AU2005299504A1 - Phosphonate substituted kinase inhibitors - Google Patents

Description

WO 2006/047507 PCT/US2005/038348 PHOSPHONATE SUBSTITUTED KINASE INHIBITORS 5 PRIORITY OF INVENTION This patent documents claims priority to United States Provisional Applications 60/623,098; 60/622,992; 60/622,881; 60/622,960; 60/622,811; 60/622,942; and 60/622,943, all of which were filed on 26 October 2004, and all of which are herein incorporated by reference. 10 FIELD OF THE INVENTION The invention relates generally to phosphonate-containing compounds with kinase-inhibitory activity, i.e., compounds that inhibit at least one kinase. BACKGROUND OF THE INVENTION Improving the delivery of drugs and other agents to target cells and 15 tissues has been the focus of considerable research for many years. Though many attempts have been made to develop effective methods for importing biologically active molecules into cells, both in vivo and in vitro, none has proved to be entirely satisfactory. Optimizing the association of the inhibitory drug with its intracellular target, while minimizing intercellular redistribution of 20 the drug, e.g., to neighboring cells, is often difficult or inefficient. Most agents currently administered to a patient parenterally are not targeted, thereby resulting in systemic delivery of the agent to cells and tissues of the body where the agent is unnecessary, and often undesirable. This systemic delivery may result in adverse side effects and often limits the dose of 25 an agent that can be administered. By comparison, oral administration of agents is generally recognized as a convenient and economical method of administration. However, oral administration of agents can result in (a) the upt-k3 of the agen through cellular and tissue barriers, such as the blood-brain barrier, epithelial, or the cell membrane, resulting in undesirable systemic 30 distribution, and/or (b) temporary residence of the agent within the gastrointestinal tract. Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues. Benefits of such treatment include avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells. 1 WO 2006/047507 PCT/US2005/038348 Thus, there is a need for therapeutic agents, e.g., agents that inhibit at least one kinase, with improved pharmacological properties, e.g., having improved kinase-inhibitory activity and/or pharmacokinetic properties, including improved oral bioavailability, greater potency and extended effective half-life in 5 vivo. Such inhibitors would have therapeutic uses, for example, as anti-cancer agents. Thus, new kinase inhibitors should have fewer side effects, less complicated dosing schedules, and be orally active. In particular, there is a need for a less onerous dosage regimen, such as one pill, once per day. Assay methods capable of determining the presence, absence or amounts 10 of kinase inhibition are of practical utility in the search for kinase inhibitors as well as for diagnosing the presence of conditions associated with kinase activity. SUMMARY OF CERTAIN EMBODIMENTS OF THE INVENTION Intracellular targeting may be achieved by methods and compositions that allow accumulation or retention of biologically active agents inside cells. 15 Certain embodiments of the present invention provide novel analogs of kinase inhibitory compounds, i.e., compounds that inhibit the activity of at least one kinase. Such novel kinase-inhibitory analogs possess utilities of the kinase inhibitory compounds and optionally provide cellular accumulation. In addition, certain embodiments of the present invention provide compositions and methods 20 useful for inhibiting at least one kinase that may have therapeutic activity against diseases associated with kinase activity, such as cancer. The present invention relates generally to the accumulation or retention of therapeutic compounds inside cells. The invention is more particularly related to attaining high concentrations of phosphonate-containing molecules in target 25 cells. Such effective targeting may be applicable to a variety of therapeutic formulations and procedures. Compositions of the invention include kinase-inhibitory compounds having at least one phosphonate group. Accordingly, in one embodiment the invention provides a conjugate comprising a compound that is linked to one or 30 more phosphonate groups; or a pharmaceutically acceptable salt or solvate thereof. 2 WO 2006/047507 PCT/US2005/038348 In another embodiment the invention provides a compound comprising at least one phosphonate group and a substructure of any one of formulae 100-106: R 29 R 3 " N R 3 2 R N -0-N O N H I NO * N N"~N III ~R 30 R3 100 101 102 H N' S NN O S N N 103 104 105 0

R

5 6 N H 106 wherein: 5 the bond represented by --- is a single or double bond; R29 is hydrogen, alkyl, or -C(=0)R36.

R

30 is hydrogen or substituted alkyl; and R 3 and R 32 are independently hydrogen, alkyl, or substituted aryl; or R3 and R 32 taken together with the nitrogen atom to which they are attached form a 10 substituted or unsubstituted heterocyclic ring;

R

33 is -0-, -NR 35 - or absent;

R

34 is -0- or absent;

R

35 is hydrogen or alkyl;

R

36 is hydrogen, alkyl, alkenyl, or alkynyl; 15 R 56 is -N-, or -CR 6 8 -; and R 8 is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof. 3 WO 2006/047507 PCT/US2005/038348 The invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. 5 This invention provides a method of increasing cellular accumulation and retention of drug compounds, thus improving their therapeutic and diagnostic value, comprising linking the compound to one or more (e.g., 1, 2, 3, or 4) phosphonate groups. The invention also provides a method of inhibiting the activity of at least 10 one kinase, comprising administering to a mammal an amount of a compound of the invention. The invention also provides a compound of the invention for use in medical therapy (preferably for use in treating a condition associated with kinase activity, e.g., elevated kinase activity), as well as the use of a compound of the 15 invention for the manufacture of a medicament useful for the treatment of a condition associated with kinase activity, e.g., associated with elevated kinase activity. The invention also provides the use of a compound of the invention to prepare a medicament for treating cancer in an animal. The invention also provides processes and novel intermediates disclosed 20 herein which are useful for preparing compounds of the invention. Some of the compounds of the invention are useful to prepare other compounds of the invention. In another aspect of the invention, the activity of a kinase is inhibited by a method comprising the step of treating a sample suspected of containing a 25 kinase with a compound or composition of the invention. DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the 30 enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the embodiments. 4 WO 2006/047507 PCT/US2005/038348 Many of the current treatment regimes for cell proliferation diseases such as psoriasis and cancer utilize compounds that inhibit DNA synthesis. Such compounds are toxic to cells generally, but their toxic effect on rapidly dividing cells, such as tumor cells, can be beneficial. Alternative approaches to anti 5 proliferative agents that act by mechanisms other than the inhibition of DNA synthesis have the potential to display enhanced selectivity of action. In recent years it has been discovered that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene i.e. a gene that, on activation, leads to the formation of malignant tumor cells 10 (Bradshaw, Mutagenesis 1986, 1, 91). Several such oncogenes give rise to the production of peptides which are receptors for growth factors. The growth factor receptor complex subsequently leads to an increase in cell proliferation. For example, several oncogenes encode tyrosine kinase enzymes, and certain growth factor receptors are also tyrosine kinase enzymes (Yarden et al., Ann. Rev. 15 Biochem., 1988, 57, 443; Larsen et al., Ann. Reports in Med. Chem. 1989, Chpt. 13). Receptor tyrosine kinases are important in the transmission of biochemical signals that initiate cell replication. They are large enzymes that span the cell membrane and possess an extracellular binding domain for growth 20 factors such as epidermal growth factor (EGF), and an intracellular portion that functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence influence cell proliferation. Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on families of growth factors that bind to different receptor tyrosine kinases. The 25 classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGFax, NEU, erbB, Xmrk, HER and let23 receptors, Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin, IGFI and insulin related receptor (IRR) receptors and Class III receptor tyrosine kinases 30 comprising the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGFa, PDGFp and colony-stimulating factor 1 (CSF1) receptors. 5 WO 2006/047507 PCT/US2005/038348 Class I kinases, such as the EGF family of receptor tyrosine kinases, are frequently present in common human cancers such as breast cancer (Sainsbury et al., Brit. J Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21 and Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73), non-small cell lung 5 cancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J Cancer, 1990, 45, 269; and Rusch et al., Cancer Research, 1993, 53, 2379) and squamous cell cancer of the lung (Hendler et al., Cancer Cells, 1989, 7, 347), bladder cancer (Neal et al., Lancet, 1985, 366), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), 10 gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen et al., Oncogene Res., 1987, 1, 149), cancer of the prostate (Visakorpi et al., Histochem. J., 1992, 24, 481), leukaemia (Konaka et al., Cell, 1984, 37, 1035) and ovarian, bronchial or pancreatic cancer (European Patent Specification No. 0400586). As further human tumor tissues are tested for the EGF family of 15 receptor tyrosine kinases, it is expected that their widespread prevalence will be established in further cancers such as thyroid and uterine cancer. EGF type tyrosine kinase activity is rarely detected in normal cells, whereas it is more frequently detected in malignant cells (Hunter, Cell, 1987, 50, 823). EGF receptors that possess tyrosine kinase activity are overexpressed in many human 20 cancers such as brain, lung squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynaecological and thyroid tumors (W. J. Gullick, Brit. Med. Bull., 1991, 47, 87). Accordingly, an inhibitor of receptor tyrosine kinases would be of value as a selective inhibitor of the growth of mammalian cancer cells (Yaish et al. 25 Science, 1988, 242, 933). Support for this view is provided by the demonstration that erbstatin, an EGF receptor tyrosine kinase inhibitor, specifically attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma that expresses EGF receptor tyrosine kinase but is without effect on the growth of another carcinoma that does not express EGF receptor tyrosine kinase (Toi et 30 al., Eur. J. Cancer Clin. Oncol., 1990, 26, 722.) Various derivatives of styrene also possess tyrosine kinase inhibitory properties (European Patent Application Nos. 0 211 363, 0 304 493 and 0 322 738) and may be used as anti-tumor agents. The in vivo inhibitory effect of two such styrene derivatives that are EGF 6 WO 2006/047507 PCT/US2005/038348 receptor tyrosine kinase inhibitors has been demonstrated against the growth of human squamous cell carcinoma inoculated into nude mice (Yoneda et al., Cancer Research, 1991, 51, 4430). Various known tyrosine kinase inhibitors are disclosed in a more recent review by T. R. Burke Jr. (Drugs of the Future, 1992, 5 17,119). Kinase inhibitors have valuable pharmacological properties and can be used, e.g., as anti-tumor drugs and as drugs against atherosclerosis. The phosphorylation of proteins has long been known as an important step in the differentiation and proliferation of cells. Phosphorylation is catalyzed by protein 10 kinases that are divided into serine/threonine kinases and tyrosine kinases. The serine/threonine kinases include protein kinase C and the tyrosine kinases include PDGF (platelet-derived growth factor)-receptor tyrosine kinase and Bcr Abl kinase. Chronic myelogenous Leukemia (CML) is a hematological stem cell 15 disorder associated with a specific chromosomal translocation known as the Philadelphia chromosome that is detected in 95% of patients with CML and 20% with acute lymphocytic leukemia (ALL). The molecular consequences of the translocation is the fusion of the abl protooncogene to the bcr gene resulting in the production of an activated from of AbI tyrosine protein kinase. The Bcr-Abl 20 protein is capable of inducing leukemias in mice, thus implicating the protein as the cause of these diseases. Thus, kinase inhibitors inhibit cellular kinases that are involved in disease states, for example, Bcr-Abl. As the tyrosine kinase activity of the Bcr-Abl protein is essential to its transforming ability, an inhibitor would be useful therapy for these disorders. 25 In addition, kinase inhibitors prevent the development of resistance (e.g., multi-drug resistance) in cancer treatment with other chemotherapeutic drugs or remove existing resistance to other chemotherapeutic drugs. Two processes, the de novo formation of vessels from differentiating endothelial cells or angioblasts in the developing embryo (vasculogenesis) and 30 the growth of new capillary vessels from existing blood vessels (angiogenesis), are involved in the development of the vascular systems of animal organs and tissues. Transient phases of new vessel formation (neovascularization) also occur in the adult body, for example, during the menstrual cycle, pregnancy and wound 7 WO 2006/047507 PCT/US2005/038348 healing. On the other hand, a number of diseases are known to be associated with deregulated angiogenesis, for example, retinopathies, psoriasis, hemangioblastoma, hemangioma, and neoplastic diseases (e.g., solid tumors). The complex processes of vasculogenesis and angiogenesis have been found to 5 involve a whole range of molecules, especially angiogenic growth factors and their endothelial receptors, as well as cell adhesion molecules. Recent findings show that at the center of the network regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth and in a wide number of 10 pathological anomalies and diseases, lies the angiogenic factor known as vascular endothelial growth factor (VEGF), along with its cellular receptors (see Breier, G., et al., Trends in Cell Biology 6, 454-6 (1996) and the references cited therein). VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein and is related to 15 platelet-derived growth factor (PDGF). It is produced by normal cell lines and tumor cell lines, is an endothelial cell-specific mitogen, shows angiogenic activity in in vivo test systems (e.g. rabbit cornea), is chemotactic for endothelial cells and monocytes, and induces plasminogen activators in endothelial cells, which are then involved in the proteolytic degradation of extracellular matrix 20 during the formation of capillaries. A number of isoforms of VEGF show comparable biological activity, but differ in the type of cells that secrete them and in their heparin-binding capacity. In addition, there are other members of the VEGF family, such as placenta growth factor (PLGF) and VEGF-C. VEGF receptors are transmembranous receptor tyrosine kinases. They 25 are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptor are known, e.g. VEGFR-1, VEGFR-2, and VEGFR-3. A large number of human tumors, especially gliomas and carcinomas, express high levels of VEGF and its receptors. This has led to the hypothesis that 30 the VEGF released by tumor cells could stimulate the growth of blood capillaries and the proliferation of tumor endothelium in a paracrine manner and thus, through the improved blood supply, accelerate tumor growth. Increased VEGF expression could explain the occurrence of cerebral edema in patients with 8 WO 2006/047507 PCT/US2005/038348 glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo has been obtained from studies in which VEGF expression or VEGF activity was inhibited. This was achieved with antibodies that inhibit VEGF activity, with dominant-negative VEGFR-2 mutants that inhibited signal 5 transduction, or with the use of antisense-VEGF RNA techniques. All approaches led to a reduction in the growth of glioma cell lines or other tumor cell lines in vivo as a result of inhibited tumor angiogenesis. In addition, hypoxia, a large number of growth factors and cytokines, e.g. Epidermal Growth Factor, Transforming Growth Factor a, Transforming Growth 10 Factor A, Interleukin 1, and Interleukin 6, induce the expression of VEGF in cell experiments. Angiogenesis is regarded as a prerequisite for those tumors that grow beyond a maximum diameter of about 1-2 mm; up to this limit, oxygen and nutrients may be supplied to the tumor cells by diffusion. Every tumor, regardless of its origin and its cause, is thus thought to be dependent on 15 angiogenesis for its growth after it has reached a certain size. Three principal mechanisms play important parts in the activity of angiogenesis inhibitors against tumors: 1) inhibition of the growth of vessels, especially capillaries, into avascular resting tumors, with the result that there is no net tumor growth owing to the balance that is achieved between apoptosis and 20 proliferation; 2) prevention of the migration of tumor cells owing to the absence of bloodflow to and from tumors; and 3) inhibition of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells that normally line the vessels. Inhibitors of cyclin-dependent kinases, e.g., Alvocidib (US Patent No. 25 4,900,727; also known as flavopiridol) have been identified as a potentially useful therapeutic agents for a variety of cancers, including gastrointestinal and colon tumors, leukemias and myelomas (see, for example, Intl. J. Oncol., 1996, 9, 1143). Inhibitors of tyrosine kinases, including Bcr-Abl, e.g., Gleevec, are 30 useful for the treatment of chronic myeloid leukemia (CML), and potentially for treatment of other cancers that express these kinases, including acute lymphocytic leukemia (ALL) and certain solid tumors. Gleevec was approved 9 WO 2006/047507 PCT/US2005/038348 for the treatment of inoperable and/or metastatic malignant gastrointestinal stromal tumors (GISTs). Inhibitors of Flt3 tyrosine kinase, e.g., CEP-701 (US Patent No. 4,923,986) and Midostaurin (US Patent No. 5,093,330), have potential utility for 5 the treatment of a variety of cancers (Cancer Res., 1999, 59, 10). Inhibitors of MAP Erk kinase, e.g., PD-184352 (U.S. Patent No. 6,251,943), have been identified as potentially useful therapeutic agents for a variety of oncological disorders, including colon, breast, pancreatic and non small-cell lung cancers (see, for example, Proc. Am. Soc. Clin. Oncol., 2003, 22, 10 abstract 816). Other kinase inhibitors, e.g., doramapimod (U.S. Patent No. 6,319,921), have been identified as potentially useful therapeutic agents for the treatment of inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. 15 Other kinase inhibitors, e.g., BAY-43-9006 (U.S. Publication No. 2002/0165394) have been identified as potentially useful therapeutic agents for a variety of cancers including gastrointestinal and colon tumors, leukemia and carcinoma (Curr. Pharm. Design, 2002, 8, 2269). Cytokine receptors are critical for the development and homeostasis of 20 immune cells. These receptors all require the cytoplasmic tyrosine kinase JAK3 for signaling (Changelian, P. S. et al., Science, 2003, 302, 875). CP-690,550 (WO 02,096,909) is an orally available Janus kinase (JAK)-3 inhibitor, for the potential treatment of transplant rejection and psoriasis. Thus, there is a need for therapeutic agents that are kinase inhibitors with 25 improved pharmacological properties, e.g., drugs having improved kinase inhibitory activity and/or pharmacokinetic properties, including improved oral bioavailability, greater potency and extended effective half-life in vivo. Such inhibitors would have therapeutic potential as, e.g., anticancer agents. The kinase inhibitory compounds provided herein may be used, e.g., to treat breast 30 cancer, non-small cell lung cancers (NSCLCs), adenocarcinomas, squamous cell cancer of the lung, oesophageal cancer, gastrointestinal cancer, colon cancer, rectal cancer, stomach cancer, prostate cancer, leukaemia, ovarian cancer, bronchial cancer, pancreatic cancer, thyroid cancer, uterine cancer, brain cancer, 10 WO 2006/047507 PCT/US2005/038348 lung squamous cell cancer, bladder cancer, gastric cancer, head and neck cancer, gynaecological and thyroid tumors, to prevent the development of resistance (multi-drug resistance) in cancer treatment with other chemotherapeutic drugs or remove existing resistance to other chemotherapeutic drugs, retinopathies, 5 hemangioblastoma, hemangioma, and neoplastic diseases, gliomas, to inhibit tumor angiogenesis, myelomas, chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), inoperable and/or metastatic malignant gastrointestinal stromal tumors (GISTs), treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, treatment of cell proliferation diseases, 10 and for the treatment of transplant rejection and psoriasis; and to prepare medicaments for such treatments. DEFINITIONS Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings: 15 When tradenames are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product. "Bioavailability" is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body. 20 Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites. The terms "phosphonate" and "phosphonate group" include functional 25 groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to a heteroatom , 3) single-bonded to a heteroatom, and 4) single-bonded to another heteroatom, wherein each heteroatom can be the same or different. The terms "phosphonate" and "phosphonate group" also include functional groups or moieties that comprise a 30 phosphorous in the same oxidation state as the phosphorous described above, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having the characteristics described above. For example, the terms "phosphonate" and 11 WO 2006/047507 PCT/US2005/038348 "phosphonate group" include phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, and phosphonthioate functional groups. In one specific embodiment of the invention, the terms "phosphonate" and "phosphonate group" include functional groups or moieties within a molecule 5 that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double bonded to an oxygen, 3) single-bonded to an oxygen, and 4) single-bonded to another oxygen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteristics. In another specific embodiment of the 10 invention, the terms "phosphonate" and "phosphonate group" include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to an oxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bonded to another oxygen or nitrogen, as well as functional groups or moieties that comprise a prodrug moiety that can 15 separate from a compound so that the compound retains a phosphorous having such characteriatics. The term "prodrug" as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed 20 chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound. "Prodrug moiety" refers to a labile functional group that separates from the active inhibitory compound during metabolism, systemically, inside a cell, by 25 hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes that are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention 30 include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, 12 WO 2006/047507 PCT/US2005/038348 bioavailability and efficacy. A prodrug moiety may include an active metabolite or drug itself. Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters -CH 2 0C(=O)R 9 and acyloxymethyl carbonates 5 -CH 2 0C(=O)OR 9 where R 9 is CI-C 6 alkyl, CI-C 6 substituted alkyl, C 6

-C

20 aryl or C 6

-C

20 substituted aryl. The acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also U.S. Patent Nos. 4816570, 4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used 10 to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) 15 -CH 2 0C(=O)C(CH 3

)

3 . An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) -CH 2

OC(=O)OC(CH

3

)

3 . The phosphonate group may be a phosphonate prodrug moiety. The prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a pivaloyloxymethyl carbonate (POC) or POM group. Alternatively, the prodrug 20 moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group. Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have 25 also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109 4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-or para-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g., esterases, 30 oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate the phosphoric acid and the quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc. Perkin Trans. II2345; Glazier WO 91/19721. Still other benzylic prodrugs have 13 WO 2006/047507 PCT/US2005/038348 been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified 5 with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996) J. Med Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of 10 phosphorus-containing compounds (Erion et al., US Patent No. 6312662). "Protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, 15 Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of 20 the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive. Protected compounds may also exhibit altered, and in some cases, 25 optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of 30 the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical 14 WO 2006/047507 PCT/US2005/038348 intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous. Any reference to any of the compounds of the invention also includes a 5 reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 * (wherein X is

CI-C

4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino 10 group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulftiric, phosphoric and sulfamic acids. Physiologically 15 acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na* and NX4j (wherein X is independently selected from H or a Ci-C 4 alkyl group). For therapeutic use, salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a 20 physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention. 25 As used herein, the term "substructure" refers to a residue wherein any hydrogen atom(s) or replaceable group(s) has been or can be removed to provide an open valence for the substitution of a group including a phosphonate group, e.g., the substructure is a scaffold, to which a substituent -link-P(O)(OR') 2 is attached. The substructures can have additional groups attached. For a kinase 30 inhibiting compound that comprises at least one phosphonate group and a substructure, it is understood that the compound includes the substructure as at least part of the overall structure of the compound. 15 WO 2006/047507 PCT/US2005/038348 "Alkyl" is CI-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (j-Bu, i-butyl, 5 CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2 propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2 butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl 1 -butyl(-CH2CH2CH(CH3)2), 2-methyl-i -butyl (-CH2CH(CH3)CH2CH3), 1 10 hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3 hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl ( C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4 methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl ( C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3 15 dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl ( CH(CH3)C(CH3))3. "Alkenyl" is C2-C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond. Examples include, but are not limited to, ethylene or vinyl 20 (-CH=CH 2 ), allyl (-CH 2

CH=CH

2 ), cyclopentenyl (-C 5

H

7 ), and 5-hexenyl (-CH 2

CH

2

CH

2

CH

2

CH=CH

2 ). "Alkynyl" is C2-C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to, acetylenic (-C=CH) and 25 propargyl (-CH 2 C=CH). "Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but 30 are not limited to, methylene (-CH 2 -) 1,2-ethyl (-CH 2

CH

2 -), 1,3-propyl

(-CH

2

CH

2

CH

2 -), 1,4-butyl (-CH 2

CH

2

CH

2

CH

2 -), and the like. 16 WO 2006/047507 PCT/US2005/038348 "Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical alkenylene radicals include, but 5 are not limited to, 1,2-ethylene (-CH=CH-). "Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but 10 are not limited to, acetylene (-C=C-), propargyl (-CH 2 C-C-), and 4-pentynyl

(-CH

2

CH

2

CH

2 C=CH-). "Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, 15 radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like. "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are 20 not limited to, benzyl, 2-phenylethan-1-yl, , naphthylmethyl, 2-naphthylethan-1 yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms. 25 "Substituted alkyl", "substituted aryl", and "substituted arylalkyl" mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Typical substituents include, but are not limited to, -X, -R, -0, -OR, -SR, -S~, -NR 2 ,

-NR

3 , =NR, -CX 3 , -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO 2 , =N 2 , -N 3 , 30 NC(=O)R, -C(=O)R, -C(=O)NRR -S(=0)20-, -S(=0) 2 0H, -S(=0) 2 R, OS(=0) 2 0R, -S(=0) 2 NR, -S(=O)R, -OP(=0)O 2 RR, -P(=0)O 2 RR -P(=O)(0-) 2 ,

-P(=O)(OH)

2 , -C(=O)R, -C(=O)X, -C(S)R, -C(O)OR, -C(O)O~, -C(S)OR, -C(O)SR, -C(S)SR, -C(O)NRR, -C(S)NRR, -C(NR)NRR, where each X is 17 WO 2006/047507 PCT/US2005/038348 independently a halogen: F, Cl, Br, or I; and each R is independently -H, alkyl, aryl, heterocycle, protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. "Heterocycle" as used herein includes, by way of example and not 5 limitation, those heterocycles described in Paquette, Leo A.; Principles of Modem Heterocyclic Chemistr (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 10 82:5566. In one specific embodiment of the invention "heterocycle" includes a "carbocycle" as defined herein, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g., 0, N, or S). Examples of heterocycles include, by way of example and not limitation, pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, 15 tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 20 decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5 thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H indolyl, 1 H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, 25 quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, p carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, 30 benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl: 18 WO 2006/047507 PCT/US2005/038348 By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, 5 pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5 10 pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2 pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3 pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 15 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or p-carboline. Still more typically, nitrogen bonded heterocycles include 1 -aziridyl, 1 -azetedyl, 1 -pyrrolyl, 1 -imidazolyl, 1 20 pyrazolyl, and 1-piperidinyl. "Carbocycle" refers to a saturated, unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 25 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1 cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1 cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and 30 naphthyl. "Linker" or "link" refers to a chemical moiety comprising a covalent bond or a chain or group of atoms that covalently attaches a phosphonate group to a drug. Linkers include portions of substituents A' and A 3 , which include 19 WO 2006/047507 PCT/US2005/038348 moieties such as: repeating units of alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine

TM

); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide. 5 The term "chiral" refers to molecules which have the property of non superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or 10 groups in space. "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may 15 separate under high resolution analytical procedures such as electrophoresis and chromatography. "Enantiomers" refer to two stereoisomers of a compound which are non superimposable mirror images of one another. The term "treatment" or "treating," to the extent it relates to a disease or 20 condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw 25 Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the 30 molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical 20 WO 2006/047507 PCT/US2005/038348 structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which 5 may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. Protecting Groups In the context of the present invention, protecting groups include prodrug 10 moieties and chemical protecting groups. Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to 15 do so, and the nature of the chemical protecting group "PG" will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PG groups do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to 20 protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free, deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan. 25 Various functional groups of the compounds of the invention may be protected. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other functions) include "ether- or ester forming groups". Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein. However, 30 some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below. 21 WO 2006/047507 PCT/US2005/038348 A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene"). See also 5 Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter 10 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below. Such groups include by way of example and not limitation, esters, amides, hydrazides, and the like. Ether- and Ester-forming protecting groups 15 Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur ester-forming groups, such as sulphonate, sulfate, and sulfinate. The phosphonate moieties of the compounds of the invention may or 20 may not be prodrug moieties, i.e. they may or may be susceptible to hydrolytic or enzymatic cleavage or modification. Certain phosphonate moieties are stable under most or nearly all metabolic conditions. For example, a dialkylphosphonate, where the alkyl groups are two or more carbons, may have appreciable stability in vivo due to a slow rate of hydrolysis. 25 Within the context of phosphonate prodrug moieties, a large number of structurally-diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997)) and are included within the scope of the present invention. An exemplary phosphonate ester-forming group is the phenyl carbocycle in substructure A 3 30 having the formula: 22 WO 2006/047507 PCT/US2005/038348 0 1O R 1 1m 1 OR 1

R

1

R

1 0 wherein Ri may be H or CI-C 1 2 alkyl; ml is 1, 2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted with 0 to 3 R 2 groups. Where Yi is 0, a lactate ester is formed, and where Yi is N(R 2 ), N(OR 2 ) or N(N(R 2

)

2 , a 5 phosphonamidate ester results. In its ester-forming role, a protecting group typically is bound to any acidic group such as, by way of example and not limitation, a -CO2H or -C(S)OH group, thereby resulting in -CO2Rx where Rx is defined herein. Also, R for example includes the enumerated ester groups of WO 95/07920. 10 Examples of protecting groups include:

C

3

-C

12 heterocycle (described above) or aryl. These aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2 and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3 and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4 15 pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl,

C

3

-C

1 2 heterocycle or aryl substituted with halo, R', R 1 -0-C-C12 alkylene, C 1

-C

12 alkoxy, CN, NO 2 , OH, carboxy, carboxyester, thiol, thioester,

C

1

-C

1 2 haloalkyl (1-6 halogen atoms), C 2

-C

12 alkenyl or C 2

-C

12 alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (C 1

-C

12 alkyl), 2-, 3- and 4 20 methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5 diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4 hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6 hydroxyphenyl, 2-, 3- and 4-0-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3 25 and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 23 WO 2006/047507 PCT/US2005/038348 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 and 3,5-dihalophenyl (including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen atoms, C 1

-C

12 alkyl including 4 5 trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (I to 5 halogen atoms, C 1

-C

12 alkyl including 4 trifluoromethylbenzyl and 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4 trichloromethylphenyl), 4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1 ethylpiperazinyl, benzyl, alkylsalicylphenyl (Ci-C 4 alkyl, including 2-, 3- and 4 10 ethylsalicylphenyl), 2-,3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (-C1OH 6 OH) and aryloxy ethyl [C 6

-C

9 aryl (including phenoxy ethyl)], 2,2' dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol, -C 6

H

4

CH

2

-N(CH

3

)

2 , trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl (C 1

.

4 alkyl); N

R

1 0(O)C N

-CH

2 -O-C(O) R OC 0 H ;C4 C8 15 esters of 2-carboxyphenyl; and C 1

-C

4 alkylene-C 3

-C

6 aryl (including benzyl, CH2-pyrrolyl, -CH 2 -thienyl, -CH 2 -imidazolyl, -CH 2 -oxazolyl, -CH2-isoxazolyl,

-CH

2 -thiazolyl, -CH 2 -isothiazolyl, -CH2-pyrazolyl, -CH 2 -pyridinyl and -CH 2 pyrimidinyl) substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, C 1

-C

12 alkoxy (including methoxy and 20 ethoxy), cyano, nitro, OH, C 1

-C

12 haloalkyl (1 to 6 halogen atoms; including CH 2 CCl 3 ), C 1

-C

1 2 alkyl (including methyl and ethyl), C 2

-C

12 alkenyl or C 2

-C

12 alkynyl; alkoxy ethyl [C I-C 6 alkyl including -CH 2

-CH

2 -0-CH 3 (methoxy ethyl)]; alkyl substituted by any of the groups set forth above for aryl, in particular OH or by 1 to 3 halo atoms (including -CH 3 , -CH(CH 3

)

2 , -C(CH 3

)

3 , 25 CH 2

CH

3 , -(CH 2

)

2

CH

3 , -(CH 2

)

3

CH

3 , -(CH 2

)

4

CH

3 , -(CH 2

)

5

CH

3 , -CH 2

CH

2 F, N 0

CH

2

CH

2 Cl, -CH 2

CF

3 , and -CH 2 CCl 3 ); ; -N-2 propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, 24 WO 2006/047507 PCT/US2005/038348

CH

2 -C(O)-N(RI)2, -CH 2 -S(O)(RI), -CH 2

-S(O)

2 (RI), -CH 2

-CH(OC(O)CH

2

RI)

CH

2

(OC(O)CH

2 RI), cholesteryl, enolpyruvate (HOOC-C(=CH 2 )-), glycerol; a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9 monosaccharide residues); 5 triglycerides such as a-D-p-diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C 6

-

26 , C 6

-

18 or C 6

-

10 fatty acids such as linoleic, lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic and the like fatty acids) linked to acyl of the parental compounds herein through a glyceryl oxygen of the 10 triglyceride; phospholipids linked to the carboxyl group through the phosphate of the phospholipid; phthalidyl (shown in Fig. 1 of Clayton et al., Antimicrob. Agents Chemo. (1974) 5(6):670-671); 15 cyclic carbonates such as (5-Rd-2-oxo-1,3-dioxolen-4-yl) methyl esters (Sakamoto et al., Chem. Pharm. Bull. (1984) 32(6)2241-2248) where Rd is RI, R4 or aryl; and -CH2C(O)N 0 The hydroxyl groups of the compounds of this invention optionally are 20 substituted with one of groups III, IV or V disclosed in WO 94/21604, or with isopropyl. Table A lists examples of protecting group ester moieties that for example can be bonded via oxygen to -C(O)O- and -P(O)(O-) 2 groups. Several amidates also are shown, which are bound directly to -C(O)- or -P(O)2. Esters of 25 structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N ,N-dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsCO 3 , N,N-dimethylaniline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone). 30 When the compound to be protected is a phosphonate, the esters of structures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide salt 25 WO 2006/047507 PCT/US2005/038348 (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate). 5 TABLE A 1. -CH 2 -C(O)-N(RI)2 *10. -CH 2 -- C(O)-C(CH 3

)

3 2. -CH 2

-S(O)(R

1 ) 11. -CH 2 -CC1 3 3. -CH 2

-S(O)

2

(R

1 ) 12. -C 6 1 5 4. -CH 2 -0-C(O)-CH 2

-C

6

H

5 13. -NH-CH 2

-C(O)O-CH

2

CH

3 10 5. 3-cholesteryl 14. -N(CH 3

)-CH

2

-C(O)O-CH

2

CH

3 6. 3-pyridyl 15. -NTI 7. N-ethylmorpholino 16. -CH 2

-O-C(O)-CI

0

H

15 8. -CH 2 -0-C(O)-C 6

H

5 17. -CH 2

-O-C(O)-CH(CH

3

)

2 9. -CH 2 -0-C(O)-CH 2

CH

3 18. -CH 2

-C#H(OC(O)CH

2

R

1

)-CH

2 15 -(OC(O)CH 2 R)* HO OHHO

-CH

2 C(O)N 0 N 19. 20. O H 21. H N N 7-CH 2 -.- C(O) 2 -CH 2

CH

2 - C 20 24. -C 2- #H O C 25.(O)C H2 1) -CH

OCH

3 -CH

OCH

3 26. OCH 3 # - chiral center is (R), (S) or racemate. Other esters that are suitable for use herein are described in EP 632048. 26 WO 2006/047507 PCT/US2005/038348 Protecting groups also includes "double ester" forming profunctionalities such as -CH20C(O)OCH3, 0 -CH2SCOCH3, -CH2OCON(CH3)2, or alkyl- or aryl-acyloxyalkyl groups of the structure -CH(R' or W 5

)O((CO)R

37 ) or -CH(R' or W 5

)((CO)OR

38 ) (linked to oxygen of the acidic group) wherein R 3 7 5 and R 38 are alkyl, aryl, or alkylaryl groups (see U.S. Patent No. 4968788). Frequently R 37 and R 38 are bulky groups such as branched alkyl, ortho substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms. An example is the pivaloyloxymethyl group. These are of particular use with prodrugs for oral 10 administration. Examples of such useful protecting groups are alkylacyloxymethyl esters and their derivatives, including OyQ

CH(CH

2

CH

2

OCH

3

)OC(O)C(CH

3

)

3 , 0

CH

2 0C(O)C 1 0

H

15 , -CH 2 0C(O)C(CH 3

)

3 , -CH(CH 2 0CH 3

)OC(O)C(CH

3

)

3 , CH(CH(CH 3

)

2

)OC(O)C(CH

3

)

3 , -CH 2 0C(O)CH 2

CH(CH

3

)

2 , 15 CH2 0

C(O)C

6

H

1 1 , -CH 2 0C(O)C 6

H

5 , -CH 2

OC(O)C

10

H

15 , CH 2

OC(O)CH

2

CH

3 , -CH 2 0C(O)CH(CH 3

)

2 , -CH 2

OC(O)C(CH

3

)

3 and CH 2

OC(O)CH

2

C

6

H

5 . In some embodiments the protected acidic group is an ester of the acidic group and is the residue of a hydroxyl-containing functionality. In other 20 embodiments, an amino compound is used to protect the acid functionality. The residues of suitable hydroxyl or amino-containing functionalities are set forth above or are found in WO 95/07920. Of particular interest are the residues of amino acids, amino acid esters, polypeptides, or aryl alcohols. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described on 25 pages 11-18 and related text of WO 95/07920 as groups LI or L2. WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920. 27 WO 2006/047507 PCT/US2005/038348 Typical esters for protecting acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication. Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R 3 1 or 5 R 3 5 ), the table on page 105, and pages 21-23 (as R). Of particular interest are esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and/or alkylestercarboxy-substituted aryl or alkylaryl, especially phenyl, ortho-ethoxyphenyl, or CI-C 4 alkylestercarboxyphenyl (salicylate C 1

-C

1 2 alkylesters). 10 The protected acidic groups, particularly when using the esters or amides of WO 95/07920, are useful as prodrugs for oral administration. However, it is not essential that the acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route. When the compounds of the invention having protected groups, in particular amino acid amidates or 15 substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydrolytic cleavage in vivo to yield the free acid. One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and 20 ester may be used. Typical hydroxy protecting groups described in Greene (pages 14-118) include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates. For example: * Ethers (methyl, t-butyl, allyl); 25 e Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2 Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2 30 chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3 Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4 Methoxytetrahydropyranyl, 4-Methoxytetrahydrothiopyranyl, 4 Methoxytetrahydropthiopyranyl SS-Dioxido, 1-[(2-Chloro-4 28 WO 2006/047507 PCT/US2005/038348 methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro 7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)); " Substituted Ethyl Ethers (1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl, 1-Methyl 5 1-methoxyethyl, 1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2 fluoroethyl, 2,2,2-Trichloroethyl, 2-Trimethylsilylethyl, 2 (Phenylselenyl)ethyl, e p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); * Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o 10 Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N Oxido, Diphenylmethyl, p,p'-Dinitrobenzhydryl, 5 -Dibenzosuberyl, Triphenylmethyl, a-Naphthyldiphenylmethyl, p methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p 15 methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4" Tris(levulinoyloxyphenyl)methyl, 4,4',4"-Tris(benzoyloxyphenyl)methyl, 3 (Imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-Bis(4 methoxyphenyl)-l'-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9 20 Phenyl-1 0-oxo)anthryl, 1,3-Benzodithiolan-2-yl, Benzisothiazolyl SS Dioxido); e Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl, Diethylisopropylsilyl, Dimethylthexylsilyl, t Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl, 25 Triphenylsilyl, Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl); " Esters (Formate, Benzoylformate, Acetate, Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, p-poly Phenylacetate, 3-Phenylpropionate, 4-Oxopentanoate (Levulinate), 4,4 30 (Ethylenedithio)pentanoate, Pivaloate, Adamantoate, Crotonate, 4 Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate)); 29 WO 2006/047507 PCT/US2005/038348 * Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2 (Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl, 2 (Triphenylphosphonio)ethyl, Isobutyl, Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S 5 Benzyl Thiocarbonate, 4-Ethoxy- 1 -naphthyl, Methyl Dithiocarbonate); " Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Nitro 4-methylpentanoate, o-(Dibromomethyl)benzoate, 2 Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate, 4 (Methylthiomethoxy)butyrate, 2-(Methylthiomethoxymethyl)benzoate); 10 Miscellaneous Esters (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro 4-(1,1,3,3 tetramethylbutyl)phenoxyacetate, 2,4-Bis(1,1 dimethylpropyl)phenoxyacetate, Chlorodiphenylacetate, Isobutyrate, Monosuccinate, (E)-2-Methyl-2-butenoate (Tigloate), o (Methoxycarbonyl)benzoate, p-poly-Benzoate, a-Naphthoate, Nitrate, Alkyl 15 N,N,N',N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate, Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and * Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate). Typical 1,2-diol protecting groups (thus, generally where two OH groups 20 are taken together with the protecting functionality) are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1 t-Butylethylidene, 1 -Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2 Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4 25 Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1 Methoxyethylidene, 1 -Ethoxyethylidine, 1,2-Dimethoxyethylidene, a Methoxybenzylidene, 1 -(NN-Dimethylamino)ethylidene Derivative, a -(NN Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); Silyl 30 Derivatives (Di-t-butylsilylene Group, 1,3-(1,1,3,3 Tetraisopropyldisiloxanylidene), and Tetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate and Phenyl Boronate. 30 WO 2006/047507 PCT/US2005/038348 More typically, 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals. Table B 7<r 0 ,0 0 0 0\,0 \0 0S 0 0 O 0 N 0 0 O O R 9 0' 0 R 9 0-N, /0 R 9 0-N 0 R00 RVO 0 5 wherein R 9 is Cl-C6 alkyl. Amino protecting groups Another set of protecting groups include any of the typical amino protecting groups described by Greene at pages 315-385. They include: 10 s Carbamates: (methyl and ethyl, 9-fluorenylmethyl, 9(2 sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9 (10,1 0-dioxo- 10,10,10,1 0-tetrahydrothioxanthyl)]methyl, 4 methoxyphenacyl); Substituted Ethyl: (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 15 1-(1 -adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2 dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4 biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)- 1 -methylethyl, 2-(2'- and 4' pyridyl)ethyl, 2-(NN-dicyclohexylcarboxamido)ethyl, t-butyl, 1 -adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N 20 hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); * Groups With Assisted Cleavage: (2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 25 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2 31 WO 2006/047507 PCT/US2005/038348 triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-choro-p acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, 2 (trifluoromethyl)-6-chromonylmethyl); e Groups Capable of Photolytic Cleavage: (m-nitrophenyl, 3,5 5 dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl(o nitrophenyl)methyl); Urea-Type Derivatives (phenothiazinyl-(10)-carbonyl, N-p-toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl); * Miscellaneous Carbamates: (t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, 10 diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(NN dimethylcarboxamido)benzyl, 1,1-dimethyl-3-(NN dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2 furanylmethyl, 2-lodoethyl, Isobornyl, Isobutyl, Isonicotinyl, p-(p' Methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1 15 methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1 methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4 pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4 (trimethylammonium)benzyl, 2,4,6-trimethylbenzyl); e Amides: (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl, N 20 trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3 pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, N-p phenylbenzoyl); e Amides With Assisted Cleavage: (N-o-nitrophenylacetyl, N-o nitrophenoxyacetyl, N-acetoacetyl, (N' 25 dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N 3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2 methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3 nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine, N-o-nitrobenzoyl, N o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one); 30 * Cyclic Imide Derivatives: (N-phthalimide, N-dithiasuccinoyl, N-2,3 diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N- 1,1,4,4 tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5 32 WO 2006/047507 PCT/US2005/038348 triazacyclohexan-2-one, 5-substituted -1,3-dibenzyl- 1,3-5-triazacyclohexan-2 one, 1-substituted 3,5-dinitro-4-pyridonyl); * N-Alkyl and N-Aryl Amines: (N-methyl, N-allyl, N-[2 (trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2 5 oxo-3-pyrrolin-3-yl), Quaternary Ammonium Salts, N-benzyl, N-di(4 methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4 methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9 fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine N'-oxide); * Imine Derivatives: (N-1,1-dimethylthiomethylene, N-benzylidene, N-p 10 methoxybenylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, N,(N,N-dimethylaminomethylene, N,AN-isopropylidene, N-p nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2 hydroxyphenyl)phenylmethylene, N-cyclohexylidene); e Enamine Derivatives: (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)); 15 e N-Metal Derivatives (N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentacarbonylchromium- or -tungsten)] carbenyl, N copper or N-zinc chelate); * N-N Derivatives: (N-nitro, N-nitroso, N-oxide); e N-P Derivatives: (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N 20 diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N diphenyl phosphoryl); e N-Si Derivatives, N-S Derivatives, and N-Sulfenyl Derivatives: (N benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl, N 25 triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives (N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4 methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6 dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N 2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl, N-4 30 methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6 dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6 sulfonyl, N-methanesulfonyl, N--trimethylsilyethanesulfonyl, N-9 33 WO 2006/047507 PCT/US2005/038348 anthracenesulfonyl, N-4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, N-phenacylsulfonyl). More typically, protected amino groups include carbamates and amides, still more typically, -NHC(O)Rl or -N=CRN(R') 2 . Another protecting group, 5 also useful as a prodrug for amino or -NH(R 5 ), is: 0 w 6 See for example Alexander, J. et al. (1996) J. Med. Chem. 39:480-486. Amino acid and polypeptide protecting group and conjugates An amino acid or polypeptide protecting group of a compound of the 10 invention has the structure R"NHCH(R' 6 )C(O)-, where R" is H, an amino acid or polypeptide residue, or R 5 , and Ri 6 is defined below. R1 6 is lower alkyl or lower alkyl (C 1

-C

6 ) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C 6

-C

7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R1 0 also is taken together 15 with the amino acid a N to form a proline residue (R" 0 = -(CH 2

)

3 -). However, R10 is generally the side group of a naturally-occurring amino acid such as H, CH 3 , -CH(CH 3

)

2 , -CH 2

-CH(CH

3

)

2 , -CHCH 3

-CH

2

-CH

3 , -CH 2

-C

6

H

5 , -CH 2

CH

2 S-CH 3 , -CH 2 OH, -CH(OH)-CH 3 , -CH 2 -SH, -CH 2

-C

6

H

4 OH, -CH 2

-CO-NH

2 , CH 2

-CH

2

-CO-NH

2 , -CH 2 -COOH, -CH 2

-CH

2 -COOH, -(CH 2

)

4

-NH

2 and 20 (CH 2

)

3 -NH-C(NH2)-NH 2 . R 10 also includes 1-guanidinoprop-3-yl, benzyl, 4 hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl. Another set of protecting groups include the residue of an amino containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHSO2R, NHC(O)R, -N(R)2, NH2 or -NH(R)(H), whereby for example 25 a carboxylic acid is reacted, i.e. coupled, with the amine to form an amide, as in

C(O)NR

2 . A phosphonic acid may be reacted with the amine to form a phosphonamidate, as in -P(O)(OR)(NR 2 ). In general, amino acids have the structure R1 7 C(O)CH(R1 6 )NH-, where

R

1 7 is -OH, -OR, an amino acid or a polypeptide residue. Amino acids are low 30 molecular weight compounds, on the order of less than about 1000 MW and 34 WO 2006/047507 PCT/US2005/038348 which contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man. Suitable amino acids typically are alpha amino acids, i.e. compounds 5 characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Of particular interest are hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the 10 parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent. Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally 15 occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally, unnatural amino acids, for example, valanine, phenylglycine and homoarginine 20 are also included. Commonly encountered amino acids that are not gene encoded may also be used in the present invention. All of the amino acids used in the present invention may be either the D- or L- optical isomer. In addition, other peptidomimetics are also useful in the present invention. For a general review, see Spatola, A. F., in Chemistry and Biochemistry of Amino Acids, 25 Peptides and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983). When protecting groups are single amino acid residues or polypeptides they optionally are substituted at R 3 of substituents A', or A3 in a compound of the invention. These conjugates are produced by forming an amide bond 30 between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example). Similarly, conjugates are formed between R 3 and an amino group of an amino acid or polypeptide. Generally, only one of any site in the parental molecule is amidated with an amino acid as described herein, 35 WO 2006/047507 PCT/US2005/038348 although it is within the scope of this invention to introduce amino acids at more than one permitted site. Usually, a carboxyl group of R3 is amidated with an amino acid. In general, the a-amino or a-carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the parental 5 functionalities, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates as described further below). With respect to the carboxyl-containing side chains of amino acids or 10 polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g., by R', esterified with R 5 or amidated. Similarly, the amino side chains R1 6 optionally will be blocked with R or substituted with R 5 . Such ester or amide bonds with side chain amino or carboxyl groups, like the esters or amides with the parental molecule, optionally are hydrolyzable in 15 vivo or in vitro under acidic (pH <3) or basic (pH >10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments. The esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl 20 groups. The free acid or base of the parental compound, for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures. When an amino acid residue contains one or more chiral centers, any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or 25 mixtures thereof may be used. In general, if the intermediates are to be hydrolyzed non-enzymatically (as would be the case where the amides are used as chemical intermediates for the free acids or free amines), D isomers are useful. On the other hand, L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more 30 efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract. Examples of suitable amino acids whose residues are represented by R' or RY include the following: 36 WO 2006/047507 PCT/US2005/038348 Glycine; Aminopolycarboxylic acids, e.g., aspartic acid, p-hydroxyaspartic acid, glutamic acid, p -hydroxyglutamic acid, p-methylaspartic acid, p-methylglutamic acid, p, p-dimethylaspartic acid, y-hydroxyglutamic acid, p, y-dihydroxyglutamic 5 acid, p -phenylglutamic acid, y-methyleneglutamic acid, 3-aminoadipic acid, 2 aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid; Amino acid amides such as glutamine and asparagine; Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine, p -aminoalanine, y -aminobutyrine, ornithine, citruline, homoarginine, 10 homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid; Other basic amino acid residues such as histidine; Diaminodicarboxylic acids such as a, a'-diaminosuccinic acid, a, a' diaminoglutaric acid, a, a'-diaminoadipic acid, a, a'-diaminopimelic acid, a, a' diamino- p-hydroxypimelic acid, a, a'-diaminosuberic acid, a, a'-diaminoazelaic 15 acid, and a, a'-diaminosebacic acid; Imino acids such as proline, hydroxyproline, allohydroxyproline, y methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2 carboxylic acid; A mono- or di-alkyl (typically C -C 8 branched or normal) amino acid 20 such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, a-methylserine, a-amino-a-methyl-y-hydroxyvaleric acid, a-amino- a methyl-6-hydroxyvaleric acid, a-amino- a-methyl-E-hydroxycaproic acid, isovaline, a-methylglutamic acid, a-aminoisobutyric acid, a-aminodiethylacetic acid, a-aminodiisopropylacetic acid, a-aminodi-n-propylacetic acid, a 25 aminodiisobutylacetic acid, a-aminodi-n-butylacetic acid, a aminoethylisopropylacetic acid, a-amino-n-propylacetic acid, a aminodiisoamyacetic acid, a-methylaspartic acid, a-methylglutamic acid, 1 aminocyclopropane-1-carboxylic acid, isoleucine, alloisoleucine, tert-leucine, 3 methyltryptophan and a-amino- p-ethyl-p-phenylpropionic acid; 30 -phenylserinyl; Aliphatic a-amino-p-hydroxy acids such as serine, p-hydroxyleucine, p hydroxynorleucine, P -hydroxynorvaline, and a-amino-p-hydroxystearic acid; 37 WO 2006/047507 PCT/US2005/038348 a-Amino, a-, y-, 6- or s-hydroxy acids such as homoserine, S hydroxynorvaline, y-hydroxynorvaline and s-hydroxynorleucine residues; canavine and canaline; y -hydroxyornithine; 2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic 5 acid; a-Amino-p-thiols such as penicillamine, p-thiolnorvaline or B thiolbutyrine; Other sulfur containing amino acid residues including cysteine; homocystine, p-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2 10 thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine; Phenylalanine, tryptophan and ring-substituted a-amino acids such as the phenyl- or cyclohexylamino acids a-aminophenylacetic acid, a aminocyclohexylacetic acid and a-amino-p-cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, 15 guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro, o-, m- or p-methyl-, 2,4,6 trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5 -nitro- and p-nitro-phenylalanine); furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and tryptophan analogues and derivatives including kynurenine, 3 20 hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan; a-Amino substituted amino acids including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N benzylphenylalanine, N-methylvaline and N-benzylvaline; and a-Hydroxy and substituted a -hydroxy amino acids including serine, 25 threonine, allothreonine, phosphoserine and phosphothreonine. Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond. Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. Proteins 30 optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which 38 WO 2006/047507 PCT/US2005/038348 one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely. The polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it 5 is administered) or against the epitopes on the remainder of the compound of this invention. Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound. The conjugates of parental 10 compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it. Accordingly, the polypeptide or protein may not need to be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final product 15 conjugate should be immunogenic in at least one of such animals. The polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures, e.g., a particular sequence of residues recognized by a peptidolytic 20 enzyme. Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases. Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences. Such enzymes 25 and their substrate requirements in general are well known. For example, a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its a-amino group to the phosphorus or carbon atoms ,of the compounds herein. In embodiments where WI is phosphonate it is expected that this peptide will be cleaved by the appropriate peptidolytic 30 enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond. Suitable dipeptidyl groups (designated by their single letter code) are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, 39 WO 2006/047507 PCT/US2005/038348 AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, 5 CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, 10 HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT, 15 MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, Fl, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, 20 WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV. Tripeptide residues are also useful as protecting groups. When a 25 phosphonate is to be protected, the sequence -X 4 -pro-X 5 - (where X 4 is any amino acid residue and X 5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X 4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond. The carboxy group of X 5 optionally is esterified with 30 benzyl. Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types. Dipeptides and tripeptides lacking an a 40 WO 2006/047507 PCT/US2005/038348 amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., (1992) Pharm Res. 9:969-978). Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds. Di- or tripeptides having one or more 5 amino acids in the D configuration are also compatible with peptide transport and can be utilized in the amidate compounds of this invention. Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N. In addition, di- or tripeptides alternatively are selected on the basis of their 10 relative resistance to hydrolysis by proteases found in the lumen of the intestine. For example, tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A, di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) are poor substrates for endopeptidase, and peptides lacking a pro residue at the 15 penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P. Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases. Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to 20 proteins in order to prepare immunogens. Specific Embodiments of the Invention Specific values described for radicals, substituents, and ranges, as well as specific embodiments of the invention described herein, are for illustration only; they do not exclude other defined values or other values within defined ranges. 25 In one specific embodiment the invention provides a compound comprising at least one phosphonate group, and a substructure of formula 100: NN N NN 100 wherein: the bond represented by --- is a single or double bond; or a pharmaceutically acceptable salt thereof. 41 WO 2006/047507 PCT/US2005/038348 In another specific embodiment the invention provides a compound comprising at least one phosphonate group, and a substructure of formula: 24 R20 N N R 21 22 R R wherein: 5 R 20 and R 2 are independently hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; R is absent, hydrogen, alkyl, or substituted alkyl; R2 is 0, or -NR R 26 ; R24 is aryl, or substituted aryl; 10 R 25 is hydrogen, or alkyl; R26 is hydrogen, alkyl, or -C(=O)NR 2 7 Ra

R

27 and R 28 are independently hydrogen, alkyl, or substituted alkyl; and the bond represented by --- is a single or double bond; wherein R 22 is 15 absent when the bond represented by --- is a double bond. In another specific embodiment of the invention R 2 0 is hydrogen; R 2 1 is substituted alkyl, or substituted aryl; R 22 is alkyl; R 23 is 0, or -NHR 26 ; R 26 is hydrogen, alkyl, or C(=O)NIR27; R2 is alkyl; and R 24 is substituted aryl. In another specific embodiment the invention provides a compound that 20 comprises at least one phosphonate, and a substructure of substructure of formula II, III, or IV OMe 'Ni C N HO N NON OMe H | H | H O NH II III IV rN or a pharmaceutically acceptable salt thereof. 25 In another specific embodiment, the invention provides a compound of any one of formulae 1-4: 42 WO 2006/047507 PCT/US2005/038348 HNH HN I H I )~. JH N >J NH H2 N N 1H-IN NN NH -' I 1 2 3 4 rN wherein: A is A; 5 A' is: Y2 M12a M12b

A

3 is: Y Y Y 2 ' 1 2 1R

P

2 2 22 Y2 R R 2 Rx M2 Ml2a j 2 10 M12b Y' is independently 0, S, N(R), N(OR), or N(N(R)( Rx)); Y2 is independently a bond, 0, N(Rx), N(OR), N(N(R)( RX)), or S(O)M2-; and when Y 2 joins two phosphorous atoms y2 can also be C(R 2

)(R

2 ); 15 R' is independently H, R 2 , W 3 , a protecting group, or the formula: R~ RY1 A Y2- y2 y2

-

M1 M12c M1c Mld 43 WO 2006/047507 PCT/US2005/038348 RY is independently H, W 3 , R2 or a protecting group; R2 is independently H, R3 or R4 wherein each R4 is independently substituted with 0 to 3 R 3 groups; 3 3a 3b 3C 3d3 5 R isR R R orR , provided that when R 3 is bound to a heteroatom, then R 3 is R 3 c or R 3 d; R 3 is F, Cl, Br, I, -CN, N 3 or -NO 2 ; R3b is Y'; R R is -Rx, -N(Rx)(Rx), -SRx, -S(O)Rx, -S(0) 2 Rx, -S(O)(ORx), 10 S(O) 2 (ORx), -OC(Yl)Rx, -OC(YI)ORx, -OC(YI)(N(Rx)(Rx)), -SC(Yl)Rx, SC(Y')ORx, -SC(Yl)(N(Rx)(Rx)), -N(Rkx)C(Yl)Rx, -N(Rx)C(Yl)ORx, or N(Rx)C(Y)(N(Rx)(Rx));

R

3 d is -C(Yl)Rx, -C(Yl)ORx or -C(Yl)(N(Rx)(Rx));

R

4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, 15 or alkynyl of 2 to 18 carbon atoms;

R

5 is R 4 wherein each R 4 is substituted with 0 to 3 R3 groups;

W

3 is W 4 or W 5 ;

W

4 is Rs, -C(Y')R 5 , -C(Y)W', -S0 2 Rs, or -S0 2

W

5 ;

W

5 is carbocycle or heterocycle wherein W 5 is independently substituted 20 with 0 to 3 R2 groups;

W

6 is W 3 independently substituted with 1, 2, or 3 A 3 groups; M2 is 0, 1 or 2; M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 25 MIa, MIc, and MId are independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and R2 is substituted alkyl or substituted aryl; or a pharmaceutically acceptable salt thereof. 44 WO 2006/047507 PCT/US2005/038348 In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula 101:

R

3 1 ,R 32 R29 R 1N' R33N N 0R3&4 N 101 wherein: R 29 is hydrogen, alkyl, or -C(=0)R36 5 R 3 0 is hydrogen or substituted alkyl; and

R

3 1 and R32 are independently hydrogen, alkyl, or substituted aryl; or R 3 and R 32 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

R

33 is -0-, -NR 3 "- or absent; 10 R 3 4 is -0- or absent;

R

35 is hydrogen or alkyl; and

R

36 is hydrogen, alkyl, alkenyl, or alkynyl; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that 15 comprises at least one phosphonate, and a substructure of formula 101 wherein

R

29 is -C(=0)R36 ; R 30 is alkyl substituted with -CHRER3', or -NR R 3 8 ; R 3 1 and R are independently hydrogen, or substituted aryl; or R 3 1 and R 32 taken together with the nitrogen atom to which they are attached form a substituted heterocyclic ring, wherein the heterocyclic ring is substituted with hydrogen or 20 alkyl; R 33 is-NR 3 s-; R 34 is -0-; R 3 5 is hydrogen; R 36 is alkenyl; and each R 37 and

R

38 is independently hydrogen, alkyl, or substituted alkyl; or NR3 R forms a substituted or unsubstituted heterocyclic ring; or a pharmaceutically acceptable salt thereof. 45 WO 2006/047507 PCT/US2005/038348 In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula 101 wherein:

-NR

3 R 32 forms a substituted piperazyl ring having the formula:

L

3 R67 CN N 5 wherein L 3 is -C(=O)NH-; and R 67 is hydrogen, substituted alkyl'or substituted aryl; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula V or VI: Br F HN -' HN CI O F H N 0 N or N O N V. VI 10 or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula VII: H N N N VII wherein R 67 is substituted aryl; or a pharmaceutically acceptable salt thereof. 15 In another specific embodiment, the invention provides a compound of formula 101 that is a compound of formula 5, 6, or 7: 46 WO 2006/047507 PCT/US2005/038348

R

3 1 -R 3 2

R

3

-R

3 2 R32 ,- A*

R

29 N N 33 N R 3A3 R3 R R A 0 :: 1 3 30N

A

0 N R3'0R34 NIRN1 3 5 6 7 wherein: AO is A'; A' is: 5 2 -Y2 x

W

6 R2 R2 M12a M12b

A

3 is: Y Y Y2 R1 1

INP

2 P' Rx Y2

R

2

R

R2 NRx M2 2 Ml 2a M12b 10 Y' is independently 0, S, N(R), N(OR), or N(N(RX)( RX)); Y2 is independently a bond, 0, N(Rx), N(OR), N(N(R)( RX)), or S(O)M2-; and when Y 2 joins two phosphorous atoms y2 can also be C(R 2

)(R

2 ; R' is independently H, R2, W3, a protecting group, or the formula: y1 R R Y A Y 2 --- y2 y2 -V MM12c M1c Mld 15

--

Mla RY is independently H, W 3 , R 2 or a protecting group; 47 WO 2006/047507 PCT/US2005/038348 R is independently H, R3 or R4 wherein each R4 is independently substituted with 0 to 3 R 3 groups; R3 3a 3b 3c 3d

R

3 is R , R , R or R , provided that when R 3 is bound to a heteroatom, then R3 is R or R 3 1; 5 R 3 a is F, Cl, Br, I, -CN, N 3 or -NO 2 ;

R

3 b is Y1; R3c is -Rx, -N(Rx)(Rx), -SRx, -S(O)Rx, -S(O) 2 Rx, -S(O)(ORx), S(O) 2 (ORx), -OC(YI)Rx, -OC(YI)ORx, -OC(Y)(N(Rx)(Rx)), -SC(Yl)Rx, SC(YI)ORx, -SC(Y)(N(Rx)(Rx)), -N(Rx)C(Yl)Rx, -N(Rx)C(YI)ORx, or 10 N(Rx)C(Yl)(N(R)(Rx)) ;

R

3 d is -C(YI)Rx, -C(Yl)ORkx or -C(Yl)(N(Rx)(Rx));

R

4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R5 is R 4 wherein each R4 is substituted with 0 to 3 R 3 groups; 15 W 3 is W 4 or W 5 ;

W

4 is R, -C(Y')R 5 , -C(Yl)W, -So 2

R

5 , or -S0 2 W ;

W

5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R2 groups;

W

6 is W 3 independently substituted with 1, 2, or 3 A 3 groups; 20 M2 is 0, 1 or 2; M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; Mla, M1c, and Mi d are independently 0 or 1; and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 25 wherein R29-R 34 have any of the values defined herein; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula 102; -0-N 0 H N 102 30 or a pharmaceutically acceptable salt thereof. 48 WO 2006/047507 PCT/US2005/038348 In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula VIII: -0-N 0 H N

(R

39 )n na

(R

40 )ma VuI wherein each R 39 and R 40 is independently hydrogen, fluorine, chlorine, bromine 5 or iodine; and na and ma are each independently 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula IX: -0-N 0 H R43 N FR42R R41 Ix 10 wherein R , R4, R1 and R 44 are independently hydrogen, fluorine, chlorine, bromine or iodine; or a pharmaceutically acceptable salt thereof. Specific values for R 41 , R 42 , and R 43 are fluorine; and a specific value for R 44 is iodine. In another specific embodiment, the invention provides a compound of any one of formulae 8-10: H H H AO N 0 HO N 0A1-N 0 A* 0 H F H 0 - O H F 0' H F HO N Ao N N F F F 15 8 9 10 wherein: A' is A'; A' is: 20 49 WO 2006/047507 PCT/US2005/038348 y 2 -2 R2 R2 M12a M12b

A

3 is: Y Y Y2 RX 2 22 Y R R2Ry M2 M12a M12b 5 Y' is independently 0, S, N(R), N(OR), or N(N(R)( RX)); Y2 is independently a bond, 0, N(R), N(ORx), N(N(Rx)( Rx)), or S(O)M2-; and when Y2 joins two phosphorous atoms, Y2 can also be C(R 2)(R2); Rx is independently H, R 2 , W 3 , a protecting group, or the formula: y1 R R Y Y 2 ' 2 11y2 ..---- RY - -M12c M1c~~ Mld 10 MM1a RY is independently H, W 3 , R 2 or a protecting group; R2 is independently H, R3 or R4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups; 3 3a 3b 3c 3 3 R is Ra, R , R or R d, provided that when R is bound to a 15 heteroatom, then R 3 is R or R31. Ra is F, Cl, Br, I, -CN, N 3 or -NO 2 ; R3b is Yl; R3c is -Rx, -N(Rx)(Rx), -SRx, -S(O)Rx, -S(O) 2 Rx, -S(O)(ORx), S(0) 2 (ORx), -OC(Y')Rx, -OC(Y')ORx, -OC(Y')(N(Rx)(Rx)), -SC(Y')Rx, 20 SC(Y')ORx, -SC(Y')(N(Rx)(Rx)), -N(Rx)C(Yl)Rx, -N(Rx)C(YI)ORx, or N(Rx)C(YI)(N(Rx)(Rx)) ; 50 WO 2006/047507 PCT/US2005/038348

R

3 d is -C(Yl)Rx, -C(Yl)ORx or -C(Yl)(N(Rx)(Rx));

R

4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R5 is R 4 wherein each R 4 is substituted with 0 to 3 R3 groups; 5 W 3 is W 4 or W';

W

4 is Ri, -C(Y')R', -C(Y')W 5 , -S0 2 R', or -S0 2

W

5 ;

W

5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R2 groups; W6 is W 3 independently substituted with 1, 2, or 3 A3 groups; 10 M2 is 0, 1 or 2; M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; MIa, MIc, and Mi d are independently 0 or 1; and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; or a pharmaceutically 15 acceptable salt thereof In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula 103 or formula 104; N HN V S N 103 104 20 or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula X: HN' Aa-R 46 S N 0 R45 x 51 WO 2006/047507 PCT/US2005/038348 wherein R 45 is hydrogen, -NH-(C 6

-C

2 0)aryl or -NH-substituted(C 6

-C

20 )aryl; Aa is carbocycle or a heterocycle; and R 46 is a substituted heterocycle; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that 5 comprises at least one phosphonate, and a substructure of formula X wherein Aa is substituted (methyl)pyrimidyl; R 46 is piperazyl substituted with alkyl or substituted alkyl; and R 45 is -NH-(substituted aryl); or a pharmaceutically acceptable salt thereof. In another embodiment the invention provides a compound comprising a 10 substructure of formula 103 or formula 104 and at least one phosphonate group; which compound comprises a substructure of the formula XVIII: 0H NN/ N H N CI -N XVIII R47-N'R48 wherein R 47 and R 48 are independently hydrogen or (CI-C 4 )alkyl, or R 47 and R 48 take together with the nitrogen atom to which they are attached form a 15 substituted or unsubstituted heterocyclic ring; or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides a compound of any one of formulae 11-14: 52 WO 2006/047507 PCT/US2005/038348 N N N N HN) N--- H N...-Ao HN N'.A* H H S 'N N 0 0 Me NH Me NH ci Cl 12 A* A* N N N N HN A N- HNA4 N N S N S N M NH Me NH ci 13 ci 14 wherein: A is A'; A' is: 5 2 -Y2 R2 R2 M12a M12b

A

3 is: Y Y Y2, ' 2 R2 2 Y

R

2

R

2 \Rx M2 M12a - - 2 M12b 10 Y' is independently 0, S, N(R), N(OR), or N(N(RX)( RX)); Y2 is independently a bond, 0, N(R), N(ORx), N(N(Rx)( Rx)), or S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(R 2

)(R

2 ); 53 WO 2006/047507 PCT/US2005/038348 R' is independently H, R 2 , W 3 , a protecting group, or the formula: y1 R R y Y 2 2 _x

-

y2 Y2R Ma M12c M1c Mld RY is independently H, W 3 , R 2 or a protecting group; R' is independently H or alkyl of I to 18 carbon atoms; 5 R 2 is independently H, R', R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups; R3 3a Ab 3c 3 R is R , R , R or R 3 , provided that when R 3 is bound to a heteroatom, then R 3 is R 3 'c or R 3;

R

3 a is F, Cl, Br, I, -CN, N 3 or -NO 2 ; 10

R

3 b is Yl;

R

3 c is -Rx, -N(Rx)(Rx), -SR, -S(O)R, -S(O) 2 R, -S(O)(ORx), S(O) 2 (OR"), -OC(Y')Rx, -OC(Yl)ORx, -OC(Y')(N(R")(R")), -SC(Y')Rx, SC(Yl)ORx, -SC(Y')(N(R)(R")), -N(Rx)C(Y')R, -N(R)C(Y')ORx, or N(Rx)C(Y)(N(Rx)(Rx)); 15 R is -C(Y )R", -C(Y')OR or -C(Y')(N(Rx)(Rx));

R

4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;

W

3 is W 4 or W 5 ; 20 W 4 is R', -C(Y)R, -C(Yl)W 5 , -So 2

R

5 , or -SO 2

W

5 ;

W

5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R2 groups; W6 is W3 independently substituted with 1, 2, or 3 A3 groups; M2 is 0, 1 or 2; 25 M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; MIa, MIc, and Mi d are independently 0 or 1; and MI2c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; or a pharmaceutically acceptable salt thereof. 54 WO 2006/047507 PCT/US2005/038348 In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula 105: S NH 105 or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that 5 comprises at least one phosphonate, and a substructure of formula XI, XII, or XIII:

R

50 S NH N R 5 ,S NH ,S NH

R

55 0NH 2 R49 R 55 0 xi XI R49 X wherein:

R

49 is hydrogen, -(C 6

-C

2 0 )aryl or -(C 6

-C

2 0)substituted aryl; 10 R 50 is hydrogen, substituted alkyl, or -C(=O)NRR 52 ;

R

5 1 and R 52 are independently hydrogen, alkyl, or substituted alkyl; and

R

55 is a bond or alkylene; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that 15 comprises a substructure of formula XI, XII, or XIII and at least one phosphonate group wherein: R 49 is substituted aryl; R 50 is -C(=0)N R 52 ; R 5 1 is hydrogen; R is -NRs 3

R

5 4

(C

1

-C

6 )alkyl; R 53 and R54 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring; and R 55 is methylene; or a pharmaceutically acceptable salt 20 thereof. In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula 105; which compound comprises a substructure of the formula XIX: 55 WO 2006/047507 PCT/US2005/038348 H. O N N S NH N\ 0

NH

2 F 0 _F Br xIx or a pharmaceutically acceptable salt thereof. In another specific embodiment, the invention provides a compound of formula 15 or 16: H H OY NW OY N ' No N'S NH NS N H / / F NH 2 F F F Br Br 5 15 16 wherein: A' is A'; A' is: -2 2 M1 2a 10 - - M12b

A

3 is: y y 22 2 22 R R 2\1aj LRx M2 -12 M12b 56 WO 2006/047507 PCT/US2005/038348 Y is independently 0, S, N(R), N(OR), or N(N(Rx)( RX)); Y2 is independently a bond, 0, N(Rx), N(ORx), N(N(Rx)(,Rx)), or S(O)M2-; and when Y 2 joins two phosphorous atoms y2 can also be C(R 2

)(R

2 ); R' is independently H, R 2 , W 3 , a protecting group, or the formula: y1 R R Y Y 2-' y2 y 2 5 -Ma M12c M1c Mld RY is independently H, W 3 , R 2 or a protecting group; R1 is independently H or alkyl of 1 to 18 carbon atoms; R2 is independently H, R1, R3 or R4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups; 3 3a, 3b' 3c 3d3 10 R is R ,R orR , provided that when R 3 is bound to a heteroatom, then R 3 is R or R3d R3a is F, Cl, Br, I, -CN, N 3 or -NO 2 ; R3b i l R Ais Yl; R3' is -Rx, -N(Rx)(Rx), -SRx, -S(O)Rx, -S(O) 2 R, -S(O)(ORx), 15 S(O) 2 (ORx), -OC(Yl)Rx, -OC(Y)ORx, -OC(Yl)(N(R)(Rx)), -SC(Yl)Rx, SC(Y')ORx, -SC(Y')(N(Rx)(Rx)), -N(Rx)C(Yl)Rx, -N(Rx)C(Yl)ORx, or N(Rx)C(YI)(N(Rx)(Rx)) ; R3d is -C(Y )Rx, -C(Y')ORx or -C(Y )(N(Rx)(Rx));

R

4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, 20 or alkynyl of 2 to 18 carbon atoms;

R

5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;

W

3 is W 4 or W 5 ;

W

4 is Rs, -C(Y')Rs, -C(Y')W', -S0 2 R', or -S0 2 W';

W

5 is carbocycle or heterocycle wherein W 5 is independently substituted 25 with 0 to 3 R2 groups;

W

6 is W 3 independently substituted with 1, 2, or 3 A 3 groups; M2 is 0, 1 or 2; M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 57 WO 2006/047507 PCT/US2005/038348 Mla, MIc, and Mi d are independently 0 or 1; and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that 5 comprises at least one phosphonate, and a substructure of formula 106:

R

56 N 106 wherein: Rs6 is -N-, or -CR 7-; and

R

57 is hydrogen, or alkyl; or a pharmaceutically acceptable salt thereof. 10 In another specific embodiment the invention provides a compound that comprises at least one phosphonaie, and a substructure of formula XIV:

R

59

-R

60

-(R

61 )nb R 58'LI 0

R

56 N H wherein: R 56 is -N-, or -CR 5 7_;

R

57 is hydrogen, or alkyl; 15 R 58 is hydrogen, halo, alkyl, a fused carbocyclic ring or a fused heterocyclic ring;

R

59 is =CR 64 - or =N-NR64-.

R

60 is phenyl or pyrrolyl; each R is independently alkyl, or a polar group; 20 R 64 is independently hydrogen, or alkyl; and nb is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula XIV wherein: 25 R56 is -N-, or -CH-; R 58 is hydrogen, halo, or a fused carbocyclic ring or a fused 58 WO 2006/047507 PCT/US2005/038348 heterocyclic ring; R 5 9 is =CH- or =N-NH-; R 60 is phenyl or pyrrolyl; each R 6 ' is independently alkyl, -C(=O)NR 62

R

63 ; or -S(=0) 2 NR6 2

R

6 ; and each R 62 and R 6 3 is independently hydrogen, alkyl, or substituted alkyl; or a pharmaceutically acceptable salt thereof. 5 In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of formula XV, XVI, or VII: O O=S-NH N N H N N r-S N-NH H H N 0I 0 I0 CN/ N N H H H XV XVI XVII or a pharmaceutically acceptable salt thereof. 10 In another specific embodiment the invention provides a compound of formula 17, 18, or 19: 0 AO O= -NH 0 A N /IO \ 5 8 H N //-S N-NH H R8 N R8 N OHNN H H H 17 18 19 wherein: 15 A 0 is A'; A' is: 59 WO 2006/047507 PCT/US2005/038348 2 2 2 RR2 M12a M12b

A

3 is: Y Y Y2 . ' 22 R 2 Y

R

2

R

2 \Rx M2 M12a - - 2 M12b Y' is independently 0, S, N(R), N(ORx), or N(N(R)( Rx)); 5 Y2 is independently a bond, 0, N(R), N(OR), N(N(R)( RX)), or S(O)M2-; and when Y2 joins two phosphorous atoms y2 can also be C(R 2

)(R

2 ); R' is independently H, R2, W , a protecting group, or the formula: y1 R R y Mia M12c M1c 10 RI is independently H, W 3 , R 2 or a protecting group; R2 is independently H, R3 or R4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups; R3 is R a, R3 , R or Rd, provided that when R 3 is bound to a 3 3c 3d heteroatom, then R is R or R 15 R 3 a is F, Cl, Br, I, -CN, N 3 or -NO 2 ; R3b is Yl', R34 is -Rx, -N(Rx)(Rx), -SRx, -S(O)Rx, -S(O) 2 Rx, -S(O)(ORx), S(0) 2 (ORx), -OC(Y')Rx, -OC(Y')ORx, -OC(Y')(N(Rx)(Rx)), -SC(Y')Rx, SC(Y )ORx, -SC(Yl)(N(Rx)(Rx)), -N(Rx)C(Yl)Rx, -N(Rx)C(Yl)ORx, or 20 N(Rx)C(YI)(N(Rx)(Rx)) ;

R

3 d is -C(YI)Rx, -C(YI)ORx or -C(Yl)(N(Rx)(Rx)); 60 WO 2006/047507 PCT/US2005/038348

R

4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;

R

5 is R4 wherein each R 4 is substituted with 0 to 3 R 3 groups;

W

3 is W 4 or W 5 ; 5 W 4 is R', -C(Y')R 5 , -C(Yl)W 5 , -So 2

R

5 , or -S0 2 W ;

W

5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;

W

6 is W 3 independently substituted with 1, 2, or 3 A3 groups; M2 is 0, 1 or 2; 10 M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; MIa, MIc, and MId are independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and

R

58 is hydrogen, or halo; or a pharmaceutically acceptable salt thereof. 15 In another specific embodiment the invention provides a compound of any one of formulae 20-24: I H NJ N N H H i ' i N- N N N NO Y N 0 AO 20 AO 21 61 WO 2006/047507 PCT/US2005/038348 H

A

0 N N 22O H H N NI A N N0 R623 22 N 24 N N"H H wherein: AO is A'; A' is: 5 RY2 M12a - - M12b.

A

3 is: Y Y Y2RxI 2

R

2

R

2 \Rx- PR 2 2 M12 1- 10 Y' is independently 0, S, N(R), N(ORx), or N(N(R)( RX)); Y2 is independently a bond, 0, N(Rx), N(OR), N(N(Rx)( Rx)), or S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(R2 )(R2); Rx is independently H, R 2 , W 3 , a protecting group, or the formula: 62 WO 2006/047507 PCT/US2005/038348 - Y 1 R R 1 Yy MMd JMla -

-

M-- t c Ml RY is independently H, W, R 2 or a protecting group; R2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups; 3 3a 3b 3c 3d3 5 R isR R , R orR , provided that when R 3 is bound to a heteroatom, then R3 is R or R3d Ra is F, Cl, Br, I, -CN, N 3 or -NO 2 ;

R

3 1 is Yl; R3c is -R-, -N(Rx)(Rx), -SR', -S(O)Rx, -S(O) 2 R, -S(O)(ORx), 10 S(O) 2 (ORx), -OC(Yl)Rx, -OC(Yl)ORx, -OC(YI)(N(Rx)(Rx)), -SC(Yl)Rx, SC(Y)ORx, -SC(Yl)(N(Rx)(Rx)), -N(Rx)C(YI)Rx, -N(Rx)C(Y )OR , or N(Rx)C(Yl)(N(Rx)(Rx)); R3d is -C(Y )Rx, -C(Yl)ORx or -C(Y )(N(Rx)(Rx));

R

4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, 15 or alkynyl of 2 to 18 carbon atoms;

R

5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;

W

3 is W 4 or W5;

W

4 is R 5 , -C(Y')R 5 , -C(Yl)W 5 , -So 2

R

5 , or -S0 2 W ;

W

5 is carbocycle or heterocycle wherein W 5 is independently substituted 20 with 0 to 3 R2 groups; W6 is W3 independently substituted with 1, 2, or 3 A3 groups; M2 is 0, 1 or 2; M12a is 1, 2,3,4,5, 6,7, 8,9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 25 MIa, MIc, and Mi d are independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R65 is hydrogen, alkyl, or halo; and R 6 is carbocycle, heterocycle, substituted carbocycle, or substituted heterocycle, and is substituted with one or more A 0 ; or a pharmaceutically 30 acceptable salt thereof. 63 WO 2006/047507 PCT/US2005/038348 In another specific embodiment the invention provides a compound that comprises at least one phosphonate, and a substructure of any one of formulae II-XVII: C1 CI 11C1IHO -J i CI S N N 0 N N N 0 H H OMe O Br H N N ' OMe ~ 0 ~ NF N N N NH H V NN NH H NO N R6 F 0N HN I HN N "O e N 5 VI VII 64 WO 2006/047507 PCT/US2005/038348 -0-N O -0-N H R43 HN'Aa-R46 HKSH Nf~ ~ N26 R39 41R42 R44 0 (R )na (R 40 ) R R45 VIII IX x R6 0

R

50 . "-NH R50 NH N\/ /S NHN\ N\/ 0 NH 2

R

55

\R

55 0 R49 R49 XI XII XIII

R

59

R

60

(R

61 )nb N

R

56 N C H H H XIV xv O=S-NH N H N /S N-NH H 1 N b zI:# S0 N 0 N~ N H H XVI XVII wherein: 5 each R 39 and R 40 is independently hydrogen, fluorine, chlorine, bromine or iodine; na and ma are each independently 1, 2, 3, or 4; R41, R42, R43 and R44 are independently hydrogen, fluorine, chlorine, bromine or iodine; 10 R 4 5 is hydrogen, -NH-(C 6

-C

2 0)aryl or -NH-substituted(C 6

-C

20 )aryl; Aa is carbocycle or a heterocycle; 65 WO 2006/047507 PCT/US2005/038348

R

46 is a substituted heterocycle;

R

4 9 is hydrogen, -(C6-C 20 )aryl or -(C 6

-C

2 0 )substituted aryl;

R

5 0 is hydrogen, substituted alkyl, or -C(=O)NRR 5; wherein R" and

R

52 are independently hydrogen, alkyl, or substituted alkyl; 5 R 55 is a bond or alkylene;

R

6 is -N-, or -CR 5 7 -;

R

57 is hydrogen or alkyl;

R*

58 is hydrogen, halo, alkyl, a fused carbocyclic ring or a fused heterocyclic ring; 59 is =CR64- =NNR4 10 R sC -or R 0 is phenyl or pyrrolyl; each R 6 1 is independently alkyl, or a polar group; each R 64 is independently hydrogen or alkyl; R 67 is substituted aryl; and 15 nb is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound that comprises a substructure of any one of formulae 1-24: NN 20 CI CI N N N 10 N 0 HNN N ~ N 0 C NN~ NINN HN N N NH ' 21I IIA"0 N AOAO AO O 0N 12 3 4 KN, 20

R

3 1 R 3 2

R

3 R R 32 N R2 R3 NN 29,R3N & N ~ R 3 4& 3 0

R

34 5 6 7 66 WO 2006/047507 PCT/US2005/038348 H H H H H F H o N 0 O'NJ F I F XF X F F F 8 9 10 N N N JN HN NZi ,-A* HN NA S N S N Me NH Me NH cI c 12 A* A* N NN N --- N HN A: N, HN lk,, N -OH N S-, N o== Me NH Me NH C1 13 ci 14 H H O0 N N S NH NS NH

NH

2 N F F Br Br 5 15 16 67 WO 2006/047507 PCT/US2005/038348 o A' OS-NH o A 17 / /I H -S N-NH N N N H~ H 0 000 H H H 17 18 19 H SH H N I N-, N N N N0

A

0 20 A 0 21 5 NI

A

0

__R

65 HH NoN N,> Na N y-a oa 0 23 22 AyisA; 24 H 10 wherein: A' is A' A' is: 68 WO 2006/047507 PCT/US2005/038348 22 x

W

6 22-Y R2 R2 M12a M12b

A

3 is: Y Y P 2 Y2~~ -- R 2 2 Y 2

R

2

R

2 Rx M2 Ml2a -M _ 2 M12b 5 Y' is independently 0, S, N(R), N(OR), or N(N(R)( RX)); Y2 is independently a bond, 0, N(R), N(OR), N(N(R)( RX)), or S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(R2)(R2); R' is independently H, R2, W3, a protecting group, or the formula: y1 R RY Y1 R~ RR Y 2 -- 2 y2 R Ma M12c M1c Mld 10 RY is independently H, W 3 , R 2 or a protecting group; R2 is independently H, R3 or R4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups; is R , R , R or R d, provided that when R 3 is bound to a heteroatom, then R 3 is R 3 R or R"; 15 R 3 a is F, Cl, Br, I, -CN, N 3 or -NO 2 ; R3b is Yl; RC is -Rx, -N(Rx)(Rx), -SRx, -S(O)Rx, -S(0) 2 Rx, -S(O)(ORx), S(0) 2 (OR), -OC(Y)Rx, -OC(Yl)ORx, -OC(Y')(N(Rx)(Rx)), -SC(Y')Rx, SC(Y')ORx, -SC(Y')(N(Rx)(Rx)), -N(Rx)C(Y)Rx, -N(Rx)C(Y)OR, or 20 N(Rx)C(YI)(N(Rx)(Rx)) ;

R

3 d is -C(Yl)Rx, -C(Yl)ORx or -C(YI)(N(Rx)(Rx)); 69 WO 2006/047507 PCT/US2005/038348

R

4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R5 is R 4 wherein each R 4 is substituted with 0 to 3 R3 groups;

W

3 is W 4 or W'; 5 W 4 is R', -C(Y')R 5 , -C(Y')W, -So 2

R

5 , or -S0 2 W ;

W

5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R2 groups;

W

6 is W 3 independently substituted with 1, 2, or 3 A3 groups; M2 is 0, 1 or 2; 10 M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; MIa, MIc, and Mid are independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R21 is substituted alkyl or substituted aryl. 15 R29 is hydrogen, alkyl, or -C(=0)R36

R

30 is hydrogen or substituted alkyl;

R

31 and R 32 are independently hydrogen, alkyl, or substituted aryl; or R3 and R 32 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring; 20 R 33 is -0-, -NR 3 5 - or absent;

R

3 4 is -0- or absent;

R

35 is hydrogen or alkyl;

R

36 is hydrogen, alkyl, alkenyl, or alkynyl;

R

58 is hydrogen, or halo; 25 R is hydrogen, alkyl, or halo; and R 66 is carbocycle, heterocycle, substituted carbocycle, or substituted heterocycle, and is substituted with one or more A 0 ; or a pharmaceutically acceptable salt thereof. In one specific embodiment of the invention A.' is of the formula: 70 WO 2006/047507 PCT/US2005/038348 2 2 A3 R2 R2 R 2 R2 Ml2a Ml2b In another specific embodiment of the invention A' is of the formula: 2 2A 3 R 2 fR2 "' _ M12a_ M12b In another specific embodiment of the invention A' is of the formula:

A

3 R2 R2 M12a In another specific embodiment of the invention A' is of the formula: wa

A

3 R2 R2 M12a 10 and W 5 a is a carbocycle or a heterocycle where W 5 a is independently substituted with 0 or 1 R2 groups. A specific value for MlI2a is 1. In another specific embodiment of the invention A' is of the formula: 71 WO 2006/047507 PCT/US2005/038348 Y 2 ,W 5 A

R

2

R

2 M12a M12b In another specific embodiment of the invention A is of the formula: 3 R2 R2 M12a In another specific embodiment of the invention A' is of the formula:

W

5 a

A

3 5

R

2

R

2 wherein W 5 a is a carbocycle independently substituted with 0 or 1 R 2 groups. In another specific embodiment of the invention A is of the formula: 0 R2 0 H H 2 O R 2 M12d 10 wherein Y2b is 0 or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention A' is of the formula: 72 WO 2006/047507 PCT/US2005/038348

A

3

R

2

R

2 M12a wherein Wsa is a carbocycle independently substituted with 0 or 1 R 2 groups. In another specific embodiment of the invention A' is of the formula: w 5 a

A

3

R

2

R

2 5 wherein W 5 a is a carbocycle or heterocycle where W 5 a is independently substituted with 0 or 1 R2 groups. In another specific embodiment of the invention A' is of the formula: 0 R2 H H 2 M12d y2b wherein y 2 b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. 10 In a specific embodiment of the invention A 3 is of the formula:

Y

1 || Y2P RX y2 2 R2 M12a 2 Ml 2b In another specific embodiment of the invention A3 is of the formula: 73 WO 2006/047507 PCT/US2005/038348 || y2y Y2 P Rx Y2

R

2

R

2 - 2 Ml12a In another specific embodiment of the invention A3 is of the formula: yla y2a Pa Rx y2a R2 R2 2 M12a wherein Ya is 0 or S; and y 2 a is 0, N(Rx) or S. 5 In another specific embodiment of the invention A 3 is of the formula: 0 0 Rx y2b R2 R2 2 M12a wherein Y is 0 or N(Rx). In another specific embodiment of the invention A3 is of the formula: 0 o P RX y2b

R

1

R

1 2 M12d 10 wherein y 2 b is 0 or N(Rx); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention A3 is of the formula: 74 WO 2006/047507 PCT/US2005/038348 0 0 P Rx y2b H H _ _ 2 M12d wherein Y 2 b is O or N(R); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention M12d is 1. In another specific embodiment of the invention A3 is of the formula:

Y

1 || 2 P Rx M12a W 5 -1- M12b . In another specific embodiment of the invention A3 is of the formula:

Y

1 || YP Rx R2 Y2 R2 R2 5 MI2a M12b In another specific embodiment of the invention W 5 is a carbocycle. 10 In another specific embodiment of the invention A3 is of the formula: 75 WO 2006/047507 PCT/US2005/038348 y 1 Y2 P RX - R M12a 0 - M12b In another specific embodiment of the invention W 5 is phenyl. In another specific embodiment of the invention A3 is of the formula: yla y 2 a P Rx 2 a R2 R2 W3 M12a y2a 5 wherein Ya is 0 or S; and y 2 a is 0, N(R) or S. In another specific embodiment of the invention A3 is of the formula: 0 0 P Rx y2b R2 R2 W3 M12a y2b wherein Y2b is 0 or N(R). In another specific embodiment of the invention A3 is of the formula: 0 O P RX y2b R0 RR RJRW3 Ml2d 10 y2b wherein Y is 0 or N(R); and Ml2d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention R' is H. 76 WO 2006/047507 PCT/US2005/038348 In another specific embodiment of the invention A3 is of the formula: 0 R O R R PO X 0 \2b R 1M12d r

OR

1 0 wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups. In another specific embodiment of the invention A3 is of the formula: O R 2 R M12d NO R1 R H 5 0 In another specific embodiment of the invention A3 is of the formula: 0 O

CH

3 H OR H H 0 In another specific embodiment of the invention A3 is of the formula: 77 WO 2006/047507 PCT/US2005/038348 09 O CH 3 OR' H H 0 In another specific embodiment of the invention A3 is of the formula: 0 0 11 0 0- 0 0 H H -2 In another specific embodiment of the invention A3 is of the formula: y1 a R 2 2 a Ya y 2 a -- ,,11R R2 2 - - 2 5 M12a wherein Ya is 0 or S; and y 2 a is 0, N(R 2 ) or S. In another specific embodiment of the invention A 3 is of the formula: O R2 y 2c yla 0 2 2 R R2 R2 2 M 12a 10 wherein Ya is O or S; y 2 b is O or N(R 2 ); and y 2 e is 0, N(Ry) or S. In another specific embodiment of the invention A3 is of the formula: 78 WO 2006/047507 PCT/US2005/038348 0 R2 11p 2d y2b R

R

1

R

1 2 M12d wheren Ya is O or S; y 2 b is O or N(R 2 ); y 2 d is O or N(Ry); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention A3 is of the formula: O R2 0T 20 H H _ _ 2 5 M12d wherein Y2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention A3 is of the formula: O R 2 00 y2b R2 H H - - 2 10 wherein Y is 0 or N(R). In another specific embodiment of the invention A3 is of the formula: 0 II 0 P 2 H H 0 2 In another specific embodiment of the invention A3 is of the formula: 79 WO 2006/047507 PCT/US2005/038348 y 1 2y Y2 P Rx 2 2 R2 R 2 3 1l2a In another specific embodiment of the invention A3 is of the formula: 1a R2 2a Y1 R y 2 a Y R R2 5 M12a y2a wherein Yla is O or S; and Y 2 a is 0, N(R 2 ) or S. In another specific embodiment of the invention A3 is of the formula: o R2 02b Rc 22 R2 R2 3 MI2a y2b 10 wherein Ya is O or S; y 2 b is 0 or N(R 2 ); and Y 2 c is 0, N(Ry) or S. In another specific embodiment of the invention A 3 is of the formula: O R 2 0 2d y 2 b- yla

R

1

R

1 RJR -"'W3 M12d y2b wherein Ya is 0 or S; Y2b is or N(R2); y2d is O or N(Ry); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. 15 In another specific embodiment of the invention A3 is of the formula: 80 WO 2006/047507 PCT/US2005/038348 O R2 0 H -H M12d y2b wherein y2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention A3 is of the formula: 0 P y2b 0 R H H -W3 y2b 5 wherein Y2b is 0 or N(R 2 ). In another specific embodiment of the invention A3 is of the formula: 0 Y2b P Rx y2b

R

1 R3 M12d 2b wherein: Y 2 b is 0 or N(R); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention A 3 is of the formula: O y 2b

OR

1

R

1

R

1 Ml2d / 10 0 wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups. In another specific embodiment of the invention A3 is of the formula: 81 WO 2006/047507 PCT/US2005/038348 ORi

.--

0 2

OOR

1 R R M12d 0 wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R 2 groups. In another specific embodiment of the invention A3 is of the formula: Me Me 0 \ O CH 3 o O OR' H H 0 5 In a specific embodiment of the invention A0 is of the formula:

O

0 (CH2)1-1 P- 0--R O R wherein each R is independently (C I-C 6 )alkyl. In a specific embodiment of the invention R' is independently H, 10 R', W 3 , a protecting group, or the formula: - Y1 - Ry RY1 R~ R Y2.- -- Y 2 y 2-------R Mla M12c M1c wherein: R is independently H, W , R2 or a protecting group; 82 WO 2006/047507 PCT/US2005/038348 R1 is independently H or alkyl of 1 to 18 carbon atoms; R2 is independently H, R', R3 or R4 wherein each R4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 5 R' groups. In a specific embodiment of the invention R' is of the formula: R 2 2c Y Yla wherein y1a is 0 or S; and y 2 c is 0, N(RY) or S. In a specific embodiment of the invention Rx is of the formula: R 2 y2d -\' RY 10 y1a wherein Ya is 0 or S; and Y2d is 0 or N(RY). In a specific embodiment of the invention Rx is of the formula: R2 ORY 0 In a specific embodiment of the invention RY is hydrogen or alkyl of 1 to 15 10 carbons. In a specific embodiment of the invention R is of the formula: R 2 O R 2 0 83 WO 2006/047507 PCT/US2005/038348 In a specific embodiment of the invention R' is of the formula: 2 Y M12a In a specific embodiment of the invention R is of the formula: R 2 R2 2 2 RR M12a 5 Y. In a specific embodiment of the invention Y' is 0 or S. In a specific embodiment of the invention Y 2 is 0, N(R ) or S. In one specific embodiment of the invention R' is a group of the formula: RY R RY vY y2 2 10 Mia Mib M12c Mic Mid Mie wherein: mia, mib, mIc, mid and mie are independently 0 or 1; ml2c is 0, 1, 2,3,4,5,6,7,8,9, 10, 11 or 12; R is H, W 3 , R 2 or a protecting group; 15 provided that: if mla, ml2c, and mld are 0, then mlb, mlc and mle are 0; if mla and ml2c are 0 and mld is not 0, then mlb and mlc are 0; if mla and mid are 0 and ml2c is not 0, then mlb and at least one of mlc and mle are 0; 20 if mla is 0 and ml2c and mld are not 0, then mlb is 0; 84 WO 2006/047507 PCT/US2005/038348 if ml2c and mld are 0 and mla is not 0, then at least two of mlb, mlc and mIe are 0; if ml2c is 0 and mla and mld are not 0, then at least one of mlb and mic are 0; and 5 if mld is 0 and mla and ml2c are not 0, then at least one of mlc and mle are 0. In compounds of the invention W 5 carbocycles and W 5 heterocycles may be independently substituted with 0 to 3 R2 groups. W5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or 10 heterocycle. W 5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms. The W 5 rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms. 15 A W 5 heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, 0, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, 0, P, and S). W 5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, 0, and S); or 20 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). W 5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, 0, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system. 25 The W 5 heterocycle may be bonded to Y 2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.

W

5 heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and 30 pyrrolyl. W5 also includes, but is not limited to, examples such as: 85 WO 2006/047507 PCT/US2005/038348 N H N NC"] N N H ( N NN S and .

W

5 carbocycles and heterocycles may be independently substituted with 0 to 3 R 2 groups, as defined above. For example, substituted W 5 carbocycles include: OH CI N OH C1 N N O NH 2 5 1O NH 1 NH -- N NH -N -N SH -- N SO 2 Examples of substituted phenyl carbocycles include: 86 WO 2006/047507 PCT/US2005/038348 HN- NH 2 HN- NMe 2 -- NH 2 0 0 0 0 O - NH NH2 C// NH2 O NH2 Linking Groups and Linkers The invention provides conjugates that comprise a kinase inhibiting 5 compound that is linked to one or more phosphonate groups either directly (e.g. through a covalent bond) or through a linking group (i.e. a linker). The nature of the linker is not critical provided it does not interfere with the ability of the phosphonate containing compound to function as a therapeutic agent. The phosphonate or the linker can be linked to the compound at any synthetically 10 feasible position on the compound by removing a hydrogen or any portion of the compound to provide an open valence for attachment of the phosphonate or the linker. In one embodiment of the invention the linking group or linker (which can be designated "L") can include all or a portions of the group A 0 , A', or W3 15 described herein. In another embodiment of the invention the linking group or linker has a molecular weight of from about 20 daltons to about 400 daltons. In another embodiment of the invention the linking group or linker has a length of about 5 angstroms to about 300 angstroms. 20 In another embodiment of the invention the linking group or linker separates the DRUG and a P(=Yl) residue by about 5 angstroms to about 200 angstroms, inclusive, in length. . In another embodiment of the invention the linking group or linker is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, 25 having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (-0-), and wherein the chain is optionally 87 WO 2006/047507 PCT/US2005/038348 substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from (Ci-C 6 )alkoxy, (C 3

-C

6 )cycloalkyl, (CI-C 6 )alkanoyl, (Ci-C6)alkanoyloxy,

(CI-C

6 )alkoxycarbonyl, (Ci-C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo (=O), carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 5 In another embodiment of the invention the linking group or linker is of the formula W-A wherein A is (Ci-C 24 )alkyl, (C 2

-C

24 )alkenyl, (C 2

-C

24 )alkynyl,

(C

3 -Cg)cycloalkyl, (C 6 -Cio)aryl or a combination thereof, wherein W is N(R)C(=O)-, -C(=O)N(R)-, -OC(=O)-, -C(=0)O-, -0-, -S-, -S(O)-, -S(0) 2 -, N(R)-, -C(=O)-, or a direct bond; wherein each R is independently H or (Ci 10 C 6 )alkyl. In another embodiment of the invention the linking group or linker is a divalent radical formed from a peptide. In another embodiment of the invention the linking group or linker is a divalent radical formed from an amino acid. 15 In another embodiment of the invention the linking group or linker is a divalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid, poly-L histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine L-tyrosine. 20 In another embodiment of the invention the linking group or linker is of the formula W-(CH 2 )n wherein, n is between about 1 and about 10; and W is N(R)C(=O)-, -C(=0)N(R)-, -OC(=0)-, -C(=O)O-, -0-, -S-, -S(0)-, -S(0) 2 -, C(=O)-, -N(R)-, or a direct bond; wherein each R is independently H or (Cl

C

6 )alkyl. 25 In another embodiment of the invention the linking group or linker is methylene, ethylene, or propylene. In another embodiment of the invention the linking group or linker is attached to the phosphonate group through a carbon atom of the linker. Intracellular Targeting 30 The phosphonate group of the compounds of the invention may cleave in vivo in stages, e.g., after they have reached the desired site of action, i.e. inside a cell. One mechanism of action inside a cell may entail a first cleavage, e.g. by esterase, to provide a negatively-charged "locked-in" intermediate. Cleavage of 88 WO 2006/047507 PCT/US2005/038348 a terminal ester grouping in a compound of the invention thus affords an unstable intermediate which releases a negatively charged "locked in" intermediate. After passage inside a cell, intracellular enzymatic cleavage or 5 modification of the phosphonate or prodrug compound may result in an intracellular accumulation of the cleaved or modified compound by a "trapping" mechanism. The cleaved or modified compound may then be "locked-in" the cell by a significant change in charge, polarity, or other physical property change which decreases the rate at which the cleaved or modified compound can exit the 10 cell, relative to the rate at which it entered as the phosphonate prodrug. Other mechanisms by which a therapeutic effect is achieved may be operative as well. Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and 15 phosphatases. From the foregoing, it will be apparent that many different drugs can be derivatized in accord with the present invention. Numerous such drugs are specifically mentioned herein. However, it should be understood that the discussion of drug families and their specific members for derivatization 20 according to this invention is not intended to be exhaustive, but merely illustrative. Kinase-Inhibitory Compounds The compounds of the invention include those with kinase-inhibitory activity. The compounds of the inventions bear one or more (e.g. 1, 2, 3, or 4) 25 phosphonate groups, which may be a prodrug moiety. The term "kinase-inhibitory compound" includes those compounds that inhibit the activity of at least one kinase. In particular, the compounds include PD 173955, PD 166326, and PD 173074; as well as, Iressa, Tarceva, MLN-518, ZD-6474 and Canertib; PD-0325901; BMS-354825; CP-547,632; and 30 Semaxanib, SU-1 1248, and GW 9499. Typically, compounds of the invention have a molecular weight of from about 400 amu to about 10,000 amu; in a specific embodiment of the invention, compounds have a molecular weight of less than about 5000 amu; in another 89 WO 2006/047507 PCT/US2005/038348 specific embodiment of the invention, compounds have a molecular weight of less than about 2500 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 1000 amu; in another specific embodiment of the invention, compounds have a molecular weight of 5 less than about 800 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 600 amu; and in another specific embodiment of the invention, compounds have a molecular weight of less than about 600 amu and a molecular weight of greater than about 400 amu. The compounds of the invention also typically have a logD (polarity) less 10 than about 5. In one embodiment the invention provides compounds having a logD less than about 4; in another embodiment the invention provides compounds having a logD less than about 3; in another embodiment the invention provides compounds having a logD greater than about -5; in another embodiment the invention provides compounds having a logD greater than 15 about -3; and in another embodiment the invention provides compounds having a logD greater than about 0 and less than about 3. Selected substituents within the compounds of the invention are present to a recursive degree. In this context, "recursive substituent" means that a substituent may recite another instance of itself. Because of the recursive nature 20 of such substituents, theoretically, a large number may be present in any given embodiment. For example, Rx contains a RY substituent. RY can be R 2 , which in turn can be R 3 . If R 3 is selected to be R 3 , then a second instance of R' can be selected. One of ordinary skill in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired 25 properties of the compound intended. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis. By way of example and not limitation, W 3 , RY and R 3 are all recursive 30 substituents in certain embodiments. Typically, each of these may independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. More typically, each of these may independently occur 12 or fewer times in a given embodiment. More typically 90 WO 2006/047507 PCT/US2005/038348 yet, W 3 will occur 0 to 8 times, Ry will occur 0 to 6 times and R 3 will occur 0 to 10 times in a given embodiment. Even more typically, W 3 will occur 0 to 6 times, Ry will occur 0 to 4 times and R 3 will occur 0 to 8 times in a given embodiment. 5 Recursive substituents are an intended aspect of the invention. One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in an embodiment of the invention, the total number will be determined as set forth above. 10 Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "Rl" or "Ra, then it will be understood that the groups may be the same or different, i.e., each group is independently selected. Wavy lines indicate the site of covalent bond attachments to the adjoining groups, moieties, or atoms. 15 In one embodiment of the invention, the compound is in an isolated and purified form. Generally, the term "isolated and purified" means that the compound is substantially free from biological materials (e.g. blood, tissue, cells, etc.). In one specific embodiment of the invention, the term means that the compound or conjugate of the invention is at least about 50 wt.% free from 20 biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 75 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 90 wt.% free from biological materials; in another specific embodiment, the term means that the 25 compound or conjugate of the invention is at least about 98 wt.% free from biological materials; and in another embodiment, the term means that the compound or conjugate of the invention is at least about 99 wt.% free from biological materials. In another specific embodiment, the invention provides a compound or conjugate of the invention that has been synthetically prepared 30 (e.g., ex vivo). In one embodiment of the invention, the compound is not an anti inflammatory compound; in another embodiment the compound is not an anti infective; in another embodiment the compound is not a compound that is active 91 WO 2006/047507 PCT/US2005/038348 against immune-mediated conditions; in another embodiment the compound is not a compound that is active against metabolic diseases; in another embodiment the compound is not an antiviral agent; in another embodiment the compound is not a nucleoside; in another embodiment the compound is not a IMPDH 5 inhibitor; in another embodiment the compound is not an antimetabolite; in another embodiment the compound is not a PNP inhibitor; in another embodiment the compound inhibits a serine/threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein 10 kinase C, insulin receptor tyrosine kinase, or an EGF receptor tyrosine kinase; in another embodiment the compound is not Gefitinib, imatinib, erlotinib, vatalanib, alvocidib, CEP-701, GLEEVEC, midostaurin, MLN-518, PD-184352, doramapimod, BAY-43-9006, or CP-690,550 substituted with one or more phosphonates. 15 Cellular Accumulation In one embodiment, the invention is provides compounds capable of accumulating in human PBMC (peripheral blood mononuclear cells). PBMC refer to blood cells having round lymphocytes and monocytes. Physiologically, PBMC are critical components of the mechanism against infection. PBMC may 20 be isolated from heparinized whole blood of normal healthy donors or buffy coats, by standard density gradient centrifugation and harvested from the interface, washed (e.g. phosphate-buffered saline) and stored in freezing medium. PBMC may be cultured in multi-well plates. At various times of culture, supernatant may be either removed for assessment, or cells may be 25 harvested and analyzed (Smith R. etal (2003) Blood 102(7):2532-2540). The compounds of this embodiment may further comprise a phosphonate or phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug can have the structure A 3 as described herein. Typically, compounds of the invention demonstrate improved 30 intracellular half-life of the compounds or intracellular metabolites of the compounds in human PBMC when compared to analogs of the compounds not having the phosphonate or phosphonate prodrug. Typically, the half-life is improved by at least about 50%; more typically at least in the range 50-100%; 92 WO 2006/047507 PCT/US2005/038348 still more typically at least about 100%; more typically yet greater than about 100%. In some embodiments of the invention the intracellular half-life of a metabolite of the compound in human PBMCs is improved when compared to an 5 analog of the compound not having the phosphonate or phosphonate prodrug. In such embodiments, the metabolite may be generated intracellularly, e.g. generated within human PBMC. The metabolite may be a product of the cleavage of a phosphonate prodrug within human PBMCs. The phosphonate prodrug may be cleaved to form a metabolite having at least one negative charge 10 at physiological pH. The phosphonate prodrug may be enzymatically cleaved within human PBMC to form a phosphonate having at least one active hydrogen atom of the form P-OH. Stereoisomers The compounds of the invention may have chiral centers, e.g., chiral 15 carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers 20 or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the 25 separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material. 30 The compounds of the invention can also exist as tautomeric isomers in certain cases. All though only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, 93 WO 2006/047507 PCT/US2005/038348 guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention. Salts and Hydrates The compositions of this invention optionally comprise salts of the 5 compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+, Ca+ 2 and Mg+ 2 . Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. Monovalent salts are preferred if a water 10 soluble salt is desired. Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable 15 metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCI, HBr, H 2 SO4, H3PO4 or organic sulfonic acids, to basic centers, typically amines, or to acidic groups. Finally, it is to be understood that the compositions herein comprise compounds of the invention in 20 their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates. Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any of the amino acids described above are suitable, especially the naturally-occurring amino acids 25 found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, seine, threonine, alanine, isoleucine, or leucine. Methods of Kinase Inhibition Another aspect of the invention relates to methods of inhibiting the 30 activity of at least one kinase comprising the step of treating a sample suspected of containing a kinase with a compound or composition of the invention. Compounds of the invention may act as kinase inhibitors, as intermediates for such inhibitors, or have other utilities as described herein. The 94 WO 2006/047507 PCT/US2005/038348 inhibitors will bind to at least one kinase. Compounds binding the kinase may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, the substantially irreversibly binding compounds are 5 useful as probes for the detection of a kinase. Accordingly, the invention relates to methods of detecting at least one kinase in a sample suspected of containing a kinase including the steps of: treating a sample suspected of containing kinase with a composition including a compound of the invention bound to a-label; and observing the effect of the sample on the activity of the label. Suitable labels are 10 well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in conventional fashion using functional groups such as hydroxyl or amino. Within the context of the invention, samples suspected of containing at 15 least one kinase include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a 20 desired glycoprotein; and the like. Typically the sample will be suspected of containing a kinase. Samples can be contained in any medium including water and organic solvent/water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures. The treating step of the invention comprises adding the compound or 25 composition of the invention to the sample or it comprises adding a precursor of the compound or composition to the sample. The addition step comprises any method of administration as described above. If desired, the activity of the kinase after application of the composition can be observed by any method including direct and indirect methods of 30 detecting kinase activity. Quantitative, qualitative, and semiquantitative methods of determining kinase activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method 95 WO 2006/047507 PCT/US2005/038348 such as observation of the physiological properties of a living organism are also applicable. Many organisms contain kinases. The compounds of this invention are useful in the treatment or prophylaxis of conditions associated with kinase 5 activation in animals, e.g., mammals, e.g., humans. However, in screening compounds capable of inhibiting kinase it should be kept in mind that the results of enzyme assays may not correlate with cell culture assays. Thus, a cell based assay should be the primary screening tool. Screens for Kinase Inhibitors 10 Compositions of the invention are screened for inhibitory activity against a kinase by any of the conventional techniques for evaluating enzyme activity. Within the context of the invention, typically compositions are first screened for inhibition of kinase in vitro and compositions showing inhibitory activity are then screened for activity in vivo. Compositions having in vitro Ki (inhibitory 15 constants) of less then about 5 X 10-6 M, typically less than about 1 X 10-7 M and preferably less than about 5 X 10-8 M are preferred for in vivo use. Useful in vitro screens have been described, e.g., Bioorg. Med. Chem. Lett., 2001, 11, 2775). Pharmaceutical Formulations 20 The compounds of this invention can be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will 25 optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily 30 about 7 to 10. While it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at 96 WO 2006/047507 PCT/US2005/038348 least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient 5 thereof. The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical 10 Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, 15 shaping the product. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or 20 as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste. A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or 25 granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active 30 ingredient therefrom. For administration to the eye or other external tissues e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% 97 WO 2006/047507 PCT/US2005/038348 w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a 5 water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, 10 sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs. 15 The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic 20 emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. 25 Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween@ 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a 30 non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl 98 WO 2006/047507 PCT/US2005/038348 palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin 5 and/or liquid paraffin or other mineral oils are used. Pharmaceutical formulations according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient 10 may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of 15 pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These 20 excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium 25 stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. 30 Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active 99 WO 2006/047507 PCT/US2005/038348 ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. 5 Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., 10 polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl 15 p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a 20 thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules of the invention suitable for 25 preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be 30 present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of 100 WO 2006/047507 PCT/US2005/038348 these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these 5 partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent. 10 The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile 15 injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending 20 medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host 25 treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition 30 can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 pg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur. 101 WO 2006/047507 PCT/US2005/038348 Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, 5 advantageously 0.5 to 10% particularly about 1.5% w/w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes 10 comprising the active ingredient in a suitable liquid carrier. Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle 15 sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder 20 administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of conditions associated with kinase activity. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing 25 in addition to the active ingredient such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of 30 the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried 102 WO 2006/047507 PCT/US2005/038348 (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection. solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations 5 are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for 10 example those suitable for oral administration may include flavoring agents. The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor. Veterinary carriers are materials useful for the purpose of administering 15 the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route. Compounds of the invention can also be formulated to provide controlled 20 release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provides compositions comprising one or more compounds of the invention formulated for sustained or controlled release. Effective dose of active ingredient depends at least on the nature of the 25 condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body 30 weight per day. More typically, from about .01 to about 5 mg/kg body weight per day. More typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 103 WO 2006/047507 PCT/US2005/038348 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses. Routes of Administration One or more compounds of the invention (herein referred to as the active 5 ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of 10 the recipient. An advantage of compounds of some embodiments of the invention is that they are orally bioavailable and can be dosed orally. Combination Therapy Active ingredients of the invention are also used in combination with other active ingredients. Such combinations are selected based on the condition 15 to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. It is also possible to combine any compound of the invention with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be 20 administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combination therapy may provide "synergy" and at least one "synergistic effect", i.e. an effect achieved when the active ingredients used 25 together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation 30 therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered 104 WO 2006/047507 PCT/US2005/038348 sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Metabolites of the Compounds of the Invention Also falling within the scope of this invention are the metabolic products, 5 e.g., in vivo metabolic products, of the compounds described herein. Such products may result, e.g., from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a 10 mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g., C 1 4 or

H

3 ) compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur 15 (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. 20 In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no kinase inhibitory activity of their own. 25 Recipes and methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37 *C. Simply because the compounds are stable to the 30 gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. The phosphonate prodrugs of the invention typically will be stable in the digestive system but are substantially hydrolyzed to the parental drug in the digestive lumen, liver or other metabolic organ, or within cells in general. 105 WO 2006/047507 PCT/US2005/038348 Exemplary Methods of Making the Compounds of the Invention. The invention also relates to methods of making the compounds and compositions of the invention. The compounds and compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques 5 are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and 10 Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modem Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing). 15 A number of exemplary methods for the preparation of the compounds and compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods. Schemes and Examples 20 General aspects of these exemplary methods are described below and in the Examples. Each of the products of the following processes is optionally separated, isolated, and/or purified prior to its use in subsequent processes. Generally, the reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for 25 the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures will be -100*C to 200*C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partition between a 30 water/organic layer system (extraction) and separating the layer containing the product. Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 *C), although for metal hydride 106 WO 2006/047507 PCT/US2005/038348 reductions frequently the temperature is reduced to 0 *C to -100 'C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions. Condensation reactions are typically carried out at temperatures near 5 room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0 'C to -100 'C) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions). Standard synthetic techniques such as azeotropic removal of reaction by 10 products and use of anhydrous reaction conditions (e.g., inert gas environments) are common in the art and will be applied when applicable. The terms "treated", "treating", "treatment", and the like, when used in connection with a chemical synthetic operation, mean contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the 15 art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities. This means that "treating compound one with compound two" is synonymous with "allowing compound one to react with compound two", "contacting compound one with compound two", "reacting compound one with compound two", and other expressions 20 common in the art of organic synthesis for reasonably indicating that compound one was "treated", "reacted", "allowed to react", etc., with compound two. For example, treating indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 1OM, typically 0.1M to IM), temperatures (-100 *C to 250 'C, typically -78 'C to 150 'C, more 25 typically -78 *C to 100 *C, still more typically 0 *C to 100 'C), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis are used in selecting the 30 conditions and apparatus for "treating" in a given process. In particular, one of ordinary skill in the art of organic synthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art. 107 WO 2006/047507 PCT/US2005/038348 Modifications of each of the exemplary schemes and in the examples (hereafter "exemplary schemes") leads to various analogs of the specific exemplary materials produced. The above-cited citations describing suitable methods of organic synthesis are applicable to such modifications. 5 In each of the exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization 10 from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer 15 chromatography, as well as techniques of small scale thin layer and flash chromatography. Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents 20 include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like. 25 Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely 30 to achieve the desired separation. A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving 108 WO 2006/047507 PCT/US2005/038348 agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with 5 chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. 10 Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-p-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional 15 crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved is reacted with 20 one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis 25 to yield the free, enantiomerically enriched xanthene. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, X-methoxy-a (trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two 30 atropisomeric diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). By method (3), a racemic mixture of two 109 WO 2006/047507 PCT/US2005/038348 enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other 5 chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism. Examples General Section A number of exemplary methods for the preparation of compounds of the invention are provided herein, for example, in the Examples hereinbelow. These 10 methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods. Certain compounds of the invention can be used as intermediates for the preparation of other compounds of the invention. For example, the interconversion of various phosphonate compounds of the invention is illustrated below. 15 Interconversions of the phosphonates R-link-P(O)(OR')2 R-link P(O)(OR')(OH) and R-link-P(O)(OH)2. The following schemes 32-38 describe the preparation of phosphonate esters of the general structure R-link-P(O)(OR') 2 , in which the groups R' may be the same or different. The R' groups attached to a phosphonate ester, or to 20 precursors thereto, may be changed using established chemical transformations. The interconversion reactions of phosphonates are illustrated in Scheme S32. The group R in Scheme 32 represents the substructure, i.e. the drug "scaffold", to which the substituent link-P(O)(OR') 2 is attached, either in the compounds of the invention, or in precursors thereto. At the point in the synthetic route of 25 conducting a phosphonate interconversion, certain functional groups in R may be protected. The methods employed for a given phosphonate transformation depend on the nature of the substituent R', and of the substrate to which the phosphonate group is attached. The preparation and hydrolysis of phosphonate esters is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. 30 Maeir, eds, Wiley, 1976, p. 9ff. In general, synthesis of phosphonate esters is achieved by coupling a nucleophile amine or alcohol with the corresponding activated phosphonate electrophilic precursor. For example, chlorophosphonate addition on to 5' 110 WO 2006/047507 PCT/US2005/038348 hydroxy of nucleoside is a well known method for preparation of nucleoside phosphate monoesters. The activated precursor can be prepared by several well known methods. Chlorophosphonates useful for synthesis of the prodrugs are prepared from the substituted-1,3-propanediol (Wissner, et al, (1992) J. Med 5 Chem. 35:1650). Chlorophosphonates are made by oxidation of the corresponding chlorophospholanes (Anderson, et al, (1984) J. Org. Chem. 49:1304) which are obtained by reaction of the substituted diol with phosphorus trichloride. Alternatively, the chlorophosphonate agent is made by treating substituted-1,3-diols with phosphorusoxychloride (Patois, et al, (1990) J. Chem. 10 Soc. Perkin Trans. I, 1577). Chlorophosphonate species may also be generated in situ from corresponding cyclic phosphites (Silverburg, et al., (1996) Tetrahedron lett., 37:771-774), which in turn can be either made from chlorophospholane or phosphoramidate intermediate. Phosphoroflouridate intermediate prepared either from pyrophosphate or phosphoric acid may also act as precursor in preparation 15 of cyclic prodrugs (Watanabe et al., (1988) Tetrahedron lett., 29:5763-66). Phosphonate prodrugs of the present invention may also be prepared from the free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1; Campbell, (1992) J Org. Chem. 57:633 1), and other acid coupling reagents including, but not limited to, carbodiimides (Alexander, et al, (1994) Collect. 20 Czech. Chem. Commun. 59:1853; Casara et al, (1992) Bioorg. Med. Chem. Lett. 2:145; Ohashi et al, (1988) Tetrahedron Lett., 29:1189), and benzotriazolyloxytris-(dimethylamino)phosphonium salts (Campagne et al (1993) Tetrahedron Lett. 34:6743). Aryl halides undergo Ni+ 2 catalyzed reaction with phosphite derivatives 25 to give aryl phosphonate containing compounds (Balthazar, et al (1980) J. Org. Chem. 45:5425). Phosphonates may also be prepared from the chlorophosphonate in the presence of a palladium catalyst using aromatic triflates (Petrakis et al (1987) J. Am. Chem. Soc. 109:283 1; Lu et al (1987) Synthesis 726). In another method, aryl phosphonate esters are prepared from 30 aryl phosphates under anionic rearrangement conditions (Melvin (1981) Tetrahedron Lett. 22:3375; Casteel et al (1991) Synthesis, 691). N-Alkoxy aryl salts with alkali met al derivatives of cyclic alkyl phosphonate provide general synthesis for heteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 111 WO 2006/047507 PCT/US2005/038348 35:4114). These above mentioned methods can also be extended to compounds where the W 5 group is a heterocycle. Cyclic-1,3-propanyl prodrugs of phosphonates are also synthesized from phosphonic diacids and substituted propane-1,3-diols using a coupling reagent such as 1,3 5 dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine). Other carbodiimide based coupling agents like 1,3-disopropylcarbodiimide or water soluble reagent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) can also be utilized -for the synthesis of cyclic phosphonate prodrugs. The conversion of a phosphonate diester S32.1 into the corresponding 10 phosphonate monoester S32.2 (Scheme 32, Reaction 1) is accomplished by a number of methods. For example, the ester S32.1 in which R1 is an aralkyl group such as benzyl, is converted into the monoester compound S32.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem. (1995) 60:2946. The reaction is 15 performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110 "C. The conversion of the diester S32.1 in which R' is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester S32.2 is effected by treatment of the ester S32.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran. Phosphonate 20 diesters S32.1 in which one of the groups R' is aralkyl, such as benzyl, and the other is alkyl, is converted into the monoesters S32.2 in which R' is alkyl by hydrogenation, for example using a palladium on carbon catalyst. Phosphonate diesters in which both of the groups R' are alkenyl, such as allyl, is converted into the monoester S32.2 in which R1 is alkenyl, by treatment with 25 chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueous ethanol at reflux, optionally in the presence of diazabicyclooctane, for example by using the procedure described in J. Org. Chem. (1973) 3 8:3224, for the cleavage of allyl carboxylates. The conversion of a phosphonate diester S32.1 or a phosphonate 30 monoester S32.2 into the corresponding phosphonic acid S32.3 (Scheme 32, Reactions 2 and 3) can be effected by reaction of the diester or the monoester with trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm., (1979) 739. The reaction is conducted in an inert solvent such as, for example, 112 WO 2006/047507 PCT/US2005/038348 dichloromethane, optionally in the presence of a silylating agent such as bis(trimethylsilyl)trifluoroacetamide, at ambient temperature. A phosphonate monoester S32.2 in which R' is aralkyl such as benzyl, is converted into the corresponding phosphonic acid S32.3 by hydrogenation over a palladium 5 catalyst, or by treatment with hydrogen chloride in an ethereal solvent such as dioxane. A phosphonate monoester S32.2 in which R1 is alkenyl such as, for example, allyl, is converted into the phosphonic acid S32.3 by reaction with Wilkinson's catalyst in an aqueous organic solvent, for example in 15% aqueous acetonitrile, or in aqueous ethanol, for example using the procedure described in 10 Helv. Chim. Acta. (1985) 68:618. Palladium catalyzed hydrogenolysis of phosphonate esters S32.1 in which R' is benzyl is described in J. Org. Chem. (1959) 24:434. Platinum-catalyzed hydrogenolysis of phosphonate esters S32.1 in which R' is phenyl is described in J. Am. Chem. Soc. (1956) 78:2336. The conversion of a phosphonate monoester S32.2 into a phosphonate 15 diester S32.1 (Scheme 32, Reaction 4) in which the newly introduced R1 group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl is effected by a number of reactions in which the substrate S32.2 is reacted with a hydroxy compound R'OH, in the presence of a coupling agent. Typically, the second phosphonate ester group is different than the first introduced phosphonate ester group, i.e. R, 20 is followed by the introduction of R2 where each of R' and R2 is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl (Scheme 32, Reaction 4a) whereby S32.2 is converted to S32.1a. Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in 25 a basic organic solvent such as pyridine, or (benzotriazol-1 yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is 30 conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine. Alternatively, the conversion of the phosphonate monoester S32.2 to the diester S32.1 is effected by the use of the Mitsunobu reaction, as described above (Scheme 7). The substrate is reacted 113 WO 2006/047507 PCT/US2005/038348 with the hydroxy compound RIOH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine. Alternatively, the phosphonate monoester S32.2 is transformed into the phosphonate diester S32.1, in which the introduced R' group is alkenyl or aralkyl, by reaction of the 5 monoester with the halide R'Br, in which R' is as alkenyl or aralkyl. The alkylation reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as cesium carbonate. Alternatively, the phosphonate monoester is transformed into the phosphonate diester in a two step procedure. In the first step, the phosphonate 10 monoester S32.2 is transformed into the chloro analog RP(O)(OR')C1 by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17, and the thus-obtained product RP(O)(OR')C1 is then reacted with the hydroxy compound R' OH, in the presence of a base such as triethylamine, to 15 afford the phosphonate diester S32.1. A phosphonic acid R-link-P(O)(OH) 2 is transformed into a phosphonate monoester RP(O)(OR')(OH) (Scheme 32, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester R-link

P(O)(OR')

2 S32.1, except that only one molar proportion of the component 20 R'OH or R 1 Br is employed. Dialkyl phosphonates may be prepared according to the methods of: Quast et al (1974) Synthesis 490; Stowell et al (1990) Tetrahedron Lett. 3261; US 5663159. A phosphonic acid R-link-P(O)(OH) 2 S32.3 is transformed into a phosphonate diester R-link-P(O)(OR) 2 S32.1 (Scheme 32, Reaction 6) by a 25 coupling reaction with the hydroxy compound R'OH, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine. The reaction is conducted in a basic solvent such as pyridine. Alternatively, phosphonic acids S32.3 are transformed into phosphonic esters S32.1 in which R' is aryl, by means of a coupling reaction employing, for example, 30 dicyclohexylcarbodiimide in pyridine at ca 70 'C. Alternatively, phosphonic acids S32.3 are transformed into phosphonic esters S32.1 in which R' is alkenyl, by means of an alkylation reaction. The phosphonic acid is reacted with the alkenyl bromide R'Br in a polar organic solvent such as acetonitrile solution at 114 WO 2006/047507 PCT/US2005/038348 reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester S32.1. Scheme 32 O 0 R-ink- OR R-Ink- OR

OR'

1 3. OH S32.2 OR 32.1 0 20 R-link -- OR R-Iink-p-OH ORS OH S32.3 S32.1 0 3 0 O O R-link--P-OR' R-Iink----O OH S322 OH S32.3 O0 R-link-- --- OR' R-ink-11-OR' OH OR S32.1 O 0 2OR S32. 0 2 0 R-ink- O R-ink- O OH OH S32.2 S32.3 0 6 0 R-I ink-P-OH R-link---OR' OH OR2 1 321 OH S32.3 OH S32.2 0 6 0 R-link-- -OH' R-ik - OR OH Rlnk 1 OR' OS32.3 .R S32.1 Preparation of phosphonate carbamates. 5 Phosphonate esters may contain a carbamate linkage. The preparation of carbamates is described in Comprehensive Organic Functional Group Transformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and in Organic Functional Group Preparations, by S. R. Sandler and W. Karo, Academic Press, 1986, p. 260ff. The carbamoyl group may be formed by 10 reaction of a hydroxy group according to the methods known in the art, including the teachings of Ellis, US 2002/0103378 Al and Hajima, US 6018049. Scheme 33 illustrates various methods by which the carbamate linkage is synthesized. As shown in Scheme 33, in the general reaction generating carbamates, an alcohol S33.1, is converted into the activated derivative S33.2 in 15 which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the like, as described herein. The activated derivative S33.2 is then reacted with an amine 115 WO 2006/047507 PCT/US2005/038348 S33.3, to afford the carbamate product S33.4. Examples 1 - 7 in Scheme 33 depict methods by which the general reaction is effected. Examples 8 - 10 illustrate alternative methods for the preparation of carbamates. Scheme 33, Example 1 illustrates the preparation of carbamates 5 employing a chloroformyl derivative of the alcohol S33.5. In this procedure, the alcohol S33.5 is reacted with phosgene, in an inert solvent such as toluene, at about 0 *C, as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, to afford the chloroformate S33.6. The latter 10 compound is then reacted with the amine component S33.3, in the presence of an organic or inorganic base, to afford the carbamate S33.7. For example, the chloroformyl compound S33.6 is reacted with the amine S33.3 in a water miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the 15 carbamate S33.7. Alternatively, the reaction is performed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine. Scheme 33, Example 2 depicts the reaction of the chloroformate compound S33.6 with imidazole to produce the imidazolide S33.8. The 20 imidazolide product is then reacted with the amine S33.3 to yield the carbamate S33.7. The preparation of the imidazolide is performed in an aprotic solvent such as dichloromethane at 0*, and the preparation of the carbamate is conducted in a similar solvent at ambient temperature, optionally in the presence of a base such as dimethylaminopyridine, as described in J. Med. Chem., 1989, 32, 357. 25 Scheme 33 Example 3, depicts the reaction of the chloroformate S33.6 with an activated hydroxyl compound R"OH, to yield the mixed carbonate ester S33.10. The reaction is conducted in an inert organic solvent such as ether or dichloromethane, in the presence of a base such as dicyclohexylamine or triethylamine. The hydroxyl component R"OH is selected from the group of 30 compounds S33.19 - S33.24 shown in Scheme 33, and similar compounds. For example, if the component R"OH is hydroxybenztriazole S33.19, N hydroxysuccinimide S33.20, or pentachlorophenol, S33.21, the mixed carbonate S33.10 is obtained by the reaction of the chloroformate with the hydroxyl 116 WO 2006/047507 PCT/US2005/038348 compound in an ethereal solvent in the presence of dicyclohexylamine, as described in Can. J. Chem., 1982, 60, 976. A similar reaction in which the component R"OH is pentafluorophenol S33.22 or 2-hydroxypyridine S33.23 is performed in an ethereal solvent in the presence of triethylamine, as described in 5 Syn., 1986, 303, and Chem. Ber. 118, 468, 1985. Scheme 33 Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole S33.8 is employed. In this procedure, an alcohol S33.5 is reacted with an equimolar amount of carbonyl diimidazole S33.11 to prepare the intermediate S33.8. The reaction is conducted in an aprotic organic 10 solvent such as dichloromethane or tetrahydrofuran. The acyloxyimidazole S33.8 is then reacted with an equimolar amount of the amine RNH 2 to afford the carbamate S33.7. The reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate S33.7. 15 Scheme .33, Example 5 illustrates the preparation of carbamates by means of an intermediate alkoxycarbonylbenztriazole S33.13. In this procedure, an alcohol ROH is reacted at ambient temperature with an equimolar amount of benztriazole carbonyl chloride S33.12, to afford the alkoxycarbonyl product S33.13. The reaction is performed in an organic solvent such as benzene or 20 toluene, in the presence of a tertiary organic amine such as triethylamine, as described in Synthesis., 1977, 704. The product is then reacted with the amine

RNH

2 to afford the carbamate S33.7. The reaction is conducted in toluene or ethanol, at from ambient temperature to about 80 *C as described in Synthesis., 1977, 704. 25 Scheme 33, Example 6 illustrates the preparation of carbamates in which a carbonate (R"O) 2 CO, S33.14, is reacted with an alcohol S33.5 to afford the intermediate alkyloxycarbonyl intermediate S33.15. The latter reagent is then reacted with the amine R'NH 2 to afford the carbamate S33.7. The procedure in which the reagent S33.15 is derived from hydroxybenztriazole S33.19 is 30 described in Synthesis, 1993, 908; the procedure in which the reagent S33.15 is derived from N-hydroxysuccinimide S33.20 is described in Tet. Lett., 1992, 2781; the procedure in which the reagent S33.15 is derived from 2 hydroxypyridine S33.23 is described in Tet. Lett., 1991, 4251; the procedure in 117 WO 2006/047507 PCT/US2005/038348 which the reagent S33.15 is derived from 4-nitrophenol S33.24 is described in Synthesis. 1993, 103. The reaction between equimolar amounts of the alcohol ROH and the carbonate S33.14 is conducted in an inert organic solvent at ambient temperature. 5 Scheme 33, Example 7 illustrates the preparation of carbamates from alkoxycarbonyl azides S33.16. In this procedure, an alkyl chloroformate S33.6 is reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl azide S33.16. The latter compound is then reacted with an equimolar amount of the amine R'NH 2 to afford the carbamate S33.7. The reaction is conducted at 10 ambient temperature in a polar aprotic solvent such as dimethylsulfoxide, for example as described in Synthesis., 1982, 404. Scheme 33, Example 8 illustrates the preparation of carbamates by means of the reaction between an alcohol ROH and the chloroformyl derivative of an amine S33.17. In this procedure, which is described in Synthetic Organic 15 Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, the reactants are combined at ambient temperature in an aprotic solvent such as acetonitrile, in the presence of a base such as triethylamine, to afford the carbamate S33.7. Scheme 33, Example 9 illustrates the preparation of carbamates by means of the reaction between an alcohol ROH and an isocyanate S33.18. In this 20 procedure, which is described in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined at ambient temperature in an aprotic solvent such as ether or dichloromethane and the like, to afford the carbamate S33.7. Scheme 33, Example 10 illustrates the preparation of carbamates by 25 means of the reaction between an alcohol ROH and an amine R'NH 2 . In this procedure, which is described in Chem. Lett. 1972, 373, the reactants are combined at ambient temperature in an aprotic organic solvent such as tetrahydrofuran, in the presence of a tertiary base such as triethylamine, and selenium. Carbon monoxide is passed through the solution and the reaction 30 proceeds to afford the carbamate S33.7. 118 WO 2006/047507 PCT/US2005/038348 Scheme 33. Preparation of carbamnates. General reaction ROH - ~ ROCOLv R'NH 2 o. O NH S33.1 S33.2 S33.3 S33.4 Examples

R'NH

2 S33.3 (1) ROI: ROCOCI - ~ ROCONHR' S33.5 S33.6 S33.7 H N (2) ROH - ~ ROCOCI S33.5 S33.6 0 S33.8

R'NH

2 S33.3 ROCONHR' S33.7 (3) ROH -' ROCOCI -"OH ROOR 'H ROCONHR' S33.5 S33.6 S33.9 S33.10 S33.3 S33.7 0 ROHK/ R - NIN R'NH 2 S33 .3 S33.5 0 S33.8 S33.7 (5) ROH 0--lNR'NH 2 ROCONHR' S33.5 S33.12 S33.13 0_J-R S33.7 119 WO 2006/047507 PCT/US2005/038348 (6) ROH (R"0 2 )C=O ROCOR" R'NH 2 ROCONHR' S33.5 S33.14 S33.15 S33.3 S33.7 (7) ROH 1 ROCOCI ROCON 3 S33.5 S33.6 S33.16

R'NH

2 33.3 ROCONHR' l' 33.7 (8) ROH R'NHCOCI ROCONHR' S33.5 S33.17 S33.7 R'NCO (9) ROH ROCONHR' S33.5 S33.18 S33.7 (10) ROH R'NH2 ROCONHR' S33.5 S33.3 S33.7 O OH ((:: N C, C R"OH= N N-OH CI CI SN' OH O C C S33.19 S33.20 S33.21 OH OH OH F F N F F F NO 2 S33.22 S33.23 S33.24 Preparation of carboalkoxy-substituted phosphonate bisamidates, monoamidates, diesters and monoesters. A number of methods are available for the conversion of phosphonic 5 acids into amidates and esters. In one group of methods, the phosphonic acid is either converted into an isolated activated intermediate such as a phosphoryl 120 WO 2006/047507 PCT/US2005/038348 chloride, or the phosphonic acid is activated in situ for reaction with an amine or a hydroxy compound. The conversion of phosphonic acids into phosphoryl chlorides is accomplished by reaction with thionyl chloride, for example as described in J. 5 Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063, or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride, as described in J. Am. Chem. Soc., 1994, 116, 3251, or J Org. Chem., 1994, 59, 6144, or by reaction with phosphorus pentachloride, as described in J. Org. Chem., 2001, 66, 329, or in J Med. Chem., 1995, 38, 1372. The resultant phosphoryl chlorides are 10 then reacted with amines or hydroxy compounds in the presence of a base to afford the amidate or ester products. Phosphonic acids are converted into activated imidazolyl derivatives by reaction with carbonyl diimidazole, as described in J. Chem. Soc., Chem. Comm. (1991) 312, or Nucleosides & Nucleotides (2000) 19:1885. Activated 15 sulfonyloxy derivatives are obtained by the reaction of phosphonic acids with trichloromethylsulfonyl chloride or with triisopropylbenzenesulfonyl chloride, as described in Tet. Lett. (1996) 7857, or Bioorg. Med. Chem. Lett. (1998) 8:663. The activated sulfonyloxy derivatives are then reacted with amines or hydroxy compounds to afford amidates or esters. 20 Alternatively, the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a diimide coupling agent. The preparation of phosphonic amidates and esters by means of coupling reactions in the presence of dicyclohexyl carbodiimide is described, for example, in J. Chem. Soc., Chem. Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987) 52:2792. The use of 25 ethyl dimethylaminopropyl carbodiimide for activation and coupling of phosphonic acids is described in Tet. Lett., (2001) 42:8841, or Nucleosides & Nucleotides (2000) 19:1885. A number of additional coupling reagents have been described for the preparation of amidates and esters from phosphonic acids. The agents include 30 Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem., 1995, 60, 5214, and J. Med. Chem. (1997) 40:3842, mesitylene-2-sulfonyl-3-nitro-1,2,4 triazole (MSNT), as described in J. Med Chem. (1996) 39:4958, diphenylphosphoryl azide, as described in J. Org. Chem. (1984) 49:1158, 1 121 WO 2006/047507 PCT/US2005/038348 (2,4,6-triisopropylbenzenesulfonyl-3-nitro- 1,2,4-triazole (TPSNT) as described in Bioorg. Med Chem. Lett. (1998) 8:1013, bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), as described in Te. Lett., (1996) 37:3997, 2-chloro-5,5-dimethyl-2-oxo-1,3,2 5 dioxaphosphinane, as described in Nucleosides Nucleotides 1995, 14, 871, and diphenyl chlorophosphate, as described in J. Med. Chem., 1988, 31, 1305. Phosphonic acids are converted into amidates and esters by means of the Mitsunobu reaction, in which the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a triaryl phosphine and a dialkyl 10 azodicarboxylate. The procedure is described in Org. Lett., 2001, 3, 643, or J. Med Chem., 1997, 40, 3842. Phosphonic esters are also obtained by the reaction between phosphonic acids and halo compounds, in the presence of a suitable base. The method is described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem. Soc. Perkin 15 Trans., I, 1993, 19, 2303, or J. Med Chem., 1995, 38, 1372, or Tet. Lett., 2002, 43,1161. Schemes 34-37 illustrate the conversion of phosphonate esters and phosphonic acids into carboalkoxy-substituted phosphonbisamidates (Scheme 34), phosphonamidates (Scheme 35), phosphonate monoesters (Scheme 36) and 20 phosphonate diesters, (Scheme 37). Scheme 38 illustrates synthesis of gem dialkyl amino phosphonate reagents. Scheme 34 illustrates various methods for the conversion of phosphonate diesters S34.1 into phosphonbisamidates S34.5. The diester S34.1, prepared as described previously, is hydrolyzed, either to the monoester S34.2 or to the 25 phosphonic acid S34.6. The methods employed for these transformations are described above. The monoester S34.2 is converted into the monoamidate S34.3 by reaction with an aminoester S34.9, in which the group R2 is H or alkyl; the group R is a divalent alkylene moiety such as, for example, CHCH 3 ,

CHCH

2

CH

3 , CH(CH(CH 3

)

2 ), CH(CH 2 Ph), and the like, or a side chain group 30 present in natural or modified aminoacids; and the group R 5 b is C 1 -C12 alkyl, such as methyl, ethyl, propyl, isopropyl, or isobutyl; C 6

-C

20 aryl, such as phenyl or substituted phenyl; or C 6

-C

20 arylalkyl, such as benzyl or benzyhydryl. The reactants are combined in the presence of a coupling agent such as a 122 WO 2006/047507 PCT/US2005/038348 carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc., (1957) 79:3575, optionally in the presence of an activating agent such as hydroxybenztriazole, to yield the amidate product S34.3. The amidate forming reaction is also effected in the presence of coupling agents such as BOP, 5 as described in J. Org. Chem. (1995) 60:5214, Aldrithiol, PYBOP and similar coupling agents used for the preparation of amides and esters. Alternatively, the reactants S34.2 and S34.9 are transformed into the monoamidate S34.3 by means of a Mitsunobu reaction. The preparation of amidates by means of the Mitsunobu reaction is described in J. Med. Chem. (1995) 38:2742. Equimolar amounts of 10 the reactants are combined in an inert solvent such as tetrahydrofuran in the presence of a triaryl phosphine and a dialkyl azodicarboxylate. The thus obtained monoamidate ester S34.3 is then transformed into amidate phosphonic acid S34.4. The conditions used for the hydrolysis reaction depend on the nature of the R 1 group, as described previously. The phosphonic acid amidate S34.4 is 15 then reacted with an aminoester S34.9, as described above, to yield the bisamidate product S34.5, in which the amino substituents are the same or different. Alternatively, the phosphonic acid S34.6 may be treated with two different amino ester reagents simulataneously, i.e. S34.9 where R 2 , R 4 b or R 5 b are different. The resulting mixture of bisamidate products S34.5 may then be 20 separable, e.g., by chromatography. Scheme 34 O 0 0 R-link- -OR' - R-ink- -OR' IN R-ink---OH : 34.7

OR

1 OH OH S34.1 S34.2 S34.6 S34.9 S34. O 0 0 R-ink- OR ink--OR1 - R-link-p-OH R-I ink-p-OR \N\R Lv R 2

NH(R

4 b)CO2R 5 b NR 2 (R4b/ S34.8 S34.9 (R 4 b) C2R 5 b CO 2 Rab S34.3 S34.4 123 WO 2006/047507 PCT/US2005/038348 O 0 R2 0 R 2 IIII '5b It _ R-link - Lv R-link--- 4b /CO 2 R R-link-P-N R-ikP-L - R-ik.\>~)I(4b)_CO 2 5 b (Lv or OH) S34.9 N (R )R )02 S34.7

(R

4 b) 'R 2 S34.9 (Lv or OH)

'CO

2 RSb S34.11 S34.5 0 0 Hal(R 4 b)CO 2

R

5 b R-link --- NH R-link-- NH 2 S34.12 4b (R4b)CO 2 R5

NH

2 (R R 2 S34.10 Ex6 ( CO2R 5 b S34.5 An example of this procedure is shown in Scheme 34, Example 1. In this procedure, a dibenzyl phosphonate S34.14 is reacted with diazabicyclooctane (DABCO) in toluene at reflux, as described in J. Org. Chem., 1995, 60, 2946, to 5 afford the monobenzyl phosphonate S34.15. The product is then reacted with equimolar amounts of ethyl alaninate S34.16 and dicyclohexyl carbodiimide in pyridine, to yield the amidate product S34.17. The benzyl group is then removed, for example by hydrogenolysis over a palladium catalyst, to give the monoacid product S34.18 which may be unstable according to J. Med. Chem. 10 (1997) 40(23):3842. This compound S34.18 is then reacted in a Mitsunobu reaction with ethyl leucinate S34.19, triphenyl phosphine and diethylazodicarboxylate, as described in J. Med. Chem., 1995, 38, 2742, to produce the bisamidate product S34.20. Using the above procedures, but employing in place of ethyl leucinate 15 S34.19 or ethyl alaninate S34.16, different aminoesters S34.9, the corresponding products S34.5 are obtained. Alternatively, the phosphonic acid S34.6 is converted into the bisamidate S34.5 by use of the coupling reactions described above. The reaction is performed in one step, in which case the nitrogen-related substituents present in 20 the product S34.5 are the same, or in two steps, in which case the nitrogen related substituents can be different. An example of the method is shown in Scheme 34, Example 2. In this procedure, a phosphonic acid S34.6 is reacted in pyridine solution with excess ethyl phenylalaninate S34.21 and dicyclohexylcarbodiimide, for example as 25 described in J. Chem. Soc., Chem. Comm., 1991, 1063, to give the bisamidate product S34.22. 124 WO 2006/047507 PCT/US2005/038348 Using the above procedures, but employing, in place of ethyl phenylalaninate, different aminoesters S34.9, the corresponding products S34.5 are obtained. As a further alternative, the phosphonic acid S34.6 is converted into the 5 mono or bis-activated derivative S34.7, in which Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc. The conversion of phosphonic acids into chlorides S34.7 (Lv = Cl) is effected by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17. 10 The conversion of phosphonic acids into monoimidazolides S34.7 (Lv = imidazolyl) is described in J Med. Chem., 2002, 45, 1284 and in J. Chem. Soc. Chem. Comm., 1991, 312. Alternatively, the phosphonic acid is activated by reaction with triisopropylbenzenesulfonyl chloride, as described in Nucleosides andNucleotides, 2000, 10, 1885. The activated product is then reacted with the 15 aminoester S34.9, in the presence of a base, to give the bisamidate S34.5. The reaction is performed in one step, in which case the nitrogen substituents present in the product S34.5 are the same, or in two steps, via the intermediate S34.11, in which case the nitrogen substituents can be different. Examples of these methods are shown in Scheme 34, Examples 3 and 5. 20 In the procedure illustrated in Scheme 34, Example 3, a phosphonic acid S34.6 is reacted with ten molar equivalents of thionyl chloride, as described in Zh. Obschei Khim., 1958, 28, 1063, to give the dichloro compound S34.23. The product is then reacted at reflux temperature in a polar aprotic solvent such as acetonitrile, and in the presence of a base such as triethylamine, with butyl 25 serinate S34.24 to afford the bisamidate product S34.25. Using the above procedures, but employing, in place of butyl serinate S34.24, different aminoesters S34.9, the corresponding products S34.5 are obtained. In the procedure illustrated in Scheme 34, Example 5, the phosphonic 30 acid S34.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991, 312, with carbonyl diimidazole to give the imidazolide S34.32. The product is then reacted in acetonitrile solution at ambient temperature, with one molar equivalent of ethyl alaninate S34.33 to yield the monodisplacement product 125 WO 2006/047507 PCT/US2005/038348 S34.34. The latter compound is then reacted with carbonyl diimidazole to produce the activated intermediate S34.35, and the product is then reacted, under the same conditions, with ethyl N-methylalaninate S34.33a to give the bisamidate product S34.36. 5 Using the above procedures, but employing, in place of ethyl alaninate S34.33 or ethyl N-methylalaninate S34.33a, different aminoesters S34.9, the corresponding products S34.5 are obtained. The intermediate monoamidate S34.3 is also prepared from the monoester S34.2 by first converting the monoester into the activated derivative 10 S34.8 in which Lv is a leaving group such as halo, imidazolyl etc, using the procedures described above. The product S34.8 is then reacted with an aminoester S34.9 in the presence of a base such as pyridine, to give an intermediate monoamidate product S34.3. The latter compound is then converted, by removal of the R' group and coupling of the product with the 15 aminoester S34.9, as described above, into the bisamidate S34.5. An example of this procedure, in which the phosphonic acid is activated by conversion to the chloro derivative S34.26, is shown in Scheme 34, Example 4. In this procedure, the phosphonic monobenzyl ester S34.15 is reacted, in dichloromethane, with thionyl chloride, as described in Tet. Letters., 1994, 35, 20 4097, to afford the phosphoryl chloride S34.26. The product is then reacted in acetonitrile solution at ambient temperature with one molar equivalent of ethyl 3-amino-2-methylpropionate S34.27 to yield the monoamidate product S34.28. The latter compound is hydrogenated in ethylacetate over a 5% palladium on carbon catalyst to produce the monoacid product S34.29. The product is 25 subjected to a Mitsunobu coupling procedure, with equimolar amounts of butyl alaninate S34.30, triphenyl phosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran, to give the bisamidate product S34.31. Using the above procedures, but employing, in place of ethyl 3-amino-2 methylpropionate S34.27 or butyl alaninate S34.30, different aminoesters S34.9, 30 the corresponding products S34.5 are obtained. The activated phosphonic acid derivative S34.7 is also converted into the bisamidate S34.5 via the diamino compound S34.10. The conversion of activated phosphonic acid derivatives such as phosphoryl chlorides into the 126 WO 2006/047507 PCT/US2005/038348 corresponding amino analogs S34.10, by reaction with ammonia, is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976. The bisamino compound S34.10 is then reacted at elevated temperature with a haloester S34.12 (Hal = halogen, i.e. F, Cl, Br, I), in a polar organic solvent such 5 as dimethylformamide, in the presence of a base such as 4, 4 dimethylaminopyridine (DMAP) or potassium carbonate, to yield the bisamidate S34.5. Alternatively, S34.6 may be treated with two different amino ester reagents simulataneously, i.e. S34.12 where R 4 b or R 5 b are different. The resulting mixture of bisamidate products S34.5 may then be separable, e.g., by 10 chromatography. An example of this procedure is shown in Scheme 34, Example 6. In this method, a dichlorophosphonate S34.23 is reacted with ammonia to afford the diamide S34.37. The reaction is performed in aqueous, aqueous alcoholic or alcoholic solution, at reflux temperature. The resulting diamino compound is 15 then reacted with two molar equivalents of ethyl 2-bromo-3-methylbutyrate S34.38, in a polar organic solvent such as N-methylpyrrolidinone at ca. 150 *C, in the presence of a base such as potassium carbonate, and optionally in the presence of a catalytic amount of potassium iodide, to afford the bisamidate product S34.39. 20 Using the above procedures, but employing, in place of ethyl 2-bromo-3 methylbutyrate S34.38, different haloesters S34.12 the corresponding products S34.5 are obtained. The procedures shown in Scheme 34 are also applicable to the preparation of bisamidates in which the aminoester moiety incorporates different 25 functional groups. Scheme 34, Example 7 illustrates the preparation of bisamidates derived from tyrosine. In this procedure, the monoimidazolide S34.32 is reacted with propyl tyrosinate S34.40, as described in Example 5, to yield the monoamidate S34.41. The product is reacted with carbonyl diimidazole to give the imidazolide S34.42, and this material is reacted with a further molar 30 equivalent of propyl tyrosinate to produce the bisamidate product S34.43. Using the above procedures, but employing, in place of propyl tyrosinate S34.40, different aminoesters S34.9, the corresponding products S34.5 are obtained. The aminoesters employed in the two stages of the above procedure 127 WO 2006/047507 PCT/US2005/038348 can be the same or different, so that bisamidates with the same or different amino substituents are prepared. Scheme 35 illustrates methods for the preparation of phosphonate monoamidates. 5 In one procedure, a phosphonate monoester S34.1 is converted, as described in Scheme 34, into the activated derivative S34.8. This compound is then reacted, as described above, with an aminoester S34.9, in the presence of a base, to afford the monoamidate product S35.1. The procedure is illustrated in Scheme 35, Example 1. In this method, a 10 monophenyl phosphonate S35.7 is reacted with, for example, thionyl chloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to give the chloro product S35.8. The product is then reacted, as described in Scheme 34, with ethyl alaninate, to yield the amidate S35.10. Using the above procedures, but employing, in place of ethyl alaninate 15 S35.9, different aminoesters S34.9, the corresponding products S35.1 are obtained. Alternatively, the phosphonate monoester S34.1 is coupled, as described in Scheme 34, with an aminoester S34.9 to produce the amidate S35.1. If necessary, the R' substituent is then altered, by initial cleavage to afford the 20 phosphonic acid S35.2. The procedures for this transformation depend on the nature of the R 1 group, and are described above. The phosphonic acid is then transformed into the ester amidate product S35.3, by reaction with the hydroxy compound R 3 OH, in which the group R 3 is aryl, heterocycle, alkyl, cycloalkyl, haloalkyl etc, using the same coupling procedures (carbodiimide, Aldrithiol-2, 25 PYBOP, Mitsunobu reaction etc) described in Scheme 34 for the coupling of amines and phosphonic acids. 128 WO 2006/047507 PCT/US2005/038348 Scheme 34 Example I O O H 2 NCH(Me)CO 2 Et O H Me R-link-p--OBn i R-link -- OH S34.16 R-link -- N Me OBn OBn O1n COOEt S34.14 S34.15 S34.17 0 w 0 H Me _R-ink-N Me H 2

NCH(CH

2 Pr)CO 2 Et R-link-1 Me OH COOEt S34.19 P NH2C< COOEt S34.18 COOEt S34.20 Scheme 34 Example 2 Bn O H 2 NCH(Bn)CO 2 Et 0 >-COOEt R-link-'--OH S34.21_ R-link-P--NH OH NH Bn-K COOEt S34.6 S34.22 Scheme 34 Example 3 OH R-ink--OH

H

2

NCH(CH

2

H)CO

2 Bu C 2 u 11 S34.24 OH CI NH S34.6 S34.23 HO O 2 B S34.25 Scheme 34 Example 4 0 o H 2

NCH

2 CH(Me)CO 2 Et 0 11 iiS34.27 11 R-Iink - P--O3no -ik II 13 -n P 1n OH cl NH S34.15 S34.26 - C-NH S34.3 HO CO 2 u Me S34.28 0 Me R-Iink -p-OH H0 )-CO 2 13u O H 2 NCH(Me)CO 2 Bu O a S34.30 R-ink- NH Me SCO 2 Et Me S34S34.28 S34.31 129 WO 2006/047507 PCT/US2005/038348 Scheme 34 Example 5 Me O 0 H 2 NCH(Me)CO 2 Et 2 CO 2 Et R-Iink--OH - R-ink-P-OH -. R-Iink-P-NH OH Im S34.33 OH S34.6 S34.32 S34.34 Me Me 0 >CO 2 Et MeNHCH(Me)CO 2 Et 2 -CO 2 Et R-ink-PP-NH _______ -l NH Im S34.33a N-Me S34.35 Me-( CO 2 Et S34.36 Scheme 34 Example 6 Pr' BrCH(Pri)CO 2 Et

CO

2 Et R-ink-P-CI - R-ink-p-NH 2 - R-link-P--NH CI

NH

2 S34.38 /NH S34.39 S34.23 S34.37 Pr

CO

2 Et Scheme 34 Example 7 HO 0 0 R-link -p-OH R-Iink -P--Im

H

2 N CO 2 Pr NH NH R-ink-P-OH -0 \Im S34.40 - CO 2 Pr - CO 2 Pr S34.32 H S34.41 HO S34.42 PrO 2 C 0 R-ink--p--NH NH - CO 2 Pr OH S34.43 HO Examples of this method are shown in Scheme 35, Examples 1-3. In the sequence shown in Example 2, a monobenzyl phosphonate S35.11 is 5 transformed by reaction with ethyl alaninate, using one of the methods described above, into the monoamidate S35.12. The benzyl group is then removed by catalytic hydrogenation in ethylacetate solution over a 5% palladium on carbon catalyst, to afford the phosphonic acid amidate S35.13. The product is then 130 WO 2006/047507 PCT/US2005/038348 reacted in dichloromethane solution at ambient temperature with equimolar amounts of 1 -(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol S35.14, for example as described in Te. Lett., 2001, 42, 8841, to yield the amidate ester S35.15. 5 In the sequence shown in Scheme 35, Example 3, the monoamidate S35.13 is coupled, in tetrahydrofuran solution at ambient temperature, with equimolar amounts of dicyclohexyl carbodiimide and 4-hydroxy-N methylpiperidine S35.16, to produce the amidate ester product S35.17. Using the above procedures, but employing, in place of the ethyl 10 alaninate product S35.12 different monoacids S35.2, and in place of trifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16, different hydroxy compounds R 3 OH, the corresponding products S35.3 are obtained. Alternatively, the activated phosphonate ester S34.8 is reacted with ammonia to yield the amidate S35.4. The product is then reacted, as described in 15 Scheme 34, with a haloester S35.5, in the presence of a base, to produce the amidate product S35.6. If appropriate, the nature of the R' group is changed, using the procedures described above, to give the product S35.3. The method is illustrated in Scheme 35, Example 4. In this sequence, the monophenyl phosphoryl chloride S35.18 is reacted, as described in Scheme 34, with 20 ammonia, to yield the amino product S35.19. This material is then reacted in N methylpyrrolidinone solution at 170' with butyl 2-bromo-3-phenylpropionate S35.20 and potassium carbonate, to afford the amidate product S35.21. Using these procedures, but employing, in place of butyl 2-bromo-3 phenylpropionate S35.20, different haloesters S35.5, the corresponding products 25 S35.6 are obtained. The monoamidate products S35.3 are also prepared from the doubly activated phosphonate derivatives S34.7. In this procedure, examples of which are described in Synlett., 1998, 1, 73, the intermediate S34.7 is reacted with a limited amount of the aminoester S34.9 to give the mono-displacement product 30 S34.11. The latter compound is then reacted with the hydroxy compound R 3 OH in a polar organic solvent such as dimethylformamide, in the presence of a base such as diisopropylethylamine, to yield the monoamidate ester S35.3. 131 WO 2006/047507 PCT/US2005/038348 The method is illustrated in Scheme 35, Example 5. In this method, the phosphoryl dichloride S35.22 is reacted in dichloromethane solution with one molar equivalent of ethyl N-methyl tyrosinate S35.23 and dimethylaminopyridine, to generate the monoamidate S35.24. The product is 5 then reacted with phenol S35.25 in dimethylformamide containing potassium carbonate, to yield the ester amidate product S35.26. Using these procedures, but employing, in place of ethyl N-methyl tyrosinate S35.23 or phenol S35.25, the aminoesters S34.9 and/or the hydroxy compounds R 3 OH, the corresponding products S35.3 are obtained. Scheme 35 0 0 0 R-link--OR R-link-p OR R-ink-P-OH - S35.3 pH S34.9 N-R2 N-R2 S34. (R4b) (R4b

R

2

NH(R

4 b)CO 2 R 'CO 2

R

5

'CO

2

R

5 b S34.9 S35.1 S35.2 o 0 HaI(R 4 b)CO 2 Rb 0 R-link-1--OR' R-link- 1-OR' S35 R-link- 1--OR' P - P\7 S35.5 Lv NH 2 NH S35.4 (R4j 'CO 2

R

5 b S34.8 S35.6 o 0 R 2

R

3 0H R-lnk(-Lv R-link-P-N R-link-1--OR3 Lv S34.9 Lv (R 4 b) N-R 2 5b 4b' S34.7 CO 2 RSb (R 'O 5b S34.11 C0 2 R 10 S35.3 132 WO 2006/047507 PCT/US2005/038348 Scheme 35 Example I 00

H

2 NCH(Me)CO 2 Et 1 R-link-P -OPh R-link-P-O- R-link--P-OPh OH CI S35.9 NH S35.7 S35.8 Me-KC2Et S35.10 Scheme 35 Example 2 O 0 0 R-link-l--OBn aiR-link-P-1OBn I -ik-(O OH NH NH Me-0E Me

CO

2 Et CO 2 Et S35.11 S35.12 S35.13 0

CF

3

CH

2 OH R-link--1-OCH 2

CF

3 S35.14 NH Me-

CO

2 Et S35.15 Scheme 35 Example 3 O 0 R-ink-l1-OH N OH -link-- N-Me Me-K Me' Me CO 2 Et S35.16 CO 2 Et S35.13 S35.17 133 WO 2006/047507 PCT/US2005/038348 Scheme 35 Example 4 O O BrCH(Bn)CO 2 Bu 0 R-link-P-OPh aR-link- -OPh 0 R-link-P-~ CI

NH

2 S35.20 NH S35.18 S35.19 Bn CO 2 Bu S35.21 Scheme 35 Example 5 HO O MeN CO 2 Et O R-ink-P-CI H R-link-P-CI CI S35.23 N-Me HO/ S35.22 - CO 2 Et S35.24 PhOH S35.25 .0 R-link-P-O \/ N-Me HO ~

-

CO

2 Et S35.26 Scheme 36 illustrates methods for the preparation of carboalkoxy substituted phosphonate diesters in which one of the ester groups incorporates a carboalkoxy substituent. 5 In one procedure, a phosphonate monoester S34.1, prepared as described above, is coupled, using one of the methods described above, with a hydroxyester S36.1, in which the groups R4b and R are as described in Scheme 34. For example, equimolar amounts of the reactants are coupled in the presence of a carbodiimide such as dicyclohexyl carbodiimide, as described in Aust. J 10 Chem., 1963, 609, optionally in the presence of dimethylaminopyridine, as described in Tet., 1999, 55, 12997. The reaction is conducted in an inert solvent at ambient temperature. The procedure is illustrated in Scheme 36, Example 1. In this method, a monophenyl phosphonate S36.9 is coupled, in dichloromethane solution in the 15 presence of dicyclohexyl carbodiimide, with ethyl 3-hydroxy-2 methylpropionate S36.10 to yield the phosphonate mixed diester S36.11. 134 WO 2006/047507 PCT/US2005/038348 Using this procedure, but employing, in place of ethyl 3-hydroxy-2 methylpropionate S36.10, different hydroxyesters S33.1, the corresponding products S33.2 are obtained. The conversion of a phosphonate monoester S34.1 into a mixed diester 5 S36.2 is also accomplished by means of a Mitsunobu coupling reaction with the hydroxyester S36.1, as described in Org. Lett., 2001, 643. In this method, the reactants S34.1 and S36.1 are combined in a polar solvent such as tetrahydrofuran, in the presence of a triarylphosphine and a dialkyl azodicarboxylate, to give the mixed diester S36.2. The RI substituent is varied 10 by cleavage, using the methods described previously, to afford the monoacid product S36.3. The product is then coupled, for example using methods described above, with the hydroxy compound R 3 OH, to give the diester product S36.4. The procedure is illustrated in Scheme 36, Example 2. In this method, a 15 monoallyl phosphonate S36.12 is coupled in tetrahydrofuran solution, in the presence of triphenylphosphine and diethylazodicarboxylate, with ethyl lactate S36.13 to give the mixed diester S36.14. The product is reacted with tris(triphenylphosphine) rhodium chloride (Wilkinson catalyst) in acetonitrile, as described previously, to remove the allyl group and produce the monoacid 20 product S36.15. The latter compound is then coupled, in pyridine solution at ambient temperature, in the presence of dicyclohexyl carbodiimide, with one molar equivalent of 3-hydroxypyridine S36.16 to yield the mixed diester S36.17. Using the above procedures, but employing, in place of the ethyl lactate S36.13 or 3-hydroxypyridine, a different hydroxyester S36.1 and/or a different 25 hydroxy compound R 3 OH, the corresponding products S36.4 are obtained. The mixed diesters S36.2 are also obtained from the monoesters S34.1 via the intermediacy of the activated monoesters S36.5. In this procedure, the monoester S34.1 is converted into the activated compound S36.5 by reaction with, for example, phosphorus pentachloride, as described in J. Org. Chem., 30 2001, 66, 329, or with thionyl chloride or oxalyl chloride (Lv = Cl), or with triisopropylbenzenesulfonyl chloride in pyridine, as described in Nucleosides and Nucleotides, 2000, 19, 1885, or with carbonyl diimidazole, as described in J. Med. Chem., 2002, 45, 1284. The resultant activated monoester is then reacted 135 WO 2006/047507 PCT/US2005/038348 with the hydroxyester S36.1, as described above, to yield the mixed diester S36.2. The procedure is illustrated in Scheme 36, Example 3. In this sequence, a monophenyl phosphonate S36.9 is reacted, in acetonitrile solution at 70 'C, with 5 ten equivalents of thionyl chloride, so as to produce the phosphoryl chloride S36.19. The product is then reacted with ethyl 4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containing triethylamine, to give the mixed diester S36.21. Using the above procedures, but employing, in place of ethyl 4 10 carbamoyl-2-hydroxybutyrate S36.20, different hydroxyesters S36.1, the corresponding products S36.2 are obtained. The mixed phosphonate diesters are also obtained by an alternative route for incorporation of the R 3 0 group into intermediates S36.3 in which the hydroxyester moiety is already incorporated. In this procedure, the monoacid 15 intermediate S36.3 is converted into the activated derivative S36.6 in which Lv is a leaving group such as chloro, imidazole, and the like, as previously described. The activated intermediate is then reacted with the hydroxy compound R 3 OH, in the presence of a base, to yield the mixed diester product S36.4. 20 The method is illustrated in Scheme 36, Example 4. In this sequence, the phosphonate monoacid S36.22 is reacted with trichloromethanesulfonyl chloride in tetrahydrofuran containing collidine, as described in J. Med Chem., 1995, 38, 4648, to produce the trichloromethanesulfonyloxy product S36.23. This compound is reacted with 3-(morpholinomethyl)phenol S36.24 in 25 dichloromethane containing triethylamine, to yield the mixed diester product S36.25. Using the above procedures, but employing, in place of with 3 (morpholinomethyl)phenol S36.24, different alcohols R 3 OH, the corresponding products S36.4 are obtained. 30 The phosphonate esters S36.4 are also obtained by means of alkylation reactions performed on the monoesters S34.1. The reaction between the monoacid S34.1 and the haloester S36.7 is performed in a polar solvent in the presence of a base such as diisopropylethylamine, as described in Anal. Chem., 136 WO 2006/047507 PCT/US2005/038348 1987, 59, 1056, or triethylamine, as described in J. Med. Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in the presence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565. The method is illustrated in Scheme 36, Example 5. In this procedure, the 5 monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionate S36.27 and diisopropylethylamine in dimethylformamide at 80 'C to afford the mixed diester product S36.28. Using the above procedure, but employing, in place of ethyl 2-bromo-3 phenylpropionate S36.27, different haloesters S36.7, the corresponding products 10 S36.4 are obtained. Scheme 36 O HOR 1 (1 equiv.) O R-link--P- OR' N R-link-l--OH (R4b S36.4 HO-R a-COORsu OH

CO

2 R Hal-R 4 b-COOR5b S33.7 0 HO-R -bCOOR 5b 00 R-link- -OR' -ik l R -ik"O S34.1 OH S36.1 \OR bCOOR 0 OR bCOORb S36.2 S36.3 SS6.1 O R-ink- --OR' 0 0 Lv R-ink-p-Lv R-ink--OR \4bCaO 5b \R4bCOO5b S36.1 -R -CORb OR COORE S36.5 S36.6 S36.4 137 WO 2006/047507 PCT/US2005/038348 Scheme 36 Example 1 0 O R-ink-P-OPh 11 HOCH 2 CH(Me)CO 2 Et 0 R-link--P-OPh 0 OH S36.10

CO

2 Et S36.9 Me S36.11 Scheme 36 Example 2 O HOCH(Me)CO 2 Et 0 0 R-link-P -O R-link-P --O R-link-P-OH OH \ S36.13 Me Me Me S36.12

CO

2 Et CO 2 Et S36.14 S36.15 OH N S36.16 0 R-Iink -1-O Me N S36.17

CO

2 Et Scheme 36 Example 3 a a R-link---OPh SOC1 2 1R-ink--OPh OH S36.18 S36.9 S36.19 a EtO 2

CCH(OH)CH

2

CH

2

CONH

2 R-Iink-0pOPh S36.20

CO

2 Et

H

2 N S36.21 138 WO 2006/047507 PCT/US2005/038348 Scheme 36 Example 4 O 0 R-link- -OH - R-ink-p -OSO 2 CCl 3 O 0 Me Me

CO

2 Et CO 2 Et S36.22 S36.23 0 R-link--P-O N S36.24 Me-K O0

CO

2 Et S36.25 Scheme 36 Example 5 O BrCH(Bn)CO 2 Et 0 R-link-P-OH - o R-ink-P-OCH(Bn)CO 2 Et

OCH

2

CF

3 S36.27 OCH 2

CF

3 S36.26 S36.28 Scheme 37 illustrates methods for the preparation of phosphonate diesters in which both the ester substituents incorporate carboalkoxy groups. The compounds are prepared directly or indirectly from the phosphonic 5 acids S34.6. In one alternative, the phosphonic acid is coupled with the hydroxyester S37.2, using the conditions described previously in Schemes 34 36, such as coupling reactions using dicyclohexyl carbodiimide or similar reagents, or under the conditions of the Mitsunobu reaction, to afford the diester product S37.3 in which the ester substituents are identical. 10 This method is illustrated in Scheme 37, Example 1. In this procedure, the phosphonic acid S34.6 is reacted with three molar equivalents of butyl lactate S37.5 in the presence of Aldrithiol-2 and triphenyl phosphine in pyridine at ca. 70 *C, to afford the diester S37.6. 139 WO 2006/047507 PCT/US2005/038348 Using the above procedure, but employing, in place of butyl lactate S37.5, different hydroxyesters S37.2, the corresponding products S37.3 are obtained. Alternatively, the diesters S37.3 are obtained by alkylation of the 5 phosphonic acid S34.6 with a haloester S37.1. The alkylation reaction is performed as described in Scheme 36 for the preparation of the esters S36.4. This method is illustrated in Scheme 37, Example 2. In this procedure, the phosphonic acid S34.6 is reacted with excess ethyl 3-bromo-2 methylpropionate S37.7 and diisopropylethylamine in dimethylformamide at ca. 10 80 'C, as described in Anal. Chem., 1987, 59, 1056, to produce the diester S37.8. Using the above procedure, but employing, in place of ethyl 3-bromo-2 methylpropionate S37.7, different haloesters S37.1, the corresponding products S37.3 are obtained. The diesters S37.3 are also obtained by displacement reactions of 15 activated derivatives S34.7 of the phosphonic acid with the hydroxyesters S37.2. The displacement reaction is performed in a polar solvent in the presence of a suitable base, as described in Scheme 36. The displacement reaction is performed in the presence of an excess of the hydroxyester, to afford the diester product S37.3 in which the ester substituents are identical, or sequentially with 20 limited amounts of different hydroxyesters, to prepare diesters S37.3 in which the ester substituents are different. The methods are illustrated in Scheme 37, Examples 3 and 4. As shown in Example 3, the phosphoryl dichloride S35.22 is reacted with three molar equivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate S37.9 in 25 tetrahydrofuran containing potassium carbonate, to obtain the diester product S37.10. Using the above procedure, but employing, in place of ethyl 3-hydroxy 2-(hydroxymethyl)propionate S37.9, different hydroxyesters S37.2, the corresponding products S37.3 are obtained. 30 Scheme 37, Example 4 depicts the displacement reaction between equimolar amounts of the phosphoryl dichloride S35.22 and ethyl 2-methyl-3 hydroxypropionate S37.11, to yield the monoester product S37.12. The reaction is conducted in acetonitrile at 70* in the presence of diisopropylethylamine. The 140 WO 2006/047507 PCT/US2005/038348 product S37.12 is then reacted, under the same conditions, with one molar equivalent of ethyl lactate S37.13, to give the diester product S37.14. Using the above procedures, but employing, in place of ethyl 2-methyl-3 hydroxypropionate S37.11 and ethyl lactate S37.13, sequential reactions with 5 different hydroxyesters S37.2, the corresponding products S37.3 are obtained. Scheme 37 O 0 R-link--P-OH - R-link-p-Lv \O(R4b)CO 2 R5b O(R )CO 2 R5 S37.5 37.4 .S37.1 S37.2 S37.2 O HO(RbCO2R O S37. 11 4b 5b R-link-P--OH S3.2 R-link-p-O(R )CO 2 R S34.6 OH HaI(R 4 b)CO 2

R

5 b

O(R

4 b)CO 2

R

5 b S37.3 S37.1 S37.2 S37.2 O 0 R-link- -- va R-link-{--Lv Lv S37.2 O(R 4 b )CO2R 5 b S34.7 S37.4 Scheme 37 Example 1 0 HOCH(CH 3

)CO

2 Bu 0 R-link-P--OH - R-ink-P--OCH(CH 3

)CO

2 Bu OH S37.5

OCH(CH

3

)CO

2 Bu S34.6 S37.6 Scheme-37 Example 2 0 BrCH 2

CH(CH

3

)CO

2 Et 0 R-ink-P--OH - R-link-P--OCH 2

CH(CH

3

)CO

2 Et OH S37.7

OCH

2

CH(CH

3

)CO

2 Et S34.6 S37.8 141 WO 2006/047507 PCT/US2005/038348 Scheme 37 Example 3 o (HOCH 2

)

2

CHCO

2 Et R-link-P-- R-ink-P-OCH 2

CH(CH

2

OH)CO

2 Et CI S37.9 S35.22

OCH

2

CH(CH

2

OH)CO

2 Et S37.10 Scheme 37 Example 4 o HOCH 2

CH(CH

3

)CO

2 Et 0 R-link-P-Cl

-OCH

2

CH(CH

3

)CO

2 Et C S37.11 CI S35.22 S37.12

HOCH(CH

3

)CO

2 Et S37.13 R-Iink-POCH 2

CH(CH

3

)CO

2 Et

OCH(CH

3

)CO

2 Et 37.14 2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be prepared by the route in Scheme 38. Condensation of 2-methyl-2 propanesulfinamide with acetone give sulfinyl imine S38.11 (J. Org. Chem. 5 1999, 64, 12). Addition of dimethyl methylphosphonate lithium to S38.11 afford S38.12. Acidic methanolysis of S38.12 provide amine S38.13. Protection of amine with Cbz group and removal of methyl groups yield phosphonic acid S38.14, which can be converted to desired S38.15 (Scheme 38a) using methods reported earlier on. An alternative synthesis of compound S38.14 is also shown 10 in Scheme 38b. Commercially available 2-amino-2-methyl-1-propanol is converted to aziridines S38.16 according to literature methods (J. Org. Chem. 1992, 57, 5813; Syn. Lett. 1997, 8, 893). Aziridine opening with phosphite give S38.17 (Tetrahedron Lett. 1980, 21, 1623). Reprotection of S38.17 affords S38.14. 142 WO 2006/047507 PCT/US2005/038348 Scheme 38a 0 0 4 acetone CH 3

P(O)(OCH

3

)

2

S-NH

2 - i S-N=K S38.11 BuLi 0 O O OCH 3 HCI OCH 3 S-N OCH 3

CH

3 0H H 2 N OCH 3 H S38.12 S38.13 0 O 1OH 1OPh

CO

2 Et CbzHN OH H 2 N O S38.14 S38.15 Scheme 38b 0 OH NR HP(O)(OCH 3

)

2

,OCH

3 H2N NR NaH RHN NOCH3

S

38 .16R = Cbz, R'SO 2 S38.17 AOH CbzHN OH 5 S38.14 The invention will now be illustrated by the following non-limiting Examples. General applicability of methods for introduction of phosphonate 10 substituents. The procedures described herein for the introduction of phosphonate moieties are, with appropriate modifications, known to one skilled in the art, and are transferable to different chemical substrates. Thus, the methods described herein for the introduction of phosphonate groups onto compounds of the 15 invention are also applicable to the introduction of phosphonate moieties onto anilines of the invention and the reverse is also true. Protection of reactive substituents. Depending on the reaction conditions employed, it may be necessary to protect certain reactive substituents from unwanted reactions by protection 20 before the sequence described, and to deprotect the substituents afterwards, according to the knowledge of one skilled in the art. Protection and deprotection of functional groups are described, for example, in "Protective Groups in 143 WO 2006/047507 PCT/US2005/038348 Organic Synthesis," by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1996. Reactive substituents that may be protected are shown in the accompanying schemes as, for example, [OH], [SH], etc. Example 1 5 Pyridopyrimidines are a class of compounds that have activity against a variety of kinases. Examples of compounds of this class are PD 173955, PD 166326, and PD 173074. Compounds E1.1 - E1.4 are representative compounds of the invention, wherein R and R' are each individually hydrogen or alkyl. HN N I R'OP-Link-N Ar Link , RO'd H I OR E1.1 O0 E1.2 Me Me N OMe N OMe HN N N NH H N NN HN N NHH ink ink -1N rNO OR' OR' 10 E1.3 E1.4 Example 2 Synthesis of Representative Compounds of Formula E1.1 In general, compounds of the formula E1.1 can be synthesized as follows. 15 144 WO 2006/047507 PCT/US2005/038348 OR Et K2C3 H C02E H2NLink.. R 0E NB ~r~ COEt r(yEO2 N TEA, THF DFN 1NH NH E2.1b E2.2b Link E2.3b Link R R 6R 0 r H ArCH 2 CN, K 2 C0 3 Ar MnO 2 , CHC1 3 NSNDMF, 105 OC N)KN I NH E2.4b Link E.b Ln RO'8R, Rr _O - 3-phenyl-2-(phenylsulfonyl) 1. Ac 2 O, reflux oxaziridine, CHC1 3 2. 6N HCI, reflux Link O Link NRORO E2.7b R O R6R' OR m-CPBA, CHCl 3 0 Link xs neat R*NH 2 , heat Ar E2.8b RO' E2.7b or _ HN6RO E2.8b HN N NO R* = aromatic amines Link *R6 RO6R E1.1, R* = 3-SMe as in PD-173955 R* = 3-Me-4-F as in PD-180970 Preparation of phosphonate E1.1 is illustrated above (see also Klutchko, S. R. et al., J. Med. Chem., 1998, 41, 3276). Condensation of commercially 5 available 5-pyrimidinecarboxylic acid ester E2.1b with commercially available amino phosphonates such as aminoethyl phosphonate, proceeds in THF to yield compound E2.2b. Reduction of the ester group using NaBH 4 in ethanol provides benzyl alcohol E2.3b (Pfeiffer, F. R. et al., J. Med Chem., 1974, 17, 112). Oxidation of the alcohol to aldehyde E2.4b is achieved using MnO 2 which 10 is then condensed with a substituted phenylacetonitrile in DMF at high temperature to provide 7-iminopyridopyrimidine E2.5b. Acetylation of the 145 WO 2006/047507 PCT/US2005/038348 imine followed by hydrolysis under boiling 6 N HCl provides the key intermediate E2.6b. Addition of inactivated amines can be achieved directly onto the thioether E2.6b, but inactivated aromatic amines are best condensed with the more reactive sulfoxide E2.7b or sulfone E2.8b. Depending on the 5 aromatic amine added to such intermediates, phosphonate analogs of PD 173955 and PD 180970 can be prepared. Example 3 Synthesis of Representative Compounds of Formula E1.2 In general, compounds of formula E1.2 can be synthesized as follows. C1A Rq C1 S R'O-P-Link-NH 2 NS)8 NN OME hat RO 6 H 1 10 E3.6a E1.2 The compound provided below is an example of general structure E1.2 in which the link contains an alkyl group. cS EtO NH2 C I EtO- 2 N6 EtO N NS)S...NN ~DMF, heat EO~~~ 15 As illustrated above, condensation of alkylamines proceed with sulfide E3.6a (reported in Klutchko, S. R. et al., J. Med Chem., 1998, 41, 3276) under forcing conditions proceeds to provide the target compound. Example 4 Synthesis of Representative Compounds of Formula E1.3 20 The synthesis of a example of a compound of type E1.3 is illustrated below. 146 WO 2006/047507 PCT/US2005/038348 OMe OMe - __N_ _ _ _NH2 N OMe N OMe ~~ N' H 2

NSO

3 H, 140-180 0 C - N

H

2 N N N NH 2 HN N N NH 2 OMe rNI NaH, DMF, then N OMe O=C=N O HNN N NH 0 OEt O N \OEt OEt N H OEt The starting material (synthesis described in: J. Med Chem., 1997, 40, 2296-2303), sulfamic acid (2 equivalents) and 4-(diethylamino)butylamine (-15 equivalents) are heated at 150 *C according to the procedure described in J. 5 Med. Chem., 1997, 40, 2296-2303. At the end of the reaction excess amine is removed in vacuo. The residue is suspended in a mixture of water and saturated aqueous sodium bicarbonate solution. This mixture is extracted with dichloromethane. The combined organic extracts are washed with saturated aqueous sodium bicarbonate solution, brine, and dried over sodium sulfate. 10 Filtration and evaporation of the solvent yields a crude product. Further purification was achieved by flash chromatography on silica gel. The required isocyanate for step 2 is prepared from 2-amino ethyl phosphonic acid diethyl ester and phosgene according to a procedure from Organikum, 17 th edition, VEB Deutscher Verlag der Wissenschaften, Berlin 15 1988, page 428. A solution of 2-amino ethyl phosphonic acid diethyl ester in an organic solvent such as dichloromethane or toluene is added to a cooled solution of phosgene in an organic solvent such as toluene or dichloromethane. After the addition of the amine, the cooling is removed and the solution was heated at 100 C with further phosgene addition. Upon cessation of hydrochloric acid 20 evolution, excess phosgene is removed and the solvents were removed in vacuo. The product of step 1 is treated with sodium hydride (-1.1 equivalents) in an organic solvent such as dimethylformamide, according to the procedure described in J. Med. Chem., 1997, 40, 2296-2303. The phosphonate-containing 147 WO 2006/047507 PCT/US2005/038348 isocyanate is added and the reaction mixture is stirred at room temperature. At the end of the reaction, the mixture is filtered and the solvent is removed in vacuo. The crude material is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the combined organic layers 5 washed with brine and dried over sodium sulfate. Filtration and evaporation of solvents yields the crude product. Further purification is achieved by flash chromatography on silica gel. The synthesis of an example of a compound of type E1.4 is illustrated below. OMe O OMe

H

2 N O 'OEt N N' OMe N/ OMe H2N N N NH2H 2

NSO

3 H, 140-180 0 C HNN N

H

2 N - N N NH 2 HNN NH 2 O-P-OEt OEt OMe NaH, DMF, then O=C=NK N OMe HN N N NH p.-OEt H 10 OEt The synthesis is performed using methods analogous to those described hereinabove. Example 5 15 Preparation of Representative Compounds of the Invention Generally, compounds of the invention can be made as illustrated below:. 148 WO 2006/047507 PCT/US2005/038348 Cbz 1. BBr 3 N 2. Ac 2

O/C

5

H

5 N N 3. SOCl2 N 0 N 4. 1-Cbz-piperazine 5. NH 4 0H, MeOH HO Intermediate E5.A H 1. Mg(OtBu) 2 , O N TfOCH 2 P(O)(OEt) 2 N OiPr 2. H 2 , Pd/C N 3. (4-OiPr)PhNH 2 , Eta % (4-N0 2 )PhOCOCI P 0 N 0 6,7-Dimethoxy-3,4-dihydroquinazolin-4-one is reacted with boron tribromide to provide a mixture of mono-demethylated products. Separation of the products may be achieved by chromatography, or achieved on the mixture of 5 acetates that arises from reaction with and acetylating reagent such as acetyl chloride in the presence of a base such as pyridine. The desired isomer is reacted with thionyl chloride (see Bioorg. Med. Chem. Lett., 2001, 11, 1911) and the resulting 4-chloroquinazoline is treated with piperazine- 1 -carboxylic acid benzyl ester. The acetyl protecting group is removed under standard conditions 10 such as by treatment with ammonia in methanol (see Greene, T., Protective Groups in Organic Synthesis, Wiley-Interscience (1999)) to generate Intermediate E5.A. Upon treatment with a base such as magnesium tert-butoxide and diethyl phosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27, 15 1477), the phosphonate-bearing moiety is introduced at the quinazoline 7 position. Thereafter, removal of the benzyl carbamate protecting group by hydrogenation over a catalyst such as palladium on charcoal in a solvent such as methanol (see Greene, ibid) and condensation with 4-isopropoxyaniline (commercially available) and 4-nitrophenyl chloroformate provides the desired 20 compound. A particular compound of the invention can be prepared as follows. 149 WO 2006/047507 PCT/US2005/038348 Cbz N 1 N N 1. DIAD, PPh3,BOCN N H N 2. TFA 3. CHOCH 2 P()(OEtH 2 , NaBH 3 CN HO N 4. As in Scheme above Intermediate E5.A N N 'OEt O' POEt Intermediate E5.A may be alkylated on the phenol by reaction with 4-(2 hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester in the presence of an azodicarboxylate diester such as diisopropyl azodicarboxylate and 5 triphenylphosphine, as described by Mitsunobu (Bull. Chem. Soc. Japan., 1971, 44, 3427). Following deprotection with trifluoroacetic acid, the liberated secondary amine is condensed with (2-oxo-ethyl)-phosphonic acid diethyl ester under reductive conditions such as those achieved through the use of sodium cyanoborohydride in a solvent such as methanol or dimethylformamide (see 10 Tetrahedron Lett. 1990, 31, 5595). The remaining steps are similar to those illustrated above. Example 6 Synthesis of Representative Compounds of The Invention Generally, compounds of the invention can be made as illustrated below: Cbz O 1. methionine/MeSO 3 H N 2. Ac 2

O/C

5

H

5 N 3. SOC1 2 H 4. 1-Cbz-piperazine N 5. NH 4 0H, MeOH 1. K 2

CO

3 , QEt H BrCH 2

CH:CHCH

2 Br O t 0 N 2. P(OEt) 3 r tI::J 3. H 2 , Pd/C 4. (4-O'Pr)PhNH 2 , 15 (4-NO 2 )PhOCOCI Following the selective demethylation, the synthesis steps are similar to those described in Example 2 up to the point where a phenol is alkylated. Here, 150 WO 2006/047507 PCT/US2005/038348 the alkylation is performed with E-1,4-dibromobutene, and the monobromide product is reacted with triethylphosphite in a solvent such as toluene toluene (or other Arbuzov reaction conditions; see Engel, R., Synthesis of Carbon phosphorus Bonds, CRC Press, (1988)) to generate the diethyl ester of the 5 desired phosphonic acid. Thereafter, the steps are again similar to those described in Example 5. Example 7 Synthesis of Representative Compounds of the Invention Generally, compounds of the invention can be made as illustrated below: 10 OH 1. TfOC H2P(O)(OEt)2, r-O,_P(O)(OEt)2 NaH, THF I 02 Nc. H2NH.fH((t 2. H 2 , Pd/C, EtOH C1 -0 ' ON' 0_P(O)(OEt)2 HN N 4-Nitrophenol is treated in a solvent such as tetrahydrofuran or dimethylformamide with a base such as sodium hydride. When bubbling ceases, 15 diethyl phosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) is added, yielding the desired phosphonate diester. Following hydrogenation to generate the aniline, condensation with the known 4-chloro 6,7-dimethoxy-quinazoline yields the desired product. Example 8 20 Synthesis of Representative Compounds of the Invention Generally, compounds of the invention can be made as illustrated below: H HO 0 R, .-N 0 H F 0 H F N 1. Activation of the acid N 2. Formation of hydroxamate ester I F I F F F 151 WO 2006/047507 PCT/US2005/038348 Representative compounds of the invention, e.g., as shown above, can be synthesized according to the following methods. The activation of 3,4-difluoro 2-(2-fluoro-4-iodophenylamino)benzoic acid (obtained according to the procedure described in patent application US 2004/0054172) can be achieved by 5 a variety of conventional methods which include initial treatment of the acid with diphenylphosphoryl chloride in the presence of a base such as N methylmorpholine in a solvent such as tetrahydrofuran. The subsequent formation of the hydroxamic esters can be achieved by treating this activated acid in situ with the corresponding phosphonate-containing N-alkoxyamines 10 under reaction conditions similar to those described in US 2004/0054172. For example, the preparation of a specific compound of the invention is illustrated below. 0 Ph II HO O TBDMSCI HO O Mg(OtBu) 2 EtO 0 O-\ HOPh Im / DMF TBDMSO TfOCH 2 P(O)(OEt) 2 TBDMSO 0 N 0 0

H

2 , Pd/C O HO EtO' OH 0 P, t 0 'N OEt ____ EtO' 0 3PMS OBDMt TBMOPh 3 P, DEAD TBDMSO 0 0 H 11 ____ EtO' O O'N O H F

NH

2

NHCH

3 PEtO - 0 1. RCOOH, OEt H EtO'1O 1 HO N O HO NH 2 Ph 2 P(O)CI, NMM/THF F 2.TFA F 15 (R)-(+)-3-Benzyloxy-1,2-propanediol can be selectively protected with the t-butyldimethylsilyl group, as described in J. Org. Chem., 2003, 68, 6760. The resulting secondary alcohol can be reacted with diethyl phosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) in the presence of a base such as magnesium t-butoxide, to yield the 20 phosphonate-containing ether. Subsequent debenzylation under hydrogen followed by coupling with N-hydroxyphthalimide under Mitsunobu reaction conditions affords the N-alkoxyphthalimide, which can then be converted to the N-alkoxyamine by treatment with a hydrazine such as methylhydrazine at room 152 WO 2006/047507 PCT/US2005/038348 temperature as described in patent application US 2004/0054172, in J. Org. Chem., 2000, 65, 676, or in J. Med Chem., 2000, 43, 971. The N-alkoxyamine can be coupled with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoic acid to afford, after removal of t-butyldimethylsilyl group, the desired hydroxamate. 5 Another specific compound of the invention can be synthesized as follows: 1. TBDMSCI TBDMSO Ph HO Im / DMFO Mg(OtBu) 2 TBDMSO HO____ ______ OE HO 2. TFA HO TfOCH 2 P(O)(OEt) 2 O 0

H

2 , Pd/C TBDMSO O\ HO'N TBDMSO N EtO , O P h OE t P 0 EtO IEt O Ph 3 P, DEAD P 0 1. RCOOH, H

NH

2

NHCH

3 tBONH 2 Ph 2 P(O)CI, Et O' F NHNC3 OEt O' NMM /THF EtiO H O I I 0i F F (R)-(+)-3-Benzyloxy-1,2-propanediol is bis-silylated by treatment with excess t 10 butyldimethylsilyl chloride, and the primary hydroxyl group is then selectively de-silylated, as described in Eur. J. Org. Chem., 2001, 20, 3797. The resulting intermediate is reacted with diethyl phosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) in the presence of a base such as magnesium t-butoxide, yielding the phosphonate-containing ether. The rest of 15 the molecule is elaborated in a manner similar to that described above. Another specific compound of the invention can be synthesized as follows: 153 WO 2006/047507 PCT/US2005/038348 o 0' EtO O\T/

CS

2

CO

3 EtO N Of HO' DMF P 1 0 0 OEt H

N

2 N H EOQEt RCOOH, Ph 2 P(O)CI, EtO'P O, N 0 F NH2NHC_ 3 EtO O'NH2 NMM / THF H F F N-Hydroxyphthalimide is reacted with diethyl phosphonomethyltriflate in the presence of a base such as cesium carbonate to yield the phosphonate-containing N-alkoxyphthalimide, which is then converted to the N-alkoxyamine by 5 methylhydrazine. The N-alkoxyamine is coupled with 3,4-difluoro-2-(2-fluoro 4-iodophenylamino)benzoic acid to afford the desired hydroxamate. Example 9 Synthesis of Representative Compounds of the Invention Generally, compounds of the invention can be made as illustrated below: N N N1N

NH

2 HN CI HN N NH S "N WO 0062778 S N piperazine S N OEt 4 4 Me NH Me NH 0 N1LN P-OR O OR' HNl'IN n 0 OOR or ST''ROR 10 Me cl E 9.1 Representative compounds of the invention, e.g., as shown above, can be synthesized according to the following methods. 2-(6-Chloro-2 methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid (2-chloro-6 methylphenyl)amide, obtained from 2-aminothiazole-5-carboxylic acid ethyl 15 ester according to a procedure described in WO 0062778, can be treated with piperazine to afford 2-(2-methyl-6-piperazin-1-ylpyrimidin-4-ylamino)thiazole 154 WO 2006/047507 PCT/US2005/038348 5-carboxylic acid (2-chloro-6-methylphenyl)amide. This piperazine derivative is N-substituted by either reductive amination with an aldehyde or N-alkylation with an alkyl bromide to afford the desired phosphonate-containing product E9.1. 5 For example, the preparation of a specific compound of the invention is illustrated below. N IN N IN - o 0 HN l ii HNN-- I I NH -H-Ot PC-OEt NBr OEt SH N OEt S" N Me NH Me NH / c/ ci The piperazine intermediate can be added to a mixture of diethyl (2-bromoethyl) 10 phosphonate and sodium carbonate in absolute ethanol and the mixture can be heated at reflux for about 16 hours. The resulting reaction mixture can be purified by silica gel chromatography to afford the diethyl 2-(piperazinyl)ethyl phosphonate (J. Med. Chem. 1998, 41, 236-246). Another specific compound of the invention can be synthesized as 15 follows: N N N N 0 -Link,"Lo HN Cl HN NLik -OR H OR' S "N 1. substitution with aminoalcohol S "N O 2. bromination of the alcohol O= Me NH Me NH Ci 3. Arbuzov reaction /'Ci E9.2 The chloropyrimidine can be transformed to an (a>-hydroxyalkyl) aminopyrimidine (according to a procedure similar to that described in WO 20 0062778), which can then be converted to the corresponding (a> phosphonoalkyl) aminopyrimidine E9.2 via bromination followed by an Arbuzov reaction. 155 WO 2006/047507 PCT/US2005/038348 For example, the preparation of a specific compound of the invention is illustrated below. N N- N' N 0 HN Cl 1. H 2 N __OH HN N 60Et H OEt S "N 2. CBr 4 , PPh 3 S "N O O Me NH 3. P(OEt) 3 Me NH / C Z CI A mixture of the chloropyrimidine and ethanolamine can be heated at about 80 5 "C for 2 hours to afford the (2-hydroxyethyl)aminopyrimidine. The hydroxyl group can then be converted to the bromide under conventional bromination conditions such as carbon tetrabromide and triphenylphosphine (Org. Lett. 2003, 5, 3519). The bromide can be heated with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis Of 10 Carbon-Phosphorus Bonds, CRC press, 1988) to generate the diethyl ester of the desired phosphonic acid. Another specific compound of the invention can be synthesized as follows: Br N zN

NH

2 HN S "N O WO 0062778 S N Me NH OEt \cI Me NH C1 C1 0 Link-P,-OR olefin cross-metathesis N N or HN oxidative cleavage of S11N the olefin followed by reductive amination Me NH E9.3 (9-Cl 15 2-(2-Allyl-6-dimethylamino-pyrimidin-4-ylamino)thiazole-5-carboxylic acid (2 chloro-6-methyl-phenyl)amide can be obtained from 2-aminothiazole-5 156 WO 2006/047507 PCT/US2005/038348 carboxylic acid ethyl ester according to a procedure similar to that described in WO 0062778. The allyl group can then be utilized to attach a phosphonate moiety to the molecule by conventional chemical methods such as olefin cross metathesis and oxidative cleavage followed by reductive amination to afford a 5 compound such as phosphonate E9.3. For example, the preparation of a specific compound of the invention is illustrated below. 0 N POEt OEt N 'N N 'N S"N Et S N O4 [Ru] Me NH (Grubbs catalyst) Me NH CI CI A solution of the allypyrimidine, diethyl vinylphosphonate and 5 mole % of 10 [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro (phenylmethylene)-(trichlorohexylphosphine)ruthenium] in dichloromethane can be refluxed for 12 hours and the resulting reaction mixture can be purified to afford the desired phosphonate-containing compound (J. Am. Chem. Soc. 2003, 125, 11360). 15 Another specific compound of the invention can be synthesized as follows: 157 WO 2006/047507 PCT/US2005/038348 Br N N

NH

2 1HN N;N...fOH S- N A S AN O WO 0062778 S 'N Me NH OEt /\CI Me NH ccl 0 Link-F,-OR N OR' olefin cross-metathesis HN , NfN./'OH or jjN oxidative cleavage of S _N the olefin followed by reductive amination M NH E9.4 2- {2-Allyl-6-[4-(2-hydroxyethyl)-piperazin-1 -yl]-pyrimidin-4-ylamino} thiazole-5-carboxylic acid (2-chloro-6-methyl-phenyl)-amide can be obtained from 2-aminothiazole-5-carboxylic acid ethyl ester according to a procedure 5 similar to that described in WO 0062778. The allyl group can then be utilized to. attach a phosphonate moiety to the molecule by conventional chemical methods such as olefin cross-metathesis and oxidative cleavage followed by reductive amination to afford a compound such as phosphonate E9.4. For example, the preparation of a specific compound of the invention is 10 illustrated below. 0 II POEt OEt N "N N "N HN QN 11HN Q N 'OH P\OEt'O S N OH OEt S"N OH O= [Ru] O= Me NH (Grubbs catalyst) Me NH CI Cl A solution of the allypyrimidine, diethyl vinylphosphonate and 5 mole % of [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene) dichloro(phenylmethylene)-(trichlorohexylphos'phine)ruthenium] in 15 dichloromethane can be refluxed for 12 hours and the resulting reaction mixture 158 WO 2006/047507 PCT/US2005/038348 can be purified to afford the desired phosphonate-containing compound (J. Am. Chem. Soc. 2003, 125, 11360). Example 10 Synthesis of Representative Compounds of the Invention 5 Generally, compounds of the invention can be made as illustrated below: H OEt O OPh O N NS NH H 2 N OEt NS P-OEt O NH 2 FO NH 2 0o 0 -F -F Br Br Representative compounds of the invention, e.g., as shown above, can be synthesized according to the following methods. [3-(4-Bromo-2,6-difluoro 10 benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester (prepared according to WO 09962890) can be heated with (2-amino-ethyl)-phosphonic acid diethyl ester in an inert solvent such as THF to generate the desired product. Example 11 Synthesis of Representative Compounds of the Invention 15 3-Substituted indolinones are a class of compounds that have activity against a variety of kinases. Examples of compounds of this class include, but is not limited to, Semaxanib, SU-1 1248, and GW 9499. Compounds E11.1-E11.3 are representative compounds of the invention wherein R and R' are each individually hydrogen or alkyl. 0 O Link-A.-OR 0 0 O= -NH OR' I~'-ORLink' -OR O Link' OR Link' OR' N / X / H N /Ts N-NH X N X H N N 0HN 0N H E1g.1 H El1.2 H E11.3 X = H, F, CI, Br, 1; 20 Link is 1-9 chain atoms 159 WO 2006/047507 PCT/US2005/038348 Example 12 Synthesis of Representative Compounds of the Invention In general, compounds such as E11.1 can be made according to the general route outlined below. O 0 OH0 0 ,ikA-OR O/OOH -O / |O H2N-Link--OR Link OR' F N OR' H H F N | N amide formation H H N 5 H A particular compound of the invention can be prepared as follows: 0 OH J. Med. Chem. 2003, F N 0 46, 1116 OH O H 0 HOBt, EDC H2N -OEt DMF, rt H 2 N QEt O 0 N OEt H F N H 5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H pyrrole-3-carboxylic acid is prepared from t-butyl acetoacetate as described in J. 10 Med Chem. 2003, 46, 1116. The acid is then condensed with a phosphonate containing amine by using amide-forming reagents such as 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt), affording the desired product. Example 13 15 Synthesis of Representative Compounds of the Invention In general, compounds of formula E11.2 can be synthesized as follows. 160 WO 2006/047507 PCT/US2005/038348 C0 2 H 1. HN(Me)(OMe), CHO CDI 2. DIBAL I \H 2

NCH

2

CH

2 P(O)(OEt) 2 , N 2.DBLN NaBH(OAc) 3 H H N OEt NOH H Example 14 Synthesis of Representative Compounds of the Invention The synthesis of an example of a compound of type E11.3 is illustrated 5 below. 0 0 0 0 -CI 1. H 2

NCH

2

CH

2 P(O)(OEt) 2 , Et 3 N O=S-N -Et 2. NaN0 2 , H* / t

O

2 N 3. SnC 2 , EtOH H 2 N-NH .HCI g2-S N-NH N O H Following condensation of 4-nitrophenylsulfonyl chloride with (2-amino-ethyl) phosphonic acid diethyl ester, the nitro group is converted to the aryl hydrazine by diazotization and reduction with sodium sulfite (Chem. Ber., 1960, 93, 540) 10 or tin(II) chloride (J. Med Chem., 2001, 44, 4031). This reagent is then condensed with 6H-thiazolo[5,4-e]indole-7,8-dione as described in W009915500 to generate the desired product. Example 15 Synthesis of Representative Compounds of the Invention 161 WO 2006/047507 PCT/US2005/038348 0 OEt ClC O-P(O)(OEt)2 O0 11-OEt N O1 0 2 N N NH 2 1.S H2N OEt ' 2. SnC 2 0 0 O F-OEt H H OEt HO N N N -N 0 ~.O F-OEt H H OEt Na N N N N S0 The route is similar to that described in WO 03040131. The (4 Chlorocarbonyl-phenoxymethyl)-phosphonic acid diethyl ester is synthesized by the reaction of methyl (4-hydroxy)benzoate with diethyl 5 phosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) using a base such as sodium hydride in a solvent such as dimethylformamide, followed by ester saponification with lithium hydroxide and acid chloride formation by treatment of the carboxylic acid with oxalyl chloride in dichloromethane in the presence of a catalytic amount of dimethylformamide. 10 Example 16 Synthesis of Representative Compounds of the Invention H BOCN N-N H HO N N H2N BOCNH BOCN N 1. SnCl4i Pol 3 BOCH Y BOICNH1 EtO 0 2. EtO OEt EtO O EtO 0 EtO OEt EtO OEt ci NN~1. N.. INC. N C l N j1 N SnBu 3 1. 3N HC N NN EtO OEt Pd(PPh 3

)

4 EtO OEt 2. CH 2 (P(O)(OEt) 2

)

2 N 0 \-t OEt The route is similar to that described in WO 03040131. The (4 Chlorocarbonyl-phenoxymethyl)-phosphonic acid diethyl ester is synthesized by 15 the reaction of methyl (4-hydroxy)benzoate with diethyl phosphonomethyltriflate .(prepared according to Tetrahedron Lett., 1986, 27, 162 WO 2006/047507 PCT/US2005/038348 1477) using a base such as sodium hydride in a solvent such as dimethylformamide, followed by ester saponification with lithium hydroxide and acid chloride formation by treatment of the carboxylic acid with oxalyl chloride in dichloromethane in the presence of a catalytic amount of dimethylformamide. 5 Example 17 Synthesis of Representative Compounds of the Invention H 0 H N N C1 HO N N C1 I H 2 N'j PNE I I EtO)D 0 dioxane, heat u N Cl N NN Ofl Et H EtO The (3-Chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine is heated with (2-amino-ethyl)-phosphonic acid diethyl ester in dioxane as 10 described in WOO 1093682 to generate the desired product. Example 18 Synthesis of Representative Compounds of the Invention 0 H0 11 N Br O H OEt NY 1 O~ NyN D~EO NEtO Y I PdCL 2 (PPh 3

)

2 , Cul, Pr 2 NH H N N OH H The 3-{4-[2-(3-Bromo-phenylamino)-pyrimidin-4-yl]-pyridin-2 15 ylamino}-propan-1-ol is synthesized by methods analogous to those described in WOO1093682. Palladium-catalyzed coupling with but-3-ynyl-phosphonic acid diethyl ester (prepared by heating 1-bromobut-3-yne with triethylphosphite in a solvent such as toluene or other Arbuzov reaction conditions: see Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988) under conditions 20 described by Sonogashira (Tetrahedron Lett., 1975, 4467) provides the desired product. All literature and patent citations herein are hereby expressly incorporated by reference at the locations of their citation. Specifically cited sections or pages of the above cited works are incorporated by reference with 25 specificity. The invention has been described in detail sufficient to allow one 163 WO 2006/047507 PCT/US2005/038348 of ordinary skill in the art to make and use the subject matter of the following embodiments. It is apparent that certain modifications of the methods and compositions of the following embodiments can be made within the scope and spirit of the invention. 5 In the embodiments hereinbelow, the subscript and superscripts of a given variable are distinct. For example, R, is distinct from R'. 164

Claims (50)

1. A compound comprising at least one phosphonate group, and a substructure of any one of formulae 100-106: R 3 . ,R 3 2 RN -R O-N O N N R" H R3o 4 100 101 102 HN' NS N N NH 103 104 105 0 R 5 6 N H 106 wherein: the bond represented by --- is a single or double bond; R29 is hydrogen, alkyl, or -C(=O)R36. R 30 is hydrogen or substituted alkyl; and R 3 and R 32 are independently hydrogen, alkyl, or substituted aryl; or R 3 1 and R 32 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring; R 33 is -0-, -NR 35 - or absent; R 3 4 is -0- or absent; R 35 is hydrogen or alkyl; R36 is hydrogen, alkyl, alkenyl, or alkynyl; R6 is -N-, or -CR 6; and R68 is hydrogen or alkyl; 165 WO 2006/047507 PCT/US2005/038348 or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 that comprises a substructure of any one of formulae II-XVII: C1 C1 S N N N H I H 0 11 H H II III OMe Br HN NOMe q N O-1& FF IHN CI N N N NH HI 'H 0 N rNj ON v H F~c N HN C HNC 0 N No -O N N O N VI VII 166 WO 2006/047507 PCT/US2005/038348 -0-N 0 -0-N 0 43 HN' Aa-R 46 H NN (R 39 )na (R 40 )ma R R42 R44 VIII Ix X R 50 R 50 /R ~.S NH R 50 S N N\ IS NH O NNH 2 R 1, R 55 0 R4 9 R49 XI XII XIII R 59 R 60 (R 61 )nb /\ R58 0 H R56 N N HH H XIV XV O=S-NH 0 H/ \ N FF N-NH N H N O H H XVI XVII wherein: each R 3 9 and R 40 is independently hydrogen, fluorine, chlorine, bromine or iodine; na and ma are each independently 1, 2, 3, or 4; R 41 , R 42 , R 4 3 and R 44 are independently hydrogen, fluorine, chlorine, bromine or iodine; R 45 is hydrogen, -NH-(C 6 -C20)aryl or -- NH-substituted(C 6 -C 20 )aryl; 167 WO 2006/047507 PCT/US2005/038348 Aa is carbocycle or a heterocycle; R4 6 is a substituted heterocycle; R 4 9 is hydrogen, -(C 6 -C 2 o)aryl or -(C 6 -C 20 )substituted aryl; Rso is hydrogen, substituted alkyl, or -C(=O)NR 5 R; 52 ; R5 and R are independently hydrogen, alkyl, or substituted alkyl; R 55 is a bond or alkylene; R1 is -N-, or -CR 5-; R 57 is hydrogen or alkyl; R is hydrogen, halo, alkyl, a fused carbocyclic ring or a fused heterocyclic ring; 51 =N 64. R 9 is =CR 6 4 - or=N-NR64_ R6o is phenyl or pyrrolyl; each Ri is independently alkyl, or a polar group; each R 64 is independently hydrogen or alkyl; R67 is substituted aryl; and nb is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 that comprises a substructure of formula 1-24: 21 o A* ON N R31 R32 R31 R32 R31 A* R29N R3 N N' N A30 R 4 Rao R 1 3 4 5 6 7 168 WO 2006/047507 PCT/US2005/038348 H H H A 0 N 0 HO -N 0 A- N0 SH F H F 0' H F HO I N ,(t: A. ~ N Nj F I F IF F F F 8 9 10 N"N N" N HNN N A* HN W A* S N N S'IN H Me NH Me NH cI1 cl 12 A* A* S'I'NSH N N OH o=j Me NH Me NH cl 13 ci 14 H H N'S NH NS NH NH 2 N F 0 F 0 \ F F Br Br 15 16 169 WO 2006/047507 PCT/US2005/038348 o A* O=S-NH o A 0 R58i H RN N-H N R 58 N H H H 17 18 19 H N A NN- H RoesH N N N H NN A 0 21 20 A HH A1 N H H N~ NN~ 23 22 N R 65 24 N N"'- OH H wherein: Ao is A; A' is: 170 WO 2006/047507 PCT/US2005/038348 x W 6

22-Y R2 R2 M12a M12b A 3 is: Y Y 2 RX Y 2 2 R R NRx M2 M12a - - 2 M12b Y' is independently 0, S, N(Rx), N(ORx), or N(N(R)( Rx)); Y2 is independently a bond, 0, N(Rx), N(ORx), N(N(RX)( Rx)), or S(O)M2-; and when Y 2 joins two phosphorous atoms y2 can also be C(R 2 )(R 2 ); R' is independently H, R 2 , W 3 , a protecting group, or the formula: Y R~ RY A Y 2 - x y2 1,y 2----R A:- -Ma M12c M1c Mld RY is independently H, W , R2 or a protecting group; R2 is independently H, R3 or R4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups; 3 3a 3b 3c M 3 R is Ra, R , R or R d, provided that when R is bound to a heteroatom, then R 3 is R 3 c or R 3 ; R 3 a is F, Cl, Br, I, -CN, N 3 or -NO 2 ; R 3 b is Yl; R is -Rx, -N(Rx)(Rx), -SRx, -S(O)Rx, -S(O) 2 Rx, -S(O)(ORx), S(0) 2 (ORx), -OC(YI)Rx, -OC(YI)ORx, -OC(Y)(N(Rx)(Rx)), -SC(Y)Rx, SC(YI)ORx, -SC(YI)(N(Rx)(Rx)), -N(Rx)C(YI)Rx, -N(Rx)C(Yl)ORx, or N(Rx)C(Y)(N(Rx)(Rx)) ; R d is -C(YI)Rx, -C(YI)ORx or -C(YI)(N(Rx)(Rx)); 171 WO 2006/047507 PCT/US2005/038348 R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups; W 3 is W 4 or W'; W 4 is RI, -C(Y')R', -C(Y')W 5 , -S0 2 R', or -S0 2 W 5 ; W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups; W 6 is W 3 independently substituted with 1, 2, or 3 A3 groups; M2 is 0, 1 or 2; M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; MIa, MIc, and Mi d are independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R21 is substituted alkyl or substituted aryl; R 29 is hydrogen, alkyl, or -C(=0)R36. R 30 is hydrogen or substituted alkyl; R 3 and R 3 2 are independently hydrogen, alkyl, or substituted aryl; or R3 and R 32 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring; R 33 is -0-, -NR 35 - or absent; R 34 is -0- or absent; R 35 is hydrogen or alkyl; R 36 is hydrogen, alkyl, alkenyl, or alkynyl; R 58 is hydrogen, or halo; R is hydrogen, alkyl, or halo; and R 6 is carbocycle, heterocycle, substituted carbocycle, or substituted heterocycle, and is substituted with one or more A 0 ; or a pharmaceutically acceptable salt thereof. 172 WO 2006/047507 PCT/US2005/038348 4. The compound of claim 3 wherein A' is of the formula: Y22 2 A3 R2 R2 M1 2a M12b 5. The compound of claim 3 wherein A' is of the formula: 2 A 3 R 2 R 2 M12a_ M12b 6. The compound of claim 3 wherein A' is of the formula: 2 VA 3 _ M12a_ M12b 7. The compound of claim 3 wherein A' is of the formula: W 6 A 3 R2 R2 M12a 173 WO 2006/047507 PCT/US2005/038348 8. The compound of claim 3 wherein A' is of the formula: - w~a A 3 R2 R2 M12a and W 5 a is a carbocycle or a heterocycle where W 5 a is independently substituted with 0 or 1 R 2 groups. 9. The compound of claim 3 wherein M12a is 1. 10. The compound of claim 3 wherein A' is of the formula: 2W R R M12a M 12b 11. The compound of claim 3 wherein A' is of the formula: A 3 2 2 M12a 12. The compound of claim 3 wherein A' is of the formula: W 5 a A 3 R 2 R 2 174 WO 2006/047507 PCT/US2005/038348 and W 5 a is a carbocycle independently substituted with 0 or 1 R 2 groups. 13. The compound of claim 3 wherein A' is of the formula: 0 R2 11 0 P--I' ~Y 2b -- 11R H H 2 2 M12d Y2b is O or N(R2); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. 14. The compound of claim 3 wherein A' is of the formula: Wsa A 3 R2 R2 M 12a and W 5 a is a carbocycle independently substituted with 0 or 1 R 2 groups. 15. The compound of claim 3 wherein A' is of the formula: W 5a A 3 R 2 R 2 and W 5 a is a carbocycle or heterocycle where W 5 a is independently substituted with 0 or 1 R2 groups. 175 WO 2006/047507 PCT/US2005/038348 16. The compound of claim 3 wherein A' is of the formula: O R 2 00 y 2 b H H 2 M12d Y2b Y2b is O or N(R2); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. 17. The compound of any one of claims 3-16 wherein A 3 is of the formula: Y 1 || 2 P Rx R2 R 2 M12a M12b 18. The compound of any one of claims 3-16 wherein A 3 is of the formula: Y 1 Y2 P Rx Y2 R 2 R 2 - - 2 M12a 176 WO 2006/047507 PCT/US2005/038348 19. The compound of any one of claims 3-16 wherein A 3 is of the formula: Y 1 a Y 2 a P Rx y 2 a 2 2 2 M12a Yia is 0 or S; and Y2a is 0, N(R) or S. 20. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 0 P Rx Y2b R 2 R 2 2 M 12a and y2b is 0 or N(Rx). 21. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 o P Rx Y2b R R 1 - - 2 M12d R' is independently H or alkyl of I to 18 carbon atoms; y 2 b is 0 or N(R); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. 177 WO 2006/047507 PCT/US2005/038348 22. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 || 0 P Rx Y2b H H 2 MM12d Y 2 is 0 or N(Rx); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

23. The compound of claim 22 wherein M12d is 1.

24. The compound of any one of claims 3-16 wherein A 3 is of the formula: Y 1 YP RX R2/ R M12a SMl2b

25. The compound of any one of claims 3-16 wherein A 3 is of the formula: Y 1 II Y P Rx 2 R M12a M12b

26. The compound of claim 25 wherein W 5 is a carbocycle. 178 WO 2006/047507 PCT/US2005/038348

27. The compound of any one of claims 3-16 wherein A 3 is of the formula: Y 1 || R2 P Rx M12a M12b

28. The compound of claim 27 wherein W 5 is phenyl.

29. The compound of claim 28 wherein M12b is 1.

30. The compound of any one of claims 3-16 wherein A 3 is of the formula: Yla y2a P Rx 2a R2 R2 W3 M12a 2a Y 2 Y1a is 0 or S; and y2a is 0, N(Rx) or S.

31. The compound of any one of claims 3-16 wherein A 3 is of the formula: O 0 P Rx 2b R2 R2 W3 M12a y2b and y2b is 0 or N(R). 179 WO 2006/047507 PCT/US2005/038348

32. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 0 P Rx 2 b M1 2d y2b R 1 is independently H or alkyl of 1 to 18 carbon atoms; Y 2 is 0 or N(Rx); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

33. The compound of claim 32 wherein R' is H.

34. The compound of claim 32 wherein M12d is 1.

35. The compound of any one of claims 3-16 wherein A 3 is of the formula: O R2 00 2 R Y 2b M12d OR R' R 1 0 wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R 2 groups. 180 WO 2006/047507 PCT/US2005/038348

36. The compound of any one of claims 3-16 wherein A 3 is of the formula: R2 O R M12d OR R' R H wherein R1 is independently H or alkyl of 1 to 18 carbon atoms.

37. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 \ .,O CH 3 N R1 H H H 0

38. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 )\ O CH 3 H H 0 181 WO 2006/047507 PCT/US2005/038348

39. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 0 1*- 0 0 0 H H 2

40. The compound of any one of claims 3-16 wherein A 3 is of the formula: yla R2 2a Y YY Y 2 aR R2 R2 2 M12a Yia is 0 or S; and Y2a is 0, N(R2) or S.

41. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 R2 0 P O 2b Rl YY R2 R2 M12a 2 Ya is 0 or S; Y2b is 0 or N(R 2 ); and y2e is 0, N(RY) or S. 182 WO 2006/047507 PCT/US2005/038348

42. The compound of any one of claims 3-16 wherein A 3 is of the formula: O R2 02 2d R 1 R 1 2 M12d R 1 is independently H or alkyl of 1 to 18 carbon atoms; y1a is O or S; Y2b is O or N(R2); Y2d is O or N(RY); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

43. The compound of any one of claims 3-16 wherein A 3 is of the formula: O R 2 y 2 b R H H 2 M12d Y2b is 0 or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

44. The compound of any one of claims 3-16 wherein A 3 is of the formula: O R 2 00 N. 2b OR2 H H -2 and Y2 is O or N(R 21 183 WO 2006/047507 PCT/US2005/038348

45. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 II o P OO''R2j 0 0 H H O 2

46. The compound of any one of claims 3-16 wherein A 3 is of the formula: Y, Y2P RX Y2 2 2 M12a y 2

47. The compound of any one of claims 3-16 wherein A 3 is of the formula: yla R2 2a Y 2 aR 2 2 R R2 M12a 2a Ya is 0 or S; and y2a is 0, N(R2) or S.

48. The compound of any one of claims 3-16 wherein A 3 is of the formula: 0 R2 0 Pc N 2 by R R 2 R 2 3 Ml2a y2b Ya is O or S; 184 WO 2006/047507 PCT/US2005/038348 Y2b is O or N(R2); and y2e is 0, N(RY) or S.

49. The compound of any one of claims 3-16 wherein A3 is of the formula: O R 2 II 2d 02b R yla R 1 R 1 M12d y2b R' is independently H or alkyl of 1 to 18 carbon atoms; Ya is 0 or S; Y2b is 0 or N(R2); Y2d is 0 or N(RI); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

50. The compound of any one of claims 3-16 wherein A 3 is of the formula: O R 2 y 2 b O R 0 H H 3 M12d 2b Y2b is 0 or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

51. The compound of any one of claims 3-16 wherein A3 is of the formula: 0 2 0 H H 1W3 y2b 185 WO 2006/047507 PCT/US2005/038348 and Y 2 b is 0 or N(R 2

52. The compound of claim 3 wherein A 0 is of the formula: 0 (C H2)1-0 P - 0- R 0 R wherein each R is independently (CI-C 6 )alkyl.

53. The compound of any one of claims 1-52, which is isolated and purified.

54. The compound of any one of claims 1-53 which inhibits a serine/threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase, and/or an EGF receptor tyrosine kinase.

55. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a-compound as described in any one of claims 1-54.

56. A unit dosage form comprising a compound as described in any one of claims 1-54 and a pharmaceutically acceptable excipient.

57. A method for inhibiting a kinase in vitro or in vivo comprising contacting a sample in need of such treatment with a compound as described in any one of claims 1-54.

58. The method of claim 57 wherein the contacting is in vivo.

59. A method of inhibiting a kinase in a mammal, comprising administering a compound as described in any one of claims 1-54 to the mammal. 186 WO 2006/047507 PCT/US2005/038348

60. The method of claim 59 wherein the compound is formulated with a pharmaceutically acceptable carrier.

61. The method of claim 60 wherein the formulation further comprises a second active ingredient.

62. The method of any one of claims 57-61 wherein the kinase is a serine/threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase, and/or an EGF receptor tyrosine kinase.

63. A method of treating cancer in a patient in need of such treatment comprising administering an effective amount of a compound as described in any one of claims 1-54 to the patient.

64. A compound as described in any one of claims 1-54 for use in medical therapy.

65. The use of a compound as described in any one of claims 1-54 to prepare a medicament for inhibiting a kinase in an animal.

66. The use of claim 65 wherein the kinase is a serine/threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase, and/or an EGF receptor tyrosine kinase.

67. The use of a compound as described in any one of claims 1-54 to prepare a medicament for treating cancer in an animal.

68. A method for preparing a compound as described in the schemes and examples herein. 187