JP4927533B2 - Substituted pyridine derivatives useful for the treatment of cancer and other diseases - Google Patents

Description

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

  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 -8 Kolch et al., (Nature 1991, 349, 426-28) further showed that inhibition of raf expression by antisense RNA blocked 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- 7 5) 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 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 use 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 remains a need to improve cancer treatment and treatment of inflammatory diseases.

The present invention is:
(i) novel compounds, their salts, metabolites and prodrugs (including diastereoisomers),
(ii) a pharmaceutical composition containing any of such compounds, and
(iii) The use of these compounds or compositions as a single agent or in combination with other active ingredients such as cytotoxic therapy for the treatment of diseases such as hyperproliferative diseases and angiogenic diseases.

  Compounds of formula (I), their salts, metabolites and prodrugs (including diastereoisomers (both isolated stereoisomers and mixtures of stereoisomers)), collectively referred to herein Referred to as “compounds of the invention”, Formula I is as follows:

  A is phenyl, naphthyl, monocyclic or bicyclic heteroaryl or formula

Independently of R ¹ , OR ¹ , S (O) _p R ¹ , C (O) R ¹ , C (O) OR ¹ , C (O) NR ¹ R ² , halogen, hydroxy, Optionally substituted with 1 to 4 substituents which are amino, cyano or nitro,
B is phenyl, naphthyl or pyridyl, independently C ₁ -C ₅ straight or branched alkyl, C ₁ -C ₅ straight or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, Optionally substituted with 1 to 4 substituents which are amino, C ₁ -C ₃ alkylamino, C ₁ -C ₆ dialkylamino, halogen, cyano or nitro.
B is preferably phenyl or pyridyl, 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, halogen, may be optionally substituted with 1-4 substituents is cyano or nitro.

L is a crosslinking group:
_{(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 ) ₁ — or (h) a single bond.

  The integers m and l are independently selected from 0-4 and are generally selected from 0-2.

  L is most preferably —O— or —S—.

M is a pyridine ring, independently C ₁ -C ₅ straight or branched chain alkyl, C ₁ -C ₅ straight or branched chain haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ ~ Optionally substituted with 1 to 3 substituents which are C ₃ alkylamino, C ₁ -C ₆ dialkylamino, halogen or nitro.

Q is:
(1) C (S) NR ⁴ R ⁵ ,
(2) C (O) NR 7 -NR 4 R 5,
(3) tetrazolyl,
(4) imidazolyl,
(5) imidazolin-2-yl,
(6) 1,3,4-oxadiazolin-2-yl,
(7) 1,3-thiazolin-2-yl,
(8) 5-Thioxo-4,5-dihydro-1,3,4-thiazolin-2-yl,
(9) 5-oxo-4,5-dihydro-1,3,4-oxadiazolin-2-yl or the formula (10)

And preferably (1), (2) or (10).
Each R ¹ , R ² , R ¹³ , R ⁴ and R ⁵ is independently
(A) hydrogen,
(B) C ₁ ~C ₅ straight, branched or cyclic alkyl,
(C) phenyl,
(D) C ₁ ~C ₃ phenylalkyl,
(E) perhalo to substituted C ₁ -C ₅ straight or branched alkyl or, (f) - a (CH _{2) q} -X.

  Substituent X contains at least one atom selected from oxygen, nitrogen and sulfur and is a saturated, partially saturated or aromatic 5- or 6-membered heterocycle or from O, N and S An 8 to 10 membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from the group consisting of

Further, R ⁴ and R ⁵ may together form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom selected from N, O or S. This is independently C ₁ -C ₅ straight-chain or alkyl branched, straight or branched chain alkyl group of C ₁ -C ₅ substituted up to perhalo, C ₁ -C ₃ alkoxy, hydroxy, oxo, carboxy, amino, C ₁ -C ₃ alkylamino, C ₁ -C ₆ dialkylamino, halogen, may be optionally substituted with 1-3 substituents is cyano or nitro.

R ⁶ is independently:
(A) hydrogen,
_(B) C 1 ~C ₅ straight, branched or cyclic alkyl,
(C) cyano,
(D) Nitro,
(E) substituted _C 1 -C ₅ straight or branched alkyl having up to perhalo, or (f) -C (O) a ^{R 8,} wherein ^{R 8} is _C 1 -C ₅ straight-chain, Branched or cyclic alkyl.

Preferably R ⁶ is independently:
(A) hydrogen,
(B) C ₁ ~C ₅ straight, branched or cyclic alkyl,
(C) cyano, or (d) nitro, most preferably R ⁶ is independently:
(A) hydrogen,
(B) a C ₁ -C ₅ straight-chain, branched or cyclic alkyl or (c) cyano,.

R ⁷ is hydrogen or linear, branched or cyclic C ₁ -C ₅ alkyl.

  The variable q is an integer of 0, 1, 2, 3 or 4. The variable p is an integer of 0, 1 or 2.

The group of compounds is a compound of formula (I), their salts, metabolites and prodrugs, including diastereoisomers (both isolated stereoisomers and mixtures of stereoisomers) ,
A is

Wherein A is on any carbon atom, R ¹ , OR ¹ , S (O) _p R ¹ , C (O) R ¹ , C (O) OR ¹ , C (O) NR ¹ R ² , independently substituted with 0 to 4 substituents which are halogen, hydroxy, amino, cyano or nitro, B, L, M and Q in formula I are as defined above.

About these compounds
B is preferably phenyl or pyridyl, 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, halogen, may be optionally substituted with 1-4 substituents is cyano or nitro.

L is preferably -O-
M is preferably a pyridine ring substituted only by Q;
Q is preferably C (S) NR ⁴ R ⁵ ,
C (O) NR ⁷ —NR ⁴ R ⁵ , or the formula

Wherein each R ¹ , R ² , R ⁴ and R ⁵ are independently:
(A) hydrogen,
(B) C ₁ ~C ₅ straight, branched or cyclic alkyl,
(C) phenyl,
(D) C ₁ ~C ₃ phenylalkyl,
(E) perhalo to substituted C ₁ -C ₅ straight or branched alkyl _{or, (f) - (CH 2} ) q A -X, variable substituents X wherein a pyridinyl q Is preferably an integer of 0 or 1,
R ⁶ is preferably independently:
(A) hydrogen,
(B) C ₁ -C ₅ linear, branched or cyclic alkyl, or (c) cyano.

Another group of such compounds are the compounds of formula (I), their salts, metabolites and prodrugs, including diastereoisomers (both isolated stereoisomers and mixtures of stereoisomers). There,
A is

Wherein B, L, M and Q of formula I are the same as defined above, and preferred values of B, L, M and Q of formula I are the same as defined above.

  When any moiety is “substituted”, it can have up to the maximum number of substituents indicated, and each substituent can be in any available position on the moiety, on the substituents It can be attached through any available atom. “Any available position” means that portion of the molecule that is chemically available through the means known in the art or taught herein and that does not create an overly unstable molecule. It means any position above. Where more than one substituent is present on any moiety, 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 so modified may be unsubstituted or substituted with certain substituents.

  Because M is pyridine, the term “hydroxy” as a substituent for pyridine includes 2-, 3- and 4-hydroxypyridine, but 1-oxopyridine, 1-hydroxy in the art. It is understood that structures referred to as pyridine and pyridine-N-oxide are also included.

  In this specification, the use of the plural forms of a compound, salt or other term shall be taken to mean a single compound, salt or the like.

The term alkyl of C ₁ -C ₅ is to mean straight or branched chain alkyl group having 1 to 5 carbon atoms, which is linear even or branches of multiple single or branched It may be a branched chain. 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 may be straight chain or one branched or multiple branched. 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 on this moiety, they may be the same or different. Examples of such halogenated alkyl substituents include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 1,1,2,2- Examples include, but are not limited to, tetrafluoroethyl.

The term C ₁ -C ₃ alkoxy is meant straight chain or branched alkoxy groups having straight or single or multiple have a branched branched, which may be 1-3 saturated carbon atoms And groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like. It also includes 2,2-dichloroethoxy, trifluoromethoxy and other halogenated groups.

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

Alkylamine C ₁ -C ₃ refers to methylamino, ethylamino, propylamino or isopropylamino.

Examples of C ₁ -C ₆ dialkylamines include, but are not limited to, diethylamino, ethylisopropylamino, methylisobutylamino, and dihexylamino.

  The term heteroaryl refers to both monocyclic and bicyclic heteroaryl rings. Monocyclic heteroaryl is 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 Means carbon. If more than one heteroatom is present in the moiety, they are independently selected from the others and may therefore be the same or different. Monocyclic heteroaryl rings include pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine and triazine However, it is not limited to these.

  A bicyclic heteroaryl is a fused bicyclic moiety wherein one of the rings is selected from the monocyclic heteroaryl ring described above and the second ring is benzene or other monocyclic heteroaryl ring described above It means that it is either. When both rings in a bicyclic moiety 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 synthetically available 5-5, 5-6 or 6-6 fused bicyclic aromatic structures such as benzoxazole (benzene and oxazole fused) ), Indazole (benzene and pyrazole fused), quinoline (phenyl and pyridine fused), quinazoline (pyrimidine and benzene fused), imidazopyrimidine (imidazole and pyrimidine fused), naphthyridine (two pyridine fused) ) Other, but not limited to.

  The term “a saturated, partially saturated or aromatic 5- or 6-membered heterocycle containing at least one atom selected from oxygen, nitrogen and sulfur” is not limited to 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 others.

R ⁴ and R ⁵ together may form a 5- or 6-membered aliphatic ring, which may be interrupted by an atom selected from N, O or S and optionally substituted Non-limiting examples of substituents Q that may be good include the following:

The term “C ₁ -C ₃ phenylalkyl” includes, but is in no way limited to, 3-phenylpropyl, 2-phenyl-1-methylethyl. Examples of substitution include 2- [2-chlorophenyl] ethyl, 3,4-dimethylphenylmethyl, and the like.

  The compounds of formula I may contain one or more asymmetric centers, depending on the position and nature of the various substituents desired. Asymmetric carbon atoms may be present in (R) or (S) or (R, S) configuration. In certain instances, there may be asymmetry due to rotational restrictions around a given bond, eg, a central bond adjacent to two substituted aromatic rings of a particular compound. Substituents on the ring may be present in either cis or trans form. All such configurations (including enantiomers and diastereomers) are intended to be included within the scope of the present invention. Preferred compounds are those having the absolute configuration 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 within the scope of the invention. Purification of the isomer and separation of the isomer mixture can be accomplished by standard techniques known in the art.

  Optical isomers can be obtained according to conventional methods, for example by resolution of racemic mixtures 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. Diastereomeric mixtures are divided 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. be able to. The optically active base or acid is then released from the separated diastereomeric salt. Another method for separating optical isomers is chiral chromatography (e.g., chiral HPLC column) optimally selected to maximize enantiomeric separation with or without conventional derivatization. ). Suitable chiral HPLC columns are manufactured by Diacel, among others many of which are routinely selectable, such as chiral OD and chiral OJ. 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 react the main compound that functions as a base with an inorganic or organic acid and acid, for example, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphor sulfate, oxalic acid, Including those forming salts of maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also function as the main compound acid and react with an appropriate base to form, for example, sodium, potassium, calcium, magnesium, ammonium and choline salts. Including 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 present invention with a suitable base by various 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, oxalate, pamoate, pectate, persulfate, 3-phenylpropion Acid salts, picrates, pyruvates, propionates, succinates, sulfonates, 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 Manufacturing Methods The particular method utilized to manufacture the compounds used in the embodiments of the invention will depend on the specific compound intended. Factors such as the choice of specific substituents, etc. play a substantial role in the route to be followed in the manufacture 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 preparation method will assist the reader in synthesizing the compounds of the present invention, with the more detailed examples presented in the experimental section which describes the examples below. 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 cannot 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 illustrated in the examples.

General method

  Compound (I) can be synthesized according to the reaction procedure shown in the general method above. That is, compound (I) can be synthesized by reacting amino compound (III) with isocyanate compound (II).

  Compound (II) is commercially available or can be synthesized according to methods well known to those skilled in the art [eg, amines and phosgene or trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), Or by treatment with an equivalent of phosgene such as N, N′-carbonyldiimidazole (CDI), or by a Curtius rearrangement of an amide or a carboxylic acid derivative such as an ester, acid halide or anhydride] . Compound (III) is commercially available, or can be synthesized by a method known to those skilled in the art.

  Furthermore, specific preparations of diarylureas 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, etc., `` 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 application 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 US 20020165394. All of these prior patent applications are incorporated herein by reference.

  It is preferable that reaction of compound (II) and (III) is performed in a solvent. Suitable solvents include common organic solvents that are inert under the reaction conditions. Non-limiting examples include ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, mineral oil fraction, dichloromethane, trichloromethane, tetrachloride Carbon, dichloroethane, halogenated hydrocarbons such as trochloroethylene, chlorobenzene, alcohols such as methanol, ethanol, n-propanol and isopropanol, esters such as ethyl acetate, ketones such as acetone, nitriles such as acetonitrile, heteroaromatics such as pyridine And polar solvents such as dimethylformamide and hexamethylphosphoric triamide, and mixtures of the above solvents. Toluene, benzene and dichloromethane are preferred.

  For 1 mol of compound (II), compound (III) is usually used in an amount of 1 to 3 mol. An equimolar amount or a slight excess of compound (III) is preferred.

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

Synthetic transformations that may be employed in the synthesis of compounds of formula I and in the synthesis of intermediates involved in the synthesis of compounds of formula I are known or available to those skilled in the art. Synthetic transformation information gathering can be found in compilations, for example:
・ 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 manufactured according to methods known to those skilled in the art of manufacturing 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.

  Parenteral compositions of the invention typically contain from about 0.5% to about 25% active ingredient 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 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 melts 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. Are listed.

  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 making such compositions in suitable dosage forms can be utilized. 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 phosphocellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch, Not limited to));
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 disintegrants (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrilin potassium, crosslinked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate 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.

  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 made by filling a standard two-part hard gelatin capsule with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsule: To form a soft gelatin capsule containing 100 mg of the active ingredient, a mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is produced and molded into the gelatin It is injected by a positive displacement pump. These capsules are washed and dried. To produce 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 g microcrystalline cellulose, 11 mg starch, and 98.8 g lactose The procedure produces a large number of tablets. 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.

  The present invention relates to a method for using the above-mentioned compounds (compounds of formula I) (including their salts and esters, their compositions) to treat mammalian hyperproliferative diseases. 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 antihyperproliferative and other indications that have other indications, and 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, procarbazi , 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 invention include Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., Publ. by McGraw-Hill, pages 1225-1287, (1996), which are recognized for use in the treatment of neoplastic diseases, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2 ′, 2′-difluorodeoxyuridine, docetaxel, erythrohydroxynonyladenine, ethinylestradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, Idarubicin, a 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 Spectroscopy TLC Thin Layer Chromatography ES Electrospray DMA N, N-dimethylacetamide HRMS High Resolution Mass Spectroscopy CDI 1, 1′-carbonyldiimidazole HOBT 1-hydroxybenzotriazole EDCI hydrochloride 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide TMSCI trimethyl chloride Silyl m-CPBA 3-chloroperbenzoic acid HEPES N- (2-hydroxyethyl) -piperazine-N ′-(2-ethanesulfonic acid)
Tris / hydrochloric acid Tris (hydroxymethyl) aminomethane
Triton X-100 tert-octylphenoxypolyethoxyethanol, Rohm & Haas, USA The percent yield in the following examples refers to the starting component used in the lowest molar amount.

  LC-MS conditions: two Gilson 306 pumps, Gilson 215 autosampler, Gilson diode array detector, YMC Pro C-18 column (2 × 23 mm, 120 A) and Micromass LCZ single quadrupole mass with z-spray electrospray ionization HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Gilson HPLC system equipped with an analyzer. The spectrum was scanned at 120-1000 amu for 2 seconds. ELSD (Evaporative Light Scattering Detector) data was also secured as an analog channel. Gradient elution at 1.5 mL / min was utilized with buffer A as a 2% acetonitrile aqueous solution containing 0.02% TFA and buffer B as a 2% water acetonitrile solution containing 0.02% TFA. . Sample elution was performed as follows: from 0.5 min at 90% A to 95% B over 3.5 min, 95% B maintained for 0.5 min, then Allow 0.1 minute to restore the column to initial conditions. The total execution time is 4.8 minutes.

  Preparative HPLC: Preparative HPLC was performed using a Gilson HPLC system equipped with two Gilson 322 pumps, a Gilson 215 autosampler, a Gilson diode array detector, and a YMC Pro C-18 column (20 × 150 mm, 120A). Gradient elution with buffer A as a 0.1% TFA aqueous solution and buffer B as a 0.1% TFA acetonitrile solution was utilized. Samples were dissolved in methanol or methanol / DMSO at a concentration of about 50 mg / mL. The injection volume was about 2-3 mL per injection. Sample elution was performed as follows: 10-90% B at a flow rate of 25 mL / min for 15 minutes, maintained for 2 minutes, and returned to 10% B. The desired fractions were collected at 254 nm or 220 nm UV and dried to dryness with GeneVac speed vacuum.

Preparation of 4- (4-aminophenoxy) pyridine-2-carboxylic acid methyl ester

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, 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, producing a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL), and made half the concentration. 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 HCl salt as a yellow solid (92.0 g, 89%).

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

A 0 ° C. suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in methanol (75 mL) 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 sodium chloride 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 ^<+> ); mp 41-43 [deg.] C.

Step 3: Preparation of 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 mL) is treated with potassium tert-butoxide (10.29 g, 91.7 mmol) and the reddish brown mixture is stirred at room temperature for 2 hours. did. 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) and then heated at 80 ° C. for 8 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (500 mL) and saturated sodium chloride 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 under reduced pressure at 35 ° C. 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 (br s, 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 ⁺ ).

Step 4: Preparation of the title compound 4- (4-aminophenoxy) pyridine-2-carboxylic acid methyl ester 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide (15.0 g, 61.7 mmol) and hydroxylation A mixture of potassium (34.6 g, 617 mmol) was stirred in ethanol (400 mL) and water (40 mL) 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 with methanol (400 mL). After the trimethylsilyl chloride (178 mL, 140 mmol, 2.27 eq) was added slowly at 0 ° C., the reaction mixture was stirred and refluxed 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 to dryness under reduced pressure. The resulting residue was further washed with water and re-extracted 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, Jf = 2.4 Hz, 1H), 7.10 (dd, J = 5. 7, 2.7 Hz, 1H), 6.86 (dt, J = 9.0, 2.4 Hz, 2H), 6.63 (dt, J = 8.7, 2.4 Hz, 2H), 5.18 (Br s, 2H), 3.86 (s, 3H); MS LC-MS [M + H] ⁺ = 245, RT = 1.04 min; TLC (75% ethyl acetate / hexane), R _f = 0.20. .

Preparation of 4- (3-aminophenoxy) pyridine-2-carboxylic acid

Step 1: Preparation of 4- (3-aminophenoxy) pyridine-2-carboxylic acid methylamide

The title compound was prepared in a similar manner as described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide using 3-aminophenol instead of 4-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), 7.15-7.07 (m, 2H), 5.51-6.47 (m, 1H), 6.31-6.24 (m, 2H), 5.40 (s) , 2H), 2.77 (d, J = 5.1 Hz, 3H).

Step 2: Preparation of title compound 4- (3-aminophenoxy) pyridine-2-carboxylic acid 4- (3-aminophenoxy) pyridine-2-carboxylic acid methylamide (5.64 g, 23.81 mmol) and potassium hydroxide ( The mixture with 13.01 g, 232 mmol) was stirred in ethanol / water (55 mL, 10: 1) at 90 ° C. for 48 hours. The mixture was concentrated under reduced pressure and the crude residue was dissolved in water (100 mL). The solution was carefully adjusted to pH = 6-7 with 1N aqueous HCl and the resulting precipitate was filtered. The filtrate was then concentrated under reduced pressure and the crude product was diluted with methanol (150 mL) and the solid collected. The filtered solids were combined and washed with CH ₂ Cl ₂ to give 5.25 g (98%) of 4- (3-aminophenoxy) pyridine-2-carboxylic acid. ¹ H-NMR (CD ₃ OD) δ 8.45 (d, 1H), 7.60 (d, 1H), 7.17 (t, 1H), 7.09 (d, 1H), 6.64 (dd , 1H), 6.47-6.45 (m, 1H), 6.40 (dd, 1H); MS LC-MS [M + H] ⁺ = 231.

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

To a 0 ° C. methanol solution (100 mL) containing TMSCl (4.72 g, 43.4 mmol) was added 4- (3-aminophenoxy) pyridine-2-carboxylic acid (0.5 g, 2.17 mmol) in methanol (5 mL). ) Was added slowly and the reaction mixture was heated to reflux for 12 hours. The solvent was removed under reduced pressure and the residue was partitioned between CH ₂ Cl ₂ and water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with hexane / ethyl acetate (gradient 3/7 to 2/3) to give 0.25 g (48%) of the desired product. 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, RT = 0.52 min.

Preparation of 4- (2- [1,3,4] oxadiazol-2-yl-pyridin-4-yloxy) phenylamine

Step 1: Preparation of 4-chloropyridine-2-carboxylic acid methyl ester

All of the mixture of 4-chloropyridine-2-carbonyl chloride HCl (1.75 g, 8.22 mmol) and triethylamine (3.8 mL, 24.14 mmol, 3.3 eq) in THF (16 mL) methanol (4 mL) was added. The mixture was stirred at 0 ° C. for 2 hours until the SM was consumed. The solvent was concentrated under reduced pressure and the resulting crude product was purified using MPLC (biotage) eluting with 25-50% ethyl acetate-hexane to give 878 mg (60.7%) of the methyl ester as a pale yellow Obtained as a brown crystalline solid. ¹ H-NMR (DMSO-d ₆ ) δ 8.69 (d, J = 5.4 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 5. 4, 2.1 Hz, 1H), 3.89 (s, 3H); TLC (50% ethyl acetate / hexane), _Rf = 0.40.

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

Hydrated hydrazine (2.48 g, 49.5 mmol) was added dropwise to methyl 4-chloropyridine-2-carboxylate (850 mg, 4.95 mmol) in anhydrous methanol (50 mL) and the reaction mixture was stirred at room temperature under argon. Stir for 18 hours. The mixture was diluted with ethyl acetate (200 mL) and the organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Recrystallization from methanol gave 500 mg (59%) of 4-chloropyridine-2-carboxylic acid hydrazide. ¹ H-NMR (acetone-d ₆ ) δ 9.38 (s, 1H), 8.60 (d, 1H), 8.08 (d, 1H), 7.64 (dd, 1H), 4.46 ( s, 2H); MS LC-MS [M + H] ⁺ = 172, RT = 0.86 min; TLC (100% ethyl acetate), R _f = 0.35.

Step 3: Preparation of 4-chloro-2- [1,3,4] oxadiazol-2-ylpyridine

A mixture of 4-chloropyridine-2-carboxylic acid hydrazide (550 mg, 2.91 mmol) in triethylorthoformate ester (10 mL) was refluxed for 48 h under argon. The mixture was diluted with ethyl acetate (200 mL) and the organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with 50% ethyl acetate / hexanes to give 360 mg (68%) of 4-chloro-2- [1,3,4] oxadiazol-2-yl-pyridine. It was. ¹ H-NMR (acetone-d ₆ ) δ 9.16 (s, 1H), 8.76 (d, 1H), 8.26 (d, 1H), 7.74 (dd, 1H); MS LC-MS [M + H] ⁺ = 182, RT = 1.36 min; TLC (100% ethyl acetate), R _f = 0.70.

Step 4: Preparation of the title compound 4- (2- [1,3,4] oxadiazol-2-yl-pyridin-4-yloxy) phenylamine 4-chloro in place of 4-chloropyridine-2-carboxylic acid In a manner similar to that described for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methylamide above using 2- [1,3,4] oxadiazol-2-yl-pyridine, The title compound was prepared. ¹ H-NMR (acetone-d ₆ ) δ 9.04 (s, 1H), 8.59 (d, J = 6.0 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7 .06 (dd, J = 2.4 Hz, 5.7 Hz, 1H), 6.96 (d, J = 6.9 Hz, 2H), 6.78 (d, J = 6.9 Hz, 2H), 4. 81 (s, 2H); MS LC-MS [M + H] ⁺ = 255, RT = 0.95 min; TLC (100% ethyl acetate) = 0.55.

Preparation of N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea

Step 1: Preparation of N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-[4- (pyridin-4-yloxy) phenyl] urea

To a solution of 4- (4-aminophenoxy) pyridine (2 g, 10.74 mmol) in DCM (10 mL) was added 4-chloro-3-trifluoromethyl isocyanate (2.4 g, 10.74 mmol). The solution was stirred at room temperature overnight. The solvent was removed by distillation and the resulting solid was washed with ethyl acetate to give 3.6 g (82%) of the title product; MS LC-MS [M + H] ⁺ = 408.

Step 2: Preparation of N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-{4-[(1-oxidepyridin-4-yl) oxy] phenyl} urea

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-[4- (pyridin-4-yloxy) phenyl] urea (3.1 g, 7.6 mmol) in DCM (40 mL) · acetone ( 10 mL) solution was added m-CPBA (1.5 g). The mixture was stirred at room temperature for 12 hours, then another portion of m-CPBA (1.5 g) was added and the solution was stirred for an additional 12 hours at room temperature. The solution was then washed with 10% aqueous sodium carbonate. The solvent was removed to give 2.9 g (90%) of the title product. MS LC-MS [M + H] ⁺ = 424.

Step 3: Preparation of the title compound N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea N- [4 -Chloro-3- (trifluoromethyl) phenyl] -N '-{4-[(1-oxidepyridin-4-yl) oxy] phenyl} urea (2 g, 4.72 mmol) in anhydrous DMF (50 mL) Trimethylsilylcyanide (0.7 g, 7.1 mmol) was added at room temperature, and then dimethylcarbamyl chloride (1.27 g, 11.8 mmol) in DMF (10 mL) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 24 hours. A 10% aqueous sodium carbonate solution (50 mL) was added dropwise, stirred for 10 minutes, and then extracted with ethyl acetate (3 times). The extracts were combined, dried over MgSO ₄ and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (ethyl acetate: hexane: methanol 45:45:10) to give 1.8 g (88%) of the title product. ¹ H-NMR (DMSO-d ₆ ) δ 9.20 (s, 1H), 9.01 (s, 1H), 8.57 (d, J = 5.7 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.66-7.56 (m, 5H), 7.19-7.14 (m, 3H); MS LC-MS [M + H] ⁺ = 433, RT = 3.56 Min; TLC (75% ethyl acetate / hexane), R _f = 0.53.

N- {4-[(2-cyanopyridin-4-yl) oxy] phenyl} -N ′-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) urea Preparation of

Step 1: Preparation of 4- (4-aminophenoxy) pyridine-2-carbonitrile

A solution of 4-aminophenol (1.0 g, 9.16 mmol) in anhydrous DMF (9.2 mL) was treated with potassium tert-butoxide (1.08 g, 9.62 mmol, 1.05 eq) to give an orange-brown color. The reaction mixture was stirred at room temperature for 1 hour. The contents were treated with 2-cyano-4-chloropyridine (1.27 g, 9.16 mmol, 1.0 equiv) and K ₂ CO ₃ (497 mg, 5.04 mmol, 0.55 equiv), then at 90 ° C. Heated for 17 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (250 mL) and saturated sodium chloride solution (100 mL). The aqueous phase was back extracted with ethyl acetate (300 mL). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. Purification by MPLC (biotage) eluting with 30% ethyl acetate-hexanes afforded 1.83 g (94.6%) of 4- (4-aminophenoxy) pyridine-2-carbonitrile as a yellow solid. . ¹ H-NMR (DMSO-d ₆ ) δ 8.52 (d, J = 6.3 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 5. 4, 2.4 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.7 Hz, 2H), 5.21 (s, 2H); MS LC MS [M + H] ⁺ = 212, RT = 0.98 min; TLC (50% ethyl acetate / hexane), R _f = 0.28.

Step 2: Title compound N- {4-[(2-cyanopyridin-4-yl) oxy] phenyl} -N ′-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin- Preparation of 6-yl) urea 4- (4-aminophenoxy) pyridine-2-carbonitrile (300 mg, 1.42 mmol) and 2,2,4,4-tetrafluoro-6-isocyanate-1,3-benzodioxene A solution of (389.2 mg, 1.56 mmol, 1.1 eq) in anhydrous 1,2-dichloroethane (7.1 mL) was stirred at 80 ° C. for 17 hours under argon, and a white solid precipitated as the reaction proceeded. The reaction mixture was cooled to room temperature and the precipitate was collected and washed with DCM (3.0 mL) and ether (3 × 5 mL) to give 355 mg (54.3%) of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.14 (s, 1H), 9.03 (s, 1H), 8.57 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.66-7.57 (m, 4H), 7.43 (d, J = 9.0 Hz, 1H), 7.19-7.14 (m, 3H); MS LC-MS [M + H] ⁺ = 461, RT = 3.59 min; TLC (75% ethyl acetate / hexane), _Rf = 0.29.

Preparation of N- {4-[(2-cyanopyridin-4-yl) oxy] phenyl} -N '-(1-methyl-1H-indazol-5-yl) urea

To a solution of 1-methyl-5-aminoindazole (230 mg, 1.56 mmol) in anhydrous DCE (2.4 mL) was added 1,1′-carbonyldiimidazole (281.5 mg, 1.70 mmol, 1.2 eq). The reaction mixture was stirred at 65 ° C. under argon. After 16 hours, a solution of 5- (4-aminophenoxy) pyridine-2-carbonitrile (300 mg, 1.42 mmol, 0.91 eq) in anhydrous THF (4.0 mL) was added at room temperature and the reaction mixture was purged under argon. And stirred at 65 ° C. for 7 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. The crude residue was triturated in DCM (10 mL) to give 382.4 mg (70%) of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 8.84 (s, 1H), 8.70 (s, 1H), 8.57 (d, J = 6.0 Hz, 1H), 7.95 (d, J = 1.0 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.60-7.54 (m, 4H), 7.36 (dd, J = 9.3, 2.. 1 Hz, 1H), 7.18-7.14 (m, 3H), 4.01 (s, 3H); MS LC-MS [M + H] ⁺ = 385, RT = 2.64 min; TLC (100% acetic acid Ethyl), R _f = 0.22.

Preparation of N- {4-[(2-cyanopyridin-4-yl) oxy] phenyl} -N'-quinolin-6-ylurea

Using 6-aminoquinoline instead of 1-methyl-5-aminoindazole, N- {4-[(2-cyanopyridin-4-yl) oxy] phenyl} -N ′-(1-methyl-1H— The title compound was prepared in a similar manner as described for indazol-5-yl) urea. ¹ H-NMR (DMSO-d ₆ ) δ 8.76 (dd, J = 2.7, 7.2 Hz, 1H), 8.58 (dd, J = 0.6, 5.7 Hz, 1H), 8. 51 (s, 1H), 8.44 (s, 1H), 8.28 (d, J = 2.7 Hz, 1H), 8.21 (dd, J = 0.6, 7.8 Hz, 1H), 7.96 (d, J = 9.3 Hz, 1H), 7.78-7.71 (m, 3H), 7.49-7.42 (m, 2H), 7.22-7.17 (m MS LC-MS [M + H] ⁺ = 382, RT = 2.03 min; TLC (100% ethyl acetate), R _f = 0.38.

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

To a solution of 4- (3-aminophenoxy) pyridine-2-carboxylic acid methyl ester (0.79 g, 5.35 mmol) in DCM (3 mL) was added 1,1′-carbonyldiimidazole (0.87 g, 5.35 mmol). 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 DCM (4 mL) was added and the mixture was stirred at room temperature for an additional 8 hours. The mixture was concentrated under reduced pressure. Purification of the crude product by column chromatography eluting with 5% methanol-DCM 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, RT = 2.91 min.

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-isocyanate-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. The homogeneous contents turned white and opaque within 1 minute of addition and stirring was continued for 12 hours at room temperature. The heterogeneous mixture was filtered and the solid product was washed repeatedly with DCM to remove residual material. 1.36 g (83%) of the desired product was obtained as a white powder. 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.

Preparation of methyl 4- [4-({[(4-chloro-3-trifluoromethylphenyl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate

Substituting 4-chloro-3- (trifluoromethyl) phenyl isocyanate for 2,2,4,4-tetrafluoro-6-isocyanate-1,3-benzodioxene and 4- (3-aminophenoxy) ) Using 4- (4-aminophenoxy) pyridine-2-carboxylic acid methyl ester instead of pyridine-2-carboxylic acid methyl ester, methyl 4- [3-({[(2,2,4,4- The title compound was prepared in a similar manner as described for tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate. ¹ H-NMR (DMSO-d ₆ ) δ 9.21 (s, 1H), 9.00 (s, 1H), 8.57 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.64-7.56 (m, 4H), 7.41 (d, J = 3.0 Hz, 1H), 7.19-7.15 (m, 3H), 3 .83 (s, 3H); MS LC-MS [M + H] ⁺ = 466.

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

Using 4- (4-aminophenoxy) pyridine-2-carboxylic acid methyl ester instead of 4- (3-aminophenoxy) pyridine-2-carboxylic acid methyl ester, methyl 4- [3-({[(2 , 2,4,4-Tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate in a manner similar to that described for the title compound. Prepared. ¹ H-NMR (acetone-d ₆ ) δ 8.85 (broads, 1H), 8.73 (broads, 1H), 8.56 (d, J = 5.7 Hz, 1H), 8.17 (d , J = 2.7 Hz, 1H), 7.75 (dd, J = 9.0, 2.4 Hz, 1H), 7.67 (dt, J = 9.0, 3.6 Hz, 2H), 7. 55 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 9.0, 1.2 Hz, 1H), 7.15-7.08 (m, 3H), 3.90 (s) , 3H); MS LC-MS [M + H] ⁺ = 494.

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

Methyl-4- [3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate (0.08 g, 0.19 mmol) and potassium hydroxide (0.03 g, 0.56 mmol) was heated in methanol / water (4 mL, 3: 1) at 40 ° C. for 3 hours. The solvent was removed under reduced pressure and the crude residue was dissolved with water (5 mL). The aqueous solution was neutralized with 1N HCl. The solid precipitate was then washed with water and then with DCM to give 0.55 g (70%) of the title compound. 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.

Preparation of {4- [3- (2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) phenoxy] phenyl} acetic acid

Instead of methyl 4- [3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate methyl 4- [3-({[(2 , 2,4,4-Tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate using 4- [3-({[( The title compound was prepared in a similar manner as described for 1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylic acid. ¹ H-NMR (DMSO-d ₆ ) δ 9.58 (s, 1H), 9.39 (s, 1H), 8.58 (d, 1H), 8.08 (d, 1H), 7.62 ( dd, 1H), 7.38-7.47 (m, 4H), 7.32 (dd, 1H), 7.18 (dd, 1H), 6.83 (dd, 1H); MS LC-MS [ M + H] ⁺ = 480.

Preparation of 4- [3-({[(4-Chloro-3-trifluoromethylphenyl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylic acid

Substituting 4- (3-aminophenoxy) pyridine-2-carboxylic acid for 4- (4-aminophenoxy) pyridine-2-carboxylic acid methyl ester, 4- [4-({[(4-chloro- The title compound was prepared in a similar manner as described for 3-trifluoromethylphenyl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate. ¹ H-NMR (CD ₃ OD) δ 8.66 (d, J = 4.2 Hz, 1H), 8.03 (d, J = 2.7 Hz, 1H), 7.77 (d, J = 2.2) Hz, 1H), 7.67 (dd, J = 1.8, 5.4 Hz, 1H), 7.60 (t, J = 2.7 Hz, 1H), 7.59-7.49 (m, 2H) ), 7.41-7.37 (m, 2H), 6.06 (dd, J = 2.4 Hz, 1 Hz, 1H); MS LC-MS [M + H] ⁺ = 452, RT = 2.54 min.

  The present invention provides, but is not limited to, the specific examples specified in the following paragraphs.

Example 1
Preparation of 4- {4-[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} pyridine-2-carboximidamide

Trimethylaluminum (1.73 mmol, 0.87 mL at 2M in toluene) was added to a mixture of ammonium chloride (1.73 mmol) in toluene at 0 ° C. and the mixture was stirred at room temperature until the reaction was clear. . N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea (0.35 mmol, 150 mg) was then added. And the mixture was heated at 90 ° C. for 18 hours. The solvent was removed and the residue was purified by flash chromatography (35: 9: 5: 1 v / v ethyl acetate: methanol: hexane: NH ₄ OH) to yield 18 mg (17%) of the title product as a white solid. Obtained. ¹ H-NMR (CD ₃ OD) δ 8.61 (s, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.58 (m, 3H), 7.52 (m , 3H), 7.10 (m, 3H); MS LC-MS [M + H] ⁺ = 450, RT = 3.13 min.

(Example 2)
Preparation of 4- {4-[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboximidamide

To a mixture of methylamine hydrochloride (117 mg, 1.73 mmol) in anhydrous toluene at 0 ° C. was added trimethylaluminum (1.73 mmol, 0.87 mL at 2 M in toluene) and the mixture was clear until the reaction was clear. Was stirred at room temperature. N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea (0.35 mmol, 150 mg) was then added. And the mixture was heated at 90 ° C. for 17 hours. The solvent was then removed and the residue was purified by flash chromatography (35: 10: 4: 1 v / v ethyl acetate: methanol: hexanes: NH ₄ OH) to yield 79 mg (49%) of the title product as a yellow solid Got as. ¹ H-NMR (DMSO-d ₆ ) δ 10.14 (s, 1H), 9.80 (s, 1H), 10.05-9.20 (broad s, 2H), 8.62 (d, J = 5.4 Hz, 1H), 8.10 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.62-7.52 (m, 4H), 7.19-7. 15 (m, 3H), 3.02 (s, 3H); MS LC-MS [M + H] ⁺ = 464, RT = 2.54 min.

(Example 3)
N-methyl-4- [4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxy Preparation of midamide

Instead of N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea, N- {4-[(2 -Cyanopyridin-4-yl) oxy] phenyl} -N '-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) urea to give 4- {4 -[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboximidamide in a manner similar to that described for the title compound. Prepared. ¹ H-NMR (DMSO-d ₆ ) δ 9.84 (s, 1H), 9.59 (s, 1H), 8.64 (d, J = 5.4 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.67-7.58 (m, 3H), 7.43 (d, J = 9.0 Hz, 1H) , 7.20-7.16 (m, 3H), 3.01 (s, 3H); MS LC-MS [M + H] ⁺ = 492, RT = 2.57 min.

Example 4
Preparation of N-methyl-4- (4-{[(quinolin-6-ylamino) carbonyl] amino} phenoxy) pyridine-2-carboximidamide

Instead of N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea, N- {4-[(2 -Cyanopyridin-4-yl) oxy] phenyl} -N'-quinolin-6-ylurea was used to give 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino}. The title compound was prepared in a similar manner as described for (carbonyl) amino] phenoxy} -N-methylpyridine-2-carboximidamide. ¹ H-NMR (DMSO-d ₆ ) δ 9.68 (s, 1H), 9.60 (s, 1H), 8.72 (dd, J = 1.2, 3.9 Hz, 1H), 8.64 (D, J = 5.71 Hz, 1H), 8.25 (d, J = 0.69 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 1.8 Hz, 1 H), 7.73 (dd, J = 2.4 Hz, 9.0 Hz, 1 H), 7.66-7.62 (m , 2H), 7.46-7.42 (m, 1H), 7.21-7.17 (m, 3H), 3.02 (s, 3H); MS LC-MS [M + H] ⁺ = 413, RT = 1.58 min; TLC (ethyl acetate: methanol: hexane: NH ₄ OH v / v 35: 10: 4: 1), R _f = 0.22.

(Example 5)
Preparation of 4- {4-[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} pyridine-2-carbothioamide

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea (230 mg, 0.53 mmol) in anhydrous DMF ( 30 mL) solution was bubbled with hydrogen sulfide gas at room temperature. After 10 minutes, diethylamine (58 mg, 0.80 mmol) was added and the reaction mixture was heated at 60 ° C. for 1 hour. The mixture was poured into ethyl acetate (200 mL) and the organic phase was washed with water (2 × 200 mL), brine (1 × 200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 50% ethyl acetate / hexanes to give 180 mg (73%) of the title product as a yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 10.2 (broad s, 1H), 9.93 (broad s, 1H), 9.23 (s, 1H), 9.02 (s, 1H), 8. 47 (d, J = 5.7 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.67-7.57. (M, 4H), 7.19-7.11 (m, 3H); MS LC-MS [M + H] ⁺ = 467, RT = 3.47 min.

(Example 6)
Preparation of 4- (4-{[(quinolin-6-ylamino) carbonyl] amino} phenoxy) pyridine-2-carbothioamide

Instead of N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea, N- {4-[(2 -Cyanopyridin-4-yl) oxy] phenyl} -N'-quinolin-6-ylurea was used to give 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl] amino}. The title compound was prepared in a similar manner as described for carbonyl) amino] phenoxy} pyridine-2-carbothioamide. ¹ H-NMR (DMSO-d ₆ ) δ 10.19 (s, 1H), 9.92 (s, 1H), 9.08 (s, 1H), 8.95 (s, 1H), 8.73 ( dd, J = 2.4, 4.5 Hz, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.24 (dd, J = 0.9, 7.8 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.97-7.92 (m, 2H), 7.71 (dd, J = 2.7, 9.0 Hz, 1H), 7. 64-7.59 (m, 2H), 7.47-7.43 (m, 1H), 7.20-7.11 (m, 3H); MS LC-MS [M + H] ⁺ = 416, RT = 2.08 min; TLC (ethyl acetate: methanol: hexane: NH ₄ OH v / v 35: 10: 4: 1), R _f = 0.75.

(Example 7)
Preparation of 4- [4-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carbothioamide

Instead of N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea, N- {4-[(2 -Cyanopyridin-4-yl) oxy] phenyl} -N ′-(1-methyl-1H-indazol-5-yl) urea was used to give 4- {4-[({[4-chloro-3- ( The title compound was prepared in a similar manner as described for trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} pyridine-2-carbothioamide. ¹ H-NMR (DMSO-d ₆ ) δ 10.18 (s, 1H), 9.92 (s, 1H), 8.80 (s, 1H), 8.68 (s, 1H), 8.46 ( d, J = 5.7 Hz, 1H), 7.96-7.89 (m, 3H), 7.60-7.54 (m, 3H), 7.36 (dd, J = 1.8, 9 .0Hz, 1H), 7.18-7.10 (m, 3H), 4.00 (s, 3H); MS LC-MS [M + H] ⁺ = 419, RT = 2.62 min.

(Example 8)
Preparation of N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (hydrazinocarbonyl) pyridin-4-yl] oxy} phenyl) urea

With methyl 4- [4-({[(4-chloro-3-trifluoromethylphenyl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate (600 mg, 1.29 mmol) in anhydrous methanol (50 mL). A mixture with hydrazine hydrate (645 mg, 12.9 mmol) was stirred at room temperature under argon for 18 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 100% ethyl acetate to give 580 mg (97%) of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.88 (s, 1H), 9.26 (s, 1H), 9.08 (s, 1H), 8.48 (d, 1H), 8.10 ( d, 1H), 7.66-7.58 (m, 4H), 7.36 (d, 1H), 7.18-7.08 (m, 3H), 4.50 (s, 2H); MS LC-MS [M + H] ⁺ = 466, RT = 2.83 min; TLC (100% ethyl acetate), R _f = 0.15.

Example 9
N- (4-{[2- (hydrazinocarbonyl) pyridin-4-yl] oxy} phenyl) -N '-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6 -Yl) Preparation of urea

Instead of methyl 4- [4-({[(4-chloro-3-trifluoromethylphenyl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate methyl 4- [4-({[(2, 2,4,4-Tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate using N- [4-chloro-3- ( The title compound was prepared in a similar manner as described for (trifluoromethyl) phenyl] -N '-(4-{[2- (hydrazinocarbonyl) pyridin-4-yl] oxy} phenyl) urea. ¹ H-NMR (DMSO-d ₆ ) δ 9.89-9.86 (m, 1H), 9.17 (s, 1H), 9.03 (s, 1H), 8.46 (d, J = 6 0.0 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 2.1, 9.0 Hz, 1H), 7.60-7.56 (m, 2H), 7.41 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.17-7.09 (m, 3H), 4.52 ( d, J = 4.5 Hz, 2H); MS LC-MS [M + H] ⁺ = 494, RT = 2.88 min; TLC (100% ethyl acetate), R _f = 0.15.

(Example 10)
N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-[3-({2-[(2,2-dimethylhydrazino) carbonyl] pyridin-4-yl} oxy) phenyl] urea Preparation of

To a solution of 4- [3-({[(4-chloro-3-trifluoromethylphenyl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylic acid (120 mg, 0.27 mmol) in anhydrous DMF (3 mL), 1,1-dimethylhydrazine (20 mg, 0.27 mmol), HOBT (80 mg, 0.58 mmol), EDCl (80 mg, 0.40 mmol) and N-methylmorphine (60 mg, 0.58 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The crude product was purified by HPLC and neutralized with aqueous sodium bicarbonate (1N) to give 100 mg (75.5%) of the title compound. ¹ H-NMR (CD ₃ OD) δ 8.48 (d, J = 5.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.63 (dd, J = 5.4) , 2.4 Hz, 1H), 7.51 (d, J = 3.0 Hz, 1H), 7.48-7.39 (m, 3H), 7.32-7.31 (m, 1H), 7 .13 (dd, J = 5.7, 3.0 Hz, 1H), 6.84 (dd, J = 7.2, 1.5 Hz, 1H), 2.68 (s, 6H); MS LC-MS [M + H] ⁺ = 494, RT = 3.46 min.

(Example 11)
Preparation of 4- {3-[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N- [2- (dimethylamino) ethyl] pyridine-2-carboxamide

Using N-aminopiperidine instead of 1,1-dimethylhydrazine, N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-[3-({2-[(2,2- The title compound was prepared in a similar manner as described for dimethylhydrazino) carbonyl] pyridin-4-yl} oxy) phenyl] urea. ¹ H-NMR (DMSO-d ₆ ) δ9.53 (s, 1H), 9.22 (s, 1H), 9.10 (s, 1H), 8.51 (d, J = 5.7 Hz, 1H ), 8.05 (d, J = 1.8 Hz, 1H), 7.60-7.58 (m, 2H), 7.47-7.17 (m, 4H), 6.82 (dd, J = 7.2, 1.5 Hz, 1H), 2.78-2.74 (m, 4H), 1.57-1.54 (m, 4H), 1.32-1.30 (m, 2H) MS LC-MS [M + H] ⁺ = 534, RT = 3.28 min.

(Example 12)
Preparation of 4- {3-[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-morpholin-4-ylpyridin-2-carboxamide

Using N-aminopiperidine instead of 1,1-dimethylhydrazine, N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-[3-({2-[(2,2- The title compound was prepared in a similar manner as described for dimethylhydrazino) carbonyl] pyridin-4-yl} oxy) phenyl] urea. ¹ H-NMR (CD ₃ OD) δ 8.48 (d, J = 4.8 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.65-7.57 (m, 2H) ), 7.48-7.30 (m, 4H), 7.11-7.09 (m, 1H), 6.82 (dd, J = 2.1, 1.0 Hz, 1H), 3.81 -3.78 (m, 4H), 2.92-2.89 (m, 4H); MS LC-MS [M + H] ⁺ = 536, RT = 3.10 min.

(Example 13)
N-piperidin-1-yl-4- [3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine Preparation of 2-carboxamide

{4- [3- (2,2,4,4-Tetrafluoro-4H-benzo [1,3] dioxin-6-yl) phenoxy] phenyl} acetic acid (100 mg, 0.21 mmol) in DMF (3 mL) To this mixture was added 1-aminopiperidine (20 mg, 0.21 mmol), HOBT (60 mg, 0.46 mmol), EDCl (60 mg, 0.31 mmol) and N-methylmorpholine (50 mg, 0.46 mmol) at room temperature. . The mixture was stirred at room temperature overnight. The solvent was removed and the residue was diluted with DCM (10 mL) and then washed with water (3 mL). The crude product was purified by HPLC and neutralized with NaHCO ₃ to give 56 mg (45%) of the title product. ¹ H-NMR (DMSO-d ₆ ) δ 9.65 (s, 1H), 9.19 (s, 1H), 9.14 (s, 1H), 8.51 (d, 1H), 8.07 ( d, 1H), 7.62 (dd, 1H), 7.38-7.49 (m, 4H), 7.30 (dd, 1H), 7.21 (dd, 1H), 6.85 (dd , 1H), 2.72-2.79 (m, 4H), 1.55-1.59 (m, 4H), 1.34 (m, 2H); MS LC-MS [M + H] ⁺ = 562 RT = 3.28 minutes.

(Example 14)
N-morpholin-4-yl-4- [3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine Preparation of 2-carboxamide

Using 4-aminomorpholine instead of N-aminopiperidine, N-piperidin-1-yl-4- [3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzo The title compound was prepared in a similar manner as described for dioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide. ¹ H-NMR (DMSO-d ₆ ) δ 9.81 (s, 1H), 9.17 (s, 1H), 9.12 (s, 1H), 8.50 (d, 1H), 8.06 ( d, 1H), 7.60 (dd, 1H), 7.37-7.48 (m, 4H), 7.29 (dd, 1H), 7.21 (dd, 1H), 6.83 (dd , 1H), 3.61-3.64 (m, 4H), 2.71-2.87 (m, 4H); MS LC-MS [M + H] ⁺ = 564, RT = 3.20 min.

(Example 15)
Preparation of 4- [3-({[(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-morpholin-4-ylpyridin-2-carboxamide

A mixture of 4- [3-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylic acid (70 mg, 0.17 mmol) in DMF (3 mL). To 4-aminomorpholine (20 mg, 0.17 mmol), HOBT (50 mg, 0.38 mmol), EDCl (50 mg, 0.26 mmol) and N-methylmorpholine (40 mg, 0.38 mmol) were added at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was diluted with methylene DCM (10 mL) and then washed with water (3 mL). The crude product was purified by HPLC and neutralized with NaHCO ₃ to give 38 mg (44%) of the title product. ¹ H-NMR (CD ₃ OD) δ 8.46 (d, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.57 (d, 1H), 7.45-7 .50 (m, 2H), 7.35-740 (m, 2H), 7.26 (dd, 1H), 7.08 (dd, 1H), 6.76 (dd, 1H), 4.04 ( s, 3H), 3.76-3.79 (m, 4H), 2.84-2.91 (m, 4H); MS LC-MS [M + H] ⁺ = 488, RT = 2.86 min.

(Example 16)
Preparation of N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (1H-tetrazol-5-yl) pyridin-4-yl] oxy} phenyl) urea

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea (300 mg, 0.23 mmol), sodium azide A mixture of (1.5 mmol, 67.6 mg) and triethylamine hydrochloride (143 mg, 1.5 mmol) was heated in toluene (20 mL) at 80 ° C. for 2 days. The solvent was removed and the residue was purified by flash chromatography (40: 30: 28: 2 v / v ethyl acetate: hexane: methanol: NH ₄ OH) to give 210 mg (63%) of the desired product ¹ H -NMR (DMSO-d ₆ ) δ 9.55 (s, 1H), 9.21 (s, 1H), 8.42 (d, 1H), 8.19 (s, 2H), 7.65 (m, 1H), 7.60 (m, 3H), 7.42 (s, 1H), 7.20 (m, 2H), 6.95 (s, 1H); MS LC-MS [M + H] ⁺ = 476, RT = 3.11 minutes.

(Example 17)
1N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (4,5-dihydro-1H-imidazol-2-yl) pyridin-4-yl] oxy} Preparation of phenyl) urea

N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-{4-[(2-cyanopyridin-4-yl) oxy] phenyl} urea (100 mg, 0.23 mmol), ethylenediamine (42 mg , 0.69 mmol) and sulfur (22 mg, 0.69 mmol) were heated in DMF (3 mL) at 80 ° C. overnight. The solvent was removed and the residue was purified by preparative HPLC to give 81 mg (73%) of the desired product. ¹ H-NMR (DMSO-d ₆ ) δ 9.22 (s, 1H), 9.05 (s, 1H), 8.50 (d, 1H), 7.60 (m, 5H), 7.39 ( s, 1H), 7.19 (m, 3H), 3.65 (s, 4H); MS LC-MS [M + H] ⁺ = 476, RT = 2.74 min.

(Example 18)
N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (1,3,4-oxadiazol-2-yl) pyridin-4-yl] oxy} Preparation of phenyl) urea

Using 4- (2- [1,3,4] oxadiazol-2-ylpyridin-4-yloxy) phenylamine in place of 4- (4-aminophenoxy) pyridine-2-carboxylic acid methyl ester, 4 The title compound was prepared in a similar manner as described for-[4-({[(4-chloro-3-trifluoromethylphenyl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxylate. ¹ H-NMR (acetone-d ₆ ) δ 9.06 (s, 1H), 8.70 (s, 1H), 8.63 (d, J = 6.0 Hz, 1H), 8.54 (s, 1H) ), 8.17 (d, J = 2.7 Hz, 1H), 7.79-7.58 (m, 4H), 7.55 (d, J = 9.3 Hz, 1H), 7.24-7 .20 (m, 2H), 7.14-7.10 (m, 1H); MS LC-MS [M + H] ⁺ = 476, RT = 3.37 min; TLC (100% ethyl acetate), R _f = 0.45.

(Example 19)
N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (4-methyl-1,3-thiazol-2-yl) pyridin-4-yl] oxy} Preparation of phenyl) urea

4- {4-[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} pyridine-2-carbothioamide (150 mg, 0.32 mmol) in absolute ethanol (20 mL) To was added chloroacetyl chloride (30.6 mL, 0.38 mmol, 1.2 eq) and the reaction mixture was refluxed under argon for 18 h. The mixture was poured into diethyl ether (100 mL) and the organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by MPLC (biotage) eluting with 50% ethyl acetate-hexanes to give 145 mg (89%) of the title product, ¹ H-NMR (acetone-d ₆ ) δ 8.60 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.43 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.79-7.68 ( m, 3H), 7.58-7.55 (m, 2H), 7.26-7.18 (m, 3H), 7.01-6.99 (m, 1H), 2.40 (s, 3H); MS LC-MS [M + H] ⁺ = 505, RT = 3.79 min; TLC (50% ethyl acetate / hexane), R _f = 0.25.

(Example 20)
N-quinolin-6-yl-N ′-(4-{[2- (5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl) pyridin-4-yl] oxy} phenyl ) Preparation of urea

4- (4-{[(Quinolin-6-ylamino) carbonyl] amino} phenoxy) pyridine-2-carbothioamide (50 mg, 0.12 mmol) in anhydrous methanol (20 mL) to hydrazine hydrate (60 mg, 1. 20 mmol) was added and the reaction mixture was stirred at room temperature under argon for 18 hours. The mixture was poured into diethyl ether (100 mL) and the organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. To the crude hydrazine amide was added anhydrous methanol (30 mL) followed by carbon disulfide (55 mg, 0.73 mmol). The reaction mixture was stirred at room temperature under argon for 18 hours and then dissolved in ethyl acetate (100 mL). The reaction mixture was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified using preparative TLC (100% ethyl acetate) to give 2 mg (6%) of the title product. ¹ H-NMR (acetone-d ₆ ) δ 8.74 (d, 1H), 8.44 (d, 1H), 8.40 (s, 1H), 7.96-7.84 (m, 4H), 7.44-7.38 (m, 2H), 7.18-7.14 (m, 2H), 7.18 (d, J = 9.0 Hz, 2H), 7.08-7.00 (m MS LC-MS [M + H] ⁺ = 473, RT = 3.16 min; TLC (100% ethyl acetate), R _f = 0.15.

(Example 21)
N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (5-oxo-4,5-dihydro-1,3,4-oxadiazole-2- Preparation of yl) pyridin-4-yl] oxy} phenyl) urea

4- (4-{[(quinolin-6-ylamino) carbonyl] amino} phenoxy) pyridine-2-carbothioamide instead of 4- {4-[({[4-chloro-3- (trifluoromethyl) phenyl ] -Amino} carbonyl) amino] phenoxy} pyridine-2-carbothioamide and using phosgene instead of carbon disulfide, N-quinolin-6-yl-N ′-(4-{[2- ( The title compound was prepared in a similar manner as described for 5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl) pyridin-4-yl] oxy} phenyl) urea. ¹ H-NMR (DMSO-d ₆ ) δ 12.75 (s, 1H), 9.21 (s, 1H), 8.99 (s, 1H), 8.55 (d, J = 5.7 Hz, 1H ), 8.10 (d, J = 2.4 Hz, 1H), 7.66-7.55 (m, 4H), 7.23 (d, J = 2.4 Hz, 1H), 7.20-7. .16 (m, 2H), 7.11-7.08 (m, 1H); MS LC-MS [M + H] ⁺ = 492, RT = 3.16 min; TLC (10% methanol / DCM), R _f = 0.84.

(Example 22)
N- (4-{[2- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) pyridin-4-yl] oxy} phenyl) -N '-(2 , 2,4,4-Tetrafluoro-4H-1,3-benzodioxin-6-yl) urea

4- {4-[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} pyridine-2-carbothioamide instead of 4- [3-({[(2, 2,4,4-Tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide and N- [4-chloro-3- (tri Fluoromethyl) phenyl] -N ′-(4-{[2- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) pyridin-4-yl] oxy} phenyl ) The title compound was prepared in a similar manner as described for urea. ¹ H-NMR (DMSO-d ₆ ) δ 12.75 (s, 1H), 9.15 (s, 1H), 9.01 (s, 1H), 8.55 (d, J = 6.0 Hz, 1H ), 8.10 (d, J = 2.7 Hz, 1H), 7.68-7.57 (m, 3H), 7.42 (d, J = 8.7 Hz, 1H), 7.23 (d , J = 2.7 Hz, 1H), 7.19-7.16 (m, 2H), 7.11-7.08 (m, 1H); MS LC-MS [M + H] ⁺ = 520, RT = 3 20 minutes; TLC (10% methanol / DCM), R _f = 0.72.

  One of ordinary skill in the art will be able to make the most of the present invention using the above information and information available in the art.

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

  Each item heading above and below is intended as a guide to specific information that can be found in this application and is intended to be the sole source for such items that can be found in this application. It is not a thing.

All publications and patents listed above are hereby incorporated by reference.

Claims (13)

Formula (I)

Or a pharmaceutically acceptable salt thereof, wherein A is phenyl, naphthyl, monocyclic or bicyclic heteroaryl or formula

Independently of R ¹ , OR ¹ , S (O) _p R ¹ , C (O) R ¹ , C (O) OR ¹ , C (O) NR ¹ R ² , halogen, hydroxy, Optionally substituted with 1 to 4 substituents which are amino, cyano or nitro,
B is phenyl, naphthyl or pyridyl and 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 May be substituted with 1 to 4 substituents which are C ₁ -C ₃ alkylamino, C ₁ -C ₆ dialkylamino, halogen, cyano or nitro,
L is (a)-(CH ₂ ) _m —O— (CH ₂ ) ₁ —,
_{(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,
m and l are integers independently selected from 0 to 4;
M is a pyridine ring and is independently C ₁ -C ₅ straight or branched alkyl, C ₁ -C ₅ straight or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ -C _{3 alkylamino,} C 1 -C ₆ dialkylamino, may be substituted with 1-3 substituents is halogen or nitro,
Q is:
(1) C (S) NR ⁴ R ⁵ ,
(2) imidazolyl,
(3) imidazolin-2-yl,
(4) 1,3,4-oxadiazolin-2-yl,
(5) 1,3-thiazolin-2-yl,
(6) 5-Thioxo-4,5-dihydro-1,3,4-thiazolin-2-yl,
(7) 5-oxo-4,5-dihydro-1,3,4-oxadiazolin-2-yl or the formula (8)

Wherein ^each of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is independently
(A) hydrogen,
_(B) C 1 ~C ₅ straight, branched or cyclic alkyl,
(C) phenyl,
_(D) C 1 ~C ₃ phenylalkyl,
(E) perhalo to substituted _C 1 -C ₅ straight or branched alkyl or, (f) - a _{(CH 2)} q -X, selected wherein X is oxygen, nitrogen and sulfur 1 to 4 heteroatoms containing at least one atom selected from the group consisting of saturated, partially saturated or aromatic 5- or 6-membered heterocycles, or consisting of O, N and S An 8-10 membered bicyclic heteroaryl having an atom;
R ⁴ and R ⁵ may further combine to form a 5- or 6-membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, and independently C ₁ -C ₅ straight or branched alkyl, substituted _C 1 -C ₅ straight or branched alkyl having up to _perhalo, C 1 -C ₃ alkoxy, hydroxy, oxo, carboxy, _amino, C 1 -C May be substituted with 1 to 3 substituents which are ₃ alkylamino, C ₁ -C ₆ dialkylamino, halogen, cyano or nitro,
R ⁶ is independently
(A) hydrogen,
_(B) C 1 ~C ₅ straight, branched or cyclic alkyl,
(C) cyano,
(D) Nitro,
(E) substituted _C 1 -C ₅ straight or branched alkyl having up to perhalo, or (f) -C (O) a ^{R 8,} wherein ^{R 8} is _C 1 -C ₅ straight-chain, Branched or cyclic alkyl,
q is an integer of 0, 1, 2, 3 or 4 and p is an integer of 0, 1 or 2.   2. The compound of claim 1, wherein B is phenyl or pyridinyl and may be substituted with 1 to 4 halogens.   The compound of claim 1, wherein L is —O—, B is phenyl or pyridinyl, and may be substituted with 1 to 4 halogens. A is phenyl, naphthyl, indazolyl, quinolinyl, pyridyl, benzo [1,3] dioxolan-5-yl, 2,3-dihydro-benzo [1,4] dioxin-6-yl or 4H-benzo [1,3] Dioxin-6-yl, optionally substituted with 1-4 substituents which are independently R ¹ and halogen, L is —O—, B is phenyl, and 1-4 2. The compound of claim 1, which may be substituted with 1 halogen. A and B are the following combinations:
A = phenyl and B = phenyl,
A = indazolyl and B = phenyl,
A = quinolinyl and B = phenyl,
A = 4H-benzo [1,3] dioxin-6-yl and B = phenyl,
A = phenyl and B = pyridyl,
A = indazolyl and B = pyridyl,
A = quinolinyl and B = pyridyl, or A = 4H-benzo [1,3] dioxin-6-yl and B = pyridyl,
The compound of claim 1 according to N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (hydrazinocarbonyl) pyridin-4-yl] oxy} phenyl) urea N- (4- {[2- (hydrazinocarbonyl) pyridin-4-yl] oxy} phenyl) -N ′-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) urea N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-[3-({2-[(2,2-dimethylhydrazino) carbonyl] pyridin-4-yl} oxy) phenyl] urea 4- {3-[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-piperidin-1-ylpyridin-2-carboxamide N-piperidine-1- IL-4 [3-({[(2,2,4,4-Tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide, 4- {3- [({{4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-morpholin-4-ylpyridin-2-carboxamide, N-morpholin-4-yl-4- [3 -({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboxamide. 4- [3-({ [(1-Methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] -N-morpholin-4-ylpyridin-2-carboxamide -[4-Chloro-3- (trifluoromethyl) phenyl] -N '-(4-{[2- (1H-tetrazol-5-yl) pyridin-4-yl] oxy} phenyl) urea N- [ 4-chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (4,5-dihydro-1H-imidazol-2-yl) pyridin-4-yl] oxy} phenyl) urea N- [4-Chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (1,3,4-oxadiazol-2-yl) pyridin-4-yl] oxy } Phenyl) urea N- [4-chloro-3- (trifluoromethyl) phenyl] -N ′-(4-{[2- (4-methyl-1,3-thiazol-2-yl) pyridine-4 -Yl] oxy} phenyl) urea / N-quinolin-6-yl- '-(4-{[2- (5-Thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl) pyridin-4-yl] oxy} phenyl) urea / N- [4-chloro -3- (trifluoromethyl) phenyl] -N '-(4-{[2- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) pyridine-4- Yl] oxy} phenyl) urea N- (4-{[2- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) pyridin-4-yl] oxy} Phenyl) -N ′-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) urea 4- {4-[({[4-chloro-3- (tri Fluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine 2-Carboximidoamide 4- {4-[({[4-Chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} pyridine-2-carboximidamide N-methyl-4 -[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carboximidamide N- Methyl-4- (4-{[(quinolin-6-ylamino) carbonyl] amino} phenoxy) pyridine-2-carboximidamide. 4- {4-[({[4-chloro-3- (trifluoromethyl) Phenyl] amino} carbonyl) amino] phenoxy} pyridine-2-carbothioamide 4- (4-{[(quinolin-6-ylamino) carbonyl] a No} phenoxy) pyridine-2-carbothioamide or a compound that is 4- [4-({[(1-methyl-1H-indazol-5-yl) amino] carbonyl} amino) phenoxy] pyridine-2-carbothioamide . Formula (I)

Or a pharmaceutically acceptable salt thereof, wherein A is

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 , Optionally substituted with 1 to 4 substituents which are halogen, hydroxy, amino, cyano or nitro,
B is phenyl, naphthyl or pyridyl and 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 May be substituted with 1 to 4 substituents which are C ₁ -C ₃ alkylamino, C ₁ -C ₆ dialkylamino, halogen, cyano or nitro,
L is (a)-(CH ₂ ) _m —O— (CH ₂ ) ₁ —,
_{(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,
m and l are integers independently selected from 0 to 4;
M is a pyridine ring and is independently C ₁ -C ₅ straight or branched alkyl, C ₁ -C ₅ straight or branched haloalkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, C ₁ -C _{3 alkylamino,} C 1 -C ₆ dialkylamino, may be substituted with 1-3 substituents is halogen or nitro,
Q is:
(1) C (S) NR ⁴ R ⁵ ,
(2) imidazolyl,
(3) imidazolin-2-yl,
(4) 1,3,4-oxadiazolin-2-yl,
(5) 1,3-thiazolin-2-yl,
(6) 5-Thioxo-4,5-dihydro-1,3,4-thiazolin-2-yl,
(7) 5-oxo-4,5-dihydro-1,3,4-oxadiazolin-2-yl or the formula (8)

Wherein ^each of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is independently
(A) hydrogen,
_(B) C 1 ~C ₅ straight, branched or cyclic alkyl,
(C) phenyl,
_(D) C 1 ~C ₃ phenylalkyl,
(E) perhalo to substituted _C 1 -C ₅ straight or branched alkyl or, (f) - a _{(CH 2)} q -X, selected wherein X is oxygen, nitrogen and sulfur 1 to 4 heteroaryls containing at least one atom selected from the group consisting of saturated, partially saturated or aromatic 5- or 6-membered heterocycles, or O, N and S An 8-10 membered bicyclic heteroaryl having an atom;
R ⁴ and R ⁵ may further together form a 5- or 6-membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, and independently C ₁ -C ₅ linear or branched alkyl, substituted C ₁ -C ₅ linear or branched alkyl up to perhalo, C ₁ -C ₃ alkoxy, hydroxy, oxo, carboxy, amino, C ₁ -C ₃ alkylamino May be substituted with 1-3 substituents which are C ₁ -C ₆ dialkylamino, halogen, cyano or nitro,
R ⁶ is independently
(A) hydrogen,
_(B) linear C 1 -C _5, branched or cyclic alkyl,
(C) cyano,
(D) Nitro,
(E) substituted _C 1 -C ₅ straight or branched alkyl having up to perhalo, or (f) -C (O) a ^{R 8,} wherein ^{R 8} is _C 1 -C ₅ straight-chain, Branched or cyclic alkyl,
q is an integer of 0, 1, 2, 3 or 4 and
p is an integer of 0, 1 or 2 .   8. The compound of claim 7, wherein B is phenyl or pyridinyl and may be substituted with 1 to 4 halogens.   8. The compound of claim 7, wherein L is -O-, B is phenyl or pyridinyl and may be substituted with 1 to 4 halogens. B is phenyl or pyridyl, L is —O—, M is a pyridine ring substituted only by Q, and Q is
C (S) NR ⁴ R ⁵ ,
Or expression

Each of R ⁴ and R ⁵ is independently:
(A) hydrogen,
_(B) C 1 ~C ₅ straight, branched or cyclic alkyl,
(C) phenyl,
_(D) C 1 ~C ₃ phenylalkyl,
(E) perhalo to substituted _C 1 -C ₅ straight or branched alkyl or, (f) - a _{(CH 2)} q -X, substituent X in the formula is a pyridinyl, variable q Ri integer der of 0 or 1,
R ⁶ is:
(A) hydrogen,
_(B) C 1 ~C ₅ straight, branched or cyclic alkyl or (c) cyano, compound of claim 7. Formula (I)

Or a pharmaceutically acceptable salt thereof, wherein A is

Wherein A may be independently substituted with 1 to 4 substituents which are R ¹ , OR ¹ or halogen,
B is phenyl or pyridinyl and 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, halogen, may be substituted with 1-4 substituents is cyano or nitro,
L is -O-
M is a pyridine ring;
Q is:
(1) C (S) NR ⁴ R ⁵ ,
(2) imidazolyl,
(3) imidazolin-2-yl,
(4) 1,3,4-oxadiazolin-2-yl,
(5) 1,3-thiazolin-2-yl,
(6) 5-Thioxo-4,5-dihydro-1,3,4-thiazolin-2-yl,
(7) 5-oxo-4,5-dihydro-1,3,4-oxadiazolin-2-yl or the formula (8)

Wherein each of R ¹ , R ⁴ and R ⁵ is independently
(A) hydrogen,
_(B) C 1 ~C ₅ straight, branched or cyclic alkyl,
(C) phenyl,
_(D) C 1 ~C ₃ phenylalkyl,
(E) perhalo to substituted _C 1 -C ₅ straight or branched alkyl or, (f) - a _{(CH 2)} q -X, selected wherein X is oxygen, nitrogen and sulfur 1 to 4 heteroaryls containing at least one atom selected from the group consisting of saturated, partially saturated or aromatic 5- or 6-membered heterocycles, or O, N and S An 8-10 membered bicyclic heteroaryl having an atom;
R ⁴ and R ⁵ may further combine to form a 5- or 6-membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, and independently C ₁ -C ₅ straight or branched alkyl, substituted _C 1 -C ₅ straight or branched alkyl having up to _perhalo, C 1 -C ₃ alkoxy, hydroxy, oxo, carboxy, _amino, C 1 -C May be substituted with 1 to 3 substituents which are ₃ alkylamino, C ₁ -C ₆ dialkylamino, halogen, cyano or nitro,
R ⁶ is independently
(A) hydrogen,
_(B) C 1 ~C ₅ straight, branched or cyclic alkyl,
(C) cyano,
(D) Nitro,
(E) substituted _C 1 -C ₅ straight or branched alkyl having up to perhalo, or (f) -C (O) a ^{R 8,} wherein ^{R 8} is _C 1 -C ₅ straight-chain, Branched or cyclic alkyl,
q is an integer of 0, 1, 2, 3 or 4.   12. The compound of claim 11 wherein B is phenyl or pyridinyl and is substituted with 1 to 4 halogens. M is a pyridine ring substituted only by Q, and Q is
C (S) NR ⁴ R ⁵ ,
Or expression

Each of R ⁴ and R ⁵ is independently:
(A) hydrogen,
_(B) C 1 ~C ₅ straight, branched or cyclic alkyl,
(C) phenyl,
_(D) C 1 ~C ₃ phenylalkyl,
(E) perhalo to substituted _C 1 -C ₅ straight or branched alkyl or, (f) - a _{(CH 2)} q -X, substituent X in the formula is a pyridinyl, variable q Ri integer der of 0 or 1,
R ⁶ is:
(A) hydrogen,
(B) C ₁ -C ₅ linear, branched or cyclic alkyl, or (c) cyano,
12. A compound according to claim 11.