JP5229853B2 - Novel bicyclic urea derivatives useful for the treatment of cancer and other diseases - Google Patents

Description

  The present invention relates to novel pharmaceutical compositions containing such compounds and to the treatment of hyperproliferative and angiogenic disease compounds, such compounds or compositions as single agents or For use as a combination with other active ingredients such as, for example, cytotoxic therapeutics.

  Activation of the ras signal transduction pathway represents a series of events that have a profound impact on cell proliferation, differentiation, and transformation. Although raf kinase is a downstream effector of ras, it is recognized as a central transmitter of these signals from cell surface receptors to the nucleus (Lowy, DR; Willumsen, BM Ann. Rev. Biochem. 1993, 62, 851; Bos, JL Cancer Res. 1989, 49, 4682). Inhibition of the effect of ras on activity by administration of a non-activating antibody to raf kinase or by inhibiting the raf kinase signaling pathway by co-expression of dominant negative raf kinase or dominant negative MEK (which is a substrate for raf kinase) Leads to the return of transformed cells to a normal proliferative phenotype (Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. Biol. Chem. 1994, 269, 30105- See 8. Kolch et al., (Nature 1991, 349, 426-28) further showed that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Inhibition of raf kinase (by antisense oligodeoxynucleotides) has been associated with inhibition of growth of various human tumor types in vitro and in vivo (Monia et al., Nat. 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 .; Eisenman-Tappe, I. Rapp, UR Recent Results Cancer Res. 1997 , 143, 237; Monia, BP; Johnston, JF; Geiger, T .; Muller, M .; Fabbro, D. Nature Medicine 1996, 2, 668).

To support progressive tumor growth beyond a size of 1-2 mm ³ , the tumor cells are more than functional substrates, ie fibroblasts, smooth muscle cells, endothelial cells, extracellular matrix proteins and soluble factors. It is recognized that a supporting structure is required (Folkman, J., Semin Oncol, 2002, 29 (6 Suppl 16), 15-8). Tumors induce the formation of matrix tissue through the secretion of soluble growth factors such as PDGF and transforming growth factor beta (TGF-β), which in turn is host cell fibroblast growth factor (FGF) Stimulate the secretion of auxiliary factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). These stimulating factors induce the formation of new blood vessels, i.e., angiogenesis, supply the tumor with oxygen and nutrients, allow for growth and provide a route for metastasis. It is believed that some of the treatments aimed at inhibiting substrate formation will inhibit the growth of epithelial tumors from a wide variety of histochemical types. (George, D. Semin Oncol, 2001, 28 (5 Suppl 17), 27-33; Shaheen, RM, et al., Cancer Res, 2001. 61 (4), 1464-8; Shaheen, RM, et al. Cancer Res, 1999. 59 (21), 5412-6). However, due to the complex nature and numerous growth factors involved in the angiogenic process and tumor progression, agents that target a single pathway may have limited effectiveness. It would be desirable to provide treatment for a number of central signaling pathways utilized by tumors to induce angiogenesis within the host matrix. These are PDGF (potential stimulator of substrate formation) (Oxtman, A. and CH Heldin, Adv Cancer Res, 2001, 80, 1-38), FGF (chemoattractant) and fibroblast and endothelial cells Includes mitogenic factors and VEGF (a potent regulator of angiogenesis).

  PDGF is another central regulator of matrix formation that is secreted by many tumors in a paracrine manner, promoting proliferation of fibroblasts, smooth muscle and endothelial cells, and promoting matrix formation and angiogenesis It is believed that. PDGF was originally identified as the v-sis oncogene product of monkey sarcoma virus (Heldin, C.H., et al., J Cell Sci Suppl, 1985, 3, 65-76). This growth factor is formed from two peptide chains called A or B chains that share 60% homology in the primary amino acid sequence. These chains are disulfide bridged to form a 30 kDa mature protein consisting of AA, BB or AB homo- or hetero-dimers. PDGF is found at high levels in platelets and is expressed by endothelial cells and vascular smooth muscle cells. In addition, PDGF production is up-regulated under hypoxic conditions as found in poorly vascularized tumor tissues (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 consisting of 1106 amino acids (Heldin, CH, A. Ostman, and L. Ronnstrand, Biochin Biophys Acta, 1998. 1378 (1), 79-113). The PDGF receptor (PDGFR) has an overall 30% homology in the amino acid sequence and is found as a homo- or heterodimeric chain with 64% homology between 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 separate kinase domains, including VEGFR2 (KDR), VEGFR3 (Flt4), c-Kit, and FLT3. PDGF receptors are predominantly expressed on fibroblasts, smooth muscle cells, and outer membrane cells, and to a lesser extent on nerve cells, renal mesangium, Leydig, and Schwann cells of the central nervous system. Upon binding to the receptor, PDGF induces receptor dimerization and undergoes autophosphorylation and transphosphorylation of tyrosine residues, which increases the kinase activity of the receptor and activates the SH2 protein binding domain. To promote replenishment of downstream effectors. A number of signal molecules, including PL-3-kinase, phospholipase C-γ, src and GAP (p21-ras GTPase-activating protein) form complexes with activated PDGFR (Soskic, V., et al Biochemistry, 1999, 38 (6), 1757-64). Through activation of PI-3-kinase, PDGF activates the Rho signaling pathway, induces cell motility and migration, and through activation of GAP activates the p21-ras and MAPK signaling pathways Induces mitosis through crystallization.

  In adults, it is believed that the primary function of PDGF is to facilitate wound healing, increase speed, and maintain vascular homeostasis (Baker, EA and DJ Leaper, Wound Repair Regen, 2000. 8 (5), 392-8; Yu, J., A. Moon, and HR Kim, Biochem Biophys Res Commun, 2001, 282 (3), 697-700). PDGF is found in high concentrations in platelets and is a potent chemoattractant for fibroblasts, smooth muscle cells, neutrophils and macrophages. In addition to its role in wound healing, PDGF is known to maintain vascular homeostasis. Upon formation of new blood vessels, PDGF recruits the pericytes and smooth muscle cells necessary for the structural integrity of the blood vessels. PDGF is thought to play a similar role in tumor neovascularization. As part of its role in angiogenesis, PDGF regulates interstitial fluid pressure and regulates vascular permeability through the regulation of interactions between connective tissue cells and the extracellular matrix. Inhibition of PDGFR activity may reduce interstitial pressure and promote influx of cytotoxins into the tumor, improving the antitumor activity of those agents (Pietras, K., et al. Cancer Res, 2002 62 (19), 5476-84; Pietras, K. et al. Cancer Res, 2001. 61 (7), 2929-34).

  PDGF promotes tumor growth through paracrine or autocrine stimulation of matrix cells or PDGFR receptors or directly to tumor cells or through receptor activation or receptor activation by recombination there is a possibility. Overexpression of PDGF can transform two types of human melanoma cells and keratinocytes that do not express the PDGF receptor, possibly by direct effects of PDGF on the induction of substrate formation and angiogenesis (Forsberg , K. et al. Proc Natl Acad Sci USA., 1993. 90 (2), 393-7; Skobe, M. and NE Fusenig, Proc Natl Acad Sci USA, 1998. 95 (3), 1050-5). This paracrine stimulation of the tumor matrix is also observed in colon, lung, breast and prostate cancers where the tumor expresses PDGF but not the receptor (Bhardwaj. B., et al. Clin Cancer Res , 1996, 2 (4), 773-82; Nakanishi, K. et al. Mod Pathol, 1997, 10 (4) .341-7; Sundberg, C. et al. Am J Pathol, 1997, 151 (2) Lindmark, G. et al. Lab Invest, 1993, 69 (6), 682-9; Vignaud, JM, et al, Cancer Res, 1994, 54 (20), 5455-63). Autocrine stimulation of tumor cell growth, where a large portion of the analyzed tumor expresses both the ligand PDGF and the receptor, is a glioblastoma (Fleming, TP, et al. Cancer Res, 1992, 52 (16) , 4550-3), soft tissue sarcoma (Wang, J., MD coltrera, and AM Gown, Cancer Res, 1994, 54 (2), 560-4) and ovarian cancer (Henriksen, R., et al. Cancer Res, 1993, 53 (19), 4550-4), prostate cancer (Fudge, K., CY Wang, and ME Stearns, Mod Pathol, 1994, 7 (5), 549-54), pancreatic cancer (Funa, K., et al. Cancer Res, 1990, 50 (3), 748-53) and lung cancer (Antoniades, HN, et al., Proc Natl Acad Sci USA, 1992, 89 (9), 3942-6) . Ligand-independent receptor activation is found to a lesser extent but has been reported in chronic myelogenous leukemia (CMML), where a chromosomal translocation occurs between the Ets-like transcription factor TEL and the PDGF receptor. Even fusion proteins form. In addition, activating mutations in PDGFR that do not involve c-Kit activation have been found in gastrointestinal matrix tumors (Heinrich, M.C., et al., Science, 2003, 9, 9). It is believed that certain PDGFR inhibitors will interfere with tumor matrix growth and inhibit tumor growth and metastasis.

  Another major regulator of angiogenesis and angiogenesis in both embryonic development and angiogenesis-dependent diseases is vascular endothelial growth factor (VEGF; also called vascular permeability factor VPF). VEGF represents a family of mitogen isoforms that exist in the form of homodimers by alternative RNA splicing. VEGF isoforms have been reported to be highly specific for vascular splenocytes (reviewed by Farrara et al. Endocr. Rev. 1992, 13, 18; Neufield et al. FASEB J. 1999, 13 , 9).

Expression of VEGF is dependent on conditions by hypoxia (Shweiki et al. Nature 1992, 359, 843) and various cytokines such as interleukin-1, interleukin-2, epidermal growth factor and transforming growth factor and the like Induced by growth factors. To date, VEGF and the members of the VEGF family have more than one of three transmembrane receptor tyrosine kinases (Mustonen et al. J. Cell Biol., 1995, 129, 895), VEGF receptor-1 (Also known as flt-1 (fms-like tyrosine kinase-1)), also known as the kinase insert domain containing VEGFR-2 (receptor (KDR)); the KDR murine analog is fetal liver kinase- 1 (also known as flk-1)) and to VEGFR-3 (also known as flt-4). KDR and flt-1 have been shown to have different signal transduction pathways (Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et al. Oncogene 1995, 10, 135) . That is, KDR undergoes strong ligand-dependent tyrosine phosphorylation in intact cells, whereas flt-1 shows a weak response. Thus, binding to KDR is believed to be one of the critical requirements for the induction of the full spectrum of VEGF-mediated biological responses.
In vivo, VEGF plays a central role in angiogenesis and induces angiogenesis and increased vascular permeability. Deregulated VEGF expression contributes to the development of numerous diseases characterized by abnormal angiogenesis and / or hyperpermeability processes. Modulation of the VEGF-mediated signal transduction cascade by several agents may provide a useful modality for the modulation of abnormal angiogenesis and / or hyperpermeability processes.

  Angiogenesis is regarded as one of the key prerequisites for tumor growth above about 1-2 mm. In smaller tumors, oxygen and nutrients can be supplied through diffusion. However, every tumor is believed to depend on angiogenesis to grow continuously after reaching a certain size. Tumor-forming cells in the hypoxic region inside the tumor respond by stimulating VEGF production, which triggers activation of quiescent vascular endothelial cells to stimulate new blood vessel formation (Shweiki et al. Proc. Nat'l. Acad. Sci., 1995, 92, 768). In addition, the production of VEGF in tumor areas without angiogenesis can proceed via the ras signal transduction pathway (Grugel et al. J. Biol. Chem., 1995, 270, 25915; Rak et al. Cancer Res. 1995, 55, 4575). In situ hybridization studies showed that VEGF mRNA was found in lung cancer (Mattern et al. Br. J. Cancer 1996, 73, 931), thyroid cancer (Viglietto et al. Oncogene 1995, 11, 1569) and breast cancer (Brown et al. Human Pathol. 1995, 26, 86), digestive tract (Brown et al. Cancer Res. 1993, 53, 4727; Suzuki et al. Cancer Res. 1996, 56, 3004), kidney and bladder cancer (Brown et al. Am) J. Pathol. 1993, 143I, 1255), ovarian cancer (Olson et al. Cancer Res. 1994, 54, 1255)), cervical cancer (Guidi et al. J. Nat'l Cancer Inst. 1995, 87, 12137), as well as angiosarcomas (Hashimoto et al. Lab. Invest. 1995, 73, 859) and several intracranial tumors (Plate et al. Nature 1992, 359, 845; Phillips et al. Int. J. Oncol 1993, 2, 913; Berkman et al. J. Clin. Invest., 1993, 91, 153) have been shown to be strongly up-regulated. Neutralizing monoclonal antibodies against KDR have been shown to be effective in blocking tumor angiogenesis (Kim et al. Nature 1993, 362, 841; Rockwell et al. Mol. Cell. Differ. 1995, 3, 315).

  For example, overexpression of VEGF under extreme hypoxic conditions can lead to intraocular neovascularization, resulting in blood vessel growth and ultimately blindness. Such a chain of events has been linked to diabetic retinopathy, ischemic retinal vascular occlusion, and retinopathy of prematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638), and numerous retinopathy, including age-related macular degeneration (AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855).

  In rheumatoid arthritis (RA), the inward elongation of vascular pannus may be mediated by the production of angiogenic factors. Immunoreactive VEGF levels were high in the synovial fluid of RA patients, while VEGF levels were low in the synovial fluid of patients with other forms of arthritis with osteoarthritis (Koch et al. J. Immunol 1994, 152, 4149). The angiogenesis inhibitor AGM-170 has been shown to suppress indirect neovascularization in a rat collagen arthritis model (Peacock et al. J. Exper. Med. 1992, 175, 1135).

  Increased VEGF expression is also shown in psoriatic skin and bullous diseases associated with subepithelial blistering, such as bullous pemphigoid, erythema multiforme and herpes zoster (Brown et al. J. Invest. Dermatol. 1995, 104, 744).

  Vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and their receptors (VEGFR2, VEGFR3) are central regulators of tumor angiogenesis as well as lymphangiogenesis. VEGF, VEGF-C and VEGF-D are expressed in most tumors primarily during the period of tumor growth and often at substantially elevated levels. VEGF expression is stimulated by oncogenes such as hypoxia, cytokines, ras, etc. or by inactivation of tumor suppressor genes (McMahon, G. Oncologist 2000, 5 (Suppl. 1), 3-10; McDonald, NQ; Hendrickson, WA Cell 1993, 73, 421-424).

  The biological activity of VEGFs is mediated through binding to their receptors. VEGFR3 (also called Flt-4) is mainly expressed on the epithelial surface of lymphatic vessels in normal tissues. The function of VEGFR3 is required for new lymphangiogenesis but not for maintenance of existing lymphatics. VEGFR3 is also up-regulated on tumor vascular endothelium. Recently, VEGF-C and VEGF-D, which are ligands for VEGFR3, have been identified as regulators of lymphangiogenesis in mammals. Lymphangiogenesis induced by tumor-associated lymphangiogenesis can promote the growth of new ducts into the tumor, providing tumor cells with access to the systemic circulation. Cells that infiltrate lymphatic vessels can find their way into the bloodstream through the thoracic duct. Tumor development studies are clinical diseases directly related to the ability of VEGF-C, VEGF-D and VEGFR3 to expand the primary tumor (eg, involvement of lymph nodes, lymphoid invasion, secondary metastasis, and disease-free survival) Allows direct comparison with physical factors. In many instances, these studies show a statistical correlation between the expression of lymphangiogenic factors and the ability of the 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. EMBO 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 VEGF production in malignant cells. Activation of p38 MAP kinase is required for VEGF induction 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, 251-257). In addition to being involved in angiogenesis through the regulation of VEGF secretion, p38 MAP kinase is responsible for malignant cell invasion and migration of various 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).

Some diarylureas have been described as having activity as inhibitors of serine-threonine kinases and / or tyrosine kinases. The usefulness of these diarylureas as active ingredients in pharmaceutical compositions for the treatment of cancer, angiogenic disorders, and inflammatory diseases has been described. 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, 220 ^th 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, 92 ^nd AACR Meeting, New Orleans, LA, USA, abstract 4956; Khire et al. , Book of Abstracts, 93 ^rd AACR Meeting, San Francisco, CA, USA, abstract 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; Carter et al., Book of Abstracts, 92 ^nd AACR Meeting, New Orleans, LA, USA, abstract 4954; Vincent et al., Book of Abstracts, 38 ^th ASCO Me eting, Orlando, FL, USA, abstract 1900; Hilger et al., Book of Abstracts, 38 ^th ASCO Meeting, Orlando, FL, USA, abstract 1916; Moore et al., Book of Abstracts, 38 ^th ASCO Meeting, Orlando, FL, USA, abstract 1816; Strumberg et al., Book of Abstracts, 38 ^th ASCO Meeting, Orlando, FL, USA, abstract 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., Book of Abstracts, 38 ^th ASCO Meeting, Orlando, FL, USA, abstract 473; Tolcher et al., Book of Abstracts, 38 ^th ASCO Meeting, Orlando, FL, USA, abstract 334; and Karp et al., Book of Abstracts, 38 ^th AACR Meeting, San Francisco, CA, USA, abstract 2753.

  Despite technological advances, there is still a need for various cancer treatments and various anticancer compounds.

The present invention is:
(I) urea compounds, salts, metabolites and prodrugs thereof, including diastereoisomeric forms,
(Ii) a pharmaceutical composition containing any of such compounds, its salts, metabolites and prodrugs, including diastereoisomeric forms, and (iii) as the sole agent or other active ingredient, eg Use of those compounds or compositions to treat diseases, eg, hyperproliferative and angiogenic diseases, in combination with cytotoxic therapy;
About.

Compounds of formula (I), including salts, metabolites and prodrugs thereof, including diastereoisomeric forms (both isolated stereoisomers and mixtures of stereoisomers), are used herein. Collectively, they are referred to as “compounds of the invention”.
Formula (I) is as follows:

[Where A is:
(1) Benzimidazolyl,
(2) 1,3-benzothiazolyl,
(3) 1,2,3-benzotriazolyl,
(4) 1,3-benzoxazolyl,
(5) 2,3-dihydro-1H-indolyl,
(6) 2,3-dihydro-1H-indenyl,
(7) 1,1-dioxide-2,3-dihydro-1-benzothienyl,
(8) 1H-indazolyl,
(9) 2H-indazolyl,
(10) 1H-in drill,
(11) 2H-chromenyl,
(12) Quinoxalinyl, or (13) Formula:

Group of
Is a bicyclic heterocycle of].
Of note are compounds of formula I wherein A is:
(1) benzimidazol-5-yl,
(2) benzimidazol-6-yl,
(3) 1,3-benzothiazol-2-yl,
(4) 1,3-benzotriazol-5-yl,
(5) 1,3-benzotriazol-6-yl,
(6) 1,2,3-benzotriazol-5-yl,
(7) 1,3-benzoxazol-2-yl,
(8) 1,3-benzoxazol-6-yl,
(9) 2,3-dihydro-1H-indol-5-yl,
(10) 2,3-dihydro-1H-endol-6-yl,
(11) 2,3-dihydro-1H-inden-4-yl,
(12) 2,3-dihydro-1H-inden-5-yl,
(13) 1,1-dioxide-2,3-dihydro-1-benzothien-6-yl,
(14) 1H-indazol-5-yl,
(15) 2H-indazol-5-yl,
(16) 1H-indazol-6-yl,
(17) 1H-indol-5-yl,
(18) 2H-chromen-7-yl,
(19) Quinoxalin-2-yl,
(20) Quinoxalin-6-yl, and (21) Formula:

Group of
Including those selected from
Preferred compounds of formula I are
(1) benzimidazol-5-yl,
(2) benzimidazol-6-yl,
(8) 1,3-benzoxazol-6-yl,
(9) 2,3-dihydro-1H-indol-5-yl,
(10) 2,3-dihydro-1H-indol-6-yl,
(11) 2,3-dihydro-1H-inden-4-yl,
(12) 2,3-dihydro-1H-inden-5-yl,
(13) 1,1-dioxide-2,3-dihydro-1-benzothien-6-yl,
(14) 1H-indazol-5-yl,
(15) 2H-indazol-5-yl,
(16) 1H-indazol-6-yl,
(17) 1H-indol-5-yl,
(18) quinoxalin-2-yl,
(19) Quinoxalin-6-yl, and (20) Formula:

Group of
Having A selected from
The bicyclic heterocycle A is independently R ¹ , OR ¹ , S (O) _p R ¹ , C (O) R ¹ , C (O) OR ¹ , C (O) NR ¹ R ² , halogen, It may be optionally substituted with 1 to 4 substituents which are oxo, cyano or nitro.

Preferred optional substituents on the bicyclic heterocycle A are independently R ¹ , OR ¹ , and halogen.

B is independently C ₁ -C ₅ linear or branched alkyl, C ₁ -C ₅ linear or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ -C ₃ alkyl Phenyl, naphthyl, pyridyl or quinolinyl optionally substituted with 1 to 4 substituents which are amino, C ₁ -C ₆ dialkylamino, carboxamide, halogen, cyano, nitro or S (O) _p R ⁷ It is.

B is preferably phenyl, pyridyl or quinolinyl, more preferably independently C ₁ -C ₅ straight chain or branched alkyl, C ₁ -C ₅ straight chain or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ -C ₃ alkylamino, C ₁ -C ₆ dialkylamino, carboxamido, halogen, cyano, 1 to 4 substituents nitro or S (O) _p R ⁷ And optionally substituted phenyl or pyridyl.

L is:
_{(A) - (CH 2)} m -O- (CH 2) l -,
_{(B) - (CH 2)} m - (CH 2) l -,
_{(C) - (CH 2)} m -C (O) - (CH 2) l -,
_{(D) - (CH 2)} m -NR 3 (CH 2) l -,
_{(E) - (CH 2)} m -NR 3 C (O) - (CH 2) l -,
_{(F) - (CH 2)} m -S- (CH 2) l -,
_{(G) - (CH 2)} m -C (O) NR 3 - (CH 2) l -, or (h) a single bond;
A linking group that is
Here, m and l are independently selected from 0 to 4, preferably an integer selected from 0 to 2.
Most preferably, L is —O— or —S—.

M is independently C ₁ -C ₅ linear or branched alkyl, C ₁ -C ₅ linear or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ -C ₃ alkyl A pyridine ring optionally substituted with 1 to 3 substituents which are amino, C ₁ -C ₆ dialkylamino, halogen, or nitro.

Q is C (O) R ⁴ , C (O) OR ⁴ or C (O) NR ⁴ R ⁵ .
Each of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is independently:
(A) hydrogen,
(B) C ₁ -C ₅ alkyl (straight, branched or cyclic alkyl),
(C) phenyl,
(D) C ₁ -C ₃ alkyl - phenyl,
(E) C ₁ -C substituted up to perhalo ₅ straight or branched chain alkyl,
_{(F) - (CH 2)} q -X, here, X is saturated, partially saturated, or aromatic, 5 or 6 comprising at least one atom selected from oxygen, nitrogen and sulfur A membered heterocyclic ring, or an 8 to 10 membered bicyclic heteroaryl having 1 to 4 heteroatoms that are O, N or S, or (g) — (CH ₂ ) _q —Y, wherein Y is C (O) R ⁶ , C (O) OR ⁶ or C (O) NR ⁶ R ⁷ ;
It is.

Each of R ¹ , R ² , R ¹³ , R ⁴ and R ⁵ is preferably independently:
(A) hydrogen,
(B) C ₁ -C ₅ alkyl,
(C) phenyl,
(D) Substituted C ₁ -C ₅ linear or branched alkyl up to perhalo.

Each of R ⁶ through R ⁷ is independently:
(A) hydrogen,
(B) C ₁ -C ₅ straight-chain, branched or cyclic alkyl,
(C) phenyl,
(D) C ₁ -C ₃ alkyl-phenyl, or (e) substituted C ₁ -C ₅ linear or branched alkyl up to perhalo.

Each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ other than perhalo-substituted C ₁ -C ₅ linear or branched alkyl is independently C ₁ -C ₅ straight chain or branched alkyl, substituted C ₁ -C ₅ straight or branched alkyl having up to perhalo, C ₁ -C ₃ alkoxy, hydroxy, carboxy, amino, C ₁ -C ₃ alkylamino, C ₁ - It may be optionally substituted with 1 to 3 substituents which are C ₆ 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 moiety is “substituted” it can have up to the maximum number of substituents indicated, each substituent can be in any available position on the moiety; "Any available position" that can be attached through any available atom on a substituent is chemically accessible via means known in the art or taught herein. By any position on the group that does not create a possible and extremely unstable molecule. When more than one substituent is present in any part, each substituent is defined independently of any other substituent and can therefore be the same or different.

  The term “optionally substituted” means that the moiety modified by the word may either be unsubstituted or substituted with that particular substituent.

  Since M is pyridine, the term “hydroxy” as a pyridine substituent includes 2-, 3- and 4-hydroxypyridine, although in the art 1-oxo-pyridine, 1-hydroxy-pyridine, and pyridine N -Also includes structures called oxides.

  Where the plural forms of the terms compound, salt, etc. are used herein, this is taken to mean also a single compound, salt, etc.

The term C ₁ -C ₅ alkyl means a straight or branched alkyl group having 1 to 5 carbon atoms, which may be straight or branched with single or multiple branches. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.

The term haloC ₁ -C ₅ alkyl means a saturated hydrocarbon group having up to 5 carbon atoms substituted with at least one halogen atom, up to perhalo. The group can be straight or branched with single or multiple branches. Halo substituents include fluoro, chloro, bromo or iodo. Fluoro, chloro and bromo are preferred, and fluoro and chloro are more preferred. The halogen substituent can be located on any available carbon. If more than one halogen substituent is present in this moiety, they may be the same or different. Examples of such halogenated alkyl substituents include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 1,1,2,2-tetrafluoroethyl and the like.

The term C ₁ -C ₃ alkoxy means a straight or branched alkoxy group having 1 to 3 saturated carbon atoms, which may be straight or branched with single or multiple branches, Has groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like. It also contains halogenated groups such as 2,2-dichloroethoxy, trifluoromethoxy and the like.

  Halo or halogen means fluoro, chloro, bromo or iodo. Fluoro, chloro and bromo are preferred, and fluoro and chloro are more preferred.

C ₁ -C ₃ alkylamine means methylamino, ethylamino, propylamino or isopropylamino. Examples of C ₁ -C ₆ dialkylamines include, but are not limited to, diethylamino, ethyl-isopropylamino, meaning methylamino, methyl-isobutylamino, dihexylamino.

  The term heteroaryl refers to both monocyclic and bicyclic heteroaryl rings. Monocyclic heteroaryl means an aromatic monocycle having 5 to 6 ring atoms, at least one of which is a heteroatom selected from N, O and S, and the remaining atoms are carbon. If more than one heteroatom is present in the moiety, they are independently selected from the others so that they may be the same or different. 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 a fused bicyclic group in which one of the rings is selected from the monocyclic heteroaryl rings described above and the second ring is either benzene or another monocyclic heteroaryl ring described above . When both rings in a bicyclic group are heteroaryl rings, they may be the same or different as long as they are chemically available by means known in the art. Bicyclic heteroaryl rings include, for example, but are not limited to, benzoxazole (fused phenyl and oxazole), quinoline (fused phenyl and pyridine), imidazopyrimidine (fused imidazole and pyrimidine), etc. Containing 5-5, 5-6 or 6-6 fused bicyclic aromatic structures which are commercially available.

  The term “a 5- or 6-membered heterocycle containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated or aromatic” is not limited, Tetrahydropyran, tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyran, dihydrofuran, dihydrothiophene, pyrrole , Furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine and the like.

The term “C ₁ -C ₃ alkyl-phenyl” includes, but is not limited to, 3-phenyl-propyl, 2-phenyl-1-methyl-ethyl. Substituted examples include 2- [2-chlorophenyl] ethyl, 3,4-dimethylphenyl-methyl, and the like.

  The compounds of formula I can contain one or more asymmetric centers, depending on the position and nature of the various substituents desired. Asymmetric carbon atoms can exist in the (R) or (S) conformation or (R, S) conformation. In certain instances, asymmetry can also be present by limited rotation about a given bond, eg, a central bond that connects two substituted aromatic rings of a particular compound. Substituents on the ring can exist in either cis or trans form. All such conformations (including enantiomers and diastereomers) are intended to be included within the scope of the present invention. Preferred compounds are those having the absolute conformation of the compound of formula I that produces the more desirable biological activity. Separated, pure or partially purified isomers or racemic mixtures of the compounds of the invention are also included within the scope of the invention. Purification of the isomer and separation of the mixture of isomers can be accomplished by standard techniques known in the art.

  Optical isomers can be obtained by resolution of racemic mixtures according to conventional methods, for example by formation of diastereomeric salts or covalent diastereomers using optically active acids or bases. Examples of suitable acids include tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomeric salts are separated into their individual diastereomers on the basis of their physical and / or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization. can do. The optically active base or acid is then liberated from the separated diastereomeric salt. Another method for separating optical isomers is chiral chromatography (eg, chiral HPLC column) optimally selected to maximize enantiomeric separation, with or without conventional derivation. With the use of. Suitable chiral HPLC columns are manufactured by Diacel, among others, for example as chiral OD and chiral OJ, all of which are routinely selectable. Enzymatic separation with or without derivatization is also useful. Optically active compounds of formula I can likewise be obtained utilizing optically active starting materials.

  The invention also relates to useful forms of all compounds of the compounds of formula (I), such as pharmaceutically acceptable salts, metabolites and prodrugs, etc., as disclosed herein.

  The term “pharmacologically acceptable salt” refers to a relatively non-toxic, inorganic or organic addition salt of a compound of the invention. See, for example, S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts also have the main compound functioning as an acid and reacting with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium and choline salts. Including things. One skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared by reaction with a suitable inorganic or organic acid by any of a number of known methods. Alternatively, alkali metal salts and alkaline earth metal salts can be prepared by reacting the compounds of the invention with the appropriate base by a variety of known methods.

  Exemplary salts of the compounds of the present invention include the conventional non-toxic salts and, for example, quaternary ammonium salts formed from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphor Acid salt, camphor sulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecyl sulfonate, ethane sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulphate, heptanoic acid Salt, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2 -Naphthalene sulfonate, nicotinate, nitrate, oxaloacetate, pamoate, pectate, persulfate, 3-phenylpropiate Examples include onnate, picrate, pyruvate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.

  Examples of the base salt include alkali metal salts such as potassium and sodium, alkaline earth metal salts such as calcium and magnesium, and ammonium salts having an organic base such as dicyclohexylamine and N-methyl-D-glucamine. In addition, basic nitrogen-containing groups include dialkyl sulfates such as chloro, bromide and halogenated lower alkyl reagents such as methyl, ethyl, propyl and butyl, dimethyl, diethyl and dibutyl sulfate; and diamyl sulfate. May be quaternized with long chain halides such as decyl chloride, bromide and iodide, lauryl, myristyl and stearyl, benzyl bromide and phenethyl and other aralkyl halides.

  Certain of the compounds of the present invention may be further modified with labile (functional) groups that are cleaved after administration in vivo to give the active drug substance and a pharmacologically inactive derivatizing group. Can do. These derivatives, commonly referred to as prodrugs, alter the pharmacokinetic and pharmacodynamic properties of the active agent to alter the physicochemical properties of the active agent and direct the active agent to specific tissues Can be used to reduce unwanted side effects.

As prodrugs of the present invention, for example, esters of suitable compounds of the present invention are well tolerated and pharmaceutically acceptable such as alkyl esters including methyl, ethyl, propyl, isopropyl, butyl or pentyl. May be mentioned. Although methyl esters are preferred, phenyl-C ₁ -C ₅ alkyl can be used as further esters.

Methods for synthesizing prodrugs are described in the following review articles on the subject matter, which are incorporated herein by reference for a description of those methods.
Higuchi, T .; Stella, V. eds. Prodrugs As Novel Drug Delivery Systems.ACS Symposium Series.American Chemical Society: Washington, DC (1975).
Roche, EB Design of Biopharmaceutical Properties through Prodrugs and Analogs.American Pharmaceutical Association: Washington, DC (1977).
・ Sinkula, AA; Yalkowsky, SH J Pharm Sci. 1975, 64, 181-210.
・ Stella, VJ; Charman, WN Naringrekar, VH Drugs 1985, 29, 455-473.
・ Bundgaard, H., ed.Design of Prodrugs.Elsevier: New York (1985).
・ Stella, VJ; Himmelstein, KJJ Med. Chem. 1980, 23, 1275-1282.
・ Han, HK; Amidon, GL AAPS Pharmsci 2000, 2, 1- 11.
・ Denny, WA Eur. J. Med. Chem. 2001, 36, 577-595.
・ Wermuth, CG in Wermuth, CG ed.The Practice of Medicinal Chemistry Academic Press: San Diego (1996), 697-715.
Balant, LP; Doelker, E. in Wolff, ME ed.Burgers Medicinal Chemistry And Drug Discovery John Wiley & Sons: New York (1997), 949-982.

  Metabolites of compounds of the present invention include oxidized derivatives of compounds of formula I, wherein one or more nitrogens are substituted with hydroxy groups, and the pyridine group nitrogen atom is in the oxide form. Certain derivatives (referred to in the art as 1-oxo-pyridine) or derivatives having a hydroxy substituent (referred to as 1-hydroxypyridine).

General Preparation Methods The particular method utilized to prepare the compounds used in the embodiments of the invention will depend on the specific compound intended. Factors such as the choice of specific substituents play a substantial role in the route to be followed in the preparation of certain compounds of the invention. Those factors will be readily recognized by those skilled in the art.

  The compounds of the present invention may be prepared by using known chemical reactions and procedures. However, the following general preparative methods are provided with more detailed examples that are presented in the experimental section below to assist the reader in synthesizing the compounds of the present invention. Presented.

  All of the various groups of these methods are described as general descriptions, if not specifically defined. When a given symbol is used more than once in a structure with various groups or substituents, each of those groups or substituents may vary independently within the definition of that symbol. I have to understand that. It should be recognized that the claimed compounds with the individual selectable functional groups may not be prepared by the individual methods listed below. Within each method, appropriate substituents that are stable to the reaction conditions are used, or the functional groups involved in the reaction are present in protected form if necessary, and removal of such protecting groups is At an appropriate stage, this is accomplished by methods well known to those skilled in the art.

  The compounds of the present invention can be made by conventional chemical methods and / or from starting materials that are commercially available as described below or can be prepared according to routine, conventional chemical methods. Can be made. General methods for the preparation of these compounds are presented below and the preparation of representative compounds is specifically described in the examples.

General Method (1) Reaction Scheme 1: Synthesis of Ureas of Formula (I)

  The preparation of ureas of formula (I) is depicted in Reaction Scheme 1, where A, B, L, M and Q are broadly defined as described above. Compound (I) can be synthesized according to the reaction sequence shown in General Methods E and F above. Using Method E, ureas of formula (I) can be converted to two arylamines in the presence of phosgene, di-phosgene, tri-phosgene, carbonyldiimidazole, or the like, in a solvent that does not react with any of the starting materials. Prepared from the condensation of fragments (II) and (III). Alternatively, compound (I) can be synthesized using method F by reacting amino compound (II) with isocyanate compound (IV).

  Isocyanates (IV) are commercially available or [for example, trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or N, N′-carbonyldiimidazole (CDI). From the treatment of amines with phosgene or phosgene equivalents; or alternatively by curtician rearrangements of amides or carboxylic acid derivatives such as esters, acid halides or anhydrides] according to methods commonly known to those skilled in the art Can be synthesized from a heterocyclic amine of formula (II) or (III).

Reaction Scheme 2: Synthesis of Starting Material of Formula (IV)

Aryl amines of formula (III) or (V) are commercially available or can be synthesized according to methods A or B or methods commonly known to those skilled in the art. Arylamines are usually synthesized by reduction of nitroaryl using a metal catalyst such as Ni, Pd or Pt and a hydride ion transfer agent such as H ₂ or formate, cyclohexadiene or borohydride (Rylander , Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryl uses a strong hydride source such as LiAlH ₄ (Seyden-Penne; Reductions by the Alumino-and borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or often Fe, Sn in acidic media. Alternatively, it can be directly reduced using a zero-valent metal such as Ca. Many methods exist for the synthesis of nitroaryl (March; Advanced Organic Chemistry, 3 rd Ed .; John Wiley: New York (1985), Larock, Comprehensive Organic Transformations; VCH Publishers: New York (1989)). Nitroaryl is usually formed by electrophilic aromatic nitration using HNO ₃ or another NO ₂ ⁺ source.

L represents — (CH ₂ ) _m O—, — (CH ₂ ) _m S—, or — (CH ₂ ) _m NH—, and B, M, Q, and m are widely defined as described above ( In the synthesis of compounds II), nitroaryl is further devised prior to reduction. In Reaction Scheme 2-Method D, a nitroaryl substituted with a potential leaving group such as F or Cl undergoes a substitution reaction upon treatment with a nucleophile such as phenoxide or thiolate under basic conditions. receive.

  Another method for the preparation of the intermediate of formula (II) is depicted in Reaction Scheme 2-Method C. The condensation of amine (V) with a suitable substituted chloropyridine has been previously described in the patent literature and can be adapted to the compounds of the invention. For example, PCT International Application, 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 International Application, WO 99 32110, Dumas, J., et al., “Inhibition of raf Kinase using Aryl-and Heteroaryl-Substituted Heterocyclic Ureas”.

Reaction Scheme 3: Alternative Synthesis of Urea of Formula (I)

The compounds of the present invention can also be prepared from compounds of formula (VII) according to the reaction sequence shown in the general methods G and H above. Using Method G, ureas of formula (VI) are treated with a Lewis acid such as magnesium chloride and a suitable substituted amine in a solvent such as THF at room temperature to give the substituted amide. . In Method H, the ureas of formula (VI) are deesterified with a base such as potassium hydroxide, lithium hydroxide or sodium hydroxide. The carboxylic acid of formula (VII) is converted to the appropriate amine according to methods commonly known to those skilled in the art [eg from treatment of the carboxylic acid with DCC / DMAP or EDCl / HOBT] in a solvent such as THF, AcCN, or DMF. To be coupled. In addition, compounds of formula (I) wherein R ₄ and R ₅ are hydrogen can be synthesized according to the reaction scheme shown in Method I. The cyano compound (VIII) can be hydrolyzed in an aqueous solvent such as acetone-water in the presence of NaOH or sodium percarbonate at a temperature of 20-100 ° C. Compounds of formula (VI) and (VIII) are synthesized according to methods A to F or methods commonly known to those skilled in the art.

A pyridine-1-oxide of formula I in which M carries a hydroxy substituent on its nitrogen atom and A, B, and L are broadly defined as described above, uses oxidation conditions known in the art and supports Can be prepared from pyridine. Some examples are as follows:
M-Chloroperbenzoic acid (Markgraf et al., Tetrahedron 1991, 47, 183) in chlorinated solvents such as dichloromethane, dichloroethane or chloroform.
(Me ₃ SiO) _{2 in} the presence of a catalytic amount of perrhenic acid in a chlorinated solvent such as dichloromethane (Coperet et al., Terahedron Lett. 1998, 39, 761).
Perfluoro-cis-2-butyl-3-propyloxaziridine in a combination of several halogens (Amone et al., Tetrahedron 1998, 54, 7831).
Hypofluorite-acetonitrile complex in chloroform (Dayan et al., Synthesis 1999, 1427).
Oxone in the presence of a base such as KOH in water (Robker et al., J. Chem. Res., Synop. 1993, 10, 412).
Magnesium monoperoxyphthalate in the presence of glacial acetic acid (Robker et al., J. Chem. Res., Synop. 1993, 10, 412).
Hydrogen peroxide in the presence of water and acetic acid (Lin AJ, Org. Prep. Proced. Int. 1991, 23 (1), 114).
-Dimethyldioxirane in acetone (Boyd et al., J. Chem. Soc., Perkin Trans. 1991, 9, 2189).

  In addition, specific preparations of diarylureas and intermediate compounds (II) have already been described in the patent literature and can be adapted to the compounds of the invention. For example, Miller S. et al, “Inhibition of p38 Kinase using Symmetrical and Unsymmetrical Diphenyl Ureas” PCT international application, WO 99 32463, Miller, S et al. “Inhibition of raf Kinase using Symmetrical and Unsymmetrical Substituted Diphenyl Ureas” PCT international application , WO 99 32436, Dumas, J. et al., “Inhibition of p38 Kinase Activity using Substituted Heterocyclic Ureas” PCT international application, 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 international application, WO 99 32106, Dumas, J. et al.,“ Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas ”PCT international application , WO 99 32110, Dumas, J., et al., “Inhibition of raf Kinase using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas” PCT International Application, WO 99 32455, Riedl, B., et al., “O-Carboxy Aryl Substituted Diphenyl Ureas as raf Kinase Inhibitors ”PCT International Application, WO 00 42012, Riedl, B., et al., “O-Carboxy Aryl Substituted Diphenyl Ureas as p38 Kinase Inhibitors” PCT International Application, WO 00 41698, Dumas, J. et al. “Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors” US Patent Published, US 20020065296, Dumas, J. et al. “Preparation of N-aryl-N '-[(acylphenoxy) phenyl] ureas as raf kinase inhibitors” PCT International Application, WO 02 62763, Dumas, J. et al. “Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas ”PCT international application, 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 Patent Application Publication, US 20020165394. All of these patent applications are hereby incorporated by reference.

  The reaction between compound (III) or (IV) and (II) is preferably carried out in a solvent. Suitable solvents include conventional organic solvents that are inert under the reaction conditions. Non-limiting examples are ethers such as diethyl ether, dioxane, tetrahydrobran, 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions; dichloromethane, trichloromethane, tetrachloride Halogenated hydrocarbons such as carbon, dichloroethane, trichloroethylene and chlorobenzene; alcohols such as methanol, ethanol, n-propanol and isopropanol; esters such as ethyl acetate; ketones such as acetone; nitriles such as acetonitrile; Heteroaromatics; polar solvents such as dimethylformamide and hexamethylphosphoric acid tris-amide; and mixtures of said solvents. Toluene, benzene and dichloromethane are preferred.

  Compound (III) is generally used in an amount of 1 to 3 moles per mole of compound (II); an equimolar amount or a slight excess of compound (III) is preferred.

  The reaction between the compounds (II) and (III) is generally performed within a relatively wide temperature range. In general, they are carried out in the range of -20 to 200 ° C, preferably 0 to 100 ° C, more preferably 25 to 50 ° C. This reaction step is generally performed under atmospheric pressure. However, it is also possible to carry out it under pressures above atmospheric pressure or under reduced pressure (for example in the range from 0.5 to 5 bar). The reaction time can generally be varied within a relatively wide range. In general, the reaction is complete after 2 to 24 hours, preferably 6 to 12 hours.

Synthetic transformations that can be used in the synthesis of compounds of formula I and intermediates involved in the synthesis of compounds of formula I are known or can be performed by those skilled in the art. A collection of composite transformations can be found in the following process.
・ J. March. Advanced Organic Chemistry, 4th ed .; John Wiley: New York (1992)
RC Larock. Comprehensive Organic Transformations, 2nd ed .; Wiley-VCH: New York (1999)
・ FA Carey; RJ Sundberg. Advanced Organic Chemistry, 2nd ed .; Plenum Press: New York (1984)
・ TW Greene; PGM Wuts. Protective Groups in Organic Synthesis, 3rd ed .; John Wiley: New York (1999)
・ LS Hegedus. Transition Metals in the Synthesis of Complex Organic Molecules, 2nd ed .; University Science Books: Mill Valley, CA (1994)
・ LA Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis; John Wiley: New York (1994)
・ AR Katritzky; O. Meth-Cohn; CW Rees, Eds. Comprehensive Organic Functional Group Transformations; Pergamon Press: Oxford, UK (1995)
・ G. Wilkinson; FG A. Stone; EW Abel, Eds. Comprehensive Organometallic Chemistry; Pergamon Press: Oxford, UK (1982)
・ BM Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon Press: Oxford, UK (1991)
・ AR Katritzky; CW Rees Eds. Comprehensive Heterocylic Chemistry; Pergamon Press: Oxford, UK (1984)
・ AR Katritzky; CW Rees; EFV Scriven, Eds. Comprehensive Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996)
・ C. Hansch; PG Sammes; JB Taylor, Eds. Comprehensive Medicinal Chemistry: Pergamon Press: Oxford, UK (1990).

  In addition, repeated reviews of synthesis methods 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 Synthesis 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-Weyl); Thieme: Stuttgart, Germany. Furthermore, examples of the synthetic conversion database include Chemical Abstracts that can be searched using CAS OnLine or SciFinder, Handbuch der Organischen Chemie (Beilstein) that can be searched using SpotFire, and REACCS.

Compositions of the compounds of the invention The invention also relates to pharmaceutical compositions comprising one or more of the compounds of the invention. These compositions can be utilized by administering to a patient in need thereof to achieve the desired pharmacological effect. For the purposes of the present invention, a patient is a mammal, including a human in need of treatment for a particular condition or disease. Accordingly, the present invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention or a salt thereof. The pharmaceutically acceptable carrier is preferably relatively non-toxic at a concentration compatible with the effective activity of the active ingredient so that the beneficial effects of the active ingredient are not compromised. Refers to a carrier that is harmless. A pharmaceutically acceptable amount of a compound is that amount which produces a result or exerts an influence on the particular condition or disease being treated. The compounds of the present invention include orally, parenterally, topically, including formulations that are released immediately, slowly and in time with pharmaceutically acceptable carriers well known in the art. It can be administered using any effective conventional dosage unit form such as nasally, ophthalmically, otically, sublingually, rectally, vaginally and the like.

  For oral administration, the compounds should be formulated into solid or liquid formulations such as capsules, pills, tablets, troches, melting agents, powders, solutions, suspensions, or emulsions. And can be prepared according to methods known to those skilled in the art of preparing pharmaceutical compositions. Solid unit dosage forms consist of ordinary hard or soft gelatin capsules containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate and corn starch. be able to.

  In another embodiment, the compounds of the present invention comprise conventional tablet bases such as lactose, sucrose and corn starch and binders such as gum arabic, corn starch, gelatin and the like, tablet disintegration and dissolution after administration Disintegrants, such as potato starch, alginic acid, corn starch and guar gum, tragacanth gum, gum arabic, etc., intended to assist in improving the fluidity of tablet granules and adhering to the surface of the mold and candy. Lubricants intended to prevent, such as talc, stearic acid or magnesium stearate, calcium or zinc, dyes, colorants, peppermint, winter green intended to enhance the aesthetic quality of tablets and make them more acceptable to patients Tablets may be made together with flavoring agents such as oil, cherry flavoring and the like. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or emulsifiers. And diluents such as water and alcohols such as ethanol, benzyl alcohol, polyethylene alcohol and the like. Various other materials may be present as coating agents or otherwise to alter the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both.

  Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. As further excipients, for example, the sweetening, flavoring and coloring agents mentioned above may also be present.

  The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifiers are: (1) naturally occurring gums such as gum arabic and tragacanth, etc., (2) naturally occurring phospholipids such as soy lecithin, (3) esters derived from fatty acids and anhydrous hexitol. Or partial esters such as sorbitan monooleate, (4) condensates of the partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may contain sweetening and flavoring agents.

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, coconut oil, or in a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Suspending agents may also be one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl, one or more colorants, one or more flavoring agents. And one or more sweeteners such as sucrose or saccharin.

  Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain preservatives and preservatives such as methyl and propylparaben and flavoring and coloring agents.

  The compounds of the present invention may also be administered parenterally, ie subcutaneously, intravenously, intraocularly, intrasynovically, intramuscularly or intraperitoneally as injectable dosage forms of the compound as water, saline, glucose. Aqueous solutions and related sugar solutions, ethanol, isopropanol, or glycols such as hexadecyl alcohol, propylene glycol, or the like, or polyethylene glycol, glycerol, 2,2-dimethyl-1,1-dioxolane-4-methanol, etc. Pharmaceuticals which may be sterile liquids or liquid mixtures such as ketals, ethers such as poly (ethylene glycol) 400, oils, fatty acids, fatty acid esters or fatty acid glycerides, or acetylated fatty acid glycerides In a pharmaceutically acceptable diluent together with an active carrier, such as soap or detergent With or without pharmaceutically acceptable surfactants, suspending agents such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifiers and other pharmacological adjuvants Can be administered.

  Oils that can be used in the parenteral formulations of the present invention are petroleum, animal oils, vegetable oils or synthetic oils such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, liquid paraffin and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Preferred fatty acid esters include, for example, ethyl oleate and isopropyl myristate. Preferred soaps include fatty acid alkali metal, ammonium, and triethanolamine salts, and preferred detergents include cationic detergents such as dimethyldialkylammonium halides, alkylpyridinium halides, and alkylamine acetates; anionic detergents, For example, alkyl, aryl, and olefin sulfonic acids, alkyl, olefins, ethers, and sulfuric monoglycerides, and sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly (oxyethyleneoxypropylene) or Ethylene oxide or propylene oxide copolymers; and amphoteric detergents such as alkyl-beta-aminopropionate and 2-alkylimidazoline quaternary ammonium salts, Mixtures thereof.

  The parenteral compositions of the invention preferably contain from about 0.5% to about 25% active ingredient typically in solution. Preservatives and buffering agents can also be used advantageously. In order to minimize or eliminate irritation at the injection site, such compositions can contain a non-ionic surfactant having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations is from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB, or may be a mixture of two or more components having the desired HLB.

  Specific examples of surfactants used in parenteral formulations are formed by the condensation of propylene oxide and propylene glycol with a group of polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and a hydrophobic base. It is a high molecular weight adduct of ethylene oxide.

  The pharmaceutical composition may be in the form of a sterile injectable aqueous suspension. Such suspensions may be prepared by using suitable dispersing or wetting agents and suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, gum arabic; Phospholipids existing in water, for example, condensates of fatty acids such as polyoxyethylene stearate and alkylene oxide, condensates of long chain fatty alcohols such as peptadeca-ethyleneoxycetanol and ethylene oxide, polyoxyethylene sorbitol monooleate, etc. A partial ester derived from a fatty acid such as a condensate of hexitol and ethylene oxide, or a partial ester derived from a fatty acid such as polyoxyethylene sorbitan monooleate. Using a dispersing or wetting agents may be as such a condensate of ether and hexitol anhydrides with ethylene oxide, may be formulated according to known methods.

  The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that can be used are, for example, Ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile, fixed oils are conventionally employed as a solvent or as a suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid and the like can be used in the preparation of injectables.

  The compositions of the present invention can also be administered in the form of suppositories, ie rectal administration of the drug. These compositions can be prepared by mixing with a suitable non-irritating excipient that is solid at ambient temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. . Such materials are, for example, cocoa butter and polyethylene glycol.

  Another formulation used in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches can be used to provide continuous or discontinuous infusion with controlled amounts of the compounds of the invention. The construction and use of transdermal patches for delivering drugs is well known in the art (see, eg, US Pat. No. 5,023,252 issued Jun. 11, 1991, which is hereby incorporated by reference). Such patches can be configured for continuous, pulsed or timely drug delivery.

  Controlled release formulations for parenteral administration include polymer microspheres and polymer gel formulations with liposomes known in the art.

  It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for drug delivery is well known in the art. For example, direct techniques for administering drugs directly into the brain typically involve inserting a drug delivery catheter into the patient's ventricular system to bypass the brain-blood barrier. One such implantable system, which is used to deliver drugs to specific anatomical regions of the body, is disclosed in US Pat. No. 5,011,472 issued April 30, 1991. Have been described.

  The compositions of the present invention may also contain other conventional pharmaceutically acceptable formulation ingredients, usually called carriers or diluents, as desired or required. Conventional methods of preparing such compositions in suitable dosage forms are available. Such components and procedures include those described in the following references, each of which is hereby incorporated by reference: Powell, MF et al, “Compendium of Excipients for Parenteral Formulations "PDA Journal of Pharmaceutical Science & Technology 1998, 52 (5), 238-311; Strickley, RG" Parenteral Formulations of Small Molecule 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.

Pharmaceutical components that can usually be used as suitable for formulating the composition for the intended route of administration include the following:
Acidifying agents (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);
Alkalizing agent (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine). ;
Absorbents (examples include, but are not limited to, powdered cellulose and activated carbon);
Aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl ₂ F ₂ , F ₂ ClC—CClF ₂ and CClF ₃ );
Air displacement agents (examples include but are not limited to nitrogen and argon);
Antifungal preservatives (examples include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);
Antimicrobial agents (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal);
Antioxidants (for example, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate , Sodium metabisulfite, but not limited to)
Binders (examples include but are not limited to block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers);
Buffering agents (including, but not limited to, potassium metaphosphate, dipotassium phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate);
Carriers (eg, acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cacao syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, antibacterial sodium chloride injection, and antibacterial Including, but not limited to, water for injection);
Chelating agents (examples include, but are not limited to, edetate disodium and edetate);
Colorant (for example, FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow No. 6, FD & C Blue No. 2, D & C Green No. 5, D & C Orange No. 5, D & C Red No. 8, Caramel Red And, but not limited to, iron oxide red);
A clarifying agent (examples include but are not limited to bentonite);
Emulsifiers (examples include but are not limited to gum arabic, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);
Encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate);
Flavoring agents (including, but not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);
A poultice (examples include but are not limited to glycerol, propylene glycol and sorbitol);
Emollients (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, liquid paraffin, hydrophilic liquid paraffin, white ointment, yellow ointment, and rose water ointment);
Permeation enhancers (for example, monohydroxy or polyhydroxy alcohols, mono- or polyhydric alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty acid esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes , Amides, ethers, ketones and ureas).
Plasticizers (examples include but are not limited to diethyl phthalate and glycerol);
Solvents (including, but not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for perfusion);
Hardeners (examples include, but are not limited to, cetyl alcohol, cetyl ester wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax);
Suppository bases (for example, but not limited to, cocoa butter and polyethylene glycols (mixtures));
Surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, octoxynonol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate);
Suspension agents (examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, tragacanth gum and bee gum);
Sweeteners (examples include, but are not limited to, aspartame, dextrose, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose);
Tablet adhesion inhibitors (examples include, but are not limited to, magnesium stearate and talc);
Tablet binders (examples include but are not limited to gum arabic, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, glucose solution, methylcellulose, uncrosslinked polyvinylpyrrolidone, and pre-grilled starch. .);
Tablet and capsule excipients (examples include dicalcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch, Not limited.);
Tablet coatings (examples include, but are not limited to, glucose solution, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate, and shellac);
Direct compression excipients (examples include but are not limited to dicalcium phosphate);
Tablet disintegrating agents (including, but not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrilin potassium, crosslinked polyvinylpyrrolidone, sodium alginate, starch glycolate sodium and starch);
Tablet lubricants (examples include, but are not limited to, colloidal silica, corn starch and talc);
Tablet lubricants (including, but not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate);
Tablet / capsule opacifier (examples include but are not limited to titanium dioxide);
Tablet abrasives (examples include, but are not limited to, carnauba wax and white wax);
Thickeners (examples include but are not limited to beeswax, cetyl alcohol and paraffin) (examples include, but are not limited to);
Isotonic agents (examples include but are not limited to glucose and sodium chloride);
Viscosity increasing agents (examples include, but are not limited to, alginic acid, bentonite, carbomers, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and tragacanth gum); and wetting agents (eg, heptadecaethyleneoxy Cetanol, lecithin, sorbitol monooleate, sorbitol monooleate polyoxyethylene acid, and polyoxyethylene stearate), but are not limited to these.

  Those skilled in the art will be able to use the above information to fully utilize the present invention. Nevertheless, the following are examples of pharmaceutical formulations that can be used in the methods of the invention. They are for illustrative purposes only and should not be construed as limiting the invention in any way.

  The pharmaceutical composition of the present invention can be described as follows:

Sterile intravenous solution: A 5 mg / mL solution of the desired compound of the invention is made using sterile water for injection and the pH adjusted if necessary. This solution is diluted for administration with sterile 5% glucose to 1-2 mg / mL and administered as an intravenous infusion over 60 minutes.

Lyophilized powder for intravenous administration: Sterile preparations comprise (i) 100-1000 mg of the desired compound of the invention as lyophilized powder, (ii) 32-327 mg / mL sodium citrate and (iii) ) Can be prepared as a lyophilized powder using 300-3000 mg of dextran 40. This formulation is reconstituted to a concentration of 10-20 mg / mL with sterile, injectable saline or 5% glucose solution, which is further 0.2-0.4 mg / mL with 5% saline or glucose. And is administered over 15-60 minutes by intravenous bolus or intravenous infusion.

Intramuscular suspension: The following solutions or suspensions can be prepared for intramuscular injection, for example. Ie:
50 mg / mL of the desired water-insoluble compound of the invention 5 mg / mL sodium carboxymethylcellulose 4 mg / mL TWEEN 80
9 mg / mL sodium chloride 9 mg / mL benzyl alcohol

Hard capsule: A multi-unit capsule is prepared by filling a standard two-part hard gelatin capsule with 100 mg powdered active ingredient, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate.

Soft gelatin capsules: A mixture of active ingredients in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and molded into a gelatin capsule to form a soft gelatin capsule containing 100 mg of the active ingredient It is injected by a positive displacement pump. These capsules are washed and dried. To prepare a water miscible drug mixture, the active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol.

Tablets: Conventional dosage unit is 100 mg active ingredient, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch, and 98.8 g lactose A number of tablets are prepared by the procedure. Preferred aqueous and non-aqueous coatings can be applied to improve mouthfeel, increase refinement and stability, or delay absorption.

Immediate release tablets / capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and drug release. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified by freeze drying and solid state extraction methods into solid tablets or capsules. The drug compound may be compressed with saccharides and polymers or effervescent components having viscoelasticity and thermoplastic properties to create a porous matrix intended for immediate release that does not require water.

Methods of treating hyperproliferative diseases The present invention uses the above compounds (compounds of formula I) (including salts and esters thereof, including their compositions) to treat hyperproliferative diseases in mammals. Related to the method. This method comprises administering to a mammal, including a human in need thereof, an amount of a compound of the present invention or an acceptable salt or ester thereof effective to treat the disease. Hyperproliferative diseases include breast, trachea, brain, genitals, gastrointestinal tract, ureter, eye, liver, skin, head and neck, thyroid, parathyroid cancer and their distant metastases. However, it is not limited to these. Those diseases also include lymphoma, sarcoma and leukemia.

  Examples of breast cancer include, but are not limited to, invasive breast cancer, invasive lobular cancer, intraepithelial breast cancer, and intraepithelial lobular cancer.

  Examples of tracheal cancer include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenoma and scleral lung blastoma.

  Examples of brain cancers include brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, and neuroectodermal and pineal tumors, It is not limited to these.

  Male genital tumors include, but are not limited to, prostate cancer and testicular cancer. Tumors of female genital organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer and genital cancer and uterine sarcoma.

  Gastrointestinal tumors include, but are not limited to anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

  Urinary tract cancers include, but are not limited to, bladder cancer, penile cancer, renal cancer, renal pelvis cancer, ureteral cancer, and urethral cancer.

  Eye cancers include, but are not limited to, intraocular black species and retinoblastoma types.

  Liver cancers include hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variants), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma. It is not limited.

  Skin cancers include squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell carcinoma, and non-melanoma skin cancer

  Head and neck cancers include, but are not limited to, larynx / hypopharynx / nasopharynx / oropharyngeal cancer, and lip cancer and oral cancer.

  Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and central nervous system lymphoma.

  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 diseases are well characterized in humans, but exist in other animals with similar etiology and can be treated by administering the pharmaceutical composition of the present invention.

  Based on standard laboratory techniques known to evaluate compounds useful in the treatment of hyperproliferative diseases, by standard toxicity tests, and to determine treatment for the above-specified conditions in animals Of the present invention for the treatment of each intended indication by standard pharmacological assays of the present invention and by comparing these results with known pharmaceutical agents used to treat these conditions. An effective dosage of the compound can be readily determined. The amount of active ingredient to be administered in the treatment of one of these conditions depends on the specific compound and the dosage unit employed, the mode of administration, the duration of treatment, the age and sex of the patient to be treated, and the nature of the condition to be treated and It can vary over a wide range according to considerations such as degree.

  The total amount of active ingredient to be administered is usually about 0.001 mg / kg to about 200 mg / kg body weight / day, preferably about 0.01 mg / kg to about 20 mg / kg body weight / day. The choice of dosing schedule is particularly important to maximize the effectiveness and safety of drugs for the treatment of proliferative diseases such as cancer. A clinically useful dosing schedule will range from 3 doses daily to 1 dose every 4 weeks. In addition, a “drug holiday” in which a patient does not receive medication over a period of time can be beneficial to the overall balance between pharmacological effects and tolerability. A unit dosage contains from about 0.5 to about 1500 mg of active ingredient and can be administered one or more times per day or less than once a day. The average daily dosage by injection, including intravenous, intramuscular, subcutaneous and parenteral injections and using the infusion method will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily topical regimen will preferably be 0.1 to 200 mg / kg administered 1 to 4 times per day. The transdermal concentration will preferably be that required to maintain a daily dosage of 0.01 to 200 mg / kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg / kg of total body weight.

  Of course, the specific initial and sustained dosing regimen for each patient will depend on the nature and severity of the condition, the activity of the specific compound used, the patient's age and general condition, administration, as determined by the diagnostician in charge. It will vary depending on the time of administration, the route of administration, the rate of drug excretion, the combination of drugs and others. Those of ordinary skill in the art can ascertain the desired mode of administration and frequency of administration of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof using routine therapeutic tests.

  The compounds of the present invention may be administered as a single pharmacological substance or in combination with one or more other pharmacological substances if the combination does not cause unacceptable side effects. Can do. For example, the compounds of the present invention can be combined with known anti-hyperproliferative and other indications and other mixtures and combinations thereof.

  Anti-proliferative agents that can optionally be added to the composition include compounds listed in cancer chemotherapy pharmacotherapy in the 11th edition (1996) of the Merck Index, which is hereby incorporated by reference, ie, asparaginase , Bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, cholaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide Irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitozantrone, prednisolone, prednisone, procarba Emissions, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and compounds such as vindesine but are not limited thereto.

  Other antiproliferative agents suitable for use with the compositions of the present invention include Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., Publ, incorporated herein by reference. by McGraw-Hill, pages 1225-1287, (1996), aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, recognized for use in the treatment of neoplastic diseases 2 ', 2'-difluorodeoxyuridine, docetaxel, erythrohydroxynonyladenine, ethinylestradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate Idarubicin , Interferon, medroxrogestrone acetate, megastrol acetate, melphalan, mitoten, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), pricamycin, semustine, teniposide, testosterone propionate, thiotepa, Examples include, but are not limited to, compounds such as trimethylmelamine, uridine, and vinorelbine.

  Other anti-proliferative agents suitable for use with the compositions of the present invention include, but are not limited to, other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifene and topotecan. .

In general, the use of cytotoxic and / or cytostatic agents in the combination of compounds or compositions of the present invention helps to:
(1) provide greater effectiveness in reducing tumor growth or even kill the tumor compared to administering either agent alone,
(2) resulting in a reduction in the amount of chemotherapeutic agent administered,
(3) provide well-tolerated chemotherapy with fewer harmful pharmacological complications than single-agent chemotherapy or other combination therapies;
(4) provide treatment of a wide range of different cancer types in mammals, especially humans,
(5) provide a high response in patients undergoing treatment;
(6) results in a longer survival time for patients undergoing treatment compared to treatment with standard chemotherapy;
(7) allow longer time for tumor progression, and / or (8) at least as much as drugs used alone compared to known cases where other anti-cancer drug combinations provide an antagonistic effect Gives good effectiveness and tolerance.

Abbreviations used in this specification DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DMF N, N-dimethylformamide DCM dichloromethane DCE 1,2-dichloroethane DMSO dimethyl sulfoxide HPLC High pressure liquid chromatography MPLC Medium pressure Liquid Chromatography ML-MS Mass Spectrometry Combined Liquid Chromatography RT Retention Time MP Melting Point NMR Nuclear Magnetic Resonance TLC Thin Layer Chromatography ES Electrospray DMAC N, N-dimethylacetamide HRMS High Resolution Mass Spectroscopy CDI 1,1 '-Carbonyldiimidazole HOBT 1-hydroxybenzotriazole DCC 1,3-dicyclohexylcarbodiimide EDCI hydrochloride 1- [3- (dimethylamino) propyl] -3-ethyl carbonate Ruvodiimide DMAP 4-dimethylaminopyridine TMSCI trimethylsilyl chloride m-CPBA 3-chloroperbenzoic acid HEPES N- (2-hydroxyethyl) -piperazine-N ′-(2-ethanesulfonic acid)
Tris / hydrochloric acid Tris (hydroxymethyl) aminomethane
^TM Triton X-100 tert-octylphenoxypolyethoxyethanol, Rohm & Haas,
USA

  The yield percentages in the following examples refer to the starting components used in the lowest molar amount.

Preparation of starting materials and intermediates General method A: Preparation of aminophenols Aminophenols are commercially available or can be prepared as described in one or more of the following examples.

Method A-1
Preparation of 5-nitroindazole-1-carboxylic acid tert-butyl ester

  Step 1: Preparation of 5-nitroindazole-1-carboxylic acid tert-butyl ester

0 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). To the slurry at 0 C was added dropwise a solution of di-tert-butyl dicarbonate (8 g, 36.8 mmol) in acetonitrile (40 mL). The resulting mixture was stirred for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in Et ₂ O (200 mL) and water (100 mL). The pH of the aqueous layer was adjusted to 2 using 1N HCl solution. The organic phase was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 5-nitroindazole-1-carboxylic acid tert-butyl ester (7.8 g, 96%) as a yellow solid: TLC (30% ethyl acetate / hexane), _Rf = 0.70; ES-LCMS (relative abundance) m / z 264 (MH ^<+> , 100%).

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

Method A-2a
Preparation of 1,1-dioxo-2,3-dihydro-1H-benzo [b] thiophen-5-ylamine

Palladium on carbon (25 mg) was placed under an inert atmosphere and suspended in 1: 1 v / v EtOH / THF (10 mL). Then a solution of 5-nitrobenzo [b] thiophene 1,1-dioxide (250 mg, 1.18 mmol) in EtOH / THF (1: 1) was added and the reaction mixture was placed under H ₂ atmosphere (1 atm). And stirred at room temperature for 3 hours. The reaction was filtered through a Celite pad and washed well with methanol to give the title compound (200 mg, 92%) as a brown solid: TLC (10% methanol / DCM w / 5% NH ₄ OH), R _f = 0.40; LC MS m / z 184.1 (MH ^<+> ).

Method A-2b
Preparation of 2-methyl-6-aminobenzoxazole

This compound was prepared from 2-methyl-6-nitrobenzoxazole (2.0 g, 13.5 mmol) in the same manner as described for 5-aminobenzo [b] thiophene 1.1-dioxide. 57 (94%) of the title compound were obtained as a brown solid. MS LC-MS (M + H) ^<+> = 149.1, RT = 0.77 min.

Method A-3a
Preparation of 1- (2-diethylamino-ethyl) -1H-indol-5-ylamine

  Step 1: Preparation of diethyl- [2- (5-nitroindol-1-yl) ethyl] amine

A slurry of 5-nitroindole (2.0 g, 12.3 mmol) and NaOH pellets (0.49 g, 1 eq) in water (2.0 mL) was stirred at room temperature. After 10 minutes, p-xylene (15.0 mL, 1.4 M), K ₂ CO ₃ (2.55 g, 1.5 eq) and N-diethylaminoethyl chloride hydrochloride (2.12 g, 12.3 mmol, 1 Equivalent) was added and the reaction mixture was heated to 100 ° C. After 4 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude residue was dissolved in p-xylene and washed with 1N NaOH (2 ×) and water (1 ×). The organic layer was dried over MgSO ₄ , filtered and evaporated under reduced pressure to give the nitro compound (1.79 g, 56%). TLC (5% methanol / ethyl acetate), _Rf = 0.25; LC MS m / z 262.2 (MH ^<+> ).

Step 2: Preparation of the title compound 1- (2-diethylamino-ethyl) -1H-indol-5-ylamine Diethyl- [2- (5-nitroindol-1-yl) ethyl] amine (1.6 g, 6.1) Mmol) was dissolved in absolute EtOH (100 mL) and syringed into a flask containing 10% Pd on carbon (160 mg) under an argon atmosphere. The reaction mixture was placed under H ₂ atmosphere (1 atm) and stirred at room temperature for 3 hours. The reaction was filtered through a celite pad and washed well with EtOH. Evaporation of the barometric solvent gave the title compound (1.4 g, 99%) as a brown solid. TLC (10% methanol / DCM), _Rf = 0.20; LC MS m / z 232.3 (MH ^<+> ).

Method A-3b
Preparation of 1- (2-diethylamino-ethyl) -1H-indazol-5-ylamine

This compound was prepared from 5-nitroindazole (2.0 g, 12.3 mmol) as described for 1- (2-diethylamino-ethyl) -1H-indazol-5-ylamine and 2.0 g (70% To give the title compound. TLC (10% methanol / DCM), _Rf = 0.20; LC MS m / z 233.2 (MH ^<+> ).

General Method B: Preparation of Bicyclic Amines of Formula (III) Compounds of formula (III) are commercially available or can be prepared as described in one or more of the following examples.

Method B-1a
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 ethyl acetate (40 mL). The mixture was stirred under H ₂ atmosphere for 4 hours and filtered through a pad of Celite®. The filtrate was evaporated under reduced pressure to give the desired product as a tan solid (940 mg, 7.39 mmol; 97% yield). ¹ H-NMR (DMSO-d ₆ ) δ 8.76 (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).

Method B-1b
Preparation of 4-amino-2-fluorophenol

This compound was prepared from 2-fluoro-4-nitrophenol (2.0 g, 12.7 mmol) as described for 4-amino-3-fluorophenol and 1.58 g (98%) of 4 -Amino-2-fluorophenol was obtained as a tan solid. ¹ H-NMR (DMSO-d ₆ ) δ 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-1c
Preparation of 4-amino-3-trifluoromethylphenol

This compound was prepared from 4-nitro-3-trifluorophenol (5.0 g, 24.1 mmol) as described for 4-amino-3-fluorophenol and 3.84 g (89.8%) Of 4-amino-3-trifluoromethylphenol as a tan solid. ¹ H-NMR (DMSO-d ₆ ) δ 8.89 (s, 1H), 6.78 to 6.67 (m, 3H), 4.85 (s, 2H); TLC (25% ethyl acetate / Hex) , R _f = 0.31.

Method B-1d
Preparation of 4-amino-2-methoxyphenol

This compound was prepared from 4-nitro-2-methoxyphenol (10.0 g, 59.1 mmol) as described for 4-amino-3-fluorophenol and 5.20 g (56.9%) of 4-Amino-2-methoxyphenol was obtained as a dark brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 7.79 (brs, 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 (brs, 2H), 3.65 (s, 3H); TLC (66% ethyl acetate / Hex), R _f = 0 42.

Method B-1e
Preparation of 5-amino-8-hydroxyquinoline

This compound was prepared from 8-hydroxy-5-nitroquinoline (5.0 g, 26.3 mmol) as described for 4-amino-3-fluorophenol and 2.4 g (51.3%) of 5-Amino-8-hydroxyquinoline was obtained. TLC (5% methanol / DCM), R _f = 0.52.

Method B-2a
Preparation of 3-amino-2,4-difluorophenol

  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 ethyl chloroformate ( 1.8 mL, 18.5 mmol) was added dropwise. The reaction was stirred at 0-25 ° C. for 90 minutes and the mixture was quenched with water (75 mL). The organic layer was washed with brine (2 × 50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the desired product as a colorless oil in quantitative yield. ¹ H-NMR (DMSO-d ₆ ) δ 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

To a solution of ethyl 2,4-difluorophenoxycarboxylate (3.27 g, 16.2 mmol) in concentrated sulfuric acid (11 mL) at 0 ° C., fuming nitric acid (1.1 mL) was added dropwise between 10-20 ° C. Maintained the internal temperature. After stirring for 1 hour, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was dissolved in methanol (50 mL) and sodium bicarbonate (2.72 g, 32.3 mmol) was added. The resulting mixture was stirred at room temperature for 64 hours and the solid was filtered. The filtrate was concentrated and the residue was taken up in water (100 mL). The pH was adjusted to 5 by the addition of concentrated hydrochloric acid and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over MgSO ₄ and evaporated under reduced pressure to give 2,4-difluoro-5-nitrophenol as a yellow solid (2.35 g, 13.4 mmol; 83% yield). ¹ H-NMR (DMSO-d ₆ ) δ 10.88 (s, 1H), 7.70 to 7.61 (m, 2H).

Step 3: Preparation of the title compound 2,4-difluoro-5-aminophenol This compound was prepared as described for 4-amino-3-fluorophenol with 2,4-difluoro-3-nitrophenol (2.35 g, 13.4 g (97%) of 2,4-difluoro-5-aminophenol as a tan solid. ¹ H-NMR (DMSO-d ₆ ) δ 9.26 (s, 1H), 6.89 (t, J = 10.7 Hz, 1H), 6.33 (t, J = 9.2 Hz, 1H), 4 .82 (s, 2H).

Method B-2b
Preparation of 5-amino-4-fluorophenol

  Step 1: Preparation of ethyl 2-bromo-4-fluorophenoxycarboxylate

This compound was prepared from 2-bromo-4-fluorophenol (3.0 g, 15.7 mmol) as described for ethyl 2,4-difluorophenoxycarboxylate, and 4.0 g (96.8%) Of ethyl 2-bromo-4-fluorophenoxycarboxylate as a pale yellow oil. ¹ H-NMR (DMSO-d ₆ ) δ 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) as described for 2,4-difluoro-5-nitrophenol and 3.14 g (87 0.5%) of 2-bromo-4-fluoro-3-nitrophenol as a yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 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 as described for 4-amino-3-fluorophenol with 2-bromo-4-fluoro-5-nitrophenol (3.1 g, 13.1 mmol) gave a quantitative yield of crude 3-amino-4-fluorophenol, which was used without further purification. ¹ H-NMR (DMSO-d ₆ ) δ 8.60 (brs, 2H), 7.12 (dd, J = 7.8, 6.6 Hz, 1H), 6.82 (dd, J = 5.1) 1.5 Hz, 1H), 6.55 to 6.61 (m, 1H).

Method B-2c
Preparation of 3-amino-6-fluorophenol

This compound was prepared from 4-bromo-2-fluorophenol (3.0 g, 15.71 mmol) as described for 3-amino-4-fluorophenol and 1.79 g (86%) of 3- Amino-6-fluorophenol was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 10.42 (s, 1H), 9.69 (brs, 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-chloro-6-fluorophenol (1.0 g, 6.82 mmol) in concentrated acetic acid (3.0 mL) was cooled to 0 ° C. Fuming nitric acid (559 mg, 8.87 mmol) was added dropwise to maintain the reaction temperature between 10 and 20 ° C. The reaction was stirred at 0 ° C. for 3 hours. The mixture was poured onto ice and allowed to warm to room temperature. The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude red solid was purified using Biotage Quad4 (25M column) eluting with 9: 1 hexane / ethyl acetate to give the title compound as a yellow solid (326 mg, 1.70 mmol; 25% yield). . ¹ H-NMR (DMSO-d ₆ ) δ 11.74 to 12.77 (roads, 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 as described for 4-amino-3-fluorophenol with 2-chloro-6-fluoro-4-nitrophenol ( 1.3 g, 6.79 mmol) to give 0.34 g (40%) of 4-amino-2-chloro-6-fluorophenol. ^{1 H-NMR (DMSO-d} 6) δ4.99 (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-1,3-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 give 6.5 g (71%) of 5-benzyloxy-1,3-difluoro-2-nitrobenzene and 1-benzyloxy-3. A 1: 1 mixture of, 5-difluoro-2-nitrobenzene was obtained. The mixture was used directly in the next step without further purification. ¹ H-NMR (CD ₂ Cl ₂ ) δ 7.46 to 7.36 (m, 5H), 6.75 to 6.60 (m, 2H), 5.19 (s, 1H), 5.11 (s , 1H); TLC (10% ethyl acetate / hexane), R _f = 0.48.

Step 2: Preparation of the title compound 4-amino-3,5-difluorophenol 5-Benzyloxy-1,3-difluoro-2-nitrobenzene and 1-benzyloxy-3,5 from Step 1 in methanol (250 ml). A solution of a 1: 1 mixture of difluoro-2-nitrobenzene (6.4 g, 24 mmol) was added to a flask containing palladium on carbon (10 wt%, 720 mg) under a nitrogen atmosphere. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give 3.4 g (97%) of 4-amino-3,5-difluorophenol and 1 of 2-amino-3,5-difluorophenol. 1 mixture was obtained. The mixture was used directly in the next step without further purification. ¹ H-NMR (DMSO-d ₆ ) δ 9.50 (brs, 1H), 6.54 to 6.22 (m, 2H), 4.36 (s, 2H); MS GC-MS (M ⁺ = 146 .1), RT = 0.87 minutes.

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) as described for 4-amino-3,5-difluorophenol and 3.0 g (72. 3%) of 4-amino-2,5-difluorophenol. ¹ H-NMR (DMSO-d ₆ ) δ 9.04 (s, 1H), 6.67 to 6.46 (m, 2H), 4.64 (s, 2H); MS GC-MSM ⁺ = 146.1 , RT = 1.04 minutes.

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) as described for 4-amino-3,5-difluorophenol and 0.60 g (84% Of 4-amino-2,3-difluorophenol. ¹ H-NMR (DMSO-d ₆ ) δ 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 / hexane), R _f = 0.08.

Method B-5
Preparation of 2-amino-5-hydroxybenzamide

  Step 1: Preparation of 5-benzyloxy-2-nitrobenzonitrile

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) at room temperature was added at 60 ° C. Stir for hours. Water (60 ml) was added to the reaction and the resulting yellow precipitate was filtered, washed with water and dried under reduced pressure to give 17.3 g (75.4%) of 5-benzyloxy-2-nitrobenzonitrile. Got. The compound was used directly in the next step without further purification. MS GC-MS M ^<+> = 211, RT = 6.15 min.

  Step 2: Preparation of 5-benzyloxy-2-nitrobenzamide

A solution of 5-benzyloxy-2-nitrobenzonitrile (4.5 g, 18 mmol) in acetone (180 ml) and water (90 ml) with sodium percarbonate (containing 25% H ₂ O ₂ , 28 g, 180 mmol). Worked and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into ethyl acetate (200 ml) and water (100 ml). The biphasic layers were separated and the organic layer was washed with water (50 ml) and brine (50 ml), dried over Na 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-MS M ^<+> = 211, RT = 6.15 min.

Step 3: Preparation of the title compound 2-amino-5-hydroxybenzamide This compound was prepared as described for 4-amino-3-fluorophenol and 5-benzyloxy-2-nitrobenzamide (2.7 g, 56 mmol). To give 1.5 g (99%) of 2-amino-5-hydroxybenzamide. ¹ H-NMR (CDCl ₃ ) δ 7.41 (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 B-6
Preparation of 5-amino-2,4-dichlorophenol

Iron powder (4.03 g, 72.1 mmol) was slowly added to a solution of 2,4-dichloro-5-nitrophenol (3.00 g, 14.4 mmol) in acetic acid (100 ml). After stirring overnight at room temperature, the reaction mixture became milky with the formation of a white precipitate. The precipitate was filtered and the filtrate was concentrated to about 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 (3 × 150 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness to give 5-amino-2,4-dichlorophenol (2.20 g, 86%) as a brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 9.91 (s, 1H), 7.10 (s, 1H), 6.42 (s, 1H), 5.34 (s, 2H); MS LC-MS (M + H) ⁺ = 178.2, RT = 2.10 min.

  Method B-7

Preparation of 4-amino-3- (methylsulfanyl) phenol

  Step 1: Preparation of 3- (methylsulfanyl) -4-nitrophenol

To a solution of 3-fluoro-4-nitrophenol (3.0 g, 19.1 mmol) in anhydrous DMF (100 mL) is added sodium thiomethoxide (2.57 mL, 38.2 mmol, 2.0 eq) dropwise. Subsequently, potassium carbonate (7.92 g, 57.3 mmol, 3.0 eq) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours. Water was then added to quench the solution and the reaction mixture was extracted with ethyl acetate (3 × 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) eluting with 20% ethyl acetate-hexanes afforded 3.25 g (91.9%) of 3- (methylsulfanyl) -4-nitrophenol as a yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 11.13 (s, 1H), 8.18 (d, J = 9.0 Hz, 1H), 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 as described for 4-amino-3-fluorophenol by 3- (methylsulfanyl) -4-nitrophenol (3. 2g, 17.3mmol) to give 2.18g (81.3%) of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ 8.56 (s, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.53 (d, J = 8.7 Hz, 1H), 6 .43 (dd, J = 8.7, 2.4 Hz, 1H), 2.28 (s, 3H).

General Methods C and D: Preparation of Arylamines of Formula (II) Compounds of formula (II) can be prepared as described in one or more of the following examples.

Method C-1a
Preparation of 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide

  Step 1: Preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride

Anhydrous DMF (6.0 mL) was slowly added to SOCl ₂ (180 mL) between 40 ° C. and 50 ° C. The solution was stirred at that temperature range for 10 minutes and then picolinic acid (60.0 g, 487 mmol) was added in several portions over 30 minutes. The resulting solution was heated at 72 ° C. for 16 hours to obtain a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to half its volume. The resulting residue was filtered and the solid was washed with toluene and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride hydrochloride as a yellow solid (92.0 g, 89%). It was.

  Step 2: Preparation of 4-chloropyridine-2-carboxylic acid methylamide

A suspension of methyl 4-chloropyridine-2-carboxylate hydrochloride (89.0 g, 428 mmol) in methanol (75 mL) at 0 ° C. was treated with a 2.0 M methylamine solution in THF (1 L). The resulting mixture was stored at 3 ° C. for 5 hours and then concentrated under reduced pressure. The resulting solid was suspended in ethyl acetate (1 L) and filtered. The filtrate was washed with saturated NaCl solution (500 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 4-chloro-N-methyl-2-pyridinecarboxamide as pale yellow crystals (71.2 g, 97% ). ¹ H-NMR (DMSO-d ₆ ) δ 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 (brd, 1H); Cl-MS m / z 171 (MH ^<+> ); m. p. 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 added to potassium tert-butoxide. (10.29 g, 91.7 mmol) and the reddish brown mixture was stirred at room temperature for 2 hours. The contents were treated with 4-chloropyridine-2-carboxylic acid methylamide (15.0 g, 87.9 mmol) and K ₂ CO ₃ (6.50 g, 47.0 mmol), then at 80 ° C. for 8 hours. Heated. The mixture was cooled to room temperature and partitioned between ethyl acetate (500 mL) and saturated NaCl solution (500 mL). The aqueous phase was back extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The obtained solid was dried at 35 ° C. under reduced pressure for 3 hours to obtain the title compound (17.9 g, 84%) as a light brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 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, 1 H), 8.73 (br d, 1 H); HPLC ES-MS m / z 244 (MH ⁺ ).

Method C-1b
Preparation of 4- (3-aminophenoxy) pyridine-2-carboxylic acid methylamide

The title compound was prepared as described in 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 3-aminophenol. ¹ H-NMR (DMSO-d ₆ ) δ 8.75 (br q, J = 4.8 Hz, 1H), 8.48 (d, J = 6.3 Hz, 1H), 7.39 (d, J = 2) .1 Hz, 1H), 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-1c
Preparation of 4- (4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide

This compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 4-amino-3-fluorophenol. ¹ H-NMR (DMSO-d ₆ ) δ 8.74 (brq, J = 7.0 Hz, 1H), 8.43 (d, J = 4.5 Hz, 1H), 7.32, (d, J = 2) .1 Hz, 1 H), 7.07 (dd, J = 4.2, 2.1 Hz, 1 H), 6.99 (dd, J = 8.7, 1.8 Hz, 1 H), 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-1d
Preparation of 4- [4-amino-3- (trifluoromethyl) phenoxy] pyridine-2-carboxylic acid methylamide

This compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 4-amino-3-trifluoromethylphenol. ¹ H-NMR (DMSO-d ₆ ) δ 8.75 (br q, J = 6.9 Hz, 1H), 8.44 (d, J = 4.2 Hz, 1H), 7.31 (d, J = 2) .1 Hz, 1 H), 7.19 to 7.16 (m, 2 H), 7.06 (dd, J = 4.2, 1.8 Hz, 1 H), 6.92 (d, J = 7.2 Hz, 1H), 5.73 (s, 2H), 2.77 (d, J = 3.6 Hz, 3H).

Method C-1e
Preparation of 4- (4-amino-3-methylphenoxy) pyridine-2-carboxylic acid methylamide

This compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 4-amino-3-methylphenol. ¹ H-NMR (acetone-d ₆ ) δ 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 (brs, 1H), 6.77-6.76 (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-1f
Preparation of 4- (4-amino-2-methylphenoxy) pyridine-2-carboxylic acid methylamide

This compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 4-amino-2-methylphenol. ¹ H-NMR (DMSO-d ₆ ) δ 8.73 (brq, 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-1g
Preparation of 4- (4-amino-3-nitrophenoxy) pyridine-2-carboxylic acid methylamide

This compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 4-amino-3-nitrophenol. ¹ H-NMR (acetone-d ₆ ) δ 8.46 (d, J = 5.7 Hz, 1H), 8.31 (brs, 1H), 7.96 (brs, 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-1h
Preparation of 4- (4-amino-2-fluorophenoxy) pyridine-2-carboxylic acid methylamide

The title compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 4-amino-2-fluorophenol. ¹ H-NMR (DMSO-d ₆ ) δ 8.75 (brq, 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).

Method C-1i
Preparation of 4- (3-amino-4-chlorophenoxy) pyridine-2-carboxylic acid methylamide

The title compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 3-amino-4-chlorophenol. ¹ H-NMR (DMSO-d ₆ ): δ 8.76 (m, 1H), 8.47 (d, 1H), 7.39 (s, 1H), 7.24 (d, 1H), 7.15 (Dd, 1H), 6.67 (s, 1H), 6.35 (dd, 1H), 5.65 (s, 2H), 2.78 (d, 3H); LC MSm / z 278.1 (MH) ) ⁺ , RT = 2.36 minutes.

Method C-1j
Preparation of 4- (3-amino-2-fluorophenoxy) pyridine-2-carboxylic acid methylamide

The title compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 5-amino-2-fluorophenol. ¹ H-NMR (DMSO-d ₆ ): δ 8.77 (brd, J = 3.3 Hz, 1H), 8.49 (d, J = 4.5 Hz, 1H), 7.35 (d, J = 1) .8 Hz, 1H), 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-1k
Preparation of 4- (3-amino-4-fluorophenoxy) pyridine-2-carboxylic acid methylamide

The title compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 3-amino-4-fluorophenol. ¹ H-NMR (DMSO-d ₆ ) δ 8.75 (brd, J = 3.9 Hz, 1H), 8.46 (d, J = 4.5 Hz, 1H), 7.35 (d, J = 1. 8 Hz, 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-1l

  Preparation of 4- (4-amino-2,5-difluorophenoxy) pyridine-2-carboxylic acid methylamide

The title compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 4-amino-2,5-difluorophenol. ¹ H-NMR (CDCl ₃ ) δ 8.34 (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-1m
Preparation of 4- (4-amino-3,5-difluorophenoxy) pyridine-2-carboxylic acid methylamide

The title compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 4-amino-3,5-difluorophenol. ¹ H-NMR (DMSO-d ₆ ) δ 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); MS GC-MS (M ⁺ = 280.1, RT = 2.27 min).

Method C-1n
Preparation of 4- (4-amino-2,3-difluorophenoxy) pyridine-2-carboxylic acid methylamide

The title compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 4-amino-2,3-difluorophenol. ¹ H-NMR (DMSO-d ₆ ) δ 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% ethyl acetate / hexane), _Rf = 0.36.

Method C-1o
Preparation of 4- (5-aminoquinolin-8-yloxy) pyridine-2-carboxylic acid methylamide

This compound was prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-aminophenol with 5-amino-8-hydroxyquinoline. ¹ H-NMR (DMSO-d ₆ ) δ 8.72 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, 1 H), 7.04 (dd, J = 5.4, 2.7 Hz, 1 H), 6.73 (d, J = 8.1 Hz, 1 H), 6.13 (s, 2 H), 2 .73 (d, J = 5.1 Hz, 3H); MS LC-MS (M + H) ⁺ = 295.2; TLC (5% methanol / DCM), R _f = 0.31.

Method C-1p
Preparation of 4- (4-amino-2-methoxyphenoxy) pyridine-2-carbonitrile

The title compound has 4-aminophenol replaced with 4-amino-2-methoxyphenol, and 4-chloropyridine-2-carboxylic acid methylamide replaced with 4-chloro-2-cyanopyridine, and 4- (4-aminophenoxy ) Prepared as described for pyridine-2-carboxylic acid methylamide. ¹ H-NMR (DMSO-d ₆ ) δ 8.50 (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 LC-MS (M + H) ⁺ = 242.1.

Method C-1q
Preparation of 4- (4-amino-3,5-difluoro-phenoxy) pyridine-2-carbonitrile

The title compound was prepared as described for 4- (4-amino-2-methoxyphenoxy) pyridine-2-carbonitrile, replacing 4-aminophenol with 4-amino-3,5-difluorophenol. . ¹ H-NMR (DMSO) δ 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 minutes).

Method C-1r
Preparation of 4- (4-amino-2,5-difluoro-phenoxy) pyridine-2-carbonitrile

The title compound was described for 4- (4-amino-2-methoxyphenoxy) pyridine-2-carbonitrile, replacing 4-amino-3,5-fluorophenol with 4-amino-2,5-difluorophenol. It was prepared in the same manner as above. ¹ H-NMR (DMSO-d ₆ ) δ 8.56 (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-1s
Preparation of 2-amino-5- (2-cyanopyridin-4-yloxy) benzamide

The title compound is as described for 4- (4-amino-2-methoxyphenoxy) pyridine-2-carbonitrile, replacing 4-amino-3,5-difluorophenol with 2-amino-5-hydroxy-benzamide. Prepared in the same manner. ¹ H-NMR (CDCl ₃ ) δ 7.41 (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-1t
Preparation of 4- (4-amino-3-chloro-phenoxy) pyridine-2-carboxamide

The title compound has 4-aminophenol replaced with 4-amino-3-chlorophenol and 4-chloropyridine-2-carboxylic acid methylamide replaced with 4-chloro-2-pyridinecarboxamide to give 4- (4-aminophenoxy ) Prepared as described for pyridine-2-carboxylic acid methylamide. ¹ H-NMR (DMSO-d ₆ ) δ 8.45 (d, J = 5.4 Hz, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.32 (d, J = 2.7 Hz, 1H), 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-1u
Preparation of 4- (4-amino-3-fluorophenoxy) pyridine-2-carboxamide

The title compound was prepared in the same manner as described for 4- (4-amino-3-chlorophenoxy) pyridine-2-carboxyand, replacing 4-amino-3-chlorophenol with 4-amino-3-fluorophenol. Prepared. ¹ H-NMR (DMSO-d ₆ ) δ 8.44 (d, J = 5.4 Hz, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 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-1v
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-chlorophenoxy) pyridine-2-carboxamide, replacing 4-amino-3-chlorophenol with 4-amino-2-chlorophenol. did. ¹ H-NMR (DMSO-d ₆ ) δ 8.46 (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); MS LC-MS (MH) ⁺ = 264.1, RT = 1.76 minutes.

Method C-1w
Preparation of 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxamide

The title compound was prepared similarly as described for 4- (4-amino-3-chloro-phenoxy) pyridine-2-carboxamide, replacing 4-amino-3-chlorophenol with 4-aminophenol. ¹ H-NMR (DMSO-d ₆ ) δ 8.43 (d, J = 5.7 Hz, 1H), 8.07 (roads, 1H), 7.66 (roads, 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, 2H), 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 N, N′-dimethylamide solution (6 mL) of 2-chloro-4-aminophenol (0.5 g, 3.48 mmol) is slowly added potassium tert-butoxide (0.39 g, 3.48 mmol). And added. After stirring for about 25 minutes, 4-chloropicolinomethylamide (0.46 g, 2.67 mmol) in N, N-dimethylamide (4 mL) was added and the contents were stirred while heating to 100 ° C. for 16 hours. did. The contents were cooled to room temperature with stirring and quenched with water (5 mL). The contents were extracted with ethyl acetate and the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude residue was chromatographed (60% → 40% ethyl acetate / hexane gradient) to give the final product as a dark yellow oil (0.25 g, 34%). ¹ H-NMR (methanol-d ₄ ): δ 8.82 (d, 1H), 7.85 (s, 1H), 7.34 (d, 1H), 7.32 (s, 1H), 7.20 (S, 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 is as described for 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-amino-2-chlorophenol with 5-amino-2,4-difluorophenol. Prepared in the same manner. ¹ H-NMR (DMSO-d ₆ ) δ 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 is as described for 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-amino-2-chlorophenol with 3-amino-2,4-dichlorophenol. Prepared in the same manner. ¹ H-NMR (DMSO-d ₆ ) δ 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- (4-amino-3-chlorophenoxy) pyridine-2-carboxylic acid methylamide

The title compound is the same as described for 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-amino-2-chlorophenol with 4-amino-3-chlorophenol. Prepared. ¹ H-NMR (DMSO-d ₆ ) δ 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-MS [M + H] ⁺ = 278.1 [M + H ] ^+, RT = 2.19 minutes.

Method C-2e
Preparation of 4- [4-amino-3- (methylsulfanyl) phenoxy] pyridine-2-carboxylic acid methylamide

The title compound is as described for 4- (4-amino-2-chlorophenoxy) pyridine-2-carboxylic acid methylamide, replacing 4-amino-2-chlorophenol with 4-amino-3-methyl-sulfanylphenol. Prepared in the same manner. ¹ H-NMR (DMSO-d ₆ ) δ 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 4- (4-amino-phenoxy) pyridine-2-carboxylic acid methyl ester

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 mL). Was stirred at 90 ° C. for 48 hours. After cooling to room temperature, 2.0N hydrochloric acid was slowly added to the reaction mixture until pH = 5. The solvent was completely removed and the residue was redissolved in methanol (400 mL). After slow addition of trimethylsilyl chloride (178 mL, 140 mmol, 2.27 equiv) at 0 ° C., the reaction mixture was stirred at reflux for 24 hours and cooled to room temperature. 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 1M aqueous sodium bicarbonate solution, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting residue was further washed with water and extracted again with ethyl acetate / hexane (1: 2 v / v) to give the desired ester (6.27 g, 42%) as a light brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 8.51 (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 (Brs, 2H), 3.86 (s, 3H); MS LC-MS [M + H] ⁺ = 245, RT = 1.04 min; TLC (75% ethyl acetate / hexane), _Rf = 0.20.

Method C-3b
Preparation of 4- (3-aminophenoxy) pyridine-2-carboxylic acid methyl ester

The title compound was obtained by replacing 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide with 4- (3-aminophenoxy) pyridine-2-carboxylic acid methylamide to give 4- (3-aminophenoxy) pyridine-2- Prepared as described for carboxylic acid methyl ester. ¹ H-NMR (CD ₃ OD) δ 8.49 (d, 1H), 7.20 (d, 1H), 7.14 (dd, 1H), 6.64 (dd, 1H), 6.45 (t , 1H), 6.40 (dd, 1H), 3.92 (s, 3H); MS LC-MS [M + 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 4-chloro-N-methoxy-N-methylpyridine-2-carboxamide

To a mixture of dimethylhydroxylamine hydrochloride (510 mg, 5.18 mmol) and triethylamine (2.16 mL, 15.5 mmol) in anhydrous THF (9.41 mL) and acetonitrile (2.35 mL) at 0 ° C. -Chloropyridine-2-carbonyl hydrochloride (1.00 g, 4.71 mmol) was added. The reaction mixture was stirred at 0 ° C. for 2 hours and then at room temperature for 16 hours. The solvent was removed under reduced pressure and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by MPLC (biotage) eluting with 30% ethyl acetate / hexanes to give 925 mg (98%) of 4-chloro-N-methoxy-N-methylpyridine-2-carboxamide as an orange oil. TLC (50% ethyl acetate / hexane), R _f = 0.31.

  Step 2: Preparation of 1- (4-chloropyridin-2-yl) ethanone

To a 0 ° C. solution of 1.4 M methylmagnesium bromide in toluene / THF (6.89 mL, 9.65 mmol) in anhydrous THF (8.77 mL) was added 4-chloro- in anhydrous THF (8.77 mL). A solution of N-methoxy-N-methylpyridine-2-carboxamide (1.06 g, 5.26 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 17 hours. Volatile solvent was removed under reduced pressure and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by MPLC (biotage) eluting with 10% ethyl acetate / hexanes to give 652 mg of 1- (4-chloropyridin-2-yl) ethanone (95.5%) as a white crystalline solid. It was. ¹ H-NMR (acetone-d ₆ ) δ 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% ethyl acetate / hexane), _Rf = 0.26.

Step 3: Preparation of 1- [4- (4-aminophenoxy) pyridin-2-yl] ethanone The title compound is 4-chloropyridin-2-carboxylic acid methylamide 1- (4-chloropyridin-2-yl) Prepared as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide, replacing with ethanone. ¹ H-NMR (acetone-d ₆ ) δ 8.53 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.08 (dd, J = 5. 4, 2.4 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 4.77 (brs, 2H), 2. LC MS m / z 229 (M + H) ⁺ , RT = 1.11 min; TLC (50% ethyl acetate / hexane), R _f = 0.30.

Method C-5a
Preparation of 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylcarbamoylmethylamide

  Step 1: Preparation of 4-chloropyridine-2-carboxylic acid methylcarbamoylmethylamide

To a solution of 4-chloropyridine-2-carbonyl chloride hydrochloride (2.00 g, 9.41 mmol) in THF (16.4 mL) and acetonitrile (9.4 mL) at 0 ° C., 2-amino-N -Methylacetamide hydrochloride (1.29 g, 10.35 mmol, 1.1 eq) and triethylamine (5.25 mL, 37.6 mmol, 4.0 eq) were added. The resulting dark brown reaction mixture was stirred at room temperature for 2 hours. Volatile solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate 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 by MPLC (biotage) eluting with 100% ethyl acetate to give 1.4 g (65.3%) of 4-chloropyridine-2-carboxylic acid methylcarbamoyl-N-methylamide as a tan solid. Obtained: TLC (75% ethyl acetate / hexane), R _f = 0.14; MS LC-MS [M + H] ⁺ = 228.

Step 2: Preparation of the title compound 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylcarbamoylmethylamide The title compound was prepared from 4-chloro-N-methyl-pyridine-2-carboxamide and 4-chloropyridine-2- Prepared as described for 4- (4-aminophenoxy) -pyridine-2-carboxamide, replacing with carboxylic acid N-methylcarbamoylmethylamide. ¹ H-NMR (DMSO-d ₆ ) δ 8.86 (t, J = 5.7 Hz, 1H), 8.48 (d, J = 5.4 Hz, 1H), 7.83 (brd, 1H), 7 .32 (d, J = 2.7 Hz, 1H), 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); MS LC -MS [M + H] ⁺ = 301; TLC (100% ethyl acetate), _Rf = 0.10.

Method C-5b
Preparation of 4- (4-aminophenoxy) pyridine-2-carboxylic acid dimethylcarbamoylmethylamide

The title compound was obtained by replacing 2-amino-N-methylacetamide hydrochloride with 2-amino-N, N′-dimethylacetamide hydrochloride and per 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylcarbamoylmethylamide. Prepared as described. ¹ H-NMR (DMSO-d ₆ ) δ 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-fluorophenoxy) pyridine-2-carboxylic acid (2-methoxyethyl) amide

The title compound was prepared in the same manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylcarbamoylmethylamide, replacing 2-amino-N-methylacetamide hydrochloride with 2-methoxyethylamine. . ¹ H-NMR (DMSO-d ₆ ) δ 8.66 (br s, 1H), 8.45 (d, J = 4.2 Hz, 1H), 7.32 (d, J = 1.8 Hz, 1H), 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-1a
Preparation of 5- (4-amino-3-fluorophenoxy) -N-methylnicotinamide

  Step 1: Preparation of 5- (4-nitro-3-fluorophenoxy) nicotinic acid methyl ester

To an ice bath cooled solution of 5-hydroxynicotinic acid methyl ester (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, 2,3-difluoro-4-nitrobenzene (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 ethyl acetate (300 mL) and water (150 mL). The aqueous layer was extracted with ethyl acetate (100 mL), the combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate was removed under reduced pressure. The crude product was purified by column chromatography eluting with 50-75% ethyl acetate / hexanes to give 2.4 g 28%) of 5- (4-nitro-3-fluorophenoxy) nicotinic acid methyl ester. ¹ H-NMR (CD ₃ OD) δ 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 [M + 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-fluorophenol, substituting 4-nitro-3-fluorophenol with methyl 5- (4-nitro-3-fluorophenoxy) nicotinate. . ¹ H-NMR (CD ₃ OD) δ 8.97 (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 to 6.97 (m, 1H), 4.06 (s, 3H); MS LC-MS (MH) + = 263.2 RT = 2.50 minutes.

  Step 3: Preparation of the title compound 5- (4-amino-3-fluorophenoxy) -N-methylnicotinamide

To a solution of 5- (4-amino-3-fluorophenoxy) nicotinic acid methyl ester (0.50 g, 1.91 mmol) in methanol (2 mL) was added methylamine (0.63 g, 19.1 mmol, in methanol). 2.0M) was added. The reaction flask was sealed and heated at 40 ° C. for 4 hours. The solvent was removed under reduced pressure and the crude product was purified by column chromatography eluting with 5% methanol / CH ₂ Cl ₂ to give 0.4 g (80%) of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ 8.65 (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-1b
Preparation of 5- (4-aminophenoxy) -N-methylnicotinamide

  Step 1: Preparation of 5- (4-aminophenoxy) nicotinic acid methyl ester

The title compound was prepared in the same manner as described for 5- (4-amino-3-fluorophenoxy) nicotinic acid methyl ester, replacing 4-amino-3-fluorophenol with 4-aminophenol. ¹ H-NMR (DMSO-d ₆ ) δ 8.71 (s, 1H), 8.54 (d, J = 2.9 Hz, 1H), 7.47 (t, J = 1.9 Hz, 1H), 6 .85 (d, J = 8.7 Hz, 2H), 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) -N-methylnicotinamide The title compound was prepared by converting 5- (4-amino-3-fluorophenoxy) nicotinic acid methyl ester to methyl 5- (4-aminophenoxy) nicotinate Prepared as described for 5- (4-amino-3-fluorophenoxy) -N-methylnicotinamide, replacing with ester. ¹ H-NMR (DMSO-d ₆ ) δ 8.65 (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-1c
Preparation of 5- (4-amino-2-fluorophenoxy) -N-methylnicotinamide

  Step 1: Preparation of 5- (4-amino-2-fluorophenoxy) nicotinic acid methyl ester

The title compound was prepared in the same manner as described for 5- (4-amino-3-fluorophenoxy) nicotinic acid methyl ester, replacing 4-amino-3-fluorophenol with 4-amino-2-fluorophenol. . ¹ H-NMR (DMSO-d ₆ ) δ 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% ethyl acetate / hexane), R _f = 0.31.

Step 2: Preparation of the title compound 5- (4-amino-2-fluorophenoxy) -N-methylnicotinamide The title compound is 5- (4-amino-3-fluorophenoxy) nicotinic acid methyl ester 5- (4 Prepared as described for 5- (4-amino-3-fluorophenoxy) -N-methylnicotinamide, replacing with -amino-2-fluorophenoxy) nicotinic acid methyl ester. ¹ H-NMR (DMSO-d ₆ ) δ 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-aminophenoxymethyl) pyridine-2-carboxylic acid methylamide

  Step 1: Preparation of 2-methylcarbamoyl-isonicotinic acid ethyl ester

A three-necked flask charged with isonicotinic acid ethyl ester (10 mL, 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 equivalent) and iron (II) sulfate heptahydrate (4.6 g, 16.4 mmol, 0.25 equivalent). Hydrogen peroxide (11.1 mL, 98.1 mmol; 30 wt% solution in water, 1.5 eq) was added dropwise to maintain the internal temperature below 25 ° C. The reaction mixture was stirred at 2.5 ° C. for 10 minutes and at room temperature for 30 minutes. The reaction mixture was poured into 1M aqueous sodium citrate (130 mL) and the resulting orange-yellow suspension was quenched with 5% aqueous sodium bicarbonate (150 mL) and the pH was adjusted to 7. Dichloromethane (100 mL) was then added and the organic layer was extracted and washed with water (2 × 100 mL) and brine (1 × 100 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. . The solid was stirred in ice-water and filtered to give 11.2 g (88.2%) of a yellow solid: TLC (50% ethyl acetate / hexanes), R _f = 0.25.

  Step 2: 4- (hydroxymethyl) -N-methylpyridine-2-carboxamide

To a solution of 2-methylcarbamoyl-isonicotinic acid ethyl ester (7.77 g, 37.3 mmol) in absolute ethanol (125 mL) was added sodium borohydride (2.82 g, 74.6 mmol, 2.0 eq). In addition, the reaction mixture was stirred at room temperature under argon for 18 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2 × 100 mL) and the combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and 5.36 g (86.5%) 4- ( Hydroxymethyl) -N-methylpyridine-2-carboxamide was obtained 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 added to triethylamine (0.11 mL, 0.77 mmol) and methanesulfonyl chloride (0. 74 mL, 0.70 mmol). The reaction was stirred at 25 ° C. for 3 hours and then quenched with water (10 mL). The layers were separated and the organic layer was concentrated under reduced pressure to give crude benzyl chloride. To a solution of crude benzyl chloride in anhydrous DMF (10 mL) was added Cs ₂ CO ₃ (688 mg, 2.11 mmol) and 4-nitrophenol (0.979 mg, 0.70 mmol). The reaction mixture was heated to 60 ° C. for 18 hours and then partitioned between ethyl acetate (15 mL) and water (10 mL). The organic layer was extracted with water (4 × 150 mL), dried, (Ma ₂ SO ₄ ) and evaporated under reduced pressure to give 150 mg (74%) of 4- (4-nitrophenoxymethyl) pyridine-2-carboxamide. Was obtained as a pale yellow oil. ¹ H-NMR (DMSO-d ₆ ): δ 8.78 (brd, 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 title compound 4- (4-aminophenoxymethyl) pyridine-2-carboxylic acid methylamide The title compound is 3-fluoro-4-nitrophenol and 4- (4-nitrophenoxymethyl) pyridine-2-carboxamide. And prepared as described for 4-amino-3-fluorophenol: MS LC-MS [M + H] ⁺ = 258.

Method D-2b
Preparation of 4- (3-aminophenoxymethyl) pyridine-2-carboxylic acid methylamide

The title compound was prepared in the same manner as described for 4- (4-aminophenoxymethyl) pyridine-2-carboxylic acid methylamide, replacing 4-nitrophenol with 3-nitrophenol. ¹ H-NMR (CD ₃ OD) δ 8.40 (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 = 1.8 Hz, 1H) 6.37 to 6.34 (m, 1H), 4.89 (s, 2H), 2.93 (s, 3H).

Method D-2c
Preparation of 4- (4-amino-3-fluorophenoxymethyl) pyridine-2-carboxamide

The title compound was prepared as described for 4- (4-aminophenoxymethyl) pyridine-2-carboxylic acid methylamide, replacing 4-nitrophenol with 3-fluoro-4-nitrophenol. ¹ H-NMR (DMSO-d ₆ ) δ 8.77 (br q, J = 6.6 Hz, 1H), 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 (brs, 2H), 2.81 (d, J = 3. 6Hz, 3H).

Preparation of ureas of formula (I) General method E: Substituted ureas via CDI-derived aniline coupling

Example 1
Method E-1a
Preparation of 4- [3-fluoro-4-({[(1-methyl-1H-indazol-5-yl) amino] carbamoyl} amino) phenoxy] -N-methylpyridine-2-carboxamide

4- (4-Amino-3-fluorophenoxy) -N-methylpyridine in a solution of 1,1′-carbonyldiimidazole (62 mg, 0.38 mmol) in benzene (2 mL) and CH ₂ Cl ₂ (1 mL). 2-Carboxamide (100 mg, 0.38 mmol) was added. The resulting solution was stirred at room temperature for 16 hours and then treated with 1-methyl-5-aminoindazole (56 mg, 0.38 mmol). The reaction was continuously stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was triturated with Et ₂ O. The solid was collected by filtration and then purified by preparative HPLC to give 44 mg (27%) of the title product. ¹ H-NMR (DMSO-d ₆ ) δ 2.78 (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), 7.52-759 (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, 1 H), 8.71-8.81 (m, 1 H), 9.06 (s, 1 H); MS LC-MS [M + H] ⁺ = 435.1; mp 231-234 ° C.

Example 2
Method E-1b
Preparation of methyl 4- [3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate

To 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) was added and the reaction mixture was stirred at room temperature for 12 hours. A solution of 1-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 hours. The mixture was concentrated in vacuo. Purification of the crude product by column chromatography eluting with CH ₂ Cl ₂ / methanol (95: 5) gave 850 mg (38%) of the title compound. ¹ H-NMR (CD ₃ OD) δ 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- {4-[(2-acetylpyridin-4-yl) oxy] phenyl} -N ′-(1-methyl-1H-indazol-5-yl) urea

To a solution of 1-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 16 hours, a solution of 1- [4- (4-aminophenoxy) pyridin-2-yl] ethanone (75 mg, 0.33 mmol, 1.0 equiv) in anhydrous DCE (3.3 mL) was brought to ambient temperature. And the reaction mixture was stirred at 65 ° C. under argon for 20 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by MPLC (biotage) eluting with 60-80% ethyl acetate / hexanes and crystallization from ethyl acetate-hexanes afforded 98.2 mg (74.4%) of the title compound as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 8.79 (s, 1H), 8.68 (s, 1H), 8.58 (d, J = 5.7 Hz, 1H), 7.93 (d, J = 1.0 Hz, 1 H), 7.89 (d, J = 1.2 Hz, 1 H), 7.58 t to 7.53 (m, 3 H), 7.35 (dd, J = 9.0, 2.. 1 Hz, 1 H), 7.26 (d, J = 2.7 Hz, 1 H), 7.21 (dd, J = 5.4, 2.4 Hz, 1 H), 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% ethyl acetate / hexanes) ), R _f = 0.11.

Example 4
Method E-3a
Preparation of 4- (4-{[(1,3-benzothiazol-6-ylamino) carbonyl] amino} phenoxy) -N-methyl-pyridine-2-carboxamide

  Step 1: Preparation of N- (1-imidazole) -N '-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea

To a slurry of 1,1′-carbonyldiimidazole (6.66 g, 41.1 mmol) and imidazole (2.80 g, 41.1 mmol) in CH ₂ Cl ₂ (40 mL) at 0 ° C., CH ₂ Cl ₂ (8 mL) solution of 4- (2- (N- methylcarbamoyl) -4-pyridyloxy) aniline (1.0 g, 4.11 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then washed quickly with cold water (40 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to about 16 ml. The crude product in CH ₂ Cl ₂ was used in subsequent reactions without further purification.

Step 2: The title compound was prepared from 4- (4 - {[(1,3-benzothiazol-6-ylamino) carbonyl] amino} - phenoxy) -N- Preparation of methyl 2-carboxamide CH ₂ Cl ₂ (4 mL) in Of crude N- (1-imidazole) -N ′-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) urea at room temperature in CH ₂ Cl ₂ (3 mL) A solution of 6-aminobenzothiazole (135 mg, 0.90 mmol) in was added slowly. The reaction mixture was heated at 40 ° C. for 2 days. The resulting precipitate was filtered and washed with CH ₂ Cl ₂ to give 256 mg (60%) of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 9.22 (s, 1H), 9.02 (s, 1H), 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- 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) -N-methylpyridine-2-carboxamide

The title compound replaces 6-aminobenzothiazole with 1-N-methyl-6-aminoindazole and 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline with 3- (2- (N Described for 4- (4-{[(1,3-benzothiazol-6-ylamino) carbamoyl] amino} phenoxy) -N-methylpyridine-2-carboxamide, substituted with -methylcarbamoyl) -4-pyridyloxy) aniline Prepared in the same manner as ¹ H-NMR (CD ₃ OD) δ 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 shown in Table 1 can be readily obtained and / or selected as appropriate starting materials whose synthesis is taught herein and the process of Method E described above or other standard chemistries known in the art. Prepared as described above by using the process.

^{* The} following are LCMS conditions: HPLC-electrospray mass spectrum (HPLC ES-MS) shows two Gilson 306 pumps, Gilson 215 autosampler, Gilson diode array detector, YMC Pro C-18 column (2 × 23 mm, 120A). ), And a Gilson HPLC system equipped with a Miramass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. The spectrum was scanned from 120 to 1000 amu for 2 seconds. ELSD (Evaporative Light Scattering Detector) data was also acquired as an analog channel. Gradient elution is used at 1.5 mL / min with buffer A as 2% acetonitrile in water containing 0.02% TFA and buffer B as 2% water in acetonitrile containing 0.02% TFA. It was. Samples were eluted as follows: slope from 90% A for 0.5 minutes to 95% B over 3.5 minutes, hold at 95% B for 0.5 minutes, and then column was adjusted to 0. Return to the initial state over 1 minute. The total execution time is 4.8 minutes.
^** comm means "commercially available".

  Other compounds of Formula I are suitable starting materials and / or intermediates using methods described herein, or other methods known in the art, and will be readily recognized by those skilled in the art. It can be prepared using the body.

General Method F: Substituted Ureas via Addition of Aniline to Aryl Isocyanate Example 104
Method F-1a
N-methyl-4- [4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide Preparation of

To a slurry of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (143 mg, 0.59 mmol) in DCM (1 mL) at 0 ° C., 2,2 in DCM (1 mL). , 4,4-Tetrafluoro-6-isocyanato-1,3-benzodioxene (150 mg, 0.60 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. The resulting precipitate was filtered and washed with DCM to give the desired product (125 mg, 41%) as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 9.14 (s, 1H), 9.00 (s, 1H), 8.76 (q, J = 4.5 Hz, 1H), 8.48 (d, J = 5.4 Hz, 1H), 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 (m, 3H), 2. 76 (d, J = 4.5 Hz, 3H); MS LC-MS [M + H] ⁺ = 493.1, RT = 3.27 min.

Example 105
Method F-1b
Preparation of methyl 4- [3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate

To a stirred solution of 2,2,4,4-tetrafluoro-6-isocyanato-1,3-benzodioxene (0.816 g, 3.28 mmol) was added 4- (3-aminophenoxy) pyridine in DCM (13 mL). 2-Carboxylic acid methyl ester (0.800 g, 3.28 mmol) was added in several portions. Within 1 minute of addition, the uniform content turned white and opaque and was stirred at room temperature for 12 hours. The heterogeneous mixture was filtered and the solid product was washed repeatedly with DCM to remove residual starting material. The desired product was collected as a white powder (1.36 g (83%)). ¹ H-NMR (DMSO-d ₆ ) δ 9.08 (d, 2H), 8.59 (s, 1H), 8.07 (s, 1H), 7.60 (dd, 1H), 7.37 ( m, 4H), 7.25 (d, 1H), 7.20 (dd, 1H), 6.80 (d, 1H), 3.82 (s, 3H); MS LC MS [M + H] ⁺ = 494 .1, RT = 3.23 minutes.

Example 107
Method F-2
Preparation of 4- (3-Fluoro-4-{[(quinoxalin-2-ylamino) carbonyl] amino} phenoxy) -N-methyl-pyridine-2-carboxamide

To a solution of 4- [4-amino-3- (fluoro) phenoxy] -N-methylpyridine-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 diisopropylethylamine (0.12 mL, 0.69 mmol, 1.2 eq) were added and the reaction mixture was stirred at 75 ° C. After 3 hours, a solution of 2-aminoquinoxaline (83.3 mg, 0.57 mmol, 1.0 equiv) in anhydrous DMF (2.8 mL) was added and the reaction mixture was stirred at 75 ° C. for 17 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with water and brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude material was absorbed onto silica and purified by MPLC (biotage) eluting with 10% methanol / ethyl acetate. Trituration from DCM / methanol gave 25.0 mg (10.1%) of the title product as a yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 11.75 (s, 1H), 10.75 (s, 1H), 8.89 (s, 1H), 8.79 (br q, 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, 2H), 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% EA), R _f = 0.20. MS LC-MS [M + H] ⁺ = 433), RT = 2.86 min.

Example 108
Method F-3
Preparation of 4- (3-{[(1H-indazol-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide dihydrochloride

  Step 1: Preparation of 5-isocyanato-indazole-1-carboxylic acid tert-butyl ester

To a 0 ° C. mixture of a 1.93M solution of phosgene in toluene (8.9 mL, 17 mmol) and CH ₂ Cl ₂ (80 mL) was added 5-amino-indazole-1-carboxylic acid in CH ₂ Cl ₂ (20 mL). A solution of tert-butyl ester (2 g, 8.5 mmol) and pyridine (3.5 mL, 43 mmol) was added dropwise. The reaction mixture was stirred for 1.5 hours and then concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (100 mL) and used without further purification.

  Step 2: Preparation of N- (1-tert-butylcarboxyl-indazo-5-yl) -N '-[(3- (2- (N-methylcarboxyl) -4-pyridyloxy) phenyl] urea

CH ₂ Cl ₂ (5 mL) solution of 4- (3-aminophenoxy) pyridine-2-carboxamide (108 mg, 0.39 mmol) to a solution of crude 5-isocyanato in CH ₂ Cl ₂ (5 mL) - indazole - A solution of 1-carboxylic acid tert-butyl ester (0.39 mmol) was added. The reaction mixture was stirred at room temperature for 12 days. The resulting slurry was diluted with about 1 mL of methanol. The resulting clear solution was purified by MPLC (Biotage) eluting with 70% ethyl acetate / hexane followed by 100% ethyl acetate to give N- (1-tert-butylcarboxyl-indazo-5-yl-N '-[(3- (2- (N-methoxycarbonyl) -4-pyridyloxy) phenyl] urea (63 mg, 32%) was obtained as a white solid: TLC (80% ethyl acetate / hexane) R _f 0. 36; ES-LCMS (relative abundance) m / z 503 (MH ⁺ , 100%); HRMS calculated 503.20344, found 503.0344.

Step 3: Preparation of the title compound 4- (3-{[(1H-indazol-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide dihydrochloride N- (1-tert-butylcarboxyl) -Indazo-5-yl) -N '-[(3- (2- (N-methylcarboxyl) -4-pyridyloxy) phenyl] urea (29 mg, 0.06 mmol) in 2M HCl solution in ether (5 mL The reaction mixture was stirred overnight and the resulting mixture was concentrated under reduced pressure to give the title compound (28 mg, 100%) as a yellow solid: free base TLC (ethyl acetate) R _f 0.27; ES-LCMS (relative abundance) m / z 403 (MH ⁺ , 100%); HRMS calculated 403.15132, found 403.15112.

  Additional compounds shown in Table 2 are readily available and / or selected from appropriate starting materials whose synthesis is taught herein and are described in the process of Method F described above, or known in the art. Prepared as described above by using other standard chemical processes.

^* LCMS conditions are shown below: HPLC-electrospray mass spectrum (HPLC ES-MS) shows two Gilson 306 pumps, Gilson 215 autosampler, Gilson diode array detector, YMC Pro C-18 column (2 × 23 mm, 120 A) ), And using a Gilson HPLC system equipped with a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. The spectrum was scanned from 120 to 1000 amu for 2 seconds. ELSD (Evaporative Light Scattering Detector) data was also acquired as an analog channel. Gradient elution with buffer A as 2% acetonitrile in water containing 0.02% TFA and buffer B as 2% water in acetonitrile containing 0.02% TFA was performed at 1.5 mL / min. Used in. The sample was eluted as follows: 90% A to 95% B slope for 0.5 minutes over 3.5 minutes, hold at 95% B for 0.5 minutes, then column was Return to initial conditions over 1 minute. The total execution time is 4.8 minutes.
^** comm means "commercially available".
Is

Other compounds of Formula I use the methods described herein, or methods known in the art, and appropriate starting materials and / or intermediates that will be readily recognized by those skilled in the art. Can be prepared.

  General methods G and H: Preparation of extended amides via ester substitution with nucleophilic alkylamines

Example 145
Method G-1a
N- [3- (1H-imidazol-1yl) propyl] -4- [4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino Preparation of] carbonyl} amino) phenoxy] pyridine-2-carboxamide

4- [4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2 in THF (2 ml) -To a mixture of methyl carboxylate (80 mg, 0.16 mmol) and magnesium chloride (16 mg, 0.16 mmol) at room temperature, 1- (3-aminopropyl) imidazole (0.04 mL, 0.32 mmol). Was added. The reaction mixture was stirred at room temperature for 3 days. The solid was filtered and washed with 10% methanol in CH ₂ Cl ₂ . The combined filtrates were concentrated to dryness and the residue was purified by column chromatography eluting with 2-5% methanol / CH ₂ Cl ₂ to give 44 mg (45%) of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 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-MS (MH) ⁺ = 587.1, RT = 3. 14 minutes.

Example 146
Method G-1b
N- (2-pyrrolidin-1-ylethyl) -4- [4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino ) Preparation of phenoxy] pyridine-2-carboxamide

In the title compound, 1- (3-aminopropyl) imidazole was replaced with 1- (2-aminoethyl) pyrrolidone, and N- [3- (1H-imidazol-1-yl) propyl] -4- [4-({ Prepared similarly as described for [(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide. ¹ H-NMR (methanol-d ₄ ) δ 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-1c
Preparation of N-cyclopropyl-4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide.

The title compound is 1- (3-aminopropyl) imidazole replaced with cyclopropylamine and 4- [4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin- 6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate methyl 4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine N- [3- (1H-imidazol-1-yl) propyl] -4- [4-({[(2,2,4,4-tetrafluoro-4H-1,3- Benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide was prepared as described. ¹ H-NMR (methanol-d ₄ / CD ₂ Cl ₂ ) δ 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 [M + H] ⁺ = 443.2, RT = 2.51 min .

Example 148
Method H-1a
Preparation of 4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N- (2-piperidin-1-ylethyl) pyridine-2-carboxamide

  Step 1: Preparation of 4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylic acid

N-methyl-4- [3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide (80 mg, 0.19 mmol) and powdered water A mixture of potassium oxide (0.03 g, 0.56 mmol) was dissolved in methanol / water (4 mL, 3: 1) and the reaction mixture was heated at 40 ° C. for 3 hours. The solvent was removed in vacuo and the crude residue was dissolved in water (5 mL) and precipitated upon neutralization with IN hydrochloric acid. The precipitated solid was washed with water and then CH ₂ Cl ₂ to give 0.55 g (70%) of the carboxylic acid. ¹ H-NMR (DMSO-d ₆ ) δ 9.97 (s, 1H), 9.77 (s, 1H), 8.46 (d, 1H), 7.93 (s, 1H), 7.90 ( s, 1H), 7.51 (d, 1H), 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: Title compound 4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N- (2-piperidin-1-ylethyl) pyridine-2- Preparation of carboxamide 4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -pyridine-2-carboxylic acid (0.07 g, 0.17 mmol) was prepared. Dissolved in DMF (2.5 mL), followed by 1- (2-aminoethyl) pyridine (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-methylmorpholine (0.04 g , 0.38 mmol) in this order. The mixture was stirred at room temperature for 12 hours and the solvent was removed in vacuo. The crude residue was dissolved in CH ₂ Cl ₂ (10 mL) and washed with water (3 mL). The solvent was removed in vacuo and the crude product was purified by preparative HPLC. The isolated product was washed with aqueous Na ₂ CO ₃ to give 0.07 g (78%) of the title compound. ¹ H-NMR (CD ₃ OD) δ 8.51 (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-1b
Preparation of 4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino] phenoxy-N-pyridin-3-ylpyridin-2-carboxamide

The title compound is a 4- [3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] in which 1- (2-aminoethyl) pyridine is replaced with 3-aminopyridine. Prepared as described for -N- (2-piperidin-1-ylethyl) pyridine-2-carboxamide. ¹ H-NMR (DMSO-d ₆ ) δ 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 (M + H) ⁺ = 480.1, RT = 2.81 min.

  Method I: General Method for the Synthesis of Carboxamide via Nitrile Hydrolysis

Example 150
Method 1
4- [3,5-difluoro-4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2 -Preparation of carboxamide

N- {4-[(2-cyanopyridin-4-yl) oxy] -2,6-difluorophenyl} -N ′-(2,2,4,4- in acetone (2 ml) and water (1 ml) A solution of tetrafluoro-4H-1,3-benzodioxin-6-yl) urea (100 mg, 0.20 mmol) was treated with sodium percarbonate (containing 25% H ₂ O ₂ , 320 mg, 2.0 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). 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 to give 42 mg (41%) of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 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); MS GC-MS M ⁺ = 515.0, RT = 3.63 Minutes.

  General method J: oxidation

Example 151
Method J-1
N-methyl-4- [3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-1-oxo Preparation of 2-carboxamide

N-methyl-4- [3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] in DCM (3 mL) and THF (3 mL) To a solution of carbonyl} amino) phenoxy] pyridine-2-carboxamide (100 mg, 0.20 mmol) was added mCPBA (140 mg, 0.81 mmol). This was stirred for 48 hours and the formed precipitate was collected and washed with DCM and methanol to give 53 mg (48%) of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 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
N-methyl-4- [3- (methylsulfonyl) -4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) Phenoxy] pyridine-2-carboxamide

N-methyl-4- [3- (methylthio) -4-({[(2,2,4,4-tetrafluoro--) in anhydrous 1: 1 v / v DCM / THF (3.0 mL) at 0 ° C. 4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide (150 mg, 0.28 mmol) and mCPBA (162.7 mg, 0.61 mmol, 2.2 Equivalent) was added and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into saturated aqueous sodium thiosulfate and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give 73.3 mg (46.1%) of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 10.31 (s, 1H), 8.81 (q, J = 5.4 Hz, 1H), 8.71 (s, 1H), 8.55 (d, J = 5.7 Hz, 1H), 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; m. p. 222-223.5 ° C.

  The additional compounds shown in Table 3 are selected from the appropriate starting materials that are readily available and / or whose synthesis is taught herein, and are described in Process G, H and / or I described above, Or prepared as described above using other standard chemical processes known in the art.

^* LCMS conditions are shown below: HPLC-electrospray mass spectrum (HPLC ES-MS) shows two Gilson 306 pumps, Gilson 215 autosampler, Gilson diode array detector, YMC Pro C-18 column (2 × 23 mm, 120A) And a Gilson HPLC system equipped with a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. The spectrum was scanned from 120 to 1000 amu for 2 seconds. ELSD (Evaporative Light Scattering Detector) data was also acquired as an analog channel. Gradient elution at 1.5 mL / min with buffer A as 2% acetonitrile in water containing 0.02% TFA and buffer B as 2% water in acetonitrile containing 0.02% TFA Using. The sample was eluted as follows: 90 minutes A to 95% B slope for 0.5 minutes over 3.5 minutes, held at 95% B for 0.5 minutes, then 0.1 minutes To return the column to the initial conditions. The total execution time is 4.8 minutes.
^** comm means "commercially available".

Biological Tests c-Raf (Raf-1) Biochemical Assay Purification of Proteins Used in the Assay The c-Raf biochemical assay was activated (phosphorylated) c-Raf enzyme by Lck kinase I went there. Lck-activated c-Raf by co-infection of cells with GST-c-Raf (from amino acid 302 to amino acid 648) and baculovirus expressing Lck (full length) under the control of the polyhedrin promoter. (Lck / c-Raf) was produced in Sf9 insect cells. Both baculoviruses were used at a multiplicity of infection of 2.5 and cells were harvested 48 hours after infection.

  Cells were infected with baculovirus expressing GST-MEK-1 (full length) fusion protein at a multiplicity of infection of 5, and then harvested 48 hours after infection, thereby allowing MEK-1 protein to be transformed into Sf9 insect cells. It was made to produce. Similar purification procedures were used with GST-c-Raf 302-648 and GST-MEK-1.

  Transfected cells are suspended at 100 mg wet cell biomass per mL in buffer containing 10 mM sodium phosphate, 140 mM sodium chloride pH 7.3, 0.5% Triton X-100 and protease inhibitor cocktail. I let you. Cells were disrupted with a Polytron homogenizer and centrifuged at 30,000 g for 30 minutes. 30,000 g supernatant was applied to 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 protein was 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 protein was dialyzed against a buffer containing 20 mM Tris, pH 7.5, 150 mM NaCl and 20% glycerol.

Biochemical assay protocol and results The compounds were serially diluted in DMSO using 3 fold dilutions to stock concentrations typically in the range of 50 μM to 20 nM (final concentrations in the assay range from 1 μM to 0.4 nM). ). The c-Raf biochemical assay was performed as a radioactivity filter mat assay in 96-well Costar polypropylene plates (Costar 3365). The plate was loaded with a 75 μL solution containing 50 mM HEPES pH 7.5, 70 mM NaCl, 80 ng Lck / c-Raf and 1 μg MEK-1. Subsequently, 2 μL of serially diluted individual compounds were added to the reaction prior to addition of ATP. The reaction was initiated with a 25 μL ATP solution containing 5 μM ATP and 0.3 μCi [33P] -ATP. The plate was sealed and incubated for 1 hour at 32 ° C. The reaction was quenched with the addition of 50 μl of 4% phosphoric acid and harvested on a P30 filter mat (PeikinElmer) using a Wallac Tomtec harvester. The filter mat was first washed with 1% phosphoric acid and second washed with deionized water. Filters were microwave dried, immersed in scintillation fluid and read on a Wallac 1205 Betaplate counter (Wallac Inc., Atlanta, GA, USA). Results were expressed as percent inhibition.

% Inhibition = [100− (T _ib / T _i )] × 100
Where
T _ib = (counts per minute with inhibitor)-(background)
T _i = (counts per minute without inhibitor) − (background)

  The compounds of Examples 1 to 174 show> 40% inhibition at 1 micromolar in this assay. Further, Examples 1, 4, 5, 8, 15, 19, 21, 23, 25, 32, 33 to 36, 39 to 43, 46 to 63, 66 to 86, 92 to 94, 96, 97, 101, 104, 107, 109 to 114, 116, 118 to 121, 123 to 131, 133, 134, 136 to 144, 149, 151, 152, 154, 164, 165, 167, and 170 to 174 have 1 micron Shows> 80% inhibition of c-Raf kinase in moller.

  Those skilled in the art will be able to make the best use of the present invention using the previous information and information available in the art.

  It should be apparent to those skilled in the art that variations and modifications of the present invention can be made without departing from the spirit or scope of the invention as described herein.

All publications and patents cited above are incorporated herein by reference.

Claims (26)

Formula (I):

Wherein A is independently R ¹ , OR ¹ , S (O) _p R ¹ , C (O) R ¹ , C (O) OR ¹ , C (O) NR ¹ R ² , halogen, Optionally substituted with 1 to 4 substituents which are oxo, cyano, or nitro:
(1) Benzimidazolyl,
(2) 1,3-benzothiazolyl,
(3) 1,2,3-benzotriazolyl,
(4) 1,3-benzoxazolyl,
(5) 2,3-dihydro-1H-indolyl,
(6) 2,3-dihydro-1H-indenyl,
(7) 1,1-dioxide-2,3-dihydro-1-benzothienyl,
(8) 1H-indazolyl,
(9) 2H-indazolyl,
(10) 1H-in drill,
(11) Formula:

A bicyclic heterocycle which is the group
B is independently C ₁ -C ₅ linear or branched alkyl, C ₁ -C ₅ linear or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ -C ₃ alkylamino, C ₁ -C ₆ dialkylamino, carboxamide, halogen, cyano, nitro, or phenyl, naphthyl, or pyridyl optionally substituted with 1 to 4 substituents that are S (O) _p R ⁷ ;
L is —O— ;
M is independently C ₁ -C ₅ linear or branched alkyl, C ₁ -C ₅ linear or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ -C ₃ alkylamino, A pyridine ring optionally substituted by 1 to 3 substituents which are C ₁ -C ₆ dialkylamino, halogen or nitro;
Q is C (O) R ⁴ , C (O) OR ⁴ or C (O) NR ⁴ R ⁵ ;
Each of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is independently:
(A) hydrogen,
_(B) C 1 -C ₅ linear, branched or cyclic alkyl,
(C) phenyl,
_(D) C 1 -C ₃ alkyl - phenyl,
(E) _C 1 -C substituted up to perhalo ₅ straight or branched chain alkyl,
(F) - (CH 2) q -X, here, X is saturated, partially saturated, or aromatic, 5 or 6 comprising at least one atom selected from oxygen, nitrogen and sulfur A membered heterocyclic ring, or an 8 to 10 membered bicyclic heteroaryl having 1 to 4 heteroatoms that are O, N or S, or (g) — (CH ₂ ) _q —Y, wherein Y Are C (O) R ⁶ , C (O) OR ⁶ and C (O) NR ⁶ R ⁷ ;
Is;
Each of R ⁶ to R ⁷ is independently:
(A) hydrogen,
_(B) C 1 -C ₅ linear, branched or cyclic alkyl,
(C) phenyl,
(D) C ₁ -C ₃ alkyl-phenyl, or (e) substituted C ₁ -C ₅ linear or branched alkyl up to perhalo;
Each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ other than perhalo-substituted C ₁ -C ₅ linear or branched alkyl is independently a C ₁ -C ₅ linear or branched-chain alkyl, substituted _C 1 -C ₅ straight or branched chain alkyl of up to _perhalo, C 1 -C ₃ alkoxy, hydroxy, carboxy, _amino, C 1 -C _{3 alkylamino,} C 1 -C ₆ dialkyl Optionally substituted with 1 to 3 substituents which are amino, 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]
Or an pharmaceutically acceptable salt thereof, or an oxidized derivative of the compound of formula (I), wherein one or two nitrogen atoms of the urea are substituted with hydroxyl groups, or the pyridine ring M A derivative in which the nitrogen atom is an oxide type. A compound according to claim 1 wherein A and B are in accordance with one of the following combinations:
A = 1H-benzimidazol-5-yl; and B = phenyl, pyridinyl or naphthyl,
A = 1H-benzimidazol-5-yl; and B = phenyl, pyridinyl or naphthyl,
A = 1,3-benzodithiazol-2-yl; and B = phenyl, pyridinyl or naphthyl,
A = 1,3-benzodithiazol-5-yl; and B = phenyl, pyridinyl or naphthyl,
A = 1,3-benzodithiazol-6-yl; and B = phenyl, pyridinyl or naphthyl,
A = 1,2,3-benzotriazol-5-yl; and B = phenyl, pyridinyl or naphthyl,
A = 1,3-benzoxazol-2-yl; and B = phenyl, pyridinyl or naphthyl, or A = 1,3-benzoxazol-6-yl; and B = phenyl, pyridinyl or naphthyl. A compound according to claim 1 wherein A and B are in accordance with one of the following combinations:
A = 1H-benzimidazolyl; 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 or pyridinyl. A compound according to claim 1 wherein A and B are in accordance with one of the following combinations:
A = 1H-benzimidazol-5-yl; and B = phenyl or pyridinyl,
A = 1H-benzimidazol-6-yl; and B = phenyl or pyridinyl,
A = 1,3-benzodioxol-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-benzothiazol-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. A compound according to claim 1 wherein A and B are in accordance with one of the following combinations:
A = 2,3-dihydro-1-benzofuran-5-yl; and B = phenyl, pyridinyl, or naphthyl,
A = 2,3-dihydro-1H-indol-5-yl; and B = phenyl, pyridinyl, or naphthyl,
A = 2,3-dihydro-1H-indol-6-yl; and B = phenyl, pyridinyl, or naphthyl,
A = 2,3-dihydro-1H-inden-4-yl; and B = phenyl, pyridinyl, or naphthyl,
A = 2,3-dihydro-1H-inden-5-yl; and B = phenyl, pyridinyl, or naphthyl,
A = 1,1-dioxide-2,3-dihydro-1-benzothien-6-yl; and B = phenyl, pyridinyl, or naphthyl. A compound according to claim 1 wherein A and B are in accordance with one of the following combinations:
A = 2,3-dihydro-1-benzofuran-5-yl; and B = phenyl or pyridinyl,
A = 2,3-dihydro-1H-indol-5-yl; and B = phenyl or pyridinyl,
A = 2,3-dihydro-1H-indol-6-yl; and B = phenyl or pyridinyl,
A = 2,3-dihydro-1H-inden-4-yl; and B = phenyl or pyridinyl,
A = 2,3-dihydro-1H-inden-5-yl; and B = phenyl or pyridinyl, or A = 1,1-dioxide-2,3-dihydro-1-benzothien-6-yl; and B = phenyl Or pyridinyl. A compound according to claim 1 wherein A and B are in accordance with one of the following combinations:
A = 1H-indazol-5-yl; and B = phenyl, pyridinyl, or naphthyl,
A = 2H-indazol-5-yl; and B = phenyl, pyridinyl, or naphthyl,
A = 1H-indazol-6-yl; and B = phenyl, pyridinyl, or naphthyl,
A = 1H-indol-5-yl; and B = phenyl, pyridinyl, or naphthyl,
Or A = 1-oxo-2,3-dihydro-1H-inden-5-yl; and B = phenyl, pyridinyl, or naphthyl. A compound according to claim 1 wherein A and B are in accordance with one of the following combinations:
A = 1H-indazol-5-yl; and B = phenyl or pyridinyl,
A = 2H-indazol-5-yl; and B = phenyl or pyridinyl,
A = 1H-indazol-6-yl; and B = phenyl or pyridinyl,
A = 1H-indol-5-yl; and B = phenyl or pyridinyl, or A = 1-oxo-2,3-dihydro-1H-inden-5-yl; and B = phenyl or pyridinyl. N-methyl-4- [3-({[(2-methyl-1,3-benzoxazol-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- [4-({[(1-acetyl-2,3-dihydro-1H-indol-6-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [4-({[(6-chloro-1,3-benzothiazol-2-yl) amino} carbonyl] amino) phenoxy] -N-methylpyridine-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-1,3-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-methylpyridine-2-carboxamide ,
4- [4-({[(6-Methoxy-1,3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [4-({[(6-Methoxy-1,3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [4-({[(5-chloro-1,3-benzooxazol-2-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [4-({[(5-chloro-1,3-benzooxazol-2-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [4-({[(6-chloro-1,3-benzothiazol-2-yl) amino] carbonyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide,
4- [4-({[(6-chloro-1,3-benzothiazol-2-yl) amino] carbonyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide,
4- (2-chloro-4-{[(2,3-dihydro-1H-inden-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
4- [4-({[(4,6-difluoro-1,3-benzothiazol-2-yl) amino] carbonyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide,
4- [3-Fluoro-4-({[(6-methoxy-1,3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- (4-{[({1- [2- (diethylamino) ethyl] -1H-indol-5-yl} amino) carbonyl] amino} -3-fluorophenoxy) -N-methylpyridine-2-carboxamide ,
4- (4-{[(2,3-dihydro-1H-inden-5-ylamino) carbonyl] amino} -3-fluorophenoxy) -N-methylpyridine-2-carboxamide,
4- [3-fluoro-4-({[(1-oxo-2,3-dihydro-1H-inden-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [4-({[(1,1-dioxide-2,3-dihydro-1-benzothien-6-yl) amino] carbonyl} amino) -3-fluorophenoxy] -N-methylpyridine-2- Carboxamide,
4- [3-fluoro-4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [2-fluoro-4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino] phenoxy] -N-methylpyridine-2-carboxamide,
4- [2,4-difluoro-5-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
N-methyl-4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) -3- (trifluoromethyl) -phenoxy] pyridine-2-carboxamide;
4- [4-fluoro-3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [2-fluoro-5-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [2-chloro-6-fluoro-4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [3-fluoro-4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N- (2-methoxyethyl) pyridine-2-carboxamide,
4- [4-({[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide ,
4- [4-({[(2-Methyl-1,3-benzothiazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
N-methyl-4- [4-({[(2-methyl-1,3-benzothiazol-5-yl) amino] carbonyl} amino) -3- (trifluoromethyl) phenoxy] pyridine-2-carboxamide ,
N-methyl-4- [3-methyl-4-({[(2-methyl-1,3-benzothiazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- [3-Fluoro-4-({[(2-methyl-1,3-benzothiazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [2-chloro-4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [3-({[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [4-({[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [2-Chloro-4-({[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide ,
4- [3-chloro-4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
N-methyl-4- [3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
N-methyl-4- [3-({[(1-methyl-1H-indazol-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- (3-{[(2,3-dihydro-1-benzofuran-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
N-methyl-4- {3-[({[2- (trifluoromethyl) -1H-benzimidazol-5-yl] amino} carbonyl) amino] phenoxy} pyridine-2-carboxamide,
4- [4-chloro-3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methyl-pyridine-2-carboxamide,
4- [4-Chloro-3-({[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide ,
4- [3-chloro-4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- [2-chloro-4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- [4-({[(2,2-difluoro-1,3-benzodioxol-5-yl) -amino] carbonyl} amino) -3-fluorophenoxy] -pyridine-2-carboxamide,
4- (4-{[(2,3-dihydro-1H-inden-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
N-methyl-4- [4-({[(1-oxo-2,3-dihydro-1H-inden-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide;
4- [4-{[(2,3-dihydro-1H-inden-5-ylamino) carbonyl] amino} -3- (trifluoromethyl) phenoxy] -N-methylpyridine-2-carboxamide,
N-methyl-4- [4-({[(1-oxo-2,3-dihydro-1H-inden-5-yl) amino] carbonyl} amino) -3- (trifluoromethyl) phenoxy] pyridine- 2-carboxamide,
4- (3-chloro-4-{[(2,3-dihydro-1H-inden-5-ylamino) carbonyl] amino} phenoxy) pyridine-2-carboxamide,
4- [3-chloro-4-({[(1-oxo-2,3-dihydro-1H-inden-5-yl) amino] carbonyl} amino) phenoxy] -pyridine-2-carboxamide,
N-methyl-4- [4-({[(1-methyl-1H-indazol-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- (4-{[(1,3-benzothiazol-6-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
N-methyl-4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- (4-{[(2,3-dihydro-1-benzofuran-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
4- [2,4-dichloro-5-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [3-Chloro-4-({[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-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-1H-inden-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
4- [3-chloro-4-({[(1-oxo-2,3-dihydro-1H-inden-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [2-chloro-4-({[(1-oxo-2,3-dihydro-1H-inden-5-yl) amino] carbonyl} amino) phenoxy] N-methylpyridine-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-1H-inden-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
4- [2,4-dichloro-5-({[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2 -Carboxamide,
N-methyl-4- {4-[({[1- (methylsulfonyl) -2,3-dihydro-1H-indol-5-yl] amino} carbonyl) amino] -phenoxy} pyridine-2-carboxamide,
4- (3-{[(1H-indazol-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide dihydrochloride 4- (3 {[(1,3-benzodioxy Sole-5-ylamino) carbonyl] amino} phenoxy-N-methylpyridine-2-carboxamide,
4- (3-{[(1,3-benzodioxol-5-ylamino) carbonyl] amino} -4-chlorophenoxy) -N-methylpyridine-2-carboxamide,
4- (4-{[(1,3-benzodioxol-5-ylamino) carbonyl] amino} -3-fluorophenoxy) pyridine-2-carboxamide,
4- (4-{[(1,3-benzodioxol-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
4- (4-{[(1,3-benzodioxol-5-ylamino) carbonyl] amino} -3-chlorophenoxy) -N-methylpyridine-2-carboxamide,
4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N- (2-piperidin-1-ylethyl) pyridine-2-carboxamide,
4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N- (2-pyrrolidin-1-ylethyl) pyridine-2-carboxamide,
4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-pyridin-3-ylpyridin-2-carboxamide,
N- [3- (1H-imidazol-1-yl) propyl] -4- [3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2 -Carboxamide,
4- [4-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N- (2-pyrrolidin-1-ylethyl) pyridine-2-carboxamide,
4- [4-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N- (2-piperazin-1-ylethyl) pyridine-2-carboxamide,
4- (4-{[(2,3-dihydro-1H-inden-5-ylamino) carbonyl] amino} -2-methoxyphenoxy) pyridine-2-carboxamide,
4- [3-fluoro-4-({[(6-nitro-1,3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
N-methyl-4- [4-({[(6-nitro-1,3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide;
4- [4-({[(4,6-difluoro-1,3-benzothiazol-2-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
N-methyl-4- [4-({[(2-methyl-1,3-benzoxazol-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- (4-{[(2,3-dihydro-1H-inden-4-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
4- [4-({[(2,2-difluoro-1,3-benzodioxol-4-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
N-methyl-4- [4-({[(2-methyl-2H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- (4-{[({1- [2- (diethylamino) ethyl] -1H-indazol-5-yl} amino) carbonyl] amino} -3-fluorophenoxy) -N-methylpyridine-2-carboxamide ,
N-methyl-4- [4-({[(2-methyl-1H-indol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
N- {4-[(2-acetylpyridin-4-yl) oxy] phenyl} -N ′-(1-methyl-1H-indazol-5-yl) urea
N- [2- (dimethylamino) -2-oxoethyl] -4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} aminophenoxy)] pyridine-2-carboxamide ,
N-methyl-4- [4-({[(2-methyl-1,3-benzothiazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
4- (3-{[(1H-1,2,3-benzotriazol-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] methyl pyridine-2-carboxylate,
4- (4-{[(1H-1,2,3-benzotriazol-5-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
4- (4-{[(1H-indazol-6-ylamino) carbonyl] amino} phenoxy) -N-methylpyridine-2-carboxamide,
N-methyl-4- {4-[({[2- (trifluoromethyl) -1H-benzimidazol-5-yl] amino} carbonyl) amino] phenoxy} pyridine-2-carboxamide,
4- [4-({[(1-ethyl-2-methyl-1H-benzimidazol-5-yl) amino] carbonyl} amino) phenoxy] -N-methylpyridine-2-carboxamide,
4- [4-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] methyl pyridine-2-carboxylate,
N- [3- (1H-imidazol-1-yl) propyl] -4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2 -Carboxamide,
4- [4-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N- (2-piperidin-1-ylethyl) pyridine-2-carboxamide,
N-cyclopropyl-4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide,
N- (cyclopropylmethyl) -4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -pyridine-2-carboxamide,
N-cyclobutyl-4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide, or N-({4- [4 -({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridin-2-yl} carbonyl) methyl glycinate;
A compound that is   A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 and a physiologically acceptable carrier.   Use of a compound according to claim 1 in combination with a further antiproliferative agent for the manufacture of a preparation for treating or preventing hyperproliferative disorders in humans or other mammals.   Use of a compound according to claim 1 in combination with a cytotoxic or cytostatic chemotherapeutic agent for the manufacture of a formulation for treating or preventing cancer in a human or other mammal.   Use of a compound according to claim 1 for the manufacture of a formulation for treating or preventing a disease in a human or other mammal regulated by a tyrosine kinase associated with an abnormality in a tyrosine kinase signal transduction pathway.   Use of a compound of claim 1 for the manufacture of a formulation for treating or preventing a disease in a human or other mammal mediated by a VEGF-induced signal transduction pathway.   Use of a compound according to claim 1 for the manufacture of a formulation for the treatment or prevention of diseases in humans or other mammals characterized by abnormal angiogenesis or hyperpermeability processes.   Manufacture of a formulation as an identical formulation or as a separate formulation with another angiogenesis inhibitor for the treatment or prevention of diseases in humans or other mammals characterized by abnormal angiogenesis or hyperpermeability processes Use of a compound according to claim 1 for.   The following conditions in humans and / or other mammals: tumor growth, retinopathy, ischemic retinal vein occlusion, retinopathy of prematurity, age-related macular degeneration; rheumatoid arthritis, psoriasis, bullous pemphigoid, polymorphism Use of a compound according to claim 1 for the manufacture of a formulation for the treatment or prevention of one or more blistering diseases associated with subepithelial blistering, including erythema or herpes zoster.   An agent for the treatment or prevention of a disease in humans and / or other mammals comprising the compound according to claim 1, wherein the disease is tumor growth, retinopathy, diabetic retinopathy, ischemic retinal vein occlusion, Retinopathy of prematurity, age-related macular degeneration; selected from the group consisting of rheumatoid arthritis, psoriasis, bullous disease associated with subepidermal blistering, bullous pemphigoid, erythema multiforme, and herpes dermatitis A pharmaceutical composition. Use of a compound according to claim 9 for the manufacture of a formulation for treating or preventing a disease mediated by the VEGF-induced signal transduction pathway. Use of a compound according to claim 9 for the manufacture of a formulation for treating or preventing cancer. Formula (I):

[Wherein Q is C (O) R ⁴ , C (O) OR ⁴ or C (O) NR ⁴ R ⁵ ;
Here, A is independently R ¹ , OR ¹ , S (O) _p R ¹ , C (O) R ¹ , C (O) OR ¹ , C (O) NR ¹ R ² , halogen, oxo Optionally substituted with 1 to 4 substituents which are cyano, or nitro:
(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-benzoxazol-2-yl,
(8) 1,3-benzoxazol-6-yl,
(9) 2,3-dihydro-1H-indol-5-yl,
(10) 2,3-dihydro-1H-indol-6-yl,
(11) 2,3-dihydro-1H-inden-4-yl,
(12) 2,3-dihydro-1H-inden-5-yl,
(13) 1,1-dioxide-2,3-dihydro-1-benzothien-6-yl,
(14) 1H-indazol-5-yl,
(15) 2H-indazol-5-yl,
(16) 1H-indazol-6-yl,
(17) 1H-indol-5-yl,
(18) 1-oxo-2,3-dihydro-1H-inden-5-yl,
Or (19) Formula:

A bicyclic heterocycle which is the group
B is independently C ₁ -C ₅ linear or branched alkyl, C ₁ -C ₅ linear or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ -C ₃ alkylamino, C ₁ -C ₆ dialkylamino, carboxamide, halogen, cyano, nitro, or phenyl, naphthyl, or pyridyl optionally substituted with 1 to 4 substituents that are S (O) _p R ⁷ ;
L is —O— ;
M is independently C ₁ -C ₅ linear or branched alkyl, C ₁ -C ₅ linear or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ -C ₃ alkylamino, A pyridine ring optionally substituted by 1 to 3 substituents which are C ₁ -C ₆ dialkylamino, halogen or nitro;
Q is C (O) R ⁴ , C (O) OR ⁴ or C (O) NR ⁴ R ⁵ ;
Each of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is independently:
(A) hydrogen,
_(B) C 1 -C ₅ linear, branched or cyclic alkyl,
(C) phenyl _(d) C 1 -C ₃ alkyl - phenyl,
(E) _C 1 -C substituted up to perhalo ₅ straight or branched chain alkyl,
(F) - (CH 2) q -X, here, X is saturated, partially saturated, or aromatic, 5 or 6 comprising at least one atom selected from oxygen, nitrogen and sulfur A membered heterocyclic ring, or an 8 to 10 membered bicyclic heteroaryl having 1 to 4 heteroatoms that are O, N or S, or (g) — (CH ₂ ) _q —Y, where Y Are C (O) R ⁶ , C (O) OR ⁶ and C (O) NR ⁶ R ⁷ ;
Is;
Each of R ⁶ to R ⁷ is independently:
(A) hydrogen,
_(B) C 1 -C ₅ linear, branched or cyclic alkyl,
(C) phenyl,
(D) C ₁ -C ₃ alkyl-phenyl, or (e) substituted C ₁ -C ₅ linear or branched alkyl up to perhalo;
Each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ other than perhalo-substituted C ₁ -C ₅ linear or branched alkyl is independently a C ₁ -C ₅ linear or branched-chain alkyl, substituted _C 1 -C ₅ straight or branched chain alkyl of up to _perhalo, C 1 -C ₃ alkoxy, hydroxy, carboxy, _amino, C 1 -C _{3 alkylamino,} C 1 -C ₆ dialkyl Optionally substituted with 1 to 3 substituents which are amino, 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]
Or a pharmaceutically acceptable salt thereof. A is
(1) benzimidazol-5-yl,
(2) benzimidazol-6-yl,
(8) 1,3-benzoxazol-6-yl,
(9) 2,3-dihydro-1H-indol-5-yl,
(10) 2,3-dihydro-1H-indol-6-yl,
(11) 2,3-dihydro-1H-inden-4-yl,
(12) 2,3-dihydro-1H-inden-5-yl,
(13) 1,1-dioxide-2,3-dihydro-1-benzothien-6-yl,
(14) 1H-indazol-5-yl,
(15) 2H-indazol-5-yl,
(16) 1H-indazol-6-yl,
(17) 1H-indol-5-yl,
And (18):

23. A compound according to claim 22 selected from the group consisting of The compound according to claim 21 , wherein any substituents on the bicyclic heterocycle A are independently R ¹ , OR ¹ , and halogen. The compound according to claim 23 , wherein B is phenyl or pyridyl optionally substituted with 1 to 4 substituents which are halogen. Q is a ^{C (O) NR 4 R 5} , each ^{R 4} and ^{R 5} are independently hydrogen or _C 1 -C ₅ alkyl as claimed in claim 24 A compound according. Formula (I):

Wherein A is independently R ¹ , OR ¹ , S (O) _p R ¹ , C (O) R ¹ , C (O) OR ¹ , C (O) NR ¹ R ² , halogen, Optionally substituted with 1 to 4 substituents which are oxo, cyano or nitro:
(1) benzimidazol-5-yl,
(2) benzimidazol-6-yl,
(8) 1,3-benzoxazol-6-yl,
(9) 2,3-dihydro-1H-indol-5-yl,
(10) 2,3-dihydro-1H-indol-6-yl,
(11) 2,3-dihydro-1H-inden-4-yl,
(12) 2,3-dihydro-1H-inden-5-yl,
(13) 1,1-dioxide-2,3-dihydro-1-benzothien-6-yl,
(14) 1H-indazol-5-yl,
(15) 2H-indazol-5-yl,
(16) 1H-indazol-6-yl,
(17) 1H-indol-5-yl,
Or (20) Formula:

A bicyclic heterocycle which is the group
B is phenyl optionally substituted with halogen;
L is —O—;
M is a pyridine ring substituted only with Q;
Q is C (O) NHR ⁵ and R ⁵ is independently hydrogen or C ₁ -C ₅ alkyl; and p is an integer selected from 0, 1 or 2]
Or an pharmaceutically acceptable salt thereof, or an oxidized derivative of the compound of formula (I), wherein one or two nitrogen atoms of the urea are substituted with hydroxyl groups, or the pyridine ring M A derivative in which the nitrogen atom is an oxide type.