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 PDGF, a potent stimulator of stroma formation (Ostman, A. and C. H. 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.
A 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 fit-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. Cell 1993, 73, 421-424)
The biological activities of the VEGFs are mediated through binding to their receptors. VEGFR3 (also called Flt-4) is predominantly expressed on lymphatic endothelium in normal adult tissues. 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). Moreover, VEGF activates the extracellular signal-regulated protein kinase (ERK) in human umbilical vein endothelial cells (HUVEC) (Yu, Y.; Sato, D. J. Cell Physiol 1999, 178, 235-246).
PDGF is another 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 Cell 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; Yu, J., A. Moon, and H. R. Kim, Biochem Biophys Res Commun, 2001. 282(3), 697-700). PDGF is found at high concentrations in platelets and is a potent chemoattractant for 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 cells 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 USA., 1993. 90(2), 393-7; Skobe, M. and N. E. Fusenig, Proc Natl Acad Sci USA, 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., C. Y. 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 USA, 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.
The link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been 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.
Cells protect their DNA by adopting a higher-order complex termed chromatin. Chromatin condensation is evident during mitosis and cell death induced by apoptosis while chromatin decondensation is necessary for replication, repair, recombination and transcription. Histones are among some of the DNA-binding proteins that are involved in the regulation of DNA condensation; and post-translational modifications of histone tails serve a critical role in the dynamic condensation/decondensation that occurs during the cell cycle. Phoshorylation of the tails of histone H3 is involved in both transcription and cell division (Prigent et al. J. Cell Science 2003, 116, 3677). A number of protein kinases have been reported to phosphorylate histone H3 and these kinases function both as signal transduction and mitotic kinases.
Pyrrolotriazine derivatives have been described as having kinase inhibitory activity in U.S. application Ser. No. 10/289,010, U.S. Pat. No. 6,670,357, WO 2001/19828, WO 2003/042172, WO 2004/009542, WO2004/009601, WO 2004/009784 and WO 2004/013145.
In one embodiment, the present invention provides a compound of formula (I)
whereinR1 is selected from the group consisting of aryl, benzyl, and heteroaryl,                wherein aryl and heteroaryl can be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of                    (C1-C4)alkyl, wherein (C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogen, 0 or 1 heterocyclyl, or 0 or 1 (C1-C3)alkoxy, wherein                            (C1-C3)alkoxy can be optionally substituted with (C1-C3)alkylamino,                                    (C1-C3)alkoxy, wherein (C1-C3)alkoxy can be optionally substituted with (C1-C3)alkylamino,            halogen,            trifluoromethyl,            trifluoromethoxy,            (C3-C6)cycloalkyl,            phenyl optionally substituted with 1 or 2 halogen,
                                     wherein X is CH2, O, S or NR1-1, and wherein R1-1 is hydrogen or (C1-C6)alkyl,            nitro,            cyano,            (C1-C3)alkylthio,            trifluoromethylthio,            (C1-C3)alkylcarbonyl,            (C1-C6)alkoxycarbonyl, and            phenoxy, wherein phenoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethoxy, and halogen,                        and        wherein benzyl can be substituted with 0, 1, 2 or 3 groups selected from halogen, (C1-C3)alkyl, and (C1-C3)alkoxy;R2 is selected from the group consisting of hydrogen, halogen, (C1-C4)alkyl and (C1-C4)alkoxy;R3 is selected from the group consisting of        carboxyl,        formyl,        (C1-C6)alkylcarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from fluorine, chlorine, hydroxy, (C1-C6)alkoxy, and heterocycle,        (C3-C6)cycloalkylcarbonyl,        (C1-C6)alkoxycarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from amino, and (C1-C6)alkoxycarbonyl,        aminocarbonyl,        (C1-C6)alkylaminocarbonyl, wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of (C3-C6)cycloalkyl, halogen, amino, (C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, (C1-C6)alkoxycarbonylamino, and methylsulfonyl, and wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with or 0 or 1 heterocyclyl, wherein heterocyclyl can optionally be substituted with 0 or 1 (C1-C6)alkyl, and wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0 or 1 phenyl, wherein phenyl can optionally be substituted with 0 or 1 halogen, (C1-C6)alkyl, or (C1-C6)alkoxy,        heterocyclylcarbonyl optionally substituted with 0 or 1 amino, (C1-C6)alkylamino, cycloalkyl, or (C1-C6)alkyl, wherein (C1-C6)alkyl can optionally be substituted with 0 or 1 amino or (C1-C6)alkylamino,        (C1-C6)alkyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of                    a) hydroxyl,            b) amino,            c) (C1-C6)alkylamino, wherein (C1-C6)alkylamino can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy, methylthio, and methylsulfonyl,            d) arylamino, wherein arylamino can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, and trifluoromethyl,            e) heterocyclyl, wherein heterocyclyl can be substituted with 0, 1 or 2 (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1 or 2 hydroxy, methoxy or pyridyl,            f) imidazolyl,            g) pyridylamino,            h) (C1-C3)alkoxy optionally substituted by fluoro up to the perfluoro level, or by heterocycle, wherein heterocycle can optionally be substituted by 0 or 1 (C1-C6)alkyl,            i) (C1-C3)alkoxy(C2-C3)alkoxy, and            j) (C1-C6)alkoxycarbonyl,            k) (C3-C6)cycloalkyl,            l) cyano,                        (C1-C6)alkoxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of amino, (C1-C6)alkylamino, and heterocyclyl, wherein heterocyclyl can be substituted with 0, 1, 2 or 3 (C1-C6)alkyl,        (C3-C6)cycloalkylaminocarbonyl optionally substituted with (C1-C3)alkyl,        cyano,        heteroaryl, wherein heteroaryl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of                    a) (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1, 2, or 3 halogen, 0 or 1 heterocyclyl, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy,            b) halogen,            c) amino,            d) alkylamino,            e) (C1-C6)alkoxycarbonyl, and            f) (C3-C6)cycloalkyl,                        heteroarylcarbonyl, which can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of (C1-C6)alkyl, (C3-C6)cycloalkyl and halogen,        heterocyclyl, wherein heterocyclyl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of (C1-C6)alkyl and (C1-C6)alkoxycarbonyl; andR4 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy and halogen;or a pharmaceutically acceptable salt thereof.
Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and to their respective mixtures. Such mixtures of enantiomers and/or diastereomers can be separated into stereoisomerically unitary constituents in a known manner.
The invention also relates to tautomers of the compounds, depending on the structure of the compounds.
A salt for the purposes of the invention is a pharmaceutically acceptable salt of the compound according to the invention.
Pharmaceutically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
Pharmaceutically acceptable salts of the compounds (I) also include salts of customary bases, such as for example alkali metal salts (for example sodium and potassium salts, alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine.
Solvates for the purposes of the invention are those forms of the compounds that coordinate with solvent molecules to form a complex in the solid or liquid state. Hydrates are a specific form of solvates, where the coordination is with water.
For the purposes of the present invention, the substituents have the following meanings, unless otherwise specified:
Alkyl represents a linear or branched alkyl radical having generally 1 to 6, 1 to 4 or 1 to 3 carbon atoms, representing illustratively methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
Alkoxy in general represents a straight-chain or branched hydrocarbon radical having generally 1 to 6, 1 to 4 or 1 to 3 carbon atoms and bound via an oxygen atom. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy. The terms “alkoxy” and “alkyloxy” can be used synonymously.
Alkylamino represents an amino radical having one or two (independently selected) alkyl substituents, illustratively representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
Alkylthio in general represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms and bound via an sulfur atom. Non-limiting examples include methylthio and ethylthio.
Arylamino represents an amino radical having one or two (independently selected) aryl substituents, illustratively representing phenylamino.
Aminoalkyl represents an alkyl radical substituted with an amino group. Non-limiting examples include aminomethyl and aminoethyl.
Aminocarbonyl represents a free amide group.
Alkylcarbonyl represents a carbonyl group having an alkyl substituent. Non-limiting examples include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, and hexanoyl.
Alkylaminocarbonyl represents an aminocarbonyl radical (free amide) having one or two (independently selected) alkyl substituents, illustratively representing methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylamino-carbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylamino-carbonyl and N-n-hexyl-N-methylaminocarbonyl.
Alkoxycarbonyl represents a carbonyl group having an alkoxy substituent. It illustratively represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
Cycloalkyl represents a monocyclic cycloalkyl radical having generally 3 to 8 or 5 to 7 carbon atoms, illustratively representing cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Aryl represents a mono- to bicyclic carbocyclic radical, which is aromatic at least in one ring, having generally 6 to 10 carbon atoms, illustratively representing phenyl and naphthyl.
Heteroaryl represents an mono- or bicyclic radical having generally 5 to 10 or 5 or 6 ring atoms and up to 5, in another embodiment up to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, which is aromatic at least in one ring. It can be attached via a ring carbon atom or a ring nitrogen atom. If it represents a bicycle, wherein one ring is aromatic and the other one is not, it can be attached at either ring. Illustrative examples are thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuryl, benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, 1,3-benzodioxinyl, 1,4-benzodioxinyl, or benzodioxolyl.
Heteroarylcarbonyl represents a heteroaryl residue bonded via a carbonyl carbon atom.
Heterocyclyl represents a mono- or bicyclic, in another embodiment monocyclic, nonaromatic, i.e. saturated or partially unsaturated radical having generally 4 to 10 or 5 to 8 ring atoms and up to 3, in another embodiment up to 2 hetero atoms and/or hetero groups selected from the group consisting of nitrogen, oxygen and sulfur, CO, SO and SO2. If bicyclic, it can be a fused or spiro-connected bicycle. It can be attached via a ring carbon atom or a ring nitrogen atom. Illustrative examples are tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinyl.
Heterocyclylcarbonyl represents a heterocyclyl residue bonded via a carbonyl carbon atom.
Methylsulfonyl represents a —S(O)2CH3 residue.
Halogen or halo represents a substituent selected from the group consisting of fluoro, chloro, bromo and iodo, in another embodiment fluoro and chloro.
(C1-C3)alkoxy(C2-C3)alkoxy represents an 2 to 3 carbon alkoxy group substituted at the 2 or 3-position with a 1 to 3 carbon alkoxy group, illustratively representing 2-methoxyethoxy (CH3—O—CH2CH2—O—), 3-ethoxypropoxy (CH3CH2—O—CH2CH2CH2—O—), 2-methoxypropoxy (CH3—O(CH3)CHCH2—O—), 2-isopropoxyethoxy (CH3(CH3)CH—O—CH2CH2—O—) 2-methoxy-1-methylethoxy (CH3OCH2(CH3)CH—O—) or 3-propoxyethoxy, (CH3CH2CH2—O—CH2CH2—O—).
(C3-C6)cycloalkylaminocarbonyl optionally substituted by (C1-C3)alkyl represents an aminocarbonyl radical (free amide) having one (independently selected) cycloalkyl substituent, which may be optionally substituted on the nitrogen atom by a (C1-C3)alkyl group and independently substituted on any available carbon atom by 1 or 2 (C1-C3)alkyl groups, illustratively representing N-cyclopropylaminocarbonyl, N-cyclopropyl-N-methylaminocarbonyl, N-(2-methylcyclopropyl)aminocarbonyl, N-cyclobutylaminocarbonyl, N-(2,2-dimethyl)cyclopropyl)aminocarbonyl, cyclopentylaminocarbonyl, N-(3-ethylcyclopentyl)aminocarbonyl, N-cyclohexylaminocarbonyl, N-cyclohexyl-N-ethylaminocarbonyl, N-(3-propylcyclohexyl)aminocarbonyl, and N-(4,4-dimethylcyclohexyl)aminocarbonyl.
A * symbol next to a bond denotes the point of attachment in the molecule. Alternatively, a dotted line (---) denotes the bond via a radical is attached to the rest of the molecule.
When prefixes such as (C1-C4) are used before substituents, they mean to indicate the respective number of carbon atoms, for example 1 to 4 in case of (C1-C4).
When more than one substituent is selected from a group, selection can be independent of each other. Unless a maximum number of substituents is indicated, substitution can take place up to the maximum number of available substitution locations, e.g. in case of halogenation to the perhalo level.
In another embodiment, the present invention provides a compound of formula (I), wherein
R1 is selected from the group consisting of phenyl and monocyclic heteroaryl having 5 or 6 ring atoms,
                wherein phenyl and heteroaryl can be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of                    (C1-C4)alkyl, wherein (C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogen, 0 or 1 pyrrolidinyl, 0 or 1 morpholinyl, or 0 or 1 (C1-C3)alkoxy wherein                            (C1-C3)alkoxy can be optionally substituted with (C1-C3)alkylamino,                                    (C1-C3)alkoxy, wherein (C1-C3)alkoxy can be optionally substituted with (C1-C3)alkylamino,            halogen,            trifluoromethyl,            trifluoromethoxy,            (C3-C6)cycloalkyl,            phenyl optionally substituted with 1 or 2 halogen,            trifluoromethylthio;R2 is selected from the group consisting of hydrogen, halogen, (C1-C4)alkyl and (C1-C4)alkoxy;R3 is selected from the group consisting of                        carboxyl,        formyl,        (C1-C6)alkylcarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from fluorine, chlorine, hydroxy, (C1-C6)alkoxy, and monocyclic heterocycle having 5 or 6 ring atoms,        (C3-C6)cycloalkylcarbonyl,        (C1-C6)alkoxycarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from amino, and (C1-C6)alkoxycarbonyl,        aminocarbonyl,        (C1-C6)alkylaminocarbonyl, wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of (C3-C6)cycloalkyl, halogen, amino, (C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, (C1-C6)alkoxycarbonylamino, and methylsulfonyl, and wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0 or 1 hydroxyl or 0 or 1 monocyclic heterocyclyl having 5 or 6 ring atoms, wherein heterocyclyl can optionally be substituted with 0 or 1 (C1-C6)alkyl, and wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0 or 1 phenyl, wherein phenyl can optionally be substituted with 0 or 1 halogen or (C1-C6)alkyl,        monocyclic heterocyclylcarbonyl having 5 or 6 ring atoms, optionally substituted with 0 or 1 amino, (C1-C6)alkylamino, (C3-C6)cycloalkyl, or (C1-C6)alkyl, wherein (C1-C6)alkyl can optionally be substituted with 0 or 1 amino or (C1-C6)alkylamino,        (C1-C6)alkyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of                    a) hydroxyl,            b) amino,            c) (C1-C6)alkylamino, wherein (C1-C6)alkylamino can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy, methylthio, and methylsulfonyl,            e) monocyclic heterocyclyl having 5 or 6 ring atoms, wherein heterocyclyl can be substituted with 0, 1 or 2 (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1 or 2 hydroxy, methoxy or pyridyl,            f) imidazolyl,            h) (C1-C3)alkoxy optionally substituted by fluoro up to the perfluoro level, or by monocyclic heterocycle having 5 or 6 ring atoms, wherein heterocycle can optionally be substituted by 0 or 1 (C1-C6)alkyl,            i) (C1-C3)alkoxy(C2-C3)alkoxy, and            j) (C1-C6)alkoxycarbonyl,            k) (C3-C6)cycloalkyl,            l) cyano,                        (C3-C6)cycloalkylaminocarbonyl optionally substituted with (C1-C3)alkyl,        cyano,        heteroaryl, wherein heteroaryl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of                    a) (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1, 2, or 3 halogen, 0 or 1 monocyclic heterocyclyl having 5 or 6 ring atoms, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy,            b) halogen,            e) (C1-C6)alkoxycarbonyl, and            f) (C3-C6)cycloalkyl,                        monocyclic heteroarylcarbonyl having 5 or 6 ring atoms,        monocyclic heterocyclyl having 5 or 6 ring atoms, wherein heterocyclyl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of (C1-C6)alkyl and (C1-C6)alkoxycarbonyl; andR4 is selected from the group consisting of hydrogen and halogen;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of formula (I), wherein
R1 is selected from the group consisting of phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, and pyrimidinyl,
                wherein phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, and pyrimidinyl can be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of                    (C1-C4)alkyl, wherein (C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogen,            (C1-C3)alkoxy, wherein (C1-C3)alkoxy can be optionally substituted with (C1-C3)alkylamino,            halogen,            trifluoromethyl,            trifluoromethoxy,            cyclopropyl,            phenyl optionally substituted with 1 or 2 halogen;R2 is selected from the group consisting of hydrogen, fluoro and chloro;R3 is selected from the group consisting of                        (C1-C6)alkylcarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from fluorine, chlorine, hydroxy, (C1-C6)alkoxy, piperazinyl, morpholinyl, pyrrolidinyl, and piperidinyl,        cyclopropylcarbonyl,        aminocarbonyl,        (C1-C6)alkylaminocarbonyl, wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of (C3-C6)cycloalkyl, halogen, amino, (C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, (C1-C6)alkoxycarbonylamino, and methylsulfonyl, and wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0 or 1 hydroxyl, piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl, wherein piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl can optionally be substituted with 0 or 1 (C1-C6)alkyl, and wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0 or 1 phenyl, wherein phenyl can optionally be substituted with 0 or 1 halogen or (C1-C6)alkyl,        heterocyclylcarbonyl selected from piperazinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl, optionally substituted with 0 or 1 amino, (C1-C6)alkylamino, (C3-C6)cycloalkyl, or (C1-C6)alkyl, wherein (C1-C6)alkyl can optionally be substituted with 0 or 1 amino or (C1-C6)alkylamino,        (C1-C6)alkyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of                    a) hydroxyl,            c) (C1-C6)alkylamino, wherein (C1-C6)alkylamino can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, alkylamino, and methoxy,            e) piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl, wherein piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl can be substituted with 0, 1 or 2 (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1 or 2 hydroxy or methoxy,            f) imidazolyl,            h) (C1-C3)alkoxy optionally substituted by fluoro up to the perfluoro level, or by monocyclic heterocycle having 5 or 6 ring atoms, wherein heterocycle can optionally be substituted by 0 or 1 (C1-C6)alkyl,            i) (C1-C3)alkoxy(C2-C3)alkoxy, and            j) (C1-C6)alkoxycarbonyl,            k) (C3-C6)cycloalkyl,            l) cyano,                        (C3-C6)cycloalkylaminocarbonyl optionally substituted with (C1-C3)alkyl,        cyano,        pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, imidazolyl or pyrimidinyl, wherein pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, imidazolyl or pyrimidinyl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of                    a) (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1, 2, or 3 halogen, 0 or 1 alkylamino, or 0 or 1 methoxy,            b) halogen, and            f) (C3-C6)cycloalkyl,                        pyrazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, pyridinylcarbonyl or pyrimidinylcarbonyl; andR4 is selected from the group consisting of hydrogen and fluoro;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of formula (I), wherein
R1 is selected from the group consisting of phenyl and monocyclic heteroaryl,
                wherein aryl and heteroaryl can be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of                    (C1-C4)alkyl, wherein (C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogen, 0 or 1 pyrrolidinyl or morpholinyl, or 0 or 1 (C1-C3)alkoxy wherein                            (C1-C3)alkoxy can be optionally substituted with (C1-C3)alkylamino,                                    (C1-C3)alkoxy, wherein (C1-C3)alkoxy can be optionally substituted with (C1-C3)alkylamino,            halogen,            trifluoromethyl,            trifluoromethoxy,            (C3-C6)cycloalkyl,            (C1-C3)alkylthio, and            phenoxy, wherein phenoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethoxy, and halogen,R2 is selected from the group consisting of hydrogen, halogen, (C1-C4)alkyl and (C1-C4)alkoxy;R3 is selected from the group consisting of                        carboxyl,        (C1-C6)alkylcarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from fluorine, chlorine, hydroxy, (C1-C6)alkoxy, and heterocycle,        (C3-C6)cycloalkylcarbonyl,        (C1-C6)alkoxycarbonyl,        aminocarbonyl,        (C1-C6)alkylaminocarbonyl, wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of (C3-C6)cycloalkyl, halogen, (C1-C6)alkylamino, hydroxy and (C1-C6)alkoxy, and wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with or 0 or 1 heterocyclyl, wherein heterocyclyl can optionally be substituted with 0 or 1 (C1-C6)alkyl, and wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0 or 1 phenyl, wherein phenyl can optionally be substituted with 0 or 1 halogen, (C1-C6)alkyl, or (C1-C6)alkoxy,        heterocyclylcarbonyl optionally substituted with 0 or 1 amino, (C1-C6)alkylamino, cycloalkyl, or (C1-C6)alkyl, wherein (C1-C6)alkyl can optionally be substituted with 0 or 1 amino or (C1-C6)alkylamino,        (C1-C6)alkyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of                    a) hydroxyl,            c) (C1-C6)alkylamino, wherein (C1-C6)alkylamino can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy, methylthio, and methylsulfonyl,            e) heterocyclyl, wherein heterocyclyl can be substituted with 0, 1 or 2 (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1 or 2 hydroxy, methoxy or pyridyl,            f) imidazolyl,            h) (C1-C3)alkoxy optionally substituted by fluoro up to the perfluoro level, or by heterocycle, wherein heterocycle can optionally be substituted by 0 or 1 (C1-C6)alkyl,            i) (C1-C3)alkoxy(C2-C3)alkoxy, and            j) (C1-C6)alkoxycarbonyl,            k) (C3-C6)cycloalkyl,                        (C3-C6)cycloalkylaminocarbonyl optionally substituted with (C1-C3)alkyl,        monocyclic heteroaryl having 5 or 6 ring atoms, wherein heteroaryl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of                    g) (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1, 2, or 3 halogen, 0 or 1 heterocyclyl, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy,            h) halogen,            i) amino,            j) alkylamino,            k) (C1-C6)alkoxycarbonyl, and            l) (C3-C6)cycloalkyl,                        monocyclic heteroarylcarbonyl having 5 or 6 ring atoms,        monocyclic heterocyclylcarbonyl having 5 or 6 ring atoms, wherein heterocyclyl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of (C1-C6)alkyl and (C1-C6)alkoxycarbonyl; andR4 is hydrogen or fluoro;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of formula (I), wherein
R1 is selected from the group consisting of phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, and pyrimidinyl,
                wherein phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, and pyrimidinyl can be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of                    (C1-C4)alkyl, wherein (C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogen,            (C1-C3)alkoxy,            halogen,            trifluoromethyl, and            phenoxy, wherein phenoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, (C1-C6)alkoxy, trifluoromethoxy, and halogen;R2 is hydrogen, fluoro, chloro, methyl, ethyl or methoxy;R3 is selected from the group consisting of                        (C1-C6)alkoxycarbonyl,        (C1-C6)alkylaminocarbonyl, wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, and        (C3-C6)cycloalkylaminocarbonyl optionally substituted with (C1-C3)alkyl,        piperazinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl; andR4 is hydrogen;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of formula (I), wherein
R1 is selected from the group consisting of phenyl, pyrazolyl, thiazolyl, pyridinyl, and pyrimidinyl,
                wherein phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, and pyrimidinyl can be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of                    methyl, ethyl, propyl or butyl, wherein methyl, ethyl, propyl or butyl can be substituted with 0, 1, 2 or 3 fluoro or chloro,            fluoro or chloro,            trifluoromethyl, and            phenoxy, wherein phenoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of methyl, ethyl, propyl or butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, fluoro and chloro;R2 is hydrogen;R3 is selected from the group consisting of                        methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl,        (C1-C4)alkylaminocarbonyl, wherein (C1-C4)alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 fluoro, and        cyclopropylaminocarbonyl optionally substituted with methyl, ethyl or propyl,        pyrrolidinylcarbonyl or piperidinylcarbonyl; andR4 is hydrogen;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of formula (Ic)
whereinR1 is selected from the group consisting of aryl, benzyl, and heteroaryl,                wherein aryl and heteroaryl can be optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of                    (C1-C4)alkyl, wherein (C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogen, 0 or 1 pyrrolidinyl, 0 or 1 morpholinyl, or 0 or 1 (C1-C3)alkoxy wherein                            (C1-C3)alkoxy can be optionally substituted with (C1-C3)alkylamino,                                    (C1-C3)alkoxy, wherein (C1-C3)alkoxy can be optionally substituted with (C1-C3)alkylamino,            halogen,            trifluoromethyl,            trifluoromethoxy,            (C3-C6)cycloalkyl,            phenyl optionally substituted with 1 or 2 halogen,
                                     wherein X is CH2, O, S or NR1-1, and wherein R1-1 is hydrogen or (C1-C6)alkyl,            nitro,            cyano,            (C1-C3)alkylthio,            trifluoromethylthio,            (C1-C3)alkylcarbonyl,            (C1-C6)alkoxycarbonyl, and            phenoxy                        and        wherein benzyl can be substituted with 0, 1, 2 or 3 groups selected from halogen, (C1-C3)alkyl, and (C1-C3)alkoxy;R2 is selected from the group consisting of hydrogen, halogen, alkyl and alkoxy;R3 is selected from the group consisting of        carboxyl,        formyl,        (C1-C6)alkylcarbonyl optionally substituted with 1, 2, or 3 fluorine,        (C1-C6)alkoxycarbonyl,        aminocarbonyl,        (C1-C6)alkylaminocarbonyl, wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy, and methylsulfonyl, and wherein (C1-C6)alkylaminocarbonyl can be substituted with 0 or 1 hydroxyl or 0 or 1 heterocyclyl,        heterocyclylcarbonyl,        (C1-C6)alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of                    a) hydroxyl,            b) amino,            c) (C1-C6)alkylamino, wherein (C1-C6)alkylamino can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy, methylthio, and methylsulfonyl,            d) arylamino, wherein arylamino can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, and trifluoromethyl,            e) heterocyclyl, wherein heterocyclyl can be substituted with 0, 1 or 2 (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1 or 2 methoxy or pyridyl,            f) imidazolyl,            g) pyridylamino,            h) (C1-C3)alkoxy optionally substituted by fluoro up to the perfluoro level,            i) (C1-C3)alkoxy(C2-C3)alkoxy, and            j) (C1-C6)alkoxycarbonyl,                        (C1-C6)alkoxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of amino, (C1-C6)alkylamino, and heterocyclyl, wherein heterocyclyl can be substituted with 0, 1, 2 or 3 (C1-C6)alkyl;        (C3-C6)cycloalkylaminocarbonyl optionally substituted with (C1-C3)alkyl,        cyano, and        heteroaryl wherein heteroaryl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of                    m) (C1-C6)alkyl, wherein (C1-C6)alkyl can be substituted with 0, 1, 2, or 3 halogen, 0 or 1 heterocycyl, 0 or 1 alkylamino, or 0 or 1 methoxy,            n) halogen,            o) amino, and            p) alkylamino;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of formula (Ic):
whereinR1 is selected from the group consisting of aryl and heteroaryl,                wherein aryl and heteroaryl can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of                    (C1-C4)alkyl,            (C1-C3)alkoxy,            halogen,            trifluoromethyl,            trifluoromethoxy,            (C3-C6)cycloalkyl,            phenyl optionally substituted with 0, 1 or 2 halogen, and
                                     wherein X is CH2, O, S or NR1-1; and wherein R1-1 is hydrogen or (C1-C6)alkyl;R2 is selected from the group consisting of hydrogen, halogen, alkyl and alkoxy;R3 is selected from the group consisting of carboxyl, (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, and heterocyclylcarbonyl,wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy and methylsulfonyl, orR3 is (C1-C6)alkyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of hydroxyl, amino, (C1-C6)alkylamino, arylamino, heterocyclyl, pyridyl, and pyridylamino,wherein (C1-C6)alkylamino can optionally be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy, methylthio, and methylsulfonyl, and wherein heterocyclyl can optionally be substituted with 0, 1 or 2 (C1-C6)alkyl, wherein (C1-C6)alkyl can optionally be substituted with 1 or 2 methoxy or pyridyl,and wherein arylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, and trifluoromethyl, orR3 is (C1-C6)alkoxy optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of amino, (C1-C6)alkylamino, and heterocyclyl, wherein heterocyclyl can optionally be substituted with 0, 1, 2 or 3 (C1-C6)alkyl;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of formula (I),
wherein
R1 is selected from the group consisting of phenyl and mono- or bicyclic heteroaryl containing 5, 6, 9 or 10 ring atoms and up to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur,
                wherein phenyl and heteroaryl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of (C1-C4)alkyl, C1-C3)alkoxy, halogen, trifluoromethyl, trifluoromethoxy, (C3-C6)cycloalkyl, phenyl optionally substituted with trifluoromethyl, and
                 wherein X is CH2, O, S or NR1-1;                    wherein R1-1 is hydrogen or (C1-C6)alkyl;R2 is selected from the group consisting of hydrogen, fluoro, chloro, methyl, and methoxy;R3 is selected from the group consisting of carboxyl, (C1-C6)alkoxycarbonyl, aminocarbonyl, and (C1-C6)alkylaminocarbonyl,wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy and methylsulfonyl, orR3 is (C1-C6)alkyl substituted with amino, (C1-C6)alkylamino, pyridyl, or 5- to 6 membered heterocyclyl containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,wherein (C1-C6)alkylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy and methylsulfonyl, and wherein heterocyclyl can optionally be substituted with 0, 1 or 2 (C1-C6)alkyl, wherein (C1-C6)alkyl can optionally be substituted with 0 or 1 methoxy or pyridyl, orR3 is (C1-C6)alkoxy optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of amino, (C1-C6)alkylamino, and a 5- to 6 membered heterocyclyl containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein heterocyclyl can optionally be substituted with 0, 1, 2 or 3 (C1-C6)alkyl;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of formula (Ic),
whereinR1 is selected from the group consisting of                phenyl optionally substituted with 1-2 groups selected from halo, (C1-C4)alkyl, OCF3, CF3, and
                 wherein X is CH2, O, S or NR1-1, wherein R1-1 is hydrogen or (C1-C6)alkyl,        pyridyl optionally substituted with CF3,        pyrazolyl option substituted with 1-2 groups selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, and phenyl optionally substituted with CF3,        isoxazolyl optionally substituted with (C1-C4)alkyl,        pyrimid-4-yl optionally substituted with (C1-C3)alkoxy        indazolyl, optionally substituted on N with (C1-C4)alkyl;R2 is hydrogen;R3 is selected from the group consisting of        CO2R3-1         CONR3-2R3-3         —(CH2)mNR3-4R3-5
                 wherein X is O or NH,
                 wherein X is O or NH,
m is 1, 2 or 3n is 1, 2, or 3;p is 1, 2 or 3;q is 2 or 3;r is 2 or 3s is 1, 2 or 3;t is 0, 1 or 2;u is 1, 2 or 3;R3-1 is H or (C1-C6)alkyl;R3-2 and R3-3 are independently selected from H and (C1-C6)alkyl;R3-4 and R3-5 are independently selected from H and (C1-C6)alkyl;R3-6 is CF3, (C1-C4)alkoxy or (C1-C4)alkyl;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of the formula (Ia),
whereinR3 is selected from the group consisting of
                 wherein X is O or NH,
                 wherein X is O or NH, and        aminocarbonyl or (C1-C6)alkylaminocarbonyl substituted as described above;n is 1, 2, or 3;R5 is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoromethoxy, and morpholino; andv is 0, 1 or 2;or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of the formula (Ib),
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of the formula (Ic), wherein R1 represents

In another embodiment, the present invention provides a compound of the formula (Ic), wherein R3 represents ethoxycarbonyl.
In another embodiment, the present invention provides a compound of the formula (Ic), wherein R3 is (C1-C6)alkylaminocarbonyl,
wherein (C1-C6)alkylaminocarbonyl can optionally be substituted with 1 or 2 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy and methylsulfonyl, and wherein arylamino can optionally be substituted with 1 or 2 methoxy or trifluoromethyl.
In another embodiment, the present invention provides a compound as described as an Operational Example Examples section of the present application.
In another embodiment, the present invention relates to a compound capable of being metabolized or hydrolyzed to a compound of formula (I) under physiological conditions. This includes e.g. ester and amide derivatives (which can be hydrolyzed to the respective acids, alcohols and amines) as well as orthoesters and aminal esters (which can be hydrolyzed to the respective acids), acetals and hemiacetals (which can be hydrolyzed to the respective keto derivatives, e.g. the oxo group of the 4-oxopyrimidine ring moiety).
In another embodiment, the present invention provides a process for preparing a compound of formula (I), wherein a compound of formula (II)
wherein R2, R3 and R4 have the meaning indicated above,is reacted with an isocyanate compound of formula (III)R1—NCO  (III)or with an carbamate of formula (VI)R1—NH—C(O)—OPh  (VI),wherein R1 has the meaning indicated above; ora compound of formula (IV)
wherein R1, R2, R3 and R4 have the meaning indicated above,is reacted with an anine of formula (V)R1—NH2  (V),wherein R1 has the meaning indicated above.
The preparation of the compounds according to the invention can be illustrated by means of the following synthetic schemes. Unless specifically defined otherwise, the substituent placeholders such as R1 to R3 have the meaning indicated above.
Methods for preparing pyrrolotriazines are also disclosed in published U.S. application Ser. No. 10/289,010 (Publication No. US 2003-0186982 A1), U.S. Pat. No. 6,670,357 (U.S. application Ser. No. 10/036,293), as well as WO 2003/042172, WO 2004/009542, WO2004/009601, WO 2004/009784 and WO 2004/013145, all of which are hereby incorporated by reference in their entirety.
General Methods of Preparation of Invention Compounds
Compounds of the present invention of Formula (I) can be conveniently prepared from the corresponding amino compounds of Formula (II) by straightforward means as described in the Reaction Schemes below or by means well known to those skilled in the art. In these Reaction Schemes, unless otherwise specifically defined, the meanings of R1-R3, R3-2, R3-3, R3-4, R4 and r are identical to those described above.
Reaction Scheme 1 illustrates the general method of preparing Formula (I) compounds from the corresponding amino compounds of Formula (II) by standard methods of urea formation. In this scheme, a Formula (II) compound is allowed to react with either an isocyanate of Formula (III), or more preferably a carbamate of Formula (VI), generally in an inert solvent, to give the compound of Formula (I) directly. Alternatively, the amine of Formula (II) can be treated first with a chloroformate of Formula (VII), in an inert solvent, to provide an intermediate carbamate of Formula (IV). The Formula (IV) compound is then allowed to react with an amine of Formula (V), in an inert solvent, to provide the compound of Formula (I).

A more specific example of the Reaction Scheme 1 method is illustrated in Reaction Scheme 2 below. In this scheme, the amine of Formula (II-1) [Formula (II), where R3 is CO2Et], is used as the starting material, reacting with an isocyanate ((III), carbamate (VI), or in a two step sequence using (VII) followed by (V), to give the compound of Formula (I-1) [Formula (I) where R3 is CO2Et]. The Formula (I-1) compound can then be used as a starting material to prepare other compounds of Formula (I) as shown, for example, in Reaction Scheme 3 below.

Reaction Scheme 3 illustrates the preparation of compounds of Formula (I) in which R3 is a variety of substituents, starting from the compound of Formula (I-1) in which R3 is CO2Et. For example, hydrolysis of (I-1), in either aqueous base or acid, provides the carboxylic acid compound of Formula (I-2). Coupling of this acid with an amine of Formula (R3-2)(R3-3)NH gives amide compounds of Formula (I-3).
Reduction of the Formula (I-1) ester with a reducing agent such as DIBAL, provides the alcohol of Formula (I-4). Oxidation of the alcohol by standard means such as the Dess-Martin periodinane gives the aldehyde of Formula (I-5). Conversion of the aldehyde to an amine compound of Formula (I-6) is accomplished by a reductive amination sequence. In this sequence, a primary amine of Formula R3-4—NH2 is added to the compound of Formula (I-5) in the presence of acetic acid, and the intermediate imine compound is not isolated but is selectively reduced with a reagent such as sodium triacetoxyborohydride to give the amine of Formula (I-6).

The alcohol of Formula (I-4) is further elaborated in Reaction Scheme 4, and the aldehyde of Formula (I-5) is further elaborated in Reaction Scheme 5, below.
In Reaction Scheme 4, the alcohol is converted to the homologous aldehyde by standard means, namely, conversion to a tosylate or mesylate with tosyl or mesyl chloride, respectively, and a base such as pyridine or Et3N, to give the intermediate of Formula (I-7). Reaction of (I-7) with a cyanide source, e.g., KCN or NaCN, in a polar solvent such as DMF gives the nitrile of Formula (I-8). Selective reduction with DIBAL with hydrolytic workup gives aldehyde of Formula (I-9). The Formula (I-9) aldehyde is converted to the compound of Formula (I-10) [(I) where R3 is (R3-4)NHCH2CH2—] by the reductive amination sequence as described for preparation of (I-6) in Reaction Scheme 3.

The aldehyde of Formula (I-5) serves as the starting material for the preparation of additional Formula (I) compounds as shown below in Reaction Scheme 5. A Wadsworth-Emmons type reaction of (I-5) with a phosphonic ester and strong base such as LiH gives the unsaturated ester of Formula (I-11); reduction of this ester to the saturated compound of Formula (I-12) is accomplished by hydrogenation using a platinum oxide catalyst in acetic acid. Reduction of the ester to the alcohol of Formula (I-13) is followed by oxidation to the compound of Formula (I-14), a 2-carbon homologue of the aldehyde of Formula (I-5). Reductive amination of (I-14), as previously described above in Reactions Schemes 3 and 4 provides the compound of Formula (I-15) [Formula (I) where R3 is (R3-4)NHCH2CH2CH2—].
General Methods of Preparation of Intermediates
The preparation of key intermediate (II-1) shown above as starting material for Reaction Scheme 2, is prepared as illustrated below in Reaction Scheme 6. A 4-nitrocinnamate of Formula (VIII) is allowed to react with the isocyanide reagent of Formula (IX) in the presence of a strong base such as lithium hexamethyldisilazide (LHMDS) in an aprotic solvent such as THF, to give the substituted pyrrole of Formula (X). Formylation of (X) under Vilsmeier conditions (e.g., DMF, POCl3) gives the 2-formylpyrrole of Formula (XI). The aldehyde (XI) is converted to the nitrile of Formula (XII) by reaction with hydroxylamine hydrochloride to form an intermediate oxime, which is dehydrated in situ to a nitrile of Formula (XII), using a reagent such as acetic anhydride. The nitrile of Formula (XII) is then N-aminated using a strong base such as NaH and an aminating reagent such as (Ph)2P(O)—O—NH2, to provide the N-amino nitrile of Formula (XIII). Reaction of (XIII) with formamide [HC(O)NH2] gives the pyrrolotriazine intermediate of Formula (XIV-1). Selective reduction of the nitro substituent of the phenyl ring is accomplished in the final step using a catalyst such as Raney-Nickel in THF, providing the intermediate (II-1). These same reduction conditions are used to convert addition compounds of general formula (XIV), prepared as shown in Reaction Schemes 8-11 below, to the corresponding formula (II) intermediates.

The cinnamates of Formula (VIII) are either commercially available or prepared as shown in Reaction Scheme 7. In this sequence, a substituted nitrotoluene of Formula (XV) is oxidized with a reagent such as potassium permanganate to give the corresponding acid of Formula (XVI); this acid is reduced to the alcohol of Formula (XVII) with a reducing agent such as borane and then oxidized to the aldehyde of Formula (XVIII) using a reagent such as the Dess-Martin periodinane. Wadsworth-Emmons type reaction of (XVIII) using (EtO)2P(O)CH2CO2Et and a strong base such as LiH gives the cinnamate of Formula (VIII).

The use of intermediate (XIV-1) for the preparation of the intermediate of Formula (II-2) is shown in Reaction Scheme 8 below. The Formula (XIV-1) compound is allowed to react with excess methyl Grignard reagent to give the tertiary alcohol of Formula (XIX). This compound is subjected to oxidative rearrangement and hydrolysis using hydrogen peroxide and a Lewis acid, such as BF3, to give the hydroxy compound of Formula (XX). Reaction of (XX) with a substituted alcohol of Formula (XXI) under Mitsunobu conditions, e.g., DEAD, TPP, gives the intermediate of Formula (XIV-2). Reduction of the nitro group in Formula (XIV-2), as described for preparation of Formula (II-1) in Reaction Scheme 6, gives the intermediate of Formula (II-2) [Formula (II) where R3 is R′R″N(CH2)rO— and R″ and R′ are as described in Reaction Scheme 8].
The compound of Formula (II-2) can be used to prepare the compound of Formula (I) [where R3 is a group of Formula R′R″N(CH2)rO—, and R″ and R′ are as described in Reaction Scheme 8] by the route outlined in Reaction Scheme 1.

The compound of Formula (XIV-1), prepared as shown above in Reaction Scheme 6, is used to prepare a variety of other intermediates of Formula (IV-3)-(XIV-7) as shown below in Reaction Scheme 9. For example, selective reduction of the ester group in Formula (XIV-1) using, for example, DIBAL in THF, gives the compound of Formula (XIV-3). Oxidation of the alcohol (XIV-3) to the aldehyde of Formula (XIV-4) is accomplished using standard conditions such as the Dess-Martin periodinane reagent in methylene chloride. The Formula (XIV-3) compound may also be converted to the corresponding chloride of Formula (XIV-5) with, for example, thionyl chloride. Reduction of both the nitro group and the chlorine in Formula (XIV-5) using Ra—Ni, provides the intermediate of Formula (II-3). Reaction of Formula (XIV-5) with an alcohol of Formula R3-9—OH and base such as sodium hydride gives the ether of Formula (XIV-6).

As shown below in Reaction Scheme 9, the compound of Formula (XIV-4) may also be used for the preparation of the nitrile of Formula (XIV-7), by a two step procedure: reaction with hydroxylamine hydrochloride and pyridine, followed by dehydration of the intermediate oxime using acetic anhydride. The Formula (XIV-4) aldehyde may also be converted to an isoxazole intermediate of Formula (XIV-8) by reaction with tosylmethylisocyanide (TosMIC) in the presence of a base such as potassium carbonate, in a protic solvent such as methanol.

The intermediate of Formula (XIV-1) may also be used for the preparation of other amides and heterocycles as shown in Reaction Scheme 11. Hydrolysis of (XIV-1) under standard conditions to the corresponding acid of Formula (XIV-9) is followed by conversion to the amide of Formula (XIV-11), either directly using an amine of formula R3-11-1—NH2, BOP, and a base such as TEA, or by prior conversion to the acid chloride of Formula (XIV-10), which is then allowed to react with the amine of formula R3-11-1—NH2. The acid chloride of Formula (XIV-10) is also used for the preparation of oxadiazoles of Formulae (XIV-12) and (XIV-13), by reaction with either 1) hydrazine and trimethyl orthoformate to give the oxadiazole of Formula (XIV-12), or 2) hydrazine, a carboxylic acid of formula R3-11-2—CO2H, and a dehydrating agent such as POCl3, to give the substituted oxadiazole Formula (XIV-13).

The intermediates of Formula (XIV-1)-(XIV-13) can then be reduced as desired to provide the corresponding amino compounds of Formula (II), and in turn the compounds of Formula (I).

It is also to be understood that starting materials are commercially available or readily prepared by standard methods well known in the art. Such methods include, but are not limited to the transformations listed herein.
If not mentioned otherwise, the reactions are usually carried out in inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether, 1,4-dioxane or tetrahydrofuran, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane or tetrachloroethane, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, alcohols, such as methanol, ethanol or iso-propanol, nitromethane, dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents.
The reactions are generally carried out in a temperature range of from 0° C. to 150° C., preferably from 0° C. to 70° C. The reactions can be carried out under atmospheric, elevated or under reduced pressure (for example from 0.5 to 5 bar). In general, they are carried out under atmospheric pressure of air or inert gas, typically nitrogen.
Pro-drugs of this invention in general may be made by conventional methods well known in the art. For example, hydroxyl groups may be converted to esters by reacting the compounds with carboxylic acid chlorides or anhydrides under standard conditions. A hydroxyl group may also be converted to carbonates by reacting the compounds with chloroformates under standard conditions.
Salts of the compounds identified herein can be obtained by isolating the compounds as hydrochloride salts, prepared by treatment of the free base with anhydrous HCl in a suitable solvent such as THF. Generally, a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art. Or, a desired salt can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. These methods are conventional and would be readily apparent to one skilled in the art.
Additionally, sensitive or reactive groups on the compound of this invention may need to be protected and deprotected during any of the above methods. Protecting groups in general may be added and removed by conventional methods well known in the art (see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999).
If used as active compounds, the compounds according to the invention are preferably isolated in more or less pure form, that is more or less free from residues from the synthetic procedure. The degree of purity can be determined by methods known to the chemist or pharmacist (see especially Remington's Pharmaceutical Sciences, 18th ed. 1990, Mack Publishing Group, Enolo). Preferably the compounds are greater than 99% pure (w/w), while purities of greater than 95%, 90% or 85% can be employed if necessary.
The compounds according to the invention exhibit an unforeseeable, useful pharmacological and pharmacokinetic activity spectrum. They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of disorders in humans and animals.
Because of their antiproliferative properties, the compounds according to the invention are useful alone or in combination with other active components for treating and/or preventing mammalian hyper-proliferative disorders. Indications mediated by hyperproliferative disorders means diseases or conditions whose progression proceeds, at least in part, via proliferation.
The present invention also relates to a method of using the compounds or compositions described herein for the treatment or prevention of, or in the manufacture of a medicament for treating or preventing, mammalian hyper-proliferative disorders. This method comprises administering to a patient (or a mammal) in need thereof, including a human, an amount of a compound, a pharmaceutically acceptable salt or ester thereof, or a composition of this invention which is effective to treat or prevent the disorder.
The present invention also relates to a method for using the compounds of this invention as prophylactic or chemopreventive agents for prevention of the mammalian hyper-proliferative disorders described herein. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt or ester thereof, which is effective to delay or diminish the onset of the disorder.
Hyper-proliferative disorders include but are not limited to 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.
The present invention also relates to a method for using the compounds of this invention as prophylactic or chemopreventive agents for prevention of the mammalian hyper-proliferative disorders described herein. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt or ester thereof, which is effective to delay or diminish the onset of the disorder.
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 hypothalamic 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, and urethral 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, and lip and oral cavity cancer.
Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to 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, and also exist with a similar etiology in other mammals which can also be treated by the administration of the compounds and/or pharmaceutical compositions of the present invention.
The assay described in this application is one of the methods by which compound activity relating to treatment of the disorders identified herein can be determined.
In another embodiment, the present invention provides a medicament containing at least one compound according to the invention. In another embodiment, the present invention provides a medicament containing at least one compound according to the invention together with one or more pharmacologically safe excipient or carrier substances, for example hydroxypropylcellulose, and also their use for the abovementioned purposes.
The active component can act systemically and/or locally. For this purpose, it can be applied in a suitable manner, for example orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, otically or as an implant.
For these application routes, the active component can be administered in suitable application forms. An overview of application forms is given in Remington's Pharmaceutical Sciences, 18th ed. 1990, Mack Publishing Group, Enolo.
Useful oral application forms include application forms which release the active component rapidly and/or in modified form, such as for example tablets (non-coated and coated tablets, for example with an enteric coating), capsules, sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, solutions and aerosols. Such sustained-release pharmaceutical compositions are described in Part 8, Chapter 91 of Remington's Pharmaceutical Sciences, 18th ed. 1990, Mack Publishing Group, Enolo.
Parenteral application can be carried out with avoidance of an absorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with inclusion of an absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Useful parenteral application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders. Such parenteral pharmaceutical compositions are described in Part 8, Chapter 84 of Remington's Pharmaceutical Sciences, 18th ed. 1990, Mack Publishing Group, Enolo.
In one embodiment, the invention relates to intravenous (i.v.) application of the active compound, e.g. as bolus injection (that is as single dose, e.g. per syringe), infusion over a short period of time (e.g. for up to one hour) or infusion over a long period of time (e.g. for more than one hour). The application can also be done by intermittent dosing. The applied volume can vary dependent on the conditions and usually is 0.5 to 30, or 1 to 20 ml for bolus injection, 25 to 500, or 50 to 250 ml for infusion over a short period of time and 50 to 1000, or 100 to 500 ml for infusion over a long period of time.
The application forms have to be sterile and free of pyrogens. They can be based on aqueous solvents or mixtures of aqueous and organic solvents. Examples are ethanol, polyethyleneglycol (PEG) 300 or 400, aqueous solutions containing cyclodextrins or emulsifiers, such as lecithin, Pluronic F68®, Solutol HS15® or Cremophor®. Aqueous solutions are preferred.
For intravenous application the solutions are generally isotonic and euhydric, for example with a pH of 3 to 11, 6 to 8 or about 7.4.
Glass or plastic containers can be employed as packaging for i.v.-solutions, e.g. rubber seal vials. They can contain liquid volumes of 1 to 1000, or 5 to 50 ml. The solution can directly be withdrawn from the vial to be applied to the patient. For this purpose, it can be advantageous to provide the active compound in solid form (e.g. as lyophilisate) and dissolve by adding the solvent to the vial directly before administration.
Solutions for infusion can advantageously be packaged in containers made from glass or plastic, for example bottles or collapsible containers such as bags. They can contain liquid volumes of 1 to 1000, or 50 to 500 ml.
Forms suitable for other application routes include for example inhalatory pharmaceutical forms (including powder inhalers, nebulizers), nasal drops/solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, milk, pastes, dusting powders or implants.
The active components can be converted into the recited application forms in a manner known per se. This is carried out using inert non-toxic, pharmaceutically suitable excipients. These include inter alia carriers (for example microcrystalline cellulose), solvents (for example liquid polyethylene glycols), emulsifiers (for example sodium dodecyl sulphate), dispersing agents (for example polyvinylpyrrolidone), synthetic and natural biopolymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), colorants (for example inorganic pigments such as iron oxides) or taste and/or odor corrigents.
For human use, in the case of oral administration, it is recommended to administer doses of from 0.001 to 100 mg/kg, or from 0.01 to 20 mg/kg. In the case of parenteral administration such as, for example, intravenously or via mucous membranes nasally, buccally or inhalationally, it is recommended to use doses of 0.001 to 0.60 mg/kg, in particular 0.01 to 30 mg/kg.
In spite of this, it can be necessary in certain circumstances to depart from the amounts mentioned, namely as a function of body weight, application route, individual behaviour towards the active component, manner of preparation and time or interval at which application takes place. It can for instance be sufficient in some cases to use less than the aforementioned minimum amount, while in other cases the upper limit mentioned will have to be exceeded. In the case of the application of larger amounts, it can be advisable to divide them into a plurality of individual doses spread through the day.
The percentages in the tests and examples which follows are, unless otherwise stated, by weight; parts are by weight. Solvent ratios, dilution ratios and concentrations reported for liquid/liquid solutions are each based on the volume.


The treatment of textile materials with various chemicals, dyestuffs, resins and the like has been long conducted by the use of aqueous baths. In such processes the fabric is essentially saturated by immersion in a water bath containing the treating chemical and eventually the water must be removed in order to continue the processing or to dry the fabric. Of the many procedures employed in the past for the treatment of fabrics, the most commonly employed is the pad-dry process in which the fabric is immersed and saturated with the aqueous treating solution, squeezed between rollers to a given wet pick-up and subsequently dried or dried and cured on a frame or heated drying roll before being taken up in a roll once again. The amount of water retained by the fabric is normally controlled by the pressure of the squeeze roll; in conventional methods a lower limit of about 50 to 70 percent water based on the weight of the fabric is still retained, depending upon the particular fabric used. This large amount of water requires a tremendous amount of energy in the form of heat to dry the fabric. It has been estimated that the amount of energy required to remove the water and dry the fabric is many times greater than the amount of energy that is needed in heating the cloth to carry out the desired chemical treating step, as for example, in the application and cure of a wash and wear finish on the fabric, or in the continuous dyeing of a fabric. In addition to the pad-dry process, in which the water is removed by squeezing between rollers, other procedures have recently been developed for more efficient removal of water. In one such procedure the saturated fabric is conveyed to a jet squeezer which employs a stream of compressed air jetting outward at the point of contact between the fabric and the nip rolls to substantially reduce the moisture content of the fabric. The use of this technique has resulted in a decrease of the water content in the fabric to about half of that normally remaining when using the squeeze roll technique discussed above. In another procedure vacuum extractor rolls are used. This process entails conveying the wet fabric as it exits from the treating bath over a perforated roll within which a vacuum is created whereby the moisture is extracted from the fabric. In some instances, roller coating methods can be used which continuously deliver aqueous treating composition to the fabric and the add-on is governed by the fabric speed and the rate of delivery of the treating composition by the coating roller. In this procedure the treating composition generally remains predominantly on or near the surface of the fabric, particularly when low add-ons are involved.
Within the past few years, several new approaches have been made to obtain uniform application of compositions to porous substrates. These recently developed procedures use foams in different form. However, the methods by which the foams had been applied to treat the fabric or yarn leave much to be desired. One such disclosure is to be found in U.S. Pat. No. 3,697,314 issued Oct. 10, 1972. In this patent there is shown a method for producing foam and then passing yarn through the foam so as to coat the exterior surface of the yarn with the foamed treating agent. It stresses that the yarn must pass through the foam agglomerate in order to assure a uniform distribution of the agent over the entire circumferential surface of the yarn as it passes through the foam. The reference shows no means by which the foam could be applied on only one surface of a fabric or material and still obtain uniform distribution or uniform penetration of the interior of the yarn or fabric. An earlier attempt to use foam for the treatment of textile materials is to be found in U.S. Pat. No. 1,948,568, issued Feb. 27, 1934. In this disclosure, a textile material is suspended in a closed container and foam is pumped into the container and forced through the textile material until the textile material is uniformally impregnated from all sides throughout the substrate structure and saturated with the textile treating agent in the form of a foam. In the batch process disclosed in this patent, the textile material is in a stationary or fixed position.
Though disclosures do exist on the use of foam for the treatment of textile materials, essentially all of the industry still uses aqueous treating baths and processes in which the fabrics are generally immersed in the bath for the application of the treating material to the textile. As previously indicated, this entails the use of a large amount of energy to subsequently remove the water from the fabric. Further, none of the literature discloses foam compositions that have the adequate stability and penetration properties needed for treating a fabric without deposition of large quantities of water to it.


As an exemplary non-volatile semiconductor memory device, a type of non-volatile semiconductor memory device has been conventionally known that accumulates electric charges into a charge accumulation layer of a memory cell transistor by means of, for instance, a quantum tunneling effect in order to execute data writing (e.g., see PTL 1). Actually, as shown in FIG. 6, a non-volatile semiconductor memory device 100 of this type has a structure that higher order bit lines 101a and 101b and word lines 102a to 102h are disposed in an intersecting manner and a plurality of memory cell transistors 103 are disposed in a row and column matrix with respect to the higher order bit lines 101a and 101b and the word lines 102a to 102h.
The higher order bit line 101a is provided with a plurality of first semiconductor switches 104a and 104c, while a single lower order bit line 105a, 105c is connected to each first semiconductor switch 104a, 104c. Further, in this exemplary embodiment, the other higher order bit line 101b is also similarly provided with a plurality of first semiconductor switches 104b and 104d, while a single lower order bit line 105b, 105d is connected to each first semiconductor switch 104b, 104d. In such non-volatile semiconductor memory device 100, each lower order bit line 105a, 105b, 105c, 105d forms a memory block 106a, 106b, 106c, 106d, while each memory block 106a, 106b, 106c, 106d has the plural memory cell transistors 103.
The first semiconductor switches 104a, 104b, 104c and 104d are herein formed by N-MOS (Metal-Oxide-Semiconductor) transistors. Further, the first semiconductor switch 104a of the memory block 106a, for instance, is connected at the source thereof to the higher order bit line 101a while being connected at the drain thereof to the lower order bit line 105a, and is also connected at the gate thereof to a first selected gate line 108a shared with another memory block 106b aligned with the memory block 106a along a row direction. Thus, by this configuration, a predetermined gate voltage can be equally applied from the shared, single first selected gate line 108a to the two first semiconductor switches 104a and 104b that are mounted on the memory blocks 106a and 106b disposed in the upper part of FIG. 6.
On the other hand, similarly also in the two memory blocks 106c and 106d aligned along the row direction in the lower part of FIG. 6, a single first selected gate line 108b is connected to the two first semiconductor switches 104c and 104d, and a predetermined gate voltage is can be configured to be equally applied to the two first semiconductor switches 104c and 104d from the shared, first selected gate line 108b.
In addition to this, a higher order source line 110a is provided with a plurality of second semiconductor switches 111a and 111b, while a single lower order source line 112a, 112b is connected to each second semiconductor switch 111a, 111b. Further, the other higher order source line 110b is also similarly provided with a plurality of second semiconductor switches 111c and 111d, while a single lower order line 112c, 112d is connected to each second semiconductor switch 111c, 111d.
Further, the second semiconductor switches 111a, 111b, 111c and 111d are formed by NMOS transistors that the polarity thereof is the same as that of the first semiconductor switches 104a, 104b, 104c and 104d.
Herein, the second semiconductor switch 111a of the memory block 106a, for instance, is connected at the source thereof to the higher order source line 110a while being connected at the drain thereof to the lower order source line 112a, and is also connected at the gate thereof to a second selected gate line 113a shared with another memory block 106b aligned along the row direction in the upper part. Thus, a predetermined gate voltage can be configured to be equally applied from the shared, single second selected gate line 113a to the two second semiconductor switches 111a and 111b that are mounted on the different memory blocks 106a and 106b disposed in the upper part.
On the other hand, similarly also in the two memory blocks 106c and 106d aligned along the row direction in the lower part, a single second selected gate line 113b is connected to the two second semiconductor switches 111c and 111d, and a predetermined gate voltage can be configured to be equally applied to the two second semiconductor switches 111c and 111d from the shared, second selected gate line 113b.
Further, each memory cell transistor 103 on the memory block 106a, for instance, is connected at one terminal thereof to the lower order bit line 105a while being connected at the other terminal thereof to the lower order source line 112a, and thus, the memory cell transistors 103 are disposed in parallel to each other between the lower order bit line 105a and the lower order source line 112a. The word lines 102a, 102b, 102c and 102d, shared by the memory block 106a and another memory block 106b aligned along the row direction, are connected to control gates of the memory cell transistors 103 of the memory block 106a. Due to this, a predetermined gate voltage can be configured to be equally applied, for instance, from the shared, single word line 102a to one of the memory cell transistors 103 of the memory block 106a in the upper part and one of the memory cell transistors 103 of another memory block 106b aligned with the memory block 106a along the row direction in the upper part.
Incidentally, all the memory cell transistors 103 have the same structure that a channel region is disposed between one terminal and the other terminal, which are formed at a predetermined interval on a semiconductor substrate, and a charge accumulation layer, an interlayer insulation layer and a control gate are sequentially laminated through a tunnel insulation layer on the channel region of the semiconductor substrate. Such memory cell transistors 103 are of an N-channel type, and are capable of executing either data writing by injecting electric charges into the charge accumulation layer or data erasing by extracting the electric charges accumulated into the charge accumulation layer by means of voltage to be applied to the control gate and the region between the one terminal and the other terminal.
The non-volatile semiconductor memory device 100 thus structured can be configured to write data in a predetermined one of the memory cell transistors 103, read data from a predetermined one of the memory cell transistors 103 and erase data written in the memory cell transistors 103 by regulating voltages to be respectively applied to the higher order bit lines 101a and 101b, the higher order source lines 110a and 110b and the word lines 102a to 102h and by controlling on/off states of the first semiconductor switches 104a to 104d and the second semiconductor switches 111a to 111d.
In FIG. 6, the memory cell transistor 103 in the first row of the memory block 106a is set as a selected memory cell transistor 115 in which data is written, whereas all the remaining memory cell transistors 103 are set as non-selected memory cell transistors 116 in which data is not written.
It should be herein noted that for the sake of explanatory convenience, the memory block 106a on which the selected memory cell transistor 115 is disposed will be referred to as a selected block 117, whereas the memory blocks 106b, 106c and 106d on which only the non-selected memory cell transistors 116 are disposed will be referred to as non-selected blocks 118.
Actually in the non-volatile semiconductor memory device 100, for instance, when data is written in only the selected memory cell transistor 115 in the first row of the selected block 117, a high voltage of 12[V] is applied to a word line 120 (hereinafter referred to as a selected word line) that is the one connected to the selected memory cell transistor 115 among the plural word lines 102a to 102h, whereas a low voltage of 4[V] is applied to the word lines 121 (hereinafter referred to as non-selected word lines) that are the other remaining ones among the plural word lines 102a to 102h.
Further, at this time, in the non-volatile semiconductor memory device 100, a low voltage of 0[V] as a writing voltage can be applied to a higher order bit line 122 (herein referred to as a selected bit line) that is the one to which the selected memory cell transistor 115 is connected, whereas a high voltage of 8[V] as a writing prevention voltage can be applied to a higher order bit line 123 (herein referred to as a non-selected bit line) that is the one to which only the non-selected memory cell transistors 116 are connected. Moreover, in the non-volatile semiconductor memory device 100, a gate voltage of 10[V], which is higher than the voltage of the non-selected bit line 123, can be applied to the first semiconductor switches 104a and 104b from the first selected gate line 108a connected to the selected block 117, whereas a gate voltage of 0[V] can be applied to the second semiconductor switches 111a and 111b from the second selected gate line 113a.
Accordingly, in the non-volatile semiconductor memory device 100, the first semiconductor switch 104b on the non-selected bit line 123 is switched on by means of the writing prevention voltage from the non-selected bit line 123 and the gate voltage from the first selected gate line 108a, and a writing prevention voltage of 8[V] can be applied to the non-selected memory cell transistor 116 on the non-selected bit line 123 that intersects with the selected word line 120. At this time, the second semiconductor switches 111a, 111b, 111c and 111d are switched off by applying a voltage of 0[V] thereto from the higher order source lines 110a and 110b and by applying a voltage of 0[V] thereto from the second selected gate lines 113a and 113b, and the lower order source lines 112a, 112b, 112c and 112d can be turned into a floating state.
Thus, in the non-selected memory cell transistor 116 at which the selected word line 120 and the non-selected bit line 123 intersect with each other, a voltage difference is reduced between the control gate and the semiconductor substrate, and as a result, electric charges cannot be injected into the charge accumulation layer without occurrence of a quantum tunneling effect.
Further, at this time, the first semiconductor switch 104a on the selected bit line 122 is switched on by means of the writing voltage from the selected bit line 122 and the gate voltage from the first selected gate line 108a, and a writing voltage of 0[V] can be applied to the selected memory cell transistor 115 on the selected bit line 122 that intersects with the selected word line 120. Accordingly, in the selected memory cell transistor 115 at which the selected word line 120 and the selected bit line 122 intersect with each other, a voltage difference is increased between the control gate and the semiconductor substrate by means of the writing gate voltage applied from the selected word line 120. As a result, a quantum tunneling effect occurs and electric charges can be injected into only the charge accumulation layer of the relevant selected memory cell transistor 115. Consequently, in the non-volatile semiconductor memory device 100, only the selected memory cell transistor 115 can be set to be in a data written state while electric charges are accumulated into the charge accumulation layer thereof.


The present invention relates to a cooking method and apparatus and in particular to such an apparatus specifically designed to cook shrimp.
In the past, a wide variety of cooking systems have been provided from simple pots to complex automated cooking ovens. Ovens having continuous conveyor belts have been provided in the past. These typically cook bakery products, and the like, and have electric or gas heating elements for baking cookies, bread, or the like, on conveyor belts passing through continuous ovens. This type of oven has a continuous flow of air at atmospheric pressure and is typically heated with electrical heat so that there is no build up of pressure as would be desirable in cooking seafood.
Shrimp are prepared utilizing a wide variety of prior art cooking methods and devices. In commercial cooking methods, however, it is generally customary to heat the shrimp with steam while applying pressure from an external source. See for example U.S. Pat. No. 3,501,317 to Veltman. In other methods such as the Hice U.S. Pat. No. 3,672,908, pressure from an external source is also applied prior to as well as during the heating of the shrimp.
An object of shrimp cooking processes is to avoid the weight loss during the heating step. As explained by Veltman, the cooking of shrimp in water, or an aqueous solutions, often causes a weight loss of between 30-50 percent resulting in a higher cost per pound of cooked shrimp.
Another object in any cooking process is to destroy or remove the bacteria present in the shrimp. Although acceptable for commercial purposes, many, if not most commercial shrimp cooking processes cannot remove bacteria below a 250,000 per gram plate count.
This invention is an improvement in my prior inventions set forth in U.S. Pat. No. 4,887,524 for a Shrimp Cooking Apparatus and my prior U.S. Pat. No. 4,966,072 for a Shrimp Cooking Apparatus. In those patents, a shrimp cooking apparatus used a frame having a motor driven endless belt conveyor with porous endless belts supported to the frame and a housing similar to the present invention. The steam is released directly beneath the belt and under the shrimp to heat the shrimp as they passed through the housing. In contrast, the present invention improves upon the prior systems by improving the housing which uses thin layers of stainless steel spaced by insulation to conserve energy in the system but which is reinforced with support brackets interconnected with a lifting mechanism formed in supporting upright channels and driven by central electric motors driving shafts to raise and lower the entire housing.