et al., Lab Invest, 1993, 69 (6), 682-9; Vignaud, J.M., et al, Cancer Res, 1994, 54 (20), 5455-63) where tumors express PDGF, but not the receptor. Autocrine stimulation of tumor cell growth, where a large fraction of tumors analyzed express both the PDGF ligand and the receptor, has been reported in glioblastomas (Fleming, TP, et al, Cancer Res, 1992, 52 (16), 4550- 3), soft tissue sarcomas (Wang, J., MD Coltrera, and AM Gown, Cancer Res, 1994, 54 (2), 560-4) and ovarian cancers (Henriksen, R., et al., Cancer Res, 1993). , 53 (19), 4550-4), prosthetics (Fudge, K., CY Wang, and ME Stearns, Mod Pathol, 1994, 7 (5), 549-54), pancreatic (Fuña, K., et al. Cancer Res, 1990, 50 (3), 748-53) and lung (Antoniades, HN, et al., Proc Nati Acad Sel USA, 1992, 89 (9), 3942-6). The ligand-independent activation of the receptor is found to a lesser extent although it has been reported in chronic myelomonocytic leukemia (CMML) where a chromosomal translocation event forms a fusion protein between the TEL transcription factor similar to Ets and the PDGF receptor. In addition, activation mutations have been found in PDGFR within gastrointestinal stromal tumors in which activation of c-Kit is not involved (Heinrich, M.C., et al., Science, 2003, 9, 9). Certain inhibitors of PDGFR will interfere with the stromal development of tumors and are thought to inhibit tumor growth and metastasis.

Another major regulator of angiogenesis and vasculogenesis in both embryonic development and in some angiogenic-dependent diseases is vascular endothelial growth factor (VEGF, also called vascular permeability factor, VPF). VEGF represents a family of mitogen isoforms that exist in homodimeric forms due to the alternative splicing of RNA. It is reported that VEGF isoforms are very specific for vascular endothelial cells (for examinations, see: Farrara et al., Endocr., Rev. 1992, 13, 18; Neufield et al., FASEB J. 1999, 13, 9). It is reported that VEGF expression will be induced by hypoxia (Shweiki et al. Na ture 1992, 359, 843), as well as by a variety of cytokines and growth factors, such as, for example, interleukin-1, int erleucine. - 6, epidermal growth factor and transforming growth factor. To date, it has been reported that VEGF and members of the VEGF family join one or. more than three transmembrane receptor tyrosine kinases (Mustonen et al., J. Cell Biol., 1995, 129, 895), VEGF receptor-1 (also known as flt-1 (tyrosine kinase-1 similar to fms)), VEGFR-2 (also known as the receptor containing the kinase insert domain (KDR); murine KDR analogue is known as fetal hepatic kinase-1 (flk-1)), and VEGFR-3 (also known as flt-4). It has been shown that KDR and flt-1 have different properties for signal transduction (Altenberger et al., J. Biol. Chem. 1994, 269, 26988).; Park et al. Oncogene 1995, 10, 135). In this way, KDR undergoes strong ligand-dependent tyrosine phosphorylation in intact cells, whereas flt-1 exhibits a weak response. In this way, it is believed that binding to KDR is a decisive requirement for the induction of the full spectrum of biological responses provided by VEGF. In vivo, VEGF plays a central role in vasculogenesis, and induces angiogenesis and permeabilization of blood vessels. The expression of deregulated VEGF contributes to the development of "various diseases, which are characterized by abnormal processes of angiogenesis and / or hyperpermeability." It is believed that regulation of the signal transduction cascade supplied by VEGF by some agents may provide a useful mode to control the abnormal processes of angiogenesis and / or hyperpermeability.

Angiogenesis is considered an important prerequisite for the growth of tumors beyond approximately 1-2 ml. Oxygen and nutrients can be delivered to cells in tumors smaller than this limit through diffusion. However, it is believed that each tumor depends on angiogenesis for continuous growth after it has reached a certain size. The tumorigenic cells within the hypoxic regions of tumors respond by stimulating the production of VEGF, which causes the activation of endothelial cells at rest to stimulate the formation of new blood vessels. (Shweiki et al., Proc. Nat'l. Acad. Sci., 1995, 92, 768). In addition, the production of VEGF in tumor regions where there is no angiogenesis can proceed through the path for ras signal transduction (Grugel et al., J. Biol. Chem., 1995, 270, 25915; Rak et al. 1995, 55, 4575). . In situ hybridization studies have shown that VEGF mRNA overregulates in a wide variety of human tumors, including lung (Mattern et al., Br. J. Cancer 1996, 73, 931), thyroid (Viglietto et al. Oncogene 1995, 11, 1569), breast (Brown et al.

Human Pathol. 1995, 26, 86), gastrointestinal tract (Brown et al., Cancer Res. 1993, 53, 4727; Suzuki et al., Cancer Res. 1996, 56, 3004), kidney and bladder (Brown et al., J. Pathol. 1993, 1431, 1255), ovarian (Olson et al., Cancer Res. 1994, 54, 1255), and cervical (Guidi et al., J. Nat'l Cancer Inst. 1995, 87, 12137) carcinomas, as well as angiosarcoma (Hashimoto et al., Lab. Invest., 1995, 73, 859) and various intracranial tumors (Piet et al., Nature 1992, 359, 845; Philips et al., Int. J. Oncol., 1993, 2, 913; Berkman et al. J. Clin. Invest., 1993, 91, 153). It has been shown that neutralizing monoclonal antibodies to KDR will be effective in blocking tumor angiogenesis (Kim et al., 1993, 362, 8 1; Rockwell et al., Cell, Differ., 1995, 3, 315). Overexpression of VEGF, for example under conditions of extreme hypoxia, can lead to intraocular angiogenesis,. resulting in hyperproliferation of blood vessels, ultimately leading to blindness. This cascade of events has been observed for various retinopathies, including diabetic retinoppathy, ischemic-venous retinal occlusion, and premature retinopathy (Aiello et al., New Engl., J. Med. 1994, 331, 1480; Peer et al., Lab.

Invest. 1995, 72, 638), and macular degeneration related to age (AMD, see, López et al., Invest. Opththalmol, Vis. Sci. 1996, 37, 855). In rheumatoid arthritis (RA), the internal growth of the vascular pannus can be produced by the production of angiogenic factors. Immunoreactive VEGF levels are high in the synovial fluid of patients with RA, whereas VEGF levels are low in the synovial fluid of patients with other forms of arthritis with degenerative joint disease (Koch et al., J. I munol 1994, 152, 4149). The angiogenesis inhibitor AGM-170 has been shown to prevent neovascularization of the joint in the arthritis model with rat collagen (Peacock et al., J. Exper. Med. 1992, 175, 1135). Increased expression of VEGF has also been shown in psoriatic skin, as well as in bullous disorders associated with the formation of subepidermal bladders, such as, for example, bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis (Brown et al., J. Invest. Dermatol, 1995, 104, 744). Vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and their receptors (VEGFR2, VEGFR3) are not only key regulators of tumor angiogenesis, but also of lymph angiogenesis. VEGF, VEGF-C and VEGF-D are expressed in most tumors, mainly during periods of tumor growth and often at substantially increased levels. Expression of VEGF is stimulated by hypoxia, cytokines, oncogenes such as for example, ras, or by inactivation of tumor suppressor genes (McMahon, G. Oncologist 2000, 5 (Suppl 1), 3-10; McDonald, N.Q .; Hendrickson, W.A. Cell 1993, 73, 421-424). The biological activities of VEGFs are supplied through binding to their receptors. VEGFR3 (also called Flt-4) is predominantly expressed in the lymphatic endothelium in normal adult tissues. The function of VEGFR3 is needed for the formation of new lymphatic vessels, although not for the maintenance of previously existing lymphatics. VEGFR3 is also over-regulated in the endothelium of blood vessels in tumors. Recently, VEGF-C and VEGF-D, ligands for VEGFR3, have been identified as regulators of lymphangiogenesis in mammals. The lymphangiogenesis Induced lymphangiogenic factors associated with tumors could stimulate the growth of new vessels in the tumor, providing access of tumor cells to the systemic circulation. The cells that invade the lymphatics could find their way into the bloodstream via the thoracic duct. Studies for the expression of tumors have allowed a direct comparison of the expression of VEGF-C, VEGF-D and VEGFR3 with clinicopathological factors that are directly related to the ability of primary tumors to spread (for example, participation of the lymph node, lymphatic invasion, secondary metastasis, and disease-free survival). In many cases, these studies demonstrate a statistical correlation between the expression of lymphangiogenic factors and the ability of a primary solid tumor to metastasize (Skobe, M., et al., Nature Med. 2001, 7 (2), 192- 198; Stacker, SA et al., Nature Med. 2001, 7 (2), 186-191; Makinen, T. et al., Nature Med. 2001, 7 (2), 199-205; Mandriota, SJ et al. J. 2001, 20 (4), 672-82; Karpanen, T. et al., Cancer Res. 2001, 61 (5), 1786-90; Kubo, H., et al., Blood 2000, 96 (2), 546-53) Hypoxia appears to be an important stimulus for the production of VEGF in malignant cells.P38 MAP kinase activation is required for the induction of VEGF by tumor cells in response to hypoxia (Blaschke, F. et al. Biochem Biophys, Res. Commun 2002, 296, 890-896, Shemirani, B. et al, Oral Oncology 2002, 38 oral, 251-257) In addition to its participation in angiogenesis through the regulation of the secretion of VEGF, p38 MAP kinase stimulates to the invasion of malignant cells, and the migration of different tumor types through the regulation of collagenase activity and the expression of urokinase plasminogen activator (Laferriere, J. et al. J. Biol. Chem. 2001, 276, 33762-33772; Westermarck, J. et al. Cancer Res. 2000, 60, 7156-7162; Huang, S. et al. J. Biol. Chem. 2000, 275, 12266-12272; Simon, C. et al. Exp. Cell Res. 2001, 271, 344-355). It has been reported that some diarylureas have activity such as serine-t-eonine kinase and / or as tyrosine kinase inhibitors. The utility of these diarylureas as an active ingredient in pharmaceutical compositions for the treatment of cancer, angiogenesis disorders, and inflammatory disorders has been demonstrated. See Redman et al., Bioorg. Med. Chem. Lett. 2001, 11, 9-12; Smith et al., Bioorg. Med. Chem. Lett. 2001, 11, 2775-2778; Dumas et al., Bioorg. Med. Chem. Lett. 2000, 10, 2047-2050; Dumas et al. , Bioorg. Med. Chem. Lett. 2000, 10, 2051 ^ 2054; Ranges et al., Book of Abstracts, 220th ACS National Meeting, Washington, DC, USA, MEDI 149; Dumas et al., Bioorg. Med. Chem. Lett. 2002, 12, 1559-1562; Lowinger et al., Clin. Cancer- Res. 2000, 6 (Suppl.), 335; Lyons et al., Endocr. -Relat. Cancer 2001, 8, 219-225; Riedl et al., Book of Abstracts, 92nd AACR Meeting, New Orleans, LA, USA, extract 4956; Khire et al., Book of Abstracts, 93rd AACR Meeting, San Francisco, CA, USA, extract 4211; Lowinger et al., Curr. Pharm. Design 2002, 8, 99-110; Regan et al., J. Med. Chem. 2002, 45, 2994-3008; Pargellis et al., Nature Struct. Biol. 2002, 9 (4), 268-272; Cárter 'et al., Book of Abstracts, 92nd AACR Meeting, New Orleans, LA, USA, extract 4954; Vincent et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, excerpt 1900; Hilger et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, excerpt 1916; Moore et al., Book of Abstracts, 38th ASCO -Meeting, Orlando, FL, USA, excerpt 1816; Strumberg et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, extract 121; Madwed JB: Book of abstracts, Protein Kinases: Novel Target Identification and Validation for Therapeutic Development, San Diego, CA, USA, March 2002; Roberts et al., Eook of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, extract 473; Tolcher et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, .extract 334; and Karp et al., Book of abstracts, 38th AACR Meeting, San Francisco, CA, USA, extract 2753.? Despite advances in the art, there remains a need for treatments for cancer and anti-cancer compounds.

DESCRIPTION OF THE INVENTION The present invention pertains to: (i) compounds. of urea, the salts, metabolites and prodrugs thereof, including the somatic diastereomeric forms, (ii) the pharmaceutical compositions containing any of these compounds, the salts, metabolites and prodrugs thereof, including the diastereoisomeric forms, and (ii) the use of those compounds or compositions for the treatment of diseases, for example, hyperproliferative disorders and by angiogenesis, as a single agent or in combination with other active ingredients, for example, cytotoxic therapies.

The compounds of the formula (I), the salts, metabolites and prodrugs thereof, including the diastereomeric forms (both the isolated stereoisomers and the mixtures of stereoisomers) are collectively referred to herein as the "compounds of the invention". Formula (I) is as follows: where ? is a bicyclic heterocycle which is: (1) benzimidazolyl (2) 1,3-benzothiazolyl (3) 1, 2, 3-benzotriazolyl (4) 1,3-benzoxazolyl (5) 2, 3-dihydro-lH-indolyl (6) 2, 3-dihydro-H-indenyl (7) 1, l-dioxide-2,3-dihydro-l-benzothienyl (8) IH-indazolyl (9) 2H-indazolyl (10) IH-indolyl (11) ) 2 H -chromenyl (12) quinoxalinyl or (13) A group of the formula Compounds of formula I that are of interest include those wherein A is selected from: (1) benzimidazol-5-yl (2) ben zimide zo 1-6-i 1 or (3) 1,3-benzothiazole- 2-yl (4) 1,3-benzothiazol-5-ylco (5) 1 > 3-benzothiazol-6-yl (6) 1, 2, 3-benzotriazol-5-yl (7) 1,3-benzoxazol-2-yl (8) 1,3-benz oxa z ol-6-i 1 or (9) 2, 3-dihydro-lH-indol-5-yl (10) 2, 3-dihydro-lH-indol-6-yl (11) 2, 3-dihydro-lH-inden-4-yl ( 12) 2, 3-dihydro-lH-inden-5-yl (13) 1,1-dioxide-2,3-dihydro-l-benzothien-6-yl (14) lH-indazol-5-yl (15) 2H-indazol-5-yl (16) lH-indazol-6-yl (17) lH-indol-5-yl (18) 2 H -chromen-7-yl (19) quinoxalin-2-yl (20) quinoxalin- 6-ilo, and (21) a group of the formula Preferred compounds of formula I have selected from (1) benzimidazol-5-yl (2) benzimidazol-5-yl (8) 1,3-benzoxazol-6-yl (9) 2, 3-dihydro-1H-indole -5-yl (10) 2, 3-dihydro-lH-indol-6-yl (11) 2, 3-dihydro-lH-inden-4-yl (12) 2, 3-dihydro-lH-inden-5 - ilo (13) 1, l-dioxide-2, 3-dihydro-1 - in zothien-6-yl (14) lH-indazol-5-yl (15) 2H-indazol-5-yl (16) lH-indazol-6-yl (17) lH-indol-5-yl (18) quinoxalin-2-yl (19) ) quinoxal in- 6-yl, and (20) a group of the formula The bicyclic heterocycle A is optionally substituted with 1-4 substituents which are independently R1, OR1, S (0) pR1, C (0) R, CtOJOR1, C (0) NR1R2, halogen, oxo, cyano, or nitro. Preferred optional substituents on the bicyclic heterocycle A are independently R1, OR1 and halogen. B is phenyl, naphthyl, pyridyl, or quinolyl optionally substituted with 1-4 substituents which are independently C1-C5 straight or branched alkyl, C1-C5 straight or branched haloalkyl, Ci ~ C3 alkoxy, hydroxy, amino, C1-C3 alkylamino , Ci-C6 dialkylamino, carboxyamide, halogen, cyano, nitro or S (0) pR7. B is preferably phenyl, pyridyl, or quinolinyl, more preferably phenyl or pyridyl, optionally substituted with 1-4 substituents which are independently Ci-C5 straight or branched alkyl, C1-C5 straight or branched haloalkyl, Ci-C3 alkoxy, hydroxy , amino, C1-C3 alkylamino, Ci-C6 dialkylamino, carboxyamide, halogen, cyano, nitro or S (0) pR7. L is a bridge group that is: (a) - (CH2) ra- 0- (CH2) i-, (b) - (CH2) m- (CH2) i-, (c) - (CH2) m- C (0) - (CH2) i-, (d) - (CH2) m- NR3- (CH2) i-, (e) - (CH2) m- NR3C (0) - (CH2) i-, (f ) - (CH2) m- S- (CH2)! -, (g) - (CH2) m- C (0) R3- (CH2) i-, (h) an individual bond, where rti and 1 are selected integers independently from 0-4, and preferably selected from 0-2. More preferably, L is -0- or -S-. M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C1-C5 straight or branched alkyl, C1-C5 straight or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1- C6 dialkylamino, halogen, or ni.tro. Q is C (0) R4, C (0) 0R4 or C (0) NR4R5 Each R1, R2, R3, R4 and R5 is independently: (a) hydrogen, (b) C1-C5 alkyl (linear, branched alkyl, or cyclic), (c) phenyl 1 or, (d) C 1 -C 3 alkyl phenyl, (e) to C 1 -C 5 linear or branched alkyl per-halo substituted, (f) - (CH 2) qX where the substituent X is a 5- or 6-membered heterocyclic ring, containing at least one atom selected from oxy-, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or an 8-10-membered bicyclic heteroaryl having 1-4 het heteroatoms which are O, N or S, or (g) - (CH2) qY where Y is C (0) R6, C (0) 0R6 or C (0) NR6R "\ Each R1, R2, R13, R4 and R5 of preference is, independently: (a) hydrogen, (b) C1-C5 alkyl (c) phenyl, (d) to C1-C5 linear or branched alkyl substituted by halo Each R6-R7 is independently: (a) hydrogen, ( b) C1-C5 linear, branched, or cyclic alkyl, (c) phenyl, (d) C1-C3 alkyl phenyl, or (e) to C1-C5 alkyl ineal or branched replaced by halo. Each R1, R2, R3, R4, R5, R6 and R7, other than C1-C5 straight or branched alkyl substituted by halo, is optionally substituted with 1-3 substituents which are independently C1-C5 straight or branched alkyl, to C1-C5 linear or branched alkyl substituted by halo, C1-C3 alkoxy, hydroxy, carboxy, amino, C1-C3 alkylamino, Ci-C6 dialkylamino, halogen, cyano, or nitro. The variable p is an integer selected from 0, 1, · or 2. The variable q is an integer selected from 1, 2, 3, or 4. When any entity is "replaced", it can have up to the highest number of indicated substituents, and each substituent may be located at any available position on the entity and may be attached through any available atom on the substituent. "Any available position" means any position available on the entity that is chemically accessible through means known in the art or shown herein and that does not create an unduly unstable molecule. When there are two or more substituents on any entity, each substituent is independently defined from any other substituent and may, therefore, be the same or different. The term "optionally substituted" means that the entity so modified may be either unsubstituted, or substituted with the identified substituents. It is understood that because M is pyridine, the term "hydroxy" as a pyridine substituent includes 2-, 3-, and 4-hydroxy-pyridine, although it also includes those structures referred to in the art as 1 -oxo-pyridine, 1 -hi droxi -pi ridine and pyridine N-oxide. When used in the present the plural form of the word compounds, salts, and the like, it must also mean an individual compound, salt, or the like. The term Ci ~ C5alkyl means straight or branched chain alkyl groups having from one to five carbon atoms, which may be straight or branched with single or multiple branching. These groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like. The term halo C1-C5 alkyl means a saturated hydrocarbon radical having up to five carbon atoms which is substituted with at least one halogen atom until perhalo. The radical can be linear or branched with single or multiple branching. Halo substituents include fluorine, chlorine, bromine, or iodine. Fluorine, chlorine and bromine are preferred, and fluorine and chlorine are more preferred. The halogen substituents can be located at any available carbon atom. When more than one halogen substituent is present in this entity, they may be the same or different. Examples of these halogenated alkyl substituents include chloromethyl, di chloromethyl, trichloromethyl, f luoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 1,2, 2-tetrafluoroethyl. , and similarity. The term C1-C3 alkoxy means a straight or branched chain alkoxy group having one to three saturated carbon atoms which may be straight or branched with single or multiple branching, and includes such groups such as, for example, methoxy, ethoxy, p-propoxy, isopropoxy, and the like. It also includes halogenated groups such as, for example, 2,2-dichloroethoxy, trifluoromethoxy, and the like. Halo or halogen means fluorine, chlorine, bromine, or iodine. Fluorine, chlorine are preferred. and bromine, fluorine and chlorine are more preferred. C1-C3alkylamino means methylamino, ethylamino, propylamino or isopropylamino. Examples of C1-C6 dialkylamine include, but are not limited to: diethylamino, eti.l -i s, opropyl amino, means methylamino, methyl-isobutylamino, dihexylamino. The term "heteroaryl" refers to both monocyclic and bicyclic heteroaryl rings. "Monocyclic heteroaryl" means an aromatic monocyclic ring having from 5 to 6 ring atoms, at least one of which is a hetero atom selected from N, O and S, the remaining atoms will be carbon. When more than one hetero atom is present in the entity, they are independently selected from the others in such a way that they may be the same or different. The monocyclic heteroaryl rings include, but are not limited to: pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine. "Bicyclic heteroaryl" means fused bicyclic entities wherein one of the rings is selected from the monocyclic heteroaryl rings described above and the second ring is benzene or another monocyclic heteroaryl ring described above. When both rings in the bicyclic entity are heteroaryl rings, they may be the same or different, as long as they are chemically accessible by means known in the art. The bicyclic heteroaryl rings include fused bicyclic aromatic structures 5-5, 5-6, or 6-6 synthetically accessible including, for example, but not limited to, benzoxazole (fused phenyl and oxazole), quinoline (fused phenyl and pyridine), imidazopyrimidine (fused imidazole and pyrimidine), and the like. The term "5 or 6 membered heterocyclic ring, containing at least one atom selected from oxygen, nitrogen and sulfur which is saturated, partially saturated, or aromatic" includes without limitation, tet rahydropyran, tetrahydrofuran, 1,3-dioxolane, 1 , 4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, t-tetrahydropyrimidone, pentamethylene sulfide, t-tetramethane sulfide, dihydropyran, dihydro furan, dihydro-iofen, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, and the like. The term "C1-C3 phenyl-alkyl" includes without limitation, 3-phenyl-1-propyl, 2-phenyl-1-methyl-ethyl. The substituted examples include 2 - [2-chlorophenyl] ethyl, 3,4-dimethyl-1-methyl, and the like. The compounds of the formula I may contain one or more asymmetric centers, which depend on the location and nature of the various desired substituents. Asymmetric carbon atoms may be present in the (R) or (S) configuration or configuration. { R, S). In certain cases, the asymmetry may also be present due to the restricted rotation on a given bond, for example, the central bond joining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in the form either cis or trans. It is intended that all these configurations (including enantiomers and diastereomers) be included within the scope of the present invention. Preferred compounds are those with the absolute configuration of the compound of formula I that produces the most convenient biological activity. Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification of isomers and the separation of the isomeric mixtures can be carried out by standard techniques known in the art. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltart aric, aryl ditoluoyltart and cansulfonic acid. Mixtures of diastereomers can be separated into their individual diastomers based on their physical and / or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then released from the separated diastomeric salts. A different process for the separation of optical isomers involves the use of chiral chromatography (eg, chiral HPLC columns), with or without conventional derivation, optimally selected to maximize separation of the enantiomers. Suitable chiral HPLC columns are produced by Diacel, eg, Chiracel OD and Chiracel OJ among many others, all can be routinely selected. Enzymatic separations, with or without derivation, are also useful. The optically active compounds of the formula I can also be obtained by chiral synthesis using optically active starting materials. The present invention also relates to useful forms of the compounds as disclosed herein, such as, for example, the pharmaceutically acceptable salts, metabolites and prodrugs of all the compounds of the formula (I). The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt, relatively non-toxic of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts", J. Pharm.

Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts also include those in which the parent compound functions as an acid and is reacted with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will additionally recognize that the acid addition salts of the claimed compounds can be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of several known methods. Alternatively, the alkaline and metal salts to the ferrous calcium are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods. Representative salts of the compounds of this invention include conventional non-toxic salts and quaternary ammonium salts that are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, these acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonat or, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cinnamate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate , hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonat or, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-f enyl-propionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate. The base salts include alkali metal salts such as, for example, potassium and sodium salts, alkaline earth metal salts such as, for example, calcium and magnesium salts, and ammonium salts with organic bases such as, for example, dicyclohexylamine and N-met il-D-glucamin.

Additionally, groups containing basic nitrogen can be quaternized with these agents as lower alkyl halides such as, for example, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as, for example, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides and others.

Certain compounds of this invention can be further modified with labile functional groups that are cleaved after in vivo administration to deliver the precursor active agent and the pharmacologically inactive (functional) derivative group. These derivatives, usually referred to as prodrugs, can be used, for example, to alter the physicochemical properties of the active agent, to direct the active agent towards a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce the effects undesirable side effects Prodrugs of the invention include, for example, esters of suitable compounds of this invention are well tolerated, pharmaceutically acceptable esters such as for example, alkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters . Additional esters can be used such as, for example, phenyl-Ci-C5 alkyl, although methyl ester is preferred. The methods for synthesizing prodrugs are described in the following reviews on the subject, and are incorporated herein by reference for description of these methods: Higuchi, T.; Stella, V. eds. Prodrugs As Novel Drug Delivery Systems. ACS Symposium Series. American Chemical Society: Washington, DC (1975). Roche, E. B. Design of Biopharmaceutical Properfies through Prodrugs and Analogs. American Pharmaceutical Association: Washington, DC (1977). Sinkula, A. A .; Yalkowsky, S. H. J Pharm Sci. 1975, 64, 181-210. Stella, V. J.; Charman, W. N. Naringrekar, V. H. Drugs 1985, 29, 455-473. Bundgaard, H., ed. Design of Prodrugs .. Elsevier: New York (1985). Stella, V. J. Himmelstein, K. J. J. Med. Chem. 1980, 23, 1275-1282. Han, H-K; Amidon, G. L. AAPS Pharmsci 2000, 2, 1-11. Denny, W. A. Eur. J. Med. Chem. 2001, 36, 577-595. Wermuth, C.G. in Wermuth, C.G. ed. The Practice of Medicinal Chemistry Academic Press: San Diego (1996), 697-715. Balant, L. P .; Doelker, E. in Wolff, M. E. ed. Burgers Medicinal Chemistry And Drug Discovery John Wiley & Sons: New York (1997), 949-982.

The metabolites of the compounds of this invention include oxidized derivatives of the compounds of the formula I, wherein one or more of the nitrogen atoms is substituted with a hydroxy group; which includes the derivatives wherein the nitrogen atom of the pyridine group is in the oxide form, is referred to in the art as 1-oxo-pyridine or has a hydroxy substituent, referred to in the art as 1-hydroxy-pyridine.

General Preparative Methods The particular process that will be used in the preparation of the compounds used in this embodiment of the invention depends on the specific compound desired. Factors such as the selection of the specific substituent play a role in the path that will be followed in the preparation of the specific compounds of this invention. Those factors will be easily recognized by someone with ordinary skill in the art. The compounds of the invention can be prepared by the use of known chemical reactions and procedures. However, the following general preparative methods are presented to assist the reader in synthesizing the compounds of the present invention, with the particular, more detailed examples presented later in the experimental section describing the examples of t abaj o. . All the variable groups of these methods are as described in the generic description if they are not specifically defined below. When a variable or substituent group with a given symbol is used more than once in a given structure, it must be understood that each of these groups or their terms can be varied independently within the range of definitions for that symbol. It is recognized that the compounds of the invention with each optional functional group claimed can not be prepared with each of the methods listed below. Within the scope of each optional method substituents that are stable to the reaction conditions are used, or functional groups that can participate in the reactions are present in the protected form when necessary, and removal of these protecting groups is completed in the suitable phases by methods well known to those skilled in the art.

The compounds of the invention can be prepared according to conventional chemical methods, and / or as set forth below, from starting materials that are either commercially available or can be produced according to routine conventional chemical methods. . General methods for the preparation of the compounds are given below, and the preparation of the representative compounds is specifically illustrated in the examples.

General Methods Reaction Scheme 1: Synthesis of the ureas of the formula (I) Method A E ill 11 The preparation of the ureas of the formula (I) is represented in Reaction Scheme 1, where A, B, L, M, and Q were broadly defined above. The compounds (I) can be synthesized according to the reaction sequence shown in General Methods E and F above. Using Method E, the ureas of the formula (I) are prepared from the condensation of the two arylamine (II) and (III) fragments in the presence of phosgene, diphosgene, tri-phosgene, carbonyldiimidazole, or the equivalents in a solvent that does not react with any of the starting materials. Alternatively, the compounds (I) can be synthesized by reacting the amino (II) compounds with the isocyanate (IV) compounds using Method F. The isocyanates (IV) are commercially available or can be synthesized from the amines heterocyclics of the formula (II) or (III), according to methods normally known to those skilled in the art [for example, from the treatment of an amine with phosgene or a phosgene equivalent such as chloroformate or trichloroacetyl (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or?,? '- carbonyldiimidazole (CDI); or, alternatively by means of a Curtius type restructuring of an amide, or a carboxylic acid derivative, such as an ester, a halide or anhydride].

Reaction Scheme 2: Synthesis from the starting materials of the formula (IV) ?,? - B - LH "Method _B H, N-B-LH u, O Method C h2N D 'M'Q' 2 ° + HakNT - V II Method D 02N-B-Hal- - + HL Q ^ 02 A Q Hal = F or Cl The aryl amines of the formulas (III) or (V) are commercially available, or can be synthesized according to Method A or B, or methods normally known to those skilled in the art. Aryl amines are usually synthesized by reducing nitroaryls using a metal catalyst, such as, for example, Ni, Pd, or Pt, and H2 or a hydride transfer agent, such as, for example, formate, cyclohexadiene, or a borohydride (Rylander, Hydrogenat ion Methods, Academic Press: London, UK (1985)). The ions can also be directly reduced using a strong hydride source, such as, for example, L iAI H 4 (Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as for example ^ Fe, Sn or Ca, often in acidic media. There are many methods for the synthesis of nitroaryls (March, Advanced Orgnic Chemistry, 3rd Ed., John Iley: New York (1985), Larock, Comprehensive Organic Transformations, VCH Publishers: New York (1989)). Nitro aryls are commonly formed by electrophilic aromatic nitration using HNO3, or an alternative source of N02 +. For synthesis of compounds of the formula (II) wherein L represents - (CH2) mO-, - (CH2) mS-, or - (CH2) mNH-, and B, M, Q, and m are as defined above wide, nitroaryls are formed additionally before reduction. In Reaction Scheme 2-method D, the substituted nitroaryls with potential leaving groups such as for example, F or Cl undergo substitution reactions on the treatment with nucleophiles, such as for example, phenoxide or thiolate, under basic conditions.

Another method for the preparation of the intermediate of the formula (II) is represented in Reaction Scheme 2-method C. Condensation of the amine- (V) with a suitable substituted chloropyridine has previously been described in patent applications. , and can be adapted to the compounds of the present invention. For example, the international application of PCT O 99 32111, Dumas, J., et al., "Method for the Treatment of Neplasm by inhibition of raf Kinase using N-Het eroaryl- '- (hetero) arylureas", international application of PCT WO 99 32110, Dumas, J. , et al., "Inhibition of raf Kinase using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas Reaction Scheme 3: Alternative synthesis of the ureas of the formula (I) VII VIII I The compounds of the invention can also be prepared from the compounds of the formula (VII) according to the reaction sequence shown above in General Methods G and H. Using Method G, the ureas of the Formula (VI) are treated with a Lewis acid such as, for example, magnesium chloride and the appropriate substituted amines, in a solvent such as, for example, THF at room temperature, to provide the substituted amides. In Method H, the ureas of the formula (VI) are de-esterified with a base such as for example potassium hydroxide, lithium hydroxide, or sodium hydroxide. The carboxylic acids of the formula (VII) are coupled with the appropriate amines according to the methods normally known to those skilled in the art [eg, from the treatment of a carboxylic acid with DCC / DMAP or EDCI / HOBT ], in a solvent such as, for example, THF, AcCN, or DF. In addition, the compounds of the formula (I) wherein R 4 and R 5 are hydrogen atoms can be synthesized according to the reaction scheme shown in Method I. The cyano compound (VIII) can be hydrolyzed in the presence of NaOH or percarbonate of sodium, in an aqueous solvent such as, for example, acetone-water, and at a temperature of 20 to 100 ° C. The compounds of formula (VI) and (VIII) are synthesized according to methods A to F, or the methods normally known to those skilled in the art. The pyridin-1-oxides of Formula I wherein M carries a hydroxide and its hydroxy at its nitrogen atom, and A, B, L as broadly defined above can be prepared from the corresponding pyridines using the conditions of oxidation known in the art. Some examples are as follows: peracids such as, for example, meta metachloroperbenzoic acids in chlorinated solvents such as, for example, dichloromethane, dichloroethane, or chloroform (Markgraf et al., Tetrahedron 1991, 47, 183). (Me 3 S 10) 2 in the presence of a catalytic amount of perrhenic acid in chlorinated solvents such as, for example, dichloromethane (Coperet et al., Terahedron Lett, 1998, 3_9, 761) Perfluoro-cis-2-butyl-3- propyloxaziridine in various combinations of halogenated solvents (Amone et al., Tetrahedron 1998, 7831). Complex of hypofluoric acid-acetonitrile in chloroform (Dayan et al., Synthesis 1999, 1427). Oxone, in the presence of a base like KOH, in water (Robker et al., J. Chem. Res., Sinop. 1993, 10, 412). Magnesium monoperoxyphthalate, in the presence of water and glacial acetic acid (Klemm et al., J. Heterocyclic Chem. 1990, 6, 1537). Hydrogen peroxide, in the presence of water and acetic acid (Lin A.J., Org. Prep. Int.Prob. 1991, 2_3_ (1), 114). Dimethyldioxirane in acetone (Boyd et al., J. Chem. Soc, Perkin Trans. 1991, 9_, 2189). In addition, the specific preparations of the aryl ureas and intermediary compounds (II) have already been described in the patent literature, and can be adapted to the compounds of the present invention. For example, Mi 11er S. et al, "Inhibition of p38 Kinase using Symmetrical and Unsymmetrical Diphenyl Ureas" PCT Int. Appl. WO 99 32463, Mi lie, S et al. "Inhibition of Raft Kinase Using Symmetrical and Unsymmetrical Substituted Diphenyl Ureas" PCT Int. Appl., WO 99 32436, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32111, Dumas, J. et al., "Method for the Treatment of Neoplasm by Inhibition of Raf Kinase using N-Heteroaryl-N '- (hetero) arylureas" PCT Int. Appl., WO 99 32106, Dumas, J. et al. al., "Inhibition of p38 Kinase Activity using Aryl-and Heteroaryl-Substuted Heterocyclic Ureas" PCT Int. Appl., WO 99 32110, Dumas, J. , et al., "Inhibition of raf Kinase using Aryl-and Heteroaryl-Substituted Heterocyclic Ureas" PCT Int Appl., WO 99 32455, Riedl, B., et al., "0-Carboxy Aryl Substituted Diphenyl Ureas as raf Kinase Inhibitors "PCT Inf. Appl., WO 00 '42012, Riedl, B., et al.," O-Carboxy Aryl Substituted Diphenyl Ureas as p38 Kinase Inhibitors "PCT Int. Appl., WO 00 41698, Dumas, J. et al. . "Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors" U.S.

Pat. Appl. Publ., US 20020065296, Dumas, J. et al. "Preparation of N-aryl- '- [(acylphenoxy) henyl] ureas as raf kinase in ibitors" PCT Int. Appl. , WO 02 62763, Dumas, J. et al. ?? Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas "PCT Int. Appl., WO 02 85857, Dumas, J. et al." Preparation of quinolyl, isoquinolyl or pyridyl-ureas as inhibitors of raf kinase for the treatment of tumors and / or cancerous cell growth "US Pat. Appl. Publ., US 20020165394. All of the above patent applications are incorporated herein by reference The reaction of the compounds (III) or (IV) with (II) is brought to Preferred solvents include suitable customary solvents which are inert under the reaction conditions.Non-limiting examples include ethers such as, for example, diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethyl oxyethane; hydrocarbons such as, for example, benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions, halogenated hydrocarbons such as, for example, di-oromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethyl no, chlorobenzene; alcohols such as for example ethanol n-propanol, isopropanol; esters such as, for example, ethyl acetate; ketones such as, for example, acetone; nitriles such as, for example, acetonitrile; heteroaromatics such as, for example, pyridine; polar solvents such as, for example, dimethyl formamide and tris-amide of hexamethyl phosphoric acid; and the mixtures of the solvents mentioned above. Toluene, benzene, and dichloromethane are preferred. The compounds (III) are generally employed in an amount of 1 to 3 mol per mol of the compounds (ii); an equimolar amount or a slight excess of the compounds (III) is preferred. The reaction of the compounds (II) with (III) is generally carried out within a relatively wide temperature range. In general, it is carried out in a variation from -20 to 200 ° C, preferably from 0 to 100 ° C, and most preferably from 25 to 50 ° C. The steps of this reaction are generally carried out under atmospheric pressure. However, it is also possible to perform them under superatmospheric pressure or under reduced pressure (for example, in a variation of 0.5 to 5 bar). The reaction time can be varied generally within a relatively broad range. In general, the reaction is terminated after a period of 2 to 24 hours, preferably 6 to 12 hours. The synthetic transformations that can be used in the synthesis of the compounds of the formula I and in the synthesis of the intermediates involved in the synthesis of the compounds of the formula I are known or are accessible to someone skilled in the art. The collections of synthetic transformations can be found in compilations, such as for example: J. March, Advanced Organic Chemistry, 4th ed.; John Wiley: New York (1992) R.C. Larock Comprehensive Organic Transformations, 2nd ed .; iley-yCH: New York (1999) F.A. Tortoiseshell; R.J. Sundberg. Advanced Organic Chemistry, 2nd ed .; Plenum Press: New York (1984) T.W. Greene; P.G.M. Wuts. Protective Groups in Organic Synthesis, 3rd ed .; John Wiley: New York (1999) L.S. Hegedus. Transition Metals in the Synthesis of Complex Organic Molecules, 2nd ed .; üniversity Science Books: Mili Valley, CA (1994) L.A. Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis; John Wiley: New York (1994). • A.R. Katritzky; 0. Meth-Cohn; C.W. Rees, Eds. Comprehensive Organic Functional Group Transformations; Pergamon Press: Oxford, UK (1995).

G. ilkinson; F.G A. Stone; E.W. Abel, Eds. Comprehensive Organometallic Chemistry; Pergamon Press: Oxford, UK (1982). B. M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon Press: Oxford, UK (1991) A.R. Katritzky; C.W. Rees Eds. Comprehensive Heterocylic Chemistry; Pergamon Press: Oxford, UK (1984) • A.R. Katritzky; C.W. Rees; E.F.V. Scriven, Eds. Comprehensive Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996) C. Hansch; P.G. Sammes; J.B. Taylor, Eds. Comprehensive Medicinal Chemistry: Pergamon Press: Oxford, UK (1990). In addition, recurring reviews of the synthetic methodology and related topics include Organic Reactions John Wiley: New York; Organic Syntheses; John Wiley: New York; Reagents for Organic Synthesis: John Wiley: New York; The Total Synthes is of Natural Products; John Wiley: New York; The Organic Chemistry of Drug Synthesis; John Wiley: New York; Annual Reports in Organic Synthesis; Academic Press: San Diego CA; and Methoden der Organischen Chemie (Houben-Wey1); Thieme: Stuttgart, Germany. In addition, databases of synthetic transformations include Chemical Abstracts, which can be investigated using either CAS OnLine or SciFinder, Handbuch der Organischen Chemie (Beilstein), which can be investigated using SpotFire, and REACCS.

Compositions of the compounds of this invention This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be used to achieve the desired pharmacological effect by administering to a patient in need thereof. A patient, for the purposes of this invention, is a mammal, including a human being, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and harmless to a patient at concentrations consistent with the effective activity of the active ingredient such that any side effects attributable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of the compound of preference is that amount which produces a result or exerts an influence on the particular condition to be treated. The compounds of the present invention can be administered with pharmaceutically acceptable carriers well known in the art using any conventional effective dosage unit forms, including immediate, slow, and time, oral, parenteral, topical, nasal, ophthalmic, optical, immediate release preparations. sublingually, rectally, vaginally, and the like. For oral administration, the compounds can be prepared in solid or liquid preparations such as for example capsules, pills, tablets, lozenges, dragees, fusions, powders, solutions, suspensions, or emulsions, and can be prepared according to methods known in the art. the technique for the manufacture of the pharmaceutical compositions. The solid unit dosage forms may be a capsule which may be of the gelatin type with normal soft or hard protection containing, for example, surfactants, lubricants, and inert fillers such as, for example, lactose, sucrose, calcium phosphate, and corn starch. In another embodiment, the compounds of this invention can be formed into tablets with conventional tablet bases such as, for example, lactose, sucrose and corn starch in combination with binders such as, for example, acacia, corn starch, or gelatin, disintegrants intended to aid in the decomposition and dissolution of the tablet after administration such as, for example, potato starch, alginic acid, corn starch, and guar gum, tragacanth gum, acacia, lubricants intended to improve the flow of the granulation of the tablet and preventing adhesion of the tablet material to the surfaces of the punches and punches of tablets, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as for example, mint, oil of wintergreen, or cherry flavoring, intended to reinforce the aesthetic qualities of the tablets and make them more acceptable p for the patient. Suitable excipients for use in liquid oral dosage forms include dicalcium phosphate and diluents such as, for example, water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant. , a suspending agent or an emulsifying agent. Other different materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with shellac, sugar or both. The dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in combination with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example those sweetening, flavoring and coloring agents described above. The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as, for example, liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) natural occurring gums such as, for example, acacia gum and tragacanth gum, (2) naturally occurring phosphatides such as, for example, soybeans and lecithin, (3) partial esters or esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil such as, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as, for example, liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, p-hydroxyben zoat or ethyl or 12-propyl; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as, for example, sucrose or saccharin. Syrups and elixirs can be prepared with sweetening agents, such as, for example, glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain an emollient, a preservative, such as, for example, methyl and propyl parabens and flavoring and coloring agents. The compounds of this invention can also be administered parenterally, i.e., subcutaneously, intravenously, infraocularly, intrasynovially, intramuscularly, or intraperitoneally, as injectable dosages of the compound preferably in a physiologically acceptable diluent with a pharmaceutical carrier that can be a sterile liquid or a mixture of liquids such as, for example, water, saline, aqueous dextrose and related sugar solutions, an alcohol such as, for example, ethanol, isopropanol, or exadeclic alcohol, glycols such as, for example, propylene glycol or pol i et i1 engl i col, glycerol ketals such as for example, 2, 2-dimethyl-l, l-dioxolan-4-methanol, ethers such as for example, poly (ethylene glycol) 400, an oil, a fatty acid, an fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as, for example, an abon or a detergent, a suspending agent such as, for example, pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or an emulsifying agent and other pharmaceutical adjuvants. Illustrative of the oils that can be used in the parenteral formulations of this invention are those derived from petroleum, animal, vegetable, or synthetic, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, oil of corn, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include alkali metal of fatty acid, ammonium, and trietholamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene-oxypropylene) s or ethylene oxide or copolymers of propylene oxide; and amphoteric detergents, for example, alkyl-beta-aminopropionate, quaternary ammonium salt with 2-alkylimidazoline, as well as mixtures. The parenteral compositions of this invention will typically contain between about 0.5% and 25% by weight of the active ingredient in solution. You can also use conservatively and shock absorbers. In order to minimize or eliminate irritation at the injection site, these compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) preferably between about 12 and 17. The amount of surfactant in this The formulation of preference varies between about 5% and 15% by weight. The surfactants may be an individual component having the above HLB or they may be a mixture of two or more components having the desired HLB. Exemplary surfactants used in parenteral formulations are the class of fatty acid esters and polyethylene sorbitan, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. These suspensions can be prepared according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum. acacia; the dispersing or wetting agents which may be a naturally occurring phosphatide such as, for example, lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long-chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as, for example, polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester, derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. The diluents and solvents that can be used are, for example, water, Ringer's solution, isotonic solutions with sodium chloride and isotonic solutions with glucose. In addition, sterile fixed oils such as solvents or suspension medium are conventionally employed. For this purpose, any insipid, fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as, for example, oleic acid can be used in the preparation of injectable solutions.

A composition of the invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable excipient that does not produce irritation that is solid that is solid at normal temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials are, for example, cocoa butter and polyethylene glycol. Another formulation employed in the methods of the present invention employs devices for transdermal delivery ("patches"). These transdermal patches can be used to provide a continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art (see, for example, U.S. Patent No. 5,023,252, filed June 11, 1991, incorporated herein by reference). reference). These patches can be constructed for continuous, pulsatile delivery, or at the demand of pharmaceutical agents.

The controlled release fornulations for parenteral administration include liposomal gel formulations, in polymeric and polymeric microspheres that are known in the art. It may be convenient or necessary to administer the pharmaceutical composition to the patient by means of a mechanical delivery device. The construction and use of the device for mechanical delivery for the delivery of pharmaceutical agents are well known in the art. For example, direct techniques for administering a drug directly to the brain involve the placement of a catheter for delivery of drugs into the patient's ventricular system to bypass the blood-brain barrier. One of these implantable delivery systems, used for transporting agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, filed April 30, 1991. The compositions of the invention also they may contain other conventional pharmaceutically acceptable composition ingredients, generally referred to as carriers or diluents, as necessary or convenient. Conventional procedures can be used to prepare these compositions in suitable dosage forms. These ingredients and methods include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52 (5), 238-311; Strickley, R.G "Parenteral Formulations of Small Olecule Therapeutics Marketed in the United States (1999) - Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53 (6), 324-349; and Nema, S. et al, "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171. The commonly used pharmaceutical ingredients that can be used as suitable to prepare the composition for its intended route of administration include: acidifying agents (examples include, but are not limited to: acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalizing agents (examples include, but are not limited to: ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, t-ethanolamine, trolamine); adsorbents (examples include, but are not limited to: powdered cellulose and activated charcoal); aerosol propellants (examples include, but are not limited to: carbon dioxide, CC12F2, F2CIC-CCIF2, and CCIF3) air displacing agents (examples include, but are not limited to, nitrogen and argon); antifungal preservatives (examples include but are not limited to: benzoic acid, butylparaben, ethylparaben, metilparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to: benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutyl, phenol, phenol alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to: ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hydrophobic acid, monotioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium sulfoxylate formaldehyde, metasulfite. of sodium ); binder materials (examples include, but are not limited to: block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers); buffering agents (examples include but are not limited to: potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrier agents (examples include but are not limited to: acacia syrup, aromatic syrup, aromatic elixir) , cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, eriostatic bac sodium chloride injection and water for bacteriostatic injection) chelating agents (examples include enunciatively: disodium edetate and edetic acid) dyes (examples include but are not limited to: FD &C Network No. 3, FD &C Network No. 20, FD &C Yellow No. 6, FD &C Blue No. 2 , D &C Green No. 5, D &C Orange No. 5, D &C Network No. 8, caramel red, and fatty oxide); clarifying agents (examples include, but are not limited to: bentonite); emulsifying agents (examples include, but are not limited to: acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene monostearate 50); encapsulating agents (examples include, but are not limited to: gelatine and cellulose acetate phthalate) flavors (examples include but are not limited to: anise essence, volatile cinnamon oil, cocoa, menthol, orange oil, mint essence and vanillin); humectants (examples include, but are not limited to: glycerol, prop i lengl icol and sorbitol); agents for levigation (examples include, but are not limited to: mineral oil and glycerin); oils (examples include but are not limited to: peanut oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include, but are not limited to: lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal supply) (examples include, but are not limited to: monohydroxy polyhydroxy alcohols, mono- or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives , cephalins, terpenes, amides, ethers, ketones and ureas) plastifying (examples include, but are not limited to: diethyl phthalate and glycerol); solvents (examples include but are not limited to: ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and water sterile for irrigation); agents for imparting rigidity (examples include, but are not limited to: cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax 1 la); base for suppositories (examples include but are not limited to: cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxinol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (examples include, but are not limited to: agar, bentonite, carbomers, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and vegetable gum); sweetening agents (examples include, but are not limited to: aspartame, dextrose, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose); anti-adhesive for tablets (examples include, but are not limited to: magnesium stearate and talc); binders for tablets (examples include, but are not limited to: acacia, alginic acid, sodium carboxymethyl cellulose, compressible sugar, and cellulose, gelatin, liquid glucose, methyl cellulose, uncrosslinked polyvinyl pyrrolidone, and pregelatinized starch); diluents for tablets and capsules (examples include but are not limited to: dibasic calcium phosphate, kaolin, lactose, mannitol, cellulose microcrystalline, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); agents for coating tablets (examples include, but are not limited to: liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, cellulose acetate, cellulose acetate phthalate and shellac); excipients for the direct compression of tablets (examples include but are not limited to: dibasic calcium phosphate); tablet disintegrants (examples include, but are not limited to: alginic acid, calcium carboxymethylcellulose, microcrystalline cellulose, polacrilin potassium, crosslinked polyvinyl pyrrolidone, sodium alginate, sodium starch glycolate); tablet sliders (examples include, but are not limited to: colloidal silica, corn starch and talc); lubricants for tablets (examples include but are not limited to: calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); opacifiers for tablets / capsules (examples include, but are not limited to: titanium dioxide); tablet polishing agents (examples include, but are not limited to: carnauba oil and white wax); thickening agents (examples include, but are not limited to: beeswax, cetyl alcohol and paraffin); agents for imparting tonicity (examples include, but are not limited to: dextrose and sodium chloride); agents for increasing viscosity (examples include, but are not limited to: alginic acid, bentonite, carbomers, sodium carboxymethylcellulose, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include, but are not limited to: heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and 1-oxy tert-1-ene stearate). It is believed that one skilled in the art, using the above information, can use the present invention to its fullest extent. However, the following are examples of pharmaceutical formulations that can be used in the method of the present invention. They are for illustrative purposes only, and should not be construed as limiting the invention in any way. The pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile IV Solution: A 5 mg / ml solution of the desired compound of this invention can be prepared using sterile injectable water, and the pH adjusted if necessary. The solution is diluted for administration at l-2mg / ml with 5% sterile dextrose and administered as an IV infusion for 60 minutes. Freeze-dried powder for IV administration: An e-sterile preparation can be provided with 100-1000 mg of the desired compound of this invention as a lyophilized powder, (ii) 32-327 mg / ml of sodium citrate, and (iii) 300- 3000 mg of Dextran 40. The formulation is reconstituted with 5% sterile or injectable saline solution at a concentration of 10 to 20 mg / ml which is further diluted with saline or 5% dextrose at 0.2-0.4 mg / ml. ml, and is administered either by IV bolus or IV infusion for 15-60 minutes. Intramuscular suspension: the following solution or suspension can be prepared for intramuscular injection: 50mg / ml of the desired water-insoluble compound of this invention, 5mg / ml sodium carboxymethylcellulose 4mg / ml TWEEN 80 9mg / ml sodium chloride sodium 9mg / ml benzyl alcohol Hard-coated capsules: Many unit capsules are prepared by filling two-piece hard gelatin capsules with 100 mg of the sprayed active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of stearate of magnesium. Soft gelatin capsules: A mixture of the active ingredient in a digestible oil such as, for example, soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump in molten gelatin to form soft gelatine capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare the water-miscible medication mixture. Tablets: Many tablets are prepared by conventional procedures in such a way that the dosage unit is 100 mg of the active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Suitable aqueous and non-aqueous coatings can be applied to increase palatability, improve elegance and stability or absorption delay. Tablets / capsules for immediate release: These are solid oral dosage forms prepared by conventional and novel processes. These units are taken orally without water for immediate dissolution and supply of the medication. The active ingredient is mixed in a liquid-containing ingredient such as, for example, sugar, gelatin, pectin and sweeteners. These liquids solidify into solid tablets or tablets by lyophilization and solid state extraction techniques. The drug compounds can be compressed with sugars and viscoelastic and thermoelastic polymers or effervescent components to produce porous matrices intended for immediate release, without the need for water.

Method for the treatment of hyperproliferative disorders The present invention relates to a method for using the compounds described above (the compounds of the formula I), including the salts and esters thereof and the compositions thereof, for treating disorders hyperproliferatives in mammals. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt or ester thereof that is effective in treating the disorder. Hyperproliferative disorders include, but are not limited to: solid tumors, such as, for example, cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, hepatic, cutaneous, head and neck, thyroid, parathyroid and distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias. Examples of breast cancer include, but are not limited to: invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to: small cell and small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to: brainstem glioma and hypophthalmic, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor. Tumors of the male reproductive organs include, but are not limited to: testicular and prostatic cancer. Tumors of the female reproductive organs include, but are not limited to: endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Tumors of the digestive tract include, but are not limited to: anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small bowel, and salivary gland cancers. Urinary tract tumors include, but are not limited to: cancers of the bladder, penis, kidney, renal pelvis, urethra, and urethra. Ocular cancers include, but are not limited to: melanoma and intraocular retina xnoblastoma. Examples of liver cancers include, but are not limited to: hepatocellular carcinoma (hepatic cell carcinomas with or without a fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Cutaneous cancers include, but are not limited to: squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Head-and-neck cancers include, but are not limited to: laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancers, and labial and cavity cancer or al. Lymphomas include, but are not limited to: AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to: soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to: acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These disorders have been well characterized in humans, although they also exist with a similar etiology in other mammals, and can be treated by administering the pharmaceutical compositions of the present invention. Based on known standard laboratory techniques for evaluating compounds useful for the treatment of hyperproliferative disorders, by standard toxicity tests and by standard pharmacological assays for- determining the treatment of conditions previously identified in mammals, and by comparison of these results with the results of known medicaments which are used to treat these conditions, the effective dosage of the compounds of this invention can be easily determined for the treatment of each desired indication. The amount of the active ingredient that will be administered in the treatment of one of these conditions can be varied widely according to these considerations according to the particular compound and dosage unit employed, the mode of administration, the treatment period, the age and the sex of the treated patient, and the nature and extent of the treated condition. The total amount of the active ingredient to be administered will generally vary between about 0.001 mg / kg and 200 mg / kg of body weight per day, and preferably between about 0.01 mg / kg and 20 mg / kg of body weight per day. It should be noted that the choice of dosing schedules is particularly important to maximize the efficacy and safety of drugs for the treatment of proliferative disorders such as, for example, cancer. Clinically useful dosing schedules will vary from three times a day to one dosage once every four weeks. In addition, the "days off" of the drug "in which a patient is not dosed with a drug for a certain period of time, may be beneficial for the total balance between the pharmacological effect and tolerability. A unit dosage may contain between about 0.5 mg and 1500 mg of the active ingredient, and may be administered one or more times a day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will preferably be 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will preferably be 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen will preferably be 0.1 to 200 mg administered between one to four times a day. The preferred transdermal concentration will be that required to maintain a daily dose of 0.01 to 200 mg / kg. The average daily inhalation dosage regimen will preferably be 0.01 to 100 mg / kg of total body weight. Of course, the specific initial and continuous dosing regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, combinations of drugs, and the like. The desired mode of treatment and the number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof, can be determined by those skilled in the art using conventional treatment tests. The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents, where the combination does not cause 'unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-hyperproliferative agents or for other indications, and the like, as well as, with mixtures and combinations thereof. Optional anti-hyperproliferative agents that can be added to the composition include, but are not limited to: the compounds listed above on drug regimens in cancer chemotherapy in the lia. Edition of the Merck Index, (1996), which is incorporated in the present reference, such as, for example, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mecloret amine, ß-mercapt opurine, mesna, methotrexate, initomycin C, mitoxant ro, prednisone, prednisone, procarbazine , Raloxifene, Streptococcus, Tamoxifen, Thioguanine, Topotecan, Vinblastine, Vincristine, and Vindesine. Other suitable anti-hyperproliferative agents for use with the composition of the invention include, without limitation, those compounds recognized for use in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., Publ. by McGraw-Hill, pages 1225-1287, (1996) which is incorporated herein by reference, such as, for example, aminoglut and imide, L-asparaginase, azathioprine, 5-zacitidine cladribine, busulfan, diethylestilbestrol, 2 ', 2'-difluorodeoxycytidine, twelve t axel, er it rohidroxinoniladenina, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogestone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentost atina , N-phosph onoacetyl-L-aspartat or (PALA), plicamycin, semustine, teniposide, t-osterone propionate, thiotepa, trimethylammelamine, uridine, and vinorelbine. Other anti-hyperproliferative agents suitable for use with the composition of the invention include, but are not limited to: other anti-cancer agents such as, for example, epothilone and its derivatives, irinotecan, raloxifene and t-opotene.

In general, the use of cytotoxic and / or cytostatic agents in combination with a compound or composition of the present invention will serve to: (1) provide better efficacy for reducing the growth of a tumor or even eliminating the tumor compared to administration of any agent alone, (2) provide administration of minor amounts of the chemotherapeutic agents administered, (3) provide a chemotherapeutic treatment that is well tolerated in the patient with fewer harmful pharmacological complications than those observed with, agent chemotherapies individual and other certain combination therapies, (4) provide treatment for a broader spectrum of different types of cancer in mammals, especially in humans, (5) provide a superior response rate among treated patients, (6) provide a longer survival time between the treated patients compared to the t standard chemotherapy treatments, (7) provide a longer time for tumor progression, and / or (8) provide efficacy and tolerability results at least as good as those of agents used alone, as compared to known cases where other combinations of carcinogenic agents produce antagonistic effects.

Abbreviations used in this specification DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene DMF AT, A / -dimethyl formamide DCM DicLoromethane DCE 1, 2-dichloroethane DMSO Dimethyl sulfoxide HPLC High efficiency liquid chromatography MPLC Medium efficiency liquid chromatography LC-MS Mass spectroscopy coupled to liquid chromatography RT Retention time MP NMR melting point TLC nuclear resonance spectroscopy Thin-layer chromatography ES Electro-dew DMAC N, N-dimethylacetamide HRMS High resolution mass spectroscopy CDI 1, 1 '- carbonyldiimidazole HOBT 1-hydroxybenzotriazole DCC 1,3-dicyclohexylcarbodiimide EDCI 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride DMAP 4-dimethylaminopyridine TMSCI Trimethylsilyl chloride m-CPBA 3-chloroperbenzoic acid HEPES N- (2-hydroxyethyl) ) -piperacin-N '- (2-ethanesulfonic acid) tris (hydroxymethyl) -aminomethane acid tris / hydrochloride hydrochloride MRTriton X-1000® tert-octyl-phenoxypolyethoxyethanol, Rohm & Haas, USA The performance percentages of the following examples refer to the starting component that was used in the lowest molar amount.

Methods LC-MS LC-MS (Method 1) MS equipment: Micromass Quattro LCZ ionization mode: ESI positive / negative HPLC equipment: HP 1100 UV detection: 208-400 nm temperature: 40 ° C Column: MRSymmetry C 18 50 mm x 2.1 mm 3.5pm Waters Gradient Provider Time A: B:% Flow [min. ] [mL / min. ] 0.00 90 10.0 0.50 4.00 10 90.0 0.50 6.00 10 90.0 0.50 A 0.05% strength solution of formic acid in water B: 0.05% resistant formic acid in acetonitrile LC-MS (Method 2) MS equipment: Microm ss LCZ ionization mode : ESI HPLC equipment: Gilson 215 detection by ÜV: 254 nm Column: YMC pro C-18 23 M x 2 n 120 A Supplier: IMC Gradient Time A:% B:% Flu or [min.] [ML / min.] 0. .50 90.0 10. .0 1. 0 3. .50 5.0 95. .0 1. 0 4, .00 5.0 95. .0 1. 0 4. .01 90.0 10. .0 1. 0 4, .80 90.0 10. .0 1. 0 ?: 0.02% resistant solution of trifluoroacetic acid in 2% acetonitrile / 98% B water: 0.02% resistant solution of trifluoroacetic acid in 98% acetonitrile / 2% water LC-MS (Method 3) HPLC equipment: Gilson 215 detection by 220 and 254 nM Temperature 25 ° C Column: YMC -Pack pro C-18 50 mm x 4.6 mm 5pm Waters Gradient Provider Time A:% B:% Flow [min. ] [mL / min. ] 0.00 10.0 90.0 00 3.50 90.0 10.0 00 4.50 90.0 10.0 00 4.60 10.0 90.0 00 5.00 10.0 90.0 00 A: 0.1% resistant solution of TFA in acetonitrile B: 0.1% resistant solution of aqueous TFA LC-MS (Method 4) HPLC equipment: Gilson 215 UV detection: 220 and 254 nM Temperature 25 ° C Column: YMC-Pack pro C-18 75 mm x 30 mm 5pm Provider: Waters Gradient Time A:% B:% Flow [min. ] [mL / min. ] 0.00 20.0 80.0 25.00 20.00 80.0 20.0 25.00 A: Acetonitrile B: 0.1% TFA resistant solution PREPARATION OF STARTING AND INTERMEDIATE MATERIALS General Method A: Preparations of Aminophenols The araino phenols are available either as food or may be prepared as described in one or more of the Examples below.

Method A-l Preparation of 5-Ni troindazole-l-carboxylic acid tert-butyl ester Step 1: Preparation of 5-nor roindazole -1 -carboxylic acid tert-butyl ester To a 0 ° C suspension of 5-nitroindazole (5 g, 30.6 mmol), Et 3 N (4.7 mL, 33.7 mmol) and 4-dimethylaminopyridine (0.75 g, 6.1 mmol) in acetonitrile (60 mL) was added dropwise a solution of di-butyl dicarbonate (8 g, 36.8 mmol) in acetonitrile (40 mL). The resulting mixture was stirred for 30 min, then concentrated under reduced pressure. The residue was dissolved in Et 2 O (200 mL) and H 2 O (100 mL). The pH of the aqueous layer was adjusted to 2 using a 1N HC1 solution. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure to give the 5-nitroindazole-1-carboxylic acid tert-butyl ester (7.8 g, 96%) as a yellow solid: TLC (30 mL). % EtOAc / hex), Rf = 0.70; ES-LCMS (rei abundance) m / z 264 (MH +, 100%).

Step 2: Preparation of the title compounds 5-aminoindazole-1-carboxylic acid fcer-butyl ester Palladium on carbon (780 mg) was placed under an inert atmosphere and suspended in EtOH (15 mL). A solution was added to give the 5-nitroindazole-1-carboxylic acid tert-butyl ester (7.78 g, 29.5) in EtOH (100 mL) and EtOAc (100 mL). The reaction mixture was placed under H2 atmosphere (pressure of 1 atm) and stirred overnight. The resulting mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to obtain a greenish foamy solid. The crude product was dissolved in CH2Cl2 and purified by Biotage Flash 40M (gradient 30% to 50% EtOAc / hex) to give the title compound (6.55 g, 95%) as a white solid: TLC (50% EtOAc / hex), Rf = 0.41; ES-LCMS (rei abundance) m / z 234 (MH +, 66%).

Method A-2a Preparation of 1,1-dioxo-2,3-dihydro-lH-benzo [b] thiophen-5-ylamine Palladium on carbon (25 rag) was placed under an inert atmosphere and suspended in 1: 1 v / v EtOH / THF (10 mL). A solution of 1,1-dioxide of 5-nitrobenzo [b] thi ofenone (250 mg, 1.18 mmol) in EtOH / THF (1: 1) was then added, and the reaction mixture was placed under H2 atmosphere (pressure of 1 Atm) and stirred at RT for 3 h. The reaction was filtered through a pad of Celite and washed well with MeOH to obtain the title compound (200 mg, 92%) as a brown solid: TLC (10% eOH / DCM w / 5% NH4OH) , Rf = 0.40; LC MS m / z 184.1 (MH +).

Method A-2b Preparation of 2-methyl-6-aminobenzoxazole This compound was prepared from 2-met i 1-6-ni troben z oxa z ol (2.0 g, 13.5 mmol) in the same manner described for 5-aminobenxo [] thiophene 1,1-dioxide, providing 1.57 (94%) of the title compound as a brown solid. MS LC-MS (M + H) + = 149.1, RT = 0.77 min.

Method A-3a Preparation of 1- (2-diylamino-yl) - lH-indol-5-amine Step 1: Preparation of diethyl- [2- (5-nitroindol-1-yl) ethylamine A suspension of 5-nitroindole (2.0 g, 12.3 mmol) and NaOH pellets (0.49 g, 1 eq) in H20 (2.0 mL) was stirred at R1. After 10 min, p-xylene (15.0 mL, 1.4 M), K2C03 (2.55 g, 1.5 equ) and N-diethylaminoethyl chloride hydrochloride (2.12 g, 12.3 mmol, 1 eq) were added and the reaction mixture was added. heated to 100 ° C. After 4 h the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was dissolved in p-xylene and washed with 1N NNaOH (2 x) and H20 (1 x). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure to yield the nitro compound (1.79 g, 56%). FTA (5% of MeOH / EtOAc), Rf = 0.25; LC MS m / z 262.2 (MH +).

Step 2: Preparation of the title compound 1 - (2-diethylamino-yl) -lH-indol-5-ylamine Diethyl- [2- (5-nitroindol-l-yl) ethyl] amine was dissolved (1.6 g, 6.1 mmol) in pure EtOH (100 mL) and injected into a flask containing 10% Pd on carbon (160 mg) under an argon atmosphere. The reaction mixture was placed under H 2 atmosphere (pressure of 1 atm) and stirred at RT for 3 h. The reaction was filtered over a pad of Celite and washed well with EtOH. Evaporation of the volatile solvent afforded the title compound (1.4 g, 99%) as a brown solid. TLC (10% MeOH / DCM), Rf = 0.20; LC MS m / z 232.3 (MH +).

Method A-3b Preparation of 1- (2-diethylamino-ethyl) -lH-indazol-5-ylamine This compound was prepared from 5-nitroindazole (2.0 g, 12.3 mmol) in the manner described for 1- (2-diethylamino-ethyl) -lH-indazol-5-ylamine, providing 2.0 g (70%) of the composed of the title. TLC (10% MeOH / DCM), Rf = 0.20; LC MS m / z 233.2 (MH +).

General Method B: Bicyclic amine preparations of the formula (III) The compounds of the formula (III) are either commercially available or can be prepared as described in one or more of the following Examples.

Method B-l Preparation of 4-amino-3-fluorophenol To a dry flask purged with argon was added 10% Pd / C (80 mg) followed by a solution of 3-fluoro-4-nitrophenol (1.2 g, 7.64 mmol) in EtOAc (40 mL). The mixture was stirred under an atmosphere of H2 for 4 h and filtered through a pad of Celite®. The filtrate was evaporated under reduced pressure to provide the desired product as a tan solid (940 mg, 7.39 mmol, 97% yield). 1H-NMR (DMSO-d6) 58.76 (s, 1H), 6.62 to 6.52 (m, 1H), 6.41 (dd, J = 2.5, 12.7 Hz, 1H), 6.35 to 6.29 (m, 1H), 4.38 (s) , 2H).

Preparation of 4-amino-2-fluorophenol This compound was prepared from 2-fluoro-4-nitrophenol (2.0 g, 12.7 mmol) in the manner described for 4-amino-3-fluorophenol, yielding 1.58 g (98%) of 4-amino-2-fluoro-enol like a cinnamon solid. 1H-NMR (DMSO-d6) d 8.53 (s, 1H), 6.59 (dd, J = 10.2, 8.5 Hz, 1H), 6.31 (dd, J = 13.1, 2.8, Hz, 1H), 6.20 to 6.14 (m , 1H), 4.66 (s, 2H).

Method B-lc Preparation of -amino-3-trifluoromethylphenol This compound was prepared from 4-nitro-3-trif luorofol (5.0 g, 24.1 mmol) in the manner described for. 4-amino-3-f luorophenol, providing 3.84 g (89.8%) of 4-amino-3-trifluoromethylphenol as a tan solid. 1H-NMR (DSO-d6) d 8.89 (s, 1H), 6.78 to 6.67 (m, 3H), 4.85 (s, 2H); TLC (25% EtOAc / Hex), Rf = 0.31.

Method B-ld Preparation of 4-amino-2-methoxyphenol This compound was prepared from 4-nitro-2-methoxy phenol (10.0 g, 59. 1 mmol) in the manner described for 4-amino-3-fluorophenol, yielding 5.20 g (56.9%) of 4-amino-2-methoxy enol as a dark brown solid. 1H-NMR (DMSO-d6) 57.79 (br s, 1H), 6.44 (d, J = 8. 1 Hz, 1H), 6.21 (d, J = 2.4 Hz 1H), 5.97 (dd, J = 8.4, 2.4 Hz, 1H), 4.43 (br s, 2H) 3.65 (s, 3H); TLC (66% EtOAc / Hex), Rf = 0.42.

B-le method This compound was prepared from 8-hydroxy-5-nitroquinoline (5.0 g, 26.3 mmol) in the manner described for 4-amino-3-fluorophenol, yielding 2.4 g (51.3%) of 5-amino-8-quinolinoline. TLC (5% MeOH / DCM), Rf = 0.52.

Method B-2a Preparation of 3-amino-2,4-difluorophetiol Step 1: Preparation of ethyl-2,4-difluorophenoxycarboxylate A solution of 2,4-difluorophenol (2.00 g, 15.4 mmol) in DCM (75 mL) at 0 ° C was treated with triethylamine (2.6 mL, 18.5 mmol), followed by the dropwise addition of ethyl chloroformate (1.8 mL, 18.5 mmol). The reaction was stirred at 0 to 25 ° C for 90 min, and the mixture was quenched with H2O (75 mL). The organic layer was washed with brine (2 x 50 itiL), dried over Na 2 SO 4, and concentrated under reduced pressure to provide the desired product as a colorless oil in quantitative yield. ??? - NMR (DMSO-d6) d 7.22 to 7.14 (m, 1H), 6.97 to 6.83 (m, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H ).

Step 2: Preparation of 2,4-Difluoro-5-nitrophenol A solution of ethyl 2,4-difluorophenoxycarboxylate (3.27 g, 16.2 mmol) concentrated H2SO4 (11 mL) at 0 ° C was added to steaming HN03 (1.1 mL) dropwise, maintaining internal temperature between 10 to 20 ° C. After stirring for 1 h, the mixture was poured into ice water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over MgSO4, and concentrated in vacuo. The residue was dissolved in MeOH (50 mL), and sodium bicarbonate (2.72 g, 32.3 mmol) was added. The resulting mixture was stirred at room temperature for 64 h and solid-filtered.

The filtrate was concentrated and the residue was extracted in H20 (100 mL). The pH was adjusted to 5 with the addition of HC1 conc, and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over MgSO 4, and evaporated under reduced pressure to provide 2, -di-f luoro-5-nitrophenol as a yellow solid (2.35 g, 13.4 mmol; 83% yield). XH-NM (DMS0-d6) d 10.88 (s, 1H), 7. 70 to 7.61 (m, 2H).

Step 3: Preparation of the title compound 2,4-d-fluoro-5-aminophenol This compound was prepared from 2,4-difluoro-3-nitrophenol (2.35 g, 13.4 mmol) in the manner described for 4-amino- 3-fluorophenol, providing 1.89 g (97%) of 2,4-difluoro-5-aminophenol as a tan solid. 1 H-NMR (DMSO-d 6) 59.26 (s, 1 H), 6.89 (t, J = 10.7 Hz, 1 H), 6.33 (t, J = 9.2 Hz, 1 H), 4.82 (s, 2 H).

Method B-2b Preparation of 5-amino-4-fluorophenol Step 1: Preparation of eth i 1-2 -bromo- -fluorophenoxycarboxylate This compound was prepared from 2-bromo-4-fluorophenol (3.0 g, 15.7 mraol) in the manner described for 2,4-difluorophenoxycarboxylate or ethyl, providing 4.0 g (96.8%) of et-1-2-bromine - 4 -f luorof enoxicarboxlat or as a light yellow oil. 1 H-NMR (DMSO-de) d 7.70 (dd, J = 6.0, 2.1 Hz, 1H), 7.46 (dd, J = 6.6, 3.9 Hz, 1H), 7.31 (dt, J = 6.6, 2.1 Hz, 1H) , 4.26 (q, J = 5.4 Hz, 2H), 1.29 (t, J = 5.4 Hz, 3H).

Step 2: Preparation of 2-Bromo-4-fluoro-5-nitrophenol This compound was prepared from ethyl-2-bromo-4-fluorophenoxycarboxylate (4.0 g, 15.2 mmol) in the manner described for 2, -di-fluoro-5-nitrophenol, providing 3.14 g (87.5%) of 2- Bromo-4-fluoro-3-nitrophenol as a yellow solid. 1H-NMR (DMS0-d5) d 11.19 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 5.1 Hz, 1H).

Step 3: Preparation of the title compound 3-amino-4-fluorophenol This compound was prepared from 2-bromo-fluoro-5-nitrophenol (3.1 g, 13.1 mmol) in the manner described for 4-amino-3 - fluorophenol, providing a quantitative yield of crude 3-amino-fluoro-phenol which was used without further purification. 1 H-NMR (DMSO-d 6) d 8.60 (br s, 2 H), 7.12 (dd, J = 7.8, 6.6 Hz, 1 H), 6.82 (dd, J = 5.1, 1.5 Hz, 1 H), 6.55 to 6.61 (m , 1 HOUR).

Preparation of 3-amino-6-lu-loforphenol This compound was prepared from 4-bromo-2-fluorophenol (3.0 g, 15.71 mmol) in the manner described for 3-amino-4-fluorophenol, yielding 1.79 g (86%) of 3-amino-6-fluorophenol. 1H-NMR (D SO- · d6) 5 l0.42 (s, 1H), 9.69 (br s, 2H), 7.22 (dd, J = 8.4, 6.6 Hz, 1H), 6.93 (dd, J = 5.7, 2.1 Hz, 1H), 6.74 to 6.99 (m, 1H).

Method B-3 Preparation of 4-amino-2-chloro-6-fluorophenol Step 1; Preparation of 2-Chloro-6-fluoro-4-nitrophenol A solution of 2-gold-6-fluoro-phenol (1.0 g, 6. 82 mmol) in concentrated acetic acid (3.0 mL) was cooled to 0 ° C. Steamy nitric acid (559 mg, · 8.87 mmol) was added dropwise, maintaining the reaction temperature between 10 to 20 ° C. The reaction was allowed to stir at 0 ° C for 3 h. The mixture was emptied on ice and allowed to warm to room temperature. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (lx 50 mL), dried over Na 2 SO 4, and evaporated under reduced pressure. The crude red solid was purified using Biotage Quad 4 (25 M column) eluting with 9: 1 Hexanes / EtOAc to yield the title compound as a yellow solid (326 mg, I.70 mmol; 25% yield). 1H-NMR (DMSO-d6) d II.74 to 12.77 (s broad, 1H), 8.10 to 8.16 (m, 2H).

Step 2: Preparation of the title compound 4-amino-2-chloro-6-fluorophenol This compound was prepared from 2-chloro-6-fluoro-4-nitrophenol (1.3 g, 6.79 mmol) · in the manner described for 4-amino-3-fluorofenol, yielding 0.34 g (40%) of 4-amino-2-chloro-6-fluorophenol. 1H-NMR (DMSO-d6) d 4.99 (s, 2H), 6.29-6. 36 (m, 2H), 8.85 (s, 1H).

Method B-4a Preparation of 4-amino-3,5-difluorophenol Step 1: Preparation of 5-Benzyloxy-l, 3-difluoro-2-nitrobenzene A mixture of 1,3,5-trifluoro-2-nitrobenzene (6.1 g, 34 mmol), benzyl alcohol (3.7 g, 34 mmol) and potassium carbonate (7.1 g, 52 mmol) in DMF (10 mL) was stirred overnight at room temperature. Water (30 ml) was added to the reaction mixture, and the reaction was refrigerated overnight. The resulting yellow precipitate was filtered, washed with water, and dried under reduced pressure to provide 6.5 g (71%) of a 1: 1 mixture of 5-benzyloxy-1,3-difluoro-2-nitrobenzene and 1-benzyloxy. -3,5-difluoro-2-nitrobenzene. The mixture was used directly for the next step without further purification. 1H-NMR (CD2C12) d 7.46 to 7.36 (m, 5H), 6.75 to 6.60 (m, 2H), 5.19 (s, 1H), 5.11 (s, 1H); TLC (10% EtOñc / Hex),. Rf = 0.48.

Step 2: Preparation of the title compound 4-amino-3,5-difluorophenol A solution of a 1: 1 mixture of 5-benzyloxy-1,3-difluoro-2-nitrobenzene and i-benzyloxy-3, 5-difluoro- 2-nitrobenzene (6.4 g, 24 mmol) from step 1 in methanol (250 ml) was added to a flask containing palladium on carbon (10 wt.%, 720 mg) under a nitrogen atmosphere. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to provide 3.4 g (97%) of a 1: 1 mixture of 4-amino-3,5-di-fluorophenol and 2- amino-3 5-difluorophenol. The mixture was used directly for the next step without further purification. "" -H-NMR (DMSO-d6) d 9.50 (br s, 1H), 6.54 to 6.22 (m, 2H), 4.36 (s, 2H); MS GC-MS (M + = 146.1), RT = 0.87 min.

Method B-4b Preparation of 4-amino-2, 5-difluorophenol This compound was prepared from 1,2,4-trifluoro-5-nitrobenzene (5.0 g, 28 mmol) in the manner described for 4-amino-3,5-difluorophenol, providing 3.0 g (72.3%) of 4- amino-2, 5-difluorophenol. 1 H-NMR (DMSO-d 6) d 9.04 (s, 1 H), 6.67 to 6.46 (m, 2 H), 4.64 (s, 2 H); MS GC- S M + = 146.1, RT = 1.04 min.

Method B-4c Preparation of 4-amino-2,3-difluorophenol This compound was prepared from 1,2,3-trifluoro-4-nitrobenzene (5.0 g, 28 mmol) in the manner described for 4-amino-3,5-difluorophenol, yielding 0.60 g (84%) of 4- amino-2, 3-difluorophenol. ^ - MR (DMSO-d6) d 9.19 (s, 1H), 6.59 to 6.53 (m, 1H), 6.48 to 6.41 (m, 1H), 4.85 (s, 2H); TLC (12% DCM / Hex), Rf = 0.08.

Method B-5 Preparation of 2-amino-5-hydroxybenzamide Step 1: Preparation of 5-Benzyloxy-2-nitrobenzoni trilo A mixture of 5-fluoro-2-nitrobenzonitrile (15 g, 90 mmol), benzyl alcohol (10.8 g, 100 mmol) and potassium carbonate (18.7 g, 135 mmol) in DMF (20 mL) was stirred at room temperature for 60h Water (60 ml) was added to the reaction, and the resulting yellow precipitate was filtered off, washed with water, and dried under reduced pressure to provide 17.3 g (75.4%) of 5-ben zi 1 oxy-2. -nitrobenzonitrile. The compound was used directly for the next step without further purification. MS GC-MS + = 211, RT = 6. 15 min.

Step 2: Preparation of 5-benzyloxy-2-nitrobenzamide A solution of 5-ben zi 1 oxy-2-nitrobenxonityl (4.5 g, 18 mmol) in acetone (180 ml) and water (90 ml) was treated with sodium percarbonate (containing 25% H202, 28 g, 180 mmol ), and the mixture was stirred at room temperature for 48 h. The reaction mixture was poured into ethyl acetate (200ml) and water (100ml). the biphasic layers were separated, and the organic layer was washed with water (50 ml) and brine (50 ml), dried over a 2 SO 4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 2.7 g (56%) of 5-benzyloxy-2-nitrobenzamide as a white solid. MS GC-MSM = 211, RT = 6.15 min.

Step 3: Preparation of the title compound 2-amino-5-hydroxybenzamide This compound was prepared from 5-benzyloxy-2-nitrobenzamide (2.7 g, 56 mmol) in the manner described for 4-amino-3-fluorophenol, providing 1.5g (99%) of 2-amino-5-hydroxybenzamide. 1H-NMR (CDC13) 57.41 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 8.1, 1.6 Hz, 1H), 7.13 (d, J = 1, 6Hz, 1H), 3.93 (s) , 3H); MS GC-MS (M + = 211, RT = 6.15 min). -amino-2,4-dichlorophenol Iron powder (4.03 g, 72.1 mmol) was slowly added to a solution of 2-dichloro-5-nitophenol (3.00 g, 14.4 mmol) in acetic acid (100 mL). After stirring at room temperature overnight, the reaction mixture became milky with the formation of a white precipitate. The precipitate was removed by filtration and the filtrate was concentrated to approximately 20 mL. The residue was diluted with water (100 mL) and neutralized by the slow addition of sodium bicarbonate. The mixture was then extracted with methylene chloride (3x150 mL). The organic layer was combined, dried over sodium sulfate, filtered and concentrated to dryness to yield 5-amino-2,4-dichlorophenol (2.20 g, 86%) as a brown solid. 1 H-NMR (DMSO-d 6) d 9.91 (s, 1 H), 7.10 (s, 1 H), 6.42 (s, 1 H), 5.34 (s, 2 H); MS LC-MS (M + H) + = 178.2, RT = 2.10 min.

Method B-7 Preparation of 4-amino-3- (methylsul anyl) phenol Step 1: Preparation of 3- (Methylsulfanyl) -4-nitrool To a solution of 3-fluoro-4-t-norphenol (3.0 g, 19.1 mmol) in anhydrous DMF (100 mL) was added dropwise thiomet sodium oxide (2.57 mL, 38.2 mmol, 2.0 eq) followed by sodium carbonate. potassium (7.92 g, 57.3 mmol, 3.0 eq), and the reaction mixture was stirred at RT for 18 h. Water was then added to inactivate the solution, and the reaction mixture was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. Purification of the crude using MPLC (biotage) eluted with 20% EtOAc-hexanes yielded 3.25 g (91.9%) of 3- (emt-sulfosyl) -4-n-trinenol as a yellow solid. 1H-NMR (DMS0-d6) d 11.13 (s, 1H), 8.18 (d, J = 9.0 Hz, 1H), 6.6.79 (d, J = 2.7 Hz, 1H), 6.71 (dd, J = 9.0, 2.4 Hz, 1H), 2.43 (s, 3H).

Step 2: Preparation of the title compound 4-amino-3- (methylsulfanyl) phenol This compound was prepared from 3- (methylsulfanyl) -4-nitrophenol (3.2 g, 17.3 mmol) in the manner described for. 4-amino-3-fluorophenol, yielding 2.18 g (81.3%) of the title compound. 1 H-NMR (DMSO-d 6) d 8.56 (s, 1 H), 6.60 (d, J = 2.7 Hz, 1 H), 6.53 (d, J = 8.7 Hz, 1 H), 6.43 (dd, J = 8.7, 2.4 Hz , 1H), 2.28 (s, 3H).

General Methods C and D: Preparations of the Arylamines of the Formula (II) The compounds of the formula (II) can be prepared as described in one or more of the following Examples: Method C-the Preparation of 4- (4-aminophexyl) pyridine-2-carboxylic acid methylamide Step 1: Preparation of 4-chloropyridin-2-carbonyl chloride hydrochloride Anhydrous DMF (6.0 mL) was added slowly to S0C12 (180 mL) between 40 ° C and 50 ° C. The solution was stirred at that temperature variation for 10 rain. , then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 ° C for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to RT, diluted with toluene (500 mL) and concentrated to half its volume. The resulting residue was filtered and the solids were washed with toluene and dried under high vacuum for 4h to yield 4-chloropyridine-2-carbonyl chloride salt HC1 as a yellow solid (92.0 g, 89%).

Step 2: Preparation of 4-clo or iridin-2-carboxylic acid methylamide A salt suspension of methyl 4-chloro-pyridine-2-carboxylate HC1 (89.0 g, 428 mmol) in MeOH (75 mL) at 0 ° C was treated with a solution of 2.0 M methylamine in THF (1 L). The resulting mixture was stored at 3 ° C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1L) and filtered. The filtrate was washed with a saturated solution of NaCl (500mL), dried over Na2SO4, and concentrated under reduced pressure to yield-gold-N-methyl-1-2-pyridinecarboxamide as pale yellow crystals (71.2g, 97%). . "" "H-NMR (DMSO-d6) d 2.81 (s, 3H), 7.74 (dd, J = 5.1, 2.2 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); Cl-MS m / z 171 (MH +); p.f. 41-43 ° C.

Step 3: Preparation of the title compound 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 mL) was treated with tetrahydrofuran. potassium butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at RT for 2 h. The contents were treated with 4-chloropi-ridin-2-carboxylic acid methylamide (15.0 g, 87.9 mmol) and K2C03 (6.50 g, 47.0 mmol) and then heated at 80 ° C for 8 h. The mixture was cooled to RT and partitioned between EtOAc (500 mL) and a solution saturated with NaCl (500 mL). The aqueous phase was extracted again with EtOAc (300 mL). The combined organic layers were washed with brine, dried over Na 2 SO, and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 ° C for 3 h to yield the title compound (17.9 g, 84%) as a light brown solid. 1H-NMR (DMSO-d6) d 2.77 (d, J = 4.8 Hz, 3H), 5.17 (brs, 2H), 6.64, 6.86 (AA'BB 'quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m / z 244 (MH ÷).

Method C-lb Preparation of 4- (3-aminophenoxy) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, substituting 3-aminophenol for 4-aminophenol. 1 H-NMR (DMSO-d 6) d 8.75 (br q, J = 4.8 Hz, 1 H), 8.48 (d, J = 6.3 Hz, 1 H), 7.39 (d, J = 2.1 Hz, 1 H), 7.15 to 7.07 (m, 2H), 5.51 to 6.47 (m, 1H), 6.31 to 6.24 (m, 2H), 5.40 (s, 2H), 2.77 (d, J = 5.1 Hz, 3H).

Method C-lc Preparation of 4- (-amino-3-fluoro-phenoxy) pyridine-2-carboxylic acid melamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-aminophenol for -amino-3-fluorophenol. 1H-NMR (D SO-d6) d 8.74 (br q, J = 7.0 Hz, 1H), 8.43 (d, J = 4.5 Hz, 1H), 7.32, (d, J = 2.1 Hz, 1H), 7.07 ( dd, J = 4.2, 2.1 Hz, 1H), 6.99 (dd, J = 8.7, 1.8 Hz, 1H), 6.82 (t, J = 6.6 Hz, 1H), 6.76 (dd, J = 6.6, 2.1 Hz, 1H ), 5.23 (s, 2H), 2.77 (d, J = 3.6 Hz, 3H).

Method C-ld Preparation of 4- [4-amino-3- (trifluororneti 1) phenoxy] pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-anainophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-aminophenol for 4-amino-3-trifluoromethylphenol. 1H-NMR (DMSO-d6) 58.75 (br q, J = 6.9 Hz, 1H), 8.44 (d, J = 4.2Hz, 1H), 7.31 (d, J = 2. 1 Hz, 1H), 7.19 a 7.16 (m, 2H), 7.06 (dd, J = 4.2, 1.8 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 5.73 (s, 2H), 2.77 (d, J = 3.6 Hz, 3H ).

Method C-le Preparation of 4- (4-amino-3-methylphenoxy) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) and ridin-2-carboxylic acid methylamide, substituting 4-aminophenol for 4-amino-3-methyl-1-enol. 1H-NMR (acetone-de) d 8.39 (d, J = 5.7 Hz, 1H), 8.29 (brs, 1H), 7.51 (dd, J = 2.7, 0.6 Hz, 1H), 6.98 (dd, J = 5.7, 2.4 Hz, 1H), 6.82 (br s, 1H), 6.77 to 6.76 (m, 2H), 4.56 (br s, 2H), 2.92 (d, J = 5.1 Hz, 3H), 2.16 (d, J = 1.0 Hz, 3H).

Method C-lf Preparation of 4 - (4-amino-2-methyl-phenoxy) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminofenoxi) pyridine-2-carboxylic acid methylamide, substituting 4-aminophenol for 4-amino-2-methylphenol. XH-NMR (DMSO-d6) 5 8.73 (br q, J = 4.8 Hz, 1H), 8.43 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 5.7, 2.7 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 6.52 (d, J = 3 Hz, 1H), 6.47 (dd, J = 8.7, 2.7 Hz, 1H), 5.09 ( s, 2H), 2.78 (d, J = 3.3 Hz, 3H), 1.91 (s, 3H).

Method C-lq Preparation of 4- (4-amino-3-nor rofenoxi) pi idin- -carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) iridin-2-carboxylic acid methylamide, substituting 4-aminophenol for 4-amino-3-nitrophenol. 1H-NMR (acetone- of) 58.46 (d, J = 5.7 Hz, 1H), 8.31 (br s, 1H), 7.96 (br s, 2H), 7.88 (d, J = 2.7 Hz, 1H), 7.56 ( dd, J = 2.7, 1.0 Hz, 1H), 7.35 (d, J = 2.7 Hz, 1H), 717 (brs, 1H), 7.10 (dd, J = 5.4, 2.7 Hz, 1H), 2.78 (d, J = 3.6 Hz, 3H).

Method C-lh Preparation of 4- (4-amino-2-fluorophenoxy) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner described for 4-aminophenoxy) iridin-2-carboxylic acid methylamide, substituting 4-aminophenol for 4-amino-2-fluorofenol. XH-NMR (D SO-d6) 6 8.75 (br q, J = 3.6 Hz, 1H), 8.46 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.11 [dd , J = 4.2, 2.1 Hz, 1H), 6.99 (t, J = 6.6 Hz, 1H), 6.50 (dd, J = 9.9, 2.1 Hz, 1H), 6.43 to 6.40 (m, 1H), 5.51 (s, 2H), 2.77 (d, J = 3.6 Hz, 3H).

C-li Method Preparation of 4- (3-amino-4-chlorofinoxy) p din-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-aminophenol for 3-amino-chlorophenol. 1 H-NMR (DMSO-d 6): d 8.76 (m, 1 H), 8.47 (d, 1 H), 7.39 (s, 1 H), 7.24 (d, 1 H), 7.15 (dd, 1 H), 6.67 (s, 1 H) ), 6.35 (dd, 1H), 5.65 (s, 2H), 2.78 (d, 3H); LC MS m / z 278.1 (MH) +, RT = 2.36 min.

Method C-lj Preparation of 4 - (3-amino-2-fluorophenoxy) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-aminophenol for 5-amino-2-fluorophenol. 1 H-NMR (DMSO-d 6): d 8.77 (br d, J = 3.3 Hz, 1 H), 8.49 (d, J = 4.5 Hz, 1 H), 7.35 (d, J = 1.8 Hz, 1 H), 7.17 (dd) , J = 4.2, 1.8 Hz, 1H), 7.08 (dd, J = 8.1, 6.6 Hz, 1H), 6.49 to 6.42 (m, 2H), 5.27 (s, 2H), 2.77 (d, J = 3.0 Hz, 3H).

Method C-lk Preparation of 4- (3-amino-4-fluoro-phenoxy) -pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-aminophenol for 3 -amin o- -f1-uoro-phenol. 1H-NMR (DMSO-d 6) d 8.75 (br d, J = 3.9 Hz, 1H), 8.46 (d, -J = 4.5 Hz, 1H), 7.35 (d, J = 1.8Hz, 1H), 7.11 ( dd, J = 4.2, 2.1 Hz, 1H), 7.06 (dd, J = 8.4, 6.3 Hz, 1H), 6.50 (dd, J = 5.7, 2.4 Hz, 1H), 6.30 to 6.26 (m, 1H), 5.46 (s, 2H), 2.77 (d, J = 3.6 Hz, 3H).

Method C-ll Preparation of 4 - (-amino-2,5-difluorophenoxy) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-aminophenol for 4-amino-2, 5-difluorofenol. 1H-NMR (CDC13) 58.34 (d, J = 5.7 Hz, 1H), 8.0 (s, 1H), 7.61 (d, J = 2.6 Hz, 1H), 6.93 (dd, J = 5.3, 2.5 Hz, 1H), 6.82 (dd, J = 10.3, 7.0 Hz, 1H), 6.60 (dd, J = 11.2, 8.4 Hz, 1H), 3.95 (s, 2H), 2.96 (d, J = 5.1 Hz, 3H); MS GC-MS (M + = 280.1, RT = 2.32 min).

Method C-lm Preparation of 4- (4-amino-3,5-difluorophenoxy) pyridin-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pi r idin-2-carboxylic acid methylamide, substituting 4-aminophenol for 4-amino-3,5-difluorofenol. 1 H-NMR (DMSO ~ d5) 5 8.35 (d, J = 5.7 Hz, 1H), 8.0 (s, 1H), 7.63 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 5.7, 2.7 Hz , 1H), 7.30 (dd, J = 7.3, 1.7 Hz, 2H), 3.75 (s, 2H), 2.97 (d, J = 5.3 Hz, 3H); S GC-MS (M + = 280.1, RT = 2.27 min).

Method C-ln Preparation of 4- (4-amino-2,3-difluorofinoxy) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-aminophenol for 4-amino-2,3-difluorophenol. 1H-NMR (D SO-d6) d 8.81-8.75 (m, 1H), 8.50 (d, J = 6.0 Hz, 1H), 7.37 (d, J = 3.0 Hz, 1H), 7.17 (dd, J = 3.0 , 6.0 Hz, 1H), 6.94 (ddd, J = 2.0, 6.0, 9.0 Hz, 1H), 6.64 (ddd, J = 2.0, 6.0, 9.0 Hz, 1H), 5.62 (s, 2H), 2.77 (d, J = 5 Hz, 3H); TLC (35% EtOAc / Hex), Rf = 0.36.

C-Lo method Preparation of 4- (5-aminoquinolin-3-yloxy) -pyridin-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pi-ridin-2-carboxylic acid methylamide, substituting 5-amino-8-quinol-ino-1 for 4-aminophenol. 1 H-NMR (DMSO-d 6) 58.72 to 8.66 (m, 2H), 8.60 (dd, J = 8.7, 1.8 Hz, 1H), 8.40 (d, J = 5.7 Hz, 1H), 7.42 (dd, J = 8.7 , 4.2 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 2.7 Hz, 1H), 7.04 (dd, J = 5.4, 2.7 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.13 (s, 2H), 2.73 (d, J = 5.1 Hz, 3H); MS LC-MS (M + H) + = 295.2; TLC (5% MeOH / DCM), Rf = 0.31.

Method C-lp Preparation of 4- (4-amino-2-methoxyphenoxy) pyridine-2-carbonitrile The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pi-ridin-2-carboxylic acid methylamide, substituting 4-aminophenol for -amino-2-methoxyphenol, and 4-methylamide. chloropyridine-2-carboxylic acid by 4-chloro-2-cyanopyridine. 1H-NMR (DMSO-d6) 58.50 (d, J = 6.0 Hz, 1H), 7.49 (d, J = 2.7 Hz, 1H), 7.00 (dd, J = 5.7, 2.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.16 (dd, J = 8.7, 2.7 Hz, 1H), 5.25 (s, 2H), 3.62 (s, 3H); MS LCTMS (M + H) + = 242.1.

Method C-lq Preparation of 4- (4-amino-3, 5-difluoro-phenoxy) pyridine-2-carbon trilel The title compound was prepared in the same manner as described for - (- amino-2-methoxyphenoxy) pyridine-2-carbonitrile, substituting 4-aminophenol for 4-amino-3,5-difluorophenol. "" "H-NMR (DM30) d 8.51 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 7.00 (dd, J = 5.7 Hz, J = 2.4 Hz, 1H) , 6.64 (dd, J = 6.7 Hz, J = 1.2 Hz, 2H), 3.57 (s, 2H), MS GC-MS (M + = 248.6, RT = 2.51 min).

Preparation of 4- (4-amino-2, 5-difluoro-phenoxy) -pi idin-2-carbonyl trile The title compound was prepared in the same manner as described for 4- (4-amino-2-methoxyphenoxy) iridin-2-carbonitrile, substituting 4-amino-3,5-difluorophenol for 4-amino-2,5-dif-luorophenol . ^! - MR (DMSO-d6) 58.56 (d, J = 5.9 Hz, 1H), 7.72 (d, J = 2.6 Hz, 1H), 7.26-7.17 (m, 2H), 6.72 (dd, J = 8.4 Hz , J = 12.5 Hz, 1H), 5.56 (s, 2H) MS GC-MS (M + = 248.2, RT = 2.98 min).

Method C-ls Preparation of 2-amino-5- (2-cyanopyridin-4-yloxy) benzamide The title compound was prepared in the same manner described for 4- (4-amino-2-methoxyphenoxy) pyridine-2-carbonitrile, substituting 4-amino-3,5-di-fluorophenol for 2-amino-5-hydroxybenzamide. 1H-NMR (CDC13) 57.41 (d, J = 8.1 Hz, 1H) 7.16 (dd, J = 8.1, 1.6 Hz, 1H), 7.13 (d, J = 1.6 Hz 1H), 3.93 (s, 3H); MS GC-MS (M + = 211, RT = 6.15 min) Method C-lt Preparation of 4- (4-amino-3-chloro-f-noxy) pyridine-2-carboxamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pi-ridin-2-carboxylic acid methylamide, substituting 4-aminophenol for 4-amino-3-chlorophenol, and substituting methyl 4-methylamide. -chloropyridine-2-carboxylic acid by 4-chloro-2-pyridinecarboxamide. 1 H-NMR (DMSO-d 6) 58.45 (d, J = 5.4 Hz, 1 H), 8.08 (s, 1 H), 7.67 (s, 1 H), 7.32 (d, J = 2.7 Hz, 1 H), 7.15 (d, J = 2.7 Hz, 1H), 7.09 (dd, J = 2.7, 5.4 Hz, 1H), 6.93 to 6.84 (m, 2H), 5.44 (s, 2H); MS LC-MS (M + H) + = 264.1, RT = 2.40 min.

Method C-lu Preparation of 4 - (4-amino-3-flurofenoxi) piridin-2 -carboxamide The title compound was prepared in the same manner as described for 4 - (-amino-3-chlorophenoxy) pyridine-2-carboxamide, substituting 4-amino-3-chlorophenol for -amino-3-fluorophenol. 1 H-NMR (DMSO-d 6) d 8.44 (d, J = 5.4 Hz, 1 H), 8.09 (s, 1 H), 7.68 (s, 1 H), 7.34 (d, J = 2.4 Hz, 1 H), 7.10 (dd) , J = 12.9 2. 7, 5.7 Hz, 1H), 7.01 (dd, J = 2.4, 11.7 Hz, 1H), 6.86 to 6.77 (m, 2H), 5.21 (s, 2H).

Method C-lv Preparation of 4- (4-amino-2-chlorophenoxy) iridin-2-carboxamide The title compound was prepared in the same manner as described for 4- (4-amino-3-chlorophenoxy) pyridine-2-carboxamide, substituting 4-amino-3-chlorophenol for 4-amino-2-chlorophenol. 1H-NMR (DMS0-d6) 58.46 (d, J = 5.7 Hz, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.25 (d, J = 2.7 Hz, 1H), 7.08 (dd, J = 2.7, 5.7 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.59 (dd, J = 2.7, 8 · .7 Hz, 1H) 5.50 (s, 2H); S LC-MS (MH) + = 264.1, RT = 1.76 min.

Method C-lw Preparation of 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxamide The title compound was prepared in the same manner as described for 4- (4-amino-3-chloro-phenoxy) iridin-2-carboxamide, substituting 4-amino-3-chlorophenol for -aminophenol. 1H-NMR (D SO-d6) d 8.43 (d, J = 5.7 Hz, 1H), 8.07 (broad s, 1H), 7.66 '(broad s, 1H),' 7.31 (d, J = 2.7 Hz, 1H ), 7.07 (dd, J = 5.7 Hz, 2.7 Hz, 1H), 6.85 (d, J = 9.0 Hz, 2 H), 6.62 (d, J = 8.7 Hz, 2H), 5.17 (broad s, 2H).

Method C-2a Preparation of 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxylic acid methylamide To a stirred solution of?,? '-dimethylamide (6 ml) of 2-chloro-4-aminophenol (0.5 g, 3.48 mmol) was slowly added potassium tert-butoxide (0.39 g, 3.48 mmol). After stirring for approximately 25 min., A solution of? '- N-dimethylamide (4 mL) of 4-chloropicolinomethylamide (0.46 g, 2.67 mmol) was added, and the contents were stirred with heating at 100 ° C for 16 minutes. h. The contents were allowed to cool to room temperature with stirring, and quenched with H2O (5 mL). The contents were extracted with EtOAc, the combined organic layers were dried over MgSC, filtered, and concentrated in vacuo. The crude residue was subjected to chromatography (60% 40% EtOAc / Hex gradients) to provide the final product as a dark yellow oil (0.25 g, 34%). XH-NMR (MeOH-d4): d 8.82 (d, 1H), 7.85 (s, 1H), 7.34 (d, 1H), 7.32 (s, 1H) r 7.20 (sf 1H), 7.05 (dd, 1H) 3.43 (s, 3H); MS LC-MS [M + H] + = 278.2, RT = 1.93 min.

Method C-2b Preparation of 4- (3-amino-2,4-difluorophenoxy) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner described for 4- (4-amylo- or 2-o-enoxyl) pyridine-2-carboxylic acid methylamide, substituting 4-amino-Z-chlorophenol for 5-amino-2 , 4 difluorophenol. 1H-NMR (DMSO-d6) d 8.82 to 8.83 (m, 1H) 8.49 (d, J = 5.3 Hz, 1H), 7.29 to 7.39 (m, 2H), 7.14 7.19 (m, 1H), 6.68 (t, J = 8.5 Hz, 1H), 5.32 (s, 2H), 2.78 (d, J = 4.7 Hz, 3H).

Method C-2c Preparation of 4 - (3-amino-2,4-dichlorophenoxy) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-amino-2-chlorophenol for 3-araino-2,4-dichlorophenol . 1H-NMR (D SO-ds) d 8.80 (q, J = 4.8 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.55 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.17 (m, 1H), 6.71 (s, 1H), 5.83 (s, 2H), 2.79 (d, J = 5.0, 3H). MS LC-MS [M + H] + = 312.0, RT = 3.17 min.

Method C-2d Preparation of 4 - (- amino - 3 - chlorophenoxy) pyridine - 2 - carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxylic acid methylamide, substituting -amino-2-chlorophenol for 4-amino-3-chlorophenol. 1H-NMR (DMSO-d6) d 8.76 (m, 1H), 8.47 (d, 1H), 7.35 (s, 1H), 7.15 (s, 1H), 7.06 (dd, 1H), 6.85 to 6.95 (m, 2H), 5.43 (s, 2H), 2.78 (d, 3H); MS LC-S [M + H] + = 278.1 [M + H] +, RT = 2.19 min.

Method C-2e Preparation of 4- [-amino-3 - (m-sulfañyl) phenoxy] pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-araino-3-methyl-sulfanylphenol for 4-amino-2-chlorophenol. . 1H-NMR (DMS0-d6) d 8.75 (broad q, J = 4.8 Hz, 1H), 8.45 (d, J = 5.7 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 5.7, 2.7 Hz, 1H), 6.99 (d, J = 2.7 Hz, 1H), 6.84 to 6.75 (m, 2H), 5.43 (s, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.35 (s, 3H).

Method C-3a Preparation of mebiláster of 4- (4-aminophenoxy) pyridine-2-carboxylic acid A mixture of 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide (15.0 g, 61.7 mmol) and potassium hydroxide (34.6 g, 617 mmol) in ethanol (400 mL) and water (40 inL) was stirred at 90 ° C for 48h. After cooling to R, 2.0 N hydrochloric acid was added slowly to the reaction mixture until pH = 5. The solvent was completely removed and the residue redissolved in MeOH (400 mL). After the slow addition of trimethylsilyl chloride (178 mL, 140 mmol, 2.27 eq) at 0 ° C, the reaction mixture was stirred under reflux for 24 h and cooled to R. The mixture was filtered, and the filtrate was concentrated under reduced pressure and then partitioned between DCM and water. The organic layer was then washed with aqueous 1M sodium bicarbonate solution, dried over Na2SC >4 was filtered, and evaporated under reduced pressure. The resulting residue was further washed with H2O and EtOAc / Hex and reextracted (1: 2 v / v) to yield the desired ester (6.27 g, 42%) as a light brown solid. 1H-NMR (DMSO-d6) 88.51 (d, J = 5.7 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 5.7, 2.7 Hz, 1H), 6.86 (dt, J = 9.0, 2.4 Hz, 2H), 6.63 (dt, J = 8.7, 2.4 Hz, 2H), 5.18 (br s, 2H), 3.86 (s, 3H); MS LC-MS [M + H] + = 245, RT = 1.04 rain; TLC (75% EtOAc / hex), Rf = 0.20.

Method C-3b Preparation of methyl ester of 4 - (3-aminophenoxy) pyridine-2-carboxylic acid The title compound was prepared in the same manner as described for 4- (3-aminophenoxy) pi-ridin-2-carboxylic acid methyl ester, substituting 4 - (4-aminophenoxy) pyridine-2-carboxylic acid methylamide for methylamide of 4- (3-aminophenoxy) pyridine-2-carboxylic acid. 1H-NR (CD3OD) 8. 49 (d, 1H), 7.20 (d, 1H), 7.14 (dd, 1H), 6.64 (dd, 1H), 6.45 (t, 1?), 6.40 (dd, 1H), 3.92 (s, 3H); MS LC-MS [+ H] + = 245.1 (MH +), RT = 0.52 min.

Method C-4 - Preparation of 1 - [4 - (4-Aminophenoxy) pyridin-2-yl ethanone Step 1: Preparation of -clo or -W-methoxy-N-methyl iridin-2 -carboxamide To a mixture of dimethyl-hydroxylamine HC1 (510 mg, 5.18 mmol) and triethylamine (2.16 mL, 15.5 rtimol) in anhydrous THF (9.41 mL) and acetonitrile (2.35 mL) was added chloropyridine-2-carbonyl chloride hydrochloride (1.00 mmol). g, 4.71 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 h then at RT for 16 h. The solvent was removed under reduced pressure and partitioned between EtOAc and water. The organic layer was washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC (biotage) eluted with 30% EtOAc / Hex to yield 925 mg (98%) of 4-chloro-N-methoxy-N-methylpyridine-2-carboxamide as an orange oil: TLC (50%). % EtOAc / Hex), Rf = 0.31.

Step 2: Preparation of 1- (4-chloropidirin-2-yl) ethanone) To a solution at 0 ° C of 1.4 M methyl magnesium bromide in toluene / THF (6.89 mL, 9.65 mmol) in anhydrous THF (8.77 mL) was added a solution of 4-chloro-1-methoxy-J \ -methylpyridin. -2-carboxamide (1.06 g, 5.26 mmol) in anhydrous THF (8.77 mL). The reaction mixture was stirred at RT under N2 for 17 h. The volatile solvent was removed under reduced pressure, and partitioned between EtOAc and water. The organic layer was washed with H2O, brine, dried over a2SO4, and concentrated under reduced pressure. The crude product was purified by MPLC (biotage) eluted with 10% EtOAc / Hex to yield 652 mg of 1- (4-chloropyridin-2-yl) ethanone (95.5%) as a white crystalline solid. XH-NMR (Acetone-d6) d 8.69 (d, J = 5.4 Hz, 1H), 7.95 (dd, J = 2.1, 1.0 Hz, 1H), 7.71 (dd, J = 5.4, 2.1 Hz, 1H), 2.65 (s, 3H); TLC (10% EtOAc / Hex), Rf = 0.26.

Step 3: Preparation of 1- [4- (4-aminophenoxy) pyridin-2-yl] ethanone The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, substituting 4-chloropyridine-2-carboxylic acid methylamide for 1- (4-chloropyridin-2-yl) ethanone. 1 H-NMR (Acetone-d 6) d 8.53 (d, J = 5.4 Hz, 1 H), 7.36 (d, J = 2.7 Hz, 1 H), 7.08 (dd, J = 5.4, 2.4 Hz, 1 H), 6.88 (d , J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 4.77 (br s, 2H), 2.59 (s, 3H); LC MS m / z 229 (M + H) +, RT = 1.11 min; TLC (50% EtOAc / Hex), Rf = 0.30.

Method C-5a Preparation of methylcarbamoylmethylamide of 4- (-aminophenoxy) pyridine-2-carboxylic acid Step 1: Preparation of 4-chloropyridin-2-carboxylic acid methylcarbamoylmethylamide To a solution of 4-chloropyridine-2-carbonyl chloride HC1 (2.00 g, 9.41 ramol) in THF (16.4 ml) and acetonitrile (9.4 ml) was added 2-amino-N-methylacetamide hydrochloride (1.29 g, 10.35 mmol). , 1.1 eq) and triethyl amine (5.25 mL, 37.6 mmol, 4.0 eq) at 0 ° C. The resulting dark brown reaction mixture was stirred at RT for 2 h. The volatile solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product was purified in MPLC (biotage) eluted with 100% EtOAc to provide 1.4 g (65.3%) of 4-cl oropyridine-2-carboxylic acid methylcarbamoyl-IV-methylamide as a tan solid: TLC ( 75% EtOAc / hex), Rf = 0.14; MS LC-MS [M + H] + = 228.

Step 2: Preparation of the title compound methylcarbamoylmethylamide of 4- (4-aminophenoxy) pyridine-2-carboxylic acid The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) -pyridine-2-carboxamide, substituting 4-chloro-JNI-methyl-pyridine-2-carboxamide for N-met ilcarbamoylmet-ilamide -chloropi idin-2-carboxylic acid. 1 H-NMR (DMSO-d 6) 58.86 (t, J = 5.7 Hz, 1 H), 8.48 (d, J = 5.4 Hz, 1 H), 7.83 (br d, 1 H), 7.32 (d, J = 2.7 Hz, 1 H ), 7.10 (q, J = 5.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 5.18 (s, 2H), 3.83 (d, J) = 5.7 Hz, 2H), 2.57 (d, J = 4.5 Hz, 3H); S LC-MS [M + H] + = 301; TLC (100% EtOAc), Rf = 0.10.

Method C-5b Preparation of 4- (-aminophenoxy) iridin-2-carboxylic acid dimethylcarbamoylmethylamide The title compound was prepared in the same manner as described for 4- (-aminophenoxy) pyridine-2-carboxylic acid methylcarbamoylmethylamide, substituting 2-amino-N, Nr -dimethylacetacytide hydrochloride for 2-amino-N-methylacetamide hydrochloride. . ^ -NMR (DMSO-d6) d 8.75 (t, J = 4.8 Hz, 1H), 8.49 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 2.7 Hz, 1H), 7.32 (d, J = 2.7 'Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 4.11 (d, J = 5.4 Hz, 2H), 2.96 (s, 3H), 2.85 (s, 3H); MS LC-MS [M + H] + = 315.

Method C-5c Preparation of 4- (4-amino-3-fluorfenoxy) pyridine-2-carboxylic acid (2-methoxyethyl) amide The title compound was prepared in the same manner as described for 4- (4-amino phenoxy) pi idin-2-carboxylic acid methylcarbamoylmethylamide, substituting 2-methoxyethylamine for 2-amino-N-methylacetamide hydrochloride. 1 H-NMR (DMSO-d 6) d 8.66 (br s, 1 H), 8.45 (d, J = 4.2 Hz, 1 H), 7.32 (d, J = 1.8 Hz, 1 H), 7.09 (dd, J = 4.2, 1.8 Hz, 1H), 6.99 (dd, J = 9.0, 2.1 Hz, 1H), 6. 83 (t, J = 6.6 Hz, 1H), 676 (dd, J = 6.6, 1.8 Hz, 1H), 5.22 (s) , 2H), 3.44 to 3.41 (m, 4H), 3.23 (s, 3H) MS LC-MS [M + H] + = 306.

Method D-the Preparation of 5- (4-amino-3-fluorophenoxy) -N-methylnicotinamide Step 1: Preparation of methyl ester of 5 - (4-nitro-3-fluoro-noxyl) icotinic acid ? a cooled solution in an ice bath of methyl ester of 5-hydroxynicotonic acid (5.00 g, 32.65 mmol) in DMF (20 mL) was added sodium hydride (0.78 g, 32.65 mmol). The reaction mixture was stirred at room temperature for 2 hours, and 2,3-difluoro-t-norni-benzene (5.12 g, 29.68 mmol) was added, and the reaction mixture was stirred at room temperature. After 3 hours the solvent was removed under reduced pressure, and the residue was partitioned between EtOAC (300 mL) and H20 (150 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers were dried over Na2SO4, filtered, and the filtrate was removed under reduced pressure. The crude product was purified by column chromatography eluted with 50 to 75% EtOAc / Hex to provide 2.4 g (28%) of 5- (-not- t-o-3-f-luor-of-enoxy) methyl ester or cotinic acid. "" "H-NMR (CD3OD) 6 9.05 (d, J = 1.8 Hz, 1H), 8.70 (d, J = 2.7 Hz, 1H), 8.31 (dd, J = 2.4, 10.5 Hz, 1H), 8.15- 8.14 (m, 1H), 9.06 (dd, J = 1.5, 2.1 Hz, 1H), 7.40 (dd, J = 8.1, 9.0 Hz, 1H), 3.97 (s, 3H), MS LC-MS [+ H] + = 293.1; RT = 3.15 min.

Step 2: Preparation of 5- (4-amino-3-fluorophenoxy) nicotinic acid methyl ester This compound was prepared in the same manner as described for 4-amino-3-phlorophenol, substituting 4-nitro-3-fluorophenol for methyl ester of 5- (4-nitro-3-p-fluorophenoxy) nicotinic acid. 1 H-NMR (CD3OD) 58.97 (d, J = 1.5 Hz, 1H), 8.71 (d, J = 3.0 Hz, 1H), 7.85 to 7.83 (m, 1H), 7.15 to 7.07 (m, 2H), 6.98 a 6.97 (m, 1H), 4.06 (s, 3H); MS LC-MS (MH) + = 263.2, RT = 2.50 min.

Step 3: Preparation of the title compound 5 - (4-amino-3-fluoro-phenoxy) -N-methylnicotinamide ? a solution of methyl ester of 5- (4-amino-3-fluorophenoxy) nicotinic acid (0.50 g, 1.91 mmol) in MeOH (2 mL) was added to the tin plate (0.63 g, 19.1 mmol, 2.0 M MeOH). The reaction flask was sealed and heated at 40 ° C for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography eluted with 5% MeOH / CH2Cl2 to provide 0.4 g (80%) of the title compound. 1 H-NMR (DMSO-d 5) 58.65 (d, J = 1.8 Hz, 1H), 8.62 to 8.60 (m, 1H), 7.54 to 7.52 (m, 1H), 6.94 (dd, J = 2.7, 12.0 Hz, 1H ), 6.81 to 6.67 (m, 3H), 5.10 (s, 2H), 2.72 (d, J = 2.4 Hz, 3H); MS LC-MS [M + H] + = 262.2, RT = 0.27 min.

Method D-lb Preparation of 5- (4-aminophenoxy) -N-me-ilnicotinamide Step 1: Preparation of 5 - (-aminophenoxy) nicotinic acid methyl ester The title compound was prepared in the same manner as described for 5- (4-amino-3-fluoro-phenoxy) nicotinic acid methyl ester, substituting 4-amino-enol for 4-amino-3-fluorofenol. 1 H NMR (DMSO-d 6) d 8.71 (s, 1 H), 8.54 (d, J = 2.9 Hz, 1 H), 7.47 (t, J = 1.9 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 2 H) , 6.61 (d, J = 8.7 Hz, 2H), 5.12 (br, 2H), 3.81 (s, 3H); MS LC-MS [M + H] + = 245.2, RT = 1.08 min.

Preparation of the title compound 5 - (4-Aminophenoxy) -jV-Methylnicotinamide The title compound was prepared in the same manner as described for 5- (4-amino-3-fluorofenoxi) -N-methynicotinamide, substituting methyl ester of the title compound. 5- (4-amino-3-fluorophenoxy) nicotinic acid by 5- (4-aminophenoxy) nicotinic acid methyl ester. ""? NMR (DMSO-d6) 58.65 (m, 2H), 8.40 (d, J = 2.7 Hz, 1H), 7.52 (t, J = 2.2 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.7 Hz, 2H), 5.01 (s, 2H), 2.75 (d, J = 4.4 Hz, 3H); MS LC-MS [M + H] + = 244.2, RT = 0.29 min.

Method D-lc Preparation of 5- (4-amino-2-luo-phenoxy) methyl-nicotinamide Step 1: Preparation of 5- (4-amino-2-fluoro-phenoxy) nicotic acid methyl ester The same described form was prepared for the methyl ester of 5- (4-amino-3-fluorophenoxy) nicotinic acid, substituting 4-amino-3-fluorophenol for 4-amino-2-fluorophenol. 1H NMR (DMSO-d6) d 7.96 (d, J = 1.5 hz, 1H), 7.64 (d, J = 3.0 Hz, 1H), 6.88 to 6.87 (m, 1H), 6.16 (t, J = 8.7 Hz, 1H), 5.79 to 5.69 (m, 2H), 4.07 (s, 2H), 3.09 (s, 3H); TLC (50% EtOAc / Hex), Rf = 0.31.

Step 2: Preparation of the title compound 5- (4-amino-2-fluoro-phenoxy) -N-s-ilnicotinamide The title compound was prepared in the same manner as described for 5- (4-amino-3-fluorophenoxy) -N- methylnicot inamide, substituting 5- (4-amino-3-fluorophenoxy) nicotinic acid methyl ester for 5- (4-amino-2-fluorophenoxy) -nicotinic acid methyl ester. HNR (DMSO-d6) d 7.80 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H), 6.83 to 6.81 (m, 1H), 6.15 (t, J = 8.7 Hz, 1H ), 5.78 to 5.67 (m, 2H), 4.07 (s, 3H), 2.07 (s, 3H).

Method D-2a Preparation of 4 - (4-aminophene imetyl) pyridine-2-carboxylic acid mebilamide Step 1: Preparation of 2-methylcarbamoyl-i-sonicotinic acid ethyl ester To a 3-necked flask loaded with isonicotinic acid ethyl ester (10 inL, 65.4 mmol) in anhydrous N-methylformamide (80.0 mL) at 2.5 ° C was added concentrated sulfuric acid (3.67 mL, 65.4 mmol, 1.0 eq) and sulfate of iron (II) heptahydrate (4.6 g, 16.4 mmol, 0.25 eq). Oxygenated water was added dropwise (11.1 mL, 98.1 mmol, 30% by weight the solution in water, 1.5 eq) to maintain the internal temperature below 25 ° C. The reaction mixture was stirred at 2.5 ° C for 10 min and at RT for 30 min. The reaction mixture was emptied into 1M aqueous sodium citrate solution (130 mL), and the resulting yellow-a-yellow suspension was quenched with 5% aqueous sodium bicarbonate solution (150 mL), adjusting the pH to 7. Dilometime (100 mL) was then added, and the organic phase was extracted, washed with water (2 x 100 mL) and brine (1 x 100 mL), dried over Na2SO, j, filtered, and filtered. evaporated under reduced pressure. The solid was stirred in ice water and filtered to yield 11.2 g (88.2%) of a yellow solid: TLC (50% EtOAc / Hex), Rf = 0.25.

Step 2: 4- (hydroxymethyl) -N-methylpyridin-2 -carboxamide ? a solution of ethyl ester of 2-methylcarbamoyl-isonicotinic acid (7.77 g, 37.3 mmol) in pure ethanol (125 mL) was added sodium borohydride (2.82 g, 74.6 mmol, 2.0 eq), and the reaction mixture was stirred at RT under argon for 18h. The solvent was evaporated under reduced pressure, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried over Na2SC, filtered, and concentrated under reduced pressure to provide 5.36 g (86.5%) of 4- (hydroxymethyl) - N-methylpyridin-2-carboxamide as a colorless solid: MS LC-MS [M + H] + = 153.

Step 3: Preparation of 4- (4-nitrophenoxymethyl) pyridine-2-carboxamide A solution of 4- (hydroxymethyl) -N-methylpyridine-2-carboxamide (117 mg, 0.70 mmol) in DCM (10 mL) was treated with triethylamine (0.11 mL, 0.77 mmol) and methanesulfonylchloride (0.74 mL, 0.70 mmol) . The reaction was stirred at 25 ° C for 3 h and then quenched with H20 (10 mL). The layers were separated, and the organic layer was concentrated under reduced pressure to yield crude benzyl chloride. To a solution of crude benzyl chloride in anhydrous DMF (10 mL) was added Cs2C03 (688 mg, 2.11 mmol) and 4-nitrophenol (0.979 mg, 0.70 mmol). The reaction mixture was heated at 60 ° C for 18 h and then partitioned between EtOAc (15 mL) and water (10 mL). The organic layer was extracted with H 2 O (4 X 150 mL), dried (Na 2 SO 4) and evaporated under reduced pressure to yield 150 mg (74%) of 4- (4-nitrophenoxymethyl) pyridine-2-carboxamide as a yellow oil. Clear. 1H-NMR (DMSO-d6) d 8.78 (br d, J = 3.6 Hz, 1H), 6.62 (d, J = 3.9 Hz, 1H), 8.21 (d, J = 7.2 Hz, 2H), 8.06 (s, 1H), 7.61 (dd, J = 3.9, 1.2 Hz, 1H), 7.23 (d, J = 6.9 Hz, 2H), 5.45 (s, 2H), 2.81 (d, J = 3.6 Hz, 3H); mp 172-174 ° C.

Step 4: Preparation of the title compound 4 - (4-aminophenoxymethyl) pyridine-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4-amino-3-fluorophenol, substituting 3-fluoro-4 -nitrophenol by 4- (4-nitrophenoxymethyl) iridin-2-carboxamide: MS LC-MS [M + H] + = 258.

Method D-2b Preparation of 4- (3-aminophenoxy-yl) pyridin-2-carboxylic acid methylamide The title compound was prepared in the same manner as described for 4- (4-aminophenoxymethyl) pyridine-2-carboxylic acid methylamide, substituting 4-nitrofenol for 3-nitrophenol. 1H-NMR (CD3OD) 58.40 (d, J = 4.5 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.13 (t, J = 6.3 Hz, 1H), 7.00 (dd, J = 4.2, 1.8 Hz, 1H), 6.62 to 6.59 (m, 1H), 6.43 (t, J = 1. 8Hz, 1H), 6.37 to 6.34 (m, 1H), 4.89 (s, 2H), 2.93, (s , 3H).

MetodD-2c Preparation of 4- (4-amino-3-fluorophenoxymethyl) pyridine-2-carboxamide The title compound was prepared in the same manner as described for 4- (4-amino-phenoxymethyl-1-pyridine-2-carboxylic acid methylamide, substituting 4-nitrophenol by 3-fluoro-4-nitrophenol. 1 H-NMR (DMSO- d 6) 68.77 (br q, J = 6.6 Hz, 1 H), 8.59 (d, J = 3.6 Hz, 1H), 8.02 (s, 1H), 7.56 (dd, J = 4.5, 1.5 Hz, 1H), 6.78 (dd, J = 9.6, 2.1 Hz, 1H), 6.68 (t, J = 7.2 Hz, 1H), 6.60 (dd, J = 6.6, 2.4 Hz, 1H), 5.15 (s, 2H), 4.68 (br s, 2H), 2.81 (d, J = 3.6 Hz, 3H).

Preparation of the Ureas of the formula (I) General Method E: Substituted Ureas via the CDI-induced Aniline Coupling EXAMPLE 1 Method The Preparation of 4 - [3-Fluoro-4 - ( { [(1-methyl-lH -indazol-5-yl) amino] carbonylamino) phenoxy] -2 y-methylpyridine-2-carboxamide To a solution of 1,1 '-carbonyldiimidazole (62 mg, 0.38 mmol) in benzene (2 mL) and CH2C12 (1 mL) was added 4- (-amino-3-fluoro-phenoxy) -2-t-methyl-pyridine-2-carboxamide ( 100 mg, 0.38 mmol). The resulting solution was stirred at room temperature for 16 h, then treated with l-methyl-5-aminoindazole (56 mg, 0.38 mmol). The reaction was continued stirring at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was triturated with Et20. The solid was collected by filtration, and then purified by preparative HPLC to yield 44 mg (27%) of the title product. 1H-NMR (DMSO-d6) 52.78 (d, J = 4.8, 3H), 4.01 (s, 3H), 7.02-7.07 (m, 1H), 7.14-7.18 (m, 1H), 7.28-7.36 (m, 2H), 7.39 (d, J = 2.9, 1H), 7.52-7.59 (m, 1H), 7.89-7.96 (m, 2H), 8.23 (t, J = 9.0, 1H), 8.49 (d, J = 4.9 , 1H), 8.57-8.63 (m, 1H), 8.71-8.81 (m, 1H), 9.06 (s, 1H); MS LC-MS [M + H] + = 435.1; p.f. 231-234 ° C.

EXAMPLE 2 Method E-lb Preparation of methyl 4- [3- ( { [(L-Methyl-lH-indazol-5-yl) amino] carbonyl) phenoxy] pyridine-2-carboxylate ? a solution of 4- (3-amino-phenoxy) -pyridine-2-carboxylic acid methyl ester (0.79 g, 5.35 mmol) in CH 2 Cl 2 (3 mL) was added 1,1'-carbonyldiimidazole (0.87 g, 5.35 mmol) , and the reaction mixture was stirred at room temperature for 12 h. A solution of l-methyl-5-aminoindazole (1.02 g, 6.96 mmol) in CH 2 Cl 2 (4 mL) was added, and the mixture was stirred at room temperature for an additional 8 h. The mixture was concentrated in vacuo. Purification of the crude product by column chromatography eluted with CH2Cl2 / MeOH (95: 5) gave 850 mg (38%) of the title compound. 1H-NMR (CD3OD) d 8.57 (dd, 1H), 7.95 (d, 1H), 7.87 (d, 1H), 7.54 (d, 1H), 7.53-7.51 (m, 2H), 7.47-7.32 (m, 2H), 7.32 (d, 1H), 7.21 (dd, 1H), 6.86 (dd, 1H), 4.07 (s, 3H), 3.96 (s, 3H); MS LC-MS [M + H] + = 418.2, RT = 2.91 min.

EXAMPLE 3 Method E-2 Preparation of N- (2-acetylpyridin-4-yl) oxy] phenyl} -N '(l-n-ethyl-lH-indazol-5-yl) urea ? a solution of l-methyl-5-aminoindazole (48.4 mg, 0.33 mmol) in anhydrous DCE (1.1 mL) and anhydrous THF (1.1 mL) was added 1.1 '-carbonyldiimidazole (65.1 mg, 0.39, 1.2 eq), and the reaction mixture was stirred at 65 ° C under argon. After 16h a solution of l- [4- (4-aminophenoxy) pyridin-2-yl] ethanone (75 mg) was added at room temperature., 0.33 mmol, 1.0 eq) in anhydrous DCE (3.3 mL), and the reaction mixture was stirred at 65 ° C under argon for 20 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with water and brine, dried over Na 2 SO, filtered, and concentrated under reduced pressure. Purification in MPLC (biotage) eluted with 60 to 80% EtOAc / Hex and crystallization from ethyl acetate-hexane afforded 98.2 mg (74.4%) of the title compound as a white solid. 1 H-NMR (DMSO-d 6) 58.79 (s, 1 H), 8.68 (s, 1 H), 8.58 (d, J = 5.7 Hz, 1 H), 7.93 (d, J = 1.0 Hz, 1 H), 7.89 (d, J = 1.2 Hz, 1H), 7.58 to 7.53 (m, 3H), 7.35 (dd, J = 9.0, 2.1 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 7.21 (dd, J = 5.4 , 2.4 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 3.99 (s, 3H), 2.59 (s, 3H); MS LC-MS [M + H] + = 4.02, RT = 2.41 min; TLC (75% EtOAc / Hex), Rf = 0.11.

EXAMPLE 4 Method E-3a Preparation of 4- (4-. {[[(1,3-benzothiazol-6-ylamino) carboni 1] amino.}. Phenoxy) -OT-methyl-pyridine-2-carboxamide Step 1: Preparation of N- (1-imidazole) -N '- (4- (2 - (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea To a suspension of 1,1 '-carbonyldiimide zol (6.66 g, 41.1 mmol) and imidazole (2.80 g, 41.1 mmol) in CH2C12 (40 mL), a solution of 4- (2- (iV-methylcarbamoyl) - 4-pyridyloxy) aniline (1.0 g, 4.11 mmol) in CH2C12 (8 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 2 h, and then washed rapidly with cold water (40 mL). The organic layer was dried with Na2SC > 4, filtered and concentrated to approximately 16 ml. The crude product in CH2C 12 was used in the subsequent reaction without further purification.

Step 2: Preparation of the title compound 4- (4-. {[[(1,3-benzothiazol-6-ylamino) carbon xl.] -phenoxy) -N-methyl iridin-2-carboxamide To a solution of N- (1-imidazole) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) urine in CH2C12 (4 mL) was slowly added a solution of 6-aminobenzothiazole (135 mg, 0.90 mmol) in CH2C12 (3 mL) at room temperature. The reaction mixture was heated at 40 ° C for 2 d. The resulting precipitate was filtered and washed with CH2C12 to yield 256 mg (60%) of the title compound as a white solid. 1H-NMR (DMS0-d6) d 9.22 (s, 1H), 9.02 (s, 1H) r 8.93 (s, 1H), 8.78 (q, J = 5.1 Hz, 1H), 8.50 (d, J = 5.7 Hz , 1H), 8.38 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 9.3 Hz, 2H), 7.51 (dd, J = 9.3, 2.4 Hz , 1H), 7.39 (d, J = 3.0 Hz, 1H), 7.19 to 7.13 (m, 3H), 2.78 (d, J = 5.4 Hz, 3H); MS LC-MS [M + H] + = 420.2, RT = 2.51 min.

EXAMPLE 5 Method E-3b Preparation of 4- (4 -. {[[(1,3-benzothiazol-6-ylamino) carbonyl] amino]} - phenoxy) -Jf-methylpyridin-2-carboxamide The title compound was prepared in the same manner as described for 4- (4. {(1,3-benzothiozol-6-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxyamide, substituting β- aminobenzothiazole for l-AJ-methyl-e-aminoindazole, and substituting 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline for 3- (2- (W-methylcarbamoyl) -4-pyridyloxy) aniline. 1 H-NMR (CD3OD) 8.58 (d, 1H), 7.94 to 7.92 (m, 2H), 7.71 (d, 1H), 7.66 (d, 1H), 7.59 (t, 1H), 7.49 (dd, 1H), 7.33 (dd, 1H), 7.24 (dd, 1H), 7.00 (dd, 1H), 6.97 (dd, 1H), 4.02 (s, 3H), 2.96 (s, 3H); MS LC-MS [M + H] + = 417.2, RT = 2.46 min. Additional compounds illustrated in Table 1 were prepared as described above by selecting the suitable starting materials that are readily available and / or the synthesis thereof is shown herein, and using the processes of Method E described above or other chemical processes standard known in the art.

TABLE 1: SYNTHETIZED EXAMPLES USING THE E METHOD Ex. Structure Rf (solvenLC / MS SynthesisSyntheLy for ([M + H] +) sis of TIS sis system) or [III) or (II) (I) RT (min) * (V) * 6 -co ^ o'p Rf = 0.27 (5% 418 A-2 Cl E-1H MeOH / DCM) 7 RT = 2.97 403 run C-l E-l 8 RT = 3.00 443 comm C-l E-l 9 RT = 2.79 417 comm C-l E-l 10 RT = 2.98 446 comm C-l E-l 11 RT = 3.15 454 comm C-l E-l 12 RT = 3.41 504 comm C-l E-l 13 RT = 2.95 438 comm C-l E-l 14 RT = 2.98 450 comm C-l E-l 15 RT = 3.19 438 comm C-l E-l 16 Rt = 0.43 416 comm Cl E-3 (1001 EtOAc) Ex. Structure Rf (solvenLC / MS SynthesisSyntent for ([+ H] +) sis of TIS system sys) or (III) or (II) (I ) RT (min) * (V) * 43 RT = 2.98 468 B-1 Cl The 44 or RT = 2.56 519 A-3 B-1 C-1 E-1 · 45 O 'RT = 2.63 520 R-3 B-1 C-l E-l 46 RT = 3.11 421 B-1 C-l E-l 47 RT = 2.49 435 B-1 C-l E-l 48 ?? ¾a. Rf = 0.38 433 B-1 C-1 E-2 (100% EtOAc) 49 Rr = 0.56 452 B-1 C-1 E-2 (100% EtOAc) 50 RT = 2.46 471 A-2 B-1 C-l E-l 51 RT = 1.94 432 B-1 C-l E-l 52 RT = 3.01 511 B-1 C-l E-l 53 RT = 2.66 461 B-1 C-l E-l 54 RT = 3.7 511 · B-1 D-l E-l Eg Structure Rf (solvenLC / MS SynthesisSyntent for (EM + H] +) sis of sis of TLC sis) or (III) or (II) (I) RT (min) * (V) * 65 Rf = 0.63 502 Bl Cl E-2 (100% EtOAc) 66 RT = 2.70 451 comm C-2 E-l 67 RT - 3.25 437 coram C-2 E-l 68 Rf = 0.41 449 comm C-2 E-2 (100% EtOAc) 69 R (= 0.52 (5% 451 comm C-2 E-l MeOH / DCM) 70 Rf = 0.37 (50% 477 comm C-2 E-l EtOAc / Hex) 71 Rf = 0.26 (50% 527 comm C-2 E-l EtOAc / Hex) 72 Rf = 0.46 (50% 451 comm C-2 E-l EtOAc / Hex) 73 Rt = 0.56 (5% 437 comm C-2 E-l MeOH / DCM) 74 Rt = 0.57 (5% 527 comm C-2 E-l MeOH / DCM] 75 Rf = 0.57 (5% 477 comm C-2 E-l MeOH / DCM) The following are the LCMS conditions: the mass spectra by electro-spray by HPLC (HPLC ES-MS) were obtained using a Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 autosampler, a Gilson diode array detector, a column YC Pro C-18 (2 x 23mm, 120 A), and a single quadruple mass spectrometer Micromass LCZ with electro-dew z-dew ionization. The spectra were examined from 120-1000 amu for 2 seconds. The ELSD (Evaporative Light Scatter Detector) data was also obtained as an analog channel. The gradient elution was used with a Shock Absorber A as 2% acetonitrile in water with 0.02% TFA and Shock Absorber B as 2% water in acetonitrile with 0.02% TFA at 1.5 rtiL / min. Samples were eluted as follows: 90% A for 0.5 min with 95% B ramp for 3.5 min and maintained at 95% B for 0.5 min and then the column was returned to the initial conditions for 0.1 min. The total run time is 4.8 min. comm means commercially available.

Other compounds of the formula I can be prepared using the methods described herein or other methods known in the art, and using the appropriate starting materials and / or intermediates that could be readily recognized "by those skilled in the art.

General Method F: Substituted Ursas via the Addition of Aniline in Aryl Isocyanates EXAMPLE 104 Method F-the Preparation of N-methyl-4- [4- ( { [(2, 2, 4, 4-tetrafluoro-4H- 1,3-benzodioxin-6-aminocarbonyl] -amino) phenoxy] pyridine-2-carboxamide To a suspension of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (143 mg, 0.59 mmol) in DCM (1 mL) at 0 ° C was added dropwise a solution of 2, 2, 4 , 4-tetrafluoro-6-isocyanato-l, 3-benzodioxene (150 mg, 0.60 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 12 h. The resulting precipitate was filtered and washed with DCM to provide the desired product (125 mg, 41%) as a white solid. 1 H-NMR (DMSO-d 6) 59.14 (s, 1 H), 9.00 (s, 1 H), 8.76 (q, J = 4.5 Hz, 1 H), 8.48 (d, J = 5.4 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 9.0, 2.7 Hz, 1H), 7.60 to 7.55 (m, 2H), 7.43 (d, J = 9.0 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.20 to 7.11 (ra, 3H), 2.76 (d, J = 4.5 Hz, 3H); MS LC-MS [M + H] + = 493.1, RT = 3.27 min.

EXAMPLE 105 Method F-lb Preparation of 4- [3- ( { [(2, 2, 4, 4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino] -carboni1.} Ami or methyl phenoxy] pyridine-2-carboxamide To an agitated solution of 2,2,4,4-t et ra fluor or -6-isoci anat or -1,3-benz-hatexene (0.816 g, 3.28 mmol) was added methyl ester of 4-methyl acid. (3-aminofenoxi) pyridine-2-carboxylic acid (0.800 g, 3.28 mmol) in DCM (13 mL). The homogeneous contents became white and opaque within 1 min. of addition, and allowed to stir at room temperature for 12 h. The heterogeneous mixture was filtered, and the solid product was washed repeatedly with DCM to remove the residual starting material.

The desired product was collected as a white powder, 1.36 g (83%). 1H-NMR (DSO-d6) d 9.08 (d, 2H), 8.59 (s, 1H), 8.07 (s, 1H), 7.60 (dd, 1H), 7.37 (m, 4H), 7.25 (dr 1H) , 7.20 (dd, 1H), 6.80 (d, 1H), 3.82 (s, 3H); MS LC MS [M + H] + = 494.1, RT = 3.23 min.

EXAMPLE 107 Method F-2 Preparation of 4- (3-Fluoro-4 - { [(Quinoxalin-2-ylamino) carbonyl] amino.}. Phenoxy) -N-methyl-pi idin-2-carboxamide To a solution of 4 - [- amino-3 - (fluoro) phenoxy] -Ji-met ilpyridin-2-carboxamide (150.0 mg, 0.57 mmol) in anhydrous THF (5.7 mL) was added triphosgene (63 mg, 0.21 mmol, 0.37 eq) and diisopropylethyl amine (0.12 mL, 0.69 mmol, 1.2 eq), and the reaction mixture was stirred at 75 ° C. After 3h a solution of 2-aminoquinoxaline (83.3 mg, 0.57 mmol, 1.0 eq) in anhydrous DMF (2.8 mL) was added, and the reaction mixture was stirred at 75 ° C for 17 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with water and brine, dried over gSO, filtered, and evaporated under reduced pressure. The crude was absorbed on silica and purified by MPLC (biotage) with 10% MeOH / EtOAc. Trituration from DCM / MeOH produced 25.0 mg (10.1%) of the title product as a yellow solid. XH-NMR (DMSO-d6) 511.75 (s, 1H), 10.75 (s, 1H), 8.89 (s, 1H), 8.79 (br, J = 5.1 Hz, 1H), 8.53 (d, J = 6.0 Hz , 1H), 8.38 (t, J = 9.0 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 3.9 Hz, 2 H), 7.70 to 7.64 (m, 1H), 7.47 to 7.42 (m, 2H), 7.20 (dd, J = 5.4, 2.4 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H) 2.78 (d, J = 4.8 Hz, 3H); TLC (100%? 7?), Rf = 0.20; S LC-MS [M + H] + = 433), RT = 2.86 min.

EXAMPLE 108 Method F-3 Preparation of 4- (3. {[[(LH-indazol-5-ylamino) carbonyl] amino] phenoxy) -Jf-methylpyridin-2-carboxamide dihydrochloride 2HCI Step 1: Preparation of 5-isoci-nato-indazole-l-carboxylic acid tert-butyl ester A mixture at 0 ° C of a 1.93M solution of phosgene in toluene (8.9 mL, 17 mmol) and CH2C12 (80 mL) was added dropwise a solution of the 5-amino-indazol-1-tert-butyl ester. carboxylic acid (2 g, 8.5 mmol) and pyridine (3.5 mL, 43 mmol) in CH2C12 (20 mL). The reaction mixture was stirred for 1.5 h, then concentrated under reduced pressure. The residue was dissolved in CH2C12 (100 mL) and used without further purification.

Step 2: Preparation of N- (1-tert-butylcarboxyl-indazo-5-yl) -N '- [(3- (2- (Jf-methylcarboxyl) -4-pyridylox) phenyl] rea To a solution of 4 - (3-aminophenoxy) iridin-2-carboxamide (108 mg, 0.39 mmol) in CH2C12 (5 mL) was added a solution of crude 5-isocyanato-indazole-l-carboxylic acid tert-butyl ester (0.39 mmol) in CH2C12 (5 mL). The reaction mixture was stirred at room temperature for 12 days. The resulting suspension was diluted with about 1 mL of MeOH. The resulting clear solution was purified by MPLC (biotage) eluted with 70% EtOAc / hex followed by 100% EtOAc to give N-. { 1-tert-butylcarboxyl-indazo-5-yl) -N- [(3- (2- (N-met i lcarboxi 1) -4-pyr id loxi) phenyl] urea (63 mg, 32%) as a white solid: TLC (80% EtOAc / hex) Rf 0.36; ES-LCMS (rei abundance) m / z 503 (MH +, 100%); HRMS cale 503.203744, found 503.20344.

Step 3: Preparation of the title compound of 4- (3. {[[(1H-indazol-5-ylamino) carbonyl] amino] -phenoxy) -V-methyl-iridin-2-carbamide amide extracted A- (1-tert-butylcarboxyl-indazo-5-yl) -I \ 7 '- [(3- (2 - (N-methylcarboxyl) - - pyridi loxi) - phenyl] urea (29 mg, 0.06 mmol) in a 2M HC1 solution in ether (5 mL, 10 mmol) The reaction mixture was stirred overnight.The resulting mixture was concentrated under reduced pressure to obtain the title compound (28 mg, 100%) as a yellow solid. : Free base TLC (EtOAc) Rf 0.27, ES-LCMS (rei abundance) m / z 403 (MH +, 100%); HRMS cale 403.15132, found 403.15112. The additional compounds illustrated in Table 2 were prepared as described above by selecting Suitable starting materials that are readily available and / or synthesized from them are shown herein, and using the processes of Method F described above or other standard chemical processes known in the art. Table 2: Examples Synthesized using Method F Ex. Structure Rf (solvenLC / MS SynthesisSyntent for ([M + H] +) sis of TIS sis system) or (V) * (II) (I) RT (min) * 109 Rf = 0.52 [5% 511 B-1 C-1 Fl of MeOH / DCM) 110 R £ = 0.22 (35% 529 B-4 C-1 F-1 EtOAc / Hex) 111 Rf = 0.07 (50% 529 B-4 C-1 F-1 EtOAc / Hex) 112 R £ = 0.11 (50% 529 B-4 C-1 Fl EtOAc / Hex) Eg Structure £ (solvenLC / MS SynthesisSyntent for ([M + H] +) sis of TLC sys sis) or (V ) * (II) (I) RT (min) * 113 R (= 0.18 (50% run 50 Cl Cl of EtOAc / Hex) 114 Rf = 0.25 (15% 544 B-l C-l F-l of eOH / DCM) 115 Rf = 0.13 (50% 527 comm C-2 F-1 EtOAc / Hex) 116 f = 0.20 (50% 527 comm C-2 F-1 EtOAc / Hex) 117 RT = 3.31 493 comm C-l F-l 118 RT = 3.97 527 comm C-l F-l 119 RT = 3.64 511 comm D-l F-l 120 Rf = 0.20 (50% 507 comm C-l F-l rYxX EtOAc / Hex) 121 Rf = 0.35 (50% 538 comm ClF of EtOAc / Hex) Ex. Structure Rf (solvenLC / MS SínteSínteSíntete para (EM + H] +) sis de sis de sis de TLC) or (V) * (II) ( I) RT (min) * 122 Rf = 0.59 (501 494 run Dl Fl EtOAc / Hex) 123 Rf = 0.45 (10% 493 comm D-l F-l MeOH / DC) 124 Rf = 0.76 (75% 561 B-6 C-2 F-1 EtOAc / Hex) 125 RT = 3.23 493 comm C-3 F-l 126 Rf = 0.35 (60% 497 B-l C-l F-l EtOAc / Hex) 127 RT = 3.37 513 comm C-l F-l 128 RT = 3.85 513 comm C-l F-l 129 RT = 3.37 513 comm C-l F-l 130 Rf = 0.16 (5% 550 comm C-5 Fl of MeOH / EtOaC) Ej- Structure Rf (solvenLC / MS SynthesisSynthe for ([M + H] +) sis of TIS sis system) or (V) * ( II) (I) RT (min) * 140 RT = 3.36 461 (Na4) comm Cl Fl 141 RT = 3.58 495 (Na4) coran C-l F-l 142 Rf = 0.40 (50% 473 comm C-l F-1 EtOAc / Hex) 143 RT = 2.84 443 B-l C-l F-l 144 RT = 3.55 539 B-7 C-2 F-l The following are the LCMS conditions: the mass spectra by electro-spray by HPLC (HPLC ES-MS) were obtained using a Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 autosampler, a Gilson diode array detector, a column YMC Pro C-18 (2 x 23mm, 120 A), and a single quadruple mass spectrometer Micromass LCZ with z-dew electro-dew ionization. The spectra were examined from 120-1000 amu for 2 seconds. The ELSD (Evaporative Light Scatter Detector) data was also obtained as an analog channel. The gradient elution was used with a Shock Absorber A such as 2% acetonitrile in water with 0.02% TFA and Shock Absorber B as 2% water in acetonitrile with 0.02% TFA at 1.5 mL / min. Samples were eluted as follows: 90% A for 0.5 min with 95% B ramp for 3.5 min and maintained at 95% B for 0.5 min and then the column was returned to the initial conditions for 0.1 min. The total run time is 4.8 min. comm means commercially available.

Other compounds of formula I can be prepared using the methods described herein or other methods known in the art, and using suitable starting materials and / or intermediates that could be readily recognized by those skilled in the art.

General Methods G and H: Expanded Amide Preparations via Displacement of Ester by Nucleophilic Alkylamines EXAMPLE 145 Method G-la Preparation of N- [3- (lH-imidazol-2-yl) propyl] - 4 - [4 - ( { [(2,2,4, -tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl.}. Amino) phenoxy J p ridin -2 -earboxamide ? a mixture of - [4 - ( { [(2, 2,, 4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino] -carbonyl} amino) phenoxy] pyridine-2-carboxylate of methyl (80 mg, 0.16 mmol) and magnesium chloride (1-6 mg, 0.16 mmol) in THF (2 ml) was added 1- (3-aminopropyl) imidazole (0.04 mL, 0.32 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 d. The solid was filtered and washed with 10% MeOH in CH2Cl2. The combined filtrate was concentrated to dryness and the residue was purified by column chromatography, eluting with 2 to 5% MeOH / CH 2 Cl 2 to yield 44 mg (45%) of the title compound as a white solid. 1H-NMR (DMSO-d6) d 9.19 (s, 1H), 9.05 (s, 1H), 8.97 (t, .1H), 8.54 (d, 1H), 8.13 (d, 1H), 7.70-7.58 (m , 4H), 7.42 (d, 1H), 7.38 (d, 1H), 7.19-7. 16 (m, 4H), 6.87- (s, 1H), 3.97 (t, 2H), 3.24 (q, 2H), 1.95 (quin, 2H); MS LC- S (MH) + = 587.1, RT = 3.14 min.

EXAMPLE 146 Method G-lb Preparation of N- (2-pyrrolidin-1-ylethyl-4- [4- ( { [(2,2,4,4-4-fluoro-4H-1, 3-benzodioxin-6- il) -amino] carboni1.}. amino) phenoxy] iridin-2-carboxamide The title compound was prepared in the same manner as described for N- [3- (lH-imide z-ol-1-yl) propyl] ~ 4- [4- ( { [(2,2,4,4- tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl.] - amino) phenoxy] pi idin-2-carboxamide, substituting l- (3-aminopropyl) imidazole for 1- (2-aminoethyl) pyrrolidone , 1H-NMR (MeOH-d4) d 8.45 (d, 1H), 8.00 (d, 1H), 7.65 (dd, 1H), 7.56 (m, 3H), 7.22 (d, 1H), 7.10 (m, 2H ), 7.04 (dd, 1H), 3.57 (t, 2H), 2.77 (t, 2H), 2.67 (m, 4H), 1.83 (m, 4H); MS LC-MS [M + H] + = 576.2, RT = 3.16 min.

EXAMPLE 147 Method G-lc Preparation of flf-cyclopronyl-4- [4- (. {[[(1-methyl-lH-indazol-5-yl) amino] -carbonyl} amino) phenoxy] pyridine-2 - carboxamide The title compound was prepared in the same manner as described for JV- [3 - (1H-imide z ol-1 -yl) propyl] -4- [4- ( { [(2,2,4, 4- tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl.] - amino) phenoxy] pyridine-2-carboxamide, substituting 1- (3-aminopropyl) imidazol for cyclopropylamine and 4 - [4 - ( . {[[(2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylic acid methyl ester - [4 - ( { [(1-methyl-lH-inda zol-5-yl) amino] -carbonyl.}. Amino) -phenoxy] pyridine-2-carboxamide. 1H-NMR (MeOH-d4 / CD2Cl2) d 8.42 (d, J = 5.5 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.45-7.57 (m, 5H) , 7.08 (m, 2H), 7.02 (dd, J = 5.5, 2.6 Hz, 1H), 4.04 (s, 3H), 2.84 (m, 1H), 0.81 (m, 2H), 0.65 (m, 2H); MS LC-MS [+ H] + = 443.2, RT = 2.51 min.

EXAMPLE 148 Method H-Preparation of 4- [3- (. {[[(L-Methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N- (2-piper din- 1-ethyl) pyridine-2-carboxamide Step 1: Preparation of 4- [3- ( { [(1-Methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylic acid A mixture of N-raet il-4 - [3- (. {[[(1-met i 1-lH-indazol-5-yl) amino] carbonyl} amino) -phenoxy] pyridine-2-carboxamide ( 80 mg, 0.19 mmol) and powdered potassium hydroxide (0.03 g, 0.56 mmol) was dissolved in MeOH / H20 (4 mL, 3: 1), and the reaction mixture was heated at 40 ° C for 3 h. The solvent was removed in vacuo, the crude residue was dissolved in H2O (5 mL), and precipitated by neutralization with aqueous 1N HC1. The precipitated solid was washed with water and then with CH2C12 to give 0.55 g (70%) of carboxylic acid. 1 H-NMR (DMSO-d 6) d 9.97 (s, 1 H), 9.77 (s, 1 H), 8.46 (d, 1 H), 7.93 (s, 1 H), 7.90 (s, 1 H), 7.51 (d, 1 H) , 7.43-7.34 (m, 5H), 7.07 (dd, 1H), 6.73 (dd, 1H), 3.97 (s, 3H); MS LC-MS (M + H) + = 404.1, RT = 2.45 min.

Step 2: Preparation of the title compound 4- [3- ( { [(1-methyl-lH-indazol-5-yl) amino] carbonyl} .amino) pheno] N- (2-piperidine -l-lethyl) pyridine-2-carboxyamide 4- [3- (. {[[(l-Methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] -pyridin-2-acid carboxylic (0.07 g, 0.17 mmol) was dissolved in DMF (2.5 mL), followed by the sequential addition of l- (2-aminoethyl) piperidine (0.02 g, 0.17 mmol), 1-hydroxybenzotriazole (0.05 g, 0.38 mmol) , 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.05 g, 0.26 mmol), and N-ethylmorpholine (0.04 g, 0.38 mmol). The mixture was stirred at room temperature for 12 h, and solvent was removed in vacuo. The crude residue was dissolved in CH2Cl2 (10 mL), and washed with H2O (3 mL). The solvent was removed in vacuo, and the crude product was purified by preparative HPLC. The isolated product was washed with aqueous a2C03 to provide 0.07 g (78%) of the title compound. 1H-NMR (CD3OD) 68.51 (d, 1H), 7.91 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.50-7.46 (m, 2H), 7.41-7.36 (m, 2H ), 7.26 (dd, 1H), 7.10 (dd, 1H), 6.81-6.77 (dd, 1H), 4.03 (s, 3H), 3.60 (t, 2H), 2.78-2. 71 (m, 6H), 1.69-1.51 (m, 6H); MS LC-MS (M + H) + = 514.3, RT = 2.62 min.

EXAMPLE 149 Method H-lb Preparation of 4- [3- (. {[[(L-Methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] -iy-pyridin-3-ylpyridin- 2 -carboxamide The title compound was prepared in the same manner as described for 4 - [3- (. {[[(1-methyl-1H-indazol-5-yl) amino] carbonyl] -amino) f-enoxy] - N- (2-piperidin-1-ylethyl) pyridin-2-carboxamide, substituting 1- (2-aminoethyl) piperidine for 3-aminopyridine. 1H-NMR (DMS0-d6) d 10.39 (s, 1H), 8.93 (s, 1H), 8.72 (s, 1H), 8.63 (d, - J = 5.4 Hz, 1H), 8.38 to 8.36 (m, 1H) ), 8.19 (d, J = 8.4 Hz, 1H), 7.91 to 7.86 (m, 3H), 7.85 to 7.51 (m, 3H), 7.42 (t, J = 2.1 Hz, 1H), 7.52 to 7.17 (m, 4H), 6.85 (dd, J = 2.4, 1.5 Hz, 1H), 3.98 (s, 3H); MS LC-MS (+ H) + = 480.1, RT = 2.81 min.

Method I: General method for the synthesis of carboxamide through nitrile hydrolysis EXAMPLE 150 Method I Preparation of 4- [3, 5-difl oro-4 - ( { [(2, 2, 4, 4-tetrafluoro - 4H-1, 3-benzodioxin-6-yl) amino] -carbonyl}. Amino) phenoxy] pi idin-2 -carboxamide A solution of N-4 - [(2-cyanopi r idin-4-yl) oxy] -2,6-difluorophenyl} -N '- (2,2,4, 4-tetra-f luoro-4H-1, 3-benzodioxin-6-yl) urea (100 mg, 0.20 mmol) in acetone (2 ml) and water (1 ml) it was treated with sodium percarbonate (containing 25% H2O2, 320mg, 2.0 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate (20ml) and water (10ml). The organic layer was washed with water (10 ml) and brine (5 ml), dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was crystallized from methanol giving 42 mg (41%) of the title compound as a white solid. XH-N (DMS0-d6) d 9.48 (s, 1H), 8.56 (d, J = 6.0 Hz, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 8.07 (d, J = 2.2 Hz) , 1H), 7.74 (s, 1H), 7.68 (dd, J = 9.2, 2.7 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.25 (m, 2H); S GC-MS M + = 515.0, RT = 3.63 min.

General Method J: Oxidations EXAMPLE 151 Method Jl Preparation N-methyl-4- [3- ( { [(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl .}. amino) phenoxy pyridin-l-oxo-2-carboxamide ? a solution of ÍV-met il- - [3 - ( { [(2, 2, 4, 4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl}. amino) phenoxy] pyridin-2-carboxamide (100 mg, 0.20 mmol) in DCM (3 mL) and THF (3 mL) was added ÍZICPBA (140 mg, 0.81 mmol). This was stirred for 48 h and the thus formed precipitate was collected, and washed with DCM and MeOH to yield 53 mg (48%) of the title compound as a white solid. ^ -NMR (DMS0-d6) d 11.37 (br q, J = 4.8 Hz, 1H), 9.14 (d, J = 15.6 Hz, 2H), 8.40 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.63 (dd, J = 9.3, 2.4 Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 7.49 (t, J = 1.8 Hz, 1H), 7.44 to 7.38 ( m, 2H), 7.33 to 7.26 (m, 2H), 6.87 to 6.83 (m, 1H), 2.85 (d, J = 5.1 Hz, 3H); MS LC-MS (M + H) + = 509.2, RT = 3.54 min.

EXAMPLE 152 Method J-2 27-methyl-4 - [3- (methylsulfonyl) -4- ( { [(2,2,4,4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino ] -carbonyl.}. amino) phenoxy] pyridine-2-carboxamide To N-methyl-4- [3- (methylthio) -4- ( { [(2, 2, 4, 4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) -amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide (150 mg, 0.28 mmol) in DCM / anhydrous THF 1: 1 v / v (3.0 mL) at 0 ° C was added JKCPBA (162.7 mg, 0.61 mmol, 2.2 eq,) and the reaction mixture was stirred at RT for 17 h. The reaction mixture was emptied into aqueous saturated sodium thiosulfate solution and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to provide 73.3 mg (46.1%) of the title compound as a white solid. 1 H-NMR (DMSO-d 6) d 10.31 (s, 1 H), 8.81 (q, J = 5.4 Hz, 1 H), 8.71 (s, 1 H), 8.55 (d, J = 5.7 Hz, 1 H), 8.23 (d , J = 9.0 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.70 to 7.59 (m, 3H), 7.47 (s, 1H), 7.45 (d, J = 6.9 Hz, 1H), 7.21 (dd, J = 5.4, 2.4 Hz, 1H), 3.37 (s, 3H), 2.79 (d, J = 5.1 Hz, 3H); MS LC-MS (M + H) + = 571.1, RT = 3.81 min; p.f. 222-223.5 ° C.

The additional compounds illustrated in Table 3 were prepared as described above by selecting the suitable starting materials that are readily available and / or syntheses thereof as shown herein, and using the processes of Methods G, H, and / or I described above or other standard chemical processes known in the art.

Table 3: Examples Synthesized using Methods G, H or I Eg Structure f (solvenLC / MS SynthesisSyntheStit for ([M + H] +) sis of the TLC system sys) O (III) Ureas (I) * RT (min) * and / or (VI) u (V) ** (VIII) 153 f = 0.46 (10% 590 C-3 Fl G of MeOH / DCM) 154 RT = 2.92 591 C-3 F-l G 155 Rf = 0.38 (67% 556 C-3 F-l G EtOAc / Hex) 156 RT = 2.52 500 C-3 E-l G 157 Rf = 0.29 (25% 515 C-3 E-l G of MeOH / DCM) 158 Rt = 0.44 (7% 515 C-3 E-l G of MeOH / DCM) 159 Rf = 0.46 (15% 504 C-3 F-l G of MeOH / DCM) 160 Rf = 0.23 (15% 511 C-3 The G of MeOH / DCM) Ex. Structure Rf (solvenLC / S SynthesisSyntest for { [M + H] +) sis of sis of TLC sis) or (III) Ureas (I) * RT (min) * and / or (VI) u (V) ** (VIII) 161 RT = 2.56 514 C-3 The G 162 Rf = 0.40 (75% 457 C-3 E-l G EtOAc / Hex) 163 Rf = 0.42 (75% 457 C-3 E-1 G EtOAc / Hex) 164 RT = 2.51 475 C-3 E-l G 165 Rt = 2.58 500 C-l E-l H 166 RT = 2.57 511 C-l E-l H 167 RT = 3.18 590 C-l E-l H 168 RT = 3.13 576 C-l F-l H 169 RT = 3.69 556 C-l F-l H 170 RT = 2.74 587 Cl Fl H Ex. Structure Rf (solvenLC / MS SínteSínteSíntete for ([M «0+) sis de sis de sis de TLC) or (III) Ureas (I) * RT (min) * y / o (VI) u (V) ** (VIII) 171 R £ = 0.33 (50% 515 B-4 The I of EtOAc / Hex) C-1 172 RT = 3.61 522 B-5 F-l I C-1 173 RT - 3.31 509 B-1 F-l I C-1 174 RT = 3.39 419 B-1 E-l I C-1 The following are the LCMS conditions: the mass spectra by electro-spray by HPLC (HPLC ES-MS) were obtained using a Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2 x 23mm, 120 A), and an icromass LCZ single-quadrupole mass spectrometer with z-dew electro-dew ionization. The spectra were examined from 120-1000 amu for 2 seconds. The ELSD (Evaporative Light Scatter Detector) data was also obtained as an analog channel. The gradient elution was used with a Shock Absorber A such as 2% acetonitrile in water with 0.02% TFA and Shock Absorber B as 2% water in acetonitrile with 0.02% TFA at 1.5 mL / min. Samples were eluted as follows: 90% A for 0.5 min with 95% B ramp for 3.5 min and maintained at 95% B for 0.5 min and then the column was returned to the initial conditions for 0.1 min. The total run time is 4.8 min. comm means commercially available.

BIOLOGICAL TESTS Biochemical analysis c-Raf (af-1) Purification of the proteins used in the analysis The c-Raf biochemical analysis was carried out with a c-Raf enzyme, which was activated (phosphorylated) by the Lck kinase. The c-Raf Lck-activated (Lck / c-Raf) was produced in Sf9 insect cells by co-infecting the cells with baculovirus expression, under the control of the polyhedrin promoter, GST-c-Raf (from amino acid 302 to amino acid 648) and Lck (from full length). Both baculoviruses were used in the multiplicity of infection of 2.5 and the cells were harvested 48 hours after infection. The MEK-1 protein was produced in the Sf9 insect cells by infecting the cells with the baculoviruses expressing the GST-MEK-1 fusion protein (total length) at the multiplicity of infection of 5 and collecting the cells 48 hours after the infection. A similar purification procedure was used for GST-c-Raf302-648 and GST-MEK-1. The transfected cells were suspended in 100 mg of moist cell biomass per mL, a buffer containing 10 mM sodium phosphate, 140 mM sodium chloride pH 7.3, 0.5% Triton X-100 and the protease inhibitor combination. The cells were disrupted with a Polytron homogenizer and 30,000g centrifuged for 30 minutes. The 30,000g of the supernatant was applied on GSH-Sepharose. The resin was washed with a buffer containing 50 mM Tris, pH 8.0, 150 mM NaCl and 0.01% Triton X-100. The GST-labeled proteins were eluted with a solution containing 100 mM Glutathione, 50 mM Tris, pH 8.0, 150 mM NaCl and 0.01% Triton X-100. The purified proteins were dialysed in a buffer containing 20 mM Tris, pH 7.5, 150 mM NaCl and 20% Glycerol.

Biochemical analysis protocol and results The compounds were consecutively diluted in DMSO using three-phase dilutions for concentrated concentrations typically ranging from 50 uM to 20 nM (final concentrations in the assay ranged from 1 μ to 0.4 NM). The c-Raf biochemical analysis was carried out as a radioactive filter mesh analysis on 96-cavity Costar polypropylene plates (Costar 3365). The plates were loaded with 75 μL of solution containing 50 mM HEPES pH 7.5, 70 mM NaCl, 80 ng Lck / c-Raf and 1 ug MEK-1. Subsequently, 2 pL of the individual compounds diluted consecutively were added to the reaction, before addition of ATP. The reaction was started with 25 uL of ATP solution containing 5 μ? of ATP and 0.3 μ ?? [33 P] -ATP. Plates were sealed and incubated at 32 ° C for 1 hour. The reaction was quenched with the addition of 50 μ? of 4% phosphoric acid and collected on filter mesh P30 (Per kinElmer) using a Wallac Tomtec Collector. The filter screens were first washed with 1% phosphoric acid and then deionized in H20. The filters were dried in a microwave, soaked in the scintillation fluid and read on a Wallac 1205 Betaplate Counter (Wallac Inc., Atlanta, GA, U.S.A.). The results were expressed as percentage of inhibition. % inhibition = [100- (Tib / Tj)] x 100 where Tib = (counts per minute with the inhibitor) - (antecedent j = (counts per minute without the inhibitor) - (background) The compounds of Examples 1- 174 shows> 40% inhibition at 1 micromolar in this analysis In addition, the compounds of Examples 1, 4, 5, 8, 15, 19, 21, 23, 25, 32, 33-36, 39-43, 46-63, 66-86, 92-94, 96, 97, 101, 104, 107, 109-114, 116, 118-121, 123-131, 133, 134, 136-144, 149, 151, 152, 154, 164, 165, 167, and 170-174 show> 80% inhibition of c-Raf kinase at 1 micromolar.It is believed by someone skilled in the art, using the above information and the information available in the art, The present invention can be used to its fullest extent It will be apparent to one of ordinary skill in the art that changes and modifications to this invention can be made without departing from the spirit or scope of the invention as set forth herein. publications and patents cited above are incorporated herein by reference

Claims

CLAIMS 1. A compound of the formula (I): or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein A is a bicyclic heterocycle which is: (I) benzimidazolyl (2) 1,3-benzothiazolyl (3) 1,2,3-benzotriazolyl (4) 1, 3-benzoxazolyl (5) 2, 3-dihydro-lH-indolyl (6) 2, 3-dihydro-lH-indenyl (7) 1, l-dioxide-2,3-dihydro-l-benzothienyl (8) lH- indazolyl (9) 2H-indazolyl (10) IH-indolyl (II) 2H-chromenyl (12) quinoxalinyl or (13) a group of the formula optionally substituted with 1-4 substituents which are independently R1, OR1, S fOlp1, CIOJR1, CfOJOR1, C (0) NR1R2, halogen, oxo, cyano, or nitro; B is phenyl, naphthyl, pyridyl, or quinolinyl optionally substituted with 1-4 substituents which are independently C1-C5 straight or branched alkyl, C1-C5 straight or branched haloalkyl, Ci-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, Ci-C6 dialkylamino, carboxyamide, halogen, cyano, nitro or
S (0) PR7. L is (a) - (CH2) m-0- (CH2) i-, (b) - (CH2) m- (CH2) 1-, (c) - (CH2) mC (0) - (CH2) i -, (d) - (CH2) m-NR3- (CH2) i-, (e) - (CH2) m-NR3C (0) - (CH2) i-, (f) - (CH2) mS- (CH2 )? -, (g) - (CH2) mC (0) NR3- (CH2) 1-, (h) an individual bond, m and 1 are integers selected independently from 0-4; M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C1-C5 straight or branched alkyl, C1-C5 straight or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, Ci ~ C6 dialkylamino, halogen, or nitro; Q is C (0) R4, C (0) OR4 or C (0) NR R5; each R1, R2, R3, R4 and R5 is independently: (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) phenyl, (d) C1-C3 alkyl-phenyl, (e) to C1-C5 linear or branched alkyl per-halo substituted, (f) - (CH2) qX where X is a 5- or 6-membered heterocyclic ring, containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms that are O, N or S, or (g) - (CH2) qY where Y is C (0) R6, C (0) OR6 and C (0) NR6R7; each R6-R7 is independently: (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) f-enyl, (d) C1-C3 alkyl-phenyl, or (e) to C1-C5 linear or branched alkyl substituted by halo; each R1, R2, R3, R4, R5, R6 and R7, other than C1-C5 straight or branched alkyl substituted by halo, is optionally substituted with 1-3 substituents which are independently C1-C5 straight or branched alkyl, up to C1- C5 linear or branched alkyl substituted by halo, C1-C3 alkoxy, hydroxy, carboxy, amino, C1-C3 alkylamino, Cj.-C6 dialkylamino, halogen, cyano, or nitro. p is an integer selected from 0, 1, or 2; and q is an integer selected from 1, 2, 3, or 4. compound according to the claim wherein? and B follows one of the following combinations: A = lH-benzimidazol-5-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = IH-benzimide zol-6-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 1,3-benzodioxin-6-yl; and phenyl, pyridinyl, naphthyl or quinolinyl, A = 1,3-benzodioxin-7-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 1, 3-ben zodi oxin-8-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 1,3-benzodioxol-4-yl; pyridinyl, naphthyl or quinolinyl, A = 1,3-benzodioxol-5-yl; B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 1,3-benzothiazol-2-ylo; B = phenyl, pyridinyl, or naphthyl or quinolinyl, A = 1,3-benzothiazol-5-yl; B = phenyl, pyridinyl, naphthyl or qunolinyl, A = 1, 3-benzothiazol-6-yl B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 1, 2, 3-benzotriazol-5-yl; phenyl, pyridinyl, naphthyl or quinolinyl, A = 1,3-benzoxazol-2-yl; phenyl, pyridinyl, naphthyl or quinolinyl, or A = 1,3-benzoxazol-6-yl; phenyl, pyridinyl, or naphthyl or quinolinyl,
3. The compound according to claim 1 wherein A and B follow one of the following combinations: A = lH-benzimidazolyl; and B = phenyl or pyridinyl, A = 1,3-benzodioxinyl; and B = phenyl or pyridinyl, A = 1,3-benzodioxolyl; and B = phenyl or pyridinyl, A = 1,3-benzothiazolyl; and B = phenyl or pyridinyl, A = 1, 2, 3-benzotriazolyl; and B = phenyl or pyridinyl, or A = 1,3-benzoxazolyl; and B = phenyl, pyridinyl.
4. The compound according to claim 1 wherein A and B follow one of the following combinations: A = lH-benzimidazol-5-yl; and B = phenyl or pyridinyl, A = lH-benzimidazol-6-yl; and B = phenyl or pyridinyl, A = 1,3-benzodioxin-6-yl; and B = phenyl or pyridinyl A = 1,3-benzodi oxin- 7 -i 1 o; and B = phenyl or pyridinyl, A = 1,3-benzodioxin-8-yl; and B = phenyl or pyridinyl,? = 1,3-benz-hatexol-4-yl; and B = phenyl or pyridinyl, A = 1,3-benzodioxol-5-yl; and B = phenyl or pyridinyl, A = 1,3-benzothiazol-2-yl; and B = phenyl or pyridinyl, A = 1,3-benzothiazol-5-yl; and B = phenyl or pyridinyl, A = 1,3-benz ot ia zol-6-yl; and B = phenyl or pyridinyl, A = 1, 2,3-benzotriazol-5-yl; and B = phenyl or pyridinyl, A = 1,3-benzoxazol-2-yl; and B = phenyl or pyridinyl, or A = 1,3-benzoxazol-6-yl; and B = phenyl or pyridinyl.
5. The compound according to claim 1 wherein A and B follow one of the following combinations: A = 2,3-dihydro-1,4,4-benzodioxin-5-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl,? -2,3-dihydro-l, 4-benzodioxin-6-ylo; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 2,3-dihydro-l-benzofuran-5-yl; = and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 2,3-dihydro-β-indol-5-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 2,3-dihydro-lH-indol-6-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 2,3-dihydro-lH-inden-4-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 2, 3-dihydro-lH-inden-5-yl and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 1, l-dioxide-2, 3-dihydro -l-benzothien-6-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl.
6. The compound according to claim 1 wherein A and B follow one of the following combinations: A = 2,3-dihydro-1, -benz-hatexin-5-yl; and B = phenyl or pyridinyl, A = 2,3-dihydro-1, -benz hatexin-6-i lo; and B = phenyl "or pyridinyl, A = 2, 3-dihydro-1-benzofuran-5-yl, and B = bemoñp or pyridinyl, A = 2, 3-dihyd or-1H-indole-5-yl; = phenyl or pyridinyl, A = 2, 3-dihydro-lH-indol-6-yl, and B = phenyl or pyridinyl, A = 2, 3-dihydro-lH-inden-4-yl, and B = phenyl or pyridinyl ,? = 2, 3-dihydro-lH-inden-5-yl, and B = phenyl or pyridinyl, or A = 1, l-dioxide-2, 3-dihodrp-l-benzot i en- 6 -i lo; and B = phenyl or pyridinyl.
7. The compound according to claim 1 wherein A and B follow one of the following combinations:. A = lH-indazol-5-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 2H-indazol-5-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = lH-indazol-6-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, α-lH-indol-5-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl, A = 2 ~ oxo-2H-chromen-7-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl or A = l-oxo-2,3-dihydro-lH-inden-5-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl.
8. The compound according to claim 1 wherein A and B follow one of the following combinations: A = lH-indazol-5-yl; and B = phenyl or pyridinyl, A = 2H-indazol-5-yl; and B = phenyl or pyridinyl, A = lH-indazol-6-yl; and B = phenyl or pyridinyl, A = lH-indol-5-yl; and B = phenyl or pyridinyl, A = 2-oxo-2H-chromen-7-yl; and B = phenyl or pyridinyl, or A = l-oxo-2,3-dihydro-lH-inden-5-yl; and B = phenyl or pyridinyl.
9. The compound according to claim 1 wherein A and B follow one of the following combinations: A = quinoxalin-2-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl or A = quinoxalin-6-yl; and B = phenyl, pyridinyl, naphthyl or quinolinyl.
10. The compound according to claim 1 wherein A and B follow the following combinations: A = quinoxalin-2-yl; B = phenyl or pyridinyl, or A = quinoxalin-6-yl; B = phenyl or pyridinyl.
11. A compound according to claim 1 wherein L is -O- or -S-.
12. A compound which is: • N-methyl-4- [3- (. {[[(2-methyl-1,3-benzoxaz-ol-6-yl) amino] carbonyl} amino) phenoxy] pyridine 2- carboxamide • 4- [4 - ( { [(I-Acetyl-2,3-dihydro-lH-indol-6-yl) -amino] carbonyl}. Amino) phenoxy] -IV-met i lpiri din-2-carboxamide • 4- [4- ( { [(6-chloro-l, 3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] -N-netylpyridine-2-carboxamide • N-methyl-4-. { 4 - [( { [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl] amino.} Carbonyl) amino] phenoxy} pyridine-2-carboxamide • 4 - [4 - ( { [(6-fluoro-1,3-benzothiazol-2-yl) amino] carbonyl}. amino) phenoxy] -N-methylpyridine-2-carboxamide • 4- [3-fluoro-4- (· { [(6-fluoro-l, 3-benzothiazol-2-yl) amino] carbonyl}. Amino) phenoxy] -N-methylpyridine-2-carboxamide • 4-. { 3-fluoro-4 - [( { [6- (trifluoromethoxy) -1,3-benzothiazol-2-yl] amino.} Carbonyl) amino] phenoxy} -N-methyl iridin-2-carboxamide; 4- [4- ( { [(6-methoxy-l, 3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide • 4 - [4 - ( { [(6-methoxy-l, 3-benzothiazol-2-yl) amino] carbonyl.}. Amino) phenoxy] -N-methylpyridine-2-carboxamide · 4- [4- ( { [ (5-chloro-l-3-benzoxazol-2-yl) amino] carbonyl}. Amino) phenoxy] -N-met ilpi idin-2-carboxamide • 4 - [4 - ( { [(5- chloro-l-3-benzoxazol-2-yl) ami or] carbonyl.}. amino) phenoxy] -N-methylpyridine-2-carboxamide • 4- [4- ( { [(6-clo ol-3- benzothiazol-2-yl) amino] carbonyl.} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide - [4 - ( { [(6-chloro-l-3-benzothiazol-2-yl) ) amino] carbonyl.] amino) -3-fluorophenoxy] -N-methyl-1-ridin-2-carba amide 4- (2-chloro-4. {[[(2,3-dihydro-lH-inden-5) -ylamino) carbonyl] amino.}. phenoxy) -N-methylpyridin-2-carboxamide 4- [(5. {[[(2,3-dihydro-lH-inden-5-ylamino) carbonyl] amino} quinoline -8-yl) oxy] -N-methylpyridin-2-carboxamide 4 - [ 4 - ( { [(, 6-difluoro-l, 3-benzothiazol-2-yl) amino] carbonyl} amino) -3-fluorophenoxy] -N-methylpyridin-2 -carbo amide 4- [3-fluoro-4- ( { [(6-methoxy-1,3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridinecarboxamide 4- (4-. {[[(. {1- [2 - (Di-ethyl-amino) -ethyl] -lH-indol-5-yl.}. ami not ) carbonyl] amino.}. -3-fluorophenoxy) -N-methyl-1-pyridin-2-carboxamide 4 - [3-fluoro-4 - (. {[[(l-oxo-2,3-dihydro-lH-inden- 5-yl) amino] carbonyl.}. Amino) phenoxy] -N-methylpyridine-carboxamide 4 - [4 - (. {[[1, l-dioxido-2,3-dihydro-l-benzothien-6-yl] ) amino] carbonyl.}. amino) -3-fluorophenoxy] -N-methyl lpyridin-2-carboxamide 4- [3-fluoro-4 - ( { [(1-met il-lH-indazol -5 -il) ) amino] carbonyl.}. amino) phenoxy] -N-met ilpi ridin- 2 -carboxami 4- [2-fluoro-4- ( { [(1-methyl 1- 1 H -indazol-5-yl) amino] carbonyl} amino) phenoxy] -I-methylpyridine-2-carboxamide 4 - [2,4-difluoro-5- ( { [(L-methyl-lH-indazol-5-yl) amino] carbonyl}. Amino) phenoxy] -W-methylpyridin-2-carboxamide N-methyl- 4- [4- ( { [(1-methyl-1Hi- da zol-5-yl) amino] carbonyl}. Amino) -3- (t-rif luoromet-yl) -phenoxy] -iridin-2-carboxamide 4 - [4-fluoro-3- ( { [(L-methyl-lH-indazol-5-yl) amino] carbonyl}. Amino) phenoxy] -W-met ilpyridin-2-carboxamide 4- [2 - Fluoro- 5 - ( { [(1-methyl-1H-inda zol-5-yl) amino] carbonyl}. amino) phenoxy] -N-methylpyridin-2-carboxamide 4- [2-chloro-6- fluoro-4- ( { [(l-Methyl-lH-indazol-5-yl) ami or] carbonyl.}. amino) pheno] -N- et ilpyridin-2-carboxamide 4- [3-fluro- 4- ( { [(1-methyl-1 H-inda zol-5-yl) amino] carbonyl.}. Amino) phenoxy] -N- (2-ethoxyethyl) pyridine-2-carboxamide 4- [3- fluoró ~ 4- ( { [(2,2,3, 3-tetraf luoro-2, 3-dihydro- 1,4-benzo dioxin-6-yl) amino] carbonyl} -amino) phenoxy] I \ J-met ilpyridin-2 -carboxamide 4 - [4 - (. {[[(2,2-difluoro-l, 3-benzodioxol-5-yl) amino] carbonyl} amino) -3-f luorophenoxy ] -N-methylpyridin-2 -carboxamide N-methyl-4- (-. {[[(Quinoxalin-6-ylamino) carbonyl] amino} phene i) pyridine-2-carboxamide 4 - (3-fluoro) -4- { [(Qui oxa-ind-6-lamino) carbonyl] amino.}. Phenoxy) -W-methylpyridine-2-carboxamide N-methyl-4- [4-. { [(quinoxalin-6-ylamino) carbonyl] amino} -3- (fluorine orne ti 1) phenoxy] -pyridine-2-carboxamide 4- (3-chloro-4-. {[[(Quinoxa 1 i n- 6- i lamino) carbonyl] amino.}. Phenoxy) -N-meti Ipi ridin-2-carboxamide N-methyl-4- [4- ( { [(2,2,3,3-tetrafluoro-2,3-dihydro-1,3-benzodioxin-6-yl) ) amino] cab'onyl.}. - amino) - 3 - (trifluoromethyl) phenoxy] pyridin din-2-carboxamide 4 - [4 - ( { [(2-methyl-1,3-benzothiazole- 5-yl) amino] carbonyl.}. - amino) phenoxy] pyridine-2-carboxamide N-methyl-4 - [4 - ( { [(2-methyl-1,3-benzothiol-5-yl) ) amino] cabonyl lamino) -3- (trifluoromethyl) phenoxy] pi i din- 2 -carbo amide N-methyl-4- [3-methyl-4- ( { [(4-methyl-2-oxo) -2H-chromen yl) amino] carbonyl.}. Amino) -phenoxy] pyridine-2-carboxamide N-methyl-4- [3-methyl-4- ( { [(2-methyl-1,3-benzothiazole il) amino] carbonyl.}. amino) -phenoxy] iridin-2-carboxamide 4- [3-fluoro-4- ( { [(2-methyl-l, 3-benzothiazol-5-yl) a ino] carbonyl.}. amino) -phenoxy] -N-methylpyridine-carboxamide N-methyl-4-. { [3 - ( { [(L-methyl-lH-indazol-5-yl) amino] carbonyl}. Amino) phenoxy] methyl} -pyridine-2-carboxamide 4 -. { [3-fluoro-4- ( { [(L-methyl-lH-indazol-5-yl) amino] carbonyl (amino) phenoxy] methyl.} - N-methylpi-ridi-2-carboxamide 4- [2 -chloro-4- ( { [(l-Methyl-lH-indazol-5-yl) amino] carbonyl}. amino) phenoxy] -N-methylpyr i din-2-carboxamide N-methyl-4 - [ 3- ( { [(2,2,3, 3-tetrafluoro-2, 3-dihydro-1,4-benzodioxin-6-yl) amino] carbonyl.} - amino) phenoxy] pyridine-2-carboxamide N-methyl-4- [4- ( { [(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) amino] carbonyl}. -amino) phenoxy ] pyridin-2-carboxamide 4 - [3 - (. {[[(2, 2-difluoro-1,3-be-zodioxol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridin-2 -carboxamide 4 - [4 - ( { [(2, 2-difluoro-1, 3-benzodioxol-5-yl) amino] carbonyl}. amino) pheno] n -methylpyridi-2-carboxamide 4 - [2-chloro-4- ( { [(2,2,3, 3-t-etrafluoro-2,3-dihydro-1,4-ber. Zodioxin-6-yl) amino] carbonyl.} Amino ) phenoxy] N-methypyridine-2-carboxamide 4- [2-chloro-4- ( { [(2, 2-difluoro-1,3-benzodioxo 1 - 5 -yl) amino] carbonyl} amino) f-enoxy] -N-methylpyridine-2-carboxamide 4- [3-chloro-4- (. {[[(l-methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridin-2-carboxamide N-methyl-4- [3- (. {[[(L-methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide N-met il- 4- [3- (. {[[(L-methyl-lH-indazol-6-yl) amino] carbonyl}. Amino) phenoxy] pyridine-2-carboxamide 4 - (3-. { [(2,3-dihydro-l-benzofuran-5-ylamino) carbonyl] amino] phenoxy) -jV-methylpyridine-2-carboxamide IV-methyl-4-. { 3- [( { [2- (tri-fluoromethyl) -1H-benzimidazol-5-yl] amino.} Carbonyl) amino] -phenoxy} pyridine-2-carboxamide 4- [4-chloro-3 - ( { [1-met il-1 H-inda z ol-5-yl) amino] carbonyl} amino) phenoxy] -N-methyl-pyridine-2-car- oxamide 4- [4 -the -3- ( { [(2, 2, 3, 3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) amino] -carbonyl} amino) phenoxy] Jtf-meti Ipiri din-2 -carboxamide 4 - [4-chloro-3 - (. {[[(2,2-difluoro-l, 3-benzodioxol-5-yl) amino] carbonyl}. amino) phenoxy] -N-methylpyridine-2-carboxamide 4- [3-chloro-4- ({[[(l-methy-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine -2-carboxamide 4- [2-chloro-4- ( { [(1-methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide 4 - [ 4 - ( { [(2,2-difluoro-l, 3-benzodioxol-5-yl) amino] carbonyl}. Ami o) -3-fluorophenoxy] -pyridine-2-carboxamide 4- [3-fluoro] -4 - ( { [(2,2,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) amino] carbonyl}. Amino) phenoxy] -pyridin-2-carboxamide 4 - (4-. {[[(2,3-dihydro-lH-inden-5-ylamino) carbonyl] amino.}. F-enoxy) -N-methyl-pyridin-2-carboxamide N-methyl-4- [4 - ( { [(1-Oxo-2, 3-dihydro-lH-inden-5-yl) amino] carbonyl}. Amino) phenoxy] -pyridine-2-carboxamide 5- [3-fluoro-4-] ( { [(2,2,3, 3- 1 etrafluoro-2, 3-dihydro-1, -benzodioxin-6-il) amino] carbonyl} -amino) phenoxy] -N-met ilnicot inamide 4- [4-. { [(2,3-dihydro-lH-inden-5-ylamino) carbonyl] amino} 3- (t-trifluoromethyl) phenoxy] -N-met ilpyr idin-2 -carboxamide N-methyl-4- [4- (. {[[(L-oxo-2,3-dihydro-lH-inden- 5 - il) amino] carbonyl.}. amino) -3- (trifluoromethyl) phenoxy] pyridine-2-carboxamide 4- (3-chloro-4-. {[[2, 3 -dihi dro- 1 H- i n- 5-ylamino) carbonyl] amino.}. Phenoxy) pyridine-2-ca rboxamide 4- [3-chloro-4- (. {[[(L-oxo-2,3-dihydro-lH-inden-5-yl) amino] carbonyl} amino} phenoxy] -pyridin-2- carboxamide N-methyl-4- [4- (. {[[(1-methyl-lH-indazol-6-yl) amino] carba i 1.}. amino) phenoxy] -pyridine-2-carboxamide 4 - (4 - { [(1, 3-benzothiazol-6-ylamino) carbonyl] amino.}. f-enoxy) -N-methylpyridine-2-carboxamide N-methyl-4- [4- ( { [(l- methyl-lH-indazol-5-yl) amino] carbonyl.}. amino) phenoxy] pyridine-2-carboxamide 4- (4-. {[[(2,3-dihydro-l-benzofuran-5-ylamino) carbonyl] amino.}. f-enoxy) -N-methyl-ir-id-2-carboxamide 4- [2,4-dichloro-5- ( { [(2,2,3,3-tetrafluoro-2, 3- dihydro-1,4-benzodioxin-6-yl) amino] carbonyl.}. amino) phenoxy] -N-methylpyridine-2-carboxamide 4 - [2, -di chloro-5- (. {[[(l-methyl) -lH-indazol-5-yl) amino] carbonyl.}. amino) phenoxy] N-methylpyridine-2-carboxamide 4 - [3-chloro-4 - ( { [(2, 2-difluoro-l , 3-be zodioxol-5-yl) amino] carbonyl.}. Amino) phenoxy] -N-met ilpyridin-2-carboxamide 4-! 3-clo ro-4- (. { [(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] N-met ilpyridin-2-carboxamide; 4- (3-chloro-4-. {[[(2,3-dihydro-1H-inden-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide • 4- (3 -chloro-4- { [(2, 3-dihydro-l-inden-5-ylamino) carbonyl] amino.}. phenoxy) -N-methylpyridine-2-carboxamide • 4- [3-chloro-4 - ( { [(l-oxo-2, 3-dihydro-lH-inden-5-yl) amino] carbonyl}. amino) f ene i] -N-met il ir i din-2-carboxamide; • 4- [2-chloro-4- (. {[[(L-oxo-2,3-dihydro-lH-inden-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridin-2 - carboxamide 4- (3-chloro-4- {[[(2,3-dihydro-lH-inden-5-ylamino) carbonyl] amino} f-enoxy) -W-me-ilpyridine-2-carboxamide • 4- (3-chloro-4-. {[[(2,3-dihydro-lH-inden-5-ylamino) carbonyl] amino} phenoxy) -iV-methylpyridine-2-carboxamide • 4- [2 , -dichloro-5 ~ ( { [(2, 2-difluoro-l, 3-benzodioxol-5-yl) amino] carbonyl}. amino) f enoxy] -W-methylpyridin-2 carboxamide • W-methyl -4-. { 4- [( { [1- (met i 1 sulfonyl) -2, 3-dihydro-lH-indol-5-yl] amino.} Carbonyl) amino] -phenoxy} pyridine-2-carboxamide • N-methyl-4- [3-nitro-4- ( { [(2,2,3,3-tetrafluoro-2, 3-dihydro-1, -benzodioxin-6-yl) amino] -carbonyl.}. amino) phenoxy] pyri din-2 -carboxamide • N-methyl-4- [2-methyl-4- ( { [(2,2,3,3-tetrafluoro-2, 3- dihydro-1,4-benzodioxin-6-yl) amino] -carbonyl}. Amino) phenoxy] pi r idin-2 -carboxamide • -4- [2,3-difluoro-4- ( { [ (2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] -carbonyl.}. Amino) phenoxy] -N-met il-iridin-2-carboxamide • 4- [3, 5-difluoro-4- ( { [(2, 2, 4, 4-t and rafluoro-4 H- 1, 3-benzodioxin-6-yl) amino] -carbonyl.} Amino) phenoxy] -N - methi lpi ridin- 2 -carboxamide · 4- [2, 5-difluoro-4- ( { [(2, 2,, 4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl.}. amino) phenoxy] -N-methyla ridin- 2 -carboxamide • N-meth trifluoroacetate 1- 4 - [4 - ( { [(2, 2, 3, 3-tetrafluoro-2, 3-dihydro-l, 4-benzodioxin-5-yl) amino] carbonyl.} Amino) phenoxy] pyridine-2-carbo xamide • 4- [3-fluoro-4- (. { [(2,2,4, 4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide · 4- [3-fluoro-4- ( { [(2, 2, 4, 4-tetrafluoro-4fi-l, 3-benzodioxin-6-yl) amino] carbonyl.}. amino) phenoxy] pyridine-2-carboxamide • N-methyl-4-. { [5- ( { ['(2,2,4, 4-tetrafluoro-4 H-l, 3-benzodioxin-6-yl) amino] carbonyl}. Amino) -quinolin-8-yl] oxy} pyridine-2-carboxamide dihydrochloride of 4- (3. {[[(1H-indazol-1-ylamino) carbonyl] ami or.}. f-enoxy) -N-methylpyridine-2-carboxamide N- [2- (met i lamino) -2-oxoethyl] -4- [4- ( { [(2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide 4- (3-fluoro-4-. {[[(quinoxalin-2-ylamino) carbonyl] amino.}. f-enoxy) -N-methyl-pyridine-2-carboxamide N- [ 2- (dimethylamino) -2-oxoethyl] -4- [4- ( { [(2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl} ami o) phenoxy] pyridine-2-carboxamide N-methyl-4- [3-methyl-4- ( { [(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6) -yl) amino] carbonyl.}. -amino) phenoxyhydridyl-2-carboxamide 4- [3- ( { [(2, 2,4,4-tetrafluoro-4H-l, 3-benzodioxin-7-yl) amino] carbonyl} methyl amino-phenoxy] pyridine-2-carboxylate 4- [3-chloro-4- ( { [ { 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6-yl amino] carbonyl} -amino) phenoxy] -N-methylpyridin-2-carboxamide 4- [3-chloro-4- (. {[[(2,2,4,4-tetrafluoro-4 Hl, 3-benzodioxin-6-yl) amino] ] carbonyl.} amino) pheno] iridin-2-carboxamide 4 - (3 -. {[[(1,3-bezodioxol-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridin-2 -carboxamide N-methyl-4- [3- ( { [(2,2,4, 4 -et afluoro-4 H- 1, 3-benzodioxin-6-yl) amino] arbonyl.}. amino) pheno i] iridin-2-carboxamide 4 - (3. {[[(2,3-dihydro-l, 4-benzodioxin-6-ylamino) carbonyl] amino] phenoxy) -N-methylpyridine-2-carboxamide 4 - [4-chloro-3- ( { [(2,2,4, 4-etho-fluoro-4H-1, 3-benzodioxin-6-yl) ami or] carbonyl.} Mi o) pheno] methylpyridin-2-carboxamide 5- [2-fluoro-4- ( { [(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] ca bonyl.} amino ) phenoxy] -N-methylnicotinamide 4- [2-chloro-4- ( { [(2,2,4,4-tetraf luoro-4H-1, 3-benzodioxin-6-yl) amino] carbonyl} amino) -phenoxy] pyridine-2-carbamoamide 4- [3-clo or-4- ( { [(2,2,4,4-tetrafluoro-4H-1, 3- benzodioxin-6-yl) amino] carbonyl} amino) -pheno i] pyridine-2-carboxamide 4- [3-f luoro-4- ( { [(2,2,4,4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino) ] carbonyl.} amino) -phenoxy] pyridine-2-carboxamide 4- [3-fluoro-4- ( { [(2,2,4,4-tetrafluoro-4H-1, 3-benzodioxin- 6-) il) amino] carbonyl.}. amino) -phenoxy] pyridin-2-carboxamide 4 - (3 -. {[[(1,3-benzodioxol-5-ylamino) carbonyl] amino.}. 4-chlorofenoxi]) -A / -met i lpi ridin-2-carboxamide 4- [4-chloro-3- ( { [(6-fluoro-4H-l, 3-benzodioxin-8-yl) ami or] carbonyl. amino) f enoxy] -N-methylpyridine-2-carboxamide 4- (4-. {[[(1,3-benzodioxol-5-ylamino) carbonyl] amino}. 3- fluorophenoxy) pyridin-2-carboxamide 4- [3-fluoro-4- ( { [(6-fluoro-4H-1, 3-benzodioxin-8-yl) amino] carbonyl} amino) phenoxy] -pyridine-2-carboxamide 4- (4-chloro-3. {[[(2,3-dihydro-l, 4-benzodioxin-6-ylamino) carbonyl] amino-phenoxy) -N-methylpyridine-2-carboxamide 4 - [3 - ( { [(7-fluoro-2, 3-dihydro-1,4-benzodioxin-5-yl) amino] carbonyl}. Amino) phenoxy] -N-met ili-ridin-2-carboxamide 4- [3-fluoro-4- ( { [(2,2,4, 4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino] carbonyl.} Mino) phenoxy] -N- met i lpi ridin- 2 -carboxamide 4 - (4 -. {[[(1, 3-benzodioxol-, 5-ylamino) carbonyl] amino Jphenoxy) -N-met ilpyridine-2-carboxamide 4- [4- (. {[2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl] amino) phenoxy] pyridine-2-carboxylic acid 5- [4- (. {(2,2,4-, 4-tetraf luoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] methyl nicotinate 4- [2, -di-chloro-5] - ( { [(2,2, '4,4-tetrafluoro-4H-l, 3-benzodioxin-6-i l) amino] carbonyl} amino) -phenoxy] ~ N-methylpyridine-2-carboamide N-methyl-5 - [4- ( { [(2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6-yl ) mino] carbonyl.}. amino) -phenoxy] nicotinamide 4 - (4 -. {[[(1,3-benzodioxol-5-ylamino) carbonyl] amino.} - 3-chlorophenoxy) -N-methylpyridin-2 -carboxamide 4- [3-chloro-4- ( { [(6-fluoro-4H-l, 3-benzodioxin-8-yl) amino] carbonyl} amino) -phenoxy] -N-met ilpyridin- 2-carboxamide N-met il-4- [2-methyl-4- ( { [(2,2,4, 4 -tet ra fl uo o- H-1,3-benzodioxin-6-yl) amino] carbonyl.} amino) -phenoxy] pyridine-2-carboxamide N-met il-4- [3-nitro-4- ( { [(2,2,4,4-tetrafluoro-4 H-1, 3 -benzodioxin-6-yl) ami or] carbonyl.}. amino) -phenoxy] iridin-2-carboxamide 1- N-meth oxide 1-4 - [3 - ( { [(2, 2, 4 , 4-tet raf luoro- 4 H-1, 3-benzodioxin-6 ~ il) amino] carbonyl.}. Amino) -phenoxy] pyridine-2-carboxamide 4 - [3 - ( { [(L-methyl -lH-indazol-5-yl) amino] carbonyl.}. amino) -phenoxy] -N- (2-piperidin-1-ylethyl) pyridine-2-carboxamide 4 - [3 - (. { [(1-met il-lH-inda zol-5-yl) amino] carbonyl} amino) -phenoxy] -N- (2-pyrrolidin-1-ylethyl) pyridine-2-carboxamide 4 - [3 - (. {[[(1-methyl-1H-inda-z-5-yl) -amino] -carbonyl] .}. amino) -phenoxy] -N-pyridin-3-ylpyridine-2-carboxamide N- [3- (IH-imidazol-1-yl) ropil] -4- [3- ( { [(1- methyl-lH-indazol-5-yl) amino] carbonyl.}. amino) -phenoxy] pyridine-2-carbo-amide N- (2-piperidin-1-ylethyl) -4- [3- ( { [( 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl}. Amino) phenoxy] iridin-2-carboxamide N- (2-pyrrolidin-1-ylethyl) -4 -. [3 - ( { [(2,2,4,4-tetrafluoro-4H-l, 3-benzodíoxin-6-yl) amino] carbonyl.}. Amino) phenoxy] pyridine-2-carboxaraide N- pyridin-3-yl-4- [3- ( { [(2,2,4,4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino] carbonyl} amino) enoxy] pyridine -2-carboxamide N- [3 - (lH-i-midazol-1-yl) propyl] -4- [3 - (([(2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6 -yl) amino] carbonyl.}. amino) phenoxy] pyridine-2-carboxamide N- [3- (lH-imidazol-1-yl) ropil] -4- [4- ( { [(2,2, 4.4 tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide - (2-pyrrolidin-1-ylethyl) -4- [4- ( { [(2,2,4,4-tetrafluoro-4H-1, 3-benzodioxin-6 -yl) amino] carbonyl.}. amino) phenoxy] pyridine-2-carboxamide N- (2-piperidin-1-ylethyl) -4- [4- ( { [(2,2,4,4-tetrafluoro 4H-1, 3-benzodioxin-6-yl) amino] carbonyl.] Ami o) phenoxy] pyridine-2-carboxamide N- (2-piperazin-1-ylethyl) -4- [4- ( { [(2,2,4,4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino] -carbonyllamino) phenoxy] iridin-2-carboxamide iV-pyridin-2-yl-4- [4- ( { [(2,2,4,4-tetrafluoro-4H-benzodioxin-6-yl) amino] carbonyl}. Amino) -phenoxy] ir idin-2-carboxamide 4 - [4 - ( { [(L-methyl-lH-indazol-5-yl) amino] carbonyl}. amino) phenoxy] -N- (2-irolidolidylethyl) pyridine-1-carboxamide 4 - [4 - ( { [(1 -met il-lH-inda zol-5-yl) amino] carbonyl.}. amino) phenoxy] -N- (2-piperazin-1-ylethyl) pyridine-2-carboxamide 4- [2-methoxy-4 - ( { [(2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl.}. Amino) phenoxy] p iri din- 2 -c arboxamide 4 - (4-. { [(2,3-dihydro-lH-inden-5-ylamino) carbonyl] amino} -2-methoxyphenoxy) pyridine-2-carboxamide 4- [2, 5-difluoro-4- ( { [(2, 2, 4, 4-tetrafluoro-4H-l, 3-benzodioxin-6-yl) amino] carbonyl} amino) -phenoxy] pi idin-2 - carboxamide 4- [3,5-di-fluoro-4- ( { [(2,2,4,4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino] carbonyl} amino) -pheno i] pyridin-2-carboxamide 4- [3- (aminocarbonyl) -4- ( { [(2,2,4,4-tetrafluoro-4H 1,3-benzodioxin-6-yl) amino] carboni 1.}. Amino) -phenoxy] pyridine-2-carboxamide N-methyl-4- [3- (methylsulfonyl) -4- ( { [ { 2,2,4,4-tetrafluoro-4H-l , 3-benzodioxin-6-yl) amino] carbonyl} amino) -phenoxy] pyridine-2-carboxamide N-methyl-4- [3- (methylthio) -4- ( { [(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-) il) amino] carbonyl.}. amino) -phenoxy] pi idin-2-carboxamide 4- [3-fluoro-4- ( { [(6-nitro-l, 3-benzothiazol-2-yl) amino] carbonyl.}. amino) phenoxy] -N-methylpyridine carboxamide N-methyl-4- [4 - ( { [(6-nitro-1,3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide 4- [4 - ( { [(4,6-difluoro-l, 3-benzothiazol-2-yl) amino] carbonyl}. amino) phenoxy] -N-methylpyridine carboxamide N -methyl-4 - [4 - ( { [(2-methyl-1-1,3-benzoxazol-6-yl) amino] carbonyl}. amino) phenoxy] pyridine-2-carboxamide 4 - (4- { [(2,3-dihydro-lH-inden-4-ylamino) carbonyl] amino.}. Phenoxy) -N-methylpyridinecarboxamide 4- [4- ( { [(2,2-difluoro-1) , 3-benzodioxol-4-yl) amino] carbonyl.}. Amino) phenoxy] -W-met ilp i idin carboxamide iV-methyl-4 - [4 - ( { [(2-methyl) 1-2 H - inda zol-5-yl) amino] carbonyl.}. amino) phenoxy] pyri din-2-carboxamide 4- (4-. { [( { 1- [2- (Diethylamino) ethyl] -1H-inda zo -5-yl.}. Amino) carbonyl] amino} -3-fluorophenoxy) -N-raet i lpiridin-2-carboxamide gives I \ J-me tyl- 4- [4 - ( { [(2-me t il- 1 H-indol- 5 -yl) amino carbonyl.}. amino) phenoxy] pyridine-2-carboxamide W-. { 4 - [(2-acetylpyridin-4-yl) oxy] phenyl} -N'- (1-methyl-lH-indazol-5-yl) urea N- [2- (dimethylamino) -2-oxoethyl] -4- [4- ( { [(1-methyl-1H indazole -5-yl) amino] carbonyl] -aminof.enoxi] pyridine-2-carboxamide iV-methyl-4- [4- ( { [(2-methyl-l, 3-benzothiazol-5-yl) amino] carbonyl.}. amino) phenoxy] pyridine-2-carboxamide N-methyl-4- { [4 - ( { [(1 -met i 1- 1 H- inda zo 1 -5 -i 1) amino] ca bonyl.}. amino) pheno]] met il.}. pyridine-2-carboxamide 4 - (3. {[[(1H-1, 2,3-benzotriazol-5-yl) amino) carbonyl] amino} pheno i) -N-methylpi idin-2-carboxamide 4 - [3 - (. {[[(l-methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2 Methylcarboxylate 4- (4-. {[[(1 H-1,2,3-benzotriazol-5-ylamino) carbonyl] amino-phenoxy) -N-methylpyridine-2-carboxamide 4 - (4 - { [(lH-indazole-6-ylamino) carbonyl] amino.}. phenoxy) -N -methylpyridine-2-carboxamide N-methyl-4- { 4- [( { [2 - (t rif luoromet il) -1H-benzimidazol-5-yl] aminojcarbonyl) amino] -f-enoxy. pyridine-2-carboxamide 4 - [4 - (. { [(1-ethyl-2-methyl-1H-benzimidazol-5-yl) amino] carbonyl} amino) phenoxy-N-methylpyridine-2-carboxamide gives 4 - [4 - (. {[[(1-met yl-lH-indazol-5-yl) amino] car onyl] amino) f enoxy] pyridine 2-carboxyl or methyl 4- [2-chloro-4- ( { [(2,2,4,4-tetrafluoro-4H-1, 3-benzodioxin-7-yl) amino] carbonyl}. ) -phenoxy] -N-met ilpyr id-2-carboxamide 4 - (4. {[[(2,3-dihydro-l, 4-benzodioxin-6-ylamino) carbonyl] amino Jphenoxy) -N- [ 3- (1H-imidazol-1-yl) propyl] pyridine-2-carboxamide 4- (4. {[[(2,3-dihydro-l, 4-benzodioxin-6-ylamino) carbonyl] amino}. phenoxy) -N- (2-pyrrolidin-1-ylethyl) pyridine-2-carboxamide N- [3- (lH-imidazol-1-yl) propyl] -4- [4- ( { [(1-methyl) -lH indazol-5-yl) air.ino] carbonyl.}. amino) -phenoxy] pyridine-2-carboxamide 4- [4 - (. {[[(l-methyl-lH-indazol-5-yl) amino] ] carbonyl.} amino) phenoxy] -N- (2-piperidin-1-ylethyl) pyridine-2-carboxamide • iV-cyclopropyl-4- [4- (. {[[(1-methyl-1H-indazole- 5-yl) amino] carbonyl.}. Amino) phenoxy] pyridine-2-carboxamide • N- (cyclopropi) lme il) -4- [4- (. { [(L-methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] -pyridine-2-carboxamide • N-cyclobutyl-4- [4- (. {[[(l-methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine 2- carboxamide or • Methyl-W- (. {4- [4- (. {[[(L-methyl-lH-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2- il.}. carbonyl) glycinate
13. A pharmaceutical composition comprising an effective amount of at least one compound according to claim 1 and a physiologically acceptable carrier.
14. A method for treating or preventing a hyperproliferative disorder in a human or other mammal that comprises administering to a human or other mammal in need thereof a compound according to claim 1 and an additional anti-proliferative agent.
15. A method for treating or preventing cancer in a human or other mammal comprising administering to a human or other mammal in need thereof a compound according to claim 1 and a cytotoxic agent or a cytostatic chemotherapeutic agent.
16. A method for treating or preventing a disease in a human or other mammal regulated by tyrosine kinase, associated with an aberration in the pathway of tyrosine kinase signal transduction, comprising administering to a human or other mammal in need thereof a compound according to claim 1.
17. A method for treating or preventing a disease in a human or other mammal produced by the VEGF-induced signal transduction path, which comprises administering to a human or other mammal in need thereof a compound according to claim 1.
18. A method for treating or preventing a disease in a human or other mammal characterized by abnormal processes of angiogenesis or hyperpermeability, comprising administering to a human or other mammal in need thereof a compound according to claim 1.
19. A method for treating or preventing a disease in a human or other mammal characterized by abnormal processes of angiogenesis or hyperpermeability, comprising administering to a human or other mammal in need thereof a compound C according to claim 1 simultaneously with another angiogenesis inhibiting agent in the same formulation or in separate formulations.
20. A method for treating or preventing one or more of the following conditions in humans and / or other mammals: tumor growth, retinopathy, ischemic retinalvenous occlusion, retinopathy of prematurity, age-related macular degeneration; rheumatoid arthritis, or psoriasis, a bullous disorder associated with the formation of subepidermal bladders, including bullous pemphigoid, erythema multiforme, or herpetiform dermatitis, which comprises administering to a human or other mammal in need thereof a compound according to the claim 1.
21. A method for treating or preventing one or more of the following conditions in humans and / or other mammals: tumor growth, retinopathy, diabetic retinopathy, ischemic retinal-venous occlusion, retinopathy of prematurity, macular degeneration related to age; rheumatoid arthritis, psoriasis, bullous disorder associated with the formation of subepidermal bladders, bullous pemphigoid, erythema multiforme, and dermatitis herpeti formi s, in combination with an infectious disease selected from the group consisting of: tuberculosis, Helicobacter pylori infection during the disease peptic ulcer, Chaga disease that is the result of Trypanosoma cruzi infection, effects of the Shiga-like toxin that is the result of E. coli infection, effects of enterotoxin A that is the result of infection by St aphilococcus , meningococcal infection, and infections caused by Borrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus, Teiler's encephalomyelitis virus, and human immunodeficiency virus (HIV), the method comprises administering to a human or other mammal which requires a compound according to claim 1 thereof.
22. A method for treating or preventing diseases caused by the VEGF-induced signal transduction path comprising administering a compound according to claim 12.
23. A method for treating or preventing cancer comprising administering a compound according to the indication 12.
24. A compound of the formula (I): or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein Q is C (0) R4, C (O) OR4 or C (0) NR4R5; where ? is a bicyclic heterocycle which is: (1) benzimidazol-5-yl (2) benzimidazol-6-yl (3) 1,3-benzothiazol-2-yl (4) 1,3-benzothiazol-5-yl (5) 1, 3-benzothiazol-6-yl (6) 1, 2, 3-benzotriazol-5-yl (7) 1,3-benz oxa zol -2 -i 1 or (8) 1,3-benz oxa zol-6-yl or (9) 2, 3-dihydro-lH-indol-5-yl (10) 2, 3-dihydro-lH-indol-6-yl (11) 2, 3-dihydro-lH-inden - 4-yl (12) 2, 3-dihydro-H-inden-5- i lo (13) 1, l-dioxide-2,3-dihydro-l-benzothien-6-yl (14) lH-indazol-5-yl (15) 2H-indazol-5-yl (16) lH-inda zol-6-yl (17) lH-indol-5-yl (18) 2-oxo-2 H-chromen- 7 -i (19) l-oxo-2,3-dihydro-lH-inden-5-yl (20) quinoxalin-2-yl (21) quinoxalin-6-yl, or (22) a group of the formula optionally substituted with 1-4 substituents which are independently R 1, OR 1, S O O p R 1, C (0) R x, C f C OR 1, C (0) NR 1 R 2, halogen, oxo, cyano, or nitro B is phenyl, naphthyl, pyridyl, or quinolinyl optionally substituted with 1-4 substituents which are independently C1-C5 straight or branched alkyl, C1-C5 straight or branched haloalkyl, Ci-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, Ci-C6 dial qui 1 amino, carboxyamide, halogen, cyano, nitro or S (0) pR7. L is: (a) - (CH2) m- 0- (CH2) y-, (b) - (CH2) m ~ (CH2)! -, (c) - (CH2) m ~ C (0) - ( CH2) 1-, (d) - (CH2) m ~ NR3- (CH2) i-, (e) - (CH2) m ~ NR3C (0) - (CH2) (f) - (CH2) m - S- (CH2) x-, (g) - (CH2) m_ C (0) NR3- (CH2) (h) an individual bond, m and 1 are integers independently selected from 0-4; M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C1-C5 straight or branched alkyl, C1-C5 straight or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, Ci- C6 dialkylamino, halogen, or nitro; Q is C (0) R4, C (0) OR4 or C (0) NR R5; each R1, R2, R3, R4 and R5 is independently: (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) phenyl, (d) C1-C3 alkyl-f-enyl, (e) ) up to C1-C5 linear or branched alkyl per-halo substituted, (f) - (CH2) qX where X is a 5 or 6 membered heterocyclic ring, containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or an 8-10 member bicyclic heteroaryl having 1-4 het eroat omos which are O, N or S, or (g) - (CH2) qY where Y is C (0 ) R6, C (0) OR6 and C (0) NR6R7; each R6-R7 is independently: (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) phenyl, (d) C1-C3 alkyl-f-enyl, or (e) to i-C5 linear or branched alkyl substituted by halo; each R1, R2, R3, R4, R5, R6 and R7, other than C1-C5 linear or branched alkyl substituted by halo, is optionally substituted with 1-3 substituents which are independently C1-C5 straight or branched alkyl, up to C1 -C5 linear or branched alkyl substituted by halo, C i -C 3 alkoxy, hydroxy, carboxy, amino, C 1 -C 3 alkylamino, Ci-Cg dialkylamino, halogen, cyano, or nitro. p is an integer selected from 0, 1, or 2; and q is an integer selected from 1, 2, 3, or 4.
25. A compound according to claim 24 wherein A is selected from (I) benzimidazol-5-yl (2) benzimidazol-6-yl (8) 1,3-benzoxazol-6-yl (9) 2, 3-dihydro- lH-indol-5-yl (10) 2, 3-dihydro-lH-indol-6-yl (II) 2, 3-dihydro-lH-inden-4-yl (12) 2,3-dihydro-lH- inden-5-yl (13) 1, l-dioxido-2,3-dihydro-l-benzothien-6-yl (14) lH-indazol-5-yl (15) 2H-indazol-5-yl (15) lH-indazol-6-yl (17) lH-indol-5-yl (18) quinoxalin-2-yl (19) quinoxalin-6-yl, and (20) a group of the formula
26. A compound according to claim 24 wherein the suggestions are optional in the bicyclic heterocycle A are independently R1, OR1, and halogen.
27. A compound according to the rei indication 26 wherein B is phenyl or pyridyl, optionally substituted with 1-4 substituents which are halogen.
28. A compound according to the rei indication 27 where L is -0-.
29. A compound according to claim 28 wherein Q is c (0) NR4R5 and each R4 and R5 is independently hydrogen or C1-C5 alkyl.
30. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein A is a bicyclic heterocycle which is: (1) benzimidaz ol -5-yl (2) benzimidazol-6-yl (8) 1,3-benz oxa z-ol-6-yl (9) 2, 3-dihydro-lH-indol-5-yl (10) 2,3-dihydro-lH-indol-6-yl (11) 2, 3-dihydro-lH- inden-4-yl (12) 2, 3-dihydro-lH-inden-5-yl (13) 1, l-dioxide-2,3-dihydro-1-benzothien-6-yl (14) lH-indazol-5-yl (15) 2H-indazol-5-yl (16) lH-indazol-6-yl (17) lH-indol-5-yl (18) quinoxalin-2-yl (19) ) quinoxalin-6-yl, and (20) a group of the formula optionally substituted with 1-4 substituents which are independently R1, OR1, S (0) pR1 / C (0) R1, C { 0) 0R1, C (0) NRxR2, halogen, oxo, cyano, or nitro B is phenyl, optionally substituted with halogen, L is -O-, M is a pyridine ring substituted only with Q, Q is C (0) NHR5 and R5 is independently hydrogen or Ci-C5 alkyl, and p is an integer selected from 0, 1, or 2.