EP1960394A2 - Pyrazolyl urea derivatives useful in the treatment of cancer - Google Patents

Pyrazolyl urea derivatives useful in the treatment of cancer

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Publication number
EP1960394A2
EP1960394A2 EP06837652A EP06837652A EP1960394A2 EP 1960394 A2 EP1960394 A2 EP 1960394A2 EP 06837652 A EP06837652 A EP 06837652A EP 06837652 A EP06837652 A EP 06837652A EP 1960394 A2 EP1960394 A2 EP 1960394A2
Authority
EP
European Patent Office
Prior art keywords
cancer
fluorophenyl
acid
pyrazol
urea
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06837652A
Other languages
German (de)
French (fr)
Inventor
Louis-David Cantin
Roger Smith
Zhi Chen
Holia N. Hatoum-Mokdad
Eric Mull
Wendy Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer Healthcare AG
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Filing date
Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1960394A2 publication Critical patent/EP1960394A2/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to novel compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper- proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients, e.g., cytotoxic therapies.
  • tumor cells require a functional stroma, a support structure consisting of fibroblast, smooth muscle cells, endothelial cells, extracellular matrix proteins, and soluble factors (Folkman, J., Semin Oncol, 2002. 29(6 Suppl 16), 15-8).
  • Tumors induce the formation of stromal tissues through the secretion of soluble growth factors such as PDGF and transforming growth factor-beta (TGF-beta), which in turn stimulate the secretion of complimentary factors by host cells such as fibroblast growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF).
  • FGF fibroblast growth factor
  • EGF epidermal growth factor
  • VEGF vascular endothelial growth factor
  • an agent targeting a single pathway may have limited efficacy. It is desirable to provide treatment against a number of key signaling pathways utilized by tumors to induce angiogenesis in the host stroma. These include, for example, PDGF, a potent stimulator of stroma formation (Ostman, A. and CH. Heldin, Adv Cancer Res, 2001, 80, 1-38), FGF, a chemo-attractant and mitogen for fibroblasts and endothelial cells, and VEGF, a potent regulator of vascularization. HGF (hepatocyte growth factor) represents an additional signaling growth factor of interest.
  • PDGF is a key regulator of stromal formation, which is secreted by many tumors in a paracrine fashion and is believed to promote the growth of fibroblasts, smooth muscle and endothelial cells, promoting stroma formation and angiogenesis.
  • PDGF was originally identified as the v-sis oncogene product of the simian sarcoma virus (Heldin, C. H., et al., J Ce// Sci Suppl, 1985, 3, 65-76).
  • the growth factor is made up of two peptide chains, referred to as A or B chains which share 60% homology in their primary amino acid sequence.
  • the chains are disulfide cross linked to form the 30 kDa mature protein composed of either AA, BB or AB homo- or heterodimmers.
  • PDGF is found at high levels in platelets, and is expressed by endothelial cells and vascular smooth muscle cells. In addition, the production of PDGF is up regulated under low oxygen conditions such as those found in poorly vascularized tumor tissue (Kourembanas, S., et al., Kidney Int, 1997, 51(2), 438-43). PDGF binds with high affinity to the PDGF receptor, a 1106 amino acid 124 kDa transmembrane tyrosine kinase receptor (Heldin, C. H., A. Ostman, and L.
  • PDGFR is found as homo- or heterodimer chains which have 30% homology overall in their amino acid sequence and 64% homology between their kinase domains (Heldin, C. H., et al.. Embo J, 1988, 7(5), 1387-93).
  • PDGFR is a member of a family of tyrosine kinase receptors with split kinase domains that includes VEGFR2 (KDR), VEGFR3 (Flt4), c-Kit, and FLT3.
  • the PDGF receptor is expressed primarily on fibroblast, smooth muscle cells, and pericytes and to a lesser extent on neurons, kidney mesangial, Leydig, and Schwann cells of the central nervous system. Upon binding to the receptor, PDGF induces receptor dimerization and undergoes auto- and trans-phosphorylation of tyrosine residues which increase the receptors' kinase activity and promotes the recruitment of downstream effectors through the activation of SH2 protein binding domains.
  • a number of signaling molecules form complexes with activated PDGFR including PI-3-kinase, phospholipase C-gamma, src and GAP (GTPase activating protein for p21-ras) (Soskic, V., et al. Biochemistry, 1999, 38(6), 1757-64).
  • PI-3-kinase phospholipase C-gamma
  • src GAP
  • PDGF central nervous system
  • PDGF vascular endothelial growth factor
  • angiogenesis PDGF controls interstitial fluid pressure, regulating the permeability of vessels through its regulation of the interaction between connective tissue cells and the extracellular matrix. Inhibiting PDGFR activity can lower interstitial pressure and facilitate the influx of cytotoxics into tumors improving the anti-tumor efficacy of these agents (Pietras, K., et al. Cancer Res, 2002. 62(19), 5476-84; Pietras, K., et al. Cancer Res, 2001. 61(7), 2929-34).
  • PDGF can promote tumor growth through either the paracrine or autocrine stimulation of PDGFR receptors on stromal cells or tumor ceils directly, or through the amplification of the receptor or activation of the receptor by recombination.
  • Over expressed PDGF can transform human melanoma cells and keratinocytes (Forsberg, K., et al. Proc Natl Acad Sci U S A., 1993. 90(2), 393-7; Skobe, M. and N.E. Fusenig, Proc Natl Acad Sci U S A, 1998. 95(3), 1050-5), two cell types that do not express PDGF receptors, presumably by the direct effect of PDGF on stroma formation and induction of angiogenesis.
  • PDGFR inhibitors will interfere with tumor stromal development and are believed to inhibit tumor growth and metastasis.
  • VEGF vascular endothelial growth factor
  • VPF vascular permeability factor
  • VEGF expression is reported to be induced by hypoxia (Shweiki et al. Nature 1992, 359, 843), as well as by a variety of cytokines and growth factors, such as interleukin-1 , interleukin-6, epidermal growth factor and transforming growth factor. To date, VEGF and the VEGF family members have been reported to bind to one or more of three transmembrane receptor tyrosine kinases (Mustonen et al. J.
  • VEGF receptor-1 also known as flt-1 (fms-like tyrosine kinase-1)
  • VEGFR-2 also known as kinase insert domain containing receptor (KDR); the murine analogue of KDR is known as fetal liver kinase-1 (flk-1)), and VEGFR-3 (also known as flt-4).
  • KDR and flt-1 have been shown to have different signal transduction properties (Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et al. Oncogene 1995, 10, 135).
  • KDR undergoes strong ligand-dependant tyrosine phosphorylation in intact cells, whereas flt-1 displays a weak response.
  • binding to KDR is believed to be a critical requirement for induction of the full spectrum of VEGF-mediated biological responses.
  • VEGF plays a central role in vasculogenesis, and induces angiogenesis and permeabilization of blood vessels.
  • Deregulated VEGF expression contributes to the development of a number of diseases that are characterized by abnormal angiogenesis and/or hyperpermeability processes. It is believed regulation of the VEGF-mediated signal transduction cascade by some agents can provide a useful mode for control of abnormal angiogenesis and/or hyperpermeability processes.
  • VEGF, VEGF-C, VEGF-D vascular endothelial growth factors
  • VEGFR2, VEGFR3 lymphangiogenesis
  • VEGF, VEGF-C and VEGF-D are expressed in most tumors, primarily during periods of tumor growth and, often at substantially increased levels.
  • VEGF expression is stimulated by hypoxia, cytokines, oncogenes such as ras, or by inactivation of tumor suppressor genes (McMahon, G. Oncologist 2000, 5(Suppl. 1), 3- 10; McDonald, N. Q.; Hendrickson, W.A. Ce// 1993, 73, 421-424)
  • VEGFR3 also called Flt-4.
  • VEGFR3 function is needed for new lymphatic vessel formation, but not for maintenance of the pre-existing lymphatics.
  • VEGFR3 is also upregulated on blood vessel endothelium in tumors.
  • VEGF-C and VEGF-D ligands for VEGFR3, have been identified as regulators of lymphangiogenesis in mammals. Lymphangiogenesis induced by tumor-associated lymphangiogenic factors could promote the growth of new vessels into the tumor, providing tumor cells access to systemic circulation.
  • VEGF-C vascular endothelial growth factor
  • VEGF-D vascular endothelial growth factor
  • VEGFR3 vascular endothelial growth factor-D
  • clinicopathological factors that relate directly to the ability of primary tumors to spread (e.g., lymph node involvement, lymphatic invasion, secondary metastases, and disease-free survival).
  • these studies demonstrate a statistical correlation between the expression of lymphangiogenic factors and the ability of a primary solid tumor to metastasize (Skobe, M. et al. Nature Med. 2001, 7(2), 192- 198; Stacker, S.A. et al.. Nature Med. 2001 , 7(2), 186-191 ; Makinen, T.
  • 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).
  • p38 MAP kinase promotes malignant cell invasion, and migration of different tumor types through regulation of collagenase activity and urokinase plasminogen activator expression (Laferriere, J. et al. J. Biol.
  • Trk-A The receptor tyrosine kinase Trk-A is another target of interest for the preparation of medicines directed at the treatment and prevention of cancer.
  • TrkA is the high affinity receptor of the nerve growth factor (NGF).
  • NGF nerve growth factor
  • the expression of TrkA and NGF in tumors is believed to be implicated in the proliferation and metastasis of tumors such as pancreatic, prostate and also breast, as well as in angiogenesis. TrkA expression is reported in pancreatic, breast, ovarian, and prostate tumors. Recent studies demonstrate that human prostate and pancreatic tumor cells can secrete NGF, which, along with its receptor, TrkA, creates an autocrine loop that promotes the growth and survival of these tumor cells (Ruggeri, B. A. et al, Curr. Med. Chem.
  • the proto-oncoogene c-Met encodes a heterodimeric complex consisting of a 140-kDa membrane-spanning Dchain and a 50-kDa extracellular O chain.
  • This heterodimeric complex acts as a high-affinity receptor for hepatocyte growth factor (HGF) or scatter factor (SF).
  • HGF hepatocyte growth factor
  • SF scatter factor
  • c-Met/HGF signaling is required for normal mammalian development and has been shown to be particularly important in cell growth, migration, morphogenic differentiation, and organization of three-dimensional tubular structures (e.g. renal tubular cells, gland formation, etc.).
  • c- Met and HGF are widely expressed in a variety of tissues, and their expression is normally confined to cells of epithelial and mesenchymal origin, respectively.
  • HGF/c-Met signaling has an important role in the development and malignant progression of tumors of various histological types.
  • Cell lines that ectopically overexpress c-Met or HGF become tumorigenic and metastatic in nude mice, whereas c-Met downregulation decreases their tumorigenic potential.
  • HGF-dependent autocrine loops are found associated with osteosarcomas, rhabdomyosarcomas and breast carcinomas (Trusolino and Comoglio, Nat Rev Cancer, 2002, 2, 289-300).
  • c-Met or HGF transgenic mice develop metastatic tumors (Wang, R. et al., J. Cell Biol. 2001 , 153, 1023-1034; Takayama et al., Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 701-706).
  • Over-expression of c-Met expression has been found in many kinds of solid tumors and correlates with poor prognosis (Birchmeier, et al. MoI. Cell Biol., 2003, 4, 915-925; Christensen, J. and Salgia, R., Can Lett, 2005, 225, 1-26).
  • HGF/SF-neutralizing antibodies Cao et al., Proc Natl Acad Sci USA 2001, 98, 7443-8
  • c-Met antisense oligonucleotides Kitamura et al., Br J Cancer 2000, 83: 668- 73
  • dominant-negative forms of the Met protein Firon et al., Oncogene 2000, 19, 2386- 97; Furge et al., Proc Natl Acad Sci USA 2001 , 98, 10722-7
  • ribozymes that target Met mRNA Abounader et al., J Natl Cancer Inst, 1999, 91, 1548-56; Abounader et al., FASEB J 2002, 16, 108 -10
  • small c-Met tyrosine kinase inhibitor small molecule c-Met tyrosine kinase inhibitor
  • Chronic myelogenous leukemia is caused by the oncogenic protein, Bcr- AbI (Groffen, J. et al., J Cell Physiol Suppl, 1984, 3, 179-191 , Sattler, M. and Griffin, J. D., Semin Hematol, 2003, 40, 4-10).
  • Bcr- AbI The Philadelphia chromosome, which is the hallmark of CML, is formed in CML patients due to a reciprocal translocation between chromosomes 9 and 22 (Rowley, J. D., Nature, 1973, 243, 290-293), and this translocation results in the formation of Bcr-Abl fusion protein (Groffen, J.
  • AbI protein is a nonreceptor tyrosine kinase whose activity is tightly regulated in the normal cells. However, the fusion protein is co ⁇ stitutively activated due to the presence of Bcr protein at the N- terminus. The constitutively active protein transforms at the myeloid the blast cell stage thus giving rise to CML (Kelliher, M. A., et al., Proc Natl Acad Sci U S A, 1990, 87, 6649-6653). Depending on the exact breakpoints at the chromosomes involved in the translocation, the size of the fusion protein varies from 185 to 230 kDa, although 210 kDa protein being the most commoon in CML.
  • BMS-354825 has been reported to be an inhibitor of Bcr-Abl and also Src family kinases.
  • BMS-354825 was reported to inhibit all the mutant forms of the protein except T315I (Shah, N. P., et al., Science, 2004, 305, 399-401).
  • the compound AMN-107 has been reported to inhibit Bcr-Abl kinase activity with 20-fold greater potency than Imatinib.
  • AMN-107 was reported to inhibit most lmanitib resistant mutations except for T315I. AMN-107 also shows weaker inhibition in a biochemical assay against E255K mutant (IC 50 of 40OnM) (Weisberg, E., et al., Cancer Cell, 2005, 7, 129-141). Therefore, there is a significant unmet medical need for new therapeutics to treat CML and Imatinib-resistant CML.
  • Certain diarylureas have been described as having activity as serine-threonine kinase and/or as tyrosine kinase inhibitors. The utility of these diarylureas as an active ingredient in pharmaceutical compositions for the treatment of cancer, angiogenesis disorders, and inflammatory disorders has been demonstrated.
  • the utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below.
  • the link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art.
  • taxol Silvestrini et al. Stem Cells 1993, 11(6), 528-35
  • taxotere Bissery et al. Anti Cancer Drugs 1995, 6(3), 339
  • topoisomerase inhibitors Edelman et al. Cancer Chemother. Pharmacol. 1996, 37(5), 385-93 were demonstrated with the use of in vitro tumor proliferation assays.
  • compositions described herein exhibit antiproliferative activity and are thus useful to prevent or treat the disorders associated with hyper-proliferation.
  • the present invention pertains to: (i) novel compounds of examples 1-82 below, which are
  • a preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (4-cyanophenyl)-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • Another preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • An additional preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (4-methylphenyl)-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • a further preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[1-(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • One additional preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyI ⁇ -N'-[3-tert-butyl-1- (3-methoxyphenyl)-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • diseases e.g., hyper-proliferative and/
  • the compounds of this invention may contain one. or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (Sj configuration or (R, S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
  • Preferred compounds are those which produce the more desirable biological activity.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivitization, are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples 1-82, preferably:
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate,
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides
  • Preferred salts include salts of: (i) salts of N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(4- cyanophenyl)-1 H-pyrazol-5-yl]urea and hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid;
  • Preferred acid addition salts also include:
  • Certain compounds of this invention can be further modified with labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharmacologically inactive derivatizing (functional) group.
  • labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharmacologically inactive derivatizing (functional) group.
  • prodrugs can be used, for example, to alter the physicochemical properties of the active agent, to target the active agent to a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce undesirable side effects.
  • Prodrugs of the invention include, e.g., the esters of appropriate compounds of this invention, are well-tolerated, pharmaceutically acceptable amides such as alkyl amide including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl(Ci-C5)alkyl may be used, although methyl amide is preferred. Solvates for the purpose of this invention are those forms of the compounds of this invention, such as
  • the compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the compounds of the present invention, with more detailed particular examples being presented below in the experimental section describing the working examples.
  • the compounds of the invention can be made according to conventional chemical methods, and/or as disclosed below, from starting materials which are either commercially available or producible according to routine, conventional chemical methods.
  • General methods for the preparation of the compounds are given below, and the preparation of representative compounds is specifically illustrated in examples.
  • Specific preparations of diaryl ureas, including pyrazolyl ureas, are already described in the patent literature, and can be adapted to the compounds of the present invention.
  • Miller S. et al "Inhibition of p38 Kinase using Symmetrical and Unsymmetrical Diphenyl Ureas" PCT int. Appl. WO 99 32463, Miller, S et al.
  • Compounds of the present invention can be prepared according to General Method 1 (Reaction Scheme 1), where 5-aminopyrazoles of Formula 1.1 and amines of Formula 1.2 are coupled together to form a urea of Formula I.
  • This process occurs in the presence of a coupling agent such as carbonyldiimidazole, carbonylditriazole, phosgene, diphosgene, triphosgene, and the like.
  • the isocyanates may or may not be formed in situ.
  • the coupling step may be performed in an inert solvent such as dioxane, diethylether, dichloromethane, chloroform, tetrahydrofuran, toluene, and the like, at a temperature selected between 0 0 C and reflux.
  • an inert solvent such as dioxane, diethylether, dichloromethane, chloroform, tetrahydrofuran, toluene, and the like.
  • Aromatic amines of Formula (1.2) are generally employed in an amount of from 1 to 3 mole per mole of compounds of Formula (1.1); an equimolar amount or slight excess of compounds of Formula (1.2) is preferred.
  • Amines of Formula (1.2) are commercially available or can be synthesized according methods commonly known to those skilled in the art. In particular, a large variety of aromatic amines of Formula (1.2) has been described in the diaryl urea patent literature cited above. Reaction Scheme 10 (below) will also illustrate one of the synthetic methods than can be used to prepare compounds of Formula (1.2).
  • the reaction of the compounds of Formula (1.1) with amines of Formula (1.2) is generally carried out within a relatively wide temperature range. In general, they are carried out in a range of from -20 to 200 0 C, preferably from 0 to 100 0 C, and more preferably from 25 to 50 0 C.
  • the steps of this reaction are generally carried out under atmospheric pressure. However, it is also possible to carry them out under super- atmospheric pressure or at reduced pressure (for example, in a range of from 0.5 to 5 bar).
  • the reaction time can generally be varied within a relatively wide range. In general, the reaction is finished after a period of from 2 to 24 hours, preferably from 6 to 12 hours.
  • the compounds of the present invention can be synthesized according to the reaction sequence shown in the General Method 2 (Reaction Scheme 2). These compounds can be synthesized by reacting arylamines of Formula (1.2) with isocyanates of Formula (2.2).
  • Compounds of Formula (2.2) can be synthesized according to methods commonly known to those skilled in the art.
  • isocyanates of Formula (2.2) may be prepared in situ or isolated from treatment of amino-pyrazoles of Formula (1.1) with phosgene or a phosgene equivalent such as trichlor ⁇ methyl chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or ⁇ /,/V'-carbonyldiimidazole (CDI), or ⁇ /, ⁇ /'-carbonylditriazole (CDT).
  • compounds of Formula 2.2 can be obtained from the corresponding pyrazole-carboxylic acid derivatives via a Curtius-type rearrangement.
  • 5-Aminopyrazo!es of Formula (1.1) can be prepared by a variety of methods. Specific preparations are already described in the patent literature, and can be adapted to the compounds of the present invention. For example, Keerigan, F. et a/., "Preparation of piperazine derivatives as therapeutic agents” PCT Int. App/., WO 9703067, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32110, Regan, J. et al., J. Med, Chem. 2003, 46 4676-4686.
  • Reaction Scheme 6 illustrates the synthesis of compounds for Formula (1.1c) where R 2 is halo as defined in examples 80 and 81 and A is as defined in examples 1- 82 below.
  • AIk optionally substituted (C 0 -C 4 ) alkyl substituted (C 1 -C 6 ) alkyl *Suitable boronic acid esters include group, or two R' groups may form a ring
  • Reaction Scheme 6 illustrates how the aminopyrazole of Formula (1.1a) may be converted to other aminopyrazoles of Formula (1.1c) by halogenation followed by Suzuki or Stille coupling reactions to introduce an R 2 group other than H.
  • the product of the Stille reaction (1.1d) can also be reduced, for example by hydrogenation, to give the saturated compound of Formula (1.1c).
  • Hydrazines of Formula (4.3) are either commercially available or can be prepared as shown in Reaction Scheme 7.
  • a substituted amine of Formula (7.1) is converted into a diazonium salt intermediate by exposure to sodium nitrite in the presence of an acid, such as HCI.
  • the diazonium salt is subsequently reduced, for example by using tin(ll)chloride as the reductant, in the presence of an acid such as HCI.
  • Compounds of Formula (8.1) can be reacted with benzophenone hydrazone (8.2) in the presence of a catalyst and ligand to afford intermediate (8.3).
  • this reaction is performed using a palladium catalyst (e.g., Pd(ll)acetate) in the presence of a phosphine ligand such as 4,5-bis(diphenylphosphino)xanthene.
  • a palladium catalyst e.g., Pd(ll)acetate
  • a phosphine ligand such as 4,5-bis(diphenylphosphino)xanthene.
  • the addition of base is favorable, in particular when using sodium ferf-butoxide.
  • the reaction is best performed under anhydrous conditions in a suitable solvent such as toluene.
  • Intermediate (8.3) can be used in Reaction Schemes 4 and 5 as an in situ form of (4.3), or it can be converted to a compound of Formula (4.3) in the presence of acid, preferably
  • 5-Amino pyrazoles of Formula (1.1) can be further functionalized [by methods well know to one skilled in the Art] before being coupled with keto-nitriles of Formula (1.2, Reaction Schemes 1-3).
  • Reaction Scheme 9 illustrates the manipulation of an alkoxyl substituted 5-amino pyrazoles.
  • Aminopyrazoles of Formula (9.1 ) are de-methylated to the corresponding hydroxy compounds of Formula (9.2) (for example, with the use of boron tribromide, methylthiolate in DMF 1 lithium diphenylphosphide, or an equivalent reagent known in the art).
  • compounds of Formula (9.2) can be further elaborated by alkylation, for example with an alkyl halide such as Y-Br, Y-I, or Y-Cl or by a Mitsunobu reaction with an alkanol such as Y-OH, to afford aminopyrazoles of Formula (9.3).
  • Reaction Scheme 10 illustrates the synthesis of compounds of Formula (1.2) where B pyridyl.
  • Reaction of a 2-carboxy pyridine of Formula (10.1) can be treated with an halogenating agent, preferably SOCI 2 /SOBr 2 , with heating to produce acid chloride 10.2.
  • Conversion to intermediate (10.3) is achieved either through Hofmann (NH 3 ; KOH 1 Br 2 ) or Curtius (NaN 3 , heat) rearrangement performed in a suitable solvent.
  • the 2-amino functional group can be masked as a 2,5-dimethylpyrrole by treatment with acetonyl acetone in the presence of a catalytic amount of acid.
  • Condensation of fragment 10.5 with intermediate 10.4 can be achieved in the presence of base in a suitable solvent, for example using potassium terf-butoxide in DMSO.
  • Unmasking of the 2-amino group can the be achieved by using hydroxyl amine in a solvent such as an alcohol in the presence of water and a mild base to provide compounds of Formula (1.2)
  • Synthetic transformations that may be employed in the synthesis of compounds of this invention and in the synthesis of intermediates involved in the synthesis of compounds of this invention are known by or accessible to one skilled in the art. Collections of synthetic transformations may be found in compilations, such as: J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York (1992) R. C. Larock. Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH: New York
  • compositions of the compounds of this invention are provided.
  • compositions containing one or more compounds of the present invention preferably one or more of:
  • compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention, preferably one or more of:
  • a pharmaceutically acceptable carrier is preferably a carrier that is relatively nontoxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
  • N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N l -[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea; can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
  • the compounds of this invention including:
  • N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention including:
  • N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify 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, a suspending agent and one or more preservatives. Suitable dispersing, or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p- hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • the compounds of this invention including:
  • N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethy!-1 ,1-dioxolane-4-methanol, ethers such as poly(
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammontum, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example di
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient, such as
  • compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions of this invention may be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcelluJose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial
  • 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 may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • a pharmaceutical composition of the invention including those which comprise
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • a suitable non- irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritation excipient are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion in controlled amounts of the compounds of the present invention, including:
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11 , 1991 , incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
  • composition of this invention such as one which includes one or more of
  • compositions of the invention including those which comprise one or more of;
  • compositions comprising a solid dispersion of the active ingredient, wherein the matrix comprises a pharmaceutically acceptable polymer, such as polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e.
  • a pharmaceutically acceptable polymer such as polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e.
  • hydroxypropyl methyl cellulose carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, polyglycolized glycerides, xanthan gum, carrageenan, chitosan, chitin, poyldextrin, dextrin, starch and proteins or a sugar and/or sugar alcohol and/or cyclodextrin, for example sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, inositol, trehalose, isomalt, inu ⁇ n, maltodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin or sulfobuty
  • Additional suitable carriers that are useful in the formation of the matrix of the solid dispersion include, but are not limited to alcohols, organic acids, organic bases, amino acids, phospholipids, waxes, salts, fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and urea.
  • the solid dispersion of the compounds of this invention in the matrix may contain certain additional pharmaceutical acceptable ingredients, such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants, detackifier, pH-modifiers, glidants and lubricants.
  • additional pharmaceutical acceptable ingredients such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants, detackifier, pH-modifiers, glidants and lubricants.
  • the solid dispersion of the invention is prepared according to methods known to the art for the manufacture of solid dispersions, such as fusion/melt technology, hot melt extrusion, solvent evaporation (i.e. freeze drying, spray drying or layering of powders of granules), coprecipitation, supercritical fluid technology and electrostatic spinning method.
  • compositions for its intended route of administration include:
  • acidifying agents include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid
  • alkalinizing agents include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine
  • adsorbents examples include but are not limited to powdered cellulose and activated charcoal
  • aerosol propellants examples include but are not limited to carbon dioxide, CCI2F2,
  • F 2 CIC-CCiF 2 and CCIF 3 air displacement agents
  • air displacement agents include but are not limited to nitrogen and argon
  • antifungal preservatives include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate
  • antimicrobial preservatives include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal
  • antioxidants include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisul
  • caramel and ferric oxide red examples include clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable
  • suspending agents examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum
  • sweetening agents examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose
  • tablet anti-adherents examples include but are not limited to magnesium stearate and talc
  • tablet binders examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-
  • tablet direct compression excipients examples include but are not limited to dibasic calcium phosphate
  • tablet disintegrants examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch
  • tablet glidants examples include but are not limited to colloidal silica, corn starch and talc
  • tablet lubricants examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate
  • tablet/capsule opaquants examples include but are not limited to titanium dioxide
  • tablet polishing agents examples include but are not limited to carnuba wax and
  • compositions according to the present invention including those which comprise one or more of:
  • Sterile IV Solution A 5 mg/mL solution of the desired compound of this invention, such as
  • the solution is diluted for administration to 1 — 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.
  • Lyophilized powder for IV administration A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention, such as
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 — 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention, preferably one or more of:
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, preferably one or more of
  • Soft Gelatin Capsules A mixture of active ingredient, preferably one or more of:
  • a digestible oil such as soybean oil, cottonseed oil or olive oil
  • a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
  • the capsules are washed and dried.
  • the active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, preferably one or more of: N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(4-cyanophenyl)-1 H- pyrazol-5-yl]urea,
  • aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient preferably one or more of:
  • the drug compounds such as one or more of:
  • the present invention relates to a method for using the compounds of the present invention, preferably
  • compositions thereof to treat mammalian hyper-proliferative disorders.
  • the compounds of this invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • the methods of this invention comprise administering to a mammal in need thereof, including a human, an amount of a compound of this invention, (Compounds of examples 1-82 or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc.) which is effective to treat the disorder.
  • Preferred embodiments of the methods of this invention comprise administering to a mammal in need thereof, including a human, one or of:
  • Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • BPH benign prostate hyperplasia
  • solid tumors such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small- cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, 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.
  • treating or “treatment” as stated throughout this discussed is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
  • the present invention also provides methods for the treatment of disorders associated with aberrant kinase activity (such as tyrosine kinase activity), including, but not limited Flk-1 (VEGFR2), Trk-A, c-MET, and/or AbI (such as Bcr-Abl), comprising administering an effective amount of a compound of the present invention.
  • disorders include cancers (such as those mentioned herein), disorders associated angiogenesis (see above), cell proliferation disorders, etc.
  • SF/HGF and/or c-MET over- expression and mutations have been found in many tumor types, including, e.g., carcinomas, sarcomas, hematopoitic cancers, and other neoplastic diseases (Table 1).
  • c-Met over-expression has been associated with the progression of the neoplastic disease.
  • the evaluation of Met levels/activity could itself be used in the identification of a subset of patients who may require an alternative treatment strategy (Cheng, H. et al., Journal of Clinical Oncology, 2002, 20, 1544-1550).
  • Trk-A expression and mutations have been reported in cancers, including, e.g., pancreatic, breast, ovarian, prostate carcinoma, papillary thyroid carcinoma, medullary thyroid carcinoma (including familial forms), and acute myeloid leukemia (AML), neuroblastoma, breast cancer, and prostate.
  • the only change leading to the transforming capacity of the TRK gene is the replacement of the extracellular domain of NTRK1 by sequences coding for the 221 amino-terminal residues of tropomyosin-3 (TPM3) (Coulier, F. et al., Molec. Cell. Biol., 1989, 9, 15-23).
  • TPM3 tropomyosin-3
  • TPM3 and NTRK1 genes Sequence rearrangements between the TPM3 and NTRK1 genes result in TRKA oncogenes and their gene products, which are associated with papillary thyroid carcinomas (Butti, M. et al., Genomics, 1995, 28, 15-24). Elevated activity or levels of Trk-A has been observed in primary tumors as well as metastatic tumors in patients with papillary thyroid carcinomas (Bongarzone, I. et al., Oncogene, 1989, 4, 1457-1462). Papillary thyroid carcinoma (PTC), the most frequent neoplasia originating from the thyroid epithelium, accounts for about 80% of all thyroid cancers.
  • PTC Papillary thyroid carcinoma
  • NTRK1 In human neuroblastoma, expression of NTRK1 is a good prognostic marker, most likely because Trk-A mediated signaling is important for growth arrest and/or differentiation of the neural crest derived cells from which these tumors originate (Brodeur, G. et al., J Pediatr. Hematol. Oncol., 1997, 19, 93-101). In both in vitro and in vivo it has been found that the product of the TRK protooncogene is sufficient to mediate signal transduction processes induced by nerve growth factor (NGF) and neurotrophin-3. TRK is expressed in monocytes, which suggests that NGF is an immunoregulatory cytokine acting on monocytes.
  • NGF nerve growth factor
  • Trk-A deletion constructs that had transforming potential have been screened in patients with acute myeloid leukemia (Reuther, G. et al., Molecular and Cellular Biology, 2000, 20, 8655-8666). Fusion products of Trk-C, a closely related homolog of Trk-A, have also been implicated in certain patients with AML (Eguchi, M. et al., Blood, 1999, 93, 1355- 63).
  • fusion product of Bcr and AbI has been observed with Chronic myeloid leukemia, aberrant translocation, Acute erythroleukemia (FAB type M6), Acute lymphoblastic leukemia/lymphoblastic lymphoma, Acute megakaryoblastic leukemia (FAB type M7), Acute myeloblasts leukemia with maturation (FAB type M2), Acute myeloblasts leukemia with minimal differentiation (FAB type MO), Acute myeloblasts leukemia without maturation (FAB type M1), Acute myeloid leukemia, NOS, Acute myelomonocytic leukemia (FAB type M4), Acute promyelocyte leukemia (FAB type M3),
  • one aspect of the instant invention is a method for treating cancer related to the elevated activity and/or levels of the above-identified genes and their gene-products.
  • Effective amounts of compounds of the present invention can be used to treat such disorders, including those diseases (e.g., cancer) mentioned in the Background section above. Nonetheless, such cancers and other diseases can be treated with compounds of the present invention, regardless of the mechanism of action and/or the relationship between the kinase and the disorder.
  • aberrant kinase activity or "aberrant tyrosine kinase activity,” includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not limited to, over-expression of the gene or polypeptide; gene amplification; mutations which produce constitutively-active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, etc.
  • the present invention also provides for methods of inhibiting a kinase activity, especially of Flk-1 , Trk-A, and/or c-MET, comprising administering an effective amount of a compound of the present invention (compounds of examples 1-82, including salts, polymorphs, metabolites, hyrates, solvates, prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof).
  • a compound of the present invention compounds of examples 1-82, including salts, polymorphs, metabolites, hyrates, solvates, prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.
  • Kinase activity can be inhibited in cells (e.g., in vitro), or in the cells of a mammalian subject, especially a human patient in need of treatment.
  • Compounds of the present invention can be used for any of the indications described in U.S. Pat. Nos.
  • the present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
  • Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
  • a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal- vein occlusion, and retinopathy of prematurity (Aiello et at. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci.
  • neovascular glaucoma neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
  • RA rheumatoid arthritis
  • restenosis in-stent restenosis
  • vascular graft restenosis etc.
  • the increased blood supply associated with cancerous and neoplastic tissue encourages growth, leading to rapid tumor enlargement and metastasis.
  • the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer.
  • compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
  • Compound and compositions of the present invention can be tested routinely for angiogenic activity, e.g., by contacting a blood vessel-forming cell population with a compound of the present invention, and determining the effect of the compound on blood vessel formation. Any cell population capable of forming blood vessels can be utilized.
  • Useful models include, e.g., in vivo Matrigel-type assays; tumor neovascularization assays; CAM assays; BCE assays; cell migration assays; HUVEC growth inhibition assays; animal models (e.g., tumor growth in athymic mice, chronically ischemic lower limb in a rabbit model, cancer models, etc.); in vivo systems, such as a heart or limb present in a patient (e.g., angiogenic therapy to treat myocardial infarction); hosts in need of treatment, e.g., hosts suffering from angiogenesis related diseases, such as cancer, ischemic syndromes, arterial obstructive disease, to promote collateral circulation, to promote vessel growth into bioengineered tissues, etc.
  • angiogenesis related diseases such as cancer, ischemic syndromes, arterial obstructive disease, to promote collateral circulation, to promote vessel growth into bioengineered tissues, etc.
  • Cells can include, e.g., endothelial, epithelial, muscle, embryonic and adult stem cells, ectodermal, mesenchymal, endodermal, neoplastic, blood, bovine CPAE (CCL-209), bovine FBHE (CRL-1395), human HUV-EC-C (CRL-1730), mouse SVEC4-10EHR1 (CRL-2161), mouse MS1 (CRL-2279), mouse MS1 VEGF (CRL-2460), stem cells, etc.
  • the phrase "capable of forming blood vessels" does not indicate a particular cell-type, but simply that the cells in the population are able under appropriate conditions to form blood vessels. In some circumstances, the population may be heterogeneous, comprising more than one cell-type, only some which actually differentiate into blood vessels, but others which are necessary to initiate, maintain, etc., the process of vessel formation.
  • a useful model to determine the effect of compounds or compositions on angiogenesis is based on the observation that, when a reconstituted basement membrane matrix, such as Matrigel, supplemented with growth factor (e.g., FGF-1), is injected subcutaneously into a host animal, endothelial cells are recruited into the matrix, forming new blood vessels over a period of several days. See, e.g., Passaniti et al., Lab. Invest., 67:519-528, 1992.
  • the growth factor can be bound to heparin or another stabilizing agent.
  • the matrix can also be periodically re-infused with growth factor to enhance and extend the angiogenic process.
  • a Matrigel plug implant comprising FGF-1 can be implanted subcutaneously into a host mouse.
  • the initial bolus of FGF attracts endothelial cells into the implant, but does not result in new blood vessel formation.
  • the implant can be re-infused with FGF-1.
  • the FGF- 1 stimulates the endothelial cells already present in the implant, initiating the process of angiogenesis.
  • neovascularization of tumor explants e.g., U.S. Pat. Nos. 5,192,744; 6,024,688
  • CAM chicken chorioallantoic membrane
  • BCE bovine capillary endothelial
  • HUVEC human umbilical cord vascular endothelial cell growth inhibition assay
  • a cell population can be contacted with the compound or composition in any manner and under any conditions suitable for it to exert an effect on the cells.
  • the means by which compound is delivered to the cells may depend upon the type of test agent, e.g., its chemical nature, and the nature of the eel! population. Generally, a compound must have access to the cell population, so it must be delivered in a form (or pro-form) that the population can experience physiologically, i.e., to put in contact with the cells.
  • the intent is for the agent to enter the cell, if necessary, it can be associated with any means that facilitate or enhance cell penetrance, e.g., associated with antibodies or other reagents specific for cell-surface antigens, liposomes, lipids, chelating agents, targeting moieties, etc.
  • Cells can also be treated, manipulated, etc., to enhance delivery, e.g., by electroporation, pressure variation, etc.
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg 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 for administration by injection 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 dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 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.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention can be combined with known anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • the additional pharmaceutical agent can be aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid,
  • Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ.
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
  • cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:
  • u Combination means for the purposes of the invention not only a dosage form which contains all the components (so-called fixed combinations), and combination packs containing the components separate from one another, but also components which are administered simultaneously or sequentially, as long as they are employed for the prophylaxis or treatment of the same disease.
  • the active ingredients of the combination according to the invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations. Examples are tablets, coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, solutions.
  • the combination according to the invention is well tolerated and in some cases is effective even in low dosages, a wide range of formulation variants is possible.
  • one possibility is to formulate the individual active ingredients of the combination according to the invention separately. In this case, it is not absolutely necessary for the individual active ingredients to be taken at the same time; on the contrary, sequential intake may be advantageous to achieve optimal effects.
  • the active ingredients are present in the primary packaging in each case in separate containers which may be, for example, tubes, bottles or blister packs.
  • Such separate packaging of the components in the joint primary packaging is also referred to as a kit.
  • compositions which are suitable and preferred for the combination according to the invention are also fixed combinations.
  • "Fixed combination” is intended here to mean pharmaceutical forms in which the components are present together in a fixed ratio of amounts.
  • Such fixed combinations may be, for example, in the form of oral solutions, but they are preferably solid oral pharmaceutical preparations, e.g. capsules or tablets.
  • Celite ® brand of diatomaceous earth filtering agent registered trademark of Celite Corporation d doublet dd doublet of doublet ddd doublet of doublet of doublet
  • Electron impact mass spectra (El-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 ⁇ M coating; 30 m x 0.25 mm). The ion source was maintained at 250 0 C and spectra were scanned from 50-800 amu at 2 sec per scan.
  • High pressure liquid chrornatography-electrospray mass spectra were obtained using either a: a) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA 1 and B: 2% water in acetonitrile with 0.018% TFA.
  • ELSD Electrode ugw Scattering Detector
  • the eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% to 90% B over 3.5 minutes at a flow rate of 1.5 mL/min was used with an initial hold of 0.5 minutes and a final hold at 90% B of 0.5 minutes. Total run time was 4.8 minutes. An extra switching valve was used for column switching and regeneration.
  • Agilent 1100 HPLC system Agilent 1100 HPLC system.
  • the Agilent 1100 HPLC system was equipped with an Agilent 1100 autosampler, quaternary pump, and a diode array.
  • the HPLC column used was a Waters Sunfire (2.1 x 30 mm, 3.5 uM).
  • the HPLC eluent was directly coupled with a 1 :4 split to a Finnigan LTQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 50-1000 amu using a variable ion time according to the number of ions in the source in either positive or negative ion mode.
  • the eluents were A: water with 0.1 Formic acid and B: aceto ⁇ itrile with 0.1% Formic acid. Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutes and a final hold at 95% B of 1.0 minutes. Total run time was 8.0 minutes.
  • Routine one-dimensional NMR spectroscopy was performed on 300/400 MHz Varian Mercury-plus spectrometers. The samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs, and transferred to 5mm ID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemical shifts were recorded on the ppm scale and were referenced to the appropriate solvent signals, such as 2.05 ppm for acetone-de, 2.49 ppm for DMSOd 6 , 1-93 ppm for CD 3 CN, 3.30 ppm for CD 3 OD, 5.32 ppm for CD2CI2 and 7.26 ppm for CDCI 3 for 1 H spectra.
  • Preparative HPLC was carried out in reversed phase mode, eluting with aqueous acetonitrile containing 0.5% TFA, typically 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 x 150 mm, 120 A). Gradient elution was used with Buffer A as water with 0.1% TFA and Buffer B as acetonitrile with 0.1 % TFA. Sample was dissolved in MeOH or MeOH/DMSO with concentration about 50 mg/mL. Injection volume was about 2-3 mL/injection.
  • Sample was typically eluted as follows: 10-90% B over 15 minutes with flow rate of 25 mL/min, hold 2 minutes, back to 10% B.
  • the desired fraction(s) were collected by UV monitoring at 254 or 220 nm and evaporated by using a GeneVac centrifugal vacuum instrument.
  • MPLC medium pressure liquid chromatography
  • Step 1 Preparation of ⁇ Benzhydrylidene-/V -(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1 > 4]- dioxin-6-yl)hydrazine
  • Step 2 Preparation of 5-fe/f-Butyl-2-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1 ,4]dioxin-6- yl)-2H-pyrazol-3-ylamine
  • the title compound was prepared in the same manner as described for 5-tert- butyl-2-(4-fluoro-phenyl)-2/-/-pyrazol-3-ylamine, replacing 4-fluorophenylhydrazine with ethyl (4-hydrazinophenyl)acetate hydrochloride (11.98 g, 51.9 mmol).
  • the title compound was obtained as a solid (HCI salt, 11.95 g) in 68% yield.
  • the reaction flask was charged with water (200 ml_) and potassium hydroxide (35.83 g, 638.68 mmol) and cooled to 5° C.
  • potassium hydroxide 35.83 g, 638.68 mmol
  • Step 1 Preparation of 1-[5-tert-butyl-2(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3- ⁇ 4-[2-(2,5- dimethyl-pyrrol-1-yl)-pyridin-4-yloxy]-phenyl ⁇ -urea
  • Step 2 Preparation of 1- ⁇ 4-(2-amino-pyridin-4-yloxy)-phenyl]-3-[5-te/t-butyl-2-(4-fluoro- phenyl)-2H-pyrazol-3-yl]-urea
  • Step 1 To a suspension of 5-te/t-butyl-2-(4-cyclobutoxy-phenyl)-2H-pyrazol-3-ylamine (Intermediate 11 , 1.05 g, 3.66 mmol) and potassium carbonate (2.02 g, 14.63 mmol) in THF (10 ml_) was added phenyl chloroformate (1.89 g, 12.07 mmol). The reaction was stirred at room temperature under nitrogen for 18 h. The mixture was then diluted with EtOAc, washed successively with NaHC ⁇ 3 (saturated aqueous solution) and brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • DCM/MeOH 99/1-95/5
  • Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the activity of the compounds of the present invention, the following assays may be used.
  • This assay was performed in 96-well opaque plates (Costar 3915) in the TR- FRET format. Reaction conditions are as follows: 10 ⁇ M ATP 1 25 nM poly GT-biotin, 2 nM Eu-labelled phospho-Tyr Ab (PY20 Perkin Elmer), 10 nM APC (Perkin Elmer), 7 nM Flk-1 (kinase domain), 1% DMSO, 50 mM HEPES pH 7.5, 10 mM MgCI 2 , 0.1 mM EDTA, 0.015% BRIJ, 0.1 mg/mL BSA, 0.1 % ⁇ -mercaptoethanol). Reaction is initiated upon addition of enzyme. Final reaction volume in each well is 100 ⁇ l_.
  • Plates are read at both 615 and 665 nM on a Perkin Elmer Victor V Multilabel counter at about 1.5- 2.0 hours after reaction initiation. Signal is calculated as a ratio: (665 nm / 615 nm) * 10000 for each well.
  • This assay uses the N-terminal HiS-tagged intracellular kinase domain of human recombinant Trk-A in 96-well plates. This involves a biotinylated-poly-GluTyr substrate and an Eu-labelled anti-phosphotyrosine antibody for detection of kinase activity in a homogeneous time-resolved FRET format.
  • the Trk-A biochemical FRET assay protocol is as follows: 10 mM stock solution of test compounds are diluted to 1 mM in 100% DMSO. These stocks are diluted with 100% DMSO by a factor of 5, in a total of 7 steps to create an 8-point IC 50 curve. The diluted compounds are combined 1 :4 with distilled water to form the 25x dilution plate for the assay.
  • a 2 ⁇ l_ aliquot of compound from the 25x dilution plate is added with 23 ⁇ l_ of assay buffer (50 mM HEPES pH 7.0, 5 mM MnCI 2 , 0.1% BSA, 0.5 mM vanadate, 0.1% ⁇ -mercaptoethanol) into a 96-well, half volume opaque (black) plate (Costar #3694).
  • ATP is added to all wells except the negative controls (5 microliters of 40 ⁇ M).
  • Five microliters of 2.2 ⁇ g/mL poly(GluTyr)-biotin (CIS US # 61 GTOBLB) and 15 ⁇ L of 6.66 nM Trk-A diluted in assay buffer are added to the plate to start the reaction.
  • the assay is stopped with addition of 5 ⁇ L of 0.5M EDTA.
  • 25 ⁇ L each of 340 ng/mL PY20 cryptate antibody (CIS US #61Y20KLA) and 40 nM streptavidin labelled APC (SA-XL - CIS US # 611 SAXLB) are added in development buffer (50 mM HEPES pH7.0, 0.8M KF, 0.1 % BSA).
  • development buffer 50 mM HEPES pH7.0, 0.8M KF, 0.1 % BSA.
  • the assay plate sits at room temperature for at least one hour, then is read on a Perkin Elmer Victor 2 instrument at 615 and 665 nM emission. A ratio of these two numbers is used in the calculations of the data.
  • the cMET LANCE assay is run in a 96-well black plate (Costar #3694) in a 60 ⁇ l volume.
  • the assay buffer contains 5OmM Hepes pH 7.3, 5mM MnCI 2 , 0.1 mM EDTA, 0.015% Brij-35, 0.01% BSA, and 5mM B-ME.
  • Assay buffer and compound are added to the plate.
  • Compound final concentration ranges from 10 ⁇ M to 128 pM in an 8-point IC 5 O curve.
  • Final DMSO concentration is 1%.
  • cMET is added to a final concentration of 160 pM.
  • Abl-T315l Kinase Filtermat Assay Inhibition of Abl-T315l kinase phosphorylation of myelin basic protein by compounds in a 33 P-ATP Filtermat Assay.
  • MBP Myelin Basic Protein
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1 -(4- methylphenyl)-1 H-pyrazol-5-yl]urea showed IC50 ⁇ 10 ⁇ M in one or more of the biochemical assays discussed above.
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-f Iuorophenyl ⁇ -N"-[1 -(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea showed IC 50 ⁇ 10 ⁇ M in one or more of the biochemical assays discussed above.
  • the cells are plated in full growth media (10,000 cells/well) in 96-well plates on day one.
  • MSD MSD recommended lysis buffer
  • non-specific antibody-binding sites on the MSD phospho-Met plates are blocked with MSD Blocking Solution A overnight at 4 0 C.
  • the adherent tumor cell proliferation assay used to test the compounds of the present invention involves a readout called Cell Titre-Glo developed by Promega (Cunningham, BA "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth” The Scientist 2001 , 15(13), 26, and Crouch, SP et al., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity” Journal of Immunological Methods 1993, 160, 81-88).
  • H460 cells lung carcinoma, purchased from ATCC
  • H460 cells are plated in 96-well plates at 3000 cells/well in complete media with 10% Fetal Calf Serum and incubated 24 hours at 37 0 C.
  • test compounds are added over a final concentration range of 10 nM to 20 ⁇ M in serial dilutions at a final DMSO concentration of 0.2 %.
  • Cells are incubated for 72 hours at 37 0 C in complete growth media after addition of the test compound.
  • On day 4 using a Promega Cell Titer GIo Luminescent ® assay kit, the cells are lysed and 100 microliters of substrate/buffer mixture is added to each well, mixed and incubated at room temperature for 8 minutes.
  • the samples are read on a luminometer to measure the amount of ATP present in the cell lysates from each well, which corresponds to the number of viable cells in that well. Values read at 24-hour incubation are subtracted as Day 0.
  • a linear regression analysis can be used to determine drug concentration which results in a 50% inhibition of cell proliferation using this assay format. This protocol was applied to different cell lines of interest, which include, but not limited to, CAKI-1, MNK45, GTL-16, HCC2998, K562, H441 , K812, MEG01, SUP15 and HCT116.
  • Compounds of this invention showed antiproliferative properties (IC 50 ⁇ 10 ⁇ M) in one or more cell lines of interest.
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (4-methylphenyl)-1H-pyrazol-5-yl]urea showed antiproliferative properties (IC 50 ⁇ 10 ⁇ M) in one or more cell lines of interest.
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[1-(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea showed antiproliferative properties (IC50 ⁇ 10 ⁇ M) in one or more cell lines of interest.
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (3-methoxyphenyl)-1H-pyrazol-5-yl]urea showed antiproliferative properties (IC 50 ⁇ 10 ⁇ M) in one or more cell lines of interest.
  • An additional cell proliferation assay used to test the compounds of the present invention involves a readout called Cell Titre-Glo developed by Promega (Cunningham, BA "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth” The Scientist 2001 , 15(13), 26, and Crouch, SP et a!., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity” Journal of Immunological Methods 1993, 160, 81-88).
  • IL-3-independent BaF3 cells overexpressing the tpr-met oncogene (Cooper, CS. , et al., "Molecular cloning of a new transforming gene from a chemically- transformed human cell line” Nature (London) 1984, 311 , 29-33) are plated in 384-well plates at 1667 cells/well in complete RPMI media with 10% Fetal Bovine Serum and 1 mg/ml G418. Immediately after plating, test compounds are added over a final concentration range of 10 ⁇ M to 128 pM in serial dilutions at a final DMSO concentration of 0.1%. Cells are incubated for 72 hours at 37 0 C in complete growth media after addition of the test compound.

Abstract

Pyrazole urea compounds, pharmaceutical compositions which contain them and methods for treating cancer using them.

Description

PYRAZOLYL UREA DERIVATIVES USEFUL IN THE TREATMENT OF CANCER
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier-filed U.S. Provisional Application Ser. No. 60/736,400, filed November 15, 2005, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
This invention relates to novel compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper- proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients, e.g., cytotoxic therapies.
BACKGROUND OF THE INVENTION
To support progressive tumor growth beyond the size of 1-2 mm3, it is recognized that tumor cells require a functional stroma, a support structure consisting of fibroblast, smooth muscle cells, endothelial cells, extracellular matrix proteins, and soluble factors (Folkman, J., Semin Oncol, 2002. 29(6 Suppl 16), 15-8). Tumors induce the formation of stromal tissues through the secretion of soluble growth factors such as PDGF and transforming growth factor-beta (TGF-beta), which in turn stimulate the secretion of complimentary factors by host cells such as fibroblast growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF). These stimulatory factors induce the formation of new blood vessels, or angiogenesis, which brings oxygen and nutrients to the tumor and allows it to grow and provides a route for metastasis. It is believed some therapies directed at inhibiting stroma formation will inhibit the growth of epithelial tumors from a wide variety of histological types. (George, D. Semin Oncol, 2001. 28(5 Suppl 17), 27-33; Shaheen, R.M., et al., Cancer Res, 2001. 61 (4), 1464-8; Shaheen, R.M., et al. Cancer Res, 1999. 59(21), 5412-6). However, because of the complex nature and the multiple growth factors involved in angiogenesis process and tumor progression, an agent targeting a single pathway may have limited efficacy. It is desirable to provide treatment against a number of key signaling pathways utilized by tumors to induce angiogenesis in the host stroma. These include, for example, PDGF, a potent stimulator of stroma formation (Ostman, A. and CH. Heldin, Adv Cancer Res, 2001, 80, 1-38), FGF, a chemo-attractant and mitogen for fibroblasts and endothelial cells, and VEGF, a potent regulator of vascularization. HGF (hepatocyte growth factor) represents an additional signaling growth factor of interest.
PDGF is a key regulator of stromal formation, which is secreted by many tumors in a paracrine fashion and is believed to promote the growth of fibroblasts, smooth muscle and endothelial cells, promoting stroma formation and angiogenesis. PDGF was originally identified as the v-sis oncogene product of the simian sarcoma virus (Heldin, C. H., et al., J Ce// Sci Suppl, 1985, 3, 65-76). The growth factor is made up of two peptide chains, referred to as A or B chains which share 60% homology in their primary amino acid sequence. The chains are disulfide cross linked to form the 30 kDa mature protein composed of either AA, BB or AB homo- or heterodimmers. PDGF is found at high levels in platelets, and is expressed by endothelial cells and vascular smooth muscle cells. In addition, the production of PDGF is up regulated under low oxygen conditions such as those found in poorly vascularized tumor tissue (Kourembanas, S., et al., Kidney Int, 1997, 51(2), 438-43). PDGF binds with high affinity to the PDGF receptor, a 1106 amino acid 124 kDa transmembrane tyrosine kinase receptor (Heldin, C. H., A. Ostman, and L. Ronnstrand, Biochim Biophys Acta, 1998. 1378(1), 79-113). PDGFR is found as homo- or heterodimer chains which have 30% homology overall in their amino acid sequence and 64% homology between their kinase domains (Heldin, C. H., et al.. Embo J, 1988, 7(5), 1387-93). PDGFR is a member of a family of tyrosine kinase receptors with split kinase domains that includes VEGFR2 (KDR), VEGFR3 (Flt4), c-Kit, and FLT3. The PDGF receptor is expressed primarily on fibroblast, smooth muscle cells, and pericytes and to a lesser extent on neurons, kidney mesangial, Leydig, and Schwann cells of the central nervous system. Upon binding to the receptor, PDGF induces receptor dimerization and undergoes auto- and trans-phosphorylation of tyrosine residues which increase the receptors' kinase activity and promotes the recruitment of downstream effectors through the activation of SH2 protein binding domains. A number of signaling molecules form complexes with activated PDGFR including PI-3-kinase, phospholipase C-gamma, src and GAP (GTPase activating protein for p21-ras) (Soskic, V., et al. Biochemistry, 1999, 38(6), 1757-64). Through the activation of PI-3-kinase, PDGF activates the Rho signaling pathway inducing cell motility and migration, and through the activation of GAP, induces mitogenesis through the activation of p21-ras and the MAPK signaling pathway.
In adults, it is believed the major function of PDGF is to facilitate and increase the rate of wound healing and to maintain blood vessel homeostasis (Baker, E.A. and D.J. Leaper, Wound Repair Regen, 2000. 8(5), 392-8; Yu1 J., A. Moon, and H. R. Kim, Biochem Biophys Res Commun, 2001. 282(3), 697-700). PDGF is found at high concentrations in platelets and is a potent chemoattractant for fibroblast, smooth muscle cells, neutrophils and macrophages. In addition to its role in wound healing PDGF is known to help maintain vascular homeostasis. During the development of new blood vessels, PDGF recruits pericytes and smooth muscle cells that are needed for the structural integrity of the vessels. PDGF is thought to play a similar role during tumor neovascularization. As part of its role in angiogenesis PDGF controls interstitial fluid pressure, regulating the permeability of vessels through its regulation of the interaction between connective tissue cells and the extracellular matrix. Inhibiting PDGFR activity can lower interstitial pressure and facilitate the influx of cytotoxics into tumors improving the anti-tumor efficacy of these agents (Pietras, K., et al. Cancer Res, 2002. 62(19), 5476-84; Pietras, K., et al. Cancer Res, 2001. 61(7), 2929-34).
PDGF can promote tumor growth through either the paracrine or autocrine stimulation of PDGFR receptors on stromal cells or tumor ceils directly, or through the amplification of the receptor or activation of the receptor by recombination. Over expressed PDGF can transform human melanoma cells and keratinocytes (Forsberg, K., et al. Proc Natl Acad Sci U S A., 1993. 90(2), 393-7; Skobe, M. and N.E. Fusenig, Proc Natl Acad Sci U S A, 1998. 95(3), 1050-5), two cell types that do not express PDGF receptors, presumably by the direct effect of PDGF on stroma formation and induction of angiogenesis. This paracrine stimulation of tumor stroma is also observed in carcinomas of the colon, lung, breast, and prostate (Bhardwaj, B., et al. Clin Cancer Res, 1996, 2(4), 773-82; Nakanishi, K., et al. Mod Pathol, 1997, 10(4), 341-7; Sundberg, C, et al. Am J Pathol, 1997, 151(2), 479-92; Lindmark, G., et al. Lab Invest, 1993, 69(6), 682-9; Vignaud, J. M., et al, Cancer Res, 1994, 54(20), 5455-63) where the tumors express PDGF, but not the receptor. The autocrine stimulation of tumor cell growth, where a large faction of tumors analyzed express both the ligand PDGF and the receptor, has been reported in glioblastomas (Fleming, T. P., et al. Cancer Res, 1992, 52(16), 4550-3), soft tissue sarcomas (Wang, J., M. D. Coltrera, and A.M. Gown, Cancer Res, 1994, 54(2), 560-4) and cancers of the ovary (Henriksen, R., et al. Cancer Res,
1993, 53(19), 4550-4), prostate (Fudge, K., CY. Wang, and M. E. Stearns, Mod Pathol,
1994, 7(5), 549-54), pancreas (Funa, K., et al. Cancer Res, 1990, 50(3), 748-53) and lung (Antoniades, H.N., et al., Proc Natl Acad Sci U S A, 1992, 89(9), 3942-6). Ligand independent activation of the receptor is found to a lesser extent but has been reported in chronic myelomonocytic leukemia (CMML) where the a chromosomal translocation event forms a fusion protein between the Ets-like transcription factor TEL and the PDGF receptor. In addition, activating mutations in PDGFR have been found in gastrointestinal stromal tumors in which c-Kit activation is not involved (Heinrich, M. C, et al., Science, 2003, 9, 9).
Certain PDGFR inhibitors will interfere with tumor stromal development and are believed to inhibit tumor growth and metastasis.
Another major regulator of angiogenesis and vasculogenesis in both embryonic development and some angiogenic-dependent diseases is vascular endothelial growth factor (VEGF; also called vascular permeability factor, VPF). VEGF represents a family of isoforms of mitogens existing in homodimeric forms due to alternative RNA splicing. The VEGF isoforms are reported to be highly specific for vascular endothelial cells (for reviews, see: Farrara et al. Endocr. Rev. 1992, 13, 18; Neufield et al. FASEB J. 1999, 13, 9).
VEGF expression is reported to be induced by hypoxia (Shweiki et al. Nature 1992, 359, 843), as well as by a variety of cytokines and growth factors, such as interleukin-1 , interleukin-6, epidermal growth factor and transforming growth factor. To date, VEGF and the VEGF family members have been reported to bind to one or more 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)), VEGFR-2 (also known as kinase insert domain containing receptor (KDR); the murine analogue of KDR is known as fetal liver kinase-1 (flk-1)), and VEGFR-3 (also known as flt-4). KDR and flt-1 have been shown to have different signal transduction properties (Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et al. Oncogene 1995, 10, 135). Thus, KDR undergoes strong ligand-dependant tyrosine phosphorylation in intact cells, whereas flt-1 displays a weak response. Thus, binding to KDR is believed to be a critical requirement for induction of the full spectrum of VEGF-mediated biological responses.
In vivo, VEGF plays a central role in vasculogenesis, and induces angiogenesis and permeabilization of blood vessels. Deregulated VEGF expression contributes to the development of a number of diseases that are characterized by abnormal angiogenesis and/or hyperpermeability processes. It is believed regulation of the VEGF-mediated signal transduction cascade by some agents can provide a useful mode for control of abnormal angiogenesis and/or hyperpermeability processes.
The vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and their receptors (VEGFR2, VEGFR3) are not only key regulators of tumor angiogenesis, but also lymphangiogenesis. VEGF, VEGF-C and VEGF-D are expressed in most tumors, primarily during periods of tumor growth and, often at substantially increased levels. VEGF expression is stimulated by hypoxia, cytokines, oncogenes such as ras, or by inactivation of tumor suppressor genes (McMahon, G. Oncologist 2000, 5(Suppl. 1), 3- 10; McDonald, N. Q.; Hendrickson, W.A. Ce// 1993, 73, 421-424)
The biological activities of the VEGFs are mediated through binding to their receptors. It is believed VEGFR3 (also called Flt-4) is predominantly expressed on lymphatic endothelium in normal adult tissues and that VEGFR3 function is needed for new lymphatic vessel formation, but not for maintenance of the pre-existing lymphatics. VEGFR3 is also upregulated on blood vessel endothelium in tumors. Recently VEGF-C and VEGF-D, ligands for VEGFR3, have been identified as regulators of lymphangiogenesis in mammals. Lymphangiogenesis induced by tumor-associated lymphangiogenic factors could promote the growth of new vessels into the tumor, providing tumor cells access to systemic circulation. Cells that invade the lymphatics could find their way into the bloodstream via the thoracic duct. Tumor expression studies have allowed a direct comparison of VEGF-C, VEGF-D and VEGFR3 expression with clinicopathological factors that relate directly to the ability of primary tumors to spread (e.g., lymph node involvement, lymphatic invasion, secondary metastases, and disease-free survival). In many instances, these studies demonstrate a statistical correlation between the expression of lymphangiogenic factors and the ability of a primary solid tumor to metastasize (Skobe, M. et al. Nature Med. 2001, 7(2), 192- 198; Stacker, S.A. et al.. Nature Med. 2001 , 7(2), 186-191 ; Makinen, T. et al. Nature Med. 2001 , 7(2), 199-205; Mandriota, S.J. 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 its involvement in angiogenesis through regulation of VEGF secretion, p38 MAP kinase promotes malignant cell invasion, and migration of different tumor types through regulation of collagenase activity and urokinase plasminogen activator expression (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).
The receptor tyrosine kinase Trk-A is another target of interest for the preparation of medicines directed at the treatment and prevention of cancer. TrkA is the high affinity receptor of the nerve growth factor (NGF). The expression of TrkA and NGF in tumors is believed to be implicated in the proliferation and metastasis of tumors such as pancreatic, prostate and also breast, as well as in angiogenesis. TrkA expression is reported in pancreatic, breast, ovarian, and prostate tumors. Recent studies demonstrate that human prostate and pancreatic tumor cells can secrete NGF, which, along with its receptor, TrkA, creates an autocrine loop that promotes the growth and survival of these tumor cells (Ruggeri, B. A. et al, Curr. Med. Chem. 1999, 6:845-857; Weeraratna, A.T. et al., The Prostate 2000, 45:140-148). Inhibition of the NGF-T rkA. signaling pathway by small molecule TrkA inhibitors (Miknyoczki, SJ. et al., Clin. Cancer Res. 1999, 5: 2205-2212; George, D.J. et al., Cancer Res. 1999, 59: 2395- 2401 ; Weeraratna, AT. et al, Clin. Cancer Res. 2001 , 7: 2237-2245) and anti-NGF antibodies (Miknyoczki, S.J. et al., Clin. Cancer Res. 2002, 8:1924-1931) has been postulated to inhibit not only growth, but also metastasis of neuroendocrine tumors in xenograft models. In addition, NGF has been shown to induce proliferation of endothelial cells (Cantarella, G. et al., FASEB J. 2002, 16:1307). These cells, which form new vascular networks to feed the growing tumor, also express VEGFR2 tyrosine kinase receptors. Activation of these receptors by their ligands leads to endothelial cell proliferation, migration, and vessel formation and stabilization (Albo, D. et al., Curr. Pharm. Des. 2004, 10:27-37; Thurston, G., Cell Tissue Res. 2003, 31 :61-68).
The proto-oncoogene c-Met, a member of the receptor tyrosine kinase family, encodes a heterodimeric complex consisting of a 140-kDa membrane-spanning Dchain and a 50-kDa extracellular O chain. This heterodimeric complex acts as a high-affinity receptor for hepatocyte growth factor (HGF) or scatter factor (SF). c-Met/HGF signaling is required for normal mammalian development and has been shown to be particularly important in cell growth, migration, morphogenic differentiation, and organization of three-dimensional tubular structures (e.g. renal tubular cells, gland formation, etc.). c- Met and HGF are widely expressed in a variety of tissues, and their expression is normally confined to cells of epithelial and mesenchymal origin, respectively. There are now several lines of compelling evidence that HGF/c-Met signaling has an important role in the development and malignant progression of tumors of various histological types. Cell lines that ectopically overexpress c-Met or HGF become tumorigenic and metastatic in nude mice, whereas c-Met downregulation decreases their tumorigenic potential. HGF-dependent autocrine loops are found associated with osteosarcomas, rhabdomyosarcomas and breast carcinomas (Trusolino and Comoglio, Nat Rev Cancer, 2002, 2, 289-300). c-Met or HGF transgenic mice develop metastatic tumors (Wang, R. et al., J. Cell Biol. 2001 , 153, 1023-1034; Takayama et al., Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 701-706). Over-expression of c-Met expression has been found in many kinds of solid tumors and correlates with poor prognosis (Birchmeier, et al. MoI. Cell Biol., 2003, 4, 915-925; Christensen, J. and Salgia, R., Can Lett, 2005, 225, 1-26). The unequivocal evidence linking c-Met and human cancer comes from the identification of germline activating mutations in patients suffering from hereditary papillary renal carcinomas (Dharmawardana, et al., Curr. MoI. Med., 2004, 4, 855-868). Finally, amplification of the c-Met gene was observed in many gastric tumors (Ponzetto, C. et al., Oncogene. 1991 , 6, 553-9).
Due to a strong link between c-Met/HGF signaling pathway and tumorigenesis and tumor progression, several therapeutic approaches have been taken by various groups. HGF/SF-neutralizing antibodies (Cao et al., Proc Natl Acad Sci USA 2001, 98, 7443-8), c-Met antisense oligonucleotides (Kitamura et al., Br J Cancer 2000, 83: 668- 73), dominant-negative forms of the Met protein (Firon et al., Oncogene 2000, 19, 2386- 97; Furge et al., Proc Natl Acad Sci USA 2001 , 98, 10722-7), ribozymes that target Met mRNA (Abounader et al., J Natl Cancer Inst, 1999, 91, 1548-56; Abounader et al., FASEB J 2002, 16, 108 -10), and small molecule c-Met tyrosine kinase inhibitor (Christensen et al., Cancer Res 2003, 63, 7345-55) are being investigated as possible strategies to block c-Met activation and suppress tumor growth, invasion, and metastasis. Identification of a potent inhibitor of c-Met kinase activity therefore has the great potential to inhibit tumor growth of various cancers types.
Chronic myelogenous leukemia (CML) is caused by the oncogenic protein, Bcr- AbI (Groffen, J. et al., J Cell Physiol Suppl, 1984, 3, 179-191 , Sattler, M. and Griffin, J. D., Semin Hematol, 2003, 40, 4-10). The Philadelphia chromosome, which is the hallmark of CML, is formed in CML patients due to a reciprocal translocation between chromosomes 9 and 22 (Rowley, J. D., Nature, 1973, 243, 290-293), and this translocation results in the formation of Bcr-Abl fusion protein (Groffen, J. and Heisterkamp, N., Baitlieres Clin Haematol, 1987, 1 , 983-999). AbI protein is a nonreceptor tyrosine kinase whose activity is tightly regulated in the normal cells. However, the fusion protein is coπstitutively activated due to the presence of Bcr protein at the N- terminus. The constitutively active protein transforms at the myeloid the blast cell stage thus giving rise to CML (Kelliher, M. A., et al., Proc Natl Acad Sci U S A, 1990, 87, 6649-6653). Depending on the exact breakpoints at the chromosomes involved in the translocation, the size of the fusion protein varies from 185 to 230 kDa, although 210 kDa protein being the most commoon in CML.
Development of lmanitib as an inhibitor of Bcr-Abl protein to treat the CML patients has pioneered the field of targeted therapy in oncology (Capdeville, R., et al., Nat Rev Drug Discov, 2002, 1 , 493-502). Patients with early phase CML were found to respond to a degree of greater than 90% at both haematological and cytogenetic levels (Deininger, M. et al., Blood, 2005, 105, 2640-2653, Talpaz, M. et al., Blood, 2002, 99, 1928-1937). However, most patients after a prolonged treatment develop resistance to lmanitib (Gorre, M. E. and Sawyers, C. L., Curr Opin Hematol, 2002, 9, 303-307). To date, more than 30 lmanitib resistant mutations have been observed in patients and most of these mutations are confined to a sub-domain within the kinase region of the fusion protein. Importantly, three mutations namely T315I, E255K and M351T represent more than 50% of the lmanitib resistance (Deininger, M., Buchdunger, E. and Druker, B. J., Blood, 2005, 105, 2640-2653).
Recently, there has been much effort in the field of oncology to overcome the lmanitib resistance in CML patients. For example, BMS-354825 has been reported to be an inhibitor of Bcr-Abl and also Src family kinases. Among the 15 Imanitib- resistance mutations tested in cell based assays, BMS-354825 was reported to inhibit all the mutant forms of the protein except T315I (Shah, N. P., et al., Science, 2004, 305, 399-401). The compound AMN-107 has been reported to inhibit Bcr-Abl kinase activity with 20-fold greater potency than Imatinib. AMN-107 was reported to inhibit most lmanitib resistant mutations except for T315I. AMN-107 also shows weaker inhibition in a biochemical assay against E255K mutant (IC50 of 40OnM) (Weisberg, E., et al., Cancer Cell, 2005, 7, 129-141). Therefore, there is a significant unmet medical need for new therapeutics to treat CML and Imatinib-resistant CML. Certain diarylureas have been described as having activity as serine-threonine kinase and/or as tyrosine kinase inhibitors. The utility of these diarylureas as an active ingredient in pharmaceutical compositions for the treatment of cancer, angiogenesis disorders, and inflammatory disorders has been demonstrated. See Redman et al., Bioorg. Med. Chem. Lett. 2001 , 11, 9-12; Smith et al., Bioorg. Med. Chem. Lett. 2001 , 11, 2775-2778; Dumas et al., Bioorg. Med. Chem. Lett. 2000, 10, 2047-2050; Dumas et al., Bioorg. Med. Chem. Lett. 2000, 10, 2051-2054; Ranges et al., Book of Abstracts, 220th ACS National Meeting, Washington, DC, USA, MEDI 149; Dumas et al., Bioorg. Med. Chem. Lett. 2002, 12, 1559-1562; Lowinger et al., Clin. Cancer Res. 2000, 6(suppl.), 335; Lyons et al., Endocr.-Relat. Cancer 2001, 8, 219-225; Riedl et al., Book of Abstracts, 92nd AACR Meeting, New Orleans, LA, USA, abstract 4956; Khire et al., Book of Abstracts, 93d 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"0AACR Meeting, New Orleans, LA, USA, abstract 4954; Vincent et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, abstract 1900; Hilger et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, abstract 1916; Moore et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, abstract 1816; Strumberg et al., Book of Abstracts, 38th 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, 38th ASCO Meeting, Orlando, FL1 USA, abstract 473; Tolcher et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA, abstract 334; and Karp et al., Book of Abstracts, 38th AACR Meeting, San Francisco, CA, USA, abstract 2753.
Despite the advancements in the art, there remains a need for cancer treatments and anti-cancer compounds.
The utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below. The link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art. For example, the therapeutic utility of taxol (Silvestrini et al. Stem Cells 1993, 11(6), 528-35), taxotere (Bissery et al. Anti Cancer Drugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al. Cancer Chemother. Pharmacol. 1996, 37(5), 385-93) were demonstrated with the use of in vitro tumor proliferation assays.
Compounds and compositions described herein, including salts and esters thereof, exhibit antiproliferative activity and are thus useful to prevent or treat the disorders associated with hyper-proliferation.
DESCRIPTION OF THE INVENTION
The present invention pertains to: (i) novel compounds of examples 1-82 below, which are
• 1-[4-(2-amino-pyridin-4-yloxy)-phenyl]-3-[5-feAt-butyl-2-(4-fluoro-phenyl)-2H-pyrazol- 3-yl]-urea;
• 1-[4-(2-Amino-pyridin-4-yloxy)-phenyl]-3-[5-fe/t-butyl-2-(4-cyciobutoxy-phenyl)-2H- pyrazol-3-yl]-urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2,6-difluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyπdin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol- 5-yl]urea;
• N-{4-ϊ(2-aminopyridin-4-yI)oxy]-2-fluorophenyl}-N'-(3-tert-butyl-1 -pyridin-4-yl-1 H- pyrazol-5-yl)urea;
• N-{4-[(2-arninopyridin-4-yl)oxy]phenyl}-N'-(3-tert-butyl-1 -pyridin-4-yl-1 H-pyrazol-5- yl)urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1 -(4-methylphenyl)-1 H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1 -(4-isopropoxyphenyl)-1 H- pyrazol-5-y)]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-ϊ3-tert-butyl-1-(4- isopropoxyphenyl)-1H-pyrazol-5-yl]urea; N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-{3-tert-butyl-1-[4- (cyclobutyloxy)phenyl]-1 H-pyrazol-5-yl}urea;
N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-{3-tert-butyl-1-[4-
(cyclopropylmethoxy)phenyi]-1H-pyrazol-5-yl}urea;
N-{4-[(2-aminopyrid!n-4-yl)oxy]-2-fluorophenyl}-N'-{3-tert-butyl-1-[4-
(cyclopropylmethoxy)phenyl]-1H-pyrazol-5-yl}urea;
N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1-(4-isopropylphenyl)-1 H- py razol-5-yl] u rea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-isopropylphenyl)- 1 H-py razol-5-yl] u rea;
N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl-1 H-pyrazol- 5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-methoxyphenyl)- 1 H-pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[1-(4-cyanophenyl)-3-isopropyl-1 H-pyrazol- 5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-isopropyl-1-(4-methoxypheny])-1H- pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-isopropyl-1-(4-methoxyphenyl)- 1 H-pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(4-cyanophenyl)-3-isopropyl- 1 H-pyrazol-5-yl}urea; methyl 3-(5-{[({4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}amino)carbonyl]amino}-3- tert-butyl-1 H-pyrazol-1 -yl)benzoate; methyl 3-(5-{[({4-[(2-aminopyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-3-tert- butyl-1 H-pyrazol-1 -yl)benzoate; ethyl 4-(5-{[({4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}amino)carbonyl]amino}-3- tert-butyl-1 H-pyrazol-1 -yl)benzoate; • ethyl 4-(5-{[({4-[(2-aminopyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-3-tert-butyl- 1 H-pyrazol-1 -yl)benzoate;
• ethyl 3-(5-{[({4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}amino)carbonyl]amino}-3- tert-butyl-1 H-pyrazol-1 -yl)benzoate;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-I1-(3-fluorophenyl)-3-isopropyl-1 H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-methylphenyl)- 1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-(3-tert-butyl-1 -{4- [(trifluoromethyl)thio]pheny!}-1H-pyrazol-5-yl)urea;
• ethyl [4-(5-{[({4-[(2-aminopyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-3-tert-bυtyl- 1 H-pyrazol-1 -yl) phenyl]acetate;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-NI-[3-isopropyl-1-(4-methylphenyl)- 1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-ethyl-1-(4-fluorophenyl)-1 H-pyrazol-5- yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-ethyl-1-(4-fluorophenyl)-1 H- pyrazo!-5-yl]urea;
• N-{4-[(2-amiπopyridiπ-4-yl)oxy]phenyl}-N'-[1 -(4-chloropheπyl)-3-isopropyl-1 H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(4-chlorophenyl)-3-isopropyl- 1 H-pyrazol-5-yljurea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2,6-d]fluorophenyl}-Nl-[3-isopropyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea trifluoroacetate;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-isopropyl-1 -(4-methylphenyl)-1 H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-Nl-[3-tert-butyl-1-(3,5-dichlorophenyl)-1 H- pyrazol-5-yl]urea; • N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1-(3,4-difluorophenyl)-1 H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1-(3,4-dichlorophenyl)-1 H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-methylphenyl)- 1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyI-1-(3-methylphenyl)-1 H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3,5- dimethylphenyl)-1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1-(3,5-dimethylphenyl)-1H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2,6-difluorophenyl}-N'-[3-tert-butyI-1-(4-fluorophenyl)- 1 H-pyrazol-5-yl]urea
• 1-[4-(2-Amino-pyridin-4-yloxy)-2-fluoro-phenyl]-3-[5-fe/τf-butyl-2-(4-fluorophenyl)-2AV- pyrazol-3-yl]urea
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol- 5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyI-1-(4-cyanophenyl)-1H-pyrazoI- 5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-{3-tert-butyl-1-[4-(trifluoromethyl)phenyl]- 1 H-pyrazol-5-yl}urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-Nl-{3-tert-butyl-1-[4-(trifluoromethoxy)phenyl]- 1 H-pyrazol-5-yl}urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-{3-tert-butyl-1-[4-(methylsulfonyl)phenyl]- 1 H-pyrazol-5-yl}urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1-(3-chloro-4-fluorophenyl)- 1 H-ρyrazol-5-yl]urea; • N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1 -(4-methoxyphenyl)-1 H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[3-tert-butyl-1 -(4-πitrophenyl)-1 H-pyrazol- 5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-(3-tert-butyl-1 -phenyl-1 H-pyrazol-5-yI)urea;
• N-^-I^-aminopyridin^-yOoxyJphenyty-N'^S-cyclopropyl-i -phenyl-1 H-pyrazol-5- yl)urea;
• N-{4-[(2-aminopyridiπ-4-yl)oxy]pheny!}-N'-[1 -(4-chloropheπyl)-3-cyclopropyl-1 H- pyrazol-5-y l]u rea ;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-Nl-[1-(4-fluorophenyl)-3-(1- methylcyclopropyl)-1H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[1 -(4-chlorophenyl)-3-cyclopentyl-1 H- pyrazol-5-yl]urea;
• N-{4-[(2-aminopyπdin-4-yl)oxy]phenyl}-N'-[3-(4-fluorophenyl)-1 -phenyl-1 H-pyrazot-5- yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-{3-tert-butyl-1-[4- (methylsulfonyl)phenyl]-1H-pyrazol-5-yl}urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-{3-tert-butyI-1-[4- (trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-fluoro-5- methoxyphenyl)-1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3,5-difluorophenyl)- 1 H-pyrazol-5-yl]urea; N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-cyanophenyl)- 1H-pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy3-2-fluorophenyl}-N'-{3-tert-butyl-1-[4- (trifluoromethoxy)phenyl]-1 H-pyrazol-5-yl}urea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(4-chlorophenyl)-3-cyclopropyl- 1 H-pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(4-fluorophenyl)-3-(1- methylcyclopropyl)-1 H-pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(4-chlorophenyl)-3-cyclopentyl-
1 H-py razol-5-yl]urea;
N-{4-[(2-aminopyridin-4-y!)oxy]-2-fluoropheny!}-N'-[3-tert-butyl-1-(3-fluorophenyl)-1H- pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy3-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-methoxyphenyl)-
1 H-pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-chlorophenyl)-
1 H-pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(2,2,3,3-tetrafluoro-
2,3-dihydro-1 ,4-benzodioxin-6-yl)-1H-pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy3phenyl}-N'-[3-tert-butyl-1-(2,2,3,3-tetrafluoro-2,3- dihydro-1 ,4-benzodioxin-6-yl)-1 H-pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-(3-tert-butyl-1-{4- [(trifluoromethyl)thio]phenyl}-1H-pyrazol-5-yl)urea;
N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-(1-benzyl-3-tert-butyl-1H-pyrazol-5-yl)urea;
N-{4-t(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(4-fluorophenyl)-3-methyl-1H- pyrazol-5-yl]urea;
N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-N'-[1-(4-fluorophenyl)-3-isopropyl-1H-pyrazol- 5-yl]urea; • N-{4-[(2-aminopyridin-4-y])oxy]-2-fluorophenyl}-N'-[1-(4-fluorophenyl)-3-isopropyl-1H- pyrazol-5-yl]urea;
• 1-[4-(2-Amino-pyridin-4-yloxy)-2-fluoro-phenyl]-3-[5-tert-butyl-4-chloro-2-(4- fluorophenyl)-2/-/-pyrazol-3-yl]urea and
• 1-[4-(2-Amino-5-chloropyridin-4-yloxy)-2-fluorophenyl]-3-[5-te/t-butyl-4-chloro-2-(4- fluorophenyl)-2/-/-pyrazol-3-yl]urea; salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
(ii) pharmaceutical compositions containing compounds of examples 1-82 below or pharmaceutically acceptable salts, metabolites, solvates, hydrates, prodrugs, polymorphs and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers), and also including combinations thereof; and
(iii) use of those compounds of (i) or compositions of (ii) for treating diseases, e.g., hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients, e.g., cytotoxic therapies.
The compounds of examples 1-82, salts, metabolites, solvates, hydrates and prodrugs thereof, including polymorphs and diastereoisomeric forms (both isolated stereoisomers and mixtures of stereoisomers) and combinations thereof, are collectively referred to herein as the "compounds of the invention".
The compounds described in the examples are intended to be representative of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention. The following compounds are preferred for various reasons and are referred to herein as the "preferred compounds of the invention."
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyi-1-(3-chloro-4- fluorophenyl)-1H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1 H-pyrazol-5-yl]urea; and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea.
More particularly, a preferred embodiment of the present invention pertains to: (i) the novel compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1- (4-cyanophenyl)-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
(ii) pharmaceutical compositions containing N-{4-[(2-aminopyridin-4-yl)oxy]-2- fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl]urea or pharmaceutically acceptable salts, metabolites, solvates, hydrates, prodrugs, polymorphs thereof and also including combinations thereof; and
(iii) the use of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- cyanophenyl)-1 H-pyrazol-5-yl]urea or compositions of (ii) for treating diseases, e.g., hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients, e.g., cytotoxic therapies.
Another preferred embodiment of the present invention pertains to: (i) the novel compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1- (3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
(ii) pharmaceutical compositions containing N-{4-[(2-aminopyridin-4-yl)oxy]-2- fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4-fluorophenyl)-1 H-pyrazol-5-yl]urea or pharmaceutically acceptable salts, metabolites, solvates, hydrates, prodrugs, polymorphs thereof, and also including combinations thereof; and
(iii) the use of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro- 4-fluorophenyl)-1H-pyrazol-5-yl]urea or compositions of (ii) for treating diseases, e.g., hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients, e.g., cytotoxic therapies.
An additional preferred embodiment of the present invention pertains to: (i) the novel compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1- (4-methylphenyl)-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
(ii) pharmaceutical compositions containing N-{4-[(2-aminopyridin-4-yl)oxy]-2- fluorophenyl}-N'-[3-tert-butyl-1-(4-methylphenyl)-1 H-pyrazol-5-yl]urea or pharmaceutically acceptable salts, metabolites, solvates, hydrates, prodrugs, polymorphs and also including combinations thereof; and
(iii) the use of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyt)-1 H-pyrazol-5-yl]urea or compositions of (ii) for treating diseases, e.g., hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients, e.g., cytotoxic therapies.
A further preferred embodiment of the present invention pertains to: (i) the novel compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
(N) pharmaceutical compositions containing N-{4-[(2-aminopyridin-4-yl)oxy]-2- fluorophenyl}-N'-[1 -(3-fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea or pharmaceutically acceptable salts, metabolites, solvates, hydrates, prodrugs, polymorphs and also including combinations thereof; and
(iii) the use of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3- isopropyl-1 H-pyrazol-5-yl]urea or compositions of (ii) for treating diseases, e.g., hyper- proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients, e.g., cytotoxic therapies.
One additional preferred embodiment of the present invention pertains to: (i) the novel compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyI}-N'-[3-tert-butyl-1- (3-methoxyphenyl)-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
(ii) pharmaceutical compositions containing N-{4-[(2-aminopyridin-4-yl)oxy]-2- fluorophenyl}-N'-[3-tert-butyl-1 -(3-methoxyphenyl)-1 H-pyrazol-5-yl]urea or pharmaceutically acceptable salts, metabolites, solvates, hydrates, prodrugs, polymorphs, and also including combinations thereof; and (iii) the use of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea or compositions of (N) for treating diseases, e.g., hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients, e.g., cytotoxic therapies.
DEFINITIONS
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
The compounds of this invention may contain one. or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (Sj configuration or (R, S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification of said isomers and the' separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples 1-82, preferably:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-t3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazoI-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1 H-pyrazol-5-yl]urea; and
• N-{4-[(2-aminopyridin-4-yI)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea.
The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et a/. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, 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, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.
Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
Preferred salts include salts of: (i) salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- cyanophenyl)-1 H-pyrazol-5-yl]urea and hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid;
(U) salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-Nl-[3-tert-butyl-1 -(3-chIoro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea and hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid;
(iii) salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea and hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid;
(iv) salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3- isopropyl-1 H-pyrazol-5-yl]urea and hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid; and
(v) salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-Nl-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea and hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid.
Preferred acid addition salts also include:
(i) acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1 -(4-cyanophenyl)-1 H- pyrazol-5-yl]urea;
(ii) acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesu!fonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl>-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1H-pyrazol-5-yl]urea;
(iii) acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-methylphenyl)-1 H- pyrazol-5-yl]urea;
(iv) acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, • glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandefate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl-1H- pyrazol-5-yl]urea; and
(v) acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate salts of N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-methoxyphenyl)- 1 H-pyrazot-5-yi]urea
Certain compounds of this invention can be further modified with labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharmacologically inactive derivatizing (functional) group. These derivatives, commonly referred to as prodrugs, can be used, for example, to alter the physicochemical properties of the active agent, to target the active agent to a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce undesirable side effects.
Prodrugs of the invention include, e.g., the esters of appropriate compounds of this invention, are well-tolerated, pharmaceutically acceptable amides such as alkyl amide including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl(Ci-C5)alkyl may be used, although methyl amide is preferred. Solvates for the purpose of this invention are those forms of the compounds of this invention, such as
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; where solvent molecules form a complex in the solid state and include, but are not limited to for example ethanol and methanol. Hydrates are a specific form of solvates where the solvent is water.
Methods for synthesizing prodrugs are described in the following reviews on the subject, which are incorporated herein by reference for their description of these methods:
Higuchi, T.; Stella, V.. eds. Prodrugs As Novel Drug Delivery Systems. ACS Symposium Series. American Chemical Society: Washington, DC (1975).
Roche, E. B. Design of Biopharmaceutical Properties through Prodrugs and Analogs. American Pharmaceutical Association: Washington, DC (1977). Sinkula, A. A.; Yalkowsky, S. H. J Pharm Sci. 1975, 64, 181-210. Stella, V. J.; Charman, W. N. Naringrekar, V. H. Drugs 1985, 29, 455-473. Bundgaard, H., ed. Design of Prodrugs. Elsevier: New York (1985). Stella, V. J.; Himmelstein, K.. J. J. Med. Chem. 1980, 23, 1275-1282. Han, H-K; Amidon, G. L. AAPS Pharmsci 2000, 2, 1- 11. Denny, W. A. Eur. J. Med. Chem. 2001 , 36, 577-595.
Wermuth, C. G. in Wermuth, C. G. ed. The Practice of Medicinal Chemistry Academic Press: San Diego (1996), 697-715. Balant, L. P.; Doeiker, E. in Wolff, M. E. ed. Burgers Medicinal Chemistry And Drug Discovery John Wiley & Sons: New York (1997), 949-982.
General Preparative Methods
The particular process to be utilized in the preparation of the compounds used in this embodiment of the invention depends upon the specific compound desired. Such factors as the selection of the specific substituents play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.
The compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the compounds of the present invention, with more detailed particular examples being presented below in the experimental section describing the working examples.
The compounds of the invention can be made according to conventional chemical methods, and/or as disclosed below, from starting materials which are either commercially available or producible according to routine, conventional chemical methods. General methods for the preparation of the compounds are given below, and the preparation of representative compounds is specifically illustrated in examples. Specific preparations of diaryl ureas, including pyrazolyl ureas, are already described in the patent literature, and can be adapted to the compounds of the present invention. For example, Miller S. et al, "Inhibition of p38 Kinase using Symmetrical and Unsymmetrical Diphenyl Ureas" PCT int. Appl. WO 99 32463, Miller, S et al. "Inhibition of raf Kinase using Symmetrical and Unsymmetrical Substituted Diphenyl Ureas" PCT Int. Appl., WO 99 32436, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32111, Dumas, J. et al., "Method for the Treatment of Neoplasm by Inhibition of raf Kinase using N-Heteroaryl-N'- (hetero)arylureas" PCT Int. Appl., WO 99 32106, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32110, Dumas, J., et al., "Inhibition of raf Kinase using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32455, Riedl, B., et al., "O-Carboxy Aryl Substituted Diphenyl Ureas as raf Kinase Inhibitors" PCT Int. Appl., WO 00 42012, Riedl, B., et al., "O-Carboxy Aryl Substituted Diphenyl Ureas as p38 Kinase Inhibitors" PCT Int. Appl., WO 00 41698, Dumas, J. et al. "Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors" U.S. Pat. Appl. Pub!., US 20020065296, Dumas, J. et al. "Preparation of N-aryl-N"-[(acylphenoxy) phenyl]ureas as raf kinase inhibitors" PCT Int. Appl., WO 02 62763, Dumas, J. et al. "Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas" PCT Int. Appl., WO 02 85857, Dumas, J. et al. "Preparation of quinolyl, isoquinolyl or pyridyl-ureas as inhibitors of raf kinase for the treatment of tumors and/or cancerous cell growth" U.S. Pat. Appl. Pubi, US 20020165394. All the preceding patent applications are hereby incorporated by reference.
Compounds of the present invention can be prepared according to General Method 1 (Reaction Scheme 1), where 5-aminopyrazoles of Formula 1.1 and amines of Formula 1.2 are coupled together to form a urea of Formula I. This process occurs in the presence of a coupling agent such as carbonyldiimidazole, carbonylditriazole, phosgene, diphosgene, triphosgene, and the like. In this process, the isocyanates may or may not be formed in situ. The coupling step may be performed in an inert solvent such as dioxane, diethylether, dichloromethane, chloroform, tetrahydrofuran, toluene, and the like, at a temperature selected between 00C and reflux. This coupling may be achieved using these reagents alone, or in the presence of an organic or inorganic base as described in the art.
General Method 1
Reaction Scheme 1
(1.1 ) (1.2) I wherein substituents R1 , R2, R3, R4 and A, phenylene group B, pyridine group M and oxygen bridge L are as defined in examples 1-82 below.
Aromatic amines of Formula (1.2) are generally employed in an amount of from 1 to 3 mole per mole of compounds of Formula (1.1); an equimolar amount or slight excess of compounds of Formula (1.2) is preferred. Amines of Formula (1.2) are commercially available or can be synthesized according methods commonly known to those skilled in the art. In particular, a large variety of aromatic amines of Formula (1.2) has been described in the diaryl urea patent literature cited above. Reaction Scheme 10 (below) will also illustrate one of the synthetic methods than can be used to prepare compounds of Formula (1.2).
The reaction of the compounds of Formula (1.1) with amines of Formula (1.2) is generally carried out within a relatively wide temperature range. In general, they are carried out in a range of from -20 to 2000C, preferably from 0 to 1000C, and more preferably from 25 to 500C. The steps of this reaction are generally carried out under atmospheric pressure. However, it is also possible to carry them out under super- atmospheric pressure or at reduced pressure (for example, in a range of from 0.5 to 5 bar). The reaction time can generally be varied within a relatively wide range. In general, the reaction is finished after a period of from 2 to 24 hours, preferably from 6 to 12 hours.
Alternatively, the compounds of the present invention can be synthesized according to the reaction sequence shown in the General Method 2 (Reaction Scheme 2). These compounds can be synthesized by reacting arylamines of Formula (1.2) with isocyanates of Formula (2.2).
General Method 2
Reaction Scheme 2.
wherein substituents R1, R2, R3, R4 and A, phenylene group B, pyridine group M and oxygen bridge L are as defined in examples 1-82 below.
Compounds of Formula (2.2) can be synthesized according to methods commonly known to those skilled in the art. For example, isocyanates of Formula (2.2) may be prepared in situ or isolated from treatment of amino-pyrazoles of Formula (1.1) with phosgene or a phosgene equivalent such as trichlorσmethyl chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or Λ/,/V'-carbonyldiimidazole (CDI), or Λ/,Λ/'-carbonylditriazole (CDT). Alternatively, compounds of Formula 2.2 can be obtained from the corresponding pyrazole-carboxylic acid derivatives via a Curtius-type rearrangement.
An additional method for the synthesis of compounds of the present invention is described in Reaction Scheme 3.
Reaction Scheme 3
(1.1) (3.1) (3.2) I wherein substituents R1, R2, R3, R4 and A, phenylene group B, pyridine group M and oxygen bridge L are as defined in examples 1-82 below.
Reaction of an amino pyrazole of Formula (1.1) with a chloroformate of Formula 3.1 provides an aryl carbamate of Formula (3.1), which can be either isolated and purified, or carried directly into the next step. Subsequent coupling of aryl carbamate (3.2) with an amine of Formula (1.2) in the presence of base yields compounds of Formula I.
Synthesis of Intermediates
Intermediates are either commercially available, or are prepared by standard methods known in the art and/or by analogy to one of the procedures shown below.
5-AminopyrazoIes
5-Aminopyrazo!es of Formula (1.1) can be prepared by a variety of methods. Specific preparations are already described in the patent literature, and can be adapted to the compounds of the present invention. For example, Keerigan, F. et a/., "Preparation of piperazine derivatives as therapeutic agents" PCT Int. App/., WO 9703067, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32110, Regan, J. et al., J. Med, Chem. 2003, 46 4676-4686. Regan et al., J. Med. Chem. 2002, 45, 2994-3008; Rudolph, J. et al., "Preparation of anilinopyrazoles for the treatment of diabetes." PCT Int. Appl. WO 2004050651, Rudolph, J. et al. "Preparation of heteroarylaminopyrazoles for the treatment of diabetes" U.S. Pat. Appl. Publ. US 2005192294. All the preceding patent applications are hereby incorporated by reference. Some of these methods are illustrated in Schemes 4-6. Reaction Scheme 4
(4.1 ) (4.2) (1.1) wherein substituents R1, R2 and A, are as defined in examples 1-82 below.
In Reaction Scheme 4, condensation of an optionally substituted acetonitrile with an appropriately substituted ester (4.1), and base, gives the cyanoketone (4.2), Esters of Formula (4.1) where R1 is an optionally substituted phenyl, can be prepared, if necessary, from the corresponding bromo compound of Formula R1-Br, for example, by reaction with BuLi and CO2 to form an acid of Formula R1-COOH, which can be esterified to (4.1). The compound of formula (4.2) is then allowed to react with a substituted hydrazine of Formula (4.3) to give the desired aminopyrazole (1.1). If the cyanoketone (4.2) is commercially available, the first step is omitted.
Reaction Scheme 5 illustrates the synthesis of compounds for Formula (1.1) where R2 = H.
Reaction Scheme 5
(1.1a)
(1.1). R2 = H wherein substituents R1 and A, are as defined in examples 1-82 below. In Reaction Scheme 5, acetonitrile is condensed with nitrile (5.1) to the aminonitrile (5.2), which then reacts with hydrazine (4.3) to form (1.1aH(1.1) where R2 = H].
Reaction Scheme 6 illustrates the synthesis of compounds for Formula (1.1c) where R2 is halo as defined in examples 80 and 81 and A is as defined in examples 1- 82 below.
Reaction Scheme 6
= optionally -Ce) alkyl
d.i d) (1.1 c)
(1.1 ) where R 2 = _ optionally
AIk = optionally substituted (C0-C4) alkyl substituted (C1-C6) alkyl *Suitable boronic acid esters include group, or two R' groups may form a ring
and trimeric boronic acid esters such as
Reaction Scheme 6 illustrates how the aminopyrazole of Formula (1.1a) may be converted to other aminopyrazoles of Formula (1.1c) by halogenation followed by Suzuki or Stille coupling reactions to introduce an R2 group other than H. The product of the Stille reaction (1.1d) can also be reduced, for example by hydrogenation, to give the saturated compound of Formula (1.1c).
Hydrazines
Hydrazines of Formula (4.3) are either commercially available or can be prepared as shown in Reaction Scheme 7.
Reaction Scheme 7
NH2 1) NaNO2, HCI -NH,
HN HCI A !
2) SnCI2, HCI A
(7.1) " (4.3) where A is as defined in the Reaction Scheme 1 above.
A substituted amine of Formula (7.1) is converted into a diazonium salt intermediate by exposure to sodium nitrite in the presence of an acid, such as HCI. The diazonium salt is subsequently reduced, for example by using tin(ll)chloride as the reductant, in the presence of an acid such as HCI.
An alternative method to the synthesis of compounds for Formula (4.3) is described in Reaction Scheme 8.
Reaction Scheme 8
H2
X = Cl1 Br, I wherein A is as defined in reaction scheme 1 above.
Compounds of Formula (8.1) can be reacted with benzophenone hydrazone (8.2) in the presence of a catalyst and ligand to afford intermediate (8.3). Preferably, this reaction is performed using a palladium catalyst (e.g., Pd(ll)acetate) in the presence of a phosphine ligand such as 4,5-bis(diphenylphosphino)xanthene. The addition of base is favorable, in particular when using sodium ferf-butoxide. The reaction is best performed under anhydrous conditions in a suitable solvent such as toluene. Intermediate (8.3) can be used in Reaction Schemes 4 and 5 as an in situ form of (4.3), or it can be converted to a compound of Formula (4.3) in the presence of acid, preferably under partly aqueous conditions.
5-Amino pyrazoles of Formula (1.1) can be further functionalized [by methods well know to one skilled in the Art] before being coupled with keto-nitriles of Formula (1.2, Reaction Schemes 1-3). As an example, Reaction Scheme 9 illustrates the manipulation of an alkoxyl substituted 5-amino pyrazoles.
Reaction Scheme 9
<9.1) (9.2) (9.3)
wherein substituents R1, R2, and A, are as defined in examples 1-82 below.
Aminopyrazoles of Formula (9.1 ) are de-methylated to the corresponding hydroxy compounds of Formula (9.2) (for example, with the use of boron tribromide, methylthiolate in DMF1 lithium diphenylphosphide, or an equivalent reagent known in the art). In turn, compounds of Formula (9.2) can be further elaborated by alkylation, for example with an alkyl halide such as Y-Br, Y-I, or Y-Cl or by a Mitsunobu reaction with an alkanol such as Y-OH, to afford aminopyrazoles of Formula (9.3). Reaction Scheme 10 illustrates the synthesis of compounds of Formula (1.2) where B pyridyl.
Reaction Scheme 10
(10 •4) (1.2a) (1. 2)
Reaction of a 2-carboxy pyridine of Formula (10.1) can be treated with an halogenating agent, preferably SOCI2/SOBr2, with heating to produce acid chloride 10.2. Conversion to intermediate (10.3) is achieved either through Hofmann (NH3; KOH1 Br2) or Curtius (NaN3, heat) rearrangement performed in a suitable solvent. The 2-amino functional group can be masked as a 2,5-dimethylpyrrole by treatment with acetonyl acetone in the presence of a catalytic amount of acid. Condensation of fragment 10.5 with intermediate 10.4 can be achieved in the presence of base in a suitable solvent, for example using potassium terf-butoxide in DMSO. Unmasking of the 2-amino group can the be achieved by using hydroxyl amine in a solvent such as an alcohol in the presence of water and a mild base to provide compounds of Formula (1.2)
Synthetic transformations that may be employed in the synthesis of compounds of this invention and in the synthesis of intermediates involved in the synthesis of compounds of this invention are known by or accessible to one skilled in the art. Collections of synthetic transformations may be found in compilations, such as: J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York (1992) R. C. Larock. Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH: New York
(1999)
F.A. Carey; R.J. Sundberg. Advanced Organic Chemistry, 2nd ed.; Plenum Press: New
York (1984)
T.W. Greene; P. G. M. Wuts. Protective Groups in Organic Synthesis, 3rd ed.; John
Wiley: New York (1999)
L. S. Hegedus. Transition Metals in the Synthesis of Complex Organic Molecules, 2nd ed.; University Science Books: Mill Valley, CA (1994)
L.A. Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis; John Wiley:
New York (1994)
A. R. Katritzky; O. Meth-Cohn; CW. Rees, Eds. Comprehensive Organic Functional
Group Transformations; Pergamon Press: Oxford, UK (1995)
G. Wilkinson; F. G A. Stone; E.W. Abel, Eds. Comprehensive Organometallic
Chemistry; Pergamon Press: Oxford, UK (1982)
B. M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon Press: Oxford,
UK (1991)
A. R. Katritzky; CW. Rees Eds. Comprehensive Heterocylic Chemistry; Pergamon
Press: Oxford, UK (1984)
A. R. Katritzky; CW. Rees; E. F. V. Scriven, Eds. Comprehensive Heterocylic Chemistry
II; Pergamon Press: Oxford, UK (1996)
C. Hansch; P. G. Sammes; J. B. Taylor, Eds. Comprehensive Medicinal Chemistry:
Pergamon Press: Oxford, UK (1990).
In addition, recurring reviews of synthetic methodology and related topics include
Organic Reactions; John Wiley: New York; Organic Syntheses; John Wiley: New York;
Reagents for Organic Synthesis: John Wiley: New York; The Total 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, databases of synthetic transformations include Chemical
Abstracts, which may be searched using either CAS OnLine or SciFinder, Handbuch der Organischen Chemie (Ηeilstein), which may be searched using SpotFire, and REACCS.
Compositions of the compounds of this invention
This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention, preferably one or more of:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazoi-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea; and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxypheπyl)-1 H-pyrazol-5-yl]urea.
These compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention, preferably one or more of:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyI-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylpheny!)-1 H-pyrazol-5-yl]urea; • N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1 H-pyrazol-5-yl]urea; and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea.
A pharmaceutically acceptable carrier is preferably a carrier that is relatively nontoxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of the present invention, including:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylpheny!)-1H-pyrazol-5-ylJurea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyI)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-Nl-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea; can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
For oral administration, the compounds of this invention, including:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea, • N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea; can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. In another embodiment, the compounds of this invention, including:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1 H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify 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, a suspending agent and one or more preservatives. Suitable dispersing, or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
The pharmaceutical compositions of this invention may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p- hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin. Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
The compounds of this invention, including:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-y|)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridϊn-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethy!-1 ,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.
Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammontum, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient, such as
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yI)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-Nl-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
■ N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea; in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB. Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions of this invention may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcelluJose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
A pharmaceutical composition of the invention, including those which comprise
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- . 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea, • N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea; may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non- irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.
Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion in controlled amounts of the compounds of the present invention, including:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea.
The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11 , 1991 , incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
It may be desirable or necessary to introduce a pharmaceutical composition of this invention, such as one which includes one or more of
N^-tC∑-aminopyridin-^yOoxyl^-fluoropheny^-N'-tS-tert-butyl-i-C^cyanophenyO-I H- pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea; to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011,472, issued April 30, 1991.
The pharmaceutical compositions of the invention, including those which comprise one or more of;
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1H-pyrazol-5-yl]urea, • N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluoropheπyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluoropheny!}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M. F. et al, "Compendium of Excipients for- Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311 ; Strickley, R. G "Parenteral Formulations of Small 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.
Another aspect of the invention is a pharmaceutical composition comprising a solid dispersion of the active ingredient, wherein the matrix comprises a pharmaceutically acceptable polymer, such as polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e. hydroxypropyl methyl cellulose), carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, polyglycolized glycerides, xanthan gum, carrageenan, chitosan, chitin, poyldextrin, dextrin, starch and proteins or a sugar and/or sugar alcohol and/or cyclodextrin, for example sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, inositol, trehalose, isomalt, inuϋn, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin or sulfobutyl ether cyclodextrin. Additional suitable carriers that are useful in the formation of the matrix of the solid dispersion include, but are not limited to alcohols, organic acids, organic bases, amino acids, phospholipids, waxes, salts, fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and urea.
The solid dispersion of the compounds of this invention in the matrix may contain certain additional pharmaceutical acceptable ingredients, such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants, detackifier, pH-modifiers, glidants and lubricants.
The solid dispersion of the invention is prepared according to methods known to the art for the manufacture of solid dispersions, such as fusion/melt technology, hot melt extrusion, solvent evaporation (i.e. freeze drying, spray drying or layering of powders of granules), coprecipitation, supercritical fluid technology and electrostatic spinning method.
Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include:
acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2,
F2CIC-CCiF2 and CCIF3) 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 preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to 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 and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerol); solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol
10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethy! cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
Pharmaceutical compositions according to the present invention, including those which comprise one or more of:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H~pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyI}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl3urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1 H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea;
can be illustrated as follows:
Sterile IV Solution: A 5 mg/mL solution of the desired compound of this invention, such as
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea, • N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea;
can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 — 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.
Lyophilized powder for IV administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention, such as
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methy!phenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea;
as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 — 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention, preferably one or more of:
• N^-^Z-aminopyridin^-yOoxyJ-Z-fluoropheny^-N'-tS-tert-butyl-i-C^cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N^ΦKZ-aminopyridin-^yOoxyl-Z-fluorophenyO-N'-lS-tert-butyl-i-CS-chloro^- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N^-KZ-aminopyridin^-yOoxyl^-fluoropheny^-N'-II-CS-fluorophenylJ-S-isopropyl- 1H-pyrazol-5-yl]urea, and
• N^-^-aminopyridin^-yOoxyJ^-fluorophenyll-N'-tS-tert-butyl-I^S- methoxyphenyl)-1 H-pyrazol-5-yl]urea;
• 5 mg/mL sodium carboxymethylcellulose
• 4 mg/mL TWEEN 80
• 9 mg/mL sodium chloride
• 9 mg/mL benzyl alcohol
Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, preferably one or more of
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methy lphenyl)-1 H-py razol-5-yl] u rea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1 H-pyrazol-5-yl]urea( and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyi-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules: A mixture of active ingredient, preferably one or more of:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yI)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol~5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy3-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1 H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea;
in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, preferably one or more of: N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)-1 H- pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-{4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyi)-3-isopropyl- 1H-pyrazol-5-yl]urea, and • N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea;
0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystaliine cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance 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 delivery of the medication. The active ingredient, preferably one or more of:
• N^-^-aminopyhdin^-yOoxyl^-fluoropheny^-N'-P-tert-butyl-i-C^cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fiuorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea;
is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds, such as one or more of:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1H-pyrazol-5-yl]urea, • N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyI)-3-isopropyl- 1H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1 -(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea;
may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Method of treating hyper-proliferative disorders
The present invention relates to a method for using the compounds of the present invention, preferably
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1 -(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluoropheny]}-N'-[3-tert-butyl-1 -(3-chloro-4- fluorophenyl)-1H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy3-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1 H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazo!-5-yl]urea;
• and compositions thereof, to treat mammalian hyper-proliferative disorders. The compounds of this invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis. In preferred methods, one or more of:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1 -(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea, • N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazol-5-yl3urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazol-5-yϊ]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazot-5-yl]urea; is used.
The methods of this invention comprise administering to a mammal in need thereof, including a human, an amount of a compound of this invention, (Compounds of examples 1-82 or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc.) which is effective to treat the disorder.
Preferred embodiments of the methods of this invention comprise administering to a mammal in need thereof, including a human, one or of:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-ch!oro-4- fluorophenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3-fluorophenyl)-3-isopropyl- 1H-pyrazot-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; in an amount which is effective to treat the disorder.
Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias. In preferred embodiments, one or more of:
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4-cyanophenyl)- 1H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3-chloro-4- fluorophenyl)-1H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(4- rnethylphenyl)-1 H-pyrazol-5-yl]urea,
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N*-[1-(3-fluorophenyl)-3-isopropyl- 1 H-pyrazol-5-yl]urea, and
• N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea; or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; is used to treat these hyper-prol iterative disorders.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to small- cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
The term "treating" or "treatment" as stated throughout this discussed is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
Methods of treating kinase disorders The present invention also provides methods for the treatment of disorders associated with aberrant kinase activity (such as tyrosine kinase activity), including, but not limited Flk-1 (VEGFR2), Trk-A, c-MET, and/or AbI (such as Bcr-Abl), comprising administering an effective amount of a compound of the present invention. Disorders include cancers (such as those mentioned herein), disorders associated angiogenesis (see above), cell proliferation disorders, etc. For example, SF/HGF and/or c-MET over- expression and mutations have been found in many tumor types, including, e.g., carcinomas, sarcomas, hematopoitic cancers, and other neoplastic diseases (Table 1).
Table 1. SF/HGF and c-Met expression and mutations in human tumors (Abounader, R. et al., 2005, 7, 436-51)
Category Cancer type HGF/SF Exp M Met Exp
Met Mutation
Carcinomas Bladder Y Y N
Breast Y Y N
Cervical N Y N
Cholangio N N N
Colorectal Y Y N
Esophageal N Y N
Gastric Y Y Y
Head &Neck Y Y Y
Kidney Y Y Y
Liver Y Y Y
Lung Y Y N
Nasopharyngeal Y Y N
Ovarian N Y Y
Pancreas/gall bladder Y Y N
Prostate Y Y N
Thyroid Y Y N
Musculoskeletal Osteosarcoma Y Y N
Synovial sarcoma Y Y N
Rhabdomyosarcoma N Y N
Soft tissue sarcomas MFH/fi brosarcoma Y Y N
Leiomyosarcoma Y Y N
Kaposi's sarcoma Y Y N
Hematopoietic Multiple myeloma Y Y N
Lymphomas Y Y N Adult T-cell leukemia N Y N
AML Y N N
Chronic myeloid leukemia Y N N
Other neoplasms Glioblastomas/astrocytomas Y Y Y
Melanoma Y Y N
Mesothelioma Y Y N Wilms' tumor Y Y N
In certain cases such as bladder cancer, c-Met over-expression has been associated with the progression of the neoplastic disease. In such instances, the evaluation of Met levels/activity could itself be used in the identification of a subset of patients who may require an alternative treatment strategy (Cheng, H. et al., Journal of Clinical Oncology, 2002, 20, 1544-1550).
Trk-A expression and mutations have been reported in cancers, including, e.g., pancreatic, breast, ovarian, prostate carcinoma, papillary thyroid carcinoma, medullary thyroid carcinoma (including familial forms), and acute myeloid leukemia (AML), neuroblastoma, breast cancer, and prostate. The only change leading to the transforming capacity of the TRK gene is the replacement of the extracellular domain of NTRK1 by sequences coding for the 221 amino-terminal residues of tropomyosin-3 (TPM3) (Coulier, F. et al., Molec. Cell. Biol., 1989, 9, 15-23). Sequence rearrangements between the TPM3 and NTRK1 genes result in TRKA oncogenes and their gene products, which are associated with papillary thyroid carcinomas (Butti, M. et al., Genomics, 1995, 28, 15-24). Elevated activity or levels of Trk-A has been observed in primary tumors as well as metastatic tumors in patients with papillary thyroid carcinomas (Bongarzone, I. et al., Oncogene, 1989, 4, 1457-1462). Papillary thyroid carcinoma (PTC), the most frequent neoplasia originating from the thyroid epithelium, accounts for about 80% of all thyroid cancers. In human neuroblastoma, expression of NTRK1 is a good prognostic marker, most likely because Trk-A mediated signaling is important for growth arrest and/or differentiation of the neural crest derived cells from which these tumors originate (Brodeur, G. et al., J Pediatr. Hematol. Oncol., 1997, 19, 93-101). In both in vitro and in vivo it has been found that the product of the TRK protooncogene is sufficient to mediate signal transduction processes induced by nerve growth factor (NGF) and neurotrophin-3. TRK is expressed in monocytes, which suggests that NGF is an immunoregulatory cytokine acting on monocytes. Trk-A deletion constructs that had transforming potential have been screened in patients with acute myeloid leukemia (Reuther, G. et al., Molecular and Cellular Biology, 2000, 20, 8655-8666). Fusion products of Trk-C, a closely related homolog of Trk-A, have also been implicated in certain patients with AML (Eguchi, M. et al., Blood, 1999, 93, 1355- 63).
Cancers involving fusion products of AbI have been very well-characterized. In humans, Abl-1 has been associated with three oncogenic fusion pairs, ETV6, BCR and NUP214. The products of these pairs are all implicated in a host range of cancers. For example, fusion product of Bcr and AbI has been observed with Chronic myeloid leukemia, aberrant translocation, Acute erythroleukemia (FAB type M6), Acute lymphoblastic leukemia/lymphoblastic lymphoma, Acute megakaryoblastic leukemia (FAB type M7), Acute myeloblasts leukemia with maturation (FAB type M2), Acute myeloblasts leukemia with minimal differentiation (FAB type MO), Acute myeloblasts leukemia without maturation (FAB type M1), Acute myeloid leukemia, NOS, Acute myelomonocytic leukemia (FAB type M4), Acute promyelocyte leukemia (FAB type M3), Acute undifferentiated leukemia, Bilineage or bipheπotypic leukemia, Burkitt lymphoma/leukemia, Chronic myeloid leukemia, t(9;22), Diffuse large B-cell lymphoma, Multiple myeloma, Myelodysplastic syndrome, NOS, Nonneoplastic myeloid disorder/lesion, Refractory anemia, Chronic Myelogenous Leukemia, Acute Lymphocytic Leukemia. Bcr-Nup214 fusion proteins have been implicated in Acute lymphoblastic leukemia/lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia.
Therefore one aspect of the instant invention is a method for treating cancer related to the elevated activity and/or levels of the above-identified genes and their gene-products. Effective amounts of compounds of the present invention can be used to treat such disorders, including those diseases (e.g., cancer) mentioned in the Background section above. Nonetheless, such cancers and other diseases can be treated with compounds of the present invention, regardless of the mechanism of action and/or the relationship between the kinase and the disorder.
The phrase "aberrant kinase activity" or "aberrant tyrosine kinase activity," includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not limited to, over-expression of the gene or polypeptide; gene amplification; mutations which produce constitutively-active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, etc.
The present invention also provides for methods of inhibiting a kinase activity, especially of Flk-1 , Trk-A, and/or c-MET, comprising administering an effective amount of a compound of the present invention (compounds of examples 1-82, including salts, polymorphs, metabolites, hyrates, solvates, prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof). Kinase activity can be inhibited in cells (e.g., in vitro), or in the cells of a mammalian subject, especially a human patient in need of treatment. Compounds of the present invention can be used for any of the indications described in U.S. Pat. Nos. 6,946,471 ; 6,921 ,763; 6,855,728; 6,723,694; 6,660,744; 6,468,529; 6,350,754; 6,297,238; 6,214,344; 6,207,152; 6,099,841; 6,057,105; 6,051 ,593; 5,734,039; 5,707,624; 5,686,292; and 5,646,036; each of which is incorporated by reference in its entirety.
Methods of treating angiogenic disorders
The present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal- vein occlusion, and retinopathy of prematurity (Aiello et at. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855), neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
Compound and compositions of the present invention can be tested routinely for angiogenic activity, e.g., by contacting a blood vessel-forming cell population with a compound of the present invention, and determining the effect of the compound on blood vessel formation. Any cell population capable of forming blood vessels can be utilized. Useful models, include, e.g., in vivo Matrigel-type assays; tumor neovascularization assays; CAM assays; BCE assays; cell migration assays; HUVEC growth inhibition assays; animal models (e.g., tumor growth in athymic mice, chronically ischemic lower limb in a rabbit model, cancer models, etc.); in vivo systems, such as a heart or limb present in a patient (e.g., angiogenic therapy to treat myocardial infarction); hosts in need of treatment, e.g., hosts suffering from angiogenesis related diseases, such as cancer, ischemic syndromes, arterial obstructive disease, to promote collateral circulation, to promote vessel growth into bioengineered tissues, etc. Cells can include, e.g., endothelial, epithelial, muscle, embryonic and adult stem cells, ectodermal, mesenchymal, endodermal, neoplastic, blood, bovine CPAE (CCL-209), bovine FBHE (CRL-1395), human HUV-EC-C (CRL-1730), mouse SVEC4-10EHR1 (CRL-2161), mouse MS1 (CRL-2279), mouse MS1 VEGF (CRL-2460), stem cells, etc. The phrase "capable of forming blood vessels" does not indicate a particular cell-type, but simply that the cells in the population are able under appropriate conditions to form blood vessels. In some circumstances, the population may be heterogeneous, comprising more than one cell-type, only some which actually differentiate into blood vessels, but others which are necessary to initiate, maintain, etc., the process of vessel formation.
A useful model to determine the effect of compounds or compositions on angiogenesis is based on the observation that, when a reconstituted basement membrane matrix, such as Matrigel, supplemented with growth factor (e.g., FGF-1), is injected subcutaneously into a host animal, endothelial cells are recruited into the matrix, forming new blood vessels over a period of several days. See, e.g., Passaniti et al., Lab. Invest., 67:519-528, 1992. To stabilize the growth factor and/or slow its release from the matrix, the growth factor can be bound to heparin or another stabilizing agent. The matrix can also be periodically re-infused with growth factor to enhance and extend the angiogenic process. More specifically, a Matrigel plug implant comprising FGF-1 can be implanted subcutaneously into a host mouse. The initial bolus of FGF attracts endothelial cells into the implant, but does not result in new blood vessel formation. After about 10-15 days, the implant can be re-infused with FGF-1. The FGF- 1 stimulates the endothelial cells already present in the implant, initiating the process of angiogenesis.
Other useful systems for studying angiogenesis, include, e.g., neovascularization of tumor explants (e.g., U.S. Pat. Nos. 5,192,744; 6,024,688), chicken chorioallantoic membrane (CAM) assay (e.g., Taylor and Folkman, Nature, 297:307-312, 1982; Eliceiri et al., J. Cell Biol., 140, 1255-1263, 1998), bovine capillary endothelial (BCE) cell assay (e.g., U.S. Pat. No. 6,024,688; Polverini, P. J. et al., Methods Enzymol., 198: 440-450, 1991), migration assays, HUVEC (human umbilical cord vascular endothelial cell) growth inhibition assay (e.g., U.S. Pat. No. 6,060,449).
A cell population can be contacted with the compound or composition in any manner and under any conditions suitable for it to exert an effect on the cells. The means by which compound is delivered to the cells may depend upon the type of test agent, e.g., its chemical nature, and the nature of the eel! population. Generally, a compound must have access to the cell population, so it must be delivered in a form (or pro-form) that the population can experience physiologically, i.e., to put in contact with the cells. For instance, if the intent is for the agent to enter the cell, if necessary, it can be associated with any means that facilitate or enhance cell penetrance, e.g., associated with antibodies or other reagents specific for cell-surface antigens, liposomes, lipids, chelating agents, targeting moieties, etc. Cells can also be treated, manipulated, etc., to enhance delivery, e.g., by electroporation, pressure variation, etc.
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg 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 for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be 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 dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 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 continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
The additional pharmaceutical agent can be aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, filgrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCI, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-2B, interferon alfa-n1 , interferon alfa-n3, interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, levothroid, levoxyl, lomustine, Ionidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6- mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, Mod renal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCI, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCI, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran, ABI- 007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin, CCI-779, CDC-501 , celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyaπin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, parnidronate disodiυm, PN-401, QS-21 , quazepam, R-1549, raloxifene, ranpimase, 13-cis -retinoic acid, satraplatin, seocalcitol, T- 138067, tarceva, taxoprexin, thymosin alpha 1 , tiazofurine, tipifamib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or combinations thereof.
Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.
Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paciitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.
Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
Generally, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:
(1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,
(2) provide for the administration of lesser amounts of the administered chemo- therapeutic agents,
(3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,
(4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,
(5) provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
The term u Combination" means for the purposes of the invention not only a dosage form which contains all the components (so-called fixed combinations), and combination packs containing the components separate from one another, but also components which are administered simultaneously or sequentially, as long as they are employed for the prophylaxis or treatment of the same disease.
The active ingredients of the combination according to the invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations. Examples are tablets, coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, solutions.
Since the combination according to the invention is well tolerated and in some cases is effective even in low dosages, a wide range of formulation variants is possible. Thus, one possibility is to formulate the individual active ingredients of the combination according to the invention separately. In this case, it is not absolutely necessary for the individual active ingredients to be taken at the same time; on the contrary, sequential intake may be advantageous to achieve optimal effects. It is appropriate with such separate administration to combine the formulations of the individual active ingredients, for example tablets or capsules, simultaneously together in a suitable primary packaging. The active ingredients are present in the primary packaging in each case in separate containers which may be, for example, tubes, bottles or blister packs. Such separate packaging of the components in the joint primary packaging is also referred to as a kit.
Further formulation variants which are suitable and preferred for the combination according to the invention are also fixed combinations. "Fixed combination" is intended here to mean pharmaceutical forms in which the components are present together in a fixed ratio of amounts. Such fixed combinations may be, for example, in the form of oral solutions, but they are preferably solid oral pharmaceutical preparations, e.g. capsules or tablets.
(8)
Abbreviations and Acronyms
A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of
Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87.
More specifically, when the following abbreviations are used throughout this disclosure, they have the following meaning:
Abbreviations
Aq aqueous
Min minute(s)
H hour(s)
ADDP 1 ,1'-(Azodicarbonyl)dipiperidine
DMA Λ/,Λ/-Dimethyl acetamide
DMF Λ/,/V-Dimethyl formamide
DCM Dichloromethane
DCE 1 ,2-Dichloroethane
EtOAc Ethyl acetate
EtOH Ethanol
MeOH Methanol
THF Tetrahydrofuran
DMSO Dimethyl sulphoxide
MTBE Methyl ferf-butyl ether
HPLC High pressure liquid chromatography
MPLC Medium pressure liquid chromatography
LC-MS Liquid chromatography - coupled mass spectroscopy
NMR Nuclear resonance spectroscopy
TLC Thin layer chromatography
ES Electrospray
CDT 1 ,1'-Carbonylditriazole
CDI 1 ,1'-Carbonyidiimic!azole
HOBT 1 -Hydroxybenzotriazole EDCI 1-[3-(Dimethylamino) propyl]-3-ethylcarbodiιmιde hydrochloride
TMSCI Trimethylsilyl chloride
Et3N Triethylamine
HEPES N-(2-hydroxyethyl)-piperazine-N'-(2-ethane sulfonic acid)
Ac acetyl
AcOH acetic acid amu atomic mass unit aq aqueous atm atmosphere
Bu butyl
Celite® brand of diatomaceous earth filtering agent, registered trademark of Celite Corporation d doublet dd doublet of doublet ddd doublet of doublet of doublet
DIBAL diisobutylaluminum hydride
DME dimethyoxyethane
Et ethyl
Et2O diethyl ether
Ex example g gram
Hex hexanes
1H NMR proton nuclear magnetic resonance
KOfBu potassium tø/f-butoxide
L liter
LHMDS lithium bϊs(trimethylsilyl)amide m rnultiplet
M molar mL milliliter m/z mass over charge Me methyl
MeCN acetonitrile
MeOH methanol mg milligram
MHz megahertz mmol millimole mol mole
NaOAc sodium acetate
Ph phenyl ppm parts per million
Pr propyl psi pounds per square inch q quartet qt quintet
Rf TLC retention factor rt room temperature
RT retention time (HPLC)
The percentage yields reported in the following examples are based on the starting component that was used in the lowest molar amount. Air and moisture sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. The term "concentrated under reduced pressure" refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (0C). Thin layer chromatography (TLC) was performed on pre-coated glass-backed silica gel 60 A F-254 250 μm plates
Electron impact mass spectra (El-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 μM coating; 30 m x 0.25 mm). The ion source was maintained at 2500C and spectra were scanned from 50-800 amu at 2 sec per scan.
High pressure liquid chrornatography-electrospray mass spectra (LC-MS) were obtained using either a: a) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA1 and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% to 95% B over 3.5 minutes at a flow rate of 1.0 ml_/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes. b) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2 x 23mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Spectra were scanned from 120-800 amu over 1.5 seconds. ELSD (Evaporative ugw Scattering Detector) data was also acquired as an analog channel. The eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% to 90% B over 3.5 minutes at a flow rate of 1.5 mL/min was used with an initial hold of 0.5 minutes and a final hold at 90% B of 0.5 minutes. Total run time was 4.8 minutes. An extra switching valve was used for column switching and regeneration. c) Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped with an Agilent 1100 autosampler, quaternary pump, and a diode array. The HPLC column used was a Waters Sunfire (2.1 x 30 mm, 3.5 uM). The HPLC eluent was directly coupled with a 1 :4 split to a Finnigan LTQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 50-1000 amu using a variable ion time according to the number of ions in the source in either positive or negative ion mode. The eluents were A: water with 0.1 Formic acid and B: acetoπitrile with 0.1% Formic acid. Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutes and a final hold at 95% B of 1.0 minutes. Total run time was 8.0 minutes.
Routine one-dimensional NMR spectroscopy was performed on 300/400 MHz Varian Mercury-plus spectrometers. The samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs, and transferred to 5mm ID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemical shifts were recorded on the ppm scale and were referenced to the appropriate solvent signals, such as 2.05 ppm for acetone-de, 2.49 ppm for DMSOd6 , 1-93 ppm for CD3CN, 3.30 ppm for CD3OD, 5.32 ppm for CD2CI2 and 7.26 ppm for CDCI3 for 1H spectra.
Preparative HPLC: Preparative HPLC was carried out in reversed phase mode, eluting with aqueous acetonitrile containing 0.5% TFA, typically 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 x 150 mm, 120 A). Gradient elution was used with Buffer A as water with 0.1% TFA and Buffer B as acetonitrile with 0.1 % TFA. Sample was dissolved in MeOH or MeOH/DMSO with concentration about 50 mg/mL. Injection volume was about 2-3 mL/injection. Sample was typically eluted as follows: 10-90% B over 15 minutes with flow rate of 25 mL/min, hold 2 minutes, back to 10% B. The desired fraction(s) were collected by UV monitoring at 254 or 220 nm and evaporated by using a GeneVac centrifugal vacuum instrument.
Preparative MPLC: Preparative medium pressure liquid chromatography (MPLC) was carried out by standard silica gel "flash chromatography" techniques (e.g., Still, W. C. et al. J. Org. Chem. 1978, 43, 2923-5), or by using silica gel cartridges and devices such as the Biotage Flash systems. A variety of eluting solvents were used, as described in the experimental protocols. By using these above described methods, the compounds of the invention may be prepared. The following specific examples are presented to further illustrate the invention described herein, but they should not be construed as limiting the scope of the invention in any way.
Preparation of Intermediates
Intermediate 1 Preparation of S-cyclopentyl-S-oxopropanenitrile
To a suspension of NaH (2.75 g, 68.7 mmol) in THF (15 mL) at 700C was added dropwise a solution of methyl cyclopentanecarboxylate (8.00 g, 62.4 mmol) and anhydrous acetonitrile (3.91 mL, 74.9 mmol) in THF (5 mL). The mixture was stirred for 16 h at 70°C-72°C, cooled to rt, and diluted with ethyl acetate and aqueous HCI. The organic layer was washed successively with water and brine and dried (MgSO4), filtered and concentrated under reduced pressure to provive the title compound, which was used without further purification. intermediate 2 Preparation of 5,5-dimethyl-3-oxohexanenitrile
To a mixture of acetonitrile (6.31 , 153.6 mmol) dissolved in THF (50 mL) was added LiHMDS (156.3 mL, 1.0 M solution in THF) at -780C, followed by the addition of a solution of methy! 3,3-dimethylbutanoate in THF (50 mL) at -78 0C. The reaction mixture was warmed to rt, and NaHCC>3 (100 mL, saturated solution) was added. The layers were separated and the aqueous layer was extracted with ether (3 x 100 mL). The combined organic layers were washed with brine, dried over NaaSC^, filtered, and concentrated under reduced pressure to give the desired product, which was used in the next step without purification. 1H NMR (300 MHz, CD2CI2) □ 3.47 (s, 2 H), 2.44 (s, 2 H), 1.03 (s, 9 H).
Intermediate 3 Preparation of 3-amino-3-(4-fluorophenyl)acrylonitrile.
To a solution of 4-fluorobenzonitrile (5.00 g, 41.3 mmol) and acetonitrile (4.35 mL, 82.5 mmol) in toluene (100 mL) was added potassium tert-butoxide (13.9 g, 124 mmol). The reaction mixture was stirred for 24 h, and then quenched by slow addition of aqueous sodium bicarbonate. The resulting suspension was extracted with dichioromethane (3 x 50 mL). The combined organic pharses were washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was triturated with EtOH/Et2O to afford 3-amino-3-(4-fluorophenyl)acrylonitrile (6.20 g, 93%) as a white solid. 1H NMR (300 MHz, acetone-d6) D4.23 (s, 1H), 6.20 (s, 2 H)1 7.22 (ddd, 2 H), 7.71 (m, 2 H).
Intermediate 4 Preparation of 3-tert-butyl-1 -(4-fluorophenyl)-1 H-pyrazoI-5-amine
To a solution of 4,4-dimethyl-3-oxopentanenitrile (7.54 g, 59.7 mmol) and A- fluorophenylhydrazine (10.0 g, 59.7 mmol) in anhydrous EtOH (100 mL) was added acetic acid (4.8 mL, 83.5 mL) dropwise. The reaction was stirred at reflux under N2 for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (150 mL) and aqueous saturated NaHCθ3 solution (100 mL). The organic layer was separated, washed successively with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by MPLC (eluting with 10-15% EtOAc/hexanes) to give 12.4 g (89 %) of the desired product. 1H-NMR (DMSO-d6) δ 7.59-7.53 (m, 2H), 7.30-7.22 (m, 2H), 5.36 (s, 1 H), 5.19 (br s, 2H), 1.19 (s, 9H); LC-MS /77/2 [M+H]+ 233.9, RT 1.95 min.
Intermediate 5
Preparation of 4-(5-amino-3-te/t-butyl-pyrazol-1 -yl)-benzonitrile
The title compound was prepared (85% yield) in the same manner as described for 5-te/?-butyl-2-<4-fluoro-phenyl)-2H-pyrazol-3-yIamine, replacing A- fluorophenyihydraztne with 4-cyanophenylhydrazine. LC-MS m/z [M+H]+ = 241 , RT = 2.39 min.
Intermediate 6 Preparation of 4-(5-amino-3-fert-butyl-pyrazol-1 -yl)benzoic acid
A mixture of 4,4-dimethyl-3-oxo-pentanenitrile (4.52 g, 36.15 mmol), A- hydrazinobenzoϊc acid (5.00 g, 32.86 mmol), and acetic acid (2 ml_) in EtOHTTHF (1 :1) was refluxed for 16 h. After cooling, the solvent was concentrated under reduced pressure, and the crude was re-dissolved in EtOAc. The organic layer was washed successively with saturated aqueous solution of Na2CO3 and brine, dried ( MgSO4), filtered, and concentrated under reduced pressure to half its volume. The resulting precipitate was filtered, and the solids were washed with cold EtOAc and dried under high vacuum to afford the title compound as a white solid (8.4 g, 99%). 1H-NMR (DMSO-d6) δ 12.91 (s, 1 H), 7.99 (d, J = 6.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 2H), 5.42 (s, 1 H), 5.39 (s, 2H), 1.21 (s, 9H); MS LC-MS [M+H]+ = 260, RT = 1.83 min.
Intermediate 7 Preparation of 4-(5-amino-3-fert-butyI-pyrazol-1-yl)benzoic acid methyl ester
To anhydrous methanol at O0C was added dropwise TMSCI (12.57 g, 115.0 mmol). After 10 min a solution of 4-(5-amino-3-teAt-butyl-pyrazol-1-ylbenzoic acid (3.00 g, 1 1.57 mmo!) in anhydrous methanol was added dropwise, and the reaction mixture was stirred at 800C for 16 h. The volatile solvent was removed under reduced pressure and the crude was partitioned between EtOAc and saturated aqueous solution of Na2CO3. The organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resultant solid was triturated from hexane, filtered, and dried under high vacuum to afford 2.23 g (71%) of the title compound as a solid. 1H-NMR (DMSO-d5) δ 8.07 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 12.0 Hz, 2H), 5.57 (s, 1 H), 4.97 (s, 2H), 3.90 (s, 3H), 1.26 (s, 9H); MS LC-MS [M+H]+ = 274, RT = 2.74 min.
Intermediate 8
Preparation of 4-(3-terf-butyl-5-phenoxycarbonylamino-pyrazol-1-yl)-benzoic acid methyl ester
To a solution of 4-(5-amino-3-te/f-butyl-pyrazol-1-yl)-beπzoic acid methyl ester (5.3 g, 19.4 mmol) in anhydrous THF (200 ml_) was slowly added phenyl chloroformate (6.81 mL, 54.3 mmol), followed by sodium carbonate (2.1 g, 19.4 mmol). The mixture was stirred at room temperature overnight. Ethyl acetate (500 mL) was added, followed by saturated sodium carbonate (30OmL). The organic layer was washed with saturated sodium carbonate (3x) and brine (1x), dried over MgSO4, and concentrated at reduced pressure. The residue was washed with ether to give 4.3 g (56%) of the desired product. 1H-NMR (DMSO-c/6) δ 10.19 (s, 1 H)1 8.10 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 9.0Hz, 2H), 7.38-7.1 1 (m, 5H), 6.41 (s, 1 H), 3.87 (s, 3H), 1.27 (s, 1 H); MS LC-MS [M+H]+ = 394.1 , RT = 3.53 min.
Intermediate 9 Preparation of 5-tert-butyl-2-(4-methoxyphenyl)-2W-pyrazol-3-ylamine
The title compound was prepared in the same manner as described for 4-(5- amino-3-terM->utyl-pyrazol-1-yl)benzoic acid, replacing 4-hydrazinobenzoic acid with A- methoxyphenylhydrazine. 1H-NMR (DMSOd6) δ 7.40 (d, J = 5.1 Hz1 2H)1 6.98 (d, J = 4.8 Hz1 2H)1 5.32 (s, 1 H)1 5.05 (s, 2H), 3.77 (s, 3H), 1 .20 (s, 9H); MS LC-MS [M+H]+ = 246, RT = 1.76 min.
Intermediate 10 Preparation of 4-(5-amino-3-fert-butyl-pyrazoM-y!)phenol
To a stirred solution of 5-tenf-butyl-2-(4-methoxyphenyl)-2H-pyrazol-3-ylamine (5.3 g, 21.6 mmol) in anhydrous DCM (43.2 mL) was added aluminum trichloride (14.4 g, 108.0 mmol, 5.0 eq) proportion wise, and the reaction was stirred at reflux for 18 h. The reaction mixture was cooled to rt, poured into ethyl acetate, and the organic layer was washed successively with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Crystallization from DCM/ether afforded the title compound (2.71 g, 54%) as a white solid. 1H-NMR (DMSO-^6) δ 9.47 (s, 1 H), 7.21 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 5.25 (s, 1H), 4.91 (broad s, 2H), 1.13 (s, 9H); MS LC-MS [M+H]+ = 232, RT = 1.13 min; TLC (35% EtOAc/hex), Rf = 0.13.
Intermediate 11 Preparation of 5-te/t-butyl-2-(4-cyclobutoxy-phenyl)-2H-pyrazoI-3-ylamine
A suspension of 4-(5-amino-3-terϊ-butyl-pyrazol-1-yl) phenol (1.7 g, 7.41 mmol), sodium iodide (0.33 g, 2.22 mmol), and potassium carbonate (2.56 g, 18.52 mmol) in n- butanol (15 mL) was treated with cyclobutyl bromide (2.00 g, 14.81 mmol). The reaction was then heated at 80 0C for 2 days, after which time the reaction mixture was diluted with EtOAc and water. The layers were separated and the organic phase was washed with brine, dried (MgSCU), filtered and concentrated reduced pressure. The residue was purified on the Biotage (Hexanes/EtOAc = 95/5-80/2O) to give 1.1 g (52%) of 5-tert- butyl-2-(4-cyclobutoxy-phenyl)-2H-pyrazo!-3-ylamine. 1H-NMR (DMSO-Qe) □ 7.37 (d, J = 9.2 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.30 (s, 1H), 5.04 (s, 2H), 4.68 (q, J = 7.2 Hz, 1 H), 2.47-2.39 (m, 2H)1 2.08-1.98 (m, 2H), 1.83-1.73 (m, 1 H), 1.70-1.56 (m, 1 H)1 1.19 (s, 9H); LC-MS m/z [M+H]+ = 286.2, RT = 2.28 min. Intermediate 12
Preparation of 5-tert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride
To a solution of 4,4-dϊmethyl-3-oxo-pentanenitriie (5.0 g, 40 mmol) and 3- methoxy-phenylhydrazine hydrochloride (7.0 g, 40 mmol) in anhydrous ethanol (200 ml_) was added acetic acid (1.2 mL). The reaction mixture was heated at reflux overnight, then cooled to room temperature and concentrated at reduced pressure. The residue was combined with ethyl acetate (200 mL), and washed with saturated aq NaHCθ3, water, and brine. The solution was dried (Na2SO4), filtered and concentrated evaporated under reduced pressure. The residue was re-dissolved in ethanol (100 mL). A solution of 2M HCI in ether was added and the mixture was stirred for 30 min. The solvent was removed at reduced pressure, the solid residue was triturated and washed with hexane (50 mL) and then dried in a vacuum oven overnight to give the product 5- fert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride (5.46 g, 56%) as a solid. 1H-NMR (DMSOd6) δ 7.50 (t, 1 H), 7.10 (m, 3H), 5.60 (s, 1 H), 3.80 (s, 3H), 1.30 (s, 9H); MS LC-MS [M+H]+ = 246.2, RT = 1.90 min.
Intermediate 13
Preparation of 3-(5-amino-3-te/*-butyl-pyrazol-1-yl)-phenol
In a 500 ml_ round bottom flask was added 5-terf-butyI-2-(3-methoxy-phenyl)- 2H-pyrazol-3-ylamiπe hydrochloride (8.42g, 30 mmol) and pyridinium hydrochloride (13.8 g, 120 mmol). The reaction mixture was heated neat at 195 0C with stirring for 3 h. The mixture was cooled to room temperature, water (300 ml_) and EtOAc (300 ml.) were added, and then the organic phase was washed with saturated aqueous solution of NaHCO3 and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC (80:20 hexane/EtOAc) to give the product 3-(5-amino-3- tert-butyl-pyrazol-1-yl)-phenol (1.3 g, 19%). 1H-NMR (DMSO-Cf6) δ 7.20 (t, 1H), 7.00 (m, 2H)1 6.50 (d, 1H)1 5.30 (s, 1 H), 5.10 (bs, 2H)1 1.30 (s, 9H); MS LC-MS [M+H]+ = 232.2, RT = 0.57 min.
Intermediate 14
Preparation of 5-terf-Butyl-2-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1 ,4]dioxin-6- yl)-2//-pyrazol-3-ylamine
Step 1 : Preparation of Λ^Benzhydrylidene-/V -(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1 >4]- dioxin-6-yl)hydrazine
To a degassed solution of 6-bromo-2,2,3,3-tetrafluoro-1 ,4-benzodioxane (1.75 g, 6.10 mmol), benzophenone hydrazone (1.32 g, 6.71 mmol, 1.1 eq), and 9,9-dtmethyl- 4,5-bis(dephenylphospino)xanthene (176 mg, 0.30 mmol, 0.05 eq) in anhydrous toluene (13 mL) was added sodium te/f-butoxide (1.41 g, 14.6 mmol, 2.4 eq) and palladium (II) acetate (68.4 mg, 0.30 mmol, 0.05 eq). The reaction mixture was stirred at 85 0C under nitrogen for 17h, cooled to rt, and then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (NSaSO4), filtered and concentrated under reduced pressure. Purification by MPLC eluted with 3% EtOAc/hexane afforded the title compound (1.31 g, 53.4%) as an oil. MS LC-MS [M+H]+ = 403.2, RT = 4.61 min; TLC [10% EtOAc/hex], Rf = 0.47.
Step 2: Preparation of 5-fe/f-Butyl-2-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1 ,4]dioxin-6- yl)-2H-pyrazol-3-ylamine
To a solution of Λ/-benzhydrylidene-/V'-(2,2,3,3-tetrafluoro-2I3-dihydro-benzo[1 ,4]-dioxin- 6-yl)hydrazine (1.31g, 3.26 mmol), 4,4-dimethyl-3-oxopentanenitrile (489 mg, 3.91 mmol, 1.2 eq) in anhydrous ethanol (21.7 mL) was added p-toluenebenzene sulfonic acid (312.9 mg, 3.26 mmol, 1.0 eq), and the reaction mixture was stirred under nitrogen at 80 0C for 18h. Concentrated HCI (3.3 mL) was added, and the reaction mixture was stirred at reflux for an additional 4 h. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc (500 ml_) and aqueous saturated NaHCO3 solution (300 mL). The organic layer was separated, and then washed successively with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by MPLC eluted from 1 to 5% EtOAc/hexane to give 910 mg (80.9%) of the title compound as an orange solid. 1H-NMR (DMSO-cfe) D 7.62 (dd, J = 1.8 Hz, 1.0 Hz, 1H), 7.56 to 7.53 (m, 2H), 5.39 (s, 1H), 5.37 (broad s, 2H), 1.19 (s, 9H); MS LC-MS [M+Hf = 346.2, RT = 3.19 min;
Intermediate 15
Preparation of ethyl [4-(5-amino-3-tert-butyl-1H-pyrazoI-1 -yl)phenyl]acetate hydrochloride
Step 1. Preparation of ethyl (4-hydrazinophenyl)acetate hydrochloride
A solution of sodium nitrite (NaNθ2, 4.04g, 58.6 mmol) in H2O (20 mL) was added to a cooled (-50C, ice-salt) solution of ethyl 4-aminophenylacetate (10 g, 55.8 mmol) in HCI (55 mL, concentrated aqueous solution), at a rate such that the temperature did not exceed O0C. The mixture was stirred at O0C for 10 min and then added portion-wise to a cooled (-50C1 ice-salt) and rapidly-stirred solution of tin(ll) chloride (SnCI2, 39.67g, 209.2 mmol) in HCI (30 ml_, concentrated aqueous solution), at a rate such that the temperature did not exceed O0C. The resulting suspension was warmed to 250C and stirred for 3 h, and then filtered. The collected solid was washed successively with water and ether, and then air-dried to afford the desired product as a solid (HCI salt). A precipitate formed in the filtrate upon standing for 16 h, and the solid was collected by filtration, washed with water and ether, and air-dried. The combined solids were afforder 11.3 g (88% yield) of the title compound. 1H-NMR (DMSO-Ct6) δ 8.85 (broad, 2H), 7.73 (broad, 1 H)1 7.10 (d, J = 8.4 Hz, 2H)1 6.82 (d, J = 8.4 Hz1 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.53 (s, 2H)1 1.16 (t, J = 7.1 Hz1 3H); MS LC-MS [M+Hf = 195.0, RT = 1.11 min.
Step 2. Preparation of ethyl [4-(5-amino-3-terf-butyl-1 H-pyrazol-1-yl)phenyl]acetate hydrochloride
The title compound was prepared in the same manner as described for 5-tert- butyl-2-(4-fluoro-phenyl)-2/-/-pyrazol-3-ylamine, replacing 4-fluorophenylhydrazine with ethyl (4-hydrazinophenyl)acetate hydrochloride (11.98 g, 51.9 mmol). The title compound was obtained as a solid (HCI salt, 11.95 g) in 68% yield. 1H-NMR (DMSO- d6) δ 7.52 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 5.59 (s, 1 H)1 4.08 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 1.27 (s, 9H), 1.20 (t, J = 7,1 Hz, 3H); MS LC-MS [M+Hf = 302.3, RT = 2.44 min.
Intermediate 16
Preparation of ethyl (4-{3-fert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazo1-1- yl}phenyl)acetate
To a suspension of ethyl [4-(5-amino-3-fe/f-butyl-1H-pyrazol-1- yl)phenyl]acetate (10 g, 33.2 mmol) and K2CO3 (9.17 g, 66.4 mmol) in THF (300 ml_) was added phenyl chloroformate (8.61 mL, 66.4 mmol), and the resulting reaction mixture was stirred at room temperature overnight. The mixture was poured into a mixture of water and EtOAc and the organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by MPLC (0% to 20% EtOAc in hexane) to afford the title compounds as a solid (10.6 g) in 76% yield. 1H-NMR (400 MHz1 CD2CI2) 6 7.51 - 7.10 (m, 10H), 6.47 (S1 1H), 4.16 (q, J = 7.1 Hz1 2H), 3.71 (S1 2H), 1.37 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H).
Intermediate 17 Preparation of 4-(4-amino-3-fluorophenoxy)pyridin-2-amine
Step 1 : Preparation of 4-chloropyridine-2-carbonyl chloride
To a suspension of pyridine-2-carboxylic acid (2 g, 16.25 mmol) in chlorobenzene (5 ml) was added thionyl bromide (0.17g, 0.81 mmol), and the reaction mixture was heated to 70 0C. Thionyl chloride (4.1 ml, 56.05 mmol) was then added at a rate that maintained the internal temperature below 800C. The reaction mixture was stirred under nitrogen for 16 h at 70 0C, cooled to rt, and then concentrated under reduced pressure. The resulting orange oil was concentrated from toluene (3 x 2OmL) then dried under mechanical vacuum for 16 h. The product, 4-chloropyridine-2-carbony! chloride hydrochloride, was a dark green oil that solidified upon standing (2.7 g, 78%). 1H-NMR (CDCI3) δ 7.60 (dd, 1 H), 8.11 (m, 1H), 8.73 (d, 1H); LC/MS RT = 1.08 min.
Step 2: Preparation of 4-chloropyridine-2-carbonyl chloride
To a chilled (0 0C) solution of ammonium hydroxide (100 ml_, 28% solution in water) was added portion-wise a solution of 4-chloropyridine-2-carbonyl chloride hydrochloride (5 g, 23.53 mmol) in THF (30 ml). A precipitate appeared, and the reaction mixture was stirred for 1 h. The solid was collected by filtration and washed successively with diethyl ether and hexane. The solid was air dried to afford 4- chloropyridine-2-carboxamide (2.3 g, 63%): 1H-NMR (DMSO-cfe) 7.74 (dd, 5.3 Hz, 1H), 7.8 (s, 1 H), 8.00 (d, 1 H), 8.19 (s, 1 H), 8.59 (d, 1H); LC/MS m/z [M+Hf = 157.2, RT = 1.86 min.
Step 3: Preparation of 4-chloropyridin-2-amine
The reaction flask was charged with water (200 ml_) and potassium hydroxide (35.83 g, 638.68 mmol) and cooled to 5° C. Upon dissolution bromine (7.4 ml_, 143.7 mmol) was added portion-wise over 1 h, then 4-chloropyridine-2-carboxamide (10 g, 63.87 mmol) was added and the reaction mixture was slowly heated to 60 0C. After holding 2 h, the reaction mixture was cooled to 15 0C and acetic acid (20 mL) was added drop-wise. The reaction mixture was heated to 55 °C for 30 min, then cooled to 5 0C. Potassium hydroxide was added to ajust to pH of the mixture to 13. The resulting mixture was extracted with ethyl acetate, and then the organic phase was washed with brine and concentrated under reduced pressure to afford the title compound as a solid (4.9 g, 60%): 1H-NMR (DMSO-d6) δ 6.23 (s, 2H), 6.44 (d, 1 H), 6.51 (dd, 1 H), 7.83 (d, 5.5Hz, 1 H); LC/MS m/z [M+H]+ = 129.1 , RT = 1.12 min.
Step 4: Preparation of 4-chloro-2-(2,5-dimethyl-1 H-pyrrol-1-yl)pyridine
A 50 (TiL flask was fitted with a thermocouple and Dean Stark apparatus and condenser. The flask was then charged with 4-chloropyridin-2-amine (2 g, 15.6 mmol), acetonyl acetone (1.95 g, 17.1 mmol), p-toluene sulfonic acid monohydrate (0.29 g, 1.56 mmol) and toluene (20 ml_). The reaction was heated to reflux and stirred under nitrogen for 8 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. The residue was dissolved in EtOAc, and the organic solution was washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting oil was filtered through a pad of silica gel (eluent: gradient from 0% to 20% EtOAc in hexanes). The desired fractions were combined and concentrated under reduced pressure to give 4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (3.1 g, 96 %): 1H-NMR (DMSO-de) δ 2.05 (s, 6H), 5.79 (s, 1 H), 7.60 (dd, 1 H), 7.63 (d, 1H), 8.54 (d, 1H); LC/MS m/z [M+H]+ = 207.1, RT = 3.43 mm.
Step 5: Preparation of 4-{[2-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-4-yl]oxy}-2-fluoroaniline
Potassium f-butoxide (3.94 g, 35.1 mmol) was added portion-wise to a cooled (0c C) mixture of 4-amino-3-fluorophenol (3.08 g, 24.2 mmol) and DMSO (35 ml_). The resulting dark mixture was stirred and flushed with nitrogen for 5 min. 4-Chloro-2-(2,5- dimethyl-1 H-pyrrol-1-yl)pyridine (5 g, 24.2 mmol) was added to the reaction and the mixture was stirred for 16 h at 90.0C. The reaction was cooled to rt, brine (30 ml) was added, and the product was extracted with EtOAc (2 x 60 ml). The combined organic phases were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10 - 30% EtOAc in hexane) to give 4-{[2-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-4- yi]oxy}-2-fluoroaniliπe (1.5 g, 21%): 1H-NMR (DMSO-d6) δ 2.02 (s,6H), 5.21 (s, 1H), 5.75 (S, 1H)1 6.73 (d, 1 H)1 6.80 (m, 2H), 6.88 (dd,1 H), 7.02 (m, 1H),8.38 (d, 1H); LC/MS m/z [M+H]+ = 298.2, RT = 3.06 min.
Step 6: Preparation of 4-(4-amino-3-fluorophenoxy)pyridin-2-amine
4-{[2-(2,5-Dimethyl-1H-pyrrol-1-yl)pyridin-4-yl]oxy}-2-fluoroaniline (6.5 g, 21.86 mmol) was treated with: ethanol (117 mL), water (43 mL), hydroxylamine hydrochloride (7.1 g, 102.75 mmol) and triethylamine (7.6 mL, 54.65 mmol). The reaction was heated to reflux and stirred under nitrogen for 16 h. The resulting solution was cooled to room temperature and extracted with EtOAc. The combined organic phases were . washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 1 % MeOH/ DCM to 3% methanolic ammonia/ DCM gradient) to give 4-(4-amino-3-fluorophenoxy)pyridin-2-amine, a solid (2.04 g, 43%): 1H- NMR (DMSO-de) δ 5.11 (s, 2H), 5.74 (d, 1 H)1 5.87 (s, 2H)1 6.08 (dd, 1H), 6.68 (m, 1 H), 6.79 (t, 1 H), 6.88 (dd, 1 H), 7.73 (d, 1 H); LC/MS m/z [M+H]+ = 220.1 , RT = 2.01 min. Intermediate 18 Preparation of 4-(4-amino-phenoxy)-pyridin-2-ylamine
Step 1. Preparation of 4-chloro-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine
A mixture of 4-chloro-pyridin-2-ylamine (15.4 g, 120 mmol), acetonylacetone (15.0 g, 132 mmol) and p-toluenesulfonate acid monohydrate (2.28 g, 12.0 mmol) in anhydrous toluene (150 mL) was heated at reflux under nitrogen gas for 4 h, using a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate (200 mL). The solution was washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by MPLC (80:20 hexanes/EtOAc) to give 19.5 g (79%) of the desired product. 1H-NMR (DMSOd6) δ 8.54 (d, J = 5.4 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.57 (dd, J = 1.8, 5.4 Hz, 1H), 5.79 (s, 2H), 2.04 (s, 6H); MS LC-MS [M+Hf = 207, RT = 3.14 min.
Step 2. Preparation of 4-[2-(2,5-dimethyl-pyrrol-1-yl)-pyridin-4-yloxy]-phenylarnine
To a solution of 4-amino-phenol (7.92 g, 72.6 mmol) in anhydrous DMF (250 mL) was added potassium te/t-butoxide (8.55 mL, 76.2 mmol), and the resulting mixture was stirred at room temperature under N2 for 1 h. A solution of 4-chloro-2-(2,5-dimethyl- pyrrol-1-yl)-pyridine (15.0 g, 72.6 mmol) in anhydrous DMF (50 mL), followed by potassium carbonate (5.52 g, 39.9 mmol) were added to the solution, and the reaction mixture was stirred at 900C under N2 for 5 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (500 m!_). The solution was washed with water and brine, dried (Na2SCM), and concentrated under reduced pressure. The residue was purified by MPLC (50:50 hexanes/EtOAc) to give 18.0 g (89%) of the title product. 1H- NMR (DMSO-d6) δ 8.37 (d, J =6.0 Hz, 1H), 6.88 to 6.84 (m, 3H), 6.65 (d, J = 2.1 Hz, 1 H), 6.61 (dd, J = 2.4, 6.6 Hz, 2H), 5.74 (s, 2H), 5.15 (s, 2H), 2.00 (s, 6H); LC-MS m/z [M+H]+ = 280, RT = 2.16 min.
Step 3. Preparation of 4-(4-amino-phenoxy)-pyridin-2-ylamine
To a solution of 4-[2-(2,5-dimethyl-pyrrol-1-yl)-pyridin-4-yloxy]-phenylamine (10.0 g, 35.8 mmol) in a mixture of EtOH (100 mL) and water (50 mL) was added hydroxylamine hydrochloride (24.9 g, 358 mmol) followed by triethylamine (7.23 g, 71.6 mmol). The resulting reaction mixture was heated at reflux for 3 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL), and the solution was washed successively with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by MPLC (50:50 hexanes/EtOAc) to give 6.5 g (90%) of the desired product. 1H-NMR (DMSO-cfe) δ 7.70 (d, J = 5.7 Hz, 1 H), 6.75 (dd, J = 2.1 , 8.7 Hz, 2H), 6.58 (dd, J = 2.1 , 8.7 Hz, 2H), 6.04 (dd, J = 2.4, 6.0 Hz, 1 H)1 5.81 (s, 2H)7 5.71 (d, J = 2.4 Hz, 1 H), 5.04 (s, 2H); MS LC-MS [M+ H]+ = 202, RT = 1.02 min.
Intermediate 19 Preparation of 4-(4-amino-3,5-difluorophenoxy)pyridin-2-amine
Step 1: Preparation of 5-(benzyloxy)-1 ,3-difluoro-2-nitrobenzene
A mixture of 1 ,3,5-trifluoro-2-nitrobenzene (5 g, 28.24 mmol), benzyl alcohol (2.92 ml, 28.24 mmol), and potassium carbonate (5.85 g, 42.35 mmol) in DMF (8 mL) was stirred at rt for 16 h. Water (24 mL) was added to the reaction mixture, which was then refrigerated for 48 h. The resulting precipitate was collected by filtration, washed with water, air dried, and purified by silica gel column (hexane : EtOAc = 9 : 1). A mixture of the desired product and its isomer of 1-(benzyloxy)-3,5-difluoro-2- nitrobenzene (about 1 :1 ratio) was obtained in 64% yield. LC-MS m/z [M+H]+ =265.7, RT = 3.58 min.
Step 2: Preparation of 4-amino-3,5-dif!uorophenol
A mixture of 5-(benzyloxy)-1 ,3-difluoro-2-nitrobenzene and its isomer of 1- (benzyloxy)-3,5-difluoro-2-nitrobenzene (4.77 g, 18 mmol) in MeOH (180 ml) and 10% palladium on carbon was stirred in H2 (1 atm) for 16 h. The excess hydrogen was evacuated and the mixture was filtered through a pad of Celite® . The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography. A mixture of 4-amino-3,5-difluorophenol and 2-amino-3,5- difluorophenol were obtained as a light brown solid (2.2 g) in 84% yield. LC-MS m/z [M+H]+ =146.2, RT = 1.11 min.
Step 3: Preparation of 4-{[2-(2,5-dimethyl-1 H-pyrrol-1-yl)pyridin-4-yl]oxy}-2,6- difluoroaniline
A mixture of 4-amino-3,5-difluorophenol and 2-amino-3,5-difluorophenol (1.95 g, 13.44 mmol) and potassium f-butoxide (2.19 g, 19.49 mmol) in DMSO (20 ml) was stirred at rt for 5 min before 4-chloro-2-(2,5-dimethyl-1 H-pyrrol-1-yl)pyridine (2.50 g, 12.09 mmol) was added at once. The resulting reaction mixture was heated at 900G overnight, then cooled to rt. Water was added, and the pH of the solution was adjusted to ~8-9 using HCI (1 N aqueous solution). The aqueous mixture was extracted with ether, and then the organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 15/85) to afford the title compound as a 1 :1 mixture with 2-{[2-(2)5-dimethyl-1H-pyrrol-1-yl)pyridin-4-yl]oxy}-4,6-difluoroaniline in 30% yield (1.26 g). The mixture was further purified using a preparative HPLC to provide the title compound as the TFA salt (0.6 g). LC-MS m/z [M+H]+ = 316.2, RT = 3.24 min.
Step 4: Preparation of 4-(4-amino-3,5-difluorophenoxy)pyridin-2-amine
A solution of 4-{[2-(2,5-dimethyl-1 H-pyrrol-1-yl)pyridin-4-yl]oxy}-2,6-difluoroaniline TFA salt (0.6 g, 1.4 mmol), hydroxylamine hydrochloride (485 mg, 6.99 mmol), and triethylamine (0.49 mi_, 3.49 mmol) in EtOH/H2O (7.5 mL/ 2.5 mL) was heated at 750C for 5 h. A saturated aqueous solution of NaHCθ3 was added, and the mixture was extracted with EtOAc. The organic phase was separated, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the title compounds as a solid (270 mg) in 81% yield. 1H-NMR (CD2CI2) δ 7.84 (d, J = 6.1 Hz, 1 H), 6.66 (m, 2H), 6.27 (dd, JJ = 2.3 Hz, 6.1 Hz, 1 H), 5.94 (d, J = 2.1Hz, 1 H), 5.03 (b, 2H), 3.76 (b, 2H); LC-MS m/z [M+H]+ = 238.2, RT = 1.26 mln.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the following invention to its fullest extent. The following specific preferred embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the forgoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
EXAMPLES
The invention will be explained below with reference to the following non-limiting examples.
Example 1
Preparation of 1-[4-(2-amino-pyridin-4-yloxy)-phenyl]-3-[5-fert-butyl-2-(4-fluoro- phenyl)-2H-pyrazol-3-yl]-urea
Step 1 : Preparation of 1-[5-tert-butyl-2(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-{4-[2-(2,5- dimethyl-pyrrol-1-yl)-pyridin-4-yloxy]-phenyl}-urea
δ
To a solution of [5-fe/t-butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-carbamic acid phenyl ester (1.27 g, 3.58 mmol) [prepared using a similar method to the one described for Intermediate 8] in anhydrous THF (20 ml_) was added 4-[2-(2,5-dimethyl-pyrrol-1- yl)-pyridin-4-yloxy]-phenylamine (Intermediate 18, step 2; 1.00 g, 3.58 mmol), the reaction mixture was stirred at 600C under N2 for 18 h. The reaction mixture was cooled to room temperature and dissolved in EtOAc (100 ml_). The solution was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The crude residue was purified by silica gel flash chromatography (Hexanes/EtOAc = 50/50) to give 1.50 g (78%) of the desired product. 1H-NMR (acetone-d6) δ 8.70 (s, 1H), 8.42 (d, J = 6.6 Hz, 1 H)1 8.03 (s, 1H)1 7.58 to 7.65 (m, 4H), 7.25 to 7.30 (m, 2H), 7.18 to 7.20 (m, 2H), 6.95 (d, J = 6.6 HZ, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.42 (s, 1H), 5.76 (s, 2H), 2.82 (s, 3H), 2.80 (s, 3H)1 2.08 (s, 9H); LC-MS m/z [M+H]+ = 539.1 , RT = 3.80 min.
Step 2: Preparation of 1-{4-(2-amino-pyridin-4-yloxy)-phenyl]-3-[5-te/t-butyl-2-(4-fluoro- phenyl)-2H-pyrazol-3-yl]-urea
To a solution of 1-[5-fert-butyl-2(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-{4-[2-(2,5- dimethyl-pyrrol-1-yl)-pyridin-4-yloxy]-phenyl}-urea (1.10 g, 2.04 mmol) in a mixture of EtOH (10 ml_) and H2O (5 ml_) was added hydroxylamine hydrochloride (1.42 g, 20.4 mmol) followed by triethylamine (0.41 g, 4.08 mmol), and the reaction mixture was refluxed for 6 h. The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc (100 mL). The solution was washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (CH2CI2/MeOH = 90/10) to give 0.14 g (15%) of the desired product. 1H-NMR (DMSO-cfe) δ 9.08 (s, 1H), 8.38 (s, 1 H)1 7.76 (d, J = 6.6 Hz, 1 H), 7.32 to 7.56 (m, 6H), 7.00 to 7.05 (m, 2H), 6.37 (s, 1 H), 6.06 to 6.09 (m, 1 H), 5.88 (S1 2H), 5.76 (s, 1 H), 1.25 (s, 9H). MS LC-MS [M+H]+ = 461.0, RT = 2.56 min.
Example 2
Preparation of 1 -[4-(2-Amino-pyridin-4-yIoxy)-phenyl]-3-[5-te/t-buty1-2-(4- cyclobutoxy-phenyl)-2H-pyrazol-3-yl]-urea.
Step 1 : To a suspension of 5-te/t-butyl-2-(4-cyclobutoxy-phenyl)-2H-pyrazol-3-ylamine (Intermediate 11 , 1.05 g, 3.66 mmol) and potassium carbonate (2.02 g, 14.63 mmol) in THF (10 ml_) was added phenyl chloroformate (1.89 g, 12.07 mmol). The reaction was stirred at room temperature under nitrogen for 18 h. The mixture was then diluted with EtOAc, washed successively with NaHCθ3 (saturated aqueous solution) and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (hexanes/EtOAc = 90/10-85/15) to give 1.22 g (82%) of [5-tørf-butyl-2-(4-cyclobutoxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid phenyl ester. 1H-NMR (DMSO-c/6) δ 9.89 (bs, 1 H), 7.36 (d, J = 9.0 Hz, 2H), 7.37-7.03 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 6.28 (s, 1 H), 4.73 (q, J = 7.1 Hz, 1H), 2.47-2.41 (m, 2H), 2.10- 2.00 (m, 2H), 1.83-1.71 (m, 1H), 1.69-1.61 (m,1 H), 1.26 (s, 9H).
Step 2: A solution of [5-te/t-butyl-2-(4-cyclobutoxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid phenyl ester (0.1 g, 0.25 mmol) and 4-(4-amino-phenoxy)-pyridin-2-ylamine (0.05 g, 0.25 mmol) in THF (1mL) was stirred at room temperature for 48 h. The reaction mixture was diluted with DCM and purified by silica gel flash chromatography (DCM/MeOH = 99/1-95/5) to give 0.12 g (96%) of the desired product. (DMSO-αy δ 9.04 (s, 1 H), 8.28 (s, 1 H), 7.74 (d, J = 5.6 Hz, 1H), 7.43 (d, J = 8.9 Hz, 2H)1 7.35 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.31 (s, 1H), 6.08 (dd, J = 2.2 & 5.7 Hz, 1H), 5.88 (bs, 2H), 5.74 (d, J = 2.1 Hz, 1 H), 4.72 (q, J = 7.1 Hz, 1H), 7.25- 2.41 (m, 2H)1 2.10-2.00 (m, 2H), 1.83-1.75 (m, 1 H), 1.71-1.61 (m, 1 H), 1.26 (s, 9H); MS LC-MS [M+H]+ = 513.2, RT = 2.82 min.
Example 3
Preparation of N-{4-[(2-aminopyridin-4-yl)oxy]-2,6-difluorophenyl}-N'-[3-tert-butyl-1-(4- methylphenyl)-1 H-pyrazoI-5-yl]urea
A solution of phenyl [3-tert-butyl-1-(4-methylphenyl)-1 H-pyrazol-5-yl]carbamate (100 mg, 0.29 mmol) [prepared using a method similar to the one described for Intermediate 8] and 4-(4-amino-3,5-difluorophenoxy)pyridin-2-amine (Intermediate 19, 65 mg, 0.27 mmol) in THF (1 ml) was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC. The product was obtained as a solid (TFA salt, 20 mg). 1H-NMR (DMSO-cfe) δ 8.67 (s, 1 H), 8.62 (s, 1 H), 7.95 (d, J = 7.3 Hz, 1 H), 7.88 (b, 1 H), 7.38 (m, 2H), 7.31 - 7.28 (m, 4H), 6.67 (dd, J = 2.5 Hz, 7.2 Hz, 1 H), 6.28 (s, 1H), 6.17 (d, J = 2.5Hz, 1H), 2.36 (s, 3H), 1.26 (s, 9H); LC-MS m/z [M+H]+ = 493.1 , RT = 2.56 min.
The following compounds were prepared using the procedure of Examples 2 and 3, and substituting for the appropriate starting materials.
Table 1 :
Example 43
Preparation of N-{4-[(2-aminopyridin-4-yl)oxy]-2,6-difluorophenyl}-N'-[3-tert-butyl-
1-(4-fluorophenyl)-1H-pyrazol-5-yl]urea
To a solution of 3-fe/t-butyl-1-(4-fluorophenyl)-1 H-pyrazol-5-amine (Intermediate 4, 60 mg, 0.26 mmol) and diisopropylethylamine (0.05 ml, 0.31 mmol) in CH2CI2 (2 mL) was added a solution of triphosgene (38 mg, 0.13 mmo!) in CH2Cl2 (1 mL). The resulting reaction mixture was stirred at rt for 1h before a cloudy solution of 4-(4-amino-3,5- difluorophenoxy)pyridin-2-amine (61 mg, 0.26 mmol) in CH2CI2/THF (0.5 mL/ 0.5 mL) was added. The reaction mixture was stirred at rt for 16 h, concentrated under reduced pressure. The residue was purified by preparative HPLC to give the tite compound as the TFA salt, which was free-based using CH2CI2 and Na2Cθ3 (saturated aqueous solution) to provide 27 mg of the title compound. 1H-NMR (DMSO-cfe) § 8.64 (s, 1 H), 8.39 (s, 1 H)1 7.81 (d, J = 5.7 Hz, 1 H), 7.53 (m, 2H), 7.33 (t, J = 8.8 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 6.29 (s, 1 H), 6.16 (dd, J = 2.2 Hz, 5.8 Hz, 1 H), 6.04 (b, 2H), 5.89 (d, J = 2.0 Hz, 1 H), 1.26 (s, 9H); LC-MS [M+H]+ = 497.1 , RT = 2.49 min.
Example 44
Preparation of 1 -[4-(2-Amino-pyridin-4-yloxy)-2-fluoro-phenyl]-3-[5-fert-butyl-2-(4- fluorophenyl)-2H-pyrazol-3-yl]urea
To a solution of 5-terf-butyl-2-(4-fluorophenyl)-2H-pyrazol-3-ylamine (Intermediate 4, 3.0 g, 12.86 mmol, 1.15 eq) in anhydrous 1 ,2-dichloroethane (20 ml_) was added CDI (2.4 g, 14.5 mmol, 1.3 eq), and the reaction was stirred under nitrogen at 50 0C for 3.5 h. A solution of 4-(4-amino-3-fiuorophenoxy)pyridin-2-y]amine (2.5 g, 11.2 mmol, 1.0 eq) in anhydrous THF (15 ml_) and 1 ,2-dichloroethane (15 ml_) was added to the reaction mixture which was stirred under nitrogen at 45 0C for 17 h. The reaction mixture was partitioned between EtOAc (500 mL) and water (300 ml_). The organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by MPLC, and then recrystallized from ethanol to give 2.5 g (46.7%) of white solid. 1H-NMR (DMSO- cfe) δ 8.9 (s, 1 H)1 8.77 (s, 1 H), 8.00 (t, J = 9 Hz, 1 H), 7.78 (d, J = 5.7 Hz, 1H), 7.56 to 7.50 (m, 2H), 7.41 to 7.33 (m. 2H), 7.14 (dd, J = 12.3 Hz, 2.7 Hz, 1 H), 6.92 (ddd, J = 9 Hz1 2.4 Hz, 1.8 Hz, 1 H), 6.37 (s, 1H), 6.11 (dd, J = 6 Hz1 2.1 Hz, 1H), 5.93 (broad s, 2H), 5.80 (d, J = 2.1 Hz, 1H), 1.25 (s, 9H); MS LC-MS [M+H]+ = 479.2, RT = 2.68 min; TLC [75% EtOAc/hex], R, = 0.14.
The following compounds were prepared using the procedure of Examples 43 and 44, and substituting for the appropriate starting materials. Table 2:
-120-
The examples described above can be further functionalized using methods known to one skilled in the art. For an example, the preparation of chlorinated compounds of is described below:
Example 80 and Example 81
Preparation of 1 -[4-(2-Amino-pyridin-4-yloxy)-2-fluoro-phenyl]-3-[5-ferf-butyI-4- chloro-2-(4-fluorophenyl)-2H-pyrazol-3-yl]urea and 1-[4-(2-Amino-5-chloropyridin- 4-yloxy)-2-fIuorophenyl]-3-[5-fe/t-butyl-4-chloro-2-(4-fluorophenyl)-2W-pyrazol-3- yl]urea.
Both products are generated from the same reaction, but they were best isolated as described below:
Preparation of 1 -[4-(2-Amino-pyridin-4-yloxy)-2-fluoro-phenyl]-3-[5-ferf-butyl-4- chloro-2-(4-fluorophenyl)-2H-pyrazol-3-yl]urea
To a solution of 1-[4-(2-aminopyridin-4-yloxy)-2-fluoro-phenyl]-3-[5-tert-butyl-2-(4- fluorophenyl)-2H-pyrazol-3-yl]urea (Example 44, 121.9 mg, 0.25 mmol) in anhydrous CHCI3 (2.5 mL) and THF (1.3 ml_) was added /V-chlorosuccinimide (37.4 mg, 0.28 mmol, 1.1 eq), and the reaction mixture was stirred at rt for 3 days. The reaction concentrated under reduced pressure and the residue purified by preparative HPLC (RT = 8.39 min) and then re crystallized from DCM - hexane to afford 10.2 mg (7.8%) of the title compound as a white solid. 1H-NMR (DMSO-c/6) δ 8.98 (s, 1 H), 8.56 (s, 1 H), 7.89 (t, J = 8.7 Hz, 1 H), 7.78 (d, J = 5.7 Hz, 1 H), 7.60 to 7.55 (m, 2H), 7.38 to 7.31 (m, 2H), 7.47 (dd, J = 11.7 Hz, 2.7 Hz, 1 H), 6.91 (ddd, J = 9.0 Hz, 3.0 Hz, 1.5 Hz, 1H), 6.14 (dd, J = 6.0 Hz, 2.1 Hz, 1 H), 6.00 (broad S1 2H), 5.81 (d, J = 2.4Hz, 1 H), 1.38 (s, 9H); LC-MS m/z [M+H]+ = 513.2, RT = 2.97 min.
Preparation of 1 -[4-(2-Amino-5-chloropyridin-4-yloxy)-2-fluorophenyl]-3-[5-te/t- butyl-4-chloro-2-(4-fluorophenyl)-2/-/-pyrazol-3-yl]urea
To a solution of 1-[4-(2-aminopyridin-4-yloxy)-2-fluoro-phenyl]-3-[5-feAf-butyl-2-(4- fluorophenyl)-2H-pyrazol-3-yl]urea (Example 44, 121.9 mg, 0.25 mmol) in anhydrous CHCI3 (2.5 ml_) and THF (1.3 mL) was added /V-chlorosucciπimide (37.4 mg, 0.28 mmol, 1.1 eq), and the reaction mixture was stirred at rt for 3 days. The reaction mixture was concentrated under reduced pressure and the residue purified by preparative HPLC (RT = 8.79 min) followed by MPLC eluted with 35% EtOAc/hexane. The product was recrystalϋzed from DCM - hexane to afford 3.5 mg (2.5%) of the title compound as a white solid. 1H-NMR (400 MHz, CD3OD) δ 7.93 to 7.85 (m, 2H), 7.60 to 7.54 (m, 2H)1 7.26 to 7.20 (m, 2H), 7.02 (dd, J = 11.7, 2.4 Hz, 1 H), 6.91 (ddd, J = 9.0 Hz, 2.7 Hz, 1.5 Hz, 1 H), 5.92 (s, 1 H), 1.44 (s, 9H); MS LC-MS m/z [M+H]+ = 547.4, RT = 3.07 min.
Example 82
Preparation of 1 -{4-r(2-aminopyridin-4-yl)oxyl-2-fluorophenyl}-3-H -(3- fluorophenvO-3-isopropyl-1H-pyrazol-5-vπurea
Step 1. Preparation of 4-methyl-3-oxopentanenitrile
To a solution of LiHMDS (500 mL, 1.0M in THF, 500 mmol) at -78 0C, was added CH3CN (26.3 mL, 500 mmol). After 60 min, methyl 2-methylpropanoate (25.2 g, 250 mmol) was added, and the reaction mixture was let to warm to rt over 16 h. Water (500 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residual aqueous mixture was extracted with ethyl ether, and the combined organic layers were extracted with 0.5N NaOH. The combined aqueous layers were acidified using HCI (cone, aqueous solution), then extracted with EtOAc. The combined organic layers were dried (^2SO4), filtered and concentrated to give the title compound (28 g, > 98% yield) as an oil. 1H-NMR (CD3CN) δ 1.07 (d, 6H), 2.74 (septet, 1 H)1 3.76 (s, 2H); LC/MS m/z [M+H]+ = 112.2, RT = 1.31 min.
Step 2. Preparation of 1-(3-fluorophenyl)-3-isopropyl-1 H-pyrazol-5-amine
To a solution of 4-methyl-3-oxopentanenitrile (15 g, 135 mmol) and 3- fluorophenylhydrazine hydrochloride (21.9 g, 135 mmol) in anhydrous EtOH (225 ml.) was added acetic acid (10.8 ml_, 188 mL) dropwise. The reaction was stirred at reflux under N2 for 18 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. The residue was partitioned between EtOAc (150 mL) and aqueous saturated NaHCO3 solution (100 mL). The organic layer was separated, washed successively with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was then triturated using a 1 :1 mixture of Et.20 and hexanes to give the title compound as a solid (18.5 g, 63% yield). 1H-NMR (CDCI3) δ 7.44-7.32 (m, 3H)1 7.03-6.96 (m, 1H)1 5.49 (s, 1 H)1 3.80 (broad, 2H)1 2.91 (sept., 1H)1 1.26 (d, 6H); LC/MS m/z [M+Hf = 220.2, RT = 2.16 min. Step 3. Preparation of phenyl ri-(3-fluorophenyl)-3-isopropyl-1 H-pyrazol-5- ylicarbamate
To a solution of 1-(3-fluorophenyl)-3-isopropyl-1H-pyrazol-5-amine (13.5 g, 61.7 mmol) in anhydrous THF (870 mL) was slowly added phenyl chloroformate (24.2 mL, 154.3 mmol), followed by potassium carbonate (34.1 g, 246.8 mmol). The mixture was stirred at room temperature for 16 h. Ethyl acetate was added, followed by sodium carbonate (saturated aqueous solution), and the phases were separated. The organic phase was washed with sodium carbonate (saturated aqueous solution) and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue purified by silica gel flash chromatography (gradient: 5% to 15%EtOAc in hexanes) to give the title compound as a solid (14.8 g, 71% yield). 1H-NMR (CDCI3) δ 7.53-7.45 (m, 1 H), 7.38 (t, 2H), 7.34-67.22 (m, 4H), 7.19-7.09 (m, 2H), 7.03 (broad, 1 H)1 6.44 (broad, 1 H), 3.00 (sept, 1 H) 1.30 (d, 6H); LC/MS m/z [M+H]+ = 340.1, RT = 3.64 min.
Step 4. Preparation of 1-f4-r(2-aminopyridin-4-yl)oxy1-2-fluorophenyl>-3-f1-(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-vπurea
To a solution of phenyl [i-tS-fluorophenyO-S-isopropyl-I H-pyrazol-δ-yllcarbamate (1.2 g, 3.51 mmol) and 4-(4-amino-3-fluorophenoxy)pyridin-2-amine (0.77 g, 3.51 mmol) in THF (15 mL) was added EXzU (0.54 mL, 3.86 mmol) was stirred at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (gradient: CH2CI2/Me0H = 99/1-95/5) to give the title compound as a solid (740 mg, 45% yield). (DMSOd6) δ 8.95 (broad, 1 H), 8.87 (s, 1H), 8.06 (t, 1 H)1 7.79 (d, 1H), 7.60-7.53 (m, 1H), 7.44-7.37 (m, 2H), 7.29-7.22 (m, 1H), 7.16 (dd, 1H), 6.96-6.91 (m, 1H), 6.36 (s, 1H), 6.12 (dd, 1 H), 5.94 (s, 2H), 5.80 (d, 1H), 2.88 (sept., 1 H), 1.21 (d, 6H); LC-MS [M+H]+ = 465.1 , RT = 2.62 min.
BIOLOGICAL EVALUATION
In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety.
Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the activity of the compounds of the present invention, the following assays may be used.
Biological Assay Examples
Flk-1 (murine VEGFR-2) biochemical assay
This assay was performed in 96-well opaque plates (Costar 3915) in the TR- FRET format. Reaction conditions are as follows: 10 μM ATP1 25 nM poly GT-biotin, 2 nM Eu-labelled phospho-Tyr Ab (PY20 Perkin Elmer), 10 nM APC (Perkin Elmer), 7 nM Flk-1 (kinase domain), 1% DMSO, 50 mM HEPES pH 7.5, 10 mM MgCI2, 0.1 mM EDTA, 0.015% BRIJ, 0.1 mg/mL BSA, 0.1 % β-mercaptoethanol). Reaction is initiated upon addition of enzyme. Final reaction volume in each well is 100 μl_. Plates are read at both 615 and 665 nM on a Perkin Elmer Victor V Multilabel counter at about 1.5- 2.0 hours after reaction initiation. Signal is calculated as a ratio: (665 nm / 615 nm) * 10000 for each well.
Trk-A FRET biochemical assay
This assay uses the N-terminal HiS-tagged intracellular kinase domain of human recombinant Trk-A in 96-well plates. This involves a biotinylated-poly-GluTyr substrate and an Eu-labelled anti-phosphotyrosine antibody for detection of kinase activity in a homogeneous time-resolved FRET format. The Trk-A biochemical FRET assay protocol is as follows: 10 mM stock solution of test compounds are diluted to 1 mM in 100% DMSO. These stocks are diluted with 100% DMSO by a factor of 5, in a total of 7 steps to create an 8-point IC50 curve. The diluted compounds are combined 1 :4 with distilled water to form the 25x dilution plate for the assay.
A 2 μl_ aliquot of compound from the 25x dilution plate is added with 23 μl_ of assay buffer (50 mM HEPES pH 7.0, 5 mM MnCI2, 0.1% BSA, 0.5 mM vanadate, 0.1% β-mercaptoethanol) into a 96-well, half volume opaque (black) plate (Costar #3694). ATP is added to all wells except the negative controls (5 microliters of 40 μM). Five microliters of 2.2 μg/mL poly(GluTyr)-biotin (CIS US # 61 GTOBLB) and 15 μL of 6.66 nM Trk-A diluted in assay buffer are added to the plate to start the reaction.
After 60 min. at room temperature, the assay is stopped with addition of 5 μL of 0.5M EDTA. 25 μL each of 340 ng/mL PY20 cryptate antibody (CIS US #61Y20KLA) and 40 nM streptavidin labelled APC (SA-XL - CIS US # 611 SAXLB) are added in development buffer (50 mM HEPES pH7.0, 0.8M KF, 0.1 % BSA). The assay plate sits at room temperature for at least one hour, then is read on a Perkin Elmer Victor 2 instrument at 615 and 665 nM emission. A ratio of these two numbers is used in the calculations of the data.
c-MET Biochemical Assay
cMET LANCE biochemical assay format
The cMET LANCE assay is run in a 96-well black plate (Costar #3694) in a 60 μl volume. The assay buffer contains 5OmM Hepes pH 7.3, 5mM MnCI2, 0.1 mM EDTA, 0.015% Brij-35, 0.01% BSA, and 5mM B-ME. Assay buffer and compound are added to the plate. Compound final concentration ranges from 10 μM to 128 pM in an 8-point IC5O curve. Final DMSO concentration is 1%. cMET is added to a final concentration of 160 pM. The reaction is started by addition of ATP (final concentration = 1 μM), streptavidin- APC (F. C. = 10 nM), europium-labeled anti pY20 antibody (final concentration = 1 nM) and poly(GluTyr)-biotin (final concentration = 0.5 δg/mL). The reaction proceeds at room temperature for 60 minutes. The assay is stopped with 10 μl of 50 mM Hepes pH 7.3, 159 mM EDTA. The plate is read on the Victor with standard LANCE europium protocol (615 and 665 nM wavelengths). A ratio of these two numbers is used in the calculations of the data. Background is calculated using wells that contain no enzyme.
Bcr-Abl wild type and mutant T315I Biochemical Assay
Abl-T315l Kinase Filtermat Assay: Inhibition of Abl-T315l kinase phosphorylation of myelin basic protein by compounds in a 33P-ATP Filtermat Assay.
Mutant Abl-T315l or Abl-wt kinases (0.17 nM) are incubated with Myelin Basic Protein (MBP, 2 μM) in assay buffer consisting of 50 mM Tris pH 7.5, 10 mM MgC^, 1 mM EGTA, 2 mM DTT, 50 uM ATP and 0.4 μCi of 33P-ATP. Compounds are added at varying concentrations (final DMSO = 1%) prior to addition of ATP. The reaction mixture is incubated for 1 hour at 32C. The reaction is then stopped with phosphoric acid (final cone 1%) and samples are transferred to filtermats and read in a betaplate reader. Inhibition of MBP phosphorylation by Abl-T315l (or Abl-wt) is analyzed using a 4 parameter fit in Analyzeδ.
Compounds of this invention showed IC50 < 10 μM in one or more of the biochemical assays discussed above.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1 -(4- cyanophenyl)-1H-pyrazol-5-yl]urea, showed IC50 < 10 μM in one or more of the biochemical assays discussed above.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1 -(3- chloro-4-fluorophenyl)-1H-pyrazol-5-yl]urea, showed IC50 < 10 μM in one or more of the biochemical assays discussed above.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1 -(4- methylphenyl)-1 H-pyrazol-5-yl]urea, showed IC50 < 10 μM in one or more of the biochemical assays discussed above. The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-f Iuorophenyl}-N"-[1 -(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea, showed IC50 < 10 μM in one or more of the biochemical assays discussed above.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1 -(3- methoxyphenyi)-1H-pyrazol-5-yl]urea showed IC50 < 10 μM in one or more of the biochemical assays discussed above.
Phospho-Met assay:
This is a cell based, ELISA-like assay (Meso Scale Discovery, Gaithersburg, MD) using MKN-45 tumor cells (gastric carcinoma, purchased from ATCC) without growth factor stimulation. The cells are plated in full growth media (10,000 cells/well) in 96-well plates on day one. On day two, after a two-hour drug treatment in serum-free media, cells are washed and then lysed (60 μl/well using MSD recommended lysis buffer) and frozen at -80 0C. Also on day two, non-specific antibody-binding sites on the MSD phospho-Met plates are blocked with MSD Blocking Solution A overnight at 40C. On day three, frozen lysates are thawed on ice and 25 ul of lysate is transferred to the MSD phospho-Met plate, for 1 hour with shaking, after washing once with Tris-buffered saline + 0.05% Tween 20 (TBST). After removing the unbound proteins, the Sulfa-TAG anti- Met antibody from MSD is added at a final concentration of 5 nM in antibody dilution buffer (following protocol of MSD) to the plate for 1 hour with shaking. The plate is then washed with TBST buffer three times before adding (1x MSD Read buffer. The plate is then read on the MSD Discovery Workstation instrument. Raw data, including wells with 10 μM of a reference compound (minimum signal), and DMSO wells without any drug treatment (maximum signal), are entered into the Analyze 5 program for IC50 value determinations.
In vitro tumor cell proliferation assay
The adherent tumor cell proliferation assay used to test the compounds of the present invention involves a readout called Cell Titre-Glo developed by Promega (Cunningham, BA "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth" The Scientist 2001 , 15(13), 26, and Crouch, SP et al., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity" Journal of Immunological Methods 1993, 160, 81-88).
H460 cells (lung carcinoma, purchased from ATCC) are plated in 96-well plates at 3000 cells/well in complete media with 10% Fetal Calf Serum and incubated 24 hours at 370C. Twenty-four hours after plating, test compounds are added over a final concentration range of 10 nM to 20 μM in serial dilutions at a final DMSO concentration of 0.2 %. Cells are incubated for 72 hours at 370C in complete growth media after addition of the test compound. On day 4, using a Promega Cell Titer GIo Luminescent® assay kit, the cells are lysed and 100 microliters of substrate/buffer mixture is added to each well, mixed and incubated at room temperature for 8 minutes. The samples are read on a luminometer to measure the amount of ATP present in the cell lysates from each well, which corresponds to the number of viable cells in that well. Values read at 24-hour incubation are subtracted as Day 0. For determination of ICso's, a linear regression analysis can be used to determine drug concentration which results in a 50% inhibition of cell proliferation using this assay format. This protocol was applied to different cell lines of interest, which include, but not limited to, CAKI-1, MNK45, GTL-16, HCC2998, K562, H441 , K812, MEG01, SUP15 and HCT116.
Compounds of this invention showed antiproliferative properties (IC50 < 10 μM) in one or more cell lines of interest.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1- (4-cyanophenyl)-1 H-pyrazol-5-yl]urea, showed antiproliferative properties (IC50 < 10 μM) in one or more cell lines of interest. -"■
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1- (3-chloro-4-fluorophenyl)-1 H-pyrazol-5-yl]urea, showed antiproliferative properties (IC50 < 10 μM) in one or more cell lines of interest.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1- (4-methylphenyl)-1H-pyrazol-5-yl]urea, showed antiproliferative properties (IC50 < 10 μM) in one or more cell lines of interest. The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea, showed antiproliferative properties (IC50 < 10 μM) in one or more cell lines of interest.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1- (3-methoxyphenyl)-1H-pyrazol-5-yl]urea showed antiproliferative properties (IC50 < 10 μM) in one or more cell lines of interest.
In vitro TPR-MET BaF3 cell proliferation assay:
An additional cell proliferation assay used to test the compounds of the present invention involves a readout called Cell Titre-Glo developed by Promega (Cunningham, BA "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth" The Scientist 2001 , 15(13), 26, and Crouch, SP et a!., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity" Journal of Immunological Methods 1993, 160, 81-88).
IL-3-independent BaF3 cells overexpressing the tpr-met oncogene (Cooper, CS. , et al., "Molecular cloning of a new transforming gene from a chemically- transformed human cell line" Nature (London) 1984, 311 , 29-33) are plated in 384-well plates at 1667 cells/well in complete RPMI media with 10% Fetal Bovine Serum and 1 mg/ml G418. Immediately after plating, test compounds are added over a final concentration range of 10 μM to 128 pM in serial dilutions at a final DMSO concentration of 0.1%. Cells are incubated for 72 hours at 37 0C in complete growth media after addition of the test compound. At the end of the 72 hour treatment, using a Promega Cell Titer GIo Luminescent assay kit, 50 microliters of CTG solution is added to each well and incubated for 5 minutes at room temperature. The samples are read on a luminometer to measure the amount of ATP present in each well which corresponds to the number of viable cells in that well. Cell numbers are determined by Cell Titer GIo at Day 0 and subtracted as background. For determination of ICso's, a linear regression analysis can be used to determine drug concentration which results in a 50% inhibition of cell proliferation using this assay format. Compounds of this invention showed antiproliferative properties (IC50 < 10 μM) in this assay.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1- (4-cyanophenyl)-1 H-pyrazol-5-yl]urea, showed antiproliferative properties (IC50 < 10 μM) in this assay.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1- (3-chloro-4-fluorophenyl)-1 H-pyrazol-5-yl]urea, showed antiproliferative properties (IC50
< 10 δ M) in this assay.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-buty!-1- (4-methylphenyl)-1H-pyrazol-5-yl]urea, showed antiproliferative properties (IC50 < 10 μM) in this assay.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1 -(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea, showed antiproliferative properties (IC50
< 10 μM) in this assay.
The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert-butyl-1 - (3-methoxyphenyl)-1H-pyrazol-5-yl]urea showed antiproliferative properties (IC50 < 10 μM) in this assay.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. It is believed that one skilled in the art, using the preceding information and information available in the art, can utilize the present invention to its fullest extent. It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein. The topic headings set forth above and below are meant as guidance where certain information can be found in the application, but are not intended to be the only source in the application where information on such topic can be found. All publications and patents cited above are incorporated herein by reference.

Claims

What is claimed is:
Claim 1. A compound selected from the group consisting of :
pharmaceutically acceptable salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof, both as an isolated stereoisomers and one within a mixture of stereoisomers.
Claim 2. The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert- butyl-1-(4-cyanophenyl)-1 H-pyrazol-5-yl]urea of the formula:
pharmaceutically acceptable salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof, both as an isolated stereoisomers and one within a mixture of stereoisomers.
Claim 3. A pharmaceutical composition comprising a compound of claim 2 and a physiologically acceptable carrier.
Claim 4. A method of treating hyper-proliferative disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 2 or a pharmaceutical composition of claim 3.
Claim 5. A method according to claim 4, wherein said hyper-proliferative disorder is cancer.
Claim 6. A method according to claim 5, wherein said cancer is of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and/or neck, thyroid, parathyroid and/or their distant metastases.
Claim 7. A method according to claim 5, wherein said cancer is lymphoma, sarcoma, or leukemia.
Claim 8. A method according to claim 6, wherein said breast cancer is invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, or lobular carcinoma in situ; said respiratory tract cancer is small-cell lung carcinoma, non-small-cell lung carcinoma, bronchial adenoma or pleuropulmonary blastoma; said brain cancer is a tumor of the brain stem, hypophtalmic glioma, cerebellar astrocytoma, cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal or pineal tumor; said tumor of the male reproductive organ is a prostate or testicular cancer; said cancer of the female reproductive organ is endometrial, cervical, ovarian, vaginal, vulvar, or sarcoma of the uterus; said cancer of the digestive tract is anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine or salivary gland; sard cancer of the urinary tract is bladder, penile, kidney, renal pelvis, ureter or urethral; said eye cancer is intraocular melanoma or retinoblastoma; said liver cancer is hepatocellular carcinoma, liver cell carcinomas with or without fibrolamellar variant, cholangiocarcinoma or mixed hepatocellular cholangiocarcinoma; said skin cancer is squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer or non-melanoma skin cancer; said head-and-neck cancer is laryngeal, hypopharyngeal , nasopharyngeal , oropharyngeal, lip or oral cavity cancer; said lymphoma is AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease or lymphoma of the central nervous system. said sarcomas is a sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma or rhabdomyosarcoma; and said leukemia is acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia or hairy cell leukemia.
Claim 9. A method of treating angiogenesis disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 2, or a composition of claim 3. ►
Claim 10. A composition of claim 3, further including an anti-hyper-proliferative agent.
Claim 11. A composition of claim 10, wherein said anti-hyper-proliferative agent is epothiline or its derivative, irinotecan, raloxifen or topotecan.
Claim 12. A composition of claim 3, further including an additional pharmaceutical agent.
Claim 13. A composition of claim 12, wherein said additional pharmaceutical agent is aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine , bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCI, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-2B, interferon alfa-n1 , interferon alfa-n3, interferon beta, interferon gamma-1 a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, levothroid, levoxyl, lomustine, Ionidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6- mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCI, orapred, oxaiiplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCI, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocϊn, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virυlizin, zinecard, zinostatin sttmalamer, zofran, ABI- 007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin, CCl-779, CDC-501 , celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101 , doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflomithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401 , QS-21 , quazepam, R-1549, raloxifene, ranpimase, 13-cis -retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin alpha 1 , tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or a combination thereof.
Claim 14. The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert- butyi-1 -(3-chloro-4-fluorophenyl)-1 H-pyrazol-5-yl]urea of the formula:
pharmaceutically acceptable salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof, both as an isolated stereoisomers and one within a mixture of stereoisomers.
Claim 15. A pharmaceutical composition comprising a compound of claim 14 and a physiologically acceptable carrier.
Claim 16. A method of treating hyper-proliferative disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 14 or a pharmaceutical composition of claim 15.
Claim 17. A method according to claim 16, wherein said hyper-proliferative disorder is cancer.
Claim 18. A method according to claim 17, wherein said cancer is of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and/or neck, thyroid, parathyroid and/or their distant metastases.
Claim 19. A method according to claim 17, wherein said cancer is lymphoma, sarcoma, or leukemia.
Claim 20. A method according to claim 18, wherein said breast cancer is invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, or lobular carcinoma in situ; said respiratory tract cancer is small-cell lung carcinoma, non-small-cell lung carcinoma, bronchial adenoma or pleuropulmonary blastoma; said brain cancer is a tumor of the brain stem, hypophtalmic glioma, cerebellar astrocytoma, cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal or pineal tumor; said tumor of the male reproductive organ is a prostate or testicular cancer; said cancer of the female reproductive organ is endometrial, cervical, ovarian, vaginal, vulvar, or sarcoma of the uterus; said cancer of the digestive tract is anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine or salivary gland; said cancer of the urinary tract is bladder, penile, kidney, renal pelvis, ureter or urethral; said eye cancer is intraocular melanoma or retinoblastoma; said liver cancer is hepatocellular carcinoma, liver cell carcinomas with or without fibrolamellar variant, cholangiocarcinoma or mixed hepatocellular cholangiocarcinoma; said skin cancer is squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer or non-melanoma skin cancer; said head-and-neck cancer is laryngeal, hypopharyngeal , nasopharyngeal , oropharyngeal, lip or oral cavity cancer; said lymphoma is AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease or lymphoma of the central nervous system. said sarcomas is a sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma or rhabdomyosarcoma; and said leukemia is acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia or hairy cell leukemia.
Claim 21. A method of treating angiogenesis disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 14, or a composition of claim 15.
Claim 22. A composition of claim 15, further including an anti-hyper-proliferative agent.
Claim 23. A composition of claim 22, wherein said anti-hyper-proliferative agent is epothiline or its derivative, irinotecan, raloxifen or topotecan.
Claim 24. A composition of claim 15, further including an additional pharmaceutical agent.
Claim 25. A composition of claim 24, wherein said additional pharmaceutical agent is aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine , bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU)1 fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCI, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritυmomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-2B, interferon alfa-n1 , interferon alfa-n3, interferon beta, interferon gamma-1 a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, levothroid, levoxyl, lomustine, Ionidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6- mercaptopurine, Mesna, methotrexate, metvix, mittefosine, minocycline, mitomycin C, mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCI, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCI, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran, ABI- 007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin, CCI-779, CDC-501 , celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101 , doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflomithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, Ionafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401 , QS-21 , quazepam, R-1549, raloxifene, ranpirnase, 13-cis -retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin alpha 1 , tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or a combination thereof.
Claim 26. The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert- butyl-1-(4-methylphenyl)-1 H-pyrazol-5-yl]urea of the formula:
pharmaceutically acceptable salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof, both as an isolated stereoisomers and one within a mixture of stereoisomers.
Claim 27. A pharmaceutical composition comprising a compound of claim 26 and a physiologically acceptable carrier.
Claim 28. A method of treating hyper-proliferative disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 26 or a pharmaceutical composition of claim 27.
Claim 29. A method according to claim 28, wherein said hyper-proliferative disorder is cancer.
Claim 30. A method according to claim 29, wherein said cancer is of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and/or neck, thyroid, parathyroid and/or their distant metastases.
Claim 31. A method according to claim 29, wherein said cancer is lymphoma, sarcoma, or leukemia.
Claim 32. A method according to claim 30, wherein said breast cancer is invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, or lobular carcinoma in situ; said respiratory tract cancer is small-cell lung carcinoma, non-small-cell lung carcinoma, bronchial adenoma or pleuropulmonary blastoma; said brain cancer is a tumor of the brain stem, hypophtalmic glioma, cerebellar astrocytoma, cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal or pineal tumor; said tumor of the male reproductive organ is a prostate or testicular cancer; said cancer of the female reproductive organ is endometrial, cervical, ovarian, vaginal, vulvar, or sarcoma of the uterus; said cancer of the digestive tract is anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine or salivary gland; said cancer of the urinary tract is bladder, penile, kidney, renal pelvis, ureter or urethral; said eye cancer is intraocular melanoma or retinoblastoma; said liver cancer is hepatocellular carcinoma, liver cell carcinomas with or without fibrolamellar variant, cholangiocarcinoma or mixed hepatocellular cholangiocarcinoma; said skin cancer is squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer or non-melanoma skin cancer; said head-and-neck cancer is laryngeal, hypopharyngeal , nasopharyngeal , oropharyngeal, lip or oral cavity cancer; said lymphoma is AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease or lymphoma of the central nervous system, said sarcomas is a sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma or rhabdomyosarcoma; and said leukemia is acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia or hairy cell leukemia.
Claim 33. A method of treating angiogenesis disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 26, or a composition of claim 27.
Claim 34. A composition of claim 27, further including an anti-hyper-proliferative agent.
Claim 35. A composition of claim 34, wherein said anti-hyper-proliferative agent is epothiline or its derivative, irinotecan, raloxifen or topotecan.
Claim 36. A composition of claim 27, further including an additional pharmaceutical agent.
Claim 37. A composition of claim 36, wherein said additional pharmaceutical agent is aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozoie, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine , bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxy uridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCI, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-2B, interferon aifa-n1 , interferon alfa-n3, interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, levothroid, levoxyl, lomustine, Ionidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6- mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCI, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCI, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin stirnalamer, zofran, ABI- 007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin, CCI-779, CDC-501 , celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101 , doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, hϊstrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, Ionafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401 , QS-21 , quazepam, R-1549, raloxifene, ranpimase, 13-cis -retinoic acid, satraplatin, seocalcitol, T- 138067, tarceva, taxoprexin, thymosin alpha 1 , tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or a combination thereof.
Claim 38. The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[3-tert- butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl]urea of the formula:
pharmaceutically acceptable salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastβreoisomeric forms thereof, both as an isolated stereoisomers and one within a mixture of stereoisomers.
Claim 39. A pharmaceutical composition comprising a compound of claim 38 and a physiologically acceptable carrier.
Claim 40. A method of treating hyper-proliferative disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 38 or a pharmaceutical composition of claim 39.
Claim 41. A method according to claim 40, wherein said hyper-proliferative disorder is cancer.
Claim 42. A method according to claim 41 , wherein said cancer is of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and/or neck, thyroid, parathyroid and/or their distant metastases.
Claim 43. A method according to claim 41 , wherein said cancer is lymphoma, sarcoma, or leukemia.
Claim 44. A method according to claim 42, wherein said breast cancer is invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, or lobular carcinoma in situ; said respiratory tract cancer is small-cell lung carcinoma, non-small-cell lung carcinoma, bronchial adenoma or pleuropulmonary blastoma; said brain cancer is a tumor of the brain stem, hypophtalmic glioma, cerebellar astrocytoma, cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal or pineal tumor; said tumor of the male reproductive organ is a prostate or testicular cancer; said cancer of the female reproductive organ is endometrial, cervical, ovarian, vaginal, vulvar, or sarcoma of the uterus; said cancer of the digestive tract is anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine or salivary gland; said cancer of the urinary tract is bladder, penile, kidney, renal pelvis, ureter or urethral; said eye cancer is intraocular melanoma or retinoblastoma; said liver cancer is hepatocellular carcinoma, liver cell carcinomas with or without fibrolamellar variant, cholangiocarcinoma or mixed hepatocellular cholangiocarcinoma; said skin cancer is squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer or non-melanoma skin cancer; said head-and-neck cancer is laryngeal, hypopharyngeal , nasopharyngeal , oropharyngeal, lip or oral cavity cancer; said lymphoma is AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease or lymphoma of the central nervous system. said sarcomas is a sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma or rhabdomyosarcoma; and said leukemia is acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia or hairy cell leukemia.
Claim 45. A method of treating angiogenesis disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 38, or a composition of claim 39.
Claim 46. A composition of claim 39, further including an anti-hyper-proliferative agent.
Claim 47. A composition of claim 46, wherein said anti-hyper-proliferative agent is epothiline or its derivative, irinotecan, raloxifen or topotecan.
Claim 48. A composition of claim 39, further including an additional pharmaceutical agent.
Claim 49. A composition of claim 48, wherein said additional pharmaceutical agent is aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine , bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, denileukiπ diftitox, depo-medrol, deslorelin, dexrazoxane, diethylstϋbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCI, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-2B, interferon alfa-n1 , interferon alfa-n3, interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, levothroid, levoxyl, lomustine, Ionidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6- mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C1 mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCI, pirarubicin, pϋcamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT1 uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran, ABI- 007, acolbifene, actimmune, affinitak, aminopterin, arzoxifeπe, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin, CCI-779, CDC-501 , celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101 , doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflomithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, Ionafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401 , QS-21 , quazepam, R-1549, raloxifene, ranpimase, 13-cis -retinoic acid, satraplatin, seocalcitol, T- 138067, tarceva, taxoprexin, thymosin alpha 1 , tiazofurine, tipifamib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or a combination thereof.
Claim 50. The compound N-{4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl}-N'-[1-(3- fluσrophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea of the formula:
pharmaceutically acceptable salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof, both as an isolated stereoisomers and one within a mixture of stereoisomers.
Claim 51. A pharmaceutical composition comprising a compound of claim 50 and a physiologically acceptable carrier.
Claim 52. A method of treating hyper-proliferative disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 50 or a pharmaceutical composition of claim 51.
Claim 53. A method according to claim 52, wherein said hyper-proliferative disorder is cancer.
Claim 54. A method according to claim 53, wherein said cancer is of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and/or neck, thyroid, parathyroid and/or their distant metastases.
Claim 55. A method according to claim 53, wherein said cancer is lymphoma, sarcoma, or leukemia.
Claim 56. A method according to claim 54, wherein said breast cancer is invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, or lobular carcinoma in situ; said respiratory tract cancer is small-cell lung carcinoma, non-small-cell lung carcinoma, bronchial adenoma or pleuropulmonary blastoma; said brain cancer is a tumor of the brain stem, hypophtalmic glioma, cerebellar astrocytoma, cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal or pineal tumor; said tumor of the male reproductive organ is a prostate or testicular cancer; said cancer of the female reproductive organ is endometrial, cervical, ovarian, vaginal, vulvar, or sarcoma of the uterus; said cancer of the digestive tract is anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine or salivary gland; said cancer of the urinary tract is bladder, penile, kidney, renal pelvis, ureter or urethral; said eye cancer is intraocular melanoma or retinoblastoma; said liver cancer is hepatocellular carcinoma, liver cell carcinomas with or without fibrolamellar variant, cholangiocarcinoma or mixed hepatocellular chσlangiocarcinoma; said skin cancer is squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer or non-melanoma skin cancer; said head-and-neck cancer is laryngeal, hypopharyngeal , nasopharyngeal , oropharyngeal, lip or oral cavity cancer; said lymphoma is AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease or lymphoma of the central nervous system. said sarcomas is a sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma or rhabdomyosarcoma; and said leukemia is acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia or hairy cell leukemia.
Claim 57. A method of treating angiogenesis disorders comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 50, or a composition of claim 51.
Claim 58. A composition of claim 51 , further including an anti-hyper-proliferative agent.
Claim 59. A composition of claim 58, wherein said anti-hyper-proliferative agent is epothiline or its derivative, irinotecan, raloxifen or topotecan.
Claim 60. A composition of claim 51 , further including an additional pharmaceutical agent.
Claim 61. A composition of claim 60, wherein said additional pharmaceutical agent is aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine , bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifturidine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, filgrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCI, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibrttumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-2B, interferon alfa-n1 , interferon alfa-n3, interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, levothroid, levoxyl, lomustine, Ionidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6- mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCI1 orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCI, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran, ABI- 007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin, CCI-779, CDC-501 , Celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101 , doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401 , QS-21 , quazepam, R-1549, raloxifene, ranpirnase, 13-cis -retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin alpha 1 , tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledroπic acid or a combination thereof.
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Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006029795A1 (en) * 2006-06-27 2008-01-03 Schebo Biotech Ag New urea derivatives and their uses
WO2009077766A1 (en) 2007-12-19 2009-06-25 Cancer Research Technology Limited Pyrido[2,3-b]pyrazine-8-substituted compounds and their use
GB0818033D0 (en) 2008-10-02 2008-11-05 Respivert Ltd Novel compound
PE20110598A1 (en) * 2008-10-02 2011-08-31 Respivert Ltd INHIBITORS OF MITOGEN P38 ACTIVATED PROTEIN KINASE ENZYMES
KR20110094127A (en) * 2008-12-11 2011-08-19 레스피버트 리미티드 P38 map kinase inhibitors
WO2010089773A2 (en) * 2009-02-02 2010-08-12 Indoco Remedies Limited Process for preparation of nitropyridine derivatives
GB0905955D0 (en) 2009-04-06 2009-05-20 Respivert Ltd Novel compounds
AU2011209586B2 (en) 2010-02-01 2016-01-21 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2h-pyrazol-3-yl)-3-[2-fluoro- 4-(1-methyl-2-oxo-2,3-dihydro-1h-imidazo [4,5-b]pyridin-7-yloxy)-phenyl] -urea and related compounds and their use in therapy
WO2012003338A1 (en) 2010-07-01 2012-01-05 Takeda Pharmaceutical Company Limited COMBINATION OF A cMET INHIBITOR AND AN ANTIBODY TO HGF AND/OR cMET
SI2712358T1 (en) 2011-05-13 2017-03-31 Array Biopharma, Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as trka kinase inhibitors
WO2014078417A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078325A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. N-(monocyclic aryl),n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078322A1 (en) * 2012-11-13 2014-05-22 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
SI2920166T1 (en) 2012-11-13 2017-01-31 Array Biopharma, Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078372A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078328A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. N-bicyclic aryl,n'-pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
CN104781255B (en) 2012-11-13 2017-10-24 阵列生物制药公司 It is used as the N pyrrolidinyls of TRKA kinase inhibitors, N ' pyrazolyls urea, thiocarbamide, guanidine and cyanoguandine compounds
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
GB201320729D0 (en) 2013-11-25 2014-01-08 Cancer Rec Tech Ltd Therapeutic compounds and their use
GB201320732D0 (en) 2013-11-25 2014-01-08 Cancer Rec Tech Ltd Methods of chemical synthesis
CR20160583A (en) 2014-05-15 2017-02-23 Array Biopharma Inc 1 - ((3S, 4R) -4- (3-FLUOROPHENYL) -1- (2-METOXYETHYL) PIRROLIDIN-3-IL) -3- (4-METHYL-3- (2-METHYLPIRIMIDIN-5-IL) - 1-FENIL-1H-PIRAZOL-5-IL) UREA AS INHIBITOR OF TRKA CINASA
WO2016091891A1 (en) 2014-12-09 2016-06-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Human monoclonal antibodies against axl
WO2016135041A1 (en) 2015-02-26 2016-09-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Fusion proteins and antibodies comprising thereof for promoting apoptosis
CN107056653B (en) * 2017-06-09 2019-07-09 丽珠医药集团股份有限公司 Synthetic method of the blonanserin intermediate to fluorobenzoyl acetonitrile
KR20220038696A (en) 2019-07-19 2022-03-29 아나제네시스 바이오테크놀로지스 에스.에이.에스. Polyaromatic urea derivatives and their use in the treatment of muscle diseases
EP4029501A1 (en) 2021-01-19 2022-07-20 Anagenesis Biotechnologies Combination of polyaromatic urea derivatives and glucocorticoid or hdac inhibitor for the treatment of diseases or conditions associated with muscle cells and/or satellite cells

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ299156B6 (en) * 1997-12-22 2008-05-07 Bayer Corporation Substituted heterocyclic ureas, pharmaceutical compositions in which they are comprised and their use
DE69834842T2 (en) * 1997-12-22 2007-05-10 Bayer Pharmaceuticals Corp., West Haven INHIBITION OF RAF-KINASE USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREA
MXPA06012394A (en) * 2004-04-30 2007-01-31 Bayer Pharmaceuticals Corp Substituted pyrazolyl urea derivatives useful in the treatment of cancer.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007059202A2 *

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